Regulatory mechanisms controlling biogenesis of ubiquitin and the proteasome

Analysis of several Saccharomyces cerevisiae ump mutants with defects in ubiquitin (Ub)-mediated proteolysis yielded insights into the regulation of the polyubiquitin gene UB14 and of proteasome genes. High-molecular weight Ub-protein conjugates accumulated in ump mutants with impaired proteasome function with a concomitant decrease in the amount of free Ub. In these mutants, transcriptional induction of UB14 was depending in part on the transcription factor Rpn4. Deletion of UB14 partially suppressed the growth defects of ump1 mutants, indicating that accumulation of polyubiquitylated proteins is deleterious to cell growth. Transcription of proteasome subunit genes was induced in ump mutants affecting the proteasome, as well as under conditions that mediate DNA damage or the formation of abnormal proteins. This induction required the transcriptional activator Rpn4. Elevated Rpn4 levels in proteasome-deficient mutants or as a response to abnormal proteins were due to increased metabolic stability. Up-regulation of proteasome genes in response to DNA damage, in contrast, is shown to operate via induction of RPN4 transcription. (C) 2004 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.info:eu-repo/semantics/publishedVersio

Does an activity based remuneration system attract young doctors to general practice?

<p>Abstract</p> <p>Background</p> <p>The use of increasingly complex payment schemes in primary care may represent a barrier to recruiting general practitioners (GP). The existing Norwegian remuneration system is fully activity based - 2/3 fee-for-service and 1/3 capitation. Given that the system has been designed and revised in close collaborations with the medical association, it is likely to correspond - at least to some degree - with the preferences of <it>current </it>GPs (men in majority). The objective of this paper was to study which preferences that young doctors (women in majority), who are the <it>potential entrants </it>to general practice have for activity based vs. salary based payment systems.</p> <p>Methods</p> <p>In November-December 2010 all last year medical students and all interns in Norway (n = 1.562) were invited to participate in an online survey. The respondents were asked their opinion on systems of remuneration for GPs; inclination to work as a GP; risk attitude; income preferences; work pace tolerance. The data was analysed using one-way ANOVA and multinomial logistic regression analysis.</p> <p>Results</p> <p>A total of 831 (53%) responded. Nearly half the sample (47%) did not consider the remuneration system to be important for their inclination to work as GP; 36% considered the current system to make general practice <it>more </it>attractive, while 17% considered it to make general practice <it>less </it>attractive. Those who are attracted by the existing system were men and those who think high income is important, while those who are deterred by the system are risk averse and less happy with a high work pace. On the question of preferred remuneration system, half the sample preferred a mix of salary and activity based remuneration (the median respondent would prefer a 50/50 mix). Only 20% preferred a fully activity based system like the existing one. A salary system was preferred by women, and those less concerned with high income, while a fully activity based system was preferred by men, and those happy with a high work pace.</p> <p>Conclusions</p> <p>Given a concern about low recruitment to general practice in Norway, and the fact that an increasing share of medical students is women, we were interested in the extent to which the current Norwegian remuneration system correspond with the preferences of potential GPs. This study suggests that an existing remuneration mechanism has a selection effect on who would like to become a GP. Those most attracted are income motivated men. Those deterred are risk averse, and less happy with a high work pace. More research is needed on the extent to which experienced GPs differ along the questions we asked potential GPs, as well as studying the relative importance of other attributes than payment schemes.</p

Mechanical Thrombectomy in Basilar Artery Occlusion: Presence of Bilateral Posterior Communicating Arteries is aPredictor of Favorable Clinical Outcome

