Mark Corson

By E. Asaru. Our Lady of the Lake University. 2018.

It has a relatively short half-life and must be adminis- tered subcutaneously daily coreg 25mg visa. Treatment with alefacept has demonstrated a rapid improvement and lessening of the se- verity of psoriasis purchase 12.5 mg coreg with visa, a disease with an autoimmune component order coreg 12.5 mg on-line. Rituximab, in combination with methotrexate, is approved for use in rheumatoid arthritis unresponsive to other therapies. Chapter 6 Autocoids, Ergots, Anti-inflammatory Agents, and Immunosuppressive Agents 167 3. This prevents complete T-cell activation, reduces T-cell proliferation, and reduces plasma cytokine levels. Efalizumab binding to T cells prevents their activation without their destruction. Gout is a familial disease characterized by recurrent hyperuricemia and arthritis with severe pain; it is caused by deposits of uric acid (the end-product of purine metabolism) in joints, car- tilage, and the kidney. Chronic gout is treated with the uricosuric agent probenecid or sulfinpyrazone, which increases the elimination of uric acid, or allopurinol, which inhibits uric acid production. Colchicine is an alkaloid with anti-inflammatory properties; it is used for relief of inflammation and pain in acute gouty arthritis. Reduction of inflammation and relief from pain occur 12–24 hours after oral administration. Colchicine prevents polymerization of tubu- lin into microtubules and inhibits leukocyte migration and phagocytosis. The adverse effects after oral administration, which occur in 80% of patients at a dose near that necessary to relieve gout, include nausea, vomiting, abdominal pain, and particularly diarrhea. Probenecid is an organic acid that reduces urate levels by acting at the anionic transport site in the renal tubule to prevent reabsorption of uric acid. Increased urinary concentration of uric acid may result in the formation of urate stones (uroli- thiasis). This risk is decreased with the ingestion of large volumes of fluid or alkalinization of urine with potassium citrate. Allopurinol is used to treat chronic, tophaceous gout because it reduces the size of the estab- lished tophi; colchicine is administered concomitantly during the first week of therapy to pre- vent gouty arthritis. Allopurinol inhibits the synthesis of uric acid by inhibiting xanthine oxidase, an enzyme that converts hypoxanthine to xanthine and xanthine to uric acid. Allopurinol is metabolized by xanthine oxidase to alloxanthine, which also inhibits xanthine oxidase. This agent more rarely causes hypersensitivity, including fever, hepatic dysfunction, and blood dyscrasias. Allopurinol should be used with caution in patients with liver disease or bone marrow depression. Glucocorticoids, cyclosporine, tacrolimus (Prograf), and siroli- mus (rapamycin) (Rapamune) inhibit the activation or actions of specific cells of the immune system and are generally less toxic than the nonspecific agents. Suppression of the immune system increases the risk of opportunistic viral, bacterial, and fun- gal infections. To overcome an allergic reaction, small quantities of antigen are administered gradually to develop tolerance, most probably as a result of the induction of IgG antibodies to neutralize a subsequent IgE reaction with the allergen. Immunosuppressive agents are used to treat syndromes or diseases that reflect imbalances in the immune system, including rheumatoid arthritis, systemic lupus erythematosus, inflamma- tory bowel disease, chronic active hepatitis, lipoid nephrosis, Goodpasture syndrome, and autoimmune hemolytic anemia. Immunosuppressive agents are also used to prevent allograft rejection, which results when cy- totoxic T lymphocytes develop in response to incompatible transplanted organs. Glucocorticoids are thought to interfere with the cell cycle of activated lymphoid cells and stimulate apoptosis in some lymphoid lineages. Glucocorticoids are important agents in suppressing allograft rejection; they are often used in combination with either cyclosporine or a cytotoxic agent. Cyclosporine has a biphasic t1/2, with a terminal phase of 10–25 hours; it is metabolized in the liver and eliminated primarily in bile. The main use of cyclosporine is in short- and long-term suppression of organ rejection in transplants of the kidney, liver, and heart. Cyclosporine as an ophthalmic emulsion (Restasis) is used to increase tear production in patients with ocular inflammation associated with keratoconjunctivitis sicca. Cyclosporine causes nephrotoxicity in 25%–75% of patients, with a reduction in glomerular filtration and renal plasma flow; hypertension in 30% of patients; neurotoxicity (tremor and seizures) in 5%–50% of patients; and hirsutism and gingival hyperplasia in 10%–30% of patients. Cyclosporine is synergistically nephrotoxic with other drugs that affect kidney function. In- hibition of hepatic microsomal enzymes elevates plasma concentration; the induction of drug-metabolizing enzymes enhances clearance. The adverse effects are similar to those with cyclosporine; tacrolimus can damage the kid- neys and nervous system, manifest by tremors, headache, and renal impairment. Sirolimus is approved for renal transplantation; its efficacy in liver transplant has not been determined. Many of the adverse effects of sirolimus follow from growth factor inhibition and include suppression of all blood elements, impaired wound healing, and rashes; metabolic effects include increased plasma cholesterol and triglycerides. Azathioprine is a cytotoxic agent that suppresses T-cell activity to a greater degree than B- cell activity. Dose reduction is necessary when azathioprine is administered with allopurinol, which reduces xanthine oxidase activity. Azathioprine is used with prednisone in transplantation procedures and in some diseases of the immune system, including systemic lupus erythematosus and rheumatoid arthritis.

