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.     

Contaminación del aire y síntomas recientes de asma,rinitis alérgica y eccema atópico en escolares de 6 y 7 años

Objective

The objective of the study was to analyze the relationship between air pollutants and the prevalence of recent symptoms of asthma, allergic rhinitis, and atopic eczema in schoolchildren aged between 6 and 7 years.

Patients and Methods

The prevalence of recent (previous 12 months) symptoms of allergic diseases was obtained by means of the questionnaire of the International Study of Asthma and Allergies in Childhood (ISAAC), Spain, with the participation of 7 centers (Asturias, Barcelona, Bilbao, Cartagena, La Coruña, Madrid, and Valencia) and 20 455 schoolchildren aged between 6 and 7 years, from 2002 to 2003. The pollutant detection systems of the aforementioned centers provided the mean annual concentrations of sulfur dioxide (SO₂), nitrogen dioxide (NO₂), carbon monoxide (CO), and total suspended particulate matter.

Results

The annual average concentration of SO₂ showed a significant association with a higher prevalence of recent severe asthma (adjusted odds ratio [aOR] between level-1 and level-3 pollution, 1.32; 95% confidence interval [CI], 1.01–1.73), rhinitis (aOR, 1.56; 95% CI, 1.39–1.75), and rhinoconjunctivitis (aOR, 1.70; 95% CI, 1.45–2.00). The annual average concentration of CO was associated with a higher prevalence of rhinitis (aOR, 1.65; 95% CI, 1.34–2.04), rhinoconjunctivitis (aOR, 1.76; 95% CI, 1.31–2.37), and eczema (aOR, 1.55; 95% CI, 1.17–2.04). The annual average concentration for NO₂ and total suspended particulate matter showed inverse associations with the prevalence of nocturnal dry cough.

Conclusions

Findings suggest that air pollutants such as SO₂ and CO increase the risk of recent symptoms of asthma and allergic rhinitis in schoolchildren aged between 6 and 7 years in Spain.     

Rectal advancement flap for the treatment of complex cryptoglandular anal fistulas: a systematic review and meta-analysis

Purpose

Rectal advancement flap is an accepted approach for treating complex fistula-in-ano. However, a diversity of technical modifications have been described. The aim of this study was to evaluate recurrence and fecal continence rates after performing rectal advancement flaps depending upon flap thickness (full-thickness, partial-thickness, or mucosal flaps) and treatment of the fistulous tract (core-out or curettage).

Methods

Medline (PubMed, Ovid), the Cochrane Library database, and ClinicalTrials.gov were searched. Studies that involved patients with complex cryptoglandular fistulas who had been treated with rectal advancement flaps were included. The outcomes measured were recurrence and fecal continence. All of the statistical analyses were performed using Comprehensive Meta-Analysis software. A fixed model was used if there was no evidence of heterogeneity; otherwise, a random effects model was used.

Results

Twenty-six studies were included (1655 patients). The pooled rate of recurrence was 21%. Full-thickness flaps showed the best results concerning recurrence (7.4%), partial flaps revealed 19% and mucosal flaps 30.1%. Core-out and curettage had a similar recurrence (19 vs 21%). Regarding anal incontinence, the pooled rate was 13.3%. Mucosal- and partial-thickness flaps showed similar rates (9.3 vs 10.2%), while full-thickness flaps disturbed it in 20.4%. Most of these alterations were minor symptoms. Otherwise, core-out and curettage showed similar rates (14.3 vs 12%).

Conclusions

1. Full-thickness rectal advancement flaps offer better results regarding the recurrence than mucosal or partial flaps. 2. All flaps cause some incontinence, which increases with the thickness of the flap. 3. The results did not suggest differences in recurrence and incontinence between core-out and curettage.

     

Megalin mediates the transport of leptin across the blood-CSF barrier

Leptin, a peptide hormone secreted by adipose tissue, exhibits a large range of central and peripheral actions. It has been proposed that the participation of leptin in diseases such as obesity is due to, at least in part, its impaired transport across the blood–brain barrier (BBB). Since, the mechanisms by which brain takes up leptin remain unclear, we set out to study how leptin may cross the BBB. We have used different immunoassays and lentiviral vectors to analyze the role of megalin in the transport of leptin in rodents and humans. We demonstrate that circulating leptin is transported into the brain by binding to megalin at the choroid plexus epithelium. Indeed, the downregulation of megalin expression in physiological and pathological situations such as aging and Alzheimer's disease was correlated with poor entry of leptin into the brain. Moreover, amyloid beta (Aβ) deposits of choroid plexus could be disturbing megalin function. The present data indicate that leptin represents a novel megalin ligand of importance in the levels and therapeutic actions of leptin into the brain.     

