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Background Gastrointestinal (GI) injury and dysbiosis are adverse events associated with nonsteroidal anti-inflammatory drug (NSAID) use in horses. Phenylbutazone has been shown to alter GI barrier function both in vitro and ex vivo, but its effects on barrier function have not been assessed in vivo. In addition, the ability of nutritional therapeutics to prevent these changes is not known. Objective Our objectives were to determine whether (a) phenylbutazone affected barrier function in vivo and (b) if phenylbutazone-induced GI injury could be ameliorated by the use of a nutritional therapeutic. Animals Thirty healthy horses were randomly assigned to 3 groups (n = 10 per group): control, phenylbutazone, or phenylbutazone plus nutritional therapeutic. Methods This study was conducted as a blinded, randomized block design. All horses were managed identically throughout the study period. Samples were collected throughout the study period to monitor fecal microbiota changes and gastric ulcers before and after treatment. Quantification of the bacterial 16S rRNA gene in blood was used as a marker of intestinal permeability. Results Phenylbutazone increased amounts of bacterial 16S rDNA in circulation 3.02-fold (95% confidence interval [CI], 0.1.89-4.17), increased gastric ulceration score by a mean of 1.1 grade (P = .02), and induced specific changes in the microbiota, including loss of Pseudobutyrivibrio of family Lachnospiraceae. These changes were attenuated by nutritional treatment. Conclusions and clinical importance Collectively, these findings suggest that phenylbutazone induces GI injury, including impaired barrier function, and that nutritional treatment could attenuate these changes.

An ongoing debate in phonology concerns the treatment of cumulative constraint interactions, or ‘gang effects’, and by extension the question of which phonological frameworks are suitable models of the grammar. This paper uses a series of artificial grammar learning experiments to examine the inferences that learners draw about cumulative constraint violations in phonotactics in the absence of a confounding natural-language lexicon. I find that learners consistently infer linear counting and ganging cumulativity across a range of phonotactic violations.

Introduction:The World Health Organization (WHO; Geneva, Switzerland) recommends lay first responder (LFR) programs as a first step toward establishing formal Emergency Medical Services (EMS) in low- and middle-income countries (LMICs) to address injury. There is a scarcity of research investigating LFR program development in predominantly rural settings of LMICs.Study Objective:A pilot LFR program was launched and assessed over 12 months to investigate the feasibility of leveraging pre-existing transportation providers to scale up prehospital emergency care in rural, low-resource settings of LMICs.Methods:An LFR program was established in rural Chad to evaluate curriculum efficacy, using a validated 15-question pre-/post-test to measure participant knowledge improvement. Pre-/post-test score distributions were compared using a Wilcoxon Signed-Rank test. For test evaluation, each pre-test question was mapped to its corresponding post-test analog and compared using McNemar’s Chi-Squared Test to examine knowledge acquisition on a by-question basis. Longitudinal prehospital care was evaluated with incident reports, while program cost was tracked using a one-way sensitivity analysis. Qualitative follow-up surveys and semi-interviews were conducted at 12 months, with initial participants and randomly sampled motorcycle taxi drivers, and used a constructivist grounded theory approach to understand the factors motivating continued voluntary participation to inform future program continuity. The consolidated criteria for reporting qualitative research (COREQ) checklist was used to guide design, analysis, and reporting the qualitative results.Results:A total of 108 motorcycle taxi participants demonstrated significant knowledge improvement (P Conclusion:Lay first responder programs appear feasible and cost-effective in rural LMIC settings. Participants demonstrate significant knowledge acquisition, and after 12 months of providing emergency care, report sustained voluntary participation due to social and financial benefits, suggesting sustainability and scalability of LFR programs in low-resource settings.

All patients with Helicobacter pylori infection should be offered eradication therapy. However, antimicrobial resistance has undermined the success rate of most current eradication therapies. This ...

BackgroundPatients with Fabry disease (FD) on reduced dose of agalsidase-beta or after switch to agalsidase-alfa show a decline in chronic kidney disease epidemiology collaboration-based estimated glomerular filtration rate (eGFR) and a worsened plasma lyso-Gb3 decrease. Hence, the most effective dose is still a matter of debate.MethodsIn this prospective observational study, we assessed end-organ damage and clinical symptoms in 78 patients who had received agalsidase-beta (1.0 mg/kg) for >1 year, which were assigned to continue this treatment (agalsidase-beta, regular-dose group, n=17); received a reduced dose of agalsidase-beta and subsequent switch to agalsidase-alfa (0.2 mg/kg) or a direct switch to 0.2 mg/kg agalsidase-alfa (switch group, n=22); or were re-switched to agalsidase-beta after receiving agalsidase-alfa for 12 months (re-switch group, n=39) with a follow-up of 88±25 months.ResultsNo differences for clinical events were observed for all groups. Patients within the re-switch group started with the worst eGFR values at baseline (p=0.0217). Overall, eGFR values remained stable in the regular-dose group (p=0.1052) and decreased significantly in the re-switch and switch groups (pConclusionsOur data suggest that a re-switch to high dosage of agalsidase results in a better biochemical response, but not in a significant renal amelioration especially in classical males.

Chronotype (CT) has been associated with predisposition to chronic noncommunicable diseases (CNCDs), such as diabetes mellitus and obesity. However, the effects of CT on individuals assisted by public health systems (PHSs) in middle-up economies are still poorly explored. The objective of this study was to evaluate the relationship between CT and clinical, sociobehavioral and nutritional aspects in adults assisted by a PHS in Brazil. This is a population-based cross-sectional study. The sample consisted of 380 individuals, selected through probabilistic sampling by clusters, in all health units in a city of approximately 100 thousand inhabitants. Data collection was performed during home visits, by means of general and nutritional interviews, anthropometric measurements and the Morningness–Eveningness Questionnaire (MEQ). Statistical analysis comprised chi-square test and principal component analysis (CPA) followed by Fisher’s discriminant analysis to determine aspects associated with each CT (morning, evening or intermediate). With the aim of explaining the variation in the CT scores, the consumption of micronutrients (corrected to the total energy intake) and other individual and sociodemographic variables were used as explanatory factors in the adjustment of a linear regression model. The morning group was characterized by older men, with less than eight years of schooling, with low body mass index (BMI) and with low intake of omega-6, omega-3, sodium, zinc, thiamine, pyridoxine and niacin. The evening group, on the other hand, was composed of younger individuals, with a high consumption of these same nutrients, with high BMI and a higher frequency of heart diseases (p &lt, 0.05). It was concluded that most morning CT individuals were elderly thin males with lower consumption of omega-6 and -3, sodium, zinc, thiamine, pyridoxine and niacin, whereas evening individuals were younger, had higher BMI and had higher consumption of the studied micronutrients. The identification of circadian and behavioral risk groups can help to provide preventive and multidisciplinary health promotion measures.

Mycobacterial species, including Mycobacterium tuberculosis, rely on lipids to survive and chronically persist within their hosts. Upon infection, opportunistic and strict pathogenic mycobacteria exploit metabolic pathways to import and process host-derived free fatty acids, subsequently stored as triacylglycerols in the form of intrabacterial lipid inclusions (ILI). Under nutrient-limiting conditions, ILI constitute a critical source of energy that fuels the carbon requirements and maintain redox homeostasis, promoting bacterial survival for extensive periods of time. In addition to their basic metabolic functions, these organelles display multiple other biological properties, emphasizing their central role in the mycobacterial life cycle. However, despite their importance, the dynamics of ILI metabolism and their contribution to mycobacterial adaptation/survival in the context of infection has not been thoroughly documented. Herein, we provide an overview of the historical ILI discoveries, their characterization and current knowledge regarding the microenvironmental stimuli conveying ILI formation, storage and degradation. We also review new biological systems to monitor the dynamics of ILI metabolism in extra- and intracellular mycobacteria and describe major molecular actors in triacylglycerol biosynthesis, maintenance and breakdown. Finally, emerging concepts regarding the role of ILI in mycobacterial survival, persistence, reactivation, antibiotic susceptibility and inter-individual transmission are also discussed.

