By F. Khabir. Walla Walla University.
A small omphalocele is usually repaired by closed once all of the organs have been returned to the surgery shortly after birth purchase sildigra 50 mg free shipping erectile dysfunction foods, where an operation is per- abdomen cheap sildigra 50mg line impotence australia. Infants are often on a breathing machine (ven- formed to return the organs to the abdomen and close the tilator) until the abdominal cavity increases in size since opening in the abdominal wall. If the omphalocele is returning the organs to the abdomen may crowd the lungs large, where most of the intestines, liver, and/or spleen in the chest area. Initially, sterile protec- tive gauze is placed over the abdominal organs whether The prognosis of an infant born with an omphalocele the omphalocele is large or small. The exposed organs depends upon the size of the defect, whether there was a are then gradually moved back into the abdomen over loss of blood flow to part of the intestines or other organs, 832 GALE ENCYCLOPEDIA OF GENETIC DISORDERS and the extent of other abnormalities. The process of cell division is necessary ORGANIZATIONS for the growth of tissues and organs of the body and for Foundation for Blood Research. Tesla, MS, CGC patient will have skin cancer; in a breast cell, breast can- cer will result, and so on. Cells that loose control of their cell cycle and repli- cate out of control are called cancer cells. Cancer cells undergo many cell divisions often at a quicker rate than IOncogene normal cells and do not have a limited life span. This Definition allows them to eventually overwhelm the body with a large number of abnormal cells and eventually affect the In a cell with normal control regulation (non-cancer- functioning of the normal cells. Cancer is the disease caused by cells that have A cell becomes cancerous only after changes occur lost their ability to control their regulation. The abnormal in a number of genes that are involved in the regulation proteins allowing the non-regulated cancerous state are of its cell cycle. The normal it to stop producing a normal regulatory protein or can gene from which the oncogene evolved is called a proto- produce an abnormal protein which does not regulate the oncogene. When changes occur in one reg- ulatory gene this often causes changes in other regulatory Description genes. Cancers in different types of cells can be caused by changes in different types of regulatory genes. History Proto-oncogenes and tumor-suppressor genes are the The word oncogene comes from the Greek term two most common genes involved in regulating the cell oncos, which means tumor. Proto-oncogenes and tumor-suppressor genes have discovered in certain types of animal viruses that were different functions in the cell cycle. Tumor-suppressor capable of inducing tumors in the animals they genes produce proteins that are involved in prevention of infected. Since two of each later found in human tumors, although most human type of gene are inherited two of each type of tumor- cancers do not appear to be caused by viruses. Both tumor suppressor their original discovery, hundreds of oncogenes have genes of a pair need to be changed in order for the pro- been found, but only a small number of them are tein produced to stop functioning as a tumor suppressor. Although different oncogenes Mutated tumor-suppressor genes therefore act in an auto- have different functions, they are all somehow involved somal recessive manner. Each proto-oncogene produces a The transformation of normal cells into different protein that has a unique role in regulating the cancerous cells cell cycles of particular types of cells. We inherit two of The process by which normal cells are transformed each type of proto-oncogene. A change in only one proto- into cancerous cells is a complex, multi-step process oncogene of a pair converts it into an oncogene. The GALE ENCYCLOPEDIA OF GENETIC DISORDERS 833 oncogene produces an abnormal protein, which is some- TRANSCRIPTION FACTORS Transcription factors are how involved in stimulating uncontrolled cell growth. An proteins found in the nucleus of the cell which ultimately oncogene acts in an autosomal dominant manner since receive the signals from the growth factor receptors. Transcription factors produced by oncogenes typi- Classes of proto-oncogene cally do not require growth factor receptor stimulation and thus can result in uncontrolled cell proliferation. There are five major classes of proto-oncogene/ Transcription factor proto-oncogenes are often changed oncogenes: (1) growth factors, (2) growth factor recep- into oncogenes by chromosomal translocations in tors, (3) signal transducers (4) transcription factors, and leukemias, lymphomas, and solid tumors. Different growth factors activate different cells have a predetermined life span and different genes receptors, found on different cells of the body. Cells that have been in growth factor proto-oncogene result in oncogenes that damaged or have an abnormal cell cycle may develop promote uncontrolled growth in cells for which they have into cancer cells. For example, platelet-derived growth factor through a process called programmed cell death (apopto- (PDGF) is a proto-oncogene that helps to promote wound sis). Cells that have developed into cancer cells, however, healing by stimulating the growth of cells around a do not undergo apoptosis.
