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The net output of platelets is decreased in severe megaloblastosis, and abnormal but reversible platelet dysfunction has been documented insomnia 4 months postpartum buy 25 mg sominex overnight delivery. Complete transformation to megaloblastic hematopoiesis is observed in florid cases and is reflected by various degrees of pancytopenia. Because these cells have adequate hemoglobin, the central pallor, which normally occupies about one-third of the cell, is decreased. Extramedullary megaloblastic hematopoiesis may also result in a leukoerythroblastic picture. Ineffective use of iron results in an increased percentage of saturation of transferrin and increased iron stores. In thalassemia, the entire erythrocyte morphology normally expected in megaloblastosis is masked8; however, megaloblastic leukopoiesis is still observed. Megaloblastosis in rapidly proliferating cells of the gastrointestinal tract leads to a variable degree of morphologic changes and atrophy of luminal epithelial cells. This leads to functional defects, which can include malabsorption of cobalamin and folate in some patients. A vicious cycle whereby megaloblastosis begets more megaloblastosis is established that can be interrupted only by specific therapy with cobalamin or folate. However, only cobalamin deficiency results in a patchy demyelination process, which is expressed clinically as cerebral abnormalities and subacute combined degeneration of the spinal cord. The demyelinating process involves patchy swelling of the myelin sheath followed by its breakdown (demyelination), leading to axonal degeneration. Microscopic foci coalesce with one another, giving the surface of the spinal cord (on cross section) a spongy appearance; later there is secondary Wallerian degeneration of long tracts. Patchy demyelination usually begins in the dorsal columns in the thoracic segments of the spinal cord. These lesions spread throughout the length of the cord and ultimately involve spinothalamic and spinocerebellar tracts. There is also degeneration of the dorsal root ganglia, celiac ganglia, the Meissner plexus, and the Auerbach plexus. Although demyelination may also extend to the white matter of the brain, it is unclear whether the peripheral neuropathy is caused by a distinct lesion or results from spinal cord disease; the clinical manifestations may be extremely varied. In contrast, the cause of cobalamin deficiency can remain obscure until specific tests to define the cause are carried out. In the past, by the time anemia was symptomatic, more than 80% of patients had neurologic manifestations, and in 50% this led to some incapacity. Perhaps as a result of widespread use of multivitamins containing folic acid among patients and even in the food given livestock in the West, the hematologic expression of cobalamin deficiency is often substantially attenuated, leading to pure neurologic presentations. Studies highlight the apparent inverse correlation between hematologic and neurologic presentations such that in a third of patients with cobalamin deficiency, the earliest signs are often purely neurologic, and symptoms related to paresthesias and diminished proprioception may cause the patient to see the physician. Based on the multiple potential causes (see box on Etiopathophysiologic Classification of Cobalamin Deficiency or box on Etiopathophysiologic Classification of Folate Deficiency), the warning that "what the mind does not know, the eyes do not see" is a caveat that cannot be taken lightly; failure to recognize cobalamin deficiency as the cause of neurologic disease and treatment of cobalamin deficiency with folate, or misdiagnosis of megaloblastosis as erythroleukemia represent significant extremes of deviation from the dictum primum non nocere. Areas of overlap in the symptoms of cobalamin or folate deficiency are related to megaloblastosis. Folate deficiency in adults has not been unequivocally shown to give rise to neurologic findings. Coexistence of folate deficiency with neurologic disease should prompt investigations to rule out cobalamin and other nutrient deficiencies arising from dietary insufficiency or malabsorption. By bacteria-stasis syndromes (blind loops, pouches of diverticulosis, strictures, fistulas, anastomosis), impaired bowel motility (scleroderma), hypogammaglobulinemia 2. Abnormal mucosal architecture/function-tropical/ nontropical sprue, Crohn disease, tuberculous ileitis, amyloidosis C. Acquired disorders (cobalamin inactivated by irreversible oxidation)-nitrous oxide Etiopathophysiologic Classification of Folate Deficiency Nutritional causes A. Physiologic-pregnancy and lactation, prematurity, hyperemesis gravidarum, infancy 2. Intrinsic hematologic diseases involving hemolysis with compensatory erythropoiesis, abnormal hematopoiesis, or bone marrow infiltration with malignant disease b. Drugs (multiple effects on folate metabolism)-alcohol, sulfasalazine, triamterene, pyrimethamine, trimethoprimsulfamethoxazole, diphenylhydantoin, barbiturates I. The cross section of the spinal cord stained with Luxol blue shows demyelination of the dorsal columns (a) and early demyelination of the lateral columns (b). Vegetarians with cobalamin neuropathy in India69 had cognitive impairment in nearly one-half of 36 patients; it was mostly global with impaired recall and serial sevens (which are useful bedside tests of attention); impaired naming was found among one-quarter of the patients. Nearly one-half had abnormal evoked potential (using the oddball auditory paradigm), which revealed P300 latency that was reversible within 3 months of cobalamin replacement; (in one-fifth P300 was unrecordable). Recent studies confirm that among elderly patients with mild cognitive impairment, lowering the homocysteine level by a cocktail that includes cobalamin and folate over 2 years did slow the rate of brain atrophy by almost 30%. Among another cohort of patients with cobalamin neuropathy from the United States, 65% had mild, about 25% had moderate, and about 10% had severe neurologic deficits. Although multiple neurologic syndromes were often seen in the same patient, the spectrum of objective signs could include loss of fine or coarse touch, decreased or increased deep tendon reflexes with spasticity or muscle weakness, urinary or fecal incontinence, orthostatic hypotension, amaurosis, dementia, psychosis, or mood disturbances. An unexplained finding is generalized melanin pigmentation that is reversible by specific nutrient replenishment. Cobalamin* (pg/mL) >300 Folate (ng/mL) >4 Provisional Diagnosis Cobalamin or folate deficiency is unlikely Consistent with cobalamin deficiency Rule out cobalamin deficiency Consistent with folate deficiency Consistent with (1) combined cobalamin plus folate deficiency or (2) isolated folate deficiency Consistent with (1) folate deficiency or (2) an anemia unrelated to vitamin deficiency Proceed With Metabolites Classical presentations of nutritional cobalamin deficiency in developing countries are often accompanied by iron deficiency, and among malnourished populations, many will also have folate deficiency. Among vegetarians in developing countries, cases with nutritional cobalamin deficiency may present in the second and third decades with pancytopenia, mild