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p27Kip1 (p27) is a cyclin-CDK inhibitor and negative regulator of cell proliferation. p27 also controls other cellular processes including migration and cytoplasmic p27 can act as an oncogene. Furthermore, cytoplasmic p27 promotes invasion and metastasis, in part by promoting epithelial to mesenchymal transition. Herein, we find that p27 promotes cell invasion by binding to and regulating the activity of Cortactin, a critical regulator of invadopodia formation. p27 localizes to invadopodia and limits their number and activity. p27 promotes the interaction of Cortactin with PAK1. In turn, PAK1 promotes invadopodia turnover by phosphorylating Cortactin, and expression of Cortactin mutants for PAK-targeted sites abolishes p27’s effect on invadopodia dynamics. Thus, in absence of p27, cells exhibit increased invadopodia stability due to impaired PAK1-Cortactin interaction, but their invasive capacity is reduced compared to wild-type cells. Overall, we find that p27 directly promotes cell invasion by facilitating invadopodia turnover via the Rac1/PAK1/Cortactin pathway.

Abstract The purpose of this study is to objectively assess by polysomnography total sleep time and sleep macrostructure in glaucomatous versus non-glaucomatous individuals after adjusting for possible confounding factors affecting the quality of sleep. This is an observational, prospective, single-center, case-controlled study using a sleep research database (MARS e-Cohort) collecting clinical data, comorbidities, medications, and sleep studies of glaucomatous and non-glaucomatous individuals. The diagnosis of glaucoma was confirmed with a full comprehensive ophthalmological examination including a visual field test. Total sleep time and the main sleep parameters (time spent in stages 1, 2, 3 and 4, microarousals, apnea–hypopnea index, and indices of hypoxic burden) were compared in glaucomatous and non-glaucomatous individuals after adjusting for age, anthropometric data, and comorbidities. The study included 33 glaucomatous and 66 non-glaucomatous individuals. The median total sleep time was 325 min [273; 398] for the control group and 311 min [244; 349] for the glaucoma group. After adjusting for the potential confounding factors, there was no significant difference in total sleep time (p = 0.3) and other sleep parameters between the control group and the glaucoma group. The sleep macrostructure was comparable in the glaucomatous and non-glaucomatous individuals after careful adjustment for confounders.

Abstract Earthquake-induced soil-liquefaction is a devastating phenomenon associated with loss of soil rigidity due to seismic shaking, resulting in catastrophic liquid-like soil deformation. Traditionally, liquefaction is viewed as an effectively undrained process. However, since undrained liquefaction only initiates under high energy density, most earthquake liquefaction events remain unexplained, since they initiate far from the earthquake epicenter, under low energy density. Here we show that liquefaction can occur under drained conditions at remarkably low seismic-energy density, offering a general explanation for earthquake far-field liquefaction. Drained conditions promote interstitial fluid flow across the soil during earthquakes, leading to excess pore pressure gradients and loss of soil strength. Drained liquefaction is triggered rapidly and controlled by a propagating compaction front, whose velocity depends on the seismic-energy injection rate. Our findings highlight the importance of considering soil liquefaction under a spectrum of drainage conditions, with critical implications for liquefaction potential assessments and hazards.

Abstract Ceratocystis canker caused by Ceratocystis destructans is a severe disease of almond, reducing the longevity and productivity of infected trees. Once the disease has established in an individual tree, there is no cure, and management efforts are often limited to removing the infected area of cankers. In this study, we present the genome assemblies of five C. destructans isolates isolated from symptomatic almond trees. The genomes were assembled into a genome size of 27.2 ± 0.9 Mbp with an average of 6924 ± 135 protein-coding genes and an average GC content of 48.8 ± 0.02%. We concentrated our efforts on identifying putative virulence factors of canker pathogens. Analysis of the secreted carbohydrate-active enzymes showed that the genomes harbored 83.4 ± 1.8 secreted CAZymes. The secreted CAZymes covered all the known categories of CAZymes. AntiSMASH revealed that the genomes had at least 7 biosynthetic gene clusters, with one of the non-ribosomal peptide synthases encoding dimethylcoprogen, a conserved virulence determinant of plant pathogenic ascomycetes. From the predicted proteome, we also annotated cytochrome P450 monooxygenases, and transporters, these are well-established virulence determinants of canker pathogens. Moreover, we managed to identify 57.4 ± 2.1 putative effector proteins. Gene Ontology (GO) annotation was applied to compare gene content with two closely related species C. fimbriata, and C. albifundus. This study provides the first genome assemblies for C. destructans, expanding genomic resources for an important almond canker pathogen. The acquired knowledge provides a foundation for further advanced studies, such as molecular interactions with the host, which is critical for breeding for resistance.

Summary: Obstructive sleep apnea (OSA) induces intermittent hypoxia (IH), an independent risk factor for non-alcoholic fatty liver disease (NAFLD). While the molecular links between IH and NAFLD progression are unclear, immune cell-driven inflammation plays a crucial role in NAFLD pathogenesis. Using lean mice exposed to long-term IH and a cohort of lean OSA patients (n = 71), we conducted comprehensive hepatic transcriptomics, lipidomics, and targeted serum proteomics. Significantly, we demonstrated that long-term IH alone can induce NASH molecular signatures found in human steatohepatitis transcriptomic data. Biomarkers (PPARs, NRFs, arachidonic acid, IL16, IL20, IFNB, TNF-α) associated with early hepatic and systemic inflammation were identified. This molecular link between IH, sleep apnea, and steatohepatitis merits further exploration in clinical trials, advocating for integrating sleep apnea diagnosis in liver disease phenotyping. Our unique signatures offer potential diagnostic and treatment response markers, highlighting therapeutic targets in the comorbidity of NAFLD and OSA.

