Tinsay Ambachew Woreta, M.D., M.P.H.

• Program Director, Transplant Hepatology Fellowship
• Assistant Professor of Medicine

https://www.hopkinsmedicine.org/profiles/results/directory/profile/4568252/tinsay-woreta

The probe exhibits minimal fluorescence in the unhybridized state when the oligonucleotide is variably folded on itself arrhythmia technologies institute order hyzaar 50 mg with visa, but exhibits strong fluorescence at defined wavelengths when the quencher becomes separated from the reporter fluorophore i blood pressure percentile by age order hyzaar visa. In this case arteria facialis linguae discount 50 mg hyzaar overnight delivery, the fluorophore accumulates in the reaction mixture in increasing quantities with each cycle blood pressure medication on empty stomach trusted hyzaar 50 mg. When these two dyes are present in close proximity on the probe blood pressure monitor walmart hyzaar 50mg cheap, the fluorescence of the F dye is quenched blood pressure kid order 50mg hyzaar otc. Furthermore, a mutation occurring in the sequence targeted by the probe would preclude the detection of the amplicon in contrast to it still being detected by analysis of the products by gel electrophoresis. Fully Integrated Automated Systems Integrated systems that perform extraction of the nucleic acid, amplification, and analysis of the findings have been developed. These allow virus diagnosis within a short period of time in a setting of minimal laboratory requirement. Examples of these are the application of the Cepheid GeneXpert to the rapid diagnosis of respiratory viruses and enteroviruses (99, 100). Annealing of the antisense primer also containing the restriction endonuclease site allows the process to continue on the newly synthesized strand. The assay has a sensitivity of 5 to 50 genome copies per ml and requires approximately one hour for completion. The restriction endonuclease introduces a cleavage in the primer sequence and the polymerase synthesizes a new strand from this site and displaces the existing strand. The restriction endonuclease is not able to cut the newly synthesized strands because of the modified nucleotides and can only introduce cuts in the sites present in the primers. The assay involves the ligation of a pair of primers complementary to the full length of the target sequence of each strand that hybridize at adjacent positions and are joined by the ligase. Increasing the temperature results in the dissociation of the primer-derived strands, to which new primers can anneal at reduced temperature, and allows the reaction to continue with the formation of the ligated primers as the end product. The assay has a sensitivity of 5 to 50 genome copies per ml and is reported to be minimally susceptible to inhibitors in the specimen. The primers are designed to bind so that the gap between them consists of a single nucleotide type. Once the gap is filled by the polymerase, the ligase joins the last nucleotide to the downstream primer. The temperature is then raised to denature the product and then lowered to allow further primer binding. Hybridization-Based Assays Hybridization with labeled probes has long been used for detection of viral genomes. The genome then further hybridizes to secondary probes, which then hybridize with an amplification multimer. The latter hybridizes further with labeled probes that allow for the detection of the branched chain structure. This structure is recognized by an antibody which is then detected by an immunoassay detection system. Such an approach has been commercially applied in the Digene Corporation Hybrid Capture assays (Qiagen, Venlo, Netherlands). These approaches are based on the assumption that the amplification efficiencies of the standard and the target are nearly equivalent. The latter being a signal amplification assay is considered less variable but also less sensitive than target amplification assays. Controls are also added to the specimen or aliquot thereof before extraction to serve as extraction controls. Each reactor can then be sorted by fluorescent signal as positive or negative delineating the presence or absence of target (113). In addition, the development of multiplex assays has allowed for an unprecedented breadth of testing for all known respiratory viruses in a patient specimen within a working day using a single test (93). Likewise, nucleic acid microarray technology is believed to have a similar potential (116). Fastidious adherence to the design of the laboratories so that amplicon contamination is avoided by restriction of movement among clean and dirty rooms is essential. Amplicon contamination of the environment can be further reduced by wiping the surfaces with household bleach, exposing working surfaces to short ultraviolet light, and working in laminar flow biological safety cabinets with appropriate clothing and use of gloves. When patients are undergoing antiviral treatment, the goal is to maintain the viral load at levels below 50 genome copies per ml of plasma, the lower limit of detection of quantitative assays (131). In another application, an increased viral load in a patient receiving antiviral therapy may suggest the development of viral resistance, which can be confirmed by specific phenotypic or genotypic resistance assays. It has proven its value by greatly simplifying the typing of enteroviruses and adenoviruses (132, 133). It allows for identifying specific genotypes of noroviruses and rotaviruses (118, 134) and for monitoring the drift of influenza A viruses at the nucleotide level over time (135). Newer sequencing technologies such as pyrosequencing and shotgun sequencing allow for even more effective application of sequencing to diagnostics, and are indicative of the future directions of these technologies in viral diagnosis (136). This includes more accurate determination of quasispecies of the virus present in a clinical specimen. Finally, high throughput sequencing allows for metagenomics analysis of the nucleic acids present in clinical specimens to comprehensively identify existing and potentially novel viruses (137, 138). For individual patients, these assays can be used for diagnosis of acute or chronic infections, determination of immune status (either as a result of natural infection or immunization), and for detection of individuals latently infected with certain viruses. Clinically, these assays are used for seroepidemiologic surveys, donor screening for prevention of transmission of blood-borne viruses. Monitoring the viral load in the blood of transplant patients, especially those in the pediatric group, and either modulating immunosuppression or using antiviral drugs such as ganciclovir is critical for their survival. A number of viruses are impossible, difficult, or even hazardous to grow in culture, or difficult to detect by other methods. Proper specimens for culture or direct detection assays may be difficult to obtain or may not be obtained because viremia or virus replication and shedding have subsided to undetectable levels when symptoms occur. In these situations, serodiagnosis is often helpful in confirming a recent or past infection with a specific virus. Sometimes, the clinical significance of detecting a virus by means of a direct assay or by molecular techniques may be uncertain. In these situations, serology may assist in establishing a causal relationship. Serology is also an invaluable tool in the public health domain, whether to assess incidence and prevalence of viral diseases for epidemiological studies, surveillance systems, or evaluation of the efficacy of prevention and control programs. Although traditional methods of viral serodiagnosis are still in use, automated