Conventional and novel anti-seizure medications reveal a particular role for GABAA in a North Sea progressive myoclonus Epilepsy Drosophila model.

OBJECTIVE: North Sea Progressive Myoclonus Epilepsy (NS-PME) is a rare genetic disorder characterized by ataxia, myoclonus and seizures with a progressive course. Although the cause of NS-PME is known, namely a homozygous mutation in the GOSR2 gene (c.430 G>T; p. Gly144Trp), sufficient treatment is lacking. Despite combinations of on average 3-5 anti-seizure medications (ASMs), debilitating myoclonus and seizures persist. Here we aimed to gain insight into the most effective anti-convulsive target in NS-PME by evaluating the individual effects of ASMs in a NS-PME Drosophila model. METHOD: A previously generated Drosophila model for NS-PME was used displaying progressive heat-sensitive seizures. We used this model to test 1. a first-generation ASM (sodium barbital), 2. common ASMs used in NS-PME (clonazepam, valproic acid, levetiracetam, ethosuximide) and 3. a novel third-generation ASM (ganaxolone) with similar mode of action to sodium barbital. Compounds were administered by adding them to the food in a range of concentrations. After 7 days of treatment, the percentage of heat-induced seizures was determined and compared to non-treated but affected controls. RESULTS: As previously reported in the NS-PME Drosophila model, sodium barbital resulted in significant seizure suppression, with increasing effect at higher dosages. Of the commonly prescribed ASMs, clonazepam and ethosuximide resulted in significant seizure suppression, whereas both valproic acid and levetiracetam did not show any changes in seizures. Interestingly, ganaxolone did result in seizure suppression as well. CONCLUSION: Of the six drugs tested, three of the four that resulted in seizure suppression (sodium barbital, clonazepam, ganaxolone) are primary known for their direct effect on GABAA receptors. This suggests that GABAA could be a potentially important target in the treatment of NS-PME. Consequently, these findings add rationale to the exploration of the clinical effect of ganaxolone in NS-PME and other progressive myoclonus epilepsies.

Mating increases Drosophila melanogaster females' choosiness by reducing olfactory sensitivity to a male pheromone.

Females that are highly selective when choosing a mate run the risk of remaining unmated or delaying commencing reproduction. Therefore, low female choosiness would be beneficial when males are rare but it would be maladaptive if males become more frequent. How can females resolve this issue? Polyandry would allow mating-status-dependent choosiness, with virgin females selecting their first mate with little selectivity and becoming choosier thereafter. This plasticity in choosiness would ensure timely acquisition of sperm and enable females to increase offspring quality during later mating. Here, we show that Drosophila melanogaster females display such mating-status-dependent choosiness by becoming more selective once mated and identify the underlying neurohormonal mechanism. Mating releases juvenile hormone, which desensitizes Or47b olfactory neurons to a pheromone produced by males, resulting in increased preference for pheromone-rich males. Besides providing a mechanism to a long-standing evolutionary prediction, these data suggest that intersexual selection in D. melanogaster, and possibly in all polyandrous, sperm-storing species, is mainly the domain of mated females since virgin females are less selective. Juvenile hormone influences behaviour by changing cue responsiveness across insects; the neurohormonal modulation of olfactory neurons uncovered in D. melanogaster provides an explicit mechanism for how this hormone modulates behavioural plasticity.

North Sea Progressive Myoclonus Epilepsy is Exacerbated by Heat, A Phenotype Primarily Associated with Affected Glia.

Progressive myoclonic epilepsies (PMEs) comprise a group of rare disorders of different genetic aetiologies, leading to childhood-onset myoclonus, myoclonic seizures and subsequent neurological decline. One of the genetic causes for PME, a mutation in the gene coding for Golgi SNAP receptor 2 (GOSR2), gives rise to a PME-subtype prevalent in Northern Europe and hence referred to as North Sea Progressive Myoclonic Epilepsy (NS-PME). Treatment for NS-PME, as for all PME subtypes, is symptomatic; the pathophysiology of NS-PME is currently unknown, precluding targeted therapy. Here, we investigated the pathophysiology of NS-PME. By means of chart review in combination with interviews with patients (n = 14), we found heat to be an exacerbating factor for a majority of NS-PME patients (86%). To substantiate these findings, we designed a NS-PME Drosophila melanogaster model. Downregulation of the Drosophila GOSR2-orthologue Membrin leads to heat-induced seizure-like behaviour. Specific downregulation of GOSR2/Membrin in glia but not in neuronal cells resulted in a similar phenotype, which was progressive as the flies aged and was partially responsive to treatment with sodium barbital. Our data suggest a role for GOSR2 in glia in the pathophysiology of NS-PME.