IntroductionVentricular outflow tract obstructions including aortic (AS) and pulmonic stenosis (PS) are the most common canine congenital heart diseases, with Boxer dogs being predominantly affected. This has led to the French Boxer club adopting a mandatory national control program against AS and PS. The objective of this retrospective study was to analyze the results of 17 years of this cardiovascular breed screening program (2005-2021).Materials and methodsThe records of untreated and non-anesthetized adult Boxer dogs screened between 2005 and 2021 were retrospectively reviewed. All dogs underwent physical examination and standard transthoracic echocardiography with concomitant ECG tracing. All examinations were reviewed by one single board-certified specialist in cardiology.ResultsOut of the 3126 dogs screened during the study period, 3001 dogs (female:male sex ratio = 2.2, median age [IQR] = 1.6 years [1.2-2.1]) were recruited for data analysis. A total of 218 operators were involved in the screening program. For most Boxer dogs (i.e., 93.8% for AS and 94.5% for PS), a single examination was required to obtain a definitive cardiac status, although most operators were non-specialist general practitioners. A left basilar systolic heart murmur was detected in all dogs with AS and PS, but also in 7.4% dogs free of heart diseases. A significantly higher proportion of the latter was detected when operators were board-certified specialists (PConclusionThis 17-year screening program has experienced a strong involvement of veterinarians, breeders, and owners throughout France. This may have contributed to reduce AS and PS prevalence in Boxer dogs at the studied referral cardiology center.

Abstract In conventional flowcytometry one detector (primary) is dedicated for one fluorochrome. However, photons usually end up in other detectors too (fluorescence spillover). ‘Compensation’ is a process that corrects the spillover signal from all detectors except the primary detector. Post ‘compensation’, the photon counting error of spillover signals become evident as spreading of the data. The spreading induced by spillover impairs the ability to resolve stained cell population from the unstained one, potentially reducing or completely losing cell populations. For successful multi-color panel design, it is important to know the expected spillover to maximize the data resolution. The Spillover Spreading Matrix (SSM) can be used to estimate the spread, but the outcome is dependent on detector sensitivity. Simply, the same single stained sample produces different spillover spread values when detector(s) sensitivity is altered. Many researchers mistakenly use this artifact to “reduce” the spread by decreasing detector sensitivity. This can result in diminished capacity to resolve dimly expressing cell populations. Here, we introduce SQI (Spread Quantification Index), that can quantify the spillover spread independent of detector sensitivity and independent of dynamic range. This allows users to compare spillover spread between instruments having different types of detectors, which is not possible using SSM.

Abstract We present a subcritical fracture growth model, coupled with the elastic redistribution of the acting mechanical stress along rugous rupture fronts. We show the ability of this model to quantitatively reproduce the intermittent dynamics of cracks propagating along weak disordered interfaces. To this end, we assume that the fracture energy of such interfaces (in the sense of a critical energy release rate) follows a spatially correlated normal distribution. We compare various statistical features from the obtained fracture dynamics to that from cracks propagating in sintered polymethylmethacrylate (PMMA) interfaces. In previous works, it has been demonstrated that such an approach could reproduce the mean advance of fractures and their local front velocity distribution. Here, we go further by showing that the proposed model also quantitatively accounts for the complex self-affine scaling morphology of crack fronts and their temporal evolution, for the spatial and temporal correlations of the local velocity fields and for the avalanches size distribution of the intermittent growth dynamics. We thus provide new evidence that an Arrhenius-like subcritical growth is particularly suitable for the description of creeping cracks.

Abstract To determine the effect of continuous positive airway pressure (CPAP), the gold standard treatment for obstructive sleep apnea syndrome (OSAS), on gait control in severe OSAS patients. We conducted a randomized, double-blind, parallel-group, sham-controlled monocentric study in Grenoble Alpes University Hospital, France. Gait parameters were recorded under single and dual-task conditions using a visuo-verbal cognitive task (Stroop test), before and after the 8-week intervention period. Stride-time variability, a marker of gait control, was the primary study endpoint. Changes in the determinants of gait control were the main secondary outcomes. ClinicalTrials.gov Identifier: (NCT02345694). 24 patients [median (Q1; Q3)]: age: 59.5 (46.3; 66.8) years, 87.5% male, body mass index: 28.2 (24.7; 29.8) kg. m−2, apnea–hypopnea index: 51.6 (35.0; 61.4) events/h were randomized to be treated by effective CPAP (n = 12) or by sham-CPAP (n = 12). A complete case analysis was performed, using a mixed linear regression model. CPAP elicited no significant improvement in stride-time variability compared to sham-CPAP. No difference was found regarding the determinants of gait control. This study is the first RCT to investigate the effects of CPAP on gait control. Eight weeks of CPAP treatment did not improve gait control in severe non-obese OSAS patients. These results substantiate the complex OSAS-neurocognitive function relationship.