hepatosplenomegaly, fever, and occasionally thrombocytopenic bleeding. Because neuropsychiatric presentations may dominate the clinical picture and the patient may not have anemia, careful review of the peripheral smear may reveal macrocytosis. Conversely, anemic patients may have no neurologic deficits, and the level of cobalamin may have no correlation with the existence or severity of neurologic disease. Continued negative cobalamin balance leads to an absolute decrease in serum cobalamin level. Laboratory tests are more likely to be accurate when there is a high pretest probability of a particular disease. This can however be more vexing in the case of diagnosis of early cobalamin deficiency when symptoms are subtle, nonspecific, or not yet fully manifest. However, in elderly patients with anemia, there may be several other causes for anemia, and depending on the population studied, cobalamin deficiency may be only one among several possible causes in the differential diagnosis. This is when a modified therapeutic trial-in which a patient is treated with full doses of both cobalamin and folate for 10 days-and the lack of objective response to cobalamin would effectively rule out cobalamin deficiency as a cause (see box on Modified Therapeutic Trials). Alternatively, attribution of the cause of anemia to cobalamin deficiency would be reasonably confirmed retrospectively if there was evidence for resolution of anemia following such therapy with cobalamin. Serum folate levels: abnormally low, less than 2 ng/mL; clinically relevant low-normal range, 2 to 4 ng/mL. Any frozen-over sample from serum folate/cobalamin determination can be subjected to metabolite tests. Cobalamin deficiency perturbs methionine synthase activity; this results in substrate (homocysteine) buildup and elevated serum levels of homocysteine, which can be measured by a sensitive assay. Rather than making the diagnosis of a deficiency, the intention is often to confirm the clinical suspicion that the patient does not have deficiency. This can be demonstrated by lack of response to full replacement doses of both vitamins (1 mg of folic acid orally for 10 days and 1 mg of cobalamin intramuscularly or subcutaneously daily for 10 days). Clinical scenarios in which such trials may be applicable (after drawing blood for serum cobalamin and folate levels) are as follows: 1. There is a clinical suspicion that the underlying disease is not caused by a vitamin deficiency, but this idea is not supported by results of clinical, morphologic, and biochemical evaluations. Such conditions include anemia with a megaloblastic bone marrow that may be secondary to chemotherapy, myelodysplastic syndromes, or acute leukemia; when time is of the essence in making the diagnosis; when the levels of cobalamin are likely to be falsely abnormal because of these diseases; or when there is underlying dehydration or renal dysfunction that predictably gives falsely high levels of metabolites. In instances when severe anemia with megaloblastosis is clinically obvious and so serious that the physician cannot wait for the results of specific tests for deficiency. Full doses of both vitamins are administered, and if there is a response manifested by brisk reticulocytosis by days 5 to 7, retrospective assignment of the deficiency is based on the results of blood samples drawn before beginning the trial. In all therapeutic trials, if there is no evidence of response within 10 days, bone marrow aspiration is indicated to identify another primary hematologic disease. The abnormally high levels of metabolites return to normal only when the patient receives replacement with the appropriate (deficient) vitamin. Conversely, therapy with folate results in a decrease in the isolated homocysteine level if folate deficiency is present. Serum Cobalamin Levels For the most part, a low serum cobalamin level is an established biochemical indicator of cobalamin deficiency.

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Family history of hypertension and African American ancestry are also risk factors for hypertension insomnia yelp buy cheap sominex line. Primary hypertension, also called essential hypertension, is a sustained increase in systolic and diastolic blood pressure without evidence of other disease. In secondary hypertension, the elevation in blood pressure results from some other disease, such as kidney disease. However, hypertension often causes no symptoms and can remain unrecognized for years. Later signs and symptoms are related to the effects of hypertension on kidneys and eyes, and the development of cardiovascular disease. Diagnosis of hypertension requires blood pressure measurements with a sphygmomanometer and stethoscope. The diagnosis of hypertension using this method is based on the average of at least two or more blood pressure readings taken on at least two separate physician office visits. Treatment of primary and secondary hypertension is aimed at reducing blood pressure to less than 140/90 mm Hg and preventing organ damage. For individuals with secondary hypertension, it is important to take control of the disease causing the hypertension. Lifestyle modifications such as weight loss, exercise, and reduction of salt intake enhance the effectiveness of medication therapy and help reduce further disease risks. The type of medication selected to treat hypertension depends on the stage of hypertension, age, other conditions, and patient-specific risk factors. You can take action to reduce your blood pressure and decrease the likelihood of stroke or heart attack in the following ways: Lose weight Weight loss is the single most effective nondrug method to reduce blood pressure. Exercise Thirty to 35 minutes of exercise three times per week can decrease blood pressure, especially when combined with weight loss. Limit alcohol consumption Alcohol raises blood pressure, even in the absence of hypertensive disease. Reduce fat intake and A diet high in vitamins and low in fats is associated with lower blood pressure. Chapter Six Diseases and Disorders of the Cardiovascular System L 101 Diseases of the Venous Circulation the venous systems in the lower extremities consist of the superficial (saphenous) veins and a number of deeper veins. Blood from the skin and the subcutaneous tissue accumulates in the superficial veins and then is transported into the deeper veins for return to the heart. Valves are located along the veins and prevent backflow of blood into the venous system. The leg muscles also assist in moving venous blood from the lower extremities to the heart. Varicose Veins Varicose veins are dilated, distorted veins that usually develop in the superficial veins of the leg, such as the greater saphenous vein. The prevalence is unknown; recognized risk factors for varicose veins include pregnancy, sedentary lifestyle, obesity, and family history. Varicose veins can be caused by pregnancy or occupations requiring long periods of sitting or standing. Normally, the leg muscle action squeezes blood up within the vein from one valve to the next. In the absence of this "milking action" Normal vein- competent valves of the muscles, the blood exerts pressure on the closed valves and thin walls of the veins. Signs and symptoms include swollen, twisted, and sometimes painful veins in the lower