Severe Skin and Soft Tissue Infections in Critical Care 305 Figure 6 Postoperative view in a diabetic patient with necrotizing fasciitis of right leg due to group G Streptococcus cheap coreg 6.25 mg online. Results are contradictory order coreg 6.25mg line, with no real epidemiologically based studies performed (for treatment refer to Table 3) discount coreg 6.25 mg with amex. It is a fulminant, rapidly progressive subcutaneous infection of the scrotum and penis, which spreads along fascial planes and may extend to the abdominal wall. Fournier gangrene occurs commonly without a predisposing event or after uncomplicated hemor- rhoidectomy. Less commonly this can occur after urological manipulation or as a late complication of deep anorectal suppuration. Fournier gangrene is characterized by necrosis of the skin and soft tissues of the scrotum and/or perineum that is associated with a fulminant, painful, and severely toxic infection (58,59). Successful treatment is again based on early recognization and vigorous surgical debridement. Clostridial Myonecrosis (Gas Gangrene) Clostridium perfringens type A is the most common organism. Although initial growth of the organism occurs within the devitalized anaerobic milieu, acute invasion and destruction of healthy, living tissue rapidly ensues. Historically, clostridial myonecrosis was a disease associated with battle injuries, but 60% of cases now occur after trauma. It is a destructive infectious process of muscle associated with infections of the skin and soft tissue. It is often associated with local crepitus and systemic signs of toxemia, which are formed by anaerobic, gas-forming bacilli of the Clostridium sp. The infection most often occurs after abdominal operations on the gastrointestinal tract; however, penetrating trauma, and frostbite, can expose muscle, fascia, and subcutaneous tissue to these organisms. Common to all these conditions is an environment containing tissue necrosis, low-oxygen tension, and sufficient nutrients (amino acids and calcium) to allow germination of clostridial spores. Clostridia are gram-positive, spore-forming, obligate anaerobes that are widely found in soil contaminated with animal excreta. They may be isolated from the human gastrointestinal tract and from the skin in the perineal area. This organism produces collagenases and proteases that cause widespread tissue destruction, as well as a-toxin, which have a role in the high mortality associated with myonecrosis. The a-toxin causes extensive capillary destruction and hemolysis, leading to necrosis of the muscle and overlying fascia, skin, and subcutaneous tissues. Patients complain of sudden onset of pain at the site of trauma or surgical wounds, which rapidly increases in severity. Examination of the wound discharge reveals abundant large, boxcar-shaped gram-positive rods with a paucity of surrounding leukocytes. The usual incubation period between injury and the onset of clostridial myonecrosis is two to three days, but may be as short as six hours. A definitive diagnosis is based on the appearance of the muscle on direct visualization by surgical exposure. As the disease process continues, the muscle becomes frankly gangrenous, black, and extremely friable. Serum creatinine phosphokinase levels are always elevated with muscle involvement. Among the signs that predict a poor outcome are leukopenia, thrombocytopenia, hemolysis, and severe renal failure. Myoglobinuria is common and can contribute significantly to worsening of renal function. Frank hemorrhage may be present and is a harbinger of disseminated intravascular coagulation. Successful treatment of this life-threatening infection depends on early recogni- tion and debridement of all devitalized and infected tissues. The role of hyperbaric oxygen therapy has not been established (100% oxygen at 3 atm), but it may have a role early in the treatment of seriously ill patients (19,20). The mainstay of treatment is surgical debridement, and this should not be delayed. In this process, the bacterial tissue invasion is primarily superficial to the fascial layer, without muscle involvement. Prompt recognition and treatment, as described earlier, can reduce the associated morbidity and mortality. Protein synthesis inhibitors such as clindamycin when combined with penicillin has had considerable better efficacy than penicillin alone. Anaerobic streptococcal myonecrosis clinically resembles subacute clostridial gas gangrene. The involved muscles are discolored, in contrast to gas gangrene, early cutaneous erythema is prominent. The infection is usually mixed; anaerobic streptococci with group A Streptococcus