Flexible Meta-Regression to Assess the Shape of the Benzene–Leukemia Exposure–Response Curve

Ba c k g r o u n d: Previous evaluations of the shape of the benzene–leukemia exposure–response curve (ERC) were based on a single set or on small sets of human occupational studies. Integrating evidence from all available studies that are of sufficient quality combined with flexible meta-regression models is likely to provide better insight into the functional relation between benzene exposure and risk of leukemia. Objectives: We used natural splines in a flexible meta-regression method to assess the shape of the benzene–leukemia ERC. Met h o d s: We fitted meta-regression models to 30 aggregated risk estimates extracted from nine human observational studies and performed sensitivity analyses to assess the impact of a priori assessed study characteristics on the predicted ERC. Re s u l t s: The natural spline showed a supralinear shape at cumulative exposures less than 100 ppmyears, although this model fitted the data only marginally better than a linear model (p = 0.06). Stratification based on study design and jackknifing indicated that the cohort studies had a considerable impact on the shape of the ERC at high exposure levels (> 100 ppm-years) but that predicted risks for the low exposure range (< 50 ppm-years) were robust. Co n c l u s i o n s: Although limited by the small number of studies and the large heterogeneity between studies, the inclusion of all studies of sufficient quality combined with a flexible meta-regression method provides the most comprehensive evaluation of the benzene–leukemia ERC to date. The natural spline based on all data indicates a significantly increased risk of leukemia [relative risk (RR) = 1.14; 95 % confidence interval (CI), 1.04–1.26] at an exposure level as low as 10 ppm-years. Key w o r d s: benzene, epidemiology, leukemia, meta-regression, quantitative risk assessment. Environ Health Perspect 118:526–532 (2010). doi:10.1289/ehp.0901127 available vi

Steering in computational science: mesoscale modelling and simulation

This paper outlines the benefits of computational steering for high performance computing applications. Lattice-Boltzmann mesoscale fluid simulations of binary and ternary amphiphilic fluids in two and three dimensions are used to illustrate the substantial improvements which computational steering offers in terms of resource efficiency and time to discover new physics. We discuss details of our current steering implementations and describe their future outlook with the advent of computational grids.Comment: 40 pages, 11 figures. Accepted for publication in Contemporary Physic

Does a 'direct' transfer protocol reduce time to coronary angiography for patients with non-ST-elevation acute coronary syndromes? A prospective observational study.

OBJECTIVE: National guidelines recommend 'early' coronary angiography within 96 h of presentation for patients with non-ST elevation acute coronary syndromes (NSTE-ACS). Most patients with NSTE-ACS present to their district general hospital (DGH), and await transfer to the regional cardiac centre for angiography. This care model has inherent time delays, and delivery of timely angiography is problematic. The objective of this study was to assess a novel clinical care pathway for the management of NSTE-ACS, known locally as the Heart Attack Centre-Extension or HAC-X, designed to rapidly identify patients with NSTE-ACS while in DGH emergency departments (ED) and facilitate transfer to the regional interventional centre for 'early' coronary angiography. METHODS: This was an observational study of 702 patients divided into two groups; 391 patients treated before the instigation of the HAC-X pathway (Pre-HAC-X), and 311 patients treated via the novel pathway (Post-HAC-X). Our primary study end point was time from ED admission to coronary angiography. We also assessed the length of hospital stay. RESULTS: Median time from ED admission to coronary angiography was 7.2 (IQR 5.1-10.2) days pre-HAC-X compared to 1.0 (IQR 0.7-2.0) day post-HAC-X (p<0.001). Median length of hospital stay was 3.0 (IQR 2.0-6.0) days post-HAC-X v 9.0 (IQR 6.0-14.0) days pre-HAC-X (p<0.0005). This equates to a reduction of six hospital bed days per NSTE-ACS admission. CONCLUSIONS: The introduction of this novel care pathway was associated with significant reductions in time to angiography and in total hospital bed occupancy for patients with NSTE-ACS

