Prefrontal multistimulus integration within a dedicated disambiguation circuit guides interleaving contingency judgment learning.

Understanding how cortical network dynamics support learning is a challenge. This study investigates the role of local neural mechanisms in the prefrontal cortex during contingency judgment learning (CJL). To better understand brain network mechanisms underlying CJL, we introduce ambiguity into associative learning after fear acquisition, inducing a generalized fear response to an ambiguous stimulus sharing nontrivial similarities with the conditioned stimulus.

The Six-Transmembrane Enzyme GDE2 Is Required for the Release of Molecularly Distinct Small Extracellular Vesicles from Neurons.

Extracellular vesicles (EVs) are implicated in a multitude of physiological and pathophysiological processes in the nervous system; however, their biogenesis and cargoes are not well defined. Glycerophosphodiester Phosphodiesterase 2 (GDE2 or GDPD5) is a six-transmembrane protein that cleaves the Glycosylphosphatidylinositol (GPI)-anchor that tethers some proteins to the membrane and has important roles in neurodevelopment and disease-relevant pathways of neuronal survival. We show here that GDE2 regulates the number of small EVs (sEVs) released from the cell surface of neurons via its GPI-anchor cleavage activity and contributes to the loading of protein cargo through enzymatic and non-enzymatic mechanisms.

A Bayesian nonparametric analysis for zero-inflated multivariate count data with application to microbiome study.

High-throughput sequencing technology has enabled researchers to profile microbial communities from a variety of environments, but analysis of multivariate taxon count data remains challenging. We develop a Bayesian nonparametric (BNP) regression model with zero inflation to analyse multivariate count data from microbiome studies. A BNP approach flexibly models microbial associations with covariates, such as environmental factors and clinical characteristics.

Imaging neurovascular, endothelial and structural integrity in preparation to treat small vessel diseases. The INVESTIGATE-SVDs study protocol. Part of the SVDs@Target project.

Background: Sporadic cerebral small vessel disease (SVD) and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) share clinical and neuroimaging features and possibly vascular dysfunction(s). However few studies have included both conditions, assessed more than one vascular dysfunction simultaneously, or included more than one centre. The INVESTIGATE-SVDs study will assess several cerebrovascular dysfunctions with MRI in participants with sporadic SVD or CADASIL at three European centres.

Muscle Stem Cell-Derived Extracellular Vesicles Reverse Hydrogen Peroxide-Induced Mitochondrial Dysfunction in Mouse Myotubes.

Muscle stem cells (MuSCs) hold great potential as a regenerative therapeutic but have met numerous challenges in treating systemic muscle diseases. Muscle stem cell-derived extracellular vesicles (MuSC-EVs) may overcome these limitations. We assessed the number and size distribution of extracellular vesicles (EVs) released by MuSCs ex vivo, determined the extent to which MuSC-EVs deliver molecular cargo to myotubes in vitro, and quantified MuSC-EV-mediated restoration of mitochondrial function following oxidative injury.

Isotopic evidence for anthropogenic lead exposure on a 17th/18th century Barbadian plantation.

Objectives: To identify and characterize anthropogenic lead sources on a 17th/18th century Barbadian plantation and to test if lead isotope analyses can be used to identify the geographic origins of first-generation African captives.

Materials And Methods: We carried out lead (Pb) isotope analyses on dental enamel samples from 24 individuals from the Newton Plantation Cemetery in Barbados, which had previously been analyzed for strontium (Sr) and oxygen (O) isotope composition (Schroeder et al., American Journal of Physical Anthropology, 2009, 139:547-557) and Pb concentrations (Schroeder et al.

Tolerability, safety and intermediary pharmacological effects of cilostazol and isosorbide mononitrate, alone and combined, in patients with lacunar ischaemic stroke: The LACunar Intervention-1 (LACI-1) trial, a randomised clinical trial.

Background: Lacunar stroke, a frequent clinical manifestation of small vessel disease (SVD), differs pathologically from other ischaemic stroke subtypes and has no specific long-term secondary prevention. Licenced drugs, isosorbide mononitrate (ISMN) and cilostazol, have relevant actions to prevent SVD progression.

Methods: We recruited independent patients with clinically confirmed lacunar ischaemic stroke without cognitive impairment to a prospective randomised clinical trial, LACunar Intervention-1 (LACI-1).

