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Many intracellular pathogens, such as mammalian reovirus, mimic extracellular matrix motifs to specifically interact with the host membrane. Whether and how cell-matrix interactions influence virus particle uptake is unknown, as it is usually studied from the dorsal side. Here we show that the forces exerted at the ventral side of adherent cells during reovirus uptake exceed the binding strength of biotin-neutravidin anchoring viruses to a biofunctionalized substrate. Analysis of virus dissociation kinetics using the Bell model revealed mean forces higher than 30 pN per virus, preferentially applied in the cell periphery where close matrix contacts form. Utilizing 100 nm-sized nanoparticles decorated with integrin adhesion motifs, we demonstrate that the uptake forces scale with the adhesion energy, while actin/myosin inhibitions strongly reduce the uptake frequency, but not uptake kinetics. We hypothesize that particle adhesion and the push by the substrate provide the main driving forces for uptake.

Receptor-mediated endocytosis requires that the energy of adhesion overcomes the deformation energy of the plasma membrane. The resulting driving force is balanced by dissipative forces, leading to deterministic dynamical equations. While the shape of the free membrane does not play an important role for tensed and loose membranes, in the intermediate regime it leads to an important energy barrier. Here we show that this barrier is similar to but different from an effective line tension and suggest a simple analytical approximation for it. We then explore the rich dynamics of uptake for particles of different shapes and present the corresponding dynamical state diagrams. We also extend our model to include stochastic fluctuations, which facilitate uptake and lead to corresponding changes in the phase diagrams.

Our ability to manage acute myeloid leukemia (AML) is limited by our incomplete understanding of the epigenetic disruption central to leukemogenesis, including improper histone methylation. Here we examine 16 histone H3 genes in 434 primary AML samples and identify Q69H, A26P, R2Q, R8H and K27M/I mutations (1.6%), with higher incidence in secondary AML (9%). These mutations occur in pre-leukemic hematopoietic stem cells (HSCs) and exist in the major leukemic clones in patients. They increase the frequency of functional HSCs, alter differentiation, and amplify leukemic aggressiveness. These effects are dependent on the specific mutation. H3K27 mutation increases the expression of genes involved in erythrocyte and myeloid differentiation with altered H3K27 tri-methylation and K27 acetylation. The functional impact of histone mutations is independent of RUNX1 mutation, although they at times co-occur. This study establishes that H3 mutations are drivers of human pre-cancerous stem cell expansion and important early events in leukemogenesis.

Ten-Eleven Translocation (TET) proteins are important epigenetic regulators that play a key role in development and are frequently deregulated in cancer. Drosophila melanogaster has a single homologous Tet gene ( dTet ) that is highly expressed in the central nervous system during development. Here, we examined the expression pattern of dTet in the third instar larval CNS and discovered its presence in a specific set of glia cells: midline glia (MG). Moreover, dTet knockdown resulted in significant lethality, locomotor dysfunction, and alterations in axon patterning in the larval ventral nerve cord. Molecular analyses on dTet knockdown larvae showed a downregulation in genes involved in axon guidance and reduced expression of the axon guidance cue Slit. Our findings point toward a potential role for dTet in midline glial function, specifically the regulation of axon patterning during neurodevelopment.

The targeting of specific tissue is a major challenge for the effective use of therapeutics and agents mediating this targeting are strongly demanded. We report here on an in vivo selection technology that enables the de novo identification of pegylated DNA aptamers pursuing tissue sites harbouring a hormone refractory prostate tumour. To this end, two libraries, one of which bearing an 11 kDa polyethylene glycol (PEG) modification, were used in an orthotopic xenograft prostate tumour mouse model for the selection process. Next-generation sequencing revealed an in vivo enriched pegylated but not a naïve DNA aptamer recognising prostate cancer tissue implanted either subcutaneous or orthotopically in mice. This aptamer represents a valuable and cost-effective tool for the development of targeted therapies for prostate cancer. The described selection strategy and its analysis is not limited to prostate cancer but will be adaptable to various tissues, tumours, and metastases. This opens the path towards DNA aptamers being experimentally and clinically engaged as molecules for developing targeted therapy strategies.

The cellular uptake of nanoparticles or viruses requires that the gain of adhesion energy overcomes the cost of plasma membrane bending. It is well known that this leads to a minimal particle size for uptake. Using a simple deterministic theory for this process, we first show that, for the same radius and volume, cylindrical particles should be taken up faster than spherical particles, both for normal and parallel orientations. We then address stochastic effects, which are expected to be relevant due to small system size, and show that, now, spherical particles can have a faster uptake because the mean first passage time profits from the multiplicative noise induced by the spherical geometry. We conclude that stochastic effects are strongly geometry dependent and may favor spherical shapes during adhesion-driven particle uptake.

Objective: We aim to identify cardiovascular risk factors in firefighters of Loire (French district) with a high cardiovascular risk and report results of a screening program using exercise tests., Methods: A retrospective descriptive study was performed in a cohort of 158 career and 400 volunteer firefighters with a high cardiovascular risk who had undergone an exercise test., Results: Five hundred fifty-eight exercise tests and cardiovascular profiles were analyzed. Prevalence was 18% for high blood pressure, 19% for dyslipidemia, and 48% for overweight. Exercise tests were positive in 91 cases (16.3%): sensitivity, 53%; specificity, 74%. Risk of onset of a predictive event was higher in the high-risk group: odds ratio, 3.2 (95% confidence interval 2.0 to 5.1). There were more events on exercise test in volunteer firefighters., Conclusion: Prevalence of cardiovascular risk factors in the cohort of firefighters was acceptable in comparison to French general population and other firefighters' cohort. Physical training of volunteer firefighters needs reinforcing.

Although essential for many cellular processes, the sequence of structural and molecular events during clathrin-mediated endocytosis remains elusive. While it was long believed that clathrin-coated pits grow with a constant curvature, it was recently suggested that clathrin first assembles to form flat structures that then bend while maintaining a constant surface area. Here, we combine correlative electron and light microscopy and mathematical growth laws to study the ultrastructural rearrangements of the clathrin coat during endocytosis in BSC-1 mammalian cells. We confirm that clathrin coats initially grow flat and demonstrate that curvature begins when around 70% of the final clathrin content is acquired. We find that this transition is marked by a change in the clathrin to clathrin-adaptor protein AP2 ratio and that membrane tension suppresses this transition. Our results support the notion that BSC-1 mammalian cells dynamically regulate the flat-to-curved transition in clathrin-mediated endocytosis by both biochemical and mechanical factors.

