Maya Petersen MD, PhD

https://publichealth.berkeley.edu/people/maya-petersen/

Usually an intermittent blood pressure chart for senior citizens amlodipine 5 mg purchase mastercard, chronic hypertension young age discount 5 mg amlodipine with visa, severely pruritic pulse pressure over 80 cheap 5 mg amlodipine with mastercard, eczematous dermatitis with scaly erythematous patches blood pressure chart record format discount amlodipine 2.5 mg on line, vesiculation hypertension benign essential 4011 purchase amlodipine uk, crusting, and fissuring. Lesions are most commonly on flexures, with prominent involvement of antecubital and popliteal fossae; generalized erythroderma in severe cases. Systemic glucocorticoids only for severe exacerbations unresponsive to topical conservative therapy. Topical calcineurin inhibitors have been used for severe disease but may carry toxicity. Lesions occur at site of contact and are vesicular, weeping, crusting; linear arrangement of vesicles is common. Most frequent allergens are resin from plants of the genus Toxicodendron (poison ivy, oak, sumac), nickel, rubber, and cosmetics. The most common area of involvement is the hands, where dermatitis is initiated or aggravated by chronic exposure to water and detergents. Lesions are generally on scalp, eyebrows, nasolabial folds, axillae, central chest, and posterior auricular area. The primary lesion is a superficial pustule that ruptures and forms a "honey-colored" crust. Most commonly due to infection with group A -hemolytic streptococci, occurring at sites of trauma or other breaks in skin. Infections frequently involve mucocutaneous surfaces around the oral cavity, genitals, or anus. Can also cause severe visceral disease including esophagitis, pneumonitis, encephalitis, and disseminated herpes simplex virus infection. Tzanck preparation of an unroofed early vesicle reveals multinucleated giant cells. Tzanck preparation reveals multinucleated giant cells; indistinguishable from herpes simplex except by culture. Postherpetic neuralgia, lasting months to years, may occur, especially in the elderly. Common sites of infection include the foot (tinea pedis), nails (tinea unguium), groin (tinea cruris), or scalp (tinea capitis). Haloprogin, undecylenic acid, ciclopirox olamine, and tolnaftate are also effective, but nystatin is not active against dermatophytes. Manifestations may be localized to the skin or rarely systemic and life-threatening. Frequent sites include the oral cavity, chronically wet macerated areas, around nails, intertriginous areas. For genital warts, application of podophyllin solution is effective but can be associated with marked local reactions; topical imiquimod also has been used. Comedones (small cysts formed in hair follicles) are clinical hallmark; often accompanied by inflammatory lesions of papules, pustules, or nodules; may scar in severe cases. Tendency toward exaggerated flushing, with eventual superimposition of papules, pustules, and telangiectasias; may lead to rhinophyma and ocular problems. Lesions are usually flush with skin surface but are indurated and have appearance of an erythematous/violaceous bruise. Three most common causes are drug reaction (particularly penicillins and sulfonamides) or concurrent herpetic or Mycoplasma infection. Can rarely affect mucosal surfaces and internal organs (erythema multiforme major or Stevens-Johnson syndrome). For Stevens-Johnson syndrome, systemic glucocorticoids have been used but are controversial; prevention of secondary infection and maintenance of nutrition and fluid/electrolyte balance are critical. Lesions range in size from papules to giant coalescent lesions (10­20 cm in diameter). Associations include infections, autoimmune diseases, primary systemic vasculitides, malignancy, hepatitis B and C, drugs (esp. Pursue identification and treatment/elimination of an exogenous cause or underlying disease. If part of a systemic vasculitis, treat based on major organ-threatening features (Chap. Immunosuppressive therapy should be avoided in idiopathic, predominantly cutaneous vasculitis as disease frequently does not respond and rarely causes irreversible organ system dysfunction. Acanthocytes (spur cells): irregularly spiculated; abetalipoproteinemia, severe liver disease, rarely anorexia nervosa. Schistocytes (schizocytes): fragmented cells of varying sizes and shapes; microangiopathic or macroangiopathic hemolytic anemia. Target cells: central and outer rim staining with intervening ring of pallor; liver disease, thalassemia, hemoglobin C, and sickle C diseases. Biopsy should precede aspiration to avoid aspiration artifact (mainly hemorrhage) in the specimen. Special Tests Histochemical staining (leukemias), cytogenetic studies (leukemias, lymphomas), microbiology (bacterial, mycobacterial, fungal cultures), Prussian blue (iron) stain (assessment of iron stores, diagnosis of sideroblastic anemias). Biopsy Performed in addition to aspiration for pancytopenia (aplastic anemia), metastatic tumor, granulomatous infection. When biopsy and aspirate are both planned, the biopsy should be performed first because of the risk of bleeding artifact from biopsy of an aspiration site. Cellularity decreases with age after age 65 years from about 50% to 25­30% with a corresponding increase in fat. Erythroid:Granulocytic (E:G) Ratio Normally about 1:2, the E:G ratio is decreased in acute and chronic infection, leukemoid reactions. Some centers use the term M:E (myeloid to erythroid) ratio; normal value is 2:1 and increases with diseases that promote myeloid activity or inhibit erythroid activity and decreases with diseases that inhibit myeloid activity or promote erythroid activity. Marrow damage, early iron deficiency, and decreased erythropoietin production or action may produce anemia of this type. Marrow damage may be caused by infiltration of the marrow with tumor or fibrosis that crowds out normal erythroid precursors or by the absence of erythroid precursors (aplastic anemia) as a consequence of exposure to drugs, radiation, chemicals, viruses. Pts with iron-deficiency anemia demonstrate all the same abnormalities plus hypochromic microcytic anemia. The tumor or fibrosis that infiltrates the marrow may originate in the marrow (as in leukemia or myelofibrosis) or be secondary to processes originating outside the marrow (as in metastatic cancer or myelophthisis). Decreased stimulation of erythropoiesis can be a consequence of inadequate erythropoietin production [e. In older people, erythropoietin levels normally increase to maintain normal hemoglobin levels. About 11% of community-dwelling adults over age 65 and up to 45% of nursing home residents have this aging-related anemia. Hepcidin, a small iron-binding molecule produced by the liver during an acute-phase inflammatory response, may bind iron and prevent its reutilization in hemoglobin synthesis. The laboratory tests shown in Table 62-1 may assist in the differential diagnosis of hypoproliferative anemias. Defects in hemoglobin synthesis usually result from insufficient iron supply (iron deficiency) or decreased globin production (thalassemia) or are idiopathic (sideroblastic anemia). Laboratory tests useful in the differential diagnosis of the microcytic anemias are shown in Table 62-2. Vitamin B12 status is best assessed by measuring serum B12, homocysteine, and methylmalonic acid levels. Homocysteine and methylmalonic acid levels are elevated in the setting of B12 