Stability of Estimated Premorbid Cognitive Ability over Time after Minor Stroke and Its Relationship with Post-Stroke Cognitive Ability.

Considering premorbid or "peak" adult intelligence (IQ) is important when examining post-stroke cognition. The stability of estimated premorbid IQ and its relationship to current cognitive ability in stroke is unknown. We investigated changes in estimated premorbid IQ and current cognitive ability up to three years post-stroke.

Angiotensin-Converting Enzyme Insertion/Deletion Polymorphism, Lower Extremity Strength, and Physical Performance in Older Adults.

Background: Evidence for associations between the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene and physical performance is conflicting. Furthermore, investigations of relationships between lower extremity strength and physical performance have usually not considered the role of the ACE genotype, and it is unclear whether there are variations in relationships between lower extremity strength and physical performance among ACE genotypes in older adults.

Objective: The objectives of this study were to investigate associations between the ACE I/D polymorphism and physical performance and to determine whether relationships between lower extremity strength and physical performance vary among ACE genotypes in older adults.

The impact of early-life intelligence quotient on post stroke cognitive impairment.

Background: Cognitive impairment can complicate minor stroke, but there is limited information on risk factors including peak cognitive ability earlier in life.

Methods: We recruited patients with clinically-evident lacunar or minor non-lacunar ischaemic stroke, recorded clinical features, vascular risk factors, magnetic resonance imaging-detected stroke sub-type and small vessel disease burden. At 1-3 and 12 months after stroke, we assessed educational attainment (years of education), current cognition (Addenbrooke's Cognitive Examination-Revised), pre-morbid intelligence (National Adult Reading Test) and dependency (modified Rankin Scale).

Functional, cognitive and physical outcomes 3 years after minor lacunar or cortical ischaemic stroke.

Objective: Many studies examining stroke outcomes focus on more severe strokes or have short follow-up periods, so the long-term outcomes post-minor ischaemic stroke are unclear.

Methods: We recruited participants from inpatient and outpatient services with a lacunar or minor cortical ischaemic stroke (National Institutes of Health Stroke Scale score <8) and assessed current and premorbid cognitive functioning (Addenbrooke's Cognitive Examination-Revised (ACE-R), National Adult Reading Test (NART)), physical functioning (Timed Get Up and Go (TUG), 9-Hole Peg Test (9HPT)), dependency (modified Rankin Scale (mRS)), depression (Beck's Depression Inventory) in-person and remotely (Stroke Impact Scale).

Results: We followed up 224/264 participants at 3 years (mean age at index stroke=67, 126 (56%) men, 25 non-contactable, 15 declined): 66/151 (44%) had cognitive impairment, mean ACE-R 88 (SD 9, range 54-100/100), 61/156 (39%) had depression and 26/223 (12%) were dependent (mRS=3-5).

Stability of Resistance Training Implement alters EMG Activity during the Overhead Press.

Kettlebells often replace dumbbells during common resistance training exercises such as the overhead press. When performing an overhead press, the center of mass of a dumbbell is in line with the glenohumeral joint. In comparison, the center of mass of the kettlebell is posterior to the glenohumeral joint.

Preventing cognitive decline and dementia from cerebral small vessel disease: The LACI-1 Trial. Protocol and statistical analysis plan of a phase IIa dose escalation trial testing tolerability, safety and effect on intermediary endpoints of isosorbide mononitrate and cilostazol, separately and in combination.

Rationale The pathophysiology of most lacunar stroke, a form of small vessel disease, is thought to differ from large artery atherothrombo- or cardio-embolic stroke. Licensed drugs, isosorbide mononitrate and cilostazol, have promising mechanisms of action to support their testing to prevent stroke recurrence, cognitive impairment, or radiological progression after lacunar stroke. Aim LACI-1 will assess the tolerability, safety, and efficacy, by dose, of isosorbide mononitrate and cilostazol, alone and in combination, in patients with ischemic lacunar stroke.

Small Vessel Disease and Dietary Salt Intake: Cross-Sectional Study and Systematic Review.

Background: Higher dietary salt intake increases the risk of stroke and may increase white matter hyperintensity (WMH) volume. We hypothesized that a long-term higher salt intake may be associated with other features of small vessel disease (SVD).

