Early adipose tissue wasting in a novel preclinical model of human lung cancer cachexia.

Cancer cachexia (CC), a syndrome of skeletal muscle and adipose tissue wasting, reduces responsiveness to therapies and increases mortality. There are no approved treatments for CC, which may relate to discordance between pre-clinical models and human CC. To address the need for clinically relevant models, we generated tamoxifen-inducible, epithelial cell specific ( ) mice.

Distinct Inflammatory Programs Underlie the Intramuscular Lipid Nanoparticle Response.

Developments in mRNA/lipid nanoparticle (LNP) technology have advanced the fields of vaccinology and gene therapy, raising questions about immunogenicity. While some mRNA/LNPs generate an adjuvant-like environment in muscle tissue, other mRNA/LNPs are distinct in their capacity for multiple rounds of therapeutic delivery. We evaluate the adjuvancy of components of mRNA/LNPs by phenotyping cellular infiltrate at injection sites, tracking uptake by immune cells, and assessing the inflammatory state.

Cross-species efficacy of enzyme replacement therapy for CLN1 disease in mice and sheep.

CLN1 disease, also called infantile neuronal ceroid lipofuscinosis (NCL) or infantile Batten disease, is a fatal neurodegenerative lysosomal storage disorder resulting from mutations in the CLN1 gene encoding the soluble lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT1). Therapies for CLN1 disease have proven challenging because of the aggressive disease course and the need to treat widespread areas of the brain and spinal cord. Indeed, gene therapy has proven less effective for CLN1 disease than for other similar lysosomal enzyme deficiencies.

Effects of chronic cannabidiol in a mouse model of naturally occurring neuroinflammation, neurodegeneration, and spontaneous seizures.

Cannabidiol (CBD) has gained attention as a therapeutic agent and is purported to have immunomodulatory, neuroprotective, and anti-seizure effects. Here, we determined the effects of chronic CBD administration in a mouse model of CLN1 disease (Cln1) that simultaneously exhibits neuroinflammation, neurodegeneration, and spontaneous seizures. Proteomic analysis showed that putative CBD receptors are expressed at similar levels in the brains of Cln1 mice compared to normal animals.

A MYT1L syndrome mouse model recapitulates patient phenotypes and reveals altered brain development due to disrupted neuronal maturation.

Human genetics have defined a new neurodevelopmental syndrome caused by loss-of-function mutations in MYT1L, a transcription factor known for enabling fibroblast-to-neuron conversions. However, how MYT1L mutation causes intellectual disability, autism, ADHD, obesity, and brain anomalies is unknown. Here, we developed a Myt1l haploinsufficient mouse model that develops obesity, white-matter thinning, and microcephaly, mimicking common clinical phenotypes.

Comparative immunogenicity of decellularized wild type and alpha 1,3 galactosyltransferase knockout pig lungs.

Decellularized pig lungs recellularized with human lung cells offer a novel approach for organ transplantation. However, the potential immunogenicity of decellularized pig lungs following exposure to human tissues has not been assessed. We found that exposure of native lungs from wildtype and transgenic pigs lacking alpha (1,3)-galactosyltransferase (α-gal KO) to sera from normal healthy human volunteers demonstrated similar robust IgM and IgG immunoreactivity, comparably decreased in decellularized lungs.

Development of alginate and gelatin-based pleural and tracheal sealants.

Pleural and tracheal injuries remain significant problems, and an easy to use, effective pleural or tracheal sealant would be a significant advance. The major challenges are requirements for adherence, high strength and elasticity, dynamic durability, appropriate biodegradability, and lack of cell or systemic toxicity. We designed and evaluated two sealant materials comprised respectively of alginate methacrylate and of gelatin methacryloyl, each functionalized by conjugation with dopamine HCl.

Adherence to Dietary Patterns and Risk of Incident Dementia: Findings from the Atherosclerosis Risk in Communities Study.

