Cognitive impairments in a Down syndrome model with abnormal hippocampal and prefrontal dynamics and cytoarchitecture

The Dp(10)2Yey mouse carries a ∼2.3-Mb intra-chromosomal duplication of mouse chromosome 10 (Mmu10) that has homology to human chromosome 21, making it an essential model for aspects of Down syndrome (DS, trisomy 21). In this study, we investigated neuronal dysfunction in the Dp(10)2Yey mouse and report spatial memory impairment and anxiety-like behavior alongside altered neural activity in the medial prefrontal cortex (mPFC) and hippocampus (HPC). Specifically, Dp(10)2Yey mice showed impaired spatial alternation associated with increased sharp-wave ripple activity in mPFC during a period of memory consolidation, and reduced mobility in a novel environment accompanied by reduced theta-gamma phase-amplitude coupling in HPC. Finally, we found alterations in the number of interneuron subtypes in mPFC and HPC that may contribute to the observed phenotypes and highlight potential approaches to ameliorate the effects of human trisomy 21

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways

Fraction of Exhaled Nitric Oxide (FeNO) Norms in Healthy Tunisian Adults

Aims. To establish FeNO norms for healthy Tunisian adults aged 18–60 years and to prospectively assess their reliability. Methods. This was a cross-sectional analytical study. A convenience sample of healthy Tunisian adults was recruited. Subjects responded to a medical questionnaire, and then FeNO levels were measured by an online method (Medisoft, Sorinnes (Dinant), Belgium). Clinical, anthropometric, and plethysmographic data were collected. All analyses were performed on natural logarithm values of FeNO. Results. 257 adults (145 males) were retained. The proposed reference equation to predict FeNO value is lnFeNO (ppb) = 3.47−0.56× height (m). After the predicted FeNO value for a given adult was computed, the upper limit of normal could be obtained by adding 0.60 ppb. The mean ± SD (minimum-maximum) of FeNO (ppb) for the total sample was 13.54±4.87 (5.00–26.00). For Tunisian and Arab adults of any age and height, any FeNO value greater than 26.00 ppb may be considered abnormal. Finally, in an additional group of adults prospectively assessed, we found no adult with a FeNO higher than 26.00 ppb. Conclusion. The present FeNO norms enrich the global repository of FeNO norms that the clinician can use to choose the most appropriate norms

Fraction of Exhaled Nitric Oxide (Fe NO ) Norms in Healthy Tunisian Adults

Aims. To establish Fe NO norms for healthy Tunisian adults aged 18-60 years and to prospectively assess their reliability. Methods. This was a cross-sectional analytical study. A convenience sample of healthy Tunisian adults was recruited. Subjects responded to a medical questionnaire, and then Fe NO levels were measured by an online method (Medisoft, Sorinnes (Dinant), Belgium). Clinical, anthropometric, and plethysmographic data were collected. All analyses were performed on natural logarithm values of Fe NO . Results. 257 adults (145 males) were retained. The proposed reference equation to predict Fe NO value is lnFe NO (ppb) = 3.47−0.56× height (m). After the predicted Fe NO value for a given adult was computed, the upper limit of normal could be obtained by adding 0.60 ppb. The mean ± SD (minimum-maximum) of Fe NO (ppb) for the total sample was 13.54 ± 4.87 (5.00-26.00). For Tunisian and Arab adults of any age and height, any Fe NO value greater than 26.00 ppb may be considered abnormal. Finally, in an additional group of adults prospectively assessed, we found no adult with a Fe NO higher than 26.00 ppb. Conclusion. The present Fe NO norms enrich the global repository of Fe NO norms that the clinician can use to choose the most appropriate norms

Inflammation and impaired endothelium-dependant vasodilatation in non obese women with gestational diabetes mellitus: Preliminary results.

International audienceBACKGROUND: To evaluate whether abnormal endothelial function, a common finding in gestational diabetes mellitus (GDM) pregnancies, can be explained by inflammatory cytokines. METHODS: Forearm skin blood flow (FSBF), into response to acetylcholine (Ach) (endothelium-dependent vasodilatation), were measured in 24 pregnant control subjects and 28 gestational diabetes mellitus (GDM) women, in the third trimester of gestation. A fasting glycemic and lipidic panel was obtained, and inflammatory cytokines (TNF-alpha and IL-6) and adiponectin were also determined. RESULTS: FSBF is significantly reduced in GDM group compared with control subjects (344.59 +/- 57.791 vs.176.38 +/- 108.52, P < 0.05). Among all subjects, FSBF showed a strong negative correlation with TNF-alpha and IL-6 (r = -0.426, P < 0.0001 and r = -0.564, P < 0.0001, respectively) and positive correlation with adiponectin (r = 0.468, P < 0.0001). CONCLUSIONS: Endothelial function, an early marker of macrovascular disease, is present in non-obese pregnancies complicated by GDM. This alteration seems to be directly related to inflammatory status, which may represent a patho-physiological link between GDM and type 2 diabetes and, later on, metabolic syndrome

Incidence of microvascular dysfunction is increased in hyperlipidemic mice, reducing cerebral blood flow and impairing remote memory

IntroductionThe development of cognitive dysfunction is not necessarily associated with diet-induced obesity. We hypothesized that cognitive dysfunction might require additional vascular damage, for example, in atherosclerotic mice.MethodsWe induced atherosclerosis in male C57BL/6N mice by injecting AAV-PCSK9DY (2x1011 VG) and feeding them a cholesterol-rich Western diet. After 3 months, mice were examined for cognition using Barnes maze procedure and for cerebral blood flow. Cerebral vascular morphology was examined by immunehistology.ResultsIn AAV-PCSK9DY-treated mice, plaque burden, plasma cholesterol, and triglycerides are elevated. RNAseq analyses followed by KEGG annotation show increased expression of genes linked to inflammatory processes in the aortas of these mice. In AAV-PCSK9DY-treated mice learning was delayed and long-term memory impaired. Blood flow was reduced in the cingulate cortex (-17%), caudate putamen (-15%), and hippocampus (-10%). Immunohistological studies also show an increased incidence of string vessels and pericytes (CD31/Col IV staining) in the hippocampus accompanied by patchy blood-brain barrier leaks (IgG staining) and increased macrophage infiltrations (CD68 staining).DiscussionWe conclude that the hyperlipidemic PCSK9DY mouse model can serve as an appropriate approach to induce microvascular dysfunction that leads to reduced blood flow in the hippocampus, which could explain the cognitive dysfunction in these mice