Tetrabenazine as anti-chorea therapy in Huntington Disease: an open-label continuation study. Huntington Study Group/TETRA-HD Investigators

<p>Abstract</p> <p>Background</p> <p>Tetrabenazine (TBZ) selectively depletes central monoamines by reversibly binding to the type-2 vesicular monoamine transporter. A previous double blind study in Huntington disease (HD) demonstrated that TBZ effectively suppressed chorea, with a favorable short-term safety profile (<it>Neurology </it>2006;66:366-372). The objective of this study was to assess the long-term safety and effectiveness of TBZ for chorea in HD.</p> <p>Methods</p> <p>Subjects who completed the 13-week, double blind protocol were invited to participate in this open label extension study for up to 80 weeks. Subjects were titrated to the best individual dose or a maximum of 200 mg/day. Chorea was assessed using the Total Maximal Chorea (TMC) score from the Unified Huntington Disease Rating Scale.</p> <p>Results</p> <p>Of the 75 participants, 45 subjects completed 80 weeks. Three participants terminated due to adverse events (AEs) including depression, delusions with associated previous suicidal behavior, and vocal tics. One subject died due to breast cancer. The other 26 subjects chose not to continue on with each ensuing extension for various reasons. When mild and unrelated AEs were excluded, the most commonly reported AEs (number of subjects) were sedation/somnolence (18), depressed mood (17), anxiety (13), insomnia (10), and akathisia (9). Parkinsonism and dysphagia scores were significantly increased at week 80 compared to baseline. At week 80, chorea had significantly improved from baseline with a mean reduction in the TMC score of 4.6 (SD 5.5) units. The mean dosage at week 80 was 63.4 mg (range 12.5-175 mg).</p> <p>Conclusions</p> <p>TBZ effectively suppresses HD-related chorea for up to 80 weeks. Patients treated chronically with TBZ should be monitored for parkinsonism, dysphagia and other side effects including sleep disturbance, depression, anxiety, and akathisia.</p> <p>Trial Registration</p> <p>Clinicaltrials.gov registration number (initial study): NCT00219804</p

Cross-platform genetic discovery of small molecule products of metabolism and application to clinical outcomes

