Greg Reece, MD

• Professor of Plastic Surgery
• Department of Plastic Surgery
• University of Texas MD Anderson Cancer Center
• Houston, Texas

When technically feasible purchase 50 mg glyset, expanding order glyset 50 mg mastercard, symptomatic cheap 50mg glyset with amex, or infected cysts are best removed in toto at surgery discount glyset 50 mg overnight delivery, with care taken to isolate and kill the cyst (with hypertonic saline [25 to 30 grams per deciliter] or other cidal agents [such as ethanol]) prior to excision, to avoid secondary spread of parasite cysts. Controversy has developed over the practice of intraoperative instillation of cidal agents, as some patients have developed sclerosing cholangitis as a late complication of surgery. Perioperative drug therapy alone may prevent spread of daughter cysts at the time of surgery. Surgical resection should include careful closure of biliary and enteric fistulas and extensive postoperative drainage of the cyst bed to prevent fluid accumulation and secondary bacterial infection. In such cases, oral drug therapy with the anthelminthics, either long-term mebendazole (40 mg per kilogram of body weight per day in three divided doses for 6 to 12 months) or albendazole (400 mg twice a day for one to eight periods of 28 days each, separated by drug-free rest intervals of 14 to 28 days), has been recommended for cure or palliation. Cure rates, particularly for difficult cases with recurrent or extrahepatic/extrapulmonary cysts, have been low (<33%), although a majority of patients show some improvement. Because the efficacy of drug therapy is limited, a combined medical-surgical approach should be formulated for each patient. Cysticercosis Cysticercosis represents human tissue infection with the intermediate cyst forms of the pork tapeworm T. Infection prevalence is approximately 1 to 10% in endemic areas of Latin America, India, Asia, Indonesia, and parts of Africa. Because of its potentially life-threatening complications, cysticercosis has greater clinical significance than does intestinal T. Cysticerci are bladder-like, fluid-filled cysts containing an invaginated protoscolex. This syndrome has an estimated mortality rate of up to 50%, and any neurologic, cognitive, or personality disorder in an individual from an endemic area should be considered a possible manifestation of undiagnosed neurocysticercosis. These cysts may be in different stages of development, with symptoms commonly arising when older cysts begin to die, lose osmoregulation, and release antigenic material to provoke significant host inflammatory response. In practice, neurocysticercosis may be divided into six discrete syndromes for management. In the acute invasive stage of cysticercosis, immediately after infection, the patient may experience fevers, headache, and myalgias associated with significant peripheral eosinophilia. Heavy infection at this stage may result in a clinical picture of "cysticercal encephalitis" associated with coma and rapid deterioration. This presentation should be treated aggressively with antiparasitic agents and anti-inflammatory drugs. Compression due to swelling or inflammation around the cysts may result in focal deficits, signs of cerebral edema, and/or hydrocephalus. Seizures may be focal (jacksonian), referring to the specific cortical locus of involvement, or may be generalized. Sensorial changes may include apathy, amnesia, dementia, hallucination, and emotional disturbance. Like other forms of basilar meningitis, pericysticercal inflammation at the base of the brain may cause obstruction or vasculitis of the cerebral arteries, leading to intermittent ischemia or stroke. Intraventricular cysticercosis (15% of cases) is, because of its location, the most difficult to diagnose and treat. Symptomatic cysts are most frequent in the fourth ventricle, where they cause outflow obstruction and increased intracranial pressure without localizing signs. An aggressive variant of ventricular neurocysticercosis, called racemose cysticercosis, frequently involves the basal cisterns. This form of cysticercosis has been noted most often in young women and involves multiple, rapidly spreading cysts in the cerebrum and around the base of the brain. Whereas symptoms due to isolated cysts may remit, racemose cysticercosis usually has a progressive, deteriorating course if therapy is not given. Those with spinal cysticercosis may present with cord compression, radiculopathy, transverse myelitis, or signs of meningitis, depending on the location of involvement. Ocular cysticercosis is a distinct syndrome that manifests as eye pain, scotomata, and decreasing vision due to iridocyclitis, clouding of the vitreous, and retinal inflammation or detachment. A definitive diagnosis of cysticercosis requires examination of biopsy material obtained from a tissue cyst. It should be noted, however, that antiparasite antibodies may persist long after infection, and a positive IgG serology merely indicates prior Taenia exposure, not necessarily active disease. The differential diagnosis of neurocysticercosis includes tumor, hydatid cyst disease, vasculitis, and chronic fungal and mycobacterial infection. Given the high prevalence of cysticercosis in some areas of the world, it is evident that most cysticerci do not cause significant symptoms. In the case of symptomatic neurocysticercosis, which carries an associated mortality of up to 50%, therapy is definitely indicated, but surgery may be risky or technically unfeasible. An alternative approach to controlling some forms of neurocysticercosis has been demonstrated in recent clinical studies. Drug therapy with either praziquantel (50 mg per kilogram per day in three divided doses for 14 to 30 days) or albendazole (15 mg per kilogram per day for 30 days) has been associated with alleviation of symptoms and regression of cyst size and number in patients with viable (nonenhancing) cysts in the cerebral parenchyma. However, drug therapy has provided only limited improvement in patients with arachnoiditis and no improvement in patients with intraventricular cysts. For these latter presentations, the treatment of choice remains surgery and/or palliation with shunting, anticonvulsants, and anti-inflammatory agents. It should be noted that in about 20% of treated