International audience; Mycobacterium abscessus (M. abscessus), a rapidly growing mycobacterium, is an emergent opportunistic pathogen responsible for chronic bronchopulmonary infections in individuals with respiratory diseases such as cystic fibrosis. Most treatments of M. abscessus pulmonary infections are poorly effective due to the intrinsic resistance of this bacteria against a broad range of antibiotics including anti-tuberculosis agents. Consequently, the number of drugs that are efficient against M. abscessus remains limited. In this context, 19 oxadiazolone (OX) derivatives have been investigated for their antibacterial activity against both the rough (R) and smooth (S) variants of M. abscessus. Several OXs impair extracellu-lar M. abscessus growth with moderated minimal inhibitory concentrations (MIC), or act intracellularly by inhibiting M. abscessus growth inside infected macrophages with MIC values similar to those of imipenem. Such promising results prompted us to identify the potential target enzymes of the sole extra and intracellular inhibitor of M. abscessus growth, i.e., compound iBpPPOX, via activity-based protein profiling combined with mass spectrometry. This approach led to the identification of 21 potential protein candidates being mostly involved in M. abscessus lipid metabolism and/or in cell wall biosynthesis. Among them, the Ag85C protein has been confirmed as a vulnerable target of iBpPPOX. This study clearly emphasizes the potential of the OX derivatives to inhibit the extracellular and/or intracellular growth of M. abscessus by targeting various enzymes potentially involved in many physiological processes of this most drug-resistant mycobacterial species.

International audience; The bacterial type VI secretion system (T6SS) is a macromolecular machine that injects effectors into prokaryotic and eukaryotic cells. The mode of action of the T6SS is similar to contractile phages: the contraction of a sheath structure pushes a tube topped by a spike into target cells. Effectors are loaded onto the spike or confined into the tube. In enteroaggregative Escherichia coli, the Tle1 phospholipase binds the C-terminal extension of the VgrG trimeric spike. Here, we purify the VgrG-Tle1 complex and show that a VgrG trimer binds three Tle1 monomers and inhibits their activity. Using covalent cross-linking coupled to high-resolution mass spectrometry, we provide information on the sites of contact and further identify the requirement for a Tle1 N-terminal secretion sequence in complex formation. Finally, we report the 2.6-Å-resolution cryo-electron microscopy tri-dimensional structure of the (VgrG) 3-(Tle1) 3 complex revealing how the effector binds its cargo, and how VgrG inhibits Tle1 phospholipase activity. The inhibition of Tle1 phospholipase activity once bound to VgrG suggests that Tle1 dissociation from VgrG is required upon delivery.

The increasing incidence of antibiotic-resistant Mycobacterium tuberculosis infections is a global health threat necessitating the development of new antibiotics. Serine hydrolases (SHs) are a promising class of targets because of their importance for the synthesis of the mycobacterial cell envelope. We screen a library of small molecules containing serine-reactive electrophiles and identify narrow-spectrum inhibitors of M. tuberculosis growth. Using these lead molecules, we perform competitive activity-based protein profiling and identify multiple SH targets, including enzymes with uncharacterized functions. Lipidomic analyses of compound-treated cultures reveal an accumulation of free lipids and a substantial decrease in lipooligosaccharides, linking SH inhibition to defects in cell envelope biogenesis. Mutant analysis reveals a path to resistance via the synthesis of mycocerates, but not through mutations to SH targets. Our results suggest that simultaneous inhibition of multiple SH enzymes is likely to be an effective therapeutic strategy for the treatment of M. tuberculosis infections.

International audience; Background: Culture conditions sometimes make it difficult to detect non-tuberculous mycobacteria (NTM), particularly Mycobacterium abscessus, an emerging cystic fibrosis (CF) pathogen. The diagnosis of NTM positive cases not detected by classical culture methods might benefit from the development of a serological assay.Methods: As part of a diagnostic accuracy study, a total of 173 sera CF-patients, including 33 patients with M. abscessus positive cultures, and 31 non-CF healthy controls (HC) were evaluated. Four M. abscessus antigens were used separately, comprising two surface extracts (Interphase (INP) and a TLR2 positive extract (TLR2eF)) and two recombinant proteins (rMAB_2545c and rMAB_0555 also known as the phospholipase C (rPLC)).Results: TLR2eF and rPLC were the most efficient antigens to discriminate NTM-culture positive CF-patients from NTM-culture negative CF-patients. The best clinical values were obtained for the detection of M. abscessus-culture positive CF-patients; with sensitivities for the TLR2eF and rPLC of 81.2% (95% CI:65.7-92.3%) and 87.9% (95% CI:71.9-95.6%) respectively, and specificities of 88.9% (95% CI:85.3-94.8%) and 84.8% (95% CI:80.6-91.5%) respectively. When considering as positive all sera, giving a positive response in at least one of the two tests, and, as negative, all sera negative for both tests, we obtained a sensitivity of 93.9% and a specificity of 80.7% for the detection of M. abscessus-culture positive CF-patients.Conclusion: High antibody titers against TLR2eF and rPLC were obtained in M. abscessus-culture positive CF-patients, allowing us to consider these serological markers as potential tools in the detection of CF-patients infected with M. abscessus.

Small intestinal damage induced by nonsteroidal anti-inflammatory drugs (NSAIDs) remains an under-recognized clinical disorder. The incomplete understanding of the pathophysiology has hampered the development of prevention and treatment strategies leading to the high morbidity and mortality rates. NSAIDs are known to modulate macroautophagy, a process indispensable for intestinal homeostasis. Whether NSAIDs stimulate or repress macroautophagy and how this correlates with the clinical manifestations of NSAID enteropathy, however, remains unknown. The objectives of this study were to determine whether NSAIDs impaired macroautophagy and how this affects macroautophagy-regulated intestinal epithelial cell (IEC) processes essential for intestinal homeostasis (i.e., clearance of invading pathogens, secretion and composition of mucus building blocks, and inflammatory response). We show that NSAID treatment of IECs inhibits macroautophagy in vitro and in vivo. This inhibition was likely attributed to a reduction in the area and/or distribution of lysosomes available for degradation of macroautophagy-targeted cargo. Importantly, IEC regulatory processes necessary for intestinal homeostasis and dependent on macroautophagy were dysfunctional in the presence of NSAIDs. Since macroautophagy is essential for gastrointestinal health, NSAID-induced inhibition of macroautophagy might contribute to the severity of intestinal injury by compromising the integrity of the mucosal barrier, preventing the clearance of invading microbes, and exacerbating the inflammatory response.

Daily iron supplementation, with or without folic acid, is a proven public health intervention. Although maintaining compliance is crucial for the success of the intervention, inconsistent findings are available on compliance and its predictors in Ethiopia. The aim of this study was to estimate the iron-folic acid (IFA) supplementation compliance rate and its predictors among pregnant women in Wolaita Zone, Southern Ethiopia. A cross-sectional study was conducted in eight randomly selected health centers in Wolaita, Southern Ethiopia. A total of 647 pregnant women were included using multistage sampling procedure. Data were entered into Epi Info (a free statistical analysis software) and exported to SPSS. Bivariate relationship was explored through correlation coefficients. A multiple linear regression model was constructed to estimate the variability coefficient of the compliance rate due to selected factors. Of 647 pregnant women, only 18 (2.8%) pregnant women had received the supplement for 90 days or more. Overall, the compliance rate was 73.2% (95% CI, 70.72 to 75.79). Experiencing heartburn and vomiting significantly reduced the compliance rate. Unintended pregnancy and better education were negatively associated with compliance. By contrast, acceptability of IFA supplement, number of antenatal care (ANC) visits, and being ever married were positive predictors. On average, a pregnant woman did not take more than one-fourth of the daily IFA supplementation. During ANC visits, addressing the issues of side effects, unintended pregnancy, and acceptability of the supplement may improve compliance rate. Overall in Ethiopia, educated, older, and unmarried Ethiopian women need additional attention for successful compliance.

