GPT2 mutations cause developmental encephalopathy with microcephaly and features of complicated hereditary spastic paraplegia.

Various genetic defects can cause intellectual and developmental disabilities (IDDs). Often IDD is a symptom of a more complex neurodevelopmental or neurodegenerative syndrome. Identifying syndromic patterns is substantive for diagnostics and for understanding the pathomechanism of a disease. Recessive glutamate pyruvate transaminase (GPT2) mutations have recently been associated with IDD in 4 families. Here, we report a novel recessive GPT2 stop mutation p.Gln24* causing a complex IDD phenotype in a homozygous state in 5 patients from 2 consanguineous Arab families. By compiling clinical information of these individuals and previously described GPT2 patients a recognizable neurodevelopmental and potentially neurodegenerative phenotype can be assigned consisting of intellectual disability, pyramidal tract affection with spastic paraplegia, microcephaly and frequently epilepsy. Because of the consistent presence of pyramidal tract affection in GPT2 patients, we further suggest that GPT2 mutations should be considered in cases with complex hereditary spastic paraplegia.

[Adverse ocular effects of vaccinations]. / Impfschäden am Auge.

Vaccinations are very effective measures for prevention of infections but are also associated with a long list of possible side effects. Adverse ocular effects following vaccination have been rarely reported or considered to be related to vaccinations. Conjunctivitis is a frequent sequel of various vaccinations. Oculorespiratory syndrome and serum sickness syndrome are considered to be related to influenza vaccinations. The risk of reactivation or initiation of autoimmune diseases (e. g. uveitis) cannot be excluded but has not yet been proven. Overall the benefit of vaccination outweighs the possible but very low risk of ocular side effects.

Poultry food products--a source of avian influenza virus transmission to humans?

Global human mobility and intercontinental connectivity, expansion of livestock production and encroachment of wildlife habitats by invasive agricultural land use contribute to shape the complexity of influenza epidemiology. The OneHealth approach integrates these and further elements into considerations to improve disease control and prevention. Food of animal origin for human consumption is another integral aspect; if produced from infected livestock such items may act as vehicles of spread of animal pathogens, and, in case of zoonotic agents, as a potential human health hazard. Notifiable zoonotic avian influenza viruses (AIV) have become entrenched in poultry populations in several Asian and northern African countries since 2003. Highly pathogenic (HP) AIV (e.g. H5N1) cause extensive poultry mortality and severe economic losses. HPAIV and low pathogenic AIV (e.g. H7N9) with zoonotic propensities pose risks for human health. More than 1500 human cases of AIV infection have been reported, mainly from regions with endemically infected poultry. Intense human exposure to AIV-infected poultry, e.g. during rearing, slaughtering or processing of poultry, is a major risk factor for acquiring AIV infection. In contrast, human infections through consumption of AIV-contaminated food have not been substantiated. Heating poultry products according to kitchen standards (core temperatures ≥70°C, ≥10 s) rapidly inactivates AIV infectivity and renders fully cooked products safe. Nevertheless, concerted efforts must ensure that poultry products potentially contaminated with zoonotic AIV do not reach the food chain. Stringent and sustained OneHealth measures are required to better control and eventually eradicate, HPAIV from endemic regions.

Transfusion-transmitted hepatitis E in Germany, 2013.

The reported IgG seroprevalence against hepatitis E virus (HEV) in German blood donations is 6.8%, and HEV RNA detected in 0.08%, but documented evidence for HEV transmission is lacking. We identified two donations from a single donor containing 120 IU HEV RNA/mL plasma and 490 IU/mL. An infectious dose of 7,056 IU HEV RNA was transmitted via apheresis platelets to an immunosuppressed patient who developed chronic HEV. Further, transmission was probable in an immunocompetent child.

Background paper to the revised recommendation for hepatitis B vaccination of persons at particular risk and for hepatitis B postexposure prophylaxis in Germany.