cases, starting drug therapy is associated with a severely symptomatic, increased inflammatory response at the site of the cyst. This inflammation may be controlled with corticosteroids, but corticosteroids are not recommended for routine use in all patients, as they may significantly alter the pharmacokinetics of the anthelminthics used to treat infection. Follow-up tomographic scanning should be repeated 3 months after therapy is stopped to ensure adequate response. If necessary, a repeat course of drug therapy with the alternate agent may be given to improve response. Because parasite-induced ocular inflammation does not respond well to systemic anti-inflammatory agents, patients with cysticercosis of the eye (20% of cases of neurocysticercosis) should not receive drug therapy until the eye disease has been controlled surgically. Coenurosis A different, but more rare, form of tissue cysticercosis may be caused by larval stages of the dog tapeworms T. Ocular involvement is common, and surgical resection is currently the only effective mode of therapy. Sparganosis Sparganosis is a tissue cestode infection caused by the plerocercoid larval stages of Spirometra, species tapeworms of cats and other carnivores. Humans may become infected by ingesting infected water fleas (Cyclops), by ingesting uncooked meat from infected animals (reptiles, birds, or mammals), or by cutaneous exposure. Occasionally, proliferation into surrounding tissues occurs by lateral budding of the parasite (termed sparganum proliferum). The treatment of choice for sparganosis is ethanol injection and/or surgical removal, as limited experience with medical anthelminthic therapy has shown no beneficial effect. It is estimated that over 200 million people are currently infected worldwide, mainly in rural agricultural and peri-urban areas. Schistosomiasis may cause a severe degree of morbidity and pathologic changes that if left undiagnosed and untreated may result in major disability or mortality. These species differ not only biologically from one another but also in their geographic distribution and in the type of disease they produce. In the Western Hemisphere it is established in Brazil, Venezuela, Surinam, Puerto Rico, Antigua, Dominican Republic, Guadeloupe, Martinique, Montserrat, Nevis, and St. The freshwater snail intermediate hosts are Biomphalaria in Africa and Biomphalaria glabrata (Australorbis) and Tropicarbis in South America and the West Indies. In some cases, the endemicity of schistosomiasis may be maintained by animal reservoirs. Rodents, monkeys, and baboons have been found infected in nature, but the role of these animals as reservoirs does not seem to be epidemiologically important. Although they are morphologically distinctive, the species of Schistosoma that infect humans share some common factors. Once deposited in the host, eggs may stay in the mesenteric vein, be trapped in the intestines, escape to intestinal lumen, and migrate by portal blood to the liver (S. After exposition by feces or urine in fresh water the eggs hatch and release ciliated motile 1980 Figure 431-1 Schistosome life cycle. After asexual multiplication in the snail, the development of cercariae, the infective forms for humans, takes 4 to 7 weeks.

Misoprostol has been used as an adjunct to cyclosporine in renal transplantation and has been found to delay renal allograft rejection in humans cheap glyset 50 mg otc. Although the mechanism for this beneficial effect is uncertain purchase glyset 50 mg line, it may be due to both the immunosuppressive and vasodilator effects of misoprostol cheap glyset 50mg without a prescription. Indomethacin augments the effects of vasopressin and diminishes the excessive water elimination in nephrogenic and lithium-induced diabetes insipidus buy glyset 50 mg free shipping. Cyclooxygenase inhibitors are currently being evaluated for the treatment of premature labor. A potential hazard of this approach is premature closure of the ductus arteriosus, although the incidence of this complication is unknown. During pregnancy, prostaglandin and thromboxane formation is significantly increased. This increment is less pronounced in patients with pregnancy-induced hypertension. TxA2 biosynthesis is also increased, thus indicating that platelet activation may be present in normal pregnancy and is further increased in patients with severe pregnancy-induced hypertension. Platelet TxA2 receptor density is also increased in women with pregnancy-induced hypertension and is highest in the most severely affected patients. TxA2 is a potent vasoconstrictor in the placental bed and may contribute to the depressed placental blood flow that is a hallmark of this disorder. Multicenter trials have been performed to determine whether low-dose aspirin will reduce the incidence of pregnancy-induced hypertension in women at risk for the disease. Studies have yielded equivocal results, with the larger trials failing to show any benefit of aspirin over placebo. It is effective in men with neurogenic, vasculogenic, and psychogenic causes, with the latter two groups appearing to require lower doses. Many of the life-threatening symptoms, particularly the bronchospasm, can be relieved by treatment with aspirin in combination with H1 - and H2 -receptor antagonists. In patients with elevated parathyroid hormone levels or when metastases to bone occur, indomethacin is not effective. Acetaminophen differs from the other compounds in being an efficient antipyretic despite weak anti-inflammatory properties in the periphery. Vasodilator prostaglandins seem to act in concert with other mediators to augment the inflammatory response. Among these may be the leukotrienes, which enhance capillary permeability and function as chemoattractants and leukocyte activators. Murata T, Ushikubi F, Matsuoka T, et al: Altered pain perception and inflammatory response in mice lacking prostacyclin receptor. For more than two decades, considerable interest has focused on endogenous factors that play a role in the regulation of water and electrolyte balance. Some of the uncertainties about their importance in physiology and pathophysiology have recently been addressed in genetic manipulation studies. Its physiology, pathophysiology, and therapeutic potential now await the availability of chemically