Harry Snyder

  • Lecturer, Health Policy and Management

Free light-chain assays are quite sensitive and may provide measurement of clonal protein in patients thought to have non-secretory disease by other methods schedule 8 medications victoria order coversyl 8mg with amex. Free light chains have a relatively short half-life (2 to 6 hours) in the circulation compared with a half-life of weeks for intact immunoglobulin molecules and may therefore be used to obtain a more rapid assessment of disease response once therapy is initiated symptoms prostate cancer discount coversyl 8mg without a prescription. In rare cases medicine buddha mantra order 4mg coversyl with visa, patients may have true non-secretory myeloma with no detectable serum or urine M protein by any assay treatment 3rd degree burns purchase coversyl from india. The clinical manifestations of multiple myeloma are the direct effects of bone marrow and bone infiltration by malignant plasma cells medicine man 1992 coversyl 8mg without a prescription, the systemic effects of the M protein 6 mp treatment 8 mg coversyl fast delivery, and the effects of the concomitant deficiency in humoral immunity that occurs in this disease. Bone radiographs typically show pure osteolytic punched-out lesions, often in association with generalized osteopenia and pathologic fractures. Bony lesions can show as expansile masses associated with spinal cord compression. Hypercalcemia caused by extensive bony involvement is common in myeloma and may dominate the clinical picture. Anemia occurs in most patients as a result of marrow infiltration and suppression of hematopoiesis and causes fatigue; granulocytopenia and thrombocytopenia are less common. Patients with myeloma are susceptible to bacterial infections because of impaired production and increased catabolism of normal immunoglobulins. Gram-negative urinary tract infections are common, as are respiratory tract infections caused by Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, and Klebsiella pneumoniae. The cause of renal failure is often multifactorial; hypercalcemia, hyperuricemia, infection, and amyloid deposition can contribute. Because of their physicochemical properties, M proteins can cause a host of diverse effects, including cryoglobulinemia, hyperviscosity, amyloidosis, and clotting abnormalities resulting from interaction of the M protein with platelets or clotting factors. Most patients with myeloma exhibit symptomatic, advanced-stage disease and require therapy. Patients with asymptomatic myeloma may have an indolent course and do not always require immediate therapy. Revised international staging system for multiple myeloma: a report from International Myeloma Working Group. High-risk chromosomal abnormalities include deletion 17p and/or translocation t(4;14) and/or t(14;16). For patients with solitary bone or extramedullary plasmacytomas, particularly in the head and neck region, local radiation therapy can induce long-term remissions and is the treatment of choice. Patients with symptomatic myeloma require systemic therapy and meticulous supportive care. Although myeloma is not a curable malignancy, systemic therapy prolongs survival and dramatically improves quality of life. These agents may be used as single agents or in combinations for more intensive therapy. The novel agents are typically administered in combination with high doses of dexamethasone, which is a potent antimyeloma therapy. These agents have largely supplanted traditional chemotherapeutic agents as the cornerstone of initial and secondary therapies because they are efficacious and well tolerated. Multiple combination regimens have been devised that also incorporate chemotherapeutic agents in modest doses. The antiangiogenic properties of thalidomide subsequently led to its development as an anticancer agent. Toxicity related to thalidomide includes peripheral neuropathy, constipation, somnolence, and rash. Myelosuppression is more likely, but neuropathy and constitutional symptoms occur less frequently. Bortezomib is the first-in-class proteasome inhibitor and is an important therapy for patients with adverse cytogenetic risk factors. Bortezomib is typically administered subcutaneously and may cause thrombocytopenia, asthenia, and neuropathy. Most patients respond to initial therapy with a reduction in bone pain, hypercalcemia, and anemia in association with a decline in the M protein level. The selection of initial therapy depends on stage, cytogenetic risk, and candidacy for high-dose chemotherapy and autologous stem cell transplantation. The use of high-dose chemotherapy with alkylating agents followed by autologous peripheral stem cell infusion during first or second remission improves progression-free survival and quality of life compared with conventional therapy. Although this approach is not curative, it does represent an important treatment option for some patients and has an acceptable toxicity profile, even in older patients. Allogenic stem cell or bone marrow transplantation may be associated with durable remission in selected patients, but it carries a high nearterm risk of morbidity and mortality. Patients who experience relapse after standard therapy or transplantation may be treated with alternative chemotherapy regimens or with novel combination therapies, including newer agents and chemotherapy drugs. The first-in-class selective inhibitor of nuclear export, selinexor was recently added to the antimyeloma armamentarium for patients with relapsed or refractory disease as a fifthline therapy. Supportive care directed toward anticipated complications of myeloma is an important aspect of management. Bone resorption can be reduced with regular injections of the diphosphonates zoledronic acid or pamidronate, reducing pain and pathologic fractures. Bony lesions, particularly those involving weight-bearing bones, may require palliative irradiation for controlling pain and preventing pathologic fractures. Vertebral bony lesions may lead to spinal cord compression, with increasing back pain and neurologic symptoms. Avoidance of nephrotoxins, including intravenous contrast media, is important to prevent renal failure. Use of erythropoietin may alleviate anemia and decrease the need for blood transfusions in patients with treatment-related anemia or concomitant renal insufficiency. Multiple myeloma is considered incurable, but the overall survival of these patients has improved considerably with the use of newer agents and autologous stem cell transplantation. Patients with an adverse karyotype, including t(14;16), t(4;14), and 17p deletion, have a less favorable prognosis and are considered for more intensive therapies or clinical investigation. High-dose therapy and autologous stem cell transplantation is effective in patients with extensive disease. For a deeper discussion of these topics, please see Chapter 178, "Plasma Cell Disorders," and Chapter 179, "Amyloidosis," in Goldman-Cecil Medicine, 26th Edition. In contrast to IgG, IgM remains largely confined to the intravascular space, and as IgM levels rise, plasma viscosity increases. Epistaxis, retinal hemorrhages, dizziness, confusion, and congestive heart failure may occur as a result of the hyperviscosity syndrome. The use of fludarabine or an alkylating agent, typically employed in combination with prednisone and rituximab, is effective in decreasing adenopathy and splenomegaly and controlling the M spike but is not curative. The use of rituximab as a single agent may be complicated by initial worsening of hyperviscosity in patients with high IgM burdens. Although complete remissions are rare, patients who respond to therapy have median survivals of 4 years, and some patients survive more than a decade. Acquired disorders of lymphocyte function are far more common than congenital disorders. Patients who have undergone allogeneic organ transplantation require potent immunosuppressive drugs. Patients are treated by reducing doses of immunosuppressive drugs whenever possible. Patients with polymorphous disease early after organ transplantation may respond well to this approach. Patients who are not candidates for withdrawal of immunosuppression because of allograft rejection or who develop late monophorphic disease may respond better to treatment with rituximab alone or in combination with chemotherapy. Rare Plasma Cell Disorders Heavy-chain disease is a rare lymphoplasmacytoid neoplasm characterized by production of a defective heavy chain of the, or type. The -type heavy-chain disease is associated with lymphadenopathy, Waldeyer ring involvement with palatal edema, and constitutional symptoms. The -type heavy-chain disease, also known as Mediterranean lymphoma, is characterized by lymphoid infiltration of the small intestine with associated diarrhea and malabsorption. Congestive heart failure, bleeding diathesis, nephrotic syndrome, and peripheral neuropathy are common complications. Patients with primary amyloidosis may respond to selected treatments similar to therapy for myeloma. The combination of bortezomib, cyclophosphamide, and dexamethasone is effective in some patients. Selected patients may respond well to high-dose chemotherapy and autologous stem cell support, but there are increased risks of morbidity and mortality if significant end-organ dysfunction such as cardiomyopathy occurs. Vascular damage initiates clotting, which results in a localized platelet-fibrin plug at the site of injury to prevent blood loss. This is followed by clot containment, wound healing, eventual clot dissolution, and tissue regeneration. In healthy individuals, procoagulant and anticoagulant reactions occur continuously and in a balanced fashion so that bleeding is contained while blood vessels simultaneously remain patent to deliver adequate organ blood flow. If any of these processes is disrupted, either from inherited defects or acquired abnormalities, disordered hemostasis may result in either bleeding diatheses or thromboembolic disease. Traditionally, hemostasis has been conceptualized in two parts: primary hemostasis, resulting in adhesion