technologies have now become the mainstream of serological testing in clinical laboratories. Use of recombinant antigens and synthetic peptides representing immunodominant regions has improved test sensitivity and specificity for detecting and confirming virus-specific antibodies. At the same time, simple-to-use commercial tests or devices capable of rapidly analyzing single specimens, such as finger prick blood samples, have been introduced for rapid point-of-care testing. Antibody Response to Viral Infections Immunoglobulins as markers of humoral response are more useful and reliable than cell-mediated immunity for diagnostic purposes. Because of the transient nature of the IgM antibody response, its presence is generally indicative of current or recent viral infection. Specimens for Serodiagnosis Serum is the specimen of choice for most serological assays; plasma can be used in some instances but is not suitable for all antibody tests unless specified by the manufacturer of the assay. In adults, 4 to 7 ml of blood obtained from venipuncture in a collection tube containing no additive or preservative is usually sufficient for most testing. The laboratory will accept smaller volumes of blood, particularly from infants and young children or when few tests are being requested. A centrifugation step allows separation of the serum from the remainder of the blood components. Collected whole blood should not be frozen as this may cause hemolysis rendering the specimen unusable for serologic testing. Icteric, lipemic, or heat-inactivated sera may also cause erroneous test results and should be avoided, if possible. Serum should be refrigerated at 4oC shortly after separation from the blood clot and during transport to the laboratory. If an extended delay in transport or testing of a specimen (beyond 5 to 7 days) is anticipated. A single serum specimen is required to determine the immune status of an individual or to detect IgM-specific antibodies. The acute-phase serum should be obtained as soon as possible during the course of the illness, and no later than 5 to 7 days after onset. The most useful results are obtained by testing acute- and convalescent-phase sera simultaneously in a single assay run. To identify congenital infection, the newborn should be younger than 3 weeks when the specimen is obtained. During primary infection, IgM appears within several days after onset of symptoms, peaks at 7 to 10 days, and normally declines to undetectable levels within 1 to 3 months. Following natural viral infection or after successful immunization, IgG antibodies appear several days after the production of IgM, reaches higher levels than IgM, and can persist for years, even life-long, in lower quantities. During reactivation or exogenous reinfection, an anamnestic response in IgG antibodies will occur and an IgM response may or may not be observed. In some instances, measurement of antibody avidity may help in distinguishing a recent infection from a past infection with associated reactivation (139, 140). Avidity refers to the accumulated strength of multiple affinities between an antibody and antigen as a result of multiple antigen-binding sites simultaneously interacting with the target antigenic epitopes. Avidity can only be measured in individuals with detectable IgG antibodies to the particular virus of interest. Although maturation of the IgG antibody response generally occurs within 6 months following infection, in some individuals this may take longer resulting in a prolonged low or intermediate avidity value and a potentially misleading interpretation as evidence of a recent infection (142). The role, onset, level, and duration of IgA, IgD, and IgE antibodies are less predictable than either IgM or IgG, and 15. Whole saliva, oral mucosal transudates rich in gingival crevicular fluid, and urine also have been evaluated as noninvasive alternatives to the collection of blood for the detection of antibodies to a number of different viruses (147). The sensitivity and specificity of urine tests are inferior to those of blood and oral fluid tests. Accordingly, several commercial devices have been developed for the collection of oral mucosal transudate specimens. The devices provide a homogeneous specimen rich in plasma-derived IgG and IgM that is passively transferred to the mouth across the mucosa and through the gingival crevices (151). Although inexpensive in material and reagents, the method is technically demanding, requires rigid standardization and titration of reagents, has a long turnaround time, and acute and convalescent serum must be tested in the same assay run. Invalid results can occur with sera possessing anticomplementary activity due to nonspecific binding of serum components to the complement used in the assay. In addition, nonspecific inhibitors and natural agglutinins need to be removed from some serum specimens before virus-specific antibodies can be detected. Detection of hemagglutinating antibodies is the current standard for assessing the immunogenicity of seasonal influenza vaccines and is often used for retrospective diagnosis of individual infections. After approximately a minute, the slides are examined for the presence or absence of red cell agglutination. If agglutination is stronger with the guinea-pig kidney mixture, the test is positive. Commercial kits for performing the monospot test are available and continue to be widely used because of their relative ease to perform, rapid results, and low cost. The specificity of the test approaches 100% while the sensitivity ranges from 70 to 90%. Procedures for Detecting Viral Antibodies A variety of methods are available for serodiagnosis of viral infections (reviewed in (67, 154, 155)). The selection of which test method(s) to perform will depend on the patient population and clinical situation, the number of specimens to be tested, turnaround time, ease of testing, and the resources and capabilities of the individual laboratory. Critical clinical information such as the date of onset of disease symptoms, recent travel history, immunization, or medical antecedents may also influence the choice of an adequate analytical strategy. Qualitative measurements of virus-induced antibody can be performed when it is useful to know simply that a specific antibody is present or absent. Quantitation is essential when it is important to know the amount of antibody present, particularly when measuring virus-specific IgG antibodies. Complement Fixation Complement fixation can be used for measuring antibodies against virtually any cultivable virus and it has the distinct advantage of assessing significant rises in antibody levels during acute viral infections (156). The assay can be performed in microtitre plates containing cell monolayers infected with approximately 100 infectious units of virus and a serially diluted antiserum. Neutralization titer is usually expressed as the reciprocal of the highest serum dilution resulting in a 90% reduction in the number of infected foci or plaques produced by a virus on a cell monolayer. Detection of neutralizing antibodies is clinically important in establishing protective immunity in response to a viral infection or vaccination. However, the assay is cumbersome, expensive, time-consuming, and in the case of highly pathogenic viruses, needs to be performed under high biosafety conditions. Rather than count plaques, immunofluorescence is used to assess changes in rabies virus replication in cell culture. Its major use is for the measurement of rabies neutralizing antibodies in persons vaccinated with the rabies vaccine and whose antibody levels are being monitored routinely due to occupational exposure to rabies virus.