The German Standing Committee on Vaccination (Ständige Impfkommission, STIKO) recommends vaccinating risk groups against hepatitis B and gives advice for postexposure prophylaxis. STIKO has recently revised this recommendation, focusing on: (i) classification of risk groups, (ii) duration of protection after primary immunization, and (iii) anti-HBs threshold that defines successful hepatitis B vaccination. Orientating literature reviews were performed for the first objective. Examples of population subgroups at increased risk were identified and classified into three indication groups. Systematic reviews on the duration of vaccine-induced protection identified one randomized controlled trial (RCT) and nine cohort studies. When applying the grading of recommendation, assessment, development, and evaluation (GRADE) methodology, evidence from RCTs was considered of very low quality regarding the question of whether hepatitis B can be prevented for 15 years after successful primary vaccination (anti-HBs ≥ 10 IU/l) with a vaccine efficacy of 96 % against chronic hepatitis, 89 % against HBsAg positivity, and 73 % against isolated anti-HBc positivity. However, seven cohort studies showed that no cases of clinical hepatitis B or HBsAg positivity occurred during a maximum follow-up period of 10 years in settings comparable to the situation in Germany when anti-HBs ≥ 10 IU/l was used to indicate vaccination success. Less than 1 % of vaccinated study participants had isolated anti-HBc positivity. GRADE assessment of two cohort studies revealed that evidence of very low quality exists that the use of anti-HBs ≥ 100 IU/l to measure vaccination success leads to a lower frequency of anti-HBc positivity during follow-up than the use of anti-HBs ≥ 10 IU/l. The recommendation was revised according to this evidence.

[Varicella vaccination in Germany. A provisional appraisal in the context of MMR vaccination]. / Die Varizellenimpfung in Deutschland. Eine Zwischenbilanz mit Blick auf die Masern-Mumps-Röteln- (MMR-)Impfung.

In 2004, a general varicella immunization was introduced in Germany for infants from the age of 11 months, followed by the subsequent recommendation in 2009 of a second vaccine dose. The vaccination is carried out at the same time as the immunization against measles, mumps, and rubella (MMR). Results of the nationwide sentinel surveillance of varicella and herpes zoster implemented by the Varicella Working Group (Arbeitsgemeinschaft Varizellen, AGV) show that the defined goals for varicella immunization (reduction of varicella-related morbidity, complications and hospitalizations) have been reached within a few years owing to the advances in vaccine coverage. Although coverage rates for varicella have not yet reached the same levels as for MMR, varicella immunization seems to have benefited from the established MMR immunization schedule. Moreover, there is no evidence for an adverse effect on the use and acceptance of the MMR vaccine. Lessons learnt in measles epidemiology (such as trends in the incidence of the disease in adolescents and infants), as well as in the history of MMR recommendations, may be useful for the evaluation of future epidemiological changes with respect to varicella and herpes zoster. In view of a rapidly waning immunity against the varicella zoster virus after vaccination with one dose and the lifelong persistence of the virus, achieving a robust and sustainable immunity in the general population seems to be an ambitious goal. However, this accomplishment will be indispensable in preventing breakthrough infections and a shift of varicella to older ages and in avoiding an increase in herpes zoster incidence.

Background paper to the recommendation for routine rotavirus vaccination of infants in Germany.

Two rotavirus (RV) vaccines were introduced to the European market in 2006. To support the decision-making process of the German Standing Committee on Vaccination ("Ständige Impfkommission", STIKO) regarding adoption of routine RV vaccination into the national vaccination schedule in Germany relevant scientific background was reviewed. According to STIKO's Standard Operating Procedures for the development of evidence-based vaccination recommendations, a set of key questions was addressed and systematic reviews were performed with a focus on the efficacy, effectiveness, impact and safety of RV vaccines. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was applied to assess the quality of available evidence. Data from 5 randomized controlled trials demonstrated a high efficacy of RV vaccines in preventing severe RV-associated gastroenteritis (91%) and hospitalization (92%) in settings comparable to Germany. Post-marketing observational studies confirmed these findings. In several countries, impact studies suggest that age groups not eligible for vaccination might also benefit from herd effects and demonstrated a decrease in the number of nosocomial RV infections after RV vaccine introduction. The vaccines were considered safe, except for a slightly increased risk of intussusception shortly after the first dose, corresponding to 1-2 additional cases per 100,000 infants vaccinated (relative risk =1.21, 95% confidence interval [CI] 0.68-2.14). RV case-fatality is extremely low in Germany. However, RV incidence among children aged <5 years is high (reported 8-14 cases per 1000 children annually), and of these almost half require hositalization. In view of the available evidence and expected benefits, STIKO recommends routine rotavirus vaccination of children under the age of 6 months with the main goal of preventing RV-associated hospitalizations in Germany, especially among infants and young children.