Background: Previous studies have suggested that adherence to healthy dietary patterns during late life may be associated with improved cognition. However, few studies have examined the association between healthy dietary patterns during midlife and incident dementia.

Objective: Our study aimed to determine the association between adherence to healthy dietary patterns at midlife and incident dementia.

Differential effects of the cystic fibrosis lung inflammatory environment on mesenchymal stromal cells.

Growing evidence demonstrates that human mesenchymal stromal cells (MSCs) modify their in vivo anti-inflammatory actions depending on the specific inflammatory environment encountered. Understanding this better is crucial to refine MSC-based cell therapies for lung and other diseases. Using acute exacerbations of cystic fibrosis (CF) lung disease as a model, the effects of ex vivo MSC exposure to clinical bronchoalveolar lavage fluid (BALF) samples, as a surrogate for the in vivo clinical lung environment, on MSC viability, gene expression, secreted cytokines, and mitochondrial function were compared with effects of BALF collected from healthy volunteers.

Spinal manifestations of CLN1 disease start during the early postnatal period.

Aim: To understand the progression of CLN1 disease and develop effective therapies we need to characterize early sites of pathology. Therefore, we performed a comprehensive evaluation of the nature and timing of early CLN1 disease pathology in the spinal cord, which appears especially vulnerable, and how this may affect behaviour.

Methods: We measured the spinal volume and neuronal number, and quantified glial activation, lymphocyte infiltration and oligodendrocyte maturation, as well as cytokine profile analysis during the early stages of pathology in Ppt1-deficient (Ppt1 ) mouse spinal cords.

Cell-autonomous expression of the acid hydrolase galactocerebrosidase.

Lysosomal storage diseases (LSDs) are typically caused by a deficiency in a soluble acid hydrolase and are characterized by the accumulation of undegraded substrates in the lysosome. Determining the role of specific cell types in the pathogenesis of LSDs is a major challenge due to the secretion and subsequent uptake of lysosomal hydrolases by adjacent cells, often referred to as "cross-correction." Here we create and validate a conditional mouse model for cell-autonomous expression of galactocerebrosidase (GALC), the lysosomal enzyme deficient in Krabbe disease.

Cross-Cultural Chronotypes: Educating Medical Students in America, Malaysia and the UAE.

This article was migrated. The article was marked as recommended. Ample data demonstrates that sleep deprivation leads to impaired functioning including cognitive performance, memory and fine motor skills.

Association of Intracranial Atherosclerotic Disease With Brain β-Amyloid Deposition: Secondary Analysis of the ARIC Study.

Importance: Intracranial atherosclerotic disease (ICAD) is an important cause of stroke and has also been recently identified as an important risk factor for all-cause dementia, but the mechanism of its association with cognitive performance is not fully understood.

Objective: To test the hypothesis that ICAD is associated with cerebral β-amyloid deposition as a marker of Alzheimer disease.

Design, Setting, And Participants: This cross-sectional analysis of data collected from August 2011 through November 2014 was a community-based cohort study conducted in 3 US communities.

Diet quality in patients with stroke.

Objective: A healthy diet is associated with reduced risk for stroke, myocardial infarction, cancer and death. We examined the prevalence of a healthy diet in patients with a recent stroke or transient ischaemic attack (TIA).

Methods: We recruited a convenience sample of 95 patients with a recent ischaemic stroke or TIA.

Lung inflammatory environments differentially alter mesenchymal stromal cell behavior.

Mesenchymal stromal (stem) cells (MSCs) are increasingly demonstrated to ameliorate experimentally induced lung injuries through disease-specific anti-inflammatory actions, thus suggesting that different in vivo inflammatory environments can influence MSC actions. To determine the effects of different representative inflammatory lung conditions, human bone marrow-derived MSCs (hMSCs) were exposed to in vitro culture conditions from bronchoalveolar lavage fluid (BALF) samples obtained from patients with either the acute respiratory distress syndrome (ARDS) or with other lung diseases including acute respiratory exacerbations of cystic fibrosis (CF) (non-ARDS). hMSCs were subsequently assessed for time- and BALF concentration-dependent effects on mRNA expression of selected pro- and anti-inflammatory mediators, and for overall patterns of gene and mRNA expression.

