Epithelial barrier impairment is a hallmark of several pathologic processes in the gut, including inflammatory bowel diseases. Several intracellular signals prevent apoptosis in intestinal epithelial ...cells. Herein, we show that in colonocytes, rictor/mammalian target of rapamycin complex 2 (mTORC2) signaling is a prosurvival stimulus. Mechanistically, mTORC2 activates Akt, which, in turn, inhibits apoptosis by phosphorylating B-cell lymphoma 2 (BCL2) associated agonist of cell death (Bad) and preventing caspase-3 activation. Nevertheless, during inflammation, rictor/mTORC2 signaling declines and Akt activity is reduced. Consequently, active caspase-3 increases in surface colonocytes undergoing apoptosis/anoikis and causes epithelial barrier breakdown. Likewise, Rictor ablation in intestinal epithelial cells interrupts mTORC2/Akt signaling and increases apoptosis/anoikis of surface colonocytes without affecting the crypt architecture. The increase in epithelial permeability induced by Rictor ablation produces a mild inflammatory response in the colonic mucosa, but minimally affects the development/establishment of colitis. The data identify a previously unknown mechanism by which rictor/mTORC2 signaling regulates apoptosis/anoikis in intestinal epithelial cells during colitis and clarify its role in the maintenance of the intestinal epithelial barrier.
SiGOAM: Web system for developing quality mobile learning objects Huerta Guerrero, Miguel A.; Cueto García, Arturo; López Domínguez, Eduardo ...
Computer applications in engineering education,
March 2020, 2020-03-00, 20200301, Letnik:
28, Številka:
2
Journal Article
Recenzirano
Mobile learning (m‐learning) refers to knowledge and abilities acquisition through the use of mobile technology anywhere at any time. Mobile learning objects (MLOs) are key elements for this teaching ...paradigm; several software tools have been proposed to support the construction of MLOs; however, they do not take into account pedagogical and technological aspects simultaneously during the construction cycle of MLOs. This paper presents the analysis, design, and development of a web system called SiGOAM, which supports specialized services to professors to generate quality MLOs. These services follow a formal MLO's construction cycle integrated into four phases: analysis, design, development, and product‐oriented assessment. As a result of this formal approach, the proposed system generates quality MLOs that are embedded in mobile devices and accessed through web browsers. We performed a usability assessment of our system SiGOAM based on a field study. The results show that professors assigned acceptable values for effectiveness, efficiency, and satisfaction.
Abstract Immune mediators affect multiple biological functions of intestinal epithelial cells (IECs) and, like Paneth and Paneth‐like cells, play an important role in intestinal epithelial ...homeostasis. IFN‐γ a prototypical proinflammatory cytokine disrupts intestinal epithelial homeostasis. However, the mechanism underlying the process remains unknown. In this study, using in vivo and in vitro models we demonstrate that IFN‐γ is spontaneously secreted in the small intestine. Furthermore, we observed that this cytokine stimulates mitochondrial activity, ROS production, and Paneth and Paneth‐like cell secretion. Paneth and Paneth‐like secretion downstream of IFN‐γ, as identified here, is mTORC1 and necroptosis‐dependent. Thus, our findings revealed that the pleiotropic function of IFN‐γ also includes the regulation of Paneth cell function in the homeostatic gut.
Abstract Objective The primary aim was to search for lower doses of Bacillus Calmette-Guerin (BCG) that are effective and have lower toxicity. Methods A low dose of BCG 27 mg was compared with BCG ...13.5 mg, using mitomycin C (MMC) 30 mg as the third arm of comparison. A total of 430 patients with intermediate-risk superficial bladder cancer were randomised into three groups. Instillations were repeated once a week for 6 wk followed by another six instillations given once every 2 wk during 12 wk. Results There was a significantly longer disease-free interval for BCG 27 mg versus MMC 30 mg ( p = 0.006). There were no statistically significant differences between BCG 27 mg and BCG 13.5 mg ( p = 0.165) or between BCG 13.5 mg and MMC 30 mg ( p = 0.183). Cox proportional hazards regression showed that disease-free interval in the multivariate analysis was significantly better for primary disease and treatment with BCG 27 mg. There were no significant differences among the three groups with regards to time to progression and cancer-specific survival time. Local and systemic toxicity were higher in both BCG treatment groups. Conclusions One third of the standard dose, BCG 27 mg, seems to be the minimum effective dose as adjuvant treatment for intermediate-risk superficial bladder cancer, being more effective than MMC 30 mg. One sixth of the standard dose, BCG 13.5 mg, has the same efficacy as MMC 30 mg but it is more toxic.