IntroductionCardiovascular diseases have been identified as a major cause of mortality and morbidity in Borneo orangutans (Pongo pygmaeus pygmaeus). Transthoracic echocardiography is usually performed under anesthesia in great apes, which may be stressful and increase risks of peri-anesthetic complications in case of cardiac alteration. The aim of the present pilot study was hence to develop a quick and non-stressful echocardiographic method (i.e., the COOLEST method) in awake Borneo orangutans (CardiOvascular examination in awake Orangutans: Low-stress Echocardiography including Speckle Tracking imaging) and assess the variability of corresponding variables.Materials and methodsFour adult Borneo orangutans trained to present their chest to the trainers were involved. A total of 96 TTE examinations were performed on 4 different days by a trained observer examining each orangutan 6 times per day. Each examination included four two-dimensional views, with offline assessment of 28 variables (i.e., two-dimensional (n = 12), M-mode and anatomic M-mode (n = 6), Doppler (n = 7), and speckle tracking imaging (n = 3)), representing a total of 2,688 measurements. A general linear model was used to determine the within-day and between-day coefficients of variation.ResultsMean±SD (minimum-maximum) images acquisition duration was 3.8±1.6 minutes (1.3-6.3). All within-day and between-day coefficients of variation but one (n = 55/56, 98%) were DiscussionHeart morphology as well as global and regional myocardial function can be assessed in awake orangutans with good to excellent repeatability and reproducibility.ConclusionsThis non-stressful method may be used for longitudinal cardiac follow-up in awake orangutans.

The surface morphology of faults controls the spatial anisotropy of their frictional properties and hence their mechanical stability. Such anisotropy is only rarely studied in seismology models of fault slip, although it might be paramount to understand the seismic rupture in particular areas, notably where slip occurs in a direction different from that of the main striations of the fault. To quantify how the anisotropy of fault surfaces affects the friction coefficient during sliding, we sheared synthetic fault planes made of plaster of Paris. These fault planes were produced by 3D-printing real striated fault surfaces whose 3D roughness was measured in the field at spatial scales from millimeters to meters. Here, we show how the 3D-printing technology can help for the study of frictional slip. The results show that fault anisotropy controls the coefficient of static friction, with μS//, the friction coefficient along the striations being three to four times smaller than μS⊥, the friction coefficient along the orientation perpendicular to the striations. This is true both at the meter and the millimeter scales. The anisotropy in friction and the average coefficient of static friction are also shown to decrease with the normal stress applied to the faults, as a result of the increased surface wear under increased loading.

In California vineyards, spore dispersal of fungi that cause grapevine trunk diseases Botryosphaeria dieback and Eutypa dieback occurs with winter rains. Spores infect through pruning wounds made to the woody structure of the vine in winter. Better timing of preventative practices that minimize infection may benefit from routine spore-trapping, which could pinpoint site-specific time frames of spore dispersal. To speed pathogen detection from environmental spore samples, we identified species-specific PCR primers and protocols. Then we compared the traditional culture-based method versus our new DNA-based method. • PCR primers for Botryosphaeria-dieback pathogen Neofusicoccum parvum and Eutypa-dieback pathogen Eutypa lata were confirmed species-specific, through extensive testing of related species (in families Botryosphaeriaceae and Diatrypaceae, respectively), other trunk-disease pathogens, and saprophytic fungi that sporulate in vineyards. • Consistent detection of N. parvum was achieved from spore suspensions used fresh or stored at -20°C, whereas consistent detection of E. lata was achieved only with a new spore-lysis method, using zirconia/silica beads in a FastPrep homogenizer (MP Biomedicals; Solon, Ohio, USA), and only from spore suspensions used fresh. Freezing E. lata spores at -20°C made detection inconsistent. • From environmental samples, spores of E. lata were detected only via PCR, whereas spores of N. parvum were detected both via PCR and in culture.

BackgroundThe symptomatic response to continuous positive airway pressure (CPAP) therapy in COPD-obstructive sleep apnea overlap syndrome (OVS) compared to OSA syndrome (OSA) alone has not been well studied so far. The aim of this study is to explore main differences in the clinical response to CPAP treatment in OVS compared to OSA alone.Study design and methodsUsing prospective data from the French National Sleep Apnea Registry, we conducted an observational study among 6320 patients with moderate-to-severe OSA, available spirometry, and at least one follow-up visit under CPAP therapy.ResultsCPAP efficacy measured on the residual apnea-hypopnea index and median adherence were similar between OVS and OSA patients. In both groups, the overall burden of symptoms related to sleep apnea improved with CPAP treatment. In a multivariable model adjusted for age, gender, body mass index, adherence to treatment and residual apnea-hypopnea index, OVS was associated with higher odds for persistent morning headaches (OR: 1.37 [95% CI; 1.04; 1.79]; P = 0.02), morning tiredness (OR: 1.33 [95% CI: 1.12; 1.59]; PInterpretationCPAP therapy was effective in normalizing the apnea-hypopnea index and significantly improved OSA-related symptoms, regardless of COPD status. CPAP should be offered to patients with OVS on a trial basis as a significant improvement in OSA-related symptoms can be expected, although the range of response may be less dramatic than in OSA alone.

The progression of chronic obstructive pulmonary disease (COPD) is characterized by episodes of acute exacerbation (AECOPD) of symptoms, decline in respiratory function, and reduction in quality-of-life increasing morbi-mortality and often requiring hospitalization. Exacerbations can be triggered by environmental exposures, changes in lifestyle, and/or physiological and psychological factors to greater or lesser extents depending on the individual’s COPD phenotype. The prediction and early detection of an exacerbation might allow patients and physicians to better manage the acute phase. We summarize the recent scientific data on remote telemonitoring (TM) for the prediction and management of acute exacerbations in COPD patients. We discuss the components of remote monitoring platforms, including the integration of environmental monitoring data; patient reported outcomes collected via interactive Smartphone apps, with data from wearable devices that monitor physical activity, heart rate, etc.; and data from medical devices such as connected non-invasive ventilators. We consider how telemonitoring and the deluge of data it potentially generates could be combined with electronic health records to provide personalized care and multi-disease management for COPD patients.