and activation of platelets, and secondary hemostasis, resulting in activation and regulation of the coagulation cascade. More recent studies, however, demonstrate a considerable amount of interplay between primary and secondary hemostatic components. This article briefly details the physiologic and interdependent mechanisms of vascular hemostasis, including the normal balance of procoagulant and anticoagulant functions of the blood vessel wall and platelets, receptor-ligand interactions that are critical for hemostasis, as well as the highly complex, interwoven pathways that represent the coagulation cascade. In the pressurized arteries, relatively minor vascular damage can rapidly result in massive exsanguination; therefore, the procoagulant response in the arteries must rapidly arrest bleeding. Platelets are critical to the arterial response; they initially contain the blood loss and then provide an active surface for soluble coagulation factors to both localize and accelerate formation of fibrin for a strong fibrin clot. In contrast, the slower flow rates in the venous circulation produce slower bleeding, a feature that makes platelets less critical; instead, the balance of venous hemostasis is most dependent on the rate of thrombin generation. These differences are underscored clinically by the antithrombotic agents used in these distinct clinical settings: antiplatelet agents such as aspirin and clopidogrel are used to prevent coronary and cerebral artery thrombosis, whereas anticoagulants such as heparins, warfarin, and direct oral anticoagulants. Subendothelial procoagulant proteins such as thrombospondin, fibronectin, and especially collagen function both as ligands to capture platelets and as activators of adherent platelets. The most important and most clinically relevant aspects of platelet anatomy are shown. Details regarding the steps leading to platelet activation and release of granules and cytosolic contents are discussed in the text. The most potent platelet activators, collagen and thrombin, interact with their specific platelet receptors to strongly activate platelets. Notably, the exact roles of different platelet agonists depend on a spatial hierarchy within the platelet plug. Downregulation of prostacyclin, coupled with preserved platelet function, tips the hemostatic balance in favor of clot formation. The normal platelet count ranges between 150,000 to 450,000/L; only approximately 7100 platelets/L are required for hemostasis per day if vascular structures are intact. The bleeding time, an in vivo measure of hemostasis, is usually less than 8 minutes if the platelet count is within the normal limit. The bleeding time is dependent on the platelet count and will naturally be prolonged if the platelet count falls to less than 100,000/L. Because the bleeding time is an Platelet Adhesion Platelet activation leads to a functional shape change of the platelet from a disk to an irregular sphere with pseudopod extensions, as well as exposure of platelet binding domains. This enhances platelet adhesion capabilities and maximizes the interaction of coagulation factors with the platelet surface. The importance of dense-granule release is illustrated by the severe bleeding seen in patients with congenital dense-granule deficiencies such as Hermansky-Pudlak syndrome or Chediak-Higashi syndrome. The importance of platelet alpha granules is illustrated in patients with gray platelet syndrome, an inherited deficiency of alpha granules leading to bleeding. Although the classical model of coagulation is workable for some clinical scenarios, more recent models have made strides to more accurately elucidate and depict the physiology and complex interplay of different components of coagulation. This model proposes that coagulation takes place on the surfaces of different cells in a three-step fashion: initiation, amplification, and propagation. This switch is of significant kinetic advantage, with the intrinsic Xase complex exhibiting a 50-fold higher efficiency than the extrinsic Xase. More than 96% of the total thrombin that is generated during clotting occurs during the propagation phase. The bleeding diathesis associated with hemophilia is a testament to the physiologic importance of the exuberant thrombin generation engendered by the switch from extrinsic to intrinsic Xase. The common pathway culminates with the generation of thrombin, which converts fibrinogen to fibrin. This pathway is also referred to as the contact activation pathway because these proteins are activated by contact with negatively charged surfaces. The large amounts of thrombin now generate enough fibrin monomers to form stable polymers and fibrin clot. In combination with membrane phospholipids and calcium, activated Xa and its cofactor Va form the prothrombinase complex, which cleaves prothrombin to thrombin. The prothrombinase complex is several hundred thousand times more efficient at converting prothrombin to thrombin than free factor Xa acting on prothrombin alone. Termination of Clotting the rapid production of thrombin at a localized site of vascular injury could quickly lead to extensive clotting if left unchecked; thus, there are several mechanisms in place to ensure proper modulation.

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Additionally 68w medications order coversyl cheap, most of these procedures can be accomplished safely on an outpatient basis symptoms 5 weeks 3 days order genuine coversyl line, either in the office or in an ambulatory surgical setting medicine man dispensary purchase coversyl visa. Success rates for minimally invasive therapies are intermediate between those achieved with medical management and those of traditional surgical therapy 7mm kidney stone treatment purchase coversyl 4 mg with visa, with 65% to 75% of patients experiencing symptomatic improvement and improved flow rates in treatment 1 coversyl 4mg discount. The long-term durability of these therapies appears to be good but is presently being evaluated treatment hepatitis c cheap coversyl 4 mg free shipping. Use of finasteride or dutasteride may result in sexual dysfunction, including decreased erectile rigidity, decreased libido, and decreased ejaculate volume. This results in lower intracellular calcium levels and, consequently, smooth muscle relaxation. This process works in the vasculature of the penis as well as the smooth muscle cells of the prostate, urethra, and bladder neck. The common side effects of these medications are headache, nasal stuffiness, and facial flushing. One of the best ways to treat these symptoms of overactive bladder is with the daily use of anticholinergic medications such as oxybutynin, tolterodine, or solifenacin. The typical side effects of this class of medications include dry mouth, constipation, nausea, and impaired cognition. The risk of urinary retention related to the use of these medications in men appears to be minimal. The goals of the surgery are to reduce the transition zone prostate tissue to the level of the prostatic capsule and to create a smooth, open appearance of the prostatic urethra and bladder neck. Improvements in the conventional technique have included bipolar electrosurgical cutting, which allows the use of normal saline irrigation and eliminates the risks associated with the potential systemic absorption of hypotonic irrigation solutions. In this procedure, the entirety of the prostatic adenoma is "enucleated" from the capsule of the prostate and then removed through the urethra after morcellation. Other procedures include various forms of vaporization of the transition zone tissue of the prostate. This has led to a number of minimally invasive therapies, primarily using various energy platforms to cause tissue destruction within the prostate. These officebased techniques are best reserved for patients with smaller prostates and may transiently increase bladder outlet obstruction for 1 to 2 weeks due to postprocedure swelling. Rates of urinary incontinence, retrograde ejaculation, and urethral stricture are all higher after operating room procedures than after office-based therapies. Surgical enucleation (simple prostatectomy) is reserved for patients with very large glands. Traditionally performed via an open lower abdominal incision, this procedure involves incision into the bladder neck or the capsule of the prostate and then removal of the prostatic adenoma from within the prostatic capsule. While success rates are high, the rate of complications such as bleeding and incontinence is higher than with any of the other traditional surgical approaches (Table 73. With advancements in robotic technology, this surgery is now being performed with a robot-assisted laparoscopic approach that has significantly reduced the associated morbidity. A thorough clinical history and physical exam alone will likely lead one to the correct diagnosis; scrotal ultrasound can be used to confirm a diagnosis or aid in finding the diagnosis for those with equivocal exam findings. Varicocele A scrotal varicocele is an abnormal dilation of the veins of the pampiniform plexus that run along the spermatic cord and can be palpated as a "bag of worms" with or without having the patient performing the Valsalva maneuver while standing. When examining a patient for any scrotal pathology, it is important to have the patient stand. Because the occurrence of varicoceles increases with age, the prevalence in the literature is highly variable. However, because of a very rare association of isolated right-sided varicocele with retroperitoneal malignancy, many clinicians perform axial imaging on patients with a unilateral right-sided varicocele. In general, a left-sided varicocele does not have clinical significance unless it can be palpated on physical examination. A varicocele that is incidentally found during ultrasonography of the scrotum and is not palpable on examination is considered a subclinical varicocele and typically does not warrant intervention. Palpable and nonpalpable varicoceles are most commonly found incidentally and, in most cases, have no clinical