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With funding from the National Institutes of Health's Community Engagement Alliance, starting in fall 2020, 11 academic medical centers and 75 community partners came together as the California Alliance Against COVID-19 to address COVID-19 inequities in California. Using data from focus groups, statewide meetings, and a statewide partner survey, we describe how promotoras and community health workers (P/CHWs; n = 540) helped to promote access to COVID-19 information, testing, and vaccination. We highlight opportunities to promote health equity among other public health collaborators with a P/CHW model. (Am J Public Health. 2024;114(S1):S45-S49. https://doi.org/10.2105/AJPH.2023.307471).

IntroductionIn the context of recurrent surges of SARS-CoV-2 infections, a detailed characterization of antibody persistence over a 6-month period following vaccine booster dose is necessary to crafting effective public health policies on repeat vaccination.MethodsTo characterize the SARS-CoV-2 antibody profile of a healthcare worker population over a 6-month period following mRNA vaccination and booster dose. 323 healthcare workers at an academic medical center in Orange County, California who had completed primary vaccination and booster dose against SARS-CoV-2 were recruited for the study. A total of 690 blood specimens over a 6-month period were collected via finger-stick blood and analyzed for the presence of antibodies against 9 SARS-CoV-2 antigens using a coronavirus antigen microarray.ResultsThe primary outcome of this study was the average SARS-CoV-2 antibody level as measured using a novel coronavirus antigen microarray. Additional outcomes measured include levels of antibodies specific to SARS-CoV-2 variants including Delta, Omicron BA.1, and BA.2. We also measured SARS-CoV-2 neutralization capacity for a subset of the population to confirm correlation with antibody levels. Although antibodies against SARS-CoV-2 wane throughout the 6-month period following a booster dose, antibody levels remain higher than pre-boost levels. However, a booster dose of vaccine based on the original Wuhan strain generates approximately 3-fold lower antibody reactivity against Omicron variants BA.1 and BA.2 as compared to the vaccine strain. Despite waning antibody levels, neutralization activity against the vaccine strain is maintained throughout the 6-month period.DiscussionIn the context of recurrent surges of SARS-CoV-2 infections, our data indicate that breakthrough infections are likely driven by novel variants with different antibody specificity and not by time since last dose of vaccination, indicating that development of vaccinations specific to these novel variants is necessary to prevent future surges of SARS-CoV-2 infections.

BackgroundWhile others have reported severe acute respiratory syndrome-related coronavirus 2(SARS-CoV-2) seroprevalence studies in health care workers (HCWs), we leverage the use of a highly sensitive coronavirus antigen microarray to identify a group of seropositive health care workers who were missed by daily symptom screening that was instituted prior to any epidemiologically significant local outbreak. Given that most health care facilities rely on daily symptom screening as the primary method to identify SARS-CoV-2 among health care workers, here, we aim to determine how demographic, occupational, and clinical variables influence SARS-CoV-2 seropositivity among health care workers.MethodsWe designed a cross-sectional survey of HCWs for SARS-CoV-2 seropositivity conducted from May 15th to June 30th 2020 at a 418-bed academic hospital in Orange County, California. From an eligible population of 5,349 HCWs, study participants were recruited in two ways: an open cohort, and a targeted cohort. The open cohort was open to anyone, whereas the targeted cohort that recruited HCWs previously screened for COVID-19 or work in high-risk units. A total of 1,557 HCWs completed the survey and provided specimens, including 1,044 in the open cohort and 513 in the targeted cohort. Demographic, occupational, and clinical variables were surveyed electronically. SARS-CoV-2 seropositivity was assessed using a coronavirus antigen microarray (CoVAM), which measures antibodies against eleven viral antigens to identify prior infection with 98% specificity and 93% sensitivity.ResultsAmong tested HCWs (n = 1,557), SARS-CoV-2 seropositivity was 10.8%, and risk factors included male gender (OR 1.48, 95% CI 1.05-2.06), exposure to COVID-19 outside of work (2.29, 1.14-4.29), working in food or environmental services (4.85, 1.51-14.85), and working in COVID-19 units (ICU: 2.28, 1.29-3.96; ward: 1.59, 1.01-2.48). Amongst 1,103 HCWs not previously screened, seropositivity was 8.0%, and additional risk factors included younger age (1.57, 1.00-2.45) and working in administration (2.69, 1.10-7.10).ConclusionSARS-CoV-2 seropositivity is significantly higher than reported case counts even among HCWs who are meticulously screened. Seropositive HCWs missed by screening were more likely to be younger, work outside direct patient care, or have exposure outside of work.

ObjectiveTo describe the early activities and lessons of the Share, Trust, Organize, Partner COVID-19 California Alliance (STOP COVID-19 CA), the California awardee of the NIH-funded multi-state Community Engagement Alliance (CEAL) against COVID-19. The Alliance was established to ensure equity in Coronavirus-19 disease (COVID-19) research, clinical practice, and public health for communities most impacted by the COVID-19 pandemic.Study settingThe STOP COVID-19 CA Alliance network of 11 universities and affiliated partner community-based organizations (CBOs) across California.Study designMixed methods evaluation consisting of an analysis of activity (August 2020 to December 2021) detailed in reports submitted by community-academic teams and a survey (August 2021) of academic investigators and affiliated community-based organization (CBO) partners.Data collectionWe summarized activities from the 11 community-academic teams' progress reports and described results from an online survey of academic investigators and CBO partners in the California Alliance.Principal findingsA review of progress reports (n = 256) showed that teams fielded surveys to 11,000 Californians, conducted 133 focus groups, partnered with 29 vaccine/therapeutics clinical trials, and led more than 300 town halls and vaccine events that reached Californians from communities disproportionately impacted by COVID-19. Survey responses from academic investigators and CBO partners emphasized the importance of learning from the successes and challenges of the California Alliance teams' COVID-19 initiatives. Both academic and CBO respondents highlighted the need for streamlined federal and institutional administrative policies, and fiscal practices to promote more effective and timely operations of teams in their efforts to address the numerous underlying health and social disparities that predispose their communities to higher rates of, and poor outcomes from, COVID-19.ConclusionsSTOP COVID-19 CA represents a new and potentially sustainable statewide community engagement model for addressing health disparities in multiethnic/multicultural and geographically dispersed communities.

