The Imperfective Past

The objective of our study was to investigate whether use of antipsychotics is associated with hip/femur fractures and whether pharmacological differences between antipsychotics are related to the occurrence of fractures.A case-control study was conducted, in which cases were defined as patients with a hip/femur fracture. Each patient was matched to one control patient. The association between use of antipsychotics and the occurrence of hip/femur fractures was evaluated using conditional logistic regression.The study included 44,500 patients from 683 general practices from different geographical areas in the UK, registered within the General Practice Research Database (GPRD). Exposure to antipsychotics was categorized as “no use”, “current use” and “prior use”.Both current and prior use of antipsychotics were associated with an approximately two-fold increased risk of fractures. After adjustment for possible confounders, a small significant effect remained (Odds Ratios (OR) of 1.3). We did not find an association between dose of antipsychotics, or between the degree of blockade of the alpha-1 adrenoceptor or histamine-1 receptor and risk of fractures. The total number of days of antipsychotic use was significantly associated with an increased risk of hip/femur fractures.We conclude that there is a small increased risk of hip/femur fractures associated with the use of antipsychotics. This risk increases with long-term use

The optical system of the H.E.S.S. imaging atmospheric Cherenkov telescopes, Part II: mirror alignment and point spread function

Mirror facets of the H.E.S.S. imaging atmospheric Cherenkov telescopes are aligned using stars imaged onto the closed lid of the PMT camera, viewed by a CCD camera. The alignment procedure works reliably and includes the automatic analysis of CCD images and control of the facet alignment actuators. On-axis, 80% of the reflected light is contained in a circle of less than 1 mrad diameter. The spot widens with increasing angle to the telescope axis. In accordance with simulations, the spot size has roughly doubled at an angle of 1.4 degr. from the axis. The expected variation of spot size with elevation due to deformations of the support structure is visible, but is completely non-critical over the usual working range. Overall, the optical quality of the telescope exceeds the specifications.Comment: 23 pages, 13 figure

Long-term exposure to outdoor air pollution and the incidence of chronic obstructive pulmonary disease in a national English cohort.

OBJECTIVES: The role of outdoor air pollution in the incidence of chronic obstructive pulmonary disease (COPD) remains unclear. We investigated this question using a large, nationally representative cohort based on primary care records linked to hospital admissions. METHODS: A cohort of 812 063 patients aged 40-89 years registered with 205 English general practices in 2002 without a COPD diagnosis was followed from 2003 to 2007. First COPD diagnoses recorded either by a general practitioner (GP) or on admission to hospital were identified. Annual average concentrations in 2002 for particulate matter with an aerodynamic diameter <10 µm (PM10) and <2.5 µm (PM2.5), nitrogen dioxide (NO2), ozone and sulfur dioxide (SO2) at 1 km(2) resolution were estimated from emission-based dispersion models. Hazard ratios (HRs) per interquartile range change were estimated from Cox models adjusting for age, sex, smoking, body mass index and area-level deprivation. RESULTS: 16 034 participants (1.92%) received a COPD diagnosis from their GP and 2910 participants (0.35%) were admitted to hospital for COPD. After adjustment, HRs for GP recorded COPD and PM10, PM2.5 and NO2 were close to unity, positive for SO2 (HR=1.07 (95% CI 1.03 to 1.11) per 2.2 µg/m(3)) and negative for ozone (HR=0.94 (0.89 to 1.00) per 3 µg/m(3)). For admissions HRs for PM2.5 and NO2 remained positive (HRs=1.05 (0.98 to 1.13) and 1.06 (0.98 to 1.15) per 1.9 µg/m(3) and 10.7 µg/m(3), respectively). CONCLUSIONS: This large population-based cohort study found limited, inconclusive evidence for associations between air pollution and COPD incidence. Further work, utilising improved estimates of air pollution over time and enhanced socioeconomic indicators, is required to clarify the association between air pollution and COPD incidence

Building a recruitment database for asthma trials: a conceptual framework for the creation of the UK Database of Asthma Research Volunteers

Funded by Asthma UK as part of the Asthma UK Centre for Applied Research (AUK-AC-2012-01). In addition, BN, IS, CS and AS acknowledge the support of the Farr Institute, which is funded by the MRC and its consortium of funders

11 beta-hydroxysteroid dehydrogenase type 1 regulates glucocorticoid-induced insulin resistance in skeletal muscle

OBJECTIVE: Glucocorticoid excess is characterized by increased adiposity, skeletal myopathy, and insulin resistance, but the precise molecular mechanisms are unknown. Within skeletal muscle, 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) converts cortisone (11-dehydrocorticosterone in rodents) to active cortisol (corticosterone in rodents). We aimed to determine the mechanisms underpinning glucocorticoid-induced insulin resistance in skeletal muscle and indentify how 11beta-HSD1 inhibitors improve insulin sensitivity. \ud RESEARCH DESIGN AND METHODS: Rodent and human cell cultures, whole-tissue explants, and animal models were used to determine the impact of glucocorticoids and selective 11beta-HSD1 inhibition upon insulin signaling and action. \ud RESULTS: Dexamethasone decreased insulin-stimulated glucose uptake, decreased IRS1 mRNA and protein expression, and increased inactivating pSer$^{307}$ insulin receptor substrate (IRS)-1. 11beta-HSD1 activity and expression were observed in human and rodent myotubes and muscle explants. Activity was predominantly oxo-reductase, generating active glucocorticoid. A1 (selective 11beta-HSD1 inhibitor) abolished enzyme activity and blocked the increase in pSer$^{307}$ IRS1 and reduction in total IRS1 protein after treatment with 11DHC but not corticosterone. In C57Bl6/J mice, the selective 11beta-HSD1 inhibitor, A2, decreased fasting blood glucose levels and improved insulin sensitivity. In KK mice treated with A2, skeletal muscle pSer$^{307}$ IRS1 decreased and pThr$^{308}$ Akt/PKB increased. In addition, A2 decreased both lipogenic and lipolytic gene expression.\ud CONCLUSIONS: Prereceptor facilitation of glucocorticoid action via 11beta-HSD1 increases pSer$^{307}$ IRS1 and may be crucial in mediating insulin resistance in skeletal muscle. Selective 11beta-HSD1 inhibition decreases pSer$^{307}$ IRS1, increases pThr$^{308}$ Akt/PKB, and decreases lipogenic and lipolytic gene expression that may represent an important mechanism underpinning their insulin-sensitizing action