significance. However, palpable varicoceles can cause ipsilateral testicular atrophy, discomfort, and/or affect semen parameters. Therefore, it is important for the clinician to compare the size of the testicles in patients who desire future fertility. If the physical examination is unclear, scrotal ultrasonography can be used to accurately measure the size of both testicles. Any patient who desires future children and has a size discrepancy greater than 20% should be monitored closely and possibly referred to a urologist. Although varicoceles are most commonly found incidentally, they may also be found during a work-up for male factor infertility, scrotal pain, or asymptomatic testicular atrophy. The pathophysiology of varicoceles is poorly understood but involves dilation of the internal spermatic vein and transmission of increased hydrostatic pressure across dysfunctional venous valves. Stasis of blood in the venous system disturbs the countercurrent heat exchange that is responsible for maintaining testicular temperature and may result in testicular parenchymal damage and impaired spermatogenesis. Varicoceles are the most common cause of both primary male infertility (patient has fathered no children) and secondary male infertility (patient has fathered at least one child), accounting for 33% of cases. However, most men with palpable varicoceles are able to father children without difficulty. If there is no or minimal response to therapy, a variety of minimally invasive and surgical options are now available that are all highly successful. Patients with acute epididymitis have significant inflammation that can also involve the testicle (epididymo-orchitis). Patients with severe epididymitis involving the testicle are often systemically ill. In most instances, initial treatment should consist of antibiotics, nonsteroidal anti-inflammatory medications, and possibly oral narcotics. In some cases, broad-spectrum antibiotics or even hospital admission may be necessary. In general, patients younger than 35 years of age should be treated with ceftriaxone and doxycycline. Older patients are usually empirically treated with a fluoroquinolone for 2 to 4 weeks. Complications associated with acute epididymitis include abscess formation, reactive hydrocele formation, testicular infarction, infertility, and chronic epididymitis or orchalgia. After surgical correction of a varicocele in a patient with infertility, semen parameters improve in 60% to 80% and subsequent pregnancy rates range from 20% to 60%. Providers often perform scrotal ultrasonography on any patient with chronic testicular pain to determine the source. Varicoceles are commonly found during this evaluation, but usually only palpable (clinical) varicoceles are considered as a source of pain. If a nonpalpable varicocele is found on an ultrasound examination, the patient should not be told that it is the cause of his pain. However, patients with palpable varicoceles and chronic testicular pain should be referred for treatment, as more than 80% of these men will have improvement in their pain after surgical correction. Common operative techniques for treatment of a varicocele include high retroperitoneal ligation of the internal spermatic vein, microsurgical inguinal and subinguinal varicocelectomy, laparoscopic varicocelectomy, and gonadal vein embolization. The inguinal approach using microscopic magnification has the highest success and lowest complication and recurrence rates. The most common complication is hydrocele formation, whereas a rare complication is inadvertent ligation of the testicular artery resulting in testicular atrophy and loss. Hydrocele A hydrocele is a sterile fluid collection located between the parietal and visceral layers of the tunica vaginalis of the scrotum. Noncommunicating hydroceles are commonly seen in adults and usually surround the testicle and spermatic cord. Communicating hydroceles are more common in children and actually represent indirect inguinal hernias. These communicating hydroceles contain only fluid and not bowel or fat because the opening into the peritoneal cavity is small. Communicating hydroceles can be distinguished from noncommunicating hydroceles on physical examination by gently pushing the fluid out of the scrotum and into the peritoneum, or by a history of fluctuation in size of the fluid collection throughout the day or with standing and lying down. Patients with a noncommunicating hydrocele usually have complaints of heaviness in the scrotum, scrotal pain, or an enlarging scrotal mass. Usually the diagnosis is easily made based on the physical examination and transillumination of the scrotum. If the testis is not palpable, an ultrasound study may be performed to rule out a testicular tumor associated with a secondary or reactive hydrocele. Noncommunicating hydroceles are caused by increased secretion or decreased reabsorption of serous fluid by the tunica vaginalis. Infection, trauma, surgery, neoplastic disease, and lymphatic disease are causative in many adults, whereas the remainder of cases are idiopathic. Asymptomatic hydroceles are benign and do not require treatment unless desired by the patient. Although the recurrence rate is significantly higher with aspiration and sclerotherapy, this approach can be a good option in patients who are considered poor surgical candidates. Hydrocelectomy procedures involve drainage of the serous fluid with either excision of the redundant tunica vaginalis or plication of the sac without excision. After surgery, the rates of hydrocele recurrence and chronic pain are 9% and 1%, respectively. Spermatocele (Epididymal Cyst) Spermatoceles and epididymal cysts are dilations of the tubes that connect the testicle to the epididymis (ductuli efferentes). Although they are technically synonymous, many clinicians refer to small lesions as epididymal cysts and larger ones as spermatoceles. These cystic lesions are very common and are found in 29% of asymptomatic men on ultrasonography. After a vasectomy, 35% of men develop a new small spermatocele, suggesting that distal obstruction of the vasa likely contributes to their development. On physical examination, spermatoceles are somewhat mobile, firm masses that are separate and distinguishable from the smooth border of the testicle. It may be possible to transilluminate larger lesions, but this is rarely performed in practice. Spermatoceles are filled with a clear fluid that usually contains abundant amounts of sperm. If the lesion cannot be transilluminated, it is advisable to perform an ultrasound study of the scrotum to distinguish a spermatocele from a solid mass or from other testicular lesions. Of note, should a solid mass be identified on the epididymis on imaging, the vast majority of solid masses of the epididymis are benign. They can be surgically removed if they are large or are causing discomfort for the patient. Acute Epididymitis Acute epididymitis is a clinical syndrome that may manifest with fever, acute scrotal pain, and impressive swelling and induration of the epididymis. Epididymitis is most often caused by retrograde bacterial spread from the bladder or urethra into the vasa and then into the epididymides. In men younger than 35 years of age, the most common causative agents are those organisms associated with sexually transmitted infections-namely, Neisseria gonococcus and Chlamydia trachomatis. In older men, acute epididymitis is usually caused by a coliform bacteria such as Escherichia coli and often occurs in association other lower urinary tract infections or bladder outlet obstruction. The most important consideration in diagnosing acute epididymitis is differentiating this disease from acute testicular torsion. Physical examination can be nonspecific, although focal epididymal swelling and tenderness are suggestive, and the presence of white cells and bacteria in the urine is indicative of an infectious etiology. Scrotal Testicular Torsion Testicular torsion is considered a true urologic emergency. The testicle receives its blood supply from the testicular artery (a branch of the aorta), the vasal artery (a branch of the inferior vesicle artery), and the cremasteric artery (a branch of the inferior epigastric artery). If detorsion is not performed within 6 to 8 hours, testicular infarction and hemorrhagic necrosis are likely to occur. Typically, patients are younger than 21 years of age, although testicular torsion can occur later in life. The characteristic signs and symptoms of acute testicular torsion are the acute onset of scrotal pain, swelling, nausea, vomiting, loss of normal rugae of the scrotal skin, absent cremasteric reflex, and a high-riding, rotated, tender testicle. The diagnosis of testicular torsion remains a clinical one; however, in equivocal cases, if ultrasound equipment is readily available and obtaining an ultrasound does not negatively affect the patient promptly proceeding to the operating room, scrotal ultrasonography may be performed prior to surgery. In many cases, surgical exploration is undertaken when the index of suspicion is high but imaging is not available. Doppler ultrasonography is extremely useful in differentiating testicular torsion from other causes of acute scrotum, such as acute epididymitis, torsion of the appendix testis, and trauma, as previously discussed. After giving the patient parenteral narcotics, the testicle can be untwisted by gently pulling down on it and, usually, rotating it laterally (like opening a book). Even if the procedure is successful, patients should still be taken to the operating room for bilateral orchiopexy to prevent future occurrences. Important surgical principles include surgical detorsion and assessment of testicular viability in the operating room. If the testis is determined to be viable, bilateral orchiopexy is performed using the technique of three-point fixation (sutures placed medially, laterally, and inferiorly). When diagnosis and surgery occur in a timely fashion, testicular salvage rates approach 70%. Delayed surgical therapy significantly decreases the salvage rate to approximately 40%.

