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Cerebrovascular alterations are a key feature of Alzheimer's disease (AD) pathogenesis. However, whether vascular damage contributes to synaptic dysfunction and how it synergizes with amyloid pathology to cause neuroinflammation and cognitive decline remain poorly understood. Here, we show that the blood protein fibrinogen induces spine elimination and promotes cognitive deficits mediated by CD11b-CD18 microglia activation. 3D molecular labeling in cleared mouse and human AD brains combined with repetitive in vivo two-photon imaging showed focal fibrinogen deposits associated with loss of dendritic spines independent of amyloid plaques. Fibrinogen-induced spine elimination was prevented by inhibiting reactive oxygen species (ROS) generation or genetic ablation of CD11b. Genetic elimination of the fibrinogen binding motif to CD11b reduced neuroinflammation, synaptic deficits, and cognitive decline in the 5XFAD mouse model of AD. Thus, fibrinogen-induced spine elimination and cognitive decline via CD11b link cerebrovascular damage with immune-mediated neurodegeneration and may have important implications in AD and related conditions.

Activation of innate immunity and deposition of blood-derived fibrin in the central nervous system (CNS) occur in autoimmune and neurodegenerative diseases, including multiple sclerosis (MS) and Alzheimer's disease (AD). However, the mechanisms that link disruption of the blood-brain barrier (BBB) to neurodegeneration are poorly understood, and exploration of fibrin as a therapeutic target has been limited by its beneficial clotting functions. Here we report the generation of monoclonal antibody 5B8, targeted against the cryptic fibrin epitope γ377-395, to selectively inhibit fibrin-induced inflammation and oxidative stress without interfering with clotting. 5B8 suppressed fibrin-induced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation and the expression of proinflammatory genes. In animal models of MS and AD, 5B8 entered the CNS and bound to parenchymal fibrin, and its therapeutic administration reduced the activation of innate immunity and neurodegeneration. Thus, fibrin-targeting immunotherapy inhibited autoimmunity- and amyloid-driven neurotoxicity and might have clinical benefit without globally suppressing innate immunity or interfering with coagulation in diverse neurological diseases.

Genome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p < 1.0 × 10-7; replication: N = 7,182, p  30%) and independent of known BP genetic variants, explaining an additional 1.4% and 2.0% of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.

Blood-brain barrier (BBB) disruption alters the composition of the brain microenvironment by allowing blood proteins into the CNS. However, whether blood-derived molecules serve as extrinsic inhibitors of remyelination is unknown. Here we show that the coagulation factor fibrinogen activates the bone morphogenetic protein (BMP) signaling pathway in oligodendrocyte progenitor cells (OPCs) and suppresses remyelination. Fibrinogen induces phosphorylation of Smad 1/5/8 and inhibits OPC differentiation into myelinating oligodendrocytes (OLs) while promoting an astrocytic fate in vitro. Fibrinogen effects are rescued by BMP type I receptor inhibition using dorsomorphin homolog 1 (DMH1) or CRISPR/Cas9 activin A receptor type I (ACVR1) knockout in OPCs. Fibrinogen and the BMP target Id2 are increased in demyelinated multiple sclerosis (MS) lesions. Therapeutic depletion of fibrinogen decreases BMP signaling and enhances remyelination in vivo. Targeting fibrinogen may be an upstream therapeutic strategy to promote the regenerative potential of CNS progenitors in diseases with remyelination failure.

Resting‐state functional magnetic resonance imaging (rs‐fMRI) is frequently used to study brain function; but, it is unclear whether BOLD‐signal fluctuation amplitude and functional connectivity are associated with vascular factors, and how vascular‐health factors are reflected in rs‐fMRI metrics in the healthy population. As arterial stiffening is a known age‐related cardiovascular risk factor, we investigated the associations between aortic stiffening (as measured using pulse‐wave velocity [PWV]) and rs‐fMRI metrics. We used cardiac MRI to measure aortic PWV (an established indicator of whole‐body vascular stiffness), as well as dual‐echo pseudo‐continuous arterial‐spin labeling to measure BOLD and CBF dynamics simultaneously in a group of generally healthy adults. We found that: (1) higher aortic PWV is associated with lower variance in the resting‐state BOLD signal; (2) higher PWV is also associated with lower BOLD‐based resting‐state functional connectivity; (3) regions showing lower connectivity do not fully overlap with those showing lower BOLD variance with higher PWV; (4) CBF signal variance is a significant mediator of the above findings, only when averaged across regions‐of‐interest. Furthermore, we found no significant association between BOLD signal variance and systolic blood pressure, which is also a known predictor of vascular stiffness. Age‐related vascular stiffness, as measured by PWV, provides a unique scenario to demonstrate the extent of vascular bias in rs‐fMRI signal fluctuations and functional connectivity. These findings suggest that a substantial portion of age‐related rs‐fMRI differences may be driven by vascular effects rather than directly by brain function. [ABSTRACT FROM AUTHOR]