or S. Treatment involves the use of high-dose penicillin and antistaphylococcal agent, if indicated, and surgical debridement. Cellulitis often develops within 12 to 24 hours, accompanied by excruciating pain, marked edema, and bullae. Infected vascular gangrene is a focal, usually indolent and primarily ischemic process in the small muscles of a distal lower extremity already gangrenous from arterial insufficiency. Diabetic patients are prone to develop this complication, which usually does not extend 308 Sharma and Saravolatz beyond the area of vascular gangrene to involve viable muscle. Bacterial infection of the muscle usually occurs after a penetrating wound, vascular insufficiency, or a contiguous spread.

If pinworms are sus- antidiuretic hormone; diabetes insipidus; oxy- pected buy 25 mg coreg with amex, transparent adhesive tape or a pinworm tocin 12.5 mg coreg sale. The eggs adhere to the sticky tape pituitary adenoma A benign tumor of the pitu- or paddle and are identified via examination under itary gland discount coreg 6.25mg without a prescription, the master gland that controls other a microscope. Although a pituitary adenoma itself is not cancerous, it may affect pituitary func- piriformis muscle See muscle, piriformis. Typically, the pain of piriformis syndrome is pituitary gigantism See gigantism, pituitary. Piriformis syn- the base of the brain, which produces hormones drome can cause difficulty walking due to pain in that control other glands and many body functions, the buttock and lower extremity. With persistent symptoms, further treatment can include local injection of anesthetic and cortisone pityriasis rosea A common mild rash of medication. Rarely, surgery is performed to relieve unknown origin that may last from several weeks to the pressure. Treatment may include medications for the itching and soothing lotions or pituitary 1 Pertaining to the pituitary gland or its skin lubricants. The goal is to nor- in childhood and disruption of the other endocrine malize the levels of phenylalanine and tyrosine in gland functions that are normally under the control the blood to prevent brain damage. The results of overfunction of treatment results in profound irreversible mental of the anterior pituitary include gigantism in retardation, microcephaly, epilepsy, and behavior children and acromegaly in adults. If an appropriate diet is not followed acromegaly; dwarfism, pituitary; gigantism, closely, especially during childhood, some impair- pituitary. The chorionic villi can go right on heart disease, growth retardation, microcephaly, through both the myometrium and the outside cov- and mental retardation. Placenta previa can cause painless bleeding in placebo A sugar pill or any other inactive sub- the last trimester of pregnancy, and it may be a rea- stance that is given instead of medication. A number of techniques may be tried to carbon dioxide and waste products from the fetus. The placental stage of labor The part of labor that placenta is expelled with the fetal membranes dur- lasts from the birth of the baby until the placenta ing the birth process; together, these structures and fetal membranes are delivered. When someone has the plague, he or she placenta, succenturiate See placenta, accessory. The plague has been responsible for dev- placenta, supernumerary See placenta, astating epidemics. Yersinia pestis infection can be easily treated placenta accreta The abnormal adherence of the with antibiotics when detected early Also known as chorion of the placenta to the myometrium of the pest and pestis. Sylvatic and the reconstituted solution is then returned to plague is sometimes seen in the western portion of the patient. When the plasma is removed, it takes plantar Having to do with the sole of the foot. Plasmapheresis carries with it the same risks as any intravenous procedure plantar response See Babinski reflex. Plasmodium The genus of the class of Sporazoa that includes the parasite that causes malaria. Blood plasma contains anti- geons also perform cosmetic surgery that is unre- bodies and other proteins. A plasma cell is a Plastic surgery is also involved with the enhance- fully differentiated, mature lymphocyte in the B cell ment of the appearance of a person through cos- lineage. Plasma cell malignan- cies include plasmacytoma, multiple myeloma, plasticity, brain See brain plasticity. Waldenstrom macroglobulinemia, and plasma cell platelet An irregular, disc-shaped element of leukemia. During normal plasma donation The donation or sale of blood blood clotting, platelets group together (aggregate). The blood platelet count The calculated number of cells are