The natural history of antibody development has been measured in wild macaques blood pressure 160 over 100 buy cheap hyzaar on-line, captive colony populations arteria gastroepiploica dextra purchase 50mg hyzaar with amex, individually imported animals hypertension from stress purchase generic hyzaar from india, experimentally infected macaques blood pressure medication used in pregnancy generic hyzaar 50mg overnight delivery, zoonotically infected humans connexin 43 arrhythmia discount 50mg hyzaar free shipping, and even vaccine trial recipients zofran arrhythmia buy generic hyzaar 50 mg on line. The humoral immune response to B-virus infection has a characteristic pattern (56, 90, 112). Antibodies begin to appear within 7 to 10 days after the infection and consist of immunoglobulin M (IgM). Within 14 to 21 days after the onset of acute infection, IgG antibodies are present. In rare cases, the infected host remains persistently antibody negative despite virus isolation. Neutralizing antibodies develop in both the natural and foreign hosts, but at significantly lower levels in the foreign host. The nature and specificity of the humoral responses make it possible to design enhanced serologic testing strategies to identify detectable antibodies rapidly and to provide the basis for future diagnostic strategies. Shedding of virus after reactivation also occurs with illness and during the breeding season of the natural host. Some survivors experience slow neurologic decline, whereas others report few if any long-term effects. Several infected individuals have subsequently given birth to healthy children with no ill effects in either mother or infant. Monitoring of the vaginal canal for virus shedding in these individuals before delivery has produced negative results. Most often, illness is apparent within days to weeks, but in some cases, there appears to be a delay in development of acute disease. The reasons for this delay are unknown, and, although rare, delays may even range from months to years, making diagnosis difficult. Once symptoms appear, the clinical progression is associated with relatively consistent symptoms, including influenza-like illness, lymphadenitis, fever, headache, vomiting, myalgia, cramping, meningeal irritation, stiff neck, limb paresthesias, and urinary retention with an ascending paralysis culminating in respiratory failure requiring ventilatory support. Cranial nerve signs, such as nystagmus and diplopia, are common in most published cases. The array of symptoms may be related to the dose of virus with which the individual was infected or the route of inoculation. A summary of descriptions of human cases can be found in two comprehensive reviews (24, 25). The highest percentage of deaths occurs within a few weeks after onset of disease. Incubation times from identifiable exposures to onset of clinical symptoms ranges from days to years, but most cases occur within days to months. Virus has been recovered from throat, buccal, and conjunctival sites as well as from lesions, vesicles, or injury sites as late as weeks to months after infection. Most clinical cases are associated with bites (50%), fomites, (8%) saliva (< 5%), and aerosols (10%). Latency A characteristic of all herpesviruses is the ability to establish latency and to reactivate when provoked by the proper stimulus. Reactivation has been described in both wild macaques and established captive colonies (25, 27, 29, 35, 101). Unequivocal evidence of latent B-virus infection in macaques came with studies on frequency of recovery of virus in monkey kidney cell culture systems. At least 1% of macaque kidneys harbor latent virus that can be reactivated in cell culture (41). Virus has been isolated from rhesus tissues (32, 79) as well as by cocultivation from a variety of neuronal tissues, including gasserian ganglia, trigeminal ganglia, dorsal route ganglia, and spinal cord (38). Cercopithecine Herpesvirus 1 (B Virus) - 453 predominant diagnostic tool in macaques and humans for many decades, but the time required for obtaining results was a drawback. This is a particularly important point with respect to diagnostic tools used to identify signs of infection for the establishment of Bvirus-free colonies. Tests dependent on monoclonal antibodies or recombinant reagents have defined sensitivity and specificity for each macaque species to be tested. Finally, evaluation of a macaque is only optimal when analysis is performed on multiple samples at different dates, especially in cases in which antibody titer is low (less than 1:50). A constellation of different tests for deployment at varying time points after infection may be necessary in some cases to determine the status of an animal with a very low antibody titer correctly, particularly when such an animal is housed in a B-virus-free colony (123). While virus isolation is the gold standard for diagnosis of infected macaques, it is not a particularly sensitive diagnostic tool and has the possibility of many false-negative results. Nonetheless, standard cell culture for virus isolation remains a valuable tool for the colony manager and for the veterinarian. Generally, a rise in B-virus-specific antibodies over several days during acute infection substantiates B virus as the etiologic agent. However, in other cases, data are equivocal, and decisions with regard to patient management must be based on a complex decision table collectively using all diagnostic tools, including clinical symptoms. As discussed previously, significant cross-reactivity of host response exists among these viruses. In the absence of these cross-reactive antibodies, diagnosis is rapid and straightforward, with confirmation using the neutralization assay, Western blot, or both. Virus isolation remains the gold standard for diagnosis but is frequently not possible, even under the best of circumstances. Because of the risk of human disease, precautionary methods must be followed in the workplace. These are usually animals that have been cohoused or housed in close proximity to B-virus-infected macaques at some time. Because many, if not all, nonhuman primates harbor indigenous alphaherpesviruses, the important diagnostic point is to differentiate specific antibodies from crossreactive ones. Euthanasia is generally advised in the case of a B-virus infection in a nonmacaque monkey because it is likely that the animal will succumb, and, in the meantime, would pose a great risk to anyone attempting to treat the infection. In each case, there is a major concern for the people responsible for care of the animal, particularly because these animals often have severe morbidity and are shedding virus. Exposure Risk Reduction Multiple levels of prevention are used to prevent B-virus