The Giant First Year

The Giant First Year
Some MS2
A HY Review of The General Senses

Some MS2
Introduction/Learning Objectives
-Welcome to GSM; this is where youll begin to build the foundation necessary for tackling a myriad of
neuroscience problems as you go on with the block.
-Theres lots of material in this block, but it is very interesting material (in addition to being really HY), so learn
it the best you can.
-The material in Neuro is tested very heavily on the boards so dont blow this off. The Neuro chapter in FA has
almost as many pages as the Micro chapter, and youre well aware of how HY Micro is.
-Work on understanding the different tracts/pathways to see how everything fits together. Details matter, so
learn them.
-Your goal by the end of the block should be to be able to localize lesions and integrate the concepts with
complicated problems.
-Pay good attention to the pictures in this document.
-Therell be practice Qs to work through as you go through this document to reinforce key concepts.
-Therell be slides with repeated information. Neuro does contain lots of information so this repetition is
mostly for the process of reinforcement. In addition, I use the repetition to keep peeling layers off different
concepts as I go from a more general overview to a more detailed discussion.
-The cerebellum is a fairly involved, but also somewhat HY subject so Ill talk about its inner workings many
times in different ways.
-A helpful study approach in Neuro is seeing how things fit together into one nice story, during the course of
our meeting (and with the slides), the goal would be to try to integrate as much as possible.
-I do understand the frustration that could arise with all the information being thrown at you (sorry..). All I can
suggest is to do the best you can and learn the slides in bits and pieces (i.e. learn 20 slides well, go do other stuff
for a while and then keep going).
-Youve come a long way in med school and you have the power to tackle and overcome whatever
lies ahead. Keep your chin up, work hard, enjoy the process, and youll reach your destination.
Q1
A 55 yo male presents to the Med19 Neuro ICU with complaints of progressive
weakness in his left lower and upper extremities. Which of the following is more
consistent with a lesion of Betz cells found in the primary motor cortex?
a.
b.
c.
d.
e.
Atrophy of skeletal muscles.

Muscle Atonia.
Tremors at rest.
Hyperactive Tendon Reflexes
Muscle Fasciculations.
Q1 Key
A 55 yo male presents to the Med19 Neuro ICU with complaints of progressive
weakness in his left lower and upper extremities. Which of the following is more
consistent with a lesion of Betz cells found in the primary motor cortex?
a.
b.
c.
d.
e.
Atrophy of skeletal muscles.

Muscle Atonia.
Tremors at rest.
Hyperactive Tendon Reflexes
Muscle Fasciculations.
Remember that Betz cells are Upper Motor Neurons that kickstart the Corticospinal
Tract that descends through the Centrum Semiovale-Corona Radiata-Cerebral
Peduncles-Decussation at the Pyramids-Lower Motor Neurons. Make sure you can
distinguish b/w UMN and LMN signs.
Q2
A 45 yo. Male presents to the ED with acute onset shortness of breath that began 3
days ago as bilateral muscle weakness in his lower extremities. He is rapidly intubated
when EMG studies reveal a decreased amplitude upon stimulation of his respiratory
muscles. Further history obtained from the patient would most likely reveal?
a.
b.
c.
d.
e.
A history of Traumatic Brain Injury as a 27 yo.

A history of diarrheal illness presenting with bloody stools.
Failure to obtain vaccinations as a child.
A history of intention tremors.
A loss of bowel and bladder control.
Q2 Key
A 45 yo. Male presents to the ED with acute onset shortness of breath that began 3
days ago as bilateral muscle weakness in his lower extremities. He is rapidly intubated
when EMG studies reveal a decreased amplitude upon stimulation of his respiratory
muscles. Further history obtained from the patient would most likely reveal?
a.
b.
c.
d.
e.
A history of Traumatic Brain Injury as a 27 yo.

A history of diarrheal illness presenting with bloody stools.
Failure to obtain vaccinations as a child.
A history of intention tremors.
A loss of bowel and bladder control.
Remember, acute onset paralysis should rule out anything with a chronic character.
This patient has Guillain Barre Syndrome secondary to C. Jejuni infection. A HY
buzzword to be aware of here is the CSF finding of Albuminocytologic Dissociation.
Q3
A 16 yo female is brought to the ED with severe swelling secondary to impaction of a 500 Lb
weight on her left wrist. PE reveals massive erythema but palpation reveals no pain in the affected
area. Muscle strength is 5/5 in all extremities but the patient (with her eyes closed) fails to
respond to an assessment of sharp sense on her shoulders and both upper extremities bilaterally.
Which of the following best represents the location of the lesion responsible for this patients
symptoms?
Q3 Key
The best answer is A.
This patient most likely has syringomyelia. Even if you dont know the actual disease,
the findings of intact muscle strength should help you rule out issues with the
Corticospinal Tract (option C) and the ventral horn (option B).
The mention of no response to assessment of sharp sense + the PE finding of no pain
upon palpation of the affected area (that a 500 Lb object landed on!) should raise giant
alarm bells in your mind relating to the loss of pain and temperature sensation. This is
controlled by the spinothalamic tract which crosses in the Anterior White Commissure
on its way to the cerebral cortex.
If you see the words, Cape like distribution on your exam, stop reading the question
and immediately pick the answer that corresponds to the spinothalamic tract.
Q4
A 42 yo male is brought to the ED by his family for new onset episodes of violence and
inappropriate speech. His wife also complains that over the last few months, he has
had weird dance-like movements in both lower and upper extremities. His father
died of an unknown neurologic illness at the age of 48. The underlying
pathophysiology behind this disorder is linked to?
a.
b.
c.
d.
Neuron death in the Substantia Nigra Pars Compacta.

Neuron death in the Posterior Limb of the Internal Capsule.
Axonal Demyelination at the level of the Superior Colliculus.
Atrophy in cells lining the caudate nucleus.
Q4 Key
A 42 yo male is brought to the ED by his family for new onset episodes of violence and
inappropriate speech. His wife also complains that over the last few months, he has
had weird dance-like movements in both lower and upper extremities. His father
died of an unknown neurologic illness at the age of 48. The underlying
pathophysiology behind this disorder is linked to?
a.
b.
c.
d.
Neuron death in the Substantia Nigra Pars Compacta.

Neuron death in the Posterior Limb of the Internal Capsule.
Axonal Demyelination at the level of the Superior Colliculus.
Atrophy in cells lining the caudate nucleus.
This man has Huntington's disease. The only real clues needed in this question are
the fact that his father died at 48 and then he (the son) started developing symptoms
at 42 (genetic principle-anticipation). Theres others but you really dont need them.
Brain Slice 1-Sacral Cord
Brain Slice 2-Lumbar Cord
Brain Slice 3-Thoracic Cord w/the Dx Lateral Horn
Brain Slice 4-Cervical Cord (note the enlargement)
Brain Slice 5-Compare/Contrast the 4 Cord Sections
Brain Slice 6-Caudal Medulla with Associated Pathways
Brain Slice 7-Caudal Medulla with Associated Pathways
Brain Slice 8-Caudal Medulla with Associated Pathways (Level of the Olives)
Brain Slice 11-Caudal Pons and Associated Pathways
Brain Slice 12-Caudal Pons and Associated Pathways
Brain Slice 13-Middle Pons and Associated Pathways
Brain Slice 14-Middle Pons and Associated Pathways
Brain Slice 15A
Brain Slice 15B
Brain Slice 15C-Rostral Pons and Associated Pathways
Brain Slice 16A-Rostral Pons and Associated Pathways
Brain Slice 16B-Rostral Pons and Associated Pathways
Brain Slice 17-Caudal Midbrain and Associated Pathways
Brain Slice 18-Rostral Midbrain and Associated Pathways
Brain Slice 19-Rostral Midbrain and Associated Pathways
The Midbrain (Looks like an inverted M on imaging)
The Circle of Willis
Vascular Territories In The Brain
Q5
The most likely location of the lesion in a patient that has lost all sensation completely
on one side of the body but still retains complete muscle strength is?
a.
b.
c.
d.
Thalamus
Posterior Limb of the Internal Capsule.
Medial Pons.
Precentral Gyrus of the cerebral cortex.
Q5 Key
The most likely location of the lesion in a patient that has lost all sensation completely
on one side of the body but still retains complete muscle strength is?
a.
b.
c.
d.
Thalamus
Posterior Limb of the Internal Capsule.
Medial Pons.
Precentral Gyrus of the cerebral cortex.
The best answer is the thalamus (remember that VPL resides here). A lesion of the
entire posterior limb of the internal capsule will result in motor deficits (not sensory
deficits). A medial pontine lesion would result mostly in cranial nerve dysfunction and
some motor symptoms from corticospinal tract damage. The precentral gyrus has the
primary motor cortex and nothing to do with sensation.
Q6
The complete loss of all sensation and cranial nerve function with the sparing of
extraocular muscle movement is associated with an aneurysm of which of the
following arteries?
Q6 Key
-The best answer is A (the basilar artery). Remember that the basilar artery supplies
the pons. Most people that have a stroke in this artery typically go into respiratory
failure and coma.
-Artery E represents Paramedian Pontine Arteries (dont worry about it).
-Artery F represents the AICA (lesion presents with problems in lateral pontine
structures like the facial nerve and the trigeminal nerve).
-Arteries D and C are the Superior Cerebellar and the Posterior Cerebral Arteries. It
may not hurt to remember the anatomical relationship b/w these arteries and the
Oculomotor Nerve (runs b/w both). Aneurysms in these arteries cause CN 3 palsies.
Also remember that a high intracranial pressure also leads to a CN 3 palsy secondary
to uncal (medial portion of the temporal lobe) herniation.
Q7
Facial droop of the lower face on the right, loss of sensation in the right upper
extremity, and an inability to understand the spoken word is most likely due to a lesion
of the?
a.
b.
c.
d.
e.
Superior Cerebellar Artery

Posterior Cerebral Artery
Anterior Communicating Artery
Middle Cerebral Artery
Anterior Cerebral Artery
Q7 Key
Facial droop of the lower face on the right, loss of sensation in the right upper
extremity, and an inability to understand the spoken word is most likely due to a lesion
of the?
a.
b.
c.
d.
e.
Superior Cerebellar Artery

Posterior Cerebral Artery
Anterior Communicating Artery
Middle Cerebral Artery
Anterior Cerebral Artery
The best answer is D. A lesion affecting all these structures could be a brainstem
lesion, but remember that understanding speech is a derivative of Wernickes area
which is in the temporal lobe. This localizes the lesion to the middle cerebral artery
which supplies this area.
Q8
An individual that has lost all motor activity in his left upper and lower extremities has
most likely lesioned which of the following vessels?
a.
b.
c.
d.
e.
The Middle Meningeal artery.

The Middle Cerebral Artery.
The Lenticulostriate Arteries.
The Anterior Communicating Artery.
Bridging veins that traverse the dura.
Q8 Key
An individual that has lost all motor activity in his left upper and lower extremities has
most likely lesioned which of the following vessels?
a.
b.
c.
d.
e.
The Middle Meningeal artery.

The Middle Cerebral Artery.
The Lenticulostriate Arteries.
The Anterior Communicating Artery.
Bridging veins that traverse the dura.
The best answer is C. This is a very HY point to be aware of. The Lenticulostriate
Arteries supply the posterior limb of the internal capsule which carries all the
information of the corticospinal tract from the cerebral cortex to the contralateral side
of the body.
The Cholinergic Synapse (focus only on relevant details)
The Cholinergic Synapse-A Tale of Flaccid Paralysis

-Choline Acetyltransferase is the enzyme that makes Ach from Choline and Acetyl coA. A KM increasing
mutation in this enzyme (decreased affinity) for Acetyl coA results in Congenital Myasthenic Syndromes.
-The Ach receptor at the NMJ is the Nicotinic type (do not choose muscarinic on your exam!) which is an ion
channel. Acetylcholine binds to this receptor which triggers the opening of Na+ channels (which lets Na+ into
the cell) and subsequent depolarization of the cell.
-Do not mix up Myasthenia Gravis-MG (antibodies to the Ach receptor) with Botulism (decreased Ach release
from the presynaptic cell) or Lambert Eaton Myasthenic Syndrome-LEMS (antibodies against the presynaptic
voltage gated Ca2+ channel). They all cause a flaccid paralysis but with different mechanisms.
-In MG, the antibodies to the Ach receptor prevent the binding of regular Ach to the synapse.
Acetylcholinesterase inhibitors like Pyridostigmine increase the amount of Ach available at the synapse which
outcompetes the bound autoantibodies. MG worsens with use (super HY!).
-Consider botulism in exam scenarios that detail a child/adult consuming canned food. The HY thing to know is
that the botulinum toxin cleaves SNARE proteins (just remember the Synapto/Syntaxin prefixes) which
prevents the fusion/release of vesicles containing Ach.
Cholinergic Synapse-A Tale of Flaccid Paralysis contd.

-In LEMS, autoantibodies are made against the presynaptic voltage gated Ca2+ channel (of the P/Q type).
Remember that this channel is opened by the depolarizing wave flying down the presynaptic neuron. The entry
of Ca2+ through this channel triggers a signaling cascade that leads to the fusion of Ach containing vesicles
with the presynaptic membrane, ultimately leading to neurotransmitter (NT) release. LEMS improves with use
(super HY!). With enough encouragement, enough Ca2+ becomes available outside the presynaptic neuron and
ultimately triggers NT release.
-Consider LEMS in an exam scenario detailing some old individual with difficulty climbing stairs/rising from a
seated position.
-For the future, lock down the fact that people with LEMS typically have an underlying pulmonary malignancy
(usually small cell carcinoma).
-Other HY things to know include the drugs that target the NMJ (more to come shortly) AND the huge safety
margin associated with Ach production/release (more made than is actually used). Repeated stimulation of Ach
release (as occurs in MG), depletes this relative excess and reduces the safety margin at the NMJ.
Anesthesia Pharmacology
-In general, there are 3 main classes of anesthetics. The first class are the inhaled/IV anesthetics which are used
for general sedation, the second class includes the local anesthetics which are used for sensation control in
localized regions of the body, and the 3rd class includes the Neuromuscular blocking agents (NMBD) which are
for muscle paralysis.
-The NMBDs are used in situations where muscle paralysis is necessary (for example, in the setting of
intubation).
-There are 2 main classes of NMBDs with the first class being the Depolarizing NMBDs (succinylcholine), and
the Non-Depolarizing NMBDs (Tubocurarine and anything ending in Curium or Curonium). These drugs all
work at the level of the nicotinic Ach receptor.
-Succinylcholine is a Depolarizing NMBD that works as an agonist at Nicotinic Ach receptors. You may
wonder, if something is depolarizing muscle, how can it be a paralytic? Succinylcholine works by stimulating
the muscle repeatedly to the point where the muscle exhausts and is unresponsive to Ach. The initial
depolarization explains the fasciculations associated with the initial administration of the drug.
Anesthesia Pharmacology-contd.
-Under normal circumstances, depolarization of the the muscle makes the muscle fire with eventual resetting of
the muscle so it can fire again. Unfortunately, Succinylcholine is not degraded by Acetylcholinesterase, and
hence it stimulates the muscle for long periods of time, effectively preventing any form of muscle reset.
Succinylcholine is degraded by Pseudocholinesterase which exists in the serum (not at the synapse).
-Succinylcholine has a quick onset of action in addition to rapid clearance so its effects wear off quickly.
However, there is no reversal agent (unlike the ND NMBD that could be reversed with acetylcholinesterase
inhibitors that can lead to Ach crowding out the bound paralytic).
-Since Succinylcholine agonizes nicotinic Ach receptors (which are ion channels), it increases the extracellular
efflux of K+ (as any normal ion channel should operate), which can give rise to hyperkalemia. Succinylcholine
is contraindicated in conditions that already predispose a patient to hyperkalemia (burns for example) as too
much K+ can stop the heart. Another HY SE of Succinylcholine is malignant hyperthermia (a hypermetabolic
state-picture a person that ingests too much thyroid hormone).
-A few patients have an atypical pseudocholinesterase that has a reduced ability to break down succinylcholine.
This occasionally puts patients into severe paralysis for many hours.
Anesthesia Pharmacology-contd.
-The Nondepolarizing NMBD are essentially competitive antagonists of the Nicotinic Ach receptor. These
agents can be reversed with the administration of an AchE inhibitor (basically anything ending in stigmine on
your test).
-Since acetylcholine is also a muscarinic agonist, administration of AchE inhibitors drops the HR. This can be
counteracted by giving a muscarinic antagonist like Atropine.
-This is very LY for your test (but who knows!), but Vecuronium and Rocuronium are eliminated by the liver,
Pancuronium is cleared by kidneys, and Atracurium/Cis-Atracurium is cleared in an organ independent
process (spontaneous metabolism in the blood stream/interstitium).
-Finally, be aware that most Local Anesthetics work by blocking Na+ channels which prevents depolarization of
the involved neurons. This is the mechanism behind the cessation of pain with anesthetics. Tetrodotoxin is a
poison found in certain foods like pufferfish that blocks Na+ channels. Consuming improperly cooked seafoods
containing this toxin can ultimately lead to death.
Embryology and CNS Orientation

-Remember from Exam 1 that the spinal cord possesses an alar plate which is sensory (i.e. the
dorsal horn of the spinal cord) and a basal plate that is motor (i.e. the ventral horn of the spinal
cord). To translate this to somatotopy within the brainstem, think of opening a round circle from
behind and making it a straight rope. The portion behind (dorsal) becomes lateral, while the
portion in front (ventral) becomes medial (this is how I remember orientation in the brainstem).
-Therefore, medial structures in the brainstem (cranial nerves in particular) are typically motor
(remember the ventral horn of the spinal cord is motor), while lateral structures are typically
sensory (remember the dorsal horn of the spinal cord is sensory).
-The motor cranial nerves (3,4,6,12-all factors of 12) are all located medially in the brainstem.
-The sensory or sensory + motor cranial nerves are more lateral in the brainstem.
-One thing I have found to be helpful in viewing brainstem sections is that white things tend to
be nuclei. Dark things tend to be axons (this is particularly helpful with CN 7).
The Purely Motor Cranial Nerves (all Medial)

-CN 3 (Oculomotor) resides in the midbrain and sends somatic motor fibers to many of the
extraocular muscles (SR/IR/IO/MR/LPS). In addition, it sends preganglionic parasympathetic
neurons (which originate in the Edinger Westphal nucleus) to the ciliary ganglion (origin of the
postganglionic parasympathetic neurons) which then supply the pupillary sphincter muscles.
-CN4 (Trochlear) exits dorsally in the midbrain and innervates the SO muscle. It is the only CN
that gives crossed findings.
-CN6 (Abducens) has its nucleus in the pons and innervates the LR muscle. It is very HY that you
know how to identify this nucleus for your test.
-CN12 (Hypoglossal) has its nucleus in the caudal medulla. This CN innervates all intrinsic
tongue muscles except palatoglossus (CN10). A HY anatomical relationship to be aware of is the
medial placement of this nucleus in relation to the dorsal nucleus of the Vagus Nerve (CN10). An
easy way to remember this is to remember the orientation of 10 and 12 on a wall clock. It fits
perfectly.
The HY Mixed Cranial Nerves

-CN 5 (Trigeminal) has a motor nucleus in the pons that innervates the muscles of mastication and one of the
ear muscles that is affixed to the tympanic membrane (tensor tympani).
-CN 7 has a motor nucleus in the pons as well that innervates the muscles of facial expression. This is LY for
your test but CN 7 also controls lacrimation, salivation, and taste sensation.
It is extremely HY to understand how CN 7 works.
-The muscles of facial expression for the upper face receive innervation from the corticobulbar tracts (UMN)
from both cerebral hemispheres. This redundancy means that a stroke on one side of the brain still leaves an
individual with the ability to wrinkle the upper forehead.
-The muscles of facial expression for the lower face receive innervation from the CONTRALATERAL
corticobulbar tract (UMN) from ONE cerebral hemisphere. Therefore, a stroke in one cerebral hemisphere will
present with facial droop on the contralateral lower face.
-However, a lesion to the facial nucleus itself (origin of LMN) will present with facial droop on both the upper
and lower face. It is important to understand the difference b/w a CN 7 UMN vs. a LMN lesion.
The Nucleus Ambiguus/Dorsal Motor Nucleus of CN 10

-Is an ambiguous nucleus located in the medulla. Basically, it is the white area
beneath the 12 0 Clock nucleus of the Hypoglossal nerve and the 10 0 Clock dorsal
nucleus of the vagus nerve.
-The Nucleus Ambiguus is the origin of LMN for the Glossopharyngeal Nerve (CN9)
and the Vagus Nerve (CN10) that goes on to supply the muscles of the pharynx and
larynx.
-The Dorsal Motor Nucleus of the Vagus Nerve (also in the medulla), controls the
autonomic functions of CN 10 that regulate heart rate, GI motility, etc (up until the
splenic flexure where CN 10 functions end).
Somatic Sensation-An Introduction

-This is a section you really want to pay attention to (especially with the tracts and pathways).
This material is going to be very richly represented on you know what..
-Somatic sensation deals primarily with the sensations of touch, proprioception (awareness of
joint position in space), pain, and temperature. These modalities are usually associated with
specific body parts that receive this stimuli (receptive field).
-Sensory receptors can be grouped in many ways, with slow adapting fibers firing upon initial
stimulation and throughout the duration of stimulation. On the other hand, fast adapting fibers
fire at the beginning and end of the application of a given stimulus. These fast adapting fibers do
not really fire in the middle of stimulation.
-The neural systems that mediate somatic sensation in general operate via a 3 neuron system. It is
important to separate where the sensation originates from-face OR body as this will determine
where the stimulus goes to in the thalamus (which is the gateway to the cerebral cortex).
Somatic Sensation-An Introduction

-The first neuron in this pathway typically receives information from the body (with the cell bodies in
the dorsal root ganglion) or the face (with the cell bodies in the trigeminal ganglion).
-The first neurons (which are pseudounipolar) typically synapse in the spinal cord (for the
spinothalamic pain/temperature/crude touch pathway-which synapses on neurons in the dorsal horn of
the spinal cord) OR the brainstem (for the dorsal column/medial lemniscus pathway/trigeminal system).
The neurons of the DC/ML pathway synapse in the caudal medulla.
-The 2nd neuron in these pathways almost always cross right after receiving the earlier synapse and then
travel to a given nucleus in the thalamus (in most cases, VPL for the body AND VPM for the face).
-The 3rd neuron then projects from the associated nucleus in the thalamus to the primary
somatosensory cortex which is in the postcentral gyrus (please dont pick precentral on your exam!) of
the cerebral cortex. The originating body parts supplying these different sensations are all aligned
according to the homunculus. You should be able to correlate arterial lesions to corresponding sensory
deficits (for example, a lesion of the middle cerebral artery should give rise to face/upper extremity
problems).
The 2 Key Ascending Sensory Systems
The Homunculus
The major types of neurons.
Somatic Sensation-The Afferent Neuron

-For sensation emanating from the body, it is HY to know if the first order neurons could be myelinated or
unmyelinated. In general, all large (golgi tendon and muscle spindles)/medium (cutaneous mechanoreceptors)
neurons are myelinated. Small neurons (which tend to carry pain/temperature sensation) could go either way.
There is a direct relationship b/w fiber size and amount of myelination.
-Larger, more myelinated fibers (with improved possibilities of saltatory conduction), tend to respond faster to
a given stimulus.
-I personally hate warm environments. Fortunately, this is a sensory modality that works with unmyelinated
fibers (this is how I remember).
-It is HY to know that of the large afferent fibers, the Muscle Spindle fibers are Type 1A fibers and detect
changes in muscle length/velocity. On the other hand, the Golgi Tendon organs are Type 1B fibers and detect
changes in muscle tension/force. Together, these are known as A-Alpha fibers.
-Of the smaller afferent neurons, C-fibers detect warm temperatures/itch and burning pain while A-delta fibers
detect cold and prickling pain (hence they are myelinated). These fibers fall under the purview of free nerve
endings.
Cutaneous Sensory Modalities

-Meissner corpuscles detect movement along the skin, Merkels Discs detect curvature
around edges and corners. These 2 are close to the skin surface. The Meissner
corpuscles have a larger receptive field than the Merkel Discs.
-Ruffini endings detect stretch, Pacinian corpuscles detect vibration. These are located
deep in the skin (dermis).
-It is HY to know that Meissner corpuscles look like stacks of coins and are found at
the dermal-epidermal junction. The Pacinian corpuscles look like an onion
histologically. Ordinarily, a Pacinian corpuscle is slowly adapting, but the presence of
the onion capsule makes it rapidly adapting.
-These cutaneous mechanoreceptors fall under the purview of A-Beta fibers.
Cutaneous Sensory Receptors (Medium Fibers)
The Basal Ganglia-Introduction

-The basal ganglia is a system that influences the execution of learned motor plans by mixing and matching
things between the thalamus and the motor cortex.
-There are 2 key pathways involved in the basal ganglia-the direct and indirect pathways. Activating the direct
pathway facilitates desired movement by stimulating the thalamus via the inhibition of The Globus Pallidus
Internus (GPi) and The Substantia Nigra Pars Reticularis (which normally inhibits the thalamus). On the flip
side, activation of the indirect pathway inhibits unwanted movement by inhibiting the thalamus.
-By virtue of D1 receptors, the nigrostriatal (NS) pathway (emanating from the SNPc in the midbrain),
stimulates the direct pathway and hence increases movement. By virtue of D2 receptors, the NS pathway
inhibits the indirect pathway which has the same end result of promoting movement.
-Decreased levels of dopamine in Parkinsons Disease leads to an overall inhibition of movement since there is
less stimulation of the direct pathway and less inhibition of the indirect pathway.
-The loss of indirect pathway neurons in Huntington's Disease (HD), leads to unopposed action by the direct
pathway which leads to the hyperkinesia that is characteristic of the disease.
-Pay particular attention to the next 2 slides.
The Basal Ganglia
The Basal Ganglia
The Basal Ganglia
The Basal Ganglia
The Direct and Indirect Pathways of The Basal Ganglia
The Pathogenesis of Parkinsons/Huntington's
Depigmentation of the Substantia Nigra in PD
Caudate Atrophy in HD-Death of Medium Spiny

Neurons
Clinical Correlate-The Pill Rolling Tremor of PD

-In PD, there are decreased levels of Dopamine (DA).
-Normally, DA inhibits the release of Acetylcholine (Ach).
-Low levels of DA in PD leads to high levels of Ach. Ach activates the indirect pathway.
-The activation of the indirect pathway leads to the suppression of unwanted
movements which leads to the pill rolling tremor that is characteristic of PD.
-These movements are not smooth because the movements are consistently stopped
in their tracks by an overactivation of the indirect pathway.
-This is LY for your exam (HY for the future) but explains why anticholinergic drugs
like Benztropine play a pivotal role in the treatment of PD.
Basal Ganglia-Other Key Takeaways

-Note that HD is an Autosomal Dominant disease characterized by an increasing number of CAG
repeats on Chromosome 4. There is the initial too much movement but with progressive death of
neurons in the basal ganglia pathways, bradykinesia (too little movement) sets in. Histological exam
typically reveals the presence of intranuclear inclusions.
-You should strongly consider HD with mention of an individual in his 40s who presents with new
onset personality changes OR weird choreiform (dance like) movements. Theres typically a family
history of disease with succeeding generations dying at earlier ages (since the trinucleotide repeats
increase with each generation) from the same disease. This illustrates the genetic principle of
anticipation (lock this down in your mind for the future).
Keep the following in mind;
Striatum = Caudate + Putamen + Nucleus Accumbens.
The caudate and thalamus lie medial to the internal capsule. The globus pallidus and putamen lie lateral
to the internal capsule.

-With the hyperkinesis that dominates the early stage of Huntington's Disease, the goal of treatment is
to antagonize the effects of dopamine (DA) in the brain. Remember that dopamine is an activator of the
direct pathway and an inhibitor of the indirect pathway.
-Antagonizing Dopamine, causes less stimulation of the direct pathway and less inhibition of the
indirect pathway which leads to an overall inhibition of movement (which treats the hyperkinesis).
-Reserpine is a drug that inhibits the pump (VMAT) that gets DA, NE, and Epi into presynaptic vesicles.
By inhibiting this pump, these neurotransmitters are left out in the cold and are promptly degraded by
Monoamine Oxidase (MAO) or Catechol-O-Methyltransferase (COMT). Tetrabenazine has a similar
MOA.
-Haloperidol (also used for Schizophrenia) is another drug that works by directly blocking Dopamine
receptors in the CNS.
-Knowing that SSRIs and SNRIs are used for the treatment of depression, anything that cuts down on
their supply could potentially have the HY side effect of depression.

-In PD (or PD dementia-GTS Psych), neurons have cytoplasmic inclusions known as Lewy Bodies (note
that these inclusions are also found in Lewy Body Dementia). It is HY to know that these bodies are
made of Alpha-Synuclein.
HY Myelination
Brainstem/Spinal Cord Pathways

-There are 31 spinal nerves. Theres 8 Cervical, 12 Thoracic, 5 Lumbar, 5 Sacral, and 1
Coccygeal.
-The Spinal Cord ends at L1-L2. This end is called the Conus Medullaris. Nerve fibers
continue after this, these continuing fibers are named after the progenitors of certain
Med19 students known as the Cauda Equina.
-Remember that the spinal cord contains grey matter (on the inside) and white matter
(on the outside). This is the reverse of what obtains in the brain.
-As you go from Coccygeal-Cervical, the amount of white matter increases because
there are more fibers running up and down. A diagnostic feature of the thoracic cord is
the presence of a lateral horn which is the origin of preganglionic sympathetic fibers.
The Labeled Cord-Ascending/Descending Pathways
The Highest of The High Yield Pathways (3)

-All the other pathways are very HY and you should certainly learn them for the test.
-However, there are 3 super HY pathways that you should know cold, most especially
in the realm of lesion localization.
-The Lateral Corticospinal Tract supplies motor fibers to the ventral horn of the spinal
cord with lesions resulting in paralysis. This is a motor pathway.
-The Dorsal Column/Medial Lemniscus Pathway (DCML) is a pathway that carries
sensory fibers that deal with fine touch and proprioception. The Spinothalamic tract is
a pathway that carries sensory fibers that deal with pain, temperature, and crude touch.
These are both sensory pathways.
-Pls note that the lower body dorsal column system is evident from T6 and below.
This is an out of the way but HY factoid.
The Spinothalamic Tract/DCML Pathway Overview
The Spinothalamic Tract

-Is a pathway that carries pain, temperature, and crude touch.
-Neuron 1 begins with the A delta and C fibers which have their cell bodies in the dorsal root
ganglion (which is neural crest derived). Remember that these are pseudounipolar neurons. These
neurons synapse in the dorsal horn of the spinal cord. The axons of these first order neurons are
known as Lissauers tract.
-After synapsing, Neuron 2 crosses in the anterior white commissure (right in front of the central
canal of the spinal cord-and hence is affected by Syringomyelia) and then extends laterally
throughout the cord/brainstem to the VPL nucleus of the thalamus.
-Neuron 3 then extends to the somatosensory cortex through the internal capsule.
-A lesion after the anterior white commissure will cause a contralateral loss of
pain/temperature/crude touch. Any lesion prior to the crossing will give rise to ipsilateral lesions
usually 2-3 levels below the lesion.
The DCML Pathway

-Carries fine touch (Meissners) and Vibration/Pressure (Pacinian).
-Neuron 1 begins as Meissners/Pacinian Corpuscles that have their cell bodies in the dorsal root ganglion. The
lower body fibers have their axons in the gracile fasciculus, while upper body fibers have their axons in the
cuneate fasciculus. These fibers ascend in the spinal cord until they get to the caudal medulla and synapse on
the Cuneate/Gracile Nucleus.
-Neuron 2 fibers decussate (cross) in the caudal medulla and then ascend as fibers of the medial lemniscus.
These fibers ascend in the brainstem and then synapse on 3rd order neurons in the VPL nucleus of the
thalamus.
-Neuron 3 fibers then ascend through the internal capsule to the primary somatosensory cortex.
-Any lesion prior to the decussation will give rise to ipsilateral sensory deficits while lesions after the
decussation will give rise to contralateral sensory deficits.
-Make sure you can localize fibers beginning in the cuneate/gracile fasciculus to the specific regions theyll get
to in the cerebral cortex (match these to the homunculus).
Block Diagram-The DCML Pathway
Block Diagram-The DCML Pathway + Jaw Proprioception + Jaw Jerk Ref.
Upper vs. Lower Motor Neurons (Memorize this!)
The Lateral Corticospinal Tract
Note This..
The Motor Pathways can be described as being medial or being lateral.
The Medial Pathways control axial/proximal musculature/posture and balance. These
pathways include;
The Vestibulospinal, Reticulospinal, Tectospinal, and Anterior Corticospinal Tracts.
The Lateral Pathways control distal musculature. These pathways include;
The Lateral Corticospinal and The Rubrospinal Tracts.
These are oversimplifications but theyll do for exam purposes.
The Lateral Corticospinal Tract

-This pathway carries voluntary motor information from the primary motor cortex (precentral gyrus-again,
make sure you can match this to the homunculus) to muscle.
-This is a 2 neuron system.
-Neuron 1 begins with an Upper Motor Neuron (UMN) that descends on the ipsilateral side in the brainstem
until a decussation is made in the caudal medulla at the level of the pyramids. These fibers then synapse on
Lower Motor Neurons (LMNs) in the anterior/ventral horn of the spinal cord.
-Neuron 2 (LMN) then goes on to innervate muscle (with all the magic that happens at the neuromuscular
junction). Medially located Neuron 2s innervate proximal/axial musculature. Laterally located Neuron 2s
innervate distal musculature (also Dorsal/Ventral Neurons innervate Flexors/Extensors respectively).
-It is HY to know that motor neurons in cranial nerve nuclei are also LMN. The motor tract that supports
them is called the Corticobulbar Tract.
-A lesion prior to the decussation gives rise to contralateral motor deficits. A lesion distal to the decussation
gives rise to ipsilateral motor deficits. DONT MIX THIS UP! THIS IS THE EXACT REVERSE FROM WHAT
HAPPENS FOR ASCENDING PATHWAYS. STOP NOW AND MAKE SURE THIS MAKES SENSE TO
YOU..
Potential Lesion Sites In The Corticospinal Tract
The Romberg Test

-Is NOT a test of cerebellar function.
-Is a test of an individuals proprioceptive ability. There are 3 major systems that
participate in proprioception-your dorsal columns, your visual system, and your
vestibular system. Of these 3, at least 2 need to work for an individual to have the right
awareness of where his/her joints are in space.
-In an individual that has a dorsal column problem (like Tabes Dorsalis in tertiary
syphilis OR Subacute Combined Degeneration-where the dorsal columns + lateral
corticospinal tracts are jointly lesioned secondary to Vitamin B12 deficiency), with
their eyes open-vision + the vestibular system helps with joint proprioception.
-When they close their eyes however, the only thing at work is the vestibular system.
With only 1 system in place, they topple over.
The Neurological Exam and The Big 3 Pathways

-Vibratory Sensation is tested with the tuning fork.
-The Up/Down toe maneuver with patients eyes closed is also another test of
proprioception.
-Testing the spinothalamic tract is done using pin pricks.
The Trigeminal System

-The trigeminal system deals with sensation and some motor activity for the face.
-This is also a 3 neuron system like the DCML/Spinothalamic Pathways.
-The first set of neurons in this system originate in a PNS ganglion (the trigeminal ganglion) and enter
the brainstem through the middle cerebellar peduncle. This is analogous to the dorsal root ganglion and
these neurons are unipolar. An unusual exception to this rule is the mesencephalic nucleus of the
trigeminal nerve which is also a first order neuron system that carries proprioceptive information (CNS)
-The first order neurons carrying touch, pressure, and vibratory information (again, pls do not confuse
this with the mesencephalic nucleus of CN 5 which carries solely proprioceptive information) project to
2nd order neurons in the Main/Principal Sensory Nucleus of the Trigeminal Nerve (in the pons).
-The first order neurons carrying pain and temperature information upon entry into the brainstem,
descend laterally to the caudal medulla. These descending fibers are called the spinal trigeminal tract.
These fibers ultimately synapse on 2nd order neurons in a nucleus known as the Spinal Trigeminal
Nucleus.
The Trigeminal System contd..

-2nd order neurons carrying touch/pressure/vibratory information from the main sensory nucleus of the
trigeminal nerve cross and ascend in the brainstem to the VPM nucleus of the thalamus (therefore
trigeminal nerve touch/pressure lesions are ipsilateral/contralateral depending to the lesion). The 3rd
order neurons then make their way to the primary somatosensory cortex of the cerebrum (on which
side of the homunculus?).
-2nd order neurons carrying pain and temperature information from the spinal trigeminal nucleus in
the medulla decussate and then ascend laterally in the brainstem with the spinothalamic tract to the
VPM nucleus of the thalamus which projects fibers to the primary somatosensory cortex as well.
-The Mesencephalic Nucleus of the trigeminal nerve is primarily concerned with the jaw jerk reflex and
is a monosynaptic reflex system. Neuron 1 comes from the mesencephalic nucleus (in the midbrain) and
then directly synapses on lower motor neurons in the motor nucleus of the trigeminal nerve which
mediate the jaw jerk reflex.
The Trigeminal System-Confusing Terminology

The TRIGEMINAL GANGLION is the source of all trigeminal nerve afferent sensory
fibers that go into the pathways described on the previous slide (with 1 exception).
The MESENCEPHALIC NUCLEUS of the Trigeminal Nerve is the specific source of
first order neurons that mediate proprioception. It is a separate primary sensory
neuron apart from those resting in the trigeminal ganglion.
The MAIN/PRIMARY SENSORY NUCLEUS of the Trigeminal Nerve is the source of
second order neurons that carry touch, pressure, and vibratory sense from the face.
The SPINAL TRIGEMINAL NUCLEUS is the source of second order neurons that
carry pain and temperature information from the face.
-The SPINAL TRIGEMINAL TRACT is a term used to refer to first order neuron
axons coming from the trigeminal ganglion that project to the spinal trigeminal
nucleus.
The Other Motor Pathways In a Nutshell
The Other Motor Pathways In a Nutshell contd.
The Pain/Temperature Trigeminal Pathway
The Cerebellum (Overview)
-Is involved in the maintenance of posture, balance, muscle tone, and the coordination (NOT INITIATION) of
movement. It is involved in the fine-tuning of skeletal muscle contractions. A good general principle to take
away is that the cerebellum ultimately tries to influence the firing of upper motor neurons in the cerebral
cortex.
-When you look at the cerebellum from the top, you should see an anterior and a posterior lobe.
-When you look at the cerebellum from the bottom, you should be able to see a flocculonodular lobe (which
has multiple connections with the vestibular nuclei, lesions give rise to signs/symptoms of nystagmus and
vertigo) in addition to the anterior/posterior lobes. The flocculonodular lobe of the cerebellum plays an
important role in the vestibulo ocular reflex which will be discussed with the next test.
-Lesions to the lateral hemispheres of the cerebellum tend to present with signs of dysmetria (patient
under/overshoots in the finger to nose test), dysdiadochokinesia (re-that CFM maneuver that requires you to
slap your hands on your thighs rapidly), and intention tremors.
-It is important to contrast the INTENTION TREMORS of cerebellar lesions (tremors show up only when
movement is initiated) with the RESTING TREMORS (tremors show up at rest but disappear with movement)
that are characteristic of Parkinsons Disease.
Cerebellum
Cerebellar Peduncles-2 Ways In, 1 Way Out.

-These are the nerve bundles that go into and out of the cerebellum.
-The SUPERIOR CEREBELLAR PEDUNCLE is the nerve bundle that leads OUT of
the cerebellum with most projections going to the contralateral motor cortex. These
nerve bundles are axons of deep cerebellar nuclei like the Dentate nucleus.
-The MIDDLE CEREBELLAR PEDUNCLE is the nerve bundle that leads INTO the
cerebellum with most fibers coming in as axons from the contralateral motor cortex.
-The INFERIOR CEREBELLAR PEDUNCLE is a major pathway into the cerebellum
from the spinal cord. The HY information carried by these fibers is proprioception.
-The fibers that carry information into the cerebellum tend to have fancy names like
Climbing fibers/Mossy Fibers.
Cerebellar Peduncles-General Principles

-In a situation requiring information exit from the cerebellum, Purkinje fibers are activated which
project to the Deep Nuclei of the cerebellum (lateral to medial-Dentate, Emboliform, Globose, and
Fastigial; Emboliform + Globose are together called the Interposed Nuclei). The Deep Nuclei then
project to the contralateral cortex via the superior cerebellar peduncle (SCP)
-It is HY to know that cerebellar lesions give rise to ipsilateral symptoms. Remember that the cerebellar
fibers cross over to the contralateral motor cortex first via the SCP and then the fibers in the
Corticospinal Tract that emanate from the motor cortex cross at the level of the pyramids in the caudal
medulla. The double crossing equalizes lesions which leads to ipsilateral findings.
-The more lateral deep nuclei tend to control the extremities while the more medial nuclei tend to
present more with gait/truncal ataxia (cant stand on one leg, cant perform the tandem walk) and
more midpoint lesions.
-In summary, the cerebellar vermis mostly controls axial/proximal musculature, the
paravermis/proximal lateral hemispheres mostly control distal musculature, the lateral hemispheres
(think Dentate Nucleus) mostly control specialized functions relating to the motor cortex.
Cerebellar Organization/Terminology
-The cerebellum is somewhat organized like the cerebral cortex. There are 3 layers in the cerebellar cortex. A
useful mnemonic is Miles Per Gallon.
-Layer 1 is the molecular cell layer that contains basket cells and stellate cells. This layer also contains the axons
of granule cells which have their cell bodies in a layer that is deeper within the cerebellum. These granule cell
axons are known as parallel fibers.
-Layer 2 is the Purkinje cell layer. These Purkinje cells project from the cerebellar cortex to the deep cerebellar
nuclei. Purkinje cells in the vermis mostly project to the fastigial nucleus. Those in the paravermis area project
to components of the interposed nuclei. Those in the lateral hemispheres project more to the dentate nucleus.
Purkinje cells are inhibitory (GABA).
-Layer 3 is the granular cell layer. These cells project to Purkinje cells and are excitatory (glutamate).
-A key generalization to make is that all neuronal synapses intrinsic to the cerebellum are inhibitory (i.e. use
GABA). The only exceptions are the granule cells which are excitatory. All inputs that are extrinsic to the
cerebellum (climbing and mossy fibers) are for the most part, excitatory.
Cerebellar Organization/Terminology
-Climbing fibers arising from the contralateral inferior olives provide excitatory input to the Purkinje
cells. They also provide excitatory input to the cells of the deep cerebellar nuclei. These fibers serve
more of an error alienating function so that the you make fewer mistakes when you perform a given
motor activity in the future.
-Mossy fibers represent all other sources of input to the cerebellum. If youre lost on your exam with
regards to a given cerebellar input, mossy fiber will probably be the right answer (with the olivary
exception mentioned above). Unlike the climbing fibers, the mossy fibers do not synapse directly on
Purkinje cells. They synapse mostly on deep cerebellar nuclei AND granule cells (which in turn provide
an excitatory input to the cerebellum).
Major Afferents to The Cerebellum
Cerebellar Cells and Their Respective Targets
The Cerebellar Mechanism
Cerebellar Efferents (commit to memory!)

-As mentioned earlier, cerebellar efferents (the HY efferent pathway to keep track of for your test is the one
emanating from the dentate nucleus) leave the cerebellum through the SCP. For context, think of this as a 3
neuron ascending system (like the DCML pathway). All the rules that applied there also apply here (neuron 2
crossing somewhere and then relaying to a thalamic nucleus). Lets work through this pathway.
Step 1-Purkinje cell (Neuron 1) in the lateral hemisphere of the cerebellar cortex projects to the dentate nucleus
(inhibitory signals with GABA).
Step 2-The dentate nucleus (Neuron 2) sends fibers out of the cerebellum through the SCP to the contralateral
motor cortex. These fibers decussate at the level of the midbrain with a relay to the thalamus (VA/VL nuclei).
Note that some of these fibers project to the red nucleus.
Step 3-The Neurons from the VA/VL nuclei of the thalamus (Neuron 3) project to the motor cortex.
Step 4-The motor cortex sends its own signals to through the Corticospinal tract to the contralateral alpha
motor neurons of the ventral spinal cord (remember the pyramidal decussation).
-This is why the cerebellar lesions result in ipsilateral deficits (there is a cross right after the SCP and a cross
cancellation at the pyramids-MAKE SURE YOU UNDERSTAND THIS!).
The Cerebellar Efferent Mechanism
Other Cerebellar Efferents
The Spinocerebellar Tracts and The Cerebellum

-A researcher looking to effect any sort of change based on experimental evidence needs to collect data. In the
same vein, the cerebellum needs to collect proprioceptive information from the upper and lower body as a
means of effecting corrections in motor movement.
-There are 3 HY Spinocerebellar Tracts that relay information to the cerebellum in relation to proprioception
from different parts of the body.
-The Dorsal Spinocerebellar Tract (DSCT) has its ascending fibers located in the dorsal portion of the lateral
funiculus of the spinal cord. The main job of the DSCT is to relay proprioceptive information from the lower
body (C8-L2). How does this work?
Step 1-Muscle Spindles and Golgi Tendon organs from the lower body (Neuron 1-with cell bodies in the dorsal
root ganglion), enter the spinal cord and synapse on Clarkes nucleus which is located in the dorsal horn of the
spinal cord (as a review, remember that some of these fibers constitute the gracile fasciculus of the spinal cord
which then ascend to synapse on the ipsilateral gracile nucleus in the caudal medulla).
Step 2-The neurons in Clarkes nucleus (Neuron 2) then send ascending fibers through the ICP to the
ipsilateral vermis of the cerebellum (remember the lower body is sort of in the middle).
The Spinocerebellar Tracts and The Cerebellum-contd.

-The Cuneocerebellar Tract takes care of upper body proprioceptive information. It is called the
Cuneocerebellar tract b/c the 2nd order neurons in this pathway have their synapses around the
cuneate nucleus which is found in the caudal medulla. How does this system work?
Step 1-Muscle spindles/Golgi tendon organs bring information from the upper body (Neuron 1).
The fibers dont synapse anywhere in the spinal cord but instead ascend to the caudal medulla to
synapse on a nucleus that is lateral to the cuneate nucleus (as a review, remember that the
cuneate nucleus is lateral to the gracile nucleus). This nucleus is known as the Lateral/External
Cuneate nucleus.
Step 2-These fibers of the Lateral Cuneate Nucleus (Neuron 2) then find their way to the
ipsilateral cerebellum through the ICP. The fibers mostly target the paravermal regions of the
cerebellar cortex (remember that the upper body is more lateral than the lower body).
Special Mention-The Ventral Spinocerebellar Tract

-This specific pathway is somewhat HY b/c it does not follow general principles and is an
exception to many rules.
-The first order neurons in this pathway are all interneurons that lie with the lateral horn of the
spinal cord. These neurons synapse on cell bodies of neurons that make up the ventral
spinocerebellar tract.
-The 2nd order neuron fibers cross in the anterior white commissure (dont forget that this is also
the crossing point of 2nd order neurons in the spinothalamic tract) and then ascend in the
brainstem.
-These fibers then get into the cerebellum through the SUPERIOR CEREBELLAR PEDUNCLE
(this is HY because the SCP is primarily an EFFERENT SYSTEM!).
-As a compensation for their horrendous course in the CNS, these fibers cross again in the
cerebellum so they end up ipsilateral to their starting point. In view of this, we can still maintain
our generalization that cerebellar lesions are ipsilateral.
The Spinocerebellar Tracts
The Spinocerebellar Tracts
Other Diseases-Polio/Spinal Muscular Atrophy

-These are both diseases of the lower motor neuron.
-Consider polio in the setting of lower extremity weakness in a child who is
unvaccinated. The virus infects and destroys neurons in the anterior/ventral horn of
the spinal cord.
-Consider Spinal Muscular Atrophy in an exam question detailing a hypotonic child
with no HY history associated with consuming honey (so that you can rule out
botulism). It is caused by a mutation that leads to the atrophy of anterior horn neurons
of the spinal cord. Babies affected with this condition typically have tongue
fasciculations with the disease rapidly progressing to death within a few months. It is
also called floppy baby syndrome.
Other Diseases-Amyotrophic Lateral Sclerosis (ALS)
-Is a combined disease that affects both UMN (corticospinal tract) and LMN (anterior horn motor neurons).
UMN symptoms typically include spasticity and exaggerated reflexes. LMN symptoms typically include muscle
fasciculations and wasting.
-It is Super HY to know that there are no sensory symptoms associated with ALS as the dorsal columns are
typically spared. In addition, urinary tract symptoms and visual deficits are rarely, if ever, found in the disease.
As an aside, visual problems that come and go in a female in her 30s-40s should strongly raise your suspicion
for Multiple Sclerosis.
-ALS for the most part shows up in the 40-60 year old age group and is often fatal within 3-5 years.
-The current treatment of choice for ALS is Riluzole which works in a number of mysterious ways that have not
been fully elucidated. It is thought to mostly decrease glutamate release from neurons (remember that
glutamate is excitotoxic, its like taking too much of a good thing) in addition to potentially being an antagonist
at NMDA receptors (which have glutamate as a NT).
-It is also HY to know that certain familial cases of ALS have an association with a Superoxide Dismutase
(SOD1) mutation. Since SOD gobbles up free radicals, a defective functioning of this pathway could potentially
explain the neuron cell death that permeates this process.
Know This Cold-Cauda Equina Syndrome

PLS MEMORIZE THE FOLLOWING CLUSTER OF SYMPTOMS.
-Bowel/Bladder Dysfunction.
-Saddle anesthesia (i.e. loss of sensation in the groin area).
-Lower Extremity Weakness.
Q9-HY Triggers
UMN pathway that decussates in the caudal medulla
Descending motor tract that excites arm flexors
UMN pathway that does not decussate in the caudal medulla
Woman with visual deficits that come and go
Contralateral pain/temp loss + Ipsilateral sensory losses
Nucleus in medulla for upper body proprioceptive information
Nucleus in the medulla for lower body proprioceptive information
Nucleus in the medulla for upper body unconscious proprioception
Afferent cerebellar pathway associated with the SCP
Lesion of the dorsal columns in the spinal cord
Axons of Sensory Information Fibers in the dorsal horn that carry pain/temp
Decussation Point of the Lateral Corticospinal Tract
Decussation Point of the Spinothalamic Tract
Decussation Point of the Rubrospinal Tract
Decussation point of the DCML pathway
Unconscious proprioception for the lower body
Unconscious proprioception for the upper body
Bilateral Loss of pain and temperature sensation
Bilateral Muscle weakness/atrophy with no sensory deficits
Random, asymmetric white matter lesions in a young female
Q9-HY Triggers Key

UMN pathway that decussates in the caudal medulla-Lateral Corticospinal Tract.
Descending motor tract that is excites arm flexors-Rubrospinal Tract.
UMN pathway that does not decussate in the caudal medulla-Anterior Corticospinal Tract.
Woman with visual deficits that come and go-Multiple Sclerosis.
Contralateral pain/temp loss + Ipsilateral sensory losses-Brown Sequard Syndrome.
Nucleus in medulla for upper body proprioceptive information-Cuneate Nucleus.
Nucleus in the medulla for lower body proprioceptive information-Gracile Nucleus.
Nucleus in the medulla for upper body unconscious proprioception-Lateral Cuneate Nucleus.
Afferent cerebellar pathway associated with the SCP-Anterior Spinocerebellar Tract.
Lesion of the dorsal columns in the spinal cord-Ipsilateral loss of vibratory/proprioceptive sense.
Axons of Sensory Information Fibers in the dorsal horn that carry pain/temp-Lissauers Tract.
Decussation Point of the Lateral Corticospinal Tract-Caudal Medulla (pyramids).
Decussation Point of the Spinothalamic Tract-Anterior White Commissure.
Decussation Point of the Rubrospinal Tract-right after the red nucleus in the midbrain.
Decussation point of the DCML pathway-Caudal Medulla as the Medial Lemniscus Fibers.
Unconscious proprioception for the lower body-Dorsal Spinocerebellar Tract.
Unconscious proprioception for the upper body-Cuneocerebellar Tract.
Bilateral Loss of pain and temperature sensation-Syringomyelia.
Bilateral Muscle weakness/atrophy with no sensory deficits-ALS.
Random, asymmetric white matter lesions in a young female-Multiple Sclerosis.
Q10-What are the deficits associated with this lesion?
Q10 Key
Bilateral loss of vibratory sense below the level of
the lesion (DCML gone)
Ipsilateral UMN signs below the level of the lesion
(LCST gone)
All the best..Its going to be ok.
A HY Review of The Special

Senses
Some MS2
-Doing well on the special senses exam depends extensively on understanding mechanisms. You need to
memorize the different pathways and tracts unfortunately, but you also need to understand how to
resolve many of the problems youll meet on the exam.
-There are a few blurry images in this document. I did not mean to include these. However, they do
illustrate certain points extremely well so I left them in. The points I try to get across are very visible
with these images so no worries.
-Make sure you understand THE EYE. It is the most HY special sense for your test.
-Well walk through a host of problems and also spent some good time talking through scenarios that
are relatively HY. Make sure you understand these scenarios/problems which will probably be very well
represented on your test.
-Since this is our last review for the year, well have a short debrief at the end.
Q1
A lesion to the artery at A would most likely result in;
a.
b.
c.
d.
e.
Ipsilateral motor arm/hand deficits.

Contralateral motor leg/foot deficits.
Ipsilateral sensory face deficits.
Contralateral sensory arm/hand deficits.
Ipsilateral motor leg/foot deficits.
Q1 Key
-The best answer is B, contralateral motor leg/foot deficits.
-The artery indicated by A is the Anterior Cerebral Artery which supplies the
anteromedial cortex. This region corresponds to the leg/foot area in the homunculus.
-The Corticospinal tract decussates in the medullary pyramids so the lesion will give
rise to contralateral motor deficits.
-Another possible correct answer (which is not one of the choices) is a contralateral
leg/foot sensory loss.
Q2
A 72 yo male with a suspected ischemic stroke is rushed to the Med19 clinic by paramedics. A
rapid neuro exam performed on admission reveals total right sided hemiplegia. When asked to
stretch out his tongue, total leftward deviation is noted. Labs obtained 30 minutes after admission
reveal a blood glucose level of 30 mg/dL with rapid correction by the administration of 2g of
dextrose. The patient tells the nurse that the sugar tastes sweet only on one half of his tongue (the
right). The most likely location of the lesion that explains these clinical findings is;
a.
b.
c.
d.
e.
f.
g.
h.
The cerebral peduncles in the left midbrain.

The interpeduncular fossa between the left and right midbrain.
The medial pons on the right.
The lateral medulla on the left.
The medial medulla on the right.
The medial pons on the left.
The medial medulla on the left.
The lateral pons on the right.
Q2 Key
The best answer is G, the medial medulla on the left.
There is loss of taste sensation on the left (taste sensation ipsilateral).
There is total hemiplegia on the right (remember that this is prior to the pyramidal
decussation, so the lesion has to be on the left).
There is tongue deviation to the left (indicating a hypoglossal nerve lesion on the
ipsilateral side).
The constellation of signs and symptoms points to a lesion in the left medial medulla.
This may seem nitpicky but it is very HY to realize that loss of pain/temperature
sensation essentially localizes lesions to the lateral, not medial brainstem.
Q3
A Med19 student on an Ophthalmology elective performs an eye exam on a 55 yo
female. He notices that shining light in the patients right eye produces no pupillary
response, but shining light in the left eye causes miosis in the right and left eye. The
most likely location of the lesion explaining these clinical findings is;
a.
b.
c.
d.
e.
f.
The right optic tract.

The right optic radiations.
The left optic nerve.
The right optic nerve.
The oculomotor nerve on the right.
The oculomotor nerve on the left.
Q3 Key
The best answer is D, the right optic nerve.
-The loss of all pupillary constriction on the left and the right when light is shone in
the right eye is indicative of an afferent pupillary defect. The restoration of the
pupillary reflex when light is shone in the left eye indicates that the optic nerve on that
side is intact. The absence of miosis in both eyes from light shining in one eye is a very
specific finding in sensory visual deficits.
-A lesion of the oculomotor nerve would present with a lack of miosis of the ipsilateral
eye with light shining in either eye. This finding is very helpful in telling a sensory
from a motor visual deficit.
-Make sure you understand why D is correct. It is very HY.
Q4
A 27 yo Asian male presents to the Careless Clinic with complaints of a 9/10 headache
and blurry vision that has been going for the past 2 hours. A neurological exam reveals
redness in the left eye. The patient recently immigrated to the US from China.
Palpation of the affected eye reveals a rock hard pupil. The Ophthalmology intern
decides to administer a pharmacologic agent to take a closer look at the patients eye. 5
minutes after administration of this agent, the patient reports that he cannot see
anything out of his left eye. The most likely cause of this lesion is;
a.
b.
c.
d.
e.
The administration of an adrenergic agonist.