BackgroundObstructive sleep apnea (OSA) is associated with cardiovascular co-morbidities and mortality. Arterial stiffness is an independent predictor of cardiovascular risk and mortality, and is influenced by the presence of OSA and related comorbidities. There is a paucity of data regarding long-term evolution of arterial stiffness in CPAP-treated OSA patients. We aimed to prospectively study long term PWV variations and determinants of PWV deterioration.MethodsIn a prospective obese OSA cohort, at time of diagnosis and after several years of follow-up we collected arterial stiffness measured by carotid-femoral pulse wave velocity (PWV), clinical and metabolic parameters, and CPAP adherence. Univariate and multivariate analyses were performed in order to determine contributing factors.ResultsSeventy two OSA patients (men: 52.8%, median age: 55.8 years and median BMI of 38.5 kg/m2) with a prevalence of hypertension: 58.3%, type 2 diabetes: 20.8%, hypercholesterolemia: 33.3%, current or past smoking: 59.7%, were evaluated after a median follow-up of 7.4 [5.8; 8.3] years. Over the period of follow-up, the median increase in PWV was 1.34 [0.10; 2.37] m/s. In multivariate analysis, the increase in PWV was associated with older age (10 extra years was associated with a 5.24 [1.35; 9.12] % increase in PWV) and hypertension (a significant increase in PWV of 8.24 [1.02; 15.57] %). No impact of CPAP adherence on PWV evolution was found.ConclusionPWV progression in CPAP-treated OSA patients is mainly related to pre-existing cardio-metabolic comorbidities and not influenced by CPAP adherence. In this high cardiovascular risk population, it is crucial to associated weight management and exercise with CPAP treatment.

BackgroundMore advanced knowledge is needed on how COPD alters the clinical presentation of obstructive sleep apnea (OSA) and how the association of both diseases, known as 'overlap syndrome' (OVS), impacts on cardiovascular health.ObjectiveTo investigate differences between patients with OVS and those with moderate-to-severe OSA alone.MethodsA cross-sectional study conducted in the French National Sleep Apnea Registry between January 1997 and January 2017. Univariable and multivariable logistic regression models were used to compare OVS versus OSA alone on symptoms and cardiovascular health.Results46,786 patients had moderate-to-severe OSA. Valid spirometry was available for 16,466 patients: 14,368 (87%) had moderate-to-severe OSA alone and 2098 (13%) had OVS. A lower proportion of OVS patients complained of snoring, morning headaches and excessive daytime sleepiness compared to OSA alone (median Epworth Sleepiness Scale score: 9 [interquartile range (IQR) 6-13] versus 10 (IQR 6-13), respectively; P ConclusionsIn adults with moderate-to-severe OSA, OVS was minimally symptomatic, but exhibited higher odds for prevalent coronary heart disease, heart failure and peripheral arteriopathy.

INTRODUCTION:Sleepiness is the main clinical expression of obstructive sleep apnea (OSA) syndrome resulting from upper airway collapse. Recent studies have discussed the fact that the presence of T. gondii cysts in the brain and the resulting biochemical and immunological mechanisms could be linked to neurobehavioral disorders. The aim of the present study was to explore the potential impact of chronic toxoplasmosis on sleepiness and on obstructive sleep apnea (OSA) severity in OSA obese patients. MATERIALS AND METHODS:A case control study on obese patients screened for OSA was performed. According to the sleep disorder and matched based on gender, age and body mass index (BMI), two groups of obese patients were selected from our sample collection database. All patients were tested for toxoplasmosis serological status measuring anti-Toxoplasma IgG and IgM levels. Univariable and multivariable logistic regression models were performed to assess the impact of chronic toxoplasmosis on sleepiness and OSA severity. RESULTS:107 obese patients suffering from OSA were included in the study (median age: 53.3 years Interquartile range (IQR): [41.9-59.9]; median BMI: 39.4 kg/m2 IQR: [35.5-44.1], apnea-hypopnea index = 27.5 events/h [10.7-49.9]). Chronic toxoplasmosis was present in 63.4% and 70.7% of patients with or without sleepiness (p = 0.48), respectively and was not associated either to sleepiness (OR: 0.76, 95% CI: [0.52; 2.33], p = 0.64) or OSA severity (OR = 1.75, 95% CI: [0.51; 5.98] p = 0.37). CONCLUSION:Although chronic Toxoplasma infection in immunocompetent humans has been associated to several behavioral disorders or pathologies in recent literature, we demonstrate here that chronic toxoplasmosis is not associated to sleepiness and to sleep apnea syndrome severity in obese patients suspected of sleep apnea syndrome.

Mechanical algesia is an important process for the preservation of living organisms, allowing potentially life-saving reflexes or decisions when given body parts are stressed. Yet, its various underlying mechanisms remain to be fully unraveled. Here, we quantitatively discuss how the detection of painful mechanical stimuli by the human central nervous system may, partly, rely on thermal measurements. Indeed, most fractures in a body, including microscopic ones, release some heat, which diffuses in the surrounding tissues. Through this physical process, the thermo-sensitive TRP proteins, that translate abnormal temperatures into action potentials, shall be sensitive to damaging mechanical inputs. The implication of these polymodal receptors in mechanical algesia has been regularly reported, and we here provide a physical explanation for the coupling between thermal and mechanical pain. In particular, in the human skin, we show how the neighboring neurites of a broken collagen fiber can undergo a sudden thermal elevation that ranges from a fraction to tens of degrees. As this theoretical temperature anomaly lies in the sensibility range of the TRPV3 and TRPV1 cation channels, known to trigger action potentials in the neural system, a degree of mechanical pain can hence be generated.

