Time of day is associated with paradoxical reductions in global signal fluctuation and functional connectivity.

The brain exhibits substantial diurnal variation in physiology and function, but neuroscience studies rarely report or consider the effects of time of day. Here, we examined variation in resting-state functional MRI (fMRI) in around 900 individuals scanned between 8 AM and 10 PM on two different days. Multiple studies across animals and humans have demonstrated that the brain's global signal (GS) amplitude (henceforth referred to as "fluctuation") increases with decreased arousal. Thus, in accord with known circadian variation in arousal, we hypothesised that GS fluctuation would be lowest in the morning, increase in the midafternoon, and dip in the early evening. Instead, we observed a cumulative decrease in GS fluctuation as the day progressed. Although respiratory variation also decreased with time of day, control analyses suggested that this did not account for the reduction in GS fluctuation. Finally, time of day was associated with marked decreases in resting-state functional connectivity across the whole brain. The magnitude of decrease was significantly stronger than associations between functional connectivity and behaviour (e.g., fluid intelligence). These findings reveal time of day effects on global brain activity that are not easily explained by expected arousal state or physiological artefacts. We conclude by discussing potential mechanisms for the observed diurnal variation in resting brain activity and the importance of accounting for time of day in future studies

Lipid control and use of lipid-regulating drugs for prevention of cardiovascular events in Chinese type 2 diabetic patients: a prospective cohort study

<p>Abstract</p> <p>Background</p> <p>Dyslipidaemia is an important but modifiable risk factor of cardiovascular disease (CVD) in type 2 diabetes. Yet, the effectiveness of lipid regulating drugs in Asians is lacking. We examined the effects of lipid control and treatment with lipid regulating drugs on new onset of CVD in Chinese type 2 diabetic patients.</p> <p>Methods</p> <p>In this prospective cohort consisting of 4521 type 2 diabetic patients without history of CVD and naïve for lipid regulating treatment recruited consecutively from 1996 to 2005, 371 developed CVD after a median follow-up of 4.9 years. We used Cox proportional hazard regression to obtain the hazard ratios (HR) of lipids and use of lipid regulating drugs for risk of CVD.</p> <p>Results</p> <p>The multivariate-adjusted HR (95% confidence interval) of CVD in patients with high LDL-cholesterol (≥ 3.0 mmol/L) was 1.36 (1.08 - 1.71), compared with lower values. Using the whole range value of HDL-cholesterol, the risk of CVD was reduced by 41% with every 1 mmol/L increase in HDL-cholesterol. Plasma triglyceride did not predict CVD. Statins use was associated with lower CVD risk [HR = 0.66 (0.50 - 0.88)]. In sub-cohort analysis, statins use was associated with a HR of 0.60 (0.44 - 0.82) in patients with high LDL-cholesterol (≥ 3.0 mmol/L) and 0.49 (0.28 - 0.88) in patients with low HDL-cholesterol. In patients with LDL-cholesterol < 3.0 mmol/L, use of fibrate was associated with HR of 0.34 (0.12 - 1.00). Only statins were effective in reducing incident CVD in patients with metabolic syndrome [(HR = 0.58(0.42--0.80)].</p> <p>Conclusions</p> <p>In Chinese type 2 diabetic patients, high LDL-cholesterol and low HDL-cholesterol predicted incident CVD. Overall, patients treated with statins had 40-50% risk reduction in CVD compared to non-users.</p

Transmission and pathogenicity of novel reassortants derived from Eurasian avian-like and 2009 pandemic H1N1 influenza viruses in mice and guinea pigs

Given the present extensive co-circulation in pigs of Eurasian avian-like (EA) swine H1N1 and 2009 pandemic (pdm/09) H1N1 viruses, reassortment between them is highly plausible but largely uncharacterized. Here, experimentally co-infected pigs with a representative EA virus and a pdm/09 virus yielded 55 novel reassortant viruses that could be categorized into 17 genotypes from Gt1 to Gt17 based on segment segregation. Majority of novel reassortants were isolated from the lower respiratory tract. Most of reassortant viruses were more pathogenic and contagious than the parental EA viruses in mice and guinea pigs. The most transmissible reassortant genotypes demonstrated in guinea pigs (Gt2, Gt3, Gt7, Gt10 and Gt13) were also the most lethal in mice. Notably, nearly all these highly virulent reassortants (all except Gt13) were characterized with possession of EA H1 and full complement of pdm/09 ribonucleoprotein genes. Compositionally, we demonstrated that EA H1-222G contributed to virulence by its ability to bind avian-type sialic acid receptors, and that pdm/09 RNP conferred the most robust polymerase activity to reassortants. The present study revealed high reassortment compatibility between EA and pdm/09 viruses in pigs, which could give rise to progeny reassortant viruses with enhanced virulence and transmissibility in mice and guinea pig models

