Congenital hydronephrosis: prenatal diagnosis and epidemiology in Europe.

OBJECTIVE: To describe prevalence, prenatal diagnosis and epidemiology of congenital hydronephrosis (CH) in Europe. MATERIAL AND METHOD: Data from a large European database for surveillance of congenital malformations (EUROCAT). The 20 participating registries are all based on multiple sources of information and include information about livebirths, fetal deaths with gestational age >or=20 weeks and terminations of pregnancy after prenatal diagnosis of malformations. Included were all cases with CH and born 1995-2004. RESULTS: There were 3648 cases with CH giving an overall prevalence of 11.5 cases per 10,000 births. The large majority of cases were livebirths (3506, 96% of total) and only 17 cases were fetal deaths and 120 were terminations of pregnancy. Almost all livebirths were alive 1 week after birth. Boys accounted for 72% of all cases. A high proportion of the cases (86%) had an isolated renal malformation. There were large regional differences in prevalence of CH ranging from 2 to 29 per 10,000 births. There was little regional variation in the prevalence of postnatally diagnosed cases while there were large regional differences in prevalence of prenatally diagnosed cases. CONCLUSION: Cases with CH are mainly livebirths, boys and survive the first week after birth. The large difference in prevalence seems to be related to the availability of prenatal screening in the region. The impact of over-diagnosis and potential over-treatment in regions with high prevalence or under-diagnosis with implications for renal function later in life in regions with low prevalence needs further investigation.

Decreased pyramidal neuron size in Brodmann areas 44 and 45 in patients with autism.

Autism is a neurodevelopmental disorder characterized by deficits in social interaction and social communication, as well as by the presence of repetitive and stereotyped behaviors and interests. Brodmann areas 44 and 45 in the inferior frontal cortex, which are involved in language processing, imitation function, and sociality processing networks, have been implicated in this complex disorder. Using a stereologic approach, this study aims to explore the presence of neuropathological differences in areas 44 and 45 in patients with autism compared to age- and hemisphere-matched controls. Based on previous evidence in the fusiform gyrus, we expected to find a decrease in the number and size of pyramidal neurons as well as an increase in volume of layers III, V, and VI in patients with autism. We observed significantly smaller pyramidal neurons in patients with autism compared to controls, although there was no difference in pyramidal neuron numbers or layer volumes. The reduced pyramidal neuron size suggests that a certain degree of dysfunction of areas 44 and 45 plays a role in the pathology of autism. Our results also support previous studies that have shown specific cellular neuropathology in autism with regionally specific reduction in neuron size, and provide further evidence for the possible involvement of the mirror neuron system, as well as impairment of neuronal networks relevant to communication and social behaviors, in this disorder.

Acute post-exercise oxygen uptake, hormone and plasma metabolite response in obese men.

This study aimed to compare oxygen uptake (  V˙O2), hormone and plasma metabolite responses during the 30 min after submaximal incremental exercise (Incr) performed at the same relative/absolute exercise intensity and duration in lean (L) and obese (O) men. Eight L and 8 O men (BMI: 22.9±0.4; 37.2±1.8 kg · m(-2)) completed Incr and were then seated for 30 min.   V˙O2 was monitored during the first 10 min and from the 25-30(th) minutes of recovery. Blood samples were drawn for the determination of hormone (catecholamines, insulin) and plasma metabolite (NEFA, glycerol) concentrations. Excess post-exercise oxygen consumption (EPOC) magnitude during the first 10 min was similar in O and in L (3.5±0.4; 3.4±0.3 liters, respectively, p=0.86). When normalized to percent change (  V˙O2END=100%), %   V˙O2END during recovery was significantly higher from 90-120 s in O than in L (p≤0.04). There were no significant differences in catecholamines (p≥0.24), whereas insulin was significantly higher in O than in L during recovery (p=0.01). The time-course of glycerol was similar from 10-30 min of recovery (-42% for L; -41% for O, p=0.85), whereas significantly different patterns of NEFA were found from 10-30 min of recovery between groups (-18% for L; +8% for O, p=0.03). Despite similar EPOC, a difference in   V˙O2 modulation between groups was observed, likely due to faster initial rates of   V˙O2 decline in L than in O. The different patterns of NEFA between groups may suggest a lower NEFA reesterification during recovery in O, which was not involved in the rapid EPOC component.

siRNA-Mediated Knock-Down of P-Glycoprotein Expression Reveals Distinct Cellular Disposition of Anticancer Tyrosine Kinases Inhibitors.