Building prediction models based on complex omics datasets such as transcriptomics, proteomics, metabolomics remains a challenge in bioinformatics and biostatistics. Regularized regression techniques are typically used to deal with the high dimensionality of these datasets. However, due to the presence of correlation in the datasets, it is difficult to select the best model and application of these methods yields unstable results. We propose a novel strategy for model selection where the obtained models also perform well in terms of overall predictability. Several three step approaches are considered, where the steps are 1) network construction, 2) clustering to empirically derive modules or pathways, and 3) building a prediction model incorporating the information on the modules. For the first step, we use weighted correlation networks and Gaussian graphical modelling. Identification of groups of features is performed by hierarchical clustering. The grouping information is included in the prediction model by using group-based variable selection or group-specific penalization. We compare the performance of our new approaches with standard regularized regression via simulations. Based on these results we provide recommendations for selecting a strategy for building a prediction model given the specific goal of the analysis and the sizes of the datasets. Finally we illustrate the advantages of our approach by application of the methodology to two problems, namely prediction of body mass index in the DIetary, Lifestyle, and Genetic determinants of Obesity and Metabolic syndrome study (DILGOM) and prediction of response of each breast cancer cell line to treatment with specific drugs using a breast cancer cell lines pharmacogenomics dataset.

METHODS:Data from women (n = 305, aged 43 [34; 53] years-old, BMI 44.2 [40.8; 48.2] kg/m2) included in the Severe Obesity Outcome Network (SOON) cohort were analyzed (i) to evaluate collinearity between the different anthropometric markers, (ii) to compare the association of markers with hypertension, type 2 diabetes, obstructive sleep apnea syndrome (OSAS) and other cardiometabolic risks. RESULTS:Hip, waist and neck circumferences correlated with BMI with respectively less collinearity (r = 0.70, r = 0.59 and r = 0.37, respectively, p

Severe obstructive sleep apnoea (OSA) can lead to neurocognitive alterations, including gait impairments. The beneficial effects of continuous positive airway pressure (CPAP) on improving excessive daytime sleepiness and daily functioning have been documented. However, a demonstration of CPAP treatment efficacy on gait control is still lacking. This study aims to test the hypothesis that CPAP improves gait control in severe OSA patients.In this prospective controlled study, twelve severe OSA patients (age = 57.2±8.9 years, body mass index = 27.4±3.1 kg·m-2, apnoea-hypopnoea index = 46.3±11.7 events·h-1) and 10 healthy matched subjects were included. Overground gait parameters were recorded at spontaneous speed and stride time variability, a clinical marker of gait control, was calculated. To assess the role of executive functions in gait and postural control, a dual-task paradigm was applied using a Stroop test as secondary cognitive task. All assessments were performed before and after 8 weeks of CPAP treatment.Before CPAP treatment, OSA patients had significantly larger stride time variability (3.1±1.1% vs 2.1±0.5%) and lower cognitive performances under dual task compared to controls. After CPAP treatment, stride time variability was significantly improved and no longer different compared to controls. Cognitive performance under dual task also improved after CPAP treatment.Eight weeks of CPAP treatment improves gait control of severe OSA patients, suggesting morphological and functional cerebral improvements. Our data provide a rationale for further mechanistic studies and the use of gait as a biomarker of OSA brain consequences.

Filling the lung with dense liquid perfluorocarbons during total liquid ventilation (TLV) might compress the myocardium, a plausible explanation for the instability occasionally reported with this technique. Our objective is to assess the impacts of TLV on the cardiovascular system, particularly left ventricular diastolic function, in an ovine model of neonatal respiratory distress syndrome.Eight newborns lambs, 3.0 ± 0.4 days (3.2 ± 0.3kg) were used in this crossover experimental study. Animals were intubated, anesthetized and paralyzed. Catheters were inserted in the femoral and pulmonary arteries. A high-fidelity pressure catheter was inserted into the left ventricle. Surfactant deficiency was induced by repeated lung lavages with normal saline. TLV was then conducted for 2 hours using a liquid ventilator prototype. Thoracic echocardiography and cardiac output assessment by thermodilution were performed before and during TLV.Left ventricular end diastolic pressure (LVEDP) (9.3 ± 2.1 vs. 9.2 ± 2.4mmHg, p = 0.89) and dimension (1.90 ± 0.09 vs. 1.86 ± 0.12cm, p = 0.72), negative dP/dt (-2589 ± 691 vs. -3115 ± 866mmHg/s, p = 0.50) and cardiac output (436 ± 28 vs. 481 ± 59ml/kg/min, p = 0.26) were not affected by TLV initiation. Left ventricular relaxation time constant (tau) slightly increased from 21.5 ± 3.3 to 24.9 ± 3.7ms (p = 0.03). Mean arterial systemic (48 ± 6 vs. 53 ± 7mmHg, p = 0.38) and pulmonary pressures (31.3 ± 2.5 vs. 30.4 ± 2.3mmHg, p = 0.61) were stable. As expected, the inspiratory phase of liquid cycling exhibited a small but significant effect on most variables (i.e. central venous pressure +2.6 ± 0.5mmHg, p = 0.001; LVEDP +1.18 ± 0.12mmHg, p

