Strategies to prevent neuronal damage in paediatric bacterial meningitis

PURPOSE OF REVIEW: The mortality of bacterial meningitis can reach 30%, and up to 50% of survivors suffer from persisting neurological deficits as a consequence of the disease. The incidence of neurological sequelae of bacterial meningitis has not improved over the last decade. Adjunctive therapeutic options are limited, and ongoing research into the pathophysiology of brain damage in bacterial meningitis aims at providing the scientific basis for future development of more efficient adjunctive options. RECENT FINDINGS: In a population with good access to health care, dexamethasone given before or at the time of initiation of antibiotic therapy acts beneficially in paediatric pneumococcal meningitis, but not in meningococcal meningitis. In experimental animal models, brain-derived neurotrophic factor protected against brain injury and improved hearing while melatonin, which has antioxidant properties among other effects, reduced neuronal death. Transgene technology can be used to provide new insights into the pathophysiology of the disease and to identify potential therapeutic targets. SUMMARY: Although dexamethasone improves outcome of bacterial meningitis under defined circumstances, the morbidity of bacterial meningitis still remains unacceptably high. Experimental models may help to identify new therapeutic strategies to further improve the neurological outcome in young children suffering from bacterial meningitis.

Mutations in Uroplakin IIIA are a rare cause of renal hypodysplasia in humans

BACKGROUND: Renal hypodysplasia, characterized by a decrease in nephron number, small overall kidney size, and maldeveloped renal tissue, is a leading cause of chronic renal failure in young children. Familial clustering and renal hypodysplasia phenotypes observed in transgenic animal models suggest a genetic contribution. Uroplakin IIIa (encoded by UPIIIA) is an integral membrane protein present in urothelial plaques, and the murine UPIIIa knockout is associated with urothelial anomalies and vesicoureteral reflux. De novo UPIIIA mutations recently were identified in 4 of 17 patients with severe bilateral renal adysplasia. METHODS: To evaluate the overall role of UPIIIA in human renal hypodysplasia pathogenesis, we performed UPIIIA mutation analysis in a cohort of 170 pediatric patients affected by severe unilateral or bilateral renal hypodysplasia. Eighty-one patients were affected by bilateral nonobstructive renal hypodysplasia; of these, 61 were without vesicoureteral reflux. Eighty-four patients presented with unilateral nonobstructive renal hypodysplasia, including 24 patients with unilateral multicystic dysplastic kidneys. Family history was positive in 11%. RESULTS: Mutation analysis showed 2 heterozygous mutations not observed in 200 race-matched control chromosomes. In only 1 family was distribution of the UPIIIA mutation consistent with a disease-causing effect. This de novo missense mutation (Gly202Asp) was identified in a patient with unilateral multicystic dysplastic kidneys. The second (intronically located) mutation appeared unlikely to be disease causing because it did not segregate with an obvious disease phenotype in the affected family. CONCLUSION: Our results indicate that de novo mutations in UPIIIA can be involved in defective early kidney development, but probably constitute only a rare cause of human renal hypodysplasia in a minor subset of individuals.

Catch-up growth in autosomal dominant isolated growth hormone deficiency (IGHD type II)

OBJECTIVE: Data on the GH-induced catch-up growth of severely GH-deficient children affected by monogenetic defects are missing. PATIENTS: Catch-up growth of 21 prepubertal children (6 females, 15 males) affected with IGHD type II was analyzed in a retrospective chart review. At start of therapy, mean age was 6.2 years (range, 1.6-15.0), mean height SDS was -4.7 (-7.6 to -2.2), mean IGF-I SDS was -6.2 (-10.1 to -2.2). GH was substituted using a mean dose of 30.5microg/kg*d. RESULTS: Catch-up growth was characterized by a mean height gain of +0.92, +0.82, and +0.61 SDS after 1, 2, and 3 years of GH therapy, respectively. Mean height velocities were 10.7, 9.2 and 7.7cm/year during the first three years. Mean duration of complete catch-up growth was 6 years (3-9). Mean height SDS reached was -0.97 (-2.3 to +1.1), which was within the range of the estimated target height of -0.60 SDS (-1.20 to -0.15). The younger and shorter the children were at start of therapy the better they grew during the first year independent of the dose. Mean bone age was delayed at start by 2.1 years and progressed by 2.5 years during the first two years of therapy. Incomplete catch-up growth was caused by late initiation or irregular administration of GH in four cases. CONCLUSIONS: Our data suggest that GH-treated children with severe IGHD show a sustained catch-up growth over 6 years (mean) and reach their target height range. This response to GH is considered to be characteristic for young children with severe growth retardation due to IGHD.