deficiency. Acute bleeding is associated with manifestations of hypovolemia, reticulocytosis, macrocytosis; chronic bleeding is associated with iron deficiency, hypochromia, microcytosis. These include antimalarials (chloroquine), sulfonamides, analgesics (phenacetin), and other miscellaneous drugs (Table 62-4). Sickle cell anemia: characterized by a single-amino-acid change in globin (valine for glutamic acid in the 6th residue) that produces a molecule of decreased solubility, especially in the absence of O2. Two types: (a) warm antibody (usually IgG): idiopathic, lymphoma, chronic lymphocytic leukemia, systemic lupus erythematosus, drugs. Similarly, acquired causes correlate with extracorpuscular factors because mostly these factors are exogenous. Mechanical trauma (macro- and microangiopathic hemolytic anemias; schistocytes): prosthetic heart valves, vasculitis, malignant hypertension, eclampsia, renal graft rejection, giant hemangioma, scleroderma, thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome, disseminated intravascular coagulation, march hemoglobinuria. Anemia of chronic disease: treat underlying disease; in uremia use recombinant human erythropoietin, 50­150 U/kg three times a week; role of erythropoietin in other forms of anemia of chronic disease is less clear; response more likely if serum erythropoietin levels are low. Thalassemia: transfusion to maintain Hb >90 g/L (>9 g/dL), folic acid, prevention of Fe overload with deferoxamine (parenteral) or deferasirox (oral) chelation; consider splenectomy and allogeneic bone marrow transplantation. Aplastic anemia: antithymocyte globulin and cyclosporine leads to improvement in 70%, bone marrow transplantation in young pts with a matched donor. Autoimmune hemolysis: glucocorticoids, sometimes immunosuppressive agents, danazol, plasmapheresis, rituximab. The pathophysiology of neutrophilia involves increased production, increased marrow mobilization, or decreased margination (adherence to vessel walls). Causes (1) Infection-subacute bacterial endocarditis, tuberculosis, brucellosis, rickettsial diseases. Causes (1) Drugs, (2) parasitic infections, (3) allergic diseases, (4) collagen vascular diseases, (5) malignant neoplasms, (6) hypereosinophilic syndromes. The pathophysiology of neutropenia involves decreased production or increased peripheral destruction. Causes (1) Drugs-cancer chemotherapeutic agents are most common cause, also phenytoin, carbamazepine, indomethacin, chloramphenicol, penicillins, sulfonamides, cephalosporins, propylthiouracil, phenothiazines, captopril, methyldopa, procainamide, chlorpropamide, thiazides, cimetidine, allopurinol, colchicine, ethanol, penicillamine, and immunosuppressive agents; (2) infections-viral. Prolonged febrile neutropenia (>7 days) leads to increased risk of disseminated fungal infections; requires addition of antifungal chemotherapy. Causes (1) Acute stressful illness, (2) glucocorticoid therapy, (3) aplastic anemia, (4) leukemia (certain types. Platelet disorders characteristically produce petechial and purpuric skin lesions and bleeding from mucosal surfaces. Defective coagulation results in ecchymoses, hematomas, and mucosal and, in some disorders, recurrent joint bleeding (hemarthroses). Bleeding time, a measurement of platelet function, is abnormally increased if platelet count <100,000/L; injury or surgery may provoke excess bleeding. Spontaneous bleeding is unusual unless count <20,000/L; platelet count <10,000/L is often associated with serious hemorrhage. Bone marrow examination shows increased number of megakaryocytes in disorders associated with accelerated platelet destruction; decreased number in disorders of platelet production. Rebound thrombocytosis may occur after marrow recovery from cytotoxic agents, alcohol, vitamin B12 replenishment. Primary thrombocytosis may be complicated by bleeding and/or thrombosis; secondary rarely causes hemostatic problems. Disorders of Platelet Function Suggested by the finding of prolonged bleeding time with normal platelet count. Causes include (1) drugs- aspirin, other nonsteroidal anti-inflammatory drugs, dipyridamole, clopidogrel or prasugrel, heparin, penicillins, esp. Dialysis and/or cryoprecipitate infusions (10 bags/24 h) may be helpful for platelet dysfunction associated with uremia. Major complication of unfractionated heparin therapy is hemorrhage-manage by discontinuing heparin; for severe bleeding, administer protamine (1 mg/100 U heparin); results in rapid neutralization. Complications include hemorrhage, warfarin-induced skin necrosis (rare, occurs in persons deficient in protein C), teratogenic effects. Potentiating agents include chlorpromazine, chloral hydrate, sulfonamides, chloramphenicol, other broad-spectrum antibiotics, allopurinol, cimetidine, tricyclic antidepressants, disulfiram, laxatives, high-dose salicylates, thyroxine, clofibrate. Some pts who are sensitive to warfarin effects have genetic defects metabolizing the drug. Antagonizing agents include vitamin K, barbiturates, rifampin, cholestyramine, oral contraceptives, thiazides. In-hospital anticoagulation is usually initiated with heparin for 4­10 days, with subsequent maintenance on warfarin after an overlap of 3 days. The new oral Xa and thrombin inhibitors are easier to use than warfarin but much more expensive. They are at least comparably effective, have lower bleeding rates, and do not require laboratory monitoring. Fibrinolytic therapy is usually followed by a period of anticoagulant therapy with heparin. Fibrinolytic agents are contraindicated in pts with (1) active internal bleeding; (2) recent (<2­3 months) cerebrovascular accident; (3) intracranial neoplasm, aneurysm, or recent head trauma. Antiplatelet agents are useful in preventing strokes, complications from percutaneous coronary interventions, and progression of unstable angina. Signs and symptoms occur because of the absence of mature cells normally produced by the bone marrow, including granulocytes (susceptibility to infection) and platelets (susceptibility to bleeding). In addition, if large numbers of immature malignant myeloblasts circulate, they may invade organs and rarely produce dysfunction. As we age, mutations may occur in normal stem cells that convey a proliferative advantage and establish so-called clonal hematopoiesis. In the setting of clonal hematopoiesis, the relative risk for developing acute leukemia increases but the absolute risk is still very small. Chromosome 5 or 7 deletions are seen in leukemias following radiation plus chemotherapy. Signs of anemia, pallor, fatigue, weakness, palpitations, and dyspnea on exertion are most common. Thrombocytopenia leads to spontaneous bleeding, epistaxis, petechiae, conjunctival hemorrhage, gingival bleeding, and bruising, especially with platelet count <20,000/L. Bacterial and fungal infection are common; risk is heightened with total neutrophil count <5000/L, and breakdown of mucosal and cutaneous barriers aggravates susceptibility; infections may be clinically occult in presence of severe leukopenia, and prompt recognition requires a high degree of clinical suspicion. Hepatosplenomegaly occurs in about one-third of pts; leukemic meningitis may present with headache, nausea, seizures, papilledema, cranial nerve palsies. With very high blast cell count in the blood, spurious hyperkalemia and hypoglycemia may occur (potassium released from and glucose consumed by tumor cells after the blood was drawn).

