Ashley Petrone

A Systematic Review of Loneliness and Common Chronic Physical Conditions in Adults

Loneliness is a prevalent and global problem for adult populations and has been linked to multiple chronic conditions in quantitative studies. This paper presents a systematic review of quantitative studies that examined the links between loneliness and common chronic conditions including: heart disease, hypertension, stroke, lung disease, and metabolic disorders. A comprehensive literature search process guided by the PRISMA statement led to the inclusion of 33 articles that measure loneliness in chronic illness populations. Loneliness is a significant biopsychosocial stressor that is prevalent in adults with heart disease, hypertension, stroke, and lung disease. The relationships among loneliness, obesity, and metabolic disorders are understudied but current research indicates that loneliness is associated with obesity and with psychological stress in obese persons. Limited interventions have demonstrated long-term effectiveness for reducing loneliness in adults with these same chronic conditions. Future longitudinal randomized trials that enhance knowledge of how diminishing loneliness can lead to improved health outcomes in persons with common chronic conditions would continue to build evidence to support the translation of findings to recommendations for clinical care.

17β-Estradiol and Inflammation: Implications for Ischemic Stroke

Although typically associated with maintenance of female reproductive function, estrogens mediate physiological processes in nearly every body tissue, including the central nervous system. Numerous pre-clinical studies have shown that estrogen, specifically 17-beta-estradiol (17β-E2), protects the brain from ischemic injury following stroke. There are multiple mechanisms of 17β-E2s neuroprotection, including activation of several neuroprotective pathways in the brain, but 17β-E2 also mediates the local and systemic immune response to ischemic stroke. This review summarizes the immune response to stroke, sex differences in stroke pathophysiology, and the role of estrogen as an immunomodulator. This review will focus almost entirely on the role of 17β-E2; however, there will be a brief review and comparison to other forms of estrogen. Understanding the immunomodulatory action of estrogens may provide an opportunity for the use of estrogens in treatment of stroke and other inflammatory disease.

Early detection of cardiac dysfunction in the type 1 diabetic heart using speckle-tracking based strain imaging.

Enhanced sensitivity in echocardiographic analyses may allow for early detection of changes in cardiac function beyond the detection limits of conventional echocardiographic analyses, particularly in a small animal model. The goal of this study was to compare conventional echocardiographic measurements and speckle-tracking based strain imaging analyses in a small animal model of type 1 diabetes mellitus. Conventional analyses revealed differences in ejection fraction, fractional shortening, cardiac output, and stroke volume in diabetic animals relative to controls at 6-weeks post-diabetic onset. In contrast, when assessing short- and long-axis speckle-tracking based strain analyses, diabetic mice showed changes in average systolic radial strain, radial strain rate, radial displacement, and radial velocity, as well as decreased circumferential and longitudinal strain rate, as early as 1-week post-diabetic onset and persisting throughout the diabetic study. Further, we performed regional analyses for the LV and found that the free wall region was affected in both the short- and long-axis when assessing radial dimension parameters. These changes began 1-week post-diabetic onset and remained throughout the progression of the disease. These findings demonstrate the use of speckle-tracking based strain as an approach to elucidate cardiac dysfunction from a global perspective, identifying left ventricular cardiac regions affected during the progression of type 1 diabetes mellitus earlier than contractile changes detected by conventional echocardiographic measurements.

Non-feminizing estrogens: A novel neuroprotective therapy

While the conflict between basic science evidence for estrogen neuroprotection and the lack of effectiveness in clinical trials is only now being resolved, it is clear that strategies for estrogen neuroprotection that avoid activation of ERs have the potential for clinical application. Herein we review the evidence from both in vitro and in vivo studies that describe high potency neuroprotection with non-feminizing estrogens. We have characterized many of the essential chemical features of non-feminizing estrogens that eliminate or reduce ER binding while maintaining or enhancing neuroprotection. Additionally, we provide evidence that these non-feminizing estrogens have efficacy in protecting the brain from AD neuropathology and traumatic brain injury. In conclusion, it appears that the non-feminizing estrogen strategy for neuroprotection is a viable option to achieve the beneficial neuroprotective effects of estrogens while eliminating the toxic off-target effects of chronic estrogen administration.

