Glutathione S-Transferase Ω 1 variation does not influence age at onset of Huntington's disease

BACKGROUND: Huntington's disease (HD) is a fully penetrant, autosomal dominantly inherited disorder associated with abnormal expansions of a stretch of perfect CAG repeats in the 5' part of the IT15 gene. The number of repeat units is highly predictive for the age at onset (AO) of the disorder. But AO is only modestly correlated with repeat length when intermediate HD expansions are considered. Circumstantial evidence suggests that additional features of the HD course are based on genetic traits. Therefore, it may be possible to investigate the genetic background of HD, i.e. to map the loci underlying the development and progression of the disease. Recently an association of Glutathione S-Transferase Ω 1 (GSTO1) and possibly of GSTO2 with AO was demonstrated for, both, Alzheimer's (AD) and Parkinson's disease (PD). METHODS: We have genotyped the polymorphisms rs4925 GSTO1 and rs2297235 GSTO2 in 232 patients with HD and 228 controls. RESULTS: After genotyping GSTO1 and GSTO2 polymorphisms, firstly there was no statistically significant difference in AO for HD patients, as well as secondly for HD patients vs. controls concerning, both, genotype and allele frequencies, respectively. CONCLUSION: The GSTO1 and GSTO2 genes flanked by the investigated polymorphisms are not comprised in a primary candidate region influencing AO in HD

A mixed methods inquiry: How dairy farmers perceive the value(s) of their involvement in an intensive dairy herd health management program

<p>Abstract</p> <p>Background</p> <p>Research has been scarce when it comes to the motivational and behavioral sides of farmers' expectations related to dairy herd health management programs. The objectives of this study were to explore farmers' expectations related to participation in a health management program by: 1) identifying important ambitions, goals and subjective well-being among farmers, 2) submitting those data to a quantitative analysis thereby characterizing perspective(s) of value added by health management programs among farmers; and 3) to characterize perceptions of farmers' goals among veterinarians.</p> <p>Methods</p> <p>The subject was initially explored by means of literature, interviews and discussions with farmers, herd health management consultants and researchers to provide an understanding (a concourse) of the research entity. The concourse was then broken down into 46 statements. Sixteen Danish dairy farmers and 18 veterinarians associated with one large nationwide veterinary practice were asked to rank the 46 statements that defined the concourse. Next, a principal component analysis was applied to identify correlated statements and thus families of perspectives between respondents. Q-methodology was utilized to represent each of the statements by one row and each respondent by one column in the matrix. A subset of the farmers participated in a series of semi-structured interviews to face validate the concourse and to discuss subjects like animal welfare, veterinarians' competences as experienced by the farmers and time constraints in the farmers' everyday life.</p> <p>Results</p> <p>Farmers' views could be described by four families of perspectives: Teamwork, Animal welfare, Knowledge dissemination, and Production. Veterinarians believed that farmers' primary focus was on production and profit, however, farmers' valued teamwork and animal welfare more.</p> <p>Conclusion</p> <p>The veterinarians in this study appear to focus too much on financial performance and increased production when compared to most of the participating farmers' expectations. On the other hand veterinarians did not focus enough on the major products, which farmers really wanted to buy, i.e. teamwork and animal welfare. Consequently, disciplines like sociology, economics and marketing may offer new methodological approaches to veterinarians as these disciplines have understood that accounting for individual differences is central to motivate change, i.e. 'know thy customer'.</p

The status of GEO 600

The GEO 600 laser interferometer with 600m armlength is part of a worldwide network of gravitational wave detectors. GEO 600 is unique in having advanced multiple pendulum suspensions with a monolithic last stage and in employing a signal recycled optical design. This paper describes the recent commissioning of the interferometer and its operation in signal recycled mode

HIV Drug Resistance (HIVDR) in Antiretroviral Therapy-Naïve Patients in Tanzania Not Eligible for WHO Threshold HIVDR Survey Is Dramatically High

