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Aim: To identify potential antischistosomal agents through 3D pharmacophore-based virtual screening of US FDA approved drugs.Materials & methods: A comprehensive virtual screening was conducted on a dataset of 10,000 FDA approved drugs, employing praziquantel as a template. Promising candidates were selected and assessed for their impact on Schistosoma mansoni viability in vitro and in vivo using S. mansoni infected mice.Results & conclusion: Among the selected drugs, betamethasone and doxazosin demonstrated in vitro efficacy, with effective concentration 50% (EC50) values ranging from 35 to 60 µM. In vivo studies revealed significant (>50%) reductions in worm burden for both drugs. These findings suggest that betamethasone and doxazosin hold promise for repurposing in treating schistosomiasis. Additionally, the study showcases a useful approach for identifying new antischistosomal drugs.

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Discovering new treatments for #schistosomiasis is crucial [Formula: see text]. Our study used virtual screening to identify potential antischistosomal drugs from US FDA approved compounds [Formula: see text]. Promising results in vitro and in vivo. [Formula: see text] #drugdiscovery #tropicaldiseases.

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Schistosoma mansoni , United States Food and Drug Administration , Animales , Ratones , Schistosoma mansoni/efectos de los fármacos , Estados Unidos , Aprobación de Drogas , Esquistosomicidas/farmacología , Esquistosomicidas/química , Esquistosomicidas/uso terapéutico , Esquistosomiasis mansoni/tratamiento farmacológico , Modelos Moleculares , Humanos , Farmacóforo

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Schistosomiasis, a parasitic disease affecting nearly 250 million individuals globally, poses a significant health challenge. With praziquantel being the sole available treatment and its limited efficacy in early stage infections, the identification of novel bioactive compounds becomes imperative. This study examines the potential of dehydrodieugenol B (1) and its methyl ether (2), derived from the leaves of the Brazilian Nectandra leucantha plant (Lauraceae), in combatting Schistosoma mansoni infections through a preclinical approach. Initially, compound 1 displayed noteworthy in vitro antiparasitic activity with an EC50 of 31.9 µM, showcasing low toxicity in mammalian cells and an in vivo animal model (Caenorhabditis elegans). Conversely, compound 2 exhibited no activity. In silico predictions pointed to favorable oral bioavailability and the absence of PAINS similarities. Subsequently, a single oral dose of 400 mg/kg of compound 1 or praziquantel was administered to mice infected with adult (patent infection) or immature parasites (prepatent infection). Remarkably, in prepatent infections, 1 resulted in a significant reduction (approximately 50%) in both worm and egg burden, while praziquantel reduced worm and egg numbers by 30%. The superior efficacy of dehydrodieugenol B (1) compared to praziquantel in premature infections holds the potential to advance the development of new molecular prototypes for schistosomiasis treatment.

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The aluminum has mechanical properties enable to a better finishing in welded region. However, it fails eventually when a dynamic load is applied. This study estimated the damage by multiaxial fatigue present in welded joints of bicycle frames, the methodologies of analysis are based on Findley's and Dang Van's Methods. Seven experiments were performed on two pipes with welded joints. These pipes were choosen according to Bike S/A data, numerical simulations in bicycle frame and previous analysis of specialized literature. Therefore, lifespan result of frame, in function the distance, is 3 × 1 0 4 km - 5.5 × 1 0 4 km.

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ABSTRACT: Lopes, TJA, Simic, M, Alves, DdS, Bunn, PdS, Rodrigues, AI, Terra, BdS, Lima, MdS, Ribeiro, FM, Vilão, P, and Pappas, E. Physical performance measures of flexibility, hip strength, lower limb power, and trunk endurance in healthy navy cadets: Normative data and differences between sex and limb dominance. J Strength Cond Res 35(2): 458-464, 2021-The objectives were to provide normative data on commonly used physical performance tests that may be associated with musculoskeletal injuries in Navy cadets and assess for sex and limb dominance differences. A large cohort of Navy cadets were assessed for physical performance tests of flexibility (ankle dorsiflexion range of motion and sit and reach), isometric hip strength, lower limb power (single-leg hop), and trunk endurance (plank and side plank tests). Besides providing normative data tables, sex and limb dominance differences were assessed by a 2-way mixed analysis of variance. A total of 545 Brazilian Navy cadets (394 men) representing 79% of the cadets in the Academy participated. Normative reference values were reported as mean ± SD, 95% confidence interval and percentiles. For tests of muscle strength, power, and endurance, men performed better than women (p < 0.001). For flexibility tests, women achieved greater distances than men for the sit and reach test (p < 0.001), but no difference for ankle dorsiflexion (p = 0.51). Overall, there were no clinically relevant differences between limbs. In conclusion, normative data for commonly used physical performance tests were provided. Although no clinically relevant side-to-side differences were found, men presented higher values for lower limb strength and power, as well as trunk endurance than women, whereas women demonstrated increased flexibility. Valuable normative data are provided to professionals who work with young, active populations from the injury prevention or rehabilitation perspective because the current study may help professionals to identify athletes or cadets whose performance is outside the normative values and may be at risk for injury.