The H1 Forward Proton Spectrometer at HERA

The forward proton spectrometer is part of the H1 detector at the HERA collider. Protons with energies above 500 GeV and polar angles below 1 mrad can be detected by this spectrometer. The main detector components are scintillating fiber detectors read out by position-sensitive photo-multipliers. These detectors are housed in so-called Roman Pots which allow them to be moved close to the circulating proton beam. Four Roman Pot stations are located at distances between 60 m and 90 m from the interaction point.Comment: 20 pages, 10 figures, submitted to Nucl.Instr.and Method

Impact of clinical trial findings on Bell's palsy management in general practice in the UK 2001-2012 : Interrupted time series regression analysis

OBJECTIVES: To measure the incidence of Bell's palsy and determine the impact of clinical trial findings on Bell's palsy management in the UK. DESIGN: Interrupted time series regression analysis and incidence measures. SETTING: General practices in the UK contributing to the Clinical Practice Research Datalink (CPRD). PARTICIPANTS: Patients ≥16 years with a diagnosis of Bell's palsy between 2001 and 2012. INTERVENTIONS: (1) Publication of the 2004 Cochrane reviews of clinical trials on corticosteroids and antivirals for Bell's palsy, which made no clear recommendation on their use and (2) publication of the 2007 Scottish Bell's Palsy Study (SBPS), which made a clear recommendation that treatment with prednisolone alone improves chances for complete recovery. MAIN OUTCOME MEASURES: Incidence of Bell's palsy per 100 000 person-years. Changes in the management of Bell's palsy with either prednisolone therapy, antiviral therapy, combination therapy (prednisolone with antiviral therapy) or untreated cases. RESULTS: During the 12-year period, 14 460 cases of Bell's palsy were identified with an overall incidence of 37.7/100 000 person-years. The 2004 Cochrane reviews were associated with immediate falls in prednisolone therapy (-6.3% (-11.0 to -1.6)), rising trends in combination therapy (1.1% per quarter (0.5 to 1.7)) and falling trends for untreated cases (-0.8% per quarter (-1.4 to -0.3)). SBPS was associated with immediate increases in prednisolone therapy (5.1% (0.9 to 9.3)) and rising trends in prednisolone therapy (0.7% per quarter (0.4 to 1.2)); falling trends in combination therapy (-1.7% per quarter (-2.2 to -1.3)); and rising trends for untreated cases (1.2% per quarter (0.8 to 1.6)). Despite improvements, 44% still remain untreated. CONCLUSIONS: SBPS was clearly associated with change in management, but a significant proportion of patients failed to receive effective treatment, which cannot be fully explained. Clarity and uncertainty in clinical trial recommendations may change clinical practice. However, better ways are needed to understand and circumvent barriers in implementing clinical trial findings.Publisher PDFPeer reviewe

Can mutations in ELA2, neutrophil elastase expression or differential cell toxicity explain sulphasalazine-induced agranulocytosis?

BACKGROUND: Drug-induced agranulocytosis, a severe side effect marked by a deficit or absolute lack of granulocytic white blood cells, is a rare side-effect of the anti-inflammatory drug sulphasalazine. Mutations in the human neutrophil elastase gene (ELA2), causing increased intracellular concentration of this serine protease, inhibits neutrophil differentiation in severe congenital neutropenia (SCN). Since the clinical symptoms of agranulocytosis and SCN are similar, we hypothesized that it may origin from a common genetic variation in ELA2 or that sulphasalazine may affect human neutrophil elastase activity and protein expression. METHODS: We screened for genetic differences in ELA2 in DNA from 36 patients who had suffered from sulphasalazine-induced agranulocytosis, and compared them with 72 patients treated with sulphasalazine without blood reactions. We also performed in vitro studies of the blood cell lines HL60 and U937 after sulphasalazine exposure with respect to cell survival index, neutrophil elastase protein expression and activity. RESULTS: None of the mutations in ELA2, which previously have been reported to be associated with SCN, was found in this material. Protein expression of human neutrophil elastase in lymphoma U937 cells was not affected by treatment with concentrations equivalent to therapeutic doses. Cell survival of lymphoma U937 and promyelocytic leukemia HL-60 cells was not affected in this concentration range, but exhibited a decreased proliferative capacity with higher sulphasalazine concentrations. Interestingly the promyelocytic cells were more sensitive to sulphasalazine than the lymphoma cell line. CONCLUSION: Neutrophil elastase expression and ELA2 mutations do, however, not seem to be involved in the etilogy of sulphasalazine-induced agranulocytosis. Why sulphasalazine is more toxic to promyelocytes than to lymphocytes remains to be explained