A Method to Test the Effect of Environmental Cues on Mating Behavior in Drosophila melanogaster.

An individual's sexual drive is influenced by genotype, experience and environmental conditions. How these factors interact to modulate sexual behaviors remains poorly understood. In Drosophila melanogaster, environmental cues, such as food availability, affect mating activity offering a tractable system to investigate the mechanisms modulating sexual behavior. In D. melanogaster, environmental cues are often sensed via the chemosensory gustatory and olfactory systems. Here, we present a method to test the effect of environmental chemical cues on mating behavior. The assay consists of a small mating arena containing food medium and a mating couple. The mating frequency for each couple is continuously monitored for 24 h. Here we present the applicability of this assay to test environmental compounds from an external source through a pressurized air system as well as manipulation of the environmental components directly in the mating arena. The use of a pressurized air system is especially useful to test the effect of very volatile compounds, while manipulating components directly in the mating arena can be of value to ascertain a compound's presence. This assay can be adapted to answer questions about the influence of genetic and environmental cues on mating behavior and fecundity as well as other male and female reproductive behaviors.

The nutritional and hedonic value of food modulate sexual receptivity in Drosophila melanogaster females.

Food and sex often go hand in hand because of the nutritional cost of reproduction. For Drosophila melanogaster females, this relationship is especially intimate because their offspring develop on food. Since yeast and sugars are important nutritional pillars for Drosophila, availability of these foods should inform female reproductive behaviours. Yet mechanisms coupling food and sex are poorly understood. Here we show that yeast increases female sexual receptivity through interaction between its protein content and its odorous fermentation product acetic acid, sensed by the Ionotropic odorant receptor neuron Ir75a. A similar interaction between nutritional and hedonic value applies to sugars where taste and caloric value only increase sexual receptivity when combined. Integration of nutritional and sensory values would ensure that there are sufficient internal nutrients for egg production as well as sufficient environmental nutrients for offspring survival. These findings provide mechanisms through which females may maximize reproductive output in changing environments.

Diurnality as an energy-saving strategy: energetic consequences of temporal niche switching in small mammals.

Endogenous daily (circadian) rhythms allow organisms to anticipate daily changes in the environment. Most mammals are specialized to be active during the night (nocturnal) or day (diurnal). However, typically nocturnal mammals become diurnal when energetically challenged by cold or hunger. The circadian thermo-energetics (CTE) hypothesis predicts that diurnal activity patterns reduce daily energy expenditure (DEE) compared with nocturnal activity patterns. Here, we tested the CTE hypothesis by quantifying the energetic consequences of relevant environmental factors in mice. Under natural conditions, diurnality reduces DEE by 6-10% in energetically challenged mice. Combined with night-time torpor, as observed in mice under prolonged food scarcity, DEE can be reduced by ∼20%. The dominant factor determining the energetic benefit of diurnality is thermal buffering provided by a sheltered resting location. Compared with nocturnal animals, diurnal animals encounter higher ambient temperatures during both day and night, leading to reduced thermogenesis costs in temperate climates. Analysis of weather station data shows that diurnality is energetically beneficial on almost all days of the year in a temperate climate region. Furthermore, diurnality provides energetic benefits at all investigated geographical locations on European longitudinal and latitudinal transects. The reduction of DEE by diurnality provides an ultimate explanation for temporal niche switching observed in typically nocturnal small mammals under energetically challenging conditions. Diurnality allows mammals to compensate for reductions in food availability and temperature as it reduces energetic needs. The optimal circadian organization of an animal ultimately depends on the balance between energetic consequences and other fitness consequences of the selected temporal niche.

Cold and hunger induce diurnality in a nocturnal mammal.

