Fragile X syndrome is X-linked recessive.

The fragile site or gap at the end of the long arm of the X chromosome is where there are trinucleotide repeats (CGG). Characteristic findings include mental retardation; enlarged, nontender testicles (present at adolescence, not at birth); a long face with a prominent jaw; a high arched palate; and protruding ears. The serum concentration of troponins I and T begin to increase 3 to 12 hours after cardiac injury, peak within 24 hours, and return to normal within 7 to 10 days; hence, these would have been increased at the time of death. Levels of CK-MB begin to increase 4 to 8 hours after infarction, peak in 24 hours, and return to normal within 1.5 to 3 days. Q waves in leads I and aVL are present in an infarction involving the lateral wall of the left ventricle, which is supplied by the left circumflex coronary artery Q waves in leads I, V4V6, and aVL occur in an anterolateral wall infarction of the left ventricle due to thrombosis of the midportion of the left anterior descending coronary artery or the circumflex coronary artery. Q waves in leads V1V4are present in an anterior wall infarction of the left ventricle and are most often due to thrombosis of the left anterior descending coronary artery. Pharmacologic treatment of disseminated malignancies such as chronic myelogenous leukemia results in the release of purine nucleotides from the dead cancer cells Uric acid is the end-product of degradation of purine nucleotides. Precipitation of uric acid crystals in the collecting ducts obstructs the nephrons (urate nephropathy), causing acute renal failure. Allopurinol, a xanthine oxidase that prevents conversion of xanthine to uric acid, is given before initiation of chemotherapy to prevent acute renal failure Increased release of pyrimidines by dead cancer cells increases carbon dioxide, ammonia, and amino acids. The ammonia derived from amino acids by oxidative deamination is metabolized to urea in the urea cycle Sessile adenomas of FAP is caused by inactivation of suppressor gene. Familial polyposis is an autosomal dominant disorder characterized by inactivation of the adenomatous polyposis coli suppressor gene located on chromosome 5. In some cases, it is associated with congenital hypertrophy of retinal pigment epithelium. Peutz-Jeghers syndrome is an autosomal dominant polyposis with hamartomatous polyps located primarily in the small bowel and in the colon and stomach to a lesser extent. It is characterized by increased melanin pigmentation of the lips and buccal mucosa. An increased serum total protein is most often due to an increase in immunoglobulin (Igs). Igs are primarily increased in chronic inflammation and malignant plasma cell disorders (e.g., multiple myeloma,RA ) Preproinsulin in the -islet cells is delivered to the Golgi apparatus, proteolytic reactions generate insulin and a cleavage peptide called C-peptide. Hence, C-peptide is a marker for endogenous synthesis of insulin. Alcohol is a common cause of hypoglycemia in the fasting state. The increase in nicotinamide adenine dinucleotide (NADH) in alcohol metabolism causes pyruvate to be converted to lactic acid. This reduces the amount of pyruvate to use as a substrate for gluconeogenesis, which is the primary source of glucose in the fasting state.

An insulin-like factor that causes hypoglycemia is most often produced by a hepatocellular carcinoma Injection of human insulin increases serum insulin and produces hypoglycemia. Hypoglycemia suppresses -islet cells, causing a decrease in endogenous synthesis of insulin and a corresponding decrease in serum C-peptide. The systolic ejection murmur indicates aortic stenosis, and the fragmented RBCs (schistocytes) in the peripheral blood indicate the presence of a microangiopathic hemolytic anemia due to intravascular destruction of the RBCs as they hit the stenotic and dystrophically calcified valve. Damaged RBC release hemoglobin directly into the blood. Haptoglobin, a protein synthesized in the liver, combines with the free hemoglobin to form complexes that are phagocytosed by macrophages in the spleen and completely degraded causing very low to absent serum haptoglobin levels. The excess hemoglobin in the plasma is then filtered into the urine producing a red color and a positive dipstick for blood. Chronic hemoglobinuria causes IDA and microcytic anemia leading to decreased serum ferritin Osmotic fragility test is used to confirm a diagnosis of hereditary spherocytosis, in which the osmotic fragility of RBCs is increased. Hereditary spherocytosis is a normocytic anemia and spherocytes in the peripheral blood Molluscum contagiosum, which is characterized by multiple, small, domed, shiny lesions with central areas of umbilication. A granular material is present in the area of umbilication and contains the cells infected by the causal poxvirus (molluscum bodies). The virus is often spread by selfinoculation. The lesions may occur in HIV infections when the CD4 helper T-cell count is 200 to 500 cells/mm3. Basal cell carcinomas are malignant tumors that develop on areas of the body that are often exposed to the sun. The lesions are dome-shaped and have telangiectasias on their walls. Central ulceration is a characteristic finding Lead, a heavy metal, denatures enzymes, deposits in the epiphyses of bone, and causes encephalopathy and peripheral neuropathy. The microcytic anemia is due to denaturation of ferrochelatase, which normally combines iron with protoporphyrin to form heme in the mitochondria. A decrease in heme causes a decrease in hemoglobin synthesis resulting in a microcytic hypochromic anemia. Lead also denatures ribonuclease, which normally degrades ribosomes. This explains the presence of coarse basophilic stippling. Lead deposits in the epiphyses of bone explain the patients growth retardation. Lead is also easily identified in an abdominal radiograph as metallic densities, which is evident in this patient. Since -aminolevulinic acid is proximal to the enzyme block in heme synthesis, it is increased and is responsible for the encephalopathy (demyelination and cerebral edema) and neuropathy in lead poisoning (abdominal colic, peripheral neuropathies). An increase in serum lead level confirms the diagnosis Alzheimers disease is the most common cause of senile dementia in patients older than 65 years of age. The arrow in the photograph shows a senile plaque containing a core of pink-staining -myloid protein surrounded by distended neurites (distal neuronal cell processes). Numerous plaques are present in the frontal, temporal, and parietal lobes in patients with Alzheimers disease. -Amyloid protein derives from amyloid precursor protein, which is normally coded for on chromosome 21. Amyloid protein when phosphorylated by activated glycogen synthase kinase-3 (GSK) acts as a signal for apoptosis of neurons, which accounts for the loss of intellectual function.

Neurofibrillary tangles are present in patients with Alzheimers disease and in elderly individuals who do not have dementia. The tangles are best visualized with silver stains and represent proteinrich filaments arranged in helical fashion within the cytoplasm of neurons. Spongiform change in the brain is a characteristic finding in Creutzfeldt-Jakob disease, which is caused by an infectious agent (prion) that is devoid of nucleic acids. Gliosis is the repair process that occurs when the brain is injured. It consists of a proliferation of astrocytes that produce a dense network of cytoplasmic processes. Activated microglial cells commonly accompany this reactive process. Septic shock is the most common cause of DIC. In DIC, fibrin clots are produced in the microcirculation that obstruct blood flow and consume coagulation factors, causing bleeding from needle puncture sites and the gastrointestinal tract. Factors that are normally consumed in a fibrin clot are fibrinogen (factor I), prothrombin (factor II), and factors V and VIII. Since coagulating factors present in the final common pathway are consumed (fibrinogen, prothrombin, factor V), there is prolongation of the PT and aPTT. Platelets are trapped in the fibrin clots leading to thrombocytopenia, which produces petechiae and ecchymoses. The fibrinolytic system is activated (secondary fibrinolysis), and plasmin cleaves the fibrin strands holding the fibrin clots together. Fibrin strands are held together by cross-links, and cleaved fragments with cross-links are detected in the d-dimer assay, which is the most sensitive test for diagnosing DIC. (HIV-1), which is an RNA retrovirus containing reverse transcriptase. The virus infects CD4 T cells and destroys the cells. Epstein-Barr virus and cytomegalovirus infections are common in AIDS. They are potent polyclonal stimulators of B cells, which produce a polyclonal gammopathy (benign increase in -globulins). However, because patients are unable to mount an antibody response to a new antigen, they are still susceptible to bacterial infections in spite of the increase in -globulins. Multiple sclerosis. It is an autoimmune disease initiated by genetic factors (e.g., HLA-DR2) and environmental triggers, the latter including microbial pathogens (e.g., Epstein Barr virus, human herpes virus 6, Chlamydophilia pneumoniae), vitamin D, and sun exposure. Environmental triggers activate helper T-cells whose antigen-specific receptors recognize CNS myelin basic protein (other antigens as well) as an antigen. T cells release cytokines that activate macrophages, which also release cytokines (e.g., tumor necrosis factor-) that destroy the myelin sheath as well as oligodendrocytes that synthesize myelin (type IV hypersensitivity). Antibodies directed against the myelin sheath and oligodendrocytes may also be involved. The episodic course of acute relapses with optic neuritis (blurry vision), scanning speech, cerebellar ataxia, and sensory and motor dysfunction, followed by remissions, are characteristic of this disease. The demyelinating plaques in multiple sclerosis occur in the white matter of the cerebral cortex. The plaques usually have a perivenular distribution and are accompanied by a perivascular lymphoid and plasma cell infiltrate with microglial cells containing phagocytosed myelin. CSF shows an increase in CSF protein. Highresolution electrophoresis of CSF shows discrete bands of immunoglobulins in the -globulin region called oligoclonal bands.They are indicative of a demyelinating process. Exposure to benzene, a solvent, is a risk factor for acute leukemia and aplastic anemia Polycyclic hydrocarbons are the primary carcinogens in cigarette smoke. Anorexia nervosa (self-starvation). Features include loss of muscle mass and subcutaneous tissue, fine downy hair (lanugo hair), distorted body image (feel fat), and secondary amenorrhea. Excessive loss of body weight (>25% of ideal weight) leads to a decrease in secretion of gonadotropin-releasing hormone from the hypothalamus and a corresponding decrease in the