There is a need for further research to inform policy and practice on Couples HIV Testing and Counselling (CHTC) in Sub-Saharan Africa (SSA). The aim of this systematic review and meta-analysis was to estimate and characterise the uptake of CHTC in the SSA. A comprehensive search of published studies was carried out in six electronic databases. Of 30,273 citations, 14 studies with a total of 97,030 study participants were identified. The pooled CHTC uptake was 31.48% (95%CI: 23.55-40.00) with significant heterogeneity between studies (

Background The arteriovenous fistula (AVF) is central to haemodialysis treatment, but up to half of surgically created AVF fail to mature. Chronic kidney disease often leads to mineral metabolism disturbances that may interfere with AVF maturation through adverse vascular effects. This study tested associations between mineral metabolism markers and vein histology at AVF creation and unassisted and overall clinical AVF maturation. Methods Concentrations of fibroblast growth factor 23, parathyroid hormone, calcium, phosphate, and vitamin D metabolites: 1,25(OH)2D, 24,25(OH)2D, 25(OH)D, and bioavailable 25(OH)D were measured in pre-operative serum samples from 562 of 602 participants in the Haemodialysis Fistula Maturation Study, a multicentre, prospective cohort study of patients undergoing surgical creation of an autologous upper extremity AVF. Unassisted and overall AVF maturation were ascertained for 540 and 527 participants, respectively, within nine months of surgery or four weeks of dialysis initiation. Study personnel obtained vein segments adjacent to the portion of the vein used for anastomosis, which were processed, embedded, and stained for measurement of neointimal hyperplasia, calcification, and collagen deposition in the medial wall. Results Participants in this substudy were 71% male, 43% black, and had a mean age of 55 years. Failure to achieve AVF maturation without assistance occurred in 288 (53%) participants for whom this outcome was determined. In demographic and further adjusted models, mineral metabolism markers were not significantly associated with vein histology characteristics, unassisted AVF maturation failure, or overall maturation failure, other than a biologically unexplained association of higher 24,25(OH)2D with overall failure. This exception aside, associations were non-significant for continuous and categorical analyses and relevant subgroups. Conclusions Serum concentrations of measured mineral metabolites were not substantially associated with major histological characteristics of veins in patients undergoing AVF creation surgery, or with AVF maturation failure, suggesting that efforts to improve AVF maturation rates should increase attention to other processes such as vein mechanics, anatomy, and cellular metabolism among end stage renal disease patients.

The identification and validation of a small molecule’s targets is a major bottleneck in the discovery process for tuberculosis antibiotics. Activity-based protein profiling (ABPP) is an efficient tool for determining a small molecule’s targets within complex proteomes. However, how target inhibition relates to biological activity is often left unexplored. Here we studied the effects of 1,2,3-triazole ureas on Mycobacterium tuberculosis (Mtb). After screening ~200 compounds, we focused on two inhibitors active against both exponentially replicating and hypoxia-induced drug-tolerant Mtb that form part of a four-compound structure-activity series. The compound with negligible activity revealed potential false positive targets not addressed in other ABPP studies. Biochemistry, computational docking, and morphological analysis confirmed that active compounds preferentially inhibit serine hydrolases with cell wall and lipid metabolism functions and that disruption of the cell wall underlies biological activity. Our findings showed that ABPP identifies the targets most likely relevant to a compound’s antibacterial activity.

The role of unhealthy dietary pattern in the association between socio-economic factors and obesity is unclear. The aim was to examine the association between socio-economic disadvantage and obesity and to assess mediation effect of unhealthy dietary pattern defined using the Mediterranean diet criteria. The data source was the Australian National Nutrition and Physical Activity Survey. The study sample included 7744 participants aged 18 years and over, 28% of whom had obesity. We used the Australian Socio-Economic Indexes for Areas (SEIFA) classification system for categorizing socio-economic disadvantage, calculated the Mediterranean Diet Score (MDS) using standard criteria, and used measured body mass index to define obesity. We conducted a mediation analysis using log–binomial models to generate the prevalence ratio for obesity and the proportion mediated by the MDS. The most disadvantaged group was associated with higher level of obesity after controlling for covariates (1.40, 95% CI 1.25, 1.56) compared to the least disadvantaged group, and in a dose–response way for each decreasing SEIFA quintile. The relationship between socio-economic disadvantage and obesity was mediated by the MDS (4.0%, 95% CI 1.9, 8.0). Public health interventions should promote healthy dietary patterns, such as the Mediterranean diet, to reduce obesity, especially in communities with high socio-economic disadvantage.

International audience; Mycobacteria share with other actinomycetes the ability to produce large quantities of triacylglycerol (tAG), which accumulate as intracytoplasmic lipid inclusions (ILI) also known as lipid droplets (LD). Mycobacterium tuberculosis (M. tb), the etiologic agent of tuberculosis, acquires fatty acids from the human host which are utilized to synthesize tAG, subsequently stored in the form of ILI to meet the carbon and nutrient requirements of the bacterium during long periods of persistence. However, environmental factors governing mycobacterial ILI formation and degradation remain poorly understood. Herein, we demonstrated that in the absence of host cells, carbon excess and nitrogen starvation promote tAG accumulation in the form of ILI in M. smegmatis and M. abscessus, used as surrogate species of M. tb. Based on these findings, we developed a simple and reversible in vitro model to regulate ILI biosynthesis and hydrolysis in mycobacteria. We also showed that tAG formation is tgs1 dependent and that lipolytic enzymes mediate TAG breakdown. Moreover, we confirmed that the nitrogen-deprived and ILI-rich phenotype was associated with an increased tolerance towards several drugs used for treating mycobacterial infections. Importantly, we showed that the presence of ILI substantially enhanced the bacterial burden and granuloma abundance in zebrafish embryos infected with lipid-rich M. abscessus as compared to embryos infected with lipid-poor M. abscessus, suggesting that ILI are actively contributing to mycobacterial virulence and pathogenesis. Upon infection with Mycobacterium tuberculosis (M. tb), the causative agent of TB, less than 5% of infected people will progress towards active infection, whereas 95% remain classified as latently infected without any symptoms or signs of illness 1. In these asymptomatic individuals, bacteria persist within granulomatous lesions in a non-replicating or "dormant" state, from which they may reactivate to induce active TB. It is hypothesized that these persistent bacterial sub-populations are characterized by both low metabolic activity and the presence of large lipid droplets (LD), referred to as intracytoplasmic lipid inclusions (ILI) that are filled with triacylglycerol (TAG) 2,3. Interestingly, TAG synthesis is a conserved feature of several bacterial species belonging to the Actinobacteria phylum, consisting largely of soil dwelling bacteria and including the Mycobacterium genus 4-6. The accumulated TAG constitute a major source of carbon and energy, sustaining survival of intra-and extracellular mycobacteria, and is also directly linked to division arrest, loss of acid-fastness and to increased drug tolerance 7-11. In recent years, a large number of in vitro and ex vivo models have been developed to mimic the ILI-inducing environment encountered by mycobacteria within their hosts 12. It has been demonstrated that within differentiated foamy macrophages (FM), the TAG content of lipid bodies (LB) can be hydrolysed and processed by intraphagosomal mycobacteria, thus leading to the formation of ILI 2,7,8,13. Moreover, several studies have reported that ILI can also be synthesized by extracellular bacteria during stressful conditions and may be considered as a metabolic strategy employed by prokaryotic cells to survive under harsh environments 4,5,14,15. While mycobacterial ILI formation has been observed in slow-and fast-growing mycobacteria such as species from the M. tb complex 9,16-21 , M. leprae 22

The lack of access to a balanced diet, rich in vitamins and minerals, can predispose people to inflammatory diseases such as obesity, diabetes mellitus, and periodontitis. We aimed to evaluate the relationship between micronutrient intake, sociodemographic behavioral characteristics, and periodontal health in adults assisted by a public health care system. Participants (n = 450) answered a food frequency questionnaire and were submitted to anthropometric and oral clinical examinations. Principal component analysis was used to summarize the number of components emerging from 17-micronutrient intake. Subsequently, cluster analysis was employed. The prevalence of at least one periodontal pocket ≥ 4 mm was 67.4%. Three clusters were identified according to periodontal status. Cluster 1 “poor periodontal status” was characterized by older individuals (n = 202, 85% females) with poor periodontal status, lower education level, mainly smokers with non-transmissible chronic diseases (NTCD), with lower energy, omega-3, fiber, Zn, K, Cu, and vitamin C intake. Cluster 3 “healthy periodontal status” included younger individuals (n = 54) with the healthiest periodontal status, a higher education level, without NTCD, and with higher energy, omega-3, fiber, Zn, calcium, retinol, and riboflavin intake. Cluster 2 was labeled as “intermediate periodontal status”. Micronutrient ingestion was associated with periodontal status and may be considered in health promotion actions for low-income populations.