legs. Spider veins are small, dense networks of veins that appear as red or blue discolorations on the skin. An elastic bandage or support hose may increase circulation and provide relief from discomfort. Symptoms can be relieved by walking, elevating the legs when seated, and losing weight. A surgical procedure called surgical vein stripping is very successful and involves removing the veins and tying off the remaining open ends. Collateral circulation tends to develop to compensate for the loss of the vein segment. Another treatment is compression sclerotherapy, in which a strong saline solution is injected into specific sites of the varicose veins. The procedure is followed by uninterrupted compression for several weeks to prevent reentry of blood. A daily walking program during the recovery period is required to activate leg muscle venous pumps. However, the risk can be reduced by alternating long periods of sitting or standing with leg movement and exercise. Signs and symptoms include tissue edema, necrosis or skin atrophy, and pain during walking. Compression stockings squeeze the leg and prevent excess blood from flowing backward. Venous Thrombosis A clot, or venous thrombosis, can develop in the superficial or the deep veins of the lower extremities. However, risk factors are understood and include venous stasis, vascular trauma, and conditions that promote blood clotting. Older adults and postsurgical patients are at increased risk for venous thrombosis because immobility reduces blood flow in the extremities. When they do occur, signs and symptoms include inflammation, pain, swelling, and deep muscle tenderness. Early detection and prevention of venous thrombosis can prevent potentially fatal complications such as emboli, or clots that travel to vital organs such as the lungs. Prevention includes walking soon after surgery or childbirth, exercising the legs, and use of compression stockings. The risk factors include hypertension, family history, sedentary lifestyle, overweight, high blood lipid levels, atherosclerosis, and smoking. Crushing pain in the chest, shortness of breath, nausea, pallor, weakness, and faintness are among the symptoms of a myocardial infarction. Additional diagnostic tests include echocardiograms, stress tests, nuclear imaging, and angiography. Lifestyle changes, such as a healthy, low-salt diet and exercise, are important to prevent further progression of the disease. A stent, which is a cylindrical wire mesh of stainless steel or other alloy, surrounds the balloon. Expansion of the balloon forces the mesh into the lining of the vessel, which physically holds the lumen open. Because the vessels commonly become occluded again (restenosis) within months or a year, stents are coated with drugs that prevent restenosis. Coronary artery bypass surgery reroutes blood flow around the clogged arteries to improve blood flow and oxygen supply to the heart. A segment of a healthy blood vessel from another part of the body is attached or grafted from the aorta to the coronary artery below the blocked area. Depending on the number of blocked arteries, one or more grafts may be surgically placed. Myocardial Diseases Myocarditis Myocarditis is an inflammatory disease of the heart muscle. Myocarditis is associated with several other types of diseases and infections, so the prevalence of myocarditis alone is not well known. Risk factors for myocarditis include viral infections such as Coxsackie virus, parvovirus, adenovirus, and echovirus. Signs and symptoms may include flu-like illness, fatigue, fever, chest pain that may feel like a heart attack, shortness of breath, and tachycardia, or a rapid heartbeat. Blood tests for heart muscle enzymes evaluate the presence and extent of myocardial cell damage.

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Beckwith-Wiedemann syndrome, characterized by enlargement of body organs (organomegaly), macroglossia, hemihypertrophy, omphalocele, and abnormal large cells in adrenal cortex (adrenal cytomegaly) insomnia urban dictionary discount sominex 25 mg free shipping. It contains the thymus gland, the anterior mediastinal lymph nodes, and the internal mammary arteries and veins. The middle mediastinum lies between the anterior and posterior mediastinum and contains the heart; the ascending and transverse arches of the aorta; the venae cavae; the brachiocephalic arteries and veins; the phrenic nerves; the trachea, main bronchi, and their contiguous lymph nodes; and the pulmonary arteries and veins. It contains the descending thoracic aorta, esophagus, thoracic duct, azygos and hemiazygos veins, and the posterior group of mediastinal lymph nodes. The most common lesions in the anterior mediastinum are thymomas, lymphomas, teratomatous neoplasms, and thyroid masses. In the posterior mediastinum, neurogenic tumors, meningoceles, meningomyeloceles, gastroenteric cysts, and esophageal diverticula are commonly found. If the epithelial cells of the thymus become neoplastic, the tumor that develops is a thymoma. The epithelial component of the tumor may consist primarily of round or oval cells derived mainly from the cortex or spindle-shaped cells derived mainly from the medulla or combinations thereof. In addition to myasthenia gravis, other paraneoplastic syndromes, such as acquiredhypogammaglobulinemia,pureredcellaplasia,Gravesdisease,pernicious anemia, dermatomyositis-polymyositis, and Cushing syndrome, can be seen. It has a rapid onset, involves more widespread skin hardening, will generally cause much internal organ damage (especifically the lungs and gastrointestinal tract), and is generally more lifethreatening. The immune-cytochemical feature of Langerhans cell histiocytosis is positivity for which of the following A 70 years old male who has been chewing tobacco for the past 50 years presents with a six months history of a large, fungating, soft papillary lesions in the oral cavity. Two biopsies take from the lesion proper show benign appearing papillomatosis with hyperkeratosis and acanthosis infiltrating the subjacent tissues. Which of the following stains is used to detect lipid in frozen section biopsy in histopathology laboratory A 14 years old girl on exposure to cold develop pallor of extremities followed by pain and cyanosis. A patient presents with mediastinal mass with sheets of epithelial cells giving arborizing pattern of keratin reactivity along with interspersed lymphoid cells. Warthin-Finkeldey cells are seen in: (a) Measles (b) Rubella (c) Influenza (d) Rickettsial pox 31. Most common second malignancy in patients with familial retinoblastoma is: (Karnataka 2004) (a) Teratoma (b) Medullary carcinoma (c) Osteosarcoma (d) Malignant melanoma 35. Epulis is (a) Tumor of gingiva (b) Tumor of enamel of tooth (c) Disarrangementoftooth (d) Dysplasticleukoplakia 43. Triad of biotin deficiency is (a) Dermatitis,glossitis,steatorrhea (b) Dermatitis,glossitis,alopecia (c) Mental changes, diarrhea, alopecia (d) Dermatitis,dementia,diarrhea 45. Basophilic stippling is seen in: (a) Cadmium poisoning (b) Lead poisoning (c) Chromium poisoning (d) Iron poisoning 46. Pleomorphic adenoma usually arises from (a) Parotid gland (b) Submandibular gland (c) Minor salivary gland (d) Superficiallobe 48. Pellagra is characterized by all except: (a) Diarrhea (b) Dementia (c) Dermatitis (d) Diplopia 59. Smoking causes all cancers except: (a) Liver (b) Pancreas (d) Lung (c) Bladder 60. Note: Most characteristic cytogenetic abnormality in neuroblastoma is 1p deletion. Because some are too small to be detected cytogenetically, they are termed as microdeletion syndromes the important microdeletion syndromes are: 1. A pair of connexins from adjacent cells joins to form a gap junction that bridges the 2-4 mm gap between the cells. Thesuprabasal acantholytic blister that forms is characteristic of pemphigus vulgaris. The bullae are tense and oral lesions are present in 10-15% of affected individuals. The disease results from formation of antibodies against gliadin and is associated with celiac disease. Bydirectimmunofluorescence,dermatitisherpetiformis shows granular deposits of IgA selectively localized in the tips of dermal papillae. Itusuallyaffectsthe scalp, face, chest, and back, and the mucous membranes are only rarely affected. The blanching, or pallor, represents the ischemic phase of the phenomenon and results from vasospasm of digitalarteries. Occasionally, persistent digital ischemia develops and may result in ulcers or gangrene. In most severe cases, the small vessels are occluded by a proliferative endarteritis. The skin lesions may be secondarily infected by bacteria such as Staphylococcusaureus or fungi like Candidaalbicans. Without treatment, the disease is fatal and affected individuals may die within a few years. Chief cells are neuroendocrine cells and are positive for regular neuroendocrine markers. It has been shown to increase in response to ventricular volume expansion and pressure overload. When somatic cells replicate a small section of the telomere is not duplicated and telomeres become progressively shortened. The loss of telomere function leads to activation of p53 dependent cell cycle checkpoints causing proliferative arrest or apoptosis. Histologically one sees a proliferation of spindle cells andendothelialcells,extravasationofredbloodcells,hemosiderin-ladenmacrophages,and,inearlycases,aninflammatorycellinfiltrate. In Niemann-Pick disease, they are widely distributed in spleen, liver, lymph nodes, bone marrow, and tonsils. Langhans giant cells Touton giant cells Tumour giant cells Foreign body giant cells Giant cells 1. They usually arise in the deep soft tissues of the proximal extremities and retroperitoneum and are notorious for developing into large tumors. Histologically, liposarcomas can be divided into well-differentiated, myxoid, round cell, and pleomorphic variants. The cells in 665 Review of Pathology well-differentiated liposarcomas are readily recognized as lipocytes. In the other variants, some cells indicative of fatty differentiation called lipoblasts are almost always present. The myxoid and round cell variant of liposarcoma has a t(12;16) chromosomal abnormality. The lymphocytes are intimately associated with basal keratinocytes which show degeneration and necrosis contributing to saw-toothing of dermo-epidermal junction. Anucleate, necrotic basal cells may get incorporated into the inflamed papillary epidermis where they are called colloid or Civatte bodies. Michaelis Gutmann bodies Seen in Malacoplakia (vesicle inflammatory reaction associated with E. These granules have a rod-like structure and terminal dilated ends (Tennis racket appearance) Miscellaneous 666 34. There are two clinical types, based on the differences in distribution of metastasis. First (Pepper type) occurs in the stillborn and in young infants and metastasizes to the liver and regional lymph nodes, then the lungs, and late in the course,thecalvariumandotherflatbones.

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Instead, the patient reports easy bruisability and the appearance of red spots, especially over dependent surfaces; gum bleeding with tooth brushing and episodic nose bleeds are common insomnia 4 hours sleep discount 25mg sominex free shipping. Mortality estimates have ranged from one case per 100,000 to one case per 1 million treatment courses. There was a suggestion of increased risk with drugs taken regularly for a prolonged period at very high doses, and in some cases, hematologic reactions were reproduced on repeat exposure. Extensive hemorrhage from any organ can occur but usually late in the course of the disease and almost always associated with infections, drug therapy. The ability to adapt to a gradual reduction in hemoglobin concentration is remarkable. Patients with anemia might mention fatigue, lassitude, shortness of breath, or ringing in the ears, but some individuals can tolerate astonishingly low hemoglobin levels without complaint. Even abrupt cessation of erythropoiesis leads to only a slow decline in hemoglobin (1 g/dL each week). The sore throat of agranulocytosis is not often observed, presumably because other alarming symptoms appear earlier. The interval can be more prolonged when pancytopenia is well tolerated or moderate. For purposes of diagnosis and management, a history of blood diseases in other family members is very important and should trigger appropriate genetic tests for constitutional causes. With identification of genetic risk factor, the family history has assumed great importance in the evaluation of pancytopenia. These mutations also are etiologic of cirrhosis and pulmonary fibrosis, which may be present as diagnoses in the pedigree. Early graying of the hair is a less reliable sign but is sometimes prominent in the telomere diseases. Findings on physical examination usually reflect the severity of the pancytopenia (Table 28-6). The patient may present with subtle variations from normal or with a dramatic, even toxic appearance. Petechiae are often present over the pretibial surface of the lower leg and the dorsal aspects of the forearm and wrist; a few petechiae can be seen in the oropharynx and on the palate. With severe thrombocytopenia, retinal hemorrhages can be present on funduscopic examination, there can be gingival oozing or blood in the nares, and hemorrhage can be apparent at the uterine cervical os. Pallor is common and is best appreciated on the mucosal membranes and palmar surfaces. A new patient can be febrile, but specific or localizing signs of infection are uncommon on presentation. A woman who desires a child can be maintained with transfusions with the understanding that any clinical deterioration is a criterion for interruption or termination of the pregnancy. Dyserythropoietic red blood cell precursors show bizarre forms with multiple or irregular nuclei. Megakaryocytes can show defective nuclear polyploidization and increased internuclear spaces, or they can be small with only a few nuclei and peculiar granulation. Typically, an uneventful episode of apparent viral hepatitis in a young man is followed in 1 to 2 months, during convalescence from the liver inflammation, by very severe pancytopenia. Patients with hepatitis-associated aplasia have markers of immune system activation and respond well to intensive immunosuppressive therapy. Acute viral hepatitis that is seronegative differs clinically from hepatitis C disease; parenteral exposure is not a risk factor, liver functions abnormalities are more severe during the acute phase, and late complications are more common. Although the history of the illness in a newly