Recent studies provide conflicting evidence on the persistence of SARS-CoV-2 immunity induced by mRNA vaccines. Here, we aim to quantify the persistence of humoral immunity following vaccination using a coronavirus antigen microarray that includes 10 SARS-CoV-2 antigens. In a prospective longitudinal cohort of 240 healthcare workers, composite SARS-CoV-2 IgG antibody levels did not wane significantly over a 6-month study period. In the subset of the study population previously exposed to SARS-CoV-2 based on seropositivity for nucleocapsid antibodies, higher composite anti-spike IgG levels were measured before the vaccine but no significant difference from unexposed individuals was observed at 6 months. Age, vaccine type, or worker role did not significantly impact composite IgG levels, although non-significant trends towards lower antibody levels in older participants and higher antibody levels with Moderna vaccine were observed at 6 months. A small subset of our cohort were classified as having waning antibody titers at 6 months, and these individuals were less likely to work in patient care roles and more likely to have prior exposure to SARS-CoV-2.

In this study, peripheral blood mononuclear cells from young and old patients with COVID-19 were examined phenotypically, transcriptionally and functionally to reveal age-, time- and severity-specific adaptations. Gene signatures within memory B cells and plasmablasts correlated with reduced frequency of antigen-specific B cells and neutralizing antibodies in older patients with severe COVID-19. Moreover, these patients exhibited exacerbated T cell lymphopenia, which correlated with lower plasma interleukin-2, and diminished antigen-specific T cell responses. Single-cell RNA sequencing revealed augmented signatures of activation, exhaustion, cytotoxicity and type I interferon signaling in memory T and natural killer cells with age. Although cytokine storm was evident in both age groups, older individuals exhibited elevated levels of myeloid cell recruiting factors. Furthermore, we observed redistribution of monocyte and dendritic cell subsets and emergence of a suppressive phenotype with severe disease, which was reversed only in young patients over time. This analysis provides new insights into the impact of aging on COVID-19.

As the nation implements SARS-CoV-2 vaccination in adults at an unprecedented scale, it is now essential to focus on the prospect of SARS-CoV-2 vaccinations in pediatric populations. To date, no children younger than 12 years have been enrolled in clinical trials. Key challenges and knowledge gaps that must be addressed include (1) rationale for vaccines in children, (2) possible effects of immune maturation during childhood, (3) ethical concerns, (4) unique needs of children with developmental disorders and chronic conditions, (5) health inequities, and (6) vaccine hesitancy. Because COVID-19 is minimally symptomatic in the vast majority of children, a higher acceptable risk threshold is required when evaluating pediatric clinical trials. Profound differences in innate and adaptive immunity during childhood and adolescence are known to affect vaccine responsiveness for a variety of childhood diseases. COVID-19 and the accompanying social disruption, such as the school shutdowns, has been disproportionately damaging to minority and low-income children. In this commentary, we briefly address each of these key issues, specify research gaps, and suggest a broader learning health system approach to accelerate testing and clinical trial development for an ethical and effective strategy to implement a pediatric SARS-CoV-2 vaccine as rapidly and safely as possible. IMPACT: As the US begins an unprecedented implementation of SARS-CoV-2 vaccination, substantial knowledge gaps have yet to be addressed regarding vaccinations in the pediatric population. Maturational changes in the immune system during childhood have influenced the effectiveness of pediatric vaccines for other diseases and conditions, and could affect SARS-CoV-2 vaccine responsiveness in children. Given that COVID-19 disease is far milder in the majority of children than in adults, the risk-benefit of a pediatric SARS-CoV-2 vaccine must be carefully weighed. The needs of children with developmental disabilities and with chronic disease must be addressed. Minority and low-income children have been disproportionately adversely affected by the COVID-19 pandemic; care must be taken to address issues of health equity regarding pediatric SARS-CoV-2 vaccine trials and allocation. Research and strategies to address general vaccine hesitancy in communities must be addressed in the context of pediatric SARS-CoV-2 vaccines.

