Pharmacological doses of melatonin impede cognitive decline in tau‐related Alzheimer models,once tauopathy is initiated,by restoring the autophagic flux

Alterations in autophagy are increasingly being recognized in the pathogenesis of proteinopathies like Alzheimer's disease (AD). This study was conducted to evaluate whether melatonin treatment could provide beneficial effects in an Alzheimer model related to tauopathy by improving the autophagic flux and, thereby, prevent cognitive decline. The injection of AAV‐hTau^P301L viral vectors and treatment/injection with okadaic acid were used to achieve mouse and human ex vivo, and in vivo tau‐related models. Melatonin (10 μmol/L) impeded oxidative stress, tau hyperphosphorylation, and cell death by restoring autophagy flux in the ex vivo models. In the in vivo studies, intracerebroventricular injection of AAV‐hTau^P301L increased oxidative stress, neuroinflammation, and tau hyperphosphorylation in the hippocampus 7 days after the injection, without inducing cognitive impairment; however, when animals were maintained for 28 days, cognitive decline was apparent. Interestingly, late melatonin treatment (10 mg/kg), starting once the alterations mentioned above were established (from day 7 to day 28), reduced oxidative stress, neuroinflammation, tau hyperphosphorylation, and caspase‐3 activation; these observations correlated with restoration of the autophagy flux and memory improvement. This study highlights the importance of autophagic dysregulation in tauopathy and how administration of pharmacological doses of melatonin, once tauopathy is initiated, can restore the autophagy flux, reduce proteinopathy, and prevent cognitive decline. We therefore propose exogenous melatonin supplementation or the development of melatonin derivatives to improve autophagy flux for the treatment of proteinopathies like AD.     

Spread of an Enterococcus faecalis sequence type 6 (CC2) clone in patients undergoing selective decontamination of the digestive tract

Enterococcus faecalis (E. faecalis) is a common cause of nosocomial infection in immunocompromised patients. The presence and dissemination of high‐risk clonal complexes, such as CC2, is an ongoing problem in hospitals. The aim of this work was to characterize 24 E. faecalis isolates from ICU patients undergoing selective decontamination of the digestive tract (SDD) by phenotypical (antimicrobial susceptibility) and genotypical (presence of virulence genes, RAPD‐PCR and MLST) methods. Our results showed high prevalence of the ST6 E. faecalis clone (91.6%), especially adapted to the hospital environment, with a multidrug resistance pattern and a multitude of putative virulence genes. In addition, ST179 (4.2%) and ST191 (4.2%) were detected. By RAPD–PCR analysis, the 22 isolates identified as ST6 showed six different DNA patterns, while the two remaining isolates, ST179 and ST191, showed two additional profiles. CC2 is a known clonal complex with high adaptability to hospital environment and worldwide distribution. The high prevalence of the ST6 clone in the studied population could be related to the presence of gentamicin in the SDD mixture since most strains were gentamicin resistant. Consequently, strict surveillance should be applied for rapid detection and control of this clone to prevent future spread outside the ICU.     

Distinct modulation by interferon-gamma (IFN-γ) of CD23 expression on B and T lymphocytes of atopic subjects

The low-affinity IgE receptor (FcεRII/CD23) plays a role in IgE production. Cytokines participating in IgE synthesis also modulate CD23 expression on lymphocytes, but whether this modulation is different in atopic subjects remains unclear. We studied CD23 expression on B and T lymphocytes in 10 asthmatic patients with Dermatophagoides pteronyssinus hypersensitivity and 10 healthy non-atopic subjects. Studies were performed by flow cytometry, in phytohaemagglutinin (PHA) or IL-4-stimulated mononuclear cell cultures, alone or in the presence of IFN-γ. Soluble CD23 (sCD23) released in the culture supernatants was measured by enzyme-linked immunoassay. Both PHA and IL-4 induced the expression of CD23 on lymphocytes of atopic and non-atopic subjects. Whereas PHA increased both the percentage and mean fluorescence intensity of CD23⁺ B and T cells, IL-4 alone did not increase the percentage of CD23⁺ T cells. The effects of IFN-γ were different in both groups, since it was able to reduce the percentage of PHA-stimulated CD23⁺ T cells only in non-atopic individuals. In non-atopic subjects more than atopic, levels of sCD23 were increased in the supernatants of PHA and IL-4 cultures. These results show that the modulation of CD23 expression is different on B and T cells, and that IFN-γ acts differently in atopic and non-atopic individuals.     

