Effects of Age on Plasma Glucose Levels in Non-diabetic Hong Kong Chinese

Aim: To analyze the relationship between age and plasma glucose levels in Hong Kong Chinese population. Methods: We performed a cross-sectional study with 15 603 non-diabetic subjects from the community of Hong Kong. Plasma glucose concentration was measured in blood specimens from the subjects. The time of blood taking varied, depending on the availability of the patients. Results: There were 11 148 (71.4%) women and 4455 (28.6%) men (mean age: 50.1 ± 16.1 years). There were 6901 (44.2%) patients who had plasma glucose measured in the fasting condition, 2999 (19.2%) who were 2-hour post-prandial, and 5703 (36.6%) who had plasma glucose measured at a random time. The correlation coefficients between age and plasma glucose levels in fasting, 2-hour post-prandial, and random group of patients were 0.159, 0.169, and 0.114, respectively (adjusted for body mass index, smoking, and gender; all P values <0.001). Fasting and random plasma glucose level increased by 0.15 mmol/L, while 2-hour post-prandial plasma glucose level increased by 0.26 mmol/L per decade-increase in age. Conclusion: Plasma glucose levels progressively increase with age in Hong Kong Chinese non-diabetic subjects

Budding yeast ATM/ATR control meiotic double-strand break (DSB) levels by down-regulating Rec114, an essential component of the DSB-machinery

An essential feature of meiosis is Spo11 catalysis of programmed DNA double strand breaks (DSBs). Evidence suggests that the number of DSBs generated per meiosis is genetically determined and that this ability to maintain a pre-determined DSB level, or "DSB homeostasis", might be a property of the meiotic program. Here, we present direct evidence that Rec114, an evolutionarily conserved essential component of the meiotic DSB-machinery, interacts with DSB hotspot DNA, and that Tel1 and Mec1, the budding yeast ATM and ATR, respectively, down-regulate Rec114 upon meiotic DSB formation through phosphorylation. Mimicking constitutive phosphorylation reduces the interaction between Rec114 and DSB hotspot DNA, resulting in a reduction and/or delay in DSB formation. Conversely, a non-phosphorylatable rec114 allele confers a genome-wide increase in both DSB levels and in the interaction between Rec114 and the DSB hotspot DNA. These observations strongly suggest that Tel1 and/or Mec1 phosphorylation of Rec114 following Spo11 catalysis down-regulates DSB formation by limiting the interaction between Rec114 and DSB hotspots. We also present evidence that Ndt80, a meiosis specific transcription factor, contributes to Rec114 degradation, consistent with its requirement for complete cessation of DSB formation. Loss of Rec114 foci from chromatin is associated with homolog synapsis but independent of Ndt80 or Tel1/Mec1 phosphorylation. Taken together, we present evidence for three independent ways of regulating Rec114 activity, which likely contribute to meiotic DSBs-homeostasis in maintaining genetically determined levels of breaks

Results of Antiretroviral Treatment Interruption and Intensification in Advanced Multi-Drug Resistant HIV Infection from the OPTIMA Trial

BACKGROUND: Guidance is needed on best medical management for advanced HIV disease with multidrug resistance (MDR) and limited retreatment options. We assessed two novel antiretroviral (ARV) treatment approaches in this setting. METHODS AND FINDINGS: We conducted a 2×2 factorial randomized open label controlled trial in patients with a CD4 count≤300 cells/µl who had ARV treatment (ART) failure requiring retreatment, to two options (a) re-treatment with either standard (≤4 ARVs) or intensive (≥5 ARVs) ART and b) either treatment starting immediately or after a 12-week monitored ART interruption. Primary outcome was time to developing a first AIDS-defining event (ADE) or death from any cause. Analysis was by intention to treat. From 2001 to 2006, 368 patients were randomized. At baseline, mean age was 48 years, 2% were women, median CD4 count was 106/µl, mean viral load was 4.74 log(10) copies/ml, and 59% had a prior AIDS diagnosis. Median follow-up was 4.0 years in 1249 person-years of observation. There were no statistically significant differences in the primary composite outcome of ADE or death between re-treatment options of standard versus intensive ART (hazard ratio 1.17; CI 0.86-1.59), or between immediate retreatment initiation versus interruption before re-treatment (hazard ratio 0.93; CI 0.68-1.30), or in the rate of non-HIV associated serious adverse events between re-treatment options. CONCLUSIONS: We did not observe clinical benefit or harm assessed by the primary outcome in this largest and longest trial exploring both ART interruption and intensification in advanced MDR HIV infection with poor retreatment options. TRIAL REGISTRATION: Clinicaltrials.gov NCT00050089