The administration of a muscarinic agonist.
The administration of an adrenergic antagonist.
The administration of a nicotinic agonist.
The administration of a nicotinic antagonist.
Q4 Key
The best answer is A, the administration of an adrenergic agonist.
-This patient has closed angle glaucoma.
-The last thing you want to do in a patient with closed angle glaucoma is to administer any agent
that dilates the pupil. This increases intraocular pressure.
-The sympathetic nervous system dilates the pupil. The parasympathetic nervous system
constricts the pupil.
-Administration of a sympathetic agonist (like phenylephrine) or a muscarinic antagonist (like
atropine, tropicamide, cyclopentolate, scopolamine, hyoscyamine, etc)leads to pupillary dilation
(make sure you understand why this is true, more to come in later slides).
-The nicotinic answers are distractors. The control of pupillary constriction/dilation works via
the autonomic, not somatic nervous system.
Ear Introduction
-The outer ear (everything lateral to the tympanic membrane) and the middle ear both contain air. The inner
ear (everything after the oval window) contains fluid.
-The inner ear contains 3 fluid filled chambers with the one on top (scala vestibuli) and the one at the bottom
(scala tympani) both containing a fluid known as perilymph. The one in the middle (the scala media OR
cochlear duct) contains cells bathed in a special extracellular fluid known as endolymph. This endolymph is
made by a specialized epithelium known as the Stria Vascularis.
-Conductive hearing loss occurs in a lesion of any structure in the outer ear (ear wax, etc) or middle ear (otitis
media, otosclerosis, etc-these wear down the ossicles and impair sound amplification).
-Sensorineural hearing loss is a common derivative of lesions in the inner ear. Ototoxic drugs like the
aminoglycosides and platinum compounds like Cisplatin play a huge role here.
-Hyperacusis (usually due to a CN 7 lesion-remember the Stapedius Nerve, a lesion prevents dampening of
incoming sound signals) occurs when theres an increased sensitivity to loud sounds.
-Presbycusis occurs secondary to a loss of hair cells at the base of the cochlea (that control high frequency
hearing). These cells are more fragile and are typically lost first.
Ear Introduction
-The 3 ossicles amplify sound primarily by concentrating the sound
intensity/energy/power over a small area (the foot plate of the stapes). This creates a
sound mechanical advantage.
-The Scala Media (or cochlea duct) is bounded by Reissners membrane on top (which
separates it from the scala vestibuli) AND the apices of the hair cells on the bottom
(which separates it from the scala tympani).
-The hair cells found in the ear/vestibular system lack any sort of regenerative ability.
These cells are the backbone of auditory reception. In addition, a special population of
these cells (outer hair cells) produce little sounds known in medical parlance as
Otoacoustic emissions that are used to determine proper ear function in babies.
The 2 Extracellular Environs of The Hair Cells

-As mentioned on the previous slide, the hair cells have their regular intracellular fluid which is
like other intracellular fluids in the body (low Na and high K) with a -ve intracellular membrane
potential.
-These cells face 2 different sorts of extracellular environs. On one hand (above), they face the
endolymph of the scala media which contains high K and low Na (and a +ve electric potential).
On the other hand (below), they face the perilymph of the scala tympani which has high Na and
low K like the other extracellular fluids in the body.
-With the similarities b/w the fluid concentrations of the top of the hair cells (endolymph) and
the insides of the hair cells (intracellular fluid), the only driving force for action potentials is the
electrical gradient that exists b/w these 2 compartments which are separated by the membranes of
the hair cells. It is HY to know that it is K (not Na) that causes a depolarization of these cells.
-However, the basal side of these cells follow the normal order of ion transmission with K ions
passively leaving the cells down their gradients into the perilymph of the scala tympani.
Audition-General Mechanism
Step 1-Sound waves from the surroundings vibrate the tympanic membrane.
Step 2-These sound waves are amplified by the 3 bones of the middle ear-the malleus, incus,
and stapes. The stapes vibrates the oval window of the inner ear which is juxtaposed to the
cochlea (which contains a special kind of fluid).
Step 3-These sound vibrations lead to the stimulation of hair cells in the Organ of Corti.
These hair cell fibers (think of them as being like those sensory mechanoreceptors we
discussed for the last test) have a given tonotopy in relation to sound frequency. In other
words, different sound frequencies activate different populations of hair cells. Cells near the
base of the cochlea respond to high frequency sounds while those at the apex respond more
to low frequency sounds. This tonotopic information is represented in the temporal lobe of
the cortex.
Step 4-The generated signals then travel in the cochlea nerve to upper levels in the brain.
The Hearing Apparatus aka The Ear
General Schematic of The Auditory Pathway
The Mechanism of Hearing Part 1
The Mechanism of Hearing Part 2
The Control of Hearing/Ear Protection Mechanism
Localizing Lesions/Other Miscellaneous Ear Factoids
-A lesion proximal to the cochlear nucleus will often result in an ipsilateral hearing loss (nothing has crossed
yet).
-However, a lesion distal to the cochlear nucleus will result in bilateral hearing loss since the fibers emanating
from the cochlear nucleus both ascend ipsilaterally and cross at the same time.
-Cochlear implants restore some sort of hearing to individuals that get them (since the neuronal apparatus is
intact). A lesion of any part of the neuronal apparatus makes this essentially impossible.
-It is postulated that high frequency hearing loss occurs first because the hair cells that handle this specific
frequency of sound have a larger SA/V ratio and higher metabolic demands (more ion pumps). With this high
dependence on energy, there is a lower margin of safety if these cells were to undergo any sort of metabolic
stress. This is in contrast to the low frequency hair cells that have a smaller SA/V ratio and lighter metabolic
demands.
-In general, the brain tries to localize sounds by integrating 2 kinds of information from both ears-the loudness
of the sound + the timing of the sound arrival at different parts of the auditory pathway.
-Early intervention in people with hearing loss improves outcomes (in addition to having money/rehab).
Perilymph/Endolymph/The Superior Olives
Q5
A lesion to the structures at A will result in;
a.
b.
c.
d.
e.
Ipsilateral loss of tactile sensation

Ipsilateral loss of pain sensation
Contralateral loss of motor movements
Ipsilateral loss of motor movements
Ipsilateral loss of vibratory sense
Q5 Key
-The best answer is D, ipsilateral loss of motor movements.
-Remember that the lower motor neurons begin in the ventral horn of the spinal cord.
-B represents the spinothalamic tract fibers.
-C represents the lateral corticospinal tract fibers.
-D represents the fibers of the dorsal column medial lemniscus pathway.
Q6
A 55 yo male comes to the Med19 clinic for his regular 6 month physical. PE reveals a
well appearing man in no acute distress. A review of his current medication list by the
med student on service reveals that the patient takes Nadolol eye drops. The most
likely mechanism of action of this drug is?
a.
b.
c.
d.
e.
The blockade of alpha receptors on ciliary muscle.

The blockade of muscarinic receptors on pupillary sphincters.
The blockade of beta receptors on ciliary epithelium.
The blockade of alpha receptors on ciliary epithelium.
The blockade of alpha receptors on pupillary dilators.
Q6 Key
-The best answer is C, the blockade of beta receptors on ciliary epithelium.
-Nadolol is a beta blocker that is used to treat glaucoma. You may not need to know
specific names but you should definitely know that things ending in olol are beta
blockers.
-Beta blockers work by blocking the beta receptors on the ciliary epithelium to prevent
the synthesis of aqueous humor.
Q7
The normal conjugate visual response is shown below. 2 patients (P1/2)present to the Med19 Eye Clinic
and are asked to look to the right during an eye exam. The patients test results are shown in 1 and 2
below. The most likely explanation for these results are?
a.
b.
c.
d.
A lesion of the left oculomotor nerve for P1 and the left CN3 nucleus for P2.
A lesion of the right CN3 nucleus for P1 and the left oculomotor nerve for P2.
A lesion of the left CN6 nucleus for P1 and the left abducens nerve for P2.
A lesion of the right abducens nerve for P1 and the right CN6 nucleus for P2.
Q7 Key
-The best answer is D.
-Patient 1 cannot abduct his right eye on conjugate gaze to the right but can adduct his
left eye.
-Patient 2 cannot abduct his right eye on conjugate gaze to the right. In addition, he
cannot adduct his left eye.
-Patient 1 has a lesion of the abducens nerve (fibers coming after the nucleus). The
Medial Longitudinal Fasciculus (MLF) is still intact.
-Patient 2 has a lesion of the abducens nucleus. Fibers originating in this nucleus
supply CN3 through the MLF so screwing up the nucleus screws up both CN3 and
CN6.
-Make sure this makes sense to you! (more to come in a later slide)
Q8
The normal conjugate visual response is shown below. 2 patients (P3/4)present to the Med19 Eye Clinic and are
asked to look to the right during an eye exam. The patients test results are shown in 3 and 4 below. The most
likely explanation for these results are? (MLF = Medial Longitudinal Fasciculus).
a.
b.
c.
d.
A lesion of the right MLF for P3 and the right cortex for P4.
A lesion of the left MLF for P3 and the left cortex for P4.
A lesion of the right MLF for P3 and the left cortex for P4.
A lesion of the left MLF for P3 and the right cortex for P4.
Q8 Key
-The best answer is B.
-Patient 3 can abduct his right eye but cannot adduct his left eye.
-Patient 4 cannot abduct his right or adduct his left eye.
-Patient 3 has a lesion of the left MLF. Remember that the left MLF controls the movement of the
ipsilateral CN3 in response to stimulation from the right CN6 nucleus. If the patient had an actual
CN3 lesion, he would have a down and out eye on the ipsilateral side, which he does not.
-Patient 4 has a lesion of the cortex on the left. Remember that the left frontal eye field projects to the
right Paramedian Pontine Reticular Formation (PPRF) which is in very close proximity to the CN6
nucleus. The right PPRF then controls the ipsilateral LR muscle and the contralateral MR muscle to
cause right conjugate gaze.
-As an added question, is there another kind of lesion that would produce the same visual deficits as that
observed in Patient 4?
Horizontal Conjugate Gaze (HCG)

-The HCG pathway is one that is tasked with moving both eyes congruently in a given direction. For
example, if you want to look left, both eyes have to look left. For both eyes to look left, you have to
abduct your left eye (left LR) and adduct your right eye (right MR).
-Control of these pathways begins in the Frontal Eye Field.
-To look left, the FEF in the right cortex sends fibers that decussate and project to the PPRF (which are
in the pons) in the left brainstem. The fibers of the PPRF on the left then project to the ipsilateral
abducens nucleus and through the right MLF to the right oculomotor nucleus (contralateral wrt to the
FEF). In this way, HCG is achieved.
-A FEF lesion causes a deviation towards the side of the lesion (ipsilateral) b/c there is an impairment of
HCG in the contralateral direction. A PPRF lesion causes a deviation away from the side of the lesion
(contralateral) b/c there is an impairment of HCG in the ipsilateral direction.
-It is very hard to have isolated lesions of the FEF and the PPRF. Affected individuals typically have
lesions of other tracts (like the corticospinal tract which are usually contralateral to the lesion).
The Horizontal Conjugate Gaze Pathway (looking right)
The Vestibulo-Ocular Reflex

-Is a HY reflex associated with maintaining gaze on an fixed object when the head
turns. It is very important that you understand how this reflex works.
There are a few key ideas to be aware of;
-There are always 2 phases of a nystagmus-a slow phase AND a fast phase.
-A nystagmus is always named with respect to the FAST phase (make sure you get this,
many lectures will make zero sense if you dont!).
-The application of cold water to a given ear basically mimics a vestibular nucleus
lesion on that side.
-The application of warm water to a given ear basically activates the vestibular nucleus
on that side (remember-high temps increase kinetic energy).

Lets assume your head turns right and youre gazing at a fixed object. To still see that object, both eyes must
look to the left. How does this happen?
Step 1-Turning the head to the right ACTIVATES the vestibular nucleus on the right (in other words, a head
turn on a given side activates that ipsilateral side).
Step 2-The activation of the right vestibular nucleus leads to the activation of the abducens nucleus (CN 6) on
the contralateral side (left). The abducens nucleus subsequently activates the ipsilateral (left) lateral rectus
muscle and the contralateral oculomotor nucleus via the Medial Longitudinal Fasciculus(left).
Step 3-The overall effect of these actions is to activate the lateral rectus muscle on the contralateral side of the
initial CN 8 stimulation and the medial rectus muscle on the ipsilateral side of the initial CN 8 stimulation.
Step 4-This leads to an abduction of the eye on the contralateral side secondary to LR stimulation and
adduction of the eye on the ipsilateral side secondary to MR stimulation. This fixes gaze on the object while the
head is turning.
It is also HY to know that while the vestibular nucleus activates the contralateral abducens nucleus in Step 2, it
also inhibits the ipsilateral abducens nucleus to shut down movement to the opposing side.
The Caloric Test Mechanism-COWS

-First off, theres a decent mnemonic for remembering what happens with the Caloric Test. COWS (Cold
Opposite, Warm Same). Dont forget the addendum that this mnemonic works primarily with the fast phase
of nystagmus.
-The Caloric Test is used to assess brainstem function in unconscious patients (i.e. those in a coma). This is
done by indirectly testing vestibular nerve function.
-By pouring cold water in an ear (say left), kinetic energy is reduced in the ipsilateral left ear, making the brain
think that the contralateral right ear was stimulated (which is analogous to turning the head on that
contralateral right side).
-This leads the brain to think the head was turned on the right side, which gives rise to eye movement to the left
(as per the mechanism in the preceding slide).
-The brain then realizes-oh no!, I did not actually turn my head to the right! and hence adjusts this by promptly
turning the eyes right back to the right to fix the mistake. The correction, by definition is the FAST phase of the
nystagmus. Note that this correction is contralateral to the ear (left) that received cold water (Cold, Opposite).
-Try working out the Warm, Same mechanism (will discuss in the session).
Vestibular Diseases
-Menieres Disease is primarily caused by issues with flow, production, or obstruction of endolymph in
the vestibular system.
-If you see this cluster on your exam-Vertigo, Tinnitus (ringing from a mix of endolymph with
perilymph), and Hearing loss (that is transient), stop thinking, and pick Menieres as your answer.
-There are lots of treatment options but a HY one to be aware of is Gentamicin. This is an example of
using a known side effect of a drug (ototoxicity-hello aminoglycosides!), to treat a medical problem.
Since the vestibular system misbehaves in Menieres, one strategy is to essentially destroy it. The only
issue is the fact that hair cells exist in other places besides the vestibular system (like the ears), so
sensorineural hearing loss could be an unwelcome side effect.
-Vertigo is another common disease associated with the vestibular system where the world seems to
bounce around in ones field of view. This is typically associated with severe nausea and vomiting.
Q9
A 66yo female who was a recent victim of a stroke presents to the Med19 clinic for
follow up after hospital discharge. A thorough exam reveals an absent gag reflex.
Further neurologic examination would most likely reveal;
a.
b.
c.
d.
e.
Decreased sensation below the nipple line bilaterally.

Decreased sensation on the forehead in a trigeminal nerve distribution.
Decreased sensation in the posterior third of the tongue.
Unilateral tongue deviation.
A bilateral loss of the pupillary reflex.
Q9 Key
-A patient with an absent gag reflex has 1 of 2 cranial nerve lesions-CN9
(Glossopharyngeal) or CN10 (Vagus). CN9 is the afferent limb of the gag reflex. CN10
is the efferent limb of the gag reflex.
-Therefore, you should immediately guide your thoughts towards anything remotely
resembling lesions of any of these nerves.
-The only option that fits is a loss of sensation (which could be general sense or taste)
in the posterior third of the tongue which is controlled by CN 9.
-Hence C is the best answer. Please do not fall for the tongue deviation distractor.
That is CN12 (hypoglossal) territory.
Q10
A 65 yo man undergoes synchronized cardioversion for the emergent treatment of new
onset atrial fibrillation. Neurologic exam 3 days after the procedure reveals a left lower
quadrantanopia. This deficit is most likely associated with embolic occlusion of a vessel
supplying the;
a.
b.
c.
d.
e.
Optic Nerve on the left

Optic Tract on the left
Right Lateral Geniculate Nucleus
Right Temporal Lobe
Right Parietal Lobe
Q10 Key
-The best answer here is E.
-A loss of vision in the inferior visual field means there is a superior lesion
somewhere.
-A loss in the left visual field means that there is a lesion in the right optic radiations.
-Remember that the information for the inferior visual field travels superiorly in the
cortex through the parietal lobe (Baums Loop).
-It is also noteworthy to remember that information from the superior visual field
travels inferiorly in the cortex through the temporal lobe (Meyers Loop).
Q11
A 23 yo female with a history of severe autoimmune disease presents to the Med19
clinic for a workup of new neurological complaints. PE reveals ptosis in the left eye.
Further examination reveals a massively dilated and unreactive pupil (to light). These
findings are best explained by a lesion to the?
a.
b.
c.
d.
e.
Facial Nucleus
Facial Nerve
Superior Cervical Ganglion
Ciliary Ganglion
Trigeminal Nerve
Q11 Key
-A pupil that is unreactive to light in the setting of mydriasis is quite concerning for an
oculomotor nerve lesion. CN 3 mediates miosis and the efferent limb of the pupillary
light reflex.
-The other answers make absolutely no sense at all.
Q12
Match the visual field defect to the appropriate letters;
Loss of vision in the right visual field for the left eye.
Loss of contralateral superior visual field information.
Loss of the left visual field in the left eye AND the right visual field in the right eye.
Q12 Key
Match the visual field defect to the appropriate letters;
Loss of vision in the right visual field for the left eye-C
Loss of contralateral superior visual field information-E
Loss of the left visual field in the left eye AND the right visual field in the right eye-B
Anatomy of The Eye
The Anatomy of The Eye (in words)

-The layers of the eye from outside to inside are the sclera which is primarily
connective tissue, the choroid layer which contains blood vessels, and the retina which
is essentially a neural layer.
-The retina converges in the back of the eye to form the optic nerve which goes
through the optic disk, giving rise to the beginning of the afferent visual system. It is
HY to know that the convergence of the retina in the back of the eye gives rise to the
BLIND SPOT.
-The area of highest visual acuity in the eye is the fovea which is part of a structure
known as the Macula. This area is infested with photosensory cells known as cones.
-There are 2 refractory surfaces in the eye-the cornea which is fixed and cannot be
adjusted (well, an ophthalmologist can) and the lens which is certainly adjustable by
virtue of its tight relationship with the autonomic nervous system.
The Anatomy of The Eye (in words)

-The term Iris is used to describe the group of muscles that adjust the amount of light getting into
the eye. The Iris also demarcates the anterior and posterior chambers which together form the
anterior segment of the eye.
-The pupil is not a structure, but is actually just the space between the iris on the left and the iris
on the right. The size of this space is adjusted by the pupillary constrictors and dilators to control
the amount of light getting to the retina.
-The actual curvature of the lens is maintained by the ciliary muscle which is innervated solely by
the parasympathetic nervous system with fibers originating from the ciliary ganglion. The
contraction of these muscles plays a role in accommodation.
-Light entering the eye gets refracted (bent) at multiple interfaces with the first being at the level
of the cornea (air/tear film which prevents eye dryness), the anterior lens (b/w aqueous humor
and the lens-remember that the lens marks the termination of the anterior segment), and the
posterior lens (b/w the lens and vitreous humor).
Anatomy of The Eye-Extraocular Muscles
Anatomy of The Eye-Extraocular Muscle Functions
Pathologies of The Extraocular Muscle Cranial Nerves

-Cranial nerve 2 lesions are associated with visual field deficits. Lesions proximal to the
optic chiasm are associated with ipsilateral VF deficits. Lesions at the optic chiasm are
associated with tunnel vision. Lesions distal to the optic chiasm are associated with
contralateral VF deficits. Lesions associated with macular sparing are caused by
Posterior Cerebral Artery occlusions (collateral circulation from the MCA). Other HY
arterial pathologies include occlusions of the posterior ciliary arteries which supply the
choroids of the eye and the optic nerve head, which marks the origin of the optic disc
(or the physiologic blind spot of the eye).
-Cranial nerve 3 lesions are associated with down and out eyes secondary to lesions
of the MR, SR, IO, IR, and Levator Palpebrae Superioris lesions. Do not forget 2 HY
anatomical relationships-CN3s close proximity to the uncus of the temporal lobe
AND CN3s passage b/w the superior cerebellar artery and the posterior cerebral
arteries.
Pathologies of The Extraocular Muscle Cranial Nerves 2

-Cranial nerve 4 lesions are associated with a contralateral extraocular movement deficit since it exits dorsally
in the brainstem before it comes out to innervate the contralateral SO muscle. The SO muscle depresses and
intorts (moves the eye towards the 12 0 Clock position). A lesion of this nerve means that the person will have
trouble depressing their eyeballs so it remains elevated. As the affected eye looks up and the unaffected eye
looks down, images are appear double to the affected individual in the vertical direction (diplopia). As a
compensation, affected individuals tend to tilt their heads away from the lesioned side (or chin towards) to pull
up the unaffected eye so things stop appearing double. This CN is classically tested in the context of an
individual having difficulty with reading books/getting down stairs.
-The only HY ocular pathology associated with CN5 is its role in the blink (or corneal reflex). It is important to
understand that the ophthalmic division of the trigeminal nerve (CN V I) controls the afferent limb of this
reflex, while CN 7 controls the efferent limb of the reflex.
-CN6 is HY in the sense that it plays roles in many reflexes/specialized eye movements like the VestibuloOcular reflex and Horizontal Conjugate Gaze. It is HY to know that the abducens nerve runs in the center of
the cavernous sinus and is frequently lesioned in the setting of high intracranial pressures or infections in the
cavernous sinus itself.
The Process of Accommodation/Convergence

-Accommodation/Convergence refers to a reflex that essentially makes it possible for an
individual to focus on a near object after they have just looked at a far object. The process of
focusing on a near object is in 3 phases;
-The first phase requires making the lens rounder/thicker to increase its refractive index. This is
accomplished by the ciliary muscle which receives postganglionic parasympathetic innervation
via short ciliary nerves from the ciliary ganglion (remember that the preganglionic signals
originate in the Edinger Westphal Nucleus in the midbrain).
-The second phase involves making the image of the to be viewed object focus on the same
portion of the retina in each eye. You accomplish this by becoming cross-eyed temporarily
(pulling your 2 MR muscles together).
-In the final phase, the depth of field is increased by making your pupils smaller. This is
accomplished by the pupillary sphincters.
-It should become obvious that CN3 (PNS) plays a huge role in all of this.
The Oculosympathetic Pathway
Oculosympathetic Lesions-Horner Syndrome

-Is an ophthalmic condition associated with any lesion of the oculosympathetic
pathway along its length. Possible lesion etiologies include Pancoast tumors
(carcinomas in the apex of the lung which may compress the sympathetic fibers), cord
hemisections, and in some cases, lateral brainstem lesions (since these fibers travel
along the same path as spinothalamic fibers).
-Any sort of lesion along this pathway presents with the classic triad of miosis
(remember that the SNS causes mydriasis so if its not there, the PNS will operate
unopposed and cause miosis), ptosis (due to a denervation of the SNS innervated
Superior Tarsal muscles), and anhidrosis (remember that the SNS innervates sweat
glands, albeit through muscarinic acetylcholine receptors).
The Droopy Eyelids of Horners Syndrome.
The Pupillary Light Reflex
The Battle of CN2 and 3

-The optic nerve (CN 2) plays its role as the afferent limb of the pupillary light reflex.
-On the flip side, the oculomotor nerve (CN3) also plays a role as the efferent limb of
the pupillary light reflex. It is very HY to know how to distinguish b/w a CN2 and a
CN3 lesion based on vignettes dealing with a description of findings in certain
pupillary reflex exams.
Make sure you understand the following scenarios.
First, an inability to constrict one or both eyes in response to light being shone in one
eye makes it likely that an individual has a CN2 or 3 lesion.
-An individual with a CN2 lesion will not have pupillary constriction in both eyes
when light is shone in the affected eye. Neurologists love to call this an afferent
pupillary defect (a lesion of the optic nerve).
The Battle of CN2 and 3 contd..

-When light is shone in the unaffected eye, pupillary constriction will be observed in both eyes
since they both have functional oculomotor nerves.
-In a CN3 lesion, pupillary constriction will not be observed in the affected eye if light is shone in
either eye. This is a very HY point to keep in mind.
CN3 lesions are not always as they seem. The inability to adduct the eye (which is the function of
the oculomotor nerve) does NOT always mean that the oculomotor nerve is lesioned. Some
structure connecting to the oculomotor nerve itself could be lesioned.
-For example, a lesion of the MLF on the ipsilateral side to a given CN3 will present with an
inability to adduct the eye on conjugate gaze. This occurs because the CN3 connection with this
specific scenario does not work.
-To be absolutely sure that CN3 is not working, test other functions that depend heavily on CN3s
ability like the accommodation-convergence response.
The Process of Seeing
Visual Field Deficits (make sure you know these!)
Visual Field (VF) Defects-HY Factoids

-The mention of the word tunnel vision on your test should promptly guide to you to
thoughts of a lesion at the level of the optic chiasm. The most common exam scenario
is to test this in the context of a pituitary tumor. The clinical term used to describe this
kind of VF defect is bitemporal heteronymous hemianopsia (as visual fields on
different sides of the eye-left and right-are lost). This in contrast with the loss of visual
fields on the same side of both eyes (i.e. left in the left eye and left in the right eye)
which is clinically known as a homonymous hemianopsia.
The Swinging Flashlight Test

-Is a very HY test that is typically used to detect relative afferent pupillary defects (RAPD). Do
not confuse this with an absolute defect-theres residual nerve function.
-RAPD are caused by lesions of Cranial Nerve 2. The swinging flashlight test is done in 3 phases;
Phase 1-When light is shone in the affected eye, both pupils do not constrict fully (since light is
not being fully transmitted through the affected nerve).
Phase 2-When light is shone in the unaffected eye, both pupils constrict fully.
Phase 3-When light is then quickly shone in the affected eye, both pupils paradoxically dilate.
This occurs because the brain interprets the new light coming in from Phase 3 as being darkness
relative to Phase 2 since theres impaired transmission.
This term is derogatory, so dont use it in the clinic, but neurologists call this the Marcus Gunn
pupil. It is a very classic finding in individuals with Multiple Sclerosis.
Eye Anatomy and Glaucoma
Anatomy of The Eye and Glaucoma

-It is important to make a distinction between eye segments and eye chambers. The segments
are big picture structures while the chambers are small picture structures that are derivatives
of the anterior segment.
-It is also important to distinguish b/w aqueous humor (which is found in the anterior segment)
and vitreous humor (which is found in the posterior segment).
-The Anterior Segment of the eye contains the cornea, iris, ciliary body, and lens. It is basically
everything in front of the vitreous humor. All else is the posterior segment.
-The Anterior Chamber of the anterior segment is everything in front of the iris.
-The Posterior Chamber of the anterior segment is everything b/w the iris and lens.
-Aqueous humor is produced in the posterior chamber, circulates through the anterior chamber,
and is then drained through the trabecular meshwork to The Canal of Schlemm.
Relevant Glaucoma Structures

-The Ciliary Body lies in the posterior chamber. The Ciliary Body = Ciliary Muscle +
Ciliary Epithelium. The Ciliary Muscle is solely under the control of the
parasympathetic nervous system and serves to adjust the width of the lens for
accommodation (a fat lens is more attuned to seeing near objects). The Ciliary
Epithelium is under the control of the Sympathetic Nervous System through beta-1
stimulation and is mainly concerned with the production of aqueous humor.
-The aqueous humor from the posterior chamber flows to the anterior chamber, drains
through the angle and gets into the trabecular meshwork. The Angle is a term used
to describe the angle b/w the cornea and the iris.
-From the trabecular meshwork, the fluid drains into the Canal of Schlemm.
The Flow of Aqueous Humor
The ANS and The Eye (Note the 2 Distinct Muscle Types)
Eye Anatomy and Glaucoma
Glaucoma Pathophysiology
-Glaucoma is defined as an increase in Intraocular Pressure (IOP) secondary to an imbalance b/w
aqueous humor production and drainage. The increased IOP (in a closed box like the eye),
squishes most of the vasculature that supplies the retina/optic nerve which can ultimately lead to
blindness. It is HY to know that peripheral vision is typically lost first in the setting of glaucoma.
-There are 2 types of glaucoma.
-Open Angle Glaucoma is glaucoma that arises secondary to decreased drainage of aqueous
humor from the anterior chamber in the presence of a grossly normal angle b/w the iris and
cornea. OAG is a painless, chronic condition.
-Closed Angle Glaucoma is glaucoma that arises secondary to a bunching up of the iris against
the cornea which essentially closes out the angle that leads into the trabecular meshwork. This
leads to a very rapid buildup of aqueous humor in the anterior/posterior chambers with a
concomitant increase in IOP. CAG is a painful, acute condition. This is a medical emergency and
must be treated rapidly to prevent impending blindness.
The Angle In Glaucoma
Glaucoma Pathophysiology
-The IOP is measured by tonometry (puff of air into the eyes if youve ever visited an
ophthalmologist).
-It is important to understand for reasons that will be discussed shortly that drugs that dilate the
eye are contraindicated in closed angle glaucoma. Mydriasis is not something youd want to
trigger in a closed angle situation.
-Glaucoma is more common in older people, African Americans, and individuals with a family
history of the disease.
-Glaucoma has a strong association with a high cup/disc ratio (normal is less than 0.3). An
increasing cup to disk ratio means that more optic nerve fibers are dying. This increases the
amount of space in the disk which manifests as the increased ratio. A good way to think about this
is a donut being the disk and the donut hole being the cup. If you keep eating a donut from the
center (death of optic nerve fibers), the donut hole gets bigger (cup/disc ratio goes up).
Increased Cup/Disc Ratio in Glaucoma (very HY!)
The ANS and Glaucoma

-Beta 1 receptors are found in the ciliary epithelium and serve to increase aqueous
humor production secondary to stimulation. Blocking Beta-1 receptors should hence
treat glaucoma. This is the MOA of Beta blockers like Timolol.
-Miosis reduces the bunched up angle b/w the iris and the cornea by contraction (or
straightening/miosis) of the constrictor muscles (iris). This is mediated by the PNS.
This is the MOA of muscarinic (M3) agonists like Pilocarpine (later slide).
-Prostaglandins are known to open up things (youll learn a ton of this in the fall).
They open up the canal of schlemm which increases aqueous humor drainage. This is
the MOA of Prostaglandin Analogs like Latanoprost (anything ending in prost)
which vasodilate the canals of schlemm (essentially small blood/lymphatic vessels). A
HY SE to be aware of is iris pigmentation (darkening) AND thinning of the orbit
secondary to fat dissolution. These analogs are first line glaucoma meds.
The ANS and Glaucoma

-Going back to SFM Pharmacology, alpha-2 receptors are found on presynaptic
adrenergic neurons (they are sort of a negative feedback mechanism). Agonizing these
receptors decreases the release of NE from the adrenergic presynaptic neuron. This
takes out the substrate for the stimulation of beta-1 receptors found on the ciliary
epithelia that produce aqueous humor. This is the MOA of Alpha-2 agonists like
Brimonidine and Apraclonidine.
-The availability of bicarbonate increases the efflux of chloride into the posterior
chamber of the eye (more to come in GTS Renal). Ions draw water by osmosis. With
more chloride in the posterior chamber, water follows, with more water, the volume of
aqueous humor is increased. By decreasing bicarbonate production, all of this can be
stopped. This is the mechanism of action of Carbonic Anhydrase Inhibitors like
Acetazolamide.
Miosis/Mydriasis and The Pharmacology of Glaucoma
Other Ocular Pathologies-Myasthenia Gravis

-Myasthenia Gravis is a disease associated with autoantibodies against the acetylcholine receptor.
-The binding of these antibodies prevents the binding of acetylcholine to its receptors. This inhibits
muscle contraction. Over time, the continued antagonism of these receptors leads to receptor
endocytosis, which decreases the amount of receptors available for acetylcholine to bind to. In addition,
the binding of these autoantibodies to the Ach receptor also triggers immune system destruction of the
receptors.
-MG is diagnosed by the administration of a short acting acetylcholinesterase inhibitor known as
Edrophonium (Tensilon Test). The administration of this agent increases the amount of acetylcholine at
the synapse, increasing the likelihood of successfully outcompeting the autoantibodies. The prompt
improvement in symptoms upon administration of this drug is diagnostic of the disease.
-Myasthenia is typically treated by administering steroids (which shut down the immune system that
produces autoantibodies) AND long acting cholinesterase inhibitors (essentially
parasympathomimetics). The over-availability of Ach at the synapse slows down the heart and
increases an individuals glandular secretions (like sweating and saliva production).
Other Ocular Pathologies-Adies Pupil

-Is an ocular pathology that is associated with a pupil that is always dilated.
-The underlying pathophysiology is thought to be due to a lesion of the postganglionic
parasympathetic fibers that innervate the pupillary constrictors.
-Diagnosis is established by exposing the tonically dilated pupil to a dilute amount of
pilocarpine which is a muscarinic agonist that constricts pupils. The dilute amount
administered in the test in general does not have enough power to constrict pupils.
-In the setting of denervation however, the cholinergic receptors on the smooth muscle
innervated by the postganglionic parasympathetics become supersensitive and even
small amounts of a muscarinic agonist would make them constrict.
-Think of an individual that hates broccoli and is stuck on an island for 7 days. With
the passage of time, his sensitivity to broccoli increases because of starvation.
The Sense of Smell
Anosmia
-Just like we have conductive and sensorineural hearing loss, theres also conductive
(odorants cant hit the receptors on the Olfactory Receptor Neurons) and
sensorineural (problems with the pathways to the brain) anosmia.
-Conductive anosmia is typically associated with traumatic/inflammatory nasal
exposures (i.e. the unfortunate contact b/w an enemys fist and an individuals face,
nasal polyps, etc).
-Injuries to the head (i.e. cribriform plate fracture-this is a classic exam scenario) and
neurodegenerative diseases like Alzheimers and Parkinsons can lead to neuronal
death which can trigger a sensorineural anosmia.
The Histology of The Tongue

Taste buds are members of histological structures known as papillae (of which there
are 4-foliate, fungiform, filiform-lack taste buds, and circumvallate).
The Sense of Taste

-The sense of taste is similar in many ways to the sense of smell with the key exception being the
presence of a thalamic relay to the cortex.
-The taste pathway begins as receptor cells in the taste buds which relay to afferent neurons (CN
5/7/9/10). These afferent neurons relay taste sensation to the solitary nucleus in the caudal medulla
which ultimately relay this information to the gustatory cortex (insula + frontal operculum) through the
VPM nucleus of the thalamus.
-The taste buds contain taste pores that serve as the entry point of tastants. The binding of these tastants
to receptors (found on microvilli) trigger either ion channels OR second messenger systems that
ultimately lead to the release of neurotransmitters at the basal regions of these cells. These
neurotransmitters trigger action potentials in afferent neurons (which are cranial nerves).
-The sensations of salt/sour operate through amiloride sensitive Na channels (Na for salt/H for sour).
The sensations of sweet/bitter/Umami operate primarily through G protein coupled receptors (sweetGs-increases Adenylate Cyclase, bitter-Gq-increases IP3, umami-possibly Gq-very HY to know this
responds to glutamate).
The Taste Pathway
The Innervation of The Tongue/Oropharynx

The Soft Palate is innervated by CN5/7. The Oropharynx is innervated by CN9/10.
Taste-A Summary/Lesions
Like many sensory pathways, the taste pathway is a 3 neuron pathway.
There are receptor cells in taste buds that sense taste information. Through chemical synapses
they relay to;
Neuron 1-which are fibers of CN 5/7/9/10. These relay to;
Neuron 2-which are neurons with cell bodies in the rostral solitary nucleus of the medulla (note
that respiratory/cardiac centers are in this general area). Unlike other Neuron 2s, these fibers
do not cross. Hence, lesions along this pathway result in an ipsilateral loss of taste sensation.
These fibers then relay to;
Neuron 3-which are neurons with cell bodies in the VPM nucleus of the thalamus. These
ultimately project to the insula/frontal operculum of the cerebral cortex.
N/B-a lesion along the taste pathway leads to a contralateral heightened unpleasant sensation (to
this day, this makes no logical sense to me. Sorry)
Metabolic Brain Disorders-Wilsons Disease

-Wilsons Disease (which also goes by the fancy term-hepatolenticular degeneration) is
a metabolic disease that arises secondary to a defect in Cu excretion in bile (due to a
mutation in a protein known as ATP7B (which is responsible for Cu transport from
the liver).
-A defect in this transporter means that Cu will not be incorporated into its
transporter in the blood (Ceruloplasmin). Cu then accumulates in the liver and with
access to the blood, ultimately gets to the brain. Cu settles preferentially in the basal
ganglia (where it causes cavitation and cystic degeneration). Common signs and sx of
this disease include dementia, parkinsonian features, and liver cirrhosis. A very classic
finding are the characteristic Kayser-Fleischer rings found in the cornea.
-Lab findings include an increased amount of free Cu in the blood AND low serum
ceruloplasmin. Treatment is with Penicillamine which is a Cu chelator.
Wilsons Disease-Cystic Degeneration of The Basal Ganglia
Wilsons Disease-Kayser-Fleischer Rings
Metabolic Brain Disorders-Wernicke-Korsakoff Syndrome

-Is a syndrome associated with massive, chronic alcohol abuse.
-Alcoholics tend to get thiamine (B1) deficiencies for many reasons. For example-ROH inhibits
the absorption of thiamine in the GI tract. Many alcoholics for reasons mentioned in the
Metabolism review, also tend to have fatty liver. This decreases the number of storage sites for
this vitamin. In addition, the upregulation of liver enzymes that utilize thiamine as a cofactor in
the breakdown/metabolism of alcohol depletes available stores very rapidly.
-Thiamine is a very important cofactor for super important enzymes like Pyruvate Dehydrogenase
(post glycolysis), Alpha Ketoglutarate Dehydrogenase (TCA Cycle), Branched Chain Keto Acid
Dehydrogenase (metabolism of branched chain FAs), and Transketolase (which plays a big role
in the non-oxidative phase of the HMP Shunt).
-The clinical findings associated with Vitamin B1 deficiency include wet beri-beri (dilated
cardiomyopathy/other cardiac troubles) AND dry beri-beri (Wernicke-Korsakoff Syndrome).
Metabolic Brain Disorders-Wernicke-Korsakoff Syndrome

-Impairments in the functioning of these pathways leads to the loss of neurons in the
cerebellum and the cerebral cortex with one classic area being the mamillary bodies. If
you see anything like hemorrhagic lesions of mamillary bodies on your test, stop
thinking and go straight to the answer that deals with WKS.
-WKS is a disease that varies along a spectrum.
-Wernickes Encephalopathy is REVERSIBLE and is associated with the classic tetrad
of confusion, ophthalmoplegia, ataxia, and nystagmus.
-Once Confabulations (making up stuff)/amnesia is added to the symptom list, the
disease is then called Korsakoff Psychosis which is IRREVERSIBLE.
-Treatment is with high dose thiamine and glucose. It is HY to know that the thiamine
is given before the glucose and not the other way around.
Metabolic Brain Disorders-Vitamin B12 Deficiency

-Vitamin B12 plays key roles in 2 metabolic pathways-folate metabolism AND the
conversion of methylmalonyl coA to succinyl coA (metabolism of odd chain FAs).
B12 Deficiency-Clinical Findings

-The HY clinical findings in B12 deficiency include megaloblastic anemia (due to the
defective folate metabolism) AND subacute combined degeneration of the spinal cord.
-The Subacute Combined Degeneration is caused by a demyelination of 3 key tracts in
the spinal cord-the posterior columns (decreased vibration and proprioceptive sense),
lateral corticospinal tract (UMN lesions), and the dorsal spinocerebellar tract (ataxia).
-Remember the HY means of telling a B12 deficiency apart from a folate deficiency.
Both deficiencies cause a megaloblastic anemia but serum methylmalonic acid levels
are increased in B12 deficiency. In addition, peripheral neuropathy is also observed
with B12 deficiency.
Lesioned Pathways in B12 Deficiency
Metabolic Disorders-Hyponatremia/CPM
-Hyponatremia (low levels of plasma Na) is an electrolyte abnormality that is caused by a whole host of
metabolic disorders (more to come in GTS Renal).
-Hyponatremia causes a lot of bad things (particularly seizures).
-However, the key thing to know for Neuro (and for future exams) is that treating hyponatremia too quickly
can cause a condition known as Central Pontine Myelinolysis/Osmotic Demyelination Syndrome. Exposing an
individual with severe hyponatremia to hypertonic solutions over a short period of time leads to massive
neuronal shrinkage (since water is being drawn out) and devastating demyelination.
-The extensive demyelination shuts off most of the brain stem. Individuals with this condition have total
quadriplegia with the only residual sensory/motor function being eye movements. This is known as locked in
syndrome.
-A very useful FA mnemonic is from low to high, your pons will die AND from high to low, your brain will
blow (for hypernatremia).
-In general, it is not a good idea to correct an electrolyte disturbance too quickly.
For The Sake of Time..

Please Review;
-Optics and The Anterior Segment.
-Diabetic Retinopathy.
-Strabismus.
-Layers of the Retina/BPPV.
-AMD
These are HY and mostly fact based so spend some time on them.
All The Best On Tuesday!

It was a pleasure working with the awesome Med19
over the past year..
Enjoy your summers..
And try to relax..
HY Epidemiology Review
Some MS2
Few Words
Why should you care about Epidemiology?
-Be able to deal with scientific literature intelligently.
-Learn how to think logically.
-Pass the test.
-Tested heavily on the boards.
-Is important for clinical decision making.
-Doing well in Epi depends primarily on having the right thought process in problem
solving, not memorizing equations.
How to think about Epidemiology

-Does not look at the individual, looks at populations.
-Essentially everything is based on ratios.
-Numerator usually deals with the cases of something.
-Denominator usually deals with those who have the potential to be in the
numerator.
-The denominator is essentially the numerator + the potential numerators
-To create a ratio, you typically have to multiply by some # like 1000.
-Note the organization of the questions in the slides
Q1
A town has a population of 18,000 people. Of these, 3600 have incurable diabetes.
There are 300 new cases and 50 deaths each year from diabetes. There are 75 deaths
per year from all causes. The prevalence of diabetes in this town is given by?
a.
b.
c.
d.
e.
300/3600
3600/18000
50/3600
75/18000
425/18000
Q1 Key
The answer is B.
Remember,
Prevalence = Total # of cases/# of people in the population that are not dead
In the Q, there are 3600 people with the disease and 18000 people in the population at
the time, so the prevalence is 3600/18000 which is answer B.
Note that the Proportionate mortality ratio in this case will be 50/75 * 1000 or 670 per
1000 deaths.
And Case Fatality rate = 50/3600.
Q2
Given the chart below of a group of competitive athletes (indicating a sample of 10 individuals with restrictive cardiomyopathyRCM);
a.
b.
c.
What is the incidence of RCM in the year 2010?

What is the prevalence of RCM in the year 2011?
What is the point prevalence of RCM on January 1 2012?
Q2 Key
For Part A,
In 2010, there were 5 new cases of RCM. Of the 10 people in the population, 1 was
dead already, and the other already had the disease (so he lacked the potential to be a
new case.
Remember, Incidence = # of new cases/# at risk to be a new case
Therefore, the incidence of RCM in 2010 is .
The prevalence of RCM in 2011 is 5/7.
The point prevalence of RCM on January 1 2012 is 4/6.
Incidence and Prevalence-Key Takeaways

-Incidence deals with new cases in the numerator, and people with the potential to
be a new case in the denominator.
-An individual that is or dead OR already has the disease cannot be at risk to be a new
case.
-Prevalence deals with total # of cases during some time period (except point
prevalence-at A time period), and the people who have the potential to be cases.
-A dead individual cannot take part in the prevalence equation.
Factors Affecting Prevalence

-Many people get the cold in the US each year.
-So the incidence of the cold is quite high.
-There is a somewhat high prevalence of HIV in the US even if fewer people are being
diagnosed with the disease.
-With better treatment, HIV is a manageable condition so people can live long with
HIV. Even if the # of new cases/yr is low, the duration of time with the diagnosis
increases the prevalence.
-Hence, prevalence = Incidence * Disease Duration.
Q3-How do these parameters change?

What happens to incidence/prevalence under the following scenarios?
-A new cure for T1DM.
-The discovery of an AIDS vaccine.
-A new therapy to slow down the course of Alzheimers Disease.
Q3 Key
-Prevalence goes down, but not incidence (decreased duration).
-Prevalence and Incidence both go down (fewer new cases and
hence fewer people having the disease).
-Prevalence increases, but there is no change to incidence
(increased duration).
-Note that incidence approximates prevalence with a short
disease duration.
Other Key Formulas
Choosing/Interpreting Diagnostic tests
-The central principle behind essentially

every diagnostic test formula is to put the
true things in the numerator, place
everything else in the denominator, and
then divide. You dont need to memorize
annoying formulas.
Q4
A new urine test to detect the presence of HIV was given to 1000 patients. Although
200 of the patients were actually infected with the virus, the test was positive in only
160 of the 200 patient population. Of the 800 patients who were not infected, the test
was negative in 720 patients and positive in 80 patients. Using the information above,
calculate the;
a.
b.
c.
d.
e.
Sensitivity
Specificity
PPV
NPV and;
The prevalence of HIV in this population.
Q4 Key
Sensitivity and Specificity

-Sensitivity is for detecting disease. It is the ability to correctly identify people who have a
disease.
-Specificity is for detecting healthy people. It is the ability to correctly identify people who
do not have a disease.
-Sensitivity/Specificity are pre-test probabilities (as a physician, you make test choices
based on these values)
-PPV/NPV are tests for the reliability OR believability of positive or negative test results
respectively.
-PPV/NPV are post-test probabilities (as a physician, your discussion with patients are
based on these values).
Q5
A 60 year old man visits his primary care physician with complaints of urinary
frequency. Examination finds a 2 cm nodule on his prostate gland. The concerned
physician orders a Prostate Specific Antigen (PSA) serum test. By common standard, a
PSA level greater than 4 ng/ml is considered abnormal. Using this standard, the test
has a sensitivity of 90% and a specificity of 80%. A recently published epidemiologic
article found that in a cross sectional study, 20% of men in this age group have
prostate cancer. The result on the patient's PSA is 8 ng/ml. What is your best estimate
of the likelihood that this man actually has prostate cancer?
Q5 Key (will solve in session)
The answer is about 53%.

-This question is essentially
looking for the PPV.
Q6
What is the incidence of Disease X in as defined by the following 2 by 2 table?
What is the prevalence of Disease X as defined by the following 2 by 2 table?
Q6 Key
-There is no incidence data that can be derived
from the table (why?)
-The prevalence of Disease X in the population is
50%.
Q7
In a particularly bad year, the total number of cases of Disease X referenced in the
previous question increases to a new high of 500, 000 people. Which of the following
statements are false?
a. The ratio of individuals detected by the test to be disease free out of the total
number of healthy people increases.
b. The likelihood of a negative test result being true increases.
c. The ratio of individuals detected by the test to be with disease out of the total
number of diseased people decreases.
d. The likelihood of a positive test result being true increases.
e. The likelihood of a negative test result being true decreases.
f. The likelihood of a positive test result being true decreases.
Q7 Key-A, B, C, and F are all false statements

-With a change in prevalence of a disease, there is no change in sensitivity or specificity of a
test.
-More people having a disease does not change the sensitivity and specificity ratios of a test.
SN/SP are intrinsic properties of a test and hence do not change with increasing
prevalence. This is why they are called pre-test probabilities.
-With increasing prevalence, the PPV increases and the NPV decreases.
-If someone were to come in saying they have the flu in June, would you get excited about
your test results?
-If the same person came in December/January, how would your reaction to a positive test
change?
Q8
Pick the points on the distribution below that correspond to the highest sensitivity,
specificity, NPV, and PPV.
Q8
Highest sensitivity is E
Highest specificity is C
Highest PPV is C
Highest NPV is E
-At the point of highest sensitivity, NPV is at a maximum.
-At the point of highest specificity, PPV is at a maximum.
-Memory Tool (The Ns and Ps match).
Q9
Which of the following points on the curve represents the best screening test?
Q9 Key
The best answer is Curve 6
ROC curves (are HY!). Curve 6 has the highest sensitivity, and
also highest specificity (because 1-specificity is at a minimum).
Other Takeaways
-Sensitivity is 1-False Negative Rate.

-Specificity is 1-False Positive Rate.
Kinds of Research Studies

-There are 2 kinds of research studies.
-Observational studies include no sort of intervention (you just observe).
-Experimental Studies include an actual intervention to hopefully cause change.
Q10
A study is designed to determine the relationship between high intracranial pressures
and peptic ulcers. To accomplish this, researchers used hospital records of patients
diagnosed with peptic ulcer disease and patients diagnosed with other disorders over
the period of December 2011-December 2014. The intracranial pressures upon
admission of these patients was determined from these records. Which of the following
should be included in the analysis of information from this study?
a.
b.
c.
d.
e.
Relative risk
Incidence
Odds Ratio
Prevalence
Absolute Risk
Q10 KEY
-This is a case control study (retrospective)
-It starts with outcomes and goes back to look at exposures.
-The only major piece of information derived from a Case Control Study is an Odds
Ratio.
-Incidence/Prevalence data cannot be determined from a CC study (why?).
-It is particularly good at detecting risk factors for a given disease (especially rare
diseases).
-Hence the best answer is C.
Q11
A study is performed to determine the effectiveness of Montelukast, a leukotriene
receptor antagonist designed to treat asthma. To do this, 25 allergic patients are
assigned to one of two groups, the Montelukast group (13 patients) or a Placebo (12
patients). The patients are then followed over a 6 month period. This study is best
described as a;
a.
b.
c.
d.
Cohort study.
Cross Sectional Study.
Case Control study.
Clinical Trial.
Q11
A study is performed to determine the effectiveness of Montelukast, a leukotriene
receptor antagonist designed to treat asthma. To do this, 25 allergic patients are
assigned to one of two groups, the Montelukast group (13 patients) or a Placebo (12
patients). The patients are then followed over a 6 month period. This study is best
described as a;
a.
b.
c.
d.
Cohort study.
Cross Sectional Study.
Case Control study.
Clinical Trial.
Observational Study Comparisons
Q12
In a suburb of Baltimore, it was reported that there were 300 Hep B positive
individuals, of whom 10 died in 2012. The case fatality rate per 100 people is;
a.
b.
c.
d.
e.
0.33%
3%
3.3%
3.5%
33%
Q12
In a suburb of Baltimore, it was reported that there were 300 Hep B positive
individuals, of whom 10 died in 2012. The case fatality rate per 100 people is;
a.
b.
c.
d.
e.
0.33%
3%
3.3%
3.5%
33%
Why?
Case Fatality Rate simply refers to the proportion of people with a given disease who
die over a defined time period.
Remember the general principle of creating a ratio in Epidemiology by multiplying by
some # (typically a multiple of 10)
In Q12, CFR = 10 dead/300 people with Hep B * 100 = 3.3%
Q13
In the Hopkins class of 120 medical students, the mean systolic blood pressure was
found to be 126 mm Hg with a SD of 6 mm Hg. If the blood pressures in this sample
are normally distributed, what portion of the medical students will have systolic blood
pressures above 132 mm Hg?
a.
b.
c.
d.
e.
2.5%
0.5%
5%
16%
32%
Q13
In the Hopkins class of 120 medical students, the mean systolic blood pressure was
found to be 126 mm Hg with a SD of 6 mm Hg. If the blood pressures in this sample
are normally distributed, what portion of the medical students will have systolic blood
pressures above 132 mm Hg?
a.
b.
c.
d.
e.
2.5%
0.5%
5%
16%
32%
Standard Curves
-For a normal distribution the mean = median = mode.
-For a right skewed curve, the tail is on the right and from the tail go in alphabetical
order (mean, median, mode). In other words, the mean is the highest value. Reverse all
of these for left skews.
-A fat normal curve has a high SD, while a thin normal curve has a small SD.
-68-95-99.7 rule (applies to 1, 2, 3 SD around the mean)
-In Q13, 1 SD above the mean is 132 mm Hg, so 50% + 34% of the class lie below that
cut off, leaving 16% unaccounted for.
Q14
In a cohort study examining the relationship between the use of exogenous estrogens
and the subsequent risk of breast cancer, a sample of 1000 premenopausal women
were followed for 8 years. The results are presented in the table below. The relative risk
associated with estrogen therapy in this study is?
a.
b.
c.
d.
e.
0.25
0.33
0.5
2
3
Q14
In a cohort study examining the relationship between the use of exogenous estrogens
and the subsequent risk of breast cancer, a sample of 1000 premenopausal women
were followed for 8 years. The results are presented in the table below. The relative risk
associated with estrogen therapy in this study is?
a.
b.
c.
d.
e.
0.25
0.33
0.5
2
3
Relative Risk
-Is simply a ratio of incidence.
-Is the typical outgrowth of a Cohort Study (because we have incidence information)
-Can a relative risk be calculated for a Case Control Study?
-In Q14, 60% of people who took estrogen got BRCA, 20% of individuals who did not
take estrogen got BRCA. Hence the ratio of incidences is 60%/20% = 3
-Be able to interpret the results of these studies in words (i.e. statements explaining
your findings)!
Q15
Serum homocysteine levels for 2 groups of Americans were recorded in 2012. The
mean homocysteine level for a group of 28 African Americans was 271 mg/dL and 184
mg/dL for a group of 28 Asian Americans. To determine if these results were
significantly different, a Med19 student performed a statistical test as part of his SC
project. Which of the following tests was most likely used by the student in his
analysis?
a.
b.
c.
d.
e.
Chi square test

Correlation Analysis
ANOVA
Regression Analysis
Students T test
Q15
Serum homocysteine levels for 2 groups of Americans were recorded in 2012. The
mean homocysteine level for a group of 28 African Americans was 271 mg/dL and 184
mg/dL for a group of 28 Asian Americans. To determine if these results were
significantly different, a Med19 student performed a statistical test as part of his SC
project. Which of the following tests was most likely used by the student in his
analysis?
a.
b.
c.
d.
e.
Chi square test

Correlation Analysis
ANOVA
Regression Analysis
Students T test
Tests In Different Circumstances

-For 2 interval variables, use the Pearson Correlation test (describes the direction and
strength of relationships but does not establish causation!)
-For 2 nominal variables, use the Chi square test.
-To compare the means of 2 small groups, use a Students T test (T for Two).
-To compare the means of more than 2 groups, use the ANOVA test (also called the F
test).
Q16
In a prospective study, the occurrence of Peptic Ulcer Disease was recorded for
smokers and nonsmokers. The difference in incidence between smokers and
nonsmokers was reported to be significant at the p<0.05 level. The most appropriate
statement that can be made about this study is that;
a. The null hypothesis may be rejected even though the results could have occurred
purely by chance a maximum of 5% of the time.
b. The null hypothesis may be accepted because there is a difference in the incidence
rates between smokers and nonsmokers only 5% of the time.
c. A causal relationship between smoking and the incidence of Peptic Ulcer Disease
may be established at a significance level of 0.05.
Q16
In a prospective study, the occurrence of Peptic Ulcer Disease was recorded for
smokers and nonsmokers. The difference in incidence between smokers and
nonsmokers was reported to be significant at the p<0.05 level. The most appropriate
statement that can be made about this study is that;
a. The null hypothesis may be rejected even though the results could have occurred
purely by chance a maximum of 5% of the time.
b. The null hypothesis may be accepted because there is a difference in the incidence
rates between smokers and nonsmokers only 5% of the time.
c. A causal relationship between smoking and the incidence of Peptic Ulcer Disease
may be established at a significance level of 0.05.
P-Value
-Reflects the probability that the results obtained from a test could have occurred by
chance.
-Think of it as a bar you never want to cross. As long as you stay below the bar, you can
reject the null and fail to reject the alternative hypothesis (and vice versa).
Q17
In a study concerning the relationship between phenylbutazone and the subsequent
risk of neutropenia, medical records of 300 children were investigated with the results
shown in the table below. What is the odds ratio in this study?
a.
b.
c.
d.
e.
3.29
2.29
5.67
3.23
7.16
Q17
In a study concerning the relationship between phenylbutazone and the subsequent
risk of neutropenia, medical records of 300 children were investigated with the results
shown in the table below. What is the odds ratio in this study?
a.
b.
c.
d.
e.
3.29
2.29
5.67
3.23
7.16
Odds Ratios
-Are the derivatives of Case Control Studies.
-When does an Odds Ratio approximate the relative risk?
-Compares the odds of a case of a disease being exposed to a given risk factor to the
odds of controls being exposed to the same risk factor (it makes sense that the odds of
exposure in a diseased case should be higher than the odds of exposure in a control
case).
-Easy calculation (The Logical People Product)/(The Weird People Product)
-Logical people (exposed and affected, not exposed and unaffected). Weird people
(exposed and unaffected, not exposed and affected).
Q18
What kinds of errors/right decisions are made given the following scenarios?
-Rejecting the null hypothesis when the null hypothesis is false?
-Accepting the null hypothesis when the null hypothesis is false?
-Rejecting the null hypothesis when the null hypothesis is true?
-Accepting the null hypothesis when the null hypothesis is true?
Q18
What kinds of errors/right decisions are made given the following scenarios?
-Rejecting the null hypothesis when the null hypothesis is false?-Correct
-Accepting the null hypothesis when the null hypothesis is false?-Type 2 Error
-Rejecting the null hypothesis when the null hypothesis is true?-Type 1 Error
-Accepting the null hypothesis when the null hypothesis is true?-Correct
Note that the Type 1 error is the Alpha error (P-Value), while the Type 2 Error is the
Beta error (1-Power). How could you increase the power of an experiment?
Types of Errors
Q19
A standardized test was used to assess the level of happiness among Hopkins medical
students. The results yielded a mean of 17.60 with confidence limits of 17.55 and 17.65.
This presented confidence limit is;
a.
b.
c.
d.
e.
Less precise, but has a higher confidence than 17.20 and 18.00
More precise, but has a lower confidence than 17.20 and 18.00
Less precise, but has a lower confidence than 17.20 and 18.00
More precise, but has a higher confidence than 17.20 and 18.00
Cannot be determined from the information given.
Q19
A standardized test was used to assess the level of happiness among Hopkins medical
students. The results yielded a mean of 17.60 with confidence limits of 17.55 and 17.65.
This presented confidence limit is;
a.
b.
c.
d.
e.
Less precise, but has a higher confidence than 17.20 and 18.00
More precise, but has a lower confidence than 17.20 and 18.00
Less precise, but has a lower confidence than 17.20 and 18.00
More precise, but has a higher confidence than 17.20 and 18.00
Cannot be determined from the information given.
Confidence Intervals
-Tighter confidence intervals have less room for error so you should be less confident
in them.
-Tighter confidence intervals are more precise because they have lower standard
deviations.
Q20
The mean blood glucose level of a sample of 81 patients taken from MGH was 170
mg/dL with a standard deviation of 15 mg/dL. Compute the 95% confidence interval
and in words interpret your results.
Q20
Mean = 170 mg/dL
Standard Error of the Mean = 15/sq. rt of 81 = 1.67 mg/dL
Z-Score for 95% Confidence Interval = 2 (1.96 for the ethically minded).
CI 170 +/- (2*1.67) = 170 +/- 3.34.
You can say with 95% confidence that the real mean blood pressure of the MGH
population falls between 166.66 and 173.34 mg/dL
Q21
4 separate drug trials were conducted to test the relative effectiveness of 4 different 3-Beta Hydroxysteroid DH agonists as a
means of increasing Testosterone levels in impotent males. The mean testosterone levels in the study with confidence intervals
(solid lines) are graphed below. Use the graph to determine if the following statements are true or false.
a.
b.
c.
d.
Drug 1 is more effective than Drug 2

Drug 3 and 4 are similar in efficacy
Drug 4 is more effective than Drug 2
Drugs 1 and 4 show similar efficacy
Q21 Key
Statements A, B, and D are true.
The general principle is this-when 2 confidence intervals cross each other, there is no
difference between those treatments. Dont be surprised by an exam scenario that
presents multiple, but similar tests with multiple confidence intervals asking you to
evaluate the relative effectiveness (or efficacy) of some kind of intervention.
Q22
The table below shows the results of 4 different cohort studies that were handed to a Med19 student by his SC
mentor trying to test his knowledge of Biostatistics. He asks the student to interpret the results using the
following 2 parameters;
a.
b.
Being significant/not significant.

