Integrated safety studies of the urate reabsorption inhibitor lesinurad in treatment of gout.

ObjectiveLesinurad (LESU) is a selective urate reabsorption inhibitor approved at 200 mg daily for use with a xanthine oxidase inhibitor (XOI) to treat hyperuricaemia in gout patients failing to achieve target serum urate on XOI. The aim of the study was to investigate the long-term safety of LESU + XOI therapy.MethodsSafety data were pooled from three 12-month phase III (core) trials evaluating LESU 200 and 400 mg/day combined with an XOI (LESU200+XOI and LESU400+XOI), and two 12-month extension studies using descriptive statistics. To adjust for treatment duration, treatment-emergent adverse events (TEAEs) were expressed as exposure-adjusted incidence rates (patients with events per 100 person-years).ResultsIn the core studies, exposure-adjusted incidence rates for total and total renal-related TEAEs were comparable for XOI alone and LESU200+XOI but higher with LESU400+XOI. Exposure-adjusted incidence rates for serum creatinine (sCr) elevations ⩾1.5×baseline were 2.9, 7.3 and 18.7, respectively. Resolution (sCr ⩽1.2×baseline) occurred in 75-90% of all events, with 66-75% occurring without any study medication interruption. Major adverse cardiovascular events were 3, 4 and 9 with XOI, LESU200+XOI and LESU400+XOI, respectively. Longer exposure in core+extension studies did not increase rates for any safety signals.ConclusionAt the approved dose of 200 mg once-daily combined with an XOI, LESU did not increase renal, cardiovascular or other adverse events compared with XOI alone, except for sCr elevations. With extended exposure in the core+extension studies, the safety profile was consistent with that observed in the core studies, and no new safety concerns were identified

Migration of northern Yellowstone elk: implications of spatial structuring

Migration can enhance survival and recruitment of mammals by increasing access to higher-quality forage or reducing predation risk, or both. We used telemetry locations collected from 140 adult female elk during 2000– 2003 and 2007–2008 to identify factors influencing the migration of northern Yellowstone elk. Elk wintered in 2 semidistinct herd segments and migrated 10–140 km to at least 12 summer areas in Yellowstone National Park (YNP) and nearby areas of Montana. Spring migrations were delayed after winters with increased snow pack, with earlier migration in years with earlier vegetation green-up. Elk wintering at lower elevations outside YNP migrated an average of 13 days earlier than elk at higher elevations. The timing of autumn migrations varied annually, but elk left their summer ranges at about the same time regardless of elevation, wolf numbers, or distance to their wintering areas. Elk monitored for multiple years typically returned to the same summer (96% fidelity, n 5 52) and winter (61% fidelity, n 5 41) ranges. Elk that wintered at lower elevations in or near the northwestern portion of the park tended to summer in the western part of YNP (56%), and elk that wintered at higher elevations spent summer primarily in the eastern and northern parts of the park (82%). Elk did not grossly modify their migration timing, routes, or use areas after wolf restoration. Elk mortality was low during summer and migration (8 of 225 elk-summers). However, spatial segregation and differential mortality and recruitment between herd segments on the northern winter range apparently contributed to a higher proportion of the elk population wintering outside the northwestern portion of YNP and summering in the western portion of the park. This change could shift wolf spatial dynamics more outside YNP and increase the risk of transmission of brucellosis from elk to cattle north of the park

Migration of northern Yellowstone elk: implications of spatial structuring

Migration can enhance survival and recruitment of mammals by increasing access to higher-quality forage or reducing predation risk, or both. We used telemetry locations collected from 140 adult female elk during 2000– 2003 and 2007–2008 to identify factors influencing the migration of northern Yellowstone elk. Elk wintered in 2 semidistinct herd segments and migrated 10–140 km to at least 12 summer areas in Yellowstone National Park (YNP) and nearby areas of Montana. Spring migrations were delayed after winters with increased snow pack, with earlier migration in years with earlier vegetation green-up. Elk wintering at lower elevations outside YNP migrated an average of 13 days earlier than elk at higher elevations. The timing of autumn migrations varied annually, but elk left their summer ranges at about the same time regardless of elevation, wolf numbers, or distance to their wintering areas. Elk monitored for multiple years typically returned to the same summer (96% fidelity, n 5 52) and winter (61% fidelity, n 5 41) ranges. Elk that wintered at lower elevations in or near the northwestern portion of the park tended to summer in the western part of YNP (56%), and elk that wintered at higher elevations spent summer primarily in the eastern and northern parts of the park (82%). Elk did not grossly modify their migration timing, routes, or use areas after wolf restoration. Elk mortality was low during summer and migration (8 of 225 elk-summers). However, spatial segregation and differential mortality and recruitment between herd segments on the northern winter range apparently contributed to a higher proportion of the elk population wintering outside the northwestern portion of YNP and summering in the western portion of the park. This change could shift wolf spatial dynamics more outside YNP and increase the risk of transmission of brucellosis from elk to cattle north of the park

Mutation in erythroid specific transcription factor KLF1 causes Hereditary Spherocytosis in the Nan hemolytic anemia mouse model

