Using small molecules to facilitate exchange of bicarbonate and chloride anions across liposomal membranes

Bicarbonate is involved in a wide range of biological processes, which include respiration, regulation of intracellular pH and fertilization. In this study we use a combination of NMR spectroscopy and ion-selective electrode techniques to show that the natural product prodigiosin, a tripyrrolic molecule produced by microorganisms such as Streptomyces and Serratia, facilitates chloride/bicarbonate exchange (antiport) across liposomal membranes. Higher concentrations of simple synthetic molecules based on a 4,6-dihydroxyisophthalamide core are also shown to facilitate this antiport process. Although it is well known that proteins regulate Cl-/HCO3- exchange in cells, these results suggest that small molecules may also be able to regulate the concentration of these anions in biological systems

Inhibition, flexibility, working memory and planning in autism spectrum disorders with and without comorbid ADHD-symptoms

<p>Abstract</p> <p>Background</p> <p>Recent studies have not paid a great deal of attention to comorbid attention-deficit/hyperactivity disorder (ADHD) symptoms in autistic children even though it is well known that almost half of children with autism spectrum disorder (ASD) suffer from hyperactivity, inattention and impulsivity. The goal of this study was to evaluate and compare executive functioning (EF) profiles in children with ADHD and in children with ASD with and without comorbid ADHD.</p> <p>Methods</p> <p>Children aged 6 to 18 years old with ADHD (n = 20) or ASD (High-Functioning autism or Asperger syndrome) with (n = 20) and without (n = 20) comorbid ADHD and a typically developing group (n = 20) were compared on a battery of EF tasks comprising inhibition, flexibility, working memory and planning tasks. A MANOVA, effect sizes as well as correlations between ADHD-symptomatology and EF performance were calculated. Age- and IQ-corrected z scores were used.</p> <p>Results</p> <p>There was a significant effect for the factor group (F = 1.55; dF = 42; p = .02). Post-hoc analysis revealed significant differences between the ADHD and the TD group on the inhibition task for false alarms (p = .01) and between the ADHD group, the ASD+ group (p = .03), the ASD- group (p = .02) and the TD group (p = .01) for omissions. Effect sizes showed clear deficits of ADHD children in inhibition and working memory tasks. Participants with ASD were impaired in planning and flexibility abilities. The ASD+ group showed compared to the ASD- group more problems in inhibitory performance but not in the working memory task.</p> <p>Conclusion</p> <p>Our findings replicate previous results reporting impairment of ADHD children in inhibition and working memory tasks and of ASD children in planning and flexibility abilities. The ASD + group showed similarities to the ADHD group with regard to inhibitory but not to working memory deficits. Nevertheless the heterogeneity of these and previous results shows that EF assessment is not useful for differential diagnosis between ADHD and ASD. It might be useful for evaluating strengths and weaknesses in individual children.</p

Short-term synaptic plasticity in the nociceptive thalamic-anterior cingulate pathway

<p>Abstract</p> <p>Background</p> <p>Although the mechanisms of short- and long-term potentiation of nociceptive-evoked responses are well known in the spinal cord, including central sensitization, there has been a growing body of information on such events in the cerebral cortex. In view of the importance of anterior cingulate cortex (ACC) in chronic pain conditions, this review considers neuronal plasticities in the thalamocingulate pathway that may be the earliest changes associated with such syndromes.</p> <p>Results</p> <p>A single nociceptive electrical stimulus to the sciatic nerve induced a prominent sink current in the layer II/III of the ACC <it>in vivo</it>, while high frequency stimulation potentiated the response of this current. Paired-pulse facilitation by electrical stimulation of midline, mediodorsal and intralaminar thalamic nuclei (MITN) suggesting that the MITN projection to ACC mediates the nociceptive short-term plasticity. The short-term synaptic plasticities were evaluated for different inputs <it>in vitro </it>where the medial thalamic and contralateral corpus callosum afferents were compared. Stimulation of the mediodorsal afferent evoked a stronger short-term synaptic plasticity and effectively transferred the bursting thalamic activity to cingulate cortex that was not true for contralateral stimulation. This short-term enhancement of synaptic transmission was mediated by polysynaptic pathways and NMDA receptors. Layer II/III neurons of the ACC express a short-term plasticity that involves glutamate and presynaptic calcium influx and is an important mechanism of the short-term plasticity.</p> <p>Conclusion</p> <p>The potentiation of ACC neuronal activity induced by thalamic bursting suggest that short-term synaptic plasticities enable the processing of nociceptive information from the medial thalamus and this temporal response variability is particularly important in pain because temporal maintenance of the response supports cortical integration and memory formation related to noxious events. Moreover, these modifications of cingulate synapses appear to regulate afferent signals that may be important to the transition from acute to chronic pain conditions associated with persistent peripheral noxious stimulation. Enhanced and maintained nociceptive activities in cingulate cortex, therefore, can become adverse and it will be important to learn how to regulate such changes in thalamic firing patterns that transmit nociceptive information to ACC in early stages of chronic pain.</p

