Genetic association of CDC2 with cerebrospinal fluid tau in Alzheimer's disease

We have recently reported that a polymorphism in the cell division cycle (CDC2) gene, designated Ex6 + 7I/D, is associated with Alzheimer's disease (AD). The CDC2 gene is located on chromosome 10q21.1 close to the marker D10S1225 linked to AD. Active cdc2 accumulates in neurons containing neurofibrillary tangles (NFT), a process that can precede the formation of NFT. Therefore, CDC2 is a promising candidate susceptibility gene for AD. We investigated the possible effects of the CDC2 polymorphism on cerebrospinal fluid (CSF) biomarkers in AD patients. CDC2 genotypes were evaluated in relation to CSF protein levels of total tau, phospho-tau and beta-amyloid (1-42) in AD patients and control individuals, and in relation to the amount of senile plaques and NFT in the frontal cortex and in the hippocampus in patients with autopsy-proven AD and controls. The CDC2 Ex6 + 7I allele was associated with a gene dose-dependent increase of CSF total tau levels (F-2,F- 626 = 7.0, p = 0.001) and the homozygous CDC2Ex6 +7II genotype was significantly more frequent among AD patients compared to controls (p = 0.006, OR = 1.57, 95% CI 1.13-2.17). Our results provide further evidence for an involvement of cdc2 in the pathogenesis of AD. Copyright (C) 2005 S. Karger AG, Basel

Exotendons for assistance of human locomotion

BACKGROUND: Powered robotic exoskeletons for assistance of human locomotion are currently under development for military and medical applications. The energy requirements for such devices are excessive, and this has become a major obstacle for practical applications. Legged locomotion in many animals, however, is very energy efficient. We propose that poly-articular elastic mechanisms are a major contributor to the economy of locomotion in such specialized animals. Consequently, it should be possible to design unpowered assistive devices that make effective use of similar mechanisms. METHODS: A passive assistive technology is presented, based on long elastic cords attached to an exoskeleton and guided by pulleys placed at the joints. A general optimization procedure is described for finding the best geometrical arrangement of such "exotendons" for assisting a specific movement. Optimality is defined either as minimal residual joint moment or as minimal residual joint power. Four specific exotendon systems with increasing complexity are considered. Representative human gait data were used to optimize each of these four systems to achieve maximal assistance for normal walking. RESULTS: The most complex exotendon system, with twelve pulleys per limb, was able to reduce the joint moments required for normal walking by 71% and joint power by 74%. A simpler system, with only three pulleys per limb, could reduce joint moments by 46% and joint power by 47%. CONCLUSION: It is concluded that unpowered passive elastic devices can substantially reduce the muscle forces and the metabolic energy needed for walking, without requiring a change in movement. When optimally designed, such devices may allow independent locomotion in patients with large deficits in muscle function

Combined In Silico, In Vivo, and In Vitro Studies Shed Insights into the Acute Inflammatory Response in Middle-Aged Mice

We combined in silico, in vivo, and in vitro studies to gain insights into age-dependent changes in acute inflammation in response to bacterial endotoxin (LPS). Time-course cytokine, chemokine, and NO2-/NO3- data from "middle-aged" (6-8 months old) C57BL/6 mice were used to re-parameterize a mechanistic mathematical model of acute inflammation originally calibrated for "young" (2-3 months old) mice. These studies suggested that macrophages from middle-aged mice are more susceptible to cell death, as well as producing higher levels of pro-inflammatory cytokines, vs. macrophages from young mice. In support of the in silico-derived hypotheses, resident peritoneal cells from endotoxemic middle-aged mice exhibited reduced viability and produced elevated levels of TNF-α, IL-6, IL-10, and KC/CXCL1 as compared to cells from young mice. Our studies demonstrate the utility of a combined in silico, in vivo, and in vitro approach to the study of acute inflammation in shock states, and suggest hypotheses with regard to the changes in the cytokine milieu that accompany aging. © 2013 Namas et al

Subclinical hyperthyroidism and dementia: the Sao Paulo Ageing & Health Study (SPAH)