The most common congenital infection is caused by (A) Varicella-zoster virus (B) Herpes simplex virus type 2 (C) Human herpesvirus 8 (Kaposi sarcoma herpesvirus) (D) Cytomegalovirus (E) Parvovirus 14 hypertension from stress amlodipine 2.5 mg on-line. Each of the following statements concerning herpesvirus latency is correct except (A) Exogenous stimuli can cause reactivation of latent infection blood pressure chart daily cheap amlodipine 5 mg buy online, with induction of symptomatic disease blood pressure vs blood sugar buy cheap amlodipine 2.5 mg online. Vaccines have been demonstrated to be efficacious in preventing herpesvirus disease in which one of the following situations A Tzanck smear of a scraping obtained from a vesicle on the skin demonstrates multinucleated giant cells heart attack test purchase amlodipine 2.5 mg otc. Which of the following viruses causes a mononucleosis-like syndrome and is excreted in the urine Which of the following tests would be most appropriate to confirm a diagnosis of herpes simplex encephalitis in this patient An outbreak of a rash called "mat herpes" occurred among high school students who had competed in a wrestling tournament arrhythmia monitoring device amlodipine 5 mg line. Each of the following statements concerning Epstein-Barr virus is correct except (A) Many infections are mild or inapparent. Hassan J, Connell J: Translational mini-review series on infectious disease: Congenital cytomegalovirus infection: 50 years on. The family encompasses a large group of agents that are similar morphologically and share a common nucleoprotein antigen. Infections with most poxviruses are characterized by a rash, although lesions induced by some members of the family are markedly proliferative. The group includes variola virus, the etiologic agent of smallpox-the viral disease that has affected humans throughout recorded history. Even though smallpox was declared eradicated from the world (in 1980) after an intensive campaign coordinated by the World Health Organization, there is concern that the virus could be reintroduced as a biologic weapon. There is a continuing need to be familiar with vaccinia virus (used for smallpox vaccinations) and its possible complications in humans. It is also necessary to be aware of other poxvirus diseases that may resemble smallpox and must be differentiated from it by laboratory means. Lastly, vaccinia virus is under intensive study as a vector for introducing active immunizing genes as live-virus vaccines for a variety of viral diseases of humans and domestic animals. Classification Poxviruses are divided into two subfamilies based on whether they infect vertebrate or insect hosts. The vertebrate poxviruses fall into nine genera, with the members of a given genus displaying similar morphology and host range as well as some antigenic relatedness. Most of the poxviruses that can cause disease in humans are contained in the genera Orthopoxvirus and Parapoxvirus; there are also several that are classified in the genera Yatapoxvirus and Molluscipoxvirus (Table 34-2). They include ectromelia (mousepox), camelpox, cowpox, monkeypox, vaccinia, and variola (smallpox) viruses. Vaccinia virus differs only in minor morphologic respects from variola and cowpox viruses. Monkeypox can infect rodents, monkeys, and humans and may resemble smallpox clinically. Some poxviruses have a restricted host range and infect only rabbits (fibroma and myxoma) or only birds. Their genomes are smaller (~135 kbp) and have a higher guanine plus cytosine content (63%) than those of the orthopoxviruses (170­250 kbp; G + C, 30­40%). Structure and Composition Poxviruses are large enough to be seen as featureless particles by light microscopy. By electron microscopy, they appear to be brick-shaped or ellipsoid particles measuring about (300­400) × 230 nm. Their structure is complex and conforms to neither icosahedral nor helical symmetry. The complete genomic sequence is known for several poxviruses, including vaccinia and variola. Poxviruses are further distinguished from all other animal viruses by the fact that the uncoating step requires a newly synthesized, virus-encoded protein. Virus Attachment, Penetration, and Uncoating Virus particles establish contact with the cell surface and fuse with the cell membrane. Because the necessary enzymes are contained within the viral core, early transcription is not affected by inhibitors of protein synthesis. The "uncoating" protein that acts on the cores is among the more than 50 polypeptides made early after infection. This process is called nongenetic reactivation and is caused by the action of the uncoating protein. Apparently, the heat-killed virus provides the template and the second virus provides the enzymes needed for transcription. Consequently, immunization with vaccinia virus affords no protection against disease induced by other genera of poxviruses. A: Negatively stained particle showing ridges or tubular elements covering the surface (228,000×). It occurs 2­6 hours after infection in discrete areas of the cytoplasm, which appear as "factories" or inclusion bodies in electron micrographs. The number of inclusion bodies per cell is proportionate to the multiplicity of infection, suggesting that each infectious particle can induce a "factory. There is a small intermediate class of genes whose expression temporally precedes the expression of the late class of genes. Maturation the assembly of the virus particle from the manufactured components is a complex process. Some of the particles are released from the cell by budding, but the majority of poxvirus particles remain within the host cell. How the multiple components of the transcription system are incorporated within the core of the assembling virus particle is unknown. Virus-Encoded Host Modifier Genes A polypeptide encoded by one of the early genes of vaccinia virus is closely related to epidermal growth factor and to transforming growth factor-. Production of growth factors similar to epidermal growth factor by virus-infected cells could account for the proliferative diseases associated with members of the poxvirus family such as Shope fibroma (rabbits), Yaba tumor (monkeys), and molluscum contagiosum viruses (humans). Examples include tumor necrosis factor receptor, interferon- receptor, interleukin-1 receptor, and a complement-binding protein. These poxvirus-encoded host defense modifiers presumably counter the complement and cytokine networks important in the host immune response to viral infection, allowing enhanced virus replication and, perhaps, facilitating virus transmission. The last Asian case occurred in Bangladesh in 1975, and the last natural victim was diagnosed in Somalia in 1977. There were several reasons for this outstanding success: There is a single serotype of virus; most infections are clinically apparent; the vaccine was easily prepared, stable, and safe; the vaccine could be given simply by personnel in the field; and mass vaccination of the world population was not necessary. Cases of smallpox were traced, and contacts of the patient and those in the