BACKGROUND:Intellectual Disability (ID) is characterized by deficits in intellectual functions such as reasoning, problem-solving, planning, abstract thinking, judgment, and learning. As new avenues are emerging for treatment of genetically determined ID (such as Down's syndrome or Fragile X syndrome), it is necessary to identify objective reliable and sensitive outcome measures for use in clinical trials. OBJECTIVE:We developed a novel visual analogical reasoning paradigm, inspired by the Progressive Raven's Matrices, but appropriate for Intellectually Disabled patients. This new paradigm assesses reasoning and inhibition abilities in ID patients. METHODS:We performed behavioural analyses for this task (with a reaction time and error rate analysis, Study 1) in 96 healthy controls (adults and typically developed children older than 4) and 41 genetically determined ID patients (Fragile X syndrome, Down syndrome and ARX mutated patients). In order to establish and quantify the cognitive strategies used to solve the task, we also performed an eye-tracking analysis (Study 2). RESULTS:Down syndrome, ARX and Fragile X patients were significantly slower and made significantly more errors than chronological age-matched healthy controls. The effect of inhibition on error rate was greater than the matrix complexity effect in ID patients, opposite to findings in adult healthy controls. Interestingly, ID patients were more impaired by inhibition than mental age-matched healthy controls, but not by the matrix complexity. Eye-tracking analysis made it possible to identify the strategy used by the participants to solve the task. Adult healthy controls used a matrix-based strategy, whereas ID patients used a response-based strategy. Furthermore, etiologic-specific reasoning differences were evidenced between ID patients groups. CONCLUSION:We suggest that this paradigm, appropriate for ID patients and developmental populations as well as adult healthy controls, provides an objective and quantitative assessment of visual analogical reasoning and cognitive inhibition, enabling testing for the effect of pharmacological or behavioural intervention in these specific populations.

The classification of obstructive sleep apnea is on the basis of sleep study criteria that may not adequately capture disease heterogeneity. Improved phenotyping may improve prognosis prediction and help select therapeutic strategies.This study used cluster analysis to investigate the clinical clusters of obstructive sleep apnea.An ascending hierarchical cluster analysis was performed on baseline symptoms, physical examination, risk factor exposure and co-morbidities from 18,263 participants in the OSFP (French national registry of sleep apnea). The probability for criteria to be associated with a given cluster was assessed using odds ratios, determined by univariate logistic regression.Six clusters were identified, in which patients varied considerably in age, sex, symptoms, obesity, co-morbidities and environmental risk factors. The main significant differences between clusters were minimally symptomatic versus sleepy obstructive sleep apnea patients, lean versus obese, and among obese patients different combinations of co-morbidities and environmental risk factors.Our cluster analysis identified six distinct clusters of obstructive sleep apnea. Our findings underscore the high degree of heterogeneity that exists within obstructive sleep apnea patients regarding clinical presentation, risk factors and consequences. This may help in both research and clinical practice for validating new prevention programs, in diagnosis and in decisions regarding therapeutic strategies.

Some pathogenic species of the Botryosphaeriaceae have a latent phase, colonizing woody tissues while perennial hosts show no apparent symptoms until conditions for disease development become favorable. Detection of these pathogens is often limited to the later pathogenic phase. The latent phase is poorly characterized, despite the need for non-destructive detection tools and effective quarantine strategies, which would benefit from identification of host-based markers in leaves. Neofusicoccum parvum infects the wood of grapevines and other horticultural crops, killing the fruit-bearing shoots. We used light microscopy and high-resolution computed tomography (HRCT) to examine the spatio-temporal relationship between pathogen colonization and anatomical changes in stem sections. To identify differentially-expressed grape genes, leaves from inoculated and non-inoculated plants were examined using RNA-Seq. The latent phase occurred between 0 and 1.5 months post-inoculation (MPI), during which time the pathogen did not spread significantly beyond the inoculation site nor were there differences in lesion lengths between inoculated and non-inoculated plants. The pathogenic phase occurred between 1.5 and 2 MPI, when recovery beyond the inoculation site increased and lesion lengths of inoculated plants tripled. By 2 MPI, inoculated plants also had decreased starch content in xylem fibers and rays, and increased levels of gel-occluded xylem vessels, the latter of which HRCT revealed at a higher frequency than microscopy. RNA-Seq and screening of 21 grape expression datasets identified 20 candidate genes that were transcriptionally-activated by infection during the latent phase, and confirmed that the four best candidates (galactinol synthase, abscisic acid-induced wheat plasma membrane polypeptide-19 ortholog, embryonic cell protein 63, BURP domain-containing protein) were not affected by a range of common foliar and wood pathogens or abiotic stresses. Assuming such host responses are consistent among cultivars, and do not cross react with other trunk/foliar pathogens, these grape genes may serve as host-based markers of the latent phase of N. parvum infection.

Despite its critical role for cardiovascular homeostasis in humans, only a few studies have directly probed the transduction of sympathetic nerve activity to regional vascular responses--sympathetic neurovascular transduction. Those that have variably relied on either vascular resistance or vascular conductance to quantify the responses. However, it remains unclear which approach would better reflect the physiology. We assessed the utility of both of these as well as an alternative approach in 21 healthy men. We recorded arterial pressure (Finapres), peroneal sympathetic nerve activity (microneurography), and popliteal blood flow (Doppler) during isometric handgrip exercise to fatigue. We quantified and compared transduction via the relation of sympathetic activity to resistance and to conductance and via an adaptation of Poiseuille's relation including pressure, sympathetic activity, and flow. The average relationship between sympathetic activity and resistance (or conductance) was good when assessed over 30-second averages (mean R(2) = 0.49±0.07) but lesser when incorporating beat-by-beat time lags (R(2) = 0.37±0.06). However, in a third of the subjects, these relations provided relatively weak estimates (R(2)0.50 in 20 of 21 individuals), and provided reproducible estimates of transduction. The gain derived from the relation of resistance (but not conductance) was inversely related to transduction (R(2) = 0.37, p