diagnosed patient is typically short-in the range of months-some patients may recall a long history of bruisability, anemia, and low blood cell counts reported to them by previous physicians during routine examinations. Pancytopenia can be first observed during the acute mononucleosis syndrome or shortly after disappearance of symptoms. Some patients have recovered spontaneously, others after therapy with corticosteroids or immunosuppressive therapy. Small numbers of lymphocytes are sufficient to produce the syndrome, which is surprisingly resistant to immunosuppressive therapy. Pancytopenia occurs in most of cases; anemia is a universal finding; thrombocytopenia and neutropenia are also common. The syndrome is associated with a large variety of diseases, including immunodeficiency, malignancy, and infections. In virus-associated hemophagocytosis, there is evidence of immune system activation. Although relative lymphocytosis is very common, most patients also have decreased absolute numbers of monocytes and lymphocytes. In challenging cases, obvious medical causes of pancytopenia usually have already been excluded. Discontinuation of exposure to the incriminated drugs or chemicals is mandatory, and in some instances, patients may then recover. However, given the difficulty of assigning blame with absolute certainty to environmental agents, the authors treat all patients similarly and do not advocate protracted observation for possible spontaneous recovery. These diseases frequently are diagnosed concurrently or sequentially in the same individual, and they share similar clinical and pathologic features. Collagen Vascular Diseases Aplastic anemia is a component of the collagen vascular syndrome called eosinophilic fasciitis. This severe, scleroderma-like disease is characterized by fibrosis of subcutaneous and fascial tissue, localized skin induration, eosinophilia, hypergammaglobulinemia, and an elevated erythrocyte sedimentation rate. Platelet size is normal and not increased as in immune peripheral destruction, but the low number can cause greater heterogeneity of size. There should be no compromise in obtaining adequate specimens and no hesitation in performing a second procedure if required. Point counting under microscopic cross hairs in many parts of a histologic section is the most accurate method of determining cellularity, but hematologists commonly rely on visual estimation only. Empty marrow with eosinophilic ground substance consistent with serous atrophy or stomal injury (A), possibly indicative of marrow damage. Scanty bone marrow aspirate in severe disease (B) showing only rare nucleated elements, many of which are from blood. The presence of plasma cells, histiocytes, and osteoblasts (C) confirms the bone marrow nature of the aspirate. Megaloblastoid erythropoiesis (D) is sometimes seen in aplastic anemia and in recovery. Bone marrow biopsy from patient with pancytopenia showing myelofibrosis and osteosclerosis associated with metastatic prostate cancer (A). Another case where the patient presented with pancytopenia and was found to have a bone marrow packed with lymphoma cells (C). Hairy cell leukemia can present with pancytopenia and with a hypocellular bone marrow (D) difficult to distinguish from aplastic anemia. In acellular specimens, the only cells visible are usually lymphocytes, plasma cells, and stromal elements-fibroblastoid and histiocytic cells. Some degree of dyserythropoiesis is common, usually the megaloblastoid features of macrocytosis and some nuclearcytoplasmic maturation asynchrony, but sometimes more complex degenerative changes in nuclei and cytoplasm can be observed by light and electron microscopy. Lymphoid aggregates, nests of tumor cells, granulomas, and infectious particles can be apparent on examination of the fixed biopsy specimen. The technique appears to be worthwhile in diagnosis because the patterns of fat and cell distribution appear to differ between aplasia and hypocellular myelodysplasia, and in prognosis, to monitor improvements in hematopoiesis after treatment. A rational diagnostic algorithm can be very helpful in establishing a correct diagnosis (see box on Diagnostic Algorithm in Aplastic Anemia). Although vitamin B12 and folate deficiencies have been reported to be associated with erythroid hypoplasia, this must be an exceedingly rare event. Often, acellular specimen precludes successful culture and generation of metaphase smears. In such cases, single nucleotide polymorphisms arrays-based karyotyping can be performed on interphase cells and may be helpful in detection of clonal abnormalities. Lives are lost, mainly because the grave consequences of severe pancytopenia go unrecognized. A, Bone marrow in a young man with severe aplastic anemia, a middleaged woman with severe aplastic anemia (B), and a middle-aged woman with myelodysplasia (C). Androgens and hematopoietic growth factors have secondary roles (see box on Treatment Algorithm in Aplastic Anemia). Platelet transfusions have substantially improved survival in patients with this disease.

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Serum iron concentration is increased, and transferrin shows an increased percentage of saturation with iron sleep aid 44386 buy 25mg sominex amex. Ineffective erythropoiesis can be confirmed by ferrokinetic measurements showing that plasma iron clearance is rapid, with subnormal retention of the iron isotope in erythrocytes after 10 to 14 days. Other features of ineffective erythropoiesis may be variably present: a mild increase in bilirubin concentration, decrease in haptoglobin levels, mild increase in lactate dehydrogenase levels, and normal or slight increase in reticulocyte numbers. The magnitude of iron overload correlates poorly with the degree of anemia in patients who are not transfused. The degree of ineffective erythropoiesis is a better predictor of the amount of iron overload. When ferrokinetics are unavailable, the extent of erythroid hyperplasia relative to normal acts as a rough measure of the magnitude of ineffective erythropoiesis. Therapy for Hereditary Sideroblastic Anemia A trial of pyridoxine (100 to 200 mg/day taken orally) is indicated for 3 months for all patients with hereditary sideroblastic anemia. Response is variable and ranges from complete correction of hemoglobin levels to no effect. About 25% to 50% of patients with hereditary sideroblastic anemia show a full or partial response to pyridoxine, and this vitamin should be continued on a lifelong basis in the responders. A lower maintenance dose should be determined for each responding patient by progressive dose reduction, because longterm therapy with pyridoxine at 100 to 200 mg/day has been associated with peripheral neuropathy. There is one report of successful allogeneic peripheral blood stem cell transplantation in a 19-year-old man with transfusiondependent hereditary sideroblastic anemia. Regular administration of packed red cells using white blood cell filters are given to relieve symptoms and permit normal childhood development. Iron overload and secondary hemosiderosis rapidly progress after transfusions begin; chelation therapy with desferrioxamine or oral deferasirox should be initiated from the onset. Iron removal may be of great benefit for patients who have mild or moderate anemia