Studies on the cellular disposition of targeted anticancer tyrosine kinases inhibitors (TKIs) have mostly focused on imatinib while the functional importance of P-glycoprotein (Pgp) the gene product of MDR1 remains controversial for more recent TKIs. By using RNA interference-mediated knockdown of MDR1, we have investigated and compared the specific functional consequence of Pgp on the cellular disposition of the major clinically in use TKIs imatinib, dasatinib, nilotinib, sunitinib and sorafenib. siRNA-mediated knockdown in K562/Dox cell lines provides a unique opportunity to dissect the specific contribution of Pgp to TKIs intracellular disposition. In these conditions, abrogating specifically Pgp-mediated efflux in vitro revealed the remarkable and statistically significant cellular accumulation of imatinib (difference in cellular levels between Pgp-expressing and silenced cells, at high and low incubation concentration, respectively: 6.1 and 6.6), dasatinib (4.9 and 5.6), sunitinib (3.7 and 7.3) and sorafenib (1.2 and 1.4), confirming that these TKIs are all substrates of Pgp. By contrast, no statistically significant difference in cellular disposition of nilotinib was observed as a result of MDR1 expression silencing (differences: 1.1 and 1.5) indicating that differential expression and/or function of Pgp is unlikely to affect nilotinib cellular disposition. This study enables for the first time a direct estimation of the specific contribution of one transporter among the various efflux and influx carriers involved in the cellular trafficking of these major TKIs in vitro. Knowledge on the distinct functional consequence of Pgp expression for these various TKIs cellular distribution is necessary to better appreciate the efficacy, toxicity, and potential drug-drug interactions of TKIs with other classes of therapeutic agents, at the systemic, tissular and cellular levels.

Infectivity of Lactobacillus rhamnosus and Lactobacillus paracasei isolates in a rat model of experimental endocarditis.

The potential pathogenicity of selected (potentially) probiotic and clinical isolates of Lactobacillus rhamnosus and Lactobacillus paracasei was investigated in a rat model of experimental endocarditis. In addition, adhesion properties of the lactobacilli for fibrinogen, fibronectin, collagen and laminin, as well as the killing activity of the platelet-microbicidal proteins fibrinopeptide A (FP-A) and connective tissue activating peptide 3 (CTAP-3), were assessed. The 90 % infective dose (ID(90)) of the L. rhamnosus endocarditis isolates varied between 10(6) and 10(7) c.f.u., whereas four of the six (potentially) probiotic L. rhamnosus isolates showed an ID(90) that was at least 10-fold higher (10(8) c.f.u.) (P<0.001). In contrast, the two other probiotic L. rhamnosus isolates exhibited an ID(90) (10(6) and 10(7) c.f.u.) comparable to the ID(90) of the clinical isolates of this species investigated (P>0.05). Importantly, these two probiotic isolates shared the same fluorescent amplified fragment length polymorphism cluster type as the clinical isolate showing the lowest ID(90) (10(6) c.f.u.). L. paracasei tended to have a lower infectivity than L. rhamnosus (ID(90) of 10(7) to > or =10(8) c.f.u.). All isolates had comparable bacterial counts in cardiac vegetations (P>0.05). Except for one L. paracasei strain adhering to all substrates, all tested lactobacilli adhered only weakly or not at all. The platelet peptide FP-A did not show any microbicidal activity against the tested lactobacilli, whereas CTAP-3 killed the majority of the isolates. In general, these results indicate that probiotic lactobacilli display a lower infectivity in experimental endocarditis compared with true endocarditis pathogens. However, the difference in infectivity between L. rhamnosus endocarditis and (potentially) probiotic isolates could not be explained by differences in adherence or platelet microbicidal protein susceptibility. Other disease-promoting factors may exist in these organisms and warrant further investigation.

