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Dutch guidelines recommend to consider intravenous magnesium sulfate (iv MgSOA questionnaire was handed out to pediatricians and pediatric residents in one academic and six community teaching hospitals.In 111 respondents, 76% reported regular use of iv MgSOIV MgSO

To describe outcomes of nonsurgical treatment for symptomatic thumb carpometacarpal joint (CMC-1) instability. Secondary, to evaluate the conversion rate to surgical treatment.Prospective cohort study.A total of 20 outpatient clinics for hand surgery and hand therapy in the Netherlands.A consecutive sample of patients with symptomatic CMC-1 instability (N=431).Nonsurgical treatment including exercise therapy and an orthosis.Pain (visual analog scale [VAS], 0-100) and hand function (Michigan Hand Outcomes Questionnaire [MHQ], 0-100) at baseline, 6 weeks, and 3 months. Conversion to surgery was recorded for all patients with a median follow-up of 2.8 years (range, 0.8-6.7y).VAS scores for pain during the last week, at rest, and during physical load improved with a mean difference at 3 months of 17 (97.5% CI, 9-25), 13 (97.5% CI, 9-18), and 19 (97.5% CI, 12-27), respectively (P.001). No difference was present at 3 months for MHQ total score, but the subscales activities of daily living, work, pain, and satisfaction improved by 7 (97.5% CI, 1-14), 10 (97.5% CI, 4-16), 5 (97.5% CI, 2-9), and 12 (97.5% CI, 2-22) points, respectively (P.001-.007). After median follow-up of 2.8 years, only 59 participants (14%) were surgically treated. Both in the subgroups that did and did not convert to surgery, VAS pain scores decreased at 3 months compared with baseline (P.001-.010), whereas MHQ total score did not improve in both subgroups. However, VAS and MHQ scores remained worse for patients who eventually converted to surgery (P.001).In this large sample of patients with symptomatic CMC-1 instability, nonsurgical treatment demonstrated clinically relevant improvements in pain and aspects of hand function. Furthermore, after 2.8 years, only 14% of all patients were surgically treated, indicating that nonsurgical treatment is a successful treatment of choice.

Exposure to a prenatal high-fat (HF) diet leads to an impaired metabolic phenotype in mouse offspring. The underlying mechanisms, however, are not yet fully understood. Therefore, this study investigated whether the impaired metabolic phenotype may be mediated through altered hepatic DNA methylation and gene expression. We showed that exposure to a prenatal HF diet altered the offspring's hepatic gene expression of pathways involved in lipid synthesis and uptake (SREBP), oxidative stress response [nuclear factor (erythroid-derived 2)-like 2 (Nrf2)], and cell proliferation. The downregulation of the SREBP pathway related to previously reported decreased hepatic lipid uptake and postprandial hypertriglyceridemia in the offspring exposed to the prenatal HF diet. The upregulation of the Nrf2 pathway was associated with increased oxidative stress levels in offspring livers. The prenatal HF diet also induced hypermethylation of transcription factor (TF) binding sites upstream of lipin 1 (Lpin1), a gene involved in lipid metabolism. Furthermore, DNA methylation of Lpin1 TF binding sites correlated with mRNA expression of Lpin1. These findings suggest that the effect of a prenatal HF diet on the adult offspring's metabolic phenotype are regulated by changes in hepatic gene expression and DNA methylation.

IntroductionBrown adipose tissue (BAT) is considered as a potential target for combating obesity in humans where active BAT metabolizes glucose and fatty acids as fuel resulting in heat production. Prospective studies in humans have been set up to further study the presence and metabolic activity of BAT mostly using Positron Emission Tomography (PET) imaging in cold-stimulated conditions with the radiolabeled glucose derivative [F-18]FDG. However, radiotracers beyond [F-18]FDG have been proposed to investigate BAT activity, targeting various aspects of BAT metabolism. It remains questionable which tracer is best suited to detect metabolic BAT activity and to what extent those results correlate with ex vivo metabolic BAT activity.MethodsPET and Single Photon Emission Computed Tomography (SPECT) imaging, targeting different aspects of BAT activation such as glucose metabolism, fatty acid metabolism, noradrenergic stimulation, blood perfusion and amino acid transport system, was performed immediately after injection of the tracer in rats under different temperatures: room temperature, acute cold (4 degrees C for 4 h) or acclimated to cold (4 degrees C for 6 h per day during 28 days). Furthermore, Magnetic Resonance Spectroscopy (MRS)-derived BAT temperature was measured in control and cold-acclimated rats.ResultsAt room temperature, only [F-18]FDG visualized BAT. Glucose metabolism, fatty acid metabolism, noradrenergic stimulation and blood perfusion showed a clear tracer-dependent twofold increase in BAT uptake upon cold exposure. Only the tracer for the amino acid transport system did not show BAT specific uptake under any of the experimental conditions. MRS demonstrated that cold-acclimated animals had BAT with a stronger heat-production compared to control animals.ConclusionBAT activity following cold exposure in rats was visualized by several tracers, while only [F-18]FDG was also able to show BAT activity under non-stimulated conditions (room temperature). The variances in uptake of the different tracers should be taken into account when developing future clinical applications in humans.

Contains fulltext : 202599.pdf (Publisher’s version ) (Closed access) BACKGROUND: Higher doses of rifampicin are being investigated as a means to optimize response to this pivotal TB drug. It is unknown whether high-dose rifampicin results in saturation of plasma protein binding and a relative increase in protein-unbound (active) drug concentrations. OBJECTIVES: To assess the free fraction of rifampicin based on an in vitro experiment and data from a clinical trial on high-dose rifampicin. METHODS: Protein-unbound rifampicin concentrations were measured in human serum spiked with increasing total concentrations (up to 64 mg/L) of rifampicin and in samples obtained by intensive pharmacokinetic sampling of patients who used standard (10 mg/kg daily) or high-dose (35 mg/kg) rifampicin up to steady-state. The performance of total AUC0-24 to predict unbound AUC0-24 was evaluated. RESULTS: The in vitro free fraction of rifampicin remained unaltered ( approximately 9%) up to 21 mg/L and increased up to 13% at 41 mg/L and 17% at 64 mg/L rifampicin. The highest (peak) concentration in vivo was 39.1 mg/L (high-dose group). The arithmetic mean percentage unbound to total AUC0-24in vivo was 13.3% (range = 8.1%-24.9%) and 11.1% (range = 8.6%-13.6%) for the standard group and the high-dose group, respectively (P = 0.214). Prediction of unbound AUC0-24 based on total AUC0-24 resulted in a bias of -0.05% and an imprecision of 13.2%. CONCLUSIONS: Plasma protein binding of rifampicin can become saturated, but exposures after high-dose rifampicin are not high enough to increase the free fraction in TB patients with normal albumin values. Unbound rifampicin exposures can be predicted from total exposures, even in the higher dose range.

Loss of histone 3 lysine 27 trimethylation (H3K27me3) has been described as a diagnostic marker for malignant peripheral nerve sheath tumor (MPNST), also discriminating MPNST with rhabdomyoblastic differentiation (malignant Triton tumor) from rhabdomyosarcoma (RMS). We studied the immunohistochemical expression of H3K27me3 in embryonal RMSs (ERMSs), performed methylation profiling in order to support the diagnosis and RNA-sequencing for comparison of the transcriptome of H3K27me3-positive and -negative cases. Of the 25 ERMS patients, 17 were males and 8 were females with an age range from 1 to 67 years (median, 6 years). None were known with neurofibromatosis type 1. One patient had Li-Fraumeni syndrome. Tumor localization included paratesticular (n = 9), genitourinary (n = 6), head/neck (n = 5), retroperitoneal (n = 4) and lower arm (n = 1). Five MPNSTs served as reference group. All ERMS had classical features including a variable spindle cell component. Immunohistochemical loss (partial or complete) of H3K27me3 was detected in 18/25 cases (72%). Based on methylation profiling, 22/22 cases were classified as ERMS. Using RNA sequencing, the ERMS group (n = 14) had a distinct gene expression profile in contrast to MPNSTs, confirming that the H3K27me3 negative ERMS cases do not represent malignant Triton tumors. When comparing H3K27me3-negative and -positive ERMSs, gene set enrichment analysis revealed differential expression of genes related to histone acetylation and normal muscle function with H3K27me3 negative ERMSs being associated with acetylation. Conclusion: Loss of H3K27me3 frequently occurs in ERMSs and correlates with H3K27 acetylation. H3K27me3 is not a suitable marker to differentiate ERMS (with spindle cell features) from malignant Triton tumor.

