Therapeutic Effect of a Novel Oxazolidinone, DA-7867, in BALB/c Mice Infected with Nocardia brasiliensis

Actinomycetoma is an infectious disease of tropical and subtropical regions produced by actinobacteria of the genera Nocardia, Streptomyces, and Actinomadura. Therapeutic alternatives are scarce and include trimethoprim-sulfamethoxazole, diaminodiphenylsulfone, amoxicillin-clavulanate, imipenem, and amikacin. Oxazolidinones are a new class of antimicrobials with a completely different cellular target; the first compound in the market, linezolid, was introduced in the year 2000. It is active against many species of Nocardia and other aerobic actinomycetes; however, the long-term application in human subjects produces side effects including peripheral neuropathy and mielossupression. Therefore, it is important to screen other oxazolidinones with higher activity and less toxicity. In the present work, we tested DA-7867, a new oxazolidinone, in an experimental mouse model. The drug is active in vivo and decreases the production of lesions using only one dose a day in contrast to linezolid, which needs to be injected three times a day. Although it was tested on N. brasiliensis, it can possibly be active (once it is accepted for its use in humans) against Actinomadura spp and Streptomyces spp, which are frequently found in places of Africa and India where actinomycetoma is also an important consult in dermatology

Comment on "Drug Screening for ALS Using Patient-Specific Induced Pluripotent Stem Cells"

Egawa et al. recently showed the value of patient-specific induced pluripotent stem cells (iPSCs) for modeling amyotrophic lateral sclerosis in vitro. Their study and our work highlight the need for complementary assays to detect small, but potentially important, phenotypic differences between control iPSC lines and those carrying disease mutations

Адаптация гидравлической модели водостока к бассейнам рек Дунай и Днестр

Гидравлическая модель водостока адаптирована к бассейну рек Дунай и Днестр. По данным орографии, атмосферных осадках или поверхностном стоке она позволяет рассчитывать объемы, расходы и уровни воды с пространственным разрешением 1 км. В модели возможно использование данные об экосистемах на земной поверхности, типах почвы. По данным наблюдений стока оценены среднемесячные величины расходов рек, которые соответствуют наблюдениям, что позволяет применять модель в дальнейших оценках стока, наносов и т.д.Hydraulic model of water inflow is adapted to the Danube and the Dniester rivers basin. According to the orography, precipitation and surface inflow data it permits to calculate water volumes, discharges and levels with spatial resolution 1 km. It is possible to use the data on ecosystems on the ground surface, types of soil in the model. According to the observations data of the inflow the average monthly values of river discharges corresponding to the observations are estimated. It permits to apply the model in the further estimations of inflow, alluvia e t.c

Road Trauma in Teenage Male Youth with Childhood Disruptive Behavior Disorders: A Population Based Analysis

Donald Redelmeier and colleagues conducted a population-based case-control study of 16-19-year-old males hospitalized for road trauma or appendicitis and showed that disruptive behavior disorders explained a significant amount of road trauma in this group

