Managing Risk After Intracerebral Hemorrhage in Concomitant Atrial Fibrillation and Cerebral Amyloid Angiopathy.

The Dunhill Medical Trust (Grant ID: RTF44/0114)This is the author accepted manuscript. The final version is available from the American Heart Association via http://dx.doi.org/10.1161/STROKEAHA.116.01332

Recent developments in the treatment of Parkinson's Disease.

Parkinson's disease (PD) is a common neurodegenerative disease typified by a movement disorder consisting of bradykinesia, rest tremor, rigidity, and postural instability. Treatment options for PD are limited, with most of the current approaches based on restoration of dopaminergic tone in the striatum. However, these do not alter disease course and do not treat the non-dopamine-dependent features of PD such as freezing of gait, cognitive impairment, and other non-motor features of the disorder, which often have the greatest impact on quality of life. As understanding of PD pathogenesis grows, novel therapeutic avenues are emerging. These include treatments that aim to control the symptoms of PD without the problematic side effects seen with currently available treatments and those that are aimed towards slowing pathology, reducing neuronal loss, and attenuating disease course. In this latter regard, there has been much interest in drug repurposing (the use of established drugs for a new indication), with many drugs being reported to affect PD-relevant intracellular processes. This approach offers an expedited route to the clinic, given that pharmacokinetic and safety data are potentially already available. In terms of better symptomatic therapies that are also regenerative, gene therapies and cell-based treatments are beginning to enter clinical trials, and developments in other neurosurgical strategies such as more nuanced deep brain stimulation approaches mean that the landscape of PD treatment is likely to evolve considerably over the coming years. In this review, we provide an overview of the novel therapeutic approaches that are close to, or are already in, clinical trials

Regenerative Therapies for Parkinson's Disease: An Update.

Parkinson's disease is the second most common neurodegenerative disorder. It is characterised by a typical movement disorder that occurs in part because of the selective degeneration of the dopaminergic neurons of the substantia nigra pars compacta. Current treatment for the motor disorder of Parkinson's disease consists of dopaminergic medications, but these come with significant adverse effects, themselves an important part of the clinical course of Parkinson's disease, particularly in advanced stages. Therefore, treatment is needed that can restore dopaminergic tone in the striatum in a physiological and targeted manner to avert these side effects. A number of potential regenerative treatments have been developed with a view to achieving this. Following decades of optimisation and development of stem-cell-based treatments and viral gene delivery, clinical trials are on the horizon. For these treatments to be widely useful, they must be clinically effective, cost efficient and safe, and a number of practical aspects regarding storage and delivery of treatment must be optimised. Many barriers have been overcome, and the field of regenerative medicine for Parkinson's disease is now increasingly focussed on how these treatments will be delivered, demonstrating the significant progress that has been made and the optimism surrounding these approaches.The authors acknowledge financial support from the following organisations: Medical Research Council, Wellcome Trust Stem Cell Institute (Cambridge), National Institute for Health Research Biomedical Research Centre, and the Cure Parkinson’s Trus

Hydrocephalus Complicating Intrathecal Antisense Oligonucleotide Therapy for Huntington's Disease.

Huntington’s disease (HD) is a genetic disorder caused by an expanded CAG repeat in the huntingtin gene, and although there are currently no disease-modifying treatments, there is much excitement about the prospect of treatments targeting huntingtin expression. In a phase I/2A trial of an antisense oligonucleotide (ASO) treatment (Tominersen), no serious adverse events were recorded, and there was a dose-dependent reduction in cerebrospinal fluid (CSF) huntingtin levels1. In an open-label extension (OLE) study, patients received monthly or bimonthly Tominersen, with preliminary data confirming the reduction in mutant huntingtin levels2. Here we report on a unique major adverse effect occurring during this OLE.Funding sources and conflict of interest – This trial was funded initially by Ionis and subsequently by Roche. The authors received no additional funding for this work and the authors declare that there are no conflicts of interest relevant to this work. Financial disclosures - RAB is supported by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre - 146281 (the views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care) and MRC/WT Stem Cell Institute (203151/Z/16/Z)

Cell therapies for Parkinson's disease: how far have we come?