PurposeTo compare urinary levels of monocyte chemoattractant protein-1 (MCP-1), an inflammatory cytokine, in healthy controls and overactive bladder (OAB) patients, to correlate changes in urinary MCP-1 with OAB treatment response and symptom severity, and to study the diagnostic potential of MCP-1 for OAB, as well as the efficacy of MCP-1 as a potential biomarker for different phenotypes of OAB.MethodsWe used enzyme-linked immunosorbent assay to measure normalized urinary MCP-1 levels in 56 individuals (43 OAB patients and 13 controls). We assessed the OAB patients at 3 visits with 2 validated symptom severity questionnaires (OAB-V8 and Patient Perception of Bladder Condition).ResultsThe mean pretreatment urinary MCP-1 level at visit 1 (229.2-pg/mg creatinine) was significantly greater than the MCP-1 levels at visit 3 in both the treatment (107.0-pg/mg creatinine) (P30%, whereas nonresponders displayed no significant MCP-1 decrease (P=0.164). The receiver operating characteristic analysis of the OAB visit 1 and control groups produced an area under the curve of 0.891. We found no significant differences in sex, race, or age between the OAB and control groups.ConclusionMCP-1 levels differed significantly between the control and OAB groups and were closely correlated with symptom severity and treatment response. The good diagnostic accuracy of MCP-1 for OAB suggests the potential usage of MCP-1 for OAB diagnosis. The varying response of urinary MCP-1 levels to treatment may indicate at least 2 potential phenotypes of OAB. MCP-1, in combination with other biomarkers and symptom severity questionnaires, could potentially aid in developing a patient-centered OAB treatment approach.

BackgroundThe use of pancreata from pre-weaned piglets has the potential to serve as an unlimited alternative source of islets for clinical xenotransplantation. As pre-weaned porcine islets (PPIs) are immature and require prolonged culture, we developed an islet maturation media (IMM) and evaluated its effect on improving the quantity and quality of PPIs over 14 days of culture.MethodsPPIs were isolated from the pancreata of pre-weaned Yorkshire piglets (8-15 days old). Each independent islet isolation was divided for culture in either control Ham's F-10 media (n = 5) or IMM (n = 5) for 14 days. On day 3, 7 and 14 of culture, islets were assessed for islet yield, isolation index, viability, insulin content, endocrine cellular composition, differentiation of beta cells, and insulin secretion during glucose stimulation.ResultsIn comparison to control islets, culturing PPIs in IMM significantly increased islet yield. PPIs cultured in IMM also maintained a stable isolation index and viability throughout 14 days of culture. The insulin content, endocrine cellular composition, and differentiation of beta cells were significantly improved in PPIs cultured in IMM, which subsequently augmented their insulin secretory capacity in response to glucose challenge compared to control islets.ConclusionsCulturing PPIs in IMM increases islet yield, isolation index, viability, insulin content, endocrine cellular composition, differentiation of endocrine progenitor cells toward beta cells, and insulin secretion. Due to the improved islet quantity and quality after in vitro culture, the use of IMM in the culture of PPIs will assist to advance the outcomes of clinical islet xenotransplantation.

Advances in therapies have led to prolonged survival from many previously lethal health threats in children, notably among prematurely born babies and those with congenital heart disease. Evidence for catch-up growth is common in these children, but in many cases the adult phenotype is never achieved. A translational animal model is required in which specific tissues can be studied over a reasonable time interval. We investigated the impact of postnatal hypoxia (HY) (12%O2 (HY12) or 10% O2 (HY10)) on growth in rats relative to animals raised in room air. Subgroups had access to running wheels following the HY period. Growth was fully compensated in adult HY12 rats but not HY10 rats. The results of this study indicate that neonatal hypoxia can be a useful model for the elucidation of mechanisms that mediate successful catch-up growth following neonatal insults and identify the critical factors that prevent successful catch-up growth.

UNLABELLED: Post-exercise leucocytosis has been found in children and adults in response to exercise. When normalized to the work performed, children demonstrate a lower lactate response to exercise than in adults. This study examines the association between leukocyte and lactate response in children following exercise. 148 healthy children participated in this study. Each subject performed a ramp exercise on a cycle ergometer followed by ten 2-minute bouts of constant work rate separated by 1-minute rest intervals. Lactate, leukocyte and leukocyte subtype levels were taken pre- and post-exercise. Older children showed a significantly higher pre-to post-exercise leukocyte compared to younger children (3599 ± 165 cells/mL, 2544 ± 163, p

Assessment of nitric oxide (NO) dynamics in immune cells, commonly measured using NO surrogates such as inducible nitric oxide synthase (iNOS) rather than NO itself, has been effective in understanding pathophysiology across a wide range of diseases. Although the intracellular measurement of NO is now feasible, many technical issues remain unresolved. The principle aim of our study was to determine the effect of storage time of whole blood on nitric oxide (NO) level expression in leukocytes. This is important because immune cells remain chemically dynamic even after they are removed from the circulation, and the impact of storage time must be known to optimally quantify the effect of a disease or condition on NO dynamics in circulating leukocytes. We measured NO levels using the fluorescent probe, diaminofluorescein (DAF-2DA), and flow cytometry in monocytes, neutrophils, and natural killer cells from healthy subjects immediately after blood draw (Time 0) and 30, 60, and 120 min following the blood draw. There was no significant difference among the 4 study time points in NO (DAF-2) levels, though there was wide intra-subject variability at all time points. Using LPS stimulation, we compared iNOS (the more traditional surrogate marker of NO dynamics) with NO (by DAF-2) in natural killer cells and monocytes and, we found no difference in the response patterns. In summary, we did find that within a 2-hour interval from blood draw to sample processing, there was a remarkably wide intra-subject variability in expression of intracellular NO (DAF-2) in leukocytes of healthy individuals at baseline and over time. The mechanism(s) for these differences are not known but could clearly confound efforts to detect changes in NO metabolism in white blood cells. We speculate that rapid pulsatility of NO could explain the wide variability seen.