Background Perinatally chikungunya infected neonates have been reported to have high rates of post-infection neurologic sequelae, mainly cognitive problems. In older children and adults chikungunya does not appear to have sequelae, but data on postnatally infected infants are lacking. Methods We performed a prospective, non-controlled, observational study of infants infected before the age of 6 months with a severe chikungunya infection during the 2014–2015 epidemic in Curaçao, Dutch Antilles. Two years post-infection cognitive and motor - (BSID-III) and social emotional assessments (ITSEA) were performed. Results Of twenty-two infected infants, two died and two were lost to follow up. Eighteen children were seen at follow-up and included in the current study. Of these, 13 (72%) had abnormal scores on the BSID-III (cognitive/motor) or ITSEA. Conclusion In the first study aimed at postnatally infected infants, using an uncontrolled design, we observed a very high percentage of developmental problems. Further studies are needed to assess causality, however until these data are available preventive measure during outbreaks should also include young infants. Those that have been infected in early infancy should receive follow up.

Does retirement lead to a short, transitory health boost, followed by a stable longer-run effect? The short-run effect has been hypothesized to be a kind of honeymoon effect, that is followed by a longer-run effect that may be either positive or negative. We examine the time path of the health effect of retirement and study effect heterogeneities between individuals along several dimensions. Moreover, we study a broad range of health outcomes, all in order to come to an understanding of the effect patterns that lie behind the diverse findings reported in previous research. For identification we use a fixed effects instrumental variable approach in which the normal and early retirement age thresholds serve as instruments. Using data for 10 countries from the Survey of Health, Retirement and Ageing in Europe (SHARE), we find that retiring both at the normal and early retirement eligibility ages significantly improves all the health aspects we consider. Other than hypothesized, results do not show a honeymoon phase-like transitory health boost. Instead, especially blue-collar workers go through an adjustment period after retiring, in which their health worsens. Afterwards, health stabilizes and improves, so that retirement has a health preserving effect in the longer run. This beneficial health effect of retirement occurs across all occupational groups, across a range of health outcomes, and for both sexes, though there are a number of heterogeneities between groups regarding which health outcomes are particularly affected.

Objectives: Individuals with attention-deficit/hyperactivity disorder (ADHD) often have heightened levels of anxiety, which has been associated with worse performance on working memory tasks. Knowledge of the neural pathways underlying the combined presence of ADHD and anxiety may aid in a better understanding of their co-occurrence. Therefore, we investigated how anxiety modulates the effect of ADHD severity on neural activity during a visuospatial working memory (VSWM) task. Methods: Neuroimaging data were available for 371 adolescents and young adults participating in the multicentre cohort study NeuroIMAGE (average age 17.1 years). We analysed the effects of ADHD severity, anxiety severity and their interaction on-task accuracy, and on neural activity associated with working memory (VSWM trials minus baseline), and memory load (high memory load trials minus low load trials). Results: Anxiety significantly modulated the relation between ADHD severity and neural activity in the cerebellum for the working memory contrast, and bilaterally in the striatum and thalamus for the memory load contrast. Conclusions: We found that ADHD with co-occurring anxiety is associated with lowered neural activity during a VSWM task in regions important for information gating. This fits well with previous theorising on ADHD with co-occurring anxiety, and illustrates the neurobiological heterogeneity of ADHD.

Contains fulltext : 177347pre.pdf (Author’s version preprint ) (Open Access) BACKGROUND: The nitric oxide synthase gene (NOS1) exon 1f (ex1f) VNTR is a known genetic risk factor for Attention-Deficit/Hyperactivity Disorder (ADHD), particularly in females. NOS1 plays an important role in neurite outgrowth and may thus influence brain development, specifically white matter (WM) microstructure, which is known to be altered in ADHD. The current study aimed to investigate whether NOS1 is associated with WM microstructure in (female) individuals with and without ADHD. METHODS: Diffusion Tensor Imaging (DTI) scans were collected from 187 participants with ADHD (33% female) and 103 controls (50% female), aged 8-26 years, and NOS1-ex1f VNTR genotype was determined. Whole-brain analyses were conducted for fractional anisotropy (FA) and mean diffusivity (MD) to examine associations between NOS1 and WM microstructure, including possible interactions with gender and diagnosis. RESULTS: Consistent with previous literature, NOS1-ex1f was associated with total ADHD and hyperactivity-impulsivity symptoms, but not inattention; this effect was independent of gender. NOS1-ex1f was also associated with MD values in several major WM tracts in females, but not males. In females, homozygosity for the short allele was linked to higher MD values than carriership of the long allele. MD values in these regions did not correlate with ADHD symptoms. Results were similar for participants with and without ADHD. CONCLUSIONS: NOS1-ex1f VNTR is associated with WM microstructure in females in a large sample of participants with ADHD and healthy controls. Whether this association is part of a neurodevelopmental pathway from NOS1 to ADHD symptoms should be further investigated in future studies.

Item does not contain fulltext OBJECTIVES: (1) To identify predictive factors for outcome after splinting and hand therapy for carpometacarpal (CMC) osteoarthritis (OA) and to identify predictive factors for conversion to surgical treatment; and (2) to determine how many patients who have not improved in outcome within 6 weeks after start of treatment will eventually improve after 3 months. DESIGN: Observational prospective multicenter cohort study. SETTING: Xpert Clinic in the Netherlands. This clinic comprises 15 locations in the Netherlands, with 16 European Board certified (FESSH) hand surgeons and over 50 hand therapists. PARTICIPANTS: Between 2011 and 2014, patients with CMC OA (N=809) received splinting and weekly hand therapy for 3 months. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Satisfaction and pain were measured with a visual analog scale and function with the Michigan Hand Questionnaire at baseline, 6 weeks, and 3 months posttreatment. Using regression analysis, patient demographics and pretreatment baseline scores were considered as predictors for the outcome of conservative treatment after 3 months and for conversion to surgery. RESULTS: Multivariable regression model explained 34%-42% of the variance in outcome (P

For children with asthma, physical activity (PA) can decrease the impact of their asthma. Thus far, effective PA promoting interventions for this group are lacking. To develop an intervention, the current study aimed to identify perspectives on physical activity of children with asthma, their parents, and healthcare providers. Children with asthma between 8 and 12 years old (n = 25), their parents (n = 17), and healthcare providers (n = 21) participated in a concept mapping study. Participants generated ideas that would help children with asthma to become more physically active. They sorted all ideas and rated their importance on influencing PA. Clusters were created with multidimensional scaling and cluster analysis. The researchers labelled the clusters as either environmental or personal factors using the Physical Activity for people with a Disability model. In total, 26 unique clusters were generated, of which 17 were labelled as environmental factors and 9 as personal factors. Important factors that promote physical activity in children with asthma according to all participating groups are asthma control, stimulating environments and relatives, and adapted facilities suiting the child&rsquo, s needs. These factors, supported by the future users, enable developing an intervention that helps healthcare providers to promote PA in children with asthma.