concentration of serum gonadotropins (follicle-stimulating hormone and luteinizing hormone). Amenorrhea is caused by decreased ovarian synthesis of estradiol, which may lead to osteoporotic changes resulting in compression fractures in the vertebral column, which is most likely causing the patients back pain. All the stress hormones are increased (e.g., ACTH, cortisol, growth hormone, catecholamines). Note that there is an ACTH, cortisol, growth hormone , but a decreased GNrh A congenital leukocyte adhesion molecule defect prevents separation of the umbilical cord. Adhesion molecules activated on neutrophils include selectins and -integrins (CD11 CD18 positive). Selectins are responsible for rolling of the neutrophils in the venules, while -integrins cause neutrophils to adhere to venules (margination). Neutrophils then release collagenase, dissolve basement membranes between contracted endothelial cells in venules, and transmigrate into the interstitial tissue. Deficiency of either type of adhesion molecule causes an absence of neutrophil adhesion (margination) and an absence of neutrophils in the interstitial tissue, because neutrophils must adhere to endothelium before they can transmigrate. Other findings in leukocyte adhesion defects include an increase in the absolute neutrophil count, problems with wound healing, and severe gingivitis. The respiratory (oxidative) burst in neutrophils and monocytes is part of the O2-dependent MPO system for killing bacteria. Activated nicotinamide adenosine dinucleotide phosphate (NADPH) oxidase in the cell membrane oxidizes reduced NADPH, converting molecular O2 to superoxide free radicals (O2-). The respiratory burst is the energy released in this reaction. In chronic granulomatous disease, an X-linked recessive disease caused by absence of NADPH oxidase, the respiratory burst is absent, resulting in a defect in microbicidal activity. In the O2-dependent MPO system, O2 is converted to peroxide (H2O2) by superoxide dismutase in the phagolysosomes of neutrophils and monocytes. MPO catalyzes a reaction that combines H2O2 with Cl to form hypochlorous free radicals that kill the phagocytosed bacteria. Deficiency of MPO results in a defect in microbicidal activity IgG and C3b are opsonizing agents that bind to the surface of bacteria. Receptors for IgG and C3b are located on the plasma membranes of phagocytic leukocytes. Binding of the opsonized bacteria to leukocytes facilitates phagocytosis of the bacteria. A deficiency of IgG or C3 produces a defect in phagocytosis; Phagolysosomes are produced by fusion of lysosomes containing hydrolytic enzymes with phagosomes. In Chdiak-Higashi syndrome, a defect in lysosomal degranulation into phagosomes is present. Leukocytes contain large azurophilic granules (lysosomes) in the cytosol and there are defects in opsonization and in the formation of phagolysosomes Travelers diarrhea is most often due to enterotoxigenic Escherichia coli, which produces a toxin that activates adenylate or guanylate cyclase in enterocytes in the small intestine causing an isotonic loss of diarrheal fluid (secretory type of diarrhea). Loss of isotonic fluid does not alter the serum Na+ concentration (serum Na+ = TBNa+/TBW); however, the decrease in TBNa+ causes signs of volume depletion (dry mucous membranes, poor skin turgor, hypotension). Regarding the fluid compartments, the extracellular fluid (ECF) compartment is contracted (loss of fluid) and the intracellular (ICF) compartment is unchanged (no osmotic effect) Acute promyelocytic leukemia is the most common leukemia associated with disseminated intravascular coagulation (DIC). In APL, the neoplastic promyelocytes contain numerous splintershaped Auer rods in the cytoplasm

CLL is the most common leukemia in patients older than 60 years of age and is also the most common cause of generalized lymphadenopathy. The peripheral smear in CLL shows numerous lymphocytes with dense nuclear chromatin and inconspicuous nucleoli Tracheoesophageal fistula, the proximal esophagus ends blindly. The distal esophagus arises from the trachea, causing the stomach to distend with air. When the infant breast-feeds, milk refluxes into the trachea, causing coughing due to aspiration of milk into the lungs. Polyhydramnios occurs during pregnancy, because the fetus cannot swallow the amniotic fluid and reabsorb it in the duodenum. Choanal atresia is caused by a bony septum between the nose and the pharynx, which forces the infant to breathe only through the mouth. The cyanosis that develops when the infant is breastfeeding ceases when the infant breaks from the breast and begins crying. Congenital pyloric stenosis does not present at birth but at approximately 2 to 4 weeks of life. Projectile vomiting of nonbile-stained fluid occurs. Duodenal atresia (lack of a lumen) occurs just distal to the entry of the common bile duct into the duodenum. Projectile vomiting of bile-stained fluid occurs at birth. Air is present in the stomach and in the duodenum proximal to the opening of the common bile duct. Polyhydramnios occurs during pregnancy, because there is not enough duodenum to reabsorb the amniotic fluid. There is an increased association with Down syndrome. Volvulus is where the bowel twists around mesenteric root producing obstruction and strangulation. The sigmoid colon is the most common site in elderly patients and the cecum in young patients. Risk factors include chronic constipation (most common), pregnancy, and laxative abuse Pernicious anemia (PA), an autoimmune disease in which impaired intestinal absorption of vitamin B12 is caused by a lack of IF. Antibodies directed against parietal cells in the body and fundus (type II hypersensitivity reaction) cause mucosal damage (chronic atrophic gastritis), achlorhydria (loss of acid production by parietal cells), and a decrease in synthesis of IF. IF normally forms a complex with vitamin B12in the duodenum which is then reabsorbed in the terminal ileum after the complex attaches to IF receptors. The peripheral smear shows large, egg-shaped macro-ovalocytes. The arrow points to a hypersegmented neutrophil (more than five nuclear lobes), a valuable and early marker of vitamin B12 deficiency (also folate deficiency). Pancytopenia is the rule in PA, because deficiency of vitamin B12 causes decreased production of DNA leading to nuclear enlargement of hematopoietic cells in the bone marrow (megaloblasts). These cells or derivatives from these cells (e.g., mature RBCs, platelets, neutrophils) are often phagocytosed and destroyed by bone marrow macrophages or are destroyed by apoptosis before they enter the peripheral blood. Reabsorption of orally administered vitamin B12 after the addition of IF confirms the diagnosis of PA. This is called the Schilling test. Vitamin B12, unlike folic acid, is involved in propionate fatty acid metabolism (odd-chain fatty acids). Propionyl CoA is converted to methylmalonic CoA, and methylmalonic CoA is converted to succinyl CoA using an enzyme reaction that requires vitamin B12 as a cofactor. Deficiency of vitamin B12 causes an increase (not a decrease) in methylmalonic acid levels (derives from methylmalonyl CoA) in the urine. It also causes an increase in propionyl CoA (also propionic acid) in the urine. Propionyl CoA replaces acetyl CoA in neuronal membranes resulting in demyelination of the posterior columns and lateral corticospinal tract of the spinal cord (subacute combined degeneration) and peripheral nerves (peripheral neuropathy). The patient has decreased vibratory