BackgroundPoor aerobic fitness is associated with worsening of asthma symptoms, and fitness training may improve asthma control. The mechanism linking fitness with asthma is not known. We hypothesized that repeated bouts of exercise would lead to a downregulation of glucocorticoid receptor (GR) expression on circulating leukocytes, reflecting a reduced responsiveness to stress.MethodsIn a prospective exercise training intervention of healthy and asthmatic adolescents, GR expression in leukocytes was measured using flow cytometry in response to an acute exercise challenge before and after the exercise training intervention. Peripheral blood mononuclear cell (PBMC) gene expression of GR, GRβ, HSP70, TGFβ1, and TGFβ2 was determined using reverse-transcriptase PCR (RT-PCR).ResultsPeak VO2 increased by 14.6±2.3%, indicating an effective training (P

IntroductionThe glucocorticoid receptor (GR) is a key receptor involved in inflammatory responses and is influenced by sex steroids. This study measured GR expression on circulating leukocyte subtypes in males and females.MethodsA total of 23 healthy adults (12 female) participated in this study. GR expression was measured in leukocyte subtypes using flow cytometry. Peripheral blood mononuclear cell (PBMC) gene expression of GR (NR3C1), GR β, TGF-β1 and 2, and glucocorticoid-induced leucine zipper (GILZ) were determined by real-time polymerase chain reaction.ResultsLeukocyte GR was lower in females, particularly in granulocytes, natural killer cells, and peripheral blood mononuclear cells (p≤0.01). GR protein expression was different across leukocyte subtypes, with higher expression in eosinophils compared with granulocytes, T lymphocytes, and natural killer cells (p

Background/aimsCardiovascular disease and protein-energy wasting are among the strongest predictors of the high mortality of dialysis patients. In the general population, the novel cardiovascular and wasting biomarker, growth differentiation factor 15 (GDF15), is associated with decreased survival. However, little is known about GDF15 in dialysis patients.MethodsAmong prevalent hemodialysis patients participating in a prospective study (October 2011 to August 2015), we examined the association of baseline GDF15 levels with all-cause mortality using unadjusted and case mix-adjusted death hazard ratios (HRs) that controlled for age, sex, race, ethnicity, diabetes, and dialysis vintage.ResultsThe mean age ± SD of the 203 patients included in the study was 53.2 ± 14.5 years, and the cohort included 41% females, 34% African-Americans, and 48% Hispanics. GDF15 levels (mean ± SD 5.94 ± 3.90 ng/mL; range 1.58-39.8 ng/mL) were higher among older patients and were inversely associated with serum creatinine concentrations as a surrogate for muscle mass. Each 1.0 ng/mL increase in GDF15 was associated with an approximately 17-18% higher mortality risk in the unadjusted and case mix models (p < 0.05). Increments of about 1 SD (a 4.0 ng/mL increase in GDF15) were associated with a nearly 2-fold higher death risk. The highest GDF15 tertile was associated with higher mortality risk (reference: lowest tertile): the HRs (95% CI) were 3.19 (1.35-7.55) and 2.45 (1.00-6.00) in the unadjusted and the case mix-adjusted model, respectively. These incremental death trends were confirmed in cubic spline models.ConclusionHigher circulating GDF15 levels are associated with higher mortality risk in hemodialysis patients. Future studies are needed to determine whether GDF15 may represent a novel therapeutic target for cardiovascular disease, wasting, and death in this population.

Objectives: To investigate monocyte chemotactic protein-1 (MCP-1) as a novel urinary biomarker to predict prolonged post prostatectomy incontinence. Methods: Men submitted urine samples prior to robotic radical prostatectomy. MCP-1 values were derived using an ELISA test. Pad usage at 7, 30, and 60 days were documented by patient post cards mailed when zero pads was reached. The primary outcome was defined as no incontinence pad usage at 30 days at prostatectomy. Results: After exclusions, 76 patients were included in analyses. Continence was reached by 29% (22/76), 56% (42/76), and (75/76) 98% at 7, 30, and 60 days, respectively. The average MCP-1 (p=0.258) was not different between the continent and incontinent groups. Highest quartile of MCP-1 (MCP > 166 pg/mL) and normalized MCP-1 (MCP-1/TV >0.53) noted a significant delay in continence at 30 days (p=0.050 and p=0.003). Only 26% (5/19) in the highest MCP1/TV quartile were continent, whereas 65% (37/57) of men in the 3 lower quartiles reached zero pad continence (p=0.003). In a logistic regression model the highest quartile of MCP1/TV had a significant chance of being incontinent at 30 days (OR 0.22; 95% CI 0.058-0.80; p=0.022). Conclusion: MCP-1/TV is a urinary biomarker that may predict prolonged urinary incontinence after radical prostatectomy.

Atherosclerosis/cardiovascular disease are major causes of morbidity/mortality in obesity and type 2 diabetes (T2D), and have been associated with activation of innate immune cells, their diapedesis to the arterial intima and formation of the atherosclerotic plaque. While in obesity/T2D immune cell activation likely depends on dysregulated metabolism, the interaction between individual metabolic factors typical of these conditions (hyperglycemia, hyperlipidemia), innate immune cell activation, and the progression of atherosclerosis remains unclear. We, therefore, measured by flow cytometry cell surface expression of CD11b, CD14, CD16, CD62L, and CD66b, known markers of granulocyte (Gc) and monocyte (Mc) activation, in five healthy, five obese, and five T2D subjects, during 4-h i.v. infusions of 20% dextrose (raising blood sugar levels to ~220 mg/dL), 20% Intralipid (raising trygliceride levels to ~6 mmol/L), or a combination of the two. We hypothesized that both glucose and lipids would increase Gc/Mc surface marker expression, and simultaneous infusion would have an additive or synergistic effect. Surprisingly, though, infusion of glucose alone had little effect, while lipids, alone or combined with glucose, significantly increased expression of several markers (such as CD11b in Gc and Mc, and CD66 b in GC) within 60-90 min. Less pronounced increases in systemic inflammatory cytokines also occurred in obese and T2D subject, with no acute changes in gene expression of the the proinflammatory genes NFκB and CCR2. Our results suggest that lipids may be stronger acute contributors to innate cell activation than acute hyperglycemia per se, possibly helping shape more effective preventive dietary guidelines in T2D.