Circulating levels of small molecules or metabolites are highly heritable, but the impact of genetic differences in metabolism on human health is not well understood. In this cross-platform, genome-wide meta-analysis of 174 metabolite levels across six cohorts including up to 86,507 participants (70% unpublished data), we identify 499 (362 novel) genome-wide significant associations (p<4.9×10 -10 ) at 144 (94 novel) genomic regions. We show that inheritance of blood metabolite levels in the general population is characterized by pleiotropy, allelic heterogeneity, rare and common variants with large effects, non-linear associations, and enrichment for nonsynonymous variation in transporter and enzyme encoding genes. The majority of identified genes are known to be involved in biochemical processes regulating metabolite levels and to cause monogenic inborn errors of metabolism linked to specific metabolites, such as ASNS (rs17345286, MAF=0.27) and asparagine levels. We illustrate the influence of metabolite-associated variants on human health including a shared signal at GLP2R (p.Asp470Asn) associated with higher citrulline levels, body mass index, fasting glucose-dependent insulinotropic peptide and type 2 diabetes risk, and demonstrate beta-arrestin signalling as the underlying mechanism in cellular models. We link genetically-higher serine levels to a 95% reduction in the likelihood of developing macular telangiectasia type 2 [odds ratio (95% confidence interval) per standard deviation higher levels 0.05 (0.03-0.08; p=9.5×10 -30 )]. We further demonstrate the predictive value of genetic variants identified for serine or glycine levels for this rare and difficult to diagnose degenerative retinal disease [area under the receiver operating characteristic curve: 0.73 (95% confidence interval: 0.70-0.75)], for which low serine availability, through generation of deoxysphingolipids, has recently been shown to be causally relevant. These results show that integration of human genomic variation with circulating small molecule data obtained across different measurement platforms enables efficient discovery of genetic regulators of human metabolism and translation into clinical insights.M.P. was supported by a fellowship from the German Research Foundation (DFG PI 1446/2-1). C.O. was founded by an early career fellowship at Homerton College, University of Cambridge. L. B. L. W. acknowledges funding by the Wellcome Trust (WT083442AIA). J.G. was supported by grants from the Medical Research Council (MC_UP_A090_1006, MC_PC_13030, MR/P011705/1 and MR/P01836X/1). Work in the Reimann/Gribble laboratories was supported by the Wellcome Trust (106262/Z/14/Z and 106263/Z/14/Z), UK Medical Research Council (MRC_MC_UU_12012/3) and PhD funding for EKB from MedImmune/AstraZeneca. Praveen Surendran is supported by a Rutherford Fund Fellowship from the Medical Research Council grant MR/S003746/1. A. W. is supported by a BHF-Turing Cardiovascular Data Science Award and by the EC-Innovative Medicines Initiative (BigData@Heart). J.D. is funded by the National Institute for Health Research [Senior Investigator Award] [*]. The EPIC-Norfolk study (https://doi.org/10.22025/2019.10.105.00004) has received funding from the Medical Research Council (MR/N003284/1 and MC-UU_12015/1) and Cancer Research UK (C864/A14136). The genetics work in the EPIC-Norfolk study was funded by the Medical Research Council (MC_PC_13048). Metabolite measurements in the EPIC-Norfolk study were supported by the MRC Cambridge Initiative in Metabolic Science (MR/L00002/1) and the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement no. 115372. We are grateful to all the participants who have been part of the project and to the many members of the study teams at the University of Cambridge who have enabled this research. The Fenland Study is supported by the UK Medical Research Council (MC_UU_12015/1 and MC_PC_13046). Participants in the INTERVAL randomised controlled trial were recruited with the active collaboration of NHS Blood and Transplant England (www.nhsbt.nhs.uk), which has supported field work and other elements of the trial. DNA extraction and genotyping was co-funded by the National Institute for Health Research (NIHR), the NIHR BioResource (http://bioresource.nihr.ac.uk) and the NIHR [Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust] [*]. Nightingale Health NMR assays were funded by the European Commission Framework Programme 7 (HEALTH-F2-2012-279233). Metabolon Metabolomics assays were funded by the NIHR 26 BioResource and the National Institute for Health Research [Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust] [*]. The academic coordinating centre for INTERVAL was supported by core funding from: NIHR Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024), UK Medical Research Council (MR/L003120/1), British Heart Foundation (SP/09/002; RG/13/13/30194; RG/18/13/33946) and the NIHR [Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust] [*].The academic coordinating centre would like to thank blood donor centre staff and blood donors for participating in the INTERVAL trial. This work was supported by Health Data Research UK, which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation and Wellcome. *The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. UK Biobank: This research has been conducted using the UK Biobank resource under Application Number 44448

Late Pliocene marine pCO2 reconstructions from the Subarctic Pacific Ocean

The development of large ice-sheets across the Northern Hemisphere during the late Pliocene and the emergence of the glacial-interglacial cycles that punctuate the Quaternary mark a significant threshold in Earth's climate history. Although a number of different mechanisms have been proposed to initiate this cooling and the onset of major Northern Hemisphere glaciation, reductions in atmospheric concentrations of CO2 likely played a key role. The emergence of a stratified (halocline) water column in the subarctic north-west Pacific Ocean at 2.73 Ma has often been interpreted as an event which would have limited oceanic ventilation of CO2 to the atmosphere, thereby helping to cool the global climate system. Here, diatom carbon isotopes (δ13Cdiatom) are used to reconstruct changes in regional carbon dynamics through this interval. Results show that the development of a salinity stratification did not fundamental alter the net oceanic/atmospheric flux of CO2 in the subarctic north-west Pacific Ocean through the late Pliocene/early Quaternary. These results provide further insights into the long-term controls on global carbon cycling and the role of the subarctic Pacific Ocean in instigating global climatic changes

Is Chinese Competition Causing Deindustrialization in Brazil?