Pneumonia due to resistant Streptococcus pneumoniae

In the past 10 to 20 years the pneumococcus, the most common pathogen of community-acquired pneumonia, has developed resistance to most antibiotics used for its treatment. Classes with important resistance problems include the beta-lactams, the macrolides and lincosamides, trimethoprim-sulfamethoxazole, and the tetracyclines. Unfortunately, resistance to more than one class of antibiotics is common in pneumococci, and their treatment is thus becoming more difficult. Patients likely to harbour resistant organisms include young children, particularly those attending day care, older patients, and subjects who have received recent antibiotic therapy, suffer from underlying diseases including HIV, or have nosocomial or polymicrobial pneumonia. The consequences of resistance development are different for different classes of antibiotics. With beta-lactams, the increase in minimal inhibitory concentrations is usually moderate in resistant strains, and because of the high concentrations that can be achieved with this class of drugs resistance does not usually lead to treatment failure. Thus, beta-lactams continue to be important drugs for the treatment of pneumococcal pneumonia, even if the organism is resistant. In contrast, resistance to other classes of antibiotics must be assumed to render these drugs ineffective. Newer quinolones represent valuable alternatives for the treatment of pneumococcal pneumonia, since their efficacy is not affected by resistance to other classes of antibiotics and they cover almost all pathogens of community-acquired pneumonia, including the atypical pathogens. However, they should be used with restraint in order to preserve this valuable class of drugs.

Paediatric antiretroviral treatment programmes in sub-Saharan Africa: a review of published clinical studies

Knowledge of the experience and outcomes of current paediatric antiretroviral treatment (ART) programmes in sub-Saharan Africa can inform new programmes in the region as well as enhance existing ones. This is urgently needed to facilitate the scale-up of treatment, which is needed to address the burden of paediatric HIV cases on the continent. We reviewed the characteristics and outcomes of programmes with clinical paediatric ART studies published prior to 1 January 2008. The outcomes of the studies were comparable to similar ones from developed countries; however, the duration of follow-up was relatively limited in almost all the studies reviewed. One-year survival probability was between 84% and 91%, and considerable improvement in the clinical, immunologic and iral status of the paediatric patients was generally recorded. Loss to follow-up was less than 10% in all but two studies. Adherence to treatment was good and few adverse events were reported. This is despite the fact that many programmes were subject to enormous constraints in terms of health services, and despite widespread use of adult fixed-dose combinations for paediatric patients, including young infants. While the majority of children commencing ART were severely ill, most children were old (median age >5 years for almost all studies) with relatively few infants and young children (age <2 years) receiving treatment. This is in contrast to knowledge of rapid disease progression in the majority of HIV-infected infants and despite the World Health Organization’s recent recommendations to commence ART in all HIV-infected infants less than one year old. There is an urgent need to address barriers to ART for infants. Studies of the outcomes of programmes treating infants as well as those with longer-term follow-up are also needed.

Vaccination of cystic fibrosis patients against Pseudomonas aeruginosa reduces the proportion of patients infected and delays time to infection