Shift work and overtime have been implicated as important work-related risk factors for cardiovascular disease (CVD). Many firefighters who contractually work on a 24-hr work schedule, often do overtime (additional 24-hr shifts) which can result in working multiple, consecutive 24-hr shifts. Very little research has been conducted on firefighters at work that examines the impact of performing consecutive 24-hr shifts on cardiovascular physiology. Also, there have been no standard field methods for assessing in firefighters the cardiovascular changes that result from 24-hr shifts, what we call "cardiovascular strain". The objective of this study, as the first step toward elucidating the role of very long (> 48 hrs) shifts in the development of CVD in firefighters, is to develop and describe a theoretical framework for studying cardiovascular strain in firefighters on very long shifts (i.e., > 2 consecutive 24-hr shifts). The developed theoretical framework was built on an extensive literature review, our recently completed studies with firefighters in Southern California, e-mail and discussions with several firefighters on their experiences of consecutive shifts, and our recently conducted feasibility study in a small group of firefighters of several ambulatory cardiovascular strain biomarkers (heart rate, heart rate variability, blood pressure, salivary cortisol, and salivary C-reactive protein). The theoretical framework developed in this study will facilitate future field studies on consecutive 24-hr shifts and cardiovascular health in firefighters. Also it will increase our understanding of the mechanisms by which shift work or long work hours can affect CVD, particularly through CVD biological risk factors, and thereby inform policy about sustainable work and rest schedules for firefighters.

Physical activity can prevent and/or attenuate atherosclerosis, a disease clearly linked to inflammation. Paradoxically, even brief exercise induces a stress response and increases inflammatory cells like monocytes in the circulation. We hypothesized that exercise would regulate the expression of genes, gene pathways, and microRNAs in monocytes in a way that could limit pro-inflammatory function and drive monocytes to prevent, rather than contribute to, atherosclerosis. Twelve healthy men (22-30year old) performed ten 2-min bouts of cycle ergometer exercise at a constant work equivalent to an average of 82% of maximum O2 consumption interspersed with 1-min rest. Blood was drawn before and immediately after the exercise. Monocytes were isolated from peripheral blood mononuclear cells. Flow cytometry was used to identify monocyte subtypes. We used Affymetrix U133 + 2.0 arrays for gene expression and Agilent Human miRNA V2 Microarray for miRNAs. A stringent statistical approach (FDR

ObjectivesWe investigated urinary nerve growth factor (NGF) as a novel urinary biomarker for high-grade prostate cancer (PCa).Methods and materialsAfter institutional review board approval for a prospective pilot study, we enrolled men at the preoperative visit before robotic-assisted radical prostatectomy. Demographics, urinary flow parameters, and urine samples were collected. Urinary NGF and urinary creatinine were obtained in the translational science laboratory. Pathologic and postoperative demographics were collected after surgery. NGF is the primary outcome variable (dependent variable). The pathologic Gleason score (ordinal variable ≤6, 7, and ≤8) served as an independent grouping variable. Multivariate analysis using a general linear model was conducted to investigate associations between independent variables and NGF (dependent variable) after adjusting for urinary concentration and volume.ResultsWe enrolled and analyzed urine samples and pathologic data from 115 subjects. Patient pathology included 24% (n = 28) Gleason score 6 or less, 68% (n = 78) Gleason score 7, and 8% (n = 9) Gleason score 8 or greater. Perineural invasion was more prevalent in higher-grade disease (P

Obesity, type 2 diabetes mellitus (DM) and metabolic syndrome (MS) are common in patients with heart failure (HF). Studies investigating the association between known biomarkers and adiposity in patient populations are limited. The aim of the present study was to investigate the association between C-reactive protein (CRP) and leptin with adiposity in a sub-group of overweight/obese patients with HF, DM and/or MS. A total of 36 patients (mean age, 56.72±9.78 years; ranging between 27 and 76 years of age; 80.6% male; 52.8% Caucasian) were enrolled and their height, weight, waist circumference and body composition (e.g. percentage body fat and lean mass), as well as the levels of CRP and leptin, were assessed. The results demonstrated that there was a significant association between CRP and leptin, CRP and body mass index (BMI) and gender and percentage body fat (P

Shift work and overtime have been implicated as important work-related risk factors for cardiovascular disease (CVD). Many firefighters who contractually work on a 24-hr work schedule, often do overtime (additional 24-hr shifts) which can result in working multiple, consecutive 24-hr shifts. Very little research has been conducted on firefighters at work that examines the impact of performing consecutive 24-hr shifts on cardiovascular physiology. Also, there have been no standard field methods for assessing in firefighters the cardiovascular changes that result from 24-hr shifts, what we call cardiovascular strain. The objective of this study, as the first step toward elucidating the role of very long (> 48 hrs) shifts in the development of CVD in firefighters, is to develop and describe a theoretical framework for studying cardiovascular strain in firefighters on very long shifts (i.e., > 2 consecutive 24-hr shifts). The developed theoretical framework was built on an extensive literature review, our recently completed studies with firefighters in Southern California, e-mail and discussions with several firefighters on their experiences of consecutive shifts, and our recently conducted feasibility study in a small group of firefighters of several ambulatory cardiovascular strain biomarkers (heart rate, heart rate variability, blood pressure, salivary cortisol, and salivary C-reactive protein). The theoretical framework developed in this study will facilitate future field studies on consecutive 24-hr shifts and cardiovascular health in firefighters. Also it will increase our understanding of the mechanisms by which shift work or long work hours can affect CVD, particularly through CVD biological risk factors, and thereby inform policy about sustainable work and rest schedules for firefighters.