The pharmacokinetic (PK) and clinical implications of combining metformin with rifampicin are relevant to increasing numbers of patients with diabetic tuberculosis (TB) across the world and are yet unclear. We assessed the impact of rifampicin on metformin PKs and its glucose-lowering effect in patients with diabetic TB by measuring plasma metformin and blood glucose during and after TB treatment. Rifampicin increased metformin exposure: plasma area under the plasma concentration-time curve from time point 0 to the end of the dosing interval (AUC0-τ ) and peak plasma concentration (Cmax ) geometric mean ratio (GMR; during vs. after TB treatment) were 1.28 (90% confidence interval (CI) 1.13-1.44) and 1.19 (90% CI 1.02-1.38; n = 22). The metformin glucose-lowering efficacy did not change (Δglucose - Cmax ; P = 0.890; n = 18). Thus, we conclude that additional glucose monitoring in this population is not warranted. Finally, 57% of patients on metformin and rifampicin, and 38% of patients on metformin alone experienced gastrointestinal adverse effects. Considering this observation, we advise patients to take metformin and rifampicin with food and preferably separated in time. Clinicians could consider metoclopramide if gastrointestinal adverse effects occur.

Background The psychometric properties of the Dutch version of the Stroke and Aphasia Quality Of Life-scale (SAQOL-39NL) have previously been assessed for people with aphasia after stroke, but not yet for stroke survivors without aphasia. Objective The objective is to evaluate the psychometric properties of the SAQOL-39NL in a stroke sample with and without aphasia. Methods The SAQOL-39NL was administered to survivors of stroke (N = 141) who received rehabilitation in specialized rehabilitation facilities, 3 and 6 months after the start of rehabilitation. Acceptability was explored by assessing floor and ceiling effects and missing items. For internal consistency, Cronbach's alpha and item-total correlations were computed. For internal validity, intercorrelations between domains, and between domains and total score, were assessed. Convergent validity was evaluated by correlation with EuroQoL-5D scores. Responsiveness to change was investigated using d' and SRM-scores. Results Mean age was 60.4 years (SD = 11.1), 62.4% were male. Mean total SAQOL-39NLg score was 3.94 (SD = 0.68, scale 1-5). No floor or ceiling effects and 2.4% missing data were found. Internal consistency was excellent (Cronbach's alpha = 0.96). Intercorrelations between domains and total scale were moderate to excellent (r = 0.57-0.88). Intercorrelations between domains were low to moderate (r = 0.22-0.63). The correlation with the EQ-5D was moderate (r = 0.57). Only small changes in SAQOL-39NLg scores were found between 3 and 6 months. Conclusions These data provide further evidence for the acceptability, internal consistency, and initial promising data on validity of the SAQOL-39NLg. Further research on structural validity and responsiveness to change is needed.

Background: Despite their potential benefits, many electronic health (eHealth) innovations evaluated in major studies fail to integrate into organizational routines, and the implementation of these innovations remains problematic. Objective: The purpose of this study was to describe health care professionals’ self-identified perceived barriers and facilitators for the implementation of a Web-based portal to monitor asthmatic children as a substitution for routine outpatient care. Also, we assessed patients’ (or their parents) satisfaction with this eHealth innovation. Methods: Between April and November 2015, we recruited 76 health care professionals (from 14 hospitals). During a period of 6 months, participants received 3 questionnaires to identify factors that facilitated or impeded the use of this eHealth innovation. Questionnaires for patients (or parents) were completed after the 6-month virtual asthma clinic (VAC) implementation period. Results: Major perceived barriers included concerns about the lack of structural financial reimbursement for Web-based monitoring, lack of integration of this eHealth innovation with electronic medical records, the burden of Web-based portal use on clinician workload, and altered patient-professional relationship (due to fewer face-to-face contacts). Major perceived facilitators included enthusiastic and active initiators, a positive attitude of professionals toward eHealth, the possibility to tailor care to individual patients (“personalized eHealth”), easily deliverable care according to current guidelines using the VAC, and long-term profit and efficiency. Conclusions: The implementation of Web-based disease monitoring and management in children is complex and dynamic and is influenced by multiple factors at the levels of the innovation itself, individual professionals, patients, social context, organizational context, and economic and political context. Understanding and defining the barriers and facilitators that influence the context is crucial for the successful implementation and sustainability of eHealth innovations.

While prenatal exposure to Ramadan has been shown to be negatively associated with general physical and mental health, studies on specific organs remain scarce. In this study, we explored whether Ramadan exposure during pregnancy affects the occurrence of wheezing, a main symptom of obstructive airway disease. Using data from the Indonesian Family Life Survey collected between 1997 and 2008 (waves 2-4), we compared wheezing occurrence among adult Muslims who had been in utero during Ramadan with that in adult Muslims who had not been in utero during Ramadan. Wheezing prevalence was higher among adult Muslims who had been in utero during Ramadan, independent of the pregnancy phase in which the exposure to Ramadan occurred. Moreover, this association tended to increase with age, being strongest among those aged about 45 years or older. This is in line with fetal programming theory, suggesting that impacts of in utero exposures often manifest only after reproductive age. Particularly strong associations were detected for smokers. The respiratory system of prenatally exposed Muslims thus seems to perform worse in mitigating later ex utero harmful influences such as smoking. This study suggests that exposure to Ramadan during pregnancy may have lasting consequences for adult lung functionality.

Contains fulltext : 168219.pdf (Publisher’s version ) (Open Access) Attention-deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) are highly comorbid disorders. ADHD has been associated with altered white matter (WM) microstructure, though the literature is inconsistent, which may be due to differences in the in- or exclusion of participants with comorbid ODD. WM abnormalities in ODD are still poorly understood, and it is unclear whether comorbid ODD in ADHD may have confounded the current ADHD literature. Diffusion Tensor Imaging (DTI) was used to compare fractional anisotropy (FA) and mean diffusivity (MD) between ADHD patients with (n = 42) and without (n = 117) comorbid ODD. All participants were between 8-25 years and groups did not differ in mean age or gender. Follow-up analyses were conducted to examine the role of antisocial behaviour (conduct problems) on FA and MD values in both groups. Comorbid ODD in ADHD was associated with lower FA in left frontotemporal WM, which appeared independent of ADHD symptoms. FA was negatively associated with antisocial behaviour in ADHD + ODD, but not in ADHD-only. Comorbid ODD is associated with WM abnormalities in individuals with ADHD, which appears to be independent of ADHD symptoms. Altered WM microstructure in comorbid ODD may play a role in inconsistencies in the current DTI literature in ADHD. Altered development of these tracts may contribute to social-emotional and cognitive problems in children with oppositional and antisocial behaviour.

Contains fulltext : 153487.pdf (Publisher’s version ) (Closed access) Impaired visuospatial working memory (VSWM) is suggested to be a core neurocognitive deficit in attention-deficit/hyperactivity disorder (ADHD), yet the underlying neural activation patterns are poorly understood. Furthermore, it is unclear to what extent age and gender effects may play a role in VSWM-related brain abnormalities in ADHD. Functional magnetic resonance imaging (fMRI) data were collected from 109 individuals with ADHD (60% male) and 103 controls (53% male), aged 8-25 years, during a spatial span working memory task. VSWM-related brain activation was found in a widespread network, which was more widespread compared with N-back tasks used in the previous literature. Higher brain activation was associated with higher age and male gender. In comparison with controls, individuals with ADHD showed greater activation in the left inferior frontal gyrus (IFG) and the lateral frontal pole during memory load increase, effects explained by reduced activation on the low memory load in the IFG pars triangularis and increased activation during high load in the IFG pars opercularis. Age and gender effects did not differ between controls and individuals with ADHD. Results indicate that individuals with ADHD have difficulty in efficiently and sufficiently recruiting left inferior frontal brain regions with increasing task difficulty.