BackgroundMechanical thrombectomy (MT) of basilar artery occlusions (BAO) is asubject of debate. We investigated the clinical outcome of MT in BAO and predictors of afavorable outcome.Material and MethodsA total of 104 MTs of BAO (carried out between 2010 and 2016) were analyzed. Favorable outcome as a modified Rankin scale (mRS) 2 at 90days was the primary endpoint. The influence of the following variables on outcome was investigated: number of detectable posterior communicating arteries (PcoAs), patency of basilar tip, completeness of BAO and posterior circulation Alberta Stroke Program early computed tomography score (PC-ASPECTS). Secondary endpoints were technical periprocedural parameters including symptomatic intracranial hemorrhage (sICH).ResultsThe favorable clinical outcome at 90days was 25% and mortality was 43%. The rate of successful reperfusion, i.e. modified thrombolysis in cerebral infarction (mTICI) 2b was 82%. Presence of bilateral PcoAs (area under the curve, AUC: 0.81, odds ratio, OR: 4.2, 2.2-8.2; p< 0.0001), lower National Institute of Health Stroke Scale (NIHSS) on admission (AUC: 0.74, OR: 2.6, 1.3-5.2; p< 0.01), PC-ASPECTS 9 (AUC: 0.72, OR: 4.2, 1.5-11.9; p< 0.01), incomplete BAO (AUC: 0.66, OR: 2.6, 1.4-4.8; p< 0.001), and basilar tip patency (AUC: 0.66, OR: 2.5, 1.3-4.8; p< 0.01) were associated with a favorable outcome. Stepwise logistic regression analysis revealed that the strongest predictors of favorable outcome at 90days were bilateral PcoAs, low NIHSS on admission, and incomplete BAO (AUC: 0.923, OR: 7.2, 3-17.3; p< 0.0001).ConclusionThe use of MT for BAO is safe with high rates of successful reperfusion. Aside from baseline NIHSS and incomplete vessel occlusion, both known predictors of favorable outcome in anterior circulation events, we found that collateral flow based on the presence or absence of PcoAs had adecisive prognostic impact

Incomplete Large Vessel Occlusions in Mechanical Thrombectomy: An Independent Predictor of Favorable Outcome in Ischemic Stroke

Background and Purpose: Cerebral large vessel occlusion (LVO) in acute ischemic stroke (AIS) may be complete (CLVO) or incomplete (ILVO). The influence of ILVO on clinical outcome after mechanical thrombectomy (MT) remains unclear. We investigated primarily the clinical outcome in patients with AIS due to ILVO or CLVO. Methods: Five hundred three consecutive AIS patients with LVO treated with stent-retriever or direct aspiration-based MT between 2010 and 2016 were analyzed. The primary endpoint was favorable clinical outcome (modified Rankin Scale <= 2) at 90 days; secondary endpoints were periprocedural parameters. Results: Forty-nine patients (11.3%) with a median National Institutes of Health Stroke Scale (NIHSS) of 11 presented with ILVO and the remainder presented with CLVO and median NIHSS of 15 (p < 0.001). The median groin puncture-to-reperfusion time was 30 vs. 67 min, respectively (p < 0.001). Successful reperfusion was reached in 47 out of 49 ILVO (95.9%) vs. 298 out of 381 CLVO (78.2%; p < 0.005) with less retrieval maneuvers (1.7 +/- 2.2 vs. 3.0 +/- 2.5; p < 0.001). The favorable outcome at 90 days was 81% in patients with ILVO vs. 29.1% in CLVO (p < 0.001); respective all-cause mortality rates were 6.4 vs. 28.5% (p < 0.001). Periprocedural complications (6.9%) occurred exclusively in CLVO patients (p < 0.05). ILVO was associated with favorable clinical outcome independent of age and NIHSS in multivariate logistic regression both in the anterior (OR 3.6; 95% CI 1.8-6.9; p < 0.001) and posterior circulation (OR 3.5; 95% CI 1.8-6.9; p < 0.001). Conclusions: AIS due to ILVO is frequent and is associated with a nearly threefold higher chance of favorable clinical outcome at 90 days, independent of age and initial NIHSS compared to CLVO. (C) 2017 S. Karger AG, Base

Carotid Artery Stenosis Contralateral to Acute Tandem Occlusion: An Independent Predictor of Poor Clinical Outcome after Mechanical Thrombectomy with Concomitant Carotid Artery Stenting

Background and Purpose: Cerebral ischemic strokes due to extra-/intracranial tandem occlusions (TO) of the anterior circulation are responsible for causing mechanical thrombectomy (MT). The impact of concomitant contralateral carotid stenosis (CCS) upon outcome remains unclear in this stroke subtype. Methods: Retrospective analysis of prospectively collected data of 4 international stroke centers between 2011 and 2017. One hundred ninety-seven consecutive patients with anterior TO were treated with MT and acute carotid artery stenting (CAS). Clinical (including demographics and National Institutes of Health Stroke Scale [NIHSS]), imaging (including angiographic evaluation of CCS) and procedural data were evaluated. Favorable clinical outcome was defined as modified Rankin Scale (mRS) 50% is an independent predictor of poor clinical outcome. This most likely cause is due to poorer collateral flow to the affected tissue. (c) 2017 S. Karger AG, Base