synthetic material permitting direct testing. The natriuretic effects of extracellular fluid volume expansion in one animal also occurred in a second animal cross-circulated with the blood of the first. The presumption was that the natriuresis was due to a circulating substance that exerted its effects directly on the renal tubular Na+ reabsorptive process without affecting renal hemodynamics. Further experiments confirmed that active extracts from plasma, urine, and tissue sources that were natriuretic in vivo had a direct effect on transepithelial sodium transport. The digoxin radioimmunoassay has been used to detect digitalis-like immunoactivity in the urine and plasma of sodium-loaded normal human subjects and in uremic and hypertensive subjects. This mammalian molecule inhibits active sodium transport in renal tubular cells and has positive inotropic and vasoconstrictive properties consistent with the natriuretic hormone hypertension hypothesis. A compound with identical physicochemical properties has been extracted from human plasma. Although less characterized biologically than the hypothalamic compound, a substance with structural similarity to the amphibian-derived bufodienolides was extracted from human cataractous lenses, and a compound indistinguishable by nuclear magnetic resonance analysis from plant-derived ouabain itself has been recovered from bovine adrenal glands, which raises the possibility that more than one digitalis-like compound may be present in mammals, including humans. The site of origin of natriuretic hormone also remains uncertain, but the brain has been favored because the natriuretic effects of extracellular fluid volume expansion appear to depend on an intact central nervous system. An ouabain-like compound has been isolated from human cerebrospinal fluid, and other evidence suggests that the adrenal gland may be a source. It is also possible that multiple tissues can produce natriuretic hormone, which could act locally as a paracrine hormone. Preliminary results using adrenal tissue suggest that biosynthetic pathways exist for natriuretic hormone, starting with known steroid precursors. Natriuretic hormone may play a role in normal volume regulation and in the pathophysiology of hypertension and secondary edema states. Natriuretic hormone may have an extrarenal action leading to enhanced vascular reactivity. The hypothesis proposed is that hereditary forms of hypertension have a persistent tendency toward renal retention of sodium, possibly because of the increased Na+ -K+ cotransport or Na+ -H+ exchange in the proximal tubule that occurs as a manifestation of a generalized genetic defect in Na+ -Na+ (Na+ -Li+) countertransport. This defect exists in the erythrocytes of some patients with essential hypertension and in their first-degree normotensive relatives. The sodium pump inhibitor acts on the renal tubule to promote sodium excretion, thus restoring extracellular fluid volume to normal levels. The same genetic polymorphism for adducin has been found in a subset of human essential hypertensive patients. One hypothesis is that altered Na+ -Ca2+ exchange resulting from partial sodium pump inhibition may account for an increase in the intracellular free Ca2+ concentration. Alternatively, enhanced norepinephrine activity caused by Na+ pump inhibition in adrenergic neurons, either in the central nervous system or peripherally, can be responsible for altered renal sodium reabsorption and vasoconstriction. Consistent with this mechanism is the observation that intrathecal administration of high NaCl, plant ouabain, and mammalian-derived ouabain-like factor stimulates renal sympathetic nerves, increased peripheral resistance, and hypertension in normal rats. Its major sites of action include the cardiovascular, renal, and endocrine systems. It has been known for several decades that membrane-bound secretory granules exist in the cardiac atria. In 1981 in a pioneering report, DeBold and colleagues observed that bolus injection of crude extracts of rat atria, but not ventricles, produced a rapid, massive, and short-lasting diuresis and natriuresis and a modest kaliuresis. This observation suggested the existence of a natriuretic hormone in the atrial granules. The amino acid sequence of the active circulating peptide and its pre-hormone forms has been defined together with their gene structure, target tissue receptors, and signal transduction pathways. All three natriuretic peptides show structural similarity, are derived from the C-terminal ends of their precursors, and interact with specific receptors. All natriuretic peptides have a 17-amino acid ring with a cysteine-cysteine disulfide cross-link that is essential for activity. They are also found, to a lesser extent, in the central nervous system, hepatocytes, colonic smooth muscle, and lung. It seems probable that the atrial peptide system has a novel receptor-mediated sequestration and clearance mechanism that is responsible, at least in part, for maintaining plasma levels of the hormone. The combined effects result in increased filtration pressure and thus an increased filtration fraction, with a higher load of salt and water being delivered to the tubules for excretion. In addition, redistribution of blood flow from the cortex to inner medulla, which dilutes the papillary interstitium, results in an increase in sodium and water excretion. This activity is followed by a decrease in cardiac output attributed to (1) a shift of volume from the intravascular to the extravascular space caused by elevated capillary hydraulic conductivity and resulting transcapillary flow and (2) pre-load reduction from relaxation of venous smooth muscle leading to an augmentation of venous capacitance and a reduction in venous return. Classically, the physiologic effects of a substance can be better elucidated by nullifying its effects through blockers or inhibitors. In this approach, gene knockout animals (mice) can be produced in which hybrid animals are normal other than for the specific gene mutated or deleted. Alternatively, transgenic mice can be created in which an extra copy of a gene is added to the genome. The homozygote mutants also had cardiomegaly and higher blood pressure in response to intermediate dietary salt than did wild-type and heterozygotes.