The aim of the present study was to evaluate the effect of the proposed organic cation transporter (OCT) inhibitor daclatasvir on the pharmacokinetics and pharmacodynamics of the OCT substrate metformin.This was an open-label, two-period, randomized, crossover trial in 20 healthy subjects. Treatment A consisted of metformin and treatment B consisted of metformin + daclatasvir. Pharmacokinetic curves were recorded at steady-state. Geometric mean ratios (GMRs) with 90% confidence intervals (CIs) were calculated for metformin area under the concentration-time curve from 0 h to 12 h (AUCThe GMRs (90% CI) of metformin AUCBioequivalence analysis showed that daclatasvir does not influence the pharmacokinetics of metformin in healthy subjects. Pharmacodynamic parameters were also comparable between treatments.

Item does not contain fulltext OBJECTIVE: The past decades have seen a surge in stimulant prescriptions for the treatment of attention-deficit/hyperactivity disorder (ADHD). Stimulants acutely alleviate symptoms and cognitive deficits associated with ADHD by modulating striatal dopamine neurotransmission and induce therapeutic changes in brain activation patterns. Long-term functional changes after treatment are unknown, as long-term studies are scarce and have focused on brain structure. In this observational study (2009-2012), we investigated associations between lifetime stimulant treatment history and neural activity during reward processing. METHODS: Participants fulfilling DSM-5 criteria for ADHD (N = 269) were classified according to stimulant treatment trajectory. Of those, 124 performed a monetary incentive delay task during magnetic resonance imaging, all in their nonmedicated state (nEARLY&INTENSE = 51; nLATE&MODERATE = 49; nEARLY&MODERATE = 9; nNAIVE = 15; mean age = 17.4 years; range, 10-26 years). Whole-brain analyses were performed with additional focus on the striatum, concentrating on the 2 largest treatment groups. RESULTS: Compared to the late-and-moderate treatment group, the early-and-intense treatment group showed more activation in the supplementary motor area and dorsal anterior cingulate cortex (SMA/dACC) during reward outcome (cluster size = 8,696 mm(3); PCLUSTER < .001). SMA/dACC activation of the control group fell in between the 2 treatment groups. Treatment history was not associated with striatal activation during reward processing. CONCLUSIONS: Our findings are compatible with previous reports of acute increases of SMA/dACC activity in individuals with ADHD after stimulant administration. Higher SMA/dACC activity may indicate that patients with a history of intensive stimulant treatment, but currently off medication, recruit brain regions for cognitive control and/or decision-making upon being rewarded. No striatal or structural changes were found.

To determine the effect of Scriptaid, a compound that can replicate aspects of the exercise adaptive response through disruption of the class IIa histone deacetylase (HDAC) corepressor complex, on muscle insulin action in obesity.Diet-induced obese mice were administered Scriptaid (1 mg/kg) via daily intraperitoneal injection for 4 weeks. Whole-body and skeletal muscle metabolic phenotyping of mice was performed, in addition to echocardiography, to assess cardiac morphology and function.Scriptaid treatment had no effect on body weight or composition, but did increase energy expenditure, supported by increased lipid oxidation, while food intake was also increased. Scriptaid enhanced the expression of oxidative genes and proteins, increased fatty acid oxidation and reduced triglycerides and diacylglycerides in skeletal muscle. Furthermore, ex vivo insulin-stimulated glucose uptake by skeletal muscle was enhanced. Surprisingly, heart weight was reduced in Scriptaid-treated mice and was associated with enhanced expression of genes involved in oxidative metabolism in the heart. Scriptaid also improved indices of both diastolic and systolic cardiac function.These data show that pharmacological targeting of the class IIa HDAC corepressor complex with Scriptaid could be used to enhance muscle insulin action and cardiac function in obesity.

Contains fulltext : 214227.pdf (Publisher’s version ) (Open Access) Many biology-based precision drugs are available that neutralize aberrant molecular pathways in cancer. Molecular heterogeneity and the lack of reliable companion diagnostic biomarkers for many drugs makes targeted treatment of cancer inaccurate for many individuals. Identifying actionable hyperactive biological pathways in individual cancers may improve this situation.To achieve this we applied a novel targeted RNA next generation sequencing (t/RNA-NGS) technique to surgically obtained glioma tissues. The test combines mutation detection with analysis of biological pathway activities that are involved in tumour behavior in many cancer types (e.g. tyrosine kinase signaling, angiogenesis signaling, immune response, metabolism), via quantitative measurement of transcript levels and splice variants of hundreds of genes. We here present proof of concept that the technique, which uses molecular inversion probes, generates a histology-independent molecular diagnosis and identifies classifiers that are strongly associated with conventional histopathology diagnoses and even with patient prognosis. The test not only confirmed known glioma-associated molecular aberrations but also identified aberrant expression levels of actionable genes and mutations that have so far been considered not to be associated with glioma, opening up the possibility of drug repurposing for individual patients. Its cost-effectiveness makes t/RNA-NGS to an attractive instrument to aid oncologists in therapy decision making.

The prevalence of fatty liver reaches alarming proportions. Fatty liver increases the risk for insulin resistance, cardiovascular disease, and nonalcoholic steatohepatitis (NASH). Although extensively studied in a preclinical setting, the lack of noninvasive methodologies hampers our understanding of which pathways promote hepatic fat accumulation in humans. Dietary fat retention is one of the pathways that may lead to fatty liver. The low (1.1%) natural abundance (NA) of carbon-13 (C-13) allows use of C-13-enriched lipids for in vivo MR studies. Successful implementation of such methodology, however, is challenging due to low sensitivity of C-13-magnetic resonance spectroscopy (C-13-MRS). Here, we investigated the use of 1-dimensional gradient enhanced heteronuclear single quantum coherence (ge-HSQC) spectroscopy for the in vivo detection of hepatic H-1-[C-13]-lipid signals after a single high-fat meal with C-13-labeled fatty acids in 5 lean and 6 obese subjects. Postprandial retention of orally administered C-13-labeled fatty acids was significant (P

For children with problematic severe asthma, achieving adequate control of asthma is difficult. The aim of this prospective observational study was to evaluate the effects of intensive multidisciplinary inpatient treatment on multiple outcome variables in children with problematic severe asthma.Participants were 89 children with problematic severe asthma (mean age 13.6 ± 2.5 years) treated in tertiary care clinics at high altitude (Switzerland) or sea level (Netherlands) and their parents (85 mothers, 55 fathers). The primary outcome variable was the Childhood Asthma Control Test (C-ACT). Other outcome variables were forced expiratory volume in 1 sec (FEVThe percentages of children showing controlled asthma (C-ACT) were 18% (pre-treatment), 69% (post-treatment), and 44% (follow-up). The vast majority of the children (80%) showed an improvement on C-ACT with 4% showing a deterioration. On C-ACT, FeNO, quality of life, and behavioral problems, improvements at post-treatment were highly significant. Improvements generally remained at a functional level at follow-up. Children's coping and parenting stress in parents did not change.The improvement in asthma control and other outcome variables suggests that multidisciplinary inpatient treatment is an effective approach for a heterogeneous group of children with asthma that remained uncontrolled in secondary care. Pediatr Pulmonol. 2017;52:588-597. © 2016 Wiley Periodicals, Inc.