Replication and spread of human viruses is based on the simultaneous exploitation of many different host functions, bridging multiple scales in space and time. Mathematical modeling is essential to obtain a systems-level understanding of how human viruses manage to proceed through their life cycles. Here, we review corresponding advances for viral systems of large medical relevance, such as human immunodeficiency virus-1 (HIV-1) and hepatitis C virus (HCV). We will outline how the combination of mathematical models and experimental data has advanced our quantitative knowledge about various processes of these pathogens, and how novel quantitative approaches promise to fill remaining gaps., (© 2016 Federation of European Biochemical Societies.)

Polycomb group (PcG) protein complexes repress transcription by modifying target gene chromatin. In Drosophila, this repression requires association of PcG protein complexes with cis-regulatory Polycomb response elements (PREs), but the interactions permitting formation of these assemblies are poorly understood. We show that the Sfmbt subunit of the DNA-binding Pho-repressive complex (PhoRC) and the Scm subunit of the canonical Polycomb-repressive complex 1 (PRC1) directly bind each other through their SAM domains. The 1.9 Å crystal structure of the Scm-SAM:Sfmbt-SAM complex reveals the recognition mechanism and shows that Sfmbt-SAM lacks the polymerization capacity of the SAM domains of Scm and its PRC1 partner subunit, Ph. Functional analyses in Drosophila demonstrate that Sfmbt-SAM and Scm-SAM are essential for repression and that PhoRC DNA binding is critical to initiate PRC1 association with PREs. Together, this suggests that PRE-tethered Sfmbt-SAM nucleates PRC1 recruitment and that Scm-SAM/Ph-SAM-mediated polymerization then results in the formation of PRC1-compacted chromatin., (© 2016 Frey et al.; Published by Cold Spring Harbor Laboratory Press.)

Aim: Physical fitness is related to injuries, attrition and military ability in military organisations. Therefore, all military organizations of the North Atlantic Treaty Organizations (NATO) test their employees' physical fitness at least once a year. The sit-up test is part of most of the fitness test batteries used. A possible alternative to the sit-up test is the global trunk muscle strength test (TMS). The aim of the present study was to compare the predictability of injuries, attrition and military ability between TMS and sit-up test performances., Methods: A total of 230 male recruits in a Swiss Army fusilier company completed TMS and sit-up tests in week 1 of military training school. During the following 13 weeks, injuries, attrition and military ability data were collected. Statistical analysis included backward binary regression and receiver operating characteristic (ROC) curve analysis to compare the discriminative power of TMS and the sit-up test to predict injuries, attrition and military ability., Results: ROC analysis revealed larger areas under the curve for total injuries, attrition and military ability for the TMS (areatotal injuries=0.58; areaattrition=0.60; areamilitary ability=0.59) than for the sit-up test (areatotal injuries=0.53; areaattrition=0.50; areamilitary ability=0.56). Binary logistic regression analysis revealed low body mass index, low TMS performance and cigarette smoking to be potential risk factors for injuries; while sit-up performance was extracted from the model., Conclusion: The TMS seems to be a valid alternative to the sit-up test in a military setting due to its appropriate results in predicting injuries in the present study.

There is evidence that progressive loading of physical demands at the beginning of basic military service and specific physical training can reduce injury incidences. Therefore, aim of this study was to measure the effects of a progressive increase in marching distances and an adapted physical training program on injury incidence and attrition rate in a Swiss Army infantry training school. One company reduced the distances covered on foot during the first 4 weeks of basic military training. A second company performed an adapted physical training program for 10 weeks. A third company participated in both interventions combined, and a fourth company served as a control group without any intervention. The injury incidences and attrition rates of 651 male recruits were registered during 21 weeks of military service. Several predictor variables for injury and attrition, such as physical fitness, previous injuries, level of previous physical activity, smoking, motivation, and socioeconomic factors, were assessed as well. The data were analyzed using binary logistic backward regressions. Each intervention separately had a favorable effect on injury prevention. However, combining the 2 interventions resulted in the greatest reduction in injury incidence rate (-33%). Furthermore, the adapted physical training successfully reduced the military service attrition rates (-53%)., (Reprint & Copyright © 2015 Association of Military Surgeons of the U.S.)

Objective: Testing for succinate dehydrogenase subunit B (SDHB) mutations is recommended in all patients with metastatic phaeochromocytomas and paragangliomas (PPGLs), but may not be required when metastatic disease is accompanied by adrenaline production. This retrospective cohort study aimed to establish the prevalence of SDHB mutations among patients with metastatic PPGLs, characterised by production of adrenaline compared with those without production of adrenaline, and to establish genotype–phenotype features of metastatic PPGLs according to underlying gene mutations., Design and Methods: Presence of SDHB mutations or deletions was tested in 205 patients (114 males) aged 42+/-16 years (range 9–86 years) at diagnosis of metastatic PPGLs with and without adrenaline production., Results: Twenty-three of the 205 patients (11%) with metastatic PPGLs had disease characterised by production of adrenaline, as defined by increased plasma concentrations of metanephrine larger than 5% of the combined increase in both normetanephrine and metanephrine. None of these 23 patients had SDHB mutations. Of the other 182 patients with no tumoural adrenaline production, 51% had SDHB mutations. Metastases in bone were 36–41% more prevalent among patients with SDHB mutations or extra-adrenal primary tumours than those without mutations or with adrenal primary tumours. Liver metastases were 81% more prevalent among patients with adrenal than extra-adrenal primary tumours., Conclusion: SDHB mutation testing has no utility among patients with adrenaline-producing metastatic PPGLs, but is indicated in other patients with metastatic disease. Our study also reveals novel associations of metastatic spread with primary tumour location and presence of SDHB mutations.