Health-related quality of life in Huntington’s Disease patients: a comparison of proxy assessment and patient self-rating using the disease-specific Huntington’s Disease health-related quality of life questionnaire (HDQoL)

Huntington’s disease (HD) is a fatal, neurodegenerative disease for which there is no known cure. Proxy evaluation is relevant for HD as its manifestation might limit the ability of persons to report their health-related quality of life (HrQoL). This study explored patient–proxy ratings of HrQoL of persons at different stages of HD, and examined factors that may affect proxy ratings. A total of 105 patient–proxy pairs completed the Huntington’s disease health-related quality of life questionnaire (HDQoL) and other established HrQoL measures (EQ-5D and SF-12v2). Proxy–patient agreement was assessed in terms of absolute level (mean ratings) and intraclass correlation. Proxies’ ratings were at a similar level to patients’ self-ratings on an overall Summary Score and on most of the six Specific Scales of the HDQoL. On the Specific Hopes and Worries Scale, proxies on average rated HrQoL as better than patients’ self-ratings, while on both the Specific Cognitive Scale and Specific Physical and Functional Scale proxies tended to rate HrQoL more poorly than patients themselves. The patient’s disease stage and mental wellbeing (SF-12 Mental Component scale) were the two factors that primarily affected proxy assessment. Proxy scores were strongly correlated with patients’ self-ratings of HrQoL, on the Summary Scale and all Specific Scales. The patient–proxy correlation was lower for patients at moderate stages of HD compared to patients at early and advanced stages. The proxy report version of the HDQoL is a useful complementary tool to self-assessment, and a promising alternative when individual patients with advanced HD are unable to self-report

Otoferlin acts as a Ca2+ sensor for vesicle fusion and vesicle pool replenishment at auditory hair cell ribbon synapses

Hearing relies on rapid, temporally precise, and sustained neurotransmitter release at the ribbon synapses of sensory cells, the inner hair cells (IHCs). This process requires otoferlin, a six C2-domain, Ca2+-binding transmembrane protein of synaptic vesicles. To decipher the role of otoferlin in the synaptic vesicle cycle, we produced knock-in mice (Otof Ala515,Ala517/Ala515,Ala517) with lower Ca2+-binding affinity of the C2C domain. The IHC ribbon synapse structure, synaptic Ca2+ currents, and otoferlin distribution were unaffected in these mutant mice, but auditory brainstem response wave-I amplitude was reduced. Lower Ca2+ sensitivity and delay of the fast and sustained components of synaptic exocytosis were revealed by membrane capacitance measurement upon modulations of intracellular Ca2+ concentration, by varying Ca2+ influx through voltage-gated Ca2+-channels or Ca2+ uncaging. Otoferlin thus functions as a Ca2+ sensor, setting the rates of primed vesicle fusion with the presynaptic plasma membrane and synaptic vesicle pool replenishment in the IHC active zone

Phosphate Energy Metabolism During Domoic Acid-Induced Seizures

The effect of domoic acid-induced seizure activity on energy metabolism and on brain pH in mice was studied by continuous EEC recording and in vivo 31 P nuclear magnetic resonance (NMR) spectroscopy. Mice were divided into ventilated (n = 6) and nonventilated (n = 7) groups. Baseline EEG was 0.1-mV amplitude with frequence of >30-Hz and of 4–5 Hz. After intraperitoneal (i.p.) administration of domoic acid (6 mg/kg), electro graphic spikes appeared at increasing frequency, pro gressing to high-amplitude (0.1-0.8 mV) continuous sei zure activity (status epilepticus). In ventilated mice, the [ 31 P]NMR spectra showed that high-energy phosphate levels and tissue pH did not change after domoic acid administration or during the intervals of spiking or status epilepticus. Nonventilated mice showed periods of EEG suppression accompanied by decreases in the levels of high-energy phosphate metabolites and in pH, corresponding to episodic respiratory suppression during the spiking interval. In all animals, status epilepticus was fol lowed by a marked decrease in EEG amplitude that pro gressed rapidly to isoelectric silence. [ 31 P]NMR spectra obtained after this were indicative of total energy failure and tissue acidosis. In a separate group of ventilated mice (n = 4), domoic acid-induced status epilepticus was ac companied initially by an increase in mean arterial blood pressure (MAP) that slowly returned to baseline level. Isoelectric silence was accompanied by a decrease in MAP to 75 ± 8 mm Hg. These experiments suggest that domoic acid-induced seizures are not accompanied by an increase in substrate demand that exceeds supply.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65953/1/j.1528-1157.1993.tb02124.x.pd