INTRODUCTION: Cystic fibrosis (CF) almost always leads to chronic airway infection with Pseudomonas aeruginosa. Despite advances in antibiotic therapy, after chronic infection rapid deterioration in lung function occurs, increasing morbidity and mortality. Prevention of infection by vaccination is desirable, but earlier trials produced disappointing results. The promising short term immunogenicity and safety of a new P. aeruginosa vaccine prompted us to evaluate its long term efficacy. We conducted a 10-year retrospective analysis of outcomes in a group of vaccinated patients. MATERIALS AND METHODS: In 1989-1990, 30 young children with CF, mean age 7 years, with no prior history of infection with P. aeruginosa, were vaccinated against P. aeruginosa with a polyvalent conjugate vaccine. We report the follow-up of 26 of these patients from 1989 to 2001. The patients were given yearly vaccine boosters. Comparisons were made with a CF patient control group matched for gender, age and, where possible, genetic mutation. Vaccinated patients and controls were attending a single CF clinic and received the same clinical management throughout the study period. Main outcomes were time to infection, proportion of patients infected, development of P. aeruginosa mucoid phenotype, lung function and body weight. RESULTS: The time to infection with P. aeruginosa was longer in the vaccination group than in the control group, and fewer vaccinated patients than controls became chronically infected (32% versus 72%; P < 0.001). The proportion of mucoid infections was higher in the control group (44%) than in the vaccinated group (25%). Patients >/=18 years of age at the end of the study had a lower mean forced expiratory volume at 1 s (FEV1) than did those 13-17 years of age, but this difference was small in the vaccinated group (73.6% versus 83.7%) compared with the controls (48.0% versus 78.7%). In the >/=18 year age category the mean FEV1% at 10 years was 73.6% (vaccinated) and 48.0% (controls) (P < 0.05). In the vaccinated group only 11 (44%) of 25 patients were underweight at the 10-year follow-up compared with 18 (72%) of 25 at the beginning of the study. In the control group 17 (68%) of 25 patients were underweight at 10-year follow-up compared with 16 (64%) of 25 at the beginning of the study. CONCLUSION: Regular vaccination of young CF patients for a period of 10 years with a polyvalent conjugate vaccine reduced the frequency of chronic infection with P. aeruginosa. This was associated with better preservation of lung function. Vaccinated patients gained more weight during the study period, a possible indication of an improved overall health status.

Decreasing risk of hepatitis a infection in león, nicaragua: evidence from cross-sectional and longitudinal seroepidemiology studies

BACKGROUND AND OBJECTIVES Nicaragua is highly endemic for hepatitis A. We aimed to provide an estimate of the change in the age-specific risk of hepatitis A virus (HAV) infection based on serological data from cross-sectional and longitudinal samples collected in León, Nicaragua, in 1995/96 (n = 979) and 2003 (n = 494). METHODS The observed age-specific prevalence of anti-HAV antibodies was correlated to the age-specific risk of infection by calculating the probability of freedom from infection at a specific age. RESULTS The proportion of seropositive children aged 1.5 to 6 years was 42% in 2003 compared to 67% in 1995/96. Estimated annual risk of infection for a 3-year old child was 30% (95% CI: 27.0%, 33.1%) in 1995 and 15.5% (95% CI: 12.4%, 19.0%) in 2003. There was good agreement between estimates based on cross-sectional and longitudinal data. The age-specific geometric mean of the quantified anti-HAV antibody levels assessed in 2003 was highest at age 4 and decreased steadily up to age 40. CONCLUSIONS The substantially lower risk of HAV infection in 2003 than in 1995 for young children indicates a beginning transition from high to intermediate endemicity in León, Nicaragua. Consecutive age-stratified serosurveys are useful to assess changes in risk of infection following public health interventions. The decreasing age-specific GMC of anti-HAV antibodies during adulthood in a country with endemic HAV indirectly suggests that ongoing HAV exposure in the community has marginal boosting effect on antibody levels once protective immunity has been established by natural infection.

Classification and pharmacological treatment of preschool wheezing: changes since 2008.

Since the publication of the European Respiratory Society Task Force report in 2008, significant new evidence has become available on the classification and management of preschool wheezing disorders. In this report, an international consensus group reviews this new evidence and proposes some modifications to the recommendations made in 2008. Specifically, the consensus group acknowledges that wheeze patterns in young children vary over time and with treatment, rendering the distinction between episodic viral wheeze and multiple-trigger wheeze unclear in many patients. Inhaled corticosteroids remain first-line treatment for multiple-trigger wheeze, but may also be considered in patients with episodic viral wheeze with frequent or severe episodes, or when the clinician suspects that interval symptoms are being under reported. Any controller therapy should be viewed as a treatment trial, with scheduled close follow-up to monitor treatment effect. The group recommends discontinuing treatment if there is no benefit and taking favourable natural history into account when making decisions about long-term therapy. Oral corticosteroids are not indicated in mild-to-moderate acute wheeze episodes and should be reserved for severe exacerbations in hospitalised patients. Future research should focus on better clinical and genetic markers, as well as biomarkers, of disease severity.

