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Background Birth cohort studies link gestational diabetes mellitus (GDM) with impaired cognitive performance in the offspring. However, the mechanisms involved are unknown. We tested the hypothesis that obesity-associated GDM induces chronic neuroinflammation and disturbs the development of neuronal circuitry resulting in impaired cognitive abilities in the offspring. Methods In rats, GDM was induced by feeding dams a diet high in sucrose and fatty acids. Brains of neonatal (E20) and young adult (15-week-old) offspring of GDM and lean dams were analyzed by immunohistochemistry, cytokine assay, and western blotting. Young adult offspring of GDM and lean dams went also through cognitive assessment. Cultured microglial responses to elevated glucose and/or fatty acids levels were analyzed. Results In rats, impaired recognition memory was observed in the offspring of GDM dams. GDM exposure combined with a postnatal high-fat and sucrose diet resulted in atypical inattentive behavior in the offspring. These cognitive changes correlated with reduced density and derangement of Cornu Ammonis 1 pyramidal neuronal layer, decreased hippocampal synaptic integrity, increased neuroinflammatory status, and reduced expression of CX3CR1, the microglial fractalkine receptor regulating microglial pro-inflammatory responses and synaptic pruning. Primary microglial cultures that were exposed to high concentrations of glucose and/or palmitate were transformed into an activated, amoeboid morphology with increased nitric oxide and superoxide production, and altered their cytokine release profile. Conclusions These findings demonstrate that GDM stimulates microglial activation and chronic inflammatory responses in the brain of the offspring that persist into young adulthood. Reactive gliosis correlates positively with hippocampal synaptic decline and cognitive impairments. The elevated pro-inflammatory cytokine expression at the critical period of hippocampal synaptic maturation suggests that neuroinflammation might drive the synaptic and cognitive decline in the offspring of GDM dams. The importance of microglia in this process is supported by the reduced Cx3CR1 expression as an indication of the loss of microglial control of inflammatory responses and phagocytosis and synaptic pruning in GDM offspring.

We have shown that both insulin and resveratrol (RSV) decrease neointimal hyperplasia in chow-fed rodents via mechanisms that are in part overlapping and involve the activation of endothelial nitric oxide synthase (eNOS). However, this vasculoprotective effect of insulin is abolished in high-fat-fed insulin-resistant rats. Since RSV, in addition to increasing insulin sensitivity, can activate eNOS via pathways that are independent of insulin signaling, such as the activation of sirtuin 1 (SIRT1) and AMP-activated kinase (AMPK), we speculated that unlike insulin, the vasculoprotective effect of RSV would be retained in high-fat-fed rats. We found that high-fat feeding decreased insulin sensitivity and increased neointimal area and that RSV improved insulin sensitivity (p < 0.05) and decreased neointimal area in high-fat-fed rats (p < 0.05). We investigated the role of SIRT1 in the effect of RSV using two genetic mouse models. We found that RSV decreased neointimal area in high-fat-fed wild-type mice (p < 0.05), an effect that was retained in mice with catalytically inactive SIRT1 (p < 0.05) and in heterozygous SIRT1-null mice. In contrast, the effect of RSV was abolished in AMKPα2-null mice. Thus, RSV decreased neointimal hyperplasia after arterial injury in both high-fat-fed rats and mice, an effect likely not mediated by SIRT1 but by AMPKα2.

Pulmonary arterial hypertension (PAH) is characterized by endothelial cell (EC) dysfunction. There are no data from living patients to inform whether differential gene expression of pulmonary artery ECs (PAECs) can discern disease subtypes, progression and pathogenesis. We aimed to further validate our previously described method to propagate ECs from right heart catheter (RHC) balloon tips and to perform additional PAEC phenotyping. We performed bulk RNA sequencing of PAECs from RHC balloons. Using unsupervised dimensionality reduction and clustering we compared transcriptional signatures from PAH to controls and other forms of pulmonary hypertension. Select PAEC samples underwent single cell and population growth characterization and anoikis quantification. Fifty-four specimens were analyzed from 49 subjects. The transcriptome appeared stable over limited passages. Six genes involved in sex steroid signaling, metabolism, and oncogenesis were significantly upregulated in PAH subjects as compared to controls. Genes regulating BMP and Wnt signaling, oxidative stress and cellular metabolism were differentially expressed in PAH subjects. Changes in gene expression tracked with clinical events in PAH subjects with serial samples over time. Functional assays demonstrated enhanced replication competency and anoikis resistance. Our findings recapitulate fundamental biological processes of PAH and provide new evidence of a cancer-like phenotype in ECs from the central vasculature of PAH patients. This “cell biopsy” method may provide insight into patient and lung EC heterogeneity to advance precision medicine approaches in PAH.