The relative risk increase/or decrease between the exposed and unexposed groups in both categories.
Q22
-A relative risk is a ratio of incidence rates.
-With similar incidence rates, the ratio (or RR) should be 1.
-Confidence intervals crossing the 1 boundary indicate similarities in incidence
between exposed and unexposed groups. The same rule obtains for Odds Ratios.
-Therefore, Comparisons B and C do not have significant results.
-However, comparison A shows significant results with a 134% increased risk and D
shows significant results with a 27% decreased risk.
-For measurements involving differences, the CI boundary should not cross zero. If it
does, the results are NOT significant.
Q23
During the 2nd look weekend, a barbecue was organized at the beginning of the year to welcome the new
Med19 class. The total number of people in attendance was 100 including the Med19 class and a few others.
Fried chicken, sandwiches, and potato salads were served. The following day, 28 of the attendees had diarrhea
and vomiting. All the attendees were questioned about what they had eaten, and the following table was
obtained. Which of the following best describes the attack rate among all of the attendees who had potato salad?
a.
b.
c.
d.
e.
11%
20%
28%
34%
47%
Q23
The attack rate is 34% (will solve in session)
Q24
Q24
Mode for Females- Zero sexual partners
Mode for Males- 1 sexual partner
Q25
Q25
Median for Males-1 sexual partner
Median for Females- 1 sexual partner
For The Sake of Time

-Review Survival Curves
-Review Group Problems
-Dont speed through the test. Doable but you have to read questions carefully/slow
down.
ALL THE BEST!
HY HEAD AND NECK REVIEW

Some MS2
GENERAL BRAIN EMBRYOLOGY
SUTURES OF THE SKULL
CRANIAL CAVITY
LAYERS OF THE SCALP
THE CRANIAL MENINGES
Key Definitions
Periosteal Dura-closely attached to the skull via sutures.
Dural Venous Sinuses-Formed from the few points of separation b/w the Periosteal
and Meningeal Dura (no valves unlike many other venous structures in the body)
Meningeal Dura Duplications/Folds-forms the Tentorium Cerebelli (separates
what?), Falx Cerebri (separates what?), Falx Cerebelli (separates what?) and
Diaphragma Sellae (Roof of?)
CSF is found in??
Venous Drainage of The Brain
VENOUS DRAINAGE OF THE HEAD
THE CAVERNOUS SINUS
CSF DRAINAGE/CIRCULATION
Venogram of The Venous Sinuses
THE NASAL MEATUSES
DRAINAGE OF THE PARANASAL SINUSES

The PARANASAL sinuses (Frontal, Maxillary, Ethmoidal, Sphenoidal) pass mucous
secretions to the three meatuses that are below the respective nasal concha.
SPHENOETHMOIDAL RECESS-Sphenoid Sinus
SUPERIOR MEATUS-Posterior Ethmoidal Cells
MIDDLE MEATUS-Anterior/Middle Ethmoidal Cells, Frontal Sinus, Maxillary Sinus
INFERIOR MEATUS-tears from the lacrimal sac (through the nasolacrimal duct)
CRANIAL NERVES/ARTERIES AND THE NOSE

-V1/V2 of CN5-supply nasal walls/nasal septum
-Glandular (think Parasympathetic) secretions come mostly from CN7
Preganglionic Fibers-Greater Petrosal Nerve (from the Facial Nerve)
Ganglion-Pterygopalatine Ganglion (in the so-named fossa)
Postganglionic fibers go to mucous glands of the nasal cavity (in addition to the oral
cavity/nasopharynx/lacrimal gland)
-Arterial supply of the nasal cavity-Maxillary Artery (ECA), Ophthalmic Artery (ICA),
Facial Artery (ECA)
CIRCLE OF WILLIS (SUPER HIGH YIELD)
CIRCLE OF WILLIS
CIRCLE OF WILLIS
LEADING UP TO THE CIRCLE OF WILLIS
Branches of The External Carotid Artery
Some Anatomists Like Freaking Out Poor Medical Students

Follows 1,3,4,5,6,8,7
-Superior Thyroid
-Ascending Pharyngeal (absent on diagram)
-Lingual
-Facial
-Occipital
-Posterior Auricular
-Maxillary (terminal branch)
-Superficial Temporal
Hematomas
Epidural Hematomas
-Between the Dura and the Skull (explains the Lens Shape)
-Middle Meningeal Artery rupture (branch of? branch of? branch of? branch of?)
-Higher Pressure (medical emergency)
-Classic Lucid Interval
-Eventual Herniation (This is Bad!!!)
-Does NOT cross suture lines (b/c the periosteal dura is attached to the skull)
Subdural Hematoma
Subdural Hematomas
-Between the Dura and Arachnoid
-Bridging Vein (starts from cortex/pierces meninges/drains into dural venous sinuses)
Tear-Rapid Acceleration/Deceleration
-Lower Pressure (longer lead time before bad stuff happens)
-Gradual Increase in Headache/Confusion
-Common in old people
-Crescent Shaped
-CROSSES suture lines (Re-Meningeal Dura is not suture bound)
Subarachnoid Hemorrhage
Subarachnoid Hemorrhage
-Between the Arachnoid/Pia
-Shaped like a Spider
-Rupture of a berry aneurysm (ACA most common)
-Classic Q Stem (Worst Headache of My Life)
The Ear Example-NCC, Mesoderm (Muscle)
take a GAP year
THE DEVELOPING PHARYNX
Keep In Mind
-NCC migrate to pharyngeal

arches
-Different embryological origins
for the GAPs
PHARYNGEAL POUCHES-ENDODERM
Keep In Mind-Pouches
-Theres a more caudal migration of 3 relative to 4 (explains the weird contrasting
origins of the IPG from Pouch 3 and the SPG from Pouch 4). Structure formation
depends on NCC.
-Ventral midline endodermal evagination-downgrowth (Thyroglossal Duct, should
fuse and disappear)-Ballooning at the tail (Thyroid gland)..... This is a common theme
in Embryology (e. g. Lungs)
CYSTS
Lateral Cervical Cyst-Incomplete filling of the
remaining pouches by Cleft/Arch 2, (embryonic
derivative-ectoderm). Overlying Superficial Neck
Muscle? Cranial Nerve?
Medial/Thyroglossal Duct Cyst-failed fusion/disappearance of
the Thyroglossal Duct, (embryonic derivative-endoderm)
PHARYNGEAL POUCH SUMMARY
THE FIRST PHARYNGEAL ARCH-M and T Structures
THE SECOND PHARYNGEAL ARCH-The S Structures
THE THIRD PHARYNGEAL ARCH
THE FOURTH PHARYNGEAL ARCH-THE THYROID ARCH
6TH PHARYNGEAL ARCH
HOW DO THE P. ARCHES RELATE TO THE TONGUE???

-Anterior formed by 1st and 2nd Arches (General SensationBranch of what cranial nerve?, Taste-Branch of what Cranial
Nerve)
-Posterior formed by Arch 3 (Cranial Nerve?-Taste and
Sensation)
-Cranial Nerve of all Intrinsic Tongue Muscles?
-Exception?
CLINICAL CONSIDERATIONS
1. Down's Syndrome (Constellation of Symptoms,
failed NCC migration)-Cleft Lip/palate,
Hirschsprung Disease , Congenital Heart
Defects, Misshapen teeth etc.
2. 3rd/4th Pouch Disease-No thymic shadow on
CXR, Susceptibility to Infection, Hypocalcemia
(Why?)
Keep In Mind
For each arch, try knowing the following;
-Nerves
-Arteries
-If you know the nerves, youll know the muscles
-Muscles (mesoderm)
-Neural Crest Cells (ultimately ectoderm, bones, cartilage, and ligaments)
STERNS LAWS- CRANIAL NERVE MEMORY TOOL (In order)

Sterns law #1: Muscles containing the word tensor are innervated by the mandibular
division of the trigeminal nerve (V3).
Sterns law #2: Muscles containing the word palat are innervated by the vagus nerve,
unless law 1 takes precedence.
Sterns law #3: Muscles containing the word glossus are innervated by the
hypoglossal nerve, unless law 1 or 2 takes precedence.
CRANIAL NERVES-AN OVERVIEW
CN1-OLFACTORY
-Starts as Fila Olfactoria
-Enters through the Cribriform Plate
-Synapses at The Olfactory Bulbs
-Carries the sense of smell
-A cribriform plate fracture leads to Anosmia
CN2-OPTIC
-Coalition of Retinal Ganglion Cells
-Traverses Optic Canal (with Ophthalmic Artery)
-Optic Nerve (Proximal), Optic Chiasm (runs above what structure?), Optic Tract (Distal), Associated
Thalamic Nucleus?, Info relayed to?
-Pituitary tumors (Adenomas/Craniopharyngiomas) cause VF defects
-Afferent limb of the pupillary light reflex
-Affected in MS (is a true CNS tract)
-Fibers go to The Lateral Geniculate Nucleus of the Thalamus/Visual Cortex in the Occipital Lobes (Calcarine
Sulcus)
LESIONS
If you lesion the Optic Nerve-One Eye Gone
If you lesion the Optic Chiasm-Tunnel Vision
If you lesion the Optic Tract-Lose the contralateral
visual field
CN3-OCULOMOTOR
-Edinger Westphal Nucleus (PSNS)/Oculomotor Nucleus (Skeletal Motor)Interpeduncular Fossa (of midbrain)-Passes b/w SCA/PCA-Cavernous Sinus-Superior
Orbital Fissure
-Innervates SR (Up), IR (Down), IO (Up and Out), MR (Adducts), LPS (Elevates)-all
skeletal muscle
-PSNS (Ciliary mm., Pupillary Sphincters)
-CN3 palsy (Down and Out)
-Uncal Relationship-affected by an ICP increase
THE OCULOMOTOR PATHWAY
LESIONS
-Complete lesion-Down and Out Eye/External Strabismus (Unopposed LR/SO)
-Ptosis/Droopy eyelid (LPS)
-Blown Pupil (Unopposed Sympathetic Activity)
-Loss of the Accommodation and Pupillary Light Reflex
-Diplopia/Double Vision
-Diabetes-Ischemia-Lose Somatic Nerve Function-Inner Fibers
-Aneurysms-Lose Parasympathetic Function-Outer Fibers
CN4-TROCHLEAR
-Midbrain
-Arises from the dorsal aspect of the midbrain below the inferior colliculus
-Fibers cross (only CN that gives contralateral findings in the setting of a lesion
-Cavernous Sinus-Superior Orbital Fissure
-Innervates SO4 (Down and Out)
-Lesions (problems w/reading, going downstairs)
-Head deviates Superomedially to correct deficit (away from the lesioned side)
PATHWAY
CN5-UNCLE TRIGEMINAL
-Pons
-3 branches (V1-Opthalmic (SOF), V2-Maxillary (FR), V3-Mandibular (FO))
-Muscles of Mastication (V3)
-Jaw closers (MTM)-Masseter, Temporalis, Medial Pterygoids
-Jaw Openers-Lateral Pterygoids
-Anterior belly of digastric, mylohyoid, tensor tympani, tensor veli palatini
-General Sensation from Anterior of tongue (V3)
CN5-CONTD
-Ophthalmic (Sensation from forehead, scalp, cornea, lesion includes loss of blink
reflex). Branches-Nasociliary/Frontal/Lacrimal Nerves.
-Maxillary (Sensation from Palate, Nasal Cavity, Face/Teeth associated with the
Maxilla)
-Mandibular-lower jaw and muscles of mastication. General sensation from Anterior
of tongue. Mylohyoid, Anterior Belly of The Digastric, Tensor Tympani, Tensor Veli
Palatini.
TRIGEMINAL SENSATION
SPECIAL MENTION-PTERYGOPALATINE FOSSA
CONNECTION TO NASAL CAVITY-SP. FORAMEN
PUTTING IT ALL TOGETHER
PTERYGOPALATINE FOSSA
-Anterior/Superior communication w/the orbit (via Inferior Orbital Fissure)
-Lateral communication w/the Infratemporal Fossa (via Pterygomaxillary Fissure)
-Medial Communication w/the Nasal Cavity (via Sphenopalatine Foramen-transmits
SP Artery/Vein, Nasopalatine branch of V2)
-Posterior communication w/the Middle Cranial Fossa/skull base (via Foramen
Rotundum, Pterygoid Canal, Palato-Vaginal Canal)
-Downward communication w/the Oral Cavity (via Greater Palatine Canal)
PTERYGOMAXILLARY FISSURE/MAXILLARY ARTERY
FORAMEN ROTUNDUM-V2 OF TRIGEMINAL/PPG suspension
PTERYGOPALATINE GANGLION
PTERYGOID CANAL-CN 7/SYMPATHETIC FIBERS
The 4 Suspended Ganglia by CN 5 Branches
CN6-ABDUCENS
-Pons
-Cavernous Sinus (Medial)-Superior Orbital Fissure
-Innervates LR (Abduction)
-Lesion produces internal strabismus
CN7-FACIAL
-Pons
-Internal Acoustic Meatus-Facial Canal (petrous part of Temporal Bone)-Parotid Gland-Stylomastoid Foramen
-Ten Zulus Bit My Chin (Temporal, Zygomatic, Buccal, Marginal Mandibular, Cervical)
-Cuts through the Parotid, but does not innervate it. Exits via The Stylomastoid Foramen
-Muscles of Facial Expression, Stylohyoid, Stapedius, Posterior Belly of The Digastric, Orbicularis Oculi/Oris.
-Taste (not general sensation, Anterior tongue)
-Lesions (Bells Palsy)
-Sensory Innervation of the Hard/Soft Palates/some parts of the outer ear
CN7-CONTD
-N/B Chorda Tympani exits the skull via The Petrotympanic Fissure
-Saliva Production (Sublingual, Submandibular Glands) via Chorda Tympani
-Tears (its ok to do this sometimes)-Lacrimal Glands via Chorda Tympani
-Mucus Production (Nasal, Palatine glands)
-Hyperacusis (stapedius lesion-sound oversensitivity), Reduced Secretions.
CN8-VESTIBULOCOCHLEAR
-Pons, Internal Acoustic Meatus
-Audition/Balance
-Acoustic Neuromas, Vertigo, Hearing Loss, Nystagmus
-Medial Geniculate Nucleus (Music)
CN9-GLOSSOPHARYNGEAL
-Medulla, Jugular Foramen
-Carotid Body/Sinus (Chemo/Baroreceptors)
-Taste/General Sensation from Posterior of tongue
-Stylopharyngeus Muscle
-Parotid Gland (via the Otic Ganglion-source of postganglionic parasympathetics)
(remember!-CN 7 cuts through but does not innervate!)
-Sensory limb of the gag reflex
-Sensation from Upper Pharynx, Tonsils, External Ear
CN10-VAGUS
-Medulla, Jugular Foramen
-Up to The Splenic Flexure
-Most thoracic/abdominal viscera
-Aortic Arch/Aortic Bodies (Chemo/Baroreceptors)-dont confuse w/Carotid Body/Sinus from CN 9.
-Pharynx/Larynx
-Tongue Muscle (palatoglossus)
-Motor limb of the gag reflex
CN10-CONTD
-Innervates all muscles of the palate except Tensor Palatini
-Innervates all muscles of the pharynx except Stylopharyngeus
-Innervates the muscles of the larynx (Recurrent Laryngeal Nerve-except
Cricothyroid), trachea, and esophagus
-Lesions (Uvula Deviation, Dysphagia, Hoarseness)
-In the neck, CN 10 traverses the carotid sheath posterior to the ICA, and medial to the
IJV
CN11-ACCESSORY
-Misplaced Spinal Nerve (C1-C6)
-Enters through the Foramen Magnum
-Exits through the Jugular Foramen
-Trapezius, Sternocleidomastoid
-Lesions (shoulder droop on affected side, inability to turn head away from affected
side, I cant comb my hair)
CN12-HYPOGLOSSAL
-Medulla, Hypoglossal Canal
-Extrinsic tongue muscles (Genioglossus, Hyoglossus, Styloglossus, and Palatoglossuscareful here!)
-All intrinsic/extrinsic tongue muscles except?
-Lesions (tongue deviates towards the side of the lesion-lick your wounds)
Cranial Nerves That Carry Parasympathetic Fibers

-Oculomotor (Ciliary Ganglion-V1)-Innervates Sphincter Pupillae/Ciliary Muscles
-Facial (Pterygopalatine-V2/Submandibular Ganglion-V3 Lingual Branch)-Lacrimal
Glands and Mucous glands of Nasal cavity/Sublingual and Submandibular Glands
-Glossopharyngeal (Otic Ganglion-V3 Auriculotemporal Branch)-Innervates The
Parotid Gland
-Vagus (the wandering nerve-has too much stuff going on)
Cranial Nerves That Carry Sympathetics

-None are Sympathetic Fiber Originators
-All come from The Superior Cervical Ganglion
-Long Ciliary Nerves (carried by The Nasociliary branch of V1, supplies dilator
pupillae)
-Deep Petrosal Nerve (carried through The Pterygopalatine Ganglion aboard V2)
CRANIAL NERVE AUTONOMIC ASSOCIATIONS
Cranial Nerves That Carry Special Sensation

-Olfactory
-Optic
-Vestibulocochlear
GO DOMINATE!
HY Heme Review
Some MS2
Objectives/Suggestions
-Hematology is unfortunately one of those blocks where much of the information is HY and applicable to the exam and
future exams.
-On a good note, Heme relies heavily on mechanistic thinking and less on memorization.
-There are 3 key principles behind learning and doing well in Heme.. The first is to rationalize every fact you learn. This
will severely cut down on what you need to memorize and also make question answering more successful. Secondly,
group things into neat boxes in your mind based on one key, overarching characteristic and then find 1-2 key things that
could help to distinguish between the different members of each little block. For example, the very first thing you
should do in any MCV < 80 question on your exam is to stare at the Ferritin levels. Finally, engage in practice drills to
apply what you know to problems. Try to explain mechanisms to yourself or a friend as added reinforcement.
-Accomplishing the 3 goals above is the key focus of this presentation.
-As mentioned in previous sessions, find a way to encode this information into an abbreviated format that can be
reviewed periodically. Subsequent reviews will take a much shorter time than the initial review.
-Theres a fair amount of repetition/redundancy/question randomization built into this presentation on purpose (for
concept reinforcement and to get you into exam thinking mode).
The Beginning-Seemingly benign/But Really HY!

-The Hematopoietic stem cell that gives rise to all blood cells is CD34+.
-Hematopoiesis follows this progression (yolk sac-liver-spleen-bone marrow).
-Red Marrow is found in flat bones and is mostly RBCs. Yellow marrow is found in long bones and is mostly fat. As you
get older, your yellow marrow as a % of your total BM increases.
-The Hematopoietic Stem Cell is CD34+ (relatively little expression) and expresses Aldehyde Dehydrogenase (ALDH)
in high measure. This cell type has a strong ability to self-renew.
-The Myeloid Stem Cell strongly expresses CD34 and weakly expresses ALDH. This cell has a limited self renewal
ability.
-2 key growth factors here include EPO (which is produced by the kidney and decreased in renal failure-anemia) and
Thrombopoietin which increases platelet production. Note that EPO acts on progenitor cells in the bone marrow.
-Chemotherapy that does not kill the progenitor cancer cell results in relapse.
-Recognize that Induced Pluripotent Stem Cells have poor hematopoietic capabilities since they revert to primitive
hematopoiesis.
Hematopoiesis-An Overview
Q1
A 7 month old infant has the sudden onset of severe abdominal pain and cramping accompanied by chest pain,
nonproductive cough, and fever. On PE, his temperature is 39 degrees, pulse is 130/min, respirations are 25/min, and
blood pressure is 90/60 mmHg. He has diffuse abdominal tenderness but no masses or organomegaly. Lab studies show
a Hematocrit of 20%. The peripheral blood smear is shown in the figure below. Assuming the infant in question had this
problem at birth, the most likely explanation for the delay in his current symptoms is?
a. The protective effect of IgG antibodies transmitted from the mom to the infant in utero.
b. The protective effect of a tetrameric hemoglobin molecule that is typically increased in Beta thalassemia minor.
c. The protective effect of a tetrameric hemoglobin molecule that has a high affinity for oxygen compared to
Hemoglobin A in utero.
d. High titers of specific immunoglobulins originating from stem cells in the peritubular capillaries of the kidney.
e. High titers of a growth factor that encourages erythropoiesis.
Q1 Key
-This child most likely has Sickle Cell Disease so the best answer is C.
-Most infants with Sickle Cell Disease begin to present with symptoms at the age of 6
months when titers of Hemoglobin F begin to reduce in red blood cells.
-Remember that Hemoglobin F contains 2 alpha and 2 gamma subunits.
-Other important Hemoglobins include Hemoglobin A (normal Hb) which has 2 alpha
and 2 beta subunits and Hemoglobin A2 which has 2 alpha and 2 delta subunits.
Sickle Cell Disease-key takeaways

-Belongs to the group of diseases known as the Hemoglobinopathies.
-The underlying pathophysiology is a mutation of the beta globin gene at position 6 which is associated with a
single base substitution (from glutamic acid to valine). Do not confuse this with the glutamic acid to lysine
substitution associated with Hemoglobin C disease. Some individuals have combinations of these 2 alleles
(Hemoglobin SC disease).
-You should strongly consider this disease on your exam if theres any mention of an African/African American
population.
-Heterozygous individuals-also known as Sickle cell trait, are asymptomatic (and protected against malaria) but
homozygous individuals present with signs and symptoms that typically begin at 6 months of age.
-The underlying pathophysiology in many sickle cell disorders involves the polymerization of the affected RBCs
when a sickle shape is assumed. Sickling is promoted by conditions of hypoxia, dehydration, or in some cases,
stress. These polymerized RBCs occlude blood vessels and create many of the presenting signs and symptoms
observed in the disease.
Sickle Cell Disease-key takeaways

-Common signs/symptoms/findings associated with Sickle Cell Disease include dactylitis (a swelling of the hands and
feet), bone pain (stemming from extramedullary hematopoiesis), asplenia (from autoinfarction of the spleen), infection
with encapsulated organisms (asplenia), Salmonella Osteomyelitis, Aplastic crises from Parvo B19 infection, and
episodes of chest/abdominal pain (also from occlusion of blood vessels in these organs).
-Infarction of the spleen is associated with the presence of Howell-Jolly bodies on blood smear (nuclear remnants in
RBCs that are normally removed by the spleen).
-You most certainly want to be familiar with the findings on Hemoglobin Electrophoresis in individuals with SCD. Hb
Electrophoresis is used extensively in detecting structural Hb diseases like SCD or synthetic Hb diseases like the
Thalassemias.
-In sickle cell trait, therell be Hemoglobin A (b/c they are heterozygous) AND Hemoglobin S (same reasons).
-In sickle cell anemia, therell be Hemoglobin S only on Hb Electrophoresis.
-The only drug currently available for SCD treatment is Hydroxyurea which is an anti-cancer drug that inhibits
Ribonucleotide Reductase. It is thought to increase HbF synthesis.
Crew Cut Appearance of the Skull seen in SCD
Q2
A 67 yo man with a history of chronic gastritis presents with increasing fatigue and a
tingling sensation in his toes and fingers that have worsened over the past few months.
Blood work is performed with results revealing a hemoglobin of 10 g/dL and a Mean
Corpuscular Volume of 117fl. Which of the following patient profiles presents with the
most similarity to the pathophysiology underlying the symptoms present in our 67 yo
patient?
a.
b.
c.
d.
e.
A history of Coronary Artery Disease secondary to beef consumption

A history of GERD secondary to esophageal atonia
A prior large bowel resection secondary to diverticulitis
A prior small bowel resection secondary to Crohns Disease
A prior gallbladder resection secondary to cystic duct inflammation
Q2 Key
-The best answer to this question is D, a prior history of small bowel resection
secondary to Crohns disease.
-Remember that the ileum is the primary site of absorption of Vitamin B12 into the
bloodstream. This absorption is mediated by the binding of B12 complexed with IF to
Transcobalamin 2 receptors.
-Anything that causes malabsorptive disease can also cause a B12 deficiency.
-Folate deficiency also presents with megaloblastic anemia (are there neurologic
symptoms??). Folate is absorbed in the duodenum and proximal jejunum (for the
future-folate is absorbed only in the jejunum).
How Does B12 get to you?

-B12 is found mostly in foods derived from animals.
-When swallowed, B12 binds to R binder in saliva.
-R binder prevents B12 degradation in the stomach.
-There are cells in the stomach (parietal cells) that secrete Intrinsic Factor. Intrinsic factor is secreted and gets to the
small intestine.
-Pancreatic enzymes released from exocrine cells in the pancreas cleave R binder from the R-Binder/B12 complex. B12 is
subsequently conjugated to Intrinsic Factor.
-The B12/Intrinsic Factor complex is then reabsorbed in the terminal ileum.
-It should be clear from this that the causes of B12 deficiency include pernicious anemia (autoimmune destruction of
parietal cells/intrinsic factor), pancreatitis (decreased enzyme production), and intestinal problems (like Crohns
Disease).
-Bacteria love B12 so overgrowth can also cause a B12 deficiency.
Megaloblastic Anemia
-Is a subset of the group of anemias known as the macrocytic anemias.
-These anemias are for the most part secondary to B12 or Folate Deficiency.
-If you have any remote mention of Neurological Symptoms on your exam, choose a B12 deficiency as the most
likely cause.
-The hallmark histologic finding in megaloblastic anemia is the presence of hypersegmented neutrophils (be
able to recognize this for your test!). These arise from cell growth without division due to a lack of DNA
synthesis. Ovalocytes may also be seen on a blood smear (RBCs that look like potatoes).
-Folate and B12 are both required for nucleotide synthesis. The absence of DNA prevents nuclear maturation in
the presence of cytoplasmic expansion (prior to mitosis). As a result, cells get bigger. Note that the cells still
have the ability to expand because they can still make mRNA and proteins which are required for cellular
expansion (membranes, etc).
Hypersegmented Neutrophils in Megaloblastic Anemia
Megaloblastic Anemia contd.

-Pernicious anemia (PA) is a common cause of megaloblastic anemia. PA is caused by an autoimmune
destruction of parietal cells of the stomach or their cellular secretions like Intrinsic Factor (IF). IF complexes to
B12 and aids in reabsorption in the terminal ileum (this is super HY!).
-Another cause of B12 deficiency is a vegan diet. B12 is found in high quantity in animal based products. The
body has B12 stores that last for years so it is quite difficult to have a B12 deficiency from just having a poor
diet.
-Folate deficiency typically stems from poor diets (especially in alcoholics) or in individuals taking certain drugs
that interfere with folate metabolism like Methotrexate. Folate stores are depleted more rapidly than B12 stores
(stores gone in months). (Mnemonic-Folate is found in foliage-leafy items. This is why vegans rarely get folate
deficiency).
-One key test that could distinguish between folate and B12 deficiency is the measurement of methylmalonic
acid levels in the serum. MMA levels will be high in B12 deficiency but normal in folate deficiency. Why?? (hintB12 catalyzes 2 reactions in the human body).
B12/Folate/Homocysteine Metabolism (in words)

-Folate is absorbed as Methylene-Tetrahydrofolate. This form cannot be used for DNA
synthesis. Tetrahydrofolate can be used for DNA synthesis.
-The methyl group from folate is passed on to B12 to form methylcobalamin and THF
(which is now useful).
-B12 transfers this methyl group to Homocysteine (Homocysteine + Methyl =
Methionine, read Methyl Ionine).
-Homocysteine can also be converted in a series of reactions to Cysteine (mediated by
Cystathionine Beta Synthase).
-It should then be clear that Folate, B12, or Cystathionine Beta Synthase deficiency can
all lead to high levels of Homocysteine in the blood which predisposes an individual to
atherosclerosis.
B12/Folate/Homocysteine Metabolic Pathway
Megaloblastic Anemia contd.

-Treatment of Megaloblastic Anemia is with Folate/B12 supplementation depending
on the underlying cause.
-It is never a good idea to empirically begin supplementation without deciphering
the underlying cause first. Why might this be so?
-Since B12/folate deficiency causes a decreased synthesis of DNA/RNA, would the
reticulocyte count be increased, decreased, or normal?
Summary Table of B12 and Folate deficiencies
Q3
A woman presents to the Med19 free clinic with signs and symptoms of leg pain and
swelling that arose over the last 3 days. Her D-dimer levels are elevated which raises
your suspicion of a DVT. In the process of conducting other blood studies, you notice
an elevated beta HCG level and Ultrasound reveals a 4 week old fetus. What is the
mechanism of action of the drug that best decreases the risk of adverse events as a
consequence of the DVT?
a.
b.
c.
d.
e.
Increases the activity of Antithrombin 3.

Binds to an ADP receptor and prevents platelet activation.
Inhibits the activation of Factors 2, 7, 9, 10, Protein C, and Protein S.
Increases the release of VWF from endothelial cells.
Irreversibly inhibits cyclooxygenase and prevents the formation of Thromboxane
A2.
Q3 Key
-This question is trying to test your ability to recognize 1 key concept.
-The best answer is A which is Heparin.
-This woman has a DVT which has a high risk of breaking off and getting to the
pulmonary artery (giving rise to a Pulmonary Embolus).
-Heparin does not lyse clots, but it prevents new ones from forming.
-Our patient is pregnant, so she should not get Warfarin which is a teratogen. Heparin
is the DOC in the treatment of hypercoagulable states in pregnancy. Heparin is protein
bound which severely decreases its bioavailability and hence its transmission to the
fetus through the placenta.
Q4
A 35 yo smoker is admitted to the hospital with signs and symptoms of acute chest
pain with radiation to the jaw. Serial ECGs indicate the presence of an ongoing
myocardial infarction. Thrombolytic therapy is rapidly initiated with prompt
resolution of the patients symptoms. 4 hours later, the patient begins to have seizures
with subsequent bleeding from his ears. Reversal of these acute symptoms can best be
established by the administration of a drug that;
a.
b.
c.
d.
e.
Activates plasminogen.
Degrades fibrin.
Activates fibrinogen.
Inhibits plasminogen conversion to plasmin.
Inhibits fibrinogen conversion to fibrin.
Q4 Key
-The best answer to this question is D.
-The patient in question most likely has an occlusion of one of his coronary arteries
leading to an acute MI.
-A clot busting drug like Streptokinase was used to open up the blockade and
reperfuse the heart. These drugs literally bust every recently formed clot in the body
and hence present a really high bleeding risk (are heavily contraindicated in lots of
patients).
-Reversing the bleeding associated with these drugs depends on preventing the
conversion of plasminogen to plasmin by the administration of Aminocaproic Acid.
This is the rescue agent in bleeding secondary to thrombolytic therapy.
Q5
A 44yo man who recently underwent a Coronary Angioplasty receives a 6 month
prescription for an injectable monoclonal antibody that interferes with platelet
aggregation. The mechanism of action of this drug produces physiological effects that
are most similar to a patient with?
a.
b.
c.
d.
e.
Bernard Soulier Disease

Von Willebrand Disease
Hemophilia A
Hemophilia B
Glanzmann Thrombasthenia
Q5 Key
-The best answer is E, Glanzmann Thrombasthenia.
-The drug in question is Abciximab which inhibits the platelet receptor, Gp 2B/3A.
-The inhibition of this receptor shuts down platelet aggregation (it is actually HY to
know the particular step in the platelet plug formation process that is inhibited by a
drug, they love testing those!).
-An individual with Glanzmann Thrombasthenia (a genetic deficiency in the Gp 2B/3A
receptor) essentially has a naturally occurring platelet aggregation problem.
Q6
A 19 yo. medical student is enrolled in a clinical trial for a new thrombolytic agent.
While signing a disclosure form, he mentions having a genetic disorder that leads to a
decreased inactivation of Factor 10 and Thrombin. To confirm this disclosure,
experimental assays are conducted with samples drawn from his serum. The most
plausible result of this experiment is;
a.
b.
c.
d.
e.
f.
g.
No change in PTT upon administration of Warfarin.

An increase in INR upon administration of Warfarin.
A decrease in PTT upon administration of Heparin.
No change in PT upon administration of Heparin.
An increase in bleeding time upon administration of Warfarin.
No change in PTT upon administration of Heparin.
An increase in PT, PTT, and Bleeding Time.
Q6 Key
-The best answer is F.
-An inability to inactivate Factor 10 and Thrombin (Factor 2) is the primary
pathophysiology behind Antithrombin 3 deficiency.
-Heparin works by increasing the activity of Antithrombin 3. Therefore, these
individuals would have no response to AT3 or would need a larger than normal dose of
Heparin to achieve the same therapeutic effect.
-For annoying questions like these, come up with your answer first before sifting
through the mess in the answer choices provided so you dont get confused and get an
unnecessary headache.
Clot Haters
-Antithrombin 3 inhibits Factors 2, 7, 9, 10, 11, and 12 (mostly know 2 and 10). It is activated by
Heparin (which is also naturally released by basophils/other blood and tissue elements).
-Prostaglandin I2/PGI2 (consider this to be a platelet gathering inhibitor) is made by
endothelial cells and inhibits platelet aggregation. PGI2 is also a powerful vasodilator. By
vasodilating, PGI2 increases blood flow to an area and washes away platelet plugs.
-Protein C and S are Vitamin K dependent proteins that inactivate Factors 5 and 8 which are
accelerating factors of the coagulation cascade (b/c they serve as cofactors for other factors in
the pathway). A thrombin-thrombomodulin complex on endothelial cells activates Protein C.
Protein S acts as a cofactor for Protein C.
-Tissue Plasminogen Activator (tPA) is made by endothelial cells. tPA converts plasminogen to
plasmin. Plasmin degrades fibrin and other coagulation factors.
Clot Lovers
-TXA2 is made by platelets and plays 2 roles. The first is the promotion of platelet aggregation. The 2nd is the
promotion of vasoconstriction. Note that vasoconstriction is pro-thrombotic because it prevents formed
platelet plugs from being washed away.
-VWF is made by platelets (stored in alpha granules) and endothelial cells (stored in Weibel Palade bodies).
VWF has 2 main functions-the first being an involvement in the adhesion step of primary hemostasis (forming
the platelet plug) and the 2nd being a carrier of Factor 8 (prevents degradation)..
-The release of VWF from Weibel Palade bodies is promoted by a drug known as Desmopressin which is an
analogue of ADH. Hence Desmopressin is the DOC in the treatment of Hemophilia A which is an X linked
recessive disease.
-Why does this make any sense? Teleologically, ADH is antidiuretic and hence prevents water losses from the
body. 1 secondary role of ADH (GTS Endo) is to constrict blood vessels. So it should make sense that it would
promote the release of something that is pro-thrombotic so you dont lose fluid from the body.
-What should be true of the PT, PTT, and Bleeding Time in Von Willebrand Disease?
Platelets and Their Properties

-Are cytoplasmic fragments derived from megakaryocytes. Thrombopoietin upregulates the production of platelets. A large pool of
our bodys platelets (33%) are stored in the spleen.
Important receptors found on platelets include;
-Gp1B-For binding to VWF in the adhesion step of primary hemostasis.
-The ADP Receptor-binds ADP to induce the release of Gp2B/3A in the activation step of primary hemostasis. This receptor is
blocked by Clopidogrel, Prasugrel, Ticlopidine, Ticagrelor, etc.
-Gp2B/3A-binds Fibrinogen (not Fibrin) to crosslink platelets in the aggregation step of primary hemostasis. This receptor is
blocked by Abciximab, Eptifibatide, Tirofiban, etc.
2 important platelet components include;
-Dense bodies which contain ADP and Calcium.
-Alpha granules which contain VWF, Fibrinogen, and Platelet Factor 4.
-It is also important to know that platelets release cytokines that maintain Adherens junctions b/w cells (especially endothelium)
which prevents leakage of RBCs into the interstitium. Hence, a platelet deficiency leads to petechiae (skin bleeds) formation.
A Comparison of Primary and Secondary Hemostasis
Formation of the platelet plug (Primary Hemostasis)
Strengthening The Platelet Plug (Secondary Hemostasis/Pharm)
Key Facts Related To The Coagulation Cascade

-Most coagulation factors are produced in the liver.
-Vitamin K dependent coagulation factors include Factors 2, 7, 9, 10, Proteins C and S (Mnemonic-diSCo started in
1972). These factors all require Calcium as a cofactor. Neonates need Vitamin K supplements at birth (b/c they lack the
gut flora necessary for Vitamin K production). How can pancreatic insufficiency cause a Vitamin K deficiency?
-Thrombin (Factor 2) has multiple functions-activating the accelerating factors 5 and 8, converting Fibrinogen (Factor
1) to Fibrin (Factor 1a), and the activation of Factor 13 which stabilizes the fibrin clot.
Platelet Function Tests

-A normal platelet count is 150-400k cells/mm3
-Bleeding Time is a measure of platelet function, not coagulation cascade function. Any disorder or drug
that interferes with platelet function will increase the bleeding time. It is pathophysiologically helpful to
try to reason out why taking Aspirin, having diseases like Bernard Soulier syndrome, Glanzmann
Thrombasthenia, VW Disease, and Thrombocytopenia increases bleeding time.
-There are 2 key tests of VWF activity/Platelet Adhesion-the Ristocetin Cofactor Assay, and the Von
Willebrand Antigen Assay. Ristocetin is an agent that causes binding between Gp1B and VWF. The Von
Willebrand Antigen Assay is one that just measures the levels of VWF in the serum. What are the 2
diseases associated with abnormal Ristocetin Cofactor Assays?
-Fibrinolytic System tests include the measurement of D-Dimers which are very sensitive at detecting
situations involving clot breakdown. D-Dimers are elevated in DIC (and also PE/DVT). An elevated DDimer will be expected in the administration of what kind of drug?
PFTs-Bleeding Time/PT/PTT (commit to memory!)

-BLEEDING TIME is solely a measure of platelet function (primary hemostasis). An
individual with a platelet deficiency will have a prolonged bleeding time. There is NO
CHANGE in PT or PTT (with one exception-what is it?). Repeating for emphasis...
-PT is a measure of the efficiency of the extrinsic (or tissue factor) pathway and the
final common pathway. It is basically a measure of how long it takes a clot to form
upon the addition of any kind of Factor 7 activator to a test tube containing a patients
plasma. This is normalized to INR and is the number that is tracked in Warfarin
users.
-PTT is a measure of the efficiency of the intrinsic pathway and the final common
pathway. It is a measure of how long it takes a clot to form upon the addition of any
kind of activator of the intrinsic cascade to a test tube containing a patients plasma.
This is the number that is tracked in Heparin users.
Coagulation Cascade Disorders-Hemophilia

-Are disorders involving deficiencies of Factors 8 (Hemophilia A-more common) and 9
(Hemophilia B). Mnemonic-A sounds like Eight and 9 sounds like Benign or B9.
-Consider this in a patient presentation detailing major bleeds (joint bleeds, bleeds
after a dental procedure, etc) with an elevated PTT.
-Are both transmitted in an X linked Recessive fashion and hence more common in
boys.
-These factors are found in the intrinsic pathway so PTT will be increased but NOT
PT.
N/B-Platelet disorders tend to present as skin bleeds (petechiae, purpura) or
nosebleeds (epistaxis). Coagulation factor disorders tend to present as delayed, major,
bleeds that could be life threatening (joint bleeds, tissue bleeds, etc).
Other Coagulation Cascade Disorders

-A Vitamin K deficiency (similar symptoms to taking Warfarin) or liver disease (decreased production of coagulation
factors, excluding Factor 8) can present with coagulation factor problems (increased PT and PTT). Liver disease is also
associated with Portal HTN and splenomegaly which leads to thrombocytopenia (increased sequestration-a double hit).
Coagulation factor deficiencies are typically corrected with the administration of plasma.
-Factor V Leiden is a mutation in Factor V that leads to decreased inactivation by Protein C and S. These patients
possess an increased risk of thrombus formation. Factor V Leiden may be detected via an Activated Protein C Resistance
Assay.
-Protein C deficiency is also associated with an increased risk of thrombosis as theres a decreased propensity to
inactivate Factors 5 and 8. This deficiency is somewhat analogous to a Vitamin K deficiency OR the administration of
Warfarin (make sure you can explain the underlying physiology to yourself!).
-An Antithrombin 3 deficiency presents with an increased risk of thrombus formation due to a decreased inactivation of
Factors 2 and 10 (and many other factors). Individuals with this condition tend to record no increase in PTT with the
administration of Heparin (or require larger than normal doses). Why???
-A G20210A mutation (at the 3 region of the Prothrombin mRNA) is one that increases the amount of translated
Prothrombin and increases an individuals risk of thrombus formation.
Weird But HY Coagulation Pathway Assays

-An Activated Protein C Resistance Assay is an experimental approach that involves
the addition of Activated Protein C to a patients plasma and detecting how long it
takes a clot to form. We know that Protein C inhibits Factor 5 (and 8). In the absence
of Protein C, a clot forms quickly. The addition of Protein C should inhibit Factor 5
and hence increase the amount of time needed to form a clot. A slight (or no change)
in the clotting time after the addition of Activated Protein C is diagnostic of factor V
Leiden.
-Mixing studies are essentially studies that involve 2 phases. In Phase 1, an increased
PT or PTT is noted. In the 2nd phase, the addition of normal plasma that selectively
contains coagulation factors of interest fixes the the problem and decreases the PT and
PTT back to a normal range.
Special Mention-Antiphospholipid Syndrome (Read with Caution!)

-Antiphospholipid syndrome (APLS) is a bizarre autoimmune disease with a poorly
understood pathophysiology. What follows is my approach to rationalize the
mechanism in my head. This is not necessarily the underlying pathophysiology but it
should make do for your exam.
-In the body, APLS autoantibodies bind to and initiate the destruction of
phospholipid binders. The removal of these phospholipid binders from circulation
leads to a physiologic excess of phospholipids which leads to an increased activation of
the coagulation cascade and thrombosis. In addition, autoantibodies are typically made
against Protein C and other anticlotting proteins (pro-thrombotic).
-In test tubes, APLS autoantibodies do not bind phospholipid binders but instead
bind actual phospholipids. The removal of actual phospholipids from circulation
leads to a decreased activation of the coagulation cascade and hence an increased
PT/PTT since it takes longer for a clot to form.
Special Mention-Antiphospholipid Syndrome (Read with Caution!),contd..

The Dilute Russell Viper Venom Time (DRVVT) is a test often used to assess APLS.
Step 1-Add Viper Venom to a sample of the patients serum. Viper Venom activates Factor 10 and leads to the
formation of a clot via the final common pathway. This is a test tube test so an individual with APLS
autoantibodies would have a low level of phospholipids and hence an increased PT/PTT (clot forming time).
Unfortunately, the increased PT/PTT could also arise from a deficiency of any member of the final common
pathway of the coagulation cascade.
Step 2-Normal plasma (which contains adequate amounts of clotting factors) is added to the mix from Step 1.
An individual that has APLS autoantibodies will not have a decrease in the PT/PTT since these autoantibodies
are still present and theres no phospholipid to fix the phospholipid deficiency problem. On the flip side, if the
increased PT/PTT stems from a final common pathway coagulation factor deficiency, the PT/PTT will be
decreased (make sure you understand this).
Step 3-A large amount of phospholipid is added. This addition overwhelms and cancels out the effect of APLS
autoantibodies present in the plasma. In this case, the PT/PTT should decrease to a normal range since the
underlying problem has been corrected (again, make sure you understand this).
Platelet Disorders-An Overview
Qualitative Platelet Disorders

-Von Willebrand Disease (VWD) is an Autosomal Dominant disease associated with a deficiency of
VWF. This is a combined platelet and coagulation cascade disorder (b/c VWF stabilizes Factor 8),
therefore Bleeding Time and PTT will be increased. The Ristocetin Cofactor Assay will be abnormal.
The ristocetin assay normalizes upon addition of normal plasma (b/c plasma contains VWF).
-Bernard-Soulier Disease is caused by a deficiency of the Gp1B receptor on the cell surfaces of platelets.
This impairs platelet adhesion. Bleeding time is prolonged and thrombocytopenia results (diminished
platelet survival). The Ristocetin cofactor assay will be abnormal and will not normalize with the
addition of normal plasma (since this is a circulating platelet problem).
-Glanzmann Thrombasthenia is an Autosomal Recessive deficiency in the platelet aggregation Gp 2B/3A
receptor. The Ristocetin Cofactor Assay will be normal but bleeding time will be increased. Think of this
as a congenital Abciximab, Eptifibatide, or Tirofiban deficiency (this is HY!).
-Renal Failure leads to the production of toxins that inhibit platelet phospholipids. As you know,
phospholipids are required for proper functioning of primary hemostasis.
Quantitative Platelet Disorders

-Immune Thrombocytopenia (ITP) is caused by the production of IgG autoantibodies
against Gp 2B/3A. This leads to the destruction of platelets by splenic macrophages
that have FC-Gamma receptors. Bleeding Time will be increased. This condition is
more common in women and may be treated with steroids/splenectomy.
-Thrombotic Thrombocytopenic Purpura (TTP) is a caused by a deficiency of the
enzyme ADAMTS13 which cleaves VWF. The absence of this enzyme leads to
widespread thrombi formation in blood vessels. Platelet count is depleted, but the
major complication here is the risk of thrombosis, not bleeding (LY now, HY later).
The thrombi sticks formed shear moving RBCs which can appear as Schistocytes on
blood smear. TTP is usually associated with Fever, Anemia (Microangiopathic
Hemolytic Anemia), Thrombocytopenia, Renal Failure, and Neurological disturbances.
Q7A
A 27 yo. pregnant woman from West Africa presents to the ER with an acute
complaint of blood in her stool. PE reveals petechiae on her skin and buccal mucosa,
HR of 35 bpm, BP of 90/50. The patient suddenly begins to cough up blood. A CBC
reveals anemia and thrombocytopenia. The patient takes a Folate supplement daily.
Choose the set of values that best agree with this patients presentation.
Q7B
A 27 yo. pregnant woman from West Africa presents to the ER with an acute
complaint of blood in her stool. PE reveals petechiae on her skin and buccal mucosa,
HR of 35 bpm, BP of 90/50. The patient suddenly begins to cough up blood. A CBC
reveals anemia and thrombocytopenia, PT and PTT are elevated. The patient takes a
Folate supplement daily. Which of the following would be expected on a blood smear
obtained from this patient?
a.
b.
c.
d.
e.
Spherocytosis
Howell Jolly Bodies
Schistocytosis
Heinz Bodies
Bite cells
Q7A/B Key
-The best answer is E for Part A and C for Part B .
-A description detailing a pregnant woman with acute complaints of hemoptysis and
blood studies revealing thrombocytopenia and anemia is classic for DIC (Disseminated
Intravascular Coagulation) which is common in this patient population.
-The best test in this scenario is a D-Dimer test which is indicative of some sort of clot
breakdown. For the future, the D-dimer test is highly sensitive but not specific (this
factoid is commonly framed as a heme question in the context of biostatistics).
-The spill about West Africa is a distractor to get you to think about some sort of
G6PD deficiency but this is usually framed in the context of exposure to some sort of
drug or consuming a meal (read your Qs carefully).
Disseminated Intravascular Coagulation

-The sudden, massive release of substances that trigger the coagulation cascade can
lead to an acute depletion of coagulation factors (and the upstream feedstockplatelets). Placental products are prime activators of the coagulation cascade. Another
common DIC scenario is in the setting of sepsis.
-The depletion of platelets leads to thrombocytopenia and increased bleeding. The
rapid increase in the activation of the coagulation cascade leads to the formation of
thrombi in many blood vessels. These thrombi sticks shear RBCs, giving rise to the
observed schistocytes on blood smear.
-Note that schistocytes are found in other conditions that involve intravascular
hemolysis like Hemolytic Uremic Syndrome/TTP or a damaged heart valve.
Key Takeaways for The Antiplatelet Medications

-Aspirin is an irreversible inhibitor (by acetylation) of COX 1 (and 2), hence decreasing the formation of
Thromboxane A2 which encourages platelet aggregation. Platelets do not have a nucleus so they cannot make
new TXA2. Therefore, Aspirin permanently inhibits platelet aggregation until new platelets are formed. A HY
SE of Aspirin is GI upset/bleeding secondary to the decreased production of protective prostaglandins in the
stomach (which are made by COX1). Aspirin administration increases bleeding time.
-Drugs like Ticlopidine, Ticagrelor, Prasugrel, and Clopidogrel are inhibitors of the ADP receptor known as
P2Y12. The ADP receptor is a G protein coupled receptor that is Gi coupled (which inhibits ATP conversion to
cAMP). Normally, a decrease in cAMP leads to platelet activation. By blocking the ADP receptor, there is an
increase in cAMP which inhibits platelet activation/ subsequent aggregation.
-Since we know that increased cAMP inhibits platelet activation/subsequent aggregation, preventing the
degradation of cAMP should achieve the same effect as the ADP receptor blockers. This is the MOA of
phosphodiesterase inhibitors (N/B PDE breaks down cAMP and cGMP) like Cilostazol and Dipyridamole.
-Gp 2B/3A receptor blockers like Abciximab, Eptifibatide, and Tirofiban prevent platelet aggregation.
-A SE that is common to all these drugs is bleeding.
Key Takeaways for The Anticoagulant Meds-Heparin

-Antithrombin 3 is a serine protease inhibitor that primarily inhibits the proteins of the intrinsic coagulation
cascade (primarily Factors 2 and 10) which are all serine proteases.
-The activity of AT 3 is massively increased (about 1000x) by Heparin. This is lower yield for your exam but AT
3 also knocks down Factors 12, 11, 9, and 7 and hence kills a huge chunk of the intrinsic clotting cascade. This is
why Heparin is measured with the PTT (increases PTT mostly but also raises PT).
-Heparin works with the bodys pre-existing anticoagulation system so it destroys what is in operation right
now. This is why Heparin has a rapid onset of action.
-Heparin is implicated in SEs like Heparin Induced Thrombocytopenia (from binding to platelet factor 4). This
complex is a powerful inducer of primary hemostasis which leads to platelet depletion.
-Heparin is the DOC in anticoagulation of pregnancy.
-The rescue agent in Heparin toxicity (bleeding) is Protamine Sulfate.
Key Takeaways for The Anticoagulant Meds-Heparin

-Heparin is a large, water soluble molecule and hence acts as an excellent hapten for the immune system.
-Heparin can bind to Platelet Factor 4 and induce antibody production against the Heparin/PF4 complex.
-This antibody binds up any new heparin that is injected, which then predisposes the individual to thrombus formation
(with concomitant depletion of platelets). This is the underlying pathophysiology of Heparin Induced
Thrombocytopenia. Unlike ITP, these people are at increased risk of thrombus formation, not bleeding (LY now, HY
later). This antibody also unilaterally activates the clotting cascade (LY as well).
-Heparin, being a large, water soluble molecule, is unable to cross lipophilic cell membranes and is thus safe in
pregnancy (cant cross the placenta). This also explains why Heparin mostly stays in the vascular space and is rapidly
eliminated from the body.
-Instead of killing both Factors 2 and 10, there are drugs that are selective for both factors.
-There are Low Molecular Weight Heparins (LMWH) that serve to inhibit only Factor Xa (Xa is in the name).
-There are direct thrombin (2a) inhibitors like Argatroban, Dabigatran and Bivalirudin (leech derived-remember that
leeches suck blood, so to keep blood flowing, they inject an anticoagulant during infection).
Key Takeaways for The Anticoagulant Meds-Warfarin

-Vitamin K in the reduced form is required for the activation (through gamma carboxylation) of Factors 2, 7, 9, 10,
Protein C, and Protein S.
-The conversion of Vitamin K from its oxidized to its reduced form is controlled by Vitamin K Epoxide Reductase
(VKORC). Warfarin inhibits this enzyme, preventing the regeneration of reduced Vitamin K.
-Warfarin inhibits many of the enzymes in the tissue factor/extrinsic pathway of coagulation so it is monitored with PT
(which is normalized as an INR, target is b/w 2-3, NL is 1). Warfarin also increases PTT.
-Warfarin does not help with coagulation factors that have already been made and is useful only for those that will be
made. This is why Warfarin has a slower onset of action compared to Heparin.
-Protein C and S have a much shorter half life than Factors 2, 7, 9, and 10 so the initial administration of Warfarin may
lead to a state of transient hypercoagulability (due to a decreased inactivation of???) which can manifest as skin necrosis.
This is prevented by a heparin bridge in the first few days of treatment.
-Warfarin should NEVER be given to pregnant women (is teratogenic). The long term rescue agent in Warfarin
toxicity is Vitamin K but immediate reversal of its effects is with Fresh Frozen Plasma which instantly supplies all the
missing coagulation factors.
A Comparison of Heparin and Warfarin
Thrombolytics
-Our innate clot busting molecule is plasmin, which is made from plasminogen by
TPA.
-Recombinant TPA can be given in the setting of an MI or Thromboembolic stroke.
-These drugs tend to end in plase-Alteplase, Tenecteplase, etc. The only key
exception is Streptokinase which is not used anymore as a result of potential immune
mediated reactions (why??).
-Since these drugs bust clots, there is a very huge associated bleeding risk.
-The rescue agent in toxicities associated with these clots include Aminocaproic Acid
and Tranexamic Acid. These drugs are competitive inhibitors of plasmin, hence
preventing the conversion of fibrin to fibrin degradation products.
Blood Drug Summary
Anemia
-There are 3 different kinds of Anemias.
-The first group are Microcytic Anemias (MCV < 80). There are 4 majors here-Fe Deficiency
Anemia, Anemia of Chronic Disease, Thalassemias, and Sideroblastic Anemias.
-The second group are the Macrocytic Anemias (MCV > 100). The major group here are anemias
secondary to B12/Folate Deficiency.
-The 3rd group are the Normocytic Anemias (MCV b/w 80-100). These anemias are typically
differentiated based on reticulocyte (an immature RBC) counts. If reticulocyte counts are low,
consider Renal Disease or Aplastic Anemia (indicative of underproduction). If reticulocyte counts
are high, consider hemolytic anemias (i.e. Sickle Cell Disease, G6PD deficiency, Hereditary
Spherocytosis, Autoimmune Hemolytic Anemia, Microangiopathic Hemolytic Anemias).
-It is very important to have anemias classified in your mind as a means of coming to a
differential on the exam and making the right diagnosis.
Q8
The photomicrograph shown below is most consistent with a patient having a prior history of?
a.
b.
c.
d.
Pain from multiple vaso-occlusive episodes in the digits.