The mammalian circadian system synchronizes daily timing of activity and rest with the environmental light-dark cycle. Although the underlying molecular oscillatory mechanism is well studied, factors that influence phenotypic plasticity in daily activity patterns (temporal niche switching, chronotype) are presently unknown. Molecular evidence suggests that metabolism may influence the circadian molecular clock, but evidence at the level of the organism is lacking. Here we show that a metabolic challenge by cold and hunger induces diurnality in otherwise nocturnal mice. Lowering ambient temperature changes the phase of circadian light-dark entrainment in mice by increasing daytime and decreasing nighttime activity. This effect is further enhanced by simulated food shortage, which identifies metabolic balance as the underlying common factor influencing circadian organization. Clock gene expression analysis shows that the underlying neuronal mechanism is downstream from or parallel to the main circadian pacemaker (the hypothalamic suprachiasmatic nucleus) and that the behavioral phenotype is accompanied by phase adjustment of peripheral tissues. These findings indicate that nocturnal mammals can display considerable plasticity in circadian organization and may adopt a diurnal phenotype when energetically challenged. Our previously defined circadian thermoenergetics hypothesis proposes that such circadian plasticity, which naturally occurs in nocturnal mammals, reflects adaptive maintenance of energy balance. Quantification of energy expenditure shows that diurnality under natural conditions reduces thermoregulatory costs in small burrowing mammals like mice. Metabolic feedback on circadian organization thus provides functional benefits by reducing energy expenditure. Our findings may help to clarify relationships between sleep-wake patterns and metabolic phenotypes in humans.

Adiponectin promotes coxsackievirus B3 myocarditis by suppression of acute anti-viral immune responses.

Adiponectin (APN) is an immunomodulatory adipocytokine that improves outcome in patients with virus-negative inflammatory cardiomyopathy and mice with autoimmune myocarditis. Here, we investigated whether APN modulates cardiac inflammation and injury in coxsackievirus B3 (CVB3) myocarditis. Myocarditis was induced by CVB3 infection of APN-KO and WT mice. APN reconstitution was performed by adenoviral gene transfer. Expression analyses were performed by qRT-PCR and immunoblot. Cardiac histology was analyzed by H&E-stain and immunohistochemistry. APN-KO mice exhibited diminished subacute myocarditis with reduced viral load, attenuated inflammatory infiltrates determined by NKp46, F4/80 and CD3/CD4/CD8 expression and reduced IFNß, IFNγ, TNFα, IL-1ß and IL-12 levels. Moreover, myocardial injury assessed by necrotic lesions and troponin I release was attenuated resulting in preserved left ventricular function. Those changes were reversed by APN reconstitution. APN had no influence on adhesion, uptake or replication of CVB3 in cardiac myocytes. In acute CVB3 myocarditis, cardiac viral load did not differ between APN-KO and WT mice. However, APN-KO mice displayed an enhanced acute immune response, i.e. increased expression of myocardial CD14, IFNß, IFNγ, IL-12, and TNFα resulting in increased cardiac infiltration with pro-inflammatory M1 macrophages and activated NK cells. Up-regulation of cardiac CD14 expression, type I and II IFNs and inflammatory cell accumulation in APN-KO mice was inhibited by APN reconstitution. Our observations indicate that APN promotes CVB3 myocarditis by suppression of toll-like receptor-dependent innate immune responses, polarization of anti-inflammatory M2 macrophages and reduction of number and activation of NK cells resulting in attenuated acute anti-viral immune responses.

Rotavirus vaccination: a risk factor for intussusception?

Recently published pharmacoepidemiological studies associate the currently authorized Rotavirus (RV) vaccines with intussusception (IS). We aimed at investigating whether, in Germany, there are excess IS cases in RV vaccinees compared with the background incidence before market authorization in 2006. Suspected cases of IS following receipt of RV vaccines reported to the Paul-Ehrlich-Institut (PEI) from 2006 to 2010 were reviewed and validated against the criteria of the Brighton Collaboration's definition for IS. An observed-versus-expected analysis was conducted using standardized morbidity ratio (SMR) methods based on age-specific incidence rates for IS ranging from 19.2 to 98.5 per 100,000 person-years. A total of 27 cases of suspected IS in RV vaccinees were reported to the PEI. No excess of IS cases could be detected 1-7 days after receipt of either RV vaccine after any dose in the first year of life; however, in infants aged 3-5 months, a significantly increased SMR for IS was found in a risk window of 1-7 days after the first dose of either RV vaccine [SMRs: Rotarix® 4.6 (95% CI 1.5-10.7); RotaTeq® 5.8 (95% CI 1.2-17.1)]. A significantly increased risk of IS in a risk window of 1-7 days after RV vaccination was not found when the first dose was administered earlier. Therefore, it is recommended to start the vaccination course at 6-12 weeks of age.

Influence of smoking and alcohol during pregnancy on outcome of VLBW infants.