Rates of Nonsteroidal Anti-Inflammatory Drug Use in Patients with Established Cardiovascular Disease: A Retrospective, Cross-Sectional Study from NHANES 2009–2010

PurposeNonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat pain, inflammation, and fever in the USA. Unfortunately, NSAIDs have been associated with an increased risk of adverse cardiovascular events, especially among NSAID users with established cardiovascular disease (CVD). In 2005, the Food and Drug Administration (FDA) released an initial warning regarding NSAID use and CVD risk, and recently, in July 2015, released an updated statement strengthening this initial warning. The purpose of this study is to evaluate the rates of NSAID use among patients with CVD following the 2005 FDA warning regarding NSAID use and increased CVD risk.MethodsThis was a retrospective, cross-sectional study of participants from the National Health and Nutrition Examination Survey, 2009–2010. Participants’ CVD status was determined by self-reported diagnosis. Current use of over the counter (OTC) NSAIDs was defined by self-reported use of ibuprofen or naproxen, and we identified the current use of prescription NSAIDs in the database of prescription medication.ResultsRespondents with CVD were 2.1 times more likely to use OTC NSAIDs or prescription NSAIDs than respondents without CVD. Among CVD patients, respondents with angina and myocardial infarction were 60% more likely to use any form of NSAID, and respondents with congestive heart failure were less likely to use any form of NSAID than those with other forms of CVD.ConclusionsOur results indicate that there is still a large proportion of CVD patients using NSAIDs. It is now crucial to determine the reasons why prescribers are still prescribing NSAIDs despite the FDA warning.

Machine-learning approach identifies a pattern of gene expression in peripheral blood that can accurately detect ischaemic stroke

Early and accurate diagnosis of stroke improves the probability of positive outcome. The objective of this study was to identify a pattern of gene expression in peripheral blood that could potentially be optimised to expedite the diagnosis of acute ischaemic stroke (AIS). A discovery cohort was recruited consisting of 39 AIS patients and 24 neurologically asymptomatic controls. Peripheral blood was sampled at emergency department admission, and genome-wide expression profiling was performed via microarray. A machine-learning technique known as genetic algorithm k-nearest neighbours (GA/kNN) was then used to identify a pattern of gene expression that could optimally discriminate between groups. This pattern of expression was then assessed via qRT-PCR in an independent validation cohort, where it was evaluated for its ability to discriminate between an additional 39 AIS patients and 30 neurologically asymptomatic controls, as well as 20 acute stroke mimics. GA/kNN identified 10 genes (ANTXR2, STK3, PDK4, CD163, MAL, GRAP, ID3, CTSZ, KIF1B and PLXDC2) whose coordinate pattern of expression was able to identify 98.4% of discovery cohort subjects correctly (97.4% sensitive, 100% specific). In the validation cohort, the expression levels of the same 10 genes were able to identify 95.6% of subjects correctly when comparing AIS patients to asymptomatic controls (92.3% sensitive, 100% specific), and 94.9% of subjects correctly when comparing AIS patients with stroke mimics (97.4% sensitive, 90.0% specific). The transcriptional pattern identified in this study shows strong diagnostic potential, and warrants further evaluation to determine its true clinical efficacy.

Peripheral blood AKAP7 expression as an early marker for lymphocyte-mediated post-stroke blood brain barrier disruption

Our group recently identified 16 genes whose peripheral blood expression levels are differentially regulated in acute ischemic stroke. The purpose of this study was to determine whether the early expression levels of any of these 16 genes are predictive for post-stroke blood brain barrier (BBB) disruption. Transcriptional expression levels of candidate genes were measured in peripheral blood sampled from ischemic stroke patients at emergency department admission, and BBB permeability was assessed at 24 hour follow up via perfusion-weighted imaging. Early heightened expression levels of AKAP7, a gene encoding a protein kinase A-binding scaffolding molecule, were significantly associated with BBB disruption 24 hours post-hospital admission. We then determined that AKAP7 is predominantly expressed by lymphocytes in peripheral blood, and strongly co-expressed with ITGA3, a gene encoding the adhesion molecule integrin alpha 3. Subsequent in vitro experiments revealed that heightened expression of AKAP7 and ITGA3 in primary human lymphocytes is associated with a highly adherent phenotype. Collectively, our results suggest that AKAP7 expression levels may have clinical utility as a prognostic biomarker for post-stroke BBB complications, and are likely elevated early in patients who later develop post-stroke BBB disruption due to the presence of an invasive lymphocyte population in the peripheral blood.