infection in both humans and nonhuman primates, ranging from attempts to eliminate virus-positive animals from colonies to designing methods to work safely in environments where there is increased risk for contracting this agent. Recognition of early infection allows removal of infected monkeys from captive colonies that are being established as B virus free. In B-virus-free colonies, it is important to remove seropositive animals and isolate animals with equivocal results to prevent infection of other colony members, or in seropositive colonies to minimize risk to humans who handle them. Macaques are not treated with antivirals because the high prevalence of infection makes it cost prohibitive. In cases in which B-virus infection is suspected, medical personnel should follow published guidelines at the time of injury or observation of symptoms of possible infection Humans Both serologic and virologic techniques are available for diagnosis of B-virus infection in humans. Nonetheless, B-virusinfected monkeys are plentiful and require handling that can be done safely if strict guidelines are followed, including barrier precautions. When B virus is detected, decontamination can be accomplished with either heat or formaldehyde (11). Other virus inactivators include detergents and bleach, but individuals who are working in a decontaminated area should still be alert for injury prevention. One B-virus infection in a human was acquired from a cage after the person sustained a scratch (57), underscoring that surface decontamination can play an important role in infection control. Ganciclovir has a greater efficacy in vitro and thus has been used in a few cases since 1989 with success. Acute ascending myelitis following a monkey bite, with the isolation of a virus capable of reproducing the disease. The immunological identity of a virus isolated from a human case of ascending myelitis associated with visceral necrosis. Encephalomyelitis due to infection with Herpesvirus simiae (herpes B virus); a report of two fatal, laboratory-acquired cases. B virus: its current significance; description and diagnosis of a fatal human infection. In Weatherall D, Ledingham J, Warrell D (ed), Concise Oxford Textbook of Medicine, 2nd ed. Endo M, Kamimura T, Aoyama Y, Hayashida T, Kinyo T, Ono Y, Kotera S, Suzuki K, Tajima Y, Ando K. Research on the antibodies neutralizing B virus in monkeys of Japanese origin and in foreign monkeys imported into Japan]. Vaccines As early as the 1930s, attempts were made to identify an effective vaccine for protection of individuals who could be exposed to this virus while working with macaques or their cells or tissues. Limited vaccine trials have been performed in volunteers (108, 109), and, although short-term antibodies were induced, they waned quickly. Recently, a recombinant vaccine was tested and found to induce antibodies in macaques, but the duration of antibody persistence and efficacy remain to be assessed (68). Exposure Management With respect to prevention, the value of first aid after a potential exposure due to a bite, scratch, splash, or other suspicious injury is very important. Acyclovir and the related family of nucleoside analogs were noted to be effective when given in high doses (90), for example, acyclovir at 10 mg/kg intravenously three times daily for 14 to 21 days. Antivirals are used by an increasing number of facilities for postinjury prophylaxis or after laboratory results indicate an animal may have been actively infected around the time of the exposure. Postinjury prophylaxis has been performed with famciclovir or valaciclovir, and both have demonstrated efficacy in vitro. Epidemiology of cercopithecine herpesvirus 1 (B virus) infection and shedding in a large breeding cohort of rhesus macaques. Prevalence of antibodies to certain viruses in sera of free-living rhesus and of captive monkeys. Risk of venereal B virus (cercopithecine herpesvirus 1) transmission in rhesus monkeys using molecular epidemiology. Activation of B virus (Herpesvirus simiae) in chronically immunosuppressed cynomolgus monkeys. Recovery of additional agents both from cultures of monkey tissues and directly from tissues and excreta. Latent infection of monkeys with B virus and prophylactic studies in a rabbit model of this disease. Heterogeneity in Herpes simiae (B virus) and some antigenic relationships in the herpes group. Recovery of herpes simiae (B virus) from both primary and latent infections in rhesus monkeys. Isolation of strains of virus B from tissue cultures of Cynomolgus and Rheusus kidney. Isolation of B virus (herpes group) from the central nervous system of a rhesus monkey. The cellular changes produced in tissue cultures by herpes B virus correlated with the concurrent multiplication of the virus. Role of the virion host shutoff protein in neurovirulence of monkey B virus (Macacine herpesvirus 1). B virus (Macacine herpesvirus 1) glycoprotein D is functional but sispensable for virus wntry into macaque and human skin cells. Herpesvirus simiae (B virus): replication of the virus and identification of viral polypeptides in infected cells. Immunological characterization of a common antigen present in herpes simplex virus, bovine mammillitis virus and herpesvirus simiae (B virus). Identification of a common antigen of herpes simplex virus bovine herpes mammillitis virus, and B virus. Biologic characteristics of a continuous kidney cell line derived from the African Green Monkey. Diagnosis and management of human B virus (Herpesvims simiae) infections in Michigan. B virus (Herpesvirus simiae) infection in humans: epidemiologic investigation of a cluster. Molecular cloning and physical mapping of the genome of simian herpes B virus and comparison of genome organization with that of herpes simplex virus type 1. Genome sequence of a pathogenic isolate of monkey B virus (species Macacine herpesvirus 1). Serological evidence for variation in the incidence of herpesvirus infections in different species of apes. Nucleotide sequence analysis of genes encoding glycoproteins D and J in simian herpes B virus. Complete nucleotide sequence of the herpesvirus simiae glycoprotein G gene and its expression as an immunogenic fusion protein in bacteria. The existence of differing monkey B virus genotypes with possible implications for degree of virulence in humans. Axonal and transsynaptic (transneuronal) spread of Herpesvirus simiae (B virus) in experimentally infected mice. Axonaltranssynaptic spread as the basic pathogenetic mechanism in B virus infection of the nervous system. Guidelines for the prevention and treatment of B-virus infections in exposed persons. A controlled seroprevalence survey of primate handlers for evidence of asymptomatic herpes B virus infection.