There has been a dramatic rise of interest in sound symbolism, systematic associations between sounds and meanings. Despite this, one aspect that is still markedly under-explored is its cumulative nature, i.e., when there are two or more sounds with the same symbolic meaning, whether these effects add up or not. These questions are important to address, since they bear on the general question of how speakers take into account multiple sources of evidence when they make linguistic decisions. Inspired by an accumulating body of research on cumulativity in other linguistic patterns, two experiments on sound symbolism using Pokemon names were conducted with native speakers of English. The experiments tested two types of cumulativity: counting cumulativity, which holds if the effects of multiple instances of the same factor add up, and ganging-up cumulativity, which holds when the effects of different factors add up. The experiments addressed whether these patterns of cumulativity hold in sound symbolism, and, more importantly, if so, how. We found that (1) three factors can show ganging-up cumulativity, (2) counting cumulativity and ganging-up cumulativity can coexist in a single system, (3) ganging-up cumulativity patterns can plausibly be considered to be linear, and (4) counting cumulativity effects can be sub-linear.

In the enteric pathogen Salmonella enterica serovar Typhimurium, invasion and motility are coordinated by the master regulator HilD, which induces expression of the type III secretion system 1 (T3SS1) and motility genes. Methyl-accepting chemotaxis proteins (MCPs) detect specific ligands and control the direction of the flagellar motor, promoting tumbling and changes in direction (if a repellent is detected) or smooth swimming (in the presence of an attractant). Here, we show that HilD induces smooth swimming by upregulating an uncharacterized MCP (McpC), and this is important for invasion of epithelial cells. Remarkably, in vitro assays show that McpC can suppress tumbling and increase smooth swimming in the absence of exogenous ligands. Expression of mcpC is repressed by the universal regulator H-NS, which can be displaced by HilD. Our results highlight the importance of smooth swimming for Salmonella Typhimurium invasiveness and indicate that McpC can act via a ligand-independent mechanism when incorporated into the chemotactic receptor array., Protein HilD of Salmonella Typhimurium coordinates motility and host cell invasion by upregulating flagellar genes and a secretion system. Here, Cooper et al. show that HilD also modulates swimming behaviour by upregulating a subunit of the chemotactic receptor array, and this is important for invasion of epithelial cells.

International audience; Tuberculosis (TB) caused by Mycobacterium tuberculosis (M. tb) still remains the deadliest infectious disease worldwide with 1.5 million deaths in 2018, of which about 15% are attributed to resistant strains. Another significant example is Mycobacterium abscessus (M. abscessus), a nontuberculous mycobacteria (NTM) responsible for cutaneous and pulmonary infections, representing up to 95% of NTM infections in cystic fibrosis (CF) patients. M. abscessus is a new clinically relevant pathogen and is considered one of the most drugresistant mycobacteria for which standardized chemotherapeutic regimens are still lacking. Together the emergence of M. tb and M. abscessus multi-drug resistant strains with ineffective and expensive therapeutics, have paved the way to the development of new classes of anti-mycobacterial agents offering additional therapeutic options. In this context, specific inhibitors of mycobacterial lipolytic enzymes represent novel and promising antibacterial molecules to address this challenging issue. The results highlighted here include a complete overview of the antibacterial activities, either in broth medium or inside infected macrophages, of two families of promising and potent anti-mycobacterial multi-target agents, i.e. oxadiazolone-core compounds (OX) and Cyclophostin & Cyclipostins analogs (CyC); the identification and biochemical validation of their effective targets (e.g., the antigen 85 complex and TesA playing key roles in mycolic acid metabolism) together with their respective crystal structures. To our knowledge, these are the first families of compounds able to target and impair replicating as well as intracellular bacteria. We are still impelled in deciphering their mode of action and finding new potential therapeutic targets against mycobacterial-related diseases.

Background Nutritional, epidemiological and demographic transitions have been associated with the emergence of the double burden of malnutrition globally. In Ethiopia, there has been no nationally representative investigation of trends and determinants of both underweight and overweight/obesity among urban women. This study examined the trends and determinants of underweight and overweight/obesity in urban Ethiopian women from 2000 to 2016. Methods Trends in the prevalence of underweight and overweight/obesity were investigated based on a series of the Ethiopia Demographic and Health Survey (EDHS) data for the years 2000 (n = 2559), 2005 (n = 1112), 2011 (n = 3569), and 2016 (n = 3106). Multivariable multinomial logistic regression was used to investigate the association between socioeconomic, demographic, behavioural, and community-level factors with underweight and overweight/obesity. Results The prevalence of underweight in urban Ethiopian women reduced significantly from 23.2% (95% confidence interval [CI]: 20.3, 26.3%) in 2000 to 14.8% (95% CI: 13.1, 16.7%) in 2016, while overweight/obesity increased significantly from 10.9% (95% CI: 9.1, 13.0%) in 2000 to 21.4% (95% CI: 18.2, 25.1%) in 2016. Urban women from rich households and those who had never married were less likely to be underweight. Urban women who were from wealthy households and those who attained at least secondary education were more likely to be overweight/obese. Women who were informally employed and listened to the radio were less likely to be overweight/obese compared to those who were unemployed and did not listen to the radio, respectively. Conclusion The prevalence of overweight/obesity increased from 2000 to 2016, with a concurrent reduction in the prevalence of underweight. Interventions aiming to reduce overweight and obesity should target urban women with higher education, those who resided in wealthier households and those who watched the television.

Summary Aim To propose an equation to estimate height and evaluate it's performance in the composition of adiposity indicators in community-dwelling older adults in Brazil. Methods It is a cross-sectional study with 675 community-dwelling older adults (≥60 anos). Interviews and anthropometric measurements were taken at subjects' homes. Body mass index (BMI), body adiposity index (BAI), waist height ratio (WHR), and conicity index (CI) were calculated. The height estimation equation was obtained by multiple linear regression. Concordance between height and the indicators measured and estimated was evaluated by the intraclass correlation coefficient (ICC) and Cohen's Kappa and Weighted Kappa indexes. Concordance was also evaluated by the Bland and Altman graphical approach. Results Equations of height estimation composed of knee height, sex, and schooling were proposed and stratified by age group (60–74 years and ≥75 years). In both age groups, almost perfect agreement (ICC ≥ 0.915 and Kappa ≥0.81) was found between height and adiposity indicators estimated and measured. Conclusion The equation proposed is suitable to estimate height of the older adults, and can be a valuable tool for the evaluation of the nutritional status of Brazilian older adults in the community.

Resumo O objetivo deste estudo foi caracterizar a disponibilidade domiciliar de alimentos a partir da classificação dos alimentos adotada no novo guia alimentar brasileiro e analisar sua relação com a (in)segurança alimentar. Trata-se de um estudo de base populacional, transversal, realizado em 95 domicílios do Estado do Tocantins. Avaliou-se a (in)segurança alimentar, por meio da Escala Brasileira de Insegurança Alimentar. A disponibilidade domiciliar de alimentos nos últimos 30 dias foi registrada e, posteriormente, classificou-se os alimentos em in natura e/ou minimamente processados, processados e ultraprocessados, conforme o novo guia alimentar brasileiro. A prevalência de insegurança alimentar foi de 55,79%. Verificou-se que os alimentos dos grupos in natura e ultraprocessados foram os que mais contribuíram para a disponibilidade domiciliar de alimentos. Verificou-se relação positiva e significante do grau de segurança alimentar com a disponibilidade dos alimentos: leite, gordura animal, enlatados e pão de queijo. A prevalência de insegurança alimentar foi elevada nessa população. Nos domicílios com maior grau de segurança alimentar, a disponibilidade de leite, gordura animal, enlatados e pão de queijo foi significantemente maior. Abstract The scope of this research was to characterize the household availability of food based on the classification adopted in the new Brazilian food guide and to analyze its relationship with food (in)security. It involved a population-based, cross-sectional study conducted in 95 households in the State of Tocantins. Food (in)security was evaluated by means of the Brazilian Food Insecurity Scale. The household availability of food in the last 30 days was recorded and, subsequently, food was classified as in natura and/or minimally processed, processed and ultra-processed according to the new Brazilian food guide. The prevalence of food insecurity was 55.79%. It was found that the foods of the in natura and ultra-processed groups contributed the most to the household availability of food. There was a positive and significant relationship between the food security and food availability rates: milk, animal fat, canned food and cheese bread. The prevalence of food insecurity was high in this population group. In households with a higher level of food security, the availability of milk, animal fat, canned goods and cheese bread was significantly higher.