BACKGROUND: Nicotine and alcohol consumption have been associated with premature delivery and adverse neonatal outcome. We wanted to analyze the influence of self-reported nicotine and alcohol consumption on outcome of VLBW infants. MATERIAL AND METHODS: In an ongoing multicenter study 2475 parents of former very low birth weight (VLBW) infants born between January 2009 and December 2011 answered questionnaires about maternal smoking habits and alcohol consumption during pregnancy. 2463 (99.5%) completed questions on alcohol consumption and 2462 (99.5%) on smoking habits. These infants were stratified to reported maternal smoking and alcohol consumption during pregnancy. We compared the reasons for premature delivery, neonatal outcome and parental reports on bronchitis during the first year of life, as well as growth and development at age 2 years to pregnancy exposure. RESULTS: In nicotine exposed infants intrauterine growth restriction (31 vs. 21%, p<0.01), a birth weight below the 10th percentile (26 vs. 17%, p<0.01) and placenta abruption (9.2 vs. 5.8%, p<0.05) was seen more often. Premature rupture of membranes (24 vs. 30%, p<0.05) or HELLP syndrome (6 vs. 11%, p<0.01) was less frequent. A birth weight below the 3rd percentile was seen more frequently in mothers with reported alcohol consumption (13 vs. 6%, p<0.05). We noted an increased rate of BPD and ROP if mothers reported smoking during pregnancy (p<0.05). Growth parameters and scores on Bayley Sscales of infant development at age 2 years did not differ. CONCLUSION: Smoking during pregnancy results in a high rate of growth restricted VLBW infants. Prenatal exposition to nicotine seems to increase postnatal complications such as BPD und ROP.

S100A12 and hBD2 correlate with the composition of the fecal microflora in ELBW infants and expansion of E. coli is associated with NEC.

OBJECTIVE: To describe the development of the gut microbiota in extremely low birth weight (ELBW) infants with and without necrotizing enterocolitis (NEC) between April 2008 and December 2009, fecal microflora was prospectively analyzed in fecal samples of all ELBW infants using real-time PCR assays. In addition, fecal inflammatory were measured. RESULTS: Fecal microflora established early in ELBW infants and microbiota composition remained stable over the first 28 days of life except for the prevalence of C. difficile which decreased with decreasing antibiotic use. Infants who subsequently developed NEC had an increase of total bacterial count (9.8-fold) 24 h prior to clinical symptoms mainly due to the expansion of E. coli species (21.6-fold), whereas microbiota composition did not differ from healthy ELBW infants five days before onset of NEC. Importantly, S100A12 and hBD2 positively correlated with the total and E. coli bacterial CFU/g feces (r (2) 0.4 and 0.64, resp.). CONCLUSIONS: In summary, we found evidence for a disturbed homeostasis between the intestinal microbiome and host immunity in ELBW infants with NEC. Moreover, S100A12 and hBD2 correlate with the fecal microbiota thus linking the intestinal innate immune response to the bacterial colonization thus possibly providing a diagnostic tool in the future.

YouTube as a source of information for children with paroxysmal episodes.

Whereas to date the internet is a main source of information for many parents, there are no restrictions regarding data presentation. Thus, the aim of this study was to assess the quality of internet material concerning paroxysmal episodes.We rated videos on YouTube for several conditions like infantile spasms, absence seizures, Sandifer syndrome, sleep myoclonus, and shuddering attacks. Videos were classified into different categories of certainty of diagnosis according to expert opinion based on a 4 point Likert scale followed by calculation of interrater reliability. Also the quality of supplemental information was assessed, as well as whether videos were helpful from a neuropaediatrican's point of view in counselling patients and their parents.In sleep myoclonus, absences and infantile spasms correlation between title of videos and classification by expert opinion was good. There was more discrepancy with the videos concerning Sandifer syndrome and shuddering attacks. Interrater reliability was low for Sandifer syndrome, fair for absences, shuddering attacks and sleep myoclonus and moderate for infantile spasms. Some supplemental information was rated to be helpful but other information was found to be misleading or even unsettling for patients and their parents.We consider that video material on YouTube can generally not be considered as helpful for parents because of a significant disagreement between experts, even for the most well defined disorders in our study.

Frequency of symptomatic zinc deficiency in very low birth weight infants.