EpsteinBarr-virus immunity and tissue distribution in a fatal case of infectious mononucleosis pulse pressure calculator buy cheap hyzaar 50mg on line. Epstein-Barr virus in a malignant lymphoproliferative disorder of B-cells occurring after thymic epithelial transplantation for combined immunodeficiency blood pressure printable chart buy generic hyzaar 50 mg on line. Reticulum cell sarcoma after renal homotransplantation and azathioprine and prednisone therapy blood pressure up at night 50 mg hyzaar with visa. Lymphoproliferative disorders following allogeneic bone marrow transplantation: the Vancouver experience hypertension guideline update jnc 8 order hyzaar 50 mg without a prescription. Pretransplantation seronegative Epstein-Barr virus status is the primary risk factor for posttransplantation lymphoproliferative disorder in adult heart hypertensive emergency hyzaar 50mg cheap, lung arrhythmia graphs order 50mg hyzaar with visa, and other solid organ transplantations. Post-transplant lymphoproliferative disorders: from epidemiology to pathogenesis-driven treatment. The frequency of Epstein-Barr virus infection and associated lymphoproliferative syndrome after transplantation and its manifestations in children. Epstein-Barr virus associated B cell lymphoproliferative disorders following bone marrow transplantation. Sugaya N, Kimura H, Hara S, Hoshino Y, Kojima S, Morishima T, Tsurumi T, Kuzushima K. Reversibility of lymphomas and lymphoproliferative lesions developing under cyclosporin-steroid therapy. Effect of acyclovir on infectious mononucleosis: a double-blind, placebo-controlled study. Interferongamma in a family with X-linked lymphoproliferative syndrome with acute Epstein-Barr virus infection. Ganciclovir and acyclovir reduce the risk of posttransplant lymphoproliferative disorder in renal transplant recipients. Reactivation of latent Epstein-Barr virus by methotrexate: a potential contributor to methotrexate-associated lymphomas. Fatal primary infection due to human herpesvirus 6 variant A in a renal transplant recipient. A prospective survey of human herpesvirus-6 primary infection in solid organ transplant recipients. Herpesvirus 6 variant A infection after heart transplantation with giant cell transformation in bile ductular and gastroduodenal epithelium. Human herpesvirus 6 reactivation and encephalitis in allogeneic bone marrow transplant recipients. Transmission of integrated human herpesvirus 6 through stem cell transplantation: implications for laboratory diagnosis. Ogata M, Satou T, Inoue Y, Takano K, Ikebe T, Ando T, Ikewaki J, Kohno K, Nishida A, Saburi M, Miyazaki Y, Ohtsuka E, Saburi Y, Fukuda T, Kadota J. Anti-B-cell monoclonal antibodies in the treatment of severe B-cell lymphoproliferative syndrome following bone marrow and organ transplantation. Anti-B-cell monoclonal antibody treatment of severe posttransplant B-lymphoproliferative disorder: prognostic factors and long-term outcome. The impact of human herpesvirus-6 and -7 infection on the outcome of liver transplantation. Human herpesvirus-6: infection and disease following autologous and allogeneic bone marrow transplantation. Prevalence and clinical significance of human herpesviruses 6 and 7 active infection in pediatric liver transplant patients. Persistent lack of human herpesvirus-6 specific T-helper cell response in liver transplant recipients. Electrochemotherapy: results of cancer treatment using enhanced delivery of bleomycin by electroporation. The impact of preexisting or acquired Kaposi sarcoma herpesvirus infection in kidney transplant recipients on morbidity and survival. Luppi M, Trovato R, Barozzi P, Vallisa D, Rossi G, Re A, Ravazzini L, Potenza L, Riva G, Morselli M, Longo G, Cavanna L, Roncaglia R, Torelli G. Treatment of herpesvirus associated primary effusion lymphoma with intracavity cidofovir. Luppi M, Barozzi P, Rasini V, Riva G, Re A, Rossi G, Setti G, Sandrini S, Facchetti F, Torelli G. Sgadari C, Barillari G, Toschi E, Carlei D, Bacigalupo I, Baccarini S, Palladino C, Leone P, Bugarini R, Malavasi L, Cafaro A, Falchi M, Valdembri D, Rezza G, Bussolino F, Monini P, Ensoli B. Long-term acyclovir for prevention of varicella zoster virus disease after allogeneic hematopoietic cell transplantation-a randomized double-blind placebo-controlled study. Discovery of a new human polyomavirus associated with trichodysplasia spinulosa in an immunocompromized patient. Treatment of polyomavirus infection in kidney transplant recipients: a systematic review. Brincidofovir for polyomavirus-associated nephropathy after allogeneic hematopoietic stem cell transplantation. Koukoulaki M, Grispou E, Pistolas D, Balaska K, Apostolou T, Anagnostopoulou M, Tseleni-Kotsovili A, Hadjiconstantinou V, Paniara O, Saroglou G, Legakis N, Drakopoulos S. Progressive multifocal leukoencephalopathy after orthotopic liver transplantation. Reducing immunosuppression preserves allograft function in presumptive and definitive polyomavirus-associated nephropathy. Indeed, viruses are among the most common inciting agents to cause a condition termed acute myocarditis. This condition may also be provoked by bacteria, other pathogens, as well as toxins and autoimmune diseases, each of which could mimic the appearance of viral myocarditis. The reason for this phenotypic mimicry is that myocarditis is a process characterized pathologically by an inflammatory infiltrate of the myocardium with death or degeneration of adjacent myocytes, not typical of the ischemic damage associated with atherosclerotic coronary artery disease. The inflammation and damage may involve myocytes, interstitium, vascular elements, and pericardium. The inflammatory process affects cardiac function adversely, causing either ventricular dysfunction, arrhythmias, or both. The acute process may persist and manifest as chronic low-grade tissue inflammation and fibrosis associated with cardiomyopathy and frank heart failure. Many viruses can cause the same syndrome, and a particular virus can cause infections leading to a highly varied constellation of manifestations. Clinically, viral heart disease and acute myocarditis most commonly commence with a "flu like" picture, followed within days by symptoms and signs of congestive heart failure, including shortness of breath, exercise intolerance, and fatigue, and may be associated with abdominal pain, chest pain, palpitations, syncope, and sudden death. In recent years, the main advances in our thinking about viral syndromes are that the attack on heart muscle is part of a more holistic viral-immune-inflammatory-pathologicalclinical