Pharmacological and non-pharmacological therapy for arrhythmias in the pediatric population: EHRA and AEPC-Arrhythmia Working Group joint consensus statement

In children with structurally normal hearts, the mechanisms of arrhythmias are usually the same as in the adult patient. Some arrhythmias are particularly associated with young age and very rarely seen in adult patients. Arrhythmias in structural heart disease may be associated either with the underlying abnormality or result from surgical intervention. Chronic haemodynamic stress of congenital heart disease (CHD) might create an electrophysiological and anatomic substrate highly favourable for re-entrant arrhythmias. As a general rule, prescription of antiarrhythmic drugs requires a clear diagnosis with electrocardiographic documentation of a given arrhythmia. Risk-benefit analysis of drug therapy should be considered when facing an arrhythmia in a child. Prophylactic antiarrhythmic drug therapy is given only to protect the child from recurrent supraventricular tachycardia during this time span until the disease will eventually cease spontaneously. In the last decades, radiofrequency catheter ablation is progressively used as curative therapy for tachyarrhythmias in children and patients with or without CHD. Even in young children, procedures can be performed with high success rates and low complication rates as shown by several retrospective and prospective paediatric multi-centre studies. Three-dimensional mapping and non-fluoroscopic navigation techniques and enhanced catheter technology have further improved safety and efficacy even in CHD patients with complex arrhythmias. During last decades, cardiac devices (pacemakers and implantable cardiac defibrillator) have developed rapidly. The pacing generator size has diminished and the pacing leads have become progressively thinner. These developments have made application of cardiac pacing in children easier although no dedicated paediatric pacing systems exist.

Morphologic-anthropological investigations in tomb K93.12 at Dra’ Abu el-Naga (Western Thebes, Egypt)

In this study we present the analysis of the human remains from tomb K93.12 in the Ancient Egyptian necropolis of Dra’ Abu el-Naga, located opposite the modern city of Luxor in Upper Egypt on the western bank of the Nile. Archaeological findings indicate that the rock tomb was originally built in the early 18th dynasty. Remains of two tomb-temples of the 20th dynasty and the looted burial of the High Priest of Amun Amenhotep have been identified. After the New Kingdom the tomb was reused as a burial place until the 26th dynasty. The skeletal and mummified material of the different tomb areas underwent a detailed anthropological and paleopathological analysis. The human remains were mostly damaged and scattered due to extensive grave robberies. In total, 79 individuals could be partly reconstructed and investigated. The age and sex distribution revealed a male predominance and a high percentage of young children (< 6 years) and adults in the range of 20 to 40 years. The paleopathological analysis showed a high prevalence of stress markers such as cribra orbitalia in the younger individuals, and other pathological conditions such as dental diseases, degenerative diseases and a possible case of ankylosing spondylitis. Additionally, 13 mummies of an intrusive waste pit could be attributed to three different groups belonging to earlier time periods based on their style of mummification and materials used. The study revealed important information on the age and sex distribution and diseases of the individuals buried in tomb K93.12.

The role of controlled attention and selective encoding for kindergarteners' learning

Selectivity in encoding, aspects of attentional control and their contribution to learning performance were explored in a sample of preschoolers. While the children are performing a learning task, their encoding of relevant and attention towards irrelevant information was recorded through an eye-tracking device. Recognition of target items was used as measure of learning outcome, and individual differences in resistance to interference and inhibition of attention to task-irrelevant stimuli (i.e. distractibility) were used as measures of executive control of attention. Results indicated well-developed selectivity during encoding in young children. Recognition performance was related to selective encoding and aspects of attentional control, explaining individual differences in learning. Copyright © 2011 John Wiley & Sons, Ltd.

Shaping the values of the next generation: Value transmission processes within the family

