Blood substitution therapy rescues the brain of mice from ischemic damage

Acute stroke causes complex, pathological, and systemic responses that have not been treatable by any single medication. In this study, using a murine transient middle cerebral artery occlusion stroke model, a novel therapeutic strategy is proposed, where blood replacement (BR) robustly reduces infarctions and improves neurological deficits in mice. Our analyses of immune cell subsets suggest that BR therapy substantially decreases neutrophils in blood following a stroke. Electrochemiluminescence detection demonstrates that BR therapy reduces cytokine storm in plasma and ELISA demonstrates reduced levels of matrix metalloproteinase-9 (MMP-9) in the plasma and brains at different time points post-stroke. Further, we have demonstrated that the addition of MMP-9 to the blood diminishes the protective effect of the BR therapy. Our study is the first to show that BR therapy leads to profoundly improved stroke outcomes in mice and that the improved outcomes are mediated via MMP-9. These results offer new insights into the mechanisms of stroke damage

Trace element geochemistry and stable isotopic (δ13C and δ15N) records of the Paleocene coals, Salt Range, Punjab, Pakistan

This is the final version. Available on open access from Elsevier via the DOI in this recordThe Paleocene coals of the Salt Range in the Punjab Province of Pakistan have great economic potential; however, their trace element and stable isotopic characteristics have not been studied in detail except for a few sporadic samples. In this study, a total of 59 coal samples of which 14 are obtained from open cast mines have been investigated for elemental composition and δ13C-δ15N isotopic signatures. Average contents of trace elements such as Co, Cr, Cu, Pb, Sr, Th, U, V, and Zn are 7.4, 41.7, 11.2, 12.5, 90.2, 4.0, 1.9, 128, and 31.1 mg/kg, respectively. These values, when compared with the World Coal Clarke values, were relatively higher in low-rank coals in comparison with Clarke values for brown coals. Likewise, As (20.4 mg/kg), Co (6.6 mg/kg), Cr (22.4 mg/kg), Cu (13.3 mg/kg), Pb (19.2 mg/kg), Sr (154.7 mg/kg), Th (2.5 mg/kg), V (47.8 mg/kg), and Zn (75.1 mg/kg) were significantly higher in the sub-bituminous to bituminous coals of the Salt Range. Mineralogical analysis, based on X-ray diffraction and energy dispersive X-ray spectroscopy, revealed that the studied samples contain illite, kaolinite calcite, gypsum, pyrite, and quartz. Elemental affinity with organic and inorganic phases of coals calculated by an indirect statistical approach indicated a positive association of ash content with Ag, Al, Co, Cr, Cs, Cu, Mn, P, Rb, Pb, Th, U, and V, suggesting the presence of inorganic components in studied coals. However, As, Fe, Sr, and Zn exhibit negative correlations that imply their association with the organic fraction. The δ13C and δ15N isotopic range and average values for 12 coal samples were − 24.94‰ to − 25.86‰ (−25.41‰) and − 2.77‰ to 3.22‰ (0.96‰), respectively, reflecting 3C type modern terrestrial vegetation were common in the palaeomires of studied coal seams. In addition, the trivial variations of 0.92‰ and 0.45‰ among 13C and 15N values can be attributed to water level fluctuations and plant assemblies

3D printing is a transformative technology in congenital heart disease

Survival in congenital heart disease has steadily improved since 1938, when Dr. Robert Gross successfully ligated for the first time a patent ductus arteriosus in a 7-year-old child. To continue the gains made over the past 80 years, transformative changes with broad impact are needed in management of congenital heart disease. Three-dimensional printing is an emerging technology that is fundamentally affecting patient care, research, trainee education, and interactions among medical teams, patients, and caregivers. This paper first reviews key clinical cases where the technology has affected patient care. It then discusses 3-dimensional printing in trainee education. Thereafter, the role of this technology in communication with multidisciplinary teams, patients, and caregivers is described. Finally, the paper reviews translational technologies on the horizon that promise to take this nascent field even further

Association of PCSK1 rs6234 with Obesity and Related Traits in a Chinese Han Population

Background: Common variants in PCSK1 have been reported to be associated with obesity in populations of European origin. We aimed to replicate this association in Chinese. Methodology/Principal Findings: Two PCSK1 variants rs6234 and rs6235 (in strong LD with each other, r 2 = 0.98) were genotyped in a population-based cohort of 3,210 Chinese Hans. The rs6234 was used for further association analyses with obesity and related traits. We found no significant association of rs6234 with obesity, overweight, BMI, waist circumference, or body fat percentage (P.0.05) in all participants. However, the rs6234 G-allele showed a significant association with increased risk of combined phenotype of obesity and overweight (OR 1.21[1.03–1.43], P = 0.0193) and a trend toward association with obesity (OR 1.25[0.98–1.61], P = 0.08) in men, but not in women (P$0.29). Consistently, the rs6234 G-allele showed significant association with increased BMI (P = 0.0043), waist circumference (P = 0.008) and body fat percentage (P = 0.0131) only in men, not in women (P$0.24). Interestingly, the rs6234 G-allele was significantly associated with increased HOMA-B (P = 0.0059) and decreased HOMA-S (P = 0.0349) in all participants. Conclusion/Significance: In this study, we found modest evidence for association of the PCSK1 rs6234 with BMI and overweight in men only but not in women, which suggested that PCSK1 rs6234 might not be an important contributor t

Longitudinal patterns in objective physical activity and sedentary time in a multi-ethnic sample of children from the UK