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Fuerza Muscular , Rendimiento Físico Funcional , Brasil , Femenino , Humanos , Extremidad Inferior , Masculino , Resistencia Física , Torso

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STUDY OBJECTIVES: Sleep spindles, a defining feature of stage N2 sleep, are maximal at central electrodes and are found in the frequency range of the electroencephalogram (EEG) (sigma 11-16 Hz) that is known to be heritable. However, relatively little is known about the heritability of spindles. Two recent studies investigating the heritability of spindles reported moderate heritability, but with conflicting results depending on scalp location and spindle type. The present study aimed to definitively assess the heritability of sleep spindle characteristics. METHODS: We utilized the polysomnography data of 58 monozygotic and 40 dizygotic same-sex twin pairs to identify heritable characteristics of spindles at C3/C4 in stage N2 sleep including density, duration, peak-to-peak amplitude, and oscillation frequency. We implemented and tested a variety of spindle detection algorithms and used two complementary methods of estimating trait heritability. RESULTS: We found robust evidence to support strong heritability of spindles regardless of detector method (h2 > 0.8). However not all spindle characteristics were equally heritable, and each spindle detection method produced a different pattern of results. CONCLUSIONS: The sleep spindle in stage N2 sleep is highly heritable, but the heritability differs for individual spindle characteristics and depends on the spindle detector used for analysis.

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Electroencefalografía , Fases del Sueño , Algoritmos , Polisomnografía , Sueño

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BACKGROUND: Extreme phenotypes of OSA have not been systematically defined. RESEARCH QUESTION: This study developed objective definitions of extreme phenotypes of OSA by using a multivariate approach. The utility of these definitions for identifying characteristics that confer predisposition toward or protection against OSA is shown in a new prospective sample. STUDY DESIGN AND METHODS: In a large international sample, race-specific liability scores were calculated from a weighted logistic regression that included age, sex, and BMI. Extreme cases were defined as individuals with an apnea-hypopnea index (AHI) ≥ 30 events/hour but low likelihood of OSA based on age, sex, and BMI (liability scores > 90th percentile). Similarly, extreme controls were individuals with an AHI < 5 events/hour but high likelihood of OSA (liability scores < 10th percentile). Definitions were applied to a prospective sample from the Sleep Apnea Global Interdisciplinary Consortium, and differences in photography-based craniofacial and intraoral phenotypes were evaluated. RESULTS: This study included retrospective data from 81,338 individuals. A total of 4,168 extreme cases and 1,432 extreme controls were identified by using liability scores. Extreme cases were younger (43.1 ± 14.7 years), overweight (28.6 ± 6.8 kg/m2), and predominantly female (71.1%). Extreme controls were older (53.8 ± 14.1 years), obese (34.0 ± 8.1 kg/m2), and predominantly male (65.8%). These objective definitions identified 29 extreme cases and 87 extreme controls among 1,424 Sleep Apnea Global Interdisciplinary Consortium participants with photography-based phenotyping. Comparisons suggest that a greater cervicomental angle increases risk for OSA in the absence of clinical risk factors, and smaller facial widths are protective in the presence of clinical risk factors. INTERPRETATION: This objective definition can be applied in sleep centers throughout the world to consistently define OSA extreme phenotypes for future studies on genetic, anatomic, and physiologic pathways to OSA.

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Apnea Obstructiva del Sueño/clasificación , Adulto , Factores de Edad , Anciano , Femenino , Humanos , Internacionalidad , Masculino , Persona de Mediana Edad , Fenotipo , Fotograbar , Estudios Retrospectivos , Factores de Riesgo , Factores Sexuales , Apnea Obstructiva del Sueño/etnología