In this contribution, we report on the experimental investigation of an ultra-dense wavelength-division multiplexing (UDWDM) upstream link with up to 700 × 2.488 Gb/s polarization-division multiplexing differential quadrature phase-shift keying parallel upstream user channels transmitted over 80 km of standard single-mode fiber. We discuss challenges of the digital signal processing in the optical line terminal arising from the joint reception of several upstream user channels. We present solutions for resource and cost-efficient realization of the required channel separation, matched filtering, down-conversion and decimation as well as realization of the clock recovery and polarization demultiplexing for each individual channel.

Non-battle injury rates are a major health problem in the armed forces today. Injury rates are related to physical demands of daily military routine. The aim of this study is to investigate the impact of different physical training patterns on incidences of injuries in 12 Swiss Army basic military training schools. Therefore, injury data of 1,676 voluntary participant recruits and objective sensor data on physical demands of 50 volunteers at each of 12 trainings schools were assembled. Multiple linear regression showed that high physical demands, decreasing development of distances covered on foot, monotony in weekly physical demands, little time spent on sport-related physical training, and little time for night rest were significant risk factors for injuries. Together, those variables describe 98.8% of the variances of total injury incidence rate between military training schools. The new method used to objectively assess training demands allowed this study to investigate the impact of training patterns on injury incidence in a large number of training schools. The results of this study are important for future interventions to reduce injury incidence rates in a military setting by quantifying the injury risk potential of a large number of training patterns., (Reprint & Copyright © 2014 Association of Military Surgeons of the U.S.)

Cognitive deficits have been found to be more prevalent in psychotic than in other disorders. Longitudinal research has shown that these deficits were generally already existent before onset of illness and are therefore not necessarily attributable to neurodegenerative processes. This study investigated whether both low IQ and markers of premorbid cognitive dysfunction independently contribute to an increased risk for psychoses. In a cross-sectional study about 50,000 young Swiss males completed a survey of intellectual problems in childhood/adolescence and other vulnerability factors during military call-up in 2005/2006. Subsequently, military IQ assessments were carried out on the entire sample. Diagnostic assessments were conducted according to International Classification of Diseases-10th edition (ICD-10). Low, especially performance, IQ was highly associated with an increased risk for psychotic disorders after adjusting for preexisting cognitive deficits and covariates, while in other disorders this association was less marked. Furthermore, preexisting intellectual problems emerged as important risk factors for psychoses. Our results confirm the importance of low IQ as characteristic of psychoses. Although premorbid intellectual deficits are common in people who go on to develop psychosis, neurodegenerative disease processes may also precipitate further declines in fluid cognitive functions. Assessment of cognitive functioning should be taken into account in early detection of psychoses., (© 2013 Elsevier Ireland Ltd. All rights reserved.)

We experimentally demonstrate the use of data-aided digital signal processing for format-flexible coherent reception of different 28-GBd PDM and 4D modulated signals in WDM transmission experiments over up to 7680 km SSMF by using the same resource-efficient digital signal processing algorithms for the equalization of all formats. Stable and regular performance in the nonlinear transmission regime is confirmed.

We experimentally generate 28-GBd 6-ary polarization-shift keying quadrature phase-shift keying (6PolSK-QPSK) signals by utilizing a high-speed 4-channel digital-to-analog converter and an integrated dual-polarization I/Q modulator. In WDM transmission experiments over up to 4800 km standard single-mode fiber, we compare the performance of 126-Gb/s 6PolSK-QPSK and 112-Gb/s polarization-division multiplexing (PDM) QPSK signals. Furthermore, we discuss the implications of applying an inner Reed-Solomon RS(511,455) forward error correction code in order to correct burst errors due to the anti-Gray mapping of 6PolSK-QPSK.

Unlabelled: BACKGROUND/ OBJECTIVE: The purpose of the present study was to analyze the prevalence of physiologic and pathologic ECG abnormalities in a cohort of young conscripts that represents the whole young generation of today., Methods: ECGs of all Swiss citizens who underwent conscription for the army during a 29-month period were analyzed manually., Results: ECGs of 43,401 conscripts (mean age 19.2 ± 1.1 years) were analyzed; 158 conscripts were female. Incomplete right bundle branch block was found in 5870 (13.5%) and left anterior fascicular block in 360 (0.83%). First-degree AV block was present in 329 (0.8%) and Mobitz type I (Wenckebach) second-degree AV block in 3 (0.01%). Early repolarization was observed in 1035 (2.4%), T-wave inversion in 39 (0.09%), and minor T-wave changes in 182 (0.42%). Brugada-like abnormalities were observed in 6 (0.01%). None of the conscripts had atrial fibrillation or flutter., Conclusion: ECG abnormalities can be found in a relatively large proportion of young individuals. Incomplete right bundle branch block, left fascicular block, and first-degree AV block are the most frequent findings. No conscript presented with atrial fibrillation or flutter., (Copyright © 2012 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Signal transduction to nuclear factor-kappa B (NF-κB) involves multiple kinases and phosphorylated target proteins, but little is known about signal termination by dephosphorylation. By RNAi screening, we have identified protein phosphatase 4 regulatory subunit 1 (PP4R1) as a negative regulator of NF-κB activity in T lymphocytes. PP4R1 formed part of a distinct PP4 holoenzyme and bridged the inhibitor of NF-κB kinase (IKK) complex and the phosphatase PP4c, thereby directing PP4c activity to dephosphorylate and inactivate the IKK complex. PP4R1 expression was triggered upon activation and proliferation of primary human T lymphocytes and deficiency for PP4R1 caused sustained and increased IKK activity, T cell hyperactivation, and aberrant NF-κB signaling in NF-κB-addicted T cell lymphomas. Collectively, our results unravel PP4R1 as a previously unknown activation-associated negative regulator of IKK activity in lymphocytes whose downregulation promotes oncogenic NF-κB signaling in a subgroup of T cell lymphomas., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Aim: The aim of this study was to quantify the discriminative power of physical performance tests to recognize conscripts with enhanced risk of acute and overuse injuries in specific, physically demanding occupational specialties of the Swiss Army. The five performance tests investigated represent the Swiss Army Physical Fitness Test Battery., Methods: Physical fitness performances were assessed during recruitment procedures prior to military service, and injury occurrences were assessed during 18 weeks of boot camp. Complete fitness and injury data of 459 volunteers from four military occupational specialties were collected. Discriminative power of volunteers' aerobic endurance capacity, trunk muscle fitness, muscle power of upper and lower extremities, and balance for predicting risk of acute injuries and for predicting risk of overuse injuries was calculated using receiver operating characteristic curve analysis., Results: The presented fitness tests had no discriminative power for predicting the risk of acute injuries. However, the trunk muscle fitness test was discriminative in predicting overuse injuries in all four military occupational specialties, progressive endurance run in three, balance test in two, and standing long jump in one. Only the seated shot put had no significant power for predicting overuse injuries in all four study groups. However, for different occupational specialties, different fitness parameters were discriminative to predict overuse injuries., Conclusion: It is possible to conclude that the fitness tests used allow detection of conscripts with enhanced overuse injury risk in physically demanding occupational specialties and therefore provide an indicator to select suitable personnel for physically demanding jobs in a military organization.