Hemoglobinuria stemming from an autoimmune process.
An enzyme deficiency subjecting RBCs to oxidative stress.
None of the above.
Q8 Key
-The best answer is A.
-The arrow points to a Howell Jolly body.
-Howell Jolly bodies are nuclear remnants that are typically removed by macrophages
in the spleen. The presence of a Howell Jolly body on microscopy is indicative of
asplenia or an auto infarcted spleen which is common in SCD patients.
-SCD patients typically present with pain in the digits (dactylitis) from recurrent vasoocclusive episodes and infarction of the wrist/hand bones.
Q9
A concerned parent brings her 3 month old child to the ER. She mentions that her son
s urine has been red for the last few days. He has never had these symptoms before.
Blood smear obtained from the child indicates RBCs lacking central pallor. Blood
studies conducted in this patient would most likely reveal?
a.
b.
c.
d.
e.
An increased MCHC.
A decreased MCHC.
Increased haptoglobin.
Conjugated hyperbilirubinemia.
An abnormally low level of reticulocytes.
Q9 Key
-RBCs without central pallor is indicative of spherocytes.
-Spherocytes have a decreased SA/V ratio and hence an increased Mean Corpuscular
Hemoglobin Concentration (MCHC).
-Know the common descriptors and morphologies of RBCs under different pathologic
conditions.
Q10
A healthy 17 yo. female suffered blunt abdominal trauma in a MVA. Her CBC on
admission showed a Hct of 33% which decreased to 25% over the next hour. In the
process of treatment and supportive care, 1L of bloody fluid was evacuated from the
patients abdomen with marked improvement of her symptoms. A CBC performed 3
days later is most likely to reveal which of the following RBC morphologies.
a.
b.
c.
d.
e.
f.
Basophilic Stippling
Hypochromic RBCs
Leukocytosis
Reticulocytosis
Schistocytosis
Spherocytosis
Q10 Key
-The acute blood loss precipitates an anemic signal which in the presence of normal
Fe stores (as is this case for this healthy female) stimulates reticulocytosis from the
bone marrow.
-A good mental exercise will be to defend why the other answers are wrong.
Q11
A 4 yo. boy from Palermo has a poor appetite and is underweight for his age. PE
reveals hepatosplenomegaly. Blood studies reveal a Hb of 6 g/dL, MCV of 60 fL,
normal levels of serum Fe, a reticulocyte count of 12%, and RBCs with widened central
pallor. Skull radiographs reveal facial deformities and expansion of marrow spaces. The
most likely cause of this childs illness is;
a.
b.
c.
d.
e.
An imbalance in alpha and beta globin gene production.

Increased fragility of RBC membranes.
Increased synthesis of HbF.
Relative deficiency of Vitamin B12 and Folate.
Fe sequestration in bone marrow macrophages.
Q11 Key
-Any mention of the Mediterranean on your exam is most likely going to be BetaThalassemia. With major symptoms like this, our patient most likely has Beta-Thal
major.
-Anemia associated with beta-thal major increases EPO synthesis from the kidneys
which leads to marrow expansion and extramedullary hematopoiesis (this explains the
hepatosplenomegaly and facial deformities).
-These patients tend to require frequent transfusions and may eventually develop
secondary hemochromatosis (from Fe overload).
Q12
A 35 yo. woman from Vietnam prematurely delivers a markedly hydropic stillborn
infant. Autopsy reveals massive hepatosplenomegaly, cardiomegaly, and fluid in
multiple body cavities. There is marked extramedullary hematopoiesis. Hb
electrophoresis of the deceased infants RBCs would most likely reveal a predominance
of;
a.
b.
c.
d.
e.
f.
HbA
HbA2
Hb Barts
HbF
HbH
HbY
Q12 Key
-The best answer is C.
-This child most likely has Alpha Thal major which is associated with a 4 alpha globin
gene deletion. A complete lack of Alpha chains prevents the formation of HbF, A, and
A2. These leads to the formation of Gamma tetramers (Hb Barts) which leads to a
severe anemia.
-The severe hypoxia in utero leads to eventual cardiac failure and hydrops fetalis
(mechanism explained in Microbiology slides).
-Do not forget the SE Asia connection with Alpha Thal major.
Anemia Classification Scheme
Other Important Considerations...

-Hb multiplied by 3 should roughly equal the Hematocrit (the percent of total blood volume that
is ascribed to RBCs).
-Fe deficiency is the most common cause of anemia worldwide.
-Many anemias start out with being Normocytic, and then progress to being micro or macrocytic.
-It is HY to know that Fe is absorbed in the duodenum, Folate is absorbed in the jejunum, and
B12 is absorbed in the terminal ileum.
-The RDW (Red Cell Distribution Width) is a measure of the variation in RBC size that can be
detected on a smear. A wider RDW is indicative of a huge variation in RBC size, which is classic
for Fe deficiency anemias (since cells start out pretty normal in size but as things get worse, the
red cell size decreases).
Key RBC Metrics

-The MCV is the Mean Corpuscular Volume which is indicative of the average
VOLUME of individual RBCs and is the primary means of classifying anemias.
-The MCHC is the Mean Corpuscular Hemoglobin Concentration, and is a measure of
the average CONCENTRATION of Hemoglobin in RBCs. MCHC is decreased in
most cases of microcytic anemias. This manifests as the increased central pallor
found in RBCs in microcytic anemias. MCHC is increased in situations that involve a
reduction in RBC membrane like Hereditary Spherocytosis. Theres essentially an
increased Hb/Membrane Ratio.
-RDW is the Red Cell Distribution Width and is a measure of the uniformity of RBC
sizes. Variation in RBC size is known as Anisocytosis. The RDW is useful in
distinguishing Fe deficiency anemia (IDA) from other causes of Microcytic Anemia. It
is increased in IDA as a result of a mixture of both normal sized and small sized RBCs.
Key Details of RBC Metabolism

-RBCs lack mitochondria and hence cannot participate in the TCA cycle or beta oxidation of fats. They also lack
a nucleus.
-The primary energy source for a RBC is Glycolysis. Lactic acid made by RBCs as a product of glycolysis is
converted by the liver in the CORI cycle back to glucose and shipped back to the RBC.
-RBCs make extensive use of offshoot pathways of glycolysis like The RL shunt for making 2,3 BPG which
improves oxygen delivery to tissue and shifts the Hb-O2 dissociation curve to the right. Theres also
Methemoglobin Reductase that converts Fe in the 3+ form (which cannot carry O2) to Fe in the 2+ form
(which can carry O2).
-The HMP Shunt provides NADPH which serves as reducing power for many RBC reactions (the reaction
mentioned above uses NADH though). 1 key RBC reductive reaction is the pathway involved in maintaining
Glutathione in a reduced state. Glutathione is the primary means used by RBCs to deal with oxidative stress.
Reduced Glutathione converts Hydrogen Peroxide to Water.
-The degradation of Heme in RBCs yields Iron and Protoporphyrin. Protoporphyrin is ultimately converted to
unconjugated bilirubin.
Q13
A 25 yo. healthy Nigerian passes dark brown urine 2 days after starting prophylactic
malaria treatment for hypnozoite forms of the offending organism. PE is unremarkable
with CBC showing a markedly decreased serum haptoglobin. The most likely
explanation for these findings is;
a.
b.
c.
d.
e.
f.
g.
Antibody mediated hemolysis.

Impaired DNA synthesis.
Impaired globin chain synthesis.
Increased susceptibility to complement mediated lysis.
Mechanical fragmentation of RBCs from vascular narrowing.
Oxidative injury to hemoglobin.
Reduced deformability of the RBC membrane.
Q13 Key
-The best answer is F.
-This patient (a person of W. African origin) was most likely taking Primaquine which
places oxidative stress on RBCs. An individual with G6PD deficiency is not able to
handle this and would have hemoglobin cells undergoing oxidative damage. These Hb
inclusions can damage the RBC membrane resulting in intravascular hemolysis with
decreased haptoglobin. RBCs with these inclusions could also be destroyed by splenic
macrophages which results in extravascular hemolysis and elevated indirect bilirubin.
-Do not forget the fact that the Hb inclusions in G6PD deficiency are known as Heinz
bodies and splenic macrophages could remove these inclusions, leading to the
formation of bite cells.
How Does Fe Move Within The Body?
Fe Studies-Ferritin
-Is the storage form of Fe and is made in the liver/bone marrow macrophages.
-Is an acute phase reactant and hence is increased in inflammation. This is partly why
Fe stores are increased in Anemia of Chronic Disease.
-Serum Ferritin is low in Fe Deficiency Anemia (when you see a problem that involves
a low MCV, the very first thing you should look for is the Ferritin level).
-Serum Ferritin is increased in Anemia of Chronic Disease and Hemochromatosis (or
any Fe overload state).
-Hemosiderin is the breakdown product of Ferritin (for your exam though, know
Hemosiderin as the super long term storage form of Fe).
Fe Studies-Serum Fe
-Is a measure of the amount of Fe bound to Transferrin.
-Serum Fe is decreased in IDA and ACD.
-Serum Fe is increased in Hemochromatosis (and other Fe
overload states).
Fe Studies-TIBC/Transferrin
-Transferrin is the protein that transports Fe in the blood (Fe is too dangerous to wander on its
own in serum).
-TIBC literally means TOTAL FE BINDING CAPACITY which is a measure of the space left
unoccupied on transferrin for Fe to bind to.
-An individual that is Fe deficient should open up more Transferrin Slots so he can get Fe to his
bone marrow. The level of Ferritin in the bone marrow has a feedback effect on the livers
production of Transferrin. High ferritin levels feedback inhibit the livers production of
Transferrin and vice-versa.
-Ferritin is low in IDA so TIBC should be high.
-ACD and Hemochromatosis are high Ferritin diseases, so TIBC is low.
Fe Studies-% Saturation of Transferrin

-Is the % of all binding sites on Transferrin that are bound to Fe.
-% saturation is decreased in IDA (as a result of the low overall Fe) and in ACD (there
s Fe available, but its locked up in bone marrow macrophages by Hepcidin).
-% saturation is increased in Hemochromatosis (not locked up in macrophages).
In Summary (commit this to memory!)
Microcytic Anemias
-Are all secondary to decreased Hb Synthesis.
Why Microcytosis?
-MCHC is a very important consideration for RBCs.
-MCHC is essentially a mass/volume relationship. In this case, the mass is Hb and the
volume is the MCV.
-With a decrease in Hb production, RBC homeostasis demands decreasing the
denominator in the equation (MCV) to achieve MCHC constancy. This is
accomplished by increasing RBC mitosis.
-At a certain point however, MCV becomes an important consideration. An MCV that
is too small makes O2 diffusion and carriage less efficient.
-When this MCV threshold is reached, RBCs resort to hypochromasia.
IRON DEFICIENCY ANEMIA (IDA)

-Iron from our diet could be in the heme form (from animal products, Fe2+ and is well absorbed) OR the NonHeme form (from plant products, Fe3+ and is not well absorbed).
-IDA is very common in addition to Fe deficiency being the most common dietary deficiency.
-The presence of low Fe leads to a reduced synthesis of Heme which then leads to a microcytic anemia.
-Clinical features include Pica (craving ice, etc), Koilonychia (spoon shaped nails), and pallor of the
conjunctiva/palmar creases.
-Histological findings include microcytosis (small RBC size to initially maintain intracellular Hb
concentration), increased central pallor (due to eventually decreased total Fe), and an increased RDW.
-Major causes include GI bleeds, Menorrhagia/Menstruation, Dietary Deficiencies, GI tract problems (for
example, a disease that denudes the microvilli of the duodenum).
-Key Findings include a reduced Ferritin, Fe, and % saturation. Others include an increased RDW and TIBC.
-Treatment is with Fe supplementation (Ferrous Sulfate).
CLINICAL/HISTOLOGICAL FEATURES OF IDA
Progressive Losses in IDA (just have a rough idea)

Step 1-Fe stores are depleted (Ferritin)
Step 2-Serum Fe goes down
Step 3-TIBC goes up
Step 4-Transferrin Saturation goes down
Step 5-Normocytic/Normochromic Anemia
Step 6-Microcytic/Hypochromic Anemia
Anemia of Chronic (or Systemic Disease)

-Bacteria require Fe to replicate effectively. Being infected by bacteria is interpreted by the body to be an
inflammatory state.
-Our body tries to fight bacterial infections by storing Fe in bone marrow macrophages and keeping it away
from the bloodstream (reducing absorption in the gut). This is accomplished by a protein made in the liver
known as Hepcidin. The release of Hepcidin from the liver is induced by acute phase cytokines like IL-6.
-In other words, Fe is available but unusable.
-For most people, this is a transient Fe deficiency. For individuals that have some sort of chronic disease (HIV
or a noninfectious disease like Rheumatoid Arthritis/Cancer), their bodies are in a constant state of
inflammation. This takes the Fe deficiency from being transient to being constant. With a chronic unavailability
of Fe, Hb production is decreased and ultimately progresses to a microcytic, hypochromic anemia.
-Lab findings in ACD include a reduced Serum Fe, % saturation, and TIBC (TIBC goes down because there is a
negative feedback on liver Transferrin production from the high Fe stores). Ferritin is increased.
-ACD is treated by treating the underlying chronic disease.
Thalassemias
-Thalassemias are diseases that involve a decreased production of the
globin part of hemoglobin. Theres Alpha and Beta Thalassemia.
-Alpha Thalassemia (Autosomal Recessive) involves a decreased
production of Alpha globin chains. There are a few HY things to note
here-alpha globin is present in ALL hemoglobin types (A, A2, and F)
and there are 4 genes (2 on each chromosome) that affect alpha globin
chain expression. Alpha Thal is common in the Asian/African
American population.
-Mild Alpha Thalassemias are not necessarily picked up on Hb
electrophoresis. Why?
Alpha Thalassemia Permutations (Gene Deletions)

There are 4 genes that produce Alpha chains.
-A 1 gene deletion is not clinically significant.
-A 2 gene deletion (Alpha Thal trait) presents with a mild anemia that is not very clinically significant.
For 1 or 2 gene deletions, Hb electrophoresis is not very helpful.
-A 3 gene deletion (observed in children-adults) is known as HbH disease. The most common Hb in adults is HbA (2
Alphas and Betas), so it makes sense that Beta chains should begin to come together to form Beta-4 tetramers. Hb in this
configuration coagulates within RBCs. These RBCs are destroyed by macrophages (hemolytic anemia). The accelerated
RBC destruction stimulates bone marrow and extramedullary hematopoiesis which leads to an increase in reticulocyte
counts and presents as the same crew cut appearance on skull Xray seen in SCD.
-A 4 gene deletion is not compatible with life. Fetal death occurs in utero (when only HbF-2 Alphas and Gammas is
around). The absence of Alpha chains leads to the formation of Gamma chain tetramers which undergo a similar
destruction as the 3 gene deletions.
For 3 or 4 gene deletions, Hb electrophoresis is very helpful. Why? Is Fe a good therapy for people w/Thalassemia?
Beta Thalassemia
-Is a defect in beta globin gene production and could be caused by a myriad of mutations (very rarely gene
deletions, so this is NOT the right choice on an exam). Beta thal is common in African Americans, Greeks, and
Italians.
-There are 2 genes involved in Beta globin gene production.
-A 1 gene mutation is known as beta thal trait. Since beta globin goes down, the only Hb that will be decreased
will be HbA. As a result of this decrease, there will be a compensatory increase in other kinds of Hemoglobin
like HbA2 which DOES NOT require beta chains. An increase in HbA2 is diagnostic of Beta Thal trait.
-A 2 gene mutation in beta globin genes is compatible with life but these individuals are heavily dependent on
transfusions. Theres a marked increase in HbA2.
-Regular transfusions predisposes an individual to Fe overload (secondary hemochromatosis) which could be
fatal. The DOC in this situation is an Fe chelator like Deferoxamine. The definitive cure for Beta Thal is a Bone
Marrow Transplant (to reconstitute the blood lineage).
Hb electrophoresis is useful in the diagnosis of all forms of Beta Thalassemia. Why?
Hemoglobin Variants
Hemoglobin Electrophoresis Results In Several RBC Disorders
Off Target Cells-Almost Pathognomonic for B-Thalassemia (not the arrow)
Summary of Lab Findings In Microcytic Anemias
Q14
A 16 yo. native of Kentucky comes to his PCP for an annual check up. He alludes to having tingling sensations
in his palms and occasional episodes of dizziness. A CBC/Blood smear reveal macrocytosis and hypersegmented
neutrophils. A diagnosis of Vit B12 deficiency is made. Prior to maintenance treatment, his PCP administers a
large, bolus IV dose of Vit B12. She subsequently administers an oral dose and tells the patient to collect and
return a urine sample the next day. Lab analysis indicates abnormally low levels of Vitamin B12 in the urine.
Concerned, the PCP administers the same oral dose of Vitamin B12 conjugated with another oral agent and
asks the patient to collect another urine sample. Measurements of B12 the next day reveal levels consistent with
experimental controls. Further work up of this patients condition would most likely reveal;
a.
b.
c.
d.
e.
Abnormally low levels of folic acid in the serum.

Low levels of methylmalonic acid in the serum.
Atrophy and denudement of the intestinal brush border.
Lymphocytic infiltrate in the gastric fundus.
Autoantibodies against the intestinal brush border.
Q14 Key
-This patient most likely has Pernicious Anemia.
-The IV dose of Vit B12 administered earlier saturates all body stores of B12.
Administration of an oral dose should be accompanied by high levels of B12 in the
urine since it is excreted by the kidneys. Low levels of B12 in this scenario could mean
one of 2 major things-the intestinal brush border has problems OR the patient has a
deficiency of intrinsic factor.
-The correction of our patients problem with the administration of IF rules out
intestinal malabsorption as the cause of his B12 deficiency.
-Youll learn more about this famous test in your GI block (The Schilling Test).
Lead Poisoning Problems

-Pb inhibits 2 key enzymes in the heme synthesis pathway-ALA Dehydratase and
Ferrochelatase (chelates Fe and Protoporphyrin).
-Pb also denatures Ribonuclease, the enzyme that degrades ribosomes in RBCs. The
persistence of these ribosomes is detected as basophilic stippling on a peripheral blood
smear.
-Ringed Sideroblasts are also found on blood smear b/c Protoporphyrin leaves Fe
hanging in the mitochondria. In anger, these mitochondria bound Fe molecules gang
around the nucleus, planning Protoporphyrins doom. (TL, DR-Protoporphyrin is not
made).
Ringed Sideroblasts (left), Basophilic Stippling (Right)
Hemolytic Anemias-An Overview
Intravascular/Extravascular Hemolysis
Hereditary Spherocytosis (Autosomal Dominant)

-Is an Autosomal Dominant defect involving structural proteins like Spectrin, Ankyrin, and
Band 3.2 (know these proteins!).
-Deficiency of these proteins results in a reduced amount of RBC membrane.
-By having a really small membrane, these cells lose their central pallor. These cells are
known as Spherocytes (do not confuse with the Schistocytes in Micro/Macroangiopathic
Hemolytic Anemias).
-The decrease in membrane volume (as per our prior Hb/MCV ratio) increases the MCHC.
-These cells are destroyed by the macrophages of the spleen. The increased destruction
leads to anemia (since RBC production cannot keep up with losses).
-Definitive treatment of this disease is splenectomy (why??).
Spherocytes In Hereditary Spherocytosis
Paroxysmal Nocturnal Hemoglobinuria

-Is an intravascular cause of hemolytic anemia secondary to a mutation in the PIGA gene.
-PIGA is responsible for the synthesis of GPI anchors on the surface of cells.
-A few important proteins like CD55 and CD59 (Decay Accelerating Factors) of the Complement Cascade
require these anchors. These proteins prevent cellular breakdown of our own cells by our complement system.
-A deficiency of these GPI anchors results in complement mediated damage of RBCs (especially at night).
-When we sleep, we hypoventilate. When you hypoventilate, your blood pH drops. When your blood pH drops,
the affinity of complement for RBC membranes increases significantly. The normal CD55/59 protective effect is
abolished in PNH and hence RBC membrane hemolysis occurs at night with hemoglobinuria in the morning.
This is the origin of the Paroxysmal Nocturnal term.
-These individuals have an increased risk of thrombosis.
-The DOC in the treatment of PNH is Eculizumab, which is a monoclonal antibody that targets the C5 protein.
This prevents the formation of the Membrane Attack Complex.
G6PD Deficiency (X Linked Recessive)

-Strongly consider this disease with any mention of Africans/Mediterraneans on your exam.
-G6PD is the Rate Limiting Enzyme in the Oxidative phase of the PPP. A deficiency of this enzyme results in a
decreased production of NADPH. NADPH is required to keep glutathione in the reduced state. Reduced
Glutathione is used to convert Peroxides to water.
-Oxidative stress causes hemoglobin coagulation within RBCs. Coagulated hemoglobin forms Heinz Bodies
which are visualized with special stains.
-These Heinz bodies are removed by Splenic Macrophages which literally take a bite out of the affected RBCs.
These cells are known as bite cells (very imaginative name). In some situations, these cells are completely
destroyed by these macrophages (extravascular hemolysis).
-Cells that are subject to oxidative stress can also spontaneously hemolyze in the bloodstream (intravascular
hemolysis).
-Oxidative stress triggers include Fava Beans and drugs like Isoniazid for TB, Primaquine for Malaria, or
Dapsone (which can be used for PCP prophylaxis/treatment of leprosy).
Glutathione Metabolism/Heinz Bodies/Bite or Helmet Cells
Autoimmune Hemolytic Anemias (AIHA)

-Are a group of antibody related hemolytic anemias.
-These antibodies could be IgG or IgM.
-IgG antibodies bind to RBCs. When these RBCs hit the spleen, macrophages use their Fc-Gamma
receptors to bind the IgG found on these RBCs. These opsonized RBCs are then destroyed by the
macrophages (extravascular hemolysis). This is a type 2 hypersensitivity reaction (LY now, HY later).
These IgG antibodies are known as warm agglutinins b/c they can agglutinate RBCs at body
temperature.
-IgM antibodies can bind to RBCs. Remember from Immuno that IgM cannot opsonize anything.
However, IgM is an excellent activator of the complement cascade (being a pentamer). The binding of
IgM to RBCs can trigger complement mediated hemolysis of RBCs (intravascular hemolysis). This is
also a Type 2 HSR. These IgM antibodies are known as cold agglutinins b/c they can agglutinate RBCs
at cold temperatures.
-The test of choice in the detection of AIHA are the Coombs Tests.
The Coombs Test (this is HY!)

There are 2 kinds of Coombs Tests (Direct and Indirect).
-The Direct Coombs test is used to test for the presence of IgG
or complement bound to RBCs.
-The Indirect Coombs test is used to test for the presence of
reactive antibodies in the serum (not on the RBC, this is a very
important distinction) of an individual. This is the primary test
used in blood typing.
Direct Coombs (Left)/Indirect Coombs (Right)
Heme Synthesis and Associated Disorders
Key Takeaways from Heme Metabolism

-ALA Synthase (ALAS) is the rate limiting enzyme of this pathway and is inhibited by the end product
(Heme-feedback inhibition) and glucose. There are 2 isoforms of ALAS. ALAS 1 is expressed in the liver
(but is turned on and off). ALAS 2 is expressed in the bone marrow and is ALWAYS ON.
-Early defects in the pathway are associated mostly with neurological problems. Skin problems are rare
(Acute Intermittent Porphyria-AIP). These individuals also tend to have abdominal pain and wine
colored urine.
-Later defects in the pathway are associated mostly with blistering skin problems upon exposure to
sunlight (Porphyria Cutanea Tarda).
-Clinical Correlate-the inhibition of ALA Synthase by Heme and Glucose is exploited in the treatment
of AIP and PCT.
-Inducers of Cytochrome P450 tend to increase flux through the Heme Synthesis pathway and aggravate
many of these problems (for the future-know the inhibitors/inducers of CYP P450 like you know your
name).
Q15-Matching Game
Match these lab measurements to the most likely pathology.
Pathologies
A-Heparin/Warfarin administration.
B-Aspirin/NSAID administration.
C-Disseminated Intravascular Coagulation
D-Hemophilia A
E-Von Willebrand Disease
F-Thrombocytopenia
Lab Measures
Q15 Key
Heparin/Warfarin administration is E.
Aspirin/NSAID administration is B.
DIC is D.
Hemophilia A is C.
VWD is E.
Thrombocytopenia is A.
Triggers
Homocysteinemia/Methylmalonic acidemia
Hemolytic Uremic Syndrome
Anemia in the setting of an elevated creatinine
Hematuria after consuming Fava Beans
Elevated bleeding time only, platelet adhesion defect
Elevated bleeding time + increased PTT, platelet adhesion defect
Single factor deficiency with elevated PT only
Bronze skin, diabetes, cirrhosis, elevated Ferritin
Receptor defect, increased bleeding time, normal Ristocetin assay
Microcytic Anemia with Basophilic Stippling
Fever,Anemia,Thrombocytopenia,Renal Failure,Neuro deficits
Increases synthesis of HbF
Characteristic Blood Smear finding in Megaloblastic Anemia
Potent platelet aggregator and vasoconstrictor
Hematuria in the setting of increased RBC osmotic fragility
Rescue agent in Heparin toxicity
Rescue agent in Warfarin Toxicity
Best test for VWD/Bernard Soulier Syndrome
Best Screening Test for Fe deficiency Anemia/Anemia of Chronic Disease
Trigger Key
Homocysteinemia/Methylmalonic acidemia-B12 deficiency
Hemolytic Uremic Syndrome-E. Coli O157:H7
Anemia in the setting of an elevated creatinine-Kidney Failure
Hematuria after consuming Fava Beans-G6PD deficiency
Elevated bleeding time only, platelet adhesion defect-Bernard Soulier Disease
Elevated bleeding time + increased PTT, platelet adhesion defect-VWD
Single factor deficiency with elevated PT only-Factor 7 deficiency
Bronze skin, diabetes, cirrhosis, elevated Ferritin-Hemochromatosis
Receptor defect, increased bleeding time, normal Ristocetin assay-Glanzmann Dz.
Microcytic Anemia with Basophilic Stippling-Lead Poisoning.
Fever,Anemia,Thrombocytopenia,Renal Failure,Neuro deficits-TTP
Increases synthesis of HbF-Hydroxyurea
Characteristic Blood Smear finding in Megaloblastic Anemia-Hypersegmented PMNs.
Potent platelet aggregator and vasoconstrictor-TXA2
Hematuria in the setting of increased RBC osmotic fragility-Hereditary Spherocytosis
Rescue agent in Heparin toxicity-Protamine Sulfate
Rescue agent in Warfarin Toxicity-Vitamin K (long term), Fresh Frozen Plasma (short term)
Best test for VWD/Bernard Soulier Syndrome-Ristocetin Cofactor Assay.
Best Screening Test for Fe deficiency Anemia/Anemia of Chronic Disease-Ferritin levels
For The Sake of Time

-Review Aplastic Anemias and the Transfusion Lecture (for the transfusion lecture, be
sure to know how much a given blood product would increase with the administration
of X units of something).
All The Best!
HY Immunology Review
Some MS2
General Advice
-The material in GTS is very important and is very heavily tested on exams youll meet
in the future (Step 1 to be precise).
-Your principal goal in GTS is to learn the material well. Down the line, youll realize
that nothing can replace a solid foundation.
-Immunology is best understood as a story. If you see how things all fit together, things
get a lot more intuitive. And immunology cuts across lots of fields in medicine.
-GTS exams focus heavily on clinical vignettes so understanding will take you a long
way in seeing the context behind the question so you can pick the right answer.
Overview of The Immune System

-Is the bodys defense against invasion.
-Is divided into 2 parts-Innate and Adaptive.
-Is a team effort amongst multiple players that interact as a cohesive whole.
-These interactions are mediated by cytokines (the messaging signals b/w cells).
-APCs include Macrophages, B cells, and Dendritic cells.
-Opsonizers (enhance phagocytosis) include antibodies and complement proteins.
A Comparison of The Innate/Adaptive Systems
Immune System Interactions
The Innate Immune System

There are 3 major branches to the innate immune
system;
a. Complement Proteins
b. Phagocytes
c. Natural Killer Cells
The Complement System

-Is a system of proteins that play a myriad of roles in the innate immune response.
-There are 3 systems that ultimately lead to complement activation-The Classic
Pathway (involving antibodies), the Alternative Pathway (that starts spontaneously),
and the Mannose Binding Lectin Pathway (that is more specific and targets bacteria).
-It may not be necessary to regurgitate all the individual steps of the complement
cascade but you should know how it works and accurately recall the functions of
complement proteins.
-The Immune System also has multiple mechanisms for turning off the complement
cascade so our own cells are not turned to mush.
An Example of Complement Activation-Alt. Pathway

-C3 is spontaneously cleaved to C3a and C3b.
-C3b binds to amino/hydroxyl groups on the surface of bacteria. With no binding, C3b is quickly inactivated by
binding to water.
-C3b is bound by factor B.
-Factor D comes along and cleaves the C3b-B complex to C3bBb which is also known as the C3 Convertase
(which can also cleave other C3 groups in a continuous chain reaction).
-C3 convertase can combine with another C3b and will ultimately form C3bBbC3b also known as the C5
Convertase.
-C5 convertase cleaves C5 to form C5a and C5b.
-C5b combines with C6-C9 to form the Membrane Attack Complex which bores holes in bacterial membranes.
C3 Spontaneous Cleavage
Formation of Alt. Pathway C3 Convertase
Chain Reaction by C3 Convertase
The Membrane Attack Complex
Turning Off This Dangerous System

-There are multiple proteins designed by the body to turn off complement.
-MCP (on our cells) activates enzymes that clip C3b to an inactive form. C3b can also be inactivated to
iC3b by Factor I (what is special about iC3b)?
-DAF (also on our cells) prevents the formation of the C3 convertases in all pathways (e.g. inhibits
Factor D association with C3b bound to B/inhibits association of C4b with C2 to prevent C2a
formation).
-CD59 (Protectin) on our cells prevents C9 incorporation into the MAC which halts its formation.
-Clinical Correlate-DAF and CD59 are anchored to membranes by GPI anchors. A deficiency in these
GPI anchors increases susceptibility to cellular degradation by complement (MAC) with the common
presentation of hemolytic anemia. A blockbuster drug, Eculizumab, prevents this by binding to C5 and
ultimately prevents MAC formation (costs $440k/year though).
-A deficiency of any of the MAC components predisposes an individual to infection with what kind of
organism?
The Lectin Pathway

-Mannose is a protein found predominantly on bacterial cells.
-Lectins are proteins that bind carbohydrates like Mannose.
-Mannose binding lectin (MBL) can bind to Mannose residues on bacterial surfaces.
-MBL can bind to a protein called MASP and together will form a Convertase that can
cleave C3. The cleaved C3 can then kick off the pathway described earlier.
-This is a more specific complement system as it is pre-built to only attach to a
PAMP (Mannose) that is generally not found on our cells.
Key Functions of The Complement System Proteins

a. C3a and C5a are anaphylatoxins-meaning that they can cause
degranulation of mast cells which can trigger a
hypersensitivity reaction.
b. C5a is a powerful chemoattractant for neutrophils and other
inflammatory cells.
c. C3b is an excellent opsonizer and participates in a modified
form of ADCC (Antibody Dependent Cellular Cytotoxicity)
which occurs upon conversion to iC3b.
Complement Protein Functions
Adaptive Immune System Development

-All starts in the bone marrow from a pluripotent stem cell.
-Could go down the myeloid/lymphoid pathway based on differing cytokine signals.
-T cells complete maturation in the thymus.
-B cells complete maturation in the bone marrow.
Immune System Development-contd.
Cells of The Immune System-Myeloid
Cells of The Immune System-Myeloid contd.
Cells of The Immune System-Lymphoid
Random, but may be HY

The Differential Diagnosis for Eosinophilia (DNAAACP)
-Drugs
-Neoplasms
-Asthma/Allergies
-Acute Interstitial Nephritis
-Adrenal Insufficiency (Addisons Disease)
-Collagen Vascular Disease
-Parasites
Lymphoid Cells
-Cannot be told apart on the basis of light microscopy (this is
simple, but HY!)
-Are told apart by virtue of CD markers.
-All T cells have CD3 with the more specific CD4 being for
helper T cells (the cell mediated bosses) and the more specific
CD8 being for the cytotoxic/cytolytic T cells.
Compare/Contrast-BCR vs TCR
The T Cell Receptor

-Is very high maintenance.
-Unlike the BCR, needs antigen to be delivered on a platter
(MHC) in a unique form (protein) that has been specially
processed by the presenting cell. This teleologically explains a
few key facts regarding the flexibility and valency of TCRs (what
are these things?).
The Secreted BCR-An Antibody/Immunoglobulin
The Immunoglobulin
-Has a variable region that determines the idiotype (antigen binding capacity).
-Has a constant region that determines isotype (generates job description). For
example, having an Alpha Isotype confers the ability to provide mucosal immunity.
-Is divalent (can bind 2 of the exact same antigen-there are exceptions like IgM!)
-Has a hinge region that confers flexibility and disulfide bonds b/w chains.
-The constant region is the C terminus of the protein and has a binding region for
complement.
-The hypervariable region (or FAB) makes up the N terminus of the protein.
TCR/BCR Signal Transduction Complexes
TCR/BCR Compare/Contrast (HY!!!)
A Little Conundrum
-There are literally millions of different bugs/antigens that run around in the
environment.
-These are all recognized by very specific BCRs and TCRs.
-If we had a gene for each of these, we would not have enough genes to go around for
all physiologic functions.
-In fact, we would need a lot more genes than we have now.
-We deal with this problem by doing some genetic tricks that involve recombinations...
Recombination Rules
-We deal with our little conundrum by using gene segment recombinations.
-These recombinations are undertaken by Recombinase genes encoded by RAG1/2.
-Heavy chain recombination occurs first (DJ then VDJ).
-Light chain recombination occurs next (VJ).
-This process occurs in T and B cells.
-The process in heavy chains (BCR) is analogous to the beta chain in TCRs.
-The process in light chains (BCR) is analogous to the alpha chains in TCRs.
-There are 2 recombination chances for heavy chains (mom and dad chromosomes).
-There are 4 recombination chances for light chains (Kappa/Lambda, Mom/Dad each).
Heavy Chain (BCR)/Beta chain (TCR) Rearrangement
Light Chain (BCR)/Alpha chain (TCR) Rearrangement
A Few Quick Things

-The first constant region to be added is Mu which encodes IgM (simply comes
first in the genome).
-Delta comes next and hence encodes IgD. The mechanism underlying IgD
expression is alternative splicing (Mu plus some other subunit).
-Other constant chain regions are inaccessible until antigen is encountered (class
switching).
-Missense/Nonsense mutations in RAG1/2 genes lead to severe immunodeficiency
diseases like Omenn Syndrome and SCID.
Other Generators of Diversity

-TdT (Terminal Deoxynucleotidyl Transferase)-adds nucleotides randomly prior to religation of DJ and VDJ segments (prior to transcription of the gene). This is in essence
a mutating enzyme. This occurs on the heavy chain only for B cells and all chains for
T cells.
-Random combination of Heavy/Light chains.
-Allelic Exclusion-if recombination with moms heavy chain works well, dads heavy
chain gene is shut off-permanently.
-Somatic hypermutation-occurs after exposure to antigen. This occurs only in B cells.
Somatic Hypermutation-The Mechanism

-SH is the mechanism behind Affinity Maturation.
-The process is kickstarted by an Adenosine Induced Deaminase (AID).
-AID deaminates cytosine to form Uracil.
-The presence of Uracil in DNA triggers mismatch repair (is uracil normally found in
DNA????)
-Upon repair, error prone DNA Polymerases fill up the mismatched areas and
introduce mutations that are carried by that B cell line.
-Note that SH occurs solely in the hypervariable (also called Complementarity
Determining) region of the antibody.
Lymphoid Organs
-Could be primary (cells are born). These include the bone marrow/thymus.
-Could be secondary (matchmaking center for exposure to antigen). These include the
spleen for blood-borne antigens, lymph nodes for lymph/tissue borne antigens, and the
Mucosa Associated Lymphoid Tissue (MALT) for Gut tube associated antigens.
-All cells are born in the bone marrow (including T cells).
-T cells mature (and undergo selection) in the thymus.
-B cells are born and mature/undergo selection only in bone marrow.
Stages of B Cell Development
B cell development
-Pro B cells are mainly at work in VDJ/heavy chain recombination.
-The production of light chains is the marker for a transition to Pre-B cells.
-The expression of IgM on the surface of a B cell marks the transition to an
Immature B cell. If this IgM binds to self antigens, it undergoes apoptosis here.
-With no binding to self antigen, a survival signal allows further development into a
mature B cell.
-This all occurs in the bone marrow and is antigen independent (exogenous antigen).
-Anything after this is antigen dependent (again, exogenous antigen).
T Cell Development
T Cell Development
-Occurs primarily in the thymus.
-Involves Positive Selection (testing the ability to bind MHC) and negative selection
(testing for the ability to bind MHC too well). This occurs in the Thymic Cortex.
-Cells that bind MHC 1 go on to become CD8+ Cytotoxic T cells (CD # * MHC #
always equals 8).
-Cells that bind MHC 2 go on to become CD4+ Helper T cells.
-One main function of the cells of the thymus is to expose the T cells to self antigens
for education prior to entry into the periphery.
Thymic Selection Algorithm
Thymic Selection Algorithm-contd.

-If you dont get positively selected-you die.
-If you get positively selected, but dont get
negatively selected-you live.
-By definition, if you undergo negative selectionyoure dead.
MHC1
-Is expressed in all nucleated cells of the body (why?).
-Presents endogenous antigen that is unique to the cell (this is a very HY Point!).
-Is a derivative of the HLA-A,B,C gene pool.
-Is codominantly expressed (mom and dad).
-Is made of an Alpha chain and Beta-2 Microglobulin.
-Is very limited in the kind of antigen it can present (why?).
MHC1
MHC2
-Is expressed only by APCs (what are they?)
-Presents exogenous antigen to CD4+ Helper T cells.
-Is a derivative of the HLA-DP,DQ,DR gene pool.
-Is codominantly expressed (mom and dad).
-Is made of an Alpha and Beta chain (please! do not confuse with the Alpha/Beta chain
that also constitutes the TCR).
-Has more leeway in the kind of antigen it can present (why?)
MHC2
Secondary Lymphoid Organ-Lymph Node
Secondary Lymphoid Organ-Lymph Nodes

-Are one of the matchmaking services where B/T cells go to find antigens (much easier than having to
search through the dilute space of the blood). Lymph Nodes are for presentation of tissue borne
antigens.
-B cells are found in the cortex which contains germinal centers (for proliferating B cells).
-T cells are found in the Paracortex. B/T cells come to the lymph node through High Endothelial
Venules (HEVs) that are found in the region of the Paracortex.
-Lymphatic fluid from the lower body/left upper torso drains from the thoracic duct into the Left
Subclavian Vein. Lymph from the right upper torso drains into the right subclavian vein.
-Knowing where things are in lymphoid organs is HY for your exam!
-Clinical Correlate-Hyperplasia of what lymph node region would be observed in response to viral
infection? In a person with DiGeorge Syndrome, there would be poor development of what primary
lymphoid organ and what region of a lymph node?
Secondary Lymphoid Organ-Spleen
Secondary Lymphoid Organ-Spleen

-Is another matchmaking center for antigen presentation (primarily for blood derived
antigens).
-Is made of red and white pulp.
-The T cells live in the Periarterial Lymphatic Sheath (PALS) which surrounds the
Splenic Artery. Note the trend of T cells living in P structures (PALS in the spleen,
Paracortex in Lymph Nodes).
-The B cells live in the Marginal Zone which surrounds the PALS.
-The PALS and Marginal Zone for the most part constitute the white pulp.
Q1
A 19 yo. sexually active male was admitted to the hospital 2 weeks ago for an acute
onset presentation of fever, chills, and other flu like symptoms. Physical exam reveals
an enlarged mass in the left posterior abdominal wall that is tender to palpation in
addition to cervical/postauricular lymphadenopathy. A biopsy was obtained for
analysis (shown below). Flow cytometry of tissues derived from the region indicated
by the white arrow would show an increased expression of?
a.
b.
c.
d.
e.
CD15
CD56
CD19
CD3
CD2
Q1 Key
-The answer is CD3.
-The history and age range are very consistent with a presentation of Infectious Mononucleosis.
-Common signs and symptoms include massive splenomegaly and lymphadenopathy (the immune response to
infection by the Epstein Barr Virus-EBV which is the most common cause).
-The term mass in the left posterior abdominal wall should point you towards the spleen.
-The red arrow points to a splenic artery so the area right around it must be the PALS.
-This is the T cell region of the Spleen.
-CD3 is a marker for all T cells.
-When studying in GTS and for exams in general, try to think of case scenarios like this that integrate multiple
disciplines. It is one of the better ways to learn things.
When an Offender Strikes (Oops..)

-Your response to initial attack by a pathogen/antigen is acute inflammation mediated
primarily by neutrophils.
-PMNs and other inflammatory cells are attracted to the site of attack by chemotactic
factors like IL-8, LTB4, C5a, and fMET (first translated codon in bacteria).
-PMNs deal with the offender primarily by phagocytosis and the respiratory burst.
-Anaphylatoxins derived from the complement cascade (C3a/C5a) cause mast cell
degranulation in an IgE independent manner.
The Mechanism of Acute Inflammation
Acute Inflammation-Clinical Correlates

-Chronic Granulomatous Disease-caused by a deficiency of NADPH Oxidase. Theres
increased susceptibility to infection with Catalase +ve organisms (essentially both
sources of PMN Peroxide are knocked out).
-Leukocyte Adhesion Deficiency (LAD) arises from integrin deficiencies (CD18).
PMNs lack the ability to extravasate and hence theres increased susceptibility to
infection. Classic Q stem involving a child with delayed separation of the umbilical
cord (in addition to not forming pus). What should be true of the WBC count in these
individuals?
Chronic Granulomatous Disease Testing (NBT test)

-A positive test indicates the absence of CGD (dont mix it up!)
Opsonization
-Is a hugely important mechanism for enhancing the efficiency of phagocytosis. They
are somewhat akin to ubiquitin degradative signals that exist intracellularly.
-Is mediated by C3b and IgG (this is HY!!!!!)
-There are receptors for these 2 mediators on the surface of PMNs and Macrophages.
-This mechanism is analogous to, but not the same as Antibody Dependent Cellular
Cytotoxicity (ADCC).
-Clinical Correlate-S. Aureus has a protein (Protein A) that binds to the constant
region of IgG and short circuits this opsonization process.
Opsonization
T Cell Activation-Big Picture (e.g. Helper Cells)

-All T cells are born in the bone marrow.
-These Pre-T cells go to the thymus for maturity.
-Cells hitting the thymus express CD4. CD8, CD3, and a TCR.
-These cells undergo positive and negative selection in the thymus.
-They are then released as naive T cells.
-These naive T cells can become TH1 cells (IL-12) or TH2 cells (IL-4).
-These cells can be activated by binding to MHC2 and the associated co-stimulatory
molecule (B7 from APC binding to CD28 on TH cell OR CD40 from a B cell binding
to CD40L on TH cell for ultimate class switching).
Antigen Presentation-Loading on MHC1

-There are 2 kinds of antigen that can be presented-endogenous (which are presented
by MHC1 to CD8+ Cytotoxic T cells) and exogenous (which are presented on MHC2
to CD4+ Helper T cells).
-Prior to loading on MHC1, viral/intracellular antigens are degraded by proteasomes.
-Degraded antigen is then led into the ER by TAP proteins.
-The antigen is then loaded on MHC1 and exocytosed to the cell surface.
Loading on MHC1-The Mechanism
Loading on MHC2-Exogenous Antigen

-Exogenous antigen is taken up via phagocytosis and degraded in phagolysosomes.
-Unlike the MHC1 loading process, MHC2 is secreted in a vesicle through the ERGolgi system that eventually binds to the phagolysosome containing the degraded
antigen.
-Prior to fusion with the phagolysosome, MHC2 is bound to an invariant chain (which
blocks the peptide binding groove). This prevents the unwanted binding of an
endogenous antigen to MHC2.
-The low pH environment of the phagolysosome degrades the invariant chain which
then enables loading of the exogenous antigen to MHC2.
Loading on MHC2-The Mechanism
Antigen Presentation and Helper T Cell Activation

-The activation of a T cell to do T cell things depends on 2 signals.
-Signal 1 is the binding of MHC2 (APC) to CD4 (Helper T).
-Signal 2 is the binding of B7 (APC) to CD28 (Helper T).
-Theres a lower yield Signal 3 that involves binding to cell surface adhesion
molecules.
-With no Signal 2, T Cell anergy is induced.
-This is a mute point, but the primary purpose of this interaction is to convert a TH0
cell to another kind of TH cell (TH1, TH2, TH17, etc).
Antigen Presentation (Macrophage)/Helper T Cell

Activation
Subsets of Helper T Cells
Subsets of Helper T Cells
Helper T Cells-Key Facts

-Differentiation down the TH1 lineage is encouraged in states of intracellular
bacterial infection. IL-12 induces differentiation to TH1 cells. These cells in turn make
IFN-Y which activates macrophages and inhibits TH2 cells. IL-12 comes from the
Macrophage.
-Differentiation down the TH2 lineage is encouraged in states demanding a humoral
response (antibody production). IL-4 induces differentiation into TH2 cells. These
cells in turn produce IL-4 which stimulates class switching to IgE, IL-5 which
stimulates class switching to IgA, in addition to promoting Eosinophil differentiation
(memory tool-imagine yourself grading a MC test and reciting 4E,5A). These cells also
produce IL-10 which inhibit TH1 cell differentiation.
The Blood Borne System-Humoral Immunity

-Humoral Immunity is centered mostly around antibodies and has the aim of dealing with
extracellular microbes.
-Remember that the default antibodies produced by naive B cells are??
-To generate a more robust humoral response, antibody class switching must occur.
-Class switching begins first with an interaction between an Helper T cell and a B cell.
-There are 3 signals here. Signal 1 (MHC2 on B cell and TCR), Signal 2 (B7 on B cell and CD28
on T cell), and Signal 3 (CD40 on B cell and CD40L on the T cell).
-The CD40L-CD40 interaction is essential for class switching and generation of memory B cells.
A deficiency of this interaction results in Hyper IgM syndrome (class switching failure).
B cell/Helper T Cell Interaction
The 2 Kinds of Antigen

-The only kind of antigen that can be presented to a T Cell is a peptide antigen.
-T Cell (or Thymus) independent antigens are typically only polysaccharides and
hence cannot be presented to helper T cells. The only humoral response generated
here would be a ? mediated response (since there is no class switching).
-T Cell (or Thymus) dependent antigens are peptides that can be presented on MHC2
to Helper T cells (or MHC1 to Cytotoxic T cells).
-Remember, an antibodys idiotype determines its antigen binding specificity. An
antibodys isotype determines what the effect of an antibody will be.
A Few Quick Definitions

-AVIDITY is a measure of the # of antigen binding sites that are available on an
antibody. Of the 5 immunoglobulins, which has the highest avidity? Who has the
second highest avidity?
-AFFINITY is a measure of how strong an antigen binds to an individual variable
region on an antibody. In general, IgG has the highest affinity of any antibody.
-Of all the Immunoglobulins, IgG and IgM are the only ones that activate the classic
complement cascade (Mnemonic-GM makes classic cars).
Q2
A 15 yo. high school student is rushed to the hospital after consuming a Peanut Butter
and Jelly sandwich. There is diffuse swelling of his tongue with impending closure of
his airway. A bolus dose of epinephrine is administered to reverse his presenting
symptoms. The antibody that mediated his first reaction to this allergen is best
described as;
a)
b)
c)
d)
e)
One that crosses the placenta

One that causes mast cell degranulation upon crosslinking by antigen
One that is never secreted from the surface of a B cell
One that has the highest avidity for antigen
One that protects against mucosal infection
Q2 Key
-Regardless of presentation, the first antibody created in response to the immune
systems first encounter with an antigen is IgM.
-Please do not make the knee jerk mistake of picking the answer that corresponds to
IgE on your exam (many do). The overwhelming presentation given in the question is
that of an anaphylactic reaction which on subsequent exposure is IgE mediated.
-The best answer is D which corresponds to IgM (is secreted as a pentamer with 2
antigen binding sites each and hence has an avidity of 10).
Response to Acute Infection-IgM First!
IgM
IgM
-Is the first antibody created by the adaptive immune system in response to an
invasion.
-Is secreted as a pentamer and hence has an avidity of 10.
-Does not cross the placenta (is too big).
-Is the best at activating the Classic complement cascade.
-Cannot participate in opsonization and hence cannot take part in ADCC (Antibody
Dependent Cellular Cytotoxicity).
IgM Class Switching to IgG-TH2 mediated
Class Switching
After Class-Switching-Extra Diversity

-With class switching from IgM, antibodies with an increased affinity for the original
antigen are produced.
-This phenomenon is known as Affinity maturation (takes place in the Germinal
Center.
-The mechanism behind this phenomenon is Somatic Hypermutation.
-Somatic Hypermutation occurs when rapidly dividing B cells (in response to
infection) begin to make errors in replication (basically DNA Polymerase is going too
fast to properly check its work).
-This explains why IgG has a higher affinity than IgM (IgM cannot undergo affinity
maturation because it does not class switch).
IgG-Does Almost Everything

-If
you blank out on the exam, IgG will quite likely be the answer.
-IgG is the only Immunoglobulin that crosses the placenta, has

the highest affinity for antigen, participates in ADCC, activates
complement (in addition to what Immunoglobulin?) and is the
primary antibody that can work as an opsonin. Class switching
from IgM is induced by IL-4. These series of statements are HY!
IgG
IgA
-Is the primary antibody involved in mucosal protection.
-Is the primary antibody secreted into the Colostrum (breast milk). Dont confuse it
with the only antibody that crosses the placenta (which is?)
-Is secreted from MALT in response to antigen presentation by M cells.
-Is secreted as a dimer with something called the secretory component which protects
it from the brutal environment of the mucosa (against proteolysis/to be secreted).
-Class switching is triggered by IL-5 and TGF-Beta.
-Does IgA have the highest avidity of all Immunoglobulins?
IgA
IgA Secretion
Immunoglobulin Comparison-Memorize Cold!!
Cell Mediated Immunity

-Is mediated primarily by 3 cell types-Macrophages, CD8+ T cells, and the NK cells.
-The primary controller of the cell mediated response is the CD4+ TH1 cell.
-This is our immune systems primary means of dealing with intracellular pathogens
and transformed cells (cancer cells).
-CD4+ TH1 cells release IFN-Y which activates macrophages and CD8+ T cells and
inhibits the TH2 cellular response.
-Upon pairing and recognition between CD8 and MHC1, T cells employ 2 primary
methods of eliminating their targets.
Mechanism 1-The Perforin/Granzyme System
Mechanism 2-The Fas-L (from T cell)/Fas System
Natural Killer (NK) Cells

-Are derived from the same lineage as lymphocytes but are considered to be part of the
innate immune system. They are activated by IL-12 released by TH1 cells in addition to
IFN-Alpha and Beta.
-Are CD16 and CD56+ (very high yield).
-Are inhibited by the presence of MHC1 (they leave this to their CD8+ brothers).
-Kill by the Perforin-Granzyme system with the killing initiation beginning in 1 of 2
ways.
-One method is via the recognition of the absence of MHC1 and the other is via ADCC
(with IgG as the mediator).
With MHC1, NK Cells Dont Kill
Without MHC1, NK Cells Kill
With IgG binding to The FC-Gamma Receptor, NK Cells Kill
An important ADCC Exception

-IgG is the principal immune mediator of ADCC in
addition to what other complement protein?
-In the unique case of a parasitic infection, IgE can
actually bind to the parasite and then have its
constant region bound by Fc-Epsilon receptors.
Q3
2 months into your rotation, a lady brings her 2 week old child to the office for his
recommended vaccinations. The mom, who has been on HAART for the past 10 years
is worried that her child may have contracted the offending organism transplacentally
or during delivery. Serum studies are conducted to allay the patients fears. The
presence of which of the following is most consistent with ruling in vertical
transmission?
a.
b.
c.
d.
e.
Anti p24 surface IgG

Anti p24 surface IgA
Anti p24 surface IgM
Anti p24 surface IgE
Anti p24 surface IgD
Q3 Key
-The best answer is C.
-The presence of IgG is not sufficient to rule in vertical transmission because IgG to
the p24 antigen may have been transmitted across the placenta to the infant.
-The presence of IgM while not conclusive, should warrant further consideration.
Remember that IgM is the first antibody produced to any infection and given the
history of birth (2 weeks), it is highly unlikely that the adaptive immune response has
kicked in to enforce class switching to any other immunoglobulin.
Types of Immunity
Antibody Patterns in the Fetus/Newborn
Special Mention-Haemophilus Influenzae

-Was previously a cause of devastating Meningitis, Otitis Media, Pneumonia, and other
debilitating conditions in infants.
-One major virulence factor is the presence of a capsule.
-The capsule is made of polysaccharide which cannot be presented to T cells (the
capsule alone would only generate a B cell response).
-They are conjugated to protein molecules which make them more immunogenic,
aid in T cell presentation, and lead to the generation of a T cell response.
Haemophilus Influenzae Vaccine
Q4
A 3 year old infant presents with severe GI distress and sinusitis. His mother reports
that he has had these symptoms on a recurrent basis about 6 months after he was born.
Serum protein electrophoresis conducted on a sample obtained from the infant
showed a predominance of a structure with heavy chains and light chains joined
together in a pentameric arrangement. The infants condition is most likely due to
which of the following pathologic processes?
a.
b.
c.
d.
e.
Failure of T cell maturation.

Failure of a ligand interaction between CD4+ cells and CD19+ cells.
Failure of a ligand interaction between CD8+ cells and CD19+ cells.
Failure of B cell maturation.
A defect in a cellular adhesion molecule found on B cells.
Q4 Key
-The best answer to this question is B.
-Serum electrophoresis indicating high levels of a pentameric immunoglobulin should guide you
towards super high levels of IgM.
-The cluster of mucosal symptoms should guide you towards a deficiency of IgA.
-A buildup of IgM (which does not require class switching) and a deficiency of another (IgA or really
any other Immunoglobulin) should hopefully clue you in on defective class switching.
-A defect in CD40L mediated class switching (remember Signal 2?) is one of the common causes of a
disease known as Hyper IgM syndrome.
-You most likely do not need to know the disease name per se, but you should understand the process
behind the disease. Be sure to read your questions carefully (CD4+ vs CD8+).
Key Concept on Live Attenuated/Killed Vaccines

-A live, attenuated vaccine still has the ability to infect cells, so it can become an
endogenous antigen, be presented on MHC1, and then generate T cell immunity.
-On the other hand, killed vaccines (like the Salk Polio Vaccine) lack the ability to
infect cells, so they remain exogenous. Exogenous antigen is presented only by APCs
on MHC2 which can only bind to Helper T cells which provide cytokines for class
switching. This is why killed vaccines only generate humoral immunity.
-This is a mute point, but it is very important.
Thymus Dependent/Independent Antigens

-Peptides are the only molecule class that can be presented on MHC1/2.
-Hence, polysaccharides cannot be presented on MHC1/2.
-Peptide antigens can induce T cell immunity, but polysaccharide antigens cannot.
-The only antibody that can be made against a polysaccharide antigen is IgM (why?)
-Other antibodies besides IgM can be made against peptide antigens (why?)
Q5
A puzzled medical team decides to crowdsource the Med19 class (currently taking
Immunology) for help with figuring out a complex case. The patient, who is currently
9 months old and has lived in the hospital all his life has had to receive treatment for a
large variety of viral infections. A possible pathophysiological process underlying this
childs disorder could be;
a.
b.
c.
d.
e.
Failed interaction of CD40 and CD40L.

A deficiency of IgM.
A defect in the recognition of LPS on bacterial cells.
Failure of antigen transportation to the Endoplasmic Reticulum.
Consumption of spoiled canned goods.
Q5 Key
-T cells are the bodys main defense against intracellular infections (viral).
-CD8+ cells require presentation of antigen on MHC1.
-This presented antigen comes from the transport of proteasome degraded antigen to
the Endoplasmic Reticulum with the aid of TAP proteins.
-A TAP deficiency can predispose an individual to recurrent viral infections.
-Again, this question tries to draw on your ability to understand processes as against
being simply able to regurgitate information (which you should still be able to do
though!).
Q6
An 18 yo. college student with a history of recurrent bacterial infections is brought in
by one of your Immunology professors for a clinical correlation. He receives specific
instructions not to disclose his diagnosis until the end of the session. This patient has a
history of recurrent infections and has so far required a constant intake of antibiotics.
His infections typically do not involve the formation of pus. Which of the following is
most likely deficient in this patient?
a.
b.
c.
d.
e.
IL-1
IL-3
IL-7
IL-8
IL-12
Q6 Key
-An inability to form pus is consistent with a failed migratory acute inflammatory
response which could potentially be secondary to defects in Neutrophil chemotaxis to
a site of injury. This will ultimately lead to recurrent bacterial infections.
-IL-8 is the only chemotactic factor listed here (what are the others?)
-Even if you dont have a clue with regards to solving this problem, eliminate what is
obviously wrong. IL-1 mediates fever, IL-3 stimulates bone marrow hematopoiesis, IL-7
mediates lymphoid lineage differentiation, and IL-12 mediates TH0-TH1 cell
differentiation.
When Your Immune System Gets Too Touchy...

-This is known as Hypersensitivity (immune system gets too
sensitive to benign items)..
-It is very important to understand the major classes of
hypersensitivity reactions, major examples, and the underlying
mechanisms behind these reactions.
-There are 4 major classes of hypersensitivity reactions.
The 4 Major Hypersensitivities
The Mechanism of Type 1 HSRs
Types of Type 1 HSRs (Know only major ones!)
Type 2 HSRs
-Mediated by antibodies binding to cells.

-The binding of antibodies to fixed cells
(especially IgG and IgM) can lead to the
activation of complement and ultimate
cellular destruction.
Examples of Type 2 HSRs
Type 3 HSRs
-Involves the formation of soluble antigen-antibody complexes.
-These complexes deposit in tissues like the kidneys.
-The antibody part of the soluble complex then triggers the complement cascade and
ultimate cellular destruction.
-A very HY example of a Type 3 HSR is Post-Streptococcal Glomerulonephritis.
-Clinical Correlate-This is a very common cause of a cluster of symptoms known as the
Nephritic Syndrome in kids with the associated hypertension, hematuria, and
periorbital edema. Classically associated with subepithelial humps on EM.
Type 4 HSR
-If you see any of the following words on your
exam-delayed type hypersensitivity, TB skin test,
coin/metal allergy-stop thinking, look for the
answer that says Type 4 HSR and move on.
-Is mediated primarily by CD4+ TH1 cells and also
by macrophages to an extent.
The Mechanism of Type 4 HSR-e.g. Poison Ivy

Step 1-Skin comes in contact with Poison Ivy.
Step 2-Poison Ivy binds to some skin antigens.
Step 3-Macrophage gobbles the antigen and presents it on MHC2 to CD4+ TH1 cell.
Step 4-CD4+ TH1 cell releases (what cytokine?).
Step 5-Macrophage is activated and returns to site of inoculation.
Step 6-Kill everything in sight (i.e. phagocytosis, release of IL-1, IL-6, and TNF-Alpha).
Step 7-You notice a skin reaction.
Transplants-HY Terms
-An AUTOGRAFT involves the transplantation of self organs-for example in burn
injuries.
-An ISOGRAFT/SYNGENEIC graft is transplantation with the relationship b/w the
donor/recipient being identical twinship (generally no problems, but still some very
minor rejection).
-An ALLOGRAFT is a transplant from a member of the same specie, i.e. the
transplants we are all familiar with.
-A XENOGRAFT is a transplant from a member of another species-very common in
heart valve transplants from pigs, cows, etc.
Types of Transplant Rejection
Immunosuppressive Pharmacology-Key Players

-Cyclosporine binds to Cyclophilin and inhibits Calcineurin which plays a role in the
transcription of IL-2 (what does IL-2 do?).
-Tacrolimus (FK506) binds to FKBP and also inhibits Calcineurin.
-Sirolimus (Rapamycin) binds to FKBP12 and inhibits mTOR which is involved in T cell
signaling. Note that Cyclosporine/Tacrolimus inhibit IL-2 production, but Sirolimus essentially
makes T cells unresponsive to IL-2.
-Mycophenolate Mofetil inhibits IMP Dehydrogenase which is involved in the conversion of IMP
to GMP and hence halts purine synthesis.
-Daclizumab and Basiliximab are monoclonal antibodies against the IL-2 receptor (CD25).
-Rituximab is another powerful immunosuppressant that is a monoclonal antibody against CD20
(which is found on what cell type?).
Immunosuppressive Pharmacology-Key Players
Cytokine Storm..Sorry fellas..

What are the cytokines that match these descriptors?
-Activates Macrophages
-Acute Phase Cytokines
-Promotes B cell growth/differentiation
-Produced by TH1 cells
-Produced by TH2 cells
-Eosinophil growth and activation
-Made by TH1 cells/NK cells/Activates macrophages
-Inhibits Macrophages/TH1 cells
-Pyrogens secreted by macrophages
-Inhibits TH2 cells
-Mediates inflammation
-IgG/IgE synthesis
-IgA Synthesis
-Released by virus infected cells
-Growth/Differentiation of Bone Marrow Stem cells
-T cell proliferation/activation/differentiation
-Activates NK Cells
Cytokine Storm..Sorry fellas.. (Memorize, this is HY!)

What are the cytokines that match these descriptors?
-Activates Macrophages-IFN-Y
-Acute Phase Cytokines-IL-1, IL-6, TNF-Alpha
-Promotes B cell growth/differentiation-IL-4 and IL-5
-Produced by TH1 cells-IL-2 and IFN-Y
-Produced by TH2 cells-IL-2, IL-4, IL-5, IL-10
-Eosinophil growth and activation-IL-5
-Made by TH1 cells/NK cells/Activates macrophages-IFN-Y
-Inhibits Macrophages/TH1 cells-IL-10
-Pyrogens secreted by macrophages-IL-1, IL-6
-Inhibits TH2 cells-IFN-Y
-Mediates inflammation-IL-1, IL-6, TNF-Alpha
-IgG/IgE synthesis-IL-4
-IgA Synthesis-IL-5
-Released by virus infected cells-IFN-Alpha, IFN-Beta
-Growth/Differentiation of Bone Marrow Stem cells-IL-3 (also GM-CSF)
-T cell proliferation/activation/differentiation-IL-2
-Activates NK Cells-Interferon-Alpha/Beta, IL-12
For the sake of time..
-Review Transplant
Immunology some more.
-All the best Thursday!
Its All Gonna Be OK..
HY METABOLISM REVIEW
Some MS2
A Word About Enzymes
General Principles
-Glucagon leads to Phosphorylation through
Protein Kinase A
-Insulin leads to Dephosphorylation through
Protein Phosphatases
Quick Review-The CAMP pathway
OVERVIEW OF ENERGY METABOLISM
THE WELL-FED STATE
And Remember...
Glycogen Synthesis precedes Fatty Acid Synthesis
(short term vs. Long Term) especially in the Liver.
THE FASTING STATE
Energy Values of Foods

Carbs-4 kcal/g
Protein-4 Kcal/g
Fat-9 Kcal/g (very efficient, hence primary store)
ETOH-7 Kcal/g
Organ Energy Requirements In Different States
Glycolysis-Entry
Entry-Contd
GLUT 5 is used specifically by Fructose to

get into cells.
Clinical Correlate-K channel openers
(Minoxidil) and Hyperglycemia.
GLYCOLYSIS-All Other Steps
Glycolysis-Trapping (Avoid Bi-directionality)
Glycolysis-Regulation
One more time
The CORI Cycle
Glycolysis Take-Aways
-Substrate Level Phosphorylation
-Hexokinase, PFK-1, and Pyruvate Kinase are heavily regulated
-PFK-1 is the Rate Limiting Step
-Consumes 2 ATPs, Makes 4 ATPs, 2 net ATPs
-Makes 2 NADH
-LDH is important in conditions of hypoxia for NAD Regeneration
Clinical Correlates
-Pyruvate Kinase Deficiency-Hemolytic Anemia
-Myocardial Infarction (Hypoxia)-Coagulative Necrosis
-2,3 BPG (infants/mountain-climbers)
-Increased KM of Glucokinase-Maturity Onset Diabetes of The Young (MODY)
-Methemoglobin Reductase and O2 carriage by Hemoglobin
Galactose Metabolism
Diseases of Galactose Metabolism

-Galactokinase Deficiency-Hereditary Lack of Galactokinase (not
very severe-Hexokinase rescue). Sx include Cataracts (Aldose
Reductase)/Galactose in the urine. Also explains optic neuropathy
with Diabetes with Glucose/Sorbitol
-Galactosemia-Hereditary Lack of Galactose-1-Phosphate
Uridyltransferase (more severe-Phosphate trapping/Osmotic
damage). Failure to thrive, Jaundice, Hepatomegaly,hyperuricemia
FRUCTOSE METABOLISM
Diseases of Fructose/Lactose Metabolism

-Essential Fructosuria-Fructokinase Deficiency
(mostly benign, but no cataracts, why?)
-Fructose Intolerance-Aldolase B deficiency (more
severe, secondary to phosphate trapping)
-Lactose Intolerance-Deficiency of Lactase (Colonic
bacteria have a field day)
Fates of Pyruvate
Special Mention-Carboxylases
Carboxylases are ABC Enzymes
Require;
A-ATP
B-Biotin (Vitamin B7)
C-CO2
The Pyruvate Dehydrogenase Complex
Tender Loving Care For Nancy
PDH Cofactors/Associated Vitamin Names

-Thiamine Pyrophosphate (Vitamin B1-deficiency in
alcoholics/Dry Beri-Beri)
-Riboflavin (Vitamin B2)
-Niacin/Nicotinic Acid (Vitamin B3)
-Pantothenic Acid for CoA (Vitamin B5)
N/B-Lipoic Acid is inhibited by Arsenic (mechanism behind
Arsenic poisoning)
Regulation of Pyruvate Dehydrogenase
The TCA Cycle
TCA Cycle Regulation
TCA Takeaways
-Per Acetyl CoA (double for glucose)-2 CO2/3 NADH/1 FADH2/1 GTP (Substrate
Level Phosphorylation)
-Its a cycle, not a pathway for De-Novo glucose synthesis (sole duty is AcCoA
oxidation)
-Steps proximal to Succinyl-CoA cannot participate in gluconeogenesis (hence
Leucine/Lysine are strictly Ketogenic Amino Acids). Steps starting from Succinyl-CoA
are gluconeogenic (hence odd chain Fatty acids can make glucose-only exception)
-Isocitrate Dehydrogenase is the Rate Limiting Step
-Alpha Ketoglutarate Dehydrogenase requires Tender Loving Care For Nancy
TCA Takeaways-Contd.
-With enough energy, Citrate builds up and takes the FA Synthesis route (explains the
lag between Glycogenesis and Lipogenesis)
Oxidative Phosphorylation
Glycogenesis
-Storage form of Glucose (Osmotic Considerations)
-Contains Alpha-1,4 and Alpha-1,6 linkages (Rapid Release Considerations)
-Glycogen Synthase is employed in states of Physiologic Plenty-should be active
when dephosphorylated (Insulin) and vice-versa
Glycogenesis/Glycogenolysis
Branching/Debranching Enzyme
Regulation of Glycogen Synthesis/Breakdown
Glucagon Regulation of Glycogen Metabolism
Glucagon Regulation of Glycogen Metabolism-contd.
Glycogen Synthase-1 Enzyme,2 Lives
No Glucagon Receptors on Skeletal Muscle,Why?

-Skeletal muscle is selfish
-Not its job to supply blood glucose under low
glucose conditions
-Also explains why it lacks Glucose-6-Phosphatase
Glycogen Storage Diseases-LY Now/HY Later
GLUCONEOGENESIS
Regulation of Gluconeogenesis
Amino Acids Contribute to Gluconeogenesis
Gluconeogenesis-Note
-Gluconeogenesis occurring in the liver is not intended to provide glucose for the
liver-its for other tissues (brain)
-The energy required for Gluconeogenesis by the Liver comes from Beta Oxidation
Alcoholic Metabolism
Chronic Alcoholism-Physiological Findings

The Central Problem is High NADH
-Favours conversion of Pyruvate to Lactate (reducing the pyruvate pool for
gluconeogenesis-hypoglycemia/metabolic acidosis)
-Favours conversion of OAA to Malate (reducing the OAA pool for Gluconeogenesis)
-Favours conversion of DHAP to Glycerol-3-Phosphate (more substrate for FA
Synthesis, explains Fatty Liver commonly found in Chronic Alcoholics)
-NADH buildup inhibits TCA Cycle and upregulates Ketogenesis (Fruity Breath of
an Alcoholic)
Clinical Correlation-Methanol/Antifreeze Poisoning/Drinking Cessation
The Pathway of Pentose Phosphate (HMP Shunt)
The HMP Shunt-Contd.
NADPH is extremely important...

-Utilized extensively in Anabolic Reactions (like FA synthesis)
-Keeps Reactive Oxygen Species at bay by keeping Glutathione in the reduced state
-Very necessary in fighting infections in Neutrophils and other Leukocytes
-Plays a role in some Hemolytic Anemias
NADPH-contd.
NADPH-contd.
Clinical Correlates
-Chronic Granulomatous Disease (susceptibility to
infection with Catalase Positive Organisms)
-G6PDH deficiency is protective against Malaria
(Why?)
Nucleic Acid Metabolism-Note

-A nucleoside is a Nitrogen Base and the associated Ribose/Deoxyribose sugar
-The addition of a Phosphate to a Nucleoside makes it a Nucleotide
-Purines (A,G) have 2 rings/Pyrimidines have 1 ring (CUT)
-For Purine Synthesis, start with the sugar and add a base
-For Pyrimidine Synthesis, start with the base and add sugar
-Theres a salvage pathway for purines
-Folates are important for Nucleotide Synthesis
Pyrimidine Synthesis
The Regulation of Ribonucleotide Reductase
Purine Synthesis/Regulation
Salvage Those Purines!
Disorders of Purine Salvage

-Lesch Nyhan Syndrome is caused by a HGPRT enzyme
deficiency. Characterized by self-mutilation, failure to thrive,
intellectual disability, and gout (tx with Allopurinol)
-Adenosine Deaminase Deficiency (one of the more common
causes of Severe Combined Immunodeficiency-SCID)
Kinds of Fatty Acids
Other FAs
Fatty Acids-Note
-Palmitic Acid is the commonly regarded endpoint of FA Synthesis.
-Linoleic Acid and Linolenic Acid are essential FAs and must be made from the diet (we cannot add double
bonds past position 9)
-Linoleic Acid is the key precursor of Arachidonic Acid (acted on by COX/LOX which are targets of many
drugs)
-There are 2 naming systems for Fatty Acids (#Cs : # Double bonds AND the Omega System)
-In general, unsaturated FAs are liquids at room temperature and are safer
-Omega 3 FAs are Cardioprotective
Fatty Acids-Contd
-FA Synthesis occurs in the Cytosol
-Insulin promotes FA Synthesis so it should be obvious that the regulation involves
some sort of dephosphorylation.
Rapid Review-The Roles of Insulin (KNOW THIS!!!)

-Induces Glucokinase in Pancreatic Beta Cells/Liver
-Dephosphorylates and Activates PFK2 in Glycolysis
-Dephosphorylates and Activates Pyruvate Dehydrogenase indirectly
-Activates Acetyl CoA Carboxylase which is the RLS of FA Synthesis
-Induces genetic expression of FA Synthase
-Upregulates GLUT4 targeting to the membranes of Adipocytes/Skeletal Muscle
-Activates Glycogen Synthase by dephosphorylation
FA Synthesis
FA Synthesis-busy slide,focus on regulation
Regulation of Acetyl CoA Carboxylase
FA Synthesis/Regulation
-Acetyl CoA Carboxylase is an ABC Enzyme. It is upregulated by Citrate and
Dephosphorylation through Insulin and inhibited by its product, Palmitoyl CoA.
-Malonyl CoA inhibits Carnitine Acyltransferase 1 which prevents newly synthesized
FAs from re-entry into the mitochondria to prevent a futile cycle with concurrent
Beta Oxidation.
-FA Synthase is a multisubunit enzyme. It holds the growing FA chain with an
enzyme known as Acyl Carrier Protein (ACP) which requires Vitamin B5 (Pantothenic
Acid).
-The only Cs found in the Final Fatty Acid come from Acetyl CoA, not CO2!
Triglyceride Synthesis
Triglyceride Synthesis
-The only source of glycerol-3-phosphate in the Adipocyte is DHAP!
-The liver in addition to DHAP has Glycerol Kinase (recycling mechanism)
-VLDL is made in the liver and is transported in the blood aboard an APOB100
Lipoprotein
-Chylomicrons are made in the small intestine and are transported aboard APOB48.
Beta Oxidation
Regulation of Hormone-Sensitive Lipase
Beta-Oxidation (takes place in the Mitochondria!)

-HSL Lyses TGLs to FFAs and Glycerol. HSL is inactive when dephosphorylated
(hormone???)
-Glycerol goes to the liver to be reconverted to Glycerol-3-Phosphate by Glycerol
Kinase for Gluconeogenesis (through DHAP)
-The FFAs are carried in the serum with Albumin to the Liver.
-The FFAs are charged in the cytoplasm with Fatty Acyl-CoA synthetase.
-They enter the mitochondrion via the CAT1/2 system. CAT is the RL enzyme.
-Energy Yield-7 FADH2, 7 NADH, and 8 AcCoA
FA Synthesis vs. Beta Oxidation
The Odd One Out
Clinical Correlate/HY Factoid

-Deficiency of Vitamin B12 and Folate both cause megaloblastic
anemia.
-Differentiating between both causes could be done by observing
an increased amount of what in the serum?
-VOMIT-Suppliers of Succinyl CoA (Valine, Odd Chain FAs,
Methionine, Isoleucine, and Threonine)
Fatty Acid Overflow-Ketone body Synthesis

-Occurs in the fasted state under conditions of too-much Acetyl CoA from Beta
Oxidation. Takes place in the mitochondria.
-KBs are used as fuel by heart/skeletal muscle, RBCs, and brain (under extreme
starvation).
-Is a form of glucose-sparing metabolism for the brain/RBCs.
-Low Insulin-Increased HSL activity-explains Diabetic Ketoacidosis
-The 3 Ketone Bodies are Acetone, Acetoacetate, and Beta hydroxybutyrate (know!)
Ketone Body Synthesis-Metabolic Reasoning..

-In the fasting state, beta oxidation increases the available Acetyl CoA
-Acetyl CoA Inhibits PDH complex but Activates Pyruvate Carboxylase (upregulating
gluconeogenesis)
-After a period of time, the buildup of NADH from Beta Oxidation shifts the
equilibrium from OAA to Malate (essentially the C.Alcoholic situation).
-This will ultimately shunt Acetyl CoA towards Ketone Body synthesis (b/c the TCA
cycle is also inhibited by high NADH).
-FA Synthesis is inhibited b/c Glucagon is available (so whats going on with AcCoA
Carboxylase and HSL??)
Ketone Body Synthesis
An Aside...
Based on what we know about Alcoholic Biochemistry, which
of the following will be detected in greatest concentration in the
serum of a chronic alcohol user?
a. Acetoacetate
b. Beta Hydroxy Butyrate
Ketone Body Synthesis-Note!

-The liver can make Ketone Bodies, but cannot use them as a source of energy (lacks
Beta-Ketoacyl coA transferase-also known as Thiophorase).
-Ketone Body utilization requires a re-conversion from Beta Hydroxybutyrate to
Acetoacetate and then to Acetoacetyl CoA by Thiophorase which is further broken
down to Acetyl CoA for TCA purposes (note that KB utilization requires no energy
investment unlike Beta Oxidation-logical, dont waste ATP in starvation)
-Brain and other Ketone Body utilizing tissues possess this important enzyme
(Thiophorase).
-Thiophorase is also known as Succinyl CoA:Acetoacetate CoA Transferase (dont
memorize this!). Succinyl CoA is the CoA donor for AcetoAcetyl CoA formation.
Quick Quiz..
The fasting state is accompanied by an increase in activity of which of the following
enzymes?
a.
b.
c.
d.
e.
Cytoplasmic HMG CoA Synthase

Mitochondrial HMG CoA Reductase
Cytoplasmic HMG CoA Reductase
Cytoplasmic HMG CoA Lyase
Mitochondrial HMG CoA Synthase
Cholesterol Biosynthesis/Pathway Regulation
Lipoprotein Metabolism-introduction
-Lipoproteins are fat carriers in the blood.
-Some are exogenously derived (diet)-Chylomicrons
-Some are endogenously derived (from liver)-VLDL
-Lipoprotein Metabolism is very important in the
pathogenesis/treatment of Artherosclerotic/Hyperlipidemic
disorders.
Lipoprotein Metabolism
HDL/LDL Metabolism
Lipoprotein Summary
Lipid Lowering Therapy (LY Now/UHY Later)
The Sources of NH3 for The Urea Cycle
Quick Quiz..
Which of the following enzymes constitute the Rate Limiting
Step of the Urea Cycle?
a.
b.
c.
d.
Cytoplasmic Carbamoyl Phosphate Synthetase 1

Mitochondrial Carbamoyl Phosphate Synthetase 2
Mitochondrial Carbamoyl Phosphate Synthetase 1
Cytoplasmic Carbamoyl Phosphate Synthetase 2
The Urea Cycle
The Urea Cycle-Note

-Protein breakdown generates Amino Acids
-Amino Acid breakdown generates Ammonia
-Ammonia breaks down lipids (i.e. cell membranes, so it should not wander freely)
-The primary N carrier in the blood is Glutamine
-There are 2 sources of NH3 for the Urea Cycle (Glutamate DH and Direct Aspartate)
-First 3 Steps (Mitochondria), all others (Cytoplasm).
-MITOCHONDRIAL CPS1 is the Rate Limiting Step! (not cytoplasmic CPS2 for
Pyrimidine Biosynthesis)
Clinical Correlation-OTC Deficiency

-High Ammonia in the blood (hyperammonemia)
-High Levels of Orotic Acid (Why?)
-Potentially Gout (Why?)
-Presentation includes Encephalopathy, Renal Failure (secondary to a lack of ureadestroys osmotic gradient)
-Cure could be achieved with a liver transplant. Treat Sx of hyperammonemia with
lactulose (takes advantage of the other urea excretion mechanism).
Key Associations with Amino Acids/Vitamins
The Synthesis of Heme
RL Enzymes of Metabolism (Know this cold!)
Final Words..
-Thanks a lot for coming..

-All the best tomorrow.
-You got this!
HY Micro Pharmacology
Some MS2
Introduction
-For Micro Pharmacology, you should be able to know the major drug classes, the
drugs that fall into each class, the mechanism of action of each drug class, unique side
effects, and general ideas about the organisms covered by the drug.
-For a few organisms (Pseudomonas, atypical causes of Pneumonia, amongst others),
you should definitely focus on knowing the Drugs of Choice in such scenarios.
-Micro Pharm is important. If you learn it well now, and get the concepts down, youll
find it very useful in coming GTS blocks and on future exams.
Antibiotics Introduction
-The Minimum Inhibitory Concentration is the lowest concentration of drug needed to inhibit bacterial growth.
Is a bacteriostatic drug term.
-The Minimum Bactericidal Concentration is the lowest concentration of drug needed to kill 99.9% of bacteria.
Is a bactericidal drug term.
-Bacteriostatic Drugs are good for immunocompetent people. It slows the rate of bacterial growth which gives
the immune system time to kill the bug.
-Bactericidal Drugs are good for immunocompromised people. It kills off the bug completely (since their
immune systems are weak).
-Combination Therapy is typically given with Antibiotics to decrease resistance AND to achieve synergism (1+1
= 3).
Antibiotics Intro. contd.

-An example of Synergism is the addition of an Aminoglycoside with a Penicillin. The penicillin blows a hole in
the cell wall. This makes it easier for the aminoglycoside to get in (note that these are 2 bactericidal drugs).
-On the other hand, taking tetracycline and an aminoglycoside (bactericidal + bacteriostatic) is not prudent
because the tetracycline decreases the synthesis of the aminoglycosides target. This is Antagonism.
-Time Dependent Killing is bactericidal activity that exists as long as you stay above the Minimum Inhibitory
Concentration. This is why you give excess drug above the MIC so you dont have to dose frequently. This is
typical of beta lactams. It is called time dependent because the drugs have a strong affinity for the bacterium
and hang on for a long time, so you dont need more of these drugs. They are effective at low doses.
-Concentration Dependent killing (as concentration increases, killing increases).
-Know about the Post-Antibiotic Effect (All beta lactams-gram +ve, Carbapenems-gram +ve and -ve,
Aminoglycosides-gram +ve)

-Certain bugs like Mycoplasma lack a cell wall, so it makes no sense to choose a cell
wall inhibitor as the DOC on your exam as a treatment for Mycoplasma (what is the
DOC in this situation?)
-One key problem with many antibiotics are associated hypersensitivity reactions. This
should make sense because many of these antibiotics are from purified microbes (like
Fungi for example). They are foreign and hence susceptible to immune system attack.
-Watch out for drug interactions with many of these antibiotics (especially Rifampin
which revs up Cytochrome P450 and Antifungals like The Azoles which inhibit
Cytochrome P450).
Bactericidal vs. Bacteriostatic

-In general, a drug that disrupts the cell wall (which is necessary for
membrane integrity) or disrupts DNA Synthesis will be bactericidal.
-Most other antibacterials are bacteriostatic.
-The only bactericidal protein synthesis (ribosome) inhibitor that is
HY for your test are the Aminoglycosides (end in acin or ycin-note
that these are not unique to this drug class-GNATS-Gentamicin,
Neomycin, Amikacin, Tobramycin, Streptomycin).
Antibacterial Mechanisms of Action
Random but Important Point

Drugs that cover MRSA include;
-Vancomycin (is the DOC).
-Clindamycin (especially for MRSA skin infections).
-Ceftaroline (a 5th gen Cephalosporin).
-Tigecycline (a newer tetracycline).
-Linezolid (a 50S inhibitor, also covers VRE-Vancomycin Resistant Enterococcus).
Cell Wall Synthesis Inhibitors-Key Facts

-Work primarily by inhibiting transpeptidase which is necessary for the crosslinking of peptides that make up a
part of the bacterial cell wall.
-Penicillin is the poster child member of this drug class. It exhibits Bactericidal killing and has a Post Antibiotic
Effect against Gram Positives only.
-The Aminopenicillins cover more bugs (gram positive cocci/gram negative rods) than the pure Penicillins.
You should know that Amoxicillin is more orally bioavailable than Ampicillin.
-Penicillinase resistant penicillins include Methicillin, Nafcillin, and Dicloxacillin. These are resistant to beta
lactamases so they kill certain S. Aureus species. However, many S. Aureus species make an altered
transpeptidase/Penicillin Binding Protein so the Penicillin cannot even bind in the first place. This is the
mechanism of resistance. A HY Side Effect of these drugs is Interstitial Nephritis.
-Cephalosporins have the same MOA but key ones to know are Ceftriaxone which is the DOC in Neisseria
treatment (and is 3rd generation) and Cefepime which is 4th Generation and is the only Anti-Pseudomonal
Cephalosporin (for your test at least). Ceftaroline is a 5th gen Cephalosporin that covers MRSA. 2nd generation
Cephalosporins cover anaerobes.

-The Carbapenems are big guns (know Meropenem and Imipenem). Key fact here is
the PAE against gram positives and negatives.
-Aztreonam has the fewest SEs of many advanced cell wall inhibitors. It covers only
gram negatives (especially rods) and does not have Penicillin cross-reactivity
(hypersensitivity reactions).
-Vancomycin binds D-Ala D-Ala which prevents transpeptidase binding. It is the DOC
in MRSA infections. Know the mechanism of resistance (highlighted later) and the HY
SE (Red Man Syndrome). It is also Ototoxic. Vancomycin works against gram positives
only (Remember that it is the DOC in MRSA which is gram +ve and you wont forget
this fact).
-Know that Colistin acts as a detergent and is a last ditch drug.

-The cell wall inhibitors do not work very well with intracellular organisms because it
is hard for them to get into the cell (this is why protein synthesis inhibitors are used
instead).
Beta Lactamase Inhibitors

-Are typically added to beta lactam antibiotics to extend coverage to beta lactamase
producing organisms.
-The key ones to know are Clavulanic Acid (added to Amoxicillin in Augmentin which
is essentially the DOC in the treatment of Otitis Media), Sulbactam, and Tazobactam
(which is typically added to the Antipseudomonal Penicillin-Piperacillin).
-These drugs work by providing dummy beta lactam rings that can be broken down
by the beta lactamase enzyme, freeing up the actual antibiotic to do its job.
The Cell Wall Inhibitors-Representative Drugs/Coverage
Mechanism of Action/Resistance Summary
Summary of Adverse Effects
Protein Synthesis Inhibitors

-Can be divided into 30S and 50S inhibitors.
-The 30S inhibitors include the Aminoglycosides and Tetracycline (which is
bacteriostatic?)
-The 50S inhibitors include Clindamycin, Chloramphenicol, Macrolides, and Linezolid.
They are all bacteriostatic.
-The mnemonic here is buy AT 30 and CCEL at 50.
-The AT stands for the Aminoglycosides and Tetracycline.
-The CCELL stands for Chloramphenicol, Clindamycin, Erythromycin and other
Macrolides, and Linezolid.
Aminoglycosides
-Disrupt formation of the initiation complex and overall cause mRNA misreads.
-Include Gentamicin, Neomycin, Amikacin, Tobramycin, and Streptomycin (at the
very least, know the bolded ones).
-These drugs are nephrotoxic and ototoxic (CN8 lesions). They should not be given
with loop diuretics.
-They exhibit Concentration Dependent killing (like the Fluoroquinolones) and for
the most part cover only aerobic gram negative rods (they are not effective against
anaerobes). They also exhibit a PAE against Gram +ves.
-They exhibit synergism with beta lactams which create a pathway for cellular entry.
Tetracyclines
-Prevent the binding of the incoming Aminoacyl tRNA to the A site of the 30S subunit.
-Include Doxycycline and the newer drug with much less resistance-Tigecycline
(covers MRSA).
-Are the DOC for the treatment of Lyme Disease/Chlamydia/Rocky Mountain Spotted
Fever.
-These drugs SHOULD NOT be taken with Antacids (or things containing) divalent
ions to avoid drug chelation. This explains the HY side effect of tooth discoloration
with the tetracyclines.
-The key mechanism of resistance is increased efflux of the drug from cells.
Chloramphenicol
-Chloramphenicol inhibits Peptidyl transferase.
-Chloramphenicol has the HY side effect of Gray Baby Syndrome which is due to the
physiologic deficiency of UDP Glucuronosyl Transferase in infants which hampers
their ability to conjugate the drug and eliminate it. Theres also the risk of Aplastic
Anemia.
-Chloramphenicol is great for treating meningitis because it crosses the BBB fairly
easily.
-The mechanism of resistance is acetylation by an acetyltransferase encoded for by
plasmids.
Clindamycin
-Clindamycin inhibits peptide bond formation by binding to and inhibiting the 50S
subunit. Its MOA is essentially identical to that of a Macrolide.
-Clindamycin is commonly used to treat Anaerobic infections (like Bacteroides,
Fusobacterium, etc). A common exam buzzword is the coverage of Anaerobes above
the belt (contrast with Metronidazole which is for anaerobes below the
belt/diaphragm).
-One HY Side effect of Clindamycin is Pseudomembranous Colitis as it is particularly
effective at killing off all your gut flora.
Macrolides
-Block the translocation step of protein synthesis.
-Bacteria have a 50S (which has a 23S subunit) and a 30S subunit which forms a 70S
subunit.
-Macrolides bind to the 23S subunit and prevent movement between the A, P, and E sites.
-HY Macrolides include Erythromycin and Azithromycin.
-Macrolides are the DOC for Atypical Organisms like Mycoplasma, Chlamydophila, and
Legionella Pneumoniae. A tougher exam Q could be to decipher the DOC in the treatment
of Pneumonia secondary to infection with an intracellular organism (which these are).
However, note that Tetracyclines are also great drugs for treating intracellular organism
infections like Chlamydia (the UTI) or Rocky Mountain Spotted Fever.
-Reach for these drugs if a pt. has Penicillin allergies.
TMP-SMX
Trimethoprim-Sulfamethoxazole (TMP-SMX)
-Inhibit Folate Synthesis. TMP inhibits Dihydrofolate Reductase while
Sulfamethoxazole acts as a PABA analog that competitively inhibits Dihydropteroate
Synthase.
-Are typically given as a combination. Are individually bacteriostatic, but in
combination, are bactericidal.
-Are used for Pneumocystis Jirovecii prophylaxis in HIV patients when the CD4 count
dips below 200 (this is super HY!).
-They are also useful for UTIs.
-They may also cause a megaloblastic anemia as folate is needed for purine/pyrimidine
synthesis.
Fluoroquinolones (all but one end in floxacin)

-Inhibit Topoisomerase 2 (DNA Gyrase).
-Have the HY SE of tendon rupture/cartilage damage.
-Excellent coverage of gram -ve rods.
-Mechanism of resistance is a Chromosome (not Plasmid) mediated mutation in the
DNA Gyrase.
-Good for UTIs in patients with Sulfa Allergies.
-Early generations cover only gram -ves , later generations cover both +ves and -ves.
Metronidazole
-Forms toxic intermediates (mostly free radicals) that destroys the bacterium. Is the
DOC for the treatment of C. Difficile colitis. Another option is to try oral Vancomycin
(normally Vancomycin is given IV). Why do we give oral Vancomycin if it has zero
oral bioavailability?
-If you a get a question about someone that went camping, drank from a stream
because they were too thirsty, got home and had foul smelling diarrhea, what is the
offending organism? Metronidazole is the DOC in the treatment of this disorder.
-Metronidazole covers the Anaerobes below the belt.
-Metronidazole also covers Entamoeba Histolytica.
Polymyxins B & E (Colistin)

-Drugs have a long hydrophobic tail but in addition possess a cationic/basic head.
-By being cationic (positively charged), they bind to negative charges very well.
-Hence, these drugs are active against Gram negatives only.
-They act as cell membrane detergents and disrupt osmotic properties.
-Nasty side effects-cause Kidney necrosis and are neurotoxic.
Daptomycin
-Creates pores/channels in the cell membrane.
-By creating these pores, ions flow down their gradients which leads to cellular
depolarization (basically the membrane potential gets thrown out of whack).
-This drug is myotoxic so a potential test question could frame this in the context of
elevated Creatine Kinase.
-Daptomycin covers only Gram +ves.
-Pay attention to the phrases, covers only...These are HY.
TB Meds
-TB Prophylaxis is accomplished with the drug Isoniazid.
-The treatment combo for TB is RIPE (Rifampin, Isoniazid, Pyrazinamide, and Ethambutol).
-All these drugs are Hepatotoxic, except Ethambutol (causes visual problems).
-Rifampin inhibits DNA dependent RNA Polymerase (in other words, it inhibits RNA Synthesis).
Read your answer choices carefully on the exam regarding the MOA. They love to mix and match
the words with things like RNA Dependent DNA Polymerase.
-Remember that Rifampin also serves as prophylaxis for N. Meningitidis (for treatment, pick
Ceftriaxone though) and H. Influenzae Type B.
-Rifampin upregulates Cytochrome P450 and hence increases the metabolism of other drugs
(contrast with Rifabutin).
TB Meds contd.
-Rifampin can cause orange tears/sweat/urine which is generally harmless. If you see
this side effect on your exam, stop thinking and pick Rifampin (could also be framed
as a change in the color of contact lenses).
-Isoniazid works to decrease the synthesis of mycolic acid.
-It is activated by Catalase-Peroxidase (expressed by the KatG gene, this is super HY!).
-INH is neurotoxic (can be prevented by giving Vitamin B6). They love framing this in
the context of a person being treated for TB developing peripheral neuropathy and
then asking what could have been done to prevent this sequelae. INH is also
hepatotoxic.
-Theres a difference in INH metabolism based on your status as being a slow/fast
acetylator.
TB Meds contd.
-Clinical Correlate/Biochemistry tie in (NOT on your test). INH inhibits the enzyme
that converts Vitamin B6 to its active form. Vitamin B6 is required for the conversion
of Glutamate to GABA via Glutamate Decarboxylase. With decreased GABA (which is
an inhibitory neurotransmitter), seizures develop as a SE of INH (neurotoxicity).
-INH resistance is mediated primarily by KatG or InH A mutations.
-Pyrazinamide inhibits the synthesis of the unusual fatty acids in the mycobacterial cell
wall. It is highly effective in low pH environments. A HY SE is gout (hyperuricemia).
-Pyrazinamide requires activation by the TB bug itself (Pyrazinamidase which is
encoded by the pncA gene).
-Knowing these TB drug genes is HY for your test.
Antifungals-in 1 slide
HIV
HIV Pharmacology
Other Antivirals-Acyclovir (Inhibits DNA Polymerase)

-Works just like an NRTI.
-Is phosphorylated by a viral encoded thymidine kinase which converts acyclovir from a prodrug to an active
drug. Since this kinase is encoded specifically by viruses, Acyclovir does not cause bone marrow suppression.
-Acyclovir is a nucleoside analog that lacks a 3 OH group so incorporation results in chain termination.
-A HY SE of Acyclovir is Nephrotoxic. Acyclovir forms crystals in renal tubules. This can be prevented with
appropriate hydration.
-Acyclovir is the DOC in the treatment of Herpes and VZV infection.
-A characteristic of Herpesviruses is their ability to lie dormant in neurons. During this phase, they do not make
any sort of real use of their DNA Polymerases which are inhibited by Acyclovir. During this phase, Acyclovir
really cannot do anything to the bug since there is nothing to target. This is why Herpes infections are not
completely cleared by these drugs.
-The HY Mechanism of Resistance is a mutation in the viral thymidine kinase.
Other Antivirals-Ganciclovir/Foscarnet
-Ganciclovir is the DOC in the treatment of CMV infections.
-Ganciclovir works exactly like Acyclovir. The only key difference is in the method of
activation which is via a CMV encoded kinase (this is why Acyclovir is not effective in
CMV).
-The primary resistance mechanism with Ganciclovir is a mutation in the viral
encoded UL97 Kinase.
-Foscarnet is somewhat analogous to Nevirapine. It is a pyrophosphate analog that
inhibits DNA Polymerase in a noncompetitive fashion and is the DOC in Acyclovir
resistant Herpes/VZV infections.
Anti-Influenza Antivirals
-Oseltamivir and Zanamivir inhibit Neuraminidase which is required for Influenza
exit from an infected cell.
-Amantadine inhibits viral uncoating but is no longer used due to massive resistance.
Amantadine increases the release of Dopamine from neurons and is now used to treat
Parkinsons Disease.
HY Microbiology Review
Some MS2
Objectives/Suggested Study Strategy

-If youre pressed for time, at the very least, go through the clinical trigger list, the
pneumonia list, the diarrhea list, the STD descriptor list, and the rashes list.
-There is some redundancy built into the slides. These were done on purpose to
reinforce high yield concepts.
-The major goal of this slide set is to highlight how the bugs are often tested on exams.
-If I were in a similar position as yourselves, Id set a modest goal of going through 30
slides for a given of the day starting Sunday morning. That way, youd have time to
go through the slides 2x and also have ample time to look at other course material.
-The 2 highest yield course materials you should evaluate are all the review lectures
and Dr. Ghanems Review Questions.
Some General Thoughts-on Micro..

-Micro is extremely HY for GTS and the boards. Learn it well now!
-Micro is the gift that keeps on giving, and on the flip side could be the thief that keeps
on hunting if you dont learn it well. Again, Micro is HY! (for emphasis..)
-Micro unfortunately relies extensively on memorization.
-You dont necessarily need to memorize every single piece of information on every
bug, but you need to memorize key associations for the different bugs youve been
exposed to. Knowing these associations will take you very far in terms of doing well on
the exam/future exams/on the wards.
-Micro Pharm is also very important. It is extensively tested and also extensively used
in clinic. This knowledge will come in handy whenever youre in the hospital (even for
the surgically minded).
Some General Thoughts-On These Slides..

-Memorize the key buzzwords/associations for the different bugs.
-Pay particular attention to slides that have important information clusters that deal
with different presentations of the same disease process but with different bugs.
-Be sure to pay attention to treatments for specific bugs when highlighted. You dont
necessarily need to memorize everything, but some are particularly high yield (like the
Pseudomonas medications).
-These slides would be both organized/disorganized at the same time to get you into
being able to quickly make connections (there is actually no really good way to
organize Micro).
Q1
2 days after paying a visit to the dentist, Mr. X begins to experience mild facial pain. 10
days later, he presents to the ER with a moderately expanded right jaw. Physical
examination reveals an abscess with draining pus of a yellow consistency. Which of the
following best describes the organism responsible for this mans symptoms?
a.
b.
c.
d.
e.
A gram positive obligate aerobe diplococcus.

A gram negative obligate anaerobe coccus.
A gram positive filamentous rod lacking catalase and superoxide dismutase.
A filamentous, gram positive obligate aerobe.
A gram positive coccobacillus.
Q1 Key
-The right answer to this question is C (Actinomyces Israelii).
-This is a gram positive filamentous rod associated with facial infections that drain as
Sulfur granules. A. Israelii is a gram positive obligate anaerobe. Anaerobes by
definition, lack catalase and superoxide dismutase.
-Key Buzzwords for this bug-Sulfur granules, draining abscess that looks like gold,
cervicofacial infection, cutting across tissue planes.
Q2
A Med19 student presents to the Charm City clinic with a fever of 103 degrees, facial
palsy, headache, and malaise. A circular, maculopapular rash was identified on his
shoulder. Which of the following routes best describes the method of infection
acquisition in this unfortunate Med19 student?
a.
b.
c.
d.
e.
Consumption of contaminated food

Arthropod vector
Sexual contact
In Utero Transmission
Respiratory secretions
Q2 Key
-The best answer to this question is B (Arthropod Vector-the Ixodes tick which carries the causative Borrelia
Burgdorferi organism).
-The infection in question is Lyme disease.
-The typical presentation is that of a maculopapular rash with central clearing with an associated
fever/migratory joint arthritis.
-Lyme disease is very HY and occurs in stages with Stage 1 having the presentation of the rash, Stage 2
involving cardiac and facial problems, and Stage 3 involving CNS problems. Treatment is with Doxycycline
(what is the MOA?)
-Key Buzzwords-Erythema Chronicum Migrans (maculopapular rash with central clearing), travel/hiking
history encompassing the Boston, Connecticut, New Hampshire area (Northeastern US), facial paralysis (Bells
Palsy), Ixodes tick, Borrelia Burgdorferi, migratory arthritis.
-Dont confuse the Erythema Migrans of Lyme Disease with the Erythema Marginatum of Group A Strep!
The Stages of Lyme Disease
Erythema Chronicum Migrans-Lyme Disease
Q3
A 4 year old child of an Eastern European immigrant family is brought to the Med19 free clinic.
The child is afebrile, but weak and exhausted from a week of relentless coughing with inspiratory
whoops that puts him out of breath. A blood sample drawn for analysis indicates a WBC of 75,000
with a predominance of lymphocytes. The symptoms present in this child would most likely have
been prevented by which of the following interventions?
a.
b.
c.
d.
Administration of an acellular vaccine as a component of a triple vaccine regimen.

Oral admission of a 30S ribosome inhibitor 2 days after delivery.
Administration of a live attenuated vaccine on a yearly basis during the winter months.
Administration of a monoclonal antibody that protects against viral infections.
Q3 Key
-The best answer is A (the DTaP vaccine).
-The causative organism here is Bordetella Pertussis which is associated with
whooping cough.
-There are 3 stages of infection-a catarrhal stage with mild flu like symptoms, a
paroxysmal stage with the whooping cough, and then a convalescent phase with a
milder cough (leading to ultimate recovery). Transmission is via respiratory droplets.
-Key Buzzwords-History of Immigration, whooping cough, history of cough for many
months. Note that the cough is associated with inspiratory whoops. Do not confuse
with the barking cough of Croup which is caused by the Parainfluenza virus.
Gram +ves vs. Gram -ves
Gram +ve Algorithm-Memorize!
Gram -ve Algorithm-Memorize!
Gram Negative Sepsis-Lipid A
Capsules/Virulence (Prevent Phagocytosis)

-Mnemonic (Even Some Pretty Nasty Killers Have Shiny Bodies) AND Cryptococcus Neoformans.
-E.Coli
-Streptococcus Pneumoniae
-Pseudomonas Aeruginosa
-Neisseria Meningitidis
-Klebsiella Pneumoniae
-Haemophilus Influenzae Type B (not the Influenza virus)
-Salmonella Typhi
-Group B Strep
Detecting Encapsulated Organisms

-Encapsulated organisms are detected via The Quellung
Reaction.
-Anti-capsular serum is added to a dish containing the bugs in
question.
-Swelling is consistent with the presence of a capsule.
-Mnemonic-Quellung causes anti-capsular swellung.
Clinical Correlate-Encapsulated Organisms/Spleen

-The spleen is the primary organ tasked with clearing our system of encapsulated
organisms.
-The absence of a spleen predisposes an individual to recurrent infection with
encapsulated organisms.
-You may potentially have to recommend vaccinations to an individual without a
spleen on your exam, so know your encapsulated organisms.
-The most common cause of Osteomyelitis in patients without a spleen is Salmonella.
Q4
Supply the name of the organism that best meets the following descriptions.
-Gram positive cocci in pairs
-Gram positive cocci in clusters
-Gram negative cocci in pairs
N/B-The words in pairs are equivalent to the word diplococci.
Q4 Key
Supply the name of the organism that best meets the following descriptions.
-Gram positive cocci in pairs-Streptococcus Pneumoniae.
-Gram positive cocci in clusters-Staphylococcus Species.
-Gram negative cocci in pairs-Neisseria Species.
N/B-The words in pairs are equivalent to the word diplococci.
Q5
What is the bug that is best described by the following info cluster?
-Acute Endocarditis
-Most common cause of Osteomyelitis
-Toxic Shock Syndrome
-Scalded Skin Syndrome
-2 hr Gastroenteritis (after consuming potato salad/mayonnaise)
Q5 Key
What is the bug that is best described by the following information cluster?
-Acute Endocarditis
-Most common cause of Osteomyelitis
-Toxic Shock Syndrome
-Scalded Skin Syndrome
-2 hr Gastroenteritis (after consuming potato salad/mayonnaise)
-Staphylococcus Aureus (is catalase and coagulase positive).
Q6
-Blood culture contaminant
-Normal skin flora
-Prosthetic valve endocarditis
-UTIs in individuals with indwelling catheters
Q6 Key
-Blood culture contaminant
-Normal skin flora
-Prosthetic valve endocarditis
-UTIs in individuals with indwelling catheters
-Staphylococcus Epidermidis (catalase positive, coagulase negative, novobiocin
sensitive).
Q7
-UTI in a sexually active young woman
-2nd most common cause of UTIs
Added question-What is the most common organism implicated in the vast majority of
UTIs?
Q7 Key
-UTI in a sexually active young woman
-2nd most common cause of UTIs
Added question-What is the most common organism implicated in the vast majority of
UTIs? (Escherichia Coli)
-Staphylococcus Saprophyticus (catalase positive, coagulase negative, Novobiocin
resistant).
Q8
-Normal vaginal flora
-Causes Neonatal Meningitis/Sepsis/Pneumonia
-Beta Hemolytic
-Bacitracin Resistant
Q8 Key
-Normal vaginal flora
-Causes Neonatal Meningitis/Sepsis/Pneumonia
-Beta Hemolytic
-Bacitracin Resistant
-Streptococcus Agalactiae (or Group B Strep, Catalase negative)
Q9
-Most common cause of Meningitis, Otitis Media, Pneumonia, and Sinusitis
Q9 Key
What is the bug that is best described by the following info
cluster?
-Most common cause of Meningitis, Otitis Media, Pneumonia,
and Sinusitis
-Streptococcus Pneumoniae (Catalase Negative, Diplococcus,
Alpha Hemolytic, has a capsule, optochin sensitive)
Q10
-Pharyngitis, Impetigo, Erysipelas.
-Cellulitis, Necrotizing Fasciitis.
-Rheumatic Fever, Glomerulonephritis.
Q10 Key
-Pharyngitis, Impetigo, Erysipelas.
-Cellulitis, Necrotizing Fasciitis.
-Rheumatic Fever, Glomerulonephritis.
-Streptococcus Pyogenes (Group A Strep, Beta Hemolytic-A does not mean alpha!,
Bacitracin sensitive)
Q11
-Subacute Bacterial Endocarditis
-Recent Dental Procedure
Q11 Key
-Subacute Bacterial Endocarditis
-Recent Dental Procedure
-Streptococcus Viridans (Alpha hemolytic, optochin resistant, no capsule, Oral Flora).
Endocarditis
-Is an inflammation of the endothelium lining the valves of the heart.
-Endocarditis is very HY for your exam. The typical presentation is that of a new onset
murmur.
-Endocarditis can be classified as being acute or subacute (more to come shortly).
Acute vs. Subacute Endocarditis
Endocarditis Clinical Scenarios

What is the bug that best fits the following scenarios.
New Onset Murmur in an IVDU
Low grade fevers weeks after a dental procedure
Heart Murmur in an individual with a Prosthetic Valve
Murmur after a recent URI
Endocarditis Clinical Scenarios Key

What is the bug that best fits the following scenarios.
New Onset Murmur in an IVDU-S. Aureus
Low grade fevers weeks after a dental procedure-Strep Viridans
Heart Murmur in an individual with a Prosthetic Valve-Staph Epidermidis
Murmur after a recent URI-Strep Pyogenes (Rheumatic Fever)
-It is HY to know that S. Pyogenes Rheumatic Fever has a predilection for the left side
of the heart (mitral valves) while S. Aureus Endocarditis has a predilection for the
right side of the heart (since IV drugs are injected into veins which drain to the R. Side
of the heart).
-S.Pyogenes rheumatic fever can be prevented with appropriate treatment.
Glomerulonephritis associated with S. Pyogenes is however not necessarily prevented
by antibiotic administration.
Q12
-Painless black eschar
-Hemorrhagic Mediastinitis
-Spore forming
-Wool sorter/Postal worker
Q12 Key
-Painless black eschar
-Hemorrhagic Mediastinitis
-Spore forming
-Wool sorter/Postal worker
-Bacillus Anthracis (capsule made of glutamate-not polysaccharide, has edema factor
as a toxin which is an Adenylate Cyclase, gram positive bacillus).
Bacillus Anthracis (Memorize This Image!)
Q13
-Grayish pseudomembrane.
-Toxin encoded by beta prophage.
-Unimmunized child having a Bulls neck appearance on physical exam
Q13 Key
-Grayish pseudomembrane.
-Toxin encoded by beta prophage.
-Unimmunized child having a Bulls neck appearance on physical exam
-Corynebacterium Diphtheriae (encodes the Diphtheria toxin for which a vaccine is
available, causes Diphtheria, can cause CNS/Cardiac problems if left untreated, gram
positive bacillus)
Q14
-Spontaneous abortion
-Mom consumed unpasteurized milk/dairy products
-Mom consumed meats at a deli
-Tumbling motility, Intracellular organism
-Uses a projectile mechanism to avoid the immune system
Q14 Key
-Spontaneous abortion
-Mom consumed unpasteurized milk/dairy products
-Mom consumed meats at a deli
-Tumbling motility, Intracellular organism
-Uses a projectile mechanism to avoid the immune system
-Listeria Monocytogenes (gram positive bacillus). Treated with Ampicillin (HY!)
Q15
-Capsule
-Bilateral Adrenal Hemorrhage
-Nuchal rigidity
-Vaccine available
Q15 Key
-Capsule
-Bilateral Adrenal Hemorrhage (Waterhouse Friderichsen)
-Nuchal rigidity (Meningitis)
-Vaccine available
-Neisseria Meningitidis (gram -ve coccus, has a capsule, associated with skin purpura).
Causes of Meningitis by Age Group
Q16
-Ophthalmia Neonatorum
-Arthritis in a young individual.
Q16 Key
-Ophthalmia Neonatorum
-Arthritis in a young individual
-Neisseria Gonorrhoeae (gram -ve coccus, no capsule, no vaccine, associated with
Urethritis, Cervicitis, Pelvic Inflammatory Disease, arthritis in a sexually active young
person-this is super HY!)
Q17
-Bloody diarrhea
-Symmetric ascending paralysis
Q17 Key
-Bloody diarrhea
-Symmetric ascending paralysis (Guillain Barre Syndrome).
-Campylobacter Jejuni (gram -ve rod, associated with beef consumption, major cause
of bloody diarrhea in the US, grows at 42 degrees).
Q18
-Bloody diarrhea special
-Hemolytic Uremic Syndrome
-Travelers Diarrhea/Montezumas Revenge/Watery Diarrhea
-Lactose Fermenter
Q18 Key (commit to memory!)

-Bloody diarrhea special-E. Coli O157:H7
-Hemolytic Uremic Syndrome-E. Coli O157:H7
-Travelers Diarrhea/Montezumas Revenge/Watery Diarrhea-ETEC
-Lactose Fermenter
-E. Coli (many strains)
Diarrhea HY points
-Diarrhea typically could be classified as being secretory, osmotic, or bloody.
-Secretory diarrhea involves the active secretion of substances into the GI tract in many cases secondary to the
activation of Adenylate Cyclase which leads to chloride and water secretion into the GI Tract. This is
characteristic of V. Cholerae and Enterotoxigenic E. Coli.
-Osmotic Diarrhea is associated with the presence of osmotically active substances within the gut that draws
water and electrolytes into the lumen. Osmotic diarrheas are in many cases secondary to metabolic problems
(like lactose intolerance).
-Consider C. Difficile as the cause of diarrhea (secretory) in an exam scenario involving diarrhea after a course
of antibiotics (notably Clindamycin). Destruction of gut flora provides ample room for C. Difficile overgrowth.
-It is extremely HY to know that in many cases, diarrhea is self limited and for the most part just requires fluid
and electrolyte replacement. They love testing this!
Mechanism of V. Cholerae/ETEC Secretory Diarrhea
Diarrheal Clinical Scenarios

Match the following scenarios to the most likely offending organism.
Watery Diarrhea after returning from a trip
Watery Diarrhea with Rice Water Stools
Watery Diarrhea in a hiker/camper
Watery Diarrhea on a cruise ship
Watery Diarrhea in an infant
Watery Diarrhea in an AIDS patient
Bloody Diarrhea after consuming beef
Bloody diarrhea after consuming poultry/eggs
Bloody diarrhea in the setting of a Lactose Fermenter
Most common cause of bloody diarrhea in the US
Diarrhea and Ascending Paralysis
Diarrhea after treatment for an anaerobic infection
Diarrhea that feels like Appendicitis (after Pork Consumption)
Protozoal cause of bloody diarrhea
Bloody Diarrhea requiring a small inoculum
Bloody Diarrhea and Hemolytic Uremic Syndrome (kidney issues)
Diarrhea after consuming Oysters/Seafood
Diarrhea after consuming Oysters + Elevated Liver Function Tests
Diarrhea after swimming in freshwater
Diarrhea with massive amounts of fluid/electrolyte loss
Diarrhea after consuming reheated rice
Diarrhea 2 hours after consuming potato salad
Diarrhea 6-15 hours after consuming meat/poultry left out for long
Diarrheal Clinical Scenarios Key-Know this one...