Distinct maternal microbiota clusters are associated with diet during pregnancy: impact on neonatal microbiota and infant growth during the first 18 months of life

ABSTRACT

Nutrition during pregnancy plays an important role in maternal–neonatal health. However, the impact of specific dietary components during pregnancy on maternal gut microbiota and the potential effects on neonatal microbiota and infant health outcomes in the short term are still limited. A total of 86 mother–neonate pairs were enrolled in this study. Gut microbiota profiling on maternal–neonatal stool samples at birth was carried out by 16S rRNA gene sequencing using Illumina. Maternal dietary information and maternal–neonatal clinical and anthropometric data were recorded during the first 18 months. Longitudinal Body Mass Index (BMI) and Weight-For-Length (WFL) z-score trajectories using the World Health Organization (WHO) curves were obtained. The maternal microbiota was grouped into two distinct microbial clusters characterized by Prevotella (Cluster I) and by the Ruminococcus genus (Cluster II). Higher intakes of total dietary fiber, omega-3 fatty acids, and polyphenols were observed in Cluster II compared to Cluster I. Higher intakes of plant-derived components were associated with a higher presence of the Christensellaceae family, Dehalobacterium and Eubacterium, and lower amounts of the Dialister and Campylobacter species. Maternal microbial clusters were also linked to neonatal microbiota and infant growth in a birth-dependent manner. C-section neonates from Cluster I showed the highest BMI z-score at age 18 months, along with a higher risk of overweight. Longitudinal BMI and WL z-score trajectories from birth to 18 months were shaped by maternal microbial cluster, diet, and birth mode. Diet was an important perinatal factor in early life that may impact maternal microbiota; in particular, fiber, lipids and proteins, and exert a significant effect on the neonatal microbiome and contribute to infant development during the first months of life.     

Localization of the cannabinoid type‐1 receptor in subcellular astrocyte compartments of mutant mouse hippocampus

Astroglial type‐1 cannabinoid (CB₁) receptors are involved in synaptic transmission, plasticity and behavior by interfering with the so‐called tripartite synapse formed by pre‐ and post‐synaptic neuronal elements and surrounding astrocyte processes. However, little is known concerning the subcellular distribution of astroglial CB₁ receptors. In particular, brain CB₁ receptors are mostly localized at cells' plasmalemma, but recent evidence indicates their functional presence in mitochondrial membranes. Whether CB₁ receptors are present in astroglial mitochondria has remained unknown. To investigate this issue, we included conditional knock‐out mice lacking astroglial CB₁ receptor expression specifically in glial fibrillary acidic protein (GFAP)‐containing astrocytes (GFAP‐CB₁‐KO mice) and also generated genetic rescue mice to re‐express CB₁ receptors exclusively in astrocytes (GFAP‐CB₁‐RS). To better identify astroglial structures by immunoelectron microscopy, global CB₁ knock‐out (CB₁‐KO) mice and wild‐type (CB₁‐WT) littermates were intra‐hippocampally injected with an adeno‐associated virus expressing humanized renilla green fluorescent protein (hrGFP) under the control of human GFAP promoter to generate GFAPhrGFP‐CB₁‐KO and ‐WT mice, respectively. Furthermore, double immunogold (for CB₁) and immunoperoxidase (for GFAP or hrGFP) revealed that CB₁ receptors are present in astroglial mitochondria from different hippocampal regions of CB₁‐WT, GFAP‐CB₁‐RS and GFAPhrGFP‐CB₁‐WT mice. Only non‐specific gold particles were detected in mouse hippocampi lacking CB₁ receptors. Altogether, we demonstrated the existence of a precise molecular architecture of the CB₁ receptor in astrocytes that will have to be taken into account in evaluating the functional activity of cannabinergic signaling at the tripartite synapse.     

Oral health and the symptoms of schizophrenia

The objectives of this study were to evaluate the oral health of a group of schizophrenic outpatients and a control group without psychiatric illness. The study also aimed to assess the influence of positive and negative symptomatology on oral health among outpatients with schizophrenia. The DMF-T Index (sum of decayed, missing and filled teeth) and the Community Periodontal Index of Treatment Needs (CPITN) were assessed in both groups. We evaluated the psychopathological state of the patient group using the Positive and Negative Syndrome Scale (PANSS). The schizophrenic patients had higher scores than the control group with respect to decayed teeth (4.39 vs. 0.72), missing teeth (5.66 vs. 1.50), the DMF-T index (13.51 vs. 7.8) and CPITN (2.32 vs. 1.04); and lower scores for filled teeth (3.53 vs. 5.54). The PANSS negative subscale score correlated positively with the oral health variables studied, whereas the PANSS positive subscale score correlated negatively and exclusively with the number of missing teeth. Age and smoking status affected oral health in both groups, but even when the influence of these factors was considered, the oral health of the patients was poorer than that of the control group.