sensation and joint dysequilibrium (cannot stand up with her eyes closed), both of which are signs of posterior column disease History of menorrhagia, easy bruisability, bleeding from superficial scratches, and epistaxis all abating with oral contraceptives and recurring again when off of them is a classic scenario for classic von Willebrand disease. Normal squamous epithelium of the exocervix derives from squamous metaplasia of mucussecreting glandular cells moving down the endocervical canal. Infection of the squamous cells by human papillomavirus types 16 or 18 initiates conversion of the metaplastic squamous epithelium to dysplastic epithelium. If the infection persists, cervical squamous cell cancer may develop. A painless testicular mass that does not transilluminate is highly predictive of testicular cancer. Adults with a cryptorchid testis are at risk for seminoma in the undescended testis (if still present) as well as the descended testis Choriocarcinoma of the testicle typically is small and does not cause enlargement of the entire testicle. The syncytiotrophoblast component of the tumor produces human chorionic gonadotropin Hydroceles is the most common cause of scrotal enlargement. It is due to a failure of closure of the tunica vaginalis. Fluid accumulates in the serous space between the layers of the tunica virginals. The mass of fluid transilluminates. It is invariably associated with an indirect inguinal hernia. Varicocele is the tortuous dilation of the veins of the spermatic cord that is often described as a bag of worms. A variocele typically occurs on the left side, not on the right side, because the left spermatic vein empties into the left renal vein, where it encounters more resistance to blood flow. The right spermatic vein empties into the inferior vena cava, where there is less resistance to blood flow. Yolk sac tumors typically occur in infants and children and are not associated with cryptorchidism. They secrete -fetoprotein Western blot assay is the confirmatory test if the ELISA test is positive for HIV. The ELISA assay detects anti gp120 antibodies. A positive Western blot assay requires the presence of p24 and gp41 antibodies and either gp120 or gp160 antibodies. The test has close to 100% specificity. The CD4 T-cell count is used to monitor the immune status of the patient. It is useful in determining when to initiate HIV treatment and when to administer prophylaxis against opportunistic infections. It is not a confirmatory test for HIV The p24 antigen is an indicator of active viral replication. It is present before anti-gp120 antibodies are developed in the patient. It is positive at two different times in HIV infectionsprior to seroconversion and when AIDS is diagnosed Muscle cramping and abdominal pain are due to a neurotoxin produced by the black widow spider (Latrodectus mactans). A glossy black spider with a red hourglass on the ventral aspect of the abdomen. Paralysis and death may occur in very young and in very old individuals. Achalasia, a motor disorder of the smooth muscle cells of the mid and distal esophagus. There is incomplete relaxation of the lower esophageal sphincter (LES) due to autoimmune destruction of ganglion cells in the myenteric plexus causing a decrease in nitric oxide (NO) synthase producing neurons. This decreases proximal smooth muscle contraction (peristalsis). There is dilation of the esophagus proximal to the LES with absent peristalsis (detected by manometry). Clinical findings include nocturnal regurgitation of undigested food; dysphagia for solids and liquids; and chest pain and/or heartburn. The proximal esophagus is dilated and has a beaklike tapering at the distal end (arrow). Nonpharmacologic treatment includes pneumatic dilation and esophagomyotomy.

Pharmacologic options include long-acting nitrates, calcium channel blockers, and botulinum toxin injection. There is an increased risk for esophageal cancer. Myasthenia gravis is a motor disorder (IgG antibodies inhibit acetylcholine receptors) that weakens the striated muscle of the upper esophagus, causing dysphagia for solids and liquids. Mid and distal esophageal motility is normal Kaposi sarcoma, a vascular malignancy closely associated with human herpesvirus 8. Kaposis sarcoma is the most common malignancy in patients with AIDS and is an AIDS-defining lesion. Lesions appear most often on the skin but may also occur in the intestinal tract, particularly on the hard palate. B. henselae is a gram-negative bacterium that causes bacillary angiomatosis, a disease that occurs almost exclusively in patients with AIDS. It produces highly vascular skin lesions that can mimic the lesions of Kaposis sarcoma. Systemic signs of the infection include fever, lymphadenopathy, and hepatomegaly. Small-cell carcinoma of the lung can ectopically produce adrenocorticotropic hormone producing Cushing syndrome (moon facies, truncal obesity with purple stria, thin extremities. It also produces ectopic secretion of antidiuretic hormone (ADH) resulting in the syndrome of inappropriate ADH. A medullary carcinoma of the thyroid derives from C cells that synthesize calcitonin. Calcitonin is a hormone that inhibits osteoclasts causing hypocalcemia. Elderly individuals frequently lose their isohemagglutinins (e.g., anti-A IgM, anti-B IgM). The patient is blood group A and should have anti-B IgM isohemagglutinins in the plasma. However, in vitro testing showed that reacting his plasma with test blood group B RBCs did not produce agglutination or hemolysis. Therefore, the infusion of donor group B RBCs did not produce a hemolytic transfusion reaction, because the patient has no anti-B IgM antibodies to attach to the B antigen on the donors RBCs. Hemolytic transfusion reactions are antibody-mediated type II hypersensitivity reactions Hirschsprungs disease (congenital megacolon), which is the most common cause of lower intestinal obstruction in neonates. The most common manifestation is failure to pass meconium within the first 24 hours after birth. There are no ganglion cells in both the Meissner submucosal and the Auerbach myenteric plexuses. In 75% of cases, the rectosigmoid is aganglionic. Characteristic findings include a narrow anal canal, absence of stool in the rectal vault in rectal examination, and an abdominal radiograph showing distended loops of colon. Peristalsis occurs in segments of colon that do contain ganglion cells. In 3% of cases, there is an association with Down syndrome. Enterocolitis, which is the most common complication of Hirschsprungs disease, is a type of ischemic necrosis related to an increase in intraluminal pressure and decreased intramural capillary blood flow. Presenting signs include fever and bloody diarrhea In pregnancy thre is an hemoglobin, and BUN (increase in plasma volume causes increased clearance of urea in the urine), but an in pH (estrogen and progesterone stimulate the CNS respiratory center causing respiratory alkalosis), increase in plasma volume increases the glomerular filtration rate causing an increase in the creatinine clearance. Acute drug-induced tubulointerstitial disease is characterized by a sudden onset of oliguria (renal failure), fever, and a rash shortly after taking a drug (e.g., synthetic penicillin). Other findings include eosinophilia, eosinophiluria (eosinophils in the urine), hematuria, pyuria (WBCs in the urine), and WBC casts. Withdrawal of the drug reverses these findings.

Chronic pyelonephritis is a complication of vesicoureteral reflux (reflux of urine from the bladder into the ureter) or postrenal obstruction caused by prostate hyperplasia or a ureteral stone. An intravenous pyelogram shows blunting of the renal calyces underlying cortical scars. A ureteral stone presents with sudden onset colicky pain with radiation to the groin McArdles disease, which is an autosomal recessive glycogen storage disease characterized by a deficiency of muscle phosphorylase. This enzyme releases glucose from glycogen stored in muscle. Deficiency of muscle phosphorylase deprives the muscle of glucose for energy, and after exercise, lactic acid is not produced as an end-product of anaerobic glycolysis. Strenuous exercise may damage muscle, causing myoglobinuria (red-colored urine). There is no hypoglycemia in these patients, because glycogenolysis in the liver is still intact. Glucose obtained by glycogenolysis in muscle is used only by the muscle and does not enter the bloodstream. -1,4-Glucosidase, a lysosomal enzyme that degrades glycogen, is deficient in Pompes disease. Glycogen accumulates in cardiac muscle, resulting in death at an early age. Glucose-6-phosphatase, a gluconeogenic enzyme that normally converts glucose 6-phosphate to glucose, is deficient in von Gierkes disease. Fasting hypoglycemia occurs, and normal glycogen (with branches) accumulates in the liver and kidneys, not in muscle. Development of colorectal cancer from a tubular adenoma follows a sequence of gene mutations, which occurs in the following order: (1) inactivation of the APCsuppressor gene; (2) activation of the RAS proto-oncogene; and (3) inactivation of the TP53 suppressor gene. This sequence accounts for 80% of cases of sporadic colorectal carcinomas. This is an important concept, because cancer is rarely due to a single mutation but a certain sequence of mutations. Recall that the TP53 suppressor gene and RAS proto-oncogene are the two most common genes associated with cancer. Henoch-Schnlein purpura is characterized by distinctive skin rash on the lower extremities and buttocks, hematuria with RBC casts, gastrointestinal bleeding, and joint inflammation. It is a type III hypersensitivity reaction involving the deposition of IgAanti-IgA immunocomplexes in small vessels, glomeruli, joints, and gastrointestinal tract. A key feature of small vasculitis is palpable purpura. It is raised and painful, because it is an example of the tumor and dolor of acute inflammation. In the glomerulus, immunocomplexes deposited in the mesangium cause an acute, nephritic type of glomerulonephritis, which explains the presence of hematuria, dysmorphic RBCs (damaged by inflammation), RBC casts, and proteinuria. Gastrointestinal bleeding and polyarthritis are also common features. Previous upper respiratory infections or group A streptococcal pharyngitis frequently act as a trigger leading to antibody formation and eventual formation of immunocomplexes. Deposition of immunocomplexes in tissue activates the complement system, and chemotactic agents act as signals for neutrophils to enter the tissue producing acute inflammation. Hyperelastic skin, which is a characteristic finding in Ehlers-Danlos syndrome (EDS). EDS is a connective tissue disorder with defects in collagen synthesis and/or structure. Other clinical features that may be present include hypermobility of joints, aortic dissection, mitral valve prolapse (present in this patient), and rupture of the colon. An acquired defect in cross-bridging of collagen fibers is associated with scurvy, which is caused by deficiency of vitamin C (ascorbic acid). The weak collagen (decreased tensile strength) produces vascular instability of small vessels, leading to skin and joint hemorrhages and bleeding gums with the loss of teeth