Valosin containing protein (VCP) disease (also known as Inclusion Body Myopathy, Paget Disease of Bone and Frontotemporal Dementia [IBMPFD] syndrome) is caused by mutations in the gene encoding VCP classically affecting the muscle, bone and brain. Although the genetic cause has been identified, details regarding the pathogenesis of IBMPFD have not been fully determined. Muscle wasting observed in VCP disease is suggestive of cytokine imbalance. We hypothesized that dysfunctional protein homeostasis caused by VCP mutations leads to cytokine imbalances thereby contributing to the muscle wasting phenotype. Circulating levels of interleukin-4 (IL-4), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF a) and epidermal growth factor (EGF) were measured in plasma of patients with VCP disease or controls. TNF a and EGF were significantly altered in VCP disease as compared to control. TNF a was up-regulated, consistent with a cachexia phenotype and EGF levels were increased. No significant differences were observed in IL-4 and IL-6. Cytokine imbalances may be associated with VCP disease and may play a contributory role in VCP myopathy. Further understanding of how VCP dysfunction leads to aberrant protein homeostasis and subsequent cytokine imbalances may also aid in the understanding of other proteinopathies and in the development of novel treatments.

BackgroundThe gaseous headspace above naïve Escherichia Coli (E. coli) cultures and whole human blood inoculated with E. coli were collected and analyzed for the presence of trace gases that may have the potential to be used as novel, non-invasive markers of infectious disease.MethodsThe naïve E. coli culture, LB broth, and human whole blood or E. coli inoculated whole blood were incubated in hermetically sealable glass bioreactors at 37°C for 24 hrs. LB broth and whole human blood were used as controls for background volatile organic compounds (VOCs). The headspace gases were collected after incubation and analyzed using a gas chromatographic system with multiple column/detector combinations.ResultsSix VOCs were observed to be produced by E. coli-infected whole blood while there existed nearly zero to relatively negligible amounts of these gases in the whole blood alone, LB broth, or E. coli-inoculated LB broth. These VOCs included dimethyl sulfide (DMS), carbon disulfide (CS2), ethanol, acetaldehyde, methyl butanoate, and an unidentified gas S. In contrast, there were several VOCs significantly elevated in the headspace above the E. coli in LB broth, but not present in the E. coli/blood mixture. These VOCs included dimethyl disulfide (DMDS), dimethyl trisulfide (DMTS), methyl propanoate, 1-propanol, methylcyclohexane, and unidentified gases R2 and Q.ConclusionsThis study demonstrates 1) that cultivated E. coli in LB broth produce distinct gas profiles, 2) for the first time, the ability to modify E. coli-specific gas profiles by the addition of whole human blood, and 3) that E. coli-human whole blood interactions present different gas emission profiles that have the potential to be used as non-invasive volatile biomarkers of E. coli infection.

IntroductionCardiovascular complications are the leading cause of mortality in type 2 diabetes (T2DM), in which onset and progression of atherosclerosis is linked to chronic inflammation. Activation status of innate immune cells (granulocytes [Gc], monocytes [Mc]), as reflected by increased CD11b, CD66b, and other surface markers, increases their endothelial and cytokines/chemokines release. Whereas this inflammatory activation seems inversely related to poor glycemic control, the effect of acute spontaneous hyperglycemia on innate immune cell activation remains unclear.MethodsExpression of key markers (CD11b, CD14, CD16, CD62L, and CD66b) was therefore determined by flow cytometry on whole blood of healthy subjects and patients with T2DM with spontaneous fasting euglycemia or hyperglycemia both at baseline and after 30, 90, and 240 minutes of incubation at room temperature.ResultsHyperglycemic patients with T2DM had significantly higher Gc and Mc CD11b and Gc CD66b surface mean fluorescence intensity compared with the euglycemic patients with T2DM whose values were similar to those of the healthy controls. CD16 expression in CD14+CD16+ Mc was elevated in all patients with T2DM, regardless of glycemic levels.ConclusionOur data suggest that whereas the presence of diabetes per se may have a proinflammatory effect, hyperglycemia seems to further acutely exacerbate innate cell inflammatory status and their consequent endothelial adhesion and vascular damage potential.