KLF1 regulates definitive erythropoiesis of red blood cells by facilitating transcription through high affinity binding to CACCC elements within its erythroid specific target genes including those encoding erythrocyte membrane skeleton (EMS) proteins. Deficiencies of EMS proteins in humans lead to the hemolytic anemia Hereditary Spherocytosis (HS) which includes a subpopulation with no known genetic defect. Here we report that a mutation, E339D, in the second zinc finger domain of KLF1 is responsible for HS in the mouse model Nan. The causative nature of this mutation was verified with an allelic test cross between Nan/+ and heterozygous Klf1(+/-) knockout mice. Homology modeling predicted Nan KLF1 binds CACCC elements more tightly, suggesting that Nan KLF1 is a competitive inhibitor of wild-type KLF1. This is the first association of a KLF1 mutation with a disease state in adult mammals and also presents the possibility of being another causative gene for HS in humans

Baseline Q-Wave Surpasses Time From Symptom Onset as a Prognostic Marker in ST-Segment Elevation Myocardial Infarction Patients Treated With Primary Percutaneous Coronary Intervention

ObjectivesWe assessed the incremental value of baseline Q waves over time from symptom onset as a marker of clinical outcome in ST-segment elevation myocardial infarction (STEMI).BackgroundTime from symptom onset is a central focus in STEMI patients. The presence of Q waves on the baseline electrocardiogram (ECG) has been suggested to be of incremental value to time from symptom onset in evaluating clinical outcomes.MethodsWe evaluated baseline Q waves and ST-segment resolution 30 min after primary percutaneous intervention (PCI) ECGs in 4,530 STEMI patients without prior infarction. Additionally, peak biomarkers; 90-day mortality; and the composite of death, congestive heart failure (CHF), or cardiogenic shock were assessed.ResultsFifty-six percent of patients had baseline Q waves: they were older, more frequently male and diabetic, and had a more advanced Killip class. Patients with baseline Q waves had greater mortality and a higher composite rate of death, CHF, and shock versus patients without baseline Q waves at 90 days (5.3% vs. 2.1% and 12.1% vs. 4.8%, respectively, both p < 0.001). Complete ST-segment resolution was highest, whereas 90-day mortality and the composite outcome were lowest among those randomized ≤3 h without baseline Q waves. After multivariable adjustment, baseline Q-wave but not time from symptom onset was significantly associated with a 78% relative increase in the hazard of 90-day mortality and a 90% relative increase in the hazard of death, shock, and CHF.ConclusionsBaseline Q waves in STEMI patients treated with primary PCI provide an independent prognostic marker of clinical outcome. These data might be useful in designing future clinical trials as well as in evaluating patients for triage and potential transfer for planned primary PCI. (Pexelizumab in Conjunction With Angioplasty in Acute Myocardial Infarction [APEX-AMI]; NCT00091637

Proteasome inhibition, the pursuit of new cancer therapeutics, and the adaptor molecule p130Cas

Current interest in proteasome inhibitors for cancer therapy has stimulated considerable research efforts to identify the molecular pathway to their cytotoxicity with a view to identifying the mechanisms of sensitivity and resistance as well as informing the development of new drugs. Zhao and Vuori describe this month in BMC Biology experiments indicating a novel role of the adaptor protein p130Cas in sensitivity to apoptosis induced not only by proteasome inhibitors but also by the unrelated drug doxorubicin

The promoter from SlREO, a highly-expressed, root-specific Solanum lycopersicum gene, directs expression to cortex of mature roots

Root-specific promoters are valuable tools for targeting transgene expression, but many of those already described have limitations to their general applicability. We present the expression characteristics of SlREO, a novel gene isolated from tomato (Solanum lycopersicum L.). This gene was highly expressed in roots but had a very low level of expression in aerial plant organs. A 2.4-kb region representing the SlREO promoter sequence was cloned upstream of the uidA GUS reporter gene and shown to direct expression in the root cortex. In mature, glasshouse-grown plants this strict root specificity was maintained. Furthermore, promoter activity was unaffected by dehydration or wounding stress but was somewhat suppressed by exposure to NaCl, salicylic acid and jasmonic acid. The predicted protein sequence of SlREO contains a domain found in enzymes of the 2-oxoglutarate and Fe(II)-dependent dioxygenase superfamily. The novel SlREO promoter has properties ideal for applications requiring strong and specific gene expression in the bulk of tomato root tissue growing in soil, and is also likely to be useful in other Solanaceous crop

Publishing and sharing multi-dimensional image data with OMERO

Imaging data are used in the life and biomedical sciences to measure the molecular and structural composition and dynamics of cells, tissues, and organisms. Datasets range in size from megabytes to terabytes and usually contain a combination of binary pixel data and metadata that describe the acquisition process and any derived results. The OMERO image data management platform allows users to securely share image datasets according to specific permissions levels: data can be held privately, shared with a set of colleagues, or made available via a public URL. Users control access by assigning data to specific Groups with defined membership and access rights. OMERO’s Permission system supports simple data sharing in a lab, collaborative data analysis, and even teaching environments. OMERO software is open source and released by the OME Consortium at www.openmicroscopy.org

Darwin -— an experimental astronomy mission to search for extrasolar planets

As a response to ESA call for mission concepts for its Cosmic Vision 2015–2025 plan, we propose a mission called Darwin. Its primary goal is the study of terrestrial extrasolar planets and the search for life on them. In this paper, we describe different characteristics of the instrument