Impact of phenotype definition on genome-wide association signals: empirical evaluation in human immunodeficiency virus type 1 infection.

Discussion on improving the power of genome-wide association studies to identify candidate variants and genes is generally centered on issues of maximizing sample size; less attention is given to the role of phenotype definition and ascertainment. The authors used genome-wide data from patients infected with human immunodeficiency virus type 1 (HIV-1) to assess whether differences in type of population (622 seroconverters vs. 636 seroprevalent subjects) or the number of measurements available for defining the phenotype resulted in differences in the effect sizes of associations between single nucleotide polymorphisms and the phenotype, HIV-1 viral load at set point. The effect estimate for the top 100 single nucleotide polymorphisms was 0.092 (95% confidence interval: 0.074, 0.110) log(10) viral load (log(10) copies of HIV-1 per mL of blood) greater in seroconverters than in seroprevalent subjects. The difference was even larger when the authors focused on chromosome 6 variants (0.153 log(10) viral load) or on variants that achieved genome-wide significance (0.232 log(10) viral load). The estimates of the genetic effects tended to be slightly larger when more viral load measurements were available, particularly among seroconverters and for variants that achieved genome-wide significance. Differences in phenotype definition and ascertainment may affect the estimated magnitude of genetic effects and should be considered in optimizing power for discovering new associations.

Monitoring of noninvasive ventilation by built-in software of home bilevel ventilators: a bench study.

BACKGROUND: Current bilevel positive-pressure ventilators for home noninvasive ventilation (NIV) provide physicians with software that records items important for patient monitoring, such as compliance, tidal volume (Vt), and leaks. However, to our knowledge, the validity of this information has not yet been independently assessed. METHODS: Testing was done for seven home ventilators on a bench model adapted to simulate NIV and generate unintentional leaks (ie, other than of the mask exhalation valve). Five levels of leaks were simulated using a computer-driven solenoid valve (0-60 L/min) at different levels of inspiratory pressure (15 and 25 cm H(2)O) and at a fixed expiratory pressure (5 cm H(2)O), for a total of 10 conditions. Bench data were compared with results retrieved from ventilator software for leaks and Vt. RESULTS: For assessing leaks, three of the devices tested were highly reliable, with a small bias (0.3-0.9 L/min), narrow limits of agreement (LA), and high correlations (R(2), 0.993-0.997) when comparing ventilator software and bench results; conversely, for four ventilators, bias ranged from -6.0 L/min to -25.9 L/min, exceeding -10 L/min for two devices, with wide LA and lower correlations (R(2), 0.70-0.98). Bias for leaks increased markedly with the importance of leaks in three devices. Vt was underestimated by all devices, and bias (range, 66-236 mL) increased with higher insufflation pressures. Only two devices had a bias < 100 mL, with all testing conditions considered. CONCLUSIONS: Physicians monitoring patients who use home ventilation must be aware of differences in the estimation of leaks and Vt by ventilator software. Also, leaks are reported in different ways according to the device used.

Cross-sectional analysis of testosterone therapies in hypopituitary men on stable pituitary hormone replacement.

OBJECTIVE: The last decade has seen a proliferation in options for testosterone replacement. However, little is known as to the benefits of different treatment modalities. Our objective was to determine the testosterone prescription pattern and to examine the impact on various outcome measures. SUBJECTS AND METHODS: A total of 816 adult-onset hypopituitary males on stable pituitary replacement for at least 1 year were identified from the KIMS database. Patients were classified as either eugonadal (n = 106), or hypogonadal (n = 710) on intramuscular (IM, n = 558), oral (n = 74), transdermal (n = 61), and depot (n = 17) testosterone. RESULTS: After 1 year of stable pituitary replacement therapy, body composition, cardiovascular parameters, GH replacement and quality of life were not significantly different in androgen-replaced hypogonadal patients compared to eugonadal patients. There were no differences in outcome variables within the hypogonadal group according to the testosterone replacement regimen used and no difference in response to GH therapy. CONCLUSIONS: The majority of hypopituitary patients in the last decade have received IM testosterone. Body composition, cardiovascular parameters, GH replacement and quality of life were not different between eugonadal and hypogonadal patients and were not differentially affected by the mode of testosterone replacement. These findings are reassuring that there is no major difference in response to different testosterone replacement regimens.