Background Dysregulation of arousal is symptomatic of numerous psychiatric disorders. Previous research has shown that the activity of dopamine (DA) neurons in the ventral periaqueductal gray (vPAG) tracks with arousal state, and lesions of vPAGDA cells increase sleep. However, the circuitry controlling these wake-promoting DA neurons is unknown. Methods This study combined designer receptors exclusively activated by designer drugs (DREADDs), behavioral pharmacology, electrophysiology, and immunoelectron microscopy in male and female mice to elucidate mechanisms in the vPAG that promote arousal. Results Activation of locus coeruleus projections to the vPAG or vPAGDA neurons induced by DREADDs promoted arousal. Similarly, agonist stimulation of vPAG alpha1-adrenergic receptors (α1ARs) increased latency to fall asleep, whereas α1AR blockade had the opposite effect. α1AR stimulation drove vPAGDA activity in a glutamate-dependent, action potential–independent manner. Compared with other dopaminergic brain regions, α1ARs were enriched on astrocytes in the vPAG, and mimicking α1AR transmission specifically in vPAG astrocytes via Gq-DREADDS was sufficient to increase arousal. In general, the wake-promoting effects observed were not accompanied by hyperactivity. Conclusions These experiments revealed that vPAG α1ARs increase arousal, promote glutamatergic input onto vPAGDA neurons, and are abundantly expressed on astrocytes. Activation of locus coeruleus inputs, vPAG astrocytes, or vPAGDA neurons increase sleep latency but do not produce hyperactivity. Together, these results support an arousal circuit whereby noradrenergic transmission at astrocytic α1ARs activates wake-promoting vPAGDA neurons via glutamate transmission.

Summary Objective To evaluate the scientific evidences on the prevalence, diagnostic criteria, and factors related to sarcopenic obesity (SO) in Brazilian older adults. Methods this systematic review was based on searches of the databases PubMed, Science Direct, Excerpta Medica Database (Embase), Web of Science, Scientific Electronic Library Online (SciELO), and Scopus. The systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). The inclusion criteria were: original articles of observational design that evaluated the presence of sarcopenic obesity in Brazilian older adults (≥60 years). Therefore, studies that investigated only obesity or sarcopenia, animal studies, review studies, congress publications, theses, dissertations, book chapters, editorials, letters to the editor, and newspaper articles were not included. Results The initial screening identified 549 records. After removing the duplicates, assessing the titles and abstracts, and the complete analysis of the papers, 12 studies were included in the review. The sample size of the studies ranged from 56 to 1373 subjects, most of them selected by convenience sampling (n = 11) and exclusively with women (n = 9). The prevalence of SO varied from 4.4% to 48.4%. No consensus was found on the diagnostic criteria for SO. The main associations identified were between SO and decrease in muscle strength, aerobic fitness, gait speed, and increase in frequency of frailty and cardiometabolic and inflammatory alterations. Conclusions Epidemiological studies conducted so far in Brazil are heterogeneous, which limits the possibility of comparison between prevalence and distribution of sarcopenic obesity among older adults. Further studies with representative samples of the population are required to understand the magnitude of SO in this group.

Objectives: To evaluate the prevalence and associated factors with general and central adiposity in older adults in Palmas (TO).Methods: Cross-sectional study with older adults (≥60 years) of both ...

Neonates of all species, including foals, are highly susceptible to infection, and neutrophils play a crucial role in innate immunity to infection. Evidence exists that neutrophils of neonatal foals are functionally deficient during the first weeks of life, including expression of cytokine genes such as IFNG. We hypothesized that postnatal epigenetic changes were likely to regulate the observed age-related changes in foal neutrophils. Using ChIP-Seq, we identified significant differences in trimethylated histone H3 lysine 4, an epigenetic modification associated with active promoters and enhancers, in neutrophils in foals at 30 days of age relative to 1 day of age. These chromatin changes were associated with genes implicated in immune responses and were consistent with age-related changes in neutrophil functional responses including ROS generation and IFN expression. Postnatal changes in epigenetic modifications suggest that environmentally-mediated cues help to promote maturation of neutrophil functional responses. Elucidating the environmental triggers and their signaling pathways could provide a means for improving innate immune responses of neonates to improve their ability to combat infectious diseases.

Aim The aim of this study was to investigate whether racial disparities in healthcare exist within a New Zealand pediatric surgical outreach service in a high indigenous Māori population. Methodology This retrospective study assessed all pediatric surgical procedures performed within a secondary center in New Zealand between May 2014 and May 2016. The days between the date of surgery booking on the waiting list and actual date of surgery were calculated and compared to their corresponding elective surgery waiting target times set by the New Zealand Ministry of Health (MoH). Patient demographic data were collated to then identify any discrepancy between ethnic groups. Results A total of 203 pediatric surgical procedures were performed on 193 patients. Of the 194 (95%) procedures that were included in the study, 30 breached a maximum waiting time. Though this represented a small proportion of patients, Māori were significantly over represented in this group. Conclusion The majority of our patients with delayed elective surgery were of Māori ethnicity, for reasons not entirely accounted for by common socioeconomic determinants of health. Our study suggests the possibility of innate systemic causes not detected by standard models of health. However, further research with larger cohorts is needed. Level of Evidence III

This article presents a case of cystinosis in a young man. Diagnosis of the disease and the problem of transition to adult care are described. Cystinosis is a rare lysosomal storage disease with first manifestation in early childhood presenting as renal Fanconi syndrome. Without treatment, the disease leads to severe health impairment. Due to the rarity of the disease, a correct diagnosis is often delayed. Without treatment, cystinosis often leads to end-stage renal failure, blindness, hypothyroidism, diabetes mellitus, and rickets. Cystine-depleting therapy with cysteamine significantly improves mortality and quality of life.

International audience; A set of 19 oxadiazolone (OX) derivatives have been investigated for their antimycobacterial activity against two pathogenic slow-growing mycobacteria, Mycobacterium marinum and Mycobacterium bovis BCG, and the avirulent Mycobacterium tuberculosis (M. tb) mc26230. The encouraging minimal inhibitory concentrations (MIC) values obtained prompted us to test them against virulent M. tb H37Rv growth either in broth medium or inside macrophages. The OX compounds displayed a diversity of action and were found to act either on extracellular M.tb growth only with moderated MIC50, or both intracellularly on infected macrophages as well as extracellularly on bacterial growth. Of interest, all OX derivatives exhibited very low toxicity towards host macrophages. Among the six potential OXs identified, HPOX, a selective inhibitor of extracellular M. tb growth, was selected and further used in a competitive labelling/enrichment assay against the activity-based probe Desthiobiotin-FP, in order to identify its putative target(s). This approach, combined with mass spectrometry, identified 18 potential candidates, all being serine or cysteine enzymes involved in M. tb lipid metabolism and/or in cell wall biosynthesis. Among them, Ag85A, CaeA, TesA, KasA and MetA have been reported as essential for in vitro growth of M. tb and/or its survival and persistence inside macrophages. Overall, our findings support the assumption that OX derivatives may represent a novel class of multi-target inhibitors leading to the arrest of M. tb growth through a cumulative inhibition of a large number of Ser- and Cys-containing enzymes involved in various important physiological processes.

Background Fabry patients on reduced dose of agalsidase-beta or after switch to agalsidase-alfa show a decline in estimated glomerular filtration rate (eGFR) and an increase of the Mainz Severity Score Index. Methods In this prospective observational study, we assessed end-organ damage and clinical symptoms in 112 patients who had received agalsidase-beta (1.0 mg/kg) for >1 year, who were (i) non-randomly assigned to continue this treatment regime (regular-dose group, n = 37); (ii) received a reduced dose of agalsidase-beta and subsequent switch to agalsidase-alfa (0.2 mg/kg) or a direct switch to 0.2 mg/kg agalsidase-alfa (switch group, n = 38); or (iii) were re-switched to agalsidase-beta after receiving agalsidase-alfa for at least 12 months (re-switch group, n = 37) with a median follow-up of 53 (38-57) months. Results eGFR of patients in the regular-dose group remained stable. Patients in the switch group showed an annual eGFR loss of - 4.6 ± 9.1 mL/min/1.73 m2 (P

Background and purpose Over the past decade, implementation of the peer review process for the development of the advanced practice nurse (APN) has been emphasized. However, little exists in the literature regarding APN peer review. The peer review process is intended to help demonstrate competency of care, enhance quality improvement measures, and foster the professional growth of the APN. Methods APNs serving on a professional governance council within a university teaching hospital developed a model of peer review for APNs. Nine months after the tool was implemented, an anonymous follow-up survey was conducted. A follow-up request was sent 4 weeks later to increase the number of respondents. Likert scales were used to elicit subjective data regarding the process. Conclusions Of 81 APNs who participated in the survey, more than half (52%) felt that the process would directly improve their professional practice. Implications for practice Survey results show that the peer review process affected APN professional practice positively. Additional research might include pathways for remediation and education of staff, evaluation of alternate methods to improve application to clinical practice, and collection of outcome data. The models presented provide a foundation for future refinement to accommodate different APN practice settings.