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STUDY OBJECTIVES: This study describes high-throughput phenotyping strategies for sleep and circadian behavior in mice, including examinations of robustness, reliability, and heritability among Diversity Outbred (DO) mice and their eight founder strains. METHODS: We performed high-throughput sleep and circadian phenotyping in male mice from the DO population (n = 338) and their eight founder strains: A/J (n = 6), C57BL/6J (n = 14), 129S1/SvlmJ (n = 6), NOD/LtJ (n = 6), NZO/H1LtJ (n = 6), CAST/EiJ (n = 8), PWK/PhJ (n = 8), and WSB/EiJ (n = 6). Using infrared beam break systems, we defined sleep as at least 40 s of continuous inactivity and quantified sleep-wake amounts and bout characteristics. We developed assays to measure sleep latency in a new environment and during a modified Murine Multiple Sleep Latency Test, and estimated circadian period from wheel-running experiments. For each trait, broad-sense heritability (proportion of variability explained by all genetic factors) was derived in founder strains, while narrow-sense heritability (proportion of variability explained by additive genetic effects) was calculated in DO mice. RESULTS: Phenotypes were robust to different inactivity durations to define sleep. Differences across founder strains and moderate/high broad-sense heritability were observed for most traits. There was large phenotypic variability among DO mice, and phenotypes were reliable, although estimates of heritability were lower than in founder mice. This likely reflects important nonadditive genetic effects. CONCLUSIONS: A high-throughput phenotyping strategy in mice, based primarily on monitoring of activity patterns, provides reliable and heritable estimates of sleep and circadian traits. This approach is suitable for discovery analyses in DO mice, where genetic factors explain some proportion of phenotypic variation.

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Ratones de Colaboración Cruzada , Sueño , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones Endogámicos , Fenotipo , Reproducibilidad de los Resultados , Sueño/genética

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INTRODUCTION: Sleepiness and cardiovascular disease share common molecular pathways; thus, genetic risk factors for sleepiness may also predict cardiovascular disease risk. This study explored the associations between subjective sleepiness and single-nucleotide polymorphisms (SNPs) in candidate genes within oxidative stress, inflammatory, and neuronal pathways, which may contribute to sleepiness and downstream cardiovascular disease risk: Cytochrome B-245, Alpha Polypeptide (CYBA), Cytochrome B-245, Beta Polypeptide (CYBB), Neutrophil Cytosolic Factor (NCF2), Tumor Necrosis Factor-Alpha (TNFA), and Phosphodiesterase 4D (PDE4D). METHODS: Adults (N = 918) from the general population who were a part of the São Paulo Epidemiologic Sleep Study (EPISONO) in São Paulo, Brazil, were genotyped using Human Omni Express BeadChip array. The average age was 42 ± 14.5 years, subjects had a mean body mass index (BMI) of 26.9 ± 5.4 kg/m2, and 44% were male. Based on the Epworth Sleepiness Scale (ESS), subjects were classified as having sleepiness (ESS ≥ 10) or no sleepiness (ESS < 10). Logistic regression models were used to examine the associations with SNPs within candidate genes and sleepiness, adjusting for age, gender, BMI, Apnea-Hypopnea Index (AHI), total sleep time, and ancestry informative principal components (PCs). Complementary analyses using linear regression to assess the relationship between SNPs and continuous ESS were performed. RESULTS: We observed a novel association between the C allele of the rs12522161 SNP on PDE4D and a decreased likelihood of sleepiness, controlling for covariates and ancestry [OR (95% CI) = 0.64 (0.50, 0.81); p = 0.0002]. CONCLUSION: We present data for a novel genetic association with sleepiness for an SNP on the PDE4D gene, rs12522161.

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Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/genética , Epidemiología Molecular , Somnolencia , Adulto , Alelos , Índice de Masa Corporal , Brasil , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/fisiopatología , Femenino , Genotipo , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Polisomnografía , Factores de Riesgo , Encuestas y Cuestionarios

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Study Objectives: Insomnia is a common sleep disorder that is associated with a range of adverse outcomes. Patients with insomnia exhibit hyperarousal in multiple domains, including an elevated metabolic rate, but specific metabolic molecular perturbations are unknown. Furthermore, objective clinical markers of insomnia are not available and current assessment of pathological extent relies on self-report. Here, we provide preliminary evidence that chronic insomnia is remarkably reflected in the periphery through detailed metabolic assessments. Methods: Serum from confirmed patients with insomnia and matched good sleepers (n = 15 per group) was sampled at high temporal resolution (every 2 hr over 48 hr). Food intake was controlled by providing hourly isocaloric snacks, and sleep architecture was assessed by overnight polysomnography. Quantitative metabolic assessments were conducted using nuclear magnetic resonance spectroscopy. Results: Global metabolic profiles differentiated patients with insomnia from healthy controls, with elevated amino acid and energy metabolites and reduced branched-chain amino acid catabolic products. Strikingly, branched-chain amino acid catabolism was found to be specifically altered during the night with ~10 per cent increased accumulation of glucose in insomnia patients. Rhythmicity analysis revealed 11 metabolites that cycled diurnally across both groups, with phase advances noted for acetone and delays for lactate and branched-chain amino acids and their products. Conclusions: These preliminary observations suggest that insomnia is associated with quantitative metabolic dysregulation and supports the hyperarousal hypothesis. Furthermore, we posit that these changes lead to a state of metabolic desynchrony in insomnia that is involved in the pathophysiology of the disorder and/or mediates its impact on health outcomes. Clinical Trials Registration: NCT01957111.