Intrathecal methotrexate can lead to brief remission order glyset 50mg overnight delivery, but the general outlook for such patients is exceedingly poor generic glyset 50mg with mastercard. The use of bisphosphonates can significantly 1379 reduce the complications of skeletal metastases in both premenopausal and postmenopausal patients generic 50mg glyset. Pamidronate (Aredia) given intravenously every 3 or 4 weeks has been shown to be effective in this setting and can be given at the same time as endocrine therapy or chemotherapy buy glyset 50 mg line. In addition, radioisotopes that localize in bone such as strontium-89 may be effective. External beam irradiation will result in significant palliation in patients with moderate to severe bone pain at specific metastatic sites. Hypercalcemia is a common complication of metastatic breast cancer and more likely to occur in patients with skeletal metastases. Calcitonin can also be effective in patients who need rapid reduction of their serum calcium. Also, patients with locoregional recurrence are best managed by surgical resection of chest wall lesions when feasible, followed by external beam irradiation of the involved area. Chest tube drainage and sclerotherapy are successful in about 70% of patients with persistent or recurrent malignant effusions that have not been controlled by systemic therapy. Patients with ipsilateral breast tumor recurrence after lumpectomy alone or with breast irradiation for early-stage breast cancer are usually best managed by mastectomy, although further lumpectomy may be appropriate in patients with smaller recurrences. Never has high-quality medical information been more accessible to the practicing clinician. In addition to journals and textbooks, the Internet has now become a major resource for a wealth of up-to-date information derived from multiple sources. Such patients are usually first seen at higher stages, probably because of difficulties in diagnosis. After the 1st trimester, definitive surgical procedures can usually be performed with minimal risk to the mother and fetus. Chemotherapy administered after the 1st trimester has not been associated with increased fetal loss or birth defects. Limited data suggest that childhood development is normal in children of mothers who have received chemotherapy during pregnancy. Alkylating agents given during pregnancy will frequently cause subsequent infertility. Major considerations relating to childbearing after breast cancer should be based on the risks of recurrence. The use of autologous blood progenitor cells (stem cells) obtained from bone marrow or peripheral blood is capable of rescuing patients from potentially lethal myelosuppression caused by the use of chemotherapeutic agents given in dosages several times higher than normal. The use of peripheral blood stem cells as opposed to bone marrow and the introduction of granulocyte-stimulating growth factors (filgrastim and others) have greatly reduced the costs as well as the morbidity and mortality of this technique. Although widely used in breast cancer, the benefits of high-dose chemotherapy and stem cell support remain controversial. A large randomized trial in the adjuvant setting comparing standard with high-dose therapy and stem cell support in women with early-stage breast cancer and 10 or more positive axillary lymph nodes is close to completion. One randomized trial in the metastatic setting showed a survival benefit for a high-dose regimen versus a lower-dose regimen, but both groups did poorly. From 10 to 25% of patients with metastatic breast cancer have shown relapse-free survival in excess of 5 years after high-dose programs; critics believe that patient selection accounts for a major proportion of these long-term survivors. Ongoing clinical trials in both the adjuvant and metastatic settings should help define the magnitude of benefit, if any, of commonly used high-dose regimens. The use of hormone replacement therapy in women with a diagnosis of breast cancer is an area of heated controversy. Current data suggest that the use of estrogens alone in patients with hysterectomy or the use of estrogens and progestins in patients with an intact uterus for 5 years or longer is associated with a relative risk of breast cancer 1. The major concerns related to the use of hormone replacement therapy after breast cancer are (1) whether such therapy will substantially increase the risk of a new primary breast cancer in a patient group already at higher risk for breast cancer and (2) whether such therapy might stimulate the growth of occult breast cancer metastases. The benefits of hormone replacement therapy in postmenopausal women are substantial and include slowing the rate of bone loss, lowering the risk of cardiovascular disease, limiting or eliminating vasomotor symptoms, and possibly lowering risks of dementia and colon cancer. In young premenopausal women, the frequent toxicity of chemotherapy-induced amenorrhea increases the long-term risk of osteoporosis and heart disease. Newer bisphosphonates (alendronate) or selective estrogen receptor modulators (raloxifene) are effective in lowering the risks of osteoporosis, and several non-hormonal agents can favorably affect lipid profiles. No highly effective methods of controlling vasomotor symptoms other than endocrine therapy have been described. Clonidine, vitamin E, and other agents are of little to no benefit but should be considered in patients with major symptoms. About 25% of patients with moderate to severe vasomotor symptoms have had major relief with a placebo in randomized, blinded clinical trials. Newer antidepressants such as venlafaxine may be helpful in reducing hot flashes and other menopausal symptoms, and trials are in progress. Megestrol acetate, an oral progestin, is as effective as estrogen in reducing vasomotor symptoms, but its long-term risks in patients with early-stage breast cancer, especially those receiving tamoxifen, are unknown. At present, this investigator would only consider hormone replacement therapy after early-stage breast cancer for patients with disabling vasomotor symptoms. The bone and cardiovascular benefits of hormone replacement therapy can be accomplished with non-endocrine agents. Hormone replacement therapy, however, does not appear to increase the risk of breast cancer in women with other major risk factors such as a strong family history. Lymphedema of the ipsilateral arm develops in about 15% of women with breast cancer following primary therapy. The incidence