Background: Obesity is associated with cardiometabolic disturbances, which may have significant implications for musculoskeletal health and exercise tolerance. Objective: We sought to determine the association between muscle structure, function, and metabolism in adolescents across the weight spectrum. Methods: This cross‐sectional case–control study included overweight and obese participants (n = 24) 8–18 years of age with a body mass index (BMI) ≥ 85th percentile for age and gender, and non‐obese participants (n = 24) with a BMI < 85th percentile. Body composition, physical activity, peak aerobic capacity, cardiometabolic blood markers and insulin resistance (measured by the homeostatic model assessment of insulin resistance, HOMA‐IR), skeletal muscle mitochondrial oxidative capacity (via 31Phosphorous‐Magnetic Resonance Spectroscopy, 31P‐MRS, to assess phosphocreatine (PCr) recovery after exercise), and extramyocellular and intramyocellular lipid (IMCL) levels (via 1Hydrogen‐MRS) were assessed. Stepwise regression was performed to examine the factors associated with oxidative capacity. Results: bese and overweight patients had similar age, height, and physical activity to non‐obese controls, but obese and overweight participants exhibited higher insulin resistance. Obese and overweight participants had longer PCr recovery than non‐obese controls following 5x30s of moderate‐intensity exercise (51.2 ± 20.1 s vs. 23.9 ± 7.5 s, p = 0.004). In univariate correlation analysis, impaired PCr recovery was associated with a higher BMI z‐score (rs = 0.51, p < 0.001), circulating triglycerides (rs = 0.41, p = 0.005), and HOMA‐IR (rs = 0.46, p = 0.001). In stepwise multivariate regression analysis, impaired PCr recovery was associated with a higher BMI z‐score (β = 0.47, p = 0.002), but not insulin resistance (β = 0.07, p = 0.07) or circulating triglycerides (β = 0.16 p = 0.33). Conclusion: A slower phosphocreatine recovery following aerobic exercise is strongly associated with increasing adiposity. A slower metabolic recovery following aerobic exercise stress suggests that endurance exercise training in obese adolescents may be an optimal strategy to target exercise intolerance in this cohort. [ABSTRACT FROM AUTHOR]

BACKGROUND: Glycerophosphocholine (GPC) metabolites modulate atherosclerosis and thus risk for cardiovascular disease (CVD). Preclinical CVD may start during adolescence. Here, we used targeted serum lipidomics to identify a new panel of GPCs, and tested whether any of these GPCs are associated, in adolescence, with classical risk factors of CVD, namely excess visceral fat (VF), elevated blood pressure, insulin resistance, and atherogenic dyslipidemia. METHODS: We studied a population-based sample of 990 adolescents (12-18 years, 48% male), as part of the Saguenay Youth Study. Using liquid chromatography-electrospray ionization-mass spectrometry, we identified 69 serum GPCs within the 450 to 680 m/z range. We measured VF with MRI. RESULTS: We identified several novel GPCs that were associated with multiple CVD risk factors. Most significantly, PC16:0/2:0 was negatively associated with VF (P=1.4×10-19), blood pressure (P=7.7×10-5), and fasting triacylglycerols (P=9.0×10-5), and PC14:1/0:0 was positively associated with VF (P=3.0×10-7), fasting insulin (P=5.4×10-32), and triacylglycerols (P=1.4×10-29). The Sobel test of mediation revealed that both GPCs mediated their respective relations between VF (as a potential primary exposure) and CVD risk factors (as outcomes, P values<1.3×10-3). Furthermore, a GPC shown recently to predict incident coronary heart disease in older adults, PC18:2/0:0, was associated with several CVD risk factors in adolescents; these associations were less strong than those with the newly identified GPCs. CONCLUSIONS: We identified novel GPCs strongly associated with multiple CVD risk factors in adolescents. These GPCs may be sensitive indicators of obesity-related risk for CVD outcomes in adults, and may improve biological understanding of CVD risk. [ABSTRACT FROM AUTHOR]