Smoking is a major health risk in young adults. We undertook a study in young Swiss military recruits to determine the impact of intensive training and of help offered on smoking cessation during Basic Military Training (BMT). A questionnaire including questions according to their smoking status, sporting activities and, alcohol use was administered to 999 conscripts at beginning and at the end of the BMT. The results were compared to a control group of BMT schools where no such intervention took place. The study shows that the prevalence of smokers in the intervention group decreased (start BMT 31.9%, end BMT 25.5%; p = 0.021), while the prevalence of smokers increased in the control group (start BMT 26.4%, end BMT 32.6%; p = 0.038). A motivation to serve in the armed forces, as well as the willingness to stop smoking in the next month were the factors associated with a subsequent cessation of smoking during BMT. A smoke stop intervention during BMT is viable and can lead to a decrease in the prevalence of smoking at the end of BMT.

Background: Sudden cardiac death can be the first clinical presentation of asymptomatic ventricular preexcitation. Recent data about prevalence of preexcitation in the electrocardiograms (ECG) of the general population are scarce., Objective: The aim of the present study was to analyze the prevalence of preexcitation in a contemporary population of young conscripts., Methods: We reanalyzed all consecutive ECGs of Swiss citizens who underwent conscription for the army between March 1, 2004, and July 31,2006. All ECGs with the diagnosis preexcitation were included in the present study., Results: We analyzed ECGs of 41,699 male conscripts. Mean age was 19.2 ± 1.1 years. Preexcitation was found in 53 individuals. The length of the delta wave was 46 ± 10 ms. The most frequent localization of the accessory pathway was the left free wall., Conclusion: The prevalence of preexcitation in young, predominantly male conscripts is 0.13%. This is comparable with previous findings in children., (©2011, The Authors. Journal compilation ©2011 Wiley Periodicals, Inc.)

In vitro, both carbohydrate sugars and artificial sweeteners (AS) stimulate the secretion of glucagon-like peptide-1 (GLP-1). It has been suggested that the gut tastes sugars and AS through the same mechanisms as the tongue, with potential effects on gut hormone release. We investigated whether the human gut responds in the same way to AS and carbohydrate sugars, which are perceived by lingual taste as equisweet. We focused on the secretion of gastrointestinal (GI) satiety peptides in relation to appetite perception. We performed a placebo-controlled, double-blind, six-way, cross-over trial including twelve healthy subjects. On separate days, each subject received an intragastric infusion of glucose, fructose or an AS (aspartame, acesulfame K and sucralose) dissolved in 250 ml of water or water only (control). In a second part, four subjects received an intragastric infusion of the non-sweet, non-metabolisable sugar analogue 2-deoxy-d-glucose. Glucose stimulated GLP-1 (P = 0·002) and peptide tyrosine tyrosine (PYY; P = 0·046) secretion and reduced fasting plasma ghrelin (P = 0·046), whereas fructose was less effective. Both carbohydrate sugars increased satiety and fullness (albeit not significantly) compared with water. In contrast, equisweet loads of AS did not affect gastrointestinal peptide secretion with minimal effects on appetite. 2-Deoxy-d-glucose increased hunger ratings, however, with no effects on GLP-1, PYY or ghrelin. Our data demonstrate that the secretion of GLP-1, PYY and ghrelin depends on more than the detection of (1) sweetness or (2) the structural analogy to glucose.

Polyunsaturated fatty acids (PUFA) have a multitude of health effects. Their incorporation into membrane phospholipids (PL) is generally believed to depend directly on dietary influx. PL influence transmembrane protein activity and thus can compensate temperature effects; e.g. PL n-6 PUFA are thought to stabilize heart function at low body temperature (T(b)), whereas long chain (>C18) n-3 PUFA may boost oxidative capacity. We found substantial remodeling of membranes in free-living alpine marmots which was largely independent of direct dietary supply. Organ PL n-6 PUFA and n-6 to n-3 ratios were highest at onset and end of hibernation after rapid increases during a brief transitional period prior to hibernation. In contrast, longer chain PL n-3 PUFA content was low at end of summer but maximal at end of hibernation. After termination of hibernation in spring, these changes in PL composition were rapidly reversed. Our results demonstrate selective trafficking of PUFA within the body, probably governed by a circannual endogenous rhythm, as hibernating marmots were in winter burrows isolated for seven months from food and external cues signaling the approaching spring. High concentrations of PL n-6 PUFA throughout hibernation are in line with their hypothesized function of boosting SERCA 2a activity at low T(b). Furthermore, we found increasing rate of rewarming from torpor during winter indicating increasing oxidative capacity that could be explained by the accumulation of long-chain PL n-3 PUFA. It may serve to minimize the time necessary for rewarming despite the increasing temperature range to be covered, because rewarming is a period of highest metabolic rate and hence production of reactive oxygen species. Considering the importance of PUFA for health our results may have important biomedical implications, as seasonal changes of T(b) and associated remodeling of membranes are not restricted to hibernators but presumably common among endothermic organisms.