Modelling study of dimerization in mammalian defensins

BACKGROUND: Defensins are antimicrobial peptides of innate immunity functioning by non-specific binding to anionic phospholipids in bacterial membranes. Their cationicity, amphipathicity and ability to oligomerize are considered key factors for their action. Based on structural information on human β-defensin 2, we examine homologous defensins from various mammalian species for conserved functional physico-chemical characteristics. RESULTS: Based on homology greater than 40%, structural models of 8 homologs of HBD-2 were constructed. A conserved pattern of electrostatics and dynamics was observed across 6 of the examined defensins; models backed by energetics suggest that the defensins in these 6 organisms are characterized by dimerization-linked enhanced functional potentials. In contrast, dimerization is not energetically favoured in the sheep, goat and mouse defensins, suggesting that they function efficiently as monomers. CONCLUSION: β-defensin 2 from some mammals may work as monomers while those in others, including humans, work as oligomers. This could potentially be used to design human defensins that may be effective at lower concentrations and hence have therapeutic benefits

Thoracic myelopathy caused by ossification of ligamentum flavum of which fluorosis as an etiology factor

PURPOSE: To evaluate the clinical feature, operative method and prognosis of thoracic ossification of ligamentum flavum caused by skeletal fluorosis. METHODS: All the patients with thoracic OLF, who underwent surgical management in the authors' hospital from 1993–2003, were retrospectively studied. The diagnosis of skeletal fluorosis was made by the epidemic history, clinical symptoms, radiographic findings, and urinalysis. En bloc laminectomy decompression of the involved thoracic levels was performed in all cases. Cervical open door decompression or lumbar laminectomy decompression was performed if relevant stenosis existed. The neurological statuses were evaluated with the Japanese Orthopaedic Association (JOA) scoring system preoperatively and at the end point of follow up. Also, the recovery rate was calculated. RESULTS: 23 cases have been enrolled in this study. Imaging study findings showed all the cases have ossification of ligamentum flavum together with ossification of many other ligaments and interosseous membranes, i.e. interosseous membranes of the forearm in 18 of 23 (78.3%), of the leg in 14 of 23 (60.1%) and of the ribs in 11 of 23 (47.8%). Urinalysis showed markedly increased urinary fluoride in 14 of 23 patients (60.9%). All the patients were followed up from 12 months to 9 years and 3 months, with an average of 4 years and 5 months. The JOA score increased significantly at the end of follow up (P = 0.0001). The recovery rate was 51.83 ± 32.36%. Multiple regression analysis revealed that the preoperative JOA score was an important predictor of surgical outcome (p = 0.0022, r = 0.60628). ANOVA analysis showed that patients with acute onset or too long duration had worse surgical result (P = 0.0003). CONCLUSION: Fluorosis can cause ossification of thoracic ligamentum flavum, as well as other ligaments. En bloc laminectomy decompression was an effective method. Preoperative JOA score was the most important predictor of surgical outcome. Patients with acute onset or too long duration had worse surgical outcome

Single-cell analysis reveals individual spore responses to simulated space vacuum

Outer space is a challenging environment for all forms of life, and dormant spores of bacteria have been frequently used to study the survival of terrestrial life in a space journey. Previous work showed that outer space vacuum alone can kill bacterial spores. However, the responses and mechanisms of resistance of individual spores to space vacuum are unclear. Here, we examined spores’ molecular changes under simulated space vacuum (~10−5 Pa) using micro-Raman spectroscopy and found that this vacuum did not cause significant denaturation of spore protein. Then, live-cell microscopy was developed to investigate the temporal events during germination, outgrowth, and growth of individual Bacillus spores. The results showed that after exposure to simulated space vacuum for 10 days, viability of spores of two Bacillus species was reduced up to 35%, but all spores retained their large Ca2 +-dipicolinic acid depot. Some of the killed spores did not germinate, and the remaining germinated but did not proceed to vegetative growth. The vacuum treatment slowed spore germination, and changed average times of all major germination events. In addition, viable vacuum-treated spores exhibited much greater sensitivity than untreated spores to dry heat and hyperosmotic stress. Among spores’ resistance mechanisms to high vacuum, DNA-protective α/β−type small acid-soluble proteins, and non- homologous end joining and base excision repair of DNA played the most important roles, especially against multiple cycles of vacuum treatment. Overall, these results give new insight into individual spore’s responses to space vacuum and provide new techniques for microorganism analysis at the single-cell level

Avoidable readmission in Hong Kong - system, clinician, patient or social factor?