Background and Purpose
Spinocerebellar ataxias (SCAs) are a family of chronic progressive neurodegenerative diseases, clinically and genetically heterogeneous, characterized by loss of balance and ...motor coordination due to degeneration of the cerebellum and its afferent and efferent connections. Unlike other motor disorders, the possible role of changes in the endocannabinoid system in the pathogenesis of SCAs has not been investigated.
Experimental Approach
The status of cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2) receptors in the post‐mortem cerebellum of SCA patients and controls was investigated using immunohistochemical procedures.
Key Results
Immunoreactivity for the CB1 receptor, and also for the CB2 receptor, was found in the granular layer, Purkinje cells, neurons of the dentate nucleus and areas of white matter in the cerebellum of SCA patients at levels notably higher than controls. Double‐labelling procedures demonstrated co‐localization of CB1 and, in particular, CB2 receptors with calbindin, supporting the presence of these receptors in Purkinje neurons. Both receptors also co‐localized with Iba‐1 and glial fibrillary acidic protein in the granular layer and white matter areas, indicating that they are present in microglia and astrocytes respectively.
Conclusions and Implications
Our results demonstrate that CB1 and CB2 receptor levels are significantly altered in the cerebellum of SCA patients. Their identification in Purkinje neurons, which are the main cells affected in SCAs, as well as the changes they experienced, suggest that alterations in endocannabinoid receptors may be related to the pathogenesis of SCAs. Therefore, the endocannabinoid system could provide potential therapeutic targets for the treatment of SCAs and its progression.
Linked Articles
This article is part of a themed section on Cannabinoids 2013. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue‐6
The spread of extended-spectrum-β-lactamase (ESBL)-producing Enterobacteriaceae (ESBL-E) is leading to increased carbapenem consumption. Alternatives to carbapenems need to be investigated. We ...investigated whether β-lactam/β-lactamase inhibitor (BLBLI) combinations are as effective as carbapenems in the treatment of bloodstream infections (BSI) due to ESBL-E. A multinational, retrospective cohort study was performed. Patients with monomicrobial BSI due to ESBL-E were studied; specific criteria were applied for inclusion of patients in the empirical-therapy (ET) cohort (ETC; 365 patients), targeted-therapy (TT) cohort (TTC; 601 patients), and global cohort (GC; 627 patients). The main outcome variables were cure/improvement rate at day 14 and all-cause 30-day mortality. Multivariate analysis, propensity scores (PS), and sensitivity analyses were used to control for confounding. The cure/improvement rates with BLBLIs and carbapenems were 80.0% and 78.9% in the ETC and 90.2% and 85.5% in the TTC, respectively. The 30-day mortality rates were 17.6% and 20% in the ETC and 9.8% and 13.9% in the TTC, respectively. The adjusted odds ratio (OR) (95% confidence interval CI) values for cure/improvement rate with ET with BLBLIs were 1.37 (0.69 to 2.76); for TT, they were 1.61 (0.58 to 4.86). Regarding 30-day mortality, the adjusted OR (95% CI) values were 0.55 (0.25 to 1.18) for ET and 0.59 (0.19 to 1.71) for TT. The results were consistent in all subgroups studied, in a stratified analysis according to quartiles of PS, in PS-matched cases, and in the GC. BLBLIs, if active in vitro, appear to be as effective as carbapenems for ET and TT of BSI due to ESLB-E regardless of the source and specific species. These data may help to avoid the overuse of carbapenems. (This study has been registered at ClinicalTrials.gov under registration no. NCT01764490.).
