Citations

AbstractIntroductionRapid eye movement (REM) sleep behavior disorder (RBD) in Parkinson's disease (PD) is associated with differences in clinical phenotype, including dementia, autonomic loss, and gait dysfunction. The pathological basis for this remains unclear.MethodsParkinson's disease subjects in a longitudinal clinicopathologic study were screened for probable RBD with the Mayo Sleep Questionnaire. After death, semiquantitative analyses were conducted for synuclein, amyloid, neurofibrillary tangles, and cerebrovascular lesions.ResultsForty cases had probable RBD (PD+RBD), and 41 did not (PD‐RBD). Despite similar age at death (∼80 y) and disease duration (∼14.5 y), PD+RBD had increased synuclein deposition in all regions examined, with nine of 10 regions significantly different. The Lewy body 10‐region total score (scale = 0‐40) was 29.5 in PD+RBD versus 24.5 in PD‐RBD (Cohen‐d effect size = 0.79, P = 0.002). Cerebrovascular lesion burden was slightly higher in PD‐RBD.ConclusionsAlthough overlap occurs between groups, PD patients with probable RBD may have greater density and range of synuclein pathology on autopsy. © 2015 International Parkinson and Movement Disorder Society

Summary Background Treatment of IBS and functional lower gastrointestinal disorders is still based predominantly on symptoms; biomarkers that reflect the mechanism or pathophysiology have been identified. Given the diverse mechanisms that result in the same clinical phenotype of IBS , it is hypothesised that identification of biomarkers may lead to individualisation of medical therapy. Aim To review the biomarkers that have been appraised in IBS . Methods A single author reviewed the published literature on biomarkers appraised in IBS . Results The current literature suggests that these biomarkers are insufficiently sensitive or specific to differentiate IBS from health or from other diseases causing similar symptoms, such as coeliac disease or inflammatory bowel disease. Most of the proposed biomarkers are not actionable, that is, they do not lead to an efficacious therapy based on the biological inference of the biomarker itself. However, among proposed biomarkers in IBS , some are actionable, as they specifically reflect a quantitative difference in a mediator of dysfunction or result in a quantifiable disturbance of function that can be specifically treated. Such biomarkers may potentially identify relevant subgroups that respond to specific therapy. The most promising actionable biomarkers are measurement of colonic transit (leading to treatments that reverse the abnormal transit) and measurements of bile acid diarrhoea to identify responders to bile acid sequestrants. Conclusions Therefore, although biomarkers are not ready for prime time as diagnostic tests in IBS , some biomarkers could identify subgroups of patients with IBS for inclusion in clinical trials that target specific dysfunctions. Such an approach may enhance treatment efficacy, and may ultimately help reduce costs in drug development and in the management of patients in clinical practice.

Objective Pulmonary hypertension (PH) is associated with increased mortality after surgical or transcatheter aortic valve replacement (TAVR) for aortic stenosis (AS), and when the pulmonary artery pressure is particularly elevated, there may be questions about the clinical benefit of TAVR. We aimed to identify clinical and haemodynamic factors associated with increased mortality after TAVR among those with moderate/severe PH. Methods Among patients with symptomatic AS at high or prohibitive surgical risk receiving TAVR in the Placement of Aortic Transcatheter Valves (PARTNER) I randomised trial or registry, 2180 patients with an invasive measurement of mean pulmonary artery pressure (mPAP) recorded were included, and moderate/severe PH was defined as an mPAP ≥35 mm Hg. Results Increasing severity of PH was associated with progressively worse 1-year all-cause mortality: none (n=785, 18.6%), mild (n=838, 22.7%) and moderate/severe (n=557, 25.0%) (p=0.01). The increased hazard of mortality associated with moderate/severe PH was observed in females, but not males (interaction p=0.03). In adjusted analyses, females with moderate/severe PH had an increased hazard of death at 1 year compared with females without PH (adjusted HR 2.14, 95% CI 1.44 to 3.18), whereas those with mild PH did not. Among males, there was no increased hazard of death associated with any severity of PH. In a multivariable Cox model of patients with moderate/severe PH, oxygen-dependent lung disease, inability to perform a 6 min walk, impaired renal function and lower aortic valve mean gradient were independently associated with increased 1-year mortality (p<0.05 for all), whereas several haemodynamic indices were not. A risk score, including these factors, was able to identify patients with a 15% vs 59% 1-year mortality. Conclusions The relationship between moderate/severe PH and increased mortality after TAVR is altered by sex, and clinical factors appear to be more influential in stratifying risk than haemodynamic indices. These findings may have implications for the evaluation of and treatment decisions for patients referred for TAVR with significant PH. Trial registration NCT00530894.