Conditional knockout of UBC13 produces disturbances in gait and spontaneous locomotion and exploration in mice.

Here we have characterized the functional impairments resulting from conditional knockout of the ubiquitin-conjugating E2 enzyme (UBC13) in rodent cerebellar granule neurons, which greatly increases the parallel fiber presynaptic boutons and functional parallel fiber/Purkinje cell synapses. We report that conditional UBC13 knockout mice exhibit reliable deficits on several gait-related variables when their velocity of ambulation is tightly controlled by a moving treadmill and by restricting space for movement. Selected gait parameters and movement patterns related to spontaneous exploration in an open field may also be affected in conditional UBC13 knockout mice.

Achievement of Guideline-Recommended Weight Loss Among Patients With Ischemic Stroke and Obesity.

Background and Purpose- The proportion of patients with acute ischemic stroke or transient ischemic attack (TIA) and obesity who successfully achieve goals for weight reduction recommended by major professional organizations is unknown. Methods- We examined the experience of participants in the placebo group of the IRIS trial (Insulin Resistance Intervention after Stroke) with a body mass index ≥30 kg/m at entry. Patients were of age ≥40 years, with a qualifying stroke or TIA within 180 days of randomization and documented insulin resistance without diabetes mellitus.

Scoring System to Optimize Pioglitazone Therapy After Stroke Based on Fracture Risk.

Background and Purpose- The insulin sensitizer, pioglitazone, reduces cardiovascular risk in patients after an ischemic stroke or transient ischemic attack but increases bone fracture risk. We conducted a secondary analysis of the IRIS trial (Insulin Resistance Intervention After Stroke) to assess the effect of pretreatment risk for fracture on the net benefits of pioglitazone therapy. Methods- IRIS was a randomized placebo-controlled trial of pioglitazone that enrolled patients with insulin resistance but without diabetes mellitus within 180 days of an ischemic stroke or transient ischemic attack.

Metabolic syndrome identifies normal weight insulin-resistant stroke patients at risk for recurrent vascular disease.

Background: The obesity paradox refers to the finding in observational studies that patients with obesity have a better prognosis after stroke than normal weight patients.

Aim: To test the hypothesis that there might be important heterogeneity within the obese stroke population, such that those with metabolic syndrome would be at higher risk for stroke or myocardial infarction and all-cause mortality compared to patients without metabolic syndrome.

Methods: The Insulin Resistance Intervention after Stroke trial enrolled non-diabetic patients with a recent ischemic stroke or transient ischemic attack and insulin resistance.

Dietary Diversity: Implications for Obesity Prevention in Adult Populations: A Science Advisory From the American Heart Association.

"Eat a variety of foods," or dietary diversity, is a widely accepted recommendation to promote a healthy, nutritionally adequate diet and to reduce the risk of major chronic diseases. However, recent evidence from observational studies suggests that greater dietary diversity is associated with suboptimal eating patterns, that is, higher intakes of processed foods, refined grains, and sugar-sweetened beverages and lower intakes of minimally processed foods, such as fish, fruits, and vegetables, and may be associated with weight gain and obesity in adult populations. This American Heart Association science advisory summarizes definitions for dietary diversity and reviews current evidence on its relationship with obesity outcomes, eating behavior, and food-based diet quality measures.

Association Between Midlife Risk Factors and Late-Onset Epilepsy: Results From the Atherosclerosis Risk in Communities Study.

Importance: The incidence of epilepsy is higher in older age than at any other period of life. Stroke, dementia, and hypertension are associated with late-onset epilepsy; however, the role of other vascular and lifestyle factors remains unclear.

Objective: To identify midlife vascular and lifestyle risk factors for late-onset epilepsy.