Retail innovation and shopping practices: consumers' reaction to self-service retailing

Authors' draft also available on Surrey eprints repository at http://epubs.surrey.ac.uk. Final version available online at http://www.envplan.com/In this paper we address the related issues of retail innovation, changing shopping practices, and shopping geographies. We do so in relation to the spread of self-service grocery stores, and particularly the supermarket, in the postwar retail environment of Britain (1950 – 70), arguing that this juncture provides a propitious opportunity to study the relationship between changing practices of retailing and consumption. We highlight shoppers’ selective adoption of new self-service formats in relation to certain product categories and argue that this can be explained in part by reference to the socially embedded nature of women food shoppers’ behaviours and in particular the influence of contemporary notions of the ‘good housewife’. We support our argument by reference to a wide range of contemporary documentary material relating to postwar shopping including market research reports, the publications of local consumer groups, and selected retailer and government archive sources

The physical and mental health of a large military cohort: baseline functional health status of the Millennium Cohort

<p>Abstract</p> <p>Background:</p> <p>The US military is currently involved in large, lengthy, and complex combat operations around the world. Effective military operations require optimal health of deployed service members, and both mental and physical health can be affected by military operations.</p> <p>Methods:</p> <p>Baseline data were collected from 77,047 US service members during 2001–2003 as part of a large, longitudinal, population-based military health study (the Millennium Cohort Study). The authors calculated unadjusted, adjusted, and weighted means for the Medical Outcomes Study Short Form 36-item Survey for Veterans physical (PCS) and mental component summary (MCS) scores over a variety of demographic and military characteristics at baseline.</p> <p>Results:</p> <p>The unadjusted mean PCS and MCS scores for this study were 53.4 (95% confidence interval: 53.3–53.4) and 52.8 (95% confidence interval: 52.7–52.9). Average PCS and MCS scores were slightly more favorable in this military sample compared to those of the US general population of the same age and sex. Factors independently associated with more favorable health status included male gender, being married, higher educational attainment, higher military rank, and Air Force service. Combat specialists had similar health status compared to other military occupations. Having been deployed to Southwest Asia, Bosnia, or Kosovo between 1998 and 2000 was not associated with diminished health status.</p> <p>Conclusion:</p> <p>The baseline health status of this large population-based military cohort is better than that of the US general population of the same age and sex distribution over the same time period, especially in older age groups. Deployment experiences during the period of 1998–2001 were not associated with decreased health status. These data will serve as a useful reference for other military health studies and for future longitudinal analyses.</p

The katG mRNA of Mycobacterium tuberculosis and Mycobacterium smegmatis is processed at its 5' end and is stabilized by both a polypurine sequence and translation initiation

<p>Abstract</p> <p>Background</p> <p>In <it>Mycobacterium tuberculosis </it>and in <it>Mycobacterium smegmatis </it>the <it>furA</it>-<it>katG </it>loci, encoding the FurA regulatory protein and the KatG catalase-peroxidase, are highly conserved. In <it>M. tuberculosis furA-katG </it>constitute a single operon, whereas in <it>M. smegmatis </it>a single mRNA covering both genes could not be found. In both species, specific 5' ends have been identified: the first one, located upstream of the <it>furA </it>gene, corresponds to transcription initiation from the <it>furA </it>promoter; the second one is the <it>katG </it>mRNA 5' end, located in the terminal part of <it>furA</it>.</p> <p>Results</p> <p>In this work we demonstrate by in vitro transcription and by RNA polymerase Chromatin immunoprecipitation that no promoter is present in the <it>M. smegmatis </it>region covering the latter 5' end, suggesting that it is produced by specific processing of longer transcripts. Several DNA fragments of <it>M. tuberculosis </it>and <it>M. smegmatis </it>were inserted in a plasmid between the <it>sigA </it>promoter and the <it>lacZ </it>reporter gene, and expression of the reporter gene was measured. A polypurine sequence, located four bp upstream of the <it>katG </it>translation start codon, increased beta-galactosidase activity and stabilized the <it>lacZ </it>transcript. Mutagenesis of this sequence led to destabilization of the mRNA. Analysis of constructs, in which the polypurine sequence of <it>M. smegmatis </it>was followed by an increasing number of <it>katG </it>codons, demonstrated that mRNA stability requires translation of at least 20 amino acids. In order to define the requirements for the 5' processing of the <it>katG </it>transcript, we created several mutations in this region and analyzed the 5' ends of the transcripts: the distance from the polypurine sequence does not seem to influence the processing, neither the sequence around the cutting point. Only mutations which create a double stranded region around the processing site prevented RNA processing.</p> <p>Conclusion</p> <p>This is the first reported case in mycobacteria, in which both a polypurine sequence and translation initiation are shown to contribute to mRNA stability. The <it>furA-katG </it>mRNA is transcribed from the <it>furA </it>promoter and immediately processed; this processing is prevented by a double stranded RNA at the cutting site, suggesting that the endoribonuclease responsible for the cleavage cuts single stranded RNA.</p

