ORK1, a potassium-selective leak channel with two pore domains cloned from Drosophila melanogaster by expression in Saccharomyces cerevisiae.

A K+ channel gene has been cloned from Drosophila melanogaster by complementation in Saccharomyces cerevisiae cells defective for K+ uptake. Naturally expressed in the neuromuscular tissues of adult flies, this gene confers K+ transport capacity on yeast cells when heterologously expressed. In Xenopus laevis oocytes, expression yields an ungated K(+)-selective current whose attributes resemble the "leak" conductance thought to mediate the resting potential of vertebrate myelinated neurons but whose molecular nature has long remained elusive. The predicted protein has two pore (P) domains and four membrane-spanning helices and is a member of a newly recognized K+ channel family. Expression of the channel in flies and yeast cells makes feasible studies of structure and in vivo function using genetic approaches that are not possible in higher animals

The effects of verbal information on children's fear beliefs about social situations

Two experiments explored the role of verbal information in changing children’s fearrelated beliefs about social situations. In Experiment 1, 118 6- to 8- and 12- to 13-year-olds heard positive, negative, or no information about individuals’ experiences of three social situations. Fear beliefs regarding each situation were assessed before and after this manipulation. Verbal information had no significant influence on children’s fear beliefs. In Experiment 2, the same paradigm was used with 80 12- to 13-year-olds, but the information took the form of multiple attitude statements about the situations expressed by groups of peers, older children, or adults. An affective priming task of implicit attitudes was used to complement the explicit questions about fear beliefs. Negative information influenced both explicit and implicit fear beliefs. The source of information and the child’s own social anxiety did not moderate these effects. Implications for our understanding of the socialisation of childhood fears are discussed

Payment for performance (P4P): any future in Italy?

<p>Abstract</p> <p>Background</p> <p>Pay for Performance (P4P) programs, based on provision of financial incentives for service quality, have been widely adopted to enhance quality of care and to promote a more efficient use of health care resources whilst improving patient outcomes. In Italy, as in other countries, the growing concern over the quality of health services provided and the scarcity of resources would make P4P programs a useful means of improving their performance. The aim of this paper is to evaluate whether it is possible to implement P4P programs in the Lombardy Region, in Italy, based on the existing data set.</p> <p>Methods</p> <p>Thirteen quality measures were identified regarding four clinical conditions (acute myocardial infarction (AMI), heart failure (HF), ischemic stroke and hip and knee replacement) on the basis of an international literature review. Data was collected using the database of three institutions, which included hospital discharge records (Scheda di Dimissione ospedaliera-SDO-) and letters of discharge. The study population was identified using both the Principal ICD-9-CM diagnosis codes and the discharge date. A Statistical Analysis System (SAS) program was used for the text analysis.</p> <p>Results</p> <p>It was possible to calculate almost all the parameters pertaining to the three hospitals as all the data required was available with the exception of inpatient mortality in two hospitals and smoking cessation advice/counseling in one hospital.</p> <p>Conclusions</p> <p>On the ground of this analysis, we believe that it is possible to implement a P4P program in the Lombardy Region. However, for this program to be initiated, all necessary data must be available in electronic format and uniformly collected. Moreover, several other factors must be assessed: which clinical conditions should be included, the threshold for each quality parameter, the amount of financial incentives offered and how they will be provided.</p

Olutasidenib (FT-2102) in patients with relapsed or refractory IDH1-mutant glioma: A multicenter, open-label, phase Ib/II trial

