Utility of 2013 American College of Cardiology/American Heart Association Cholesterol Guidelines in HIV-Infected Adults With Carotid Atherosclerosis.

BackgroundAlthough HIV is associated with increased atherosclerotic cardiovascular disease (CVD) risk, it is unknown whether guidelines can identify HIV-infected adults who may benefit from statins. We compared the 2013 American College of Cardiology/American Heart Association and 2004 Adult Treatment Panel III recommendations in HIV-infected adults and evaluated associations with carotid artery intima-media thickness and plaque.Methods and resultsCarotid artery intima-media thickness was measured at baseline and 3 years later in 352 HIV-infected adults without clinical atherosclerotic CVD and not on statins. Plaque was defined as IMT >1.5 mm in any segment. At baseline, the median age was 43 (interquartile range, 39-49), 85% were men, 74% were on antiretroviral medication, and 50% had plaque. The American College of Cardiology/American Heart Association guidelines were more likely to recommend statins compared with the Adult Treatment Panel III guidelines, both overall (26% versus 14%; P<0.001), in those with plaque (32% versus 17%; P=0.0002), and in those without plaque (16% versus 7%; P=0.025). In multivariable analysis, older age, higher low-density lipoprotein cholesterol, pack per year of smoking, and history of opportunistic infection were associated with baseline plaque. Baseline IMT (hazard ratio, 1.18 per 10% increment; 95% confidence interval, 1.05-1.33; P=0.005) and plaque (hazard ratio, 2.06; 95% confidence interval, 1.02-4.08; P=0.037) were each associated with all-cause mortality, independent of traditional CVD risk factors.ConclusionsAlthough the American College of Cardiology/American Heart Association guidelines recommended statins to a greater number of HIV-infected adults compared with the Adult Treatment Panel III guidelines, both failed to recommend therapy in the majority of HIV-affected adults with carotid plaque. Baseline carotid atherosclerosis but not atherosclerotic CVD risk scores was an independent predictor of mortality. HIV-specific guidelines that include detection of subclinical atherosclerosis may help to identify HIV-infected adults who are at increased atherosclerotic CVD risk and may be considered for statins

A metabolite-derived protein modification integrates glycolysis with KEAP1-NRF2 signalling.

Mechanisms that integrate the metabolic state of a cell with regulatory pathways are necessary to maintain cellular homeostasis. Endogenous, intrinsically reactive metabolites can form functional, covalent modifications on proteins without the aid of enzymes1,2, and regulate cellular functions such as metabolism3-5 and transcription6. An important 'sensor' protein that captures specific metabolic information and transforms it into an appropriate response is KEAP1, which contains reactive cysteine residues that collectively act as an electrophile sensor tuned to respond to reactive species resulting from endogenous and xenobiotic molecules. Covalent modification of KEAP1 results in reduced ubiquitination and the accumulation of NRF27,8, which then initiates the transcription of cytoprotective genes at antioxidant-response element loci. Here we identify a small-molecule inhibitor of the glycolytic enzyme PGK1, and reveal a direct link between glycolysis and NRF2 signalling. Inhibition of PGK1 results in accumulation of the reactive metabolite methylglyoxal, which selectively modifies KEAP1 to form a methylimidazole crosslink between proximal cysteine and arginine residues (MICA). This posttranslational modification results in the dimerization of KEAP1, the accumulation of NRF2 and activation of the NRF2 transcriptional program. These results demonstrate the existence of direct inter-pathway communication between glycolysis and the KEAP1-NRF2 transcriptional axis, provide insight into the metabolic regulation of the cellular stress response, and suggest a therapeutic strategy for controlling the cytoprotective antioxidant response in several human diseases