Kawasaki disease (mucocutaneous lymph node syndrome), which is the most common acquired heart disease in children. Characteristic findings include fever, painful cervical lymph nodes, cracked lips, oral erythema, swelling of the hands and feet, a desquamating rash involving the fingers and toes (see photograph), and vasculitis of the coronary arteries. Vasculitis often leads to coronary artery thrombosis and acute myocardial infarction. The treatment is intravenous gamma globulin. Corticosteroids are contraindicated, because they increase the risk for aneurysms in the coronary arteries. Cyanide (CN) is a systemic asphyxiant that inhibits cytochrome oxidase in the electron transport chain, hence preventing formation of adenosine triphosphate (ATP). CN poisoning may be caused by drugs (e.g., nitroprusside) or combustion of polyurethane products in house fires. It produces an initial CNS and cardiovascular stimulation, followed by CNS depression and death. Treatment is amyl nitrite (produces methemoglobin which combines with CN to form cyanmethemoglobin) followed by thiosulfate (CN is converted to thiocyanate, which is excreted). Viral-induced acute myocarditis. Clinical findings include left-sided heart failure (dyspnea, bibasilar inspiratory crackles, alveolar infiltrates); right-sided heart failure (neck vein distention, hepatomegaly, dependent pitting edema); tricuspid and mitral valve regurgitation (pansystolic murmur due to dilated valve rings) with S3 and S4 heart sounds related to volume increases in both ventricles; a decreased ejection fraction (systolic dysfunction due to decreased contractility); and myocardial damage (increased cardiac-specific troponin levels and CK-MB). Adenovirus is the most common viral cause of myocarditis. In this patient, the myocarditis has produced dilated (congestive) cardiomyopathy. Centrilobular hemorrhagic necrosis is an example of an intrahepatic obstruction of blood flow. It is most often due to a combination of left-sided heart failure (LHF) and right-sided heart failure (RHF). LHF decreases cardiac output causing hypoperfusion of the liver (produces liver cell necrosis) and RHF causes a back-up of systemic venous blood into the hepatic veins and then to the central veins and sinusoids producing an enlarged, painful liver with a mottled red appearance; and into the portal veins producing ascites and splenomegaly. ECG showing short QT intervals and a widened T wave is highly suggestive of hypercalcemia. Most common cause of hypercalcemia in ambulatory individuals is primary hyperparathyroidism due to a parathyroid adenoma. In this patient, primary hyperparathyroidism is complicated by hypertension, peptic ulcer disease, and a renal calculus composed of calcium oxalate. Hypercalcemia causes contraction of the smooth muscle cells of the peripheral resistance arterioles, which causes hypertension. Furthermore, hypercalcemia stimulates gastrin release, which causes peptic ulcer disease. Excess calcium in the urine predisposes to formation of calciumcontaining calculi. A decrease in both PTH and serum calcium is characteristic of primary hypoparathyroidism, which is most often due to previous thyroid surgery A decrease in PTH and an increase in serum calcium is characteristic of hypercalcemia due to malignancy (most common cause) or other non-parathyroid-gland-related disorders (e.g., sarcoidosis, hypervitaminosis D). Hypercalcemia suppresses the release of PTH by the parathyroid gland An increase in PTH and decrease in serum calcium is characteristic of secondary hyperparathyroidism. Hypovitaminosis D is a common pathologic cause of hypocalcemia leading to

secondary hyperparathyroidism. Secondary hyperparathyroidism is a compensatory phenomenon that brings the serum calcium to up to or within the normal range Helicobacter pylori is the most common cause of peptic ulcer disease, which includes gastric and duodenal ulcers. Production of urease by the bacteria produces ammonia, which damages the protective mucus layer covering the pylorus and antrum of the stomach and the duodenum, sites colonized by H. pylori. Cytokines released by the bacteria cause chronic atrophic gastritis of the body and fundus with intestinal metaplasia (presence of Paneth cells and goblet cells), which is the precursor lesion for gastric adenocarcinoma at this location. Cytokines also elicit a marked lymphoid inflammatory response in the mucosa predisposing to a low-grade malignant lymphoma. Therefore, treatment of H. pylori not only prevents peptic ulcer disease, but also decreases the risk for malignant lymphoma of the stomach and gastric adenocarcinoma in the body and fundus. Down syndrome (epicanthal folds, flat nasal bridge). The presence of 46 chromosomes in the child indicates that a translocated chromosome, inherited from one of the parents, is responsible. Translocation occurs when one part of a chromosome is transferred to a nonhomologous chromosome. In balanced (robertsonian) translocation, the translocated fragment is functional. In this case, the long arm of chromosome 21 was translocated onto chromosome 14 in the mother, creating one long chromosome (14;21). The mother also has one chromosome 14 and one chromosome 21. The father has the normal 46 chromosomes. The affected child has 46 chromosomes with three functional 21 chromosomes including chromosome (14;21) and chromosome 21 from the mother and chromosome 14 and chromosome 21 from the father. Point mutation involves the substitution of a single nucleotide base. If the altered DNA codes for the same amino acid, there is no change in the phenotypic effect (silent mutation). If the altered DNA codes for a different amino acid, there is a change in the phenotypic effect (missense mutation). If the altered DNA codes for a stop codon (e.g., UAA), there is premature termination of protein synthesis (nonsense mutation). Sigmoid diverticulosis is most often caused by increased intraluminal pressure secondary to chronic constipation. The weakness occurs in the area where the vessels penetrate the bowel wall. The most common complication is diverticulitis due to impaction of stool (fecalith) in the diverticula sac, leading to ischemia and mucosal injury (same pathogenesis as acute appendicitis in adults). Patients with diverticulitis have fever, left lower quadrant pain, and rebound tenderness (left-sided acute appendicitis). A CT scan is the best diagnostic tool for diagnosing diverticulitis. Increased fiber in the diet is important in preventing sigmoid diverticulosis, because it prevents constipation. In children, appendicitis is most often a complication of lymphoid hyperplasia induced by a previous viral infection (e.g., adenovirus, measles). In adults, it usually is due to impaction of stool in the lumen (fecalith) and with ischemia and mucosal injury. Addisons disease is suggested when a case with hyperpigmentation of the buccal mucosa. This, along with the history of fatigue, weakness, and signs of hypovolemia when supine (decreased blood pressure and increased pulse rate). It is due to autoimmune destruction of the adrenal cortex. This produces deficiencies of mineralocorticoids (e.g., aldosterone), glucocorticoids (e.g., cortisol), and sex hormones (e.g., androstenedione, testosterone). Hypocortisolism causes an increase in plasma ACTH due to a negative feedback relationship. ACTH has melanocyte-stimulating properties that increase the synthesis of melanin on the skin and mucosal surfaces. Hypovolemia is related to the loss of sodium in the urine due to mineralocorticoid deficiency.

Metyrapone is a drug that blocks 11-hydroxylase in the adrenal cortex. This enzyme is normally responsible for conversion of the glucocorticoid 11-deoxycortisol to cortisol. Therefore, a normal response to metyrapone is a decrease in cortisol with a subsequent increase in ACTH and 11deoxycortisol The episodic history of hematuria following upper respiratory infections is characteristic of IgA glomerulopathy, which is the most common type of glomerulonephritis. Urine sediment shows an RBC cast Primary stomach cancer that has hematogenously metastasized to both ovaries (Krukenberg tumors). A maxim in medicine states that palpable ovaries in a postmenopausal woman represent cancer until proven otherwise. The photograph shows classic signet ring cells (mucin pushes the nucleus to the periphery), which are primarily seen in the diffuse type of adenocarcinoma of the stomach. Stomach cancer is the most common primary cancer that metastasizes to the left supraclavicular nodes (Virchow nodes). Common signs of stomach cancer are weight loss, epigastric pain, hematemesis, and melena. Smoking is not a risk factor for gastric cancer. Most pancreatic cancers involve the head of the pancreas and are associated with obstructive jaundice, light-colored stools, and a palpable gallbladder. Pain usually radiates to the back, because the pancreas is located in the retroperitoneum. Pancreatic cancer can metastasize to the ovaries and is most commonly associated with smoking Surfactant synthesis is enhanced by glucocorticoids, thyroxine, and prolactin and decreased by insulin. Bronchopneumonia refers to an acute infection that begins in the bronchus and extends into the surrounding lung parenchyma producing microabscesses. Streptococcus pneumoniae is the most common cause of bronchopneumonia. AAT deficiency is an autosomal dominant disease, whose alleles are inherited codominantly (each allele expresses itself). The normal allele is M (95% frequency in United States), and MM is the normal genotype with AAT in the normal range. Deficient variants (decreased AAT levels) involve the Z allele and the S allele. Severe deficiency most commonly occurs in the homozygous ZZ variant. It is associated with panacinar emphysema and cirrhosis of the liver. In children, who are homozygous for ZZ, in 50% of cases, AAT is not secreted properly from hepatocytes. Pathologic accumulation of AAT in hepatocytes causes liver damage. Liver biopsies with PAS stains show red cytoplasmic granules (see photograph). It presents as neonatal hepatitis with intrahepatic cholestasis, with the hepatitis progressing into cirrhosis. In other cases, where there is no problem with secreting AAT, but levels of AAT are decreased, panacinar emphysema may develop later in life. Obstructive sleep apnea is characterized by excessive snoring with intervals of apnea (breath cessation) and may be caused by nasal polyps.