Tracking smell loss to identify healthcare workers with SARS-CoV-2 infection

Introduction Healthcare workers (HCW) treating COVID-19 patients are at high risk for infection and may also spread infection through their contact with vulnerable patients. Smell loss has been associated with SARS-CoV-2 infection, but it is unknown whether monitoring for smell loss can be used to identify asymptomatic infection among high risk individuals. In this study we sought to determine if tracking smell sensitivity and loss using an at-home assessment could identify SARS-CoV-2 infection in HCW. Methods and findings We performed a prospective cohort study tracking 473 HCW across three months to determine if smell loss could predict SARS-CoV-2 infection in this high-risk group. HCW subjects completed a longitudinal, behavioral at-home assessment of olfaction with household items, as well as detailed symptom surveys that included a parosmia screening questionnaire, and real-time quantitative polymerase chain reaction testing to identify SARS-CoV-2 infection. Our main measures were the prevalence of smell loss in SARS-CoV-2-positive HCW versus SARS-CoV- 2-negative HCW, and timing of smell loss relative to SARS-CoV-2 test positivity. SARS-CoV-2 was identified in 17 (3.6%) of 473 HCW. HCW with SARS-CoV-2 infection were more likely to report smell loss than SARS-CoV-2-negative HCW on both the at-home assessment and the screening questionnaire (9/17, 53% vs 105/456, 23%, P < .01). 6/9 (67%) of SARS-CoV-2-positive HCW reporting smell loss reported smell loss prior to having a positive SARS-CoV-2 test, and smell loss was reported a median of two days before testing positive. Neurological symptoms were reported more frequently among SARS-CoV-2-positive HCW who reported smell loss compared to those without smell loss (9/9, 100% vs 3/8, 38%, P < .01). Conclusions In this prospective study of HCW, self-reported changes in smell using two different measures were predictive of SARS-CoV-2 infection. Smell loss frequently preceded a positive test and was associated with neurological symptoms

Innate Immune Responses to Bacterial Ligands in the Peripheral Human Lung – Role of Alveolar Epithelial TLR Expression and Signalling

It is widely believed that the alveolar epithelium is unresponsive to LPS, in the absence of serum, due to low expression of TLR4 and CD14. Furthermore, the responsiveness of the epithelium to TLR-2 ligands is also poorly understood. We hypothesised that human alveolar type I (ATI) and type II (ATII) epithelial cells were responsive to TLR2 and TLR4 ligands (MALP-2 and LPS respectively), expressed the necessary TLRs and co-receptors (CD14 and MD2) and released distinct profiles of cytokines via differential activation of MAP kinases. Primary ATII cells and alveolar macrophages and an immortalised ATI cell line (TT1) elicited CD14 and MD2-dependent responses to LPS which did not require the addition of exogenous soluble CD14. TT1 and primary ATII cells expressed CD14 whereas A549 cells did not, as confirmed by flow cytometry. Following LPS and MALP-2 exposure, macrophages and ATII cells released significant amounts of TNFα, IL-8 and MCP-1 whereas TT1 cells only released IL-8 and MCP-1. P38, ERK and JNK were involved in MALP-2 and LPS-induced cytokine release from all three cell types. However, ERK and JNK were significantly more important than p38 in cytokine release from macrophages whereas all three were similarly involved in LPS-induced mediator release from TT1 cells. In ATII cells, JNK was significantly more important than p38 and ERK in LPS-induced MCP-1 release. MALP-2 and LPS exposure stimulated TLR4 protein expression in all three cell types; significantly more so in ATII cells than macrophages and TT1 cells. In conclusion, this is the first study describing the expression of CD14 on, and TLR2 and 4 signalling in, primary human ATII cells and ATI cells; suggesting that differential activation of MAP kinases, cytokine secretion and TLR4 expression by the alveolar epithelium and macrophages is important in orchestrating a co-ordinated response to inhaled pathogens

2D characterization of near-surface V P/V S: surface-wave dispersion inversion versus refraction tomography

