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Fatigue may also be a non-specific response to the systemic manifestations of heart failure, such as chronic increases in catecholamines and circulating levels of cytokines, sleep disorders, and anxiety. Elevated right atrial pressures increase the capillary hydrostatic pressures in the systemic circulation, with resultant transudation. Most commonly, edema accumulates in the extremities and resolves at night when the legs are not dependent. Edema may occur only in the feet and ankles; but if it is more severe, it may accumulate in the thighs, scrotum, and abdominal wall. Edema is more likely and more severe in patients with accompanying venous disease (or who have had veins harvested for coronary bypass surgery) and those on calcium channel blockers, which themselves cause edema. Fluid may also accumulate in the peritoneal cavity and in the pleural or pericardial space. Ascites occurs as a result of elevated pressures in the hepatic, portal, and systemic veins draining the peritoneum. Ascites is unusual in heart failure and almost always is associated with peripheral edema. Most commonly, there is severe tricuspid regurgitation, with potential damage to the liver. Otherwise, significant primary liver disease should be suspected as an exacerbating factor or cause of ascites. Pleural effusions are fairly common in chronic heart failure, especially when it is accompanied by both left- and right-sided manifestations. The effusions result from an increase in transudation of fluid into the pleural space and impaired lymphatic drainage due to elevated systemic venous pressures. Passive congestion of the liver may lead to right upper quadrant pain and tenderness and even mild jaundice. Usually only mild elevations of transaminase levels and modest increases in bilirubin levels are observed. With severe, acute rises in central venous pressures, especially when associated with systemic hypotension, a severe congestive and ischemic hepatopathy may occur with striking elevations in liver function tests and hypoglycemia. Recovery is usually rapid and complete if the hemodynamic abnormalities are corrected. Bowel wall edema may lead to early satiety (a common symptom in heart failure), nausea, diffuse abdominal discomfort, malabsorption, and a rare form of protein-losing enteropathy. The potential role of heart failure in producing these non-specific gastrointestinal symptoms is often overlooked, leading to extensive diagnostic testing or unnecessary discontinuation of medications. Periods of nocturnal oxygen desaturation to below 80 to 85% are relatively common in patients with heart failure, coincide with episodes of apnea, and often are preceded or followed by episodes of hyperventilation. These are similar to , and may represent truncated forms of, Cheyne-Stokes respiration. Supplemental oxygen appears to reverse some of the ventilatory disorders, and the apneic spells respond to nasal positive-pressure ventilation. In some patients, these interventions may have a striking beneficial effect on fatigue and other symptoms of heart failure. However, in advanced heart failure, cerebral hypoperfusion may cause impairment of memory, irritability, limited attention span, and altered mentation. In chronic, severe heart failure, unintentional chronic weight loss may occur, leading to a syndrome of cardiac cachexia. The etiology of this syndrome is unclear, but it may result from a number of factors, including elevated levels of proinflammatory cytokines. Physical Findings the physical findings associated with heart failure generally reflect elevated ventricular filling pressures and, to a lesser extent, reduced cardiac output. Importantly, in chronic heart failure many of these findings are absent, often obscuring the correct diagnosis. Compensated patients may be quite comfortable, but patients with more severe symptoms are often restless, dyspneic, and pale or diaphoretic. Although the heart rate is usually at the high end of the normal range or above (>80 beats per minute), it may be lower in chronic, stable patients. Pulsus alternans (alternating amplitude of successive beats) is a sign of advanced heart failure (or a large pericardial effusion). The blood pressure may be normal or high, but in advanced heart failure it is usually on the low end of normal or below. Examination of the jugular veins is one of the most useful aspects of the evaluation of heart failure patients.

