Epilepsy in patients with GRIN2A alterations: Genetics, neurodevelopment, epileptic phenotype and response to anticonvulsive drugs.

OBJECTIVE: To delineate the genetic, neurodevelopmental and epileptic spectrum associated with GRIN2A alterations with emphasis on epilepsy treatment. METHODS: Retrospective study of 19 patients (7 females; age: 1-38 years; mean 10.1 years) with epilepsy and GRIN2A alteration. Genetic variants were classified according to the guidelines and recommendations of the American College of Medical Genetics (ACMG). Clinical findings including epilepsy classification, treatment, EEG findings, early childhood development and neurodevelopmental outcome were collected with an electronic questionnaire. RESULTS: 7 out of 19 patients fulfilled the ACMG-criteria of carrying "pathogenic" or "likely pathogenic variants", in twelve patients the alterations were classified as variants of unknown significance. The spectrum of pathogenic/likely pathogenic mutations was as follows: nonsense n = 3, missense n = 2, duplications/deletions n = 1 and splice site n = 1. First seizures occurred at a mean age of 2.4 years with heterogeneous seizure types. Patients were treated with a mean of 5.6 AED. 4/5 patients with VPA had an improved seizure frequency (n = 3 with a truncation: n = 1 missense). 3/5 patients with STM reported an improvement of seizures (n = 2 truncation, n = 1 splicing). 3/5 CLB patients showed an improvement (n = 2: truncation; n = 1 splicing). Steroids were reported to have a positive effect on seizure frequency in 3/5 patients (n = 1 each truncation, splicing or deletion). CONCLUSIONS: Our data indicate that children with epilepsy due to pathogenic GRIN2A mutations present with different clinical phenotypes and a spectrum of seizure types in the context of a pharmacoresistant epilepsy providing information for clinicians treating children with this form of genetically determined epileptic syndrome.

Mechanisms, patterns and outcomes of paediatric polytrauma in a UK major trauma centre.

Introduction Paediatric trauma is a significant burden to healthcare worldwide and accounts for a large proportion of deaths in the UK. Methods This retrospective study examined the epidemiological data from a major trauma centre in the UK between January 2012 and December 2014, reviewing all cases of moderate to severe trauma in children. Patients were included if aged ≤16 years and if they had an abbreviated injury scale score of ≥2 in one or more body region. Results A total of 213 patients were included in the study, with a mean age of 7.8 years (standard deviation [SD]: 5.2 years). The most common cause of injury was vehicle related incidents (46%). The median length of hospital stay was 5 days (interquartile range [IQR]: 4-10 days). Approximately half (52%) of the patients had to stay in the intensive care unit, for a median of 1 day (IQR: 0-2 days). The mortality rate was 6.6%. The mean injury severity score was 19 (SD: 10). Pearson's correlation coefficient showed a positive correlation for injury severity score with length of stay in hospital (p<0.001). Conclusions There is significant variation in mechanism of injury, severity and pattern of paediatric trauma across age groups. A multidisciplinary team approach is imperative, and patients should be managed in specialist centres to optimise their care and eventual functional recovery. Head injury remained the most common, with significant mortality in all age groups. Rib fractures and pelvic fractures should be considered a marker for the severity of injury, and should alert doctors to look for other associated injuries.

ELISA-Based Crossmatching Allowing the Detection of Emerging Donor-Specific Anti-HLA Antibodies through the Use of Stored Donors' Cell Lysates.

About forty years ago the complement-dependent crossmatch assay (CDC-CM) was developed as standard procedure in order to select recipients without donor-specific antibodies directed against human leukocyte antigens of their given donors since the negative outcome of pretransplant crossmatching represents one of the most important requirements for a successful kidney graft survival. However, as a functional assay the CDC-CM strongly depends on the availability of donors' isolated lymphocytes and in particular on their vitality highly limiting its applicability for recipients treated with special drugs and therapeutic antibodies or suffering from underlying autoimmune diseases. In the great majority of these cases ELISA-based crossmatching has been demonstrated to be an adequate alternative procedure nevertheless leading to valid results. With these case reports we show for the first time that ELISA-based crossmatching is suitable to demonstrate the upcoming donor-specific anti-HLA antibodies as a consequence of allografting using deep-frozen deceased donor's material such as blood or spleen detergent lysate. Thus, this ELISA-based procedure first provides the option to routinely perform crossmatching using stored material of deceased donors in order to substitute or at least to complement virtual crossmatching, that is, the comparison of the recipients' anti-HLA antibody specificities with the donors' historically identified HLA types.

