Basic Medical Science Notes

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. PGE2 is one of the prostaglandins that causes fever. It acts on four subtypes of prostaglandin receptorsEP1, EP2, EP3, and EP4and knockout of the EP3 receptor impairs the febrile response to PGE2, 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 Ca2+ 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, folliclestimulating 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 HCO3 transport. The total length of the nephrons, including the collecting ducts, ranges from 45 to 65 mm.