immediate area were vaccinated. Even though there has been no evidence of smallpox transmission anywhere in the world, the World Health Organization coordinated the investigation of 173 possible cases of smallpox between 1979 and 1984. All were diseases other than smallpox, most commonly chickenpox or other illnesses that produce a rash. Even so, a potential case of smallpox becomes a public health emergency and must be promptly investigated by means of clinical evaluation, collection of laboratory specimens for diagnosis, and contact isolation. The presence of stocks of virulent smallpox virus in laboratories is of concern because of the danger of laboratory infection and subsequent spread into the community. Variola virus stocks supposedly were destroyed in all laboratories except two World Health Organization collaborating centers (one in Atlanta and one in Moscow) that pursue diagnostic and research work on variola-related poxviruses. This process, called variolation, was dangerous but decreased the disastrous effects of major epidemics, reducing the case-fatality rate from 25% to 1%. In 1967, the World Health Organization introduced a worldwide campaign to eradicate smallpox. Epidemiologic features of the disease (described later) made it feasible to attempt total eradication. At that time, there were 33 countries with endemic smallpox and 10­15 million cases per year. Smallpox virus is considered to be a dangerous potential biothreat agent, and it is theoretically possible that virus frozen in permafrost could reinfect the human population. Research scientists may obtain portions of the variola virus genome from the collaborating centers but not a complete genome. Restriction endonuclease maps of the genome of vaccinia virus are distinctly different from those of cowpox virus, which was believed to be its ancestor. Variola has a narrow host range (only humans and monkeys), but vaccinia has a broad host range that includes rabbits and mice. Some strains of vaccinia can cause a severe disease in laboratory rabbits that has been called rabbitpox. Vaccinia virus has also infected cattle and water buffalo, and the disease in buffalo has persisted in India (buffalopox). Both vaccinia and variola viruses grow on the chorioallantoic membrane of the 10- to 12-day-old chick embryo, but the latter produce much smaller pocks. The nucleotide sequences of variola (186 kb) and vaccinia (192 kb) are similar, with the most divergence in terminal regions of the genomes. Of 187 putative proteins, 150 were markedly similar in sequence between the two viruses; the remaining 37 diverged or were variola-specific and may represent potential virulence determinants. The sequences do not reveal variola virus origins or explain its strict human host range or its particular virulence. By the sixth to ninth day, lesions in the mouth tended to ulcerate and discharge virus. Thus, early in the disease, infectious virus originated in lesions in the mouth and upper respiratory tract. Later, pustules broke down and discharged virus into the environment of the smallpox patient. Histopathologic examination of the skin showed proliferation and cytoplasmic inclusions of the stratum spinosum. There was infiltration with mononuclear cells, particularly around dermal vessels. Epidermal cells became swollen through distention of cytoplasm and underwent "ballooning degeneration," with enlargement of cytoplasmic vacuoles. The cell membrane broke down and coalesced with neighboring, similarly affected cells, resulting in the formation of vesicles. Similar histopathology is seen with vaccinia, although vaccinia virus ordinarily causes localized pustular lesions only at the site of inoculation. One to 5 days of fever and malaise preceded the appearance of the exanthems, which began as macules, then papules, then vesicles, and finally pustules. These formed crusts that fell off after about 2 weeks, leaving pink scars that faded slowly. In each affected area, the lesions were generally found in the same stage of development (in contrast to chickenpox). In the less common and more benign variola minor strain (also eradicated), or in vaccinated persons, the mortality rate was under 1%. Immunity All viruses within the Orthopoxvirus genus are so closely related antigenically that they cannot be easily differentiated serologically. Infection with one induces an immune response that reacts with all other members of the group. Vaccination with vaccinia induced immunity against variola virus for at least 5 years and sometimes longer. In the human host, neutralizing antibodies develop within a few days after the onset of smallpox but do not prevent progression of lesions, and patients may die in the pustular stage with high antibody levels. Cell-mediated Pathogenesis and Pathology of Smallpox Although smallpox has been eradicated, the pathogenesis of the disease (described here in the past tense) is instructive for other poxvirus infections. The portal of entry of variola virus was the mucous membranes of the upper respiratory tract. A "Smallpox Recognition Card" from the World Health Organization illustrates the distribution and nature of the typical rash of smallpox in an unvaccinated child. Patients with hypogammaglobulinemia generally react normally to vaccination and develop immunity despite the apparent absence of antibody. Patients who have defects in both cellular immune response and antibody response develop a progressive, usually fatal disease upon vaccination. Irradiated animals without detectable antibody or delayed hypersensitivity recovered from vaccinia infection as rapidly as untreated control animals. Orthopoxviruses cannot be distinguished from one another by electron microscopy because they are similar in size and morphology. Viral antigen can be detected by immunohistochemistry in tissues and in material collected from skin lesions. Cell cultures can be used for virus isolation, though culture of variola virus is only attempted in Biosafety Level 4 facilities. The orthopoxviruses grow well in cultured cells; parapoxviruses and tanapoxvirus grow less well, and molluscum contagiosum virus cannot be cultured. Virus isolation can also be carried out by inoculation of vesicular fluid onto the chorioallantoic membrane of chick embryos. This test can distinguish cases of smallpox from generalized vaccinia because the lesions produced by these viruses on the membrane differ markedly. In 2­3 days, vaccinia pocks are large with necrotic centers; Laboratory Diagnosis Several tests are available to confirm the diagnosis of smallpox. Now that the disease is presumably eradicated, it is important to diagnose any cases that resemble smallpox. Isolation and Identification of Virus Skin lesions are the specimen of choice for viral detection and isolation. Poxviruses are stable and remain viable in specimens for weeks even without refrigeration. The parapoxviruses, molluscum contagiosum virus, and tanapoxvirus do not grow on the membrane. World Health Organization standards require that smallpox vaccines have a potency of no fewer than 108 pockforming units per milliliter.