Postpartum thyroid dysfunction occurs in 5 to 10% of women in the year after delivery. Most affected women have goiters (which are not normally present during pregnancy). Additional risk factors include a family or personal history of postpartum thyroid dysfunction and the presence of antimicrosomal antibodies. Affected individuals typically develop transient hyperthyroidism, associated with a low iodine uptake, 6 to 12 weeks post partum. Hypothyroidism also usually is temporary and managed with several months of thyroid replacement, with an attempt to stop therapy after 6 months. A serum glucose level greater than 140 mg/dL or whole blood glucose level greater than 170 mg/dL is considered positive. Classes B and C include women requiring insulin but without other complications from diabetes. Those women in classes D (benign retinopathy), F (nephropathy), R (proliferative retinopathy), and H (heart disease) have the greatest potential for complications during pregnancy. Because "tight" blood glucose control during this interval decreases congenital malformations and miscarriages, optimal blood glucose especially is appropriate when diabetic women are considering pregnancy and early in gestation. Women taking oral hypoglycemic agents should be switched to insulin before conception, because these agents cross the placenta, may be teratogenic, and can cause prolonged fetal hyperinsulinemia. The therapeutic goal is "tight" glucose control, with fasting and preprandial levels of 60 to 90 mg/dL, and 1-hour postprandial values less than 140 mg/dL. Women must be able to monitor their blood glucose and obtain several values per day (fasting, following breakfast, late afternoon, and evenings). Ketonemia adversely affects the fetus, and care must be taken to prevent starvation ketosis and weight loss. Hospitalization for intense patient education and glucose control may be appropriate early in gestation. Additional indications for hospitalization include nausea and vomiting, poor glucose control that is unresponsive to insulin adjustments, and persistent ketonuria. The recommended diet is 30 to 35 kcal/kg/day based on ideal body weight, with a composition of 60% carbohydrate, 15 to 20% protein, and 20 to 25% fat. Calories are divided as three meals and two snacks a day: 20% breakfast, 30% lunch, 35% dinner, 10% evening snack, and 5% midmorning snack. Insulin therapy usually is initiated when the fasting blood glucose level is greater than 105 mg/dL or 2 hours postprandial glucose exceeds 120 mg/dL on two occasions within 2 weeks. In general, insulin requirements decrease slightly during the first trimester, then increase until term, when requirements are approximately 50% greater than preconception. Insulin requirements decrease after delivery and are reduced by approximately 50% at 1 week post partum. Risk factors for maternal morbidity and relative contraindications to pregnancy include established renal disease (creatinine >2. If the creatinine clearance is less than 80 mL/min or urine protein more than 2 g/day, up to 50% of women will experience permanent further renal impairment during pregnancy. Because diabetic retinopathy progresses in 10 to 50%, patients should be examined by an ophthalmologist each trimester. Follow-up fasting glucose values should be obtained approximately 2 months post partum. The mean levels of alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, and bilirubin are slightly lower during pregnancy. Alkaline phosphatase, coming primarily from the placenta, increases slowly during the first and second trimester and rises to four times the prepregnant values at term. Because of the expanded plasma volume, the serum albumin value decreases 10 to 50%. Evaluation of the jaundiced pregnant patient is altered, owing to conditions unique to pregnancy and urgency to confirm and treat the pregnancy-associated life-threatening hepatic disorders.

