Display omitted
•Murine leprosy is a chronic mycobacterial disease that does not infect the nervous system, however alterations in the prefrontal cortex, ventral hippocampus and amygdala have been ...associated with neurocognitive impairment.•Murine-leprosy infection elicited a suppressive immune response with high levels of IL-10 and IL-4 and spleno-hepatomegaly.•Chronic infection induces BBB disruption and neuroinflammation.•Murine leprosy atrophy the adrenal glands and increase levels of epinephrine, norepinephrine and corticosterone.•The immunosuppressive environment generated by the infection may affect the nervous and endocrine system integrity and function.
Murine leprosy is a systemic infectious disease of mice caused by Mycobacterium lepraemurium (MLM) in which the central nervous system (CNS) is not infected; nevertheless, diseased animals show measurable cognitive alterations. For this reason, in this study, we explored the neurobehavioral changes in mice chronically infected with MLM. BALB/c mice were infected with MLM, and 120 days later, the alterations in mice were evaluated based on immunologic, histologic, endocrine, neurochemical, and behavioral traits. We found increases in the levels of IL-4 and IL-10 associated with high bacillary loads. We also found increase in the serum levels of corticosterone, epinephrine, and norepinephrine in the adrenal gland, suggesting neuroendocrine deregulation. Mice exhibited depression-like behavior in the tail suspension and forced swimming tests and anxiolytic behavior in the open field and elevated plus maze tests. The neurobehavioral alterations of mice were correlated with the histologic damage in the prefrontal cortex, ventral hippocampus, and amygdala, as well as with a blood–brain barrier disruption in the hippocampus. These results reveal an interrelated response of the neuroimmune-–endocrinological axis in unresolved chronic infections that result in neurocognitive deterioration.
In this research, a microlearning strategy for Software Engineering supported by a mobile application was designed and implemented. The goal is to evaluate the motivation and learning outcomes in the ...specific context of Software Project Management, with the Scrum framework, in participants of a Software Engineering course at a Latin American higher education institution. An empirical investigation was conducted using a quantitative approach, a quasi‐experimental design, and pretest–posttest measurements without a control group. A one‐sample t‐test for comparison of the means of a sample was used. Statistically significant differences were found between the theoretical and empirical mean of the variable motivation to learn in the specific context and the variable Stimulus for learning after interacting with the mobile application. The means were higher than the theoretical average of the scale, which suggests that the participants valued the mobile application positively. Regarding the learning outcomes of the Scrum framework, a paired sample t‐test for comparison of means revealed an increase in posttest scores, although this rise was not statistically significant. Microlearning can increase the participants' motivation and promote learning in the specific context of Software Project Management. The mobile application has the potential to support microlearning since the participants felt highly motivated and agreed that its use facilitates learning, a key aspect of success in a microlearning strategy.
To determine the accuracy and role of rapid C-reactive protein (CRP) testing in human immunodeficiency virus (HIV) infected individuals with presumed tuberculosis (TB).
We enrolled HIV-infected ...adults (≥18 years)with a cough of ≥2 weeks and negative sputum smears for acid-fast bacilli in KwaZulu-Natal, South Africa. Participants were evaluated for pulmonary TB (PTB) by a nurse with rapid CRP, and independently by a physician by chest radiograph. Rapid CRP test results were compared with laboratory CRP and sputum sent for confirmation of TB.
Among 93 participants, 55 (59%) were female, the mean age was 35 years, and the median CD4 count was 177/mm3. Forty-five (54%) participants were diagnosed with PTB. Diagnostic sensitivity and specificity were respectively 95% (95%CI 74–99) and 51%(95%CI 35–66) for rapid CRP >8 mg/l, 87% (95%CI 73–96) and 53% (95%CI 38–68) for nurse assessment, and 69% (95%CI 52–83) and 76% (95%CI 61–87) for physician examination. Combining a negative rapid CRP(≤8 mg/l) with nurse and physician assessments reduced the post-test probability of PTB from 22% to 6% and from 32% to 6%, respectively.
Rapid CRP testing helped exclude PTB,and may be a valuable test in assisting nurses and physicians in TB-endemic regions.
The liver controls metabolic homeostasis in response to fasting and refeeding periods. Glucokinase (GCK) adjusts hepatic glucose phosphorylation to blood glucose levels, acting as a glucose sensor. ...Our objective was to determine whether PAS kinase (PASK), a nutrient sensor, could be affecting the expression or activity of liver GCK and the response to fasting and refeeding states of key hepatic metabolic pathways. PASK-deficient mice have impaired insulin signaling (AKT overactivation). Furthermore, PASK deficiency modified the expression of several transcription factors involved in the adjustment to fasting and refeeding. Foxo1 decreased under fasting conditions, while Ppara and Pparg were overexpressed in PASK-deficient mice. However, PEPCK protein levels were similar or higher, while the expression of Cpt1a decreased in PASK-deficient mice. By contrast, Lxra and Chrebp were overexpressed after refeeding, while the expression of Acc and Fas decreased in PASK-deficient mice. Likewise, with a decreased expression of Gck and increased nuclear location of the complex GCK-GCKR, GCK activity decreased in PASK-deficient mice. Therefore, PASK regulated some of the genes and proteins responsible for glucose sensing, such as glucokinase, and for insulin signalling, affecting glucose and lipid metabolism and consequently certain critical hepatic functions.