Brain penetration; Mutant; OlutasidenibPenetració cerebral; Mutant; OlutasidenibPenetración cerebral; Mutante; OlutasidenibBackground Olutasidenib (FT-2102) is a highly potent, orally bioavailable, brain-penetrant and selective inhibitor of mutant isocitrate dehydrogenase 1 (IDH1). The aim of the study was to determine the safety and clinical activity of olutasidenib in patients with relapsed/refractory gliomas harboring an IDH1R132X mutation. Methods This was an open-label, multicenter, nonrandomized, phase Ib/II clinical trial. Eligible patients (≥18 years) had histologically confirmed IDH1R132X-mutated glioma that relapsed or progressed on or following standard therapy and had measurable disease. Patients received olutasidenib, 150 mg orally twice daily (BID) in continuous 28-day cycles. The primary endpoints were dose-limiting toxicities (DLTs) (cycle 1) and safety in phase I and objective response rate using the Modified Response Assessment in Neuro-Oncology criteria in phase II. Results Twenty-six patients were enrolled and followed for a median 15.1 months (7.3‒19.4). No DLTs were observed in the single-agent glioma cohort and the pharmacokinetic relationship supported olutasidenib 150 mg BID as the recommended phase II dose. In the response-evaluable population, disease control rate (objective response plus stable disease) was 48%. Two (8%) patients demonstrated a best response of partial response and eight (32%) had stable disease for at least 4 months. Grade 3‒4 adverse events (≥10%) included alanine aminotransferase increased and aspartate aminotransferase increased (three [12%], each). Conclusions Olutasidenib 150 mg BID was well tolerated in patients with relapsed/refractory gliomas harboring an IDH1R132X mutation and demonstrated preliminary evidence of clinical activity in this heavily pretreated population.This study was funded by Forma Therapeutics, Inc., Watertown, MA, USA

Political Regimes and Sovereign Credit Risk in Europe, 1750-1913

This article uses a new panel data set to perform a statistical analysis of political regimes and sovereign credit risk in Europe from 1750 to 1913. Old Regime polities typically suffered from fiscal fragmentation and absolutist rule. By the start of World War I, however, many such countries had centralized institutions and limited government. Panel regressions indicate that centralized and?or limited regimes were associated with significant improvements in credit risk relative to fragmented and absolutist ones. Structural break tests also reveal close relationships between major turning points in yield series and political transformations

Functional results after chest wall stabilization with a new screwless fixation device

OBJECTIVES This is the experience with the Stratos system in two surgical centres for the management of two types of rib fractures: flail chest and multiple dislocated rib fractures with significant chest wall deformity. METHODS From January 2009 to May 2012, 94 consecutive patients were included. Selected indications were extended anterolateral flail chest (n = 68) and dislocated painful rib fractures (n = 26). The open reduction internal fixation (ORIF) system consists of flexible titanium rib clamps and connecting plates. The postoperative course was assessed. Clinical and functional outcomes were evaluated at 6 months. Functional assessment consisted of measurement of the functional vital capacity (FVC) and magnetic resonance imaging (MRI) examination with determination of the radiological vital capacity (rVC) in patients with a flail chest. RESULTS The median operation time and length of hospital stay were 122 min and 19 days, respectively, in patients with a flail chest, and 67 min and 11 days, respectively, in patients with dislocated painful rib fractures. The morbidity rate was 6.4% and the overall 30-day mortality rate was 1.1%. Clinical evaluation and pulmonary function testing at 6 months revealed no deformity of the chest wall, symmetrical shoulder girdle mobility in 88% and a feeling of stiffness on the operated side in 19% of the patients operated for a flail chest. Median ratio of FVC was 88%, not suggesting any restriction after stabilization. MRI was performed in 53% (36 of 68) of the patients with a flail chest. The analysis of the rVC showed, on average, no clinically relevant restriction related to the operation, with a mean rVC of the operated relative to the non-operated side of 92% (95% confidence interval: 83, 100). Stabilization of more than four ribs was associated with a lower median rVC than stabilization of four or less ribs. CONCLUSIONS Our results suggest that stabilization of the chest wall with this screwless rib fixation device can be performed with a low morbidity and lead to early restoration of chest wall integrity and respiratory pump function, without clinically relevant functional restriction. Owing to the simplicity of the fixation technique, indications for stabilization can be safely enlarged to selected patients with dislocated and painful rib fracture

Activity-regulated RNA editing in select neuronal subfields in hippocampus

RNA editing by adensosine deaminases is a widespread mechanism to alter genetic information in metazoa. In addition to modifications in non-coding regions, editing contributes to diversification of protein function, in analogy to alternative splicing. However, although splicing programs respond to external signals, facilitating fine tuning and homeostasis of cellular functions, a similar regulation has not been described for RNA editing. Here, we show that the AMPA receptor R/G editing site is dynamically regulated in the hippocampus in response to activity. These changes are bi-directional, reversible and correlate with levels of the editase Adar2. This regulation is observed in the CA1 hippocampal subfield but not in CA3 and is thus subfield/celltype-specific. Moreover, alternative splicing of the flip/flop cassette downstream of the R/G site is closely linked to the editing state, which is regulated by Ca(2+). Our data show that A-to-I RNA editing has the capacity to tune protein function in response to external stimuli