Mutations in the ROMK1 potassium channel gene (KCNJ1) cause antenatal/neonatal Bartter syndrome type II (aBS II), a renal disorder that begins in utero, accounting for the polyhydramnios and premature delivery that is typical in affected infants, who develop massive renal salt wasting, hypokalaemic metabolic alkalosis, secondary hyperreninaemic hyperaldosteronism, hypercalciuria and nephrocalcinosis. This BS type is believed to represent a disorder of the infancy, but not in adulthood. We herein describe a female patient with a remarkably late-onset and mild clinical manifestation of BS II with compound heterozygous KCNJ1 missense mutations, consisting of a novel c.197T > A (p.I66N) and a previously reported c.875G > A (p.R292Q) KCNJ1 mutation. We implemented and evaluated the performance of two different bioinformatics-based approaches of targeted massively parallel sequencing [next generation sequencing (NGS)] in defining the molecular diagnosis. Our results demonstrate that aBS II may be suspected in patients with a late-onset phenotype. Our experimental approach of NGS-based mutation screening combined with Sanger sequencing proved to be a reliable molecular approach for defining the clinical diagnosis in our patient, and results in important differential diagnostic and therapeutic implications for patients with BS. Our results could have a significant impact on the diagnosis and methodological approaches of genetic testing in other patients with clinical unclassified phenotypes of nephrocalcinosis and congenital renal electrolyte abnormalities.

espanolIntroduccion: el comportamiento sedentario (CS) se ha asociado de forma independiente con resultados perjudiciales para la salud en diferentes regiones del mundo. El objetivo de esta revision sistematica fue examinar si el CS especifico de cada dominio se asocia o no a enfermedades cardiometabolicas (ECM) y sus biomarcadores relacionados en adultos sudamericanos. Metodos: se realizaron busquedas en nueve bases de datos electronicas para identificar todos los estudios que habian analizado la asociacion entre CS y ECM –por ejemplo, obesidad, diabetes, hipertension, sindrome metabolico y agrupacion de enfermedades cronicas (AEC)– y sus biomarcadores relacionados en adultos sudamericanos. Dos revisores independientes realizaron evaluaciones de los resumenes/textos completos, el resumen de los datos y evaluaciones de calidad. El protocolo de revision esta registrado en la base de datos PROSPERO (CRD42018099319). Resultados: de los 1262 articulos identificados en la busqueda, 262 se revisaron en su totalidad y 20 se utilizaron en el analisis de acuerdo con los criterios de inclusion. El gran CS (principalmente, tiempo sentado y de television) se asocio a una mayor probabilidad de obesidad (n = 8), diabetes (n = 6) y AEC (n = 3), asi como a valores altos de IMC (n = 8), WC (n = 7), % BF (n = 4), lipidos plasmaticos (n = 4) y glucemia (n = 5). Once de los 20 estudios fueron de alta calidad. Conclusion: la gran cantidad de tiempo invertido en el CS, principalmente el tiempo sentado y de television, se asocio positivamente con la aparicion de ECM y sus biomarcadores relacionados en adultos de America del Sur. EnglishIntroduction: sedentary behavior (SB) has been independently associated with detrimental health outcomes in different regions worldwide. The aim of this systematic review was to examine whether domain-specific SB is associated with cardiometabolic diseases (CMD) and related biomarkers in South American adults. Methods: nine electronic databases were searched to identify all studies that analyzed the association between SB and CMD–e.g. obesity, diabetes, hypertension, metabolic syndrome (MetS) and clustering of chronic diseases (CCD)–and related biomarkers in South American adults. Two independent reviewers performed the necessary abstract/full-text screening, data abstraction, and quality assessments. The review protocol was registered in the PROSPERO database (CRD42018099319). Results: from the 1,262 articles identified in the search 262 were reviewed in full and 20 were used in the analysis in accordance to the inclusion criteria. High SB (mainly sitting and TV time) was associated with an increased likelihood of obesity (n = 8), diabetes (n = 6), and CCD (n = 3), as well as high values of BMI (n = 8), WC (n = 7), % BF (n = 4), plasma lipids (n = 4), and glycemia (n = 5). Eleven out of 20 studies were of higher quality. Conclusion: long time spent in SB, mainly sitting and TV time, was positively associated with the occurrence of CMD and related biomarkers in South American adults.

Purpose Fabry disease frequently includes pain as an early disease feature, which was characterized as a dysfunctional processing of somatosensory information in various studies. The pathomechanism involves the mutation in the x-chromosomal GLA-gene and a consequent reduction of the α-galactosidase. This results in an insufficient reduction of globotriaosylceramide (GL3). Interestingly, an accumulation of GL3 was shown in both vascular endothelial cells and nerve tissue. This implicates that both an endothelial and nerve-dependent dysfunction may be considered as prominent mechanisms in pain pathogeneses. Patients and methods The exploration of endothelial and C-fiber-dependent microcirculatory changes was conducted in a healthy cohort (n = 22) and in patients with polyneuropathy (n = 21) and Fabry disease (n = 15). Microcirculatory measurements were conducted using a laser speckle contrast analysis (LASCA) in combination with a thermoprobe controlling system, which applied a constant heat stimulus (42°C). Additionally, nerve fiber function was assessed via Quantitative Sensory Testing and heart rate variability (HRV). Results The results indicated a characteristic perfusion profile in the control group as well as both patient groups. Fabry patients had the smallest increase of endothelial-dependent perfusion as compared to the others [% increase as compared to Fabry: control + 129% (p = 0.002), PNP + 126% (p = 0.019)]. The sensory testing indicated a dysfunctional processing of A-delta fibers in Fabry disease as compared to healthy controls [cold detection threshold (CDT): p = 0.004, mechanical pain threshold (MPT): p = 0.007] and PNP patients (MPT: p = 0.001). Conclusion Our results point to both an endothelial and a nerve-dependent dysfunction in Fabry disease. Therefore, not only direct changes in nerve fiber tissue may contribute to an altered sensory processing. Indeed, evidence of a perfusion change in vasa nervorum could also contribute to the dysfunctional processing of sensory information, which likely occurs under physical stress.

Distal limb wounds are common injuries sustained by horses and their healing is fraught with complications due to equine anatomy, prevalence of infection, and challenges associated with wound management. Gallium is a semi-metallic element that has been shown to possess antimicrobial properties and aid in wound healing in various preclinical models. The effects of Gallium have not been studied in equine wound healing. Therefore, the objective of this study was to compare healing rates between gallium-treated and untreated wounds of equine distal limbs and to demonstrate the antimicrobial effects of gallium on wounds inoculated with S. aureus. Using an established model of equine wound healing we demonstrated beneficial effects of 0.5% topical gallium maltolate on equine wound healing. Specifically we documented reduced healing times, reduced bioburden, and reduced formation of exuberant granulation tissue in wounds treated with gallium maltolate as compared with untreated wounds. Gallium appeared to exert its beneficial effects via its well-described antimicrobial actions as well as by altering the expression of specific genes known to be involved in wound healing of horses and other animals. Specifically, gallium maltolate appeared to increase expression of transforming growth factor-β in both infected and un-infected wounds. Further work is needed to document the effects of gallium on naturally occurring equine wounds and to compare the effects of gallium with other wound treatment options. These data, however, suggest that gallium may be an attractive and novel means of improving equine distal limb wound healing.