Abstract Activation of acid sphingomyelinase (ASM) leads to ceramide accumulation and induces apoptotic cell death in cancer cells. In the present study, we demonstrate that the activation of ASM by targeting cancer-overexpressed 67-kDa laminin receptors (67LR) induces lipid raft disruption and inhibits receptor tyrosine kinase (RTK) activation in multiple myeloma cells. Sphingosine kinase 1 (SphK1), a negative regulator of ceramide accumulation with antiapoptotic effects, was markedly elevated in multiple myeloma cells. The silencing of SphK1 potentiated the apoptotic effects of the green tea polyphenol epigallocatechin-3-O-gallate (EGCG), an activator of ASM through 67LR. Furthermore, the SphK1 inhibitor safingol synergistically sensitized EGCG-induced proapoptotic cell death and tumor suppression in multiple myeloma cells by promoting the prevention of RTK phosphorylation and activation of death-associated protein kinase 1 (DAPK1). We propose that targeting 67LR/ASM and SphK1 may represent a novel therapeutic strategy against multiple myeloma. Mol Cancer Ther; 14(10); 2303–12. ©2015 AACR.

AbstractAbstract In a nested, matched case-cohort design of 384 anesthesia residents who developed substance use disorder (SUD) and 768 controls who did not, receiving medical education in the United States, but not anesthesia knowledge early in residency, was associated with risk of developing SUD. By the end of follow-up, 54 anesthesiology residents (14.1%) with SUD and 10 controls (1.3%) were dead. Those with SUD were 15-, 10-, and 7-fold more likely to not complete residency, to not become board certified, or have adverse medical licensure actions, respectively. Background: The goal of this work is to evaluate selected risk factors and outcomes for substance use disorder (SUD) in physicians enrolled in anesthesiology residencies approved by the Accreditation Council for Graduate Medical Education. Methods: For each of 384 individuals with evidence of SUD while in primary residency training in anesthesiology from 1975 to 2009, two controls (n = 768) who did not develop SUD were identified and matched for sex, age, primary residency program, and program start date. Risk factors evaluated included location of medical school training (United States vs. other) and anesthesia knowledge as assessed by In-Training Examination performance. Outcomes (assessed to December 31, 2013, with a median follow-up time of 12.2 and 15.1 yr for cases and controls, respectively) included mortality and profession-related outcomes. Results: Receiving medical education within the United States, but not performance on the first in-training examination, was associated with an increased risk of developing SUD as a resident. Cases demonstrated a marked increase in the risk of death after training (hazard ratio, 7.9; 95% CI, 3.1 to 20.5), adverse training outcomes including failure to complete residency (odds ratio, 14.9; 95% CI, 9.0 to 24.6) or become board certified (odds ratio, 10.4; 95% CI, 7.0 to 15.5), and adverse medical licensure actions subsequent to residency (hazard ratio, 6.8; 95% CI, 3.8 to 12.2). As of the end of follow-up, 54 cases (14.1%) were deceased compared with 10 controls (1.3%); 28 cases and no controls died during residency. Conclusion: The attributable risk of SUD to several adverse outcomes during and after residency training, including death and adverse medical license actions, is substantial.