Adolescents who exhibit exaggerated blood pressure (BP) reactivity to physical and mental challenges are at increased risk of developing hypertension in adulthood. BP at rest and in response to challenges is higher in males than females, beginning in early adolescence. CYP17A1 is one of the well-established gene loci of adult hypertension. Here, we investigated whether this gene locus is associated with elevated BP at rest and in response to physical (active standing) and mental (math stress) challenges in adolescence. We studied 496 male and 532 female adolescents (age 12–18 years) who were recruited from a genetic founder population. Our results showed that the variant of CYP17A1 rs10786718 was associated with enhanced BP reactivity to the mental but not physical challenge and in males but not females. In males, BP increase in response to math stress was higher in major versus minor allele homozygotes by 7.6 mm Hg (P=8.3×10-6). Resting BP was not associated with the CYP17A1 variant in either sex. These results suggest that, in adolescent males but not females, CYP17A1 enhances BP reactivity to mental stress. Whether this effect contributes to the higher prevalence of hypertension in males than females later in life remains to be determined. [ABSTRACT FROM AUTHOR]

Objective To study the relationships between parameters of glucose and insulin metabolism and visceral and abdominal ectopic fat in youth. Methods A cross sectional study of 50 children (24 females), 8-18 years old. Anthropometrics, body composition, blood-work and visceral and ectopic fat by magnetic resonance imaging were assessed. Insulin secretion, insulin sensitivity and beta cell function were calculated from an oral glucose tolerance test. Results BMI z-scores ranged between −1.3 and 4.5. The hepatic fat fraction (HFF) ranged between 0 and 36% and pancreatic fat fraction (PFF) between 0 and 14%. Visceral fat, HFF and PFF were associated with clinical and biochemical metabolic abnormalities, and correlated with markers of insulin sensitivity ( r = −0.60, P < 0.01; r = −0.64, P < 0.01; r = −0.48, P < 0.01, respectively) insulin secretion ( r = 0.55, P < 0.01; r = 0.57, P < 0.01; r = 0.41, P < 0.01, respectively), and beta cell function ( r = −0.49, P < 0.01; r = −0.59, P < 0.01; r = −0.39, P < 0.01, respectively). Conclusions Accumulations of pancreatic and hepatic fat have complementary clinical consequences in youth. While visceral and hepatic fat demonstrated a dominant effect, even relatively small degrees of pancreatic fat deposition may contribute to metabolic alterations. [ABSTRACT FROM AUTHOR]

Background and Objectives Turner syndrome ( TS) confers increased lifetime risk of type 2 diabetes mellitus and cardiovascular disease. We compared cardiometabolic risk factors and measures of subcutaneous, visceral adipose tissue and intra-myocellular lipid between young TS girls and an age- and BMI-standard deviation scores ( SDS)-matched healthy female cohort. Patients and Methods A cross-sectional cohort study was conducted at the Hospital for Sick Children, Toronto. Nineteen TS and 17 control girls (13·7 ± 2·5 vs 12·7 ± 3·4 years of age, respectively, P = 0·30). Multiple-sample oral glucose tolerance test with measurement of fasting insulin, LDL, HDL, triglycerides, adiponectin and highly sensitive C-reactive protein (hs CRP) was performed. Subcutaneous adipose tissue, visceral adipose tissue intramyocellular lipid levels evaluated by magnetic resonance techniques. Insulin secretion ( IS), sensitivity (Si) and the insulin secretion-sensitivity index ( ISSI-2) were calculated from oral glucose tolerance test data. Results Five TS and no controls had impaired fasting glucose or impaired glucose tolerance; none had type 2 diabetes mellitus. Insulin sensitivity and insulin secretion were similar between groups; ISSI-2 was lower in TS (923·5 ± 307·3 vs 659·1 ± 387·3; P = 0·03). TS girls had higher blood pressure (82·5 ± 13·6 vs 73·5 ± 5·5 mmHg; P = 0·0146), waist circumference (76·0 ±11·8 vs 65·9 ± 9·7; P = 0·0087) and subcutaneous adipose tissue (135·6 ± 88·6 vs 69·3 ± 59·9; P = 0·01) than controls. Visceral adipose tissue, intramyocellular lipid levels and adiponectin were not different between groups. TS girls also had higher triglycerides (1·1 ± 0·6 vs 0·7 ± 0·3; P = 0·003), total cholesterol (4·4 ± 0·7 vs 3·9 ± 0·4; P = 0·02) and hs CRP (2·0 ± 1·9 vs 0·8 ± 0·3; P = 0·01). Conclusions TS girls exhibit more cardiometabolic risk factors and reduced beta cell function compared with age- and BMI- SDS-matched girls. Increased awareness of early risk of type 2 diabetes mellitus and hypertension in TS girls is needed. [ABSTRACT FROM AUTHOR]

