To study the role of L‐type voltage‐gated Ca++ channels in oligodendrocyte development, we used a mouse model of Timothy syndrome (TS) in which a gain‐of‐function mutation in the α1 subunit of the ...L‐type Ca++ channel Cav1.2 gives rise to an autism spectrum disorder (ASD). Oligodendrocyte progenitor cells (OPCs) isolated from the cortex of TS mice showed greater L‐type Ca++ influx and displayed characteristics suggestive of advanced maturation compared to control OPCs, including a more complex morphology and higher levels of myelin protein expression. Consistent with this, expression of Cav1.2 channels bearing the TS mutation in wild‐type OPCs triggered process formation and promoted oligodendrocyte–neuron interaction via the activation of Ca++/calmodulin‐dependent protein kinase II. To ascertain whether accelerated OPC maturation correlated with functional enhancements, we examined myelination in the TS brain at different postnatal time points. The expression of myelin proteins was significantly higher in the corpus callosum, cortex and striatum of TS animals, and immunohistochemical analysis for oligodendrocyte stage‐specific markers revealed an increase in the density of myelinating oligodendrocytes in several areas of the TS brain. Along the same line, electron microscopy studies in the corpus callosum of TS animals showed significant increases both in the percentage of myelinated axons and in the thickness of myelin sheaths. In summary, these data indicate that OPC development and oligodendrocyte myelination is enhanced in the brain of TS mice, and suggest that this mouse model of a syndromic ASD is a useful tool to explore the role of L‐type Ca++ channels in myelination.
Main Points
Elevated activity of the L‐type Ca++ channel Cav1.2 promotes oligodendrocyte maturation.
Oligodendrocyte development and myelination is enhanced in a mouse model of Timothy syndrome.
Cancer is the leading cause of death in older adults aged 60 to 79 years. The biology of certain cancers and responsiveness to therapy changes with the patient's age. Advanced age alone should not ...preclude the use of effective treatment that could improve quality of life or extend meaningful survival. The challenge of managing older patients with cancer is to assess whether the expected benefits of treatment are superior to the risk in a population with decreased life expectancy and decreased tolerance to stress. These guidelines provide an approach to decision-making in older cancer patients based on comprehensive geriatric assessment and also include disease specific issues related to age in the management of some cancer types in older adults.
More than 50 individuals with activating variants in the receptor tyrosine kinase PDGFRB have been reported, separated based on clinical features into solitary myofibromas, infantile myofibromatosis, ...Penttinen syndrome with premature aging and osteopenia, Kosaki overgrowth syndrome, and fusiform aneurysms. Despite their descriptions as distinct clinical entities, review of previous reports demonstrates substantial phenotypic overlap. We present a case series of 12 patients with activating variants in PDGFRB and review of the literature. We describe five patients with PDGFRB activating variants whose clinical features overlap multiple diagnostic entities. Seven additional patients from a large family had variable expressivity and late‐onset disease, including adult onset features and two individuals with sudden death. Three patients were treated with imatinib and had robust and rapid response, including the first two reported infants with multicentric myofibromas treated with imatinib monotherapy and one with a recurrent p.Val665Ala (Penttinen) variant. Along with previously reported individuals, our cohort suggests infants and young children had few abnormal features, while older individuals had multiple additional features, several of which appeared to worsen with advancing age. Our analysis supports a diagnostic entity of a spectrum disorders due to activating variants in PDGFRB. Differences in reported phenotypes can be dramatic and correlate with advancing age, genotype, and to mosaicism in some individuals.
Resistance to the novel β-lactam/β-lactamase inhibitor combination ceftazidime-avibactam (CAZ-AVI) among carbapenem-resistant Enterobacteriaceae (CRE) has infrequently been reported in the United ...States. We report unexpectedly high rates of resistance to CAZ-AVI in CRE bloodstream isolates at our institution associated with the nonoutbreak spread of New Delhi metallo-β-lactamase in diverse Enterobacteriaceae species.
Impacts of the prescription opioid epidemic have not yet been examined in the context of heart transplantation. We examined a novel database in which national U.S. transplant registry records were ...linked to a large pharmaceutical claims warehouse (2007‐2016) to characterize prescription opioid use before and after heart transplant, and associations (adjusted hazard ratio, 95% LCLaHR95% UCL) with death and graft loss. Among 13 958 eligible patients, 40% filled opioids in the year before transplant. Use was more common among recipients who were female, white, or unemployed, or who underwent transplant in more recent years. Of those with the highest level of pretransplant opioid use, 71% continued opioid use posttransplant. Pretransplant use had graded associations with 1‐year posttransplant outcomes; compared with no use, the highest‐level use (>1000 mg morphine equivalents) predicted 33% increased risk of death (aHR 1.101.331.61) in the year after transplant. Risk relationships with opioid use in the first year posttransplant were stronger, with highest level use predicting 70% higher mortality (aHR 1.461.701.98) over the subsequent 4 years (from >1 to 5 years posttransplant). While associations may, in part, reflect underlying conditions or behaviors, opioid use history is relevant in assessing and providing care to transplant candidates and recipients.