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Ritmo Circadiano/fisiología , Metabolismo Energético/fisiología , Trastornos del Inicio y del Mantenimiento del Sueño/fisiopatología , Sueño/fisiología , Vigilia/fisiología , Adulto , Aminoácidos/sangre , Biomarcadores , Glucemia/análisis , Femenino , Humanos , Espectroscopía de Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Polisomnografía/métodos

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Study Objectives: A recent study of patients with moderate-severe obstructive sleep apnea (OSA) in Iceland identified three clinical clusters based on symptoms and comorbidities. We sought to verify this finding in a new cohort in Iceland and examine the generalizability of OSA clusters in an international ethnically diverse cohort. Methods: Using data on 972 patients with moderate-severe OSA (apnea-hypopnea index [AHI] ≥ 15 events per hour) recruited from the Sleep Apnea Global Interdisciplinary Consortium (SAGIC), we performed a latent class analysis of 18 self-reported symptom variables, hypertension, cardiovascular disease, and diabetes. Results: The original OSA clusters of disturbed sleep, minimally symptomatic, and excessively sleepy replicated among 215 SAGIC patients from Iceland. These clusters also generalized to 757 patients from five other countries. The three clusters had similar average AHI values in both Iceland and the international samples, suggesting clusters are not driven by OSA severity; differences in age, gender, and body mass index were also generally small. Within the international sample, the three original clusters were expanded to five optimal clusters: three were similar to those in Iceland (labeled disturbed sleep, minimal symptoms, and upper airway symptoms with sleepiness) and two were new, less symptomatic clusters (labeled upper airway symptoms dominant and sleepiness dominant). The five clusters showed differences in demographics and AHI, although all were middle-aged (44.6-54.5 years), obese (30.6-35.9 kg/m2), and had severe OSA (42.0-51.4 events per hour) on average. Conclusions: Results confirm and extend previously identified clinical clusters in OSA. These clusters provide an opportunity for a more personalized approach to the management of OSA.

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Internacionalidad , Apnea Obstructiva del Sueño/clasificación , Apnea Obstructiva del Sueño/diagnóstico , Adulto , Anciano , Índice de Masa Corporal , Enfermedades Cardiovasculares/clasificación , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/epidemiología , Análisis por Conglomerados , Estudios de Cohortes , Comorbilidad , Diabetes Mellitus/clasificación , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiología , Trastornos de Somnolencia Excesiva/clasificación , Trastornos de Somnolencia Excesiva/diagnóstico , Trastornos de Somnolencia Excesiva/epidemiología , Femenino , Humanos , Hipertensión/clasificación , Hipertensión/diagnóstico , Hipertensión/epidemiología , Islandia/epidemiología , Masculino , Persona de Mediana Edad , Apnea Obstructiva del Sueño/epidemiología

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BACKGROUND: Musculoskeletal disorders are common among military personnel, especially during the initial basic training period. Prior studies have reported the prevalence rate of overall musculoskeletal symptoms or injuries in different military population and nationalities, especially from North America and Europe; however, very limited information regarding the military population of South America exists. Although Brazil has one of the biggest military forces worldwide (≈335,000 military personnel), currently, to our knowledge, there is no study reporting musculoskeletal symptoms or injury statistics in the Brazilian Armed Forces. Thus, the aims of this study were to describe the 12-month prevalence rate of self-reported musculoskeletal symptoms in cadets and to compare this prevalence rate between sexes and school years. METHODS: We conducted a cross-sectional study that took place from January to March 2016. Participants were Navy cadets, of both sexes and from three different school years of a Brazilian Merchant Navy Academy. All volunteers completed an adapted version of the Brazilian Nordic Musculoskeletal Questionnaire that assessed the past 12-month prevalence of musculoskeletal symptoms over eight body regions of the trunk and lower extremity. The Pearson's χ2 test was conducted to compare prevalence of symptoms per body region between sexes and among the 3 school years. The study has been approved by the Naval Hospital's ethical committee. RESULTS: A total of 545 cadets (394 males), corresponding to 79% of all 688 cadets enrolled at the Merchant Navy Academy, volunteered to participate on this study. Among all cadets, 266 (49%) reported symptoms in at least one body region in the past 12-months. The knee with 116 (21%) and lower back with 96 (18%), were the most prevalent regions. In terms of sex differences, there was higher prevalence of symptoms among females 90 (60%) than males 176 (45%). Furthermore, females reported almost double the prevalence for lower back symptoms (27% vs. 14%, p = 0.001) and 11% higher prevalence of knee symptoms (29% vs. 18%, p = 0.006) than males. Finally, it is important to highlight that cadets from the second (127 [65%]) and third (77 [55%]) school years had higher prevalence of symptoms than cadets from the first year (62 [29%]). The knee and lower back were consistently the two most prevalent regions among all school years, but shin symptoms increased from 3% to 17% (p < 0.001) between the first and second school years. CONCLUSION: The prevalence of musculoskeletal symptoms in the Brazilian Merchant Navy Academy doubles between initial enrollment and the beginning of the second school year. Females have consistently higher rates of symptoms than males, particularly reporting higher prevalence of knee and lower back pain which are the two most prevalent regions in this population. Prevention efforts should concentrate on the basic training period in an attempt to decrease the prevalence of musculoskeletal symptoms in this population. Finally, prospective studies are required to verify the cause and effect relationship between training and musculoskeletal symptoms.