Comparisons of intensity-duration patterns of physical activity in the US, Jamaica and 3 African countries.

BACKGROUND: This difference in how populations living in low-, middle or upper-income countries accumulate daily PA, i.e. patterns and intensity, is an important part in addressing the global PA movement. We sought to characterize objective PA in 2,500 participants spanning the epidemiologic transition. The Modeling the Epidemiologic Transition Study (METS) is a longitudinal study, in 5 countries. METS seeks to define the association between physical activity (PA), obesity and CVD risk in populations of African origin: Ghana (GH), South Africa (SA), Seychelles (SEY), Jamaica (JA) and the US (suburban Chicago). METHODS: Baseline measurements of objective PA, SES, anthropometrics and body composition, were completed on 2,500 men and women, aged 25-45 years. Moderate and vigorous PA (MVPA, min/d) on week and weekend days was explored ecologically, by adiposity status and manual labor. RESULTS: Among the men, obesity prevalence reflected the level of economic transition and was lowest in GH (1.7%) and SA (4.8%) and highest in the US (41%). SA (55%) and US (65%) women had the highest levels of obesity, compared to only 16% in GH. More men and women in developing countries engaged in manual labor and this was reflected by an almost doubling of measured MPVA among the men in GH (45 min/d) and SA (47 min/d) compared to only 28 min/d in the US. Women in GH (25 min/d), SA (21 min/d), JA (20 min/d) and SEY (20 min/d) accumulated significantly more MPVA than women in the US (14 min/d), yet this difference was not reflected by differences in BMI between SA, JA, SEY and US. Moderate PA constituted the bulk of the PA, with no study populations except SA men accumulating > 5 min/d of vigorous PA. Among the women, no sites accumulated >2 min/d of vigorous PA. Overweight/obese men were 22% less likely to engage in manual occupations. CONCLUSION: While there is some association for PA with obesity, this relationship is inconsistent across the epidemiologic transition and suggests that PA policy recommendations should be tailored for each environment.

Glucose metabolism, gray matter structure, and memory decline in subjective memory impairment.

OBJECTIVE: To identify biological evidence for Alzheimer disease (AD) in individuals with subjective memory impairment (SMI) and unimpaired cognitive performance and to investigate the longitudinal cognitive course in these subjects. METHOD: [¹⁸F]fluoro-2-deoxyglucose PET (FDG-PET) and structural MRI were acquired in 31 subjects with SMI and 56 controls. Cognitive follow-up testing was performed (average follow-up time: 35 months). Differences in baseline brain imaging data and in memory decline were assessed between both groups. Associations of memory decline with brain imaging data were tested. RESULTS: The SMI group showed hypometabolism in the right precuneus and hypermetabolism in the right medial temporal lobe. Gray matter volume was reduced in the right hippocampus in the SMI group. At follow-up, subjects with SMI showed a poorer performance than controls on measures of episodic memory. Longitudinal memory decline in the SMI group was associated with reduced glucose metabolism in the right precuneus at baseline. CONCLUSION: The cross-sectional difference in 2 independent neuroimaging modalities indicates early AD pathology in SMI. The poorer memory performance at follow-up and the association of reduced longitudinal memory performance with hypometabolism in the precuneus at baseline support the concept of SMI as the earliest manifestation of AD.