systemic syndrome with multiorgan involvement, and that there is a temporal connection between acute viremic states and long-standing immunovirological perturbation and cardiomyopathy. Certainly, the contribution of inflammatory mediators in transient, acute cardiac dysfunction is also now recognized (1). Yet the challenge often arises that a thorough evaluation of the myocardial tissue in biopsies or at autopsy is not possible or inconclusive for accepted features of myocarditis. Early detection of viral infection relies on viral isolation and serology; however, these diagnostic approaches lack sensitivity and specificity. Molecular detection of viral genomes in heart tissue derived from biopsy, explants, or autopsy has enhanced these approaches. This form of cardiomyopathy was identified in children until the late 1960s, with an incidence of 1 in 5000 live births in the United States. Since that time, the incidence has declined significantly due to mumps immunization, and the status of mumps myocarditis in mumps-susceptible populations has not been recognized in recent years. In addition to the frequently detected viruses mentioned above, other viral causes of myocarditis have also been doi:10. The acute stage of infection with chikungunya virus is characterized by fever, polyarthritis, and occasional rash and can be complicated by myocarditis and pericarditis (43, 44). Pericarditis is frequently a part of the phenotype of myocardial involvement by cardiotropic viruses, including classical clinical signs of friction rubs and pleuritic pain, and such membranous inflammation may become persistent (9). The thresholds for defining myocarditis are variable and depend on whether the diagnosis is derived clinically, serologically, pathologically, and/or molecularly. This variability contributes to the uncertainty surrounding the incidence of the condition (49). Intrauterine myocarditis occurs during community epidemics as well as sporadically (50). Postnatal spread of coxsackievirus is via the fecal-oral or respiratory route (51, 52). Other important viral causes, like adenoviruses (53, 54) and influenza A virus, are transmitted primarily via the respiratory route. The elicitation of antigen-specific humoral and cellular immune responses in lymphoid tissues has a dominant influence on the pathophysiology of the viral infection, including the potential for immunopathologic responses within the heart. Virus titers subsequently decline, with infectivity being rarely detectable beyond 14 days after inoculation, depending on the mouse strain and viral variant. Neutralizing antibody concentrations decline as virus titers increase, supporting a role for such antibodies in the viral clearance process. Risk factors for severe myocarditis include age, mouse strain, viral variant, exercise, and gender (12). Animals with absent or blocked T-cell function may have less evident myocardial injury, although the recognition that an extensive amount of damage is already done by viral mechanisms before immune cell responses occur is now widely appreciated. In most murine strains, the adolescent period is the one of most severe in viral heart disease. Estradiol has been shown to decrease severity, and testosterone increases immune-mediated 7. Either a preferential stimulation of T-helper cells or an inadequate stimulation of T-regulatory (cytolytic/suppressor) cells could explain why antibody responses to various antigens may be enhanced and cellular immune responses depressed in female murine models. Presumably, the more efficiently viral clearance occurs, the less virally induced neoantigen production occurs, reducing recognition by cytotoxic T lymphocytes. T cells can effect injury by multiple mechanisms-causing accumulation of activated macrophages, helping with production of antibody, mediating antibody-dependent cell-mediated cytotoxicity, direct lysis by antibody and complement, and direct action of cytotoxic T cells (69). Host genetic factors have been shown to affect the severity of disease, as well as the pathogenic mechanisms that participate in disease development (55, 60, 62, 74). Complement depletion increases the amount of inflammation in this species, and no reactive immunoglobulin G (IgG) antibody is found in the myocytes. Cytolytic T cells are produced but apparently are not pathogenic; IgG antibody is found in the myocytes. Adenoviruses have a number of strategies for modulating the immune response that could affect the number of activated lymphocytes in the adenovirus-infected myocardium (57). Pathophysiologic Consequences In the heart, viral infection triggers both interstitial inflammation and myocardial injury, resulting in loss of myocardial integrity, with consequent cardiac chamber enlargement and an increase in the ventricular end-diastolic volume (47, 52, 54, 82). Normally, an increase in volume results in an increased force of contraction, improved ejection fraction, and improved cardiac output as described by the Starling mechanism. However, in the setting of myocarditis, the myocardium is unable to respond to these stimuli and cardiac output is compromised. A series of interacting adverse changes occurs, reflecting the composite pathophysiological response of patients afflicted by myocarditis: 1. Interactions with the sympathetic nervous system may preserve systemic blood flow via vasoconstriction and elevated cardiac afterload. This sympathetic nervous system input results in tachycardia, a feeling of weakness, and diaphoresis. A progressive increase in ventricular end-diastolic volume and pressure results in increased left atrial pressure. This pressure elevation is transmitted retrograde to the pulmonary venous system, causing increasing hydrostatic forces that overcome the colloid osmotic pressure that normally prevents fluid transudation across capillary membranes. The associated symptoms include increasing shortness of breath, anxiety and even chest pain, and the consequence may be overt pulmonary edema. This dilation, in addition to poor ventricular function, creates worsening pulmonary edema and worsening cardiac function. Ventricular dilation also results in stretching of the mitral annulus and resultant mitral regurgitation, further increasing left atrial volume and pressure. Patients with unrelated disorders had no virus-specific sequences (75), suggesting that viral genomic material persists in patients with congestive cardiomyopathy or healing myocarditis for weeks or months. Although viral cultures are usually negative, continued viral replication may occur at a low level or abortively.