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Factores de Edad , Educación/estadística & datos numéricos , Personal Militar/estadística & datos numéricos , Factores Sexuales , Brasil/epidemiología , Estudios Transversales , Femenino , Humanos , Masculino , Dolor Musculoesquelético/epidemiología , Prevalencia , Estudios Prospectivos , Factores de Riesgo , Autoinforme , Encuestas y Cuestionarios , Adulto Joven

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Study objectives: Debate persists as to whether obstructive sleep apnea (OSA) is an independent risk factor for atherosclerosis. The purpose of this study was to compare carotid intima-media thickness (IMT), an early sign of atherosclerosis, in obese and nonobese adults with OSA before and following positive airway pressure (PAP) treatment. Methods: A total of 206 adults newly diagnosed with OSA with an apnea-hypopnea index (AHI) of 15-75 events/hour and 53 controls with AHI <10 were studied. Waist circumference was used to classify participants as obese and nonobese. Bilateral common carotid artery B-mode ultrasound was performed at baseline to assess IMT, arterial diameter, arterial-wall mass, and circumferential wall stress. Measurements were repeated in 118 participants with OSA who completed a 4-month PAP treatment and had an average daily use over that period of ≥4 hours/day. Results: No significant differences in carotid IMT, diameter, or arterial-wall mass were present at baseline between participants with OSA and controls stratified by waist circumference, after adjusting for other cardiovascular risk factors. In participants with OSA, who had adequate PAP adherence over the 4-month treatment, carotid artery diameter significantly increased (mean change [95% confidence interval] = 0.13 [0.06, 0.20] mm; p = .0004), but no significant changes in carotid IMT, arterial-wall mass, and circumferential stress were observed in obese and nonobese participants. Conclusions: Regardless of obesity status, carotid IMT is not increased in adults with moderate to severe OSA versus controls and does not change following 4 months of PAP treatment.

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Arterias Carótidas , Grosor Intima-Media Carotídeo , Obesidad/complicaciones , Respiración con Presión Positiva , Apnea Obstructiva del Sueño/complicaciones , Apnea Obstructiva del Sueño/terapia , Adulto , Anciano , Aterosclerosis/complicaciones , Aterosclerosis/fisiopatología , Arterias Carótidas/diagnóstico por imagen , Enfermedades de las Arterias Carótidas/complicaciones , Enfermedades de las Arterias Carótidas/diagnóstico por imagen , Enfermedades de las Arterias Carótidas/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Obesidad/diagnóstico , Factores de Riesgo , Apnea Obstructiva del Sueño/fisiopatología , Circunferencia de la Cintura

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Objectives: To determine if the large and highly reproducible interindividual differences in arousal intensity and heart rate response to arousal (ΔHR) during non-REM sleep are heritable. Methods: Polysomnograms of 55 monozygotic (14 male and 41 female pairs) and 36 dizygotic (15 male and 21 female pairs) same-sex twin pairs were analyzed. Arousals were scored using the 2012 American Academy of Sleep Medicine criteria. Arousal intensity was scaled (between 0 and 9) using an automatic algorithm based on the change in electroencephalogram time and frequency characteristics. The ΔHR was determined at each arousal. We calculated average arousal duration, average arousal intensity, average overall ΔHR, average ΔHR at a given arousal intensity, slope of ΔHR per arousal intensity, and arousal intensity threshold of ΔHR. Results: The intraclass correlations among monozygotic and dizygotic twin pairs were 0.663 and 0.146, respectively, for average arousal intensity, and 0.449 and 0, respectively, for arousal intensity threshold of ΔHR controlling for age, sex, and race. These values imply large broad sense heritability (H2) for these traits. This evidence was confirmed by a robust maximum likelihood-based variance components estimation approach, with an additive genetic heritability of 0.64 (95% confidence interval: 0.48 to 0.80) for average arousal intensity and a combined additive and dominance genetic heritability and of 0.46 (0.25 to 0.68) for arousal intensity threshold of ΔHR. Results also suggested significant additive genetic effects for average arousal duration, ΔHR at arousal intensity scale 4 and the overall average ΔHR. Conclusion: Genetic factors explain a significant fraction of the phenotypic variability for average arousal intensity and arousal intensity threshold of ΔHR. Results suggest that the duration of arousals and specific average ΔHR values may also be heritable traits. Clinical trial registration: NCT02827461.