Metabolic dysfunction in the liver is the cause of numerous pathologies, which are associated with an altered redox state. PASK (PAS Domain Kinase) is a nutrient and bioenergetic sensor. We contend ...that PASK could act as an oxidative stress sensor in liver and/or control the metabolic balance, playing a role in the mitochondrial homeostasis. Using PASK-deficient mice, we observed that PASK deficiency promotes antioxidant response mechanisms: a lower production of ROS/RNS under non-fasting conditions, overexpression of genes coding to ROS-detoxifying enzymes and mitochondrial fusion proteins (MnSod Gpx, Mfn1 and Opa1), coactivator Ppargc1a, transcription factors (Pparg and FoxO3a) and deacetylase Sirt1. Also, under fasting conditions, PASK deficiency induced the overexpression of Ppargc1a, Ppara, Pparg, FoxO3a and Nrf2 leading to the overexpression of genes coding to antioxidant enzymes such as MnSOD, Cu/ZnSOD, GPx, HO1 and GCLm. Additionally, inducing PINK1 involved in cell survival and mitophagy. These changes kept ROS steady levels and improved the regenerative state. We suggest a new role for PASK as a controller of oxidative stress and mitochondrial dynamics in the liver. In fact, antioxidant response is PASK dependent. PASK-targeting could therefore be a good way of reducing the oxidative stress in order to prevent or treat liver diseases.
To develop and validate a nomogram and web-based calculator to predict overall survival (OS) in Caucasian-advanced oesophagogastric adenocarcinoma (AOA) patients undergoing first-line combination ...chemotherapy.
Nine hundred twenty-four AOA patients treated at 28 Spanish teaching hospitals from January 2008 to September 2014 were used as derivation cohort. The result of an adjusted-Cox proportional hazards regression was represented as a nomogram and web-based calculator. The model was validated in 502 prospectively recruited patients treated between October 2014 and December 2016. Harrell's c-index was used to evaluate discrimination.
The nomogram includes seven predictors associated with OS: HER2-positive tumours treated with trastuzumab, Eastern Cooperative Oncology Group performance status, number of metastatic sites, bone metastases, ascites, histological grade, and neutrophil-to-lymphocyte ratio. Median OS was 5.8 (95% confidence interval (CI), 4.5-6.6), 9.4 (95% CI, 8.5-10.6), and 14 months (95% CI, 11.8-16) for high-, intermediate-, and low-risk groups, respectively (P<0.001), in the derivation set and 4.6 (95% CI, 3.3-8.1), 12.7 (95% CI, 11.3-14.3), and 18.3 months (95% CI, 14.6-24.2) for high-, intermediate-, and low-risk groups, respectively (P<0.001), in the validation set. The nomogram is well-calibrated and reveals acceptable discriminatory capacity, with optimism-corrected c-indices of 0.618 (95% CI, 0.591-0.631) and 0.673 (95% CI, 0.636-0.709) in derivation and validation groups, respectively. The AGAMENON nomogram outperformed the Royal Marsden Hospital (c-index=0.583; P=0.00046) and Japan Clinical Oncology Group prognostic indices (c-index=0.611; P=0.03351).
We developed and validated a straightforward model to predict survival in Caucasian AOA patients initiating first-line polychemotherapy. This model can contribute to inform clinical decision-making and optimise clinical trial design.
The potential impact on patient outcome of different Minimal residual disease (MRD) levels at time of transplant in patients with lymphoblastic leukemia undergoing allogeneic hematopoietic SCT (HSCT) ...remains uncertain. In this study, we quantified MRD levels at time of transplant using multiparameter flow cytometry (MFC). Mononuclear cells from marrow aspirates were obtained from 102 adult and child patients before their conditioning regimen. Quantification of MRD levels was carried out by detecting patient-specific leukemia-associated immunophenotypes using four-color MFC. Thirty patients exhibited measurable levels of MRD at the time of transplant, with low levels (0.01 to 0.1%) in 12 cases, intermediate levels (>0.1 to 1%) in 8 cases and high levels (>1%) in 10 cases. The leukemia-free survival (LFS) rates were 65.9±7.0%, 42.9±15.7% and 0% for negative, low levels 0.1% and intermediate-high levels >0.1%, respectively (P<0.001, log-rank test). Overall survival (OS) was 52.3±7.6%, 28.6±13.8% and 0% for MRD-negative, low levels 0.1% and intermediate-high levels >0.1%, respectively (P<0.001, log-rank test). Multivariate Cox analysis confirmed that detection of leukemia cells by flow cytometry at transplant was the most significantly adverse factor for OS, LFS and EFS after transplant.
We present a new characterization of the relations between star-formation rate, stellar mass and molecular gas mass surface densities at different spatial scales across galaxies (from galaxy wide to ...kpc-scales). To do so we make use of the largest sample combining spatially-resolved spectroscopic information with CO observations, provided by the EDGE-CALIFA survey, together with new single dish CO observations obtained by APEX. We show that those relations are the same at the different explored scales, sharing the same distributions for the explored data, with similar slope, intercept and scatter (when characterized by a simple power-law). From this analysis, we propose that these relations are the projection of a single relation between the three properties that follows a distribution well described by a line in the three-dimension parameter space. Finally, we show that observed secondary relations between the residuals and the considered parameters are fully explained by the correlation between the uncertainties, and therefore have no physical origin. We discuss these results in the context of the hypothesis of self-regulation of the star-formation process.
Here we describe the results of a genome-wide study conducted in 11 939 COVID-19 positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE ...consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (p < 5x10-8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (p = 1.3x10-22 and p = 8.1x10-12, respectively), and for variants in 9q21.32 near TLE1 only among females (p = 4.4x10-8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (p = 2.7x10-8) and ARHGAP33 (p = 1.3x10-8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, p = 4.1x10-8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥ 60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.
PDF