and evidence of iron overload. All patients with iron overload should avoid ingestion of ascorbic acid supplements, which enhance iron absorption and increase the tissue toxicity of elemental iron. Differential Diagnosis Hemoglobin (g/dL) Other Nonsyndromic and Syndromic Hereditary Sideroblastic Anemias X-linked sideroblastic anemia is considered the most common inherited sideroblastic anemia; however, a number of rare forms have recently been identified. These consist of two nonsyndromic sideroblastic anemias, which have a similar phenotype to X-linked sideroblastic anemia, and four syndromic forms where heme synthesis is affected in a variety of other tissues in addition to red cells. Pyridoxine 20 15 80 70 60 Chapter 36 Heme Biosynthesis and Its Disorders: Porphyrias and Sideroblastic Anemias 469 In addition to genetically defined forms of hereditary sideroblastic anemia, four syndromic types have been described, which present with anemia in combination with either muscle, neurologic, or pancreatic tissue involvement. The first of these disorders to be defined by molecular genetics, the Pearson syndrome, is a rare entity that manifests in early infancy with anemia and exocrine pancreatic dysfunction. The anemia is normocytic or macrocytic, reticulocyte counts are low, and variable degrees of neutropenia and thrombocytopenia are present. Some indirect evidence exists for a primary mitochondrial lesion, perhaps in the mitochondrial respiratory chain, which impairs the reduction of Fe3+ because Fe2+ is essential for heme synthesis. Etiology Clonal chromosomal changes are found in bone marrow cells in approximately 60% of patients with acquired sideroblastic anemia. Characteristic changes are monosomy 7; trisomy 8; deletions involving chromosomes 5, 7, 11, or 20; and a number of balanced translocations. This concept is in accord with the view that multiple genetic events underlie the pathogenesis of other myelodysplastic syndromes and acute myeloid leukemia176,186 (see box on Clinical and Laboratory Evaluation of Sideroblastic Anemia). Acquired Sideroblastic Anemia Acquired sideroblastic anemia is categorized within the myelodysplastic syndromes and may appear de novo or occur after chemotherapy or irradiation (see Table 36-5). The clonal nature of hemopoiesis in this condition was first suggested by Dacie et al. Acquired idiopathic sideroblastic anemia falls within the diagnostic category of refractory anemia with ring sideroblasts as defined by the French-American-British group and World Health Organization classification. Distinguishing between idiopathic myelofibrosis and myelodysplasia is Differential Diagnosis Ring sideroblasts are not limited to acquired sideroblastic anemia; they also occur in other myelodysplastic conditions, such as refractory anemia with excess blasts, in which the blast count is higher than 5%. Family surveys are very useful in distinguishing acquired from hereditary forms of sideroblastic anemia, because the latter may present in late adult life. When changes are confined to dyserythropoiesis, the condition has been called pure sideroblastic anemia. Cytogenetic analysis of marrow aspirates provides important information, because a normal karyotype predicts long survival in any type of acquired sideroblastic anemia. A trial of pyridoxine at 100 to 200 mg/day for 3 months is worthwhile in patients who have anemia but who do not display neutropenia or thrombocytopenia. However, few patients with acquired idiopathic sideroblastic anemia respond to this vitamin. If any response is achieved, maintenance therapy with pyridoxine at lower dosage is indicated. Cyclosporin (5 to 6 mg/kg/day) has been reported to benefit the anemia of the closely related myelodysplastic condition of refractory anemia, although the response appeared limited to those with hypoplastic bone marrows. Red blood cells show dimorphic morphology; evidence in the marrow of folate deficiency is present in half of cases. The ring sideroblasts gradually disappear over 4 to 12 days when alcohol is withdrawn202; during this period, there may be a rebound erythroid hyperplasia, reticulocytosis, and thrombocytosis. Folic acid should be given for the associated megaloblastic changes after blood is taken for vitamin B12 and folate assays. First is the severity of the anemia, because repeated transfusions markedly increase iron overload and invariably lead to the organ dysfunction characteristic of secondary hemosiderosis. The second factor is whether neutropenia and thrombocytopenia are associated with the anemia. These cytopenias form the basis of a simple prognostic scoring system in which two or more of the following place the patient in a poor prognostic category: hemoglobin level less than 10 g/dL, neutrophil count less than 2. Conversely, monosomy 7 or a partial loss of the long arm of chromosome 7 as a single defect imparts a high probability of transformation to acute myeloid leukemia. Multiple chromosomal abnormalities and del(20q) are also associated with an increased risk for progression to leukemia; in contrast, trisomy 8 has no adverse prognostic significance. Isoniazid Administration of the antituberculous drug isoniazid occasionally has been associated with development of a sideroblastic anemia after 1 to 10 months of therapy. The anemia is hypochromic and microcytic, with a dimorphic blood smear and ring sideroblasts in the marrow. This complication is thought to occur only in slow acetylators of isoniazid, allowing this drug to react nonenzymatically with pyridoxal and to form a hydrazone that is rapidly excreted in the urine. The anemia can be fully reversed by coadministration of pyridoxine (25 Chapter 36 Heme Biosynthesis and Its Disorders: Porphyrias and Sideroblastic Anemias 471 to 50 mg/day) with isoniazid or by withdrawing isoniazid. This effect is predictable and separate from the rare idiosyncratic side effect of aplastic anemia in approximately 1 of 20,000 exposed persons. Nearly all patients given chloramphenicol (>2 g/day) develop vacuolation of the erythroid precursors and ring sideroblasts. Chloramphenicol inhibits mitochondrial protein synthesis and reduces cytochrome a, a3, and b levels. Other Drugs A reversible acquired sideroblastic anemia has been described with penicillamine therapy and with the use of triethylene tetramine hydrochloride, a copper-chelating agent used in the treatment of Wilson disease. In some reports, patients present with neurologic symptoms such as paresthesias, weakness, or ataxia; and demyelination is seen on the magnetic resonance image of the brain. Serum copper and ceruloplasmin levels are low, whereas serum iron and transferrin saturation levels are normal. Large quantities of ingested zinc interfere with copper absorption and produce the neutropenia and sideroblastic anemia characteristic of copper deficiency. Sideroblastic anemia has also been ascribed to zinc toxicity arising from the ingestion of coins over a period of many years. Zinc must be discontinued for 9 to 12 weeks for full reversal of the anemia and neutropenia. The zinc complex of protoporphyrin is produced because ferrochelatase uses Zn2+ during iron-deficient erythropoiesis. The bone marrow aspirate showed a left shift in granulopoiesis with vacuolization of immature granulocytic and erythroid precursors (B and C).