HIV-1 gp41 Core with Exposed Membrane-Proximal External Region Inducing Broad HIV-1 Neutralizing Antibodies

The membrane-proximal external region (MPER) of the HIV-1 gp41 consists of epitopes for the broadly cross-neutralizing monoclonal antibodies 2F5 and 4E10. However, antigens containing the linear sequence of these epitopes are unable to elicit potent and broad neutralizing antibody responses in vaccinated hosts, possibly because of inappropriate conformation of these epitopes. Here we designed a recombinant antigen, designated NCM, which comprises the N- and C-terminal heptad repeats that can form a six-helix bundle (6HB) core and the MPER domain of gp41. Two mutations (T569A and I675V) previously reported to expose the neutralization epitopes were introduced into NCM to generate mutants named NCM(TA), NCM(IV), and NCM(TAIV). Our results showed that NCM and its mutants could react with antibodies specific for 6HB and MPER of gp41, suggesting that these antigens are in the form of a trimer of heterodimer (i.e., 6HB) with three exposed MPER tails. Antigen with double mutations, NCM(TAIV), elicited much stronger antibody response in rabbits than immunogens with single mutation, NCM(TA) and NCM(IV), or no mutation, NCM. The purified MPER-specific antibodies induced by NCM(TAIV) exhibited broad neutralizing activity, while the purified 6HB-specific antibodies showed no detectable neutralizing activity. Our recombinant antigen design supported by an investigation of its underlying molecular mechanisms provides a strong scientific platform for the discovery of a gp41 MPER-based AIDS vaccine

Attention bias to emotional faces varies by IQ and anxiety in Williams syndrome

Individuals with Williams syndrome (WS) often experience significant anxiety. A promising approach to anxiety intervention has emerged from cognitive studies of attention bias to threat. To investigate the utility of this intervention in WS, this study examined attention bias to happy and angry faces in individuals with WS (N=46). Results showed a significant difference in attention bias patterns as a function of IQ and anxiety. Individuals with higher IQ or higher anxiety showed a significant bias toward angry, but not happy faces, whereas individuals with lower IQ or lower anxiety showed the opposite pattern. These results suggest that attention bias interventions to modify a threat bias may be most effectively targeted to anxious individuals with WS with relatively high IQ

SAD phasing using iodide ions in a high-throughput structural genomics environment

The Seattle Structural Genomics Center for Infectious Disease (SSGCID) focuses on the structure elucidation of potential drug targets from class A, B, and C infectious disease organisms. Many SSGCID targets are selected because they have homologs in other organisms that are validated drug targets with known structures. Thus, many SSGCID targets are expected to be solved by molecular replacement (MR), and reflective of this, all proteins are expressed in native form. However, many community request targets do not have homologs with known structures and not all internally selected targets readily solve by MR, necessitating experimental phase determination. We have adopted the use of iodide ion soaks and single wavelength anomalous dispersion (SAD) experiments as our primary method for de novo phasing. This method uses existing native crystals and in house data collection, resulting in rapid, low cost structure determination. Iodide ions are non-toxic and soluble at molar concentrations, facilitating binding at numerous hydrophobic or positively charged sites. We have used this technique across a wide range of crystallization conditions with successful structure determination in 16 of 17 cases within the first year of use (94% success rate). Here we present a general overview of this method as well as several examples including SAD phasing of proteins with novel folds and the combined use of SAD and MR for targets with weak MR solutions. These cases highlight the straightforward and powerful method of iodide ion SAD phasing in a high-throughput structural genomics environment