Current concepts on zinc requirements for premature infants rely on studies dating back more than 20 years. Given that nowadays more premature infants frequently survive we aimed to obtain recent frequency data on zinc deficiency in very low birth weight (VLBW) infants.226 VLBW infants born between July 2005 and December 2009 were retrospectively included in this study. Mean gestational age (GA) was 28.7 weeks (range 23+0 to 38+0) and mean birth weight 1120g (range 354-1495). All infants received zinc supplementation according to the ESPGHAN guidelines. 26 (11.5%) patients showed clinical signs for zinc deficiency of whom 15 had serum zinc concentrations < 50µg/dl, 9 between 50 and 70 µg/dl and 2 > 70 µg/dl. Infants presenting with dermatitis had significantly lower concentrations (mean 26.7 µg/dl, range 19-31) when compared to infants with diarrhoea or isolated peripheral oedema (35.3 µg/dl and 51.8 µg/dl respectively). Strongest independent risk factors were low GA, being small for GA and suffering from intestinal resection due to necrotizing enterocolitis. Frequency of zinc concentrations <50 µg/dl were calculated to be 6.6% in VLBW infants.Even though current guidelines for zinc supplementation were followed the frequency of zinc deficiency was found to be unexpectedly high in ELBW and SGA infants. Despite the retrospective nature of this single centre study, our data strongly suggest that recommendations on zinc supplementation in ELBW and SGA infants should be reviewed.

Intestinal alpha-defensin expression in pediatric inflammatory bowel disease.

BACKGROUND: Reduced alpha-defensin expression has been reported in the terminal ileum (TI) of adult patients with ileal Crohn's disease (CD). However, little is known about alpha-defensin expression in children with chronic inflammatory bowel disease (IBD). METHODS: In all, 283 intestinal biopsies were obtained from children with CD, ulcerative colitis (UC), and healthy controls. Absolute mRNA copy numbers for HD5, HD6, IL-8, Villin 1, and Tcf-4 were analyzed by reverse-transcription polymerase chain reaction (RT-PCR). HD5 immunostaining was performed on biopsy sections and patients genotyped for NOD2 mutations. RESULTS: Equal expression levels of alpha-defensins (HD5 and HD6) were found in TI biopsies of children with ileal CD (L1+L3) compared to patients with colonic disease (L2) and healthy controls. In contrast, we found significantly higher levels of alpha-defensins in the TI of children with UC compared to CD and controls. Reduced expression of Tcf-4 was observed exclusively in the duodenum and TI of CD patients with L1+L3 phenotype. We demonstrate significantly increased expression of HD5 and HD6 in the inflamed colon of IBD children (UC and CD) attributable to the presence of metaplastic Paneth cells. CONCLUSIONS: In this study no difference in alpha-defensin expression was found in the TI of CD children and controls. However, significant reduction of Tcf-4 in L1+L3 phenotype suggests that a possibly impaired PC differentiation may lead to altered HD5 and HD6 expression at some stage of disease. Additionally, substantially increased expression of alpha-defensins in the inflamed colonic mucosa of children with IBD raises the question for their potential involvement in modulating inflammation in these patients.

Incidence of intussusception in early infancy: a capture-recapture estimate for Germany.

BACKGROUND: Rotavirus (RV) vaccination with the first generation vaccine (Rotashield) has been associated with intussusception (IS). Reliable age specific baseline incidence data for children ≤6 months of age in particular is fundamental for further post marketing monitoring of potential effects of recently introduced new RV vaccines. METHODS: IS incidence was estimated by a 2-source capture-recapture calculation (CRC) based on ESPED (German Paediatric Surveillance Unit) reports and on hospital discharge records for 2006 and 2007. ESPED as well as hospital records were validated according to the Brighton Collaboration's Group definition for definite IS. PATIENTS: Children that have been treated for IS in a hospital in one of two states of Germany (North-Rhine Westphalia and Bavaria). RESULTS: The annual IS incidence for infants <1 year in Germany calculated with the CRC estimate in Germany was 61.7/100 000 (95% CI: 54.5-70.1). However, the incidence appeared to vary by month of age over a range of 19.2/100 000 cases (95% CI: 12.5-30.4) in the first 3 months of life to 98.5/100 000 cases (95% CI: 80.9-120.6) during the 6 (th) to 8 (th) month. The male to female ratio for infants was 1.7:1 (95%CI: 1.6-1.8). CONCLUSION: The average incidence estimate for IS in infants (< 1 year) confirms previous estimates in Germany and Switzerland. However, age specific baseline incidence estimates for IS substantially vary during the first year of life. This has to be taken into account when analysing episodes of IS potentially associated with RV vaccination.