of this complication may be slightly higher in 1380 women treated with lumpectomy and radiation and may be less in women who are staged via sentinel lymph node procedures. In some affected women symptom are mild, but in many they are persistent, and slowly progressive edema can lead to functional loss. Early recognition is key, and patients should be asked about this complication at each clinic visit. Affected patients should be referred to physical therapists and other health professionals skilled in lymphedema management. Treatment consists of avoidance of trauma, special exercises, elevation of the extremity, and the use of compression pumps and specially fitted compression stockings. Recently, manual lymphatic drainage procedures have gained wide use and may be more effective than compression pumping. No effective medications have as yet been identified; diuretics are rarely effective and should be avoided. American Society of Clinical Oncology: Recommended breast cancer surveillance guidelines. A collection of excellent graphs that allows accurate estimation of risk in women without a strong history of breast cancer and who receive yearly mammography. An excellent series of tables to estimate breast cancer risk in women with strong family histories. Genetic Testing Guidelines: Statement of the American Society of Clinical Oncology: Genetic testing for cancer susceptibility. Best all-around text with excellent reviews on all aspects of breast cancer biology and management. Productive human papillomavirus infections of the cervix are accompanied by cytologic atypia, binucleation, hyperchromatism, alterations in chromatin distribution, and perinuclear clearing, which when accompanied by nuclear atypia is known as "koilocytosis. Screening for cervical cancer and its precursors is one of the most successful and cost-effective methods of cancer detection yet devised. The Pap smear is the standard screening test and relies on microscopic examination of a glass slide onto which exfoliated cells from the lower female genital tract have been placed. The usual technique in preparing a Pap smear is to scrape the squamocolumnar junction and immature transformation zone of the cervix with a wooden spatula and sample the endocervical canal with a small brush. Cells from both of these sampling instruments are then transferred onto a glass slide and stained and examined by a cytopathologist. Pap smears have a high degree of specificity (95% or greater), but the sensitivity is in the range of 70 to 80%. Because the Pap smear is a screening test-not a diagnostic test-and is designed to be relatively inexpensive and cost-effective, its efficacy in detecting cervical neoplasms is dependent on repeating the test at regular intervals.

A primary abnormality of transepithelial phosphate transport in the nephron discount 50 mg glyset free shipping, resulting in renal phosphate wasting 50mg glyset, underlies the majority of the phosphopenic disorders buy glyset 50 mg lowest price. As a rule trusted glyset 50 mg, patients with these disorders maintain a normal serum calcium concentration, whereas the serum phosphorus level is characteristically low. Whereas the elevated calcitriol level underlies increased gastrointestinal absorption of calcium and hypercalciuria in these diseases, the impact of abnormal vitamin D metabolism on the phenotypic expression of the phosphopenic disorders is less certain. In those diseases with normal serum calcium and phosphorus concentrations, laboratory abnormalities are unique to each form of the disease. Nevertheless, alkaline phosphatase activity in plasma is generally elevated in all forms of rickets and osteomalacia. Even severe forms of disease, however, particularly those due to renal tubular disorders, may be associated with normal or only marginally elevated enzyme activity. The variable biochemical abnormalities associated with these disparate disorders are summarized in Table 263-2. Although many of these diseases are no longer common causes of rickets and osteomalacia, others are often hidden causes of bone disease in a varying population of patients. Adequate exposure to sunlight and fortification of dairy products with vitamin D have eliminated vitamin D deficiency secondary to inadequate endogenous production or nutrition in the majority of countries. However, in several populations, such as Asian immigrants in Britain, rickets and osteomalacia secondary to vitamin D deficiency occurs in neonates and infants, adolescents during pubertal growth, and less frequently among adults. Insufficient vitamin D intake secondary to using unfortified foods, racial pigmentation (which interferes with ultraviolet transmission through the skin), genetic factors, and social customs (such as avoiding sun exposure) contribute to the development of disease in these subjects. Moreover, in the United States and other developed countries, a surprisingly frequent occurrence of vitamin D deficiency osteomalacia has been recognized recently in alcoholics, institutionalized patients, and the elderly. Poor diet, in some cases including avoiding milk and milk products due to lactose intolerance, lack of sunlight exposure, and an age-related decline in the dermal synthesis of 7-dehydrocholesterol are among the factors predisposing to the vitamin D deficiency and consequent bone disease. Measurement of this metabolite therefore serves to identify populations at risk for and facilitates early detection of vitamin D deficiency rickets and osteomalacia. Introducing vitamin D supplements (400 U/day) may, under these circumstances, prevent development of clinically significant disease. Regardless, treating clinically evident vitamin D-deficient rickets and osteomalacia invariably results in healing of the bone disease. The disorder is best treated with vitamin D and restoration of normal dietary calcium and phosphorus intake. Ergocalciferol (vitamin D2) is preferred because it provides the missing substrate that submits to physiologic regulation of vitamin D metabolite production. In general, malabsorption of vitamin D occurs as a consequence of steatorrhea, which disturbs fat emulsification and chylomicron-facilitated absorption (see Chapter 134). However, most affected patients are asymptomatic, and many exhibit only reduced bone volume rather than evidence of defective bone mineralization. Intestinal bypass surgery and adult celiac disease are common examples of disorders in which vitamin D malabsorption occurs and in which the suspicion for osteomalacia should