A literature on systematic treatment protocols for patients after resuscitation for cardiac arrest is lacking. We evaluated a systematic protocol, including ECG, echocardiogram, urgent cardiac catheterisation ("STEMI-like" workflow), CT scans, laboratory findings, IABP, hypothermia, and cMRI, prospectively over 5 years. The primary endpoint was the Cerebral Performance Category Scale (CPCS). During the period from January 2008 to December 2012, 212 patients were included. The mean age was 66.7 years, n = 151 (71.2 %) were male, mean time from the first medical contact to start of catheterisation was 76.6 min, and ventricular fibrillation (VF) was present in n = 99 (46.7 %). A significant coronary artery stenosis was seen in n = 130 (61.3 %), PCI was performed in n = 101 (47.6 %), an ACS was found in n = 100 (47.2 %), n = 91 patients (42.9 %) had another cardiac cause, an extra-cardiac cause was found in n = 12 (5.7 %, mostly a cerebral process), and in 9 patients (4.3 %), no cause was identifiable. A significant difference in mortality was found for patients with TIMI flow 2/3 vs. 0/1 (65.4 vs. 95.7 %, p

There are very few studies on the long-term outcome of children and adolescents with ADHD-combined type in Europe. The objective of the present study is to assess the 6-year outcome (including pharmacological treatment) of a large cohort of participants with ADHD-combined type (N = 347, mean age 11.4 years) in late adolescence and early adulthood. At study entry and follow-up (mean age 17.4 years), participants were comprehensively assessed on ADHD and comorbid disorders by structured psychiatric interviews and multi-informant questionnaires. Overall functioning was assessed by the Children’s Global Assessment Scale. The retention rate was 75.6 %. The majority of participants (86.5 %) persisted in a DSM-5 ADHD diagnosis, 8.4 % had a subthreshold diagnosis, and 5.1 % remitted from the disorder at follow-up. Comorbidities decreased strongly; oppositional defiant disorder: 58 > 31 %, conduct disorder: 19 > 7 %. At follow-up, mood- and anxiety disorders were virtually non-existent following strict criteria (1–3 %). Percentage of children having had pharmacological treatment at any time increased from 79 to 91 %. On the Children’s Global Assessment Scale, 48.5 % of participants were still functionally impaired at follow-up. Parental ADHD, higher ADHD symptom severity at baseline and higher parent-reported impairment at baseline positively predicted current ADHD symptom severity (R2 = 20.9 %). Younger baseline age, higher ADHD symptom severity at baseline and higher parent-reported impairment at baseline were positively associated with poorer overall functioning (R2 = 17.8 %). Pharmacological treatment had no (beneficial) impact on either ADHD symptom severity or overall functioning. Results confirm that ADHD is largely persistent into late adolescence with severity and family history for the disorder as important risk factors. Electronic supplementary material The online version of this article (doi:10.1007/s00787-016-0820-y) contains supplementary material, which is available to authorized users.

van de Weijer T, van Ewijk PA, Zandbergen HR, Slenter JM, Kessels AG, Wildberger JE, Hesselink MK, Schrauwen P, Schrauwen-Hinderling VB, Kooi ME. Geometrical models for cardiac MRI in rodents: comparison of quantification of left ventricular volumes and function by various geometrical models with a full-volume MRI data set in rodents. Am J Physiol Heart Circ Physiol 302: H709-H715, 2012. First published November 18, 2011; doi:10.1152/ajpheart.00710.2011.-MRI has been proven to be an accurate method for noninvasive assessment of cardiac function. One of the current limitations of cardiac MRI is that it is time consuming. Therefore, various geometrical models are used, which can reduce scan and postprocessing time. It is unclear how appropriate their use is in rodents. Left ventricular (LV) volumes and ejection fraction (EF) were quantified based on 7.0 Tesla cine-MRI in 12 wild-type (WT) mice, 12 adipose triglyceride lipase knockout (ATGL(-/-)) mice (model of impaired cardiac function), and 11 rats in which we induced cardiac ischemia. The LV volumes and function were either assessed with parallel short-axis slices covering the full volume of the left ventricle (FV, gold standard) or with various geometrical models [modified Simpson rule (SR), biplane ellipsoid (BP), hemisphere cylinder (HC), single-plane ellipsoid (SP), and modified Teichholz Formula (TF)]. Reproducibility of the different models was tested and results were correlated with the gold standard (FV). All models and the FV data set provided reproducible results for the LV volumes and EF, with interclass correlation coefficients >= 0.87. All models significantly over-or underestimated EF, except for SR. Good correlation was found for all volumes and EF for the SR model compared with the FV data set (R-2 ranged between 0.59-0.95 for all parameters). The HC model and BP model also predicted EF well (R-2 >= 0.85), although proved to be less useful for quantitative analysis. The SP and TF models correlated poorly with the FV data set (R-2 >= 0.45 for EF and R-2 >= 0.29 for EF, respectively). For the reduction in acquisition and postprocessing time, only the SR model proved to be a valuable method for calculating LV volumes, stroke volume, and EF.

Contains fulltext : 88810.pdf (Publisher’s version ) (Closed access) BACKGROUND: To evaluate the potential drug-drug interaction between raltegravir and pravastatin. METHODS: This was an open-label, randomized, 3-period, cross-over, single-centre trial in 24 healthy volunteers. Subjects received the following treatments: pravastatin 40 mg every day for 4 days, raltegravir 400 mg twice a day for 4 days, and pravastatin 40 mg every day + raltegravir 400 mg twice a day for 4 days. The treatments were separated by washout periods of 10 days. On day 4 of each treatment period, blood samples for pharmacokinetics were collected throughout a 24-hour period. RESULTS: Geometric mean ratios (90% confidence interval) for pravastatin + raltegravir versus pravastatin alone were 0.96 (0.83 to 1.11) for AUC0-24 and 1.04 (0.85 to 1.26) for Cmax. The mean low-density lipoprotein cholesterol decrease after 4 days of pravastatin was 0.42 mmol/L both in the presence and the absence of raltegravir. The geometric mean ratio (90% confidence interval) AUC0-12, Cmax, and C12 for raltegravir + pravastatin versus raltegravir alone were 1.13 (0.77 to 1.65), 1.31 (0.81 to 2.13), and 0.59 (0.39 to 0.88), respectively. CONCLUSIONS: Raltegravir did not influence the pharmacokinetics or the short-term lipid-lowering effects of pravastatin, whereas pravastatin increased the Cmax but decreased the C12 of raltegravir. The effects of pravastatin on raltegravir pharmacokinetics are not likely to be clinically relevant.

Background Representative, population-based epidemiologic data for gastroenteritis caused by rotavirus (RV) are rare. RV vaccines were first licensed in Europe in 2006 and recommended in 5 western federal states in 2008 or thereafter. This study establishes a baseline for assessing the impact of vaccination and delineates the RV disease burden in Germany today. Methods Nationwide data obtained from hospitals for children 0 to 10 years of age and transferred to the Federal Statistical Office were analyzed retrospectively. Acute gastroenteritis cases because of RV were identified by the International Classification of Diseases code (ICD-10) combined with the referring diagnosis-related group code. Coding quality was validated by random sampling the patient records (n=1003). Crude and age-standardized rates per 100,000 person-years were calculated. The rate ratios of seasonal effects and recommended immunization adjusted for year, federal state and age were estimated using Poisson regression. Results Between 2005 and 2010, 5,843,730 children were hospitalized; 520,606 cases were hospitalized because of acute gastroenteritis. RV caused 152,636 of these cases or an age-standardized rate of 302 hospitalizations per 100,000 person-years. Rates were slightly higher in boys than girls, decreased with age, and differed by federal state, year and season. Rate ratios decreased in those western federal states that recommended immunization and were inversely associated with vaccine doses sold. Conclusions With an average of 25,440 children hospitalized yearly, RV infection has a great impact on the German healthcare system. Our findings indicate that RV immunization will lead to a decline in in-patient treatment and associated costs.