Demographic and Clinical Factors Associated with Response to Smallpox Vaccine in Preimmunized Volunteers

CONTEXT: In March 2003, the French Ministry of Health implemented a program on preparedness and response to a biological attack using smallpox as weapon. This program included the establishment of a preoutbreak national team that could be revaccinated against smallpox. OBJECTIVE: To identify demographic and clinical factors associated with vaccination success defined as the presence of a pustule at the inoculation site at day 8 (days 7-9), with an undiluted vaccinia virus derived from a Lister strain among preimmunized volunteers. VOLUNTEERS AND METHODS: From March 2003 to November 2006, we have studied prospectively 226 eligible volunteers. Demographic data were recorded for each volunteer (age, sex, number of previously smallpox vaccinations and date of the last vaccination). Smallpox vaccine adverse reactions were diagnosed on the basis of clinical examination performed at days 0, 7, 14, 21 and 28 after revaccination. RESULTS: A total of 226 volunteers (sex ratio H/F = 2.7) were revaccinated. Median age was 45 years (range: 27-63 yrs). All volunteers completed follow-up. Median number of vaccinations before revaccination was 2 (range: 1-8). The median delay between time of the study and the last vaccination was 29 years (range; 18-60 yrs). Sixty-one volunteers (27%) experienced one (n = 40) or more (n = 21) minor side effects during the 2-14 days after revaccination. Successful vaccination was noted in 216/226 volunteers (95.6%) at day 8 and the median of the pustule diameter was 5 mm (range: 1-20 mm). Size of the pustule at day 8 was correlated with age (p = 0.03) and with the presence of axillary adenopathy after revaccination (p = 0.007). Sex, number of prior vaccinations, delay between the last vaccination and revaccination, and local or systemic side effects with the exception of axillary adenopathy, were not correlated with the size of the pustule at day 8. CONCLUSIONS: Previously vaccinated volunteers can be successfully revaccinated with the Lister strain

Star-forming cores embedded in a massive cold clump: Fragmentation, collapse and energetic outflows

The fate of massive cold clumps, their internal structure and collapse need to be characterised to understand the initial conditions for the formation of high-mass stars, stellar systems, and the origin of associations and clusters. We explore the onset of star formation in the 75 M_sun SMM1 clump in the region ISOSS J18364-0221 using infrared and (sub-)millimetre observations including interferometry. This contracting clump has fragmented into two compact cores SMM1 North and South of 0.05 pc radius, having masses of 15 and 10 M_sun, and luminosities of 20 and 180 L_sun. SMM1 South harbours a source traced at 24 and 70um, drives an energetic molecular outflow, and appears supersonically turbulent at the core centre. SMM1 North has no infrared counterparts and shows lower levels of turbulence, but also drives an outflow. Both outflows appear collimated and parsec-scale near-infrared features probably trace the outflow-powering jets. We derived mass outflow rates of at least 4E-5 M_sun/yr and outflow timescales of less than 1E4 yr. Our HCN(1-0) modelling for SMM1 South yielded an infall velocity of 0.14 km/s and an estimated mass infall rate of 3E-5 M_sun/yr. Both cores may harbour seeds of intermediate- or high-mass stars. We compare the derived core properties with recent simulations of massive core collapse. They are consistent with the very early stages dominated by accretion luminosity.Comment: Accepted for publication in ApJ, 14 pages, 7 figure

Effects of sex, age, and visits on receipt of preventive healthcare services: a secondary analysis of national data