Over the past three decades, significant progress has been made in the development of potential regenerative cell-based therapies for neurodegenerative disease, with most success being seen in Parkinson's disease. Cell-based therapies face many challenges including ethical considerations, potential for immune-mediated rejection with allogeneic and xenogeneic tissue, pathological spread of protein-related disease into the grafted tissue as well as the risk of graft overgrowth and tumorigenesis in stem cell-derived transplants. Preclinical trials have looked at many tissue types of which the most successful to date have been those using fetal ventral mesencephalon grafts, which led to clinical trials, which have shown that in some cases they can work very well. With important proof-of-concept derived from these studies, there is now much interest in how dopaminergic neurons derived from stem cell sources could be used to develop cell-based therapies suitable for clinical use, with clinical trials poised to enter the clinic in the next couple of years.The authors acknowledge financial support from the following organisations: Medical Research Council, Wellcome Trust, Cambridge Stem Cell Institute, and National Institute for Health Research Biomedical Research Centre.This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by Future Medicine

A common polymorphism in SNCA is associated with accelerated motor decline in GBA-Parkinson's disease.

A growing number of genetic susceptibility factors have been identified for Parkinson’s disease (PD). The combination of inherited risk variants is likely to affect not only risk of developing PD but also its clinical course. Variants in the GBA gene are particularly common, being found in approximately 5 to 10% of patients, and they lead to more rapid disease progression1. However, the effect of concomitant genetic risk factors on disease course in GBA-PD is not known.The CamPaIGN study has received financial support from the Wellcome Trust, the Medical Research Council, Parkinson’s UK and the Patrick Berthoud Trust. CHWG is supported by an RCUK/UKRI Innovation Fellowship awarded by the Medical Research Council. RAB is supported by the Wellcome Trust Stem Cell Institute (Cambridge). TBS received financial support from the Cure Parkinson’s Trust. The study is also supported by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre Dementia and Neurodegeneration Theme (reference number 146281). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. CRS' work is supported in part by NIH grants R01AG057331, U01NS100603, R01AG057331, and the American Parkinson Disease Association. Illumina MEGA Chip genotyping was made possible by a philanthropic investment from Dooley LLC (to Brigham & Women's Hospital and CRS)

Impact of GBA1 variants on long-term clinical progression and mortality in incident Parkinson’s disease

Funder: Foundation for the National Institutes of Health; FundRef: http://dx.doi.org/10.13039/100000009Funder: Van Geest FoundationFunder: Patrick Berthoud Charitable Trust; FundRef: http://dx.doi.org/10.13039/501100004218Funder: Cure Parkinson's TrustFunder: Michael J Fox FoundationFunder: Innovate UK; FundRef: http://dx.doi.org/10.13039/501100006041Funder: Dooley LLCFunder: American Parkinson's disease associationFunder: Medical Research Council; FundRef: http://dx.doi.org/10.13039/501100000265Funder: Cambridge Centre for Parkinson-PlusFunder: Parkinson's UK; FundRef: http://dx.doi.org/10.13039/501100000304Funder: John Black charitable foundationFunder: Wellcome Trust; FundRef: http://dx.doi.org/10.13039/100004440Funder: National Institute for Health Research; FundRef: http://dx.doi.org/10.13039/501100000272Funder: Van Andel Research Institute; FundRef: http://dx.doi.org/10.13039/100006019Introduction: Variants in the GBA1 gene have been identified as a common risk factor for Parkinson’s disease (PD). In addition to pathogenic mutations (those associated with Gaucher disease), a number of ‘non-pathogenic’ variants also occur at increased frequency in PD. Previous studies have reported that pathogenic variants adversely affect the clinical course of PD. The role of ‘non-pathogenic’ GBA1 variants on PD course is less clear. In this study, we report the effect of GBA1 variants in incident PD patients with long-term follow-up. Methods: The study population consisted of patients in the Cambridgeshire Incidence of Parkinson’s disease from General Practice to Neurologist and Parkinsonism: Incidence, Cognition and Non-motor heterogeneity in Cambridgeshire cohorts. Patients were grouped into non-carriers, carriers of ‘non-pathogenic’ GBA1 variants and carriers of pathogenic GBA1 mutations. Survival analyses for time to development of dementia, postural instability and death were carried out. Cox regression analysis controlling for potential confounders were used to determine the impact of GBA1 variants on these outcome measures. Results: GBA1 variants were identified in 14.4% of patients. Pathogenic and ‘non-pathogenic’ GBA1 variants were associated with the accelerated development of dementia and a more aggressive motor course. Pathogenic GBA1 variants were associated with earlier mortality in comparison with non-carriers, independent of the development of dementia. Discussion: GBA1 variants, including those not associated with Gaucher disease, are common in PD and result in a more aggressive disease course