Clinical assessment of non-suicidal self-injury: A systematic review of instruments

There has been an increase in the number of assessment instruments for non-suicidal self-injury (NSSI). However, previous reviews are inconsistent and do not provide a comprehensive psychometric assessment of the instruments. This study aimed to systematically assess and compare the psychometric properties of clinically relevant instruments to measure NSSI in any population. Through a systematic review guided by COSMIN and PRISMA, two searches were conducted in English and Spanish in February 2020 in 13 databases including grey literature. Of the 7,813 initial records, 152 validations were extracted. From these, 83 instruments (22 versions or adaptations) were excluded for not measuring NSSI, having no potential clinical utility or not including psychometric properties. Finally, 26 (22 versions, 35 adaptations and 19 creations) instruments measuring NSSI were included. Predominantly, the studies were North American self-reports in English for community adolescents, adaptations or versions emanating from a small number of instruments. Twenty-six indicators were categorized to assess NSSI. The most frequent instruments are structured interviews, and their indicators were related to NSSI function and topography. Evidence of validity and reliability was positive but limited. Despite the high number of instruments and diversity of evaluations, we found no instrument with sufficient evidence for clinical assessment. Findings broadly overview NSSI assessment instruments' current use and future improvement in clinical and research settings.     

Continuous Glucose Monitoring Versus Capillary Point-of-Care Testing for Inpatient Glycemic Control in Type 2 Diabetes Patients Hospitalized in the General Ward and Treated With a Basal Bolus Insulin Regimen

Background:

Continuous glucose monitoring (CGM) may improve the management of patients with type 2 diabetes hospitalized in the general ward by facilitating the detection of hyper- and hypoglycemic episodes. However, the lack of data on the accuracy and safety of CGM have limited its application.

Methods:

A prospective pilot study was conducted including 38 patients hospitalized in the general ward with a known diagnosis of type 2 diabetes mellitus (DM) and hyperglycemic individuals without a history of DM with a blood sugar of 140-400 mg on admission treated with a basal bolus insulin regimen. Inpatient glycemic control and the incidence of hypoglycemic episodes were compared between detection by CGM of interstitial fluid for up to 6 days and point-of-care (POC) capillary blood glucose monitoring performed pre- and postprandially, before bedtime and at 3 am.

Results:

No differences in average daily glucose levels were observed between CGM and POC (176.2 ± 33.9 vs 176.6 ± 33.7 mg/dl, P = .828). However, CGM detected a higher number of hypoglycemic episodes than POC (55 vs 12, P < .01). Glucose measurements were clinically valid, with 91.9% of patients falling within the Clarke error grid A and B zones.

Conclusions:

Our preliminary results indicate that the use of CGM in type 2 patients hospitalized in the general ward provides accurate estimation of blood sugar levels and is more effective than POC for the detection of hypoglycemic episodes and asymptomatic hypoglycemia.     

Human mesenchymal stromal cells modulate T‐cell responses through TNF‐α‐mediated activation of NF‐κB

Although mesenchymal stromal cells (MSCs) possess the capacity to modulate immune responses, little is known about the mechanisms that underpin these processes. In this study, we show that immunosupression is mediated by activation of nuclear factor kappa B (NF‐κB) in human MSCs. This pathway is activated by TNF‐α that is generated following TCR stimulation of T cells. Inhibition of NF‐κB through silencing of IκB kinase β or the TNF‐α receptor abolishes the immunosuppressive capacity of MSCs. Our data also indicate that MSC‐associated NF‐κB activation primarily leads to inhibition of T‐cell proliferation with little effect on expression of the activation markers CD69 and CD25. Thus, our data support the hypothesis that the TNF‐α/NF‐κB signalling pathway is required for the initial priming of immunosuppressive function in human MSCs. Interestingly, drugs that interfere with NF‐κB activation significantly antagonise the immunoregulatory effect of MSCs, which could have important implications for immunosuppression regimens in the clinic.