CD40 ligand (CD40L) deficiency or X-linked hyper-IgM syndrome (X-HIGM) is a well-described primary immunodeficiency in which Pneumocystis jiroveci pneumonia is a common clinical feature. We have identified an unusual high incidence of fungal infections and other not yet described infections in a cohort of 11 X-HIGM patients from nine unrelated Brazilian families. Among these, we describe the first case of paracoccidioidomycosis (PCM) in X-HIGM. The molecular genetic analysis of CD40L was performed by gene sequencing and evaluation of CD40L protein expression. Nine of these 11 patients (82%) had fungal infections. These included fungal species common to CD40L deficiency ( P. jiroveci and Candida albicans ) as well as Paracoccidioides brasiliensis . One patient presented with PCM at age 11 years and is now doing well at 18 years of age. Additionally, one patient presented with a simultaneous infection with Klebsiella and Acinetobacter , and one with condyloma caused by human papilloma virus. Molecular analysis revealed four previously described CD40L mutations, two novel missense mutations (c.433 T > G and c.476 G > C) resulting in the absence of CD40L protein expression by activated CD4 + cells and one novel insertion (c.484_485insAA) within the TNFH domain leading to a frame shift and premature stop codon. These observations demonstrated that the susceptibility to fungal infections in X-HIGM extends beyond those typically associated with X-HIGM ( P. jiroveci and C. albicans ) and that these patients need to be monitored for those pathogens.

Abstract Twenty-seven neonate piglets (range from 0.35 to 1.17 kg) were evaluated for the effectiveness of blunt force trauma as a method of on-farm cull. Brainstem function, brain injury, and hemorrhage scores (increasing from 0 to 3) were assessed after striking the head against a concrete floor. Electroencephalograms (EEG) from a subset of 15 piglets were recorded before and after blunt force trauma for electrophysiological assessments. Blunt force trauma was performed by a single experienced farmer in a commercial farm by holding the piglet by its both hind legs and striking the head against the concrete floor. All piglets remained recumbent and did not show brainstem reflexes. Only one piglet did not presented tonic/clonic physical activity. The mean time to the onset of persistent isoelectric EEG was 64.3 ± 7.3 s (range 18 to 115). Total power, theta, alpha, and beta power decreased to approximately 45%, 30%, 20%, and 15% from pretreatment power, respectively, by 15-s post-impact. There were no periods of normal-like EEG after the culling. Bruises in the neck and shoulder were found in 67% and 70% of piglets, respectively. All piglets presented skull fractures with 20% having the nasal bone(s) fractured. Brain damage was found in all piglets, mainly in the frontal lobe(s). The occipital lobe(s) presented the greatest frequency of severe damage. The analysis of the radiographs also found a high frequency of fractures in this region. Hemorrhage was most frequent in the frontal, parietal, occipital lobes, and midbrain. When performed correctly with the appropriate weight class, blunt force trauma can be used as an effective method for the on-farm killing of nursing piglets resulting in death. However, this method should not be promoted over more reliable and repeatable cull methods such as captive bolt gun. As with blunt force trauma, there is a significant potential for animal welfare harm associated with inappropriate practice, lack of accuracy, issues with repeatability, and operator fatigue.

Différences entre les sexes en matière d’évolution de l’autonomie fonctionnelle après un traitement endovasculaire consécutif à un AVC ischémique aigu.