The spectrum of risk and concomitant factors in stuttering is generally thought to be wide and heterogeneous. However, only a few studies have examined these factors using information from large databases. We examined the data on 11,905 Swiss conscripts from 2003. All cases with high psychiatric screening scores indicating "caseness" for a psychiatric disorder were excluded, among them potential malingerers, so that 9,814 records remained. The analyses rely on self-reported information about stuttering in childhood, problems at birth, problems in school, mental disorders of parents and relatives, childhood adversity and socio-demographic information. Statistical modelling was done using logistic regression and path analysis models. Risk factors determined in the logistic regression include premature birth, probable attention deficit hyperactive disorder, alcohol abuse of the parents, obsessive-compulsive disorder in parents and relatives, having a disabled mother and having a parent from a foreign country. There is no overwhelmingly strong risk factor; all odds ratios are about 2 or below. In conclusion, large databases are helpful in revealing less obvious and less frequent risk factors for heterogeneous disorders such as stuttering. Obviously, not only secondary analyses, but also systematical large scale studies would be required to complete the complex epidemiological puzzle in stuttering. An extensive examination of young adults who were initially assessed in childhood might provide the most promising design.

Objective: To determine the performance of a newly developed examination chair as compared with the clinical standard of assessing internal rotation (IR) of the flexed hip with a goniometer., Methods: The examination chair allowed measurement of IR in a sitting position simultaneously in both hips, with hips and knees flexed 90 degrees, lower legs hanging unsupported and a standardized load of 5 kg applied to both ankles using a bilateral pulley system. Clinical assessment of IR was performed in supine position with hips and knees flexed 90 degrees using a goniometer. Within the framework of a population-based inception cohort study, we calculated inter-observer agreement in two samples of 84 and 64 consecutive, unselected young asymptomatic males using intra-class correlation coefficients (ICC) and determined the correlation between IR assessed with examination chair and clinical assessment., Results: Inter-observer agreement was excellent for the examination chair (ICC right hip, 0.92, 95% confidence interval [CI] 0.89-0.95; ICC left hip, 0.90, 95% CI 0.86-0.94), and considerably higher than that seen with clinical assessment (ICC right hip, 0.65, 95% CI 0.49-0.77; ICC left hip, 0.69, 95% CI 0.54-0.80, P for difference in ICC between examination chair and clinical assessment

Background: Breathing dry, cold air may cause bronchoconstriction in asthmatics working with self-contained breathing apparatus (SCBA). Air delivered by SCBA is cooler than ambient air. It is unclear whether a bronchial challenge test using mannitol (BCTM) can predict a fall in forced expiratory volume in one second (FEV(1)) during exercise with SCBA., Methods: A prospective study of army recruits assigned to work with SCBA was carried out. Participants completed self-administered questionnaires on respiratory symptoms, BCTM, and measurement of exhaled nitric oxide. A subgroup of participants with a positive BCTM (BTCM+) and with negative BCTM underwent exercise test on bicycle ergometer (ET) while using SCBA., Results: One hundred and six recruits participated in this study. One hundred and two underwent BCTM and 28 ET. Nineteen out of 97 participants had a positive BCTM and 6 out of 27 had a positive ET. Seventeen out of 19 participants with a positive BCTM had current respiratory symptoms such as wheeze, cough, chest tightness, or dyspnea. Sensitivity, specificity, positive predictive value, and negative predictive value for a positive ET under SCBA were 100%, 64%, 43%, and 100% for the BCTM, respectively. BCTM-positive participants with respiratory symptoms had more physician consultations during MBT compared to BCTM-negative participants., Conclusion: Despite medical evaluation and exclusion of asthmatics by a physician during conscription, a high proportion of recruits assigned to work with SCBA smoke, have respiratory symptoms, and have a positive BCTM suggesting current asthma. BCTM has a high sensitivity to predict a significant fall in FEV(1) after exercise with SCBA and participants with a positive BCTM tend to use more health care resources during basic military training. Recruits should be counseled about smoking cessation prior and during basic military training.

Background: Respiratory diseases such as asthma may affect individuals' fitness for military service. In order to assess fitness for military service in subjects with asthma symptoms at conscription, objective and reliable tests are needed., Objective: To prospectively determine the diagnostic value of the mannitol and methacholine bronchial provocation test (BPT) as well as exhaled nitric oxide in assessing physician-diagnosed asthma in a group of Swiss Armed Forces conscripts., Methods: Questionnaire, spirometry, BPT with methacholine and mannitol, exhaled nitric oxide (FeNO) and skin prick testing were conducted in 18-20-year-old male conscripts. Asthma was diagnosed by a military physician not involved in this study according to the medical record, results of BPT, current respiratory symptoms and use of asthma medication., Results: Two hundred and eighty four subjects participated in the study. Complete data for the BPT with methacholine, mannitol and measurement of FeNO were available on 235 subjects. Forty-two conscripts (17.9%) had physician-diagnosed asthma. The sensitivity/specificity of mannitol to identify physician-diagnosed asthma was 41%/93% and for methacholine it was 43%/92%. Using a cut-off point of 36.5 p.p.b., FeNO had a similar negative predictive value to rule out physician-diagnosed asthma as BPT with mannitol or methacholine., Conclusion: BPT with mannitol has a sensitivity and specificity similar to methacholine for the diagnosis of physician-diagnosed asthma in military conscripts but is less costly to perform without the need to use and maintain a nebulizer.

In larvae of Drosophila paramelanica, eggs and larvae of the endoparasitic wasp Leptopilina heterotoma succumb to an effective host reaction that does not involve blood cell-mediated melanotic encapsulation, a response that characterizes cellular immunity in various species of Drosophila and in many insects and other arthropods. A significant increase occurs, however, in the number of lamellocytes, a type of blood cell that functions in encapsulation reactions. The appearance of activated lamellocytes in D. paramelanica is viewed as an early response to infection, one most likely initiated by non-self-recognition processes that similarly function in other wasp-infected Drosophila. However, ensuing cytotoxic responses, about which little is presently known, are not accompanied by melanotic encapsulation in D. paramelanica. Concurrent analyses of the cell-signaling molecule nitric oxide (*NO) revealed significant alterations in the levels of this free radical during the early stages of infection, most notably a dramatic increase immediately upon infection, and precipitous decreases occurring at times when parasites were killed. Injections of a specific inhibitor of nitric oxide synthase (NOS) into the host's body cavity prior to infection significantly increased parasite survival. These observations suggest some involvement of *NO in the host immune response, either in recruiting hemocytes to sites of infection or as a component of the insect's cytotoxic arsenal, given the capacity of the radical to generate toxic molecules through interactions with various intermediates of oxygen and nitrogen.