Cardiovascular complications are the leading cause of mortality in type II diabetes (T2DM), in which onset and progression of atherosclerosis is linked to chronic inflammation. Activation status of innate immune cells (granulocytes Gc, monocytes Mc), as reflected by increased CD11b, CD66b and other surface markers, increases their endothelial and cytokines/chemokines release. While this inflammatory activation appears inversely related to poor glycemic control, the effect of acute spontaneous hyperglycemia on innate immune cell activation remains unclear. Expression of key markers (CD11b, CD14, CD16, CD62L, and CD66b) was therefore determined by flow cytometry on whole blood of healthy subjects and patients with T2DM with spontaneous, fasting eu- or hyper-glycemia both at baseline and after 30, 90, and 240 min. of room temperature incubation. Hyperglycemic patients with T2DM had significantly higher Gc and Mc CD11b and Gc CD66b surface mean fluorescence intensity (MFI) as compared to euglycemic patients with T2DM whose values were similar to healthy controls. CD16 expression in CD14+CD16+ Mc was elevated in all patients with T2DM, regardless of glycemic levels. Our data suggest that while the presence of diabetes per se may have a pro-inflammatory effect, hyperglycemia seems further acutely exacerbate innate cell inflammatory status, and their consequent endothelial adhesion and vascular damage potential.

BackgroundHypoxia is an important disease mechanism in prematurity, childhood asthma and obesity. In children, hypoxia results in chronic inflammation.MethodsWe investigated the effects of hypoxia (Hx) (12% O2) during postnatal day 2 to 20 in rats. Control groups were normoxic (Nc), and normoxic growth restricted (14 pup liters) (Gr).ResultsHypoxia decreased growth similar Gr. Hx increased plasma TNFα and IL-6 and decreased IGF-I and VEGF. Hypoxia resulted in right ventricular (RV) hypertrophy but disproportionate decrements in limb skeletal muscle (SM) growth. miR206 was depressed in the hypertrophied RV of Hx rats while increased in growth retarded SM. Hx resulted in a decreased RV mRNA for myostatin but had no effect on SM myostatin. The mRNA for hypoxia sensitive factors such as HIFα was depressed in the RV of Hx rats suggesting negative feedback.ConclusionThe results indicate that Hx induces a proinflammatory state that depresses growth regulating mechanisms and that tissues critical for survival, such as the heart, can escape from this general regulatory program to sustain life. This study identifies accessible biomarkers for evaluating the impact of interventions designed to mitigate the long-term deleterious consequences of hypoxia that all too often occur in babies born prematurely.

Natural killers (NK) cells are unique innate immune cells that increase up to fivefold in the circulating blood with brief exercise and are known to play a key role in first-response defense against pathogens and cancer immunosurveillance. Whether exercise alters NK cell gene and microRNA (miRNA) expression is not known. Thirteen healthy men (20–29 yr old) performed ten 2-min bouts of cycle ergometer exercise at a constant work equivalent to an average of 77% of maximum O2 consumption interspersed with 1-min rest. Blood was drawn before and immediately after the exercise challenge. NK cells were isolated from peripheral blood mononuclear cells using a negative magnetic cell separation method. We used Affymetrix U133+2.0 arrays for gene expression and Agilent Human miRNA V2 Microarray for miRNAs. A stringent statistical approach (false discovery rate < 0.05) was used to determine that exercise significantly altered the expression of 986 genes and 23 miRNAs. Using in silico analysis, we found exercise-related gene pathways where there was a high likelihood of gene-miRNA interactions. These pathways were predominantly associated with cancer and cell communication, including p53 signaling pathway, melanoma, glioma, prostate cancer, adherens junction, and focal adhesion. These data support the hypothesis that exercise affects the gene and miRNA expression pattern in the population of NK cells in the circulation and suggest mechanisms through which physical activity could alter health through the innate immune system.

Diet plays an important role in modulating exercise responses, including activation of the growth hormone (GH)/insulin-like growth factor-I (IGF-1) axis. Obesity and fat ingestion were separately shown to reduce exercise GH responses, but their combined effect, especially important in children, has not been studied. We therefore measured the GH response to exercise [30-min intermittent cycling, ten 2-min bouts at ∼80% maximal aerobic capacity (V̇o2max), separated by 1-min rest], started 45 min after ingestion of a high-fat meal (HFM) in 16 healthy [controls; body mass index percentile (BMI%ile) 51 ± 7], and 19 obese (Ob, BMI%ile 97 ± 0.4) children. Samples were drawn at baseline (premeal), and at start, peak, and 30 min postexercise. In the Ob group, a marked ∼75% suppression of the GH response (ng/ml) to exercise was observed (2.4 ± 0.6 vs. 10.6 ± 2.1, P < 0.001). This level of suppression was also significantly greater compared with age-, fitness-, and BMI-matched historical controls that had performed identical exercise in fasting conditions. Our data indicate that the reduction in the GH response to exercise, already present in obese children vs. healthy controls, is considerably amplified by ingestion of fat nutrients shortly before exercise, implying a potentially downstream negative impact on growth factor homeostasis and long-term modulation of physiological growth.

MicroRNAs are increasingly seen as targets of drug discovery because they influence gene function acting both to silence and subtly modulate protein translation. Little is known about effects of dynamic physiological states on microRNA regulation in humans. We hypothesized that microRNA expression in peripheral blood mononuclear cells (PBMCs) would be affected by brief exercise. Twelve young men performed brief bouts of heavy exercise. PBMC microRNA was analyzed before and immediately after exercise using the Agilent Human microRNA V2 Microarray. Exercise altered expression level of 34 microRNAs (FDR < 0.05). Many of them play roles in inflammatory processes (e.g., miR-125b[↓], down-regulated by proinflammatory factor LPS; and miR-132[↑], 125b[↓] and let-7e[↓] involved inTLR4 signaling). Using previous exercise data in PBMCs, we linked the microRNA changes to specific gene pathways. This analysis identified 12 pathways including the TGF-β and MAPK signaling. We also compared exercise-associated microRNA changes in PBMCs with the exercise-associated microRNAs previously identified in neutrophils. Nine microRNAs were affected in both PBMCs and neutrophils, but only six changed in the same direction. A commonly occurring physiologic perturbation, brief heavy exercise, changes microRNA profiles in PBMCs, many of which are related to inflammatory processes. The pattern of change suggests that exercise differentially influences microRNAs in leukocyte subtypes.