Objective: Dysregulation of the autonomic nervous system is thought to be involved in craniopharyngioma-related hypothalamic obesity (CRHO). Increased parasympathetic activity and decreased sympathetic activity have been suggested. We aimed to study autonomic activity using heart rate variability (HRV) and biochemical measures in youth with CRHO compared with controls and to explore relationships between obesity and autonomic indices. Design: A cross-sectional study of 16 youth with CRHO and 16 controls matched for sex, age, and BMI. Methods: Anthropometrics, fasting blood-work, resting energy expenditure (REE), 24-h HRV, and 24-h urine catecholamines were assessed. Quality of life, sleepiness, and autonomic symptoms were evaluated. Power spectral analysis of the HRV was performed. Results: HRV power spectral analysis parameters of both parasympathetic activity (mean high frequency (HF (ms²)) 611 ± 504 vs 459 ± 336, P = 0.325) and sympathetic activity (median low frequency/HF 1.62 (1.37, 2.41) vs 1.89 (1.44, 2.99), P = 0.650) did not differ between the groups. Parasympathetic activity negatively correlated with central adiposity in both groups (r = -0.53, P = 0.034 and r = -0.54, P = 0.029) and sympathetic activity positively correlated with central adiposity in CRHO (r = 0.51, P = 0.043). Youth with CRHO had significantly lower REE; lower health and activity scores in the quality of life questionnaires, and higher sleepiness scores. Conclusions: Autonomic activity was similar in CRHO and control subjects. The degree of central adiposity correlated negatively with parasympathetic activity and positively with sympathetic activity in children with CRHO. These results provide a new perspective regarding autonomic balance in this unique patient population. [ABSTRACT FROM AUTHOR]

Objective. To assess the effect of combined diazoxide-metformin therapy in obese adolescents treated for craniopharyngioma. Design. A prospective open-label 6-month pilot treatment trial in 9 obese subjects with craniopharyngioma. Diazoxide (2mg/kg divided b.i.d., maximum 200 mg/day) and metformin (1000 mg b.i.d.). Whole body insulin sensitivity index (WBISI) and areaunder- the-curve insulin (AUCins) were calculated. Results. Seven subjects completed: 4M/3F, mean ± SD age 15.4 ± 2.9 years, weight 99.7 ± 26.3 kg, BMI 35.5 ± 5.6 kg/m2, and BMI SDS 2.3 ± 0.3. Two were withdrawn due to vomiting and peripheral edema. Of participants completing the study, the mean ± SD weight gain, BMI, and BMI SDS during the 6 months were reduced compared to the 6 months prestudy (+1.2 ± 5.9 versus +9.5 ± 2.7 kg, P = .004; -0.3 ± 2.3 versus +2.2 ± 1.5 kg/m2, P = .04; -0.04 ± 0.15 versus +0.11 ± 0.08, P = .021, resp.). AUCins correlated with weight loss (r = 0.82, P = .02) and BMI decrease (r = 0.96, P = .009). Conclusion. Combined diazoxide-metformin therapy was associated with reduced weight gain in patients with hypothalamic obesity. AUCins at study commencement predicted effectiveness of the treatment [ABSTRACT FROM AUTHOR]

In industrialized countries, prenatal exposure to maternal cigarette smoking (PEMCS) is the most common environmental insult to the fetus. Here, we tested the hypothesis that PEMCS amplifies accumulation of abdominal fat during the accelerated weight gain occurring in late puberty. This hypothesis was tested in 508 adolescents (12–18 years, 237 exposed prenatally to maternal cigarette smoking) in whom subcutaneous and intra-abdominal fat were quantified with magnetic resonance imaging (MRI). We found that, in early puberty, exposed and nonexposed adolescents did not differ in MRI-based measures of adiposity. In late puberty, on the other hand, exposed compared with nonexposed adolescents demonstrated markedly higher quantities of both subcutaneous fat (by 26%, P = 0.004) and intra-abdominal fat (by 33%, P = 0.001). These group differences remained virtually unchanged after adjusting for sex and potential confounders, including birth weight and breastfeeding. As such, our results suggest that PEMCS may represent a major risk factor for the development of abdominal obesity at the later stages of puberty. [ABSTRACT FROM AUTHOR]

