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By S. Pakwan. Ramapo College of New Jersey.

These factors are normally produced in the body also show promise as immunostimulators buy 10 mg bentyl otc gastritis ct, principally as by monocytes, fibroblasts, and endothelial cells. GM- adjuvants in the treatment of viral and malignant disor- CSF induces bone marrow progenitor cells belonging to ders. It is in clinical trials in pa- Results of several phase 1 and phase 2 clinical trials tients with refractory cancer and myelodysplastic syn- suggest that these cytokines are well tolerated. Trials also are ongoing with rIL-3, a multipotent effects are those commonly observed following the ad- factor that stimulates the growth of monocytes, erythro- ministration of molecules produced by biotechnological cytes, neutrophils, and megakaryocytes. Cytotoxic agents such as azathioprine are effective globulin contains antibodies against the Rh antigen. Azathioprine is a phase-specific cytotoxic agent by inhibiting purine synthesis that functions by inhibiting purine synthesis. The (D) Induce the synthesis of antiidiotype antibodies other answers are wrong because azathioprine is (E) Alkylate and cross-link DNA, preventing blas- nonspecific, is not an alkylating agent, has no effect togenesis on immune complexes, and does not induce anti- 3. IL-2 stimulates the immune system by binding (A) Attach to the HIV virus, making it more sus- to the IL-2 receptors on responsive immune cells, ceptible to phagocytosis causing differentiation and proliferation of T helper (B) Bind to IL-2 receptors on responsive immune and T cytotoxic cells. It has no direct effect on the cells and stimulate the production of T helper and T HIV virus, complement. The boy has significantly reduced serum anti- (C) Cross-link antibodies on mast cell surfaces body levels and a reduced ability to mount an anti- leading to degranulation. The most (D) Activate the complement cascade by binding probably cause is a primary immunodeficiency dis- to the C5a fragment. The primary side effect of cyclosporine therapy stimulating the immune response is nephrotoxicity, occurring in up to 75% of cases. A 4-year-old boy has significantly reduced levels of Unwanted hair growth and neurotoxicity are also IgA, IgM, IgD and IgE in his blood. The other answers are wrong be- strates that he did not develop the appropriate anti- cause cyclosporine therapy is associated with hyper- body titer following standard childhood vaccina- tension, hyperkalemia, and hyperglycemia. The most probable cause of these deficiencies are no references to cyclosporine having cardiac or is immune complex effects or causing hemorrhagic (A) Deficiency in macrophage function that is pre- cystitis. Exploring treatment op- ment cascade tions in renal transplantation: The problems of (C) Alcohol abuse by the mother during pregnancy chronic allograft dysfunction and drug-related (D) A primary immunodeficiency disease that is nephrotoxicity. Immunosuppressive agents in trans- (E) An autoimmune disease targeted at basophil plantation: Mechanisms of action and current anti- surface receptors rejection strategies. New Immunosuppressive (B) Nephrotoxicity, neurotoxicity, hirsutism Modalities and Anti-rejection Approaches in Organ (C) Thrombocytopenia, hypokalemia Transplantation. Growth Factors: Cell (E) Increase circulating immune complexes, car- Growth, Morphogenesis, and Transformation. In choosing tissues and organs for transplan- Fplant, Mary Smith developed jaundice and a tation, the HLA antigens of donors and patients are skin rash on her hands, feet, and face. She also had matched as closely as possible to decrease the risk occasional episodes of vomiting and diarrhea. However many minor antigenic mark- Clinical chemistry results showed her serum liver ers that can cause immunological incompatibility enzymes (LDH, ALT) and bilirubin level to be ele- differ between individuals. Such reactions usually occur when reaction is diagnosed, treatment with corticoste- immunologically competent cells are introduced roids, such as prednisone and prednisolone, is usu- into an immunocompromised host. Lazo and Jennifer Rubin Grandis Most drugs used today are designed to treat symp- tient in a phase I gene therapy protocol. Notable stimulated a substantial review of the oversight mecha- exceptions include cytotoxic chemotherapeutic agents, nisms in human gene transfer research. One of the first as described in Chapter 56, and agents that restore or successes of gene therapy was reported in 2000, when modulate hormone function, as outlined in Chapter 57. The first disease-associated gene, -globin, was C transgene expression in T- and NK cells was de- cloned over 25 years ago. It is now theoretically possible tected and T-, B-, and NK-cell counts and function were to isolate, sequence, and analyze genes causally associ- comparable to those of age-matched controls. Moreover, with the com- orous approach to investigating the safety and efficacy plete sequencing of the human genome, many of the es- of gene transfer will ensure that clinical strategies em- timated 100,000 human genes may become candidates ploying genetic manipulation are rationally incorpo- for genetic manipulations. GENE THERAPY: DEFINITION Germ cell gene therapy will require considerable dis- AND GOALS cussion about ethical issues and extensive information before it can be applied to humans, but somatic cell gene The broadest definition of human gene therapy includes therapy in humans is now being extensively explored.