Obesity (Ob) and type 1 diabetes (T1DM) are associated with increased inflammation and oxidative stress, which are major pathogenetic pathways toward higher cardiovascular risks. Although long-term exercise protects against systemic inflammation and oxidation, acute exercise actually exerts pro-inflammatory and oxidative effects, prompting the necessity for better defining these molecular processes in at-risk patients; in particular, very little is known regarding obese and T1DM children. We therefore examined key inflammatory and oxidative stress variables during exercise in 138 peripubertal children (47 Ob, 12.7 ± 0.4 yr, 22 F, BMI% 97.6 ± 0.2; 49 T1DM, 13.9 ± 0.2 yr, 20 F, body mass index% [BMI] 63.0 ± 3.6; 42 healthy, CL, 13.5 ± 0.5 yr, 24 F, BMI% 57.0 ± 3.6), who performed 10 bouts of 2-min cycling ~80% VO(2max) , separated by 1-min rest intervals. Blood samples were drawn at baseline and peak exercise. Ob displayed elevated baseline interleukin-6 (IL-6, 2.1 ± 0.2 pg/mL, p < 0.005) vs. CL (1.5 ± 0.3), whereas T1DM displayed the greatest maximum exercise-induced change in IL-6 (1.2 ± 0.3) than in both Ob (0.7 ± 0.1, p < 0.001) and CL (0.6 ± 0.1, p < 0.0167). Myeloperoxidase (MPO) was elevated in T1DM (143 ± 30 ng/mL, p < 0.0167) vs. CL (89 ± 10) and Ob (76 ± 6), whereas increases in exercise only occurred in Ob and CL. Disparate baseline and exercise responses were also observed for 8-hydroxy-2'-deoxyguanosine, glutathione, and F(2) -isoprostane. This data show distinct patterns of dysregulation in baseline and adaptive immunologic and oxidative responses to exercise in Ob and T1DM. A full understanding of these alterations is required so that developing exercise regimens aimed at maximizing health benefits for specific dysmetabolic states can be achieved based on complete scientific characterization rather than empirical implementation.

Circulating leukocytes increase rapidly with exercise then quickly decrease when the exercise ends. We tested whether exercise acutely led to bidirectional interchange of leukocytes between the circulation and the lung, spleen, and active skeletal muscle. To accomplish this it was necessary to label a large number of immune cells (granulocytes, monocytes, and lymphocytes) in a way that resulted in minimal perturbation of cell function. Rats were injected intravenously with a single bolus of carboxyfluorescein diacetate succinamidyl ester (CFSE) dye which is rapidly and irreversibly taken up by circulating cells. The time course of the disappearance of labeled cells and their reappearance in the circulation following exercise was determined via flow cytometry. The majority of circulating leukocytes were labeled at 4h. post-injection and this proportion slowly declined out to 120 h. At both 24 and 120 h, running resulted in an increase in the proportion of labeled leukocytes in the circulation. Analysis of the skeletal muscle, spleen and lung indicated that labeled leukocytes had accumulated in those tissues and were mobilized to the circulation in response to exercise. This indicates that there is an ongoing exchange of leukocytes between the circulation and tissues and that exercise can stimulate their redistribution. Exchange was slower with muscle than with spleen and lung, but in all cases, influenced by exercise. Exercise bouts redistribute leukocytes between the circulation and the lung, spleen and muscle. The modulatory effects of exercise on the immune system may be regulated in part by the systemic redistribution of immune cells.

Exercise-induced bronchoconstriction (EIB) is common; however, key aspects of its pathogenesis are still unclear. We investigated the feasibility of adapting an established animal model of asthma to investigate the earliest stages of EIB. The hypothesis was that a single exposure to a normally innocuous, and brief, exercise challenge could trigger EIB symptoms in rats previously sensitized to ovalbumin (OVA) but otherwise unchallenged. Brown-Norway rats were sensitized by intraperitoneal injection of OVA at 0 and 2 wk. At week 3, animals were exposed to either aerosolized OVA (SS) or exercise (EXS). A trained, blinded, clinical observer graded EIB by respiratory sounds. Plasma and lung cytokine levels were analyzed. No control rats with or without exercise (EX, CON) showed evidence of EIB. Eighty percent of the SS group demonstrated abnormal breath sounds upon exposure to aerosolized OVA. Approximately 30% of EXS rats sensitized to OVA but exposed only to exercise had abnormal breath sounds. Lung tissue levels of TNF-α, IL-1α, growth-related oncogene/keratinocyte/chemoattractant, and IFN-γ were significantly higher (P < 0.001) in the SS group, relative to all other groups. Changes in most of these cytokines were not notable in the EXS rats, suggesting a different mechanism of EIB. Remarkably, IFN-γ, but not the other cytokines measured, was significantly elevated following brief exercise in both sensitized and unsensitized rats. Exercise led to detectable breathing sound abnormalities in sensitized rats, but less severe than those observed following classical OVA challenge. Precisely how this immune crossover occurs is not known, but this model may be useful in elucidating essential mechanisms of EIB.

PurposeInhaled corticosteroids (ICS) improve symptoms in