Background: Children of South Asian decent born in the UK display lower levels of physical activity than British Caucasians although no longitudinal data are available. Objectives: We aimed to investigate change in activity levels over 1 year in a diverse ethnic sample of children residing in London, UK. Methods: Children were categorized into ethnic groups (Caucasian/mixed, Black, South Asian). At baseline and 1-year follow-up, children’s objective physical activity was monitored (Actigraph accelerometer) for at least 1 day. Mixed models were employed to investigate differences in change in activity levels between ethnic groups. Results: A total of 281 children were included in the analyses. South Asians had a significantly greater increase in time spent sedentary at follow-up than those of a Caucasian/mixed ethnicity (B [ratio sedentary/wear time] = 0.024; 95% confidence interval 0.003, 0.046). South Asian children recorded lower moderate to vigorous physical activity at baseline (B = 6.5, 95% confidence interval, 11.1, 1.9 min d1, p = 0.006) although levels remained relatively stable over follow-up and changes did not differ across ethnic group. Conclusions: In a diverse ethnic sample of children from inner city London, those of a South Asian ethnicity exhibited a significantly greater increase in sedentary time over a period of 12 months in comparison with Caucasian/mixed and Black children

Congenital Hypogonadotropic Hypogonadism and Kallmann Syndrome: Past, Present, and Future

The proper development and coordination of the hypothalamic-pituitary-gonadal (HPG) axis are essential for normal reproductive competence. The key factor that regulates the function of the HPG axis is gonadotrophin-releasing hormone (GnRH). Timely release of GnRH is critical for the onset of puberty and subsequent sexual maturation. Misregulation in this system can result in delayed or absent puberty and infertility. Congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS) are genetic disorders that are rooted in a GnRH deficiency but often accompanied by a variety of non-reproductive phenotypes such as the loss of the sense of smell and defects of the skeleton, eye, ear, kidney, and heart. Recent progress in DNA sequencing technology has produced a wealth of information regarding the genetic makeup of CHH and KS patients and revealed the resilient yet complex nature of the human reproductive neuroendocrine system. Further research on the molecular basis of the disease and the diverse signal pathways involved will aid in improving the diagnosis, treatment, and management of CHH and KS patients as well as in developing more precise genetic screening and counseling regime

Melanocortin receptor accessory proteins in adrenal disease and obesity.

Melanocortin receptor accessory proteins (MRAPs) are regulators of the melanocortin receptor family. MRAP is an essential accessory factor for the functional expression of the MC2R/ACTH receptor. The importance of MRAP in adrenal gland physiology is demonstrated by the clinical condition familial glucocorticoid deficiency type 2. The role of its paralog melanocortin-2-receptor accessory protein 2 (MRAP2), which is predominantly expressed in the hypothalamus including the paraventricular nucleus, has recently been linked to mammalian obesity. Whole body deletion and targeted brain specific deletion of the Mrap2 gene result in severe obesity in mice. Interestingly, Mrap2 complete knockout (KO) mice have increased body weight without detectable changes to food intake or energy expenditure. Rare heterozygous variants of MRAP2 have been found in humans with severe, early-onset obesity. In vitro data have shown that Mrap2 interaction with the melanocortin-4-receptor (Mc4r) affects receptor signaling. However, the mechanism by which Mrap2 regulates body weight in vivo is not fully understood and differences between the phenotypes of Mrap2 and Mc4r KO mice may point toward Mc4r independent mechanisms

Genome wide association study identifies KCNMA1 contributing to human obesity

<p>Abstract</p> <p>Background</p> <p>Recent genome-wide association (GWA) analyses have identified common single nucleotide polymorphisms (SNPs) that are associated with obesity. However, the reported genetic variation in obesity explains only a minor fraction of the total genetic variation expected to be present in the population. Thus many genetic variants controlling obesity remain to be identified. The aim of this study was to use GWA followed by multiple stepwise validations to identify additional genes associated with obesity.</p> <p>Methods</p> <p>We performed a GWA analysis in 164 morbidly obese subjects (BMI:body mass index > 40 kg/m²) and 163 Swedish subjects (> 45 years) who had always been lean. The 700 SNPs displaying the strongest association with obesity in the GWA were analyzed in a second cohort comprising 460 morbidly obese subjects and 247 consistently lean Swedish adults. 23 SNPs remained significantly associated with obesity (nominal <it>P</it>< 0.05) and were in a step-wise manner followed up in five additional cohorts from Sweden, France, and Germany together comprising 4214 obese and 5417 lean or population-based control individuals. Three samples, n = 4133, were used to investigate the population-based associations with BMI. Gene expression in abdominal subcutaneous adipose tissue in relation to obesity was investigated for14 adults.</p> <p>Results</p> <p>Potassium channel, calcium activated, large conductance, subfamily M, alpha member <it>(KCNMA1) </it>rs2116830*G and <it>BDNF </it>rs988712*G were associated with obesity in five of six investigated case-control cohorts. In meta-analysis of 4838 obese and 5827 control subjects we obtained genome-wide significant allelic association with obesity for <it>KCNMA1 </it>rs2116830*G with <it>P </it>= 2.82 × 10^-10and an odds ratio (OR) based on cases vs controls of 1.26 [95% C.I. 1.12-1.41] and for <it>BDNF </it>rs988712*G with <it>P </it>= 5.2 × 10^-17and an OR of 1.36 [95% C.I. 1.20-1.55]. <it>KCNMA1 </it>rs2116830*G was not associated with BMI in the population-based samples. Adipose tissue (<it>P </it>= 0.0001) and fat cell (<it>P </it>= 0.04) expression of <it>KCNMA1 </it>was increased in obesity.</p> <p>Conclusions</p> <p>We have identified <it>KCNMA1 </it>as a new susceptibility locus for obesity, and confirmed the association of the <it>BDNF </it>locus at the genome-wide significant level.</p