[Concepts, effectiveness, and perspectives of pandemic and seasonal influenza vaccines]. / Konzepte, Wirksamkeit und Perspektiven pandemischer und nichtpandemischer Influenzaimpfungen.

For the first time in history, the conditions to influence the course of an influenza pandemic through vaccination were set during the influenza A H1N1 pandemic in 2009. The specific requirements for pandemic vaccines are to be highly immunogenic in immunologically naive individuals and to be producible quickly in large quantities. In contrast, seasonal influenza vaccines induce a booster response and a broadening of preexisting immunity. In this article the concepts of seasonal and pandemic influenza vaccines and data on their immunogenicity and clinical efficacy are reviewed and discussed. In the upcoming years, seasonal influenza vaccination will continue to be based on inactivated split-virion and subunit vaccines or the live attenuated cold-adapted vaccine. The pandemic vaccines used in 2009 proved to be more immunogenic than expected from prepandemic vaccine trials, while the adverse events observed with AS03-adjuvanted vaccines call their future use into question. However, neither seasonal nor pandemic influenza vaccines can be regarded to be an ideal solution, because they have to be frequently adapted to new virus strains and they lack effectiveness in particular risk groups. They can be regarded as interim approaches to highly immunogenic vaccines that hopefully become available in the future. The underlying principles of future vaccines are also presented in this article.

Epidemiological impact and disease burden of congenital cytomegalovirus infection in Europe.

In Europe, congenital cytomegalovirus (CMV) infection is the leading cause of neurological disabilities in children, causing severe sequelae such as sensorineural hearing loss, neurodevelopmental delay or blindness. The infection causes high disease burden and costs. Nevertheless, there is little awareness of CMV among medical officials and the general public.

Low dose oral combination chemoprophylaxis with oseltamivir and amantadine for influenza A virus infections in mice.

In the present study, the effect of combining anti-influenza drugs active at different steps of the influenza virus replication cycle, oseltamivir as a neuraminidase (NA) inhibitor and amantadine targeting M2 protein, was investigated in vivo by oral administration in a mouse model of aerosol influenza virus infection and in vitro in MDCK cells. In mice, doses of oseltamivir and amantadine providing 50-60% survival against A/Hongkong/1/68 (H3N2) or A/PR/8/34 (H1N1) were capable of conferring complete protection when used simultaneously, suggesting that increased inhibition of influenza virus replication by combining oseltamivir and amantadine in vitro translates into protection from lethal infection of mice. The combination of amantadine with oseltamivir required 15-fold less oseltamivir than monotherapy to confer complete protection against lethal aerosol influenza virus infection. Remarkably, amantadine-based combination chemoprophylaxis was even effective against amantadine-resistant A/PR/8/34 influenza virus. Thus, combination chemotherapy may be more efficacious than monotherapy against newly emerging Influenza A subtypes.

Corking the bottleneck: the transporter associated with antigen processing as a target for immune subversion by viruses.

In this chapter, mechanisms are reviewed that viruses use to inhibit the function of the peptide transporter associated with antigen processing (TAP), which translocates cytosolic peptides into the endoplasmic reticulum (ER) for binding to MHC class I molecules. Although some DNA viruses, such as adenovirus or EBV, downmodulate TAP expression on the transcriptional level, members of the alpha and beta subfamily of herpesviruses, such as herpes simplex virus (HSV) and human cytomegalovirus (HCMV), express proteins that bind to TAP and interfere with peptide translocation. The modes of action of the HSV-encoded cytosolic TAP inhibitor ICP47 and the HCMV-encoded ER-resident TAP inhibitor gpUS6 are discussed in detail. Viral interference with antigen presentation through TAP inhibition is not only relevant for the immunobiology of persistent viral infections but also contributes to the understanding of the translocation mechanism utilized by the ATP-binding cassette transporter TAP.