then returned to the donor intravenously. Platelets are the smallest cell-like structures plasmacytoma Cancer of the plasma cells (white in the blood and are important for blood clotting blood cells that produce antibodies) that may turn and plugging damaged blood vessels. Platelets can also be counted with the help need for decortication (opening the pleural space of a microscope. Normal platelet counts are in the and removing portions of one or two ribs in order range of 150,000 to 400,000 per microliter These to clear scar tissue and remove pus and debris). For example, the Marfan gene is pleurodesis A procedure that causes the mem- pleiotropic, potentially causing such diverse effects branes around the lungs to stick together and pre- as long fingers and toes (arachnodactyly), disloca- vents the buildup of fluid in the space between the tion of the lens of the eye, and dissecting aneurysm membranes (pleural space). During pleurodesis, an pleomorphic tumor would be a growth that is com- irritant is instilled inside the pleural space in order posed of different types of tissues. This procedure thereby permanently oblit- erates the space between the pleura and prevents plethoric Florid, red-faced. There is normally a small quantity (about Plummer-Vinson syndrome The combination 3 to 4 teaspoons) of fluid that is spread thinly of iron deficiency anemia, esophageal webs, and between the visceral and parietal pleurae. The iron defi- ral fluid acts as a lubricant between the two mem- ciency is typically chronic and severe. Treatment is iron supplementation and, if needed, dilation of the web to permit normal swal- pleural space The tiny area between the two lowing and the passage of food. Also known as pleurae, which is normally filled with a small Paterson-Kelly syndrome; sideropenic dysphagia. A physician can often hear with a stethoscope the friction generated by the rub- pneumatic larynx A device that uses air to pro- bing of the two inflamed layers of pleurae with each duce sound, helping a person whose larynx has breath. Removal of pleu- ral fluid, when present, with a needle and syringe is pneumococcal immunization A vaccine that pre- key in diagnosing the cause of pleurisy and can also vents one of the most common and severe forms of relieve the pain and shortness of breath associated pneumonia, the form that is caused by Streptococcus with pleurisy. Radiation pneu- pneumoconiosis Inflammation and irritation monitis typically occurs after radiation treatments caused by deposition of dust or other particulate for cancer within the chest or breast.

However its use is limited by seri- relatively lower glutathione levels buy coreg 12.5 mg without prescription, and therefore antioxidant ous side effects including neuro- purchase coreg 25 mg without prescription, nephro- and ototoxicity buy generic coreg 12.5 mg line. There is also a most vulnerable cells for cisplatin cytotoxicity in the inner ear gradient of outer hair cell glutathione levels in the cochlea, ris- are outer hair cells, followed by inner hair cells. This may help to explain the vulner- and the stria vascularis are the least damaged. Survival pathways In the last decade many genes associated with hearing loss have that oppose hair cell death are also activated, including an hRas- been identified in humans, as well as in animal models (20). Many of the the balance of activity in these damage and survival pathways that mutations that result in hearing loss are characterized by loss of determine the fate of the cell. Relatively little is known about the intracellular or stimulating survival pathways can protect hair cells. Exposure to sound of sufficient intensity produces a threshold shift in hearing level. Hearing function can recover completely or residual or permanent threshold shift might occur. With Protecting hair cells: Prevention of repeated exposure, a permanent threshold shift can accumulate, leading to increasingly debilitating hearing loss. Common his- hair cell damage and recovery tological findings affect the spiral limbus, the ligament with the organ of Corti, as well as the stria vascularis. As in ototoxicity, cell signalling edge that danger is ahead to counteract the toxic event before networks involving cell death as well as cell survival pathways it occurs. Since ototoxic drugs are administered by intention, identified to link noise exposure to hair cell death are Src their effect is predictable, as is ageing. They empha- (antioxidants) have been studied intensively in vitro as well as sized the occurrence of relatively isolated degeneration in either in vivo in different animal models (for a detailed summary