Circulating extracellular DNA levels are acutely elevated in ischaemic stroke and associated with innate immune system activation

ABSTRACT Objective: The objective of this work was to assess the ability of peripheral blood cell-free DNA (cfDNA) levels to identify ischaemic stroke early in the acute phase of care, as well as to examine the relationship between peripheral blood cfDNA levels and stroke-induced innate immune system activation. Methods: Upon emergency department admission, peripheral blood samples were obtained from 43 patients experiencing acute ischaemic stroke and 20 patients identified as stroke mimics. Plasma cfDNA levels were measured using quantitative polymerase chain reaction (qPCR), infarct volume and NIH stroke scale (NIHSS) were used to assess injury severity, and peripheral blood neutrophil count was used as a measure of innate immune system status.Results: Peripheral blood cfDNA levels were significantly elevated in patients suffering stroke relative to those diagnosed as stroke mimics, and could differentiate between groups with 86% (95% CI = 72–95%) sensitivity and 75% (95% CI = 51–91%) specificity. Furthermore, cfDNA levels displayed significant positive associations between both infarct volume and peripheral blood neutrophil count within the stroke group. Conclusions: These findings suggest that assessment of peripheral blood cfDNA levels may be useful for the identification of ischaemic stroke in the acute care setting, and provide associative evidence that cfDNA is a potential activator of the peripheral innate immune system in response to cerebral ischaemia.

Immune biomarkers for the diagnosis of mild traumatic brain injury

BACKGROUND In 2010, there were approximately 2.2 million emergency room visits associated with traumatic brain injury (TBI), with 80 percent diagnosed as mild TBI or concussion. In addition, there are a large number of TBIs, especially mild TBIs, which go either unreported by patients or initially undiagnosed by clinicians. Our team has previously identified a panel of immune-related genes that can diagnose ischemic stroke at triage, and due to shared pathophysiological mechanisms of TBI and stroke, we hypothesized that this panel of genes may also be utilized for the diagnosis of TBI. OBJECTIVES The primary aims of this pilot study were to: (1) characterize changes in a panel of immune-related genes in TBI; (2) identify immune-related biomarkers that may be used to diagnose TBI and (3) describe the peripheral immune response following TBI. METHODS Blood was drawn from TBI patients no later than 24 h of injury onset and matched control subjects. Real-time PCR was used to measure gene expression, and a white blood cell differential was performed to obtain neutrophil and lymphocyte percentages. RESULTS Relative mRNA expression of ARG1, LY96, MMP9, s100a12 was significantly increased and CCR7 was significantly decreased in peripheral blood of TBI patients within 24 hours of injury compared to control subjects. We also observed a different pattern of leukocyte dynamics following TBI between mild and severe TBI. CONCLUSIONS We have described a panel of immune-related genes that can accurately predict/diagnose TBI with higher sensitivity and specificity of other biomarkers to date.

Leukocyte Dynamics Influence Reference Gene Stability in Whole Blood: Data-Driven qRT-PCR Normalization Is a Robust Alternative for Measurement of Transcriptional Biomarkers

Background The use of reference genes for normalization of whole blood qRT-PCR data may be problematic in conditions such as stroke which induce alterations in white blood cell differential. In this study, we assessed the influence of stroke on the stability of commonly employed reference genes, and we evaluated data-driven normalization as an alternative. Methods Peripheral whole blood was sampled from 33 stroke patients and 29 controls, and qRT-PCR was used to measure the expression levels of 10 target genes whose transcripts are known stroke biomarkers. Target gene expression levels were normalized via those of 2 frequently cited reference genes (ACTB and B2M) as well as with the NORMA-Gene data-driven normalization algorithm. Results Whole blood expression levels of reference genes were significantly altered in stroke patients relative to controls. In comparison to normalization via reference genes, NORMA-Gene produced more robust target gene expression data in terms of differential expression dynamics, variance properties, and diagnostic performance. Conclusions Our findings suggest that whole blood expression levels of commonly used reference genes may be sensitive to changes in white blood cell differential, and that data-driven qRT-PCR normalization approaches offer a powerful alternative.