Intra-abdominal accumulation of fat is a hallmark of male body-fat distribution and a major risk factor for hypertension. Sympathoactivation may be one of the mechanisms linking intra-abdominal obesity to hypertension. The aim of the present study was to investigate whether a functional variation in the androgen-receptor gene (AR, a variable number of CAG repeats in exon 1) is associated with intra-abdominal adiposity, sympathetic modulation of vasomotor tone, and blood pressure in adolescent boys but not girls. We studied 223 boys and 259 girls (age 12 to 18 years) from a French-Canadian founder population. Intra-abdominal fat and subcutaneous-abdominal fat were quantified with an MRI. Blood pressure was recorded beat-to-beat during an hour-long protocol including physical and mental challenges, and these blood pressure time series were used to assess sympathetic modulation of vasomotor tone by power spectral analysis. The results showed that boys with a "low" versus "intermediate" or "high" CAG-repeat number in AR demonstrated higher intra-abdominal fat (by 28% and 48%, respectively) but not subcutaneous-abdominal fat. These intra-abdominal fat differences remained significant after adjusting for serum levels of sex hormones and subcutaneous-abdominal fat. Furthermore, boys with low versus intermediate or high CAG-repeat numbers also showed higher blood pressure, with the differences being most pronounced during mental stress (8.0 and 8.5 mm Hg, respectively) and higher sympathetic modulation of vasomotor tone. As expected, no such differences were seen among girls. In adolescent boys, low CAG-repeat numbers in AR may be a genetic risk factor for intra-abdominal obesity and hypertension; sympathoactivation may be an underlying link between the 2 conditions. [ABSTRACT FROM AUTHOR]

The article discusses a study about the association of the common variant of the fat mass and obesity (FTO) gene with an increase in adiposity and in blood pressure (BP) among French Canadians. The study involved 485 adolescents who were subjected to detailed body-composition and cardiovascular phenotyping. It notes that those having the FTO-risk genotype presented greater adiposity and higher systolic BP as compared to those without the genotype. The study suggests that FTO can increase the risk for both obesity and hypertension.

Objective:Visceral fat (VF) increases cardiometabolic risk more than fat stored subcutaneously. Here, we investigated how well routine clinical measures of adiposity, namely body mass index (BMI) and waist circumference (waist), predict VF and subcutaneous fat (SF) in a large population-based sample of adolescents. As body-fat distribution differs between males and females, we performed these analyses separately in each sex. Design and Methods:VF and SF were measured by magnetic resonance imaging in 1,002 adolescents (482 males, age 12–18 years). Relationships of BMI and waist with VF and SF were tested in multivariable analyses, which adjusted for potentially confounding effects of age and height. Results:In both males and females, BMI and waist were highly correlated with VF and SF, and explained 55–76% of their total variance. When VF was adjusted for SF, however, BMI and waist explained, respectively, only 0% and 4% of VF variance in males, and 4% and 11% of VF variance in females. In contrast, when SF was adjusted for VF, BMI and waist explained, respectively, 36% and 21% of SF variance in males, and 48% and 23% of SF variance in females. These relationships were similar during early and late puberty. Conclusions and Relevance:During adolescence, routine clinical measures of adiposity predict well SF but not VF. This holds for both sexes and throughout puberty. Further longitudinal studies are required to assess how well these measures predict changes of VF and SF over time. Given the clinical importance of VF, development of cost-effective imaging techniques and/or robust biomarkers of VF accumulation that would be suitable in everyday clinical practice is warranted. [ABSTRACT FROM AUTHOR]