Deposits of the sandy braided South Saskatchewan River: Implications for the use of modern analogs in reconstructing channel dimensions in reservoir characterization

Estimation of the dimensions of fluvial geobodies from core data is a notoriously difficult problem in reservoir modeling. To try and improve such estimates and, hence, reduce uncertainty in geomodels, data on dunes, unit bars, cross-bar channels, and compound bars and their associated deposits are presented herein from the sand-bed braided South Saskatchewan River, Canada. These data are used to test models that relate the scale of the formative bed forms to the dimensions of the preserved deposits and, therefore, provide an insight as to how such deposits may be preserved over geologic time. The preservation of bed-form geometry is quantified by comparing the Alluvial architecture above and below the maximum erosion depth of the modem channel deposits. This comparison shows that there is no significant difference in the mean set thickness of dune cross-strata above and below the basal erosion surface of the contemporary channel, thus suggesting that dimensional relationships between dune deposits and the formative bed-form dimensions are likely to be valid from both recent and older deposits. The data show that estimates of mean bankfull flow depth derived from dune, unit bar, and cross-bar channel deposits are all very similar. Thus, the use of all these metrics together can provide a useful check that all components and scales of the alluvial architecture have been identified correctly when building reservoir models. The data also highlight several practical issues with identifying and applying data relating to cross-strata. For example, the deposits of unit bars were found to be severely truncated in length and width, with only approximately 10% of the mean bar-form length remaining, and thus making identification in section difficult. For similar reasons, the deposits of compound bars were found to be especially difficult to recognize, and hence, estimates of channel depth based on this method may be problematic. Where only core data are available (i.e., no outcrop data exist), formative flow depths are suggested to be best reconstructed using cross-strata formed by dunes. However, theoretical relationships between the distribution of set thicknesses and formative dune height are found to result in slight overestimates of the latter and, hence, mean bankfull flow depths derived from these measurements. This article illustrates that the preservation of fluvial cross-strata and, thus, the paleohydraulic inferences that can be drawn from them, are a function of the ratio of the size and migration rate of bed forms and the time scale of aggradation and channel migration. These factors must thus be considered when deciding on appropriate length:thickness ratios for the purposes of object-based modeling in reservoir characterization.

Strokes in the anterior circulation: comparison between bridging and intravenous thrombolysis.

BACKGROUND AND PURPOSE: To compare safety and efficacy of bridging approach with intravenous (IV) thrombolysis in patients with acute anterior strokes and proximal occlusions. PATIENTS AND METHODS: Consecutive patients with ischemic anterior strokes admitted within a 4 h 30 min window in two different centers were included. The first center performed IV therapy (alteplase 0.6 mg/kg) during 30 min and, in absence of clinical improvement, mechanical thrombectomy with flow restoration using a Solitaire stent (StS); the second carried out IV thrombolysis (alteplase 0.9 mg/kg) alone. Only T, M1 or M2 occlusions present on CT angiography were considered. Endpoints were clinical outcome and mortality at 3 months. RESULTS: There were 63 patients in the bridging and 163 in the IV group. No significant differences regarding baseline characteristics were observed. At 3 months, 46% (n = 29) of the patients treated in the combined and 23% (n = 38) of those treated in the IV group had a modified Rankin scale (mRS) of 0-1 (P < 0.001). A statistical significant difference was observed for all sites of occlusion. In a logistic regression model, National Institute of Health Stroke Scale (NIHSS) and bridging therapy were independent predictors of good outcome (respectively, P = 0.001 and P = 0.0018). Symptomatic hemorrhage was documented in 6.3% vs 3.7% in the bridging and in the IV group, respectively (P = 0.32). There was no difference in mortality. CONCLUSIONS: Our results suggest that patients treated with a bridging approach were more likely to have minimal or no deficit at all at 3 months as compared to the IV treated group.

Learning-induced gene expression in the heads of two Nasonia species that differ in long-term memory formation.