The randomized, controlled STOP-IgAN trial in patients with IgA nephropathy (IgAN) and substantial proteinuria showed no benefit of immunosuppression added on top of supportive care on renal function over three years. As a follow-up we evaluated renal outcomes in patients over a follow-up of up to ten years in terms of serum creatinine, proteinuria, end-stage kidney disease (ESKD), and death. The adapted primary endpoint was the time to first occurrence of a composite of death, ESKD, or a decline of over 40% in the estimated glomerular filtration rate (eGFR) compared to baseline at randomization into STOP-IgAN. Data were analyzed by Cox-regression models. Follow-up data were available for 149 participants, representing 92% of the patients originally randomized. Median follow-up was 7.4 years (inter quartile range 5.7 to 8.3 years). The primary endpoint was reached in 36 of 72 patients randomized to supportive care and 35 of 77 patients randomized to additional immunosuppression (hazard ratio 1.20; 95% confidence interval 0.75 to 1.92). ESKD occurred in 17 of the patients with supportive care and in 20 of the patients with additional immunosuppression. Additionally, the rates of eGFR loss over 40% and annual eGFR loss did not differ between groups. Two patients died with supportive care and three with additional immunosuppression. Thus, within the limitations of a retrospective study, over a follow-up of up to ten years, and using an adapted primary endpoint, we failed to detect differences in key clinical outcomes in IgAN patients randomized to receive added immunosuppression on top of supportive care versus supportive care alone.

Objective To assess the relationship between food availability, food insecurity and socioeconomic and demographic characteristics of households in the urban area of the state of Tocantins. Methods Population-based, cross-sectional study conducted in 594 households in the urban area of 22 municipalities in the state of Tocantins. A survey was carried out in the households, to collect socioeconomic and data, and assess food insecurity using the Brazilian Food Insecurity Scale. Further a food availability questionnaire was applied by the interviewer with the head of the family, who reported on the food and drinks available at home in the last 30 days. The description of the food available in the households resulted in a total of 142 food items that were grouped according to the NOVA classification of foods. demographic Results It was found that 63.3% of households were in a situation of food insecurity. The median caloric availability found was 2,771.4kcal/per capita/day, with the largest caloric contribution coming from fresh and minimally processed foods, regardless of the degree of food insecurity. Food availability was affected by socioeconomic vulnerability and the situation of food insecurity in the families. RESUMO Objetivo Avaliar a relação entre a disponibilidade alimentar, a situação de insegurança alimentar e características socioeconômicas e demográficas de domicílios da zona urbana do Estado do Tocantins. Métodos Estudo de base populacional, do tipo transversal, realizado em 594 domicílios da área urbana de 22 municípios do Estado do Tocantins. A coleta de dados foi realizada nos domicílios, com levantamento de dados socioeconômicos e demográficos, avaliação da insegurança alimentar por meio da Escala Brasileira de Insegurança Alimentar e avaliação da disponibilidade dos alimentos a partir de um questionário de disponibilidade alimentar aplicado pelo entrevistador ao chefe da família, que informou sobre os alimentos e bebidas disponíveis no domicílio nos últimos 30 dias. A descrição dos alimentos disponíveis nos domicílios resultou em um total de 142 itens alimentares que foram agrupados de acordo com a classificação NOVA de alimentos. Resultados Constatou-se que 63,3% dos domicílios encontravam-se em situação de insegurança alimentar. A disponibilidade calórica mediana encontrada foi de 2.771,4kcal/per capita/dia, sendo a maior contribuição calórica advinda de alimentos in natura e minimamente processados, independente do grau de insegurança alimentar. Conclusão A disponibilidade alimentar foi afetada pela vulnerabilidade socioeconômica e pela situação de insegurança alimentar das famílias.

Atypical responses to sensory stimuli are considered as a core aspect and early life marker of autism spectrum disorders (ASD). Although recent findings performed in mouse ASD genetic models report sensory deficits, these were explored exclusively during juvenile or adult period. Whether sensory dysfunctions might be present at the early life stage and rescued by therapeutic strategy are fairly uninvestigated. Here we identified that neonatal mice lacking the autism-associated gene Magel2 fail to react to cool sensory stimuli, while autonomic thermoregulatory function is active. This neonatal deficit was mimicked in control neonates by chemogenetic inactivation of oxytocin neurons. Importantly, intranasal administration of oxytocin was able to rescue the phenotype and brain Erk signaling impairment in mutants. This preclinical study establishes for the first-time early life impairments in thermosensory integration and shows the therapeutic potential benefits of intranasal oxytocin treatment on neonatal atypical sensory reactivity.

Fabry's disease (FD) is an X-linked lysosomal storage disorder caused by the deficient activity of the lysosomal enzyme alpha-galactosidase A (alpha-Gal A) leading to intracellular accumulation of globotriaosylceramide (Gb3). Patients with amenable mutations can be treated with migalastat, a recently approved oral pharmacologic chaperone to increase endogenous alpha-Gal A activity. We assessed safety along with cardiovascular, renal, and patient-reported outcomes and disease biomarkers in a prospective observational multicenter study after 12 months of migalastat treatment under real-world conditions. Fifty-nine (28 females) patients (34 (57.6%) pretreated with enzyme replacement therapy) with amenable mutations were recruited. Migalastat was generally safe and well tolerated. Females and males presented with a reduction of left ventricular mass index (primary end point) (-7.2 and -13.7 g/m(2), P = 0.0050 and P = 0.0061). FD-specific manifestations and symptoms remained stable (all P > 0.05). Both sexes presented with a reduction of estimated glomerular filtration rate (secondary end point) (-6.9 and -5.0 mL/minute/1.73 m(2); P = 0.0020 and P = 0.0004, respectively), which was most prominent in patients with low blood pressure (P = 0.0271). alpha-Gal A activity increased in male patients by 15% from 29% to 44% of the normal wild-type activity (P = 0.0106) and plasma lyso-Gb3 levels were stable in females and males (P = 0.3490 and P = 0.2009). Reevaluation of mutations with poor biochemical response revealed no marked activity increase in a zero activity background. We conclude that therapy with migalastat was generally safe and resulted in an amelioration of left ventricular mass. In terms of impaired renal function, blood pressure control seems to be an unattended important goal.

BackgroundUnintended pregnancy rates are substantially higher in developing regions, have significant health consequences, and disproportionately affect subgroups with socio-economic disadvantage. We aimed to examine whether there is an association between husbands' education status and their wives unintended pregnancy in southern Ethiopia.MethodsThe data source for this study was from a cross-sectional study on iron-folate supplementation and compliance in Wolaita, South Ethiopia. Data were collected from October to November 2015 in 627 married pregnant women regarding their husbands' education status, socio-demographic characteristics, and if they wanted to become pregnant at the time of survey using an interviewer administered questionnaire. Logistic regression was used to estimate Odds Ratios (ORs) with associated z-tests and 95% Confidence Intervals (95% CI) for variables associated with unintended pregnancy.ResultsThe proportion of unintended pregnancy in this sample was 20.6%. Husbands' education status, age, residence, and using family planning methods were associated with unintended pregnancy (all P-values < 0.05). Multivariable models consistently showed that being married to a husband with at least some college or university education was associated with a decreased OR for unintended pregnancy after controlling for age and use of family planning at conception period (OR 0.36 [95%CI: 0.17, 0.82]) and age and rural residence (OR 0.40 [95%CI: 0.18, 0.90]).ConclusionUnintended pregnancy among Ethiopian woman was consistently associated with being married to least educated husbands in southern Ethiopia. Increasing age and living in a rural vs urban area were also independently associated with unintended pregnancy. Strategies for addressing family planning needs of women with poorly educated husbands should be the subject of future research.

Mycobacterium tuberculosis (Mtb), the pathogen causing human tuberculosis, has evolved multiple strategies to successfully prevent clearance by immune cells and to establish dissemination and long-term survival in the host. The modulation of host immunity to maximize pathogen elimination while minimizing inflammation-mediated tissue damage may provide another tool to fight drug-resistant Mtb strains. Metabolic reprogramming of immune cell populations can dramatically influence the outcome of immune responses and modulate antimicrobial properties of infected host cells, nicely demonstrating that metabolites are tightly linked to immune cell effector functions. One important endogenous metabolite of the Krebs cycle is itaconate, which has potent bactericidal activity by inhibiting isocitrate lyase and the glyoxylate shunt within prokaryotes including mycobacteria. Recent findings show that itaconate and the catalytic enzyme responsible for its generation in mammalian cells, i.e. IRG1 (immune-responsive gene 1), also modify inflammatory signaling of infected cells enhancing host defense pathways. Here, we demonstrate that IRG1 is recruited to Mtb-containing phagosomes and that it influences the host response controlling Mtb infection. While IRG1 deficiency does not affect uptake of Mtb by macrophages and dendritic cells (DCs) in vitro, it increases the intracellular replication of Mtb. Concomitantly, in comparison to wild type cells, IRG1-deficient macrophages and DCs have increased levels of lipid droplets, a correlate of inflammation. These intracellular organelles store triacylglycerol and phospholipids that are hijacked by Mtb as reservoir of host nutrients. Exposure of IRG1-deficient mice to M. bovis BCG via the intranasal route induced neither lethality nor severe lung immunopathology, while IRG1-deficient mice were highly susceptible to Mtb infection resulting in animal death three weeks post-infection linked to exacerbated inflammation and high mycobacterial burden. The lungs of infected IRG1-deficient mice displayed large areas of necrotizing granulomatous inflammation and neutrophil infiltration, accompanied by reduced levels of B and T lymphocytes and increased levels of alveolar and interstitial macrophage populations, compared to their wild type counterparts. Therefore, our findings demonstrate that IRG1 is a major player in controlling the acute phase of Mtb infection with a specific effect on pathogenic mycobacteria.