Match the following scenarios to the most likely offending organism.
Watery Diarrhea after returning from a trip-Enterotoxigenic E. Coli
Watery Diarrhea with Rice Water Stools-Vibrio Cholerae
Watery Diarrhea in a hiker/camper-Giardia Lamblia
Watery Diarrhea on a cruise ship-Norovirus/Norwalk Virus.
Watery Diarrhea in an infant-Rotavirus
Watery Diarrhea in an AIDS patient-Cryptosporidium Parvum
Bloody Diarrhea after consuming beef-Shigella (maybe EHEC as well)
Bloody diarrhea after consuming poultry/eggs-Salmonella (Enteritidis)
Bloody diarrhea in the setting of a Lactose Fermenter-EHEC
Most common cause of bloody diarrhea in the US-Campylobacter Jejuni
Diarrhea and Ascending Paralysis-Campylobacter Jejuni (Guillain Barre Syndrome)
Diarrhea after treatment for an anaerobic infection-Clostridium Difficile
Diarrhea that feels like Appendicitis (after Pork Consumption)-Yersinia Enterocolitica
Protozoal cause of bloody diarrhea-Entamoeba Histolytica
Bloody Diarrhea requiring a small inoculum-Shigella
Bloody Diarrhea and Hemolytic Uremic Syndrome (kidney issues)-EHEC
Diarrhea after consuming Oysters/Seafood-Vibrio Parahaemolyticus
Diarrhea after consuming Oysters + Elevated Liver Function Tests-Vibrio Vulnificus
Diarrhea after swimming in freshwater-Aeromonas (theres also an Aquarium association)
Diarrhea with massive amounts of fluid/electrolyte loss-Vibrio Cholerae (most likely cause)
Diarrhea after consuming reheated rice-Bacillus Cereus
Diarrhea 2 hours after consuming potato salad-S. Aureus
Diarrhea 6-15 hours after consuming meat/poultry left out for long-Clostridium Perfringens (nonspecific, but they may say something about
an anaerobe causing diarrhea/an organism that forms spores).
Q19
-Typhoid Fever
-Bloody diarrhea
-Osteomyelitis in a sickle cell patient
Q19 Key
-Typhoid Fever-Salmonella Typhi (Rose Spots on the Abdomen)
-Bloody diarrhea
-Osteomyelitis in a sickle cell patient
-Salmonella Species
Q20
-Fecal Oral Transmission
-Only about 10 organisms required
-Really nasty bloody diarrhea preceded by watery diarrhea
-Toxin mediated Gastroenteritis
Q20 Key
-Fecal Oral Transmission
-Only about 10 organisms required
-Really nasty bloody diarrhea preceded by watery diarrhea
-Toxin mediated Gastroenteritis
-Shigella
Q21
-MALT Lymphoma
-Peptic Ulcer Disease
-Urease positive
-Gastric Cancer
-Triple Therapy
Q21 Key
-MALT Lymphoma
-Peptic Ulcer Disease
-Urease positive
-Gastric Cancer
-Triple Therapy (Clarithromycin, Amoxicillin, and a Proton Pump Inhibitor)
-Helicobacter Pylori
Q22
Supply the organisms that are associated with the following.
-Whooping Cough
-Undulant fevers
-Gram -ve cause of Otitis Media
-Pneumonia from air-conditioning/water source
-Pseudoappendicitis like diarrhea.
Q22 Key
Supply the organisms that are associated with the following.
-Whooping Cough-Bordetella Pertussis
-Undulant fevers-Brucella
-Gram -ve cause of Otitis Media-Haemophilus Influenzae
-Pneumonia from air-conditioning/water source-Legionella Pneumophila
-Pseudoappendicitis like diarrhea-Yersinia Enterocolitica
Q23
-Burn patients/Wet environments
-Pneumonia in Diabetic patients
-Otitis Externa
-Osteomyelitis in diabetics
-Hot Tub Folliculitis
-Blue green pigment
-Ticarcillin/Piperacillin treatment
Q23 Key-Commit to Memory!

-Burn patients/Wet environments
-Pneumonia in Diabetic patients
-Otitis Externa
-Osteomyelitis in diabetics
-Hot Tub Folliculitis
-Blue green pigment
-Ticarcillin/Piperacillin treatment
-Pseudomonas Aeruginosa (oxidase positive-super HY!)
Pneumonia
-Pneumonia is extremely high yield for your exam.
-Is associated with alveolar inflammation.
-Can be grouped as being typical with the patient feeling really ill and having a lobar infiltrate on CXR OR being
atypical with the patient having fairly mild symptoms and an interstitial infiltrate on CXR (CXR looks worse than the
patient).
-Theres also aspiration pneumonias that have very strong associations with obtunded states like Alcoholism,
Nasogastric Tubes, etc. Obtunded states suppress the cough reflex which is important for microbe clearance.
-Ventilators are associated with Pneumonia because the patients respiration effectively bypasses the mucosal
protection of the Upper RT and grants direct entry to the lungs.
-The Drug of Choice in the treatment of Pneumonias secondary to Anaerobic Infection is Clindamycin (the so-called
Anaerobes above the belt).
-Your key Pneumonia takeaways are the associations tested on the next slide. I would strongly recommend committing
these to memory.
Pneumonia Time
Pneumonia in an immunocompromised patient/HIV patient
Most common cause of walking pneumonia
Pneumonia in an alcoholic
Pneumonia in an alcoholic/obtunded state that is foul smelling
Interstitial pneumonia in a bird handler
Pneumonia in the setting of bats/bat dropping exposure/spelunking/KY-OH Travel Hx
Pneumonia in the setting of a visit to SoCal/NM/W.Texas
Pneumonia associated with Red Currant Jelly Sputum
Pneumonia associated with Rust colored sputum
Pneumonia transmitted via Air Conditioning
Pneumonia in an individual with Q Fever
Pneumonia associated with Cystic Fibrosis/Ventilator patients
Pneumonia associated with hyponatremia (low yield)
3 most common causes of atypical pneumonia
Pneumonia in a neonate with gram +ve coccus staining
Pneumonia in a neonate with gram -ve rod staining
Viral Pneumonia in a kid less than 1 yr old
Pneumonia in a wool sorter/associated with Hemorrhagic Mediastinitis
Most common cause of Pneumonia in a young adult
Most common cause of Pneumonia overall
Most common cause of viral pneumonia
Pneumonia with a lung abscess
Pneumonia in an IV Drug User
Pneumonia associated with Air-Fluid Levels on CXR
Pneumonia Time Key (Memorize!!!)

Pneumonia in an immunocompromised patient/HIV patient-Pneumocystis Jirovecii
Most common cause of walking pneumonia-Mycoplasma Pneumoniae
Pneumonia in an alcoholic-Klebsiella Pneumoniae
Pneumonia in an alcoholic/obtunded state that is foul smelling-Anaerobe
Interstitial pneumonia in a bird handler-Chlamydia Psittaci
Pneumonia in the setting of bats/bat dropping exposure/spelunking/KY-OH Travel Hx-Histoplasma Capsulatum
Pneumonia in the setting of a visit to SoCal/NM/W.Texas-Coccidioides Immitis
Pneumonia associated with Red Currant Jelly Sputum-Klebsiella Pneumoniae
Pneumonia associated with Rust colored sputum-Streptococcus Pneumoniae
Pneumonia transmitted via Air Conditioning-Legionella Pneumophila
Pneumonia in an individual with Q Fever-Coxiella Burnetii
Pneumonia associated with Cystic Fibrosis-Burkholderia Cepacia (P. Aeruginosa for diabetics/ventilator patients)
Pneumonia associated with hyponatremia (low yield)-Legionella Pneumophila (HY for future exams)
3 most common causes of atypical pneumonia-Mycoplasma/Chlamydia/Legionella Pneumophila
Pneumonia in a neonate with gram +ve coccus staining-Group B Strep (Streptococcus Agalactiae)
Pneumonia in a neonate with gram -ve rod staining-Escherichia Coli
Viral Pneumonia in a kid less than 1 yr old-Respiratory Syncytial Virus
Pneumonia in a wool sorter or Postal Worker/associated with Hemorrhagic Mediastinitis-Bacillus Anthracis
Most common cause of Pneumonia in a young adult-Mycoplasma Pneumoniae
Most common cause of Pneumonia overall-Streptococcus Pneumoniae
Most common cause of viral pneumonia-Respiratory Syncytial Virus
Pneumonia with a lung abscess-Anaerobe/Klebsiella Pneumoniae
Pneumonia in an IV Drug User-Staphylococcus Aureus
Pneumonia associated with Air-Fluid Levels on CXR-Anaerobe (Peptostreptococcus,Prevotella,Fusobacterium,Bacteroides)
Common Causes of Pneumonia by Age Group
Q24
What is the organism that best matches the following info cluster?
-Cellulitis secondary to an infection with an anaerobe
-Gas Gangrene
-Food poisoning
-Produces Alpha toxin
Q24 Key
-Cellulitis secondary to an infection with an anaerobe
-Gas Gangrene
-Food poisoning
-Produces Alpha toxin
-Clostridium Perfringens
Q25
-Causes Spastic Paralysis
-Prevents the release of GABA/Glycine from inhibitory neurons
-Vaccine Preventable
Q25 Key
-Causes Spastic Paralysis
-Prevents the release of GABA/Glycine from inhibitory neurons
-Clostridium Tetani (releases Tetanospasmin, classic association with being stung by a
sharp object).
Q26
-Toxin prevents release of Acetylcholine
-An adult that bought canned soup from a store
-A baby that consumed honey
Q26 Key
-Toxin prevents release of Acetylcholine
-An adult that bought canned soup from a store
-A baby that consumed honey
-Clostridium Botulinum (causes a FLACCID, not SPASTIC paralysis)
Q27
A 23 yo. female presents with abdominal pain and intense diarrhea that started 3 days
ago. Past medical history is unremarkable save for recent treatment for a respiratory
infection that was notable for copious bouts of foul smelling sputum. Empiric
treatment is started with subsequent resolution of her symptoms. The drug of choice
that resolved this womans symptoms is associated with which of the following side
effects?
a.
b.
c.
d.
e.
Aplastic Anemia
Hypersensitivity skin reactions
Sensorineural hearing loss
A metallic taste in the posterior tongue
Diffuse flushing over the entire skin upon IV infusion of the drug
Q27 Key
-The best answer to this question is D
-Her PMH is significant for a lung infection with an anaerobe (foul smelling sputum is
pathognomonic).
-The DOC for treating Anaerobic lung infection is Clindamycin.
-Clindamycin is associated with the HY SE of Pseudomembranous Colitis secondary to
C. Difficile overgrowth.
-The DOC for treating C. Difficile associated Pseudomembranous Colitis is
Metronidazole.
-A HY SE of Metronidazole is a metallic taste in the mouth.
Q28
What is the organism that best matches the following Info Cluster?
-Transmission via exposure to bodies of water containing animal urine.
-?????????? (this is a legit hint btw)
Q28 Key
What is the organism that best matches the following Info Cluster?
-Transmission via exposure to bodies of water containing animal urine.
-?????????? (this is a legit hint btw-think of the question mark as being interrogated)
-Leptospira Interrogans (causing Leptospirosis)
Q29
What is the organism that best matches the following Info cluster?
-No cell wall
-Susceptible to treatment with Erythromycin
-CXR shows diffuse interstitial infiltrates
-Patient has very mild symptoms
Q29 Key
-No cell wall (does not gram stain). Consider this bug if you get an exam question
about a person in their 20s-40s with low grade fevers and a mild headache.
-Susceptible to treatment with Erythromycin
-CXR shows diffuse interstitial infiltrates
-Patient has very mild symptoms
-Mycoplasma Pneumoniae
Pneumonia Generalities (not 100% though)

-In the Super Young (Neonates), consider Group B Strep (and Listeria).
-In the 2-10 range, consider Viruses.
-In the teenage range-early 40s (consider Mycoplasma).
-In the older population, seriously consider S. Pneumoniae.
-The overall most common cause of Pneumonia though is S. Pneumoniae.
Q30
-Conjunctivitis in Neonates
-Lymphogranuloma Venereum
-Blindness
-Urethritis and Pelvic Inflammatory Disease
-Could be treated with Doxycycline or a Macrolide
Q30 Key (you may want to memorize this slide)

-Conjunctivitis in Neonates (Serovars D-K)
-Lymphogranuloma Venereum (Serovars L1-L3)
-Blindness (Serovars A-C)
-Urethritis and Pelvic Inflammatory Disease (D-K Serovars)
-Could be treated with Doxycycline or a Macrolide
-Chlamydia Trachomatis
The Key Takeaways from Chlamydia

-Chlamydia is an obligate intracellular organism that causes UTIs (they require ATP
from the host).
-Chlamydia can be detected with the Giemsa stain (just like Rickettsia).
-Chlamydia causes Pelvic Inflammatory Disease (but you should also consider N.
Gonorrhoeae). A good exam question would be the test that could be administered to
distinguish the cause of a UTI. Remember that N. Gonorrhoeae is a gram negative
diplococcus. PID can lead to infertility (know this!).
-The primary means of transmission is via sexual contact OR vertical transmission
from mom to fetus.
-The DOC in the treatment of chlamydial infection is a tetracycline (like Doxycycline)
or a Macrolide like Azithromycin.
The Key Takeaways from Chlamydia

-People with Chlamydia are often treated empirically with Ceftriaxone to cover
potential N. Gonorrhoeae coinfection.
-Sexual partners of an individual with Chlamydia (at least within the last 60 days)
should be treated.
-Chlamydia gets into a cell as an elementary body, transforms into a reticulate body
(which divides within cells), reorganizes into an elementary body, and is then released
from a cell. It is HY to know that the elementary body is the infective form while the
reticulate body is the form that replicates within cells.
The Infection Cycle of Chlamydia
Chlamydia Serovars/Associated Chlamydial Diseases
Q31
What is the organism that best matches the following associations?
Diarrhea in an AIDS patient
Pneumonia in an AIDS patient
Meningitis in an AIDS patient
-Fever, Cough, and Night Sweats with cavitation in the upper lobe of the lung
-Rash starts on the palms and soles and migrates centrally
Q31 Key
What is the organism that best matches the following associations?
Diarrhea in an AIDS patient-Cryptosporidium
Pneumonia in an AIDS patient-Pneumocystis Jirovecii
Meningitis in an AIDS patient-Cryptococcus Neoformans
-Fever, Cough, and Night Sweats with cavitation in the upper lobe of the lungMycobacterium Tuberculosis
-Rash starts on the palms and soles and migrates centrally-Rocky Mountain Spotted
Fever (caused by Rickettsia Rickettsii)
HY Rashes to be aware of.

-Rash on the palms, soles, and trunk after a painless chancre is classic for Secondary Syphilis.
-A sandpaper rash on the trunk (in addition to a clinical history of strawberry tongue) is classic for
Scarlet Fever associated with S. Pyogenes (GAS).
-Rash that starts on the face and migrates caudally is classic for Measles.
-Rash that starts on the palms and soles and radiates centrally (outward in) is classic for Rocky
Mountain Spotted Fever which is caused by Rickettsia Rickettsii.
-The presence of a rash specifically on the hand, foot, and mouth is classic for Coxsackie A Virus.
-A rash lasting for 3 days is classic for Rubella (also known as German Measles).
-Knowing these rash patterns could help with rapidly narrowing your Ddx/coming to an answer on
the exam.
Q32-STD Descriptions
Match the following STD buzzwords to the offending organism.
Painless chancre (or ulcer)
Granuloma Inguinale
Epithelial Cells with Inclusion Bodies
Lymphogranuloma Venereum
Genital Warts
Urethral discharge (gram -ve diplococci)
Diagnosis with Darkfield Microscopy
Painless ulcers with no lymph node enlargement
Painful ulcers with bilateral inguinal lymphadenopathy
Painful vesicles on the genitalia
Painless genital ulcer that progresses to massive inguinal lymphadenopathy
Urethral discharge in the setting of septic arthritis
DOC is Doxycycline
DOC is Ceftriaxone
Q32-STD Descriptions (another useful set to know)

Match the following STD buzzwords to the offending organism.
Painless chancre (or ulcer)-Treponema Pallidum (Syphilis)
Granuloma Inguinale-Klebsiella Granulomatis
Epithelial Cells with Inclusion Bodies-Herpes Simplex (likely HSV 2)
Lymphogranuloma Venereum-(Chlamydia Trachomatis-L1-L3 Serovars)
Genital Warts-HPV 6/11
Urethral discharge (gram -ve diplococci)-Neisseria Gonorrhoeae
Diagnosis with Darkfield Microscopy-Treponema Pallidum (Syphilis)
Painless ulcers without inguinal lymphadenopathy-Klebsiella Granulomatis (bleeds a lot)
Painful ulcers with bilateral inguinal lymphadenopathy-Haemophilus Ducreyi (chancroid)
Painful vesicles on the genitalia-HSV 2
Painless genital ulcer that progresses to massive inguinal lymphadenopathy-Lymphogranuloma
Venereum-Chlamydia Trachomatis (L1-L3 Serovars)
Urethral discharge in the setting of septic arthritis-Neisseria Gonorrhoeae
DOC is Doxycycline-Chlamydia Trachomatis (D-K Serovars)
DOC is Ceftriaxone-Neisseria Gonorrhoeae
The World of Treponema Pallidum
Random But Important

-Erythema Chronicum Migrans is the skin finding in Lyme Disease.
-Erythema Marginatum is the skin finding in Scarlet Fever.
-Erythema Infectiosum is the slapped cheek finding associated with Parvovirus B19.
-Ecthyma Gangrenosum is the skin finding in infection with Pseudomonas.
-These words all sound alike and seem to trip people up on exams so just take note.
Mycobacterial Species
-Are obligate aerobes, having a predilection for the lung apices.
-Cell wall is rich in mycolic acids which makes it acid fast (the ability to take up
Carbolfuchsin in the Ziehl-Neelsen stain).
-Key members of this bug class to be aware of include M. Tuberculosis, M. Avium
Intracellulare, M. Marinum, M. Kansasii, and M. Leprae.
-You should seriously consider this bug if you get a vignette talking about foreign
countries and constitutional symptoms like Fevers, Night Sweats, Weight loss, and
Hemoptysis (however, when you get to Heme-Onc, substitute the TB thought for
cancer!). Another trigger statement is sputum sample positive for Acid Fast Bacilli.
-TB is destroyed via cell mediated immunity.
The Progression of TB
Mycobacterial Species contd.

-TB is transmitted via aerosolized respiratory secretions and is an obligate aerobe.
-A Ghon Focus is the granulomatous lesion that TB establishes in the lung. A Ghon
Complex is the lung lesion + granulomatous lesions in perihilar lymph nodes. Having
a Ghon complex is indicative of a resolved infection OR a current primary infection.
-TB is treated with a multidrug regimen because resistance is super high. The only
monotherapy situation currently used with TB is a 9 month Isoniazid regimen for
latent TB (together with Vitamin B6 to prevent peripheral neuropathy).
-Isoniazid causes peripheral neuropathy because it induces certain liver enzymes that
lead to the metabolism and depletion of Vitamin B6.
-Not necessarily HY for your test but it's helpful to know that Isoniazid inhibits CYP
P450 and Rifampin induces CYP P450.
Mycobacterial Species contd.

-TB is hard to kill because it is an intracellular bug. In addition TB cavities lack blood
supply which makes drug delivery difficult. TB also grows very slowly and bugs are
more susceptible to drugs if they grow quickly.
-The PPD skin test in TB indicates prior exposure to some sort of TB antigen (this is
super HY to know). The TB skin test is a Type 4 Hypersensitivity Reaction.
-It is also HY to know that a negative PPD does not rule out infection with TB. A
person with defective cell immunity may have TB but lacks enough T cells to generate
an immune response.
-Primary TB infection typically starts in the lower/middle lung lobe. TB reactivation
tends to occur in the upper lobes.
-Aspergillus loves to form fungus balls in TB cavities.
Other Mycobacterial Species

-M. Avium Intracellulare causes pulmonary infection in AIDS patients.
Treatment/prophylaxis is with Azithromycin. Consider this if theres mention of an
acid fast stain in the presence of constitutional symptoms in an AIDS patient. Do not
always knee jerk to P. Jirovecii (although its the most common cause).
-Another HY MAC/MAI association is Hot tub lung (dont confuse with the hot tub
folliculitis of Pseudomonas).
-M. Marinum should be strongly considered if you get an exam question involving skin
infection in someone that does some sort of work relating to water (contrast with
Sporothrix Schenckii which is a fungal cause of somewhat similar skin infections).
Viral Basics
-Viruses can be classified in multiple ways-some as DNA and some as RNA Viruses.
-They could also be classified as being double or single stranded viruses.
-The +ve sense viruses have the ability to infect the host cell as they are essentially
mRNA (this is really important!). The -ve sense RNA viruses require an RNA
dependent RNA Polymerase to make the + strand that can infect the cell.
-All RNA viruses are single stranded (except Rotavirus that is double stranded).
-All DNA viruses are double stranded (except Parvovirus B19-transmitted via
respiratory aerosols).
Viral Hooks for The Boards (may not be HY now but is super HY later)
-All DNA viruses are double stranded except Parvo B19.
-All RNA Viruses are single stranded except Rotavirus.
-Any DNA virus ending with the letter A has a circular genome. The others have linear
genomes.
-The only DNA Virus that replicates in the cytoplasm is the Poxvirus (carries its own DNA
Dependent RNA Polymerase).
-All DNA viruses are enveloped with the key exceptions being Parvovirus, Adenovirus, and
Papovaviruses (Polyoma and Papillomaviruses). Others are naked.
-Most DNA viruses get their envelope from the plasma membrane with the exception of
Herpes (gets its envelope from the nucleus).
RNA Viruses-Introduction
RNA Viruses
HY Factoids on the RNA Viruses

-Coronavirus is a SS +ve sense RNA virus that causes SARS.
-The Mumps virus is a common cause of Orchitis and Parotitis (and could also cause meningitis-LY).
-The Measles virus has the constellation of symptoms including cough, coryza (annoying medical term for
runny nose), conjunctivitis, and a rash.
-The Rabies Virus (which belongs to the Rhabdovirus family) is contracted through exposure to animals like
bats, raccoons, and wild dogs. It has a super long incubation period and ascends via motor neurons to the CNS.
Is treated with the administration of IVIG (for immediate immunity) with subsequent killed vaccine
immunization (for active, long term immunity). Once Rabies hits the CNS, it is typically 100% fatal.
-All RNA Viruses are replicated in the cytoplasm with the exception of the Retroviruses and the Influenza
Virus.
RNA Viruses-The Influenza Virus

-The Influenza virus causes the flu (NOT Haemophilus Influenzae).
-It is highly segmented and REASSORTMENT of viral segments with segments of other animal viruses leads to
an antigenic SHIFT (which is more severe and causes pandemics).
-Point mutations in the genes coding for Hemagglutinin and Neuraminidase leads to an antigenic DRIFT
(which is less severe and causes epidemics).
-Hemagglutinin is the molecule that enables the attachment of the influenza virus to the host and permits entry.
This is what is targeted by the Influenza Vaccine.
-Neuraminidase is the enzyme that cleaves viral particles (from sialic acid) and allows the virus to leave the cell
and infect others. This is the target of the drugs Zanamivir and Oseltamivir.
RNA Viruses-The Parainfluenza Virus/RSV Virus

-Belongs to the group known as the Paramyxoviruses.
-Causes Laryngotracheobronchitis (also known as CROUP).
-If you see the words seal like barking cough on your exam, stop thinking and pick
Parainfluenza/Paramyxovirus (if they want to make it more difficult).
-The RSV (Respiratory Syncytial Virus) is the most common cause of Bronchiolitis in
infants. If you see an exam question talking about viral Pneumonia in an infant, pick
RSV.
Common Exam Mistake-Rubella vs. Rubeola vs. Roseola

-The Rubella virus is a member of the Togavirus family and
causes German Measles (also known as the 3 day measles).
-The Rubeola Virus is the cause of Regular Measles (rash that
starts on the head and then moves to the toes).
-The Roseola Virus refers to HHV-6 (Human Herpesvirus 6)
which causes fever and a rash in infants.
-Please do not mix these up on an exam!
DNA Viruses
HY DNA Virus Factoids

-Adenovirus is commonly implicated as the offending organism in infantile cases of
conjunctivitis and hemorrhagic cystitis (classic Q stem involving a child at a daycare
who has red urine).
-The Poxvirus causes Smallpox (a little obvious but just making sure).
HY DNA Viruses-Parvovirus B19

-Is a single stranded DNA Virus that causes 5th Disease.
-The classic clinical presentation is a child with a slapped cheek appearance in the setting of a
rash and arthralgias (joint pains). The buzzword here is Erythema Infectiosum
-Parvo B19 has a predilection for Erythroid Stem Cells in bone marrow and hence causes aplastic
anemia.
-The method of transmission is via respiratory inoculation.
-In normal hosts, the transient aplastic crisis from Parvo B19 is tolerable. In patients with Sickle
Cell Disease/Thalassemia, the aplastic crisis from Parvo B19 could be fatal.
-The contraction of Parvo B19 infection in utero is associated with Hydrops Fetalis (more on the
next slide).
Clinical Correlate-The Mechanism Behind Hydrops Fetalis

-Anemia secondary to Parvo B19 infection of erythroid precursors leads to tissue
hypoxia.
-Tissue hypoxia places a larger demand on the fragile heart of the fetus (heart does its
best to pump more blood).
-As time goes on, the pumping ability of the heart is compromised.
-When the heart gives up, all proximal organs begin to accumulate fluid (hydrops).
-Since this phenomenon occurs in utero, it is called Hydrops Fetalis.
HY DNA Viruses-HPV
-Is a DNA Virus that causes most of the cervical cancer cases in women.
-There are low and high risk HPVs.
-The low risk ones include HPV 6 and 11 which cause genital warts (also known as
Condyloma Acuminata-please do not confuse with Condyloma Lata that is found in what
stage of what disease?).
-The high risk HPVs include HPV 16 and 18 which cause Cervical Cancer. The proteins
implicated in this process are E6 (which inhibits p53) and E7 (which inhibits Rb).
-Rb and p53 are involved in the transition from the G1-S phase.
-In the presence of E6/E7 there is unchecked continuation through the cell cycle even in the
presence of DNA damage with an increased risk of malignancy.
HY DNA/RNA Viruses-The Hepatitis Virus (only DNA Virus is Hep B)

-Hep A (Picornavirus) is associated with fecal oral transmission but does not progress to chronic
hepatitis.
-Hep B (Hepadnavirus-A DNA virus) is transmitted via sexual contact/IVDU. It can become chronic
and presents an increased risk of hepatocellular carcinoma. It is vaccine preventable.
-Hep C (Flavivirus) is transmitted sexually and most commonly via IVDU. It presents the highest risk of
progression to a chronic infection (can also progress to Hepatocellular Carcinoma) and is treated with
super expensive drugs like Sofosbuvir (about 80k dollars).
-Hep D is dependent on Hep B for infectivity (super HY!)
-Hep E is transmitted via the fecal-oral route and is associated with high mortality in pregnant women.
-A/E are the first/last letters of the Hepatitis alphabet so translate that to mean fecal-oral transmission (i.
e. the first and last orifices of your body).
Hepatitis Summary
HY DNA Virus-Human Herpes Viruses

-HHV1 (or HSV 1) is typically associated with Herpes Labialis which is oral. It could be associated with genital herpes as well.
-HHV2 (or HSV 2) is typically associated with Genital Herpes but could also be associated with oral herpes.
-HHV3 or (VZV) is associated with chickenpox for the primary childhood infection and shingles for the reactivation later in life. A Super,
Super HY Buzzword here is the presence of pain and vesicles in a dermatomal distribution.
-HHV4 (EBV) is associated with Infectious Mononucleosis. HY history here is a sexually active teenager with cervical lymphadenopathy and
splenomegaly. The virus infects/remains latent in B cells. EBV causes a Monospot +ve mononucleosis syndrome.
-HHV5 (CMV) is typically spread via renal transplantation or blood transfusions. The clinical presentation in an infant with disease is the
presence of an enlarged liver (hepatomegaly) and a blueberry muffin rash. CMV can also cause Colitis and Retinitis in
HIV/Immunocompromised patients. The virus remains latent in mononuclear cells. CMV causes a Monospot -ve mononucleosis syndrome.
-HHV6 (Roseola) is associated with a high fever followed days later by a rash (in an infant). This sequence of events is almost pathognomonic
for Roseola (also known as 6th disease).
-HHV8 is associated with Kaposis Sarcoma, classically in AIDS patients (classically described as violaceous nodules on the skin).
-Most viruses get their envelopes from the CELL MEMBRANE, not so for Herpes (nuclear membrane).
Kaposis Sarcoma (HHV 8)
Viral Disease Presentation Triggers

Rash with slapped cheek appearance
Cough,Coryza,Conjunctivitis (3Cs) + Koplik Spots
Descending maculopapular rash
Gastroenteritis + Eventual Paralysis
Cervical Cancer in the Sexually Active
Parotitis, Orchitis, Male Sterility
Cataracts/Blindness in a Newborn
Painful skin lesions in a dermatomal pattern
Virus remains dormant in Dorsal Root Ganglion
Retinitis in an AIDS patient
Genital Warts
Painful vesicles on the genitals
Hepatitis in a Pregnant Woman with high mortality
Gastroenteritis on a cruise ship
Fatigue + Splenomegaly + Atypical Lymphocytes on Blood Smear in a young person
Childhood Gastroenteritis
2 common causes of the Common Cold
Bronchiolitis in an infant
Segmented Genome + Epidemic Shift Pneumonia
Animal Bite + Fatal Encephalitis
Encephalitis in a Neonate
Viral Disease Presentation Triggers-Key

Rash with slapped cheek appearance-Parvovirus B19
Cough,Coryza,Conjunctivitis (3Cs) + Koplik Spots-Measles (Rubeola)
Descending maculopapular rash-Measles (Rubeola)
Gastroenteritis + Eventual Paralysis-Poliovirus (an Enterovirus)
Cervical Cancer in the Sexually Active-HPV 16 and 18
Parotitis, Orchitis, Male Sterility-Mumps Virus
Cataracts/Blindness in a Newborn-Rubella
Painful skin lesions in a dermatomal pattern-Varicella Zoster Virus (HHV3)
Virus remains dormant in Dorsal Root Ganglion-Varicella Zoster Virus (HHV3)
Retinitis in an AIDS patient-Cytomegalovirus (CMV)
Genital Warts-HPV 6 and 11 (read your exam Qs carefully, DO NOT PICK 16/18)
Painful vesicles on the genitals (HSV2, occasionally HSV1)
Hepatitis in a Pregnant Woman with high mortality-Hepatitis E
Gastroenteritis on a cruise ship-Norovirus/Norwalk Virus
Fatigue + Splenomegaly + Atypical Lymphocytes on Blood Smear in a young person-EBV
Childhood Gastroenteritis-Rotavirus
2 common causes of the Common Cold-Coronavirus and Rhinovirus (Rhinovirus is the most common cause)
Bronchiolitis in an infant-Respiratory Syncytial Virus (RSV-treat with Palivizumab)
Segmented Genome + Epidemic Shift Pneumonia-Influenza Virus
Animal Bite + Fatal Encephalitis-Rabies Virus (a Rhabdovirus)
Encephalitis in a Neonate (HSV or CMV)
Q33
A 75yo. man is being evaluated for a 3 day history of productive cough, fever, and
chills. The medical student on service collects some of the patients rust colored
phlegm for evaluation prior to beginning empiric treatment. PE reveals a febrile
patient with a temperature of 103 degrees F and crackles in the right lower posterior
lung field. Which of the following best explains a key virulence factor associated with
the offending organism?
a.
b.
c.
d.
e.
Makes a glycopeptide that allows attachment to the Upper Respiratory Tract

Crosslinks IgE on the surface of mast cells leading to nonspecific degranulation
Binds to the constant region of monomeric immunoglobulins
Cleaves a dimeric immunoglobulin
Inhibits protein synthesis by binding to the 60S ribosomal subunit
Q33 Key
-The best answer here is D.
-The offending organism is S. Pneumoniae which has an IgA protease.
-The rust-colored sputum is pathognomonic for S. Pneumo (which is a catalase
negative, alpha hemolytic, gram positive diplococcus that grows in chains).
-Not sure how HY this is but Salmon colored Sputum is associated with S. Aureus
pneumonia.
-Treatment with Pneumonia caused by S. Pneumo is typically Penicillin but increasing
resistance has tilted the balance towards Ceftriaxone (which belongs to what
generation of Cephalosporins??)
Q34 HY Clinical Presentations-Triggers

Neonatal encephalitis from a mom that handles cats
Bloody diarrhea from undercooked chicken
Hyaluronic acid capsule with M protein
Ataxia and loss of sensation in a sexually active female
Encephalitis weeks after consuming undercooked pork
CT scan shows ring enhancing lesions in the brain of a HIV patient
Bloody diarrhea and hepatomegaly (liver abscess)
AFB staining in the stool sample of an AIDS patient
Sexually active male with arthritis and skin petechiae
Inflammation of the testicles/parotid gland
Sickle Cell patient with super low hemoglobin
Permanent flaccid paralysis in an unvaccinated child
Nuchal rigidity in a 2 week old child
Most common bacterial cause of STDs in the US
Most common cause of UTIs in the US
Elevated liver enzymes in a pregnant woman that subsequently dies
Genetic property associated with a worldwide Influenza Epidemic/Pandemic
Viral Conjunctivitis
Black eschar in a diabetic
Viral Myocarditis
Flu Like Symptoms after visiting Hawaii
Q34 HY Clinical Presentations-Triggers

Neonatal encephalitis from a mom that handles cats-Toxoplasma Gondii
Bloody diarrhea from undercooked chicken-Campylobacter Jejuni
Hyaluronic acid capsule with M protein-Streptococcus Pyogenes
Ataxia and loss of sensation in a sexually active female-Tabes Dorsalis of Tertiary Syphilis
Encephalitis weeks after consuming undercooked pork-Taenia Solium (Neurocysticercosis)
CT scan shows ring enhancing lesions in the brain of a HIV patient-T. Gondii reactivation.
Bloody diarrhea and hepatomegaly (liver abscess)-Entamoeba Histolytica
AFB staining in the stool sample of an AIDS patient-Cryptosporidium Parvum
Sexually active male with arthritis and skin petechiae-Neisseria Gonorrhoeae
Inflammation of the testicles/parotid gland-Mumps Virus
Sickle Cell patient with super low hemoglobin-Parvovirus B19
Permanent flaccid paralysis in an unvaccinated child-Poliomyelitis (Polio-an Enterovirus)
Nuchal rigidity in a 2 week old child-Group B Strep (S. Agalactiae)
Most common bacterial cause of STDs in the US-Chlamydia Trachomatis (D-K Serovars)
Most common cause of UTIs in the US-Escherichia Coli
Elevated liver enzymes in a pregnant woman that subsequently dies-Hepatitis E
Genetic property associated with a worldwide Influenza Epidemic/Pandemic-A Segmented Genome.
Viral Conjunctivitis-Adenovirus
Black eschar in a diabetic-Pseudomonas Aeruginosa (Ecthyma Gangrenosum)
Viral Myocarditis-Coxsackie B Virus
Flu Like Symptoms after visiting Hawaii-Leptospirosis
Q35 HY Clinical Presentation Triggers

Cellulitis in a burn patient
Bulls eye rash
Strawberry Tongue
Strawberry Cervix
Diarrhea after returning from Mexico and drinking water
Maculopapular rash a few weeks after returning from Spring Break
Fever, Nuchal Rigidity, Altered Mental Status
Meningitis in a college student
Next best step in the management of a patient with nuchal rigidity
Meningitis in an older individual (60s)
Meningitis in an unimmunized infant
DOC in the treatment of N. Meningitidis
Meningitis in a neonate
Q35 HY Clinical Presentation Triggers-Key

Cellulitis in a burn patient-Pseudomonas Aeruginosa
Bulls eye rash-Lyme Disease
Strawberry Tongue-Scarlet Fever (S.Pyogenes)
Strawberry Cervix-Trichomonas Vaginalis.
Diarrhea after returning from Mexico and drinking water-Enterotoxigenic E. Coli.
Maculopapular rash a few weeks after returning from Spring Break-Secondary Syphilis.
Fever, Nuchal Rigidity, Altered Mental Status-Meningitis
Meningitis in a college student-Neisseria Meningitidis
Next best step in the management of a patient with nuchal rigidity-Lumbar Puncture
Meningitis in an older individual (60s)-S. Pneumoniae
Meningitis in an unimmunized infant-N. Meningitidis OR H. Influenzae.
DOC in the treatment of N. Meningitidis-Ceftriaxone (3rd Gen Cephalosporin).
Meningitis in a neonate-Group B Strep or E. Coli.
Q36 Match the Picture to A Bug

AIDS patient
Q36 Key Match the Picture to A Bug

AIDS patient-Toxoplasma Gondii
Fungi Introduction
-Fungi could be grouped as being molds or yeasts.
-Certain fungi function as both molds or yeasts, depending on the surrounding
temperature.
-One unusually HY thing to know about fungi for your exam are the pictures of the
different organisms. They love testing these!
-Most exam questions introduce fungal skin infections by talking about KOH preps.
Candida Albicans-Yeast
-Common colonizer of the skin, GI tract, and female genital tract.
-In the immunocompromised, C. Albicans is associated with oral thrush and
esophagitis (inflammation of the esophagus).
-In females, Candida causes vaginitis (associated with severe itching).
-Candida is also associated with diaper rashes and intertrigo. Strongly consider
intertrigo when a descriptor is given of an obese individual developing rashes under
skin folds. Candida rashes typically have 2 things-Redness with shaggy borders +
smaller surrounding satellite lesions.
-The classic exam Q stem is typically a description of a cottage cheese discharge from
the vagina or a picture of oral thrush OR an AIDS patient complaining of difficulty
with swallowing (esophagitis).
Candida Albicans-Yeast contd.

-As a colonizer of the skin, C. Albicans could gain access to the blood through catheter
insertions and then cause bloodstream infections.
-Common bloodstream infections could involve the back of the eye (endophthalmitis)
and abscesses in multiple organs.
-If you see an exam question that talks about the growth of germ tubes on blood
cultures, pick the answer that relates in any way, shape, or form to C. Albicans (this is
the primary method of diagnosis).
-Oral thrush is treated with Nystatin (swish and swallow).
-Systemic candidal infections are treated with Caspofungin, Micafungin, or
Anidulafungin (more to come in Pharm-know these!)
Oral Thrush
Q37
What is the bug that best matches the following info cluster?
-Bird/Pigeon droppings
-Meningitis in an AIDS patient
-Soap bubble appearance on India Ink staining
-DOC is Amphotericin B + Flucytosine
Q37 Key
-Bird/Pigeon droppings
-Meningitis in an AIDS patient
-Soap bubble appearance on India Ink staining
-DOC is Amphotericin B + Flucytosine
-Cryptococcus Neoformans (another yeast)
Q38
-Atypical/interstitial Pneumonia
-AIDS/Immunocompromised Patient
-Prophylaxis with Trimethoprim-Sulfamethoxazole
-Prophylaxis with a CD4 count < 200
-Cannot be treated with Amphotericin B
Q38 Key
-Atypical/interstitial Pneumonia
-AIDS/Immunocompromised Patient
-Prophylaxis with Trimethoprim-Sulfamethoxazole
-Prophylaxis with a CD4 count < 200
-Cannot be treated with Amphotericin B (lacks cell wall Ergosterol)
-Pneumocystis Jirovecii
Q39
-Fungus Ball
-Causes invasive infections in immunocompromised individuals
-Causes allergic lower airway infections
-Narrow septate hyphae at acute angles (45 degrees)
-DOC is Voriconazole
Q39 Key
-Fungus Ball
-Causes invasive infections in immunocompromised individuals
-Causes allergic lower airway infections
-Narrow septate hyphae at acute angles (45 degrees)
-DOC is Voriconazole
-Aspergillus Fumigatus (a mold)
Aspergillus Hyphae (know this picture!)
Q40
-Life threatening facial infections
-Diabetics and Immunocompromised patients
-Broad, aseptate hyphae, branching at right angles (90 degrees)
Q40 Key
-Life threatening facial infections
-Diabetics and Immunocompromised patients
-Broad, aseptate hyphae, branching at right angles (90 degrees)
-Mucor/Rhizopus species (a mold)
Mucor/Rhizopus Hyphae (know this!)
Q41-Match the infection to the organism

Animal reservoir (dog/cat) causing dermatophytosis
Common cause of Onychomycosis
Spaghetti and Meatballs appearance
Tinea Versicolor
Q41 Key-Match the infection to the organism

Animal reservoir (dog/cat) causing
dermatophytosis-Microsporum Species
Common cause of Onychomycosis-Trichophyton
Spaghetti and Meatballs appearance-Malassezia
Furfur
Tinea Versicolor-Malassezia Furfur
Tinea Versicolor
Spaghetti/Meatballs-Malassezia Furfur (know this!)
The Tineas
Dermatophytes spread a host of skin infections including
-Tinea Pedis (Athletes foot)
-Tinea Cruris (Jock Itch)
-Tinea Corporis (generally anywhere on the body, ringworm)
-Tinea Capitis (head)
-Tinea Unguium/Onychomycosis (affects the nails)
-Are commonly treated with topical Terbinafine.
Dimorphic Fungi
-Are famous for assuming 2 forms-a mold form which grows at lower temperatures
AND a yeast form that grows at higher temperatures.
-Memory tool (Mold in the cold, and yeast in the heat).
-For these bugs, be sure to pay attention to geographical locations AND pictures which
are the highest yield testable bits of information.
Q42
-Spelunking/going on a cave trip.
-Bird/bat droppings.
-Ohio/Mississippi/KY
-Pulmonary Disease
-Hides in macrophages
Q42 Key
-Spelunking/going on a cave trip.
-Bird/bat droppings.
-Ohio/Mississippi/KY
-Pulmonary Disease
-Hides in macrophages
-Histoplasma Capsulatum (remember the other bird connections on your exam like C.
Neoformans with pigeon droppings and Chlamydophila Psittaci with parrots and the
H5N1 bird flu).
Histoplasma Capsulatum in a Macrophage
Q43
What is the bug that best meets the following info cluster?
-Mississippi/Ohio River Valley
-Pulmonary Infections
-Skin and Bone lesions
-Broad based budding yeast
Q43 Key
What is the bug that best meets the following info cluster?
-Mississippi/Ohio River Valley
-Pulmonary Infections
-Skin and Bone lesions
-Broad based budding yeast
-Blastomyces Dermatitidis
Broad Based Budding Yeasts of Blastomyces
Q44
-Spherules
-Pulmonary infections
-Common in Texas/California/SW United States
-Not necessarily a yeast/mold
-Transmission via inhalation from the soil
Q44 Key
-Spherules (if you forget everything else about this bug, dont forget this word!)
-Pulmonary infections
-Common in Texas/California/SW United States
-Not necessarily a yeast/mold
-Transmission via inhalation from the soil
-Coccidioides Immitis
The Spherule of Coccidioides Immitis
Q45
What is the bug that best matches the following description?
-Lives in soil
-Rose gardener pricked by a thorn
-Painless nodules in a single file on the extremities
Q45 Key
What is the bug that best matches the following description?
-Lives in soil
-Rose gardener pricked by a thorn
-Painless nodules in a single file on the extremities
-Sporothrix Schenckii
Single File Arrangement of lesions in S. Schenckii
Fungal Clinical Triggers

Diffuse markings on CXR in an AIDS patient
White lesions in the tongue of an individual on chemotherapy
Meningitis in an AIDS patient
Pulmonary Infection + Ohio River Valley
Tinea Cruris, Corporis, Pedis
California + Pulmonary Infection + Spherules
Invades blood vessels + Fungus Ball
Bone/Lung/Skin Lesions + Broad based bud
Ascending Skin Lesions + Skin prick by a thorn
Rhinocerebral infection in a Diabetic
Septate hyphae + Branching at 45 degrees
Non-Septate hyphae + Branching at 90 degrees
Fungal Clinical Triggers-Key (know this one!)

Diffuse markings on CXR in an AIDS patient-Pneumocystis Jirovecii
White lesions in the tongue of an individual on chemotherapy-Candida Albicans
Meningitis in an AIDS patient-Cryptococcus Neoformans
Pulmonary Infection + Ohio River Valley-Histoplasma Capsulatum
Tinea Cruris, Corporis, Pedis-Microsporum, Epidermophyton, Trichophyton
California + Pulmonary Infection + Spherules-Coccidioides Immitis
Invades blood vessels + Fungus Ball-Aspergillus Fumigatus
Bone/Lung/Skin Lesions + Broad based bud-Blastomyces Dermatitidis
Ascending Skin Lesions + Skin prick by a thorn-Sporothrix Schenckii
Rhinocerebral infection in a Diabetic-Mucormycosis
Septate hyphae + Branching at 45 degrees-Aspergillus Fumigatus
Non-Septate hyphae + Branching at 90 degrees-Mucor/Rhizopus species
HY Parasitology
-Entamoeba Histolytica is a common cause of bloody diarrhea as a parasite. It is associated with
liver abscesses. It is transmitted via the fecal-oral route. EH is lytic to the colon.
-Giardia is classically associated with hikers/campers who decide to take the bad decision of
drinking water from a stream. Giardia causes a watery diarrhea that smells really, really, really bad
(due to the presence of fat).
-Cryptosporidium is a common cause of long lasting diarrhea in AIDS patients. A HY method of
transmission for your exam is via unclean water supplies. It is detected by Acid Fast staining of
oocysts on a stool sample (do not knee jerk and pick TB upon mention of acid fastness on your
exam). Do not confuse with Cryptococcus which is a fungus that causes Meningitis in AIDS
patients.
-Trichomonas is a sexually transmitted parasitic infection that is associated with a foul smelling,
gas bubbly, greenish vaginal discharge. A HY association is the physical exam finding of a
Strawberry Cervix.
Giardia (Left)/Trichomonas (Right)
HY Parasitology-contd.
-Toxoplasma Gondii is a parasite that has domestic cats as its primary host. Consider this
bug in an exam scenario dealing with cat feces/litter in a pregnant woman. T. Gondii is
associated with ring enhancing lesions on MRI.
-Leishmania Donovani is transmitted via the sand fly. This bug causes visceral and
cutaneous infections. Classic Sx triad of Spiking Fevers, Hepatosplenomegaly, and
Pancytopenia (low levels of all blood cells) in Visceral Leishmaniasis. Dx requires finding
amastigotes in macrophages. Cutaneous Leishmaniasis is associated with skin lesions
(ulcers) that take a very long time to heal.
-The DOC in the treatment of Giardia, Entamoeba, and Trichomoniasis is Metronidazole.
HY Parasitology-Malaria (know this one well!)

-Caused by 4 plasmodium species (Vivax, Ovale, Falciparum, and Malariae).
-Transmission is via the Anopheles Mosquito.
-Strong association with cyclic fevers that coincide with the release of merozoites from RBCs. Fevers could be in
48 or 72 hour cycles.
-48 hour cycle fevers are associated with P. Vivax and Ovale.
-72 hour fevers are associated with P. Malariae.
-Associated symptoms include Headaches and Anemia (the organism lyses RBCs).
-P. Vivax and Ovale are not as terrible as P. Falciparum but they create dormant forms in the liver. Targeting
these dormant forms requires Primaquine.
-P. Falciparum is the worst (no dormant phase) and causes RBC aggregation which can cause CNS problems.
-The Hypnozoite is the dormant form that stays in the liver.
The Malaria Life Cycle
RBC Trophozoites of Malaria (Erythrocytic Life Cycle)
Malaria and Confusing Terminology

-Sporozoite is the form that is injected into the human and infects hepatocytes.
-Schizonts are the stages of maturity in hepatocytes/RBCs.
-Merozoites are the forms released by hepatocytes that go on to infect RBCs. Merozoites are also released by
RBCs and mature into gametophytes (banana shaped) that are then consumed by the Anopheles Mosquito.
-Hypnozoites are dormant derivatives of sporozoites that remain in the liver (P. Vivax and P. Ovale).
-Trophozoites are ring shaped intermediate forms that exist in RBCs.
-The definitive host is the Anopheles Mosquito while the secondary host is the human.
-Recrudescence is symptom recurrence that arises from parasites that survive in the bloodstream. Improper
treatment is the primary culprit here.
-Relapse is symptom recurrence that arises from dormant forms that survive in the liver (P. Vivax/Ovale).
Malaria Treatment
-Chloroquine if susceptible.
-Add Primaquine to deal with the dormant Hypnozoites.
-In chloroquine resistance, consider one of 4 options (Doxycycline + Quinine,
Atovaquone + Proguanil, or Artemether + Lumefantrine, OR Mefloquine). These are
quite low yield for your exam.
Worms-General Principles
-Nematodes are Roundworms, Cestodes are Tapeworms, Trematodes are Flukes.
-Enterobius, Ascaris, and Trichinella (EAT) are acquired via Fecal-Oral Transmission.
They are Nematodes.
-Strongyloides, Ancylostoma, and Necator (SAND) are acquired through direct skin
inoculation. These are also Nematodes.
-Many of these bugs take a circuitous route from the lymphatic system to the lungsOropharynx-swallowed-get to the intestine-back to lymphatics-rinse and repeat.
-Many of these bugs are treated with drugs ending in the term Bendazole.
-Focus mostly on the HY history and Characteristics of these bugs.
Disgusting #1-Enterobius Vermicularis (Pinworm)

-Transmitted via the fecal oral route.
-You should strongly consider this bug on the exam if you see something about a child
with constant itching in the anus at night.
-The Diagnostic Test of Choice is the Scotch Tape Test.
-The itching occurs because the mom comes out at night to lay eggs on the anus (the
child can then scratch the anus and reinfect him/herself).
-This is the most common helminthic infection in the US.
-Hopefully this is obvious but the mom here is the worms mom and the child here is
the actual human getting the infection.
Disgusting #2-Ascaris Lumbricoides (Giant Roundworm)

-Afflicts almost 25% of the worlds population and is the 2nd
most common US helminthic infection.
-A HY exam association is an Eosinophilic Pneumonia also
known as Loeffler's Pneumonitis. Remember the NAACP
pneumonic from Immuno, the P stands for Parasites.
Disgusting #3-Trichinella
-Acquired primarily by consumption of undercooked meat.
-Consider this bug if you get a question about an individual that
consumed undercooked meat and then had muscle aches and
visual problems (edema behind the orbit).
Trichinella Cysts in Muscle
Disgusting #4-Strongyloides Stercoralis

-Acquired via direct inoculation into the skin.
-Causes an Eosinophilic Pneumonitis like Ascaris.
-Causes a mild diarrhea that could be accompanied by sepsis
secondary to infection with a gram -ve organism.
Disgusting #5-Hookworms (Necator/Ancylostoma)

-Acquired through direct inoculation into skin.
-Attaches to the wall of the small intestine and sucks blood.
-Consider this bug if you get an exam question about an
individual with unexplained anemia who also has stomach
trouble.
Disgusting #6-Taenia Solium/Saginatum (this one is HY!)

-Is a tapeworm (Cestode).
-Taenia Solium is acquired from consuming larvae in undercooked pork.
-Taenia Saginatum is acquired from consuming larvae in undercooked beef.
-Cysts of Taenia Solium can be acquired from consuming eggs in contaminated
food/water (dont confuse this with consuming larvae!!!, they love this annoying but
important point). These eggs can then germinate in weird places like muscle and brain,
and ultimately form larvae giving rise to a condition known as Cysticercosis. In the
brain, this is known as Neurocysticercosis (this looks like a ring enhancing lesion on
MRI-presents with CNS symptoms. If you see a similar lesion but with mention of cats
in the Q stem, consider Toxoplasmosis instead).
Disgusting #7-Schistosoma Species (this is also HY!)

-Individuals infected with this parasite pass this on by defecating in the environment.
-The eggs are then taken up and mature in the Intermediate host (the freshwater snail,
KNOW THIS!).
-These worms are acquired through direct skin inoculation.
-If you see any question about an Egyptian/Mediterranean on the exam with blood in
the urine, you really want to think about S. Haematobium. Again, any question that
remotely mentions The Nile on your exam should direct your thoughts straight to S.
Haematobium.
-S. Mansoni (Caribbean OR S. America) has a predilection for infecting the intestines.
-You should also strongly consider these bugs with any mention of liver infection.
Schistosoma Mansoni (top), Haematobium (bottom)
Disgusting #8-Wuchereria Bancrofti

-Causes Filariasis.
-Obstructs lymphatics and causes Elephantiasis.
Q46-Protozoal Clinical Triggers

Amebic Dysentery + Liver Abscess
Foul smelling diarrhea from drinking contaminated water
Diarrhea in an AIDS patient
Vaginal Infection with a green discharge
Fevers that come and go every 48 hours
Fevers that come and go every 72 hours
Dormant stage in the liver
Cat Feces + Ring Enhancing Brain Lesions
Hemolysis after Malaria Treatment
Intestinal Infection from Pork Consumption
Cysts in the brain
Perianal itching
Attaches to intestine, causing anemia
Hematuria after swimming in The Nile
Egg with Terminal Spine
Snail Consumption + Liver Abscess
Undercooked Beef
Q46-Protozoal Clinical Triggers-Key (know this one!)

Amebic Dysentery + Liver Abscess-Entamoeba Histolytica
Foul smelling diarrhea from drinking contaminated water-Giardia Lamblia
Diarrhea in an AIDS patient-Cryptosporidium Parvum
Vaginal Infection with a green discharge-Trichomonas Vaginalis
Fevers that come and go every 48 hours-Plasmodium Vivax and Ovale
Fevers that come and go every 72 hours-Plasmodium Malariae
Dormant stage in the liver-Plasmodium Vivax and Ovale
Cat Feces + Ring Enhancing Brain Lesions-Toxoplasma Gondii
Hemolysis after Malaria Treatment-G6PD Deficiency (Hemolytic Anemia)
Intestinal Infection from Pork Consumption-Taenia Solium
Cysts in the brain-Taenia Solium (after consuming eggs)
Perianal itching-Enterobius Vermicularis
Attaches to intestine, causing anemia-Ancylostoma Duodenale OR Necator Americanus
Hematuria after swimming in The Nile-Schistosoma Haematobium.
Egg with Terminal Spine-Schistosoma Haematobium.
Snail Consumption + Liver Abscess-Schistosoma Mansoni + Schistosoma Japonicum
Undercooked Beef-Taenia Saginatum
Stay Tuned...
-HIV to come tomorrow (makes more sense to discuss HIV with Pharmacology).
HY Oncology Review
Some MS2
Objectives/Suggestions
-Oncology is mostly about being able to group things, so you should focus on learning distinguishing
characteristics of the different cancers which are well highlighted in your lecture slides (and in this
document).
-The actual final contains Heme material, so dont blow that off.
-Unfortunately, theres little in the way of rationalization (much unlike Heme) involved with Oncology
so you should do your best in knowing how to identify different diseases by clinical presentation and lab
findings (flow cytometry, translocations).
-In view of this, the goal of this review is twofold-A)To provide you with vignettes detailing how these
different disorders are typically tested and then B)To provide you with summaries of the key features
underlying the different diseases/underlying pharmacology.
-Theres intentional repetition built into these slides to drive certain key points home. In addition,
theres questions admixed with the content to promote active learning. The answers to these questions
are usually on the next slide (and in a few cases, in later slides).
Q1
A 7 month old infant was brought by his parents to the ED with acute complaints of
severe hand pain. PE reveals tender DIPs and PIPs with massive swelling. After the
administration of analgesics to reduce the pain, the physician prescribes a drug that
could potentially decrease future symptoms in the infant. The boys parents recently
immigrated to the US from Nigeria. Which of the following represents the most likely
mechanism of action of the drug that was prescribed by the physician.
a.
b.
c.
d.
e.
Inhibition of Thymidylate Synthase.

Inhibition of Ribonucleotide Reductase.
Inhibition of Dihydrofolate Reductase.
Inhibition of Glutamine PRPP Amidotransferase.
Inhibition of Carbonic Anhydrase.
Q1 Key
-The best answer is B, Ribonucleotide Reductase.
-The drug in this case is Hydroxyurea, which inhibits Ribonucleotide Reductase.
-Hydroxyurea increases the synthesis of HbF which would hopefully ameliorate future
episodes of dactylitis secondary to sickle cell disease (which this child has).
-This is one of many ways they could integrate Heme material with the material from
Oncology.
Q2
A 67 yo male presents to the Med19 clinic with complaints of fatigue and low energy.
He mentions having frequent episodes of low back pain which has required the
repeated use of Ibuprofen. Lab studies reveal a hematocrit of 36% and a blood calcium
level of 15 g/dL (normal is between 8.5-10.2 g/dL). The most likely finding on a blood
smear obtained from this patient is?
a.
b.
c.
d.
e.
Aggregations of discoid shaped RBCs.

Proliferation of immature hematopoietic stem cells.
RBCs having a decreased volume and increased central pallor.
RBCs having an increased volume in the setting of PMN hypersegmentation.
RBCs having an increased Mean Corpuscular Hemoglobin Concentration
(MCHC).
Q2 Key
-The question is a bit nonspecific, but there are several important clues-bone pain
(lytic lesions), fatigue (anemia), high calcium (hypercalcemia), age (in his 60s).
-The most likely diagnosis here is Multiple Myeloma.
-MM is associated with the classic Rouleaux formation on blood smear.
Q3
A 53 yo female presents to the Med19 clinic for her yearly checkup. PE reveals a firm, non tender mass in the
anterolateral neck. During the course of the interview, the patient mentions having low grade fevers over the last 6
months in addition to an unintended 19 Lb weight loss. A tissue biopsy is obtained from the patient with the results
shown below. Increased survival in patients having a similar condition is predicted by?
a.
b.
c.
d.
e.
An abundance of eosinophils within the tumor stroma.