Introduction: Electrocardiographic criteria for left ventricular hypertrophy (LVH) have been limited by low sensitivity at acceptable levels of specificity. A number of studies have demonstrated that body mass index (BMI) is associated with decreased sensitivity of ECG LVH classification in hypertensive patients. The objective of this study is to investigate the correlation relationship between LVH voltage criteria and BMI in Swiss conscripts., Methods: A database of 41,806 young Swiss people, who underwent compulsory conscription for the Swiss Army, was compiled. Along with other medical data, an ECG was taken. Statistical analyses, such as linear regression and calculation of correlation coefficient, were carried out between LVH voltage criteria and BMI., Results: The mean age in the studied population was 19.2 +/- 1.1 years with a median age of 19 years (range from 17 to 38 years). We found an overweight prevalence of 25.1%. The results showed that body habitus had significant association with Sokolow-Lyon voltages. A mean decrease of 13%, 5%, 19%, 14%, and 12% for the five studied Sokolow-Lyon indexes were found between normal range subjects (18.5 < or = BMI < 25) and obese subjects (25< or = BMI)., Conclusions: Our study confirms the hypothesis that people with higher BMI, a growing section of the population, have lower ECG amplitudes. Therefore, the Sokolow-Lyon voltage criteria may underestimate the presence of LVH for subjects with higher BMI, which is not the case for the Cornell voltage. Our analysis suggests that computerized electrocardiography for the diagnosis of left ventricular hypertrophy based on Sokolow-Lyon voltages should incorporate the BMI factor.

We reviewed research on wildlife overpasses in the context of their genetic effectiveness to provide connectivity between population patches that have been isolated by road construction. The potential ecological consequences of such habitat fragmentation include reduction of gene flow between subpopulations and hence an increase in genetic differentiation and a decrease in genetic diversity. Among the solutions to provide connectivity between patches isolated by roads, wildlife overpasses are one of the most expensive alternatives. Despite the high costs associated with their construction, most of the studies assessing their use by wildlife remain observational, reporting evidence for passage use but few data on the number of individual crossings. Moreover, the use itself of wildlife overpasses does not appear sufficient to assess their effectiveness from a genetic viewpoint because a minimum number of individuals is required to assure gene flow between population patches and because the spatiotemporal dimension of individual movements and demographic parameters of subpopulations must be considered. So far, there is no evidence that wildlife overpasses do or do not efficiently address genetic issues. This lack of data is probably due to the fact that few mitigation efforts have implemented monitoring programs that incorporate sufficient experimental designs into pre- and postconstruction evaluation. To assess the genetic effectiveness of wildlife overpasses, long-term monitoring programs, including fieldwork and genetic analyses, are needed., (©2009 Society for Conservation Biology.)

Background: Abnormally long and short QT intervals are recognized to be associated with an increased risk for life-threatening ventricular arrhythmias. It is therefore important to define the upper and lower border of the normal QT., Objective: The aim of this study was to describe the normal distribution of the QT interval in a contemporary population of young conscripts and to define long and short limits of the QT interval., Methods: In Switzerland, all young male citizens must undergo compulsory conscription for the Swiss Army at the age of 18 to 19 years. In every conscript, an electrocardiogram (ECG) is performed. Retrospectively, 41,767 consecutive ECGs of Swiss citizens who underwent conscription for the army between March 1, 2004, and July 31, 2006, were analyzed., Results: The mean QTc Bazett interval was 394 +/- 22 ms. One percent of the conscripts had a Bazett QTc shorter than 347 ms, and one percent had a Bazett QTc longer than 445 ms, respectively. None of the subjects presented a QTc Bazett < 300 ms; the prevalence of a QTc Bazett < 320 ms was 0.02%., Conclusion: The present study shows the distribution of QT intervals in an unselected young population. Because none of the subjects presented a QTc < 300 ms, it may be concluded that the short QT syndrome is a very rare entity in the population of young male adults.

This study aimed to investigate prevalence and correlates of alcohol consumption frequency in a sample of Swiss conscripts (n=25,611) in order to identify factors that predispose for frequent consumption. A self-report of drinking frequencies, as well as socio-demographic and psychosocial variables, was collected at psychiatric baseline screening. Based on univariate analyses, relevant variables were included in a multivariate multinomial logistic regression model. Six percent were abstainers, 15% reported rarely drinking, 53% occasional drinking, 24% regular drinking and 2% daily drinking. Except for substance use, most associations followed a "J"-shaped curve across the categories of alcohol frequency. Abstinence and frequent drinking can be perceived as deviations from the social norm. Both behaviors are associated with more psychosocial stressors and might be therefore special targets for further studies and new prevention programs.

Coevolutionary arms races between hosts and parasites would not occur without genetic variation for traits involved in the outcome of parasitism. Genetic variations in resistance and virulence have only rarely been described in pairwise host-parasitoid interactions and have never been analysed in multi-species interactions, in contrast to well-characterized plant-pathogen interactions. This paper reports genetic variation in resistance of Drosophila yakuba to the parasitoid wasp Leptopilina boulardi. The genetic basis and geographic distribution of resistance is analysed. On the basis of these and previous findings, we demonstrate that there are different resistance patterns to the parasitoid species L. boulardi in D. melanogaster and D. yakuba, as well as different specificity levels in the parasitoid species, suggesting complex ecological interactions in the field. This first description of resistance-virulence genetic interactions between a parasitoid and its two host species provides empirical data showing that multi-species interactions may greatly influence coevolutionary processes.