Acetylcarnitine formation is suggested to be crucial in sustaining metabolic flexibility and glucose homeostasis. Recently, we introduced a method to detect acetylcarnitine in vivo with long TEAcquisition of spectra with an inversion recovery sequence was alternated with standard signal acquisition to suppress short TUsing the new TThe T

Parental high-fat feeding was proposed to negatively impact metabolic health in offspring. Here, the ectopic fat storage in heart and liver in offspring was investigated, and the effects on mitochondrial function, de novo lipogenesis, and postprandial lipid metabolism were explored in detail.Male and female mice received either a high-fat (HF) or standard chow (LF) diet during mating, gestation and lactation. All offspring animals received the HF diet.Abdominal visceral adipose tissue tended to be higher in HF/HF mice. Cardiac lipid content was also higher in the HF/HF mice (LF/HF vs.1.03% ± 0.08% vs. 1.33% ± 0.07% of water signal, P = 0.01). In contrast, hepatic lipid content tended to be lower in HF/HF mice compared to LF/HF mice. A severely disturbed postprandial lipid clearance was revealed in HF/HF mice by the results from the triglyceride (TG) tolerance tests (LF/HF vs.6,753 ± 2,213 vs. 14,367 ± 1,978 mmol l(-1) min(-1) , P = 0.01) and (13) C-fatty acid retention test (LF/HF vs.2.73% ± 0.85% vs. 0.89% ± 0.26% retention from bolus, P = 0.04), which may underlie the lower hepatic lipid content.Here it is shown that HF diet negatively impacts postprandial TG clearance in offspring and results in an overall metabolic unfavorable phenotype and ectopic lipid deposition in the heart and in visceral storage sites.

Elevated hepatic lipid content (IntraHepatic Lipid, IHL) increases the risk of metabolic complications. Although prolonged exercise training lowers IHL, it is unknown if acute exercise has the same effect. Furthermore, hepatic ATP content may be related to insulin resistance and IHL. We aimed to investigate if acute exercise leads to changes in IHL and whether this is accompanied by changes in hepatic ATP. Twenty-one men (age 54.8 ± 7.2 years, BMI 29.7 ± 2.2 kg/m2) performed a 2 h cycling protocol, once while staying fasted and once while ingesting glucose. IHL was determined at baseline, 30 min post-exercise and 4 h post-exercise. Additionally ATP/Total P ratio was measured at baseline and 4 h post-exercise. Compared with baseline values we did not observe any statistically significant changes in IHL within 30 min post-exercise in neither the fasted nor the glucose-supplemented condition. However, IHL was elevated 4 h post-exercise compared with baseline in the fasted condition (from 8.3 ± 1.8 to 8.7 ± 1.8%, p = 0.010), an effect that was blunted by glucose supplementation (from 8.3 ± 1.9 to 8.3 ± 1.9%, p = 0.789). Acute exercise does not decrease liver fat in overweight middle-aged men. Moreover, IHL increased 4 h post-exercise in the fasted condition, an increase that was absent in the glucose-supplemented condition. These data suggest that a single bout of exercise may not be able to lower IHL.

Brain white matter (WM) tracts, playing a vital role in the communication between brain regions, undergo important maturational changes during adolescence and young adulthood, a critical period for the development of nicotine dependence. Attention‐deficit/hyperactivity disorder (ADHD) is associated with increased smoking and widespread WM abnormalities, suggesting that the developing ADHD brain might be especially vulnerable to effects of smoking. This study aims to investigate the effect of smoking on (WM) microstructure in adolescents and young adults with and without ADHD. Diffusion tensor imaging was performed in an extensively phenotyped sample of nonsmokers (n = 95, 50.5% ADHD), irregular smokers (n = 41, 58.5% ADHD), and regular smokers (n = 50, 82.5% ADHD), aged 14–24 years. A whole‐brain voxelwise approach investigated associations of smoking, ADHD and their interaction, with WM microstructure as measured by fractional anisotropy (FA) and mean diffusivity (MD). Widespread alterations in FA and MD were found for regular smokers compared to irregular and nonsmokers, mainly located in the corpus callosum and WM tracts surrounding the basal ganglia. Several regions overlapped with regions of altered FA for ADHD versus controls, albeit in different directions. Irregular and nonsmokers did not differ, and ADHD and smoking did not interact. Results implicate that smoking and ADHD have independent effects on WM microstructure, and possibly do not share underlying mechanisms. Two mechanisms may play a role in the current results. First, smoking may cause alterations in WM microstructure in the maturing brain. Second, pre‐existing WM microstructure differences possibly reflect a risk factor for development of a smoking addiction. Hum Brain Mapp 36:1180–1189, 2015. © 2014 Wiley Periodicals, Inc.

There is increasing evidence that circumstances very early in our lives, and particularly during pregnancy, can affect our health for the remainder of life. Studies that have looked at this relationship have often used extreme situations, such as famines that occurred during wartime. Here we investigate whether less extreme situations during World War II also affected later-life mortality for cohorts born in Belgium, France, The Netherlands, and Norway. We argue that these occupied countries experienced a considerable deterioration in daily life situations and show that this resulted in strongly increased mortality rates and lower probabilities of survival until age 55 among civilian populations who had been prenatally exposed to wartime circumstances. However, this mortality effect among the prenatally exposed is entirely concentrated in the first years of life, particularly infanthood. Once we condition on having survived the first years of life, those who had been prenatally exposed do not have higher mortality rates. This suggests that "culling" is important and that effects found in earlier studies may have been biased downward substantially.

Contains fulltext : 50676.pdf (Publisher’s version ) (Closed access) BACKGROUND: Limited data are available about the effect of lopinavir and low-dose ritonavir on glucuronidation. Lamotrigine undergoes glucuronidation. We studied the effect of lopinavir/ritonavir on the pharmacokinetics of lamotrigine and vice versa. METHODS: Twenty-four healthy subjects received 50 mg lamotrigine once daily on days 1 and 2 and 100 mg twice daily on day 3 through day 23. Lopinavir (400 mg twice daily)/ritonavir (100 mg twice daily) was added on day 11. Depending on the decrease in lamotrigine trough level between days 10 and 20, either the study was stopped (

Objective To examine different conceptual models of negative symptoms in Alzheimer's disease. Design Confirmatory factor analysis of cross-sectional data. Subjects Alzheimer patients (n=281) admitted to a psychogeriatric observation ward. Materials Nurses' Behavioural observation scale for psychogeriatric inpatients (GIP). Global clinical ratings of severity of dementia and depression based on the Cambridge Examination for Mental Disorders of the Elderly-Dutch version (CAMDEX-N). Results A unidimensional model of dementia fitted the data poorly. Multidimensional models produced better results. In two- and three-factor models negative symptoms were separated from cognitive impairment and mood disturbances. The more severe the memory impairment, the more socially withdrawn patients were. In this sense negative symptoms may have been secondary to cognitive decline. However, no association was found between negative symptoms and mood disturbances. Conclusions Negative symptoms are a prominent clinical feature of Alzheimer's disease and they are related to memory impairment but not to mood disturbances. Copyright © 2003 John Wiley & Sons, Ltd.

Vestibular schwannomas (VS) are rare tumors that can cause different symptoms due to their anatomical relationship to the cranial nerves in the inner auditory canal. So far little data is known to the effect of VS on the somatosensory function of the intermediate nerve. This study aimed to investigate the taste function of patients suffering from single sided VS. Therefore the well validated psychophysical test "Taste Strips" has been used. 26 patients who consulted our outpatient clinic at a university hospital could be included in the study. All patients were asked carefully for their medical history. A full ENT examination was done. Each side of the anterior two thirds of the tongue was tested separately using the Taste Strips. The average age was 52 years with both gender equally represented. Throughout all age groups the taste score was lower on the tumor vs. the non affected side. Testing for significance just failed the level of 0.05. No correlation between tumor size and location of the tumor with the taste score could be detected. Only 2 patients complained of taste dysfunction. They had a taste score below the 10. percentile of their age group on tumor while normal scores on the non affected side. To sum up a decreased taste score on the tumor side vs. the non affected side could be confirmed. Only 8% of the patients complained of taste disturbance as a symptom. That supports the observation that taste is a whole mouth experience and dysfunction can be compensated.