A depletion of lymphoid cells within the tumor stroma.
An abundance of Polymorphonuclear Leukocytes within the tumor stroma.
An abundance of antigen presenting cells within the tumor stroma.
The presence of large numbers of lymphoid cells within the tumor stroma.
Q3 Key
-The best answer is E.
-The patient has Hodgkin's Lymphoma, with Reed Sternberg Cells (RS cells) being
pathognomonic.
-HL associated with large titers of lymphocytes (lymphocyte predominant) have an
excellent prognosis.
Q4
A 5 yo boy is brought by his concerned parents to the Med19 clinic with complaints of
fatigue, anorexia, night sweats, and a 15 Lb weight loss over the past 3 weeks. He has
since been walking on a limp with complaints of dull back pain. PE reveals bilateral
conjunctival pallor, hepatosplenomegaly, painless lymphadenopathy, and skin
petechiae. CBC reveals a massive proliferation of blasts with positive staining for
Terminal Deoxynucleotidyl Transferase. The most likely diagnosis in this infant has a
strong association with?
a.
b.
c.
d.
e.
A translocation between Chromosomes 12 and 21.

A translocation between Chromosomes 9 and 22.
Flow cytometry studies indicating CD3 positivity.
Flow cytometry studies indicating CD99 positivity.
The presence of Auer Rods on a peripheral blood smear.
Q4 Key-Resolving Oncology Problems

-When approaching these questions, your first task is to determine if youre dealing with a leukemia or a
lymphoma. The mention of CBC (peripheral blood process) should take you down the leukemia pathway.
-Your next question is to then determine if theres increased blasts or an increased number of mature cells. They
have to give some clue in the question relating to this (if not the Q will be unanswerable). Theyll usually
mention some genetic marker or straightaway mention the presence of blasts (which is the case here, so it is an
acute leukemia).
-Once this determination is made, search the question for other clues that support a diagnosis of ALL vs AML
(again, they have to give you something-in this case TDT positivity so were dealing with ALL).
-Theres no mention of a thymic mass and the age range (a super young child, usually less than 10) is more
characteristic of B-ALL, than T-ALL (which is relatively rare).
-12:21 translocations are almost pathognomonic for B-ALL, so A is the best answer. Be methodical when solving
these problems and youll almost invariably arrive at the right answer.
Q5
A 23 yo. woman has experienced low grade fevers, night sweats, and generalized
malaise for the last 2 months. PE reveals non-tender cervical lymphadenopathy. A
Lymph node biopsy reveals CD15/30-/20+ Reed Sternberg cells. The Med19 student on
service assures the patient that her prognosis is excellent, but mentions that there is a
small risk of progression to;
a.
b.
c.
d.
e.
Acute Myelogenous Leukemia.

Chronic Lymphocytic Lymphoma.
Primary Myelofibrosis.
Mantle Cell Lymphoma.
Diffuse Large B Cell Lymphoma.
Q5 Key
-This patient has Lymphocyte Predominant Hodgkins Lymphoma.
-Theres a small risk of progression to a Diffuse Large B Cell Lymphoma.
Q6
A 21 yo female presents with symptoms of fatigue and malaise for the past 2 weeks. PE
reveals painful cervical lymphadenopathy with prominent splenomegaly. A lymph
node biopsy reveals extensive hyperplasia of the paracortical zone. A potential sequelae
of this patients illness is the future development of;
a.
b.
c.
d.
e.
A leukemia involving a 9:22 translocation.

A lymphoma involving a 15:17 translocation.
A lymphoma involving an 8:14 translocation.
Q6 Key
-The best answer here is D.
-A history of painful lymphadenopathy in a young individual is very concerning for
EBV infection. Most instructors dont even give the extra history of a LN biopsy
showing paracortical hyperplasia (note that in some cases, mention would be made of
the presence of atypical lymphocytes on a blood smear).
-EBV infection is known to have a strong association with Burkitts Lymphoma which
is associated with an 8:14 translocation (the MYC oncogene being translocated to the
Immunoglobulin heavy chain locus).
Q7
A 62 yo woman comes for a follow up visit with her oncologist after a previous
consultation for suspicious masses in her breast. Assuming a diagnosis of Stage 3 breast
cancer, an axillary lymph node biopsy obtained from this patient would most likely
reveal;
a. A massive paracortical proliferation of CD68+ cells.
b. A massive paracortical proliferation of CD3+ cells.
c. An expansion of a lymph node region that feeds the efferent arteriole with a
prominence of CD3+ cells.
d. An expansion of a lymph node region that feeds afferent lymphatic vessels with a
prominence of CD68+ cells.
e. An expansion of a lymph node region that feeds the efferent lymphatic vessels
with a prominence of CD68+ cells.
Q7 Key
-This lady has breast cancer which classically drains into axillary lymph nodes.
-Hyperplasia of the medullary sinuses (i.e. the region that feeds efferent lymphatic
vessels) would be the most likely pathologic finding.
-Remember that histiocytes (macrophages that express CD68) are the prominent cells
that populate this area of the lymph node.
Q8
A 53 yo woman presents to her Med19 PCP with complaints of vaginal dryness and
sudden feverish feelings that last for a few hours at a time and then go away. She has
also had 2 compression fractures over the past year. The appropriate agent is
prescribed which leads to a marked reduction in her symptoms over the next few
weeks. The drug administered to this patient most likely works by;
a. Agonizing estrogen receptors in breast and endometrial tissue.
b. Antagonizing estrogen receptors in breast and endometrial tissue.
c. Antagonizing estrogen receptors in the breast and agonizing estrogen receptors in
endometrial tissue.
d. Agonizing estrogen receptors in breast and rectal tissue.
Q8 Key
-The best answer here is B. This lady is most likely experiencing symptoms of
menopause/osteoporosis which are best treated with Raloxifene which is a Selective Estrogen
Receptor Modulator (SERM) that decreases breast/endometrial cancer risk (so Im calling it an
antagonist here) and also slows the progression of osteoporosis. The MOA is not as simplistic as
explained here (will discuss more during the review).
-C is a description of Tamoxifen which is also a SERM that decreases breast cancer risk
(antagonist) but increases endometrial cancer risk (agonist). Tamoxifen is primarily used in
breast cancer treatment/prophylaxis.
-Do not forget male drugs like Finasteride and Dutasteride that are the DOCs in the treatment
of male pattern baldness and BPH. DHT promotes growth of the prostate and the evolution of
male pattern baldness. Finasteride/Dutasteride work by inhibiting 5-Alpha reductase which
converts Testosterone to Dihydrotestosterone (DHT). These drugs are essentially useless in the
prevention/treatment of cancer and in some cases present with deleterious effects.
The Actions of Raloxifene/Tamoxifen in Different Tissues
Cancer Pharmacology-Key Terms

-Anticancer drugs work by killing a fixed percentage of cells with every dose given (not a fixed number).
They therefore operate on first order kinetics. This is why people being treated for cancer undergo
multiple rounds of chemotherapy. This is the basis of the log kill hypothesis.
-Anticancer drugs are especially effective against cells that are rapidly dividing (i.e. cells with a high
growth fraction). A similar concept was discussed in our antibiotic review. In addition to cancer cells,
cells in the GI tract, bone marrow, and hair follicles divide rapidly (and hence are affected by these
drugs). This is the basis of the diarrhea/bone marrow suppression/alopecia seen with chemotherapy.
-Anticancer drugs are typically divided into cell cycle specific and non-cell cycle specific agents. Cell
cycle specific agents do a good job of killing rapidly dividing cancer cells. Why??...By dividing rapidly, the
cancer cells have to by definition go through the cell cycle and hence would be markedly affected by
these agents (antimetabolites, microtubule inhibitors, etc). The non-cell cycle specific drugs are great for
rapidly dividing cancers and also indolent cancers of less rapidly dividing cells b/c they work through
mechanisms that destroy cells regardless of DNA synthesis status. The Alkylating agents fall into this
drug category.
Cancer Pharmacology-Drug Overview

-There are many classes of anti-cancer medications. These include the antimetabolites,
topoisomerase inhibiting drugs, the alkylating agents which include the Nitrogen
Mustards/Platinum agents, microtubule inhibitors, and designer drugs that target very
specific mutations associated with cancers. Theres also the SERMS which are used to
prevent/treat Gynecological cancers.
-Bone Marrow Suppression is the main side effect of many cancer drugs. BMS can be
tackled with the administration of G-CSF/GM-CSF (Granulocyte Colony Stimulating
Factor). Key things to learn are unique side effects and MOAs associated with the
different medications.
Antineoplastic Agents and The Cell Cycle
Antineoplastic Agents-MOA Overview
Antimetabolite Pathway Overview (Do not memorize!)
The Pharmacology of Antimetabolites

-By definition, antimetabolites are compounds that act like other naturally occurring compounds. By acting
like other compounds they fool enzymes and inhibit them. These drugs also cause double stranded DNA breaks
from the failed incorporation of nucleotides.
-The 2 major enzyme classes inhibited by Antimetabolites are DNA Polymerase (where the drug acts like a
nucleotide) AND key enzymes required for purine/pyrimidine synthesis. These drugs all act in the S phase of
the cell cycle.
-Drugs belonging to the 1st class include Cytarabine and Gemcitabine (cytosine analogs).
-Drugs belonging to the second class include Methotrexate, 6-Mercaptopurine, Hydroxyurea, and 5Fluorouracil.
-A key side effect of all these drugs is bone marrow suppression (so focus on unique SEs).
-These drugs typically require transport into the cell and activation by an enzyme, so a mutation in any of these
processes could result in a markedly reduced effectiveness of the drug.
Class 1-Cytarabine/Gemcitabine
-These are both cytosine analogs that get mistakenly incorporated by DNA Polymerase
into DNA.
-These drugs typically have a 2 or 3 carbon replaced by a group that prevents the next
normal nucleotide from being incorporated. They therefore cause chain termination
and in some cases, double stranded breaks in the DNA.
-In normal DNA replication, phosphates must be added to nucleosides before
incorporation. The same holds true for these drugs, therefore a mutation in the
activating kinase is one key mechanism of resistance. Cancer cells could also be
mutated to where they do not get the actual drug into the cell.
Class 2-MTX/5-FU/HU/6-MP
-Methotrexate (MTX) is an inhibitor of Dihydrofolate Reductase (DHFR) which regenerates reduced
tetrahydrofolate for the conversion of dUMP to dTMP. Folic acid is also required for the synthesis of purines.
Prior to DHFR inhibition, MTX receives multiple glutamates from Polyglutamyl Synthase which could be
mutated, leading to a reduced activation of the drug.
-Since MTX inhibits DHFR, rapidly dividing cells that require the regular synthesis of DNA like leukocytes
are particularly affected by this drug. Rescue from increased toxicity is via the administration of a folinic acid
analog, Leucovorin (a rescuer of LEUkocytes). A HY SE of MTX is Pulmonary Fibrosis (LY now, SHY later).
-5-Fluorouracil (5-FU) acts as a uridine analog which requires initial activation by a kinase. Upon activation, 5FU inhibits Thymidylate Synthase (TS). From the pathway 3 slides ago, it is seen that active THF is required for
dUMP to dTMP conversion by TS. It should therefore make sense that the administration of Leucovorin
increases 5-FU toxicity since youre basically supplying more cofactor. For the future, what is the drug you
learnt about in Micro that works like 5-FU?
-Hydroxyurea (HU) inhibits Ribonucleotide Reductase (RR). RR makes the deoxy form of most nucleotides.
With no deoxy form, DNA synthesis is effectively inhibited.
Class 2-MTX/5-FU/HU/6-MP contd.

-6-Mercaptopurine (6-MP) and its prodrug, Azathioprine, shut down purine nucleotide synthesis by inhibiting
the rate limiting enzyme, Glutamine PRPP Amidotransferase.
-6-MP is activated by an enzyme of the purine salvage pathway, Hypoxanthine Guanine Phosphoribosyl
Transferase (HGPRT) which is a key enzyme in the purine salvage pathway.
As clinical correlations for future exams,
-HGPRT is the deficient enzyme in Lesch Nyhan Syndrome (hyperuricemia and self mutilation), so these drugs
may be less effective in affected individuals.
-6-MP is eliminated from the body by the enzyme Xanthine Oxidase (XO), which makes uric acid. A XO
inhibitor like Allopurinol or Febuxostat, works great in the treatment of gout (associated with hyperuricemia).
Unfortunately, an individual being treated for gout that takes 6-MP may have very severe bone marrow
suppression from decreased 6-MP inactivation. This is a commonly tested scenario to lock in your mind for the
future.
Alkylating Agents
-Are drugs that work mainly by cross linking DNA strands. These cross links hold the strands tightly together and
prevent DNA replication. Irreparable cross links activate mechanisms that lead to cell death by apoptosis.
-HY Drugs in this category include the Nitrogen Mustards like Cyclophosphamide and Ifosfamide (LY ones include the
mustines and mechlorethamine)AND Platinum Compounds like Cis, Carbo, and Oxaliplatin.
-Cyclophosphamide/Ifosfamide are prodrugs that must be converted to active metabolites in the liver. They both work
by attacking N-7 Guanine residues on DNA. A HY SE of these 2 drugs is Hemorrhagic Cystitis secondary to a free
radical damage inducing agent (Acrolein-a cyclophosphamide metabolite). This is prevented with the drug Mesna.
Cyclophosphamide has a strong association with vomiting.
-Cisplatin has the HY SE of Nephrotoxicity (prevented with Amifostine) and vomiting (emesis). The HY drug to be
aware of in terms of preventing emesis is Ondansetron, which is a 5-HT3 (Serotonin) receptor antagonist. Blocking
Dopamine receptors also relieves emesis.
-It is important to know the progression in susceptibility of blood cells (stem cells-progenitors/blasts-mature cells) to
alkylating agents. Stem cells (express ALDH) are somewhat resistant to all alkylating agents with cyclophosphamide
having zero effect. Blasts/progenitors are utterly destroyed by all these drugs. These drugs have essentially zero effect on
mature cells. ALDH, in a series of steps, oxidizes cyclophosphamide to inactive metabolites.
Other Chemotherapy Agents

-Topoisomerases are enzymes that act to relieve supercoils in the process of DNA replication. Doing this requires
making strand breaks in the DNA (1 for Topo 1 which does not require ATP, and 2 for Topo 2 which does require ATP).
After making strand breaks, the DNA molecule is re-ligated. An inhibition of this enzyme basically locks up
Topoisomerase and prevents re-ligation of the DNA strand, leading to strand breakage which triggers cell death. Topo 1
is inhibited by Irino/Topotecan while Topo 2 is inhibited by Etopo/Teniposide.
-Of particular importance is Irinotecan which is hydrolyzed to SN-38. SN-38 is the active compound that inhibits Topo
1. Clearance of Irinotecan depends on Glucuronidation by the liver (remember Phase 2 metabolism from last year).
Diseases involving low levels of UDP-Glucuronosyl Transferase (Gilbert Syndrome, Crigler Najjar Syndrome), lead to
severe toxicities with Irinotecan (especially diarrhea).
-Doxo/Daunorubicin are anthracyclines that intercalate DNA. They generate free radicals which can damage cancer cells
AND cardiac myofibers. A HY SE of these drugs is dilated cardiomyopathy. Consider this as an answer choice in an
individual that is being treated for cancer and then develops shortness of breath/cardiac complaints.
-Actinomycin D is an RNA Polymerase inhibitor that is used to treat many childhood cancers like Ewings Sarcoma.
-Bortezomib is a proteasome inhibitor that is used to treat MM. The inhibition of the proteasome leads to a decreased
degradation of factors that kill cancer cells. This leads to increased cancer cell death.
Other Chemotherapy Agents

-The Taxanes and Vinca Alkaloids are anti-cancer agents that work primarily in the M phase of the cell
cycle. The Taxanes (like Paclitaxel), work by binding to Tubulin found in microtubule polymers. This
binding prevents the depolarization of already formed microtubule polymers, which leaves the cell
hanging in Metaphase/Anaphase (giving rise to a mitotic arrest). The Vincas (like Vincristine and
Vinblastine) work by preventing the conversion of tubulin monomers to tubulin polymers (so lined
up chromosomes cannot come apart in anaphase). It is important that you understand the difference in
mechanism behind these drugs which ultimately accomplish the same goal. The HY SE to be aware of
here is the peripheral neuropathy associated with these drugs (especially Vincristine). Remember that
microtubules are the primary media for the movement of neurotransmitters in neurons.
-Again, Taxanes prevent microtubule depolymerization. Vincas prevent microtubule polymerization.
-Imatinib (Gleevec) is the DOC in the treatment of CML. It binds to and inhibits BCR-ABL, which is
the anomalous tyrosine kinase formed by the 9:22 translocation characteristic of CML.
Special Mention-Rituximab
-Is a chimeric murine IgG monoclonal antibody that binds to CD20 on normal and neoplastic B
lymphocytes.
-From Immunology, we know that IgG and IgM (remember the GM makes classic cars
mnemonic) activate complement. One killing mechanism employed by Rituximab is complement
mediated lysis of cancer cells.
-From Immunology, we know that Macrophages and NK cells possess FC-Gamma receptors that
recognize the constant region of IgG. Rituximab (IgG) when bound to CD20 on a neoplastic cell,
promotes Antibody Dependent Cellular Cytotoxicity (ADCC) which is another killing
mechanism.
-By a poorly understood mechanism, bound Rituximab also induces apoptosis of neoplastic cells.
-It is HY to know that Rituximab does not affect plasma cells (these do not express CD20).
The Lymph Node
Reactive Lymph Node Changes

-These are changes to the lymph node that occur in response to a non-oncologic
process. These changes include an increase in the # of cells (for example, upon
detection of a new antigen, the generation of memory/effector B/T cells depends on
cellular proliferation which would be observed histologically) OR a destruction of the
actual node by some infectious process (also termed lymphadenitis).
-The lymph node is divided into well defined regions that contain very particular cell
types. Starting from the outside in, there is the cortex which contains follicles (B cell
area, CD20+), the paracortex, which is juxtaposed to the cortex (T cell area,
CD3/4/8+), and the medulla which is divided into the medullary sinuses that contain
macrophages (also called histiocytes-CD68+), and the medullary cords which contain
plasma cells.
LN Pathologies-Follicular Hyperplasia
-Is a pattern observed with infectious/inflammatory agents that activate B cells.
-These activated B cells migrate to the germinal center and proliferate in response to antigens that
have been presented by Follicular Dendritic cells. These reactive germinal centers also contain
Tingible Body Macrophages which serve more of a garbage clearing role.
-Common inciting agents that are implicated in follicular hyperplasia include Rheumatoid
Arthritis, SLE, Toxoplasmosis, and early HIV infection.
-It is easy to get Follicular Hyperplasia confused with Follicular Lymphoma so key distinguishing
features (that are found only in follicular hyperplasia) include the preservation of the LN
architecture, a variation in the size and shape of germinal centers, and the presence of phagocytic
activity (from tingible body macrophages) in germinal centers (this is HY!).
LN Pathologies-Paracortical/Sinus Hyperplasia
-Caused primarily by immune reactions involving T cells.
-T cells are our bodys primary mechanism for dealing with intracellular organisms.
-Paracortical Hyperplasia is typically encountered in response to viral infections (a HY
virus for your exam is EBV), after vaccinations (smallpox for example), and in certain
drug reactions (like Phenytoin which is an antiepileptic medication).
-Hyperplasia of medullary sinuses is typically observed in situations involving LN
drainage of malignancies. The enlargement arises from the hypertrophy of the
endothelial cells lining the lymphatic sinusoids and a massive infiltrate of
macrophages.
Special Mention-Cat Scratch Disease (CSD)

-CSD is an inflammation that occurs in lymph nodes secondary to Bartonella Henselae
infection.
-The common clinical presentation is in a child with a history of a cat bite followed 2-3
weeks later by axillary/cervical lymphadenopathy.
-The histology observed with CSD is the presence of granulomas in LNs with a central
core of necrosis (with an infiltration of Neutrophils).
-Consider CSD on your exam with any mention of cats (duh!) or the presence of
necrotizing, non-caseating granulomas (that are stellate/star shaped) on a LN biopsy.
Next Few Questions

-Are entirely pictures.
-Will give you very little information to go on.
-The goal is to get you to make the choice of what is most likely
given the clinical vignette and the image.
-This images/scenarios are very HY! (try to answer them first
before looking up the answers).
Q9
19 yo college student with splenomegaly. This picture is associated with hyperplasia of what lymph node region?
What is the most likely diagnosis?
Q9 Key
-Acute EBV Infection.
-The age is fairly consistent (young person) with a HY history (splenomegaly).
-Hyperplasia of the Paracortex would be expected in this scenario since this is a viral
infection.
Q10
63 yo female that has felt tired over the last 6 months. PE reveals splenomegaly and axillary lymphadenopathy.
WBC Count is >63000/uL. What is the most likely diagnosis?
Q10 Key
-The most likely diagnosis is CLL.
-The cells in the picture look a lot like lymphocytes.
-The WBC count is high.
-The vignette mentions the presence of lymphadenopathy (raising the possibility of a
lymphoma).
-The patients age is very concerning for CLL (which is the most common
leukemia/lymphoma in this age group). There is a nice smudge cell in the image as
well which should confirm the diagnosis.
Q11
25 yo with a history of recurrent bleeding and multiple hospitalizations for infections over the last 6 weeks. PE
reveals axillary lymphadenopathy and splenomegaly. WBC count > 100k. What is the most likely diagnosis?
Q11 Key
-The most likely diagnosis here is AML.
-The Auer Rods in the image are essentially all you need to clinch the diagnosis.
-Remember that Auer Rods are characteristic of the 15:17 translocation associated with
Acute Promyelocytic Leukemia.
-Treatment of this condition is with ATRA which binds to the defective retinoic acid
receptor and promotes maturation.
Q12
72 yo male with bone pain.
Q12 Key
-This is Multiple Myeloma.
-This should be one of the very first thoughts on your exam with any mention of an
old individual with bone pain.
-Dont forget other HY associations like the M spike on Serum Protein
Electrophoresis, CRAB Symptoms, and Amyloid deposition in different organs (Apple
Green birefringence under polarized light).
Q13
What is the most likely cytoplasmic inclusion associated with this picture?
Q13 Key
-This patient has sickle cell disease.
-Remember the association with a Glutamic Acid to Valine substitution.
-Consider this in an exam question describing a young person with dactylitis.
-Most SCD patients auto infarct their spleens.
-The lack of a spleen is associated with the presence of Howell Jolly bodies on a blood
smear which is the answer to this question.
Q14
A 23 yo who just delivers a baby goes into shock and starts bleeding from multiple orifices. What is the best
screening test in an individual with this condition?
Q14 Key
-This is most likely DIC (Disseminated Intravascular Coagulation).
-The D-Dimer test is one of the screening tests of choice in ruling out DIC.
-The image on the preceding slide shows a few sheared RBCs (Schistocytes).
Q15
What should be expected on flow cytometry studies in an individual with this
condition?
Q15 Key
-These are Reed Sternberg cells which are classic for Hodgkins Lymphoma.
-These cells are CD15/30+.
Q16
65 yo male with painless axillary lymphadenopathy. What should flow cytometry
studies of these cells reveal?
Q16 Key
-Again, this is CLL.
-These cells should be CD5+.
-I dont mean to be annoying with the many CLL questions but CLL should be one of
your top diagnosis in an old male (typically >60).
Q17
In an individual with this condition, what can you say about Ferritin, TIBC/Transferrin, and % Transferrin
Saturation levels? What can you say about the RDW?
Q17 Key
-This person most likely has Fe deficiency anemia.
-Ferritin and % transferrin saturation levels should be low.
-Transferrin/TIBC levels should be high.
-The Red Cell Distribution Width (RDW) should be increased.
An Introduction To Hematologic Malignancies
Blood Cancers-An Overview

-Going back to the original theme of Heme-Onc, there are 2 major kinds of blood
cells-myeloid and lymphoid.
-Lymphoid cancers include ALL, CLL (which is associated with what characteristic cell
type?), Hodgkins and Non-Hodgkins Lymphomas, Multiple Myeloma, and associated
Plasma Cell dyscrasias.
-Lymphomas revolve around cancers with a significant involvement of lymph nodes.
-Leukemias revolve around cancers with a significant involvement of the bone marrow
and peripheral blood. Theres blurred lines here (e.g. CLL and SLL).
-Myeloid cancers include AML, Myelodysplastic Syndromes which can all progress to
AML/ALL, Myeloproliferative disorders which include CML, Polycythemia Vera,
Essential Thrombocytosis, Primary Myelofibrosis, etc.
Blood Cancers-General Principles, contd.

-There are multiple types of myeloid precursors, hence AML (accumulation of blast cells) has multiple
subtypes depending on the defective cell, e.g. Acute Promyelocytic Leukemia (which is associated with
what translocation/cellular inclusion/treatment strategy?).
-Myelodysplastic Syndromes arise from mutant stem cells (have the capability to make all myeloid
lineages) that takes over the bone marrow but is incapable of producing derivative myeloid cells. This is
why individuals with this condition have anemia, thrombocytopenia, and infections. Because this is a
mutation of stem cells, these syndromes all present with the possibility of progressing to AML. What is
the characteristic PMN blood smear morphology associated with this condition? Is there a kind of
microcytic anemia morphology associated with this condition?. It is important to note that
myelodysplastic syndromes have an association with DNA hypermethylation of tumor suppressor genes,
which explains their neoplastic potential. This association with hypermethylation informs a key
treatment strategy for this disease (which is?).

-Myeloproliferative disorders (pls do not confuse with myelodysplastic syndromes) are
problems with progenitor cells that lead to an overproduction of mature myeloid cells
(usually all types, with one kind dominating). CML, the poster child of
myeloproliferative disorders, has a strong association with a certain chromosomal
translocation (which is?).
-Primary Myelofibrosis is a myeloproliferative disorder associated with defective
megakaryocytes that leads to extensive collagen deposition in the bone marrow. When
you cover your bone marrow with collagen, the end result is hypocellularity which
leads to decreased numbers of many myeloid cells. RBCs have a hard time getting out
of the bone marrow in this disease (what is the characteristic RBC morphology?). With
the bone marrow unavailable for hematopoiesis, your body adjusts by switching to
extramedullary hematopoiesis, giving rise to the characteristic hepatosplenomegaly
seen in this disease.

-These cancers are typically associated with painless lymphadenopathy. Contrast this
with painful lymphadenopathy that indicates more of a reactive lymphocytosis (think
nasty infection).
-Fatigue, night sweats, weight loss, anorexia, and fever are constitutional/B Sx that are
commonly associated with cancers.
-The presence of these cancers in the bone marrow crowds out regular hematopoiesis.
Hence, pancytopenias are common observations with these diseases. These explain the
underlying pathophysiology of the symptoms-fatigue (anemia), infection (leukopenia),
increased bleeding (thrombocytopenia). With a nuked bone marrow, the body seeks
new sites of hematopoiesis including the liver and spleen, giving rise to
hepatosplenomegaly.
HY Triggers
Cancer associated with lymphoblast accumulation
B cell neoplasm with smudge cells on peripheral smear
Cell morphology associated with Hodgkins Lymphoma
Plasma cell tumor
Hypercalcemia, Renal Failure, Anemia, Bone Pain
General class including Follicular, Mantle Cell, and Marginal Zone Lymphomas
Early myeloid lineage neoplasms
Stem cell with ineffective hematopoiesis that replaces bone marrow
Clonal proliferation of a myeloid stem cell giving rise to multiple cell types with 1 type predominating.
8:14 translocation, C-myc activation
14:18 translocation, BCL-2 overexpression
11:14 translocation, Cyclin D overexpression
Neoplasm associated with H. Pylori Infection
Large % of myeloid blasts in the bone marrow
Auer Rods
Bence Jones Proteins in the urine
Philadelphia Chromosome
HY Trigger Key-commit these to memory!

Cancer associated with lymphoblast accumulation-ALL.
B cell neoplasm with smudge cells on peripheral smear-CLL/SLL.
Cell morphology associated with Hodgkins Lymphoma-Reed Sternberg Cells.
Plasma cell tumor-Plasmacytoma.
Hypercalcemia, Renal Failure, Anemia, Bone Pain-Multiple Myeloma.
General class including Follicular, Mantle Cell, and Marginal Zone Lymphomas-Non Hodgkins Lymphoma.
Early myeloid lineage neoplasms-AML.
Stem cell with ineffective hematopoiesis that replaces bone marrow-Myelodysplastic Syndromes.
Clonal proliferation of a myeloid stem cell giving rise to multiple cell types with 1 type predominatingMyeloproliferative Dzs.
8:14 translocation, C-myc activation-Burkitts Lymphoma.
14:18 translocation, BCL-2 overexpression-Follicular Lymphoma.
11:14 translocation, Cyclin D overexpression-Mantle Cell Lymphoma.
Neoplasm associated with H. Pylori Infection-Marginal Zone Lymphoma/MALToma.
Large % of myeloid blasts in the bone marrow-AML.
Auer Rods-Acute Promyelocytic Leukemia (M3 AML subtype).
Bence Jones Proteins in the urine-Multiple Myeloma.
Philadelphia Chromosome-CML (and a few rare cases of ALL)
Distinction between Leukemia and Lymphoma
Acute Leukemias
Pseudo Pelger-Huet Anomaly found in MDS (i.e. PMN with glasses)
Key Takeaways-Acute Leukemias

-The fusion of the Promyelocytic Leukemia gene with the Retinoic
Acid Receptor gene to form a defective Retinoic Acid receptor shuts
down cellular maturation of the immature myeloid cell.
Administration of All Trans Retinoic Acid fixes this problem.
-In many cases, patients with these disorders (Myelodysplastic
Syndromes or Leukemias) tend to have low counts of other blood
elements like platelets (bleeding), RBCs (anemia), WBCs
(infections), etc.
Auer Rods In Acute Promyelocytic Leukemia
Chronic Leukemias-Key Takeaways

-Are best grouped into 2 categories-CLL (Chronic Lymphocytic Leukemia) AND Myeloproliferative
Disorders (CML, P. Vera, Essential Thrombocytosis, Primary Myelofibrosis).
-CLL is a cancerous, monoclonal proliferation of mature lymphoid cells in the peripheral blood/bone
marrow (little to no blasts). The HY marker for your exam is CD5 positivity (detected by flow
cytometry).
-CLL is a disease of the elderly with a 2:1 M/F predominance ratio. Patients are usually asymptomatic,
with the occasional complaint of fever and weight loss.
-Bad prognosis lesions include those having deletions of odd numbered chromosomes b/w 11 and 17
(except 15).
-Remember that Small Lymphocytic Lymphoma (SLL) is CLL that lives in a lymph node.
-CLL is the most common leukemia in the US with most being B cell derived. Many of these neoplastic
cells are fragile, and hence rapidly destroyed in histological processing. This is how smudge cells arise.
Chronic Leukemias-Key Takeaways contd.

-CML is a neoplastic proliferation of mature granulocytes (Eosinophils, Basophils, and Macrophages). All these
cell types will be increased in number in the bone marrow.
-The key cytogenetic anomaly associated with CML is the 9:22 translocation which produces BCR-ABL, a
constitutively active tyrosine kinase receptor that promotes cell proliferation (which is inhibited by Imatinibthe DOC in CML infection).
-Theres typically an increased number of basophils (which is almost pathognomonic) and the risk of a blast
crisis with progression to an acute leukemia. The WBC count in CML is typically super high.
-The other myeloproliferative disorders apart from CML have a strong association with a JAK2 mutation (this
is super HY!). From best to worst in terms of progression to leukemia, theres Essential Thrombocytosis (ET),
Polycythemia Vera (PV), and Primary Myelofibrosis (PM).
-ET is characterized by a massive proliferation of megakaryocytes with platelet counts approaching 600-700K in
many instances. Common presenting symptoms/sequelae include erythromelalgia (burning pain/redness in
hands/feet) and a high risk of bleeding OR thrombosis (secondary to blood hyperviscosity).
Chronic Leukemias-Key Takeaways contd.

-Polycythemia Vera (PV) is characterized by an increased RBC count but low erythropoietin since
negative feedback is intact. The HY common presenting symptom is a ruddy complexion (plethora), and
itching after taking a warm bath. These patients have a really high risk of coming down with
thromboembolic disease secondary to serum hyperviscosity which increases blood vessel resistance and
causes vessel occlusion.
-Primary myelofibrosis is a condition associated with almost total coverage of the bone marrow with
collagen fibers. It is primarily a problem with abnormal megakaryocytes (which are increased in
number) that produce elevated levels of Fibroblast Growth Factor, which encourages collagen
deposition in the bone marrow. This cuts out one key hematopoietic source and shunts things to
places like the liver and spleen, with resultant enlargement of those organs. Teardrop shaped RBCs are
pathognomonic for this condition (at least for your exam). PM presents with the highest risk of
progression to acute leukemia.
Age Algorithm With Acute/Chronic Leukemias (Use at your own risk..)

0-14 is usually ALL
15-39 is usually AML (occasionally with a mention of Auer Rods in the Q stem)
40-59 is usually AML or CML (with a high percentage of blasts-AML, with a low
percentage of blasts or mention of a 9,22 translocation, go with CML).
60 or greater is usually CLL (which is also the most common leukemia).
Please do not depend on these rules, they work really well under certain scenarios but I
would reserve these as more of a last resort measure when trying to answer questions.
Cell Marker Associations With Leukemias-A Summary..
Hodgkin's Lymphoma (HL)

-Is a hematopoietic neoplasm that is more common in males (except the nodular sclerosing subtype which is
more common in females). The prevalence of HL has a bimodal distribution with a peak at 20 and about 50
years of age respectively.
-Most patients have B symptoms (fevers, night sweats, and weight loss) with painless cervical
lymphadenopathy.
-It is extremely HY to keep in mind that HL affects lymph nodes that are clustered together (which makes
surgical correction an option) and very rarely has extranodal involvement. The affected lymph nodes are in
many cases confined to the mediastinum and the neck.
-There are 2 kinds of cells found in any HL-the actual cancerous cell (Reed Sternberg-a kind of B cell) AND
cells that react to mediators released by the RS cell like PMNs and Eosinophils.
-Male gender, advanced age, the presence of B Sx, and extranodal involvement, are all associated with poor
outcomes.
-HL, in general has a good prognosis and is cured in most instances.
Hodgkin's Lymphoma (HL)-contd.

-There are 2 general classes of Hodgkins lymphoma. The first major class is the classic type which includes 4
subclasses (Lymphocyte Rich, Lymphocyte Depleted, Nodular Sclerosing, and Mixed Cellularity). The second
major category includes the Lymphocyte Predominant HL (LPHL).
-These 2 are distinguished solely by the CD markers they express with the classic HL types expressing CD15
and 30 and the LPHL expressing only CD20 (-ve for CD15/30).
-Key things to keep in mind are the fact that the nodular sclerosing subtype is the most common and LPHL
while having a good prognosis, presents with a small risk of progressing to Diffuse Large B Cell Lymphoma
which is a kind of Non-Hodgkins Lymphoma.
-HL could be classified as being Stage 1 with 1 LN involved, Stage 2 with 2 or more LNs on the same side of the
diaphragm, Stage 3 with 2 or more LNs on opposing sides of the diaphragm, and Stage 4 being disseminated
disease.
-It is HY to know that HL is associated with Epstein Barr Virus (EBV) infection, especially the classical subtype.
Not HY for your exam-Lymphocyte Rich vs. Lymphocyte Predominant

-These 2 subtypes of HL are regarded as distinct entities on the basis of the Reed
Sternberg cell morphology.
-Lymphocyte Rich HL RS cells look like the regular RS cell with a bilobed nucleus,
expressing CD15 and 30.
-Lymphocyte Predominant HL RS cells look very different, in many cases having
multilobed nuclei. In addition, these cells DO NOT express CD15/30 but instead
express CD20.
-Both HL subtypes have a decent prognosis though.
The Reed Sternberg Cells of HL
Non-Hodgkins Lymphomas (NHL)

-Are a grab bag of other lymph node (LN) neoplasms, mostly of B cell origin that are not characterized by the
presence of Reed Sternberg cells.
-It is important that you understand the pathophysiology behind each kind of neoplasm.
-These lymphomas tend to involve diffuse LN groups (non-contiguous) with most having extranodal
involvement. The spleen is typically involved.
-The common clinical presentation is painless lymphadenopathy (neck, inguinal, axillary) in the setting of B Sx.
As this is common in other kinds of hematologic neoplasms, more information has to be given for you to
answer a question correctly.
-NHL are best classified as being indolent or aggressive. The indolent NHLs include Follicular Lymphoma and
Small Lymphocytic Lymphoma which is CD5/23+ (re-CLL that involves LNs). These are generally incurable but
patients survive for a long time with them. The aggressive ones (Burkitts Lymphoma and Diffuse Large B Cell
Lymphoma-DLBCL) can kill an untreated patient quickly, but in a fair number of instances are actually curable.
Mantle Cell Lymphoma is a special case and is typically regarded as the NHL with the worst prognosis.
MALTomas are associated with H. Pylori infection.
NHL-Follicular Lymphoma
-Follicular Lymphomas tend to affect older patients with males and females affected equally.
-The HY cytogenetic abnormality to be aware of here is the 14/18 translocation. The translocated proteins are
BCL-2 which is anti-apoptotic and the Ig Heavy chain gene. We always need to make Igs so the Ig Heavy chain
gene is constitutively expressed. Moving the BCL-2 gene to a gene locus that is heavily transcribed basically
confers immortality to the cell line having that kind of translocation as anti-apoptotic proteins are transcribed
all the time. This is the underlying pathophysiology in Follicular Lymphoma.
-Note that these cells would be CD10/19/20+ since they are all B cells. Immunofluorescence should also reveal
+ve staining for BCL-2 which is not a common finding in germinal center B cells since they need to die in the
process of +ve and -ve selection.
-Follicular Lymphomas in many cases progress to Diffuse Large B cell Lymphomas or Burkitts Lymphoma.
-The underlying histology is basically a lymphoid follicles that is completely covered with circles (of equal size)
which represent the proliferating follicles of B cells that do not want to die.
Follicular Lymphoma
NHL-Diffuse Large B Cell Lymphoma (DLBCL)

-DLBCL tends to arise in the older population and is the most common kind of NHL.
-Most cases arise in the setting of a 14/18 translocation that was initially a follicular
lymphoma. Some are associated with Epstein Barr Virus (EBV) infection.
-These cells are CD19/20/79a+.
-On histology, DLBCL resembles sheets of cells that all look the same and have
prominent nucleoli.
DLBCL
NHL-Burkitts Lymphoma
-Represents a common type of childhood NHL.
-Has 2 subtypes with the Sporadic type being more common in the US with a predilection for the abdomen
AND the Endemic type being more common in Africa with a predilection for the neck. Both are associated with
EBV infection.
-The most common cytogenetic abnormality is a translocation of the MYC gene (on chromosome 8) to the Ig
heavy chain locus (Chromosome 14). As discussed with Follicular Lymphomas, the underlying pathophysiology
involves the over-transcription of a gene that is transcribed less frequently under normal circumstances. MYC is
a gene that encourages cell proliferation so there is a massive proliferation of the affected cells. These cells are
CD10/19/20+ (since they are B cells).
-This is the primary reasoning behind Burkitts Lymphoma being very aggressive.
-The gene involved here does not involve apoptosis, so these rapidly churned out cells eventually die and are
phagocytosed by macrophages found in the LN. This is what differentiates the histology of Burkitts Lymphoma
from the histology of follicular lymphoma with the starry sky appearance that is characteristic of this
neoplasm.
Burkitts Lymphoma-The Starry Sky Appearance.
Rapid Diagnostic Summary (That 1 Key Feature).

ALL-CD10+, TDT+, 12:21 translocation.
CLL-CD5+, old people, smudge cells.
AML-CD13/33/117+, 15:17 translocation for APML, MPO+, Auer Rods, T(8:21) is good.
CML-9:22 translocation.
Myeloproliferative Disorders-JAK2 mutation.
Multiple Myeloma-CRAB Symptoms, lytic bone lesions in an old person.
Hodgkins Lymphoma-CD15/30+ (classic), CD15/30-/20+(Lymphocyte Predominant).
Mantle Cell Lymphoma-11:14 translocation.
Follicular Lymphoma-14:18 translocation.
Burkitts Lymphoma-8:14 translocation, child from Africa, Starry Sky appearance.
Myelodysplastic Syndromes-Pseudo Pelger-Huet Anomaly, Ringed Sideroblasts.
Cell Markers/Genetic Anomalies in HL/NHL
NHL-Mantle Cell Lymphoma-MCL/MALToma

-MCL is a lymphoma that affects older males.
-The HY cytogenetic anomaly to be aware of here is the translocation of Cyclin D1
(which promotes transit through the cell cycle) on Chromosome 11 to the
Immunoglobulin Heavy Chain Locus on Chromosome 14. The cells are CD5/19/20+
and CD23-.
-MALTomas (also called Marginal Zone Lymphomas) do not typically involve LNs but
instead involve unencapsulated lymphoid tissue in the GI tract. They have a super
strong association with H. Pylori infection. MALTomas are CD5/10/23-.
Plasma Cell Dyscrasias

-Encompass a group of disorders that involve a monoclonal proliferation of mature B cells (plasma cells).
-The hallmark feature of all these diseases is a monoclonal increase in 1 kind of immunoglobulin (Ig) and a
corresponding light chain. The Immunoglobulin heavy chain is known as the M protein. The light chain (usually
lambda), when found in the urine is known as a Bence Jones Protein. The most common Ig is IgG.
-Testing for this group of diseases depends on conducting certain serum and urine studies.
-One key serum study is The Serum Protein Electrophoresis (SPEP) which can detect the monoclonal (M) spike
corresponding to the given Ig. It tells you there is a problem (monoclonality), but it does NOT tell you what Ig is
elevated. SPEP is essentially a quantitative M spike assessment tool. Determining the exact Ig that is elevated requires
the use of Immunofixation Electrophoresis. (Goal Post Appearance is a key buzzword).
-Detecting the light chain in the urine (Bence Jones Protein) depends on the use of a Urine Protein Electrophoresis
(UPEP). Similar to the SPEP above, UPEP helps with quantitative determinations, Urine Immunofixation
Electrophoresis determines exactly what light chain is elevated (Kappa or Lambda).
-Key plasma cell disorders include Multiple Myeloma, Monoclonal Gammopathy of Undetermined Significance
(MGUS-an isolated M spike minus all other MM Sx), Waldenstrom Macroglobulinemia, and Plasmacytomas.
Plasma Cell Dyscrasias-Multiple Myeloma

-MM is more common in African Americans and shows up mostly in the 60-70 age range.
-In addition to the M spike (>10% plasma cells in a bone marrow aspirate or >3g/dL), there has to be evidence of CRAB
Sx like hyperCalcemia, Renal Insufficiency, Anemia, and lytic Bone lesions.
-These monoclonal plasma cells arise from genetic anomalies-translocations AND deletions.
-Bad prognosis genetic lesions include 4/14 and 14/16 translocations AND Chromosome 1/17 deletions. Good prognosis
lesions include 6/14 and 11/14 translocations.
-The defective plasma cells secrete cytokines that prevent the differentiation of osteoblasts and encourage the activation
of osteoclasts. You should very strongly consider MM on your exam in situations describing a man in his 60s with bone
pain who may have experienced some pathologic fractures.
-Other HY MM associations include kidney failure secondary to light chain deposition AND the formation of misfolded
proteins (primary AL amyloid, beta pleated sheets, 8-10 nm nonbranching fibrils) consisting of light chains that deposit
in multiple organs in the body. Please note that Amyloid is detected with Congo Red stain that shows Apple-Green
Birefringence under polarized light (BURN THIS FACTOID INTO YOUR BRAIN FOREVER!).
-Patients with MM are typically anemic (with the characteristic Rouleaux formation on blood smear).
Plasma Cell Dyscrasias-Multiple Myeloma

-The Rouleaux formation is due primarily to the agglutination of RBCs by bound
immunoglobulin.
-Renal failure arises from a constellation of factors. Light chains get filtered by the
kidney. In the process of reabsorption, the light chains damage the tubular epithelium.
In addition, the light chain, if misfolded into amyloid, also serves to destroy the tubular
epithelium. One other common cause of renal damage is the formation of kidney
stones secondary to hypercalcemia.
-Hypercalcemia (one of the defining features of MM) presents with Sx of confusion,
muscle weakness, and constipation.
Bone Marrow Monoclonality/Lytic Lesions/Rouleaux Formation
Other Plasma Cell Dyscrasias AND Amyloid

-A Monoclonal Gammopathy of Undetermined Significance (MGUS) is essentially a sub multiple myeloma disease
with no evidence of CRAB symptoms. The key definition here is having a monoclonal M spike in addition to a <10%
plasma cell amount in the bone marrow or <3g/dL plasma cell amount in peripheral blood. 1% of patients with MGUS
progress to having MM every year. It is HY to know that MGUS is actually the most common cause of an SPEP M spike.
-Plasmacytomas are tumors that consist solely of plasma cells.
-Amyloid is something you want to make sure you understand as you go through GTS. It is tested in most blocks and on
the boards because there are many types.
-Amyloid is a term that describes proteins that misfold into beta pleated sheets and decide to deposit in organs, giving
rise to a wide variety of problems.
-With regards to MM, the misfolded proteins are lambda light chains (AL amyloid).
-Chronic inflammation involves an accumulation of acute phase proteins (produced by the liver). These proteins can
misfold and form secondary (or AA amyloid).
-Transthyretin is a serum protein that carries thyroid hormone. This protein can misfold and form amyloid in an
autosomal dominant disease known as Familial Amyloidosis.
Q18-Match the Clue to the potential diagnosis

Woman delivers a hydropic fetus.
A 23 yo is recently started on lifelong anticoagulation. He has always seemed to wake up with
blood in his urine.
A woman who is 33 weeks pregnant presents to her PCP with complaints of fatigue over the last
month.
A 2 yo is scheduled for a splenectomy which resolves symptoms of hematuria that have been
present from birth.
A 12 yo child presents to the ED with PE revealing yellow sclera. Ultrasonography reveals no
spleen.
Possible choices-Hereditary Spherocytosis, Fe deficiency anemia, Paroxysmal Nocturnal
Hemoglobinuria, Sickle Cell Disease, Alpha Thalassemia Major.
Q18 Key-Match the Clue to the potential diagnosis

Woman delivers a hydropic fetus-Alpha Thal Major.
A 23 yo is recently started on lifelong anticoagulation. He has always seemed to wake up with
blood in his urine-Paroxysmal Nocturnal Hemoglobinuria.
A woman who is 33 weeks pregnant presents to her PCP with complaints of fatigue over the last
month-Fe deficiency anemia (pregnancy induced).
A 2 yo is scheduled for a splenectomy which resolves symptoms of hematuria that have been
present from birth-Hereditary Spherocytosis.
A 12 yo child presents to the ED with PE revealing yellow sclera. No spleen on ultrasonographySickle Cell Disease (Spleen has been auto infarcted).
Possible choices-Hereditary Spherocytosis, Fe deficiency anemia, Paroxysmal Nocturnal
Hemoglobinuria, Sickle Cell Disease, Alpha Thalassemia Major.
HY Triggers
Blood smear result from spleen auto infarction
DOC in the treatment of a patient with a blood smear showing Auer Rods
MCV low, Ferritin high, TIBC low, % Transferrin saturation low
Biopsy reveals LN architectural effacement with a dense collection of BCL-2+ cells
Low platelets in the setting of anticoagulant treatment
Spontaneous abortion in the setting of anticoagulant treatment.
Hematuria in the setting of RBCs lacking central pallor
Histological finding in the setting of hematuria after Fava beans consumption
Increased bleeding time + Increased PTT + Normal PT
Hematuria in the setting of chemotherapy
CBC changes expected after splenectomy
Blood smear result in the setting of a high MCV + Peripheral Neuropathy
Glutamic Acid to Valine mutation
Glutamic Acid to Lysine mutation
Hx of multiple thrombotic events + Activated Protein C Resistance
2 diseases associated with an abnormal Ristocetin Cofactor Assay
Blood smear result in the setting of an MCV<80 in an individual living in an old apartment
Blood smear reveals bite cells
Blood studies reveal an increase in Hemoglobin A2
Dry tap on BM biopsy
High Ferritin + Low TIBC + High % Transferrin Saturation
Blood smear reveals RBCs stacked like poker chips
HY Triggers Key
Blood smear result from spleen auto infarction-Howell Jolly Bodies.
DOC in the treatment of a patient with a blood smear showing Auer Rods-ATRA.
MCV low, Ferritin high, TIBC low, % Transferrin saturation low-Anemia of Chronic Disease.
Biopsy reveals LN architectural effacement with a dense collection of BCL-2+ cells-Follicular Lymphoma.
Low platelets in the setting of anticoagulant treatment-Heparin Induced Thrombocytopenia.
Spontaneous abortion in the setting of anticoagulant treatment-Warfarin Teratogenicity.
Hematuria in the setting of RBCs lacking central pallor-Hereditary Spherocytosis.
Histological finding in the setting of hematuria after Fava beans consumption-Heinz Bodies.
Increased bleeding time + Increased PTT + Normal PT-Von Willebrand Disease.
Hematuria in the setting of chemotherapy-Cyclo/Ifosfamide induced hemorrhagic cystitis.
CBC changes expected after splenectomy-an increase in platelet count (secondary thrombocytosis).
Blood smear result in the setting of a high MCV + Peripheral Neuropathy-Hypersegmented PMNs.
Glutamic Acid to Valine mutation-Sickle Cell Disease.
Glutamic Acid to Lysine mutation-Hemoglobin C Disease.
Hx of multiple thrombotic events + Activated Protein C Resistance-Factor V Leiden.
2 diseases associated with an abnormal Ristocetin Cofactor Assay-VWD and Bernard Soulier Disease.
Blood smear result in the setting of an MCV<80 in an individual living in an old apartment-Basophilic Stippling/ringed
sideroblasts.
Blood smear reveals bite cells-G6PD deficiency.
Blood studies reveal an increase in Hemoglobin A2-Beta Thal minor.
Dry tap on BM biopsy-Aplastic Anemia.
High Ferritin + Low TIBC + High % Transferrin Saturation-Hemochromatosis.
Blood smear reveals RBCs stacked like poker chips-Multiple Myeloma (Rouleaux formation).
For The Sake of Time..

-Look through the earlier lectures that brushed on the different cancer hypothesis
(Norton Simon, etc). Those are HY.
-Also look through the Telomerase/Intro to Cancer/Key Concepts from the Intro to
RadOnc lectures.
HY Pharmacology Review
Some MS2
A Few Words..
-Pharm/Path look benign but they are one of the very HY courses of
M1 (if not the highest yield)
-The principles/drugs you learn will keep hunting you throughout GTS
(and for the rest of your time in med school/medicine)
-For example, Beta blockers come up in GTS Neuro, GI, Cardio, Renal,
Pulmonary, and even some TIME courses.
-So, learn this material as best as you can.
-Pay particular attention to the BOLDED words.
Drug Development
-Fraught with a few challenges.
-Problems include-associated costs of drug development, very few validated targets,
etc.
-Most drugs target G Protein Coupled receptors
-Theres a shift from the use of Natural Products to the use of Synthetic Analogs.
-There are very few novel drugs approved by the FDA each year (new molecular
entities).
2 Key Definitions
-Pharmacokinetics is what the body does to

the drug (ADME)
-Pharmacodynamics is what the drug does
to the body (efficacy/potency)
Anatomy of the Efferent NS-Autonomic + Somatic
LY Now (Not sure???), Super HY Later

QCs HAVe 1 M&M-Cutesies have 1 M&M (Gq, Protein Kinase
C, H1, Alpha 1, V1, M1, and M3)
MAD2s (Gi, inhibit Adenylate Cyclase, M2, Alpha 2, D2)
All others are Gs (stimulate Adenylate Cyclase)
-Gi coupled receptors decrease intracellular calcium and open K
channels (cause hyperpolarization)
The Parasympathetic Nervous System-Vision
The Sympathetic Nervous System-Vision
The Parasympathetic Nervous System

-Is the rest and digest system.
-The main neurotransmitter involved is Acetylcholine.
-For test taking purposes, think of the PSNS as the leaky system.
-Works through Nicotinic (Ion channels) and Muscarinic (G protein Coupled
Receptor) receptors.
-In general, the PSNS promotes digestion, urination, smaller pupils, saliva secretion,
erection.
-Note that these are all things that you do when youre not running from a predator.
Parasympathetic System-Actions.
THE CHOLINERGIC SYNAPSE (HY!)
Drug Classes
There are 2 general drug classes in ANS
Pharmacology (and all of Pharmacology in general)
-AGONISTS
-ANTAGONISTS
DRUG CLASSIFICATION SCHEME
PARASYMPATHETIC DRUG CLASSIFICATION-Memorize!
Direct Muscarinic Receptor Agonists

-Pilocarpine
-Used mainly for eye problems.
-Causes Pupillary Sphincter constriction which creates space for aqueous humor to
flow through in open angle glaucoma-reduces the high intraocular pressure from
backed up aqueous humor.
-Metoclopramide (is a Pro-Kinetic, primarily a dopamine receptor antagonist but
works like a muscarinic agonist)
-Makes things move quickly through the GI tract (treats Gastroparesis) and prevents
vomiting (anti-emetic). Clinical correlate-Parkinsonian side effects limit use.
Acetylcholinesterase Inhibition
-Is the turn off mechanism after Acetylcholine secretion.
-With inhibition, ACH persists and hence builds up.
-2 types; Neuronal (more important) and Serum (made by liver).
-Can be inhibited for good purposes as in the treatment of Post-op Ileus (anesthesia
grinds your GI tract to a halt). Remember that ACH makes your GI tract leaky.
-Can be inhibited for bad purposes in the setting of Sarin nerve gas. What should
happen with the increased levels of Acetylcholine? (DUMBBELSS!)
-Clinical Correlate-The Drooling Farmer (Organophosphate poisoning).
Rescue Agents in Acetylcholinesterase Inhibitor Toxicity

-The problem is too much Acetylcholine.
-So a muscarinic antagonist (first line drug is Atropine) must be given.
-A regenerator like Pralidoxime also helps if ACHE has not been aged.
-As an Anti-PSNS agent, atropine also helps in leaky GI tract problems (diarrhea),
dilated eye exams (PSNS makes your pupils small, antagonism makes them big), or
bradycardia (PSNS slows down the heart, antagonism speeds things up).
-Mentally take the opposites of the DUMBBELSS mnemonic and youll know all the
Atropine side effects.
The Vestibular System

-Is controlled mainly by Acetylcholine (more to come in GTS Neuro)
-With too much stimulation/dysregulation-Vertigo.
-Blocking the PSNS shuts this down.
-This is the job of Scopolamine (first line agent in Motion Sickness).
Asthmatics/COPD patients
-The biggest problem with Asthma is excessive bronchoconstriction.
-The PSNS loves to bronchoconstrict.
-Blocking the PSNS causes bronchodilation.
-This is accomplished by Ipratropium (used in COPD and Asthma).
-What does the Sympathetic Nervous System do to the bronchus? Through what
receptor?
-What other drug class is used in achieving an Ipratropium like effect?
The Adrenergic Synapse
Key Takeaways
-EAT increases NE release from the presynaptic cell (Ephedrine, Amphetamines, and Tyramine).
Clinical correlate-MAOIs and the Tyramine crisis.
-The primary turnoff mechanism for NE is reuptake.
-Reuptake is blocked by CAT (Cocaine, Amphetamines, and Tricyclic Antidepressants).
-Bretylium and Guanethidine inhibit NE release.
-Epinephrine is not released by neurons. It is a purely endocrine hormone. PNMT is found only
in the Adrenal Medulla.
-The SNS is less specific than the PSNS (why?)
-NE can be broken down by MAO (clinical correlate-MAOIs for depression)
Adrenergic Actions
Memorization Reduction Tools for SNS Pharm

-Any drug ending in olol is a beta
blocker/antagonist (A-M are beta-1 selective, N-Z
are non-selective).
- Zosin drugs are Alpha-1 receptor antagonists.
- Terol drugs are Beta-Agonists
SNS DRUG CLASSIFICATION
Alpha-1 Agents
-The SNS is a fight or flight system (so it raises BP and prevents poop/urine formation)
-The major Alpha-1 effect is vasoconstriction so agonizing this should increase total peripheral
resistance and hence increase BP (reduced BV diameter increases resistance to the 4th power).
Alpha-1 is also important in constricting the bladder sphincter and preventing urination.
-Agonizing Alpha-1 can treat hypotension by increasing TPR (Phenylephrine). Constricting blood
vessels also decreases nasal secretions (explains the nasal decongestant Phenylephrine effects).
-Antagonizing Alpha-1 can treat BPH (prostate grows too much and constricts the bladder
sphincter hence promoting urinary retention). A good antagonist is Prazosin.
Alpha-2 agents
-The primary Alpha-2 effect is to decrease SNS outflow by reducing the release of NE
(via negative feedback). With less NE, the Alpha-1 vasoconstrictive and Beta-1 heart
rate increasing effects are abolished (hence BP is lowered). Less NE also somewhat
reduces the pleasurable sensations felt from addictive substances.
-Agonizing these receptors should accomplish all the effects listed above.
-A good agonist is Clonidine.
Beta-1 agents
-The primary beta-1 effect is to increase HR and contractility.
-Agonizing these receptors can help in heart failure/cardiac stress tests. This is the
MOA of Dobutamine and Isoproterenol (Nonselective Beta-1 and 2 agonist)
-Antagonizing these receptors could lower blood pressure by slowing the heart (also
help in Heart Failure) and shutting down the RAAS system (clinical correlate). This is
the MOA of Propranolol.
Beta-2 agents
-The primary Beta-2 effect is to promote bronchodilation and vasodilation.
-Agonizing these receptors is very useful in treating Asthma. This is the MOA of
Albuterol.
-Is there some other drug class that causes bronchodilation?
-Clinical Correlate-Why would Propranolol be contraindicated in an asthmatic? Why
would a beta blocker be contraindicated in a cocaine overdose situation?
A Word on Specials
-Epinephrine is the first line agent in the treatment of
Anaphylaxis.
-Norepinephrine is the first line agent in the treatment of Shock.
-Dopamine is also considered to be a first line agent in the
treatment of shock but is used mostly in special situations.
Matching Game
What would you use in the following conditions?
-Nasal decongestion
-Asthma/COPD
-Shock
-Anaphylaxis
-Substance use withdrawal
-Hypotension
-Hypertension
-Cardiac Stress Tests/Heart Failure
-BPH
-Motion Sickness
-Acetylcholinesterase Inhibitor toxicity (Sarin)
-Open Angle Glaucoma
-Post-Op Ileus
-Gastroparesis
-Vomiting associated with Chemotherapy
Game Key-Associations in 1 spot (HY!)