Abstract: Research on human values within the family focuses on value congruence between the family members (Knafo & Schwartz, 2004), based on the assumption that transmission of values is part of a child’s socialization process. Within the family, values are not only implicitly transmitted through this process but also explicitly conveyed through the educational goals of parents (Grusec et al., 2000; Knafo & Schwartz, 2003; 2004, 2009). However, there is a lack of empirical evidence on the role of family characteristics in the value transmission process, especially for families with young children. Thus, the study presented had multiple aims: Firstly, it analyzed the congruency between mothers’ and fathers’ values and their value-based educational goals. Secondly, it examined the influence of mothers’ and fathers’ socio-demographic characteristics on their educational goals. Thirdly, it analyzed the differences in parental educational goals in families with daughters and families with sons. Finally, it examined the congruency between children’s values and the value-based educational goals of their parents. The value transmission process within families with young children was analyzed using data from complete families (child, mother and father) in Switzerland (N = 265). The survey of children consisted of 139 boys and 126 girls aged between 7 and 9 years. Parents’ values and parental educational goals were assessed using the Portrait Value Questionnaire (PVQ-21) (Schwartz, 2005). Children’s’ values were assessed using the Picture-Based Value Survey for Children (PBVS-C) (Döring et al., 2010). Regarding the role of the family context in the process of shaping children’s values, the results of the study show that, on average, parents are similar not only with respect to their value profiles but also with regard to their notion as to which values they would like to transmit to their children. Our findings also suggest that children’s values at an early age are shaped more strongly by mothers’ values than by fathers’ values. Moreover, our results show differences in value transmission with respect to the child’s gender. In particular, they suggest that value transmission within the family has a greater influence on female than on male offspring.

Horizontal head titubation in infants with Joubert syndrome: a new finding

AIM Head thrusts are well documented in Joubert syndrome and ocular motor apraxia. We provide a detailed clinical characterization of head titubation in 13 young children with Joubert syndrome. METHOD Detailed characterization of head titubation was assessed by targeted clinical evaluation and/or analysis of videos. RESULTS In 12 of 13 children (eight males, five females; median age 6y, range 2mo-15y) head titubation was first recognized in the first 2 months of age and decreased in severity until spontaneous resolution. In all children, the head titubation was horizontal, high frequency (~3Hz), had small amplitude (5-10°), was never present during sleep, and did not interfere with the neurodevelopment during infancy. In the majority of children, emotion, anxiety, and tiredness were worsening factors for head titubation. INTERPRETATION Head titubation is a benign, early presentation of Joubert syndrome. Head titubation in hypotonic infants should prompt a careful search for Joubert syndrome. Awareness of its occurrence in Joubert syndrome may avoid unnecessary investigations.

Mefloquine at the crossroads? Implications for malaria chemoprophylaxis in Europe

Since its introduction to the market in 1985, mefloquine has been used for malaria chemoprophylaxis by more than 35 million travellers. In Europe, in 2014, the European Medicines Agency (EMA) issued recommendations on strengthened warnings, prescribing checklists and updates to the product information of mefloquine. Some malaria prevention advisors question the scientific basis for the restrictions and suggest that this cost-effective, anti-malarial drug will be displaced as a first-line anti-malaria medication with the result that vulnerable groups such as VFR and long-term travellers, pregnant travellers and young children are left without a suitable alternative chemoprophylaxis. This commentary looks at the current position of mefloquine prescribing and the rationale of the new EMA recommendations and restrictions. It also describes the new recommendations for malaria prophylaxis that have been adapted by Switzerland, Germany, Austria and Italy where chemoprophylaxis use is restricted to high-risk malaria-endemic areas.

Childhood cancer and residential exposure to highways: a nationwide cohort study.

Children living near highways are exposed to higher concentrations of traffic-related carcinogenic pollutants. Several studies reported an increased risk of childhood cancer associated with traffic exposure, but the published evidence is inconclusive. We investigated whether cancer risk is associated with proximity of residence to highways in a nation-wide cohort study including all children aged <16 years from Swiss national censuses in 1990 and 2000. Cancer incidence was investigated in time to event analyses (1990-2008) using Cox proportional hazards models and incidence density analyses (1985-2008) using Poisson regression. Adjustments were made for socio-economic factors, ionising background radiation and electromagnetic fields. In time to event analysis based on 532 cases the adjusted hazard ratio for leukaemia comparing children living <100 m from a highway with unexposed children (≥500 m) was 1.43 (95 % CI 0.79, 2.61). Results were similar in incidence density analysis including 1367 leukaemia cases (incidence rate ratio (IRR) 1.57; 95 % CI 1.09, 2.25). Associations were similar for acute lymphoblastic leukaemia (IRR 1.64; 95 % CI 1.10, 2.43) and stronger for leukaemia in children aged <5 years (IRR 1.92; 95 % CI 1.22, 3.04). Little evidence of association was found for other tumours. Our study suggests that young children living close to highways are at increased risk of developing leukaemia.