remain high. In contrast, patients with cholestatic liver disease, extrahepatic biliary obstruction, and diseases of the distal portions of the small intestine, such as regional enteritis, may develop bone disease secondary not only to poor vitamin D absorption but to disruption of enterohepatic circulation as well. Osteomalacia may also develop in patients who have had partial or total gastrectomy for peptic ulcer disease or other indications. Loss of gastrointestinal acidity or malfunction of the proximal small bowel underlies the vitamin D malabsorption in such circumstances. Absence of sufficient absorbing surface or failure of intestinal mucosal cells to respond to vitamin D or its metabolites may also cause vitamin D malabsorption and consequent bone disease. The prevalence of osteomalacia in patients with gastrointestinal malabsorption varies widely from country to country. However, as many as 25 to 50% of British and European patients with partial gastrectomy, inflammatory bowel disease, and cholestatic liver disease have bone biopsy-proven osteomalacia. Treatment of established disease generally requires pharmacologic amounts of vitamin D or its metabolites to overcome the defective absorption and the aberrant enterohepatic circulation or to offset end-organ resistance at the intestinal mucosa. If the severity of malabsorption makes oral vitamin D ineffective, parenteral ergocalciferol, 12,500 to 25,000 mug, given intramuscularly once a month, is a practical alternative. Because magnesium deficiency often co-exists in malabsorptive diseases and may slow healing of the osteomalacia, adjunctive therapy with magnesium oxide may facilitate bone mineralization. These patients, however, rarely manifest biochemical or histologic evidence of osteomalacia. Consequently, therapy for biopsy-proven osteomalacia, when present, is similar to that secondary to malabsorption of vitamin D. These multiple influences commonly result in a bone disorder that may be mild osteomalacia or hyperparathyroid bone disease. Treatment of the bone disease and hypocalcemia generally requires modest vitamin D supplementation (150 to 400 mug/week). Vitamin D-dependent rickets type 1 is such a genetic disorder, transmitted as an autosomal recessive trait and characterized by hypocalcemia, hypophosphatemia, and elevated alkaline phosphatase activity. In addition to these biochemical abnormalities, within the first year of life patients exhibit muscle weakness and hypotonia, motor retardation, and stunted growth. With progression, patients develop the classic radiographic signs of vitamin D-deficiency rickets and bone biopsy evidence of osteomalacia. This abnormality has been substantiated by (1) experiments in humans that demonstrate serum calcitriol levels do not increase in response to classic stimuli of enzyme activity, and (2) the absence of enzyme activity in renal cortical homogenates from the porcine homologue of this disease. Regardless of the therapy used, in the majority of affected patients, therapy with vitamin D or its metabolites must be continued for life to prevent relapse. However, in a minority of subjects with a syndrome clinically identical to vitamin D-dependent rickets type 1, stopping treatment does not result in reappearance of biochemical or radiographic signs of the disease. Osteomalacia is common in patients with chronic renal failure and often tends to be the predominant type of renal osteodystrophy in younger patients (see Chapter 266). In addition, in some patients aluminum accumulated in bone underlies the abnormal mineralization. Indeed, the presence of aluminum may render the bone abnormality vitamin D-resistant. Under such circumstances, treatment with deferoxamine may be necessary to mobilize the aluminum from bone and other tissues and improve mineralization. Osteomalacia only rarely occurs in patients with hypoparathyroidism (see Chapter 264). However, the underlying reason for the variable occurrence of bone pathology remains uncertain. Bone pain suggests the diagnosis, and generally the diagnosis depends on histomorphometric analysis of a bone biopsy. Surprisingly, however, affected patients often manifest bone disease marked by increased resorptive activity and osteomalacia. Indeed, severe demineralization, including frank osteitis fibrosa cystica and occasionally rickets or osteomalacia, has been observed in 24 patients with pseudohypoparathyroidism. More commonly, the bone disease is silent and diagnosis often depends on histomorphometric analysis of a bone biopsy. They have not only calciopenic rickets and/or osteomalacia but variably associated abnormalities, including alopecia (in 60% of patients) and, in a minority of subjects, additional ectodermal anomalies, such as multiple milia, epidermal cysts, and oligodontia. Effective treatment of this disease likely depends on the nature of the underlying abnormality. In contrast, patients with other forms of the disease generally remain refractory to treatment with vitamin D or its analogues. If the abnormalities of the syndrome do not normalize in response to this treatment, clinical remission may be achieved by administering high-dose oral calcium or long-term intracaval infusion of calcium. Most typically, these diseases have in common abnormal proximal renal tubular function, which results in an increased renal clearance of inorganic phosphorus and hypophosphatemia. However, the biochemical abnormalities characteristic of these disorders are quite variable (Table 263-3) (Table Not Available). The mildest abnormality is hypophosphatemia without clinically evident bone disease, and the most common clinically evident manifestation is short stature. Nevertheless, the majority of children with the disease exhibit enlargement of the wrists and/or knees secondary to rickets, as well as bowing of the lower extremities. Additional early signs of the disease may include late dentition, tooth abscesses secondary to poor mineralization of the interglobular dentine, and premature cranial synostosis. Despite marked variability in the clinical presentation, bone biopsies in affected children and adults invariably reveal osteomalacia, the severity of which has no relationship to gender, the extent of the biochemical abnormalities, or the severity of the clinical disability. Indeed, studies in Hyp mice, the murine homologue of the human disease, have established that defective regulation is confined to enzyme localized in the proximal convoluted tubule, the site of the abnormal phosphate transport.