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Symptoms are more often neurologic in children and psychiatric in adults medications safe during breastfeeding order coversyl 4 mg fast delivery, but in most cases symptoms zyrtec overdose buy coversyl 8 mg on line, symptoms progress to a similar syndrome symptoms in dogs order coversyl paypal. In contrast medicine zyprexa purchase coversyl 8 mg on line, patients with limbic encephalitis are generally older than 45 years and have symptoms including confusion treatment yeast infection child buy coversyl with visa, seizures symptoms questions generic 4mg coversyl overnight delivery, behavioral changes, and distinct memory deficits in which they have trouble forming new memories but old ones are preserved. Diagnosis the initial laboratory testing of an individual should include a complete blood count, tests of renal and hepatic function, coagulation studies, and serum and urine toxicology studies. A low white blood cell count, low platelet count, and elevated liver transaminase levels may suggest Ehrlichia or Anaplasma infection. A baseline chest radiograph should be obtained because a focal infiltrate can suggest particular pathogens. Concomitant serum viral studies are sometimes helpful in diagnosing viral encephalitis. A serum specimen collected during the acute phase of the illness should be stored and tested in parallel when the convalescent serum sample is drawn. Detection of intrathecal IgM antibody is a specific and sensitive method for the diagnosis of West Nile virus infection. Louis encephalitis virus, Japanese encephalitis virus); plaque-reduction neutralization assays may be helpful in distinguishing which flavivirus is involved in the event of elevated titers. Serologic testing for Rickettsia, Ehrlichia, and Anaplasma species should be performed for all encephalitis patients during the appropriate season and with travel to or residence in endemic areas, especially because these are treatable causes. Empiric therapy should not be withheld from patients with a compatible clinical presentation because antibodies are not always detectable early in the course of illness. Diagnosis should lead to the search for a tumor in female patients; the tumor is almost always an ovarian teratoma. In patients with autoimmune encephalitis, the current approach includes immunotherapy and removal of the immunologic trigger. Most patients are treated with glucocorticoids, intravenous immune globulin, or plasma exchange. If there is no clinical response to these treatments, then rituximab or cyclophosphamide may be used. Additionally, early identification and removal of this trigger is important for achieving a good outcome. Time to recovery, degree of residual deficit, and risk of relapse vary depending on the type of autoimmune encephalitis. Pathology and Pathophysiology Brain abscesses produce symptoms and findings similar to those of other space-occupying lesions. Brain abscesses may arise from several mechanisms, the most common of which is spread from a contiguous focus of infection; examples include infections of the middle ear, mastoid cells, paranasal sinuses, as well as dental infections. A second mechanism is hematogenous dissemination from a distant focus of infection. Brain abscesses resulting from hematogenous spread are usually multiple and mutliloculated, and they are associated with higher mortality. Traumas, particularly those involving dural breach, and invasive neurosurgical procedures, are also a pathogenic mechanism of brain abscess development. The infection is often polymicrobial, and the pathogen(s) involved depend on the mechanism of spread as well as the host characteristics. Commonly isolated pathogens are aerobic and microaerobic streptococci and gram-negative anaerobes such as Bacteroides and Prevotella. In immunosuppressed individuals, Aspergillus and Toxoplasma are important causes of abscesses. Surgical specimens are culture positive in 70% of antibiotic-treated patients and 95% of patients undergoing surgery before antibiotic administration. Treatment One of the most important first steps in managing encephalitis is to consider treatable causes. Therefore, acyclovir (10 mg/kg intravenously every 8 hours in adults with normal renal function) should be administered to patients with encephalitis. Empirical therapy for acute bacterial meningitis should be initiated when clinical and laboratory testing is compatible with bacterial infection. If rickettsial or ehrlichial infections are suspected, empirical doxycycline should be administered. Clinical Presentation the clinical course of brain abscess ranges from indolent to fulminant. Elements of one or two categories are often absent in a given case, particularly early in the disease course. The classic triad of fever, headache, and focal neurologic deficit is found only in about 20% of patients on admission. However, headache may be moderate to severe and hemicranial or generalized but often lacks distinguishing features. Toxoplasma abscesses are often associated with movement disorders due to their propensity for the basal ganglia. The period of evolution may be as brief as hours or as long as days to weeks with more indolent organisms. The location of the brain abscess can correlate with clinical presentation (Table 92. Sudden worsening of a headache with new onset of meningismus may signify rupture of the abscess into the ventricular space. Lumbar puncture in the setting of a mass lesion carries the risk of transtentorial herniation. Because the brain abscess is seeded from a peripheral site of infection, a search for other sites of infection can help to identify the causative organisms and determine appropriate treatment. It can demonstrate cerebritis, the extent of a mass effect, and associated venous thrombosis. On T1-weighted images, the area of cerebritis is seen initially as a low-signal-intensity, ill-defined area. T1-weighted images in the later stages of infection may show the formation of a rim of slightly higher signal intensity and central necrosis. Differentiating a brain abscess from tumor is important for the stereotactic approach to ring-enhancing lesions before biopsy or surgical excision. An abscess should be drained centrally, whereas a tumor should be biopsied along its rim. Findings of cerebral infarcts that develop into single or multiple brain abscesses usually in the frontal or temporal lobes in a patient with risk factors for invasive aspergillosis should suggest that diagnosis. Unless the surgical procedure poses a substantial risk, aspiration of the lesion is needed for microbial diagnosis. Corticosteroids should be administered to patients with significant edema, with mass effect causing increased intracranial pressure, or with a predisposition to transtentorial herniation. High-dose intravenous dexamethasone (16 to 24 mg/day in four divided doses) may be used for short periods until surgical intervention is possible. Corticosteroids may retard formation of a capsule around the brain abscess in its early stages and the immune response to infection. Seizures should be controlled because the tonic phase