Exercise intolerance in COPD seems to combine abnormal ventilatory mechanics, impaired O2 transport and skeletal muscle dysfunction. However their relative contribution and their influence on symptoms reported by patients remain to be clarified. In order to clarify the complex interaction between ventilatory and neuromuscular exercise limiting factors and symptoms, we evaluated respiratory muscles and quadriceps contractile fatigue, dynamic hyperinflation and symptoms induced by exhaustive high-intensity cycling in COPD patients. Fifteen gold II-III COPD patients (age = 67 ± 6 yr; BMI = 26.6 ± 4.2 kg.m(-2)) performed constant-load cycling test at 80% of their peak workload until exhaustion (9.3 ± 2.4 min). Before exercise and at exhaustion, potentiated twitch quadriceps strength (Q(tw)), transdiaphragmatic (P(di,tw)) and gastric (P(ga,tw)) pressures were evoked by femoral nerve, cervical and thoracic magnetic stimulation, respectively. Changes in operational lung volumes during exercise were assessed via repetitive inspiratory capacity (IC) measurements. Dyspnoea and leg discomfort were measured on visual analog scale. At exhaustion, Q(tw) (-33 ± 15%, >15% reduction observed in all patients but two) and Pdi,tw (-20 ± 15%, >15% reduction in 6 patients) were significantly reduced (P15% reduction in 3 patients). Percentage reduction in Q(tw) correlated with the percentage reduction in P(di,tw) (r = 0.66; P

BackgroundThe higher mortality rate in untreated patients with obesity-associated hypoventilation is a strong rationale for long-term noninvasive ventilation (NIV). The impacts of comorbidities, medications and NIV compliance on survival of these patients remain largely unexplored.MethodsObservational cohort of hypercapnic obese patients initiated on NIV between March 2003 and July 2008. Survival curves were estimated by the Kaplan-Meier method. Anthropometric measurements, pulmonary function, blood gases, nocturnal SpO(2) indices, comorbidities, medications, conditions of NIV initiation and NIV compliance were used as covariates. Univariate and multivariate Cox models allowed to assess predictive factors of mortality.ResultsOne hundred and seven patients (56% women), in whom NIV was initiated in acute (36%) or chronic conditions, were followed during 43±14 months. The 1, 2, 3 years survival rates were 99%, 94%, and 89%, respectively. In univariate analysis, death was associated with older age (>61 years), low FEV1 (ConclusionCardiovascular comorbidities represent the main factor predicting mortality in patient with obesity-associated hypoventilation treated by NIV. In this population, NIV should be associated with a combination of treatment modalities to reduce cardiovascular risk.

RationaleIn obstructive sleep apnea patients (OSA), continuous positive airway pressure (CPAP) adherence is crucial to improve symptoms and cardiometabolic outcomes. The choice of mask may influence CPAP adherence but this issue has never been addressed properly.ObjectiveTo evaluate the impact of nasal pillows, nasal and oronasal masks on CPAP adherence in a cohort of OSA.MethodsNewly CPAP treated OSA participating in "Observatoire Sommeil de la Fédération de Pneumologie", a French national prospective cohort, were included between March 2009 and December 2011. Anthropometric data, medical history, OSA severity, sleepiness, depressive status, treatment modalities (auto-CPAP versus fixed pressure, pressure level, interface type, use of humidifiers) and CPAP-related side effects were included in multivariate analysis to determine independent variables associated with CPAP adherence.Results2311 OSA (age = 57(12) years, apnea+hypopnea index = 41(21)/h, 29% female) were included. Nasal masks, oronasal masks and nasal pillows were used by 62.4, 26.2 and 11.4% of the patients, respectively. In univariate analysis, oronasal masks and nasal pillows were associated with higher risk of CPAP non-adherence. CPAP non-adherence was also associated with younger age, female gender, mild OSA, gastroesophageal reflux, depression status, low effective pressure and CPAP-related side effects. In multivariate analysis, CPAP non-adherence was associated with the use of oronasal masks (OR = 2.0; 95%CI = 1.6; 2.5), depression, low effective pressure, and side effects.ConclusionAs oronasal masks negatively impact on CPAP adherence, a nasal mask should be preferred as the first option. Patients on oronasal masks should be carefully followed.

Beyond obesity, sleep apnea syndrome is frequently associated with excess abdominal adiposity that could contribute to the deteriorated cardiometabolic risk profile of apneic patients.The present study addressed the respective contribution of the severity of sleep apnea syndrome and excess abdominal adiposity to the cardiometabolic risk profile of 38 non obese men with polysomnography-diagnosed sleep apnea syndrome (apnea-hypopnea index >15 events/hour). These otherwise healthy men performed a 75g-oral glucose tolerance test (OGTT) with plasma lipid/inflammatory and redox profiles. Twenty-one apneic men with high-waist circumference (>94 cm) were compared to 17 apneic men with low-waist circumference.Apneic men with high-waist circumference had higher AUC glucose and AUC insulin than apneic men with low-waist circumference. Accordingly, apneic men with high-waist circumference had higher hepatic insulin resistance as reflected by higher HOMA-resistance index, and lower global insulin sensitivity as reflected by lower insulin sensitivity index of Matsuda (derived from OGTT). The sleep structure and the apnea-hypopnea index were not different between the two groups. However, apneic men with high-waist circumference presented with lower mean nocturnal oxyhemoglobin (SpO2). In the 38 men, waist circumference and mean nocturnal SpO2 were inversely correlated (r = -0.43, p = 0.011) and were both associated with plasma glucose/insulin homeostasis indices: the higher the waist circumference, the lower the mean nocturnal SpO2, the lower the insulin-sensitivity. Finally, in multivariable regression model, mean nocturnal SpO2 and not waist circumference was associated with insulin-resistance.Thus, excess abdominal adiposity in non obese apneic men was associated with a deteriorated insulin-sensitivity that could be driven by a more severe nocturnal hypoxemia.