The World Health Organization (WHO) has recommended guidelines for a HIV drug resistance (HIVDR) survey for resource-limited countries. Eligibility criteria for patients include age below 25 years in order to focus on the prevalence of transmitted HIVDR (tHIVDR) in newly-infected individuals. Most of the participating sites across Africa have so far reported tHIVDR prevalences of below 5%. In this study we investigated whether the rate of HIVDR in patients <25 years is representative for HIVDR in the rest of the therapy-naïve population. HIVDR was determined in 88 sequentially enrolled ART-naïve patients from Mwanza, Tanzania (mean age 35.4 years). Twenty patients were aged <25 years and 68 patients were aged 25-63 years. The frequency of HIVDR in the study population was 14.8% (95%; CI 0.072-0.223) and independent of NVP-resistance induced by prevention of mother-to-child transmission programs. Patients >25 years had a significantly higher HIVDR frequency than younger patients (19.1%; 95% CI 0.095-0.28) versus 0%, P = 0.0344). In 2 out of the 16 patients with HIVDR we found traces of antiretrovirals (ARVs) in plasma. ART-naïve patients aged over 25 years exhibited significantly higher HIVDR than younger patients. Detection of traces of ARVs in individuals with HIVDR suggests that besides transmission, undisclosed misuse of ARVs may constitute a significant factor in the generation of the observed high HIVDR rate. The current WHO tHIVDR survey that is solely focused on the transmission of HIVDR and that excludes patients over 25 years of age may therefore result in substantial underestimation of the prevalence of HIVDR in the therapy-naïve population. Similar studies should be performed also in other areas to test whether the so far reported optimistic picture of low HIVDR prevalence in young individuals is really representative for the rest of the ART-naïve HIV-infected population

Darbepoetin alfa for treating chemotherapy-induced anemia in patients with a baseline hemoglobin level < 10 g/dL versus ≥10 g/dL: an exploratory analysis from a randomized, double-blind, active-controlled trial

<p>Abstract</p> <p>Background</p> <p>Several studies have shown that darbepoetin alfa, an erythropoiesis-stimulating agent (ESA), can reduce transfusions and increase hemoglobin (Hb) levels in patients with chemotherapy-induced anemia (CIA). Recent safety concerns, however, have prompted changes to ESA product information. In the European Union and United States, ESA therapy initiation for CIA is now recommended at a Hb level ≤10 g/dL. The present exploratory analysis examined how ESA initiation at this Hb level may impact patient care.</p> <p>Methods</p> <p>Data from a phase 3 randomized trial were retrospectively reanalyzed. CIA patients with nonmyeloid malignancies were randomized 1:1 to 500 mcg darbepoetin alfa every three weeks (Q3W) or 2.25 mcg/kg darbepoetin alfa weekly (QW) for 15 weeks. A previously published report from this trial showed Q3W dosing was non-inferior to QW dosing for reducing transfusions from week 5 to end-of-the-treatment period (EOTP). In the present analysis, outcomes were reanalyzed by baseline Hb <10 g/dL and ≥10 g/dL. Endpoints included transfusion rates, Hb outcomes, and safety profiles.</p> <p>Results</p> <p>This study reanalyzed 351 and 354 patients who initiated ESA therapy at a baseline Hb of <10 g/dL or ≥10 g/dL, respectively. From week 5 to EOTP, the estimated Kaplan-Meier transfusion incidence (Q3W vs QW) was lower in the ≥10 g/dL baseline-Hb group (14% vs 21%) compared with the <10 g/dL baseline-Hb group (36% vs 41%). By week 5, the ≥10 g/dL baseline-Hb group, but not the <10 g/dL baseline-Hb group, achieved a mean Hb ≥11 g/dL. The Kaplan-Meier estimate of percentage of patients (Q3W vs QW) who achieved Hb ≥11 g/dL from week 1 to EOTP was 90% vs 85% in the ≥10 g/dL baseline-Hb group and 54% vs 57% in the <10 g/dL baseline-Hb group. Both baseline-Hb groups maintained mean Hb levels <12 g/dL and had similar safety profiles, though more patients in the ≥10 g/dL baseline-Hb group reached the threshold Hb of ≥13 g/dL.</p> <p>Conclusion</p> <p>In this exploratory analysis, darbepoetin alfa Q3W and QW raised Hb levels and maintained mean Hb at <12 g/dL in both baseline-Hb groups. The ≥10 g/dL baseline-Hb group had fewer transfusions and faster anemia correction. Additional studies should prospectively evaluate the relationship between Hb levels at ESA initiation and outcomes.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov Identifier NCT00118638.</p

Search for gravitational wave bursts in LIGO's third science run

We report on a search for gravitational wave bursts in data from the three LIGO interferometric detectors during their third science run. The search targets subsecond bursts in the frequency range 100-1100 Hz for which no waveform model is assumed, and has a sensitivity in terms of the root-sum-square (rss) strain amplitude of hrss ~ 10^{-20} / sqrt(Hz). No gravitational wave signals were detected in the 8 days of analyzed data.Comment: 12 pages, 6 figures. Amaldi-6 conference proceedings to be published in Classical and Quantum Gravit

