Recent progress in translational research on neurovascular and neurodegenerative disorders

The already established and widely used intravenous application of recombinant tissue plasminogen activator as a re-opening strategy for acute vessel occlusion in ischemic stroke was recently added by mechanical thrombectomy, representing a fundamental progress in evidence-based medicine to improve the patient’s outcome. This has been paralleled by a swift increase in our understanding of pathomechanisms underlying many neurovascular diseases and most prevalent forms of dementia. Taken together, these current advances offer the potential to overcome almost two decades of marginally successful translational research on stroke and dementia, thereby spurring the entire field of translational neuroscience. Moreover, they may also pave the way for the renaissance of classical neuroprotective paradigms. This review reports and summarizes some of the most interesting and promising recent achievements in neurovascular and dementia research. It highlights sessions from the 9th International Symposium on Neuroprotection and Neurorepair that have been discussed from April 19th to 22nd in Leipzig, Germany. To acknowledge the emerging culture of interdisciplinary collaboration and research, special emphasis is given on translational stories ranging from fundamental research on neurode- and -regeneration to late stage translational or early stage clinical investigations

Residential Proximity to a Major Roadway Is Associated with Features of Asthma Control in Children

BACKGROUND: While several studies suggest that traffic-related air pollutants are detrimental for respiratory health, few studies have examined relationships between residential proximity to a major roadway and asthma control in children. Furthermore, a major limitation of existing research is reliance on self-reported outcomes. We therefore determined the spatial relationship between the distance from a major roadway and clinical, physiologic and inflammatory features of asthma in a highly characterized sample of asthmatic children 6-17 years of age across a wide range of severities. We hypothesized that a closer residential proximity to a major roadway would be associated with increased respiratory symptoms, altered pulmonary function and a greater magnitude of airway and systemic inflammation. METHODOLOGY/PRINCIPAL FINDINGS: 224 children 6-17 years with confirmed asthma completed questionnaires and underwent spirometry, plethysmography, exhaled nitric oxide determination, exhaled breath condensate collection and venipuncture. Residential distance from a major roadway was determined by mapping the geographic coordinates of the residential address in Geographic Information System software. The distance between the home address and the nearest major roadway was calculated according to the shortest distance between the two points (i.e., "as the crow flies"). Asthmatic children living in closer proximity to a major roadway had an increased frequency of wheezing associated with increased medication requirements and more hospitalizations even after controlling for potential confounders. These children also had increased airway resistance, increased airway inflammation reflected by a lower breath condensate pH, and higher plasma EGF concentrations. CONCLUSIONS/SIGNIFICANCE: These findings suggest that closer residential proximity to a major roadway is associated with poorer asthma control in school-age children. Assessment of residential proximity to major roadways may be useful in the clinical evaluation of asthma in children

Polygenic prediction of educational attainment within and between families from genome-wide association analyses in 3 million individuals

We conduct a genome-wide association study (GWAS) of educational attainment (EA) in a sample of ~3 million individuals and identify 3,952 approximately uncorrelated genome-wide-significant single-nucleotide polymorphisms (SNPs). A genome-wide polygenic predictor, or polygenic index (PGI), explains 12-16% of EA variance and contributes to risk prediction for ten diseases. Direct effects (i.e., controlling for parental PGIs) explain roughly half the PGI's magnitude of association with EA and other phenotypes. The correlation between mate-pair PGIs is far too large to be consistent with phenotypic assortment alone, implying additional assortment on PGI-associated factors. In an additional GWAS of dominance deviations from the additive model, we identify no genome-wide-significant SNPs, and a separate X-chromosome additive GWAS identifies 57

New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk

To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10−8), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk

Формирование эмоциональной культуры как компонента инновационной культуры студентов

Homozygosity has long been associated with rare, often devastating, Mendelian disorders1 and Darwin was one of the first to recognise that inbreeding reduces evolutionary fitness2. However, the effect of the more distant parental relatedness common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity, ROH), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power3,4. Here we use ROH to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts and find statistically significant associations between summed runs of homozygosity (SROH) and four complex traits: height, forced expiratory lung volume in 1 second (FEV1), general cognitive ability (g) and educational attainment (nominal p<1 × 10−300, 2.1 × 10−6, 2.5 × 10−10, 1.8 × 10−10). In each case increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing convincing evidence for the first time that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples5,6, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein (LDL) cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection7, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been

New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk

To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P <5 x 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.Peer reviewe

Plasma epidermal growth factor (EGF) concentrations in children with a residential proximity (A) within 417 meters (<417 meters, n = 26; >417 meters, n = 91) and (B) within 150 meters (<150 meters, n = 10; >150 meters, n = 108) of a major roadway.

<p>Whiskers represent the 10^th to 90^th percentile and dots represent individual data points. Significance testing was adjusted for payor status, race, parental history of asthma, environmental tobacco smoke exposure, and gastroesophageal reflux.</p

Deaerated breath pH in children with a residential proximity (A) within 417 meters (<417 meters, n = 25; >417 meters, n = 99) and (B) within 150 meters (<150 meters, n = 10; >150 meters, n = 114) of a major roadway.

<p>Whiskers represent the 10^th to 90^th percentile and dots represent individual data points. Significance testing was adjusted for payor status, race, parental history of asthma, environmental tobacco smoke exposure, and gastroesophageal reflux.</p

Associations between residential proximity to a major roadway (<150 meters [N = 18] versus >150 meters [N = 206]) and outcomes in asthmatic children identified through exploratory analyses.

1<p>Adjusted for payor status (private insurance versus Medicaid), race (white versus non-white), parental history of asthma (yes versus no), environmental tobacco smoke exposure at least one day per week (yes versus no), and history of gastroesophageal reflux (yes versus no).</p

Airway resistance (Raw) percent predicted values in children with a residential proximity (A) within 417 meters (<417 meters, n = 37; >417 meters, n = 96) and (B) within 150 meters (<150 meters, n = 17; >150 meters, n = 116) of a major roadway.

<p>Whiskers represent the 10^th to 90^th percentile and dots represent individual data points. Significance testing was adjusted for payor status, race, parental history of asthma, environmental tobacco smoke exposure, and gastroesophageal reflux.</p