The Nerves and Muscles of the Hip 141 e nerves of the arm have many branches and typically supply many di erent muscles heart attack 6 fragger buy 50mg hyzaar amex. When we looked at them it made sense to examine the path and branches of each nerve rst blood pressure chart video hyzaar 50 mg sale, and then its associated sensory and motor functions pulse pressure low diastolic buy hyzaar once a day. Hip exion is facilitated by the iliopsoas muscle blood pressure guidelines 2014 generic 50 mg hyzaar with amex, which lies in the posterior compartment of the abdominal cavity hypertension lab tests hyzaar 50 mg with amex. Hip extension is achieved by the powerful gluteus maximus blood pressure medication side effects order 50 mg hyzaar free shipping, which attaches the sacrum to the posterior side of the femur. Hip adduction is provided by the obturator nerve (L2, L3 and L4), which innervates a group of muscles simply referred to as the adductors. Hip abduction is achieved by the gluteus minimus and gluteus medius through the superior gluteal nerve (L4, L5 and S1). The gluteus maximus is responsible for hip extension and is innervated by the inferior gluteal nerve. The adductors are responsible for hip adduction and are innervated by the obturator nerve. The gluteus minimus and gluteus medius are responsible for hip abduction and are innervated by the superior gluteal nerve. The Nerves and Muscles of the Knee 143 e knee only has two possible movements: extension and exion. Knee extension is performed by the quadriceps which, as the name implies, is actually made up of four di erent muscles (the rectus femoris, vastus lateralis, vastus medialis, and vastus intermedius). Knee extension is so critical to life, as it is the main muscle involved in standing, that innervating the quads is the sole motor function of the massive femoral nerve. As we mentioned, the common peroneal nerve and tibial nerve initially travel together in the thigh as the sciatic nerve (L4, L5, S1, S2, S3). Again, this is a composite muscle and is made up of the semi-tendinous muscle, the semi-membranous muscle and the biceps femoris. Take Home Messages the quadriceps are responsible for knee extension and are innervated by the femoral nerve. The hamstrings are responsible for knee flexion and are innervated by the sciatic nerve. The Nerves and Muscles of the Ankle: I 145 Like the hip joint, the ankle has four possible types of movement: foot dorsi exion, in which the angle between the foot and the leg is decreased, foot plantar exion, in which the angle between the foot and the leg is increased, foot inversion and foot eversion. Routinely, the toes are not assessed, with one major exception: extension of the rst toe. On its way, it innervates the gastrocnemius and soleus, which together attach the femur, tibia and bula to the posterior aspect of the foot, and are responsible for ankle plantar exion. Slightly more distally, the tibial nerve also innervates the tibialis posterior, which is responsible for foot inversion. Take Home Messages the gastrocnemius and soleus are innervated by the tibial nerve and are responsible for ankle plantar flexion. The tibialis posterior is also innervated by the tibial nerve and is responsible for inversion of the foot. As it does so, it divides into the super cial peroneal nerve and the deep peroneal nerve. Take Home Messages the powerful tibialis anterior is responsible for ankle dorsiflexion and is innervated by the deep peroneal nerve. The extensor hallucis longus is responsible for extension of the first toe, and is also innervated by the deep peroneal nerve. The peroneus muscle is responsible for foot eversion and is innervated by the superficial peroneal nerve. Your road map of the nervous system is complete, and you can start to practice localizing in the accompanying 25 cases. While there are multiple ways to approach any neurology problem, some localization algorithms are much more straightforward than others, and the one we present here can be applied to the vast majority of neurological cases you will see. Once we have decided on this, we can draw that level in cross section and then decide what components are a ected, which produces our nal localization. For example, if the patient presents with right sided weakness and also has aphasia then the neuroanatomical level is the cortex. Similarly right sided weakness and a sensory level would localize to the spinal cord. At this point we will have nished localizing longitudinally and have our initial localization. Since we now know the initial localization, we can draw that level in cross section and determine what components are a ected. If they do, then the next step is to gure out where the lesion is along the path of the nerve. To do so, begin distally, and walk up the length of the nerve, until you come across a muscle that has not been a ected by the lesion. If the symptoms do not match to a radiculopathy or neuropathy, then by process of elimination, the lesion must lie in the plexus. Based on whether both the arms and the legs are a ected, determine whether the lesion lies in the cervical, thoracic, lumbar or sacral spinal cord. However, following the logic laid out above will always give you a good idea of where the lesion is in the vast majority of cases. Case Primer 159 Case Primer Before you sink your teeth into the cases, we need brie y to talk about how to do a typical neurological screening exam. However, given an ideal patient, a screening examination tests the following components: Language: e patient may be aphasic. Cranial nerves: A formal exam usually begins by assessing visual acuity using a Snellen eye chart, but in routine screening exam this is usually omitted. Motor system: Before assessing power, inspect the limbs brie y and look for atrophy and fasciculations. However, if the patient complains of very speci c weakness, such as hand or foot weakness, more muscle groups may need to be tested. For example, when examining a 91-yearold the "full resistance" applied by the examiner is often signi cantly less than that which is applied when examining a 24-year-old, and may show considerable interexaminer variability. Importantly, for a muscle to be graded at a certain level of power, it must be able to move against the resistance applied by the examiner across the entire range of motion of the muscle. Many clinicians also employ uno cial subgrades, the most common of which is the 4 -, 4. Since this is so common we have chosen to use this convention in our Cases (Chapter 7). Finally, if the patient is able, it is often very instructive to watch their gait to look for any subtle abnormalities. An unfortunate