Category: Hot Topics in Research - Page 22

Visualization of regional tau deposits using 3H-THK5117 in Alzheimer brain tissue

katheride March 31, 2016 Alzheimer Disease, Hot Topics in Research

Visualization of regional tau deposits using 3H-THK5117 in Alzheimer brain tissue

Abstract

The accumulation of neurofibrillary tangles, composed of aggregated hyperphosphorylated tau protein, starts spreading early in specific regions in the course of Alzheimer’s disease (AD), correlating with the progression of memory dysfunction. The non-invasive imaging of tau could therefore facilitate the early diagnosis of AD, differentiate it from other dementing disorders and allow evaluation of tau immunization therapy outcomes. In this study we characterized the in vitro binding properties of THK5117, a tentative radiotracer for positron emission tomography (PET) imaging of tau brain deposits.

Results

Saturation and competition binding studies of ³H-THK5117 in post-mortem AD brain tissue showed the presence of multiple binding sites. THK5117 binding was significantly higher in hippocampal (p < 0.001) and temporal (p < 0.01) tissue homogenates in AD compared to controls. Autoradiography studies with ³H-THK5117 was performed on large frozen brain sections from three AD cases who had been followed clinically and earlier undergone in vivo ¹⁸F-FDG PET investigations. The three AD cases showed distinct differences in regional THK5117 binding that were also observed in tau immunohistopathology as well as in clinical presentation. A negative correlation between in vivo ¹⁸F-FDG PET and in vitro ³H-THK5117 autoradiography was observed in two of the three AD cases.

Conclusions

This study supports that new tau PET tracers will provide further understanding on the role of tau pathology in the diversity of the clinical presentation in AD.

Acta Neuropathologica Communications20153:40, DOI: 10.1186/s40478-015-0220-4; Lemoine et al. 2015; Received: 14 June 2015; Accepted: 15 June 2015; Published: 2 July 2015

Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report

katheride March 2, 2016 Blood, Hot Topics in Research, Lung, Research Commentary

Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report
BACKGROUND: We update recommendations on 12 topics that were in the 9th edition of these guidelines, and address 3 new topics.
METHODS: We generate strong (Grade 1) and weak (Grade 2) recommendations based on high- (Grade A), moderate- (Grade B), and low- (Grade C) quality evidence.
RESULTS: For VTE and no cancer, as long-term anticoagulant therapy, we suggest dabigatran (Grade 2B), rivaroxaban (Grade 2B), apixaban (Grade 2B), or edoxaban (Grade 2B) over vitamin K antagonist (VKA) therapy, and suggest VKA therapy over low-molecular-weight heparin (LMWH; Grade 2C). For VTE and cancer, we suggest LMWH over VKA (Grade 2B), dabigatran (Grade 2C), rivaroxaban (Grade 2C), apixaban (Grade 2C), or edoxaban (Grade 2C). We have not changed recommendations for who should stop anticoagulation at 3 months or receive extended therapy. For VTE treated with anticoagulants, we recommend against an inferior vena cava filter (Grade 1B). For DVT, we suggest not using compression stockings routinely to prevent PTS (Grade 2B). For subsegmental pulmonary embolism and no proximal DVT, we suggest clinical surveillance over anticoagulation with a low risk of recurrent VTE (Grade 2C), and anticoagulation over clinical surveillance with a high risk (Grade 2C). We suggest thrombolytic therapy for pulmonary embolism with hypotension (Grade 2B), and systemic therapy over catheter-directed thrombolysis (Grade 2C). For recurrent VTE on a non-LMWH anticoagulant, we suggest LMWH (Grade 2C); for recurrent VTE on LMWH, we suggest increasing the LMWH dose (Grade 2C).
CONCLUSIONS: Of 54 recommendations included in the 30 statements, 20 were strong and none was based on high-quality evidence, highlighting the need for further research.

CHEST 2016; 149(2):315-352
Clive Kearon, MD, PhD; Elie A. Akl, MD, MPH, PhD; Joseph Ornelas, PhD; Allen Blaivas, DO, FCCP; David Jimenez, MD, PhD, FCCP; Henri Bounameaux, MD; Menno Huisman, MD, PhD; Christopher S. King, MD, FCCP; Timothy A. Morris, MD, FCCP; Namita Sood, MD, FCCP; Scott M. Stevens, MD; Janine R. E. Vintch, MD, FCCP; Philip Wells, MD; Scott C. Woller, MD; and COL Lisa Moores, MD, FCCP

Atrial fibrillation as risk factor for cardiovascular disease and death in women compared with men: systematic review and meta-analysis of cohort studies

katheride Atrial Fibrillation, Cardiology, Hot Topics in Research

Atrial fibrillation as risk factor for cardiovascular disease and death in women compared with men: systematic review and meta-analysis of cohort studies
Abstract

Objective To determine whether atrial fibrillation is a stronger risk factor for cardiovascular disease and death in women compared with men.

Design Meta-analysis of cohort studies.

