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Physiology

Toxins from bacteria such as endotoxin act on monocytes, macrophages, and Kupffer cells to produce
cytokines that act as endogenous pyrogens (EPs). There is good evidence that IL-1 , IL-6, -IFN,
-IFN, and TNF-can act independently to produce fever. These cytokines are polypeptides and it is
unlikely that circulating cytokines penetrate the brain. Instead, evidence suggests that they act on the
OVLT, one of the circumventricular organs. This in turn activates the preoptic area of the hypothalamus.
The fever produced by cytokines is probably due to local release of prostaglandins in the hypothalamus.
Intrahypothalamic injection of prostaglandins produces fever. In addition, the antipyretic effect of
aspirin is exerted directly on the hypothalamus, and aspirin inhibits prostaglandin synthesis. PGE
2
is one
of the prostaglandins that causes fever. It acts on four subtypes of prostaglandin receptorsEP
1
, EP
2
,
EP
3
, and EP
4
and knockout of the EP
3
receptor impairs the febrile response to PGE
2
, IL-1 , and
bacterial lipopolysaccharide (LPS).
Many microorganisms grow best within a relatively narrow temperature range and a rise in temperature
inhibits their growth. In addition, antibody production is increased when body temperature is elevated.
Before the advent of antibiotics, fevers were artificially induced for the treatment of neurosyphilis and
proved to be beneficial. Hyperthermia benefits individuals infected with anthrax, pneumococcal
pneumonia, leprosy, and various fungal, rickettsial, and viral diseases. Hyperthermia also slows the
growth of some tumors.
In malignant hyperthermia, various mutations of the gene coding for the ryanodine receptor
lead to excess Ca
2+
release during muscle contraction triggered by stress. This in turn leads to
contractures of the muscles, increased muscle metabolism, and a great increase in heat
production in muscle. The increased heat production causes a marked rise in body temperature
that is fatal if not treated.
Periodic fevers also occur in humans with mutations in the gene for pyrin, a protein found in
neutrophils; the gene for mevalonate kinase, an enzyme involved in cholesterol synthesis; and
the gene for the type 1 TNF receptor, which is involved in inflammatory responses. However,
how any of these three mutant gene products cause fever is unknown.
Neural connections run between the hypothalamus and the posterior lobe of the pituitary
gland, and vascular connections between the hypothalamus and the anterior lobe of the
pituitary.
In most mammals, the hormones secreted by the posterior pituitary gland are vasopressin
and oxytocin. Vasopressin increases the permeability of the collecting ducts of the kidney
to water, thus concentrating the urine. Oxytocin acts on the breasts (lactation) and the
uterus (contraction).
The anterior pituitary secretes six hormones: adrenocorticotropic hormone (corticotropin,
ACTH), thyroid-stimulating hormone (thyrotropin, TSH), growth hormone, follicle-
stimulating hormone (FSH), luteinizing hormone (LH), and prolactin (PRL).
Other complex autonomic mechanisms that maintain the chemical constancy and
temperature of the internal environment are integrated in the hypothalamus.
Well-differentiated squamous cell carcinomas elaborate keratin, just as well-differentiated
hepatocellular carcinomas elaborate bile.
Dysplasia is encountered principally in the epithelia. It is a loss in the uniformity
of individual cells and in their architectural orientation. Dysplastic cells exhibit
considerable pleomorphism and often possess hyperchromatic nuclei that are abnormally large
for the size of the cell. Mitotic figures are more abundant than usual. Frequently the mitoses
appear in abnormal locations within the epithelium. In dysplastic stratified squamous epithelium,
mitoses are not confined to the basal layers, where they normally occur, but may appear at all
levels and even in surface cells
When dysplastic changes are marked and involve the entire thickness of the epithelium, the
lesion is referred to as carcinoma in situ, a pre-invasive stage of cancer.
Although dysplastic changes are often found adjacent to foci of malignant transformation, and
long-term studies of cigarette smokers show that epithelial dysplasia almost invariably antedates
the appearance of cancer, the term dysplasia without qualifications does not indicate cancer, and
dysplasias do not necessarily progress to cancer. Mild-to-moderate changes that do not
involve the entire thickness of epithelium may be reversible, and with removal of the
putative inciting causes, the epithelium may revert to normal.
Recently, cancer stem cells, sometimes called tumor-initiating cells, were
identified in breast cancer, glioblastoma multiforme (a brain tumor), and acute myeloid
leukemia.
At one extreme are basal cell carcinomas of the skin and most primary tumors of
the central nervous system that are highly invasive in their primary sites of origin but
rarely metastasize. At the other extreme are osteogenic (bone) sarcomas, which usually
have metastasized to the lungs at the time of initial discovery.
Malignant neoplasms disseminate by one of three pathways: (1) seeding within body cavities, (2)
lymphatic spread, or (3) hematogenous spread.
Lymphatic spread is more typical of carcinomas, whereas hematogenous spread is favored by
sarcomas usually.
Carcinoma of the breast usually arises in the upper outer quadrant and first spreads to the
axillary nodes. However, medial breast lesions may drain through the chest wall to the nodes
along the internal mammary artery.
A "sentinal lymph node" is defined as the first lymph node in a regional lymphatic basin that
receives lymph flow from a primary tumor.
Cancers arising near the vertebral column often embolize through the paravertebral plexus; this
pathway probably is involved in the frequent vertebral metastases of carcinomas of the thyroid
and prostate.
prostatic carcinoma preferentially spreads to bone.
bronchogenic carcinomas tend to involve the adrenals and the brain.
neuroblastomas spread to the liver and bones.
The macula, the neighboring lacis cells, and the renin-secreting juxtaglomerular cells in the
afferent arteriole form the juxtaglomerular apparatus.
The epithelium of the collecting ducts is made up of principal cells (P cells) and intercalated
cells (I cells). The P cells, which predominate, are relatively tall and have few organelles. They
are involved in Na
+
reabsorption and vasopressin-stimulated water reabsorption.
The I cells, which are present in smaller numbers and are also found in the distal tubules, have
more microvilli, cytoplasmic vesicles, and mitochondria. They are concerned with acid
secretion and HCO
3

transport. The total length of the nephrons, including the collecting


ducts, ranges from 45 to 65 mm.

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