The pulmonary pathology in all these entities is that of hemorrhagic infarction and pneumonia cheap 50mg glyset otc. These processes often combine to produce a "target lesion" pathologically discount glyset 50 mg without prescription, consisting of a necrotic center surrounded by a ring of hemorrhage buy 50 mg glyset with visa. The sputum culture is positive in only 8 to 34% of cases buy glyset 50mg, and obtaining tissue is necessary to make the diagnosis. Prospective culturing of the nose of granulocytopenic patients has been of some value, because a positive nasal culture (and particularly the presence of nasal Aspergillus lesions) has led to the early diagnosis of concurrent pulmonary or sinus disease. Targets of disseminated disease include the central nervous system, where abscesses are characteristic. Dissemination can result in Budd-Chiari syndrome, myocardial infarction, gastrointestinal disease, or skin lesions. Endocarditis is associated with cardiac surgery, particularly prostheses, or intravenous drug abuse. Major arterial emboli occur in 83% of patients, and neurologic presentations are common. Only 8% have positive blood cultures, and this positivity usually is delayed 14 to 20 days, contributing to the poor record of diagnosis ante mortem, which is usually made on histologic examination of an embolus. The disease should be suspected in any post-cardiac surgery patient who presents with endocarditis or emboli and negative blood cultures. The typical picture of an aspergilloma is a fungus ball (matted hyphae and debris) in a cavity in an upper lobe (Fig. This has been reported as a complication in as many as 11% of old tuberculous cavities. The patients present with cough (87%), hemoptysis (81%), dyspnea (61%), weight loss (61%), fatigue (61%), chest pain (31%), or fever (25%). Allergic bronchopulmonary aspergillosis is usually seen superimposed on a background of chronic asthma or cystic fibrosis. It is characterized by episodic airway obstruction, fever, eosinophilia, mucous plugs, positive sputum cultures, and the presence of grossly visible brown flecks in the sputum (hyphae), transient infiltrates and parallel "tram-line" or ring markings on chest radiographs, proximal bronchiectasis, upper lobe contraction, and elevated levels of total immunoglobulin E (IgE), especially when the patient is symptomatic. It is more common in agricultural areas and in the winter, presumably representing an association with stored agricultural products (especially moldy hay) and spore production. The mucous plugs contain mycelia, and the plugs may be the cause of the infiltrates, with collapse and inflammation occurring peripherally, or inflammatory edema may be responsible. The parallel or ring markings are caused by thickened ectatic bronchi, and the upper lobe changes are a result of progressive apical fibrosis. The infiltrates may be nonsegmental and transient, with a clinical presentation of "eosinophilic pneumonia" and asthma, with eosinophils in blood and sputum; alternatively, they may be segmental, associated with the blocking of bronchi by plugs, and asthma and eosinophilia may be absent. A scratch test with Aspergillus antigens produces an immediate wheal and flare reaction, mediated by IgE and blocked by antihistamines, but not by corticosteroids. An intracutaneous test with the antigens produces a later (6 to 8 hours) reaction, mediated by IgG antibody and complement and blocked by steroids. The other is a restrictive defect occurring peripherally, which may be associated with influenza-like symptoms, fever, leukocytosis, and infiltrates. These reactions are associated with IgG precipitins and are believed to account for some transient infiltrates. Extrinsic allergic alveolitis is an unusual form of Aspergillus lung disease and has been most associated with A. The patients develop a hypersensitivity pneumonitis with dyspnea and fever 4 hours after exposure. The patients have IgG precipitins and cell-mediated immune reactions against Aspergillus antigens, and granulomas are present on biopsy. The scratch test is negative, although an intradermal test produces a reaction in 4 hours, with immunoglobulins and complement present on biopsy. Bronchial challenge produces a reaction in 4 hours, with systemic symptoms and a restrictive defect but without airway resistance. The same pathophysiology may be involved in episodes following massive inhalation of spores, usually in farm environments. Superficial bronchial disease, an acute or chronic bronchitis with brown-flecked sputum, extrinsic asthma due to airborne conidia, and bronchocentric granulomatosis, peribronchial destructive disease with wheezing or fever and weight loss, are other important pulmonary diseases. The aspergilloma, allergic, alveolitis, and superficial forms rarely progress to invasive disease. However, more invasive airway disease with ulcerative, pseudomembranous, or plaquelike tracheobronchitis occurs, particularly in immunocompromised hosts, and may presage parenchymal invasion. Chronic necrotizing pulmonary aspergillosis is a poorly defined entity that usually occurs in patients with underlying lung disease, often with features of invasive disease and aspergilloma. These include invasion of burn