Most of the drugs used in cancer treatment have a thera- peutic index that approaches unity 120mg sildigra with amex erectile dysfunction quran, exerting toxic effects on both normal and tumor tissues even at optimal CANCER THERAPY AND THE IMMUNE dosages purchase 25mg sildigra free shipping zocor impotence. Rapidly pro- Although manipulation of the host immune response in liferating normal tissues, such as bone marrow, gastroin- animal tumor models has at times yielded impressive testinal tract, and hair follicles, are the major sites of therapeutic results, attempts to extend these results to acute toxicity of these agents. The most commonly Several proteins that stimulate subsets of lympho- encountered toxicities of antineoplastic agents are de- cytes involved in various aspects of the immune re- scribed in the following section; more detailed informa- sponse are now produced by recombinant DNA tech- tion on individual agents is presented in Chapter 56. Bone Marrow Toxicity Interleukin (IL) 2, originally described as a T-cell growth factor, induces the production of cytotoxic lym- Chemotherapy may result in the destruction of actively phocytes (lymphokine-activated killer cells, or LAK proliferating hematopoietic precursor cells. IL-2 produces remissions in 10 to 20% of patients blood cell and platelet counts may in turn be decreased, with melanoma or renal cell carcinoma when infused at resulting in an increased incidence of life-threatening high doses either alone or with lymphocytes that were infections and hemorrhage. Maximum toxicity usually is previously harvested from the patient and incubated observed 10 to 14 days after initiation of drug treat- with IL-2 in vitro. In contrast, the ni- The ability of certain anticancer agents to suppress trosourea drugs exhibit hematological toxicity that is both humoral and cellular immunity has been exploited delayed until 4 to 6 weeks after beginning treatment. In particular, the alkylating agents cy- clophosphamide and chlorambucil have been used in toxicity or hypoplastic state may develop after long-term this context, as have several of the antimetabolites, in- treatment with nitrosoureas, other alkylating agents, and cluding methotrexate, mercaptopurine, azathioprine, mitomycin C. Thus, patients frequently will require a pro- gressive reduction in the dosages of myelosuppressive drugs when they are undergoing long-term therapy, since such treatment may result in chronic pancytopenia. These symptoms are ameliorated by treatment with phenothiazines and other centrally acting Detoxification Tubulins antiemetics. Although this symptom is distressing to patients, it is rarely severe enough to re- quire cessation of therapy. Continuous in- Damage to the normally proliferating mucosa of the fusion or frequent administration of cytarabine hy- gastrointestinal tract may produce stomatitis, dyspha- drochloride is superior to intermittent injection of the gia, and diarrhea several days after treatment. Bleomycin is another drug for which continuous cerations, esophagitis, and proctitis may cause pain and infusion may increase therapeutic efﬁcacy. Administration of some anticancer drugs by contin- uous infusion has been shown to improve their thera- peutic index through selective reduction of toxicity with Hair Follicle Toxicity retained or enhanced antitumor efﬁcacy. Patients should be Routes of Administration warned of this reaction, especially if paclitaxel, cy- clophosphamide, doxorubicin, vincristine, methotrex- In addition to the usual intravenous or oral routes, some ate, or dactinomycin is used. Hair usually regrows nor- anticancer agents have been administered by regional mally after completion of chemotherapy. Thus, patients with metastatic carcinomas of the PHARMACOKINETIC CONSIDERATIONS liver and little or no disease elsewhere (a common oc- IN CANCER CHEMOTHERAPY currence in colorectal cancer) can be treated with a con- tinuous infusion of ﬂuorouracil or ﬂoxuridine through a catheter implanted in the hepatic artery. Pharmacokinetic Sanctuaries Intracavitary administration of various agents has The existence of the