Positive end-expiratory pressure (PEEP) is commonly used in critical care medicine to improve gas exchange. Altitude sickness is associated with exaggerated reduction in arterial oxygenation. We assessed the effect of PEEP and pursed lips breathing (PLB) on arterial and tissue oxygenation under normobaric and hypobaric hypoxic conditions.Sixteen healthy volunteers were exposed to acute normobaric hypoxia (Laboratory study, FiO₂=0.12). The protocol consisted in 3-min phases with PEEPs of 0, 5 or 10 cmH₂O, PLB or similar ventilation than with PEEP-10, interspaced with 3-min phases of free breathing. Arterial (pulse oximetry) and quadriceps (near-infrared spectroscopy) oxygenation, ventilation, cardiac function, esophageal and gastric pressures and subjects' subjective perceptions were recorded continuously. In addition, the effect of PEEP on arterial oxygenation was tested at 4,350 m of altitude in 9 volunteers breathing for 20 min with PEEP-10 (Field study).During the laboratory study, PEEP-10 increased arterial and quadriceps oxygenation (arterial oxygen saturation +5.6±5.0% and quadriceps oxyhemoglobin +58±73 µmol.cm compared to free breathing; p0.05) compared to PEEP-0. During the field study, PEEP-10 increased arterial oxygen saturation by +6.7±6.0% after the 3(rd) minute with PEEP-10 without further significant increase until the 20(th) minute with PEEP-10. Subjects did not report any significant discomfort with PEEP.These data indicate that 10-cmH₂O PEEP significantly improves arterial and muscle oxygenation under both normobaric and hypobaric hypoxic conditions in healthy subjects. PEEP-10 could be an attractive non-pharmacological tool to limit blood oxygen desaturation and possibly symptoms at altitude.

Forty percent of people with Down syndrome exhibit heart defects, most often an atrioventricular septal defect (AVSD) and less frequently a ventricular septal defect (VSD) or atrial septal defect (ASD). Lymphoblastoid cell lines (LCLs) were established from lymphocytes of individuals with trisomy 21, the chromosomal abnormality causing Down syndrome. Gene expression profiles generated from DNA microarrays of LCLs from individuals without heart defects (CHD(-); n = 22) were compared with those of LCLs from patients with cardiac malformations (CHD(+); n = 21). After quantile normalization, principal component analysis revealed that AVSD carriers could be distinguished from a combined group of ASD or VSD (ASD+VSD) carriers. From 9,758 expressed genes, we identified 889 and 1,016 genes differentially expressed between CHD(-) and AVSD and CHD(-) and ASD+VSD, respectively, with only 119 genes in common. A specific chromosomal enrichment was found in each group of affected genes. Among the differentially expressed genes, more than 65% are expressed in human or mouse fetal heart tissues (GEO dataset). Additional LCLs from new groups of AVSD and ASD+VSD patients were analyzed by quantitative PCR; observed expression ratios were similar to microarray results. Analysis of GO categories revealed enrichment of genes from pathways regulating clathrin-mediated endocytosis in patients with AVSD and of genes involved in semaphorin-plexin-driven cardiogenesis and the formation of cytoplasmic microtubules in patients with ASD-VSD. A pathway-oriented search revealed enrichment in the ciliome for both groups and a specific enrichment in Hedgehog and Jak-stat pathways among ASD+VSD patients. These genes or related pathways are therefore potentially involved in normal cardiogenesis as well as in cardiac malformations observed in individuals with trisomy 21.

BACKGROUND:Obesity hypoventilation syndrome (OHS) is associated with increased cardiovascular morbidity. What moderate chronic hypoventilation adds to obesity on systemic inflammation and endothelial dysfunction remains unknown. QUESTION:To compare inflammatory status and endothelial function in OHS versus eucapnic obese patients. METHODOLOGY:14 OHS and 39 eucapnic obese patients matched for BMI and age were compared. Diurnal blood gazes, overnight polysomnography and endothelial function, measured by reactive hyperemia peripheral arterial tonometry (RH-PAT), were assessed. Inflammatory (Leptin, RANTES, MCP-1, IL-6, IL-8, TNFalpha, Resistin) and anti-inflammatory (adiponectin, IL-1Ra) cytokines were measured by multiplex beads immunoassays. PRINCIPAL FINDINGS:OHS exhibited a higher PaCO(2), a lower forced vital capacity (FVC) and tended to have a lower PaO(2) than eucapnic obese patients. (HS)-CRP, RANTES levels and glycated haemoglobin (HbA1c) were significantly increased in OHS (respectively 11.1+/-10.9 vs. 5.7+/-5.5 mg x l(-1) for (HS)-CRP, 55.9+/-55.3 vs 23.3+/-15.8 ng/ml for RANTES and 7.3+/-4.3 vs 6.1+/-1.7 for HbA1c). Serum adiponectin was reduced in OHS (7606+/-2977 vs 13,660+/-7854 ng/ml). Endothelial function was significantly more impaired in OHS (RH-PAT index: 0.22+/-0.06 vs 0.51+/-0.11). CONCLUSIONS:Compared to eucapnic obesity, OHS is associated with a specific increase in the pro-atherosclerotic RANTES chemokine, a decrease in the anti-inflammatory adipokine adiponectin and impaired endothelial function. These three conditions are known to be strongly associated with an increased cardiovascular risk. TRIAL REGISTRATION:ClinicalTrials.gov NCT00603096.