lack of convention has developed wherein some clinicians will write down the name of the muscle tested. Usually the function of the muscle is written down because it can be shortened. You need to be familiar with all potential names, so we have included this chart so you can always see what muscle groups we reference in the cases. Part Two the Cases Case 1: the 72-year-old woman who talked only gibberish 179 Case 1: the 72-year-old woman who talked only gibberish You are asked by your friends on the Internal Medicine team to come down and see a 72-year-old woman who is in their clinic for routine follow-up of her diabetes. When her daughter went to pick her up for her appointment, she found the patient "talking gibberish," but decided not to take her to the Emergency Department, since they were "going to go see a doctor anyway. Formal power testing is impossible, but you notice she is not moving her right side. Unfortunately this pattern is nonspeci c, and possible localizations include the cortex, internal capsule and brainstem. In addition, she appears to be globally aphasic, as her uency, comprehension and ability to repeat are all impaired; aphasia is one the symptoms that is an Immediate Localization to the cortex. Since these tracts decussate at the level of the medulla, the left motor cortex and sensory cortex must be involved. Putting it all together, we see that nearly all of the left parietal and temporal lobe is involved, as well as some of the frontal lobe. Case 1: Clinical Pearl 183 Clinical Pearl: Causes of Stroke A stroke, also called a cerebral infarction, is caused by an interruption of blood ow to an area of the brain and results in the permanent loss of brain tissue. Understandably, the economic impact of this disability is tremendous; Americans spent over $34 billion on the direct cost of treating stroke in 2013. Hemorrhagic strokes are usually due to focal bleeding from rupture of the brain tissue and associated blood vessels. If the blood clot was generated near the site of the stroke it is called a thrombus. If the blood clot broke o from another location and travelled to the site of the stroke it is called an embolus. Carotid artery disease and cardioembolism each account for 25% of ischemic stroke cases. While carotid stenosis can serve as a source for embolism in ischemic stroke, it should be noted that no neurological symptoms are caused by the stenosis itself; "neurological angina" does not exist, unlike chest pain due to stenosed cardiac arteries. Rarely, ischemic strokes can be caused by insu cient blood pressure to perfuse the brain, which is usually associated with cardiac arrest. Other causes of embolus formation include prosthetic valves, congestive heart failure, and myocardial infarction. If the underlying problem is not correctable, the patient will need to take anticoagulation medication. Note that, despite aggressive investigation, about 20% of strokes remain cryptogenic, meaning no cause can be found. Case 2: the 79-year-old man who whose legs felt funny 185 Case 2: the 79-year-old man who whose legs felt funny You are asked to see a 79-year-old man who has had a recent string of unfortunate luck. He developed intense abdominal pain and was diagnosed with a ruptured abdominal aortic aneurysm for which he was operated on emergently. When he awoke from the coma yesterday, he was thankful to be alive but quickly realized he could not move his legs. His re exes are 3+ in the knee bilaterally, and 4+ in the ankle bilaterally (which, by de nition, induces subsequent clonus). His power examination is listed below, but he is barely antigravity in the proximal part of both legs. You run the pin down his trunk and he states that all of a sudden it feels dull around the umbilicus. In order to di erentiate between the two, we have to hope for a clue in the sensory exam. In this case we are quite fortunate as the sensory examination reveals an Immediate Localization; our patient has a sensory level. Since we now know that we are in thoracic spinal cord, we can draw it in cross section. Joining these areas together, we see that he has almost two-thirds of his cord involved. In this case, prolonged clamping of the aorta during the emergency surgery likely caused unavoidable ischemia to the spinal cord. Case 2: Clinical Pearl 189 Clinical Pearl: Other Patterns of Intrinsic Spinal Cord Disease For reasons that are incompletely understood, the spinal cord is particularly vulnerable to many di erent kinds of nutritional and infectious insults. Tabes dorsalis Tabes Dorsalis is a late complication of syphilis caused by infection with Treponema pallidum. Vitamin B12 de ciency rst a ects the peripheral nerves, causing a painful neuropathy. However, they are are exic because by the time the corticospinal tract is involved, the di use neuropathy is so advanced that muscles can no longer respond to the re ex stimulus. Poliomyelitis While the poliovirus endemic of the rst half of the 20th century is over, poliomyelitis remains a common topic for examinations. Due to the extreme weakness, patients lose their re exes, as the muscles can no longer respond to the re ex stimulus. Initial treatment was mainly supportive and led to the development of the infamous "iron lung," until a vaccine became available in the 1950s. Case 3: the 21-year-old man who was near death 191 Case 3: the 21-year-old man who was near death You have decided to do some locum work to help pay down your medical school debt and are stationed in a remote region of Northern Ontario in Canada. You nd a 21-year-old man who seems to be clutching his right arm in pain, but is able to tell you his story. Unfortunately he fell out of the tree but he was able to brie y grab a branch with his right hand, slowing his descent. At this point, one of his friends noticed his pupils were not equal and insisted he come to the Emergency Department. Initial x-rays are negative for any fractures, so you wonder about a neurological problem. He has full visual elds, but his right pupil is 2 mm wide and his left pupil is 3 mm wide. His sensory examination shows a loss of pinprick over the entire lateral aspect of the right arm. Coordination was not tested in the left arm, due to loss of strength, but was normal everywhere else. Our patient complains of arm weakness in the context of decreased right arm tone and a decreased biceps re ex. In this case the three muscles that are weak correspond to three di erent nerves; the deltoid is innervated by the axillary nerve, the bicep is innervated by the musculocutaneous nerve and the extensor carpi are innervated by the radial nerve.

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