Incidence and Etiology About 3000 cases occur each year heart attack piano amlodipine 2.5 mg purchase without prescription, mainly in persons >50 years old (median age arteria technologies cheap amlodipine 5 mg without prescription, 68) arteria gallery 2.5 mg amlodipine purchase amex. Chromosome abnormalities occur in up to 80% of cases hypertension 5 year old amlodipine 2.5 mg buy on-line, including deletion of part or all of chromosomes 5 blood pressure bulb replacement 5 mg amlodipine buy otc, 7, and 9 (20 or 21 less commonly) and addition of part or all of chromosome 8. Clinical and Laboratory Features Symptoms depend on the affected lineages, 85% of pts are anemic, 50% have neutropenia, and about one-third have thrombocytopenia. Lenalidomide (10 mg/d), a thalidomide analogue with fewer central nervous system effects, causes a substantial fraction of pts with the 5q­ syndrome to become transfusion-independent. Pts with low erythropoietin levels may respond to erythropoietin, and a minority of pts with neutropenia respond to granulocyte colony-stimulating factor. The mutation is seen in 90% of pts with polycythemia vera and ~45% of pts with idiopathic myelofibrosis and essential thrombocytosis. Polycythemia vera is associated with very low erythropoietin levels; in other causes of erythrocytosis, erythropoietin levels are high. However, many entities may lead to marrow fibrosis and extramedullary hematopoiesis, and the diagnosis of primary idiopathic myelofibrosis is made only when the many other potential causes are ruled out. Like myelofibrosis, many conditions can produce elevated platelet counts; thus, the diagnosis is one of exclusion. Although usually asymptomatic, pts should be treated if they develop migraine headache, transient ischemic attack, or other bleeding or thrombotic disease manifestations. Treatment should not be given just because the absolute platelet count is high in the absence of other symptoms. When bone marrow and peripheral blood involvement dominate the clinical picture, the disease is classified as a lymphoid leukemia. When lymph nodes and/or other extranodal sites of disease are the dominant site(s) of involvement, the tumor is called a lymphoma. Although the new system bases the definitions of disease entities on histology, genetic abnormalities, immunophenotype, and clinical features, its organization is based on cell of origin (B cell vs. Table 66-1 lists the disease entities according to a more clinically useful schema based on the clinical manifestations and natural history of the diseases. The malignant cells are monoclonal and often contain numerous genetic abnormalities. In most cases, translocations involve insertion of a distant chromosome segment into the antigen receptor genes (either immunoglobulin or T cell receptor) during the rearrangement of the gene segments that form the receptors. Both the virus and the disease are endemic to southwestern Japan and the Caribbean. Inherited or acquired immunodeficiencies and autoimmune disorders predispose individuals to lymphoma. Needle aspirates of nodal or extranodal masses are not adequate diagnostic procedures. Leukemia diagnosis and lymphoma staging include generous bilateral iliac crest bone marrow biopsies. In acute leukemia, peripheral blood blast counts are most significant in assessing prognosis. In follicular lymphoma, the last two factors are Hb <120 g/L (<12 g/dL) and more than four nodal sites of involvement. In aggressive lymphoma, more than one extranodal site and performance status predict outcome. In myeloma, serum levels of paraprotein, creatinine, and 2-microglobulin levels predict survival. Prognosis is related to stage; stage is determined mainly by the degree to which the tumor cells crowd out normal hematopoietic elements from the marrow (Table 66-2). Nodal involvement may be related to the expression of an adhesion molecule that allows the cells to remain in the node rather than recirculate. Up to 20% have autoimmune antibodies that may produce autoimmune hemolytic anemia, thrombocytopenia, or red cell aplasia. At that time, tests are indicated to assess the cause of the anemia or thrombocytopenia. Rituximab (375­500 mg/m2 day 1), fludarabine (25 mg/m2 days 2­4 on cycle 1 and 1­3 in subsequent cycles), plus cyclophosphamide (250 mg/m2 with fludarabine) induce complete responses in nearly 70% of pts but the regimen is associated with significant myelotoxicity. Glucocorticoids increase the risk of infection without adding a substantial antitumor benefit. Young pts may be candidates for high-dose therapy and autologous or allogeneic hematopoietic cell transplantation; long-term disease-free survival has been noted. Minitransplant, in which the preparative regimen is immunosuppressive but not myeloablative, may be less toxic and as active or more active in disease treatment than high-dose therapy. Follicular lymphoma is the most common indolent lymphoma, accounting for about one-third of all lymphoid malignancies. The tumor has a follicular or nodular growth pattern reflecting the follicular center origin of the malignant cell. The t(14;18) is present in 85% of cases, resulting in the overexpression of bcl-2, a protein involved in prevention of programmed cell death. The normal follicular center B cell is undergoing active mutation of the immunoglobulin variable regions in an effort to generate antibody of higher affinity for the selecting antigen. Follicular lymphoma cells also have a high rate of mutation that leads to the accumulation of genetic damage. The majority of pts dying from follicular lymphoma have undergone histologic transformation. This transformation occurs at a rate of about 7% per year and is an attribute of the disease, not the treatment. Although many forms of treatment induce tumor regression in advanced-stage pts, disease cure has been elusive. More than 90% of pts are responsive to treatment; complete responses are seen in about 50­75% of pts treated aggressively. Younger pts are being treated experimentally with high-dose therapy and autologous hematopoietic stem cells or minitransplant. Remissions appear to last longer with chemotherapy plus rituximab; some data suggest that the longer remissions are leading to improved survival. Diffuse large B-cell lymphoma is the most common histologic diagnosis among the aggressive lymphomas, accounting for 35­45% of all lymphomas. About 85% of aggressive lymphomas are of mature B-cell origin; 15% are derived from peripheral (postthymic) T cells. The use of a sequential high-dose chemotherapy regimen in pts with high-intermediate and high-risk disease has yielded long-term survival in about 75% of pts in some institutions. About 30­45% of pts not cured with initial standard combination chemotherapy may be salvaged with high-dose therapy and autologous hematopoietic stem cell transplantation. Lymphomas occurring in iatrogenically immunosuppressed pts may regress when immunosuppressive medication is withheld. Lymphomas occurring post­allogeneic marrow transplant may regress with infusions of donor leukocytes. Pts with rapidly growing bulky aggressive lymphoma may experience tumor