Methods: We recruited consecutive patients with mild stroke presenting to the Lothian regional stroke service.

White matter hyperintensity reduction and outcomes after minor stroke.

Objective: To assess factors associated with white matter hyperintensity (WMH) change in a large cohort after observing obvious WMH shrinkage 1 year after minor stroke in several participants in a longitudinal study.

Methods: We recruited participants with minor ischemic stroke and performed clinical assessments and brain MRI. At 1 year, we assessed recurrent cerebrovascular events and dependency and repeated the MRI.

Sample size considerations for trials using cerebral white matter hyperintensity progression as an intermediate outcome at 1 year after mild stroke: results of a prospective cohort study.

Background: White matter hyperintensities (WMHs) are commonly seen on in brain imaging and are associated with stroke and cognitive decline. Therefore, they may provide a relevant intermediate outcome in clinical trials. WMH can be measured as a volume or visually on the Fazekas scale.

Endothelial Function, Inflammation, Thrombosis, and Basal Ganglia Perivascular Spaces in Patients with Stroke.

Background And Objective: Recent studies suggest perivascular spaces are a marker of small vessel disease, blood-brain barrier permeability, and inflammation, but little is known about their risk factors and associations with peripheral blood markers.

Materials And Methods: In prospectively recruited patients with recent minor ischemic stroke, we investigated the influence of age, sex, hypertension, diabetes, and smoking on the severity of perivascular spaces in the basal ganglia seen on T2-weighted magnetic resonance imaging. We assessed plasma markers of endothelial function (von Willebrand factor, intracellular adhesion molecule-1), inflammation (interleukin-6, tumor necrosis factor-alpha, C-reactive protein), and thrombosis (fibrinogen, prothrombin fragments 1 + 2, thrombin-antithrombin complex, tissue plasminogen activator, D-dimer).

Integrity of normal-appearing white matter: Influence of age, visible lesion burden and hypertension in patients with small-vessel disease.

White matter hyperintensities accumulate with age and occur in patients with stroke, but their pathogenesis is poorly understood. We measured multiple magnetic resonance imaging biomarkers of tissue integrity in normal-appearing white matter and white matter hyperintensities in patients with mild stroke, to improve understanding of white matter hyperintensities origins. We classified white matter into white matter hyperintensities and normal-appearing white matter and measured fractional anisotropy, mean diffusivity, water content (T1-relaxation time) and blood-brain barrier leakage (signal enhancement slope from dynamic contrast-enhanced magnetic resonance imaging).

Rationale, design and methodology of the image analysis protocol for studies of patients with cerebral small vessel disease and mild stroke.

Rationale: Cerebral small vessel disease (SVD) is common in ageing and patients with dementia and stroke. Its manifestations on magnetic resonance imaging (MRI) include white matter hyperintensities, lacunes, microbleeds, perivascular spaces, small subcortical infarcts, and brain atrophy. Many studies focus only on one of these manifestations.

ABCD2 score and secondary stroke prevention: meta-analysis and effect per 1,000 patients triaged.

Objective: Patients with TIA have high risk of recurrent stroke and require rapid assessment and treatment. The ABCD2 clinical risk prediction score is recommended for patient triage by stroke risk, but its ability to stratify by known risk factors and effect on clinic workload are unknown.

Methods: We performed a systematic review and meta-analysis of all studies published between January 2005 and September 2014 that reported proportions of true TIA/minor stroke or mimics, risk factors, and recurrent stroke rates, dichotomized to ABCD2 score View Article and Find Full Text PDF

Approaches to improve adherence to pharmacotherapy in patients with schizophrenia.

Purpose: In patients with schizophrenia, nonadherence to prescribed medications increases the risk of patient relapse and hospitalization, key contributors to the costs associated with treatment. The objectives of this review were to evaluate the impact of nonadherence to pharmacotherapy in patients with schizophrenia as it relates to health care professionals, particularly social workers, and to identify effective team approaches to supporting patients based on studies assessing implementation of assertive community treatment teams.

Materials And Methods: A systematic review of the medical literature was conducted by searching the Scopus database to identify articles associated with treatment adherence in patients with schizophrenia.