A mouse model for cytomegalovirus infection.

This unit describes procedures for infecting newborn and adult mice with murine cytomegalovirus (mCMV). Methods are included for propagating mCMV in cell cultures and for preparing a more virulent form of mCMV from salivary glands of infected mice. A plaque-forming cell (PFC) assay is provided for measuring mCMV titers of infected tissues or virus stocks. In addition, a method is described for preparing the murine embryonic fibroblasts used for propagating mCMV and for the PFC assay.

Association of myocardial infarction with mononuclear cell expression of the cytomegalovirus chemokine receptor US28 in patients with NIDDM.

BACKGROUND: Infectious agents have been linked to atherosclerosis and its acute manifestations; however, little is known about their influence in the context of established risk factors. OBJECTIVE: To elucidate the role of the cytomegalovirus (CMV)-encoded chemokine receptor US28 in myocardial infarction (MI) afflicting patients with or without type II diabetes mellitus (NIDDM) on a molecular level. PATIENTS AND METHODS: In a group of patients (n=112) with a high prevalence of NIDDM and coronary artery disease, CMV serology was performed, and mRNA expression of US28 and immediate early 1 gene as markers of CMV reactivation were analyzed in peripheral mononuclear blood cells by a nested reverse transcription-polymerase chain reaction. Moreover, transendothelial chemotaxis assays using mononuclear cells transfected with or without US28 were performed in vitro. RESULTS: While the incidence of smoking was higher in nondiabetic patients with MI than in those without MI, significant differences in other risk factors, such as cholesterol, low density lipoprotein, fibrinogen, blood pressure, and Chlamydia pneumoniae immunoglobulin G or CMV immunoglobulin G titres, were not observed. In contrast, the levels of C-reactive protein reflecting inflammation or infection were raised in NIDDM patients with or without MI. Notably, mRNA expression of intermediate early 1 gene and US28 indicative of CMV reactivation was detected in a small subset (four of 21) of NIDDM patients with MI but not in those without MI (P<0.03). Transfection of US28 in mononuclear cells conferred transendothelial chemotaxis to monocyte chemokines, inferring a mechanism for deleterious effects of CMV under permissive conditions. CONCLUSIONS: Results show that MI was associated with mononuclear expression of CMV genes such as functional chemokine receptor US28 in a subset of patients with NIDDM, inferring that this association may predispose to MI. Ongoing infection or inflammation in NIDDM patients as shown by increased C-reactive protein may account for susceptibility to CMV reactivation and MI.

MHC class I-subversive gene functions of cytomegalovirus and their regulation by interferons-an intricate balance.

Multiple glycoproteins of human cytomegalovirus (HCMV) encoded by the genes US2, US3, US6 and US11 interrupt the MHC class I pathway of antigen presentation at distinct checkpoints to avoid recognition of infected cells by cytotoxic CD8+ T lymphocytes. The action of cytokines like interferon (IFN)-gamma, IFN-alpha/beta and tumour necrosis factor alpha (TNF-alpha) compensate for the viral inhibition and restore antigen presentation in HCMV-infected cells. This finding was explained by their effects on cellular rather than viral genes and reflected by an increase in the production, assembly and maturation of MHC class I molecules resulting in an escape of MHC I from viral control. Here we reproduce the IFN-gamma-mediated effect when MHC I-subversive gene functions of HCMV are tested in isolation, but the efficacy of IFN-gamma to restore MHC I surface expression in US2-, US6- and US11-transfectants differs significantly. In addition, in HCMV-infected cells IFN-gamma strongly affects the synthesis of the US6-encoded glycoprotein. Despite the capability of HCMV to block the interferon signaling pathway the IFN-gamma driven enhancement of MHC class I and class II expression remains effective provided that cells are exposed to IFN-gamma before infection. Our findings illustrate a complex interplay between host immune factors and viral immune evasion functions.