see the organ of Corti, afferent neurones or the stria vascularis (18). Iron chelators, like deferoxamine, 2,2 -dipyridyl, sali- These separate mechanisms have been seen in various animal cylate, D-methionine and 2,3 dihydroxybenzoate, which models such as mice, cats and guinea pigs (14). Ahl1 codes for cadherin 23 (Cdh 23), which is a con- platin toxicity in vitro and in vivo in different animal models. Products for the ahl2 and ahl3 genes day) reduced gentamicin-induced hearing loss in humans. Hair cells are generated to survive––with- contrast, cisplatin ototoxicity does not appear to be mediated out renewal––for a whole lifetime. Downstream in the apoptotic pathways, various caspase inhibitors have proven to attenuate hair cell loss from noise, cisplation and aminoglycoside damage (4,8). However, effector caspases are activated late and typically after mitochondrial Replacing hair cells: hair cell damage. Therefore, inhibition of effector caspases may only regeneration by trans-differentiation delay hair cell loss but not rescue hair cells, since the apoptotic signal may be diverted upstream due to metabolic enzymes and of supporting cells other effectors take over for caspases. In addition to damaged pathways, cellular stress may lead to Non-mammalian vertebrates, especially birds and amphibians, enhanced cell damage by interruption of pro-survival pathways regenerate hair cells constantly throughout their lives (37). Alternatively, they may derive from sup- from various damage (25–28) possibly by activation of survival porting cells, either by asymmetrical cell division or straight- signalling. Supporting cells of the Finally, insertion of a bacterial resistance gene into the mammalian inner ear are post mitotic in vivo, and therefore mammalian genome has been shown to protect hair cells from unable to go through cell division and therefore regeneration. Raphael and colleagues (39,40) demonstrated that in vivo Understanding the embryonic inoculation of adenovirus with the Atoh1 gene into the development of the organ of corti— cochlear endolymph of mature guinea pigs led to the expression of the gene in supporting cells of the organ of Corti as well as key knowledge for cell replacement adjacent cells. In addition, of the embryo, which invaginates and forms the early otocyst in some spiral ganglion dendrites extended towards the new the first trimester of development in humans. In their later publication they develops outgrowths, which extend to form the vestibular and confirmed these results in previously deafened adult guinea pigs, cochlear divisions of the membranous labyrinth. In addition they observed ated sensory epithelia form on the walls of the developing normal surface morphology and orientation of new hair cells labyrinth. Just after the time at which cell division ceases in the within the organ of Corti, leading to a partial recovery of hear- epithelia, the hair cells differentiate from the surrounding cells, ing function in these animals with a threshold as low as 65 db which become supporting cells. Surprisingly they detected an increase in the number of The signalling events that lead to the specification of indi- nuclei in the supporting cell area of the organ of Corti after vidual cell types in the inner ear and their exit from the cell Atoh1 treatment. However, a variety of cellular fied supporting cell precursors capable of replicating. Different cues are needed for for transdifferentiation, as identified by the yield of hair cells initiation, completion and stabilization of differentiation. These findings suggest that these cells may be the source for the previously described regenerative capability of the mammalian utricular sensory epithelium (48). They also have In addition to these two studies, the work of Malgrange the capacity for self renewal (symmetrical division) and therefore et al. The latter data suggest a for diabetes (43) and motor neurones for spinal cord injuries (44). The application of epidermal the clinical standpoint since they are more readily accessible. Withdrawal of growth fac- tors, the mitogenic stimuli, led to further differentiation of the generated cells. Mechanisms for hair cell protection and regeneration in the mammalian organ of Corti 311 Nevertheless, most studies investigating cell death mecha- death through interconnections between apoptotic and necrotic nisms in the cochlea have been performed in vitro with oto- pathways. In addition, nearly terminal kinaxe protects against both aminoglycoside and acoustic all studies cited in this chapter have been carried out on animal trauma-induced auditory hair cell death and hearing loss.