<p>Abstract</p> <p>Background</p> <p>Studies that identify reasons for readmissions are gaining importance in the light of the changing demographics worldwide which has led to greater demand for hospital beds. It is essential to profile the prevalence of avoidable readmissions and understand its drivers so as to develop possible interventions for reducing readmissions that are preventable. The aim of this study is to identify the magnitude of avoidable readmissions, its contributing factors and costs in Hong Kong.</p> <p>Methods</p> <p>This was a retrospective analysis of 332,453 inpatient admissions in the Medical specialty in public hospital system in Hong Kong in year 2007. A stratified random sample of patients with unplanned readmission within 30 days after discharge was selected for medical record reviews. Eight physicians reviewed patients' medical records and classified whether a readmission was avoidable according to an assessment checklist. The results were correlated with hospital inpatient data.</p> <p>Results</p> <p>It was found that 40.8% of the 603 unplanned readmissions were judged avoidable by the reviewers. Avoidable readmissions were due to: clinician factor (42.3%) including low threshold for admission and premature discharge etc.; patient factor (including medical and health factor) (41.9%) such as relapse or progress of previous complaint, and compliance problems etc., followed by system factor (14.6%) including inadequate discharge planning, inadequate palliative care/terminal care, etc., and social factor (1.2%) such as carer system, lack of support and community services. After adjusting for patients' age, gender, principal diagnosis at previous discharge and readmission hospitals, the risk factors for avoidable readmissions in the total population i.e. all acute care admissions irrespective of whether there was a readmission or not, included patients with a longer length of stay, and with higher number of hospitalizations and attendance in public outpatient clinics and Accident and Emergency departments in the past 12 months. In the analysis of only unplanned readmissions, it was found that the concordance of the principal diagnosis for admission and readmission, and shorter time period between discharge and readmission were associated with avoidable readmissions.</p> <p>Conclusions</p> <p>Our study found that almost half of the readmissions could have been prevented. They had been mainly due to clinician and patient factors, in particular, both of which were intimately related to clinical management and patient care. These readmissions could be prevented by a system of ongoing clinical review to examine the clinical practice/decision for discharge, and improving clinical care and enhancing patient knowledge of the early warning signs for relapse. The importance of adequate and appropriate ambulatory care to support the patients in the community was also a key finding to reduce avoidable readmissions. Education on patient self-management should also be enhanced to minimize the patient factors with regard to avoidable readmission. Our findings thus provide important insights into the development of an effective discharge planning system which should place patients and carers as the primacy focus of care by engaging them along with the healthcare professionals in the whole discharge planning process.</p

Common Variants at 10 Genomic Loci Influence Hemoglobin A(1C) Levels via Glycemic and Nonglycemic Pathways