<p>Abstract</p> <p>Background</p> <p>Several epidemiologic studies have shown a possible association between thyroid function and cognitive decline. Our aim was to evaluate the association of subclinical hyperthyroidism and dementia in a population sample of older people</p> <p>Methods</p> <p>A cross-sectional study - São Paulo Ageing & Health Study (SPAH) - in a population sample of low-income elderly people ≥ 65 years-old to evaluate presence of subclinical thyroid disease as a risk factor for dementia. Thyroid function was assessed using thyrotropic hormone and free-thyroxine as well as routine use of thyroid hormones or antithyroid medications. Cases of dementia were assessed using a harmonized one-phase dementia diagnostic procedure by the "10/66 Dementia Research Group" including Alzheimer's disease and vascular dementia. Logistic regression models were used to test a possible association between subclinical hyperthyroidism and dementia.</p> <p>Results and discussion</p> <p>Prevalence of dementia and of subclinical hyperthyroidism were respectively of 4.4% and 3.0%. After age adjustment, we found an association of subclinical hyperthyroidism and any type of dementia and vascular dementia (Odds Ratio, 4.1, 95% Confidence Interval [95% CI] 1.3-13.1, and 5.3 95% CI, 1.1-26.4; respectively). Analyzing data by gender, we found an association of subclinical hyperthyroidism with dementia and Alzheimer's disease only for men (OR, 8.0; 95% CI, 1.5-43.4; OR, 12.4; 95% CI, 1.2-128.4; respectively). No women with subclinical hypothyroidism presented Alzheimer's disease in the sample.</p> <p>Conclusion</p> <p>The results suggest a consistent association among people with subclinical hyperthyroidism and dementia.</p

Positive and negative well-being and objectively measured sedentary behaviour in older adults: evidence from three cohorts

Background: Sedentary behaviour is related to poorer health independently of time spent in moderate to vigorous physical activity. The aim of this study was to investigate whether wellbeing or symptoms of anxiety or depression predict sedentary behaviour in older adults. Method: Participants were drawn from the Lothian Birth Cohort 1936 (LBC1936) (n = 271), and the West of Scotland Twenty-07 1950s (n = 309) and 1930s (n = 118) cohorts. Sedentary outcomes, sedentary time, and number of sit-to-stand transitions, were measured with a three-dimensional accelerometer (activPAL activity monitor) worn for 7 days. In the Twenty-07 cohorts, symptoms of anxiety and depression were assessed in 2008 and sedentary outcomes were assessed ~ 8 years later in 2015 and 2016. In the LBC1936 cohort, wellbeing and symptoms of anxiety and depression were assessed concurrently with sedentary behaviour in 2015 and 2016. We tested for an association between wellbeing, anxiety or depression and the sedentary outcomes using multivariate regression analysis. Results: We observed no association between wellbeing or symptoms of anxiety and the sedentary outcomes. Symptoms of depression were positively associated with sedentary time in the LBC1936 and Twenty-07 1950s cohort, and negatively associated with number of sit-to-stand transitions in the LBC1936. Meta-analytic estimates of the association between depressive symptoms and sedentary time or number of sit-to-stand transitions, adjusted for age, sex, BMI, long-standing illness, and education, were β = 0.11 (95% CI = 0.03, 0.18) and β = − 0.11 (95% CI = − 0.19, −0.03) respectively. Conclusion: Our findings indicate that depressive symptoms are positively associated with sedentary behavior. Future studies should investigate the causal direction of this association