blood-brain barrier is an important been used for patients with malignant pleural or peri- consideration in the chemotherapy of neoplastic dis- toneal effusions. Poor drug penetration etoposide, bleomycin, 5-ﬂuorouracil, and interferon are into the CNS has been a major cause of treatment fail- well tolerated and are being evaluated in patients with ure in acute lymphocytic leukemia in children. The testes also are organs in given intrathecally or intraventricularly to prevent re- which inadequate antitumor drug distribution can be a lapses in the meninges in acute lymphocytic leukemia cause of relapse of an otherwise responsive tumor. Thiotepa and The multidrug transporter P-glycoprotein is ex- bleomycin have been administered by intravesical in- pressed in the endothelial lining of the brain and testis stillation to treat early bladder cancers. Fluorouracil can but not in other organs and is thought to be a major be applied topically for certain skin cancers. Drug Interactions Antineoplastic drugs may participate in several types of Schedules of Administration drug interactions. Methotrexate, for example, is highly Although the effects of various schedules are not al- bound to serum albumin and can be displaced by sali- ways predictable, drugs that are rapidly metabolized, cylates, sulfonamides, phenothiazines, phenytoin, and excreted, or both, especially if they are phase speciﬁc other organic acids. Methotrexate fective than fractionated treatment, since cyclophos- is secreted actively by the renal tubules, and its renal phamide acts on all phases of the cell cycle and almost clearance may be delayed by salicylates. Procarbazine is also a ment should allow time for recovery from the monoamine oxidase (MAO) inhibitor and may potenti- acute toxic effects of antineoplastic agents, pri- ate the effects of drugs that are substrates for this en- marily bone marrow toxicity. Several cycles of treatment should be given, since be inhibited by other drugs that are also transported by one or two cycles of therapy are rarely sufﬁcient P-glycoprotein. The combined use of two or more regimen (mechlorethamine, Oncovin [vincristine sul- drugs often is superior to single-agent treatment in fate], procarbazine, prednisone), alternating with ABVD many cancers, and certain principles have been used in (Adriamycin [doxorubicin hydrochloride], bleomycin, designing such treatments: vinblastine, dacarbazine), has resulted in cure rates of 50 to 60%. The combined modality approach to A drug that is not active against a tumor when several childhood tumors (e. Drugs that act by different mechanisms may plastic drugs when surgery or radiation therapy has have additive or synergistic therapeutic ef- eradicated the primary tumor but historical experience fects.
Androgens also possess protein ana- the adrenals are capable of androgen synthesis order sildigra 25 mg without prescription erectile dysfunction medication causes, less bolic activity that is manifested in skeletal muscle cheap sildigra 25mg with mastercard erectile dysfunction over 40, bone, than 10% of the circulating androgens in men are pro- and kidneys. Testosterone is synthesized by drugs, having limited and relatively predictable side ef- Leydig cells of the testes at the rate of about 8 mg/24 fects. In females, the ovaries contribute approxi- mately one-third of the total androgens synthesized, CHEMISTRY AND BIOSYNTHESIS while the adrenals contribute the rest. The basic structure of all steroid hormones is similar Androstenedione, dehydroepiandrosterone (DHEA), (see Chapter 60, Fig. The addition of a hydrogen and dehydroepiandrosterone sulfate (DHEA-S) are atom at position 5 and an angular methyl group at posi- other mildly androgenic compounds of secondary im- tions 18 and 19 establishes the basic chemical frame- portance in males and females. Com- pared with the diurnal variation seen with cortisol, STEROIDOGENESIS plasma testosterone concentrations are reasonably con- The main steroidogenic components of the testis are the stant. Plasma androgen concentrations also vary greatly interstitial cells of Leydig found between