Examination of integrated U.S. transplant registry data and records from a nationwide pharmacy claims warehouse demonstrates that pretransplant prescription opioid use is associated with a 33% increased risk of death over the first year posttransplant, that most high‐level opioid users continue to fill at high levels in the year after transplant, and that posttransplant prescription opioid use has even stronger prognostic significance, with highest level use predicting 70% increased risk of death over the subsequent 4 years.
To assess the introduction of telemedicine as an alternative to the traditional face-to-face encounters with vascular surgery patients in the era of the coronavirus disease 2019 (COVID-19) pandemic.
...A retrospective review of prospectively collected data on face-to-face and telemedicine interactions was conducted at a multisite health care system from January to August 2020 in vascular surgery patients during the COVID-19 pandemic. The end point is direct patient satisfaction comparison between face-to-face and telemedicine encounters/interactions prior and during the pandemic.
There were 6262 patient encounters from January 1, 2020, to August 6, 2020. Of the total encounters, 790 (12.6%) were via telemedicine, which were initiated on March 11, 2020, after the World Health Organization's declaration of the COVID-19 pandemic. These telemedicine encounters were readily adopted and embraced by both the providers and patients and remain popular as an option to patients for all types of visits. Of these patients, 78.7% rated their overall health care experience during face-to-face encounters as very good and 80.6% of patients rated their health care experience during telemedicine encounters as very good (P = .78).
Although the COVID-19 pandemic has produced unprecedented consequences to the practice of medicine and specifically of vascular surgery, our multisite health care system has been able to swiftly adapt and adopt telemedicine technologies for the care of our complex patients. Most important, the high quality of patient-reported satisfaction and health care experience has remained unchanged.
Transcriptome-wide association analysis is a powerful approach to studying the genetic architecture of complex traits. A key component of this approach is to build a model to impute gene expression ...levels from genotypes by using samples with matched genotypes and gene expression data in a given tissue. However, it is challenging to develop robust and accurate imputation models with a limited sample size for any single tissue. Here, we first introduce a multi-task learning method to jointly impute gene expression in 44 human tissues. Compared with single-tissue methods, our approach achieved an average of 39% improvement in imputation accuracy and generated effective imputation models for an average of 120% more genes. We describe a summary-statistic-based testing framework that combines multiple single-tissue associations into a powerful metric to quantify the overall gene-trait association. We applied our method, called UTMOST (unified test for molecular signatures), to multiple genome-wide-association results and demonstrate its advantages over single-tissue strategies.
Cystic fibrosis is a recessive genetic disease characterized by dehydration of the airway surface liquid and impaired mucociliary clearance. As a result, individuals with the disease have difficulty ...clearing pathogens from the lung and experience chronic pulmonary infections and inflammation. Death is usually a result of respiratory failure. Newly introduced therapies and aggressive management of the lung disease have resulted in great improvements in length and quality of life, with the result that the median expected survival age has reached 36 years. However, as the number of treatments expands, the medical regimen becomes increasingly burdensome in time, money, and health resources. Hence, it is important that treatments should be recommended on the basis of available evidence of efficacy and safety.
The Cystic Fibrosis Foundation therefore established a committee to examine the clinical evidence for each therapy and to provide guidance for the prescription of these therapies.
The committee members developed and refined a series of questions related to drug therapies used in the maintenance of pulmonary function. We addressed the questions in one of three ways, based on available evidence: (1) commissioned systematic review, (2) modified systematic review, or (3) summary of existing Cochrane reviews.
It is hoped that the guidelines provided in this article will facilitate the appropriate application of these treatments to improve and extend the lives of all individuals with cystic fibrosis.
One of the potential benefits of using data-independent acquisition (DIA) proteomics protocols is that information not originally targeted by the study may be present and discovered by subsequent ...analysis. Herein, we reanalyzed DIA data originally recorded for global proteomic analysis to look for isomerized peptides, which occur as a result of spontaneous chemical modifications to long-lived proteins. Examination of a large set of human brain samples revealed a striking relationship between Alzheimer's disease (AD) status and isomerization of aspartic acid in a peptide from tau. Relative to controls, a surprising increase in isomer abundance was found in both autosomal dominant and sporadic AD samples. To explore potential mechanisms that might account for these observations, quantitative analysis of proteins related to isomerization repair and autophagy was performed. Differences consistent with reduced autophagic flux in AD-related samples relative to controls were found for numerous proteins, including most notably p62, a recognized indicator of autophagic inhibition. These results suggest, but do not conclusively demonstrate, that lower autophagic flux may be strongly associated with loss of function in AD brains. This study illustrates that DIA data may contain unforeseen results of interest and may be particularly useful for pilot studies investigating new research directions. In this case, a promising target for future investigations into the therapy and prevention of AD has been identified.
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