of a generalized seizure may increase intracranial pressure. Seizure prophylaxis should be initiated in all patients with cortical or temporal lobe abscesses. Successful treatment of brain abscesses relies on rapid verification of the abscess, identification of the responsible pathogen, timely surgical intervention, and appropriate antimicrobial therapy. If the organism is unknown, empirical therapy may include vancomycin, metronidazole, and a third- or fourth-generation cephalosporin. In brain stem abscesses, the possibility of Listeria infection should be considered, and treatment should include intravenous ampicillin. Voriconazole is the recommended antifungal therapy for patients with risk factors and imaging findings concerning for invasive aspergillosis. An important aspect of the management strategy is eradication of the predisposing condition or cause of the brain abscess, such as an oral, ear, cardiac, or pulmonary infection. Subdural Empyema Definition Subdural empyema refers to infection in the space separating the dura and arachnoid. Pathology and Pathophysiology Cranial subdural empyemas account for 15% to 20% of all localized intracranial infections. Two thirds of subdural empyemas result from frontal or ethmoid sinus infections, 20% from inner ear infections, and the remainder from trauma or neurosurgical procedures. The empyema is caused by direct or indirect extension from infected paranasal sinuses through a retrograde thrombophlebitis. As the use of epidural catheters has increased for pain management, epidural abscess and hematoma have been increasingly reported. Because the size of the intravertebral canal remains relatively constant but the circumference of the spinal cord changes, abscess formation is maximal in the thoracic and lumbar regions and minimal at the cervical spine. Due to the loose connections between the dura and the bones of the spine, the abscess can extend to multiple levels, causing severe and extensive neurologic manifestations. Tuberculous abscesses may occur in as many as 25% of patients in high-risk populations. In a previous epidemic, iatrogenic infection occurred with rare fungi after epidural injections of corticosteroids that were contaminated with a plant pathogen, Exserohilum rostratum, which rarely infects humans. The infection is metastatic in about 5% of patients, primarily from a pulmonary source. In some patients, the subdural empyema may be associated with an epidural abscess or meningitis. Clinical Presentation the clinical presentation of cranial subdural empyema can be rapidly progressive with signs and symptoms resulting from increased intracranial pressure, meningeal irritation, or focal cortical inflammation. These include fever, intractable headache, vomiting, nuchal rigidity, focal neurologic deficits. If untreated, mental status may decline to obtundation, and the septic mass and swollen underlying brain can lead to venous thrombosis or death from herniation. The clinical presentation of spinal subdural empyema may consist of radicular pain and symptoms of spinal cord compression including saddle anesthesia, lower extremity weakness, and bowel or bladder incontinence. Nuchal rigidity and obtundation occur in meningitis and cranial subdural empyema, but papilledema and lateralizing deficits are more common in cranial subdural empyema. Clinical Presentation the classic triad of fever, back pain, and neurologic deficits may not be identified in all patients, leading to a delay in diagnosis. An important physical finding is focal tenderness over the affected spinous processes. The pain can be mistaken for sciatica, a visceral abdominal process, chest wall pain, or cervical disk disease. If it goes unrecognized at this stage, the symptoms can evolve over a few hours to a few days to weakness, loss of lower extremity reflexes, and paralysis distal to the spinal level of the infection. In this clinical setting, urgent neuroradiologic imaging should be pursued followed by empiric antibiotics with concurrent corticosteroids, and surgical evaluation. Diagnosis Lumbar puncture should be avoided in patients with cranial subdural empyema to prevent cerebral herniation. The differential diagnosis includes transverse myelitis, intervertebral disk herniation, epidural hemorrhage, and metastatic tumor. Epidural abscess is often accompanied by diskitis or osteomyelitis of the vertebral bodies. Treatment Treatment requires prompt surgical drainage of the empyema cavity and prompt administration of intravenous antibiotics directed at organisms found at the time of craniotomy. Concomitant use of corticosteroids to reduce edema and increased intracranial pressure, as well as anticonvulsants to control seizures, are also important to reduce morbidity and mortality. Treatment Unless culture and sensitivities dictate otherwise, a penicillinase-resistant penicillin should be started empirically as antistaphylococcal treatment for presumed bacterial infection. Considering the severity of the disease, additional gram-negative coverage with a third- or fourth-generation cephalosporin or a fluoroquinolone may be needed. Other empiric agents, including antifungals, can be considered based on clinical suspicion and patient risk factors. These patients should be monitored closely, and if signs of neurologic deterioration emerge, surgical intervention may be necessary. Symptoms include headache or lateralized facial pain, followed Pathology and Pathophysiology Infections of the spinal epidural space originate from contiguous spread or through hematogenous routes from a distant source. Cutaneous infection, particularly in the back, is the most common remote source, especially among injection drug users. In some instances, sensory dysfunction occurs in the first and second divisions of the trigeminal nerve along with a decrease in the corneal reflex. Further involvement of the contiguous orbital contents follows, with mild papilledema and decreased visual acuity that sometimes progresses to blindness. Extension to the opposite cavernous sinus or to other intracranial sinuses with cerebral infarction or increased intracranial pressure due to impaired venous drainage can result in stupor, coma, and death. Radiologic evaluation includes imaging of the sphenoidal and ethmoidal sinuses, which may require drainage if infected. Treatment includes an empirical regimen of broad-spectrum intravenous antibiotics to cover staphylococci, gram-negative bacilli, and anaerobes. Septic Sagittal Sinus Thrombosis Septic sagittal sinus thrombosis is uncommon and occurs as a consequence of purulent meningitis, infections of the ethmoidal or maxillary sinuses spreading through venous channels, face, scalp, subdural space, compound skull fractures, or neurosurgical wound infections (rare). Similar to other sinus thromboses, the likely microorganisms depend on the associated primary condition. Diagnosis and treatment are similar to the lateral venous sinus thrombosis described earlier. Lateral Sinus Thrombosis Septic thrombosis of the lateral sinus results from acute or chronic infections of the middle ear, including otitis media and mastoiditis.