Data sources Studies published between January 1966 and March 2015, identified through a systematic search of Medline and Embase and review of references.

Eligibility for selecting studies Cohort studies with a minimum of 50 participants with and 50 without atrial fibrillation that reported sex specific associations between atrial fibrillation and all cause mortality, cardiovascular mortality, stroke, cardiac events (cardiac death and non-fatal myocardial infarction), and heart failure.

Data extraction Two independent reviewers extracted study characteristics and maximally adjusted sex specific relative risks. Inverse variance weighted random effects meta-analysis was used to pool sex specific relative risks and their ratio.

Results 30 studies with 4 371 714 participants were identified. Atrial fibrillation was associated with a higher risk of all cause mortality in women (ratio of relative risks for women compared with men 1.12, 95% confidence interval 1.07 to 1.17) and a significantly stronger risk of stroke (1.99, 1.46 to 2.71), cardiovascular mortality (1.93, 1.44 to 2.60), cardiac events (1.55, 1.15 to 2.08), and heart failure (1.16, 1.07 to 1.27). Results were broadly consistent in sensitivity analyses.

Conclusion Atrial fibrillation is a stronger risk factor for cardiovascular disease and death in women compared with men, though further research would be needed to determine any causality.

Connor A Emdin, DPhil; Christopher X Wong; Allan J Hsiao; Douglas G Altman; Sanne AE Peters; Mark Woodward; Ayodele A Odutayo
BMJ 2016; 352 doi: http://dx.doi.org/10.1136/bmj.h7013 (Published 19 January 2016)

Zebrafish Reel in Phenotypic Suppressors of Autism

katheride Brain, Hot Topics in Research

Zebrafish Reel in Phenotypic Suppressors of Autism
Chemical genetics can help decipher novel pathways underlying neurodevelopmental psychiatric impairments. Hoffman et al. (2016) utilized behavioral profiling of psychoactive compounds in zebrafish and identified estrogens as suppressors of a phenotype resulting from loss of an autism risk gene.

Neuron, Volume 89, Issue 4, 17 February 2016, Pages 673–675

Mental Health of Transgender Children Who Are Supported in Their Identities

katheride Hot Topics in Research, Pediatrics

Mental Health of Transgender Children Who Are Supported in Their Identities

OBJECTIVE: Transgender children who have socially transitioned, that is, who identify as the gender “opposite” their natal sex and are supported to live openly as that gender, are increasingly visible in society, yet we know nothing about their mental health. Previous work with children with gender identity disorder (GID; now termed gender dysphoria) has found remarkably high rates of anxiety and depression in these children. Here we examine, for the first time, mental health in a sample of socially transitioned transgender children.

METHODS: A community-based national sample of transgender, prepubescent children (n= 73, aged 3–12 years), along with control groups of nontransgender children in the same age range (n = 73 age- and gender-matched community controls; n = 49 sibling of transgender participants), were recruited as part of the TransYouth Project. Parents completed anxiety and depression measures.

RESULTS: Transgender children showed no elevations in depression and slightly elevated anxiety relative to population averages. They did not differ from the control groups on depression symptoms and had only marginally higher anxiety symptoms.

CONCLUSIONS: Socially transitioned transgender children who are supported in their gender identity have developmentally normative levels of depression and only minimal elevations in anxiety, suggesting that psychopathology is not inevitable within this group. Especially striking is the comparison with reports of children with GID; socially transitioned transgender children have notably lower rates of internalizing psychopathology than previously reported among children with GID living as their natal sex.

Kristina R. Olson, Lily Durwood, Madeleine DeMeules, Katie A. McLaughlin
Copyright © 2016 by the American Academy of Pediatrics
March 2016, VOLUME 137 / ISSUE 3

Disseminating Justified, Well-Designed, and Well-Executed Studies Despite Nonsignificant Tests

katheride February 8, 2016 Hot Topics in Research, Research Commentary

Disseminating Justified, Well-Designed, and Well-Executed Studies Despite Nonsignificant Tests
To the Editor
In her editorial¹ published in JAMA Psychiatry, Dr Kraemer gives important insights into using covariates, thereby adding to her large body of highly valuable publications…

Gunther Meinlschmidt, PhD; Jan K. Woike, PhD; Marion Tegethoff, PhD

JAMA Psychiatry. 2016;73(1):88-89. doi:10.1001/jamapsychiatry.2015.2259.

Disseminating Justified, Well-Designed, and Well-Executed Studies With Nonsignificant Tests—Reply

katheride Hot Topics in Research, Research Commentary

Disseminating Justified, Well-Designed, and Well-Executed Studies With Nonsignificant Tests—Reply
In Reply I wholeheartedly agree with the main point made by Meinlschmidt et al that well-justified, well-designed, and well-executed (non–poorly justified, designed, or executed [PJDE]) randomized clinical trials warrant dissemination—statistically significant or not. Crucial is whether a randomized clinical trial advances knowledge…

Helena Chmura Kraemer, PhD¹
JAMA Psychiatry. 2016;73(1):89-90. doi:10.1001/jamapsychiatry.2015.2301.