 A) Isotonic loss of fluid (e.g., secretory diarrhea in cholera and travelers diarrhea; loss of whole blood). Serum sodium remains normal (also POsm) when equal amounts of water and sodium are lost B) Hypertonic loss of fluid (e.g., diuretics, Addisons disease, 21-hydroxylase deficiency). Loss of hypertonic fluid produces a hyponatremia C) Isotonic gain of fluid (e.g., excessive infusion of normal (0.9%) saline. The serum sodium remains normaltherefore, the POsm is normal. D) congestive heart failure, the cardiac output is decreased and the kidney reabsorbs a slightly hypotonic fluid producing. An increase in total body sodium (TBNa+) is clinically manifested by weight gain, dependent pitting edema, and body effusions E) hypotonic loss of sodium (e.g., sweating, osmotic diuresis, glucosuria). The serum sodium is increased , causing an increase in POsm and an increase in the height of the interrupted squares F) hypertonic gain of sodium (e.g., excessive infusion of sodium bicarbonate; infusion of a sodium containing antibiotic). The serum sodium is increased, causing an increase in POsm and an increase in the height of the interrupted squares Microscopic polyangiitis. It is a small vessel type of vasculitis (palpable purpura) that can by precipitated by drugs (penicillin in this case), infections, and immune disorders. Whatever the triggering event is in this disease, it results in increased production of p-ANCA antibodies in more than 80% of cases. These antibodies are directed against myeloperoxidase in neutrophils, which cause degranulation and thus the release of toxins causing endothelial injury to small vessels throughout the body as well as to those in the glomeruli. Renal failure is most often due to rapidly progressive crescentic glomerulonephritis, which is associated with a nephritic presentation (hematuria, RBC casts, mild proteinuria) In cirrhosis, the urea cycle is dysfunctional; hence, ammonia is not converted into urea and increases in the blood. It is most likely responsible for the tiredness and mental status abnormalities in the patient, who is in an early stage of hepatic encephalopathy. There is a decreased cardiac output, causing the kidneys to reabsorb a slightly hypotonic fluid: serum Na+ = total body Na+/ total body water. Aldosterone is increased for two reasons: decreased metabolism of aldosterone by the liver and decreased cardiac output activating the renin-angiotensin-aldosterone system. Secondary aldosteronism increases renal exchange of Na+ for K+ leading to hypokalemia. Decreased liver synthesis of albumin automatically results in a decrease in the bound fraction of calcium and a decreased total serum calcium. Hypoglycemia is more likely to occur in cirrhosis than hyperglycemia. Due to liver dysfunction in cirrhosis, glycogen stores are depleted and there is defective gluconeogenesis, both of which lead to hypoglycemia in the fasting state.

Centrilobular necrosis of liver (nutmeg liver), which is most often caused by left-sided heart failure (LHF) and right-sided heart failure (RHF). LHF decreases cardiac output causing hypoperfusion of the liver. This results in ischemic necrosis of hepatocytes located around the central vein. RHF causes a backup of systemic venous blood into the central veins and sinusoids, which produces congestion of central veins and sinusoids and necrosis of hepatocytes around the central vein. Clinical findings include painful hepatomegaly with or without jaundice. Increased transaminases are caused by ischemic necrosis. Left untreated, it may progress to cardiac cirrhosis with fibrosis around the central veins. Pituitary Cushings syndrome (aka Cushings disease) caused by an adenoma-secreting excess ACTH is characterized by a moon facies, truncal obesity, and purple striae. There is a mass lesion in the sella turcica. Dexamethasone, a cortisol analogue, is used as a suppression test to differentiate pituitary Cushings syndrome from adrenal Cushings syndrome (cortisol-secreting adenoma) or ectopic Cushings syndrome (e.g., ACTH-secreting small cell carcinoma of the lung). A normal response to dexamethasone is suppression of ACTH (negative feedback) and a decrease in cortisol production in the adrenal cortex. A low dose of dexamethasone is used as a screening test for hypercortisolism. It does not suppress cortisol production in pituitary, adrenal, or ectopic Cushings syndrome. However, a high dose of dexamethasone suppresses ACTH production in pituitary Cushings syndrome leading to a drop in cortisol levels. Cortisol remains increased in adrenal and ectopic Cushings syndromes. Vitamin B6 (pyridoxine) deficiency is most often associated with isoniazid therapy for tuberculosis. Clinical findings include sideroblastic anemia, convulsions, and peripheral neuropathies. These findings are not present in this patient. Impetigo. The rash usually begins on the face. Vesicles and pustules rupture to form honeycolored, crusted lesions, which are evident in this patient. Staphylococcus aureus is the most common cause of this superficial skin lesion. Streptococcus pyogenes is the second most common cause of impetigo. Impetigo is highly contagious, which explains why the childs sister developed similar lesions. Treatment is with mupirocin ointment plus dicloxacillin. (PDA). This neonate has hypoxemia (decreased arterial Po2) secondary to RDS; therefore, closure of the ductus is not stimulated. When oxygenated blood (Sao2 95%) is shunted into a chamber or vessel with venous blood (Sao2 75%), there is a step-up of Sao2 (approximately 80%) in the venous blood; this is called a left-to-right shunt. Similarly, when venous blood is shunted into a chamber or vessel with oxygenated blood, there is a step-down of the Sao2 (80%) leading to clinical cyanosis; this is called a right-to-left shunt. In PDA, there is a left-to-right shunt causing blood to flow from the aorta (where pressure is high) through the PDA to the pulmonary artery (where pressure is low), which causes a step-up of Sao2 in the pulmonary artery (85% versus normal of 75%). The cytochrome P-450 system in the liver converts acetaminophen into a free radical. A large dose of acetaminophen produces numerous free radicals, which damage hepatocytes causing release of transaminases. Hepatocytes around the central vein normally receive the least amount of O2; therefore, they are most susceptible to injury caused by hypoxia and free radicals derived from drugs. Recall that mixed blood from the hepatic artery and portal vein tributaries in the portal triad at the periphery of the hepatic lobule flows into the sinusoids, which drain into the central vein in the center of the lobule. Therefore, hepatocytes closest to the triad receive the most O2(zone 1 hepatocytes) and are less likely to be damaged than those located around the central vein (zone 3 hepatocytes). In many cases of acetaminophen overdose, necrosis can eventually involve the entire

lobule causing fulminant hepatic failure. Acetaminophen overdose is the most common cause of drug-induced fulminant hepatic failure. Treatment with N-acetylcysteine is useful, because it increases the production of glutathione, an antioxidant that can neutralize acetaminophen free radicals. Psoriasis. The photograph shows a salmon-colored plaque covered by loosely adherent silverwhite scales. Psoriasis is a chronic inflammatory dermatosis with unregulated proliferation of squamous epithelial cells (epithelial hyperplasia). Other microscopic findings include downward extension of the rete pegs, retention of nuclei in the stratum corneum (parakeratosis), and thinning of the epidermis overlying the tips of dermal papillae. Peeling of the scales shows bleeding points due to exposure of vessels in the dermal papillae (Auspitz sign). Pitting of the nails is another common finding. Patients who have the HLA-B27 genotype may develop seronegative (rheumatoid factornegative) spondyloarthropathy, which is characterized by inflammation in the sacroiliac joints and peripheral arthritis, as noted in this patient. Dysplastic basal cells are seen in actinic (solar) keratosis, which is a precursor lesion for squamous cell carcinoma associated with excessive exposure to sunlight. The skin lesions show scaling papules and plaques that lack the salmon coloration and silver-white scales. Liquefactive degeneration is a characteristic finding of systemic lupus erythematosus. DNAantiDNA immunocomplexes deposit along the dermal-epidermal junction, causing immunologic destruction of the basal layer of the epithelium. Scaling red plaques mainly develop in sun-exposed areas (e.g., face). CML occurs in patients between 40 and 60 years of age. It is caused by translocation of the ABL proto-oncogene on chromosome 9 to chromosome 22 (Philadelphia chromosome), where it forms a fusion gene with the break cluster region. The Philadelphia chromosome is present in >95% of patients with CML; however, detection of the fusion gene has much greater specificity for confirming the diagnosis. The presence of neutrophils in all stages of development and a myeloblast count of <10% in the bone marrow indicate a chronic, not an acute leukemia. CML commonly metastasizes to the lymph nodes (lymphadenopathy), liver, and spleen (hepatosplenomegaly). Leukemia cells positive for tartrate-resistant acid phosphatase are present in hairy cell leukemia, which is a B-cell leukemia. The leukemia cells have hairlike cytoplasmic projections in the peripheral blood subdural hematoma is disruption of cortical veins that penetrate the dura and empty into the superior sagittal sinus. A venous bleed results in the formation of a blood clot in the subdural space. The photograph shows a well-formed blood clot beneath the reflected dural membrane. The pressure of the venous clot is evenly dispersed over the gyri and within the sulci, and there is no flattening of the convexities of the gyri. Rupture of the middle meningeal artery causes an epidural hematoma. Because the artery is firmly attached to the periosteum of the temporal bone, a fracture of the temporal bone causes the vessel to rupture. Blood under arterial pressure creates a space between the periosteum and the dura. Patients usually are unconscious after the initial trauma and then have a lucid interval followed by progressive loss of consciousness and death. emphysema related to smoking cigarettes. The chest radiograph shows hyperinflation in both lung fields, depression of both diaphragms, and a vertically oriented cardiac silhouette. Emphysema is a chronic obstructive pulmonary disease involving permanent enlargement of all or part of the