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Other fall prevention measures include eliminating medications that cause dizziness or postural hypotension (if possible) symptoms vitamin d deficiency buy generic coversyl from india, assessing the need for assistive devices medications to treat bipolar cheap coversyl 4mg without prescription. The benefits of hip protectors for hip fracture reduction are disappointing and controversial symptoms 0f pregnancy buy generic coversyl canada, and compliance with these products is often poor symptoms congestive heart failure buy coversyl 8 mg mastercard. Zoledronic acid is given at a dose of 5 mg intravenously once per year for treatment and 5 mg intravenously every 24 months for prevention symptoms ibs buy coversyl canada. There is not a simple guide for which bisphosphonate is chosen 911 treatment center purchase cheap coversyl, since the order of medication selection is often determined by the cost of the medication and insurance consideration. Generally, alendronate is the most commonly used because it is usually the least expensive. Because oral bisphosphonates are poorly absorbed, they must be taken first thing in the morning on an empty stomach with a full glass of water. Patients must wait 30 minutes (when taking alendronate and risedronate) to 60 minutes (when taking ibandronate) before eating and must not lie down. Potential side effects of bisphosphonates include epigastric distress, heartburn, and esophagitis. Intravenous bisphosphonates have been associated with an influenza-like syndrome after infusion. These fractures may manifest with a prodrome of unilateral or bilateral thigh pain, and fractures may occur with minimal activity. These fractures are rare after osteoporosis treatment but common in cancer patients receiving frequent high doses intravenously. Raloxifene reduces the risk for invasive breast cancer in postmenopausal women with osteoporosis and in women at high risk for invasive breast cancer. Patients have the same small risk of deep vein thrombosis or pulmonary embolus that is found with hormone therapy. Raloxifene does not relieve postmenopausal symptoms and may exacerbate hot flashes. Raloxifene can be given with or without food in a daily oral dose of 60 mg per day. In addition to improvements in bone mass, benefits include an improved lipid profile, decreased colon cancer incidence, and decreased menopausal symptoms. A combination of conjugated estrogen/bazedoxifene is also approved for prevention in postmenopausal osteoporosis and other menopausal symptoms (hot flashes). It is associated with a 65% reduction in vertebral fractures and a 53% reduction in nonvertebral fractures. Teriparatide is taken for up to 2 years as a subcutaneous, 20-g daily dose for postmenopausal women and men at high risk for fracture including patients on glucocorticoids. Side effects include nausea, headache, and dizziness and may be associated with bone loss at some sites if initiated following denosumab discontinuation. Denosumab is approved for postmenopausal women and men with osteoporosis, men with prostate cancer on androgen deprivation therapy, postmenopausal women with breast cancer on aromatase inhibitors, and men and women on glucocorticoids. Denosumab may cause hypocalcemia so calcium intake by diet or supplement is encouraged. When therapy is stopped, bone loss and vertebral compression fractures can occur, especially in patients with a previous vertebral fracture. Following denosumab discontinuation, teriparatide (a recombinant version of human parathyroid hormone) treatment (see later) can lead to bone loss at some sites. The pivotal trial reported a reduction of vertebral fractures by 86% and nonvertebral fractures by 43%. It can be administered as a daily subcutaneous injection of 80 mg for up to 2 years for postmenopausal women. This increase was associated with an approximate 50% reduction in vertebral fractures. Treatment was associated with improved lipid status, as shown by decreased total and low-density lipoprotein cholesterol. Romosozumab Romosozumab is a monoclonal antibody to sclerostin that has a dual effect mechanism of action since it increases bone formation and decreases bone resorption. In pivotal trials compared to placebo, after 12 months romosozumab increased bone density by 13. It is approved for postmenopausal women with osteoporosis for 12 months as a subcutaneous monthly injection of 210 mg. Calcitonin Calcitonin is a 32-amino-acid peptide produced by the parafollicular cells of the thyroid gland. The pivotal clinical treatment trial did not show significant changes in bone mineral density after 3 years. Recent studies have demonstrated greater vertebral fracture risk reduction with an anabolic therapy compared to an antiresorptive therapy. Combination therapy with an anabolic and potent antiresorptive (denosumab) has been shown to increase bone mineral density more than monotherapy, but fracture reduction studies are needed. Duration of Treatment Osteoporosis is a chronic disease and requires lifelong management and follow-up. It is recommended that patients be reevaluated after 5 years of oral or 3 years of intravenous bisphosphate therapy. If they are osteopenic and without fracture risk they can begin a bisphosphate holiday, but reevaluation is suggested in 1 to 2 years. If they still have osteoporosis, have fractured on therapy, or are still at risk for fracture, therapy can be continued but a change to an alternative agent should be considered. After 2 years of an anabolic therapy with teriparatide or abaloparatide or 1 year of romosozumab, an antiresorptive therapy is suggested. There is no limit to the duration for denosumab, but following discontinuation of therapy an alternative antiresorptive therapy should be considered to prevent bone loss. Choice of Therapy and Sequential Versus Combination Therapy the initial choice of medication and sequence of therapy is important and under investigation. The choice of therapy is usually driven by the insurance provider, and often an oral antiresorptive bisphosphonate such as alendronate is the least expensive and provides fracture risk reduction at key vertebral, nonvertebral, and hip sites. The concept of "treat-to-target" is based on the premise that starting any therapy may not be sufficient to achieve an acceptable level of risk. For high-risk patients with severe osteoporosis, the initial choice of therapy may be based on using the most potent therapy first Vertebroplasty and Kyphoplasty Vertebroplasty involves injection of cement. Kyphoplasty introduces a balloon into the vertebral body to expand it, followed by cement placement inside the vertebral body. Some studies suggest a significant reduction in pain early on, but the long-term pain reduction may be similar to that of placebo. Ongoing studies are needed to determine whether differences in outcomes can be found between vertebroplasty and kyphoplasty. These procedures are recommended only for patients with significant pain from vertebral fractures and are not routinely performed in asymptomatic patients with vertebral osteoporosis. Differentiating localized from systemic processes, executing logical diagnostic procedures, and embarking on appropriate therapeutic courses demand careful clinical evaluation. Confirmation or exclusion of systemic connective tissue disease on the basis of laboratory results is unreliable and therefore unwise. Features in the medical history that are useful for distinguishing different types of arthritis are listed in Tables 78. The first step is to confirm that the complaint originates from the musculoskeletal system and is not referred pain caused by other organ system pathology. The next step is to define whether the problem is articular or extra-articular based on the history and clinical presentation. Asymmetrical pain and swelling in the knees have different connotations in a 70-year-old patient than in a 20-year-old patient. Inflammatory arthritis is characterized by pain at rest, morning stiffness (typically greater than 60 minutes), gelling phenomenon. In osteoarthritis and nonarthritic musculoskeletal problems, pain usually does not occur at rest and is precipitated or worsened by activity. The onset of disease is abrupt in crystal-induced arthritis, less so in septic arthritis, and slow and insidious in most other disorders. Constitutional features such as fatigue, weight loss, and fever are seen in systemic autoimmune disease and infection but not in localized conditions. A thorough review of systems can provide clues to the primary diagnosis by defining associated systemic syndromes. Although there are many exceptions to these demographic and clinical generalizations, they provide helpful starting points when a patient is being evaluated for the first time. Patients are frequently unaware of detectable joint abnormalities, including deformity and effusion, which are signs of joint disease. Reported pain may be referred from another site, which can be determined by examination. Pain in the knee is often a sign of hip disease and may be reproduced on examination of the hip. Different diseases have distinctive patterns of joint involvement, which provide critical diagnostic information. For example, prominent disease of distal interphalangeal joints is seen in psoriasis and inflammatory osteoarthritis. Wrist and metacarpophalangeal involvement are almost universal in rheumatoid arthritis but rare in osteoarthritis. Examination of the axial skeleton may reveal diminished lumbar