Paradoxical Motor Recovery From a First Stroke After Induction of a Second Stroke: Reopening a Postischemic Sensitive Period

katheride Brain, Cardiology, Hot Topics in Research

Paradoxical Motor Recovery From a First Stroke After Induction of a Second Stroke: Reopening a Postischemic Sensitive Period
Abstract Background and objective. Prior studies have suggested that after stroke there is a time-limited period of increased responsiveness to training as a result of heightened plasticity—a sensitive period thought to be induced by ischemia itself. Using a mouse model, we have previously shown that most training-associated recovery after a caudal forelimb area (CFA) stroke occurs in the first week and is attributable to reorganization in a medial premotor area (AGm). The existence of a stroke-induced sensitive period leads to the counterintuitive prediction that a second stroke should reopen this window and promote full recovery from the first stroke. To test this prediction, we induced a second stroke in the AGm of mice with incomplete recovery after a first stroke in CFA. Methods. Mice were trained to perform a skilled prehension (reachto-grasp) task to an asymptotic level of performance, after which they underwent photocoagulation-induced stroke in CFA. After a 7-day poststroke delay, the mice were then retrained to asymptote. We then induced a second stroke in the AGm, and after only a 1-day delay, retrained the mice. Results. Recovery of prehension was incomplete when training was started after a 7-day poststroke delay and continued for 19 days. However, a second focal stroke in the AGm led to a dramatic response to 9 days of training, with full recovery to normal levels of performance. Conclusions. New ischemia can reopen a sensitive period of heightened responsiveness to training and mediate full recovery from a previous stroke.

Steven R. Zeiler, MD, PhD , Robert Hubbard , Ellen M. Gibson , Tony Zheng , Kwan Ng, MD, PhD , Richard O’Brien, MD, PhD , and John W. Krakauer, MD

Schizophrenia risk from complex variation of complement component 4

katheride Dementia, Hot Topics in Research, Memory Impairment

Schizophrenia risk from complex variation of complement component 4
Abstract
Schizophrenia is a heritable brain illness with unknown pathogenic mechanisms. Schizophrenia’s strongest genetic association at a population level involves variation in the major histocompatibility complex (MHC) locus, but the genes and molecular mechanisms accounting for this have been challenging to identify. Here we show that this association arises in part from many structurally diverse alleles of the complement component 4 (C4) genes. We found that these alleles generated widely varying levels of C4A and C4B expression in the brain, with each common C4 allele associating with schizophrenia in proportion to its tendency to generate greater expression of C4A. Human C4 protein localized to neuronal synapses, dendrites, axons, and cell bodies. In mice, C4 mediated synapse elimination during postnatal development. These results implicate excessive complement activity in the development of schizophrenia and may help explain the reduced numbers of synapses in the brains of individuals with schizophrenia.

Corresponding Author: McCarroll, Steven A.

Nature (2016), doi:10.1038/nature16549, Published online 27 January 2016

Association between sleeping difficulty and type 2 diabetes in women

katheride Diabetes, Hot Topics in Research

Association between sleeping difficulty and type 2 diabetes in women

Abstract

Aims/hypothesis

Sleeping difficulty has been associated with type 2 diabetes in some prior studies. Whether the observed associations are independent of health behaviours, other cardiovascular risk factors or other sleep disorders is unclear.

Methods

We analysed data from 133,353 women without diabetes, cardiovascular disease and cancer at baseline in the Nurses’ Health Study (NHS, 2000–2010) and the NHSII (2001–2011). Sleeping difficulty was assessed as having difficulty falling or staying asleep ‘all of the time’ or ‘most of the time’ at baseline (2000 in NHS and 2001 in NHSII).

Results

We documented 6,407 incident cases of type 2 diabetes during up to 10 years of follow-up. After adjustment for lifestyle factors at baseline, comparing women with and without sleeping difficulty, the multivariate-adjusted HR (95% CI) for type 2 diabetes was 1.45 (95% CI 1.33, 1.58), which changed to 1.22 (95% CI 1.12, 1.34) after further adjustment for hypertension, depression and BMI based on the updated repeated measurements. Women who reported all four sleep conditions (sleeping difficulty, frequent snoring, sleep duration ≤6 h and sleep apnoea in NHS or rotating shift work in NHSII) had more than a fourfold increased likelihood of type 2 diabetes (HR 4.17, 95% CI 2.93, 5.91).

Conclusions/interpretation

Sleeping difficulty was significantly associated with type 2 diabetes. This association was partially explained by associations with hypertension, BMI and depression symptoms, and was particularly strong when combined with other sleep disorders. Our findings highlight the importance of sleep disturbance in the development and prevention of type 2 diabetes.

Yanping Li, Xiang Gao, John W. Winkelman, Elizabeth M. Cespedes, Chandra L. Jackson, Arthur S. Walters, Eva Schernhammer, Susan Redline, Frank B. Hu