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Nivel de Alerta/fisiología , Frecuencia Cardíaca/genética , Frecuencia Cardíaca/fisiología , Gemelos Monocigóticos/genética , Adulto , Algoritmos , Nivel de Alerta/genética , Electroencefalografía , Femenino , Humanos , Funciones de Verosimilitud , Masculino , Fenotipo , Polisomnografía

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Study objective: To assess differences in gene expression in cholinergic basal forebrain cells between sleeping and sleep-deprived mice sacrificed at the same time of day. Methods: Tg(ChAT-eGFP)86Gsat mice expressing enhanced green fluorescent protein (eGFP) under control of the choline acetyltransferase (Chat) promoter were utilized to guide laser capture of cholinergic cells in basal forebrain. Messenger RNA expression levels in these cells were profiled using microarrays. Gene expression in eGFP(+) neurons was compared (1) to that in eGFP(-) neurons and to adjacent white matter, (2) between 7:00 am (lights on) and 7:00 pm (lights off), (3) between sleep-deprived and sleeping animals at 0, 3, 6, and 9 hours from lights on. Results: There was a marked enrichment of ChAT and other markers of cholinergic neurons in eGFP(+) cells. Comparison of gene expression in these eGFP(+) neurons between 7:00 am and 7:00 pm revealed expected differences in the expression of clock genes (Arntl2, Per1, Per2, Dbp, Nr1d1) as well as mGluR3. Comparison of expression between spontaneous sleep and sleep-deprived groups sacrificed at the same time of day revealed a number of transcripts (n = 55) that had higher expression in sleep deprivation compared to sleep. Genes upregulated in sleep deprivation predominantly were from the protein folding pathway (25 transcripts, including chaperones). Among 42 transcripts upregulated in sleep was the cold-inducible RNA-binding protein. Conclusions: Cholinergic cell signatures were characterized. Whether the identified genes are changing as a consequence of differences in behavioral state or as part of the molecular regulatory mechanism remains to be determined.

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Prosencéfalo Basal/citología , Neuronas Colinérgicas/metabolismo , Perfilación de la Expresión Génica , Privación de Sueño/metabolismo , Sueño/genética , Vigilia/genética , Acetilcolina/metabolismo , Animales , Proteínas CLOCK/genética , Colina O-Acetiltransferasa/genética , Masculino , Ratones , Pliegue de Proteína , Receptores de Glutamato Metabotrópico/genética , Privación de Sueño/patología

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Study Objective: To validate that the symptomless Multi-Variable Apnea Prediction index (sMVAP) is associated with Obstructive Sleep Apnea (OSA) diagnosis and assess the relationship between sMVAP and adverse outcomes in patients having elective surgery. We also compare associations between Bariatric surgery, where preoperative screening for OSA risk is mandatory, and non-Bariatric surgery groups who are not screened routinely for OSA. Methods: Using data from 40 432 elective inpatient surgeries, we used logistic regression to determine the relationship between sMVAP and previous OSA, current hypertension, and postoperative complications: extended length of stay (ELOS), intensive-care-unit-stay (ICU-stay), and respiratory complications (pulmonary embolism, acute respiratory distress syndrome, and/or aspiration pneumonia). Results: Higher sMVAP was associated with increased likelihood of previous OSA, hypertension and all postoperative complications (p < .0001). The top sMVAP quintile had increased odds of postoperative complications compared to the bottom quintile. For ELOS, ICU-stay, and respiratory complications, respective odds ratios (95% CI) were: 1.83 (1.62, 2.07), 1.44 (1.32, 1.58), and 1.85 (1.37, 2.49). Compared against age-, gender- and BMI-matched patients having Bariatric surgery, sMVAP was more strongly associated with postoperative complications in non-Bariatric surgical groups, including: (1) ELOS (Orthopedics [p < .0001], Gastrointestinal [p = .024], Neurosurgery [p = .016], Spine [p = .016]); (2) ICU-stay (Orthopedics [p = .0004], Gastrointestinal [p < .0001], and Otorhinolaryngology [p = .0102]); and (3) respiratory complications (Orthopedics [p =.037] and Otorhinolaryngology [p =.011]). Conclusions: OSA risk measured by sMVAP correlates with higher risk for select postoperative complications. Associations are stronger for non-Bariatric surgeries, where preoperative screening for OSA is not routinely performed. Thus, preoperative screening may reduce OSA-related risk for adverse postoperative outcomes.