Carbamazepine can induce its own metabolism such as cerebellovestibular changes leading to dizziness purchase 10 mg bentyl otc gastritis diet v8, (autoinduction) after prolonged administration, de- diplopia, ataxia, and blurred vision. Disseminated in- creasing its clearance rate, half-life, and serum concen- travascular coagulation has been reported. Topiramate is most useful in patients with generalized Carbamazepine also can induce the enzymes that tonic–clonic seizures and those with partial complex metabolize other anticonvulsant drugs, including seizures. Topiramate causes a higher incidence of CNS- phenytoin, primidone, phenobarbital, valproic acid, related side effects (primarily cognitive slowing and clonazepam, and ethosuximide, and metabolism of confusion) than other AEDs. Similarly, other cause a significant incidence of rashes or other hyper- drugs may induce metabolism of carbamazepine; the sensitivity reactions; however, a significantly higher in- end result is the same as for autoinduction, and the dose cidence of kidney stones has been observed in persons of carbamazepine must be readjusted. A common receiving topiramate than in a similar untreated popu- drug–drug interaction is between carbamazepine and lation. After a few days of antibiotic therapy, symp- Zonisamide toms of carbamazepine toxicity develop; this is readily Zonisamide has only recently been approved for use in reversible if either the antibiotic or carbamazepine is the United States, although it has been available in discontinued. It is effective in partial complex Cimetidine, propoxyphene, and isoniazid also have and generalized tonic–clonic seizures and also appears been reported to inhibit metabolism of carbamazepine. It has a It is essential to monitor blood levels and adjust the long half-life (about 60 hours) and requires about 2 dose if necessary whenever additional drugs are given weeks to achieve steady-state levels. In addi- Oxcarbazepine tion, it appears to cause an increased incidence of kid- Oxcarbazepine is chemically and pharmacologically ney stones. This Valproic Acid (Sodium Valproate) property decreases the problems associated with drug Although it is marketed as both valproic acid interactions when oxcarbazepine is used in combination (Depakene) and as sodium valproate (Depakote), it is with other drugs. The clinical uses and adverse effect the valproate ion that is absorbed from the gastroin- profile of oxcarbazepine appear to be similar to those of testinal tract and is the active form. This com- Lamotrigine pound has broad anticonvulsant activity, both in exper- Lamotrigine has a broad spectrum of action and is ef- imental studies and in the therapeutic management of fective in generalized and partial epilepsies. Valproic acid has been shown to block mechanism of action appears to be blockage of voltage- voltage-dependent sodium channels at therapeutically dependent sodium channels, although its effectiveness relevant concentrations. In several experimental stud- against absence seizures indicates that additional mech- ies, valproate caused an increase in brain GABA; the anisms may be active. There is evidence that valproate 380 IV DRUGS AFFECTING THE CENTRAL NERVOUS SYSTEM may also inhibit T-calcium channels and that this may Drugs That Primarily Enhance the Action be important in its mechanism of action in patients with of GABA absence epilepsy. A major effort has been directed to the search for Valproic acid is well absorbed from the gastroin- agents that can mimic, facilitate, prolong, or enhance the testinal tract and is highly bound (~90%) to plasma pro- actions of GABA, with the expectation that such com- tein, and most of the compound is therefore retained pounds will likely be beneficial in the treatment of con- within the vascular compartment. Although there have been some dis- ters the brain from the circulation; the subsequent de- appointments, in general this appears to be a fruitful cline in brain concentration parallels that in plasma, in- approach in the search for better and safer antiepileptic dicating equilibration between brain and capillary compounds. A large number