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Ependymomas are found most frequently in the fourth ventricle, while the choroid plexus papilloma, a variant of the ependymoma, is found most commonly in the lateral ventricles of young boys insomnia 2012 sominex 25mg on-line. The medulloblastoma is a tumor that arises exclusively in the cerebellum and has its highest incidence toward the end of the first decade. In children medulloblastomas are located in the midline, while in adults they are found in more lateral locations. Schwannomas 590 Central Nervous System (neurilemomas) are single, encapsulated tumors of nerve sheaths, usually benign, occurring on peripheral, spinal, or cranial nerves. Acoustic neuromas typically located at the cerebellopontine angle or in the internal acoustic meatus. Involvement of the facial nerve produces facial weakness and loss of corneal reflex. Histologically, an acoustic neuroma consists of cellular areas (Antoni A) and loose edematous areas (Antoni B). Verocay bodies (foci of palisaded nuclei) may be found in the more cellular areas. Tuberous sclerosis Tuberous sclerosis is an autosomal dominant syndrome characterized by the clinical triadofangiofibromas("adenomasebaceum"),seizures,andmentalretardation. Patients develop hamartomas in the central nervous system including "tubers", which are film areas with haphazardly arranged neurons and glia with stout processes. The syndrome is associated with the development of several different types of tumors, including subepedymal giant cell tumor, rhabdomyoma of the heart, and angiomyolipoma of the kidney. Clinical triad of tuberous sclerosis is angiofibromas ("adenoma sebaceum"), seizures, and mental retardation. These include hemangioblastomas of retina and brain (cerebellum and medulla oblongata), angiomas of kidney and liver, and renal cell carcinomas (multiple and bilateral) in 25 to 50% of cases. It is characterized by cafe-au-laitskinmacules,axillaryfreckling,multipleneurofibromas,plexiform neurofibromas, and Lisch nodules (pigmented iris hamartomas). It encodes for neurofibromin, a protein that regulates the function of p21 oncoprotein. Only the central, or acoustic, form produces bilateral acoustic neuromas; the classic form may produce unilateral acoustic neuroma. Which of the following would distinguish hydrocephalus due to aqueductal stenosis when compared to 10. Locomotor ataxia, a late manifestation of syphilis due (e) Rabies to parenchymatous involvement of the spinal cord is 18. Allofthe following are seen in thymoma except (a) Hypogamma globulinemia (b) Hyperalbuminemia (c) Red cell aplasia (d) Myasthenia Gravis 22. Commonest type of intracranial tumor is: (b) Medulloblastoma (a) Astrocytoma (c) Meningioma (d) Secondaries 30. Lewy bodies are found in the substantia nigra neurons (b) Pituitary tumour in (c) Astrocytoma (a) Alzheimer disease (d) Glioma (b) Parkinson disease 37. Worst prognosis meningioma is: (Jharkhand 2005) (a) Syncytial (b) Fibroblastic (d) Atypical (c) Anaplastic CentralNervousSystem 27. Which of the following receptor on neuronal membrane that induces development of glioma Damage to nervous tissue is repaired by: (b) Fibroblasts (a) Neuroglia (c) Axons (d) Microglia 594 Central Nervous System 3 9. Assertion: Berry aneurysm is the commonest cause of subarachnoid hemorrhage Reason: Rupture of the aneurysm occurs commonly in childhood 2. Assertion: B12 deficiency causes subacute combined degeneration of the spinal cord Reason: B12 deficiency causes degeneration of both the ascending and descending tracts of the spinal cord 3. Assertion: Shy-Dragger syndrome is characterized by autonomic dysfunction Reason: Lewy bodies are found in nigrostriatal neurons 5. Since the gray matter is the location where pain fibers cross to join the contralateral spinothalamic tract, the interruption of the lateral spinothalamic tracts results in segmental sensory dissociation with loss of pain and temperature sense, but preservation of the sense of touch and pressure or vibration, usually over the neck, shoulders, and arms. The most common location of a syrinx is the cervicothoracic region and therefore, the loss of pain and temperature sensation affects both arms. Other features of syringomyelia include wasting of the small intrinsic hand muscles (claw hand) and thoracic scoliosis. As the cavity enlarges, spasticity and weakness of the legs, bladder and bowel dysfunction as well as Horner syndrome appear due to compression of the long tracts. Concept It is different from other causes of aneurysm (atherosclerosis, trauma, infections) which cause only cerebral infarction and not subarachnoid hemorrhage. Salient points about Berry aneurysm (saccular aneurysm) Saccularaneurysm is the most common type of intracranialaneurysm. Riskfactors Smoking and hypertension are the important risk factors for Berry aneurysm. Berry aneurysms are called congenital, although the aneurysm itself is not present at birth. Location Commonest location is in the circle of Willis, typically at the junction of the anterior communicating artery with the anterior cerebral arteryQ. It is also present at the junction of the middle cerebral artery and the posterior communicating artery. Clinically It is responsible for a clinically significant subarachnoid hemorrhage. In fact, excluding trauma, berry aneurysm is the commonest cause of subarachnoid hemorrhage. The chance of rupture of berry aneurysms increases with age (rupture is rare in childhood). Concept It is different from other causes of aneurysm (atherosclerosis, trauma, infections) which cause onlycerebralinfarction and not subarachnoid hemorrhage. Its value increases in abscess, cerebral hemorrhage and infarction and in primary or metastatic malignant disease. Its value increases in abscess, cerebral hemorrhage and infarction and in metastatic malignant disease. Its value increases in associated with meningitis, cerebral hemorrhage and infarction. Microscopic examination shows lesions in the white matter which is an area of demyelination, in the center of which are scattered lipid-laden macrophages and a reduced number of axons. At the edge of the lesion are greatly enlarged oligodendrocyte nuclei whose chromatin is replaced by glassy amphophilic viral inclusion. Prion diseases may manifest as infectious, genetic, and sporadic disorders; no other group of illnesses with a single etiology presents with such a wide spectrum of clinical manifestations. This alpha-to-beta structural transition in the prion protein (PrP) is the fundamental event underlying prion diseases. Kuru is an infectious prion disease thought to have resulted from the consumption of brains from dead relatives during ritualistic cannibalism in New Guinea. Spongiform degeneration is characterized by many 1- to 5-micrometers vacuoles in the neuropil between nerve cell bodies. These changes occur especially in the subcortical white matter, diencephalon, and brainstem. An important component of the microglial nodule is the macrophage-derived multinucleated giant cell. This causes impaired joint position sense and ataxia (locomotor ataxia); loss of pain sensation, leading to skin and joint damage (Charcot joints); other sensory disturbances like the characteristic "lightning pains"; and absence of deep tendon reflexes.

