Elevated alpha-synuclein caused by SNCA gene triplication impairs neuronal differentiation and maturation in Parkinson's patient-derived induced pluripotent stem cells

We have assessed the impact of α-synuclein overexpression on the differentiation potential and phenotypic signatures of two neural-committed induced pluripotent stem cell lines derived from a Parkinson´s disease patient with a triplication of the human SNCA genomic locus. In parallel, comparative studies were performed on two control lines derived from healthy individuals and lines generated from the patient iPS-derived neuroprogenitor lines infected with a lentivirus incorporating a small hairpin RNA to knock down the SNCA mRNA. The SNCA triplication lines exhibited a reduced capacity to differentiate into dopaminergic or GABAergic neurons and decreased neurite outgrowth and lower neuronal activity compared with control cultures. This delayed maturation phenotype was confirmed by gene expression profiling, which revealed a significant reduction in mRNA for genes implicated in neuronal differentiation such as delta-like homolog 1 (DLK1), gamma-aminobutyric acid type B receptor subunit 2 (GABABR2), nuclear receptor related 1 protein (NURR1), G-protein-regulated inward-rectifier potassium channel 2 (GIRK-2) and tyrosine hydroxylase (TH). The differentiated patient cells also demonstrated increased autophagic flux when stressed with chloroquine. We conclude that a two-fold overexpression of α-synuclein caused by a triplication of the SNCA gene is sufficient to impair the differentiation of neuronal progenitor cells, a finding with implications for adult neurogenesis and Parkinson´s disease progression, particularly in the context of bioenergetic dysfunction.Fil: Oliveira, L. M. A.. Max-Planck-Institut für biophysikalische Chemie; AlemaniaFil: Falomir Lockhart, Lisandro Jorge. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata ; Argentina. Max-Planck-Institut für biophysikalische Chemie; AlemaniaFil: Botelho, M. G.. Max-Planck-Institut für biophysikalische Chemie; Alemania. Universidade Federal do Rio de Janeiro; BrasilFil: Lin, K. H.. Max-Planck-Institut für biophysikalische Chemie; AlemaniaFil: Wales, P.. Universität Göttingen; AlemaniaFil: Koch, J. C.. Universität Göttingen; AlemaniaFil: Gerhardt, Elizabeth. Universität Göttingen; AlemaniaFil: Taschenberger, H.. Max-Planck-Institut für biophysikalische Chemie; AlemaniaFil: Outeiro, T. F.. Universität Göttingen; AlemaniaFil: Lingor, P.. Universität Göttingen; AlemaniaFil: Schüele, B.. The Parkinson’s Institute; Estados UnidosFil: Arndt Jovin, D. J.. Max-Planck-Institut für biophysikalische Chemie; AlemaniaFil: Jovin, T. M.. Max-Planck-Institut für biophysikalische Chemie; Alemani

Epidural anesthesia and cancer outcomes in bladder cancer patients : is it the technique or the medication? A matched-cohort analysis from a tertiary referral center

Peer reviewedPublisher PD

Principles of International Law Relevant for Consideration in the Design and Implementation of Trade-Related Climate Measures and Policies. Report of an International Legal Expert Group.

The report offers independent guidance for governments and stakeholders by eminent legal experts on principles of international law relevant for consideration in the design and implementation of trade-related climate measures and policies. The report reviews a set of recognized principles of international law that the expert group deems especially relevant for consideration including: Sovereignty; Prevention; Cooperation; Prohibition of Arbitrary & Unjustifiable Discrimination; Sustainable Development, Equity, & CBDR-RC; and Transparency & Consultation. The vision driving this report is that shared understandings on such principles could help foster dialogue and international cooperation on the design and implementation of trade-related climate measures and policies in the context of sustainable development priorities. According to the expert group, trade-related climate measures and policies should be approached as legal hybrids. Their rationale, design, and the debates about them draw from different areas of international law relating to the environment, climate, international trade and general international law. The principles are analysed in a way that presents them as cumulative and simultaneously applicable, in a mutually supportive and coherent manner, giving full effect to all relevant parts of international law, insofar as possible

Preterm neonatal morbidity and mortality by gestational age: a contemporary cohort

Although preterm birth less than 37 weeks gestation is the leading cause of neonatal morbidity and mortality in the United States, the majority of data regarding preterm neonatal outcomes come from older studies, and many reports have been limited to only very preterm neonates. Delineation of neonatal outcomes by delivery gestational age is needed to further clarify the continuum of mortality and morbidity frequencies among preterm neonates

Robotic Assisted Laparoscopic Partial Cystectomy as Treatment for Pseudosarcomatous Fibromyxoid Tumor of the Bladder