There has been a lively debate in Brazil in recent years, involving sectors of business, the labor movement, and academics, over deindustrialization and the future of the manufacturing sector. This is often linked to the growing relation between Brazil and China, which is now the country’s most significant trade partner. Brazil has experienced relative deindustrialization in the sense of a declining share of the manufacturing sector in gross domestic product that is mainly attributable to the changes in the country’s trade balance in manufactures. The direct and indirect impacts of China on Brazilian manufacturing have contributed to this relative deindustrialization

Factors affecting the reaction of lecithin cholesterol acyltransferase with water-soluble substrates

To separate interfacial binding from the catalytic reactions of LCAT, the first investigation of its reaction with water soluble substrates was performed to characterize the molecular specificity of the active site as well as the effects of external modulators on the enzyme. Two substrates were chosen: fatty acid esters of p-nitrophenol and 1,2-Bis (4-(1-pyreno)butanoyl) -sn-glycero-3-phosphocholine (DPydPC).The fatty acid esters of p-nitrophenol were used to determine the chain length specificity of LCAT. The kinetics of the LCAT reaction were measured for the PNP esters with fatty acids having up to six (C-6) carbons in length. With increasing acyl chain lengths, the initial velocity of PNP ester hydrolysis went through a maximum at the C-5 esters. The Km and Vmax values decreased progressively, while the kcat/km values increased with increasing acyl chain length.Both water soluble substrates were used to study the effects of modulators of the LCAT reaction (e.g., lysolecithin, salt concentration, and apolipoprotein A-I) on the enzyme itself. Inhibition of the LCAT reaction by lysolecithin, fatty acids, and detergents of the hydrolysis of the water soluble substrates by LCAT indicated that the effects of these compounds are due to a direct interaction with the enzyme.The effects of anions, cations, and increasing salt concentration had no effect on the hydrolysis of the water soluble substrates, in contrast to their effects on the LCAT reaction in the presence of an interface. Thus, these effects are mediated primarily on the interaction of the enzyme with the interface. The involvement of cationic residues on LCAT in interfacial binding is also postulated.Hydrolysis of the water soluble substrates occurred at high reaction rates relative to rHDL containing apolipoprotein A-I. This observation as well as the fact that solubilized apolipoproteins do not affect hydrolysis of the water soluble substrates suggests that activation of the LCAT reaction by apolipoprotein A-I also is exclusively an interfacial effect.U of I OnlyETDs are only available to UIUC Users without author permissio

Articulation du soin et du pédagogique en hôpital de jour : le psy et l'instit parlent-ils du même enfant ?

Contexte : la question de la place des apprentissages pédagogiques au sein d'un hôpital de jour accueillant des enfants présentant un TED, s'interroge pour trouver au mieux comment articuler soin et pédagogie. Méthode : étude de trois situations cliniques. Résultats/conclusion : la mise en perspective d'une évaluation comportementaliste (PEP-R) et de la compréhension psychodynamique des observations cliniques à propos de trois situations permet d'aborder la complémentarité des outils

225Ac-DOTA-Substance P as a potential radiopharmaceutical for targeted alpha therapy of glioblastoma multiforme

Gliomas, particularly WHO grade IV glioblastoma multiforme (GBM) are one of the most common and aggressive primary types of the cancer of the central nervous system and are composed of morphologically diverse population of cells in the tumour mass. Despite all current forms of treatment such as advanced surgery techniques, radiation therapy and chemotherapy, the life expectancy of patients diagnosed with GBM is 12 to 15 months displaying the worst median overall survival among all human neoplasms. Targeted alpha therapy has been shown to overcome chemo- and radioresistance in vitro and thus presents a promising new approach for therapy of GBM. The findings that high affinity Substance P receptor NK1 is high consistently expressed in primary malignant gliomas and in the intratumoral and peritumoral vasculature makes this receptor a very attractive target for glioma cancer therapy.JRC.G.I.5-Advanced Nuclear Knowledg