Nomad rover field experiment, Atacama desert, Chile 2. Identification of paleolife evidence using a robotic vehicle: Lessons and recommendations for a Mars sample return mission

This is the publisher's version, also available electronically from "http://onlinelibrary.wiley.com".During the Nomad Rover Field Experiment in the Atacama Desert (Chile), a potential fossil was identified in a boulder by the science team remotely located at NASA Ames Research Center, California. The science team requested the collecting of the boulder that was returned for laboratory analysis. This analysis confirmed the evidence of paleolife. As the first fossil identified and sampled by a remotely located science team using a rover, we use the case of sample I-250697 to describe the process, both in the field and later in the laboratory during the rock analysis, which led to the identification, characterization, and confirmation of the evidence of paleolife evidence in I-250697. We point out the lessons that this case provides for future Mars sample return missions

Can the outcome of pelvic-floor rehabilitation in patients with fecal incontinence be predicted?

Purpose: Pelvic-floor rehabilitation does not provide the same degree of relief in all fecal incontinent patients. We aimed at studying prospectively the ability of tests to predict the outcome of pelvic-floor rehabilitation in patients with fecal incontinence. Materials and methods: Two hundred fifty consecutive patients (228 women) underwent medical history and a standardized series of tests, including physical examination, anal manometry, pudendal nerve latency testing, anal sensitivity testing, rectal capacity measurement, defecography, endoanal sonography, and endoanal magnetic resonance imaging. Subsequently, patients were referred for pelvic-floor rehabilitation. Outcome of pelvic-floor rehabilitation was quantified by the Vaizey incontinence score. Linear regression analyses were used to identify candidate predictors and to construct a multivariable prediction model for the posttreatment Vaizey score. Results: After pelvic-floor rehabilitation, the mean baseline Vaizey score (18, SD±3) was reduced with 3.2 points (p<0.001). In addition to the baseline Vaizey score, three elements from medical history were significantly associated with the posttreatment Vaizey score (presence of passive incontinence, thin stool consistency, primary repair of a rupture after vaginal delivery at childbed) (R2, 0.18). Th

A measurement of the W boson mass using large rapidity electrons

We present a measurement of the W boson mass using data collected by the D0 experiment at the Fermilab Tevatron during 1994--1995. We identify W bosons by their decays to e-nu final states where the electron is detected in a forward calorimeter. We extract the W boson mass, Mw, by fitting the transverse mass and transverse electron and neutrino momentum spectra from a sample of 11,089 W -> e nu decay candidates. We use a sample of 1,687 dielectron events, mostly due to Z -> ee decays, to constrain our model of the detector response. Using the forward calorimeter data, we measure Mw = 80.691 +- 0.227 GeV. Combining the forward calorimeter measurements with our previously published central calorimeter results, we obtain Mw = 80.482 +- 0.091 GeV