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Procedimientos Quirúrgicos Electivos/efectos adversos , Complicaciones Posoperatorias/epidemiología , Síndromes de la Apnea del Sueño/diagnóstico , Apnea Obstructiva del Sueño/complicaciones , Adulto , Cirugía Bariátrica/efectos adversos , Femenino , Humanos , Hipertensión/complicaciones , Unidades de Cuidados Intensivos , Tiempo de Internación , Masculino , Persona de Mediana Edad , Obesidad Mórbida/complicaciones , Oportunidad Relativa , Complicaciones Posoperatorias/etiología , Cuidados Preoperatorios , Factores de Riesgo , Síndromes de la Apnea del Sueño/complicaciones , Apnea Obstructiva del Sueño/diagnóstico

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Introduction: In mammals, there is evidence that glutamate has a role as a wake-active neurotransmitter. So using video-based analysis of Drosophila behavior, we undertook a study to examine if glutamate, which has been previously shown to have an excitatory role in neuromuscular junctions in Drosophila, may have a conserved wake-active role in the adult brain. Aims and Methods: Using 6- to 9-day-old female flies, we examined the effect of perturbations of the glutamatergic signaling on total wakefulness and wake bout architecture. We increased and decreased neuronal activity of glutamatergic neurons in the brains of adult flies using Upstream Activating Sequence (UAS) NaChBac and UAS EKO, respectively. We blocked neurotransmission from glutamatergic neurons in adult flies using the UAS-driven temperature-sensitive dynamin mutation shibirets. We examined the behavior of flies with loss of function mutations of individual subunits of brain-specific ionotropic glutamate receptors. Results: Increasing the activity of glutamatergic neurons in the adult brain led to a significant increase in wakefulness compared to the control groups both in the daytime and nighttime and decreasing the activity of these same neurons reduced wakefulness in the nighttime. Blocking neurotransmitter release in glutamatergic neurons significantly reduced wake in the nighttime. The ionotropic receptor mutants had significantly less wake in the nighttime than their respective genetic background controls. Conclusion: The results show the following: glutamate is indeed a wake-active neurotransmitter in Drosophila; there is a major time of day effect associated with loss of glutamatergic neurotransmission; and it is a major wake-active neurotransmitter in the nighttime.

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Drosophila melanogaster/fisiología , Ácido Glutámico/fisiología , Neurotransmisores/fisiología , Sueño/fisiología , Vigilia/fisiología , Animales , Animales Modificados Genéticamente , Encéfalo/fisiología , Femenino , Locomoción/fisiología , Mutación/fisiología , Neuronas/fisiología , Transducción de Señal/fisiología , Grabación en Video

RESUMEN

Pain-producing animal venoms contain evolutionarily honed toxins that can be exploited to study and manipulate somatosensory and nociceptive signaling pathways. From a functional screen, we have identified a secreted phospholipase A2 (sPLA2)-like protein, BomoTx, from the Brazilian lancehead pit viper (Bothrops moojeni). BomoTx is closely related to a group of Lys49 myotoxins that have been shown to promote ATP release from myotubes through an unknown mechanism. Here we show that BomoTx excites a cohort of sensory neurons via ATP release and consequent activation of P2X2 and/or P2X3 purinergic receptors. We provide pharmacological and electrophysiological evidence to support pannexin hemichannels as downstream mediators of toxin-evoked ATP release. At the behavioral level, BomoTx elicits nonneurogenic inflammatory pain, thermal hyperalgesia, and mechanical allodynia, of which the latter is completely dependent on purinergic signaling. Thus, we reveal a role of regulated endogenous nucleotide release in nociception and provide a detailed mechanism of a pain-inducing Lys49 myotoxin from Bothrops species, which are responsible for the majority of snake-related deaths and injuries in Latin America.

Asunto(s)

Adenosina Trifosfato/metabolismo , Bothrops/fisiología , Fosfolipasas A2 Grupo II/toxicidad , Dolor/metabolismo , Proteínas de Reptiles/toxicidad , Células Receptoras Sensoriales/efectos de los fármacos , Mordeduras de Serpientes/metabolismo , Toxinas Biológicas/toxicidad , Venenos de Víboras/enzimología , Animales , Bothrops/genética , Brasil , Femenino , Fosfolipasas A2 Grupo II/genética , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Dolor/etiología , Dolor/genética , Dolor/parasitología , Ratas , Receptores Purinérgicos/metabolismo , Proteínas de Reptiles/genética , Células Receptoras Sensoriales/metabolismo , Transducción de Señal , Mordeduras de Serpientes/genética , Mordeduras de Serpientes/parasitología , Venenos de Víboras/toxicidad