International audienceThe joint study of pressure (P-) and shear (S-) wave velocities (Vp and Vs ), as well as their ratio (Vp /Vs), has been used for many years at large scales but remains marginal in near-surface applications. For these applications, and are generally retrieved with seismic refraction tomography combining P and SH (shear-horizontal) waves, thus requiring two separate acquisitions. Surface-wave prospecting methods are proposed here as an alternative to SH-wave tomography in order to retrieve pseudo-2D Vs sections from typical P-wave shot gathers and assess the applicability of combined P-wave refraction tomography and surface-wave dispersion analysis to estimate Vp/Vs ratio. We carried out a simultaneous P- and surface-wave survey on a well-characterized granite-micaschists contact at Ploemeur hydrological observatory (France), supplemented with an SH-wave acquisition along the same line in order to compare Vs results obtained from SH-wave refraction tomography and surface-wave profiling. Travel-time tomography was performed with P- and SH- wave first arrivals observed along the line to retrieve Vtomo p and Vtomo s models. Windowing and stacking techniques were then used to extract evenly spaced dispersion data from P-wave shot gathers along the line. Successive 1D Monte Carlo inversions of these dispersion data were performed using fixed Vp values extracted from Vtomo p the model and no lateral constraints between two adjacent 1D inversions. The resulting 1D Vsw s models were then assembled to create a pseudo-2D Vsw s section, which appears to be correctly matching the general features observed on the section. If the pseudo-section is characterized by strong velocity incertainties in the deepest layers, it provides a more detailed description of the lateral variations in the shallow layers. Theoretical dispersion curves were also computed along the line with both and models. While the dispersion curves computed from models provide results consistent with the coherent maxima observed on dispersion images, dispersion curves computed from models are generally not fitting the observed propagation modes at low frequency. Surface-wave analysis could therefore improve models both in terms of reliability and ability to describe lateral variations. Finally, we were able to compute / sections from both and models. The two sections present similar features, but the section obtained from shows a higher lateral resolution and is consistent with the features observed on electrical resistivity tomography, thus validating our approach for retrieving Vp/Vs ratio from combined P-wave tomography and surface-wave profiling

A Multi-Center Randomized Trial to Assess the Efficacy of Gatifloxacin versus Ciprofloxacin for the Treatment of Shigellosis in Vietnamese Children

The bacterial genus Shigella is the most common cause of dysentery (diarrhea containing blood and/or mucus) and the disease is common in developing countries with limitations in sanitation. Children are most at risk of infection and frequently require hospitalization and antimicrobial therapy. The WHO currently recommends the fluoroquinolone, ciprofloxacin, for the treatment of childhood Shigella infections. In recent years there has been a sharp increase in the number of organisms that exhibit resistance to nalidixic acid (an antimicrobial related to ciprofloxacin), corresponding with reduced susceptibility to ciprofloxacin. We hypothesized that infections with Shigella strains that demonstrate resistance to nalidixic acid may prevent effective treatment with ciprofloxacin. We performed a randomized controlled trial to compare 3 day ciprofloxacin therapy with 3 days of gatifloxacin, a newer generation fluoroquinolone with greater activity than ciprofloxacin. We measured treatment failure and time to the cessation of individual disease symptoms in 249 children with dysentery treated with gatifloxacin and 245 treated with ciprofloxacin. We could identify no significant differences in treatment failure between the two groups or in time to the cessation of individual symptoms. We conclude that, in Vietnam, ciprofloxacin and gatifloxacin are similarly effective for the treatment of acute dysentery

Bitter Taste Receptors Influence Glucose Homeostasis

TAS1R- and TAS2R-type taste receptors are expressed in the gustatory system, where they detect sweet- and bitter-tasting stimuli, respectively. These receptors are also expressed in subsets of cells within the mammalian gastrointestinal tract, where they mediate nutrient assimilation and endocrine responses. For example, sweeteners stimulate taste receptors on the surface of gut enteroendocrine L cells to elicit an increase in intracellular Ca2+ and secretion of the incretin hormone glucagon-like peptide-1 (GLP-1), an important modulator of insulin biosynthesis and secretion. Because of the importance of taste receptors in the regulation of food intake and the alimentary responses to chemostimuli, we hypothesized that differences in taste receptor efficacy may impact glucose homeostasis. To address this issue, we initiated a candidate gene study within the Amish Family Diabetes Study and assessed the association of taste receptor variants with indicators of glucose dysregulation, including a diagnosis of type 2 diabetes mellitus and high levels of blood glucose and insulin during an oral glucose tolerance test. We report that a TAS2R haplotype is associated with altered glucose and insulin homeostasis. We also found that one SNP within this haplotype disrupts normal responses of a single receptor, TAS2R9, to its cognate ligands ofloxacin, procainamide and pirenzapine. Together, these findings suggest that a functionally compromised TAS2R receptor negatively impacts glucose homeostasis, providing an important link between alimentary chemosensation and metabolic disease

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease