Geographical, linguistic, and cultural influences on genetic diversity: Y-chromosomal distribution in Northern European populations

Peer reviewe

Association of Aortic Stiffness With Biomarkers of Neuroinflammation, Synaptic Dysfunction, and Neurodegeneration

OBJECTIVES: To test the hypothesis that increased aortic stiffening is associated with greater cerebrospinal fluid (CSF) evidence of core Alzheimer's disease pathology (Aβ, phosphorylated tau (p-tau)), neurodegeneration (total tau (t-tau)), synaptic dysfunction (neurogranin), neuroaxonal injury (neurofilament light (NFL)), and neuroinflammation (YKL-40, sTREM2), we analyzed pulse wave velocity (PWV) data and CSF data among older adults. METHODS: Participants free of stroke and dementia from the Vanderbilt Memory and Aging Project, an observational community-based study, underwent cardiac magnetic resonance to assess aortic pulse wave velocity (PWV, m/sec) and lumbar puncture to obtain CSF. Linear regressions related aortic PWV to CSF Aβ, p-tau, t-tau, neurogranin, NFL, YKL-40, and sTREM2 concentrations adjusting for age, race/ethnicity, education, apolipoprotein (APOE) ε4 status, Framingham Stroke Risk Profile, and cognitive diagnosis. Models were repeated testing PWV interactions with age, diagnosis, APOE-ε4, and hypertension on each biomarker. RESULTS: 146 participants were examined (72±6 years). Aortic PWV interacted with age on p-tau (β=0.31, p=0.04), t-tau, (β=2.67, p=0.05), neurogranin (β=0.94, p=0.04), and sTREM2 (β=20.4, p=0.05). Among participants over age 73 years, higher aortic PWV related to higher p-tau (β=2.4, p=0.03), t-tau (β=19.3, p=0.05), neurogranin (β=8.4, p=0.01), and YKL-40 concentrations (β=7880, p=0.005). Aortic PWV had modest interactions with diagnosis on neurogranin (β=-10.76, p=0.03) and hypertension status on YKL-40 (β=-18020, p<0.001). CONCLUSIONS: Among our oldest participants, age 74 years and older, greater aortic stiffening is associated with in vivo biomarker evidence of neuroinflammation, tau phosphorylation, synaptic dysfunction, and neurodegeneration, but not amyloidosis. Central arterial stiffening may lead to cumulative cerebral microcirculatory damage and blood flow delivery to tissue, resulting in neuroinflammation and neurodegeneration in more advanced age

Prevalence of Dysglycemia Among Coronary Artery Bypass Surgery Patients with No Previous Diabetic History

<p>Abstract</p> <p>Background</p> <p>Dysglycemia is a major risk factor for atherosclerosis. In many patient populations dysglycemia is under-diagnosed. Patients with severe coronary artery disease commonly have dysglycemia and there is growing evidence that dysglycemia, irrespective of underlying history of diabetes, is associated with adverse outcome in coronary artery bypass graft (CABG) surgery patients, including longer hospital stay, wound infections, and higher mortality. As HbA1c is an easy and reliable way of checking for dysglycemia we routinely screen all patients undergoing CABG for elevations in HbA1c. Our hypothesis was that a substantial number of patients with dysglycemia that could be identified at the time of cardiothoracic surgery despite having no apparent history of diabetes.</p> <p>Methods</p> <p>1045 consecutive patients undergoing CABG between 2007 and 2009 had HbA1c measured pre-operatively. The 2010 American Diabetes Association (ADA) diagnostic guidelines were used to categorize patients with no known history of diabetes as having diabetes (HbA1c ≥ 6.5%) or increased risk for diabetes (HbA1c 5.7-6.4%).</p> <p>Results</p> <p>Of the 1045 patients with pre-operative HbA1c measurements, 40% (n = 415) had a known history of diabetes and 60% (n = 630) had no known history of diabetes. For the 630 patients with no known diabetic history: 207 (32.9%) had a normal HbA1c (< 5.7%); 356 (56.5%) had an HbA1c falling in the increased risk for diabetes range (5.7-6.4%); and 67 (10.6%) had an HbA1c in the diabetes range (6.5% or higher). In this study the only conventional risk factor that was predictive of high HbA1c was BMI. We also found a high HbA1c irrespective of history of DM was associated with severe coronary artery disease as indicated by the number of vessels revascularized.</p> <p>Conclusion</p> <p>Among individuals undergoing CABG with no known history of diabetes, there is a substantial amount of undiagnosed dysglycemia. Even though labeling these patients as "diabetic" or "increased risk for diabetes" remains controversial in terms of perioperative management, pre-operative screening could lead to appropriate post-operative follow up to mitigate short-term adverse outcome and provide high priority medical referrals of this at risk population.</p

Timing in talking: What is it used for, and how is it controlled?