Medium-to-long term DEXA analysis of an uncemented (AML) femoral component.

We present medium-to-long-term bone mineral density studies assessing bone resorption and remodelling around the cementless femoral component of a total hip arthroplasty (Depuy AML prosthesis). Bone mineral densities were compared with the unoperated side at a time interval of eight years between scans using dual energy X-ray absorptiometry. Initial proximal stress shielding is known but we show that this response continues into the medium to long term in relative terms. We have also found an overall trend for bone mineral density to increase around the prosthesis with the greatest changes occurring distally. The greatest real increase in bone mineral density occurred in Gruen zones 2, 3 and 5 with smaller increases in zones 1, 4, 6 and 7. However, when compared with the contralateral unoperated femur (thus considering systemic changes in bone mineral density), we found these changes only reached statistical significance in Gruen zones 5, 6 and 7.

The WHO Global Influenza Program and its Animal Influenza Network.

The World Health Organization (WHO) Global Influenza Program makes annual recommendations on influenza vaccine formulation and related activities. This results in 230 million annual doses of vaccine produced for human use. The success of this program is based on the collection and genetic and antigenic analyses of influenza viruses collected by the WHO Global Influenza Surveillance Program. New programs focus on pandemic preparedness and include development and distribution of testing reagents for emerging or potentially emerging human influenza viruses. WHO Animal Influenza Network focuses on aspects of ecology and molecular biology of animal influenza viruses in the context of human health.

Overview of the WHO Global Influenza Programme.

The major focus of the WHO Influenza Programme has been on the annual recommendations of the influenza vaccine formulation and related activities committees. The Programme's main structural components are National Influenza Centres (NIC) which sample patients with influenza-like-illness and WHO Collaborating Centres (WHO CC) which receive representative isolates from NICs for antigenic and genetic analyses. In addition, WHO CCs, jointly with key national reference laboratories, conduct annual studies on whether the current vaccines induce satisfactory antibody levels to new epidemic strains. They also make available high yielding reassortant viruses for vaccine production as well as vaccine potency testing reagents. The WHO Global Influenza Programme jointly with its partners published Pandemic Preparedness Guidelines and Recommendations on the Use of Inactivated Influenza Vaccine. It has recently initiated the development of a Global Agenda on Influenza (www.who.int/influenza) and expanded its mission from surveillance to pandemic preparedness, assessment of impact of influenza and increasing influenza vaccine usage.

An assessment of antimicrobial consumption in food producing animals in Kenya.

Antimicrobial agents are useful for control of bacterial infections in food animals and man. Their prudent use in these animals is important to control any possible development and transfer of resistance between animals and man. The objective of this study was to generate quantitative information to evaluate antimicrobial usage patterns by animal species, route of administration, antimicrobial class and type of use from 1995 to 1999 in Kenya. Theses data are essential for risk analysis and planning and can be helpful in interpreting resistance surveillance data, and evaluating the effectiveness of prudent use efforts and antimicrobial resistance mitigation strategies. Data on quantities of active substance classes were collected from the official records of the Pharmacy and Poisons Board of the Ministry of Health and analysed in MS Excel 2000 program. The mean antimicrobial consumption for the 5-year period was 14 594 +/- 1457 kg per year. This was distributed in the various antimicrobial classes as follows: 7975 kg (54.65%) of tetracyclines, 3103.96 kg (21.27%) of sulfonamides and 954.5 kg (6.56%) of aminoglycosides, 905 kg (6.20%) of beta-lactams, 94 kg (0.64%) of quinolones, 35 kg (0.24%) of macrolides and 24 kg (0.16%) of others (tiamulin). Mean consumption per year among the various food animals was: 10 989 +/- 357 kg in large animals (cattle, sheep, pigs and goats), 2906 +/- 127 kg in poultry alone and 699 +/- 427 kg in both large animals and poultry. These quantities represented 56.56% (8255 kg) consumption per year for parenteral use, 41.79% (6098 kg) for oral use and 1.65% (241 kg) for topical use (intramammary and eye ointments) in cattle. With respect to intended use in food producing animals, the mean consumption per year was: 13 178 kg (90.30%) for therapeutic use (ST), 4 kg (0.03%) for prophylactic treatment (PT) and 1411 +/- 246 kg (9.67%) was used both for therapeutic and prophylactic purposes (GPT). The study confirmed that antimicrobials are not used for growth promotion in Kenya. There was no specific trend in the quantities of active antimicrobial classes. This study has revealed that the tetracyclines, sulfonamides and trimethoprim, nitrofurans aminoglycosides, beta-lactams and the quinolones are the most commonly used drugs in food-producing animals in Kenya. Tetracyclines contributed approximately 55% of the total consumption, and there was an increasing trend in the consumption of quinolones from 1998.