of metabolites have been identi- fied, but it is not known whether they play a role in the Benzodiazepines anticonvulsant effect of the parent drug. Valproic acid inhibits the metabolism of several drugs, including phe- Several benzodiazepines are used in the management of nobarbital, primidone, carbamazepine, and phenytoin, epileptic seizures, although only a few are approved for leading to an increased blood level of these compounds. At high doses, valproic acid can inhibit its own metabo- Since the benzodiazepines share many properties, they lism. It can also displace phenytoin from binding sites will be discussed as a class; individual members will be on plasma proteins, with a resultant increase in un- mentioned for specific indications. In The primary action of the benzodiazepines as anti- this instance, the dosage of phenytoin should be ad- convulsants is to enhance inhibition through their inter- justed as required. These examples reinforce the need action with the GABAA receptor at the benzodiazepine to determine serum anticonvulsant levels in epileptic binding site. It is highly effective against absence but is likely a factor in their use in the treatment of sta- seizures and myoclonic seizures. In the treatment of clonic epilepsy and for partial seizures with complex status epilepticus, the preferred route is usually intra- symptoms. Benzodiazepines are extensively metabolized The most serious adverse effect associated with val- by the microsomal drug-metabolizing system; fre- proic acid is fatal hepatic failure. Fatal hepatotoxicity is quently an active compound is broken down to another most likely to occur in children under age 2 years, espe- agent that is also active pharmacologically.

Aerobic exercise purchase 10 mg bentyl with visa gastritis diarrhea, that is, compound similar to ATP, in that it has a high energy exercise that increases oxygen consumption, such as run- bond that releases energy when it is broken. During strenuous activity, tine phosphate to promote endurance however, a person may not be able to breathe in oxygen An exercise program should include all three meth- rapidly enough to meet the needs of the hard-working ods—stretching, aerobic exercise, and resistance train- muscles. At first, the myoglobin, glycogen, and creatine ing—with periods of warm-up and cool-down before and phosphate stored in the tissues meet the increased de- after working out. The vasodilation (vas-o-di- process generates ATP rapidly and permits greater magni- LA-shun), or widening of blood vessel diameter, that oc- tude of activity than would otherwise be possible, as, for curs during exercise allows blood to flow more easily to example, allowing sprinting instead of jogging. The Anaerobic metabolism can continue only until the buildup resting heart rate of a trained athlete is lower than the av- of lactic acid causes the muscles to fatigue. Circulation in the capillaries surrounding to take in extra oxygen by continued rapid breathing the alveoli (air sacs) is increased, and this brings about (panting) until the debt is paid in full. In ad- moderate regular exercise has the additional benefits of dition, the glycogen, myoglobin, and creatine phosphate weight control, strengthening of the bones, decreased that are stored in the cells must be replenished. The after strenuous exercise during which extra oxygen is effects of exercise on the body are studied in the fields of THE MUSCULAR SYSTEM ✦ 159 8 Box 8-2 Hot Topics Anabolic Steroids: Winning at All Costs? Steroids damage the liver, making it more susceptible Amone testosterone by promoting metabolism and stimu- to disease and cancer, and suppress the immune system, in- lating growth. However, athletes also purchase them illegally, using tility, and the development of female sex characteristics such them to increase muscle size and strength and improve en- as breasts (gynecomastia). They increase blood cholesterol levels, which may increase the risk for baldness and, especially in men, cause lead to atherosclerosis, heart disease, kidney failure, and mood swings, depression, and violence. Types of Muscle Contractions ◗ Isometric (i-so-MET-rik) contractions are those in which there is no change in muscle length but there is Muscle tone refers to a partially contracted state of the a great increase in muscle tension. The maintenance of this tone, or tonus (TO-nus), is For example, if you push the palms of your hands hard due to the action of the nervous system in keeping the against each other, there is no movement, but you can muscles in a constant state of readiness for action. When walking, sible for muscle tone, there are two other types of con- for example, some muscles contract isotonically to propel tractions on which the body depends: the body forward, but at the same time, other muscles are contracting isometrically to keep your body in position. All of the connective tissue within and around Insertion the muscle merges to form the tendon, which then at- taches directly to the periosteum of the bone (see Fig. Radius In moving the bones, one end of a muscle is attached to Ulna a more freely movable part of the skeleton, and the other Humerus end is attached to a relatively stable part. The less movable Tendon (more fixed) attachment is called the origin; the attachment to the part of the body that the muscle puts into action is Figure 8-7 Muscle attachments to bones. Figure 8-7 shows the action of the biceps sistance and the effort; a see-saw or a scissors is an exam- brachii (in the upper arm) in flexing the arm at the elbow. The second-class lever has the The insertion on the radius of the forearm is brought to- resistance located between the fulcrum and the effort; a ward the origin at the scapula of the shoulder girdle. The musculoskeletal system can be considered a sys- tem of levers, in which the bone is the lever, the joint is Muscles Work Together the fulcrum, and the force is applied by a muscle. A move- ample of a first-class lever in the body is using the mus- ment is performed by a muscle called the prime mover; cles at the back of the neck to lift the head at the joint be- the muscle that produces an opposite movement to that tween the occipital bone of the skull and the first cervical of the prime mover is known as the antagonist. A second-class lever is ex- for any given movement, the antagonist must relax when emplified by raising your weight to the ball of your foot the prime mover contracts. In addition to prime movers and an- over a joint and exerts force between the fulcrum and the tagonists, there are also muscles that serve to steady body resistance. As shown in Figure 8-8 C, when are called synergists (SIN-er-jists), because they work the biceps brachii flexes the forearm at the elbow, the with the prime movers to accomplish a movement. The As the muscles work together, body movements are co- weight of the hand and forearm creates the resistance, ordinated, and a large number of complicated movements and the fulcrum is the elbow joint, which is behind the can be carried out. By understanding and applying knowledge of levers to Think of a child learning to walk or to write, and consider body mechanics, the healthcare worker can improve his the number of muscles she or he uses unnecessarily or for- or her skill in carrying out numerous clinical maneuvers gets to use when the situation calls for them. A number of freedom from strain and fatigue; conversely, such ailments different characteristics are used in naming muscles, in- as lower back pain—a common complaint—can be traced cluding the following: to poor body mechanics. Body mechanics have special sig- nificance to healthcare workers, who are frequently called ◗ Location, named for a nearby bone, for example, or for on to move patients and handle cumbersome equipment. There are three classes of levers, (oblique) which differ only in the location of the fulcrum (F), the ef- ◗ Number of heads (attachment points) as indicated by fort (E), or force, and the resistance (R), the weight or load. The muscle surrounding each eye is called the to Figures 8-9 and 8-10 as you study the locations and orbicularis oculi (OK-u-li), whereas the muscle of the functions of some of the skeletal muscles and try to figure lips is the orbicularis oris.