lysis syndrome when treated (Chap. The majority of cases have tumor cells that appear to be of thymic origin, and pts may have mediastinal masses. Prognosis is adversely affected by high presenting white count, age >35 years, and the presence of t(9;22), t(1;19), and t(4;11) translocations. Vincristine, l-asparaginase, cytarabine, daunorubicin, and prednisone are particularly effective agents. The role and timing of bone marrow transplantation in primary therapy are debated, but up to 30% of relapsed pts may be cured with salvage transplantation. It is associated with translocations involving the c-myc gene on chromosome 8 rearranging with immunoglobulin heavy or light chain genes. Pts often have disseminated disease with large abdominal masses, hepatomegaly, and adenopathy. Aggressive leukemia regimens that include vincristine, cyclophosphamide, 6-mercaptopurine, doxorubicin, and prednisone are active. Hypercalcemia occurs in nearly all pts and is related to cytokines produced by the tumor cells. The intact immunoglobulin molecule, or the heavy chain or light chain produced by the abnormal plasma cell clone, is detectable in the serum and/or urine and is called the M (for monoclonal) component. The amount of the M component in any given pt reflects the tumor burden in that pt. In some, the presence of a clonal light chain in the urine (Bence Jones protein) is the only tumor product that is detectable. M components may be seen in pts with other lymphoid tumors, nonlymphoid cancers, and noncancerous conditions such as cirrhosis, sarcoidosis, parasitic infestations, and autoimmune diseases. Disease manifestations result from tumor expansion, local and remote actions of tumor products, and the host response to the tumor. About 70% of pts have bone pain, usually involving the back and ribs, precipitated by movement. Bone lesions are multiple, lytic, and rarely accompanied by an osteoblastic response. The production of osteoclast-activating cytokines by tumor cells leads to substantial calcium mobilization, hypercalcemia, and symptoms related to it. Decreased synthesis and increased catabolism of normal immunoglobulins lead to hypogammaglobulinemia, and a poorly defined tumor product inhibits granulocyte migration. These changes create a susceptibility to bacterial infections, especially the pneumococcus, Klebsiella pneumoniae, and Staphylococcus aureus affecting the lung and Escherichia coli and other gram-negative pathogens affecting the urinary tract. Neurologic symptoms may result from hyperviscosity, cryoglobulins, and rarely amyloid deposition in nerves. Anemia occurs in 80% related to myelophthisis and inhibition of erythropoiesis by tumor products. Diagnosis Marrow plasmacytosis >10%, lytic bone lesions, and a serum and/or urine M component are the classic triad. Pts with solitary plasmacytoma and extramedullary plasmacytoma are usually cured with localized radiation therapy. Supportive care includes early treatment of infections; control of hypercalcemia with glucocorticoids, hydration, and natriuresis; chronic administration of bisphosphonates to antagonize skeletal destruction; and prophylaxis against urate nephropathy and dehydration. Initial therapy is usually one of several approaches, based on whether the pt is a candidate for high-dose therapy and autologous stem cell transplant. Transplant ineligible: melphalan, 8 mg/m2 orally for 4­7 days every 4­6 weeks, plus prednisone. About 60% of pts have significant symptomatic improvement plus a 75% decline in the M component. Experimental approaches using sequential high-dose pulses of melphalan plus two successive autologous stem cell transplants have produced complete responses in about 50% of pts <65 years. Palliatively treated pts generally follow a chronic course for 2­5 years, followed by an acceleration characterized by organ infiltration with myeloma cells and marrow failure. Most tumors are derived from B cells in that immunoglobulin genes are rearranged but not expressed. Most of the cells in an enlarged node are normal lymphoid, plasma cells, monocytes, and eosinophils. The etiology is unknown, but the incidence in both identical twins is 99-fold increased over the expected concordance, suggesting a genetic susceptibility. Distribution of histologic subtypes is 75% nodular sclerosis, 20% mixed cellularity, with lymphocyte predominant and lymphocyte depleted representing about 5%. Superior vena cava obstruction or spinal cord compression may be presenting manifestation. Differential Diagnosis · Infection: mononucleosis, viral syndromes, Toxoplasma, Histoplasma, primary tuberculosis · Other malignancies: especially head and neck cancers · Sarcoidosis: mediastinal and hilar adenopathy Immunologic and Hematologic Abnormalities · Defects in cell-mediated immunity (remains even after successful treatment of lymphoma), cutaneous anergy, diminished antibody production to capsular antigens of Haemophilus and pneumococcus · Anemia; elevated erythrocyte sedimentation rate, leukemoid reaction, eosinophilia, lymphocytopenia, fibrosis and granulomas in marrow Staging the Ann Arbor staging classification is shown in Table 66-5. Staging laparotomy should be used, especially to evaluate the spleen, if pt has early-stage disease on clinical grounds and radiation therapy is being contemplated. Therapy should be performed by experienced clinicians in centers with appropriate facilities. Most pts are clinically staged and treated with chemotherapy alone or combined-modality therapy. About one-half of pts (or more) not cured by their initial chemotherapy regimen may be rescued by high-dose therapy and autologous stem cell transplant. It may be possible to avoid radiation exposure by using combination chemotherapy alone in early-stage disease as well as in advancedstage disease. Melanoma has been diagnosed in 73,870 people in the United States in 2015 and caused 9940 deaths. Superficial spreading melanoma: Most common; begins with initial radial growth phase before invasion. Acral lentiginous: Most common form in darkly pigmented pts; occurs on palms and soles, mucosal surfaces, in nail beds and mucocutaneous junctions; similar to lentigo maligna melanoma but with more aggressive biologic behavior. These mutations have been targeted by therapeutic agents that have antitumor activity. Clinical Appearance Generally pigmented (rarely amelanotic); color of lesions varies, but red, white, and/ or blue are common, in addition to brown and/or black. Suspicion should be raised by a pigmented skin lesion that is >6 mm in diameter, asymmetric, has an irregular surface or border, or has variation in color. Prognosis Best with thin lesions without evidence of metastatic spread; with increasing thickness or evidence of spread, prognosis worsens. Elective lymph node dissection offers no advantage in overall survival compared with deferral of surgery until clinical recurrence. Types Five general types: noduloulcerative (most common), superficial (mimics eczema), pigmented (may be mistaken for melanoma), morpheaform (plaquelike lesion with telangiectasia-with keratotic is most aggressive), keratotic (basosquamous carcinoma).