Inertio-elastic focusing of bioparticles in microchannels at high throughput

Controlled manipulation of particles from very large volumes of fluid at high throughput is critical for many biomedical, environmental and industrial applications. One promising approach is to use microfluidic technologies that rely on fluid inertia or elasticity to drive lateral migration of particles to stable equilibrium positions in a microchannel. Here, we report on a hydrodynamic approach that enables deterministic focusing of beads, mammalian cells and anisotropic hydrogel particles in a microchannel at extremely high flow rates. We show that on addition of micromolar concentrations of hyaluronic acid, the resulting fluid viscoelasticity can be used to control the focal position of particles at Reynolds numbers up to Re≈10,000 with corresponding flow rates and particle velocities up to 50 ml min[superscript −1] and 130 m s[superscript −1]. This study explores a previously unattained regime of inertio-elastic fluid flow and demonstrates bioparticle focusing at flow rates that are the highest yet achieved.National Institute for Biomedical Imaging and Bioengineering (U.S.) (P41 BioMicroElectroMechanical Systems Resource Center)National Institute for Biomedical Imaging and Bioengineering (U.S.) (P41 EB002503)National Science Foundation (U.S.). Graduate Research FellowshipUnited States. Army Research Office (Institute for Collaborative Biotechnologies Grant W911NF-09-0001

Neuroprotective Effect of Transplanted Human Embryonic Stem Cell-Derived Neural Precursors in an Animal Model of Multiple Sclerosis

BACKGROUND: Multiple sclerosis (MS) is an immune mediated demyelinating disease of the central nervous system (CNS). A potential new therapeutic approach for MS is cell transplantation which may promote remyelination and suppress the inflammatory process. METHODS: We transplanted human embryonic stem cells (hESC)-derived early multipotent neural precursors (NPs) into the brain ventricles of mice induced with experimental autoimmune encephalomyelitis (EAE), the animal model of MS. We studied the effect of the transplanted NPs on the functional and pathological manifestations of the disease. RESULTS: Transplanted hESC-derived NPs significantly reduced the clinical signs of EAE. Histological examination showed migration of the transplanted NPs to the host white matter, however, differentiation to mature oligodendrocytes and remyelination were negligible. Time course analysis of the evolution and progression of CNS inflammation and tissue injury showed an attenuation of the inflammatory process in transplanted animals, which was correlated with the reduction of both axonal damage and demyelination. Co-culture experiments showed that hESC-derived NPs inhibited the activation and proliferation of lymph node-derived T cells in response to nonspecific polyclonal stimuli. CONCLUSIONS: The therapeutic effect of transplantation was not related to graft or host remyelination but was mediated by an immunosuppressive neuroprotective mechanism. The attenuation of EAE by hESC-derived NPs, demonstrated here, may serve as the first step towards further developments of hESC for cell therapy in MS

Problematic Internet Use in High School Students in Guangdong Province, China

BACKGROUND: Problematic Internet Use (PIU) is a growing problem in Chinese adolescents. There are many risk factors for PIU, which are found at school and at home. This study was designed to investigate the prevalence of PIU and to investigate the potential risk factors for PIU among high school students in China. METHODOLOGY/PRINCIPAL FINDINGS: A cross-sectional study was conducted. A total of 14,296 high school students were surveyed in four cities in Guangdong province. Problematic Internet Use was assessed by the 20-item Young Internet Addiction Test (YIAT). Information was also collected on demographics, family and school-related factors and Internet usage patterns. Of the 14,296 students, 12,446 were Internet users. Of those, 12.2% (1,515) were identified as problematic Internet users (PIUs). Generalized mixed-model regression revealed that there was no gender difference between PIUs and non-PIUs. High study-related stress, having social friends, poor relations with teachers and students and conflictive family relationships were risk factors for PIU. Students who spent more time on-line were more likely to develop PIU. The habits of and purposes for Internet usage were diverse, influencing the susceptibility to PIU. CONCLUSIONS/SIGNIFICANCE: PIU is common among high school students, and risk factors are found at home and at school. Teachers and parents should pay close attention to these risk factors. Effective measures are needed to prevent the spread of this problem

A Novel Biclustering Approach to Association Rule Mining for Predicting HIV-1–Human Protein Interactions

Identification of potential viral-host protein interactions is a vital and useful approach towards development of new drugs targeting those interactions. In recent days, computational tools are being utilized for predicting viral-host interactions. Recently a database containing records of experimentally validated interactions between a set of HIV-1 proteins and a set of human proteins has been published. The problem of predicting new interactions based on this database is usually posed as a classification problem. However, posing the problem as a classification one suffers from the lack of biologically validated negative interactions. Therefore it will be beneficial to use the existing database for predicting new viral-host interactions without the need of negative samples. Motivated by this, in this article, the HIV-1–human protein interaction database has been analyzed using association rule mining. The main objective is to identify a set of association rules both among the HIV-1 proteins and among the human proteins, and use these rules for predicting new interactions. In this regard, a novel association rule mining technique based on biclustering has been proposed for discovering frequent closed itemsets followed by the association rules from the adjacency matrix of the HIV-1–human interaction network. Novel HIV-1–human interactions have been predicted based on the discovered association rules and tested for biological significance. For validation of the predicted new interactions, gene ontology-based and pathway-based studies have been performed. These studies show that the human proteins which are predicted to interact with a particular viral protein share many common biological activities. Moreover, literature survey has been used for validation purpose to identify some predicted interactions that are already validated experimentally but not present in the database. Comparison with other prediction methods is also discussed