Public health implications of emerging zoonoses.

Many new, emerging and re-emerging diseases of humans are caused by pathogens which originate from animals or products of animal origin. A wide variety of animal species, both domestic and wild, act as reservoirs for these pathogens, which may be viruses, bacteria or parasites. Given the extensive distribution of the animal species affected, the effective surveillance, prevention and control of zoonotic diseases pose a significant challenge. The authors describe the direct and indirect implications for public health of emerging zoonoses. Direct implications are defined as the consequences for human health in terms of morbidity and mortality. Indirect implications are defined as the effect of the influence of emerging zoonotic disease on two groups of people, namely: health professionals and the general public. Professional assessment of the importance of these diseases influences public health practices and structures, the identification of themes for research and allocation of resources at both national and international levels. The perception of the general public regarding the risks involved considerably influences policy-making in the health field. Extensive outbreaks of zoonotic disease are not uncommon, especially as the disease is often not recognised as zoonotic at the outset and may spread undetected for some time. However, in many instances, the direct impact on health of these new, emerging or re-emerging zoonoses has been small compared to that of other infectious diseases affecting humans. To illustrate the tremendous indirect impact of emerging zoonotic diseases on public health policy and structures and on public perception of health risks, the authors provide a number of examples, including that of the Ebola virus, avian influenza, monkeypox and bovine spongiform encephalopathy. Recent epidemics of these diseases have served as a reminder of the existence of infectious diseases and of the capacity of these diseases to occur unexpectedly in new locations and animal species. The need for greater international co-operation, better local, regional and global networks for communicable disease surveillance and pandemic planning is also illustrated by these examples. These diseases have contributed to the definition of new paradigms, especially relating to food safety policies and more generally to the protection of public health. Finally, the examples described emphasise the importance of intersectorial collaboration for disease containment, and of independence of sectorial interests and transparency when managing certain health risks.

Zoonoses and fertility control in wildlife--requirements for vaccines.

This paper reflects on public health considerations on the voluntary release of anti-fertility vaccines for wildlife in the environment. The World Health Organization (WHO) has established a variety of recommendations on safety and efficacy requirements for the voluntary release of rabies vaccines used for oral immunization of animals. These requirements cover aspects of control of rabies and possible biological consequences in the target population. They also deal with the protection of the health of humans and other non-target species that might come into contact with the different oral rabies vaccines used in various parts of the world. These recommendations are laid down in several WHO publications. They are specific to the disease concerned, the target animal reservoir, the relationship and types of contact between humans and target animals, the vaccines and baits used and the respective conditions of oral immunization of wildlife in densely-populated areas. Many of these recommendations also apply to the development and application of contraceptive vaccines for wildlife carnivores. Additional safety requirements concern the transmissibility of the antigen, the reversibility of the intervention within an individual animal and in animal populations, as well as the species specificity of the antigen used. The management of animal populations that are reservoirs for zoonotic diseases is a possible means by which diseases that are transmissible from animals to humans could be prevented. Oral contraception by means of vaccines is an appealing method, provided that requirements for protecting public and animal health, as well as ensuring environmental safety, are precisely defined and strictly adhered to.

Foodborne salmonellosis.

Foodborne diseases caused by non-typhoid Salmonella are a very important public health problem and an economic burden in many parts of the world. Salmonellosis data from the WHO Global Databank on Foodborne Disease, from the literature and from the WHO Surveillance Programme in Europe were reviewed for the years 1985-1995, showing an apparent increase in the incidence of salmonellosis in many parts of the world. In industrialized countries, this increase may be due to the emergence and increase of S. enteritidis and S. typhimurium DT104. In order to reduce the incidence of human foodborne salmonellosis, measures should be taken simultaneously during the production, processing, distribution, retail marketing and handling/preparation of food to prevent the introduction of Salmonella and its multiplication. These control measures need to be supported by effective foodborne disease surveillance programmes which make it possible to recognize and investigate outbreaks and emerging pathogens, and to assess the need for and evaluate interventions by monitoring longer term trends.