Reducing the Risk of Cognitive Decline and Dementia: WHO Recommendations

With population ageing worldwide, dementia poses one of the greatest global challenges for health and social care in the 21st century. In 2019, around 55 million people were affected by dementia, with the majority living in low- and middle-income countries. Dementia leads to increased costs for governments, communities, families and individuals. Dementia is overwhelming for the family and caregivers of the person with dementia, who are the cornerstone of care and support systems throughout the world. To assist countries in addressing the global burden of dementia, the World Health Organisation (WHO) developed the Global Action Plan on the Public Health Response to Dementia 2017–2025. It proposes actions to be taken by governments, civil society, and other global and regional partners across seven action areas, one of which is dementia risk reduction. This paper is based on WHO Guidelines on risk reduction of cognitive decline and dementia and presents recommendations on evidence-based, multisectoral interventions for reducing dementia risks, considerations for their implementation and policy actions. These global evidence-informed recommendations were developed by WHO, following a rigorous guideline development methodology and involved a panel of academicians and clinicians with multidisciplinary expertise and representing geographical diversity. The recommendations are considered under three broad headings: lifestyle and behaviour interventions, interventions for physical health conditions and specific interventions. By supporting health and social care professionals, particularly by improving their capacity to provide gender and culturally appropriate interventions to the general population, the risk of developing dementia can be potentially reduced, or its progression delayed

IPTF Search for An Optical Counterpart to Gravitational-Wave TransientT GW150914

The American Astronomical Society. All rights reserved..The intermediate Palomar Transient Factory (iPTF) autonomously responded to and promptly tiled the error region of the first gravitational-wave event GW150914 to search for an optical counterpart. Only a small fraction of the total localized region was immediately visible in the northern night sky, due both to Sun-angle and elevation constraints. Here, we report on the transient candidates identified and rapid follow-up undertaken to determine the nature of each candidate. Even in the small area imaged of 126 deg2, after extensive filtering, eight candidates were deemed worthy of additional follow-up. Within two hours, all eight were spectroscopically classified by the Keck II telescope. Curiously, even though such events are rare, one of our candidates was a superluminous supernova. We obtained radio data with the Jansky Very Large Array and X-ray follow-up with the Swift satellite for this transient. None of our candidates appear to be associated with the gravitational-wave trigger, which is unsurprising given that GW150914 came from the merger of two stellar-mass black holes. This end-to-end discovery and follow-up campaign bodes well for future searches in this post-detection era of gravitational waves

Prevalence, Distribution, and Impact of Mild Cognitive Impairment in Latin America, China, and India: A 10/66 Population-Based Study

A set of cross-sectional surveys carried out in Cuba, Dominican Republic, Peru, Mexico, Venezuela, Puerto Rico, China, and India reveal the prevalence and between-country variation in mild cognitive impairment at a population level

Conditional deletion of epithelial IKKβ impairs alveolar formation through apoptosis and decreased VEGF expression during early mouse lung morphogenesis

<p>Abstract</p> <p>Background</p> <p>Alveolar septation marks the beginning of the transition from the saccular to alveolar stage of lung development. Inflammation can disrupt this process and permanently impair alveolar formation resulting in alveolar hypoplasia as seen in bronchopulmonary dysplasia in preterm newborns. NF-κB is a transcription factor central to multiple inflammatory and developmental pathways including dorsal-ventral patterning in fruit flies; limb, mammary and submandibular gland development in mice; and branching morphogenesis in chick lungs. We have previously shown that epithelial overexpression of NF-κB accelerates lung maturity using transgenic mice. The purpose of this study was to test our hypothesis that targeted deletion of NF-κB signaling in lung epithelium would impair alveolar formation.</p> <p>Methods</p> <p>We generated double transgenic mice with lung epithelium-specific deletion of IKKβ, a known activating kinase upstream of NF-κB, using a cre-<it>loxP </it>transgenic recombination strategy. Lungs of resulting progeny were analyzed at embryonic and early postnatal stages to determine specific effects on lung histology, and mRNA and protein expression of relevant lung morphoreulatory genes. Lastly, results measuring expression of the angiogenic factor, VEGF, were confirmed <it>in vitro </it>using a siRNA-knockdown strategy in cultured mouse lung epithelial cells.</p> <p>Results</p> <p>Our results showed that IKKβ deletion in the lung epithelium transiently decreased alveolar type I and type II cells and myofibroblasts and delayed alveolar formation. These effects were mediated through increased alveolar type II cell apoptosis and decreased epithelial VEGF expression.</p> <p>Conclusions</p> <p>These results suggest that epithelial NF-κB plays a critical role in early alveolar development possibly through regulation of VEGF.</p