Use of Non-Steroidal Anti-Inflammatory Drugs and Prostate Cancer Risk: A Population-Based Nested Case-Control Study

BACKGROUND: Despite strong laboratory evidence that non-steroidal anti-inflammatory drugs (NSAIDs) could prevent prostate cancer, epidemiological studies have so far reported conflicting results. Most studies were limited by lack of information on dosage and duration of use of the different classes of NSAIDs. METHODS: We conducted a nested case-control study using data from Saskatchewan Prescription Drug Plan (SPDP) and Cancer Registry to examine the effects of dose and duration of use of five classes of NSAIDs on prostate cancer risk. Cases (N = 9,007) were men aged ≥40 years diagnosed with prostatic carcinoma between 1985 and 2000, and were matched to four controls on age and duration of SPDP membership. Detailed histories of exposure to prescription NSAIDs and other drugs were obtained from the SPDP. RESULTS: Any use of propionates (e.g., ibuprofen, naproxen) was associated with a modest reduction in prostate cancer risk (Odds ratio = 0.90; 95%CI 0.84-0.95), whereas use of other NSAIDs was not. In particular, we did not observe the hypothesized inverse association with aspirin use (1.01; 0.95-1.07). There was no clear evidence of dose-response or duration-response relationships for any of the examined NSAID classes. CONCLUSIONS: Our findings suggest modest benefits of at least some NSAIDs in reducing prostate cancer risk

The Adoption of Mediterranean Diet Attenuates the Development of Acute Coronary Syndromes in People with the Metabolic Syndrome

OBJECTIVES: In this work we investigated the effect of the consumption of the Mediterranean diet on coronary risk, in subjects with the metabolic syndrome. METHODS: During 2000–2002, we randomly selected, from all Greek regions, 848 hospitalised patients (695 males, 58 ± 10 & 153 females, 65 ± 9 years old) with a first event of acute coronary syndrome and 1078 frequency matched, by sex, age, region controls, without any suspicious for cardiovascular disease. Nutritional habits were evaluated through a validated questionnaire, while the metabolic syndrome was defined according to the NCEP ATP III criteria. Mediterranean diet was defined according to the guidelines of the Division of Nutrition/Epidemiology, of Athens Medical School. RESULTS: Of the 1926 participants, 307 (36.2%) of the patients and 198 (18.4%) of the controls (P < 0.001) met the ATP III criteria. This was related with 2fold adjusted coronary risk (odds ratio = 2.35, 95% 1.87 – 2.84) in subjects with the metabolic syndrome as compared with the rest of them. No differences were observed concerning the prevalence of the metabolic syndrome and sex of subjects, after adjustment for group of study (P > 0.1). Eighty (26%) of the patients and 70 (35%) of the controls (P < 0.01) with the metabolic syndrome were "closer" to the Mediterranean diet. Multivariate analysis revealed that the adoption of this diet is associated with a 35% (odds ratio = 0.65, 95% 0.44 – 0.95) reduction of the coronary risk in subjects with the metabolic syndrome, after adjusting for age, sex, educational and financial level and the conventional cardiovascular risk factors. CONCLUSION: Consequently, the adoption of Mediterranean diet seems to attenuate the coronary risk in subjects with the metabolic syndrome