Mutation frequency of NS5A in patients vertically infected with HCV genotype 1 predicts sustained virological response to peginterferon alfa-2b and ribavirin combination therapy.

Viral genome analyses performed in adult HCV-patients yielded very inconsistent results and are not transferable to children who are often infected vertically during a state of high immune tolerance. We analysed the mutational frequency in the PKR-binding domain (PKR-BD) of NS5A and PePHD of E2 protein pre- and post-treatment with peginterferon-alfa-2b and ribavirin in children chronically infected with HCV genotype 1. Amino acid sequences of NS5A (2 209-2 274) and E2 (618-681) were determined in serum samples using standard PCR procedures. Concerning the PKR-BD a significant higher number of mutations was observed in vertically compared to horizontally infected patients (2.14 vs 1.24, P-value = 0.03). This difference was exclusively based on the increased number of mutations in responders vs non-responders in vertically infected patients (2.95 vs 1.33; P-value = 0.02). While all patients with at least four mutations (n = 3) did respond to therapy, no other predictive parameters could be identified. In the PePHD no differences could be observed between either of these groups. These findings support the idea that viral properties, mode and therewith time of infection in terms of immune tolerance are equally important factors for predicting SVR in children. However given the low number of cases further studies are required to confirm this hypothesis.

[Cardiorespiratory effects of heliox using a model of upper airway obstruction]. / Kardiorespiratorische Effekte von Heliox an einem Modell der oberen Atemwegsobstruktion.

Heliox is a mixture of Oxygen and Helium. The low density of Helium allows this mixture to flow in a laminar pattern where oxygen, nitrogen or air flow would be turbulent. Therefore the force necessary to move a volume of gas (e.g. Heliox) is greatly reduced in comparison to a turbulent gas flow. In a respiratory loading experiment we investigated the effects which Heliox exerts on hemodynamic as well respiratory variables. 10 volunteers were breathing spontaneously and through three different endotracheal (ET-) tubes (ID 4.0, 4.5, 5.0 mm). The subjects were switched from room air to Heliox and differences in the variables heart rate (HR), blood pressure (BP), stroke volume (SV), stroke index (SI), peripheral vascular resistance (TPRI) and left ventricular work index (LVWI) were measured. Furthermore the (PhAng) between abdomen and thorax was detected using respiratory inductance plethysmography (n=2) and the sense of dyspnoe under the different conditions was assessed by the use of a dyspnea score (DS). The means of BP, SV, SI, TPRI and LVWI did not significantly differ between the resting and the different loading conditions irrespective of the gas that was used. The variability of hemodynamic measures was significant larger during loaded vs. unloaded breathing. Heliox could significantly reduce this degree of variability. In two subjects Heliox could also significantly reduce the PhAng as well as DS. Heliox showed effects on hemodynamic as well as respiratory and subjective variables. These effects can be interpreted as a reduction of the extent of pressure variations in the intrapleural space leading to less impact on hemodynamic variables while breathing Heliox vs. room air in a resistive loading experiment. In the future the combined measurement of hemodynmic variables as well as non-invasive assessment of respiration might shed new light on cardio-respiratory interaction and effects of Heliox during airway obstruction.

Clinical features and biochemical data of Caucasian children at diagnosis of autoimmune hepatitis.

OBJECTIVE: Evaluation of systematic epidemiological data regarding clinical characteristics, sex distribution and autoantibody pattern in Caucasian children with autoimmune hepatitis (AIH). STUDY DESIGN: Data of 142 children presenting with AIH (97 girls and 45 boys) have been analysed for their clinical, serological, and histological profile. RESULTS: Clinical findings were jaundice (58%), unspecific weakness (57%), anorexia (47%), abdominal pain (38%) and paleness (26%). One hundred and three children (73%) (68 girls, 35 boys, 1.9:1) had AIH type 1 and 35 patients (25%) (27 girls, 8 boys, 3.4:1) type 2 due to specific autoantibodies. Four children could not be classified. Histology of 122 children revealed active hepatitis in 64 (52%), cirrhosis in 46 (38%), and mild inflammatory activity in 12 individuals (10%). The most prevalent HLA type was B8. CONCLUSION: In our cohort the prevalence of AIH was half as frequent in boys as in girls. Type 1 was the most frequent diagnosis (73%) and was more prevalent in older children. Type 2 was equally age distributed. The clinical presentation of AIH in children was unspecific and type I and type II could only be differentiated by the determination of the specific autoantibodies. Ninety percent of patients presented with high inflammatory activity or liver cirrhosis.