The role of veterinary public health in the prevention of zoonoses.

Veterinary public health is a component of public health activities devoted to the application of professional veterinary skills, knowledge, and resources for the protection and improvement of public health. VPH activities involve a very diverse range of functions within public health which reflect the broad community of interests between veterinary and human medicine. Zoonoses continue to represent an important health hazard in most parts of the world, where they cause considerable expenditure and losses for the health and agricultural sectors. Although the situation is improving in the industrialized world, zoonoses prevention and control will remain an area of major concern in most developing countries. Recent observations in these countries show that expenses related to the prevention of zoonotic diseases in humans are likely to increase dramatically in the near future. Programmes for their control and eventual elimination in animal reservoirs are urgently needed. The technical knowledge exists to bring diseases such as brucellosis, rabies, and bovine tuberculosis under control during the first decade of the next century. To achieve this goal, constant efforts will be needed for the next 15 to 20 years. In addition, as trade in animal products and the movement of human populations continues to increase, the risk that zoonotic diseases will be introduced or reintroduced into certain areas is likewise increasing. Over the past five years, a number of zoonotic diseases have emerged as either new pathological entities or known agents appearing in new areas or as new strains. Through its coordinating and information gathering functions, the WHO Emerging Disease Surveillance and Control Division provides a source of both practical and technical guidance that can help solve these and other threats to human health posed by animals.

Progress and setbacks in the oral immunisation of foxes against rabies in Europe.

The oral immunisation of foxes has led to a substantial decrease in the number of rabies cases in Europe. Between 1989 and 1994 the prevalence of rabies in animals was reduced to less than 20 per cent of the 1989 level in countries which had been conducting oral immunisation campaigns since 1992 or before. Since 1978 more than 73.7 million baits have been spread over an area of 4-9 million km2. However, large areas have not yet been declared rabies-free, so the economic and public health benefits stemming from the reduced prevalence of rabies have so far remained marginal. Setbacks have occurred which have slowed the progress of vaccination, particularly towards the end of the 1980s and during the early 1990s. The reasons for the territorial differences in progress are discussed and the factors which have contributed to greater success in vaccination campaigns are identified. Unfortunately, the many positive and negative experiences with oral immunisation of foxes in Europe have resulted in only a limited number of scientifically validated recommendations for strategies to be applied under the different ecological and epidemiological conditions in Europe. Solutions have not yet been found to questions such as the duration of vaccination campaigns, the level of surveillance during and after campaigns and the appropriate countermeasures to compensate for the obvious increase in the density of the fox population.

Pattern analysis of human Salmonella enteritidis infection.

Information on salmonella serovar, community, and date of isolation concerning 10,368 cases of S. enteritidis (SE) infection and 1163 cases of S. typhimurium (ST) infection reported in 1992 to the Salmonella Data Bank of the Land of Brandenburg have been analyzed for clusters and trends on case/time diagrams. A breakdown by district provided a suitable degree of "resolution" for discrimination of "Episodes of Increased Case Frequency" (EICF) and 7 days moving averages. Thus 39 of the 44 districts of the Land were included in the evaluation of SE cases. The population size of the remaining 5 districts was too high for clear episode discrimination. EICFs were subdivided into (a) 16 outbreaks (another 10 outbreaks occurred outside EICFs), which had also been identified and officially reported by local health services as a result of compulsory investigation of cases and their social environment, and (b) 44 "case accumulations" (ACCs), which were only identified by retrospective analysis of the case/time diagrams. By this procedure, three case categories of distinct properties have been found for SE transmission from the animal reservoir to the human population: outbreaks, ACCs, and "truly sporadic cases" scattered over the district outside outbreaks and ACCs (Table 3). Truly sporadic cases (Table 6) represented the largest proportion of SE cases. ACCs accounted for 37% and outbreaks, for 12%. The most striking result concerns the ACCs, which cover slightly larger geographical areas (mean: 3.5 communities) and last longer (mean: 3 weeks, but up to 7 weeks) than officially recorded outbreaks (means: 2 communities and 2 weeks). SE-ACCs differed from SE outbreaks also in the seasonal pattern. Otherwise, ACCs met outbreak characteristics including the average number of persons involved (mean: 64, for outbreaks: 42; Table 4). The results suggest that SE-ACCs represent an important and distinct element in the SE epidemic. This conclusion is supported by a comparison of the findings with results obtained by the same procedure for ST cases. ST outbreaks do not differ from ST-ACCs in any respect, and both types of ST-episodes are of significantly shorter duration and comprise less people than episodes due to SE. The public health significance of the SE-ACCs as a newly detected and particular element of the current SE epidemic is discussed. In view of the epidemiological significance, i.e. the high proportion of all SE cases involved, it appears justified to develop methods for the early detection of ACCs and the search for the "missing link" between the cases and their source at the community level.