flexion, decreased rotational motion of the spine, and decreased chest expansion, features of ankylosing spondylitis and other spondyloarthropathies. Patients may report symptoms in only a single joint, but finding additional affected joints on physical examination can change the entire evaluation. Because rheumatic diseases may involve any organ system, a complete physical examination should be performed for all patients. The onset of systemic rheumatic diseases is usually insidious, and the clinical course is prolonged. However, presentation sometimes can be acute depending on the organ system involved. Acute joint inflammation, fever, and systemic signs such as chills, night sweats, and leukocytosis provide supporting evidence for infection. Gouty arthritis may share some or all of these clinical features, but its onset tends to be more abrupt. Inflammation extending beyond the margins of the joint is characteristic of septic arthritis and is otherwise seen only in crystal disease. Nonarticular processes such as cellulitis, septic bursitis, tenosynovitis, and phlebitis may mimic infectious arthritis. Acute nerve entrapment or spinal cord compression, tendon rupture, and fractures may occur in the absence of obvious trauma. Spinal cord compression may be the result of a herniated disk or vertebral subluxation. Tendon rupture may occur in inflammatory arthritides, particularly in the wrist of patients with rheumatoid arthritis. Pelvic and other insufficiency fractures may be seen in patients with osteoporosis or osteomalacia. Renal crisis may occur in scleroderma, with vasculopathy leading to renal infarcts, azotemia, microangiopathy, and severe hypertension. Acute blindness is a potential complication of giant cell arteritis, and the diagnosis requires urgent therapy even before confirmatory biopsy. Acute inflammatory myositis should be promptly treated because it may progress rapidly and involve the respiratory musculature. Recurrent otorhinolaryngologic complaints, such as sinusitis, should raise suspicion for granulomatosis with polyangiitis. Lesions of psoriasis in the scalp, umbilicus, and anal crease, thickening of the skin on the fingers in scleroderma, and mucous membrane ulcers are often overlooked. It helps to distinguish between inflammatory and noninflammatory arthritis, and results can be diagnostic of infectious arthritis or crystal disease. Synovial fluid consists of an ultrafiltrate of plasma plus hyaluronic acid that is secreted by synovial lining cells. Evaluation of synovial fluid should include a cell count and differential, examination for sodium urate and calcium phosphate dehydrate crystals, Gram stain, and culture. Synovial fluid examination should be performed for all acute arthritides and all situations in which joint infection is likely. Aspiration and analysis of fluid before therapy are essential for appropriate decision making. Although autoantibodies are often considered the hallmark of rheumatic diseases, their utility in diagnosing individual patients is much less than commonly assumed. Rheumatoid factor is found in approximately 80% of patients with rheumatoid arthritis but also found in other rheumatic diseases, chronic infection, neoplasia, and almost any disease state that can cause chronic hyperglobulinemia. Neither positive nor negative test results are diagnostic, and the results should be interpreted only in the clinical context. Although the specificity of the rheumatoid factor is low, it does predict more aggressive joint disease and extra-articular joint manifestations. Antibodies to cyclic citrullinated peptides are helpful in diagnosing rheumatoid arthritis because they have a high specificity (>90%). Antibody tests should be ordered and repeated only if they can help in making the diagnosis, assessing the prognosis, or altering the treatment plan. Tests for acute phase proteins, C-reactive protein, and the erythrocyte sedimentation rate are nonspecific, but positive results suggest an inflammatory disease. In many instances, diagnosis can be made with certainty only by pathologic examination of tissue. Muscle biopsy may be necessary to establish a diagnosis of inflammatory muscle disease, and nerve biopsy may be needed to detect vasculitis.

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In adults professional english medicine cheap coversyl 8 mg otc, acute leukemias are relatively uncommon and occur in 8 to 10 of 100 symptoms diagnosis purchase coversyl 4 mg,000 people (compared with 42 of 100 symptoms quad strain buy 8 mg coversyl otc,000 for prostate cancer and 62 of 100 medications 2 generic coversyl 4mg on line,000 for breast cancer) medications given im purchase coversyl 8 mg line. Transplantation treatment 7th march order coversyl 4 mg on line, however, remains the only known curative therapy for these patients. Pathology the pathogenesis of acute leukemia is complex and characterized by a high degree of biologic heterogeneity. Many patients with acute leukemia have detectable characteristic clonal chromosomal abnormalities and mutations that drive malignant transformation of normal hematopoietic stem cells bearing myeloid or lymphoid lineage markers. The resultant unchecked proliferation of these immature cells incapable of further differentiation. Known risk factors for leukemia include high-dose radiation exposure and occupational exposure to chemicals including benzene. Patients with chromosomal instability disorders such as Down syndrome, Bloom syndrome, Fanconi anemia, and ataxia telangiectasia also have an increased incidence of leukemia. Further immunophenotyping of blast cells using cell surface antigens, cytochemistry, and immunohistochemistry confirms cells as having a myeloid or lymphoid origin. Treatment consists of leukapheresis, hydroxyurea, and initiation of induction chemotherapy to inhibit further production of circulating tumor cells. Hydration, urine alkalinization to reduce uric acid crystallization, allopurinol, or rasburicase, or a combination, should be initiated as indicated. Red blood cell transfusions are often contraindicated in patients with high numbers of circulating blast cells because of the risk of further increases in blood viscosity. Severe thrombocytopenia, normocytic anemia, and circulating peripheral blasts are common. Bone marrow aspirate and biopsy typically show a profusion of myeloblasts (20% to 100%) and depressed production of normal mature cells. Clinical Presentation Patients exhibit clinical evidence of bone marrow failure similar to other hematopoietic disorders. Complications of disease include anemia, infection, and bleeding from peripheral cytopenias. Blasts may also invade other organs and lead to peripheral, mediastinal, and abdominal lymphadenopathy, hepatosplenomegaly, skin infiltration, and meningeal involvement. Induction therapy is directed at reducing the number of leukemic blasts to an undetectable level and restoring normal hematopoiesis. At complete remission, however, significant subclinical disease persists, requiring further therapy. Subsequent consolidation therapy involves continuing chemotherapy with the same agents to induce elimination of additional leukemic cells. With development of a wider range of effective agents, intensification therapy has been introduced. Maintenance therapy employs low-dose, intermittent chemotherapy given over a prolonged period to prevent subsequent disease relapse. The goal of therapy is to induce remission (>5% blasts in the bone marrow and recovery of normal peripheral blood counts). In both leukemias, cytogenetic and molecular abnormalities represent the best independent predictors of overall survival (Tables 47. Long-term cure rates (survival >5 years) range from 5% to 60% after chemotherapy alone, with an overall cure rate of 20% to 30%. Clinical Presentation Patients most often have complications related to progressively severe cytopenia, such as infection due to leukopenia, shortness of breath or fatigue due to anemia, or bleeding due to thrombocytopenia. Extramedullary disease includes leukemic involvement in the central nervous system, skin and soft tissues (myeloid or granulocytic sarcoma), and any other organ involvement outside of the bone marrow and peripheral blood. However, recent advances in genomic and Patients who are younger than 60 years and/or fit for intensive chemotherapy. The "traditional" induction regimens administered in the inpatient setting consist of 7 days of cytosine arabinoside. Some cytogenetic aberrations confer poor prognosis and are associated with resistance to and/or early relapse following standard chemotherapy regimens. These "poor-risk" cytogenetics include deletions in chromosome 5 or 7, inv(3q), t(3;3), t(6;9), t(9;22) (also known as the Philadelphia chromosome), monosomal karyotype, and three or more karyotypic abnormalities. These patients have a 30% to 45% long-term survival rate with standard 7+3 chemotherapy (see Table 47. These include substitution of higher-dose intermittent-dosed cytarabine instead of 7-day infusional cytarabine and the addition of other agents (such as cladribine or fludarabine) to cytarabine and anthracycline in attempts to enhance responses. However, the long-term survival rates after autologous transplantation range from 20% to 40% and are at least equivalent to consolidation chemotherapy regimens for these patients. Infectious complications remain the major cause of morbidity and mortality during intensive inpatient chemotherapy despite advances in prophylactic growth factor