Individuals who exhibit exaggerated blood pressure (BP) reactivity to physical and mental challenges at a young age are at increased risk of developing hypertension in adulthood. Hypertension is a complex genetic trait that is more prevalent in men than women during reproductive age. CYP17A1 is one of the best-established gene loci of hypertension. It encodes a key enzyme in the steroidogenic pathway that produces mineralocorticoids, glucocorticoids, androgens, and estrogens; as such, it may influence BP reactivity in a sex-specific manner. Here, we investigated whether CYP17A1 is associated with BP reactivity to physical and mental challenges in adolescence. In 285 male and 311 female adolescents (age 12-18 years), we measured systolic BP (SBP) and diastolic BP (DBP) beat-by-beat during a 52-minute protocol, which included a physical (10-min standing) and mental (2-min math test) challenge and we genotyped 8 tagging single nucleotide polymorphisms (SNPs) that covered the entire region of CYP17A1. Genotype-phenotype association tests were performed separately in males and females, while adjusting for age, height and initial BP. Our results showed that 6 SNPs were associated with higher SBP and DBP reactivity (p=0.003-0.0001), but only in response to mental stress and only in boys. At rs619824, minor allele homozygotes differed from major allele homozygotes by 8.7 mm Hg of SBP (p=3x10-4) and 4.8 mm Hg of DBP (p=1x10-4) in boys, and the two groups varied only by 2.0 mm Hg of SBP (p=0.31) and 0.9 mm Hg of DBP (p=0.42) in girls. These results suggest that CYP17A1 may contribute to the development of hypertension through the regulation of the stress response and that, at least in adolescence, this effect appears to be present in males but not in females. [ABSTRACT FROM AUTHOR]

Context: Visceral fat (VF), more than fat elsewhere in the body [mostly subcutaneous fat (SF)], promotes systemic inflammation and related disease. The mechanisms of preferentially visceral accumulation of body fat are largely unknown., Objective: To identify genetic loci and mechanistic pathways of preferential accumulation of VF and associated low-grade systemic inflammation., Design: Genome-wide association study (GWAS)., Setting and Participants: Population-based cohort of 1586 adolescents (aged 12 to 19 years) and adults (aged 36 to 65 years)., Main Outcome Measures: Abdominal VF and SF were measured with MRI, total body fat (TBF) was assessed with bioimpedance, and low-grade systemic inflammation was examined by serum C-reactive protein (CRP) measurement., Results: This GWAS of preferential accumulation of VF identified a significant locus on chromosome 6 at rs803522 (P = 1.1 × 10-9 or 4.3 × 10-10 for VF adjusted for SF or TBF, respectively). The major allele was associated with more VF; the association was similar in adolescents and adults. The allele was also associated with higher CRP level, but this association was stronger in adults than adolescents (P for interaction = 4.5 × 10-3). In adults, VF was a significant mediator (P = 1.9× 10-4) in the association between the locus and CRP, explaining 30% of the mediation. The locus was near ATG5, encoding an autophagy molecule reported to modulate adipocyte size and macrophage polarization., Conclusion: A genetic locus near ATG5 regulates preferential accumulation of VF (vs SF) in youth and adulthood and contributes to the development of systemic inflammation in adulthood., (Copyright © 2019 Endocrine Society.)

Hypoxia-like tissue alterations, characterized by the upregulation of hypoxia-inducible factor-1 α (HIF-1 α ), have been described in the normal appearing white matter and pre-demyelinating lesions of multiple sclerosis (MS) patients. As HIF-1 α regulates the transcription of a wide set of genes involved in neuroprotection and neuroinflammation, HIF-1 α expression may contribute to the pathogenesis of inflammatory demyelination. To test this hypothesis, we analyzed the effect of cell-specific genetic ablation or overexpression of HIF-1 α on the onset and progression of experimental autoimmune encephalomyelitis (EAE), a mouse model for MS. HIF-1 α was mainly expressed in astrocytes and microglia/macrophages in the mouse spinal cord at the peak of EAE. However, genetic ablation of HIF-1 α in astrocytes and/or myeloid cells did not ameliorate clinical symptoms. Furthermore, conditional knock-out of Von Hippel Lindau, a negative regulator of HIF-1 α stabilization, failed to exacerbate the clinical course of EAE. In accordance with clinical symptoms, genetic ablation or overexpression of HIF-1 α did not change the extent of spinal cord inflammation and demyelination. Overall, our data indicate that despite dramatic upregulation of HIF-1 α in astrocytes and myeloid cells in EAE, HIF-1 α expression in these two cell types is not required for the development of inflammatory demyelination. Despite numerous reports indicating HIF-1 α expression in glia, neurons, and inflammatory cells in the CNS of MS patients, the cell-specific contribution of HIF-1 α to disease pathogenesis remains unclear. Here we show that although HIF-1 α is dramatically upregulated in astrocytes and myeloid cells in EAE, cell-specific depletion of HIF-1 α in these two cell types surprisingly does not affect the development of neuroinflammatory disease. Together with two recently published studies showing a role for oligodendrocyte-specific HIF-1 α in myelination and T-cell-specific HIF-1 α in EAE, our results demonstrate a tightly regulated cellular specificity for HIF-1 α contribution in nervous system pathogenesis.