INTRODUCTION: Asthma control is considered the major goal of asthma management, while many determinants of control are difficult to modify. We studied the association between respiratory infection episodes (RTIs) of various types and asthma control. METHODS: Cross-sectional data were used from children aged 4-18 years with physician-diagnosed asthma who participated in a web-based electronic portal for children with asthma, allergies or infections. Asthma control was measured using the Childhood Asthma Control Test (C-ACT) or the Asthma Control Test (ACT). Linear regression was used to analyse the association between categories of numbers of various types of RTIs sustained in the preceding 12 months (categorized) and asthma control, adjusted for potential confounders. RESULTS: Asthma control was assessed in 654 children, and 68.5% were clinically well controlled (ACT ≥ 20). Higher total numbers of RTIs in the last 12 months were strongly associated with a lower level of asthma control (ptrend < 0.001). Similarly strong statistically significant associations were found for subtypes of RTI: ≥4 vs. 0 otitis episodes: coefficient -1.7 (95% CI -3.3 to -0.2); ≥5 vs.0 colds: coefficient -2.3 (95% CI -3.0 to -1.6); ≥3 vs. 0 bronchitis episodes: coefficient -3.1 (95% CI -4.0 to -2.3), each with ptrend < 0.05. CONCLUSION: Higher numbers of reported respiratory tract infections are associated with lower level of asthma control. The different type of respiratory tract infections contribute equally to less controlled asthma.

Background: In Germany, about 20% of the total population have a migration background. Differences exist between migrants and non-migrants in terms of health care access and utilisation. Colorectal cancer is the second most common malignant tumour in Germany, and incidence, staging and survival chances depend, amongst other things, on ethnicity and lifestyle. The current study investigates whether stage at diagnosis differs between migrants and non-migrants with colorectal cancer in an area of high migration and attempts to identify factors that can explain any differences. Methods/Design: Data on tumour and migration status will be collected for 1,200 consecutive patients that have received a new, histologically verified diagnosis of colorectal cancer in a high migration area in Germany in the previous three months. The recruitment process is expected to take 16 months and will include gastroenterological private practices and certified centres for intestinal diseases. Descriptive and analytical analysis will be performed: the distribution of variables for migrants versus non-migrants and participants versus non-participants will be analysed using appropriate χ2-, t-, F- or Wilcoxon tests. Multivariable, logistic regression models will be performed, with the dependent variable being the dichotomized stage of the tumour (UICC stage I versus more advanced than UICC stage I). Odds ratios and associated 95%-confidence intervals will be calculated. Furthermore, ordered logistic regression models will be estimated, with the exact stage of the tumour at diagnosis as the dependent variable. Predictors used in the ordered logistic regression will be patient characteristics that are specific to migrants as well as patient characteristics that are not. Interaction models will be estimated in order to investigate whether the effects of patient characteristics on stage of tumour at the time of the initial diagnosis is different in migrants, compared to non-migrants. Discussion: An association of migration status or other socioeconomic variables with stage at diagnosis of colorectal cancer would be an important finding with respect to equal health care access among migrants. It would point to access barriers or different symptom appraisal and, in the long term, could contribute to the development of new health care concepts for migrants. Trial registration: German Clinical Trials Register DRKS00005056.

Item does not contain fulltext OBJECTIVE: The aim of this study was to (a) test the usefulness of visuospatial working memory (VSWM) as an endophenotype for ADHD and (b) study the developmental trajectory of VSWM in ADHD. METHOD: A total of 110 ADHD patients, 60 unaffected siblings, and 109 controls, aged 8 to 29 years, were assessed on VSWM functioning. Multilevel analyses were carried out to account for the correlation between measurements within families. RESULTS: ADHD patients showed impaired VSWM performance compared with unaffected siblings and controls, with comparable performance between unaffected siblings and controls. Impaired VSWM in ADHD patients was not more pronounced on higher memory loads, signifying executive rather than storage deficits as an underlying mechanism. ADHD patients, unaffected siblings, and controls showed parallel developmental trajectories of VSWM. CONCLUSION: Current findings question the usefulness of VSWM as a neurocognitive endophenotype for ADHD and provide unique insights into the developmental trajectory of VSWM in ADHD.

Thus far, 13 genes for autosomal dominant hearing loss have been localized to specific chromosomal regions, but none of the genes has been cloned. Only a single family has been linked to each of these loci, with the exception of DFNA2. DFNA2 was originally mapped in two extended families originating from Indonesia and the United States. In this study we report linkage to DFNA2 in three additional large families with autosomal dominant hearing loss from Belgium and The Netherlands. These five DFNA2 families show a similar progressive sensorineural hearing loss, starting in the high frequencies and also affecting the middle and low frequencies later in life. Combining the information from all linked families, the candidate region that is most likely to contain the DFNA2 gene was reduced to a 1.25-Mb region between markers D1S432 and MYCL1. Different haplotypes segregating with the hearing loss were found in all five families, suggesting that different mutations are present in the same gene. These results indicate that DFNA2 is most likely an important gene for autosomal dominant hearing loss.

Studies on the early events in the differentiation of the nonspecific immune system require the identification and isolation of myeloid-committed progenitor cells. Using the monoclonal antibodies (mAb) ER-MP12 and ER-MP20, generated against immortalized macrophage precursors, we have shown previously that the earliest macrophage colony-stimulating factor (M-CSF)-responsive cells in the bone marrow have the ER-MP12(hi)20- phenotype. In addition, we found that the ER-MP12(hi)20- subset (comprising about 2% of total nucleated marrow) contains progenitor cells of all hematopoietic lineages. Aiming at the identification and purification of the myeloid progenitor cells within the ER-MP12(hi)20- subset, we used ER-MP58, a marker expressed at high level by all M-CSF-responsive bone marrow progenitors. With this marker the ER-MP12(hi)20- cell population could be divided into three subfractions: one with absent or low level ER-MP58 expression, one with intermediate, and one with high ER-MP58 expression. These subfractions were isolated by fluorescence-activated cell sorting and tested in vitro and in vivo for their differentiation capacities. In addition, the expression of ER-MP58 on stem cell subsets was examined in the cobblestone area-forming cell (CAFC) assay. Our data indicate that in the ERMP12(hi)20- subpopulation myeloid-committed progenitors are characterized by high-level expression of the ER-MP58 antigen, whereas cells with other or broader differentiation capacities have an ER-MP58 negative/low or intermediate phenotype. These myeloid-committed progenitors have no significant repopulating ability in vivo, in contrast to the ER-MP58 intermediate cells. Primitive CAFC-28/35, corresponding to cells providing long-term hematopoietic engraftment in vivo, also did not express the ER-MP58 Ag at a high level. Thus, cells committed to the myeloid lineage can be separated from progenitor cells with other differentiation capacities by means of multiparameter cell sorting using ER-MP58 in combination with ER-MP12 and ER-MP20.

Burns are common in children but it is not always clear whether the burn is accidental or not. Child abuse should always be considered. We present two children in which the diagnosis only became clear after admission and further investigation. Patient A, a 15-month-old boy, had a burn on his left shoulder. The burn was assumed suspect in view of the unclear history given by the parents and a possible delay in their seeking help. The patient was ultimately diagnosed with impetigo bullosa and successfully treated with antibiotics. Patient B, a 24-month-old girl, had burns on both feet and her right hand, which were infected as a result of the delay in seeking help. The burns were identified as abuse-related. The child was removed from her mother's care and sent to a foster home. A well-defined work-up should be followed in case of burns in children.