support, antibiotics, and antifungal agents. The low expected remission rates (30% to 50%) and high mortality and morbidity rates associated with induction are additional reasons for many patients to decline aggressive therapy. Fortunately, multiple therapeutic options are now available specifically for treatment of these older adults who in the recent past would have been offered only supportive therapy with hydroxyurea, transfusion support alone, and hospice. Patients older than 75 years old and/or those unfit for and who choose not to receive intensive therapy now have a panoply of low-dose chemotherapy options. These regimens have been well tolerated, but both are associated with disappointing response rates and median survival duration of less than 6 to 7 months. Adverse events included significant myelosuppression with risk of infection, sepsis, and pneumonia leading to early death in a proportion of patients. Treatment was well tolerated with relatively little myelosuppression or cytopenia. The excellent tolerability of this regimen with relatively little myelosuppression and the ability to treat patients completely in the outpatient setting makes it an option for select individuals. These agents, originally evaluated in the relapsed/refractory setting, result in overall response rates of approximately 40% and are well tolerated without myelosuppression. This serositis-like disorder is attributed to adhesion of differentiating neoplastic cells to the pulmonary vasculature and carries a 5% to 10% mortality rate. Treatment consists of early initiation of corticosteroids and aggressive diuresis. Most deaths result from uncontrolled hemorrhage, differentiation syndrome, and complications of prolonged myelosuppression after cytotoxic therapy, particularly in older individuals. Clinical Presentation Patients often present with life-threatening cytopenias, or complications of leukostasis. Several clinical and biologic features at diagnosis have traditionally been identified as poor prognostic factors for survival (see Table 47. These include age (in pediatrics <2 years or >10 years, in adults >35 years), elevated white blood cell count at presentation (>100,000/mcL), precursor T phenotype, chromosome number (pseudo/hypodiploidy or near tetraploidy) and specific chromosome abnormalities (such as complex karyotype or Philadelphia chromosome). The poorer outcomes for adults are attributed to differences in the biologic mechanisms of disease in the different age groups and the inability of older patients to tolerate the intensive chemotherapy or transplantation procedures required to achieve long-term responses. Induction chemotherapy typically includes vincristine, corticosteroids, and l-asparaginase with the addition of an anthracycline, cytarabine, or cyclophosphamide (or a combination) for adult patients. Current complete remission rates following induction chemotherapy range from 97% to 99% for children and 75% to 90% for adults. After normal hematopoiesis returns, patients typically undergo consolidation and intensification therapy with the same drugs, including high-dose methotrexate, cytarabine, and asparaginase to eradicate disease. Thereafter, maintenance chemotherapy given for up to 2 to 3 years after initial remission achievement is usually recommended for all patients. The median age of onset was 15 years with 27% diagnosed in individuals older than 45 years. No significant benefit has been seen with autologous transplantation over standard chemotherapy for these patients. This is due to significantly higher rates of treatment-related toxicities and death in older individuals with medical comorbidities and decreased tolerance of prolonged chemotherapy. Overall response rates to multiagent salvage chemotherapy incorporating the same agents used in frontline therapy range from 20% to 50% with duration of second remissions lasting less than 6 months. Each drug induces clinical responses in up to a third of heavily pretreated patients as a single agent with tolerable toxicities. Unique side effects of therapy include neurologic symptoms (ranging from change in mental status to seizures to encephalopathy) and cytokine release syndrome characterized by fever, hemodynamic instability, and life-threatening organ damage. As the first successful therapy based on an understanding of pathogenesis, imatinib has become emblematic of the translation of an understanding of disease pathogenesis into tangible innovations in clinical care. Acute Leukemia Acute leukemias are clinically aggressive malignancies with survival rates of weeks to a few months if untreated. The availability of multiple targeted and nontargeted agents for distinct biological subsets has changed the therapeutic landscape for these diseases. Patients with relapsed disease are eligible to receive the latest advances in novel immunotherapeutic approaches. Future directions include moving agents known to be effective in the relapsed/refractory setting to earlier in the treatment course during induction and/or consolidation. The latter results in overall response rates of 60% to 70% and provides a new backbone regimen on which to potentially add novel experimental agents. Similar approaches may soon provide therapeutic entry points into the treatment of other acute leukemias associated with pathognomonic chromosomal translocations and genetic and molecular aberrations. Hasford J, Pfirrmann M, Hehlmann R, et al: A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon 48 Disorders of Red Blood Cells Ellice Wong, Michal G. It has a biconcave disk shape that maximizes the membrane surface area for gas exchange, and it has a cytoskeleton and membrane structure that allow it to deform sufficiently to pass through the microvasculature. Passage through capillaries whose diameter may be one fourth the resting diameter of the erythrocyte is made possible by interactions between proteins in the membrane (band 3 and glycophorin) and underlying cytoplasmic proteins that make up the erythrocyte cytoskeleton (spectrin, ankyrin, and protein 4. The remainder is mainly enzymatic proteins, such as those required for anaerobic metabolism and the hexose monophosphate shunt. Defects in any of the intrinsic structural features of the erythrocyte can result in hemolytic anemia. Abnormalities of the membrane or cytoskeletal proteins are the causes of alterations in erythrocyte shape and flexibility. Inborn defects in the enzymatic pathways for glucose metabolism decrease the resistance to oxidant stress, and inherited abnormalities of hemoglobin structure and synthesis lead to polymerization of abnormal hemoglobin (sickle cell disease) or to the precipitation of unbalanced hemoglobin chains (thalassemia). Oxygen is transported by hemoglobin, a tetramer composed of two chains, two -like (, or) chains, and four heme molecules, each of which is composed of a protoporphyrin molecule complexed with iron. In fetal life, the main hemoglobin is fetal hemoglobin (HbF: 2, 2); the switch from HbF to adult hemoglobin (HbA: 22) occurs in the perinatal period. By 4 to 6 months of age, the level of HbF has fallen to about 1% of total hemoglobin. HbA2 (22) is a minor adult hemoglobin, representing about 1% of adult hemoglobin (Table 48. The investigation of anemia is a critical component of the evaluation of the patient and commonly provides valuable insight into systemic illness. The symptoms of anemia reflect both the severity and the rapidity with which the reduction in erythrocyte mass has occurred. Usual complaints are fatigue, decreased exercise tolerance, dyspnea, and palpitations. The number of reticulocytes in the peripheral blood therefore reflects the response of the bone marrow to anemia. It may be caused by decreased production of erythrocytes from nutritional deficiencies, primary hematologic disease, or a response to systemic illness. Alternatively, anemia may be caused by increased blood loss or cellular destruction from hemolysis. Hypersegmented neutrophils and large platelets support the diagnosis of megaloblastic anemia, and the presence of immature blast forms may be diagnostic of leukemia. In patients with anemia and an elevated reticulocyte count, the vigorous production of new erythroid cells suggests that marrow function is normal and is responding appropriately to the stress of the anemia. Bone marrow examination in this situation is rarely indicated because the marrow will simply show erythroid hyperplasia, usually without revealing any primary pathologic anomaly of the marrow. In contrast, bone marrow examination is more often required for the evaluation of hypoproliferative anemia. After common abnormalities such as iron deficiency and other nutritional deficiencies have been ruled out, marrow aspiration and biopsy are indicated to search for abnormalities such as marrow infiltration, marrow involvement with granulomatous disease, marrow aplasia, or myelodysplasia. Evaluation of the peripheral blood smear may provide important clues to the cause of anemia. Microcytosis and hypochromia are the hallmarks of anemias caused by defects in hemoglobin synthesis, which can reflect either failure of heme synthesis or abnormalities in globin production. The leading cause of microcytic anemia is iron deficiency, in which lack of heme synthesis results from the absence of iron to incorporate into the porphyrin ring (see later discussion). Lead poisoning blocks the incorporation of iron into heme, also resulting in a microcytic anemia.

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