Searching for a Stochastic Background of Gravitational Waves with LIGO

The Laser Interferometer Gravitational-wave Observatory (LIGO) has performed the fourth science run, S4, with significantly improved interferometer sensitivities with respect to previous runs. Using data acquired during this science run, we place a limit on the amplitude of a stochastic background of gravitational waves. For a frequency independent spectrum, the new limit is $\Omega_{\rm GW} < 6.5 \times 10^{-5}$. This is currently the most sensitive result in the frequency range 51-150 Hz, with a factor of 13 improvement over the previous LIGO result. We discuss complementarity of the new result with other constraints on a stochastic background of gravitational waves, and we investigate implications of the new result for different models of this background.Comment: 37 pages, 16 figure

Shared communication processes within healthcare teams for rare diseases and their influence on healthcare professionals' innovative behavior and patient satisfaction

<p>Abstract</p> <p>Background</p> <p>A rare disease is a pattern of symptoms that afflicts less than five in 10,000 patients. However, as about 6,000 different rare disease patterns exist, they still have significant epidemiological relevance. We focus on rare diseases that affect multiple organs and thus demand that multidisciplinary healthcare professionals (HCPs) work together. In this context, standardized healthcare processes and concepts are mainly lacking, and a deficit of knowledge induces uncertainty and ambiguity. As such, individualized solutions for each patient are needed. This necessitates an intensive level of innovative individual behavior and thus, adequate idea generation. The final implementation of new healthcare concepts requires the integration of the expertise of all healthcare team members, including that of the patients. Therefore, knowledge sharing between HCPs and shared decision making between HCPs and patients are important. The objective of this study is to assess the contribution of shared communication and decision-making processes in patient-centered healthcare teams to the generation of innovative concepts and consequently to improvements in patient satisfaction.</p> <p>Methods</p> <p>A theoretical framework covering interaction processes and explorative outcomes, and using patient satisfaction as a measure for operational performance, was developed based on healthcare management, innovation, and social science literature. This theoretical framework forms the basis for a three-phase, mixed-method study. Exploratory phase I will first involve collecting qualitative data to detect central interaction barriers within healthcare teams. The results are related back to theory, and testable hypotheses will be derived. Phase II then comprises the testing of hypotheses through a quantitative survey of patients and their HCPs in six different rare disease patterns. For each of the six diseases, the sample should comprise an average of 30 patients with six HCP per patient-centered healthcare team. Finally, in phase III, qualitative data will be generated via semi-structured telephone interviews with patients to gain a deeper understanding of the communication processes and initiatives that generate innovative solutions.</p> <p>Discussion</p> <p>The findings of this proposed study will help to elucidate the necessity of individualized innovative solutions for patients with rare diseases. Therefore, this study will pinpoint the primary interaction and communication processes in multidisciplinary teams, as well as the required interplay between exploratory outcomes and operational performance. Hence, this study will provide healthcare institutions and HCPs with results and information essential for elaborating and implementing individual care solutions through the establishment of appropriate interaction and communication structures and processes within patient-centered healthcare teams.</p

The Assembly of the Plasmodial PLP Synthase Complex Follows a Defined Course

Background: Plants, fungi, bacteria and the apicomplexan parasite Plasmodium falciparum are able to synthesize vitamin B6 de novo, whereas mammals depend upon the uptake of this essential nutrient from their diet. The active form of vitamin B6 is pyridoxal 5-phosphate (PLP). For its synthesis two enzymes, Pdx1 and Pdx2, act together, forming a multimeric complex consisting of 12 Pdx1 and 12 Pdx2 protomers. Methodology/Principal Findings: Here we report amino acid residues responsible for stabilization of the structural and enzymatic integrity of the plasmodial PLP synthase, identified by using distinct mutational analysis and biochemical approaches. Residues R85, H88 and E91 (RHE) are located at the Pdx1:Pdx1 interface and play an important role in Pdx1 complex assembly. Mutation of these residues to alanine impedes both Pdx1 activity and Pdx2 binding. Furthermore, changing D26, K83 and K151 (DKK), amino acids from the active site of Pdx1, to alanine obstructs not only enzyme activity but also formation of the complex. In contrast to the monomeric appearance of the RHE mutant, alteration of the DKK residues results in a hexameric assembly, and does not affect Pdx2 binding or its activity. While the modelled position of K151 is distal to the Pdx1:Pdx1 interface, it affects the assembly of hexameric Pdx1 into a functional dodecamer, which is crucial for PLP synthesis. Conclusions/Significance: Taken together, our data suggest that the assembly of a functional Pdx1:Pdx2 complex follows