SUMMARY Immunosuppressive retrovirus-related proteins, like p15E, are involved in tumour-associated immunosuppression. In the present study we investigated whether such proteins could be used as targets in tumour immunotherapy using MoAbs. Immunotherapy was performed in mice inoculated with the Rauscher virus-transformed myeloid cell line RMB-1. RMB-1 cells express retroviral antigens at their cell surface. In order to obtain constant scrum titres of MoAbs over a prolonged period of time during therapy, anti-pl 5E antibody-producing hybridoma ceils were encapsulated in alginate and injected intraperitoneally in tumour-bearing mice. Using this technique, serum antibody titres of 50–100μg/ml were obtained, which remained constant over a period of at least 3 weeks. Therapy experiments were performed using anti-p15E antibodies 1F8, which recognizes both cell surface-associated as well as circulating pi 5E. and ER-1S5, which did not react with surface-bound p15E beyond background, but which neutralizes circulating p15E. Inoculation of alginates containing anti-p15E hybridoma cell lines in RMB-1 tumour-bearing mice showed inhibition of tumour cell growth. In survival experiments, 19F8 cured eight of 23 tumour-bearing mice. The p 15E neutralizing antibody ER-IS5 caused a significant longer survival, but therapy with this MoAb alone was not sufficient to cure the animals of the RMB-1 tumour.

BACKGROUND: Respiratory viral infections are an important cause of morbidity in patients with chronic respiratory diseases, such as cystic fibrosis (CF). We hypothesized that patients with CF are more susceptible to human rhinovirus (HRV) infections than healthy controls. METHODS: In a 6-months winter period 20 young children with CF (0-7 years) and 18 age-matched healthy controls were sampled bi-weekly for HRV-PCR using nasopharyngeal swabs, irrespective of respiratory symptoms. Respiratory symptoms were scored twice a week. If any symptom was present an additional sample was obtained. All HRV positive samples were genotyped to distinguish HRV subtypes. RESULTS: We analyzed 645 samples, with comparable total numbers of samples in both groups. HRV was detected in 40.8% of all analyzed samples. Children with CF had significantly more HRV positive samples compared to healthy controls, with a mean number (± SD) of 8.1 ± 2.3 versus 5,7 ± 2.9 positive samples per individual (p2 weeks) with the same HRV subtype occurred more frequently in the CF patients (p

We have addressed the question whether the epithelial stroma in the thymus is derived from a common stem cell or whether cortical and medullary epithelial cells are derived from different embryonic stem cells emerging, for example, from endoderm and ectoderm. By the use of rapidly expanding cultures of thymic epithelial cells (TEC) from 14 to 16 day-old murine fetuses and by specific antibodies against cortical and medullary epithelium, respectively, we were able to demonstrate a small subpopulation of double-labeled TEC in the cultures. These cells were not present in TEC cultures initiated from thymuses of neonatal mice. Double-labeled TEC were also found in tissue sections from fetal thymuses. These findings may indicate that TEC populations of the cortex and the medulla are derived from a common stem cell, with potential for differentiation toward both cortical and medullary TEC.

Because studies showed similar viral suppression with lower raltegravir doses and because Asians usually have high antiretroviral concentrations, we explored low-dose raltegravir therapy in Thais. Nineteen adults on raltegravir at 400 mg twice daily (BID) with HIV RNA loads of 0-12 ) was 15.6 mg/liter-h and the minimum plasma drug concentration ( C trough ) was 0.22 mg/liter; for raltegravir given at 800 mg QD, the AUC 0-24 was 33.6 mg/liter-h and the C trough was 0.06 mg/liter; and for raltegravir given at 400 mg QD, the AUC 0-24 was 18.6 mg/liter-h and the C trough was 0.08 mg/liter. The HIV RNA load was 0-24 for Westerners on raltegravir at 400 mg BID, Thais on the same dose had double the AUC 0-24 and those on raltegravir at 400 mg QD had a similar AUC 0-24 . More patients had a C trough of C trough values. Low-dose raltegravir could be a cost-saving option for maintenance therapy in Asians or persons with low body weight. However, raltegravir at 400 mg QD was associated with a low C trough and with a risk for HIV viremia. Raltegravir at 200 or 300 mg BID should be studied, but new raltegravir formulations will be needed.

From human urine the following metabolites of sulfamethoxazole (S) were isolated by preparative HPLC: 5-methylhydroxysulfamethoxazole (SOH), N4-acetyl-5-methylhydroxysulfamethoxazole (N4SOH) and sulfamethoxazole-N1-glucuronide (Sgluc). The compounds were identified by NMR, mass spectrometry, infrared spectrometry, hydrolysis by beta-glucuronidase and ratio of capacity factors. The analysis of S and the metabolites N4-acetylsulfamethoxazole (N4), SOH, N4-hydroxysulfamethoxazole (N4OH), N4SOH, and Sgluc in human plasma and urine samples was performed with reversed-phase gradient HPLC with UV detection. In plasma, S and N4 could be detected in high concentrations, while the other metabolites were present in only minute concentrations. In urine, S and the metabolites and conjugates were present. The quantitation limit of the compounds in plasma are respectively: S and N4 0.10 micrograms/ml; N4SOH 0.13 micrograms/ml; N4OH 0.18 micrograms/ml; SOH 0.20 micrograms/ml; and Sgluc 0.39 microgram/ml. In urine the quantitation limits are: N4 and N4OH 1.4 micrograms/ml; S 1.5 micrograms/ml; N4SOH 1.9 micrograms/ml; SOH 3.5 micrograms/ml; and Sgluc 4.1 micrograms/ml. The method was applied to studies with healthy subjects and HIV positive patients.

A gradient reversed-phase HPLC analysis for the direct measurement of salicylic acid (SA) with the corresponding glycine and glucuronide conjugates in plasma and urine of humans was developed. The glucuronides were isolated by preparative HPLC from human urine samples. The concentration of the glucuronides in the isolated fraction were determined after enzymatic hydrolysis. Salicylic acid acyl glucuronide (SAAG) was not present in plasma. No isoglucuronides were present in acidic and alkaline urine of the volunteer. The limits of quantitation in plasma are: SA 0.2 microgram/ml, salicyluric acid (SU) 0.1 microgram/ml, salicylic acid phenolic glucuronide (SAPG) 0.4 microgram/ml and salicyluric acid phenolic glucuronide (SUPG) 0.2 microgram/ml. The limit of quantitation in urine is for all compounds 5 micrograms/ml. Salicylic acid acyl glucuronide is stable in phosphate buffer pH 4.9 during 8 h at 37 degrees C; thereafter it declines to 80% after 24 h. The subject's urine was therefore acidified by the oral intake of 4 x 1.2 g of ammonium chloride/day. With acidic urine, hardly any salicylic acid is excreted unchanged (0.6%). It is predominantly excreted as salicyluric acid (68.7%).

Indomethacin is metabolized in humans by O-demethylation, and by acyl glucuronidation to the 1-O-glucuronide. Indomethacin, its metabolite, and their conjugates can be measured directly by gradient high-pressure liquid chromatographic analysis without enzymic deglucuronidation. The pharmacokinetic profile of indomethacin and some preliminary pharmacokinetic parameters of indomethacin obtained from one human volunteer are given. In plasma only the parent drug indomethacin is present, while in urine the acyl and ether glucuronides are present in high concentrations. This confirms other reports that indomethacin and O-desmethylindomethacin may be glucuronidated in the kidney. Probenecid is a known substrate for renal glucuronidation. If indomethacin is glucuronidated in the human kidney like probenecid, then this glucuronidation might be reduced or inhibited under probenecid co-medication. This pilot experiment shows that probenecid reduced the acyl glucuronidation of indomethacin by 50% and completely inhibited the formation of O-desmethylindomethacin acyl and ether glucuronide.