respiratory unit (respiratory bronchioles, alveolar ducts, and alveoli). Elastic tissue destruction in these airways by elastases produced by neutrophils causes small airway collapse on expiration with trapping of air and distention of the distal air space. This increases the residual volume, which is the volume of air left in the lung after maximal expiration. An increase in residual volume automatically increases total lung capacity, which causes hyperinflation of the lungs, an increase in the anteroposterior diameter, depression of the diaphragms, and vertical orientation of the heart. In emphysema, lung compliance (ability to fill the lung with air) is increased and elasticity (recoil of the lung) is decreased because of destruction of elastic tissue. The FEV1sec, or the amount of air expelled from the lungs in 1 second after a maximal inspiration, is decreased (e.g., to 1 L versus the normal of 4 L) because of the trapping of air in the distended distal airways. The FVC, or total amount of air expelled after a maximal inspiration, is also decreased (e.g., to 3 L versus the normal of 5 L). Therefore, the ratio of FEV1sec to FVC is decreased (not increased) in emphysema. The patient has emphysema, with increased residual volume. As the residual volume increases, the tidal volume (volume of air that enters or leaves the lungs during normal quiet respiration) is either normal or slightly decreased (not increased). Upregulation of telomerase activity, which preserves the telomere length and ensures that there is no loss of genetic material after each cell division, is an indication of malignancy. The presence of hyperchromatic cells with atypical mitotic spindles in an endometrial biopsy specimen is also characteristic of malignancy. The cells in malignant tumors lose intercellular adhesion by decreasing the production of Ecadherin, an intercellular adhesion agent. Decreased intercellular adhesion must occur before these cells are able to invade through the basement membrane into the extracellular matrix. Malignant cells secrete vascular endothelial growth factor and basic fibroblast growth factor, which stimulate angiogenesis. Angiogenesis is necessary to provide oxygen and nutrients to the malignant cells. Bacterial meningitis (nuchal rigidity, neutrophils in CSF with phagocytosed bacteria). In sickle cell anemia, the spleen is typically dysfunctional, which causes the patient to be susceptible to sepsis and meningitis resulting from Streptococcus pneumoniae, a Gram-positive diplococcus. Sepsis due to S. pneumoniae is the most common cause of death in children with sickle cell disease Seborrheic keratosis a rough pigmented lesion that has the stuck-on, warty appearance. This common epidermal tumor shows a proliferation of pigmented basal cells on histologic examination. When such lesions develop suddenly, especially in the setting of epigastric pain and weight loss, they indicate the presence of an underlying gastric adenocarcinoma (Leser-Trlat sign). Angiodysplasia, there is dilation of mucosal and submucosal venules in cecum and right.It usually occurs in elderly individuals, because vascular ectasias in the cecum increase with age. Increased wall stress in the cecum stretches the venules producing these lesions. It presents with the loss of large volumes of blood, that can produce signs of hypovolemic shock as in this patient. Sigmoid diverticulosis is the most common cause of hematochezia. However, sigmoid diverticulitis is not, because the blood vessel next to the inflamed diverticular sac is often fibrosed and destroyed. The rule of thumb for diverticular disease causing hematochezia is: -osisyes; itis no. (HSV-2), a sexually transmitted disease. The figure shows a multinucleated squamous cell with ground glass nuclei, which will eventually develop into more discrete eosinophilic inclusions. The

virus remains latent in sacral sensory ganglia and recurs in the same location. Acyclovir decreases the number of recurrences but does not cure the infection. Human papillomavirus causes koilocytotic atypia in squamous cells. Infected cells have pyknotic (condensed chromatin) nuclei surrounded by a clear halo. Wound healing by primary intention involves approximation of the wound edges by sutures or other materials. On day 1, a fibrin clot (hematoma) develops at the wound site and neutrophils infiltrate the wound margins. Neutrophils have no role in scar tissue formation. Macrophages begin replacing neutrophils in 2 to 3 days and have no role in scar tissue formation On day 3, granulation tissue, the precursor of scar tissue, begins to develop. Fibroblasts synthesize type III collagen, and blood vessels are formed (angiogenesis) to supply O2and nutrients. On days 4 to 6, granulation tissue formation is at its peak. Fibronectin is the key glycoprotein involved in granulation tissue formation. It is chemotactic for endothelial cells and fibroblasts and is an adhesive agent. At the end of 1 month, collagenase remodeling of the wound occurs with replacement of type III collagen by type I collagen, which increases the tensile strength of the wound. Collagenase contains zinc. A prolonged bleeding time associated with a normal platelet count, normal PT, and normal aPTT indicates a defect in platelet function (adhesion and/or aggregation). The most common cause of a prolonged bleeding time is aspirin or other NSAIDs. The patient has SLE complicated by an autoimmune hemolytic anemia. These are subdivided into warm types (IgG-mediated) and cold types (IgM-mediated). The former type is usually an extravascular hemolytic anemia, while the latter type is usually intravascular but sometimes extravascular. The direct Coombs test detects IgG and/or C3b on the surface of RBCs and must be positive in order to confirm the diagnosis of any type of immune hemolytic anemia, warm or cold. Immune hemolytic anemias that involve IgG (e.g., SLE) have macrophage removal of RBCs coated by IgG (extravascular hemolysis). The end-product of macrophage destruction of RBCs is unconjugated bilirubin, which produces jaundice (yellow eyes). Macrophage removal of portions of the RBC membrane produces spherocytes, which are characteristic findings in extravascular hemolytic anemias. Cold autoimmune hemolytic anemias involving IgM antibodies that produce hemoglobinuria and jaundice are not as likely to be present. Serum ferritin correlates with the amount of ferritin stores in bone marrow macrophages. It is usually normal in autoimmune hemolytic anemias. Ferritin levels are only decreased in iron deficiency anemia. Absence of urine urobilinogen occurs in complete obstruction of bile outflow into the intestines. Colonic bacteria normally convert bilirubin in bile into urobilinogen, which is responsible for the color of stool. A small amount of urobilinogen reabsorbed from the intestine into the blood enters the urine, where it produces the normal color of urine. In autoimmune hemolytic anemia, the urine urobilinogen is increased (not absent), because greater amounts of bilirubin from the hemolytic anemia are converted to urobilinogen in the colon and proportionately more urobilinogen is recycled into the urine. The patient has a sterile pyuria, which refers to the presence of neutrophils in the urine (positive reagent strip for leukocyte esterase), a negative reagent strip for nitrites, and no growth of organisms with a standard urine culture. Due to the close proximity of the patients urinary findings with a previous sexual encounter, the patient most likely has urethritis due to C. trachomatis.

. In lower urinary tract infections due to E. coli, the reagent strip is positive for nitrites and leukocyte esterase and routine cultures isolate the organism Distal adenocarcinoma of the esophagus secondary to Barretts esophagus, which, in turn, is secondary to GERD. The photograph shows a raised lesion at the junction of the distal esophagus and proximal stomach. GERD is associated with reflux of gastric acid and bile into the distal esophagus due to relaxation of the lower esophageal sphincter (LES). It is the most common causes of Barretts esophagus. Squamous epithelium reacts to acid injury by replacing the epithelium with mucus-secreting cells (glandular metaplasia). Esophageal ulceration, stricture, and adenocarcinoma are complications of Barretts esophagus. Treatment of GERD is important, because it decreases the risk for developing distal adenocarcinoma of the esophagus, which is the most common primary cancer of the esophagus in the United States. Treatment includes histamine (H2) blockers, proton inhibitors, and prokinetic agents. Polycystic ovary syndrome (PCOS). The photograph shows a cross-section of an enlarged ovary with abundant central stroma and subcapsular follicles and the ultrasound shows similar findings. Serum LH is increased in PCOS. This stimulates the ovaries to produce increased amounts of 17ketosteroids (DHEA and androstenedione) and testosterone. These androgen compounds cause hirsutism (abnormal hairiness, especially in areas where hair would be found on a man). In obese patients, an increase in adipose allows greater conversion of these androgens to estrogens by aromatase (aromatization). Aromatase converts androstenedione to estrone and testosterone to estradiol. Hyperestrinism, in turn, causes endometrial hyperplasia in patients with PCOS. Increased estrogen has a negative feedback on the release of FSH and a positive feedback on LH; therefore, LH remains increased and FSH is suppressed. Decreased FSH causes degeneration of the follicles, resulting in the formation of subcapsular cysts. In PCOS, the LH:FSH ratio > 2. Cyclooxygenase converts arachidonic acid to prostaglandin H2, which is the precursor for prostaglandins, thromboxanes, and prostacyclins. Aspirin and nonsteroidal anti-inflammatory drugs inhibit cyclooxygenase and prevent the synthesis of prostaglandins, some of which are associated with the genesis of pain (e.g., prostaglandin E2).