RESUMEN

La colitis seudomembranosa es una severa y a veces mortal afección que puede ocurrir tras la administración de antibióticos y supresión de la flora intestinal normal, seguida de colonización por Clostridium difficile; se caracteriza por la inflamación aguda y presencia de seudomembranas necróticas en la mucosa colónica. Se presenta el caso de un paciente varón de nueve años de edad, proveniente de una zona rural de Honduras, con antecedente de fiebre intermitente de cuatro semanas de evolución, escalofríos, mialgias, náuseas e ictericia de una semana de evolución. Atendido previamente en Centro de Atención Primaria, fue tratado con antipiréticos, sin mejoría. Al examen físico el paciente estaba lúcido, se halló hipotensión, taquicardia, y fiebre; dolor abdominal epigastrio y ambos hipocondrios a la palpación superficial y profunda, hepatomegalia, ictericia, petequias. En los exámenes de laboratorio se encontraron pancitopenia severa, falla renal aguda, trastornos hidroelectrolíticos e hipoalbuminemia. Fue ingresado al servicio de urgencias pediátricas. Luego de una mala evolución clínica, falleció diecinueve después del ingreso. La autopsia reveló seudomembranas necróticas colónicas e imagen histológica de tipo volcán compatibles con colitis seudomembranosa.

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Pseudomembranous colitis is a severe and often fatal condition that may occur after the administration of some antimicrobial agents. There is suppression of the normal intestinal flora, followed by colonization by Clostridium difficile; and this condition is characterized by acute inflammation and presence of necrotic tissue pseudomembranes in the colon mucosa. We present the case of a nine-year-old boy from a rural area in Honduras, with a history of intermittent fever lasting four weeks, accompanied by chills, myalgia, nausea, and jaundice in the last week. He was previously seen in a primary care center with antipyretics, without improvement. The physical examination showed a lucid patient with hypotension, tachycardia, and fever; epigastric and bilateral hypochondrial abdominal pain on superficial and deep palpation was evidenced. Hepatomegaly, jaundice, and petechiae were also found. Laboratory tests showed severe pancytopenia, acute renal failure, hydroelectrolytic disturbances, and hypoalbuminemia. The patient was admitted to the Pediatric Urgency service. After a poor progression, he passed away nineteen days after admission. The necropsy showed necrotic pseudomembranes in the colon and a histological image resembling the shape of a volcano, compatible with pseudomembranous colitis.

Asunto(s)

Humanos , Masculino , Niño , Autopsia , Choque Séptico , Enterocolitis Seudomembranosa

RESUMEN

BACKGROUND: Despite pronounced increases in central pulse wave velocity (PWV) with aging, reflected wave transit time (RWTT), traditionally defined as the timing of the inflection point (TINF) in the central pressure waveform, does not appreciably decrease, leading to the controversial proposition of a "distal-shift" of reflection sites. TINF, however, is exceptionally prone to measurement error and is also affected by ejection pattern and not only by wave reflection. We assessed whether RWTT, assessed by advanced pressure-flow analysis, demonstrates the expected decline with aging. METHODS AND RESULTS: We studied a sample of unselected adults without cardiovascular disease (n=48; median age 48 years) and a clinical population of older adults with suspected/established cardiovascular disease (n=164; 61 years). We measured central pressure and flow with carotid tonometry and phase-contrast MRI, respectively. We assessed RWTT using wave-separation analysis (RWTTWSA) and partially distributed tube-load (TL) modeling (RWTTTL). Consistent with previous reports, TINF did not appreciably decrease with age despite pronounced increases in PWV in both populations. However, aging was associated with pronounced decreases in RWTTWSA (general population -15.0 ms/decade, P<0.001; clinical population -9.07 ms/decade, P=0.003) and RWTTTL (general -15.8 ms/decade, P<0.001; clinical -11.8 ms/decade, P<0.001). There was no evidence of an increased effective reflecting distance by either method. TINF was shown to reliably represent RWTT only under highly unrealistic assumptions about input impedance. CONCLUSIONS: RWTT declines with age in parallel with increased PWV, with earlier effects of wave reflections and without a distal shift in reflecting sites. These findings have important implications for our understanding of the role of wave reflections with aging.

Asunto(s)

Envejecimiento/fisiología , Presión Sanguínea/fisiología , Arterias Carótidas/fisiología , Enfermedad de la Arteria Coronaria/fisiopatología , Insuficiencia Cardíaca/fisiopatología , Hipertensión/fisiopatología , Anciano , Enfermedades Cardiovasculares/fisiopatología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Manometría , Persona de Mediana Edad , Análisis de la Onda del Pulso

Asunto(s)

ADN , Apnea Obstructiva del Sueño , Humanos , Metilación