Trueness, precision and stability of the LIAISON 1-84 parathyroid hormone (PTH) third-generation assay: comparison to existing intact PTH assays

BACKGROUND: Over the past few decades, parathyroid hormone (PTH) immunoassays have progressed through successive generations resulting in increased specificity and accuracy for detecting circulating PTH. With the introduction of third-generation assays, in which the biologically active PTH(1-84) is specifically targeted, the PTH(7-84) and other fragments are not detected. The specific recognition of only PTH(1-84) whole molecule allows for more reliable standardization and calibration than with the existing assays. METHODS: Samples from patients on hemodialysis or with primary hyperparathyroidism and apparently healthy subjects were examined in different collection matrices (EDTA plasma, unspun EDTA plasma and SST) stored for 0, 24 or 72 h at room temperature to reflect the prevailing sample collection methods, shipping and processing conditions of centralized labs in the United States. Samples were analyzed by the LIAISON 1-84 PTH and N-TACT assays, and by three additional commercially available intact PTH assays. RESULTS: Defined samples, prepared using two different standards (WHO 95/646 international standard and the synthetic Bachem PTH(1-84)), show little bias with the LIAISON 1-84 PTH assay, but not with the other intact PTH assays. Furthermore, PTH is stable for up to 72 h in plasma, but less stable in serum beyond 24 h. CONCLUSIONS: The FDA-approved LIAISON 1-84 PTH assay is accurate and reliably measures the biologically active PTH molecule in plasma or serum stored at room temperature for up 72 and 24 h, respectively

1,25-Dihydroxyvitamin D to PTH(1–84) Ratios Strongly Predict Cardiovascular Death in Heart Failure

<div><p>Objectives</p><p>Vitamin D deficiency and hyperparathyroidism are common in patients with heart failure (HF). There is a growing body of evidence supporting the role of vitamin D and parathyroid hormone (PTH) in cardiac remodeling and worsening of HF. Lack of reliable automated testing of 1,25-dihydroxyvitamin D (1,25(OH)₂D), the biologically active metabolite of vitamin D, has limited its contribution to the prognostic assessment of HF. Here, the association of 1,25(OH)₂D and PTH(1–84) levels was evaluated for prediction of cardiovascular death in chronic HF patients.</p><p>Methods</p><p>We conducted a single center prospective cohort including 170 chronic HF patients (females n = 36; males n = 134; NYHA II-IV; mean age: 67 years; etiology: ischemic n = 119, dilated cardiomyopathy n = 51; mean LVEF: 23%). The primary outcome was cardiovascular death.</p><p>Results</p><p>Serum levels of 1,25(OH)₂D decreased markedly with increased HF severity. Medians were 33.3 pg/mL for NYHA-II patients, 23.4 pg/mL for NYHA-III, and 14.0 pg/mL for NYHA-IV patients (p<0.001). Most patients had levels of 25(OH)D below 30ng/mL, and stratification by NYHA functional class did not show significant differences (p = 0.249). The 1,25(OH)₂D to PTH(1–84) ratio and the (1,25(OH)₂D)² to PTH(1–84) ratio were found to be the most significantly related to HF severity. After a median follow-up of 4.1 years, 106 out of 170 patients reached the primary endpoint. Cox proportional hazard modeling revealed 1,25(OH)₂D and the 1,25(OH)₂D to PTH(1–84) ratios to be strongly predictive of outcomes.</p><p>Conclusions</p><p>1,25(OH)₂D and its ratios to PTH(1–84) strongly and independently predict cardiovascular mortality in chronic HF.</p></div