In the first part of the paper, we summarize the linguistic factors that shape speech timing patterns, including the prosodic structures which govern them, and suggest that speech timing patterns are used to aid utterance recognition. In the spirit of optimal control theory, we propose that recognition requirements are balanced against requirements such as rate of speech and style, as well as movement costs, to yield (near-)optimal planned surface timing patterns; additional factors may influence the implementation of that plan. In the second part of the paper, we discuss theories of timing control in models of speech production and motor control. We present three types of evidence that support models of speech production that involve extrinsic timing. These include (i) increasing variability with increases in interval duration, (ii) evidence that speakers refer to and plan surface durations, and (iii) independent timing of movement onsets and offsets

To screen or not to screen for peripheral arterial disease in subjects aged 80 and over in primary health care: a cross-sectional analysis from the BELFRAIL study

<p>Abstract</p> <p>Background</p> <p>Peripheral arterial disease (PAD) is common in older people. An ankle-brachial index (ABI) < 0.9 can be used as an indicator of PAD. Patients with low ABI have increased mortality and a higher risk of serious cardiovascular morbidity. However, because 80% of the patients are asymptomatic, PAD remains unrecognised in a large group of patients. The aims of this study were 1) to examine the prevalence of reduced ABI in subjects aged 80 and over, 2) to determine the diagnostic accuracy of the medical history and clinical examination for reduced ABI and 3) to investigate the difference in functioning and physical activity between patients with and without reduced ABI.</p> <p>Methods</p> <p>A cross-sectional study embedded within the BELFRAIL study. A general practitioner (GP) centre, located in Hoeilaart, Belgium, recruited 239 patients aged 80 or older. Only three criteria for exclusion were used: urgent medical need, palliative situation and known serious dementia. The GP recorded the medical history and performed a clinical examination. The clinical research assistant performed an extensive examination including Mini-Mental State Examination (MMSE), Geriatric Depression Scale (GDS-15), Activities of Daily Living (ADL), Tinetti test and the LASA Physical Activity Questionnaire (LAPAQ). ABI was measured using an automatic oscillometric appliance.</p> <p>Results</p> <p>In 40% of patients, a reduced ABI was found. Cardiovascular risk factors were unable to identify patients with low ABI. A negative correlation was found between the number of cardiovascular morbidities and ABI. Cardiovascular morbidity had a sensitivity of 65.7% (95% CI 53.4-76.7) and a specificity of 48.6% (95% CI 38.7-58.5). Palpation of the peripheral arteries showed the highest negative predictive value (77.7% (95% CI 71.8-82.9)). The LAPAQ score was significantly lower in the group with reduced ABI.</p> <p>Conclusion</p> <p>The prevalence of PAD is very high in patients aged 80 and over in general practice. The clinical examination, cardiovascular risk factors and the presence of cardiovascular morbidity were not able to identify patients with a low ABI. A screening strategy for PAD by determining ABI could be considered if effective interventions for those aged 80 and over with a low ABI become available through future research.</p

Biomechanical analyses of the performance of Paralympians: From foundation to elite level

Biomechanical analysis of sport performance provides an objective method of determining performance of a particular sporting technique. In particular, it aims to add to the understanding of the mechanisms influencing performance, characterization of athletes, and provide insights into injury predisposition. Whilst the performance in sport of able-bodied athletes is well recognised in the literature, less information and understanding is known on the complexity, constraints and demands placed on the body of an individual with a disability. This paper provides a dialogue that outlines scientific issues of performance analysis of multi-level athletes with a disability, including Paralympians. Four integrated themes are explored the first of which focuses on how biomechanics can contribute to the understanding of sport performance in athletes with a disability and how it may be used as an evidence-based tool. This latter point questions the potential for a possible cultural shift led by emergence of user-friendly instruments. The second theme briefly discusses the role of reliability of sport performance and addresses the debate of two-dimensional and three-dimensional analysis. The third theme address key biomechanical parameters and provides guidance to clinicians, and coaches on the approaches adopted using biomechanical/sport performance analysis for an athlete with a disability starting out, to the emerging and elite Paralympian. For completeness of this discourse, the final theme is based on the controversial issues on the role of assisted devices and the inclusion of Paralympians into able-bodied sport is also presented. All combined, this dialogue highlights the intricate relationship between biomechanics and training of individuals with a disability. Furthermore, it illustrates the complexity of modern training of athletes which can only lead to a better appreciation of the performances to be delivered in the London 2012 Paralympic Games

Destabilizing Protein Polymorphisms in the Genetic Background Direct Phenotypic Expression of Mutant SOD1 Toxicity

Genetic background exerts a strong modulatory effect on the toxicity of aggregation-prone proteins in conformational diseases. In addition to influencing the misfolding and aggregation behavior of the mutant proteins, polymorphisms in putative modifier genes may affect the molecular processes leading to the disease phenotype. Mutations in SOD1 in a subset of familial amyotrophic lateral sclerosis (ALS) cases confer dominant but clinically variable toxicity, thought to be mediated by misfolding and aggregation of mutant SOD1 protein. While the mechanism of toxicity remains unknown, both the nature of the SOD1 mutation and the genetic background in which it is expressed appear important. To address this, we established a Caenorhabditis elegans model to systematically examine the aggregation behavior and genetic interactions of mutant forms of SOD1. Expression of three structurally distinct SOD1 mutants in C. elegans muscle cells resulted in the appearance of heterogeneous populations of aggregates and was associated with only mild cellular dysfunction. However, introduction of destabilizing temperature-sensitive mutations into the genetic background strongly enhanced the toxicity of SOD1 mutants, resulting in exposure of several deleterious phenotypes at permissive conditions in a manner dependent on the specific SOD1 mutation. The nature of the observed phenotype was dependent on the temperature-sensitive mutation present, while its penetrance reflected the specific combination of temperature-sensitive and SOD1 mutations. Thus, the specific toxic phenotypes of conformational disease may not be simply due to misfolding/aggregation toxicity of the causative mutant proteins, but may be defined by their genetic interactions with cellular pathways harboring mildly destabilizing missense alleles