Uterus has multiple, well-circumscribed, gray-white nodules (leiomyomas) that distort the uterus. Leiomyomas are benign smooth-muscle tumors. Those that are submucosally located are associated with excessive menstrual bleeding (menorrhagia) and often require removal by hysterectomy, as in this patient. Menorrhagia is the most common cause of iron deficiency in women < 50 years of age. In an acute anterior myocardial infarction, aspirin is used to prevent thrombus formation either in the coronary arteries or the damaged endothelium in the left ventricle. Aspirin prevents platelet aggregation causing prolongation of the bleeding time without affecting the platelet count. Patients are frequently anticoagulated with heparin and warfarin. Heparin enhances antithrombin III activity leading to neutralization of many of the coagulation factors including thrombin and X in the final common pathway. This prolongs the PT and the PTT, although the latter test is a better test to follow heparin therapy. Warfarin inhibits further activation of the vitamin Kdependent coagulation factors (II, VII, IX, and X). Since factors II and X are in the final common pathway, the PT and PTT are both

prolonged; however, the former test is a better test to follow warfarin therapy when it is converted into the international normalized ratio. Heparin works by enhancing the activity of anti-thrombin III; therefore, if the patient is deficient in ATIII, a standard dose of heparin is not sufficient to neutralize the clotting factors to prolong the PTT. However, using larger doses of heparin will enhance the activity of what little ATIII is present in plasma causing prolongation of the PTT. An antibody screen (indirect Coombs test) detects atypical antibodies that could potentially attack donor RBC antigens. If the antibody screen is negative, then the major crossmatch (recipient serum + donor RBCs) should be compatible Febrile transfusion reactions are due to recipient anti-human leukocyte antigen antibodies reacting against donor leukocytes (type II hypersensitivity reaction). Destruction of donor leukocytes releases pyrogens causing fever. In chronic renal failure there is tubular cell dysfunction resulting in retention of K+ (hyperkalemia with peaked T waves on an ECG) and an increased anion gap type of metabolic acidosis due to retention of organic acids like sulfuric and phosphaturic acid. Cystic teratoma of the ovary with hair and teeth (arrow). This type of tumor is derived from germ cells or midline embryonic rests, and contains tissues derived from more than one germ cell layer (e.g., bone, muscle, glands, and neural tissue) In most cases, the tumor presents with abdominal pain, as in this patient. Histamine is the primary chemical mediator of type I hypersensitivity reactions. It is stored and released by mast cells, the primary effector cell of type I hypersensitivity reactions. It contracts the venular endothelial cells and exposes the basement membrane, causing increased vessel permeability and swelling of the tissue. Causes arteriolar vasodilation, which produces redness (rubor) of the skin and increased heat (calor) and pruritus. Activated coagulation factor XII converts high-molecular-weight kininogen to bradykinin. Bradykinin causes vasodilation of arterioles, increased vessel permeability, and pain in acute inflammation N.gonorrhoeae is the mcc of septic arthritis. A characteristic pattern of disseminated gonococcemia is the presence of a purulent monoarthritis (usually the knee); tenosynovitis involving the wrist and/or ankles; and pustules on the palms, soles, or trunk. N. gonorrhoeae is always disseminated, because the membrane attack complex is important in the phagocytosis of the pathogen. Acute hemolytic anemia caused by glucose-6-phosphate dehydrogenase (G6PD) deficiency, an Xlinked recessive disorder. G6PD deficiency is most common in persons of black and Mediterranean descent (i.e., Greeks, Italians). G6PD deficiency leads to decreased synthesis of glutathione, which is necessary to neutralize H2O2, an oxidant product in RBC metabolism. Oxidant stresses that induce hemolysis include infection (most common) and drugs (e.g., primaquine, dapsone, trimethoprim). H2O2 accumulation in the RBC damages the RBC membrane (intravascular hemolysis) and denatures hemoglobin, forming discrete inclusions called Heinz bodies. Splenic macrophages often remove damaged RBC membranes, leaving cells with membrane defects, called bite cells, circulating in the peripheral blood . Dairy products should be avoided in lactase deficiency and galactosemia. Lactase, a brush border disaccharidase, catalyzes the conversion of lactose to glucose and galactose. Phenylalanine is increased in phenylketonuria, an autosomal recessive disease characterized by a deficiency of phenylalanine hydroxylase. This enzyme converts phenylalanine to tyrosine.

Phenylalanine-containing products must be eliminated (e.g., certain sweeteners) to prevent mental retardation and tyrosine must be added to the diet. Tyrosine should be eliminated from the diet in patients with tyrosinosis, an autosomal recessive disease caused by a deficiency of fumarylacetoacetate hydrolase, to prevent chronic liver disease, causing hepatocellular carcinoma. Chronic pancreatitis can show irregular densities in the left upper quadrant of the radiograph are foci of dystrophic calcification (calcification of damaged tissue) in the parenchyma of the pancreas. Pain radiating into the back is also highly suggestive of pancreatitis and is related to the retroperitoneal location of the pancreas. In chronic pancreatitis, recurrent attacks of acute pancreatitis lead to repair by fibrosis and loss of both exocrine and endocrine function. Loss of the pancreatic enzymes results in malabsorption, which is the cause of the patients chronic diarrhea and malnutrition. Loss of islet cells leads to type 1 diabetes mellitus. Ingestion of methyl alcohol can cause optic atrophy due to Alcohol dehydrogenase converts methyl alcohol to formic acid, which causes inflammation of the optic nerve (optic neuritis) and metabolic acidosis. Optic atrophy occurs, leading to decreased visual acuity, visual field defects, and night blindness. CGD is X-linked recessive and is caused by a deficiency of nicotinamide adenosine dinucleotide phosphate (NADPH) oxidase. This is the key enzyme in the O2-dependent MPO system, which is the most effective microbicidal system in neutrophils and monocytes. In this system, NADPH oxidase, using NADPH as a cofactor, converts molecular O2 to superoxide free radicals. This reaction releases energy called the respiratory or oxidative burst. Superoxide free radicals are normally converted to peroxide, which is then combined with chloride ions by MPO to produce hypochlorous acid to kill bacteria. A small amount is converted by iron into hydroxyl free radicals. The NBT test detects whether the respiratory burst is functioning. In CGD, the respiratory burst is absent; hence, the abnormal leukocyte NBT test. Peroxide is also absent; therefore, the cells cannot synthesize hypochlorous acid to kill bacteria. S. aureus is the primary cause of death in CGD. S. aureus is catalase-positive, and catalase degrades H2O2. Therefore, any H2O2 produced by the bacteria in the phagolysosome that could potentially be used to synthesize hypochlorous free radicals (HOCl) is neutralized and the bacteria cannot be killed. Bacteria such as Streptococcus pyogenes are catalase negative; hence, when they supply the missing peroxide in the phagolysosome, hypochlorous acid is generated and the bacteria are killed. Primary squamous cell carcinoma of the lung that ectopically secretes parathyroid hormone-related peptide, causing hypercalcemia. These tumors are centrally located (note the centrally located mass in the radiograph) and strongly associated with smoking. medullary carcinomas of the thyroid secrete calcitonin and hypocalcemia is a potential complication hepatocellular carcinomas secrete an insulin-like factor that can produce hypoglycemia. Hydatidiform mole, which is a benign neoplasm of the chorionic villus. They do not contain embryos and have a 46,XX karyotype, which is produced when an egg with no chromosomes is fertilized by two spermatozoa with a 23,X karyotype. Histologically, the villi are devoid of blood vessels and are surfaced by trophoblastic tissue (syncytiotrophoblast and cytotrophoblast). Hydatidiform moles have the capacity to transform into a choriocarcinoma, a malignancy of trophoblastic tissue. Hydatidiform moles develop in the first trimester. The ultrasound shows a snow storm appearance A benign neoplasm with a triploid karyotype describes a partial hydatidiform mole, in which only some of the villi are neoplastic and an embryo usually is present. The neoplastic chorionic villi