wounds, keratitis, external otitis (particularly in the tropics), focal rhinitis (particularly in immunosuppressed and/or granulocytopenic hosts), sinusitis (in these hosts or following dental procedures) and osteomyelitis or endophthalmitis (after fungemia, trauma, or surgery). Bloodborne disease in addicts can produce foci of dissemination that are similar to those associated with the invasive pulmonary form of the disease. A noninvasive form of sinus disease has a predominantly allergic component and eosinophilia. Antibody to Aspergillus has been detected by a variety of techniques and with a variety of antigen preparations. Data from the more commonly reported techniques suggest a high degree of sensitivity in allergic disease or aspergillomas, but generally a low sensitivity in invasive disease. Because the frequency of false-positive reactions, even in the presence of other mycoses, is low, a positive test in invasive disease may be useful. IgE and IgG antibody specific to Aspergillus antigens is another serodiagnostic adjunct in allergic disease. Detection of antigenemia and of antigen in bronchoalveolar lavage fluid also is promising in diagnosis of invasive disease. The problem with all serodiagnostic modalities is the lack of a generally available, standardized technique. The physician should know the background data for the laboratory to which the specimens may be sent, i. In severe disease, an aggressive, invasive approach, as well as making a tissue diagnosis early in the illness, appears to be a key to survival. In the appropriate clinical setting, such as an immunocompromised 1877 host with fever and a pulmonary infiltrate, repeated isolation of the same species in culture, and particularly a bronchial lavage or other endobronchial culture, correlates with invasive disease; sometimes even a single sputum culture (especially with heavy growth) may have to be the stimulus for therapy if invasive procedures cannot be done. In endocarditis, in addition to prompt, aggressive chemotherapy, valve replacement appears necessary. Locally invasive disease in other sites also requires systemic or local chemotherapy, particularly intravitreal therapy or nephrostomy irrigation in renal disease. Surgical excision has an important role in the invasion of bone, burn wounds, epidural abscesses, vitreal disease, sinus disease of noncompromised hosts, and removal of catheters for peritonitis and of silk sutures in bronchial stump (postpneumonectomy) aspergillosis. It may have a function in invasive pulmonary disease for which chemotherapy has failed or where disease impinges on major vascular structures. In cases involving aspergilloma, there is evidence that patients with fever, cough, weight loss, malaise, and hemoptysis have an element of allergy, which can be demonstrated by bronchial challenge or the presence of specific IgG and IgE. Intravenous amphotericin B therapy of patients with aspergilloma produces results no better than those with routine pulmonary toilet. Intracavitary antifungals, instilled through a catheter, are an heroic form of therapy that has been attempted in some patients. The overall operative mortality aggregated from several series is 7%, but may be as high as 14% in some large series. The frequency of various operative complications is 22%, aggregated from several series, with a range of 7 to 60%. On the other hand, in various series, 18 to 26% of patients with adequate follow-up treated without surgery died of disease complications, usually hemoptysis, whereas 50% have shown significant improvement symptomatically and radiographically. If any consensus exists, it is that surgical resection has a role in recurrent, significant hemoptysis. An alternative temporary therapy, particularly for the nonsurgical patient, is selective bronchial arterial embolization to the bleeding vessel. In pleural disease, locally instilling nystatin, amphotericin, or miconazole has succeeded. In allergic disease, measures that have not worked include hyposensitization, avoidance of sites in the environment, and aerosolized corticosteroids.

References

• Cutler CS, Lee SJ, Greenberg P, et al. A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood 2004;104(2):579-585.
• Amaro S, Llull L, Urra X, et al. Risks and benefits of early antithrombotic therapy after thrombolytic treatment in patients with acute stroke. PLoS ONE 2013;8:e71132.
• Barentsen JA, Visser E, Hofstetter H, et al: Severity, not type, is the main predictor of decreased quality of life in elderly women with urinary incontinence: a population-based study as part of a randomized controlled trial in primary care, Health Qual Life Outcomes 10:153, 2012.
• Devore GR, Donnerstein RL, Kleinman CS, et al: Fetal echocardiography. I: Normal anatomy as determined by realtime-directed M-mode ultrasound. Am J Obstet Gynecol 1982; 144:249-260.
• Lepor H, Kaplan SA, Klimberg I, et al: Doxazosin for benign prostatic hyperplasia: long-term efficacy and safety in hypertensive and normotensive patients. The Multicenter Study Group, J Urol 157(2):525n530, 1997.
• Ishida T, Kaneko S, Tateishi M, et al. Large cell carcinoma of the lung. Prognostic implications of histopathologic and immunohistochemical subtyping. Am J Clin Pathol 1990;93:176-82.