The PINK1 (phosphatase and tensin homologue-induced putative kinase 1)/Parkin-dependent mitochondrial quality control pathway mediates the clearance of damaged organelles, but appears to be disrupted in Parkinson's disease (PD) [Springer and Kahle (2011) Autophagy 7, 266–278]. Upon mitochondrial stress, PINK1 activates the E3 ubiquitin (Ub) ligase Parkin through phosphorylation of the Ub-like (UBL) domain of Parkin and of the small modifier Ub itself at a conserved residue [Sauvé and Gehring (2014) Cell Res. 24, 1025–1026]. Recently resolved partial crystal structures of Parkin showed a ‘closed’, auto-inhibited conformation, consistent with its notoriously weak enzymatic activity at steady state [Wauer and Komander (2013) EMBO J. 32, 2099–2112; Riley et al. (2013) Nat. Commun. 4, 1982; Trempe et al. (2013) Science 340, 1451–1455; Spratt et al. (2013) Nat. Commun. 4, 1983]. It has thus become clear that Parkin must undergo major structural rearrangements in order to unleash its catalytic functions. Recent published findings derived from X-ray structures and molecular modelling present a complete structural model of human Parkin at an all-atom resolution [Caulfield et al. (2014) PLoS Comput. Biol. 10, e1003935]. The results of the combined in silico simulations-based and experimental assay-based study indicates that PINK1-dependent Ser65 phosphorylation of Parkin is required for its activation and triggering of ‘opening’ conformations. Indeed, the obtained structures showed a sequential release of Parkin's intertwined domains and allowed docking of an Ub-charged E2 coenzyme, which could enable its enzymatic activity. In addition, using cell-based screening, select E2 enzymes that redundantly, cooperatively or antagonistically regulate Parkin's activation and/or enzymatic functions at different stages of the mitochondrial autophagy (mitophagy) process were identified [Fiesel et al. (2014) J. Cell Sci. 127, 3488–3504]. Other work that aims to pin-point the particular pathogenic dysfunctions of Parkin mis-sense mutations have been recently disseminated (Fabienne C. Fiesel, Thomas R. Caulfield, Elisabeth L. Moussaud-Lamodiere, Daniel F.A.R. Dourado, Kotaro Ogaki, Owen A. Ross, Samuel C. Flores, and Wolfdieter Springer, submitted). Such a structure–function approach provides the basis for the dissection of Parkin's regulation and a targeted drug design to identify small-molecule activators of this neuroprotective E3 Ub ligase.

The accumulation of Aβ (amyloid β-protein) peptides in the brain is a pathological hallmark of all forms of AD (Alzheimer's disease) and reducing Aβ levels can prevent or reverse cognitive deficits in mouse models of the disease. Aβ is produced continuously and its concentration is determined in part by the activities ofseveral degradative enzymes, including NEP (neprilysin), IDE (insulin-degrading enzyme), ECE-1 (endothelinconverting enzyme 1) and ECE-2, and probably plasmin. Decreased activity of any of these enzymes due to genetic mutation, or age- or disease-related alterations in gene expression or proteolytic activity, may increase the risk for AD. Conversely, increased expression of these enzymes may confer a protective effect. Increasing Aβ degradation through gene therapy, transcriptional activation or even pharmacological activation of the Aβ-degrading enzymes represents a novel therapeutic strategy for the treatment of AD that is currently being evaluated in cell-culture and animal models. In this paper, we will review the roles of NEP, IDE, ECE and plasmin in determining endogenous Aβ concentration, highlighting recent results concerning the regulation of these enzymes and their potential as therapeutic targets.

Cystic fibrosis, one of the major human inherited diseases, is caused by defects in the CFTR (cystic fibrosis transmembrane conductance regulator), a cell-membrane protein. CFTR acts as a chloride channel which can be opened by ATP. Low-resolution structural studies of purified recombinant human CFTR are described in the present paper. Localization of the C-terminal decahistidine tag in CFTR was achieved by Ni2+-nitriloacetate nanogold labelling, followed by electron microscopy and single-particle analysis. The presence of the gold label appears to improve the single-particle-alignment procedure. Projection structures of CFTR from two-dimensional crystals analysed by electron crystallography displayed two alternative conformational states in the presence of nucleotide and nanogold, but only one form of the protein was observed in the quiescent (nucleotide-free) state.