contain 69 chromosomes and have an XXY karyotype, which is produced when a haploid egg with a 23,X karyotype is fertilized by two spermatozoa, one having a 23,X and the other a 23,Y karyotype. Partial hydatidiform moles do not progress into a choriocarcinoma. Cervical cancer shows a history of bleeding post sex and malodorus discharge are common. Cervical cancers are associated with HPV 16/18 STD. Cigarette smoking and OCP are risk for cervical squamous cancer. Pap smear can detect cervical squamous dysplasia precursors. If a pregnant woman is given DES pre-pregnancy is predisposed to clear cell adenocarcinoma involving the upper third of the vagina and cervix. Oral contraceptives actually decrease the risk for developing endometrial adenocarcinoma. Celiac disease will show villous atrophy and hyperplastic glands in the lamina propria. Dermatitis hereptiformis is 100% correlated with celiac disease and can present with vesicular lesions. Celiac disease is a multiorgan autoimmune disease characterized by an inappropriate T-cell and IgAmediated response against gluten in genetically predisposed persons (HLA DQ2 and HLA DQ8). Reed-Sternberg (RS) cell, the neoplastic cell found in Hodgkins lymphoma. It is a large, multilobed cell with prominent nucleoli surrounded by a halo of clear nucleoplasm. In most cases, it is a transformed germinal center B-cell that is CD15 and CD30 positive. Creutzfeldt-Jakob disease (CJD) is due to iatrogenic transmission of infectious agents called prions (proteins without nucleic acids). These disorders occur in humans (and may also be transmitted from eating infected cows (bovine spongiform encephalopathy, or mad cow disease). CJD is characterized by progressive dementia, startle myoclonus (abnormal jerking movements), and ataxia. There is no known cure, and death is inevitable. Multinucleated microglial cells are a characteristic finding in patients with AIDS dementia due to HIV. The virus causes the microglial cells to fuse. Microglial cells are the reservoir cell in the brain for HIV. In idiopathic Parkinsons disease, neurons in the substantia nigra contain pink-staining Lewy bodies (damaged neurofilaments) in the cytoplasm. Anxiety induced respiratory alkalosis can cause tetany. Adduction of the thumb into the palm, plus numbness and tingling at the tips of the fingers, are classic signs of tetany. Tetany is due to a decreased concentration of ionized calcium in the blood. This increases neuromuscular excitability by bringing the threshold potential of neuromuscular tissue closer to the resting membrane potential. Therefore, less of a stimulus is required to initiate the action potential, which results in sustained muscle contractions. Myasthenia gravis, which is characterized by drooping eyelids, history of tiredness, diplopia (double vision), and dysphagia for solids and liquids in the upper esophagus. This autoimmune disorder is characterized by the production of IgG antibodies that react against acetylcholine receptors in the neuromuscular junction of striated muscle (type II hypersensitivity reaction). The most common initial presentation is muscle weakness involving the ocular muscles, resulting in ptosis and diplopia toward the end of the day. Note drooping of the left eye in photograph. The confirmatory test is the Tensilon test. Tensilon inhibits acetylcholine esterase causing an increase in acetylcholine in the synapse, enough to bind to receptors causing a reversal of the muscle weakness Multiple sclerosis is the most common demyelinating disorder Amyotrophic lateral sclerosis is an example of an upper and/or lower motor neuron disorder. Muscle weakness begins in the hands and progresses throughout the body.

SIADH due to excessive stimulation of ADH release by chlorpropamide, a oral hypoglycemic agent. ADH reabsorbs electrolyte-free water from the collecting tubules causing a dilutional hyponatremia (serum Na+ = TBNa+/TBW). The mental status abnormalities are due to hyponatremia, which creates an osmotic gradient that favors the movement of water into the cells in the brain. Acute bacterial endocarditis involving the mitral valve. Mitral valve regurgitation produces a pansystolic murmur that does not increase in intensity with deep, held inspiration. S. aureus is the most common pathogen in acute infective endocarditis associated with intravenous drug abuse. Aortic regurgitation is associated with a high-pitched diastolic blowing murmur that occurs immediately after S2. As with all left-sided valvular murmurs and abnormal heart sounds, it does not increase in intensity with deep, held inspiration Mitral stenosis begin with an opening snap in early of mid diastole followed by a mid-diastolic rumbling murmur. Bacterial endocarditis that is not associated with intravenous drug abuse is most often due to S. viridans, which is a pathogen that can only seed a previously damaged valve S. epidermidis is the most common cause of ABE associated with prosthetic heart valves. Carcinogens in cigarette smoke can produce cervical cancer. However, the biopsy shows koilocytotic atypia (not cancer) due to HPV. Diffuse membranous glomerulopathy shows granular immunofluorescence with irregular deposits located in the glomerular capillaries. The chronic hepatitis B infection, hypertension, dependent pitting edema, heavy proteinuria, and fatty casts with Maltese crosses is compatible with a diagnosis of nephrotic syndrome due to diffuse membranous glomerulopathy. The glomerular injury is due to immunocomplex deposition in a subepithelial location (type III hypersensitivity reaction). Focal segmental glomerulosclerosis is most often associated with AIDS in young black males and with intravenous heroin addiction. It is now considered the most common adult cause of nephrotic syndrome. Glomerular injury is due to cytokine damage of the visceral epithelial cells. It is not an immunocomplex disease; therefore, the immunofluorescent study is negative. It is a very common cause of end stage renal disease. Necator americanus (hookworm) is the most common parasite causing iron deficiency. The adult worms of Ascaris lumbricoides cause intestinal obstruction. Trichuris trichiura, or whipworm, is the most common parasite causing rectal prolapse in children Enterobius vermicularis (pinworm). The eggs are characteristically flattened on one side. The female worms lay their eggs in the anus, which causes irritation leading to anal pruritus. TREATMENT with mebendazole Serum transaminase levels are primarily elevated in diffuse liver cell necrosis (e.g., viral hepatitis) ARF is associated with an increase in serum creatinine and serum BUN and the urine sediment shows renal tubular cell casts. In prerenal azotemia there is oliguria and an increased serum BUN and creatine with a ratio > 15. Patient has osteosarcoma and a history of retinoblastoma, which together indicate inactivation of the RB suppressor gene on chromosome 13. Osteosarcoma is a tumor of the connective tissue that arises from osteocytes The BRCA1 suppressor gene is involved in DNA repair. Inactivation of the gene is associated with breast cancer in women and prostate cancer in men.

The c-MYC and n-MYC proto-oncogenes are involved in nuclear transcription. Activation of the cMYC proto-oncogene by a t(8;14) translocation produces Burkitts lymphoma, whereas activation of the n-MYCproto-oncogene produces a neuroblastoma. The RAS proto-oncogene is a signal transducer that generates second messengers. RAS is activated by a point mutation and accounts for 30% of human cancers (e.g., cancers of the lung, colon, and pancreas; leukemias). Adrenal crisis presents as hypotension, tachycardia, hypoglycemia with history of vomiting,weightloss, abdo pain, and hyperpigmentation and should be treated with corticosteroids. MCC of portal HTN is alcohol abuse Portal HTN is caused by increased resistance of blood flow to the liver due to compression of sinusoids and central veins. It is caused by esophageal varcies, ascites, congestive splenomegaly, hemorrhoids, and caput medusa. Esophageal varacies are due to increased portal vein pressure leading to the dilatation of the left gastric coronary arteries. Which usually drain in the distal esophagus and portal vein. Folate deficiency causes microcytic anemia with hypersegmented nuetrophils and causes a decreased in N5 methyltetrahydrofolate and B12 which leads to an increase in plasma homocystenie and methionine which contribute to a MI by causing endothelial damage. Alcoholism causes poor reabsorption in the jejunum. Hence during folate metabolism and B12 metabolism is impaired and cant remove N5 methyltetrahydrofolate Homocystinuria is deficiency of cystathionine synthase which decreases the conversion of homocysteine to cystathionine increasing homocystiene leading to mental retardation and thrombosis Vitamin B12 deficiency causes microcytic anemia pancytopenia and demylelination of posterior and lateral cortico spinal tract When the plasma glucose concentration is low, there is an increase in the body secretion of epinephrine, glucagon, and, to a lesser extent cortisol and growth hormone. The increase in sympathetic activity stimulates lipolysis in the peripheral tissues and gluconeogenesis in the liver and decreases peripheral glucose consumption. The brain relies heavily on glucose as an energy source, and the level of glucose uptake by the brain is not regulated by insulin. If hypoglycemia persists despite this autonomic reaction, the activity of higher brain centers diminishes in order to reduce glucose requirements. Thus, there are two types of hypoglycemic symptoms: 1. Adrenergic symptoms such as sweating, tremor, palpitations, hunger, and nervousness occur due to epinephrine and norepinephrine release. (Recall that sweating is a cholinergic process under sympathetic control.) Adrenergic symptoms are the early signs of hypoglycemia. 2. CNS symptoms develop later and at lower glucose levels. They include behavioral changes, confusion, visual disturbances, stupor, and seizures. Prolonged CNS hypoglycemia leads to irreversible neurological deficits and death. Adult lead poising presents as colicky abdominal pain , constipation, headaches, impaired concentration, bluish pigment on gum tooth line, wrist or foot drop due to peripheral nueropathyand microcytic hyopchromic anemia with basophilic stippling. Acute bronchial constriction begins when an allergen interacts with IgE antibody attached to a mast cell which stimulates mediators like histamine, leukotrienes, PGs, PAF, IL4, IL5, and TNF alpha and beta that cause bronchial constriction, bronchial wall edema, chemotaxis, and increased mucus production.