Twelve new Cyclophostin and Cyclipostins analogues (CyC19-30) were synthesized, thus extending our series to 38 CyCs. Their antibacterial activities were evaluated against four pathogenic mycobacteria (Mycobacterium abscessus, Mycobacterium marinum, Mycobacterium bovis BCG, and Mycobacterium tuberculosis) and two Gram negative bacteria. The CyCs displayed very low toxicity toward host cells and were only active against mycobacteria. Importantly, several CyCs were active against extracellular M. abscessus (CyC17/CyC18β/CyC25/CyC26) or intramacrophage residing mycobacteria (CyC7(α,β)/CyC8(α,β)) with minimal inhibitory concentrations (MIC50) values comparable to or better than those of amikacin or imipenem, respectively. An activity-based protein profiling combined with mass spectrometry allowed identification of the potential target enzymes of CyC17/CyC26, mostly being involved in lipid metabolism and/or in cell wall biosynthesis. Overall, these results strengthen the selective activity of the CyCs against mycobacteria, including the most drug-resistant M. abscessus, through the cumulative inhibition of a large number of Ser- and Cys-enzymes participating in key physiological processes.

Phthiocerol dimycocerosates and phenolic glycolipids (PGL) are considered as major virulence elements of Mycobacterium tuberculosis, in particular because of their involvement in cell wall impermeability and drug resistance. The biosynthesis of these waxy lipids involves multiple enzymes, including thioesterase A (TesA). We observed that purified recombinant M. tuberculosis TesA is able to dimerize in the presence of palmitoyl-CoA and our 3D structure model of TesA with this acyl-CoA suggests hydrophobic interaction requirement for dimerization. Furthermore, we identified that methyl arachidonyl fluorophosphonate, which inhibits TesA by covalently modifying the catalytic serine, also displays a synergistic antimicrobial activity with vancomycin further warranting the development of TesA inhibitors as valuable antituberculous drug candidates., info:eu-repo/semantics/published

BACKGROUND: Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium-glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS: In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to 300 to 5000) and were treated with renin-angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of

International audience; An increasing prevalence of cases of drug-resistant tuberculosis requires the development of more efficacious chemotherapies. We previously reported the discovery of a new class of cyclipostins and cyclophostin (CyC) analogs exhibiting potent activity against Mycobacterium tuberculosis both in vitro and in infected macrophages. Competitive labeling/enrichment assays combined with MS have identified several serine or cysteine enzymes in lipid and cell wall metabolism as putative targets of these CyC compounds. These targets included members of the antigen 85 (Ag85) complex (i.e. Ag85A, Ag85B, and Ag85C), responsible for biosynthesis of trehalose dimycolate and mycolylation of arabinogalactan. Herein, we used biochemical and structural approaches to validate the Ag85 complex as a pharmacological target of the CyC analogs. We found that CyC7β, CyC8β, and CyC17 bind covalently to the catalytic Ser124 residue in Ag85C; inhibit mycolyltransferase activity (i.e. the transfer of a fatty acid molecule onto trehalose); and reduce triacylglycerol synthase activity, a property previously attributed to Ag85A. Supporting these results, an X-ray structure of Ag85C in complex with CyC8β disclosed that this inhibitor occupies Ag85C's substrate-binding pocket. Importantly, metabolic labeling of M. tuberculosis cultures revealed that the CyC compounds impair both trehalose dimycolate synthesis and mycolylation of arabinogalactan. Overall, our study provides compelling evidence that CyC analogs can inhibit the activity of the Ag85 complex in vitro and in mycobacteria, opening the door to a new strategy for inhibiting Ag85. The high-resolution crystal structure obtained will further guide the rational optimization of new CyC scaffolds with greater specificity and potency against M. tuberculosis.

International audience; Within tuberculous granulomas, a subpopulation of Mycobacterium tuberculosis resides inside foamy macrophages (FM) that contain abundant cytoplasmic lipid bodies (LB) filled with triacylglycerol (TAG). Upon fusion of LB with M. tuberculosis-containing phagosomes, TAG is hydrolyzed and reprocessed by the bacteria into their own lipids, which accumulate as intracytosolic lipid inclusions (ILI). This phenomenon is driven by many mycobacterial lipases, among which LipY participates in the hydrolysis of host and bacterial TAG. However, the functional contribution of LipY's PE domain to TAG hydrolysis remains unclear. Here, enzymatic studies were performed to compare the lipolytic activities of recombinant LipY and its truncated variant lacking the N-terminal PE domain, LipY(ΔPE). Complementarily, an FM model was used where bone marrow-derived mouse macrophages were infected with M. bovis BCG strains either overexpressing LipY or LipY(ΔPE) or carrying a lipY deletion mutation prior to being exposed to TAG-rich very-low-density lipoprotein (VLDL). Results indicate that truncation of the PE domain correlates with increased TAG hydrolase activity. Quantitative electron microscopy analyses showed that (i) in the presence of lipase inhibitors, large ILI (ILI+3) were not formed because of an absence of LB due to inhibition of VLDL-TAG hydrolysis or inhibition of LB-neutral lipid hydrolysis by mycobacterial lipases, (ii) ILI+3 profiles in the strain overexpressing LipY(ΔPE) were reduced, and (iii) the number of ILI+3 profiles in the ΔlipY mutant was reduced by 50%. Overall, these results delineate the role of LipY and its PE domain in host and mycobacterial lipid consumption and show that additional mycobacterial lipases take part in these processes.

International audience; Previously in Current Protein & Peptide Science, Cerk et al. (2018) reported an updated review of concepts and knowledge regarding structure, function and regulatory mechanism of the adi-pose triglyceride lipase (ATGL), one of the key-enzyme required for intracellular lipolysis. Until recently, lipid droplets (LDs) were just considered as neutral lipid storage sites, thus providing energy through lipolysis and β-oxidation pathway when required during stressful conditions [1]. Nowadays, it is clearly established that LDs are well-organized and extremely dynamic cellular organelles, conserved in eubacteria, fungi, plants and animals plants and animals where they are essential for lipid homeostasis and energy maintenance [2]. Alteration of these two critical physiological processes can lead to important metabolic disorders [3]. The " conventional snapshot representation " of LDs remains a suitable model for defining their general composition which is based on a central organic core of neutral lipids (mainly triacylglycerol (TAG) and sterol esters) surrounded by a phospholipid monolayer [4], associated with a wide range of structural [5], enzymatic [6] and membrane-trafficking proteins [7]. However, we also know that proteins and lipid species of such structures can be extremely diversified depending on the different cell types or metabolic status. Interestingly, LDs anabolism and catabo-lism are well-balanced, and tightly-controlled biological mechanisms involving a large number of actors at both tran-scriptional, translational and post-translational levels [8]. TAG-containing LDs breakdown is achieved during extended starvation period or enhanced energy demand, and this phenomenon is mainly mediated by three distinct lipolytic enzymes (i.e., the adipose triglyceride lipase (ATGL), the hormone-sensitive lipase (HSL) and the mono-glyceride lipase (MGL)) that act sequentially to finally generate free fatty acids (FFA) and glycerol molecules [8]. Since ATGL catalyzes the first step of this essential lipolytic pathway , it is thus crucial to fully define the physiological func-tion(s) and structural properties of this protein, but also to get insights onto the regulatory mechanisms governing ATGL action towards LDs [9].