[Integrated quality assurance]. / Integrierte Qualitätssicherung.

The definition of terms and connotation of "Quality", "Quality Assurance" and "Integration" lead to an analysis and understanding of inhibiting and fostering factors of the "Health Triad" of people, animals and environment. Although "Quality" is largely or ultimately determined by the consumer, there are considerable differences as this term is applied by (a) the individual consumer, (b) the dynamic producer defending or gaining markets, (c) those engaged in traditional product manufacturing, or (d) governments setting (minimum) requirements for the sake of free trade. "Quality Assurance" offers cooperation of partners all along the food chain from "pasture to table". The managerial process turned into a continuum of responsibility and agreement on processes and product characteristics. This overcomes the disadvantages of strategies stressing distinct defense barriers. In practice this philosophy of a predominant role of defence barriers proved largely partnership destructive, in that it permitted to shift responsibilities for failures and to claim administrative competence according to momentary situations and interests. "Integrated Quality Assurance" means mutual agreement of two or more partners along the food chain (e. g. feed producers, farmers, animal health industry, veterinarians and food processors) on product characteristics and production methods. It involves essential system elements including facilities, materials, manpower, information, transport, management etc. Different principles and procedures of quality assurance have been introduced in practice, including agriculture and food processing. These different approaches are not mutually exclusive but largely of complementary nature.(ABSTRACT TRUNCATED AT 250 WORDS)

[Epidemiologic pattern of Salmonella enteritidis and Salmonella typhimurium in man--analysis of Salmonella cases in the Brandenburg federal territory]. / Epidemiologische Muster von Salmonella enteritidis und Salmonella typhimurium beim Menschen--Analyse der Salmonellenfälle im Bundesland Brandenburg.

It is the aim of this study (a study that is part of several investigations suggested and coordinated by the WHO) to highlight the characteristics of transmission of Salmonella in humans. To achieve this, the data collected on the basis of the Federal German Law governing Epidemic Diseases as well as additionally available data (sex, serovar, differentiation between diseased and symptomatic, allocation to the respective place of residence) have been evaluated. In this manner it became possible to determine different patterns of incidence of the presently most frequently occurring salmonella serovars S. enteritidis and S. typhimurium in respect of distribution according to age and sex, as well as the dynamics of distribution and incidence in terms of time. The incidence is particularly remarkable among children, where S. enteritidis is not so frequent as S. typhimurium. There is a distinct trend towards the male sex among children in respect of the infestation. The fact that women are particularly often asymptomatic carriers points to the special nature of the sources and paths of infection. In respect of seasonal dynamics S. typhimurium does not have a specific summer peak, contrary to S. enteritidis, and this too indicates that the mechanisms of transmission or multiplication differ from one another. The study presented here is supplemented by the evaluation of further parameters to support and promote on-target epidemiological investigation into the various problems raised by this and other studies.

[Experiences with the aerial distribution of baits for the oral immunization of foxes against rabies in eastern Germany]. / Erfahrungen mit der Flugzeugausbringung von Ködern zur oralen Immunisierung der Füchse gegen Tollwut in Ostdeutschland.

Since the first test in spring 1990, aerial distribution of baits has been developed as the main bait distribution variant in the new federal states of Germany. Experiences are given in respect of organisation, management and enforcement of oral immunization campaigns and cooperation between veterinary agencies and flight enterprises. Practical aspects are described to ensure bait density, preparation of maps, creation of technical preconditions and realisation of dropping rhythm. Aerial dropping in comparison with hand distribution of baits was shown to be equivalent at least in respect of bait uptake and seroconversion rate.