Background: Family studies point to important genetic determinants of diabetic nephropathy (DN). Blood pressure (BP) is higher in offspring of patients with type 2 diabetes and DN, but the pathomechanisms involved have not been elucidated., Methods: We examined the salt sensitivity of BP after 5 days equilibration on a low (20 mmol/day) vs high salt diet (220 mmol/day) in three matched groups of 15 subjects each: (i) control individuals; (ii) offspring of type 2 diabetic parents without DN (DN-); and (iii) offspring of type 2 diabetic parents with DN (DN+). Ambulatory BP and hormones involved in sodium homeostasis [plasma renin activity (PRA), aldosterone and atrial natriuretic peptide (ANP)] as well as the tetrahydrocortisol + 5-allotetrahydrocortisol/tetrahydrocortisone (THF + 5alphaTHF)/THE) ratio in the urine as an index of 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2) activity were analysed., Results: In offspring of DN+ patients on a high salt diet, systolic and diastolic BP was 137/82+/-10/8 mmHg vs 125/77+/-12/8 mmHg in offspring of DN- patients (P<0.01 for systolic BP). The salt-induced difference in mean BP between high and low salt diet was 5.2+/-3.3 mmHg in offspring of DN+ patients vs 0.7+/-4.7 mmHg in offspring of DN- patients (P<0.002). The proportion of 'salt-sensitive' individuals was 67% in offspring of DN+ patients vs 20% in offspring of DN- patients (P<0.05). In all groups, a high salt diet caused a comparable decrease of PRA and p-aldosterone accompanied by an increase in ANP. The urinary (THF + 5alphaTHF)/THE ratio was 1.23+/-0.36 in salt-sensitive individuals and 0.99+/-0.33 (P<0.03) in salt-resistant subjects, consistent with increased activity of 11betaHSD2., Conclusions: BP is more salt sensitive in offspring of type 2 diabetic patients with diabetic nephropathy. The salt sensitivity of BP may be an intermediate phenotype in individuals with a high risk of future diabetic nephropathy.

Avirulent strains of the endoparasitoid Leptopilina boulardi succumb to a blood cell-mediated melanotic encapsulation response in host larvae of Drosophila melanogaster. Virulent wasp strains effectively abrogate the cellular response with substances introduced into the host that specifically target and effectively suppress one or more immune signaling pathways, including elements that control phenoloxidase-mediated melanotic encapsulation. The present study implicates involvement of the Drosophila Toll pathway in cellular innate immunity by regulating the serine protease inhibitor Serpin 27A (Spn27A), which normally functions as a negative regulator of phenoloxidase. The introduction of Spn27A into normally highly immune competent D. melanogaster larvae significantly reduced their ability to form melanotic capsules around eggs of L. boulardi. This study confirms the role of Spn27A in the melanization cascade and establishes that this pathway and associated blood cell responses can be activated by parasitization. The activation of phenoloxidase and the site-specific localization of the ensuing melanotic response are such critical components of the blood cell response that Spn27A and the signaling elements mediating its activity are likely to represent prime targets for immune suppression by L. boulardi.

Host larvae of Drosophila melanogaster injected with the eicosanoid biosynthesis inhibitor, dexamethasone, prior to parasitization by the wasp Leptopilina boulardi, exhibited significantly reduced rates of melanotic encapsulation in comparison with control and saline-injected larvae. The results of this investigation suggest that prostaglandins and other eicosanoids are involved as cell-signaling molecules in the hemocytic encapsulation reaction of D. melanogaster larvae.

The gastrointestinal tracts of 76 free-living alpine marmots ( Marmota marmota) shot during a population control program in Switzerland were collected and analysed for patterns of change in morphology and function over the period from emergence from hibernation in April to just before re-entry into hibernation in September. Between first emergence and mid-summer (July) the fresh tissue mass of the stomach increased by 105%, the small intestine by 259% (among the largest recorded for a mammal), caecum by 185%, proximal colon by 138%, and distal colon by 144%. Mitotic activity was greatest in the small intestine; the mitotic index was high (40%) compared with indexes in the stomach and hindgut (approximately 4%) even at emergence, and increased to approximately 60% by mid-summer. Microbial activity in the caecum was also significant at emergence. The stomach (length) and caecum (length and fresh mass) increased in response to ingested food earlier than did the small intestine. Between mid-summer and September there were decreases in small intestinal tissue mass and mitotic activity. It is concluded that the gastrointestinal tract of alpine marmots probably continues to function throughout hibernation at a low level, with a mid-winter trough as part of an endogenous circannual rhythm. However, after emergence in spring, increases in size and activity of the tract appear to be a response to ingested food rather than to an endogenous signal. The early signs of down-regulation of the small intestine before re-entry into hibernation, together with its delayed up-regulation in response to food in spring, are consistent with the high costs of maintaining this section of the digestive system.

The augmented production of nitric oxide (NO) was observed during the hemocyte-mediated melanotic encapsulation responses of Drosophila melanogaster and D. teissieri. When introduced into the hemocoel of D. melanogaster larvae, NO activated the gene encoding the antimicrobial peptide Diptericin. These observations, together with previous studies documenting the production of superoxide anion (O(*-)(2)) and H(2)O(2) in immune-challenged Drosophila, provide evidence that reactive intermediates of both oxygen (ROI) and nitrogen (RNI) constitute a part of the cytotoxic arsenal employed by Drosophila in defense against both microbial pathogens and eukaryotic parasites. These ROI and RNI appear to represent an evolutionarily conserved innate immune response that is mediated by regulatory proteins that are homologous to those of mammalian species., (Copyright 2000 Academic Press.)

Insect hosts can survive infection by parasitoids using the encapsulation phenomenon. In Drosophila melanogaster the abilities to encapsulate the wasp species Leptopilina boulardi and Asobara tabida each involve one major gene. Both resistance genes have been precisely localized on the second chromosome, 35 centimorgans apart. This result clearly demonstrates the involvement of at least two separate genetic systems in Drosophila resistance to parasitoid wasps. The resistance genes to L. boulardi and A. tabida are not clustered as opposed to many plant resistance genes to pathogens cloned to date.