For a more detailed discussion blood pressure chart during exercise amlodipine 2.5 mg overnight delivery, see Gucalp R pulse pressure variation normal values purchase amlodipine uk, Dutcher J: Oncologic Emergencies blood pressure medication metoprolol side effects purchase cheap amlodipine line, Chap blood pressure low diastolic discount 10 mg amlodipine with mastercard. Carbon monoxide and cyanide poisoning are termed histotoxic hypoxemia because they cause a direct impairment of the respiratory chain arrhythmia getting worse buy amlodipine 10 mg cheap. However, with hypoxia-ischemia, such as occurs with circulatory arrest, consciousness is lost within seconds. If circulation is restored within 3­5 min, full recovery may occur, but with longer periods permanent cerebral damage usually results. It may be difficult to judge the precise degree of hypoxia-ischemia, and some pts make a relatively full recovery even after 8­10 min of global ischemia. The distinction between pure hypoxemia and hypoxia-ischemia is important, because a PaO2 as low as 2. Clinical examination at different time points after an insult (especially cardiac arrest) helps to assess prognosis. Absence of these reflexes and the presence of persistently dilated pupils that do not react to light are grave prognostic signs. A low likelihood of a favorable outcome is suggested by the absence of a pupillary light reflex or an extensor or absent motor response to pain on day 3 following the injury. Administration of mild hypothermia after cardiac arrest may change the time points when these clinical and electrophysiologic predictors become reliable in identifying patients with a very low likelihood of clinically meaningful recovery. Long-term consequences include persistent coma or vegetative state, dementia, visual agnosia, parkinsonism, choreoathetosis, ataxia, myoclonus, seizures, and an amnestic state. Delayed postanoxic encephalopathy is an uncommon phenomenon in which pts appear to make an initial recovery following an insult and then have a relapse with a progressive course often characterized by widespread demyelination on imaging studies. This includes securing a clear airway, ensuring adequate oxygenation and ventilation, and restoring cerebral perfusion, whether by cardiopulmonary resuscitation, fluids, pressors, or cardiac pacing. The duration of seizure activity to meet the definition has traditionally been 15­30 min. Irreversible neuronal injury may occur from persistent seizures, even when a pt is paralyzed from neuromuscular blockade. Both disorders are associated with absolute or relative insulin deficiency, volume depletion, and altered mental status. Laboratory evaluation reveals hyperglycemia, ketosis (-hydroxybutyrate > acetoacetate), and metabolic acidosis (arterial pH 6. Despite a total-body potassium deficit, the serum potassium at presentation may be normal or mildly high as a result of acidosis. Similarly, phosphate may be normal at presentation despite total-body phosphate depletion. Hyperamylasemia is usually of salivary origin but may suggest a diagnosis of pancreatitis. The measured serum sodium is reduced as a consequence of osmotic fluid shifts due to hyperglycemia (1. Hyperglycemia induces an osmotic diuresis that leads to profound intravascular volume depletion. Although plasma levels may be normal or high at presentation, total-body stores are usually depleted. The prototypical pt is an elderly individual with a several week history of polyuria, weight loss, and diminished oral intake. Although the measured serum sodium may be normal or slightly low, the corrected serum sodium is usually increased (add 1. The calculated free water deficit (usually 9­10 L) should be reversed over the next 1­2 days, using 0. Overly rapid fluid replacement should be avoided to prevent worsening of neurologic status. Admit to hospital; intensive-care setting may be necessary for frequent monitoring or if pH <7. Assess pt: What precipitated the episode (noncompliance, infection, trauma, infarction, cocaine) Measure capillary glucose every 1­2 h; measure electrolytes (especially K+, bicarbonate, phosphate) and anion gap every 4 h for first 24 h. Monitor blood pressure, pulse, respirations, mental status, fluid intake and output every 1­4 h. Continue above until pt is stable, glucose goal is 150­250 mg/dL, and acidosis is resolved. The insulin infusion should be continued until the pt has resumed eating and can be transitioned to a subcutaneous insulin regimen. Hypoglycemia should be considered in any pt with confusion, altered level of consciousness, or seizures. Counterregulatory responses to hypoglycemia include insulin suppression and the release of catecholamines, glucagon, growth hormone, and cortisol. The laboratory diagnosis of hypoglycemia is usually defined as a plasma glucose level <2. Drugs: insulin, insulin secretagogues (especially chlorpropamide, repaglinide, nateglinide), alcohol, high doses of salicylates, sulfonamides, pentamidine, quinine, quinolones 2. Critical illness: hepatic, renal, or cardiac failure; sepsis; prolonged starvation 3. Hormone deficiencies: adrenal insufficiency, hypopituitarism (particularly in young children) 4. Insulinoma (pancreatic cell tumor), cell hyperplasia (nesidioblastosis; congenital or after gastric or bariatric surgery) 5. Signs of autonomic discharge, such as tachycardia, elevated systolic blood pressure, pallor, and diaphoresis, are typically present in a pt with hypoglycemia awareness but may be absent in a pt with pure neuroglycopenia. Recurrent hypoglycemia shifts thresholds for the autonomic symptoms and counterregulatory responses to lower glucose levels, leading to hypoglycemic unawareness. Under these circumstances, the first manifestation of hypoglycemia is neuroglycopenia, placing pts at risk of being unable to treat themselves. Nevertheless, blood should be drawn at the time of symptoms, whenever possible before the administration of glucose, to allow documentation of hypoglycemia as the cause of symptoms. These should include insulin, proinsulin, C-peptide, sulfonylurea levels, cortisol, and ethanol. In the absence of documented spontaneous hypoglycemia, overnight fasting or food deprivation during observation in the outpatient setting will sometimes elicit hypoglycemia and allow diagnostic evaluation. An extended (up to 72 h) fast under careful supervision in the hospital may be required-the test should be terminated if plasma glucose drops below 2. This involves a shift of glycemic thresholds for sympathetic autonomic symptoms back to higher glucose concentrations. Acute therapy of hypoglycemia requires administration of oral glucose or, if unavailable, rapidly absorbable sugar. Hypoglycemia from sulfonylureas is often prolonged, requiring treatment and monitoring for 24 h or