the seminifer- in women through the menstrual cycle, with peak levels ous tubules. Biochemical studies of Leydig cell steroidogenic function have shown that testosterone SEX HORMONE–BINDING PROTEINS synthesis begins with acetate derived either from glucose or products of lipid metabolism. Acetate is converted Circulating testosterone is reversibly bound to two major to cholesterol through numerous reactions in or on plasma proteins, albumin and gamma globulin. Cholesterol, once to albumin is a relatively nonspeciﬁc low-afﬁnity and formed, is stored in lipid droplets in an esteriﬁed form. In contrast, binding to the The cholesterol required for steroidogenesis is trans- speciﬁc -globulin fraction, called sex hormone–binding ferred into the mitochondria, where the side chain is globulin (SHBG), is a high-afﬁnity steroid-speciﬁc in- cleaved by enzymes on the inner membranes to form teraction. This reaction is the rate-limiting step in testosterone is protein bound, 40% to albumin and 58% testosterone biosynthesis and is the step stimulated by to SHBG. Free testosterone reﬂects the amount turned to the cytoplasm, where it serves as the principal that is biologically active and available for interaction precursor of testosterone. Testosterone synthesis from pregnenolone can oc- SHBG levels are known to be inﬂuenced by a variety cur along two distinct metabolic pathways (Fig. In females, the high estrogen levels The names given to these two routes of metabolism re- of pregnancy or the use of oral contraceptives result in in- fer to the position in the steroid molecule where an un- creased SHBG concentrations. Thus, in the delta-4 path- SHBG are seen most commonly in individuals with liver way an unsaturated position is between C4 and C5 of cirrhosis or during normal aging. Elevated SHBG levels ring A, whereas in the delta-5 pathway, the unsaturated are also seen in hyperthyroidism and hypogonadism. In the human of these conditions are associated with elevated estrogen testis, the delta-5 pathway is the predominant (but not ex- levels, which result in increased hepatic SHBG synthesis. SHBG levels are suppressed by androgen replacement or Sertoli cells, in the seminiferous tubule wall, are chronic glucocorticoid therapy. Elevations of SHBG do known to be important in spermatogenesis, in part not necessarily result in a fall in free testosterone levels. ABP, when secreted into the lumen of the sem- whether male or female, it is necessary to measure both to- iniferous tubules, selectively binds testosterone of tal and free testosterone plasma levels. Leydig cell origin and serves as a hormone reservoir Plasma testosterone levels also exhibit age-associated and transport protein for the androgen. The levels of the hormone are very low through- out childhood and until early adolescence, when in- creasing testicular steroidogenesis precedes the onset of REGULATION OF PLASMA puberty in boys. Levels peak in the early 20s, and begin- TESTOSTERONE ning at about age 30, testicular production of testos- terone begins to decline. Urinary 17-ketosteroid excre- The regulation of plasma testosterone is accomplished tion declines slowly as a result of a concomitant through a dynamic feedback interaction among the hy- decrease in the metabolic clearance rate of testos- pothalamus, pituitary, and testis (Fig. Therefore, there is a relatively constant serum amus synthesizes and releases gonadotropin releasing testosterone concentration that often does not decline hormone (GnRH) into the hypothalamic–hypophyseal signiﬁcantly until after age 70. Pulsatile release of GnRH stimulates the free testosterone levels do decrease as a result of in- release of the pituitary gonadotropins LH and follicle- creased SHBG levels. LH and FSH then reach the 726 VII DRUGS AFFECTING THE ENDOCRINE SYSTEM CH3 C O HO Delta-4 Pregnenolone Delta-5 pathway (1) pathway (2) CH3 CH3 C O C O OH O Progesterone HO 17 -Hydroxypregnenolone CH3 C O O OH O 17 -Hydroxyprogesterone HO Dehydroepiandrosterone O OH O 4-Androstenedione HO Androstenediol OH O Testosterone FIGURE 63.
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