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This heterogeneity arises from the variable severities of the primary biosynthetic defects and coinherited modifying factors, such as increased synthesis of fetal globin subunits or diminished or increased synthesis of -globin subunits sleep aid while breastfeeding 25mg sominex for sale. Palliative treatment of the severe forms by blood transfusion is eventually compromised by the concomitant problems of iron overload, alloimmunization, and bloodborne infections. As a group, the thalassemias represent the most common single genetic disorder known. Laboratory analysis of these disorders has been one of the most productive and enlightening endeavors of biomedical research. Study of the molecular defects underlying the thalassemia syndromes has led to fundamental advances in our understanding of eukaryotic gene structure and function. For each of these reasons, a thorough understanding of thalassemia and its related disorders is essential to hematologists. Readers wanting more detailed information than can be included here are referred to more comprehensive monographs elsewhere. Therefore, readers of this chapter should first familiarize themselves with the material presented in Chapter 31. The material presented in this chapter is also substantially clarified by prior reading of Chapters 33 and 34 because the principles underlying the pathophysiology of and therapy for thalassemia draw heavily on knowledge of iron metabolism. The most common forms of thalassemia arise from total absence of structurally normal globin chains or a partial reduction in their synthesis. However, some rare forms of thalassemia are characterized by the production of structurally abnormal globin chains in reduced amounts. These thalassemic hemoglobinopathies share features of thalassemia as well as those of structural hemoglobinopathies. These conditions, called hereditary persistence of fetal hemoglobin, are not generally associated with clinical symptoms; nonetheless, they merit consideration in this chapter. Their importance lies in their role as modulating factors when coinherited with other hemoglobinopathies; in their usefulness as models for investigating the molecular basis for globin gene regulation during human development; and as paradigms for rational therapy for the major -chain hemoglobinopathies, namely, sickle cell anemia and -thalassemia. Thalassemias have been encountered in virtually every ethnic group and geographic location. They are most common in the Mediterranean basin and tropical or subtropical regions of Asia and Africa. The "thalassemia belt" extends along the shores of the Mediterranean and throughout the Arabian peninsula; Turkey; Iran; India; and southeastern Asia, especially Thailand, Cambodia, and southern China. Similar to sickle cell anemia, thalassemia is most common in areas historically affected by endemic malaria. Malaria seems to have conferred selective survival advantage to thalassemia heterozygotes in which infection with the malarial parasite is believed to result in milder disease and less impact on reproductive fitness. Individual syndromes are named according to the globin chain whose synthesis is adversely affected. Thus, -globin chains are absent or reduced in patients with -thalassemia, -globin chains in patients with -thalassemia, -globin and -globin chains in patients -thalassemia, and so forth. In some contexts, it is also useful to subclassify the syndromes according to whether synthesis of the affected globin chain is totally absent. Therefore, detailed consideration of these syndromes is best deferred to their individual subsections. This section considers only mechanisms common to the pathogenesis of all of these syndromes. For all practical purposes, the major impact on clinical well-being occurs only when these 505 506 Part V Red Blood Cells lesions affect the - or -globin chains necessary for the synthesis of hemoglobin (Hb A; 22). As a result, hypochromia and microcytosis are characteristic of virtually all patients with thalassemia. The second consequence of impaired globin biosynthesis is unbalanced synthesis of the individual - and -subunits. Hemoglobin tetramers are highly soluble and have reversible oxygen-carrying properties exquisitely adapted for oxygen transport and delivery under physiologic conditions. Free or "unpaired" -, -, and -globin chains are either highly insoluble or form homotetramers (Hb H and Hb Bart) that are incapable of releasing oxygen normally and are relatively unstable and precipitate as the cell ages. For poorly understood reasons, no compensatory regulatory mechanism exists whereby impaired synthesis of one globin subunit leads to a compensatory downward adjustment in the production of the other (partner) globin chain of the hemoglobin tetramer. Thus, whereas useless excess -globin chains continue to accumulate and precipitate in -thalassemia, excess -globin chains form Hb H in -thalassemia. During uterine development, excess -globin chains form Hb Bart in individuals with -thalassemia. The abnormal solubility or oxygen-carrying properties of these chains lead to a variety of physiologic derangements. Indeed, in the severe forms of thalassemia, it is the behavior of the unpaired globin chains accumulating in relative excess that dominates the pathophysiology of the syndrome rather than the mere underproduction of functioning hemoglobin tetramers. The precise complications of this pathophysiologic phenomenon are diverse and depend on the amount and the identity of the globin chain accumulating in excess. For the moment, the fundamental principle that must be appreciated is that thalassemias cause symptoms by underproduction of hemoglobin and by accumulation of unpaired globin subunits. The predominant circulating hemoglobin at the moment of birth is fetal hemoglobin (Hb F22) (see Chapter 31). Although the switch from - to -globin biosynthesis begins before birth, the composition of hemoglobin in the peripheral blood changes much later because of the long life span of normal circulating red blood cells. Hb F is thus slowly replaced by adult hemoglobin (Hb A) so that infants do not depend heavily on normal amounts and function of Hb A until they are between 4 and 6 months old. The pathophysiologic consequences of these considerations are that whereas -chain hemoglobinopathies tend to be symptomatic in utero and at birth, individuals with -chain abnormalities are asymptomatic until 4 to 6 months of age. These differences in the onset of phenotypic expression arise because -chains are needed to form Hb F and Hb A, but -chains are required only for Hb A. The term -thalassemia intermedia is applied to a less severe clinical phenotype in which significant anemia occurs but chronic transfusion therapy is not absolutely required. It usually results from the inheritance of two -thalassemia mutations, one mild and one severe; the inheritance of two mild mutations; or, occasionally, the inheritance of complex combinations, such as a single -thalassemia defect and an excess of normal -globin genes, or two -thalassemia mutations coinherited with heterozygous -thalassemia (in this last form, known as -thalassemia, the -thalassemia allele reduces the burden of unpaired -chains). It is characterized by profound microcytosis with hypochromia but mild or minimal anemia. Most types of -thalassemia are caused by point mutations affecting one or a few bases. It has been determined that five or six mutations usually account for more than 90% of the cases of -thalassemia in a given ethnic group or geographic area (see Table 38-1). They are inherited in a multitude of genetic combinations responsible for a heterogeneous group of clinical syndromes. The anemia of thalassemia major is so severe that long-term blood transfusions are usually required. A third type of splicing aberration results from mutations that are not in the immediate vicinity of a normal splice site. These alter regions within the gene, called cryptic splice sites, which resemble consensus splicing sites but do not normally sustain splicing. The mutation responsible for the most common form of -thalassemia among Greeks and Cypriots. Premature translation termination also results indirectly from frameshift mutations. Other Sites Rare mutations that affect gene function by intriguing mechanisms have been described. An extremely large deletion of the -globin gene cluster has been described that removes the -, -, and -genes. The important aspect of this deletion is that it removes the critical locus control region18,31 located thousands of bases upstream from the beginning of the globin gene cluster at the 5 end of the -globin gene; loss of this region severely impairs -gene expression. A number of additional deletions involving the locus control region and various portions of the -gene cluster, but sparing the -gene itself, have the same phenotype. Haplotypes differ according to whether each restriction site is present or absent along the gene cluster. More than 12 haplotypes have been defined by examination of several restriction sites located along the cluster that are present or absent in a polymorphic manner in normal individuals. The differences in physiologically important functions among haplotypes that modulate severity remain unknown, but a possible explanation lies in the variable abilities of the -globin genes on different chromosomes to respond to severe erythroid stress by increased expression during postnatal life. The -globin genes carried on some haplotypes differ in the degree to which they can respond in this manner.