Background. Extended-spectrum β-lactamase (ESBL)–producing Escherichia coli, particularly those producing CTX-M types of ESBL, are emerging pathogens. Bacteremia caused by these organisms represents ...a clinical challenge, because the organisms are frequently resistant to the antimicrobials recommended for treatment of patients with suspected E. coli sepsis. Methods. A cohort study was performed that included all episodes of bloodstream infection due to ESBL-producing E. coli during the period from January 2001 through March 2005. Data on predisposing factors, clinical presentation, and outcome were collected. ESBLs were characterized using isoelectric focusing, polymerase chain reaction, and sequencing. Results. Forty-three episodes (8.8% of cases of bacteremia due to E. coli) were included; 70% of the isolates produced a CTX-M type of ESBL. The most frequent origins of infection were the urinary (46%) and biliary tracts (21%). Acquisition was nosocomial in 21 cases (49%), health care associated in 14 cases (32%), and strictly community acquired in 8 cases (19%). Thirty-eight percent and 25% of patients had obstructive diseases of the urinary and biliary tracts, respectively, and 38% had recently received antimicrobials. Nine patients (21%) died. Compared with β-lactam/β-lactamase–inhibitor and carbapenem-based regimens, empirical therapy with cephalosporins or fluoroquinolones was associated with a higher mortality rate (9% vs. 35%; P = .05) and needed to be changed more frequently (24% vs. 78%; P = .001). Conclusions. ESBL-producing E. coli is a significant cause of bloodstream infection in hospitalized and nonhospitalized patients in the context of the emergence of CTX-M enzymes. Empirical treatment of sepsis potentially caused by E. coli may need to be reconsidered in areas where such ESBL-producing isolates are present.
•The legs of T. infestans, although structurally similar, showed differentiation.•The greatest morphometric differences were observed between fore- and hind legs.•Segments differed between legs, ...femur and tibia showed the greatest differences.•There were strong correlations between linear measurement within each leg.•The number of significant correlations decreased from the fore- to the hind leg.
In triatomines, vectors of Chagas disease, active dispersal takes place by walking and flying. Flight has received more attention than walking although the last is the dispersal modality used by nymphs due to their lack of wings and also used by adults, which would facilitate the colonization and reinfestation of houses after vector control actions. The present work studied the morphometrical variation of Triatoma infestans legs, the main vector of Chagas disease the Southern Cone of South America. We described morphometric traits and the natural variation of each leg segment. Different linear, size and shape variables of each component of the three right legs of fifth instar nymphs of T. infestans were analyzed using morphometric tools. We analyzed differentiation, variation and correlation for each segment across the fore-, mid and hind legs using different statistical approaches such as general linear model, canonical variates analysis, test of equality of coefficient of variation and partial least square analysis. We also analyzed variation and correlation between segments within each leg with partial least square and morphometric disparity analyses. Our results showed that the segments differed between legs, as general trends, the dimensions (length, width and/or size) were greater in the hind legs, smaller in the forelegs and intermediate in the mid ones. The femur and tibia (length and/or width) showed differences in morphometric variation between legs and the femur and tibia showed the highest levels of correlation between legs. On the other hand, in the fore- and mid legs, the femur (length or width) showed similar variation with tibia and tarsus lengths, but in the hind legs, the femur showed similar variation with all segments and not with the tibia length, and there were strong correlations between linear measurement within each leg. Our results suggest that the femur and tibia could play a determining role in the coordination between the legs that determines the walking pattern. Considering that these segments would also be linked to the specific function that each leg has, this study suggests a preponderant role of the femur and tibia in the walking locomotion of T. infestans.
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We investigated the prognostic impact and clinical utility of serum free light chains (sFLC) and serum heavy-light chains (sHLC) in patients with multiple myeloma treated according to the ...GEM2005MENOS65, GEM2005MAS65, and GEM2010MAS65 PETHEMA/GEM phase III clinical trials. Serum samples collected at diagnosis were retrospectively analyzed for sFLC (n = 623) and sHLC (n = 183). After induction or autologous transplantation, 309 and 89 samples respectively were available for sFLC and sHLC assays. At diagnosis, a highly abnormal (HA) sFLC ratio (sFLCr) (<0.03 or >32) was not associated with higher risk of progression. After therapy, persistence of involved-sFLC levels >100 mg/L implied worse survival (overall survival OS, P = 0.03; progression-free survival PFS, P = 0.007). Among patients that achieved a complete response, sFLCr normalization did not necessarily indicate a higher quality response. We conducted sHLC investigations for IgG and IgA MM. Absolute sHLC values were correlated with monoclonal protein levels measured with serum protein electrophoresis. At diagnosis, HA-sHLCrs (<0.29 or >73) showed a higher risk of progression (P = 0.006). Additionally, involved-sHLC levels >5 g/L after treatment were associated with shorter survival (OS, P = 0.001; PFS, P = 0.018). The HA-sHLCr could have prognostic value at diagnosis; absolute values of involved-sFLC >100 mg/L and involved-sHLC >5 g/L could have prognostic value after treatment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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