Background: Turner Syndrome women are at high risk of vascular disease and the assessment of early risk factors in Turner Syndrome girls is an emerging focus of research. Our objective was to evaluate endothelial function (EF), a preclinical measure of atherosclerosis, in Turner Syndrome girls compared with controls., Methods: A cross-sectional case-control study of Turner Syndrome girls and healthy controls. Subjects underwent fasting insulin and glucose with calculation of HOMA-IR, fasting lipid profile, anthropometrics, and EF testing using peripheral arterial tonometry (PAT). Subjects, aged 10-18 years, had karyotype-confirmed Turner Syndrome; growth hormone (GH), thyroxine and estrogen use were not exclusion criteria. Controls were age- and BMI-matched healthy girls. Fifteen Turner Syndrome and 15 controls were recruited., Results: Turner Syndrome girls had lower height, higher HDL and higher waist:height ratio than controls. PAT-hyperemia ratio (RH-PAT) scores were lower in Turner Syndrome (1.64 ± 0.34 vs. 2.08 ± 0.32, p = 0.002) indicating impaired EF. Among Turner Syndrome, RH-PAT did not vary with estrogen therapy or with karyotype 45,XO compared with other karyotypes. However, endothelial function was better in GH-treated compared with GH-untreated Turner Syndrome (1.80 ± 0.36 vs. 1.4 + 0.22, p = 0.02) although there were no differences in HOMA-IR, adiponectin or IGF-1., Conclusion: Girls with Turner Syndrome exhibit impaired endothelial function compared with controls, which may explain higher risk for vascular disease. GH may protect endothelial function in Turner Syndrome.

The search for genes of complex traits is aided by the availability of multiple quantitative phenotypes collected in geographically isolated populations. Here we provide rationale for a large-scale study of gene-environment interactions influencing brain and behavior and cardiovascular and metabolic health in adolescence, namely the Saguenay Youth Study (SYS). The SYS is a retrospective study of long-term consequences of prenatal exposure to maternal cigarette smoking (PEMCS) in which multiple quantitative phenotypes are acquired over five sessions (telephone interview, home, hospital, laboratory, and school). To facilitate the search for genes that modify an individual's response to an in utero environment (i.e. PEMCS), the study is family-based (adolescent sibships) and is carried out in a relatively geographically isolated population of the Saguenay Lac-Saint-Jean (SLSJ) region in Quebec, Canada. DNA is acquired in both biological parents and in adolescent siblings. A genome-wide scan will be carried out with sib-pair linkage analyses, and fine mapping of identified loci will be done with family-based association analyses. Adolescent sibships (12-18 years of age; two or more siblings per family) are recruited in high schools throughout the SLSJ region; only children of French-Canadian origin are included. Based on a telephone interview, potential participants are classified as exposed or nonexposed prenatally to maternal cigarette smoking; the two groups are matched for the level of maternal education and the attended school. A total of 500 adolescent participants in each group will be recruited and phenotyped. The following types of datasets are collected in all adolescent participants: (1) magnetic resonance images of brain, abdominal fat, and kidneys, (2) standardized and computer-based neuropsychological tests, (3) hospital-based cardiovascular, body-composition and metabolic assessments, and (4) questionnaire-derived measures (e.g. life habits such as eating and physical activity; drug, alcohol use and delinquency; psychiatric symptoms; personality; home and school environment; academic and vocational attitudes). Parents complete a medical questionnaire, home-environment questionnaire, a handedness questionnaire, and a questionnaire about their current alcohol and drug use, depression, anxiety, and current and past antisocial behavior. To date, we have fully phenotyped a total of 408 adolescent participants. Here we provide the description of the SYS and, using the initial sample, we present information on ascertainment, demographics of the exposed and nonexposed adolescents and their parents, and the initial MRI-based assessment of familiality in the brain size and the volumes of grey and white matter., ((c) 2007 Wiley-Liss, Inc.)