The profiles of diffuse layers, which are present in diffraction patterns of urea inclusion compounds, are interpreted quantitatively by a longitudinal positional paracrystalline order of the alkane guest molecules within the channels of the urea-host framework structure, in agreement with the expected behaviour of a one-dimensional system. With decreasing temperature there is a gradual transition into long-range order behaviour. This ordering process remains unaffected by structural changes related to lateral correlations within and between both host and guest substructures, including a structural phase transformation. The differing behaviour of a mixed system (pentadecane/hexadecane) with average period almost commensurate with the urea host lattice is explained by the superposition of main and satellite layers. The distribution of both molecules within each tunnel is random.

Drosophila melanogaster larvae usually react against eggs of the parasitoid wasp Leptopilina boulardi by surrounding them with a multicellular melanotic capsule. The genetic determinism of this response has been studied previously using susceptible (non-capsule-forming) and resistant (capsule-forming) strains. The results suggest that differences in their encapsulation response involve a single gene, resistance to Leptopilina boulardi (Rlb), with two alleles, the resistant one being dominant. Rlb confers specific protection against Leptopilina boulardi and is thus probably involved in parasitoid recognition. Recent studies have localized this gene on the right arm of the second chromosome and our aim was to precisely determine its genetic and molecular location. Using strains bearing deletions, we demonstrated that resistance to Leptopilina boulardi is conferred by the 55C; 55F3 region and that the 55E2-E6; F3 region is particularly involved. A physical map of the 55C; 56A region was then constructed, based on a set of overlapping cosmid and P1 phage clones. Using single and double digests, cross hybridization of restriction fragments, and location of genetically mapped genes and STSs, a complete, five-enzyme restriction map of this 830-kb region was obtained.

Encapsulation has evolved as an efficient mechanism whereby an insect host can survive infection by parasitoids This ability is controlled by a major gene in Drosophila melanogaster hosts. The parasitoid Leptopilina boulardi (Hymenoptera Eucoilidae) can suppress the Drosophila immune reaction by injecting viruslike particles. Analysis of Mendelian crosses between strains of L. boulardi of opposite immune suppressive abilities indicated that the trait is controlled by a single chromosomal factor with semidominant effect. We developed a method to test the monogenic hypothesis. The range of possible genotypic values in back-crosses was studied using various progeny that were genotypically homogenous. These could be obtained because of the arrhenotokous mode of reproduction. The progeny groups were divided into two clusters according to the major gene classification and the hypothesis of another unlinked genetic factor was rejected. Lastly, there was a residual progeny effect within the major groups, indicating that minor genes are also present. This study rules out the polygenic effect for a trait governing the interaction between the insect and parasitoid. It demonstrates that the gene-for-gene model commonly found in plant-parasite interactions may also explain natural variations in insect-parasitoid traits.

Larvae of Drosophila melanogaster produce a haemocytic reaction against eggs of the parasitoid, Asobara tabida, which leads to the formation of a multicellular capsule surrounding the foreign object. The same phenomenon was observed with the parasitoid, Leptopilina boulardi. Concerning the resistance of D. melanogaster to L. boulardi, a single major segregating locus with the resistant allele dominant to the susceptible one was found. The host strain susceptible to this parasitoid species was found to be highly immune reactive against the eggs of A. tabida. The inheritance of the capacity to encapsulate A. tabida was analysed by comparing reciprocal crosses made using inbred resistant and susceptible parental strains. We conclude that differences in the encapsulation capacity are inherited autosomally, with the reactive phenotype showing complete dominance over the non-reactive one. These data suggest the existence of two independent gene systems, each being concerned with the recognition of one species only.

Since the bacterial ability to develop resistance against various factors of their surroundings is a well-known phenomenon, resistance against iodine and specifically against povidone-iodine (PVP-I) has been widely investigated. Yet there is little known about bacterial resistance in long-term daily use of disinfectants in continuous ambulatory peritoneal dialysis (CAPD) patients. The aim of our study was to investigate whether on daily use of PVP-I over a period of at least 6 months coagulase-negative staphylococci (CNS)--the predominant infective organisms of peritonitis--developed resistance against PVP-I. At the catheter exit site of 40 CAPD patients we isolated 36 CNS. 23 CNS (CNS + PVP) orginate from patients using PVP-I, 13 CNS (CNS + CI) from patients using sodium hypochlorite (NaOCl) as disinfectant. The strains were biotyped, antibiotic resistance patterns were determined and resistance against PVP-I or NaOCl was calculated as reduction factor using the quantitative suspension test combined with a turbidimetric standardization. Resistance against PVP-I 0.01% and against NaOCl 0.005% was determined at two contact times (30 and 300 s) for each patient group. In addition, we investigated the effects of plasmid loss on sensitivity to PVP-I. Out of 5 multiple-antibiotic-resistant CNS, 3 strains showed no difference in reduction factor against PVP-I before and after curing. There was no significant difference in reduction factor against NaOCl. CNS + PVP were even significantly more sensitive to PVP-I than CNS + Cl. Taken together, our results demonstrate that long-term use of PVP-I does not cause any bacterial resistance in CNS of CAPD patients.

The Eucoilid parasitoid Leptopilina boulardi is able to suppress its host Drosophila melanogaster immune reaction. Some strains, however, are non-immune suppressive to that host. Virus-like particles (VLPs) responsible for the immune suppressive ability were investigated in different strains of L. boulardi with histochemical and ultrastructural techniques. Membrane-bound particles containing vesicles were observed in the reservoir of the long gland and also in the egg canal of the ovipositor. These particles are homologous with the immune suppressive VLPs already described in the reservoir of L. heterotoma. Similarities were also observed with the L2 particles described previously around the chorion of the parasitoid egg after infestation. A weak positive DNA specific histochemical reaction was observed inside the reservoir and at the ultrastructural level. Feulgen-derived techniques demonstrated that the reaction was localized inside the particles. The morphology of the particles as well as the immune suppressive ability varied between strains. Two morphotypes of VLPs are described; the 'Is' morphotype (always observed in immune suppressive or Is strains) and the 'NIs' morphotype (observed in the non-immune suppressive or NIs strain). The hybrids between Is and NIs strains produce a third type of particle, the 'HIs' morphotype with half-immune suppressive ability and intermediate morphology. The origin of the particles' immune suppressive activity against D. melanogaster is discussed within the scope of host specificity.