more. Prevention of recurrent hypoglycemia requires treatment of the underlying cause of hypoglycemia, including discontinuation or dose reduction of offending drugs, treatment of critical illnesses, replacement of hormonal deficiencies, and surgery of insulinomas or other tumors. Diazoxide or octreotide therapy can be used to control hypoglycemia in inoperable metastatic insulinoma or nesidioblastosis. Treatment of other forms of hypoglycemia is dietary, with avoidance of fasting and ingestion of frequent small meals. About 85% of cases are due to lung cancer; lymphoma and thrombosis of central venous catheters are also causes. Dilated neck veins and increased collateral veins on anterior chest wall are noted on physical examination. Clotted central catheters producing this syndrome should be removed and anticoagulation therapy initiated. Most commonly seen in pts with lung or breast cancers, leukemias, or lymphomas, pericardial tamponade may also develop as a late complication of mediastinal radiation therapy (constrictive pericarditis). Pleural effusion, sinus tachycardia, jugular venous distention, hepatomegaly, and cyanosis are frequent physical findings. Paradoxical pulse, decreased heart sounds, pulsus alternans, and friction rub are less common with malignant than nonmalignant pericardial disease. Echocardiography is diagnostic; pericardiocentesis may show serous or bloody exudate, and cytology usually shows malignant cells. On physical examination, pts have a loss of sensation below a horizontal line on the trunk, called a sensory level, which usually corresponds to one or two vertebrae below the site of compression. Weakness and spasticity of the legs and hyperactive reflexes with upgoing toes on Babinski testing are often noted. Spine radiographs may reveal erosion of the pedicles (winking owl sign), lytic or sclerotic vertebral body lesions, and vertebral collapse. Collapse alone is not a reliable indicator of tumor; it is a common manifestation of a more common disease, osteoporosis. Surgery results in better recovery rates but may be extensive (vertebral body resection with spine stabilization). Pts usually present with nonspecific symptoms: fatigue, anorexia, constipation, weakness. When serum sodium falls to <115 meq/L, pts may experience anorexia, depression, lethargy, irritability, confusion, weakness, and personality changes. If the pt has mental status changes with sodium levels <115 meq/L, normal saline infusion plus furosemide to increase free water clearance may provide more rapid improvement. In addition, the immunologic checkpoint inhibiting antibodies, ipilimumab, nivolumab, and pembrolizumab can produce an autoimmune hypophysitis that leads to adrenal insufficiency. Symptoms such as nausea, vomiting, anorexia, and orthostatic hypotension may be attributed to progressive cancer or to treatment side effects. In nonemergent but stressful circumstances, 100­200 mg/d oral hydrocortisone is the beginning dose, tapered to maintenance of 15­37. Toxicity may be either related to the agents used to treat the cancer or from the response of the cancer to the treatment. Fever and neutropenia and tumor lysis syndrome will be discussed here; others are discussed in Chap. When peripheral blood granulocyte counts are <1000/L, the risk of infection is substantially increased (48 infections/100 pts). Any fluid collections should be tapped, and urine and/or fluids should be examined under the microscope for evidence of infection. If an obvious infectious site is found, the antibiotic regimen is designed to cover organisms that may cause the infection. Usually therapy should be started with an agent or agents that cover both gram-positive and -negative organisms. Persistence of febrile neutropenia after 7 days should lead to addition of amphotericin B (or another broad-spectrum antifungal agent like posaconazole) to the antibiotic regimen. The increased uric acid, especially in the setting of acidosis, can precipitate in the renal tubules and lead to renal failure. Atopy does not seem to predispose to anaphylaxis from penicillin or venom exposures. Epinephrine provides both - and -adrenergic effects, resulting in vasoconstriction and bronchial smooth-muscle relaxation. Beta blockers are relatively contraindicated in persons at risk for anaphylactic reactions. Individuals should wear an informational bracelet and have immediate access to an unexpired epinephrine kit. Pasteurella multocida and Bartonella henselae (the agent of cat-scratch disease) are important cat-associated pathogens. Because of deep tissue penetration by narrow, sharp feline incisors, cat bites are more likely than dog bites to cause septic arthritis or osteomyelitis. Sometimes, espeAdminister anticially with venomous venin for venomous snakes snakebite. These suggestions for empirical therapy need to be tailored to individual circumstances and local conditions. Disease can progress to metastatic abscesses, endocarditis, meningitis, and pneumonia. After thorough cleansing, facial wounds are usually sutured for cosmetic reasons and because the abundant facial blood supply lessens the risk of infection. For wounds elsewhere on the body, many authorities do not attempt primary closure, preferring instead to irrigate the wound copiously, debride devitalized tissue, remove foreign bodies, and approximate the margins. Puncture wounds due to cat bites should be left unsutured because of the high rate at which they become infected. Antibiotics are typically given for 3­5 days (as prophylaxis in pts presenting within 8 h of the bite) or for 10­14 days (as treatment for established infections). A tetanus booster for pts immunized previously but not boosted within 5 years should be considered, as should primary immunization and tetanus immune globulin administration for pts not previously immunized against tetanus. The victim must be carried to medical care, because walking will disperse venom from the bite site regardless of its anatomic location. In the United States, round-the-clock assistance is available from regional poison control centers. Any evidence of systemic envenomation (systemic symptoms or signs, laboratory abnormalities) and significant, progressive local findings. Treating physicians should seek advice from snakebite experts regarding indications for and dosing of antivenom. The duration of antivenom administration depends on the offending snake species, but multiple doses are not effective in reversing bite responses that have already been established. A trial of acetylcholinesterase inhibitors should be undertaken for pts with objective evidence of neurologic dysfunction because this treatment may cause neurologic improvement in pts bitten by snakes with postsynaptic neurotoxins.

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