This case is of a 26 year old female evaluated for gross hematuria and suprapubic pain found to have a large bladder tumor. She subsequently underwent successful robotic assisted laparoscopic partial cystectomy. Pathology revealed pseudosarcomatous fibromyxoid tumor, an uncommon lesion that occurs most frequently among young females and must be distinguished from other malignant lesions, as treatment may differ. Partial cystectomy via robotic approach has never been described in the literature as a treatment option for this type of bladder lesion. In this case, the patient did exceptionally well upon follow-up. As such, robotic assisted laparoscopic partial cystectomy is presented a viable option for treatment of select patients with pseudosarcomatous fibromyxoid tumor

Primary Ewing sarcoma of the kidney: a symptomatic presentation and review of the literature

The objective of this review is to discuss the unique nature of primary renal Ewing sarcoma, including incidence, presentation and management. We also report on a common pattern of presentation, consisting of acute flank pain mimicking a renal stone colic, with or without hydronephrosis, and a renal mass discovered during imaging studies of renal Ewing sarcoma. We present our case of renal Ewing sarcoma along with imaging and pathological analysis. We also performed a retrospective review of all cases of renal Ewing sarcoma using PubMed. A total of 48 cases of renal EWS sarcoma have been reported and analyzed in this review. A mean age of 30.4 years was found along with a 61% male predominance. The mean survival was 26.14 months with a lower median survival in patients with advanced metastatic disease. Primary Ewing sarcoma of the kidney is rare. The diagnosis of primary renal EWS can be difficult and is based on a combination of electron microscopy, immunohistochemistry, chromosomal analysis, fluorescence in situ hybridization (FISH) and light microscopy

A Single-Institution Experience with Metallic Ureteral Stents: A Cost-Effective Method of Managing Deficiencies in Ureteral Drainage

Introduction: The limitations of traditional ureteral stents in patients with deficiencies in ureteral drainage have resulted in frequent stent exchanges. The implementation of metallic stents was introduced to improve the patency rates of patients with chronic upper urinary tract obstruction, obviating the need for frequent stent exchanges. We report our clinical experiences with the use of metallic ureteral stents in the management of poor ureteral drainage. Materials and Methods: Fifty patients underwent metallic ureteral stent placement from 2009 to 2012. Stent failure was defined as an unplanned stent exchange, need for nephrostomy tube placement, increasing hydronephrosis with stent in place, or an elevation in serum creatinine. Stent life was analyzed using the Kaplan-Meier methodology, as this was a time dependent continuous variable. A cost analysis was similarly conducted. Results: A total of 97 metallic stents were placed among our cohort of patients: 63 in cases of malignant obstruction, 33 in the setting of cutaneous ureterostomies, and 1 in an ileal conduit urinary diversion. Overall, stent failure occurred in 8.2% of the stents placed. Median stent life was 288.4 days (95% CI: 277.4-321.2 days). The estimated annual cost for traditional polymer stents (exchanged every 90 days) was $9,648-$13,128, while the estimated cost for metallic stents was $4,211-$5,313. Conclusion: Our results indicate that metallic ureteral stent placement is a technically feasible procedure with minimal complications and is well tolerated among patients. Metallic stents can be left in situ for longer durations and provide a significant financial benefit when compared to traditional polymer stents

A Single-Institution Experience with Metallic Ureteral Stents: A Cost-Effective Method of Managing Deficiencies in Ureteral Drainage

IntroductionThe limitations of traditional ureteral stents in patients with deficiencies in ureteral drainage have resulted in frequent stent exchanges. The implementation of metallic stents was introduced to improve the patency rates of patients with chronic upper urinary tract obstruction, obviating the need for frequent stent exchanges. We report our clinical experiences with the use of metallic ureteral stents in the management of poor ureteral drainage.Materials and MethodsFifty patients underwent metallic ureteral stent placement from 2009 to 2012. Stent failure was defined as an unplanned stent exchange, need for nephrostomy tube placement, increasing hydronephrosis with stent in place, or an elevation in serum creatinine. Stent life was analyzed using the Kaplan-Meier methodology, as this was a time dependent continuous variable. A cost analysis was similarly conducted.ResultsA total of 97 metallic stents were placed among our cohort of patients: 63 in cases of malignant obstruction, 33 in the setting of cutaneous ureterostomies, and 1 in an ileal conduit urinary diversion. Overall, stent failure occurred in 8.2% of the stents placed. Median stent life was 288.4 days (95% CI: 277.4-321.2 days). The estimated annual cost for traditional polymer stents (exchanged every 90 days) was $9,648-$13,128, while the estimated cost for metallic stents was $4,211-$5,313.ConclusionOur results indicate that metallic ureteral stent placement is a technically feasible procedure with minimal complications and is well tolerated among patients. Metallic stents can be left in situ for longer durations and provide a significant financial benefit when compared to traditional polymer stents