What would you use in the following conditions?
-Nasal decongestant-Phenylephrine (Alpha-1 agonist)
-Asthma/COPD-Albuterol (asthma), Ipratropium (COPD) (Beta 2 agonist, Muscarinic Antagonist)
-Shock-Norepinephrine, Dopamine (all receptors, no Beta-2 for NE)
-Anaphylaxis-Epinephrine (all Alpha and Beta receptors)
-Substance use withdrawal-Clonidine (Alpha-2 agonist)
-Hypotension-Phenylephrine (Alpha-1 agonist)
-Hypertension-Metoprolol, Propranolol (M-Beta 1 selective antagonist, P-Nonselective antagonist)
-Cardiac Stress Tests/Heart Failure-Dobutamine (Beta-1 agonist)
-BPH-Prazosin (Alpha-1 antagonist)
-Motion Sickness-Scopolamine (Muscarinic Antagonist)
-Acetylcholinesterase Inhibitor toxicity (Sarin)-Atropine (M Antagonist) and Pralidoxime (Regenerator)
-Open Angle Glaucoma-Pilocarpine (Direct Muscarinic Agonist)
-Post-Op Ileus-Metoclopramide (Dopamine receptor antagonist, Pro-Muscarinic effects)
-Gastroparesis-Metoclopramide (Dopamine receptor antagonist, Pro-Muscarinic effects)
-Vomiting associated with Chemotherapy-Metoclopramide (Dopamine receptor antagonist, Pro-Muscarinic
effects)
PK Equations (For the logic minded)
PK Equations/Key Facts (HY!!!!)
PK Practice 1
If a drug is known to be distributed in total body
water, what dose in mg is needed to obtain an initial
plasma level of 5 mg/L in a patient weighing 80 kg
assuming total body water is 60% of his weight?
What is the Q asking for?
Solution
The Q is asking for a loading dose
Loading Dose = Css * Volume of Distribution
VD = 60% of 80 kg = 48 L
LD = 4 mg/L * 48 L = 192 mg.
PK Practice 2
Which statement is correct for Drug X with the following PK elimination parameters?
80-40 mg in 2 hrs, 40-20 mg in 2 hrs, and 20-10 mg in 2 hrs.
a.
b.
c.
d.
e.
The rate of elimination is constant

The elimination half life varies with the dose
The volume of distribution varies with the dose
The clearance varies with the dose
The rate of elimination varies directly with the dose
Solution
Drug X exhibits first order kinetics.
The half life of the drug is constant regardless of dose.
The amount of drug eliminated will vary based on the starting amount in the blood
stream.
Therefore, E is the best answer.
Re-In zero order elimination, the rate of elimination of the drug is constant, but the
half life of the drug varies (a constant amount of drug is eliminated per unit of time
versus a constant fraction per unit of time in 1st order kinetics).
PK Practice 3
Drug Y has a normal VD of 80L and a clearance of 350 ml/min. If Drug Y was
administered to a patient with 50% renal function, what parameter will differ from
normal?
a.
b.
c.
d.
e.
f.
Maintenance dose will be higher

Maintenance dose will be lower
Loading dose will be higher
The half life will be shorter
VD will be 35L
CL would be 700ml/min
Solution
With renal dysfunction, the affected variable here will be clearance.
Clearance is found only in the MD equation, not the LD equation. LD is not affected
b/c you need to give the same amount of drug at first to hit a Minimum Effective
Concentration. With clearance impaired, you just need to be a lot more careful with
subsequent doses since the drug hangs around longer.
Therefore the best answer is B
The half life of the drug will increase because less is cleared per unit of time.
The VD will stay constant.
PK Practice 4
At 6 hours after IV administration of bolus dose, the plasma level of a drug is 5 mg/L, If
the VD is 10L and the elimination half life is 3 hours, what was the dose administered?
a.
b.
c.
d.
e.
100 mg
150 mg
180 mg
200 mg
540 mg
Solution
2 half lives have elapsed.
If the current level is 5 mg/L, one half life ago, it must have been 10 mg/L, another one
half life ago, it must have been 20 mg/L.
So the loading dose is equal to the plasma concentration * volume of distribution.
20 mg/L * 10L = 200 mg.
So D is the best answer.
PK Practice 5
An IV Infusion of Hopkinolol is started at 600 mg/hr. If the drug is cleared at a rate of
37.5L in 30 minutes, what is the anticipated plasma level at steady state?
If the levels of Hopkinolol build up to toxic levels of 700 mg in every L of the patients
serum, how long will it take for the drug to be cleared from the body if the half life is 7
hours?
What drug class does Hopkinolol belong to? (N/B-It is not a real drug!)
Clinical Correlate-What is the rescue agent in toxicities of drugs belonging to the
Hopkinolol class?
Solution
The question is asking for a steady state plasma concentration.
MD/Dosing regimen is 600 mg/hr
Clearance is 75L/hr (how did I get this???). Be careful with units.
So CSS = 600 mg/hr / 75L/hr = 8 mg/L.
It will take 28-35 hrs to clear Hopkinolol (a beta-1 selective antagonist) from
circulation (remember the whole 4-5 half lives business?, dont forget it!)
Glucagon is the rescue agent in beta blocker toxicity (why does this make sense?)
Drug Metabolism
Drug Metabolism-Phase 1
-The liver receives most orally absorbed drugs via the portal circulation.
-Theres Phase 1 and 2 metabolism.
-Phase 1 reactions include ROH (remember this functional group?)-Reduction,
Oxidation, and Hydrolysis.
-Phase 1 reactions are undertaken by CYP P450 enzymes which require NADPH as a
cofactor.
-Oxidation reactions are undertaken by Oxidases (can you think of one that operates
at the Adrenergic Synapse?)
-Phase 1 usually produces metabolites that are still active.
Drug Metabolism-Phase 1
-The most important CYP enzyme is CYP3A4.
-The CYP enzyme involved in Alcohol metabolism is CYP2E1.
-CYP2E1 is also involved in the minor metabolism of Acetaminophen.
-CYP2E1 can be induced by the intake of large amounts of alcohol.
-Grapefruit juice is a CYP P450 inhibitor (irreversible) and can cause drug toxicities in
patients taking medications that are metabolized by CYP P450.
-Extensive metabolizers with CYP2D6 mutations can run into trouble when being
treated with Codeine (classic Q stem-sudden death upon initiation of a new drug
regimen for cough).
Acetaminophen Toxicity
Clinical Correlate
The rescue agent in Acetaminophen toxicity is NAcetylcysteine. It is essentially exogenous
Glutathione. This takes care of the NAPQI induced
oxidative stress.
Alcohol Metabolism/Genetic Polymorphisms
Phase 2 Metabolism
-Are conjugation reactions (add something big to aid excretion)
-Most important reactions are Glucuronidation, Sulfation, and Acetylation.
-Mediated by Transferases.
-Most metabolites are inactive and readily excretable (notable exception is Morphine
which is converted to Morphine-6-Glucuronide by UGT2B7).
-Glucuronosyltransferases require UDP-GA as a cofactor.
-Conjugation with Glutathione requires reduced glutathione (Clinical correlatedrugs eliminated in this way could be harmful in G6PD deficient patients).
Phases of Drug Development (HY for 2 exams!)
Homeopathic Medicine
-Is based on the like cures like premise.

-Dilutes active ingredients to super low
concentrations (which makes them more
active-that is the belief)
Final Words
-Pay attention to.
-Pharm is Fun (even if it may not seem like it now).
-Pharm is extremely important for patient care.
-Pharm (in addition to Physiology/Pathology/Microbiology) are HY for all of med
school/future exams/clinical practice.
-Focus on understanding (makes the memorization much easier).
-Understanding Pharm makes you a powerful test taker in med school.
HY Histology Review
Some MS2
General Histology Recommendation
-Try to learn Diagnostic Features of each

organ youre studying.
-Histology is the foundation of all the
Pathology youll learn going forward, so try
to have it down.
Q1
Which of the following best represents the relative abundance of inflammatory cells in
the blood stream (in descending order)?
a.
b.
c.
d.
e.
Neutrophils, Monocytes, Eosinophils, Basophils, Lymphocytes

Neutrophils, Basophils, Monocytes, Eosinophils, Lymphocytes
Neutrophils, Lymphocytes, Basophils, Monocytes, Eosinophils
Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils
Neutrophils, Eosinophils, Basophils, Lymphocytes, Monocytes
Never Let Monkeys Eat Bananas

-Correct ordering-Neutrophils (or PMNs), Lymphocytes, Monocytes, Eosinophils,
Basophils.
-Granulocytes include BEN-Basophils, Eosinophils, and Neutrophils.
-Agranulocytes include Monocytes and Lymphocytes.
-You cannot tell between B cells and T cells on the basis of histology (this is HY!)
Q2-What is the cell in the center of the image?
Neutrophils
-Multilobed Nucleus
-Primary responder in the setting of acute inflammation
-Contain granules that are toxic to bacteria.
-Clinical Correlate-A PMN with much more than 4 lobes on a
blood smear has a strong correlation with B12/Folate deficiency.
Q3
What is the primary function of the following leukocyte after it exits the blood?
a.
b.
c.
d.
Phagocytosis
Histamine release
Collagen Synthesis
Complement Activation
Monocytes
-Kidney/Bean Shaped Nucleus
-Involved primarily in Phagocytosis and Antigen Presentation to T cells
-Called Monocytes in the blood
-Become Macrophages in peripheral tissue with different names
-What are macrophages in the following organs called? (Liver, CNS, Skin, Bone,
Kidneys, Lungs)
-Wall off infection by forming Multinucleated Giant Cells
Macrophage Cells
-Liver (Kupffer)
-Lungs (Alveolar Macrophages-also called dust cells)
-Kidneys (Mesangial Cells)
-Bone (Osteoclasts)
-Skin (Langerhans Cells)
-CNS (Microglia)
Q4
The cells shown at the tip of the arrow are responsible for the bodys defence against?
a.
b.
c.
d.
Fungi
Parasites
Bacteria
Other humans
Eosinophils
-Have a bilobed nucleus
-If you have very pink granules on your exam in a cell that you can pick with your
fingers-think Eosinophils.
-Dont forget the Ddx for Eosinophilia (HY)-NAACP (for your test)
Neoplasm, Asthma, Allergy, Collagen Vascular Disease, Parasites (Helminths via
Major Basic Protein)
For the boards/wards-use DNAAACP (Drugs,Atopic Diseases, Asthma, Addisons
Disease, Collagen Vascular Disease, and Parasites)
Q5
Identify the leukocyte shown in the following image.
a.
b.
c.
d.
e.
Neutrophil
Lymphocyte
Basophil
Eosinophil
Monocyte
Lymphocytes
-Include B/T cells that are part of our Adaptive Immune System and NK cells which
are a part of the Innate Immune System
-B cells differentiate into? (These form antibody factories)
-Can you tell B and T cells apart on histology?
-T cells are involved in cell mediated immunity and Bs are involved in humoral or
blood based immunity
-The cell is essentially filled with the nucleus with a thin rim of cytoplasm around it
Other HY Factoids with the blood smear

-RBCs (Erythrocytes) stain pale pink with the Giemsa stain.
-Platelets are basically cell fragments derived from?
-Is protein synthesis possible in a RBC?
-Basophils are the primary cells indicated in allergies (they degranulate and release
histamine). Basophils are found in blood. What is the analogous cell type in tissue?
Blood Cells in one field of view (make IDs)
Q6
A section of the small intestine is collected on Autopsy of a patient that recently died
of a Cardiac Arrhythmia. PAS +ve organisms were identified in the Lamina Propria of
the patient's bowel. PAS is particularly useful for identifying which of the following
biological materials?
a.
b.
c.
d.
e.
Collagen
Lipids
Nucleic Acids
Sugars
Proteins
Periodic-Acid Schiff (this is Super HY!)

-Is used to stain for areas with sugars, particularly glycogen.
-Is used to visualize the basement membrane and goblet cells (wouldnt be surprising if
youre asked about the stain used to identify a particular cell type in the GI tract on the
test)
-Stains the Basement Membrane magenta (i.e. the kidneys)
-Clinical Correlate-Used in the definitive Diagnosis of Whipples Disease caused by the
PAS +ve organism, Tropheryma Whippelii.
Q7
A specimen of a small muscular artery is being examined in the Forensics lab by a
Med19 student. The smooth muscle fibers in the tunica media appear red, and the
collagen bundles in the tunica adventitia appear blue. The slide was most likely colored
using which of the following stains?
a.
b.
c.
d.
Hematoxylin and Eosin

Masson Trichrome
Mucicarmine
Periodic Acid Schiff
Masson Trichrome/Other Stains

-Used primarily to stain collagen.
-Very good at detecting tissue fibrosis especially in the Liver
-The VVG stain is used to stain elastic fiber containing tissue like large arteries
-The nucleus contains nucleic acids and should be stained for by a basic stain like Hematoxylin (blue).
-The cytosol contains tons of proteins which are basic and should be stained for by an acidic stain like Eosin
(pink).
-Gram +ve organisms stain blue (like S. Aureus), Gram -ve organisms stain pink (like E. Coli)
-What is the agent responsible for the pale pink color of Erythrocytes?
Q8
Which of the following types of cartilage or bone is found in the epiphyseal growth
plates of children and adolescents?
a.
b.
c.
d.
e.
Articular Cartilage
Elastic Cartilage
Hyaline Cartilage
Fibrocartilage
Mature bone
Hyaline Cartilage
-Primary skeleton in Embryo
-Bone Precursors
-Cells are Chondrocytes
-Avascular (poor repair)
-Chondroitin Sulfate (attracts water)
-Found in trachea (HY!)
Q9
Which of the following connective tissue cells initiates the mineralization of the bone
matrix during growth and bone remodeling throughout life?
a.
b.
c.
d.
e.
Osteoclasts
Osteocytes
Osteoblasts
Bone lining cells
Osteoprogenitor cells
Q10
Bone obtained from the autopsy of a 99 yo. man is examined by Light Microscopy. ID
the structures indicated by the circles.
a.
b.
c.
d.
e.
Haversian Systems
Haversian Canals
Bony spicules
Canaliculi
Volkmann Canals
Q11
A high magnification bone specimen is obtained from the tibia of a Med19 student. ID the thin lines indicated
by the arrows.
a.
b.
c.
d.
Lacunae containing osteoclasts

Lacunae containing osteocytes
Canaliculi containing Osteocyte processes
Haversian canals w/nerves
Q12
The following specimen was obtained from the skull of a small infant during a BMT.
Match the structures indicated by the pointers (Arrow, Arrowhead)
a.
b.
c.
d.
e.
Endosteum, Osteoclast
Periosteum, Osteoblast
Osteoid, Osteoblast
Lacuna, Osteocyte
Lamella, Osteoblast
Q13
The multinucleated cells indicated at the tips of the arrows are primarily for;
a.
b.
c.
d.
Bone formation
Bone resorption
Bone mineralization
Bone maturation
Bone Cells (Bone is vascular!)

-Osteoblasts (new matrix, chemical generated?, they are the huge cells right by the surface of trabecular bone)
-Osteocytes (lacunae entrapment)
-Osteoclasts (bone breakers, derived from?, # of nuclei?, structure formed in enabling bone breakdown?)
-Osteoprogenitors (Osteoblast precursors)
-Haversian System (includes a Haversian canal that contains blood vessels)
-Canaliculi (are intercellular projections b/w Osteocytes for communication, contain Gap Junctions)
-Theres 2 major kinds of bone-spongy bone AND compact bone
-The CT around bone is called Periosteum (Perichondrium for cartilage)
-Know and be able to ID the layers of the epiphyseal plate
Q14
Identify the structures at the tips of the arrows;
a.
b.
c.
d.
e.
Z discs
Intercalated discs
M lines
Intercalated lines
I bands
Q15
A diagnosis of GERD is made in a 50 yo. obese male based on a biopsy of his Esophagus. The tissue seen in this
specimen was obtained from the same biopsy. Which of the following best describes the characteristics of this
tissue type?
a.
b.
c.
d.
e.
Is under the control of the Somatic NS

Is under the control of the Autonomic NS
Has multiple nuclei
Is found in the walls of blood vessels
B and D are correct
Q16
Which of the following best represents the next hierarchy in skeletal muscle
organization following the structure circled in the photomicrograph below?
a.
b.
c.
d.
e.
Myofibril
Myofiber
Z lines
Actin and Myosin
Sarcomeres
Muscle Tissue
-Skeletal (Multinucleated) and Cardiac muscle (1-3 nuclei) are striated.
-Cardiac and Smooth Muscle are under Involuntary (Autonomic Nervous System)
control.
-Skeletal muscle is under somatic control (voluntary), is the largest of all muscle types,
and progresses from Fascicle-Myofiber (actual cell)-myofibril-Sarcomeres-Actin and
Myosin filaments.
-In general, muscle can undergo hypertrophy (cell size increase) but not hyperplasia (#
of cell increase).
Q17
A 45 yo. man presents with small nodules on his hands. A biopsy of the lesion reveals
Basal Cell Carcinoma and adjacent areas of normal skin shown in this image. The area
indicated by the arrows is composed of which of the following tissue types.
a.
b.
c.
d.
e.
Dense Irregular CT
Dense Regular CT
Smooth muscle
Skeletal Muscle
Glandular Epithelium
Follow Up
Which of the following types of connective tissue is found directly beneath the
basophilic surface epithelium in the preceding picture?
a.
b.
c.
d.
e.
Adipose Tissue
Dense Regular Connective Tissue
Elastic Connective Tissue
Loose Connective Tissue
Reticular Connective Tissue
Q18
A 26 yo. female presents to the Med19 free clinic with complaints of myalgias which started 2 days ago. She was
recently placed on Ciprofloxacin as a means of combating an uncomplicated UTI. Which of the following best
describes the tissue type found in the biopsy taken of the patients tendon?
a.
b.
c.
d.
e.
Loose connective tissue

Elastic connective tissue
Dense Irregular CT
Dense Regular CT
Areolar CT
Connective Tissue Takeaways

-Q17 (Dense Irregular Connective Tissue), Follow Up (Loose Connective Tissue), Q18-Dense Regular
CT.
-Loose CT is primarily for support and contains multiple cell types like adipocytes and inflammatory
cells (i.e. mast cells-analogous to what cell type found in blood?)
-Dense Regular CT is found primarily in tendons and ligaments.
-Dense Irregular CT is found primarily in the dermis of the skin and the sclera of the eyes.
-Elastic tissue is found in tissues that require distensibility like the outer ear and muscular arteries.
-Collagen is the primary matrix found in CT. Elastin is the principal constituent of elastic fibers.
Q19
What is the general function undertaken by the cells indicated at the tips of the
arrows?
a.
b.
c.
d.
Protection
Allows for passive diffusion
Absorption and Excretion
Antibody production
Q20
What is the apical surface modification associated with the following cell type that is
also found in the Duodenum?
Simple Columnar Epithelium

-Primarily for absorption
-In the GI tract, have microvilli for increasing absorptive surface area.
-In the proximal convoluted tubule, simple cuboidal epithelium also possess the same
modifications for increased absorption.
-In the fallopian tubes, have cilia for pushing things through the female reproductive
tract.
-Apical Surface Modifications are very HY for Histology exams!
Q21
The cells lining this vascular channel demonstrate what kind of epithelial cell
morphology?
Simple Squamous Epithelium

-Diffusion epithelium
-Found on absorptive surfaces like the tunica intima of blood vessels, Type 1
Pneumocytes of the lungs, etc.
Q22
The following biopsy obtained from a patient presenting with complaints of dysphagia
to both solids and liquids demonstrates what kind of epithelial cell morphology?
Q23
If a biopsy of the same organ was taken from a different patient and indicated the
epithelium shown below, what is the term that best describes the underlying
mechanism behind the morphological change observed?
a.
b.
c.
d.
e.
Hyperplasia
Hypertrophy
Dysplasia
Metaplasia
Dyscrasia
Stratified Squamous Epithelium

-Q22 is Non-Keratinized Stratified Squamous Epithelium in the Esophagus (common
exam mistake is to not read carefully and pick Keratinized SSE which is found
primarily in skin)
-Q23 is Metaplasia which is found in the setting of individuals with chronic GERD
(acid reflux into the Esophagus-Barretts Esophagus). Gastric Epithelium (what kind?)
is better suited to deal with acidic stress so Esophageal Metaplasia occurs which can
eventually progress to Dysplasia and then Esophageal Adenocarcinoma.
Q24
The following biopsy obtained from a patient presenting with signs and symptoms of
painless hematuria demonstrates what kind of epithelial cell morphology?
Epithelial Takeaways
-Q24 is Urothelium (also known as Transitional Cell Epithelium) which lines most of
the GU tract (starting from the calyces of the kidneys).
-Pseudostratified Ciliated Columnar Epithelium are found in the respiratory tract
(possessing what kind of surface modification?) and whip up all the bad things we
inhale.
-Be able to distinguish between cilia (motile/non-motile, locomotory, made of
microtubules) and microvilli (non-motile, absorptive, made of actin).
-Be familiar with the different kinds of Intercellular Junctions (Tight Junctions,
Adherens Junctions, Desmosomes, and Gap junctions-which make up the intercalated
disks of cardiomyocytes).
Epithelium Matching Game (key on next slide-DIY first)

-Pseudostratified Ciliated Columnar Epithelium
-Simple Columnar Epithelium with Microvilli
-Simple Cuboidal Epithelium with Microvilli
-Simple Ciliated Columnar Epithelium
-Transitional Epithelium with Umbrella Cells
-Stratified Squamous Non-Keratinized Epithelium
-Simple Cuboidal Epithelium making Surfactant
-Simple Cuboidal Epithelium making T3/T4
-Simple Squamous Epithelium that reabsorbs water
Epithelium Matching Game Key (HY List!)

-Pseudostratified Ciliated Columnar Epithelium-Trachea, Upper respiratory Tract
-Simple Columnar Epithelium with Microvilli-Absorptive Cells of the Small Intestine
-Simple Cuboidal Epithelium with Microvilli-Proximal Convoluted Tubule (PAS+)
-Simple Ciliated Columnar Epithelium-Fallopian Tubules
-Transitional Epithelium with Umbrella Cells-Urothelium of the Bladder/Kidney Collecting System
-Stratified Squamous Non-Keratinized Epithelium-Esophagus
-Simple Cuboidal Epithelium making Surfactant-Type 2 Pneumocytes of the Lung
-Simple Cuboidal Epithelium making T3/T4-Follicular Cells of the Thyroid
-Simple Squamous Epithelium that reabsorbs water-Thin Loop of Henle in the Kidney
Q25
What is the general term used to describe the circle as a whole? What are the 3
individual constituents of the circle? Blood from 2 members of the circle ultimately
drain into - through -?
Q25 Key
-Portal Tract/Triad
-Includes Hepatic Artery (O2 rich), Portal Vein (Nutrient Rich), Bile Ducts (simple
cuboidal epithelium)
-Drain through the Sinusoidal Capillaries (lined by what kind of epithelium? What is
special about this epithelium? Is there a basement membrane?)
-Ultimately drain into the Central Vein which returns blood to the IVC through the
Hepatic Vein.
-Dont forget the resident macrophages of the liver (what are they?)
Q26
The cells shown below receive blood from the - side of the cell and secrete bile into the
- side of the cell.
a.
b.
c.
d.
Apical, Basolateral
Lateral, Basolateral
Apical, Basal
Basolateral, Apical
Liver-contd.
-Bile is secreted into the bile canaliculi on the APICAL side of the hepatocyte.
-Bile travels from the HEPATOCYTE to the PORTAL TRACT through the bile
canaliculi (and ultimately to the bile ducts).
-Blood is received from the BASOLATERAL side of the hepatocyte.
-Blood flows from the PORTAL TRACT through the sinusoids towards the
HEPATOCYTE.
-Take note of the distinction in directionality of blood and bile flow (HY!)
Liver Histology
Q27
What is the apical surface modification associated with the cells of the structure shown
below? What does this structure receive flow from? What does this structure drain
into? Outline the pathway of flow through the organ this section was taken from.
Q27 Key
-Microvilli of the Proximal Convoluted Tubule
-Receives ultrafiltrate from Bowmans space
-Drains into the Loop of Henle
Q28
Identify the structure at the tip of the arrow.
Q28
Is the Macula Densa
Q29
Identify the structure at the tip of the arrow.
Q29
Is the Transitional
Epithelium of the Bladder
The Renal Corpuscle/Glomerulus
Pathway of Kidney Flow
Clinical Correlate
-The Renin Angiotensin Aldosterone system is one of the more important blood
pressure control mechanisms. The Sensor that kicks off this system is the Macula
Densa.
-The Proximal Tubules are the site of action of Parathyroid Hormone in activating the
enzyme that makes active Vitamin D.
-Many BP control medications work at different sites throughout the Nephron.
-Many drugs exert Nephrotoxic side effects by targeting several sections of the
Nephron (classic Q stem-a person being treated for Bipolar Disorder presenting with
signs and symptoms of Polyuria).
Q30
What is the hormone secreted by the cell circled below? What is the hormone secreted
by the other cells? What is the term used to describe the red material?
Parafollicular/Clear Cells/C-cells
-Secrete Calcitonin
-Reduces blood Ca levels (Calcitones down your blood Ca)
-Released in response to high Ca levels in the blood.
-Are clear, large cells found in the thyroid (derived from Neural Crest)
-The thyroid gland contains cuboidal cells in follicles which secrete T3 and T4. These
hormones are stored (bound to thyroglobulin) in the red material known as Colloid.
-The thyroid gland is derived from the thyroglossal duct which descends from the base
of the tongue.
Q31
The following section was most likely obtained from what organ? Identify the layer outlined by the arrow.
The Colon (as other parts of the GI tract)

-3 layers (Mucosa, Submucosa, and Muscularis Propria/Externa)
-Mucosa has 3 subdivisions (Epithelium-Simple Columnar in this case, Lamina
Propria-contains what?, and Muscularis Mucosa)
-Muscularis Propria has 2 layers-Inner Circular and Outer Longitudinal (take note of
the second letter-I in circular, O in longitudinal-memory tools)
Theres a serosa below the muscularis propria that is lined by what kind of epithelium?
-Goblet cells contain Mucin. What stains Mucin? (PAS-Magenta)
HY Lung Factoids
-What is the kind of epithelium found in the trachea?
-What is the apical surface modification found on the epithelium of the trachea?
-What is the diagnostic connective tissue type that differentiates the trachea/bronchi from the bronchioles?
-What are the components of the conducting zone?
-What are the components of the respiratory zone?
-What kind of epithelium is found in the terminal bronchioles?
-What kind of epithelium is found in the respiratory bronchioles?
-What is the specialized cuboidal cell that shows up at irregular intervals within the respiratory zone?
Key
-Pseudostratified Ciliated Columnar Epithelium
-Cilia
-The presence of hyaline cartilage
-Nose, Pharynx, Larynx, Trachea, Bronchi, Terminal Bronchioles.
-Respiratory bronchioles, Alveolar Ducts-Sacs-Alveoli (no smooth muscle here)
-Ciliated Columnar Epithelium
-Cuboidal Epithelium
-Clara Cells
Pneumocytes/Lung blood supply
Q32
The image shown below demonstrates what type of cellular adaptive process?
Atrophy
-Is the outgrowth of decreased stress
-Occurs via a decrease in cell size or cell number.
-Occurs in the setting of degenerative disease (Alzheimers) or immobilization
(nursing home).
-Also occurs in menopause/death of nervous tissue/decreased endocrine stimulation.
Q33
The following pathology specimen was obtained post-mortem from an individual that was brought into
the ER with blood pressures of 280/160. What is the adaptive mechanism underlying the change
observed below?
Hypertrophy
-Remember that Cardiac Myocytes are permanent cells.
-They cannot increase in cell number (hyperplasia).
-They can only increase in cell size (hypertrophy).
-Hyperplasia is often observed in response to endocrine stimulation (uterus in
pregnancy-which also undergoes hypertrophy).
-Hypertrophy occurs in the setting of an increased workload-breast (pregnancy),
muscle (exercise, physiologic OR hypertension, pathologic).
Q34
A 60 yo. man presents to the ER with complaints of crushing chest pain. A biopsy of his heart muscle is shown
below? What is the pathologic process indicated by the cells shown on this slide?
Coagulative Necrosis
-Cellular outline is usually preserved (early on).
-Very common in the heart and kidneys.
-Mechanism involved is the loss of blood supply to tissues (i.e in the setting of an
embolus or complete occlusion of a blood vessel).
-When cells die, they spill contents into the circulation. These contents are very
useful in evaluation of disease (for example Troponin in Myocardial Infarction,
AST/ALT in Hepatitis, etc.)
Q35
The change observed below is the sequelae observed in individuals with a long history
of a.
b.
c.
d.
Smoking
Coffee drinking
Alcoholism
Drug abuse
Cellular Adaptations
Progression to Necrosis (Follow the Arrows)
Necrosis vs. Apoptosis
The Mechanism of Acute Inflammation
Acute Inflammation
-Primary cell involved is the Neutrophil (24-48 hrs post-infection)
-With increased vascular permeability, there is the movement of blood into interstitial
spaces. This results in edema.
-Transudate is transparent with low protein(helps you remember that it has a
specific gravity of less than 1.012-mechanism is increased hydrostatic pressure, vessel
wall is mostly intact).
-Exudate is the only option left (SG greater than 1.012-mechanism is increased vascular
permeability, high protein content).
-In addition to histamines, leukotrienes are also responsible for the increased vascular
permeability.
For the sake of time...

-Review chronic inflammation
-Review the Nervous System material
-Go through MScope/Inversus
Micro Rapid Review

Some MS2
Gram Positives
-Mostly rods (Bacilli), Cocci, or Filamentous Rods.
HY Pictures-What are these organisms?
Key
Top left-Gram Positive Cocci in chains-Streptococcus
Top Right-Gram Positive Rods-Listeria
Bottom Left-Gram Negative Rods-E.Coli
Bottom Right-Gram Negative Cocci-Neisseria
Gram Positive Cocci

-Are differentiated by the Catalase test
-All Strep species are catalase negative. Further distinctions are made by hemolysis on
blood agar.
-All Staph species are catalase positive. The next best test in distinguishing Staph is the
coagulase test. S. Aureus is Coagulase +ve with the others being Coagulase negative.
-The coagulase negative Staph species include S. Epidermidis (contaminates blood
cultures) and S. Saprophyticus (UTI in a sexually active young female). These can be
differentiated with the Novobiocin test (Epidermidis is sensitive, Saprophyticus is
resistant)
Strep Species
-When you see the words, Gram +ve Diplococci, you should begin to think of S. Pneumo.
-The next best test in the evaluation of a catalase positive organism is its hemolysis pattern on blood agar.
-Alpha hemolysis is partial hemolysis with the colonies appearing green. This is characteristic of S. Pneumo and
S. Viridans.
-Beta Hemolysis is complete hemolysis with a clear zone produced on blood agar. This is characteristic of S.
Pyogenes (GAS) and S. Agalactiae (GBS).
-Please do not think that Group A Strep is Alpha Hemolytic!! (common mistake many make).
-Gamma Hemolysis means no hemolysis and is characteristic of Enterococcus species.
Blood Agar Hemolysis
Gram Positive Rods

-Best grouped as being spore OR non-spore forming.
-Spore formers could be aerobic or anaerobic.
-The Aerobic, Spore Forming, Gram +ve rods are the Bacillus species.
-B. Cereus is motile, B. Anthracis is nonmotile (this is HY!)
-The Anaerobic, Spore Forming, Gram +ve rods are the Clostridia Species.
-C. Difficile, C. Tetani, and C. Botulinum are all motile, C. Perfringens is non-motile.
-Of the non-spore forming Gram Positive Rods, theres L. Monocytogenes AND C. Diphtheriae.
-Listeria is motile, C. Diphtheriae is nonmotile.
-Theres also Gram +ve filamentous rods. Actinomyces and Nocardia are characteristic.
-Nocardia is Aerobic and Acid Fast, Actinomyces is Anaerobic and not acid fast.
Q1
What is the organism that best fits the following info cluster?
-Vomiting 2-6 hrs after eating potato salad/custard
-Generates a pre-formed toxin that causes a nasty gastroenteritis.
-Beta Hemolytic.
-Gram +ve cocci in clusters.
-Superantigen causes skin sloughing
-Sepsis in a woman leaving super-absorbent tampons in for a few days
Q1 Key
-Vomiting 2-6 hrs after eating potato salad/custard
-Generates a pre-formed toxin (which is heat resistant) that causes a nasty
gastroenteritis.
-Beta Hemolytic.
-Gram +ve cocci in clusters.
-Superantigen causes skin sloughing
-Sepsis in a woman leaving super-absorbent tampons in for a few days
-Staphylococcus Aureus.
S. Aureus
-Is a HY bug (know it like you know your name)
-Has Protein A which binds to the constant region of IgG and hence prevents
phagocytosis/opsonization.
-Has the ability to convert fibrinogen to fibrin by virtue of what virulence factor?
-You should definitely know the Superantigens associated with S. Aureus.
-Theres the Exfoliative Toxin that causes Scalded Skin Syndrome.
-Theres also the TSST-1 toxin that causes TSS which is accompanied by massive
hand/sole desquamation (by bridging MHC2 and the V-beta region of the TCR in a
nonspecific fashion)
S. Aureus contd.
-The TSST-1 toxin is strongly associated with leaving a foreign bloody body in for
too long. Classic exam scenarios include Super-Absorbent tampons left in a for a few
days/nasal packing.
-You should seriously consider S. Aureus if you get a question in a person that goes
into sepsis days after covering some internal injury with something made of cotton.
-S. Aureus is gram +ve, so it does not have LPS.
-Note that all Staph toxins are exotoxins. Exotoxins are characteristic of Gram +ves
while Endotoxins (LPS) are characteristic of Gram -ves.
S. Aureus contd.
-Presents in hospitals as MRSA which typically colonizes the nares of hospital workers.
-MRSA is MRSA because it has an altered penicillin binding protein (PBP 2A). This is
the differentiator b/w MSSA and MRSA. It is relatively HY to know the mechanisms of
resistance in select bugs to certain drugs with S. Aureus being one of them.
-Methicillin is resistant to beta-lactamase, so it is not the presence of beta lactamase
that makes MRSA virulent.
-Note that Transpeptidase is an example of a PBP.
S. Aureus contd.
-If you see a question about a person that has the flu and then gets a pneumonia after
the flu goes away, pick S. Aureus as the offending organism. This is important (dont
choose S. Pneumo).
-S. Aureus is also the most common cause of ACUTE bacterial endocarditis. Especially
in a drug user (this is HY!)
Q2
What is the organism that best fits the following Info cluster?
-Endocarditis in a patient with a prosthetic valve
-Produces Biofilm that enables adhesion to indwelling catheters
-Contaminates blood cultures
Q2 Key
-Endocarditis in a patient with a prosthetic valve
-Produces Biofilm that enables adhesion to indwelling catheters
-Contaminates blood cultures
-S. Epidermidis
Q3
-Most common cause of lobar pneumonia in adults/the elderly.
-Gram positive cocci in pairs/lancet shaped
-Most important virulence factor is the capsule
-Pneumolysin causes alpha hemolysis
-Rust colored sputum
Q3 Key
-Most common cause of lobar pneumonia in adults/the elderly.
-Gram positive cocci in pairs/lancet shaped
-Most important virulence factor is the capsule
-Pneumolysin causes alpha hemolysis
-Rust colored sputum
-Streptococcus Pneumoniae
S. Pneumoniae
-How would you detect the capsule of S. Pneumo???
-Produces IgA protease which cleaves IgA and renders it ineffective.
-This is the primary reasoning behind S. Pneumo being a powerful mucosal bug.
-Remember that IgA is the Guardian of the Mucosa.
Q4
-Produces biofilm that enables binding to tooth enamel.
-Common cause of Subacute Endocarditis by binding to fibrin
-Dental Procedures
Q4 Key
-Produces biofilm that enables binding to tooth enamel.
-Common cause of Subacute Endocarditis by binding to fibrin
-Dental Procedures
-Streptococcus Viridans
Q5
-Causes rheumatic fever.
-M protein is very antigenic.
-Child with a beefy red/strawberry tongue.
-Honey crusted lesions on the mouth.
Q5
-Causes rheumatic fever.
-M protein is very antigenic.
-Child with a beefy red/strawberry tongue/Sandpaper Rash (Scarlet Fever)
-Honey crusted lesions on the mouth (Impetigo)
-Streptococcus Pyogenes (GAS)
-Also causes Necrotizing Fasciitis/Cellulitis (leg issues) and Glomerulonephritis in
kids.
Scarlet Fever
Q6
-Intrapartum penicillin given to a pregnant woman with this bug.
-Common cause of neonatal meningitis
Q6 Key
-Intrapartum penicillin given to a pregnant woman with this bug.
-Common cause of neonatal meningitis
-Group B Strep (Streptococcus Agalactiae)
Q7
What is the organism that best fits the following associations?
Reheated Rice
Painless Black Eschar
Edema/Lethal Factor/Protective Antigen
Hemorrhagic Mediastinitis/Widened Mediastinum on CXR
Q7 Key
Reheated Rice-Bacillus Cereus
Painless Black Eschar-Bacillus Anthracis
Edema/Lethal Factor/Protective Antigen-Bacillus Anthracis
Hemorrhagic Mediastinitis/Widened Mediastinum on CXR-Bacillus Anthracis
Q8
Toxin inhibits ACH release/causes flaccid paralysis
Spoiled Canned Goods (Preformed Toxins)
Honey in babies (Spores)
Floppy baby syndrome
Pseudomembranous Colitis
Diarrhea after taking Antibiotics (especially Clindamycin)
Q8 Key
Toxin inhibits ACH release/causes flaccid paralysis-C. Botulinum
Spoiled Canned Goods (Preformed Toxins)-C. Botulinum
Honey in babies (Spores)-C. Botulinum
Floppy baby syndrome-C. Botulinum
Pseudomembranous Colitis-C. Difficile
Diarrhea after taking Antibiotics (especially Clindamycin)-C. Difficile
Clostridium Species (Form Spores)

-C. Botulinum produces a toxin that inhibits Ach release from presynaptic neurons and hence causes flaccid paralysis.
-The toxin is ingested preformed in adults, but the spore is what is consumed in kids. The spores can germinate in the
gut of infants (not so well in adults).
-When you take antibiotics, you destroy your gut flora. C. Difficile sees this as a chance to overgrow. In the process, it
causes Pseudomembranous Colitis.
-Toxin A of C. Difficile is an enterotoxin that disrupts the cytoskeleton by depolymerizing actin, Toxin B is a cytotoxin.
-C. Tetani produces tetanospasmin, an exotoxin that causes tetanus by blocking the release of inhibitory
neurotransmitters, hence causing spastic paralysis (contrast with the flaccid paralysis of C. Botulinum!)
-Choose C. Tetani if you get a question dealing with an organism that gains entry via a wound. Classic buzzwords
associated with this bug include lockjaw, Risus Sardonicus, etc.
-C. Perfringens causes gas gangrene. This is mediated by Alpha Toxin. It also causes a Watery Diarrhea.
Q8
Tumbling motility
Grows well in the cold (4 degrees)
Granulomatosis Infantisepticum
Nausea/Diarrhea/Fever/Myalgia in a pregnant woman
Beta Hemolytic
Deli Meat/Unpasteurized milk consumption by a pregnant woman
Treat w/Ampicillin
Q8 Key
Tumbling motility
Grows well in the cold (4 degrees)
Granulomatosis Infantisepticum
Nausea/Diarrhea/Fever/Myalgia in a pregnant woman
Beta Hemolytic
Treat w/Ampicillin
Deli Meat/Unpasteurized Milk consumption by a pregnant woman
-Listeria Monocytogenes (travels with Actin Rockets)
Neonatal Meningitis
-The most common cause is Group B Strep.
-The second most common cause is E. Coli.
-The 3rd most common cause is Listeria (which is
facultatively intracellular)
Corynebacterium Diphtheriae
-Causes Bulls Neck
-If you get a question about an immigrant with Pseudomembranous Pharyngitis (that
looks grey), you should strongly consider C. Diphtheriae
-The MOA of its exotoxin is the inhibition of protein synthesis (HY)
-Grows as a club shaped/catalase positive rod.
-Transmitted via respiratory secretions.
-Can be prevented with the DTaP vaccine.
-Corynebacterium nukes the heart/the brain (HY)
HY Corynebacterium Picture (Pseudomembranous Pharyngitis/Bulls Neck)
Gram Negatives
-Best classified as Diplococci, Coccobacilli, and Rods.
-The main Gram -ve Diplococci are Neisseria Meningitidis and Gonorrhea (careful
when you see diplococci on your exam, look for the gram staining pattern first before
picking an answer, dont always knee jerk to S. Pneumo).
-N. Meningitidis/Gonorrhea both ferment glucose. Only N. Meningitidis ferments
maltose.
-In terms of rods, Klebsiella and E. Coli are the big guns. They ferment lactose (i.e. they
grow on Macconkey's agar-pink). A key differentiator is the fact that E. Coli is indole
positive while Klebsiella is not.
Gram Negatives-Lactose Non-Fermenters

-Best grouped as being oxidase negative or positive.
-Important Oxidase Negative bugs include Salmonella, Shigella, and Proteus.
-Salmonella is motile and produces hydrogen sulfide. Shigella is nonmotile and does
not produce hydrogen sulfide.
-Proteus is oxidase negative but urease positive. Proteus swarms on agar plates.
-Important oxidase positive bugs include the Vibrio species and Pseudomonas.
Q9
-Oxidase +ve
-S/Comma shaped
-Ascending paralysis after infection
-Bloody diarrhea
-Poultry consumption
Q9 Key
-Oxidase +ve
-S/Comma shaped
-Ascending paralysis after infection (Guillain Barre)
-Bloody diarrhea
-Poultry consumption
-Campylobacter Jejuni
Other HY Gram Negatives (Coccobacilli)

-Haemophilus Influenzae (requires Factors X/V for growth)
-Theres also Haemophilus Ducreyi that causes Chancroid which is painful (vs painless
Syphilis)
-Legionella (associated with Pneumonia from air-conditioning systems/water supplies)
-Bordetella Pertussis (that causes cough with inspiratory whoops/the 100 day cough)
OUT OF PLACE-Aeromonas (non-bloody diarrhea from freshwater exposure)
Q10
What is the organism that best meets the following Info Cluster?
-Polysaccharide Capsule
-Hemorrhagic Adrenal Gland Necrosis
-Treat with Ceftriaxone, prophylaxis with Rifampin
-Has a lipo-oligosaccharide
Q10 Key
-Polysaccharide Capsule
-Hemorrhagic Adrenal Gland Necrosis (Waterhouse Friderichsen-very HY!)
-Treat with Ceftriaxone, prophylaxis with Rifampin
-Has a lipo-oligosaccharide
-Neisseria Meningitidis (be suspicious of the words stiff neck/nuchal rigidity on an
exam)
Q11
-No capsule
-No vaccine
-Pili is a strong virulence factor
-Arthralgias w/Purpura in a young individual (Septic Arthritis)
-Sequelae include Pelvic Inflammatory Disease/Female Infertility
-Treat with Ceftriaxone
Q11 Key
-No capsule
-No vaccine
-Pili is a strong virulence factor
-Arthralgias w/Purpura in a young individual (Septic Arthritis-very HY!)
-Sequelae include Pelvic Inflammatory Disease/Female Infertility
-Treat with Ceftriaxone
-Neisseria Gonorrhoeae
Q11 Key
-Aspiration Pneumonia in an alcoholic
-Red currant jelly sputum
-Thick, mucoid colonies
-Empyema/Lung cavitation
Q11 Key
-Aspiration Pneumonia in an alcoholic
-Red currant jelly sputum
-Thick, mucoid colonies
-Empyema/Lung cavitation
-Klebsiella Pneumoniae (if the sputum is foul smelling, dont pick Klebsiella, pick
Bacteroides or the answer that says anaerobe)
E. Coli
-ETEC causes watery diarrhea that is analogous to that caused by the Cholera toxin.
-ETEC is the most common cause of travelers diarrhea (Montezumas Revenge)
-If you get a question about some guy traveling/going on a vacation and then coming
down with watery diarrhea upon return, you really want to think about ETEC.
-EHEC (O157:H7) produces Shiga Like Toxin and causes bloody diarrhea which is
usually preceded by a watery diarrhea(also characteristic of Shigella, inactivates the
60S ribosomal subunit). EHEC also causes Hemolytic Uremic Syndrome.
-Note that Shigella invades the intestinal mucosa but EHEC does not.
Shigella vs. Salmonella (HY!)

-They are both oxidase negative.
-Shigella (Sonnei is the most common) is nonmotile and does not produce Hydrogen
Sulfide. The opposite holds for Salmonella. Salmonella is transmitted by turtles.
-Shigella requires very few organisms for infection (super HY!)
-Salmonella Enteritidis/Typhimurium cause bloody diarrhea. Salmonella Typhi causes
Typhoid Fever (be aware of this distinction!). S. Typhi is strongly associated with
Rose Spots on the abdomen.
-Salmonella causes Osteomyelitis in Sickle Cell patients!
-However, the most common cause of Osteomyelitis is S. Aureus.
The Rose Spots of S. Typhi
Q12
What is the organism that is best associated with the following Info cluster?
-Infections in Diabetics
-Otitis Externa
-Hot tub folliculitis (ear/skin infection in a swimmer)
-Drug of Choice is Ticarcillin/Piperacillin with Tazobactam
-Produces a blue green pigment (Pyocyanin)
-Grape like Odor
-Ecthyma Gangrenosum
Q12 Key (please commit to memory)

-Infections in Diabetics
-Otitis Externa
-Hot tub folliculitis (ear/skin infection in a swimmer)
-Drug of Choice is Ticarcillin/Piperacillin with Tazobactam
-Produces a blue green pigment (Pyocyanin)
-Grape like Odor
-Ecthyma Gangrenosum
-Pseudomonas Aeruginosa (also causes infections in burn victims)
Q13
-Watery Diarrhea
-Treat with fluid/electrolyte replacement
-Toxin causes increased cAMP activation
-Diarrhea with Rice-Water Stools
Q13 Key
-Watery Diarrhea
-Treat with fluid/electrolyte replacement
-Toxin causes increased cAMP activation
-Diarrhea with Rice-Water Stools
-Vibrio Cholerae
Other Vibrio Species

-V. Parahaemolyticus/Vulnificus are associated with seafood
consumption, especially shellfish and oysters.
-The Key Differentiator is that V. Vulnificus is associated liver
disease (usually cirrhosis).
Q14
What is the organism that is best described by the following Info cluster?
-Non-bloody diarrhea
-Pork consumption
-Diarrhea associated with Appendicitis like pain?
Q14 Key
What is the organism that is best described by the following Info cluster?
-Non-bloody diarrhea
-Pork consumption
-Diarrhea associated with Appendicitis like pain?
-Yersinia Enterocolitica
Random but HY!

-Stenotrophomonas ferments Maltose faster than
Glucose
-Burkholderia Cepacia causes Pneumonia in Cystic
Fibrosis patients
Treponema Pallidum-Know Your Syphilis!
Chlamydia
Antibiotics Introduction
-The Minimum Inhibitory Concentration is the lowest concentration of drug needed to inhibit bacterial growth.
Is a bacteriostatic drug term.
-The Minimum Bactericidal Concentration is the lowest concentration of drug needed to kill 99.9% of bacteria.
Is a bactericidal drug term.
-Bacteriostatic Drugs are good for immunocompetent people. It slows the rate of bacterial growth which gives
the immune system time to kill the bug.
-Bactericidal Drugs are good for immunocompromised people. It kills off the bug completely (since their
immune systems are weak).
-Combination Therapy is typically given with Antibiotics to decrease resistance AND to achieve synergism (1+1
= 3).

-An example of Synergism is the addition of an Aminoglycoside with a Penicillin. The penicillin blows a hole in
the cell wall. This makes it easier for the aminoglycoside to get in (note that these are 2 bactericidal drugs).
-On the other hand, taking tetracycline and an aminoglycoside (bactericidal + bacteriostatic) is not prudent
because the tetracycline decreases the synthesis of the aminoglycosides target. This is Antagonism.
-Time Dependent Killing is bactericidal activity that exists as long as you stay above the Minimum Inhibitory
Concentration. This is why you give excess drug above the MIC so you dont have to dose frequently. This is
typical of beta lactams. It is called time dependent because the drugs have a strong affinity for the bacterium
and hang on for a long time, so you dont need more of these drugs. They are effective at low doses.
-Concentration Dependent killing (as concentration increases, killing increases).
-Know about the Post-Antibiotic Effect
HY Mechanisms of Antibiotic Resistance

-Cell wall synthesis inhibitors are ineffective against Mycoplasma because it lacks a cell
wall.
-Production of beta lactamases leads to premature inactivation of many beta lactam
antibiotics before they can act on the bacterium. This is countered by the use of Beta
Lactamase inhibitors like Clavulanate/Tazobactam.
-Alteration in Penicillin Binding Proteins (PBPs) is the HY mechanism of resistance
for S. Aureus (which explains its reduced susceptibility to Methicillin).
-Mutation of D-Ala D-Ala to D-Ala D-Lac is the mechanism of S. Aureus resistance to
Vancomycin.
Some HY Adverse Effects

-Most Beta-Lactams are associated with Hypersensitivity reactions.
-Tetracycline causes tooth discoloration in children.
-Chloramphenicol causes Gray Baby Syndrome (due to a physiologic deficiency in
UDP Glucuronosyl Transferase).
-Vancomycin causes Red Man Syndrome and is Ototoxic.
-Aminoglycosides are also Ototoxic/Nephrotoxic.
-Know all if possible, but dont forget the last two. Easy points on an exam.

-Work primarily by inhibiting transpeptidase which is necessary for the crosslinking of peptides that make up a
part of the bacterial cell wall.
-Penicillin is the poster child member of this drug class. It exhibits Bactericidal killing and has a Post Antibiotic
Effect against Gram Positives only.
-The Aminopenicillins cover more bugs (gram positive cocci/gram negative rods) than the pure Penicillins.
You should know that Amoxicillin is more orally bioavailable than Ampicillin.
-Penicillinase resistant penicillins include Methicillin, Nafcillin, and Dicloxacillin. These are resistant to beta
lactamases so they kill certain S. Aureus species. However, many S. Aureus species make an altered
transpeptidase/Penicillin Binding Protein so the Penicillin cannot even bind in the first place. This is the
mechanism of resistance. A HY Side Effect of these drugs is Interstitial Nephritis.
-Cephalosporins have the same MOA but key ones to know are Ceftriaxone which is the DOC in Neisseria
treatment (and is 3rd generation) and Cefepime which is 4th Generation and is the only Anti-Pseudomonal
Cephalosporin (for your test at least). Ceftaroline is a 5th gen Cephalosporin that covers MRSA.

-The Carbapenems are big guns (know Meropenem and Imipenem). Key fact here is
the PAE against gram positives and negatives.
-Aztreonam has the fewest SEs of many advanced cell wall inhibitors. It covers only
gram negatives and does not have Penicillin cross-reactivity (hypersensitivity
reactions).
-Vancomycin binds D-Ala D-Ala which prevents transpeptidase binding. It is the DOC
in MRSA infections. Know the mechanism of resistance (highlighted earlier) and the
HY SE (Red Man Syndrome). It is also Ototoxic.
-Know that Colistin acts as a detergent and is a last ditch drug.
Ribosome Inhibitors
For the sake of time
-Know which is 30S and 50S
-Know the mechanism of action of each
-Know the side effects of aminoglycosides, tetracyclines, chloramphenicol (mentioned
earlier).
-Know which is bactericidal and which is bacteriostatic.
All the best Tuesday!

The Giant First Year

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The Giant First Year

A HY Review of The General Senses

Atrophy of skeletal muscles.

Atrophy of skeletal muscles.

A history of Traumatic Brain Injury as a 27 yo.

A history of Traumatic Brain Injury as a 27 yo.

Neuron death in the Substantia Nigra Pars Compacta.

Neuron death in the Substantia Nigra Pars Compacta.

Brain Slice 1-Sacral Cord

Brain Slice 2-Lumbar Cord

Brain Slice 3-Thoracic Cord w/the Dx Lateral Horn

Brain Slice 4-Cervical Cord (note the enlargement)

Brain Slice 5-Compare/Contrast the 4 Cord Sections

Brain Slice 6-Caudal Medulla with Associated Pathways

Brain Slice 7-Caudal Medulla with Associated Pathways

Brain Slice 11-Caudal Pons and Associated Pathways

Brain Slice 12-Caudal Pons and Associated Pathways

Brain Slice 13-Middle Pons and Associated Pathways

Brain Slice 14-Middle Pons and Associated Pathways

Brain Slice 15A

Brain Slice 15B

Brain Slice 15C-Rostral Pons and Associated Pathways

Brain Slice 16A-Rostral Pons and Associated Pathways

Brain Slice 16B-Rostral Pons and Associated Pathways

Brain Slice 17-Caudal Midbrain and Associated Pathways

Brain Slice 18-Rostral Midbrain and Associated Pathways

Brain Slice 19-Rostral Midbrain and Associated Pathways

The Midbrain (Looks like an inverted M on imaging)

The Circle of Willis

Vascular Territories In The Brain

Superior Cerebellar Artery

Superior Cerebellar Artery

The Middle Meningeal artery.

The Middle Meningeal artery.

The Cholinergic Synapse (focus only on relevant details)

The Cholinergic Synapse-A Tale of Flaccid Paralysis

Cholinergic Synapse-A Tale of Flaccid Paralysis contd.

Embryology and CNS Orientation

The Purely Motor Cranial Nerves (all Medial)

The HY Mixed Cranial Nerves

The Nucleus Ambiguus/Dorsal Motor Nucleus of CN 10

Somatic Sensation-An Introduction

Somatic Sensation-An Introduction

The 2 Key Ascending Sensory Systems

The major types of neurons.

Somatic Sensation-The Afferent Neuron

Cutaneous Sensory Modalities

Cutaneous Sensory Receptors (Medium Fibers)

The Basal Ganglia-Introduction

The Basal Ganglia

The Basal Ganglia

The Basal Ganglia

The Basal Ganglia

The Direct and Indirect Pathways of The Basal Ganglia

The Pathogenesis of Parkinsons/Huntington's

Depigmentation of the Substantia Nigra in PD

Caudate Atrophy in HD-Death of Medium Spiny

Clinical Correlate-The Pill Rolling Tremor of PD

Basal Ganglia-Other Key Takeaways

Basal Ganglia-Other Key Takeaways

Basal Ganglia-Other Key Takeaways

Brainstem/Spinal Cord Pathways

The Labeled Cord-Ascending/Descending Pathways