Duodenum—Portion of the small intestine nearest Pancreas—An organ located in the abdomen that the stomach; the first of three parts of the small secretes pancreatic juices for digestion and hor- intestine discount 10 mg bentyl visa chronic gastritis rheumatoid arthritis. Endoscopic retrograde cholangiopancreatography Pancreatitis—Inflammation of the pancreas. Exocrine pancreas—The secreting part of the pan- Radiation—High energy rays used in cancer treat- creas. Familial adenomatous polyposis (FAP)—Inherited Staging—A method of describing the degree and syndrome causing large numbers of polyps and location of cancer. Whipple procedure—Surgical removal of the pan- Fine needle aspiration (FNA)—Insertion of a thin creas and surrounding areas including a portion of needle through the skin to an area of sample tissue. Familial pancreatic cancer “registries” of familial pancreatic cancer cases for research purposes. Some families with increased pancreatic cancer rates do not have a known genetic syndrome as the cause. It is Demographics possible that environmental factors or chance could explain some cases of pancreatic cancer in families; how- Pancreatic cancer is the fifth leading cause of cancer- ever, it is also possible that other as yet unknown genetic related death for both men and women in the United causes could explain some cases of familial pancreatic States. While genetic testing may not be available in ized countries, with African Americans in the United some cases, some families do participate in collections or States having one of the highest rates. The rate of pan- 878 GALE ENCYCLOPEDIA OF GENETIC DISORDERS creatic cancer increases with age, with most patients diagnosed between the ages of 60 and 80. Signs and symptoms Since the symptoms of pancreatic cancer are not spe- cific to the disease, and typically do not develop until the cancer has progressed, it is difficult to diagnosis pancre- atic cancer at an early stage. The symptoms of pancreatic cancer can include: • weight loss • loss of appetite • abdominal or back pain • jaundice (yellow color to skin and eyes) • digestive problems including greasy stool • sudden diabetes Diagnosis If pancreatic cancer is suspected, regardless of the cause, a physical exam often is done first and then certain body imaging tests may be recommended. This exam creates pictures of the interior of the body from computer-analyzed differences in x rays pass- ing through the body. The of biopsy is performed by inserting a thin needle through gallbladder and gallstones at top right of image are green, the skin into a suspicious area (called fine needle aspira- and the pink c-shaped tube at left and center are the tion or FNA) and a sample of tissue is removed. Staging can be Ultrasound is another method of viewing internal body used to help determine the treatment and prognosis for a structures. Since tissues bounce sound waves differently, a computer is able to develop an image based on the Treatment and management returned sound waves. Ultrasound is generally less expensive and more easily available than CT; however, Surgery there are limitations to the use of ultrasound in viewing the pancreas. So, ultrasound may be used in addition to While surgery oftens provides the best chance of a CT. Endoscopic retrograde cholangiopancreatography cure, frequently, it is not possible due to the spread of (ERCP) is a method of viewing the pancreas by inserting cancer. Removal of all or part of the pancreas and other a thin tube down the throat, injecting of dye into the pan- areas such as the duodenum (the first part of the small creatic and bile ducts and then x rays are taken. Complications of this surgery include infection and Once the tumor and any metastasis has been identi- bleeding. Cancer-killing medicine, chemotherapy, has been One simple staging system ranks cancers from 0 to IV found to increase survival in some patients. This medi- GALE ENCYCLOPEDIA OF GENETIC DISORDERS 879 Pancreatic Cancer (Gale Group) cine can be given intravenously or by mouth. Once in the pancreatic cancer at an early age (before age 50) or two bloodstream, chemotherapy agents reach other parts of or more distant relatives (second degree) with one the body. Side effects may gical removal of the pancreas before any cancer develop- include nausea, hair loss, low blood counts, and other ment, has been considered in cases with a hereditary risk. The concern with prophylactic pancreatectomy is that there is a risk of serious complications and so the deci- Radiation therapy sion must be weighed carefully. Recent improvements in radiation, high-energy rays directed at cancer cells, have made this therapy more Prognosis effective. Although cures due to radiation therapy are It is difficult to diagnose pancreatic cancer early and uncommon, relief from pain and increased survival are so, frequently, the cancer has spread to other locations in possible. Side effects of radiation therapy may include the body such as the liver or lymph nodes (part of the skin changes, upset stomach, and other effects.

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