The discovery of low mean corpuscular volume and hemoglobin on automated complete blood counts has increased the number of such referrals. In the presence of normal iron status, increased levels of Hb A2 (to 4 to 6%) and/or increased Hb F (to 5 to 20%) by quantitative hemoglobin analysis supports the diagnosis. Unfortunately, differentiation between iron deficiency anemia and beta- or alpha-thalassemia trait can be difficult in practice if no reciprocal increases in Hb A2 levels and/or Hb F are present. Moreover, in the presence of concomitant iron deficiency, Hb A2 levels in beta-thalassemic individuals may fall into the normal range. In these instances, the demonstration of a modified beta/alpha-globin synthetic chain ratio, generally using 3 H-leucine to analyze globin chain production in reticulocytes, would be required for a conclusive diagnosis. These procedures generally carry a risk of miscarriage of 1% and 5%, respectively. Some deletions of one (alphaalpha/-alpha) or two (-alpha/-alpha, -/alphaalpha) alpha-globin genes are asymptomatic, and no therapy is indicated. For Hb H disease (three-gene deletion, -/-alpha), folic acid, 889 1 mg orally, should be administered daily to compensate for folate loss from accelerated red cell turnover. Splenectomy may be indicated for progressive anemia and is often associated with a mean rise in hemoglobin of 2 to 3 g/dL. Despite a nearly comprehensive understanding of the molecular and cellular pathogenesis of the beta-thalassemia syndromes, a widely available curative form of treatment for homozygotes remains elusive. Nonetheless, dramatic improvement in life expectancy and morbidity has been observed over the last two decades, primarily because of aggressive transfusion support and the institution of effective iron chelation therapy in these regularly transfused patients. Thus except for curative allogeneic bone marrow transplantation, therapy is considered symptomatic and supportive. As treatment of severe beta-thalassemia has improved, so has morbidity and median survival. Thus whereas non-transfused patients in the 1920s had a median survival of 2 years, transfusion therapy aimed at maintenance of a hemoglobin concentration of 11 to 13 g/dL (pre-transfusion level, >10 g/dL) has been shown to extend the average survival into the second decade, as well as minimize the bony abnormalities and improve sexual development. Transfusion support is generally initiated once the hemoglobin level drops below 7 g/dL and remains there in the absence of infection, blood loss, etc. To minimize febrile reactions and so as not to prejudice the potential future application of bone marrow transplantation (see below), leukocyte-poor red cells should be administered. An accurate record of the date and amount of blood administered, along with pre- and post-transfusion hemoglobin levels and the occurrence of any transfusion reactions, facilitates optimal therapy. Patients should be tested for the presence of hepatitis B antibodies; those testing negative should be immunized. Splenectomy is usually recommended in children or adolescents (6 to 7 years of age) when their transfusion requirements exceed 1. Before elective splenectomy, all patients should receive polyvalent pneumococcal vaccine and pediatric patients should also be given Haemophilus influenzae and Neisseria meningitidis vaccine. Although intensive transfusion programs have led to markedly improved survival, patients will die of iron overload unless chelation therapy is appropriately instituted and maintained. Currently, this therapy involves subcutaneous deferoxamine, a parenterally administered iron chelator, although a search for an effective oral chelator is currently under way. Many patients can be placed in iron balance by receiving a 12- to 24-hour infusion of deferoxamine 5 or 6 days a week. Chelation therapy should be individualized according to age, risks, compliance history, and other factors. For younger patients who are not yet at risk for the complications of iron overload, 1. Patients with high liver iron concentrations (>6000 mug/g dry tissue) or those with evidence of cardiac involvement. Periodic assessment of the effectiveness of chelation therapy should include an estimate of iron burden. A yearly cardiac evaluation should be performed in an effort to detect clinical evidence of cardiac disease and should include a complete history and physical examination, electrocardiogram, echo-cardiogram, and chest radiograph. A Holter monitor should be used in any patient who complains of palpitations or who is noted on physical examination to have an irregular heartbeat. Potential iron-induced damage to the endocrine glands should be evaluated by glucose tolerance testing, thyroid function tests, and cortisol determinations.