BACKGROUND: Sex and age may exert a combined influence on receipt of preventive services with differences due to number of ambulatory care visits. METHODS: We used nationally representative data to determine weighted percentages and adjusted odds ratios of men and women stratified by age group who received selected preventive services. The presence of interaction between sex and age group was tested using adjusted models and retested after adding number of visits. RESULTS: Men were less likely than women to have received blood pressure screening (aOR 0.44;0.40–0.50), cholesterol screening (aOR 0.72;0.65–0.79), tobacco cessation counseling (aOR 0.66;0.55–0.78), and checkups (aOR 0.53;0.49–0.57). In younger age groups, men were particularly less likely than women to have received these services. In adjusted models, this observed interaction between sex and age group persisted only for blood pressure measurement (p = .016) and routine checkups (p < .001). When adjusting for number of visits, the interaction of age on receipt of blood pressure checks was mitigated but men were still overall less likely to receive the service. CONCLUSION: Men are significantly less likely than women to receive certain preventive services, and younger men even more so. Some of this discrepancy is secondary to a difference in number of ambulatory care visits

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation

Cytokine Profiles in Sepsis Have Limited Relevance for Stratifying Patients in the Emergency Department: A Prospective Observational Study

INTRODUCTION: Morbidity, mortality and social cost of sepsis are high. Previous studies have suggested that individual cytokines levels could be used as sepsis markers. Therefore, we assessed whether the multiplex technology could identify useful cytokine profiles in Emergency Department (ED) patients. METHODS: ED patients were included in a single tertiary-care center prospective study. Eligible patients were >18 years and met at least one of the following criteria: fever, suspected systemic infection, ≥ 2 systemic inflammatory response syndrome (SIRS) criteria, hypotension or shock. Multiplex cytokine measurements were performed on serum samples collected at inclusion. Associations between cytokine levels and sepsis were assessed using univariate and multivariate logistic regressions, principal component analysis (PCA) and agglomerative hierarchical clustering (AHC). RESULTS: Among the 126 patients (71 men, 55 women; median age: 54 years [19-96 years]) included, 102 had SIRS (81%), 55 (44%) had severe sepsis and 10 (8%) had septic shock. Univariate analysis revealed weak associations between cytokine levels and sepsis. Multivariate analysis revealed independent association between sIL-2R (p = 0.01) and severe sepsis, as well as between sIL-2R (p = 0.04), IL-1β (p = 0.046), IL-8 (p = 0.02) and septic shock. However, neither PCA nor AHC distinguished profiles characteristic of sepsis. CONCLUSIONS: Previous non-multiparametric studies might have reached inappropriate conclusions. Indeed, well-defined clinical conditions do not translate into particular cytokine profiles. Additional and larger trials are now required to validate the limited interest of expensive multiplex cytokine profiling for staging septic patients

A New Eusuchian Crocodyliform with Novel Cranial Integument and Its Significance for the Origin and Evolution of Crocodylia

Crocodyliforms were one of the most successful groups of Mesozoic tetrapods, radiating into terrestrial, semiaquatic and marine environments, while occupying numerous trophic niches, including carnivorous, insectivorous, herbivorous, and piscivorous species. Among these taxa were the enigmatic, poorly represented flat-headed crocodyliforms from the late Cretaceous of northern Africa. Here we report a new, giant crocodyliform from the early Late Cretaceous (Cenomanian) Kem Kem Formation of Morocco. Represented by a partial braincase, the taxon has an extremely long, flat skull with large jaw and craniocervical muscles. The skull roof is ridged and ornamented with a broad, rough boss surrounded by significant vascular impressions, likely forming an integumentary structure unique among crocodyliforms. Size estimates using endocranial volume indicate the specimen was very large. The taxon possesses robust laterosphenoids with laterally oriented capitate processes and isolated epipterygoids, features allying it with derived eusuchians. Phylogenetic analysis finds the taxon to be a derived eusuchian and sister taxon to Aegyptosuchus, a poorly understood, early Late Cretaceous taxon from the Bahariya formation. This clade forms the sister clade of crown-group Crocodylia, making these taxa the earliest eusuchian crocodyliforms known from Africa. These results shift phylogenetic and biogeographical hypotheses on the origin of modern crocodylians towards the circum-Tethyean region and provide important new data on eusuchian morphology and evolution