Smoking cessation, alcohol intake and transient increase in the risk of metabolic syndrome among Japanese smokers at one health checkup institution

<p>Abstract</p> <p>Background</p> <p>Metabolic syndrome (MetS) is potentially effective measures to identify individuals at risk of coronary heart disease (CHD) and type 2 diabetes. To verify the hypothesis that smoking cessation may increase the risk of MetS, a follow-up study taking drinking habit into account was conducted for the examinees at one health checkup institution.</p> <p>Methods</p> <p>Subjects were the examinees who visited the Institution for Disease Prevention and Health Checkup, Seirei Mikatabara Hospital for annual health checkup from January 2003 to December 2006. Among them, 5,872 smokers (5,479 men, 93.3%) free from MetS at the first year in two consecutive years were selected. For the long term follow-up, the risk of MetS among those who maintained their nonsmoking status for 1 or 2 additional years was evaluated.</p> <p>Results</p> <p>Relative to non-quitters, quitters showed a significantly elevated adjusted hazard ratio (aHR) of MetS in two consecutive years (aHR = 2.09, 95% confidence interval: 1.43–3.04, <it>P </it>< 0.001). The aHR was higher among the quitters who had a drinking habit at the first year (aHR = 2.42, 95% CI: 1.48–3.94, <it>P </it>< 0.001). Analyses for 1 or 2 additional years of follow-up revealed that this significant increase in risk of MetS was transient.</p> <p>Conclusion</p> <p>The present study revealed that smoking cessation elevated the risk of MetS significantly, especially among drinkers. Although this detrimental effect of smoking cessation was found to be during only a short term, our results suggested that we should take measures, presumably including interventions for alcohol cessation, not to expose smoking quitters to this adverse effect. Further investigations are required to confirm our findings.</p

The economic burden of musculoskeletal disease in Korea: A cross sectional study

<p>Abstract</p> <p>Background</p> <p>Musculoskeletal diseases are becoming increasingly important due to population aging. However, studies on the economic burden of musculoskeletal disease in Korea are scarce. Therefore, we conducted a population-based study to measure the economic burden of musculoskeletal disease in Korea using nationally representative data.</p> <p>Methods</p> <p>This study used a variety of data sources such as national health insurance statistics, the Korea Health Panel study and cause of death reports generated by the Korea National Statistical Office to estimate the economic burden of musculoskeletal disease. The total cost of musculoskeletal disease was estimated as the sum of direct medical care costs, direct non-medical care costs, and indirect costs. Direct medical care costs are composed of the costs paid by the insurer and patients, over the counter drugs costs, and other costs such as medical equipment costs. Direct non-medical costs are composed of transportation and caregiver costs. Indirect costs are the sum of the costs associated with premature death and the costs due to productivity loss. Age, sex, and disease specific costs were estimated.</p> <p>Results</p> <p>Among the musculoskeletal diseases, the highest costs are associated with other dorsopathies, followed by disc disorder and arthrosis. The direct medical and direct non-medical costs of all musculoskeletal diseases were $4.18 billion and$338 million in 2008, respectively. Among the indirect costs, those due to productivity loss were $2.28 billion and costs due to premature death were$79 million. The proportions of the total costs incurred by male and female patients were 33.8% and 66.2%, respectively, and the cost due to the female adult aged 20-64 years old was highest. The total economic cost of musculoskeletal disease was $6.89 billion, which represents 0.7% of the Korean gross domestic product.</p> <p>Conclusions</p> <p>The economic burden of musculoskeletal disease in Korea is substantial. As the Korean population continues to age, the economic burden of musculoskeletal disease will continue to increase. Policy measures aimed at controlling the cost of musculoskeletal disease are therefore required.</p