These oncoproteins are structurally identical to their normal forms but are either expressed inappropriately in the cell cycle or in inappropriate tissues. In lymphoid tissues, the result is expansion of the pre-B-cell compartment in myc containing transgenic mice and ultimately to the emergence of a monoclonal lymphoid malignancy. In this group, oncogenic potential is activated by expression in an inappropriate cell type: tal-1 is normally expressed in erythroid and myeloid precursors and not T cells; lyl-1 is expressed only in myeloid and B-lymphoid cells; and Ttg-2 transcripts are found in liver, spleen, and kidney but not in activated T cells. In each case, the inappropriate expression of a transcription factor serves as a molecular switch to induce a malignancy. To this end, well-known tumor suppressor genes such as the retinoblastoma gene (Rb-1) and p53 can act as "brakes" to cellular proliferation, and each appears to function through distinct pathways. Rb-1 negatively regulates an important transcription factor, E2F, and the deletion of the Rb gene (as seen in congenital retinoblastoma) or sequestration of its protein product (as seen in the presence of the adenovirus E1A protein, or the human papilloma viral protein, E7) releases the suppression of E2F. That both Rb and p53 are involved in the genesis of cancer is supported by the identification of germline mutations in patients with cancer predisposition syndromes such as congenital retinoblastoma (Rb) and the Li-Fraumeni multicancer syndrome (p53). As is the case with transforming oncogenes, the presence of a single abnormal tumor suppressor allele is insufficient for cancer to form; lesions at other genetic loci are necessary. For example, both Rb and p53 may need to be inactivated for some primary cells to be rendered immortal, one of the first steps in transformation. In malignant melanoma, the loss of both p16 alleles identified in most primary tumors led to the finding that inactivating germline mutations in p16 segregate with familial melanomas and with some familial pancreatic cancer syndromes. The story of p16 reiterates the importance of viewing cancer genetics in the context of signaling relays. Current evidence suggests that the abrogation of programmed cell death (apoptosis) may be an important concomitant to neoplastic transformation. The cell exerts exquisite control of this process using redundant systems to induce or to block apoptosis, and some of these control switches are involved in cancer induction and in the response to cancer treatment. The clearest example of an oncogene modulating the apoptotic process is bcl-2, found to be the important oncogene in patients with the t(14q;18q) translocation frequently detected in follicular lymphomas. In experimental lymphomas, bcl-2 does not cause cancer directly but allows the cell to survive to undergo subsequent mutations involving rearrangements at other oncogenes, such as the c- myc, that result in accelerated progression of the lymphoma. This bcl-2/ myc interaction underscores another principle of oncogene action: more than one cancer gene must be perturbed for a malignancy to arise. Significantly, this set point is associated with responsiveness to irradiation and chemotherapy. More recently, growth factor receptors and other surface signaling molecules have been directly linked with the control of apoptosis. Therefore, augmented Akt function induced by certain ligand receptor interactions is predicted to have a significant antiapoptotic effect. It is not clear why certain tumors directly alter bcl-2 to modulate apoptotic potential whereas others primarily use alternative pathways to accomplish the same ends. Nevertheless, the underlying principle is that normal cells have self-policing mechanisms that activate suicide programs: when the mutational load of a cell exceeds a critical level, self-destruct processes are activated. Cancer, however, may result when genetically aberrant cells are not cleared but rather permitted to proliferate, thus accumulating mutations in important cancer genes. A second principle that has emerged is that many of the common oncogenes known to transform cells paradoxically also have proapoptotic functions. For example, myc is capable of transforming rat fibroblasts; however, in situations of cellular stress, such as serum starvation or when coupled with exposure to certain chemotherapeutic agents, myc triggers cell death in the same cells. Activated ras oncogenes, which are potent transforming genes in immortalized cell lines, also induce apoptosis under similar stress conditions. However, when myc and ras are co-introduced into primary murine fibroblasts, unequivocal transformation occurs. Taken together, it now appears that oncogenes can induce both growth and death, and that modulation of cooperating pathways. These observations raise the intriguing possibility that transformation is not an inevitable outcome of oncogene activation and that biochemical manipulation of pro-apoptotic signals can result in clearing mutant cells before they convert to cancers or can augment therapeutic responses. In addition, these individuals also harbor a heightened risk for endometrial cancer. These animals have a high potential of developing hematopoietic malignancies and intestinal adenocarcinomas and adenomas. The clinical consequence of this molecular defect in humans is the emergence of colon cancers that differ from the sporadic variety and are characterized by fewer ras and p53 mutations, as well as less allelic losses. Lastly, rearrangements of the bcl-2 locus and translocations involving the myc proto-oncogene are found solely in lymphomas.