OBJECTIVE-Glycated hemoglobin (HbA(1c)), used to monitor and diagnose diabetes, is influenced by average glycemia over a 2- to 3-month period. Genetic factors affecting expression, turnover, and abnormal glycation of hemoglobin could also be associated with increased levels of HbA(1c). We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbA(1c) levels.RESEARCH DESIGN AND METHODS-We studied associations with HbA(1c) in up to 46,368 nondiabetic adults of European descent from 23 genome-wide association studies (GWAS) and 8 cohorts with de novo genotyped single nucleotide polymorphisms (SNPs). We combined studies using inverse-variance meta-analysis and tested mediation by glycemia using conditional analyses. We estimated the global effect of HbA(1c) loci using a multilocus risk score, and used net reclassification to estimate genetic effects on diabetes screening.RESULTS-Ten loci reached genome-wide significant association with HbA(1c), including six new loci near FN3K (lead SNP/P value, rs1046896/P = 1.6 x 10(-26)), HFE (rs1800562/P = 2.6 x 10(-20)), TMPRSS6 (rs855791/P = 2.7 x 10(-14)), ANK1 (rs4737009/P = 6.1 x 10(-12)), SPTA1 (rs2779116/P = 2.8 x 10(-9)) and ATP11A/TUBGCP3 (rs7998202/P = 5.2 x 10(-9)), and four known HbA(1c) loci: HK1 (rs16926246/P = 3.1 x 10(-54)), MTNR1B (rs1387153/P = 4.0 X 10(-11)), GCK (rs1799884/P = 1.5 x 10(-20)) and G6PC2/ABCB11 (rs552976/P = 8.2 x 10(-18)). We show that associations with HbA(1c) are partly a function of hyperglycemia associated with 3 of the 10 loci (GCK, G6PC2 and MTNR1B). The seven nonglycemic loci accounted for a 0.19 (%HbA(1c)) difference between the extreme 10% tails of the risk score, and would reclassify similar to 2% of a general white population screened for diabetes with HbA(1c).CONCLUSIONS-GWAS identified 10 genetic loci reproducibly associated with HbA(1c). Six are novel and seven map to loci where rarer variants cause hereditary anemias and iron storage disorders. Common variants at these loci likely influence HbA(1c) levels via erythrocyte biology, and confer a small but detectable reclassification of diabetes diagnosis by HbA(1c) Diabetes 59: 3229-3239, 201

Synergistic Association of PTGS2 and CYP2E1 Genetic Polymorphisms with Lung Cancer Risk in Northeastern Chinese

BACKGROUND: Lung cancer is the most common cause of cancer-related deaths worldwide. The aim of this study was to investigate the association of five extensively-studied polymorphisms in PTGS2 (rs689466, rs5275, rs20417) and CYP2E1 (rs2031920, rs6413432) genes with lung cancer risk in a large northeastern Chinese population. METHODOLOGY/PRINCIPAL FINDINGS: This is a hospital-based case-control study involving 684 patients with lung cancer and 604 cancer-free controls. Genotyping was performed using the PCR-LDR method. Data were analyzed using Haplo.stats and MDR programs. There were significant differences between patients and controls in allele/genotype distributions of rs5275 (P = 0.002/0.003) and rs6413432 (P = 0.037/0.044), as well as in genotype distributions of rs689466 (P = 0.02). The risk for lung cancer associated with the rs5275-C mutant allele was decreased by 60% (95% CI [confidence interval]: 0.21-0.74; P = 0.004) under the recessive model. Carriers of rs689466-G mutant allele had a 28% (95% CI: 0.57-0.92; P = 0.008) reduced risk of developing lung cancer relative to the AA genotype carriers. In haplotype analysis, haplotype G-C-C-T (in order of rs689466, rs5275, rs2031920 and rs6413432) decreased the odds of lung cancer by 28% (95% CI: 0.51-0.93; P = 0.019) after adjusting for confounding factors, whereas haplotype A-T-T-T had 1.49-fold (95% CI: 1.21-1.79; P = 0.012) increased risk for lung cancer. Using MDR method, the overall best model including rs5275, rs689466 and rs6413432 polymorphisms was identified with a maximal testing accuracy of 66.1% and a maximal cross-validation consistency of 10 out of 10 (P = 0.003). CONCLUSIONS/SIGNIFICANCE: Our findings demonstrated a potentially synergistic association of PTGS2 and CYP2E1 polymorphisms with the underlying cause of lung cancer in northeastern Chinese

Chemical Basis of Metabolic Network Organization

Although the metabolic networks of the three domains of life consist of different constituents and metabolic pathways, they exhibit the same scale-free organization. This phenomenon has been hypothetically explained by preferential attachment principle that the new-recruited metabolites attach preferentially to those that are already well connected. However, since metabolites are usually small molecules and metabolic processes are basically chemical reactions, we speculate that the metabolic network organization may have a chemical basis. In this paper, chemoinformatic analyses on metabolic networks of Kyoto Encyclopedia of Genes and Genomes (KEGG), Escherichia coli and Saccharomyces cerevisiae were performed. It was found that there exist qualitative and quantitative correlations between network topology and chemical properties of metabolites. The metabolites with larger degrees of connectivity (hubs) are of relatively stronger polarity. This suggests that metabolic networks are chemically organized to a certain extent, which was further elucidated in terms of high concentrations required by metabolic hubs to drive a variety of reactions. This finding not only provides a chemical explanation to the preferential attachment principle for metabolic network expansion, but also has important implications for metabolic network design and metabolite concentration prediction