BACKGROUND: Cellular processes underlying memory formation are evolutionary conserved, but natural variation in memory dynamics between animal species or populations is common. The genetic basis of this fascinating phenomenon is poorly understood. Closely related species of Nasonia parasitic wasps differ in long-term memory (LTM) formation: N. vitripennis will form transcription-dependent LTM after a single conditioning trial, whereas the closely-related species N. giraulti will not. Genes that were differentially expressed (DE) after conditioning in N. vitripennis, but not in N. giraulti, were identified as candidate genes that may regulate LTM formation. RESULTS: RNA was collected from heads of both species before and immediately, 4 or 24 hours after conditioning, with 3 replicates per time point. It was sequenced strand-specifically, which allows distinguishing sense from antisense transcripts and improves the quality of expression analyses. We determined conditioning-induced DE compared to naïve controls for both species. These expression patterns were then analysed with GO enrichment analyses for each species and time point, which demonstrated an enrichment of signalling-related genes immediately after conditioning in N. vitripennis only. Analyses of known LTM genes and genes with an opposing expression pattern between the two species revealed additional candidate genes for the difference in LTM formation. These include genes from various signalling cascades, including several members of the Ras and PI3 kinase signalling pathways, and glutamate receptors. Interestingly, several other known LTM genes were exclusively differentially expressed in N. giraulti, which may indicate an LTM-inhibitory mechanism. Among the DE transcripts were also antisense transcripts. Furthermore, antisense transcripts aligning to a number of known memory genes were detected, which may have a role in regulating these genes. CONCLUSION: This study is the first to describe and compare expression patterns of both protein-coding and antisense transcripts, at different time points after conditioning, of two closely related animal species that differ in LTM formation. Several candidate genes that may regulate differences in LTM have been identified. This transcriptome analysis is a valuable resource for future in-depth studies to elucidate the role of candidate genes and antisense transcription in natural variation in LTM formation.

What does your neighbourhood say about you? : a study of life expectancy in 1.3 million Swiss neighbourhoods

BACKGROUND: Switzerland had the highest life expectancy at 82.8 years among the Organisation for Economic Co-operation and Development (OECD) countries in 2011. Geographical variation of life expectancy and its relation to the socioeconomic position of neighbourhoods are, however, not well understood. METHODS: We analysed the Swiss National Cohort, which linked the 2000 census with mortality records 2000-2008 to estimate life expectancy across neighbourhoods. A neighbourhood index of socioeconomic position (SEP) based on the median rent, education and occupation of household heads and crowding was calculated for 1.3 million overlapping neighbourhoods of 50 households. We used skew-normal regression models, including the index and additionally marital status, education, nationality, religion and occupation to calculate crude and adjusted estimates of life expectancy at age 30 years. RESULTS: Based on over 4.5 million individuals and over 400,000 deaths, estimates of life expectancy at age 30 in neighbourhoods ranged from 46.9 to 54.2 years in men and from 53.5 to 57.2 years in women. The correlation between life expectancy and neighbourhood SEP was strong (r=0.95 in men and r=0.94 women, both p values <0.0001). In a comparison of the lowest with the highest percentile of neighbourhood SEP, the crude difference in life expectancy from skew-normal regression was 4.5 years in men and 2.5 years in women. The corresponding adjusted differences were 2.8 and 1.9 years, respectively (all p values <0.0001). CONCLUSIONS: Although life expectancy is high in Switzerland, there is substantial geographical variation and life expectancy is strongly associated with the social standing of neighbourhoods.

Thermoregulation and microhabitat choice in the polymorphic asp viper (Vipera aspis).

In ectotherms, thermoregulation strongly depends on environmental conditions, as well as on intrinsic factors, such as skin colour. Indeed, due to its physical properties, melanin pigments allow melanistic morphs to benefit of a more efficient thermoregulation compared to non-melanistic ones. Despite thermal benefits of melanism have often been highlighted under experimental conditions, such field data remain scarce. In this study, we investigated the influence of colouration on body temperature and microhabitat choice in a montane population of colour polymorphic asp viper (Vipera aspis) characterized by a strong presence of melanism (64%). Results highlighted a difference in internal body temperature, but only within gravid females, with melanistic individuals having higher body temperatures compared to non-melanistic ones. No differences were found when considering both sexes. We also showed that melanistic and non-melanistic vipers were found in different microhabitat types, i.e. melanistic snakes used areas marked by a scarcer sun exposure and by higher vegetation cover compared to non-melanistic ones. This result has important implications. Indeed, besides providing a possible explanation for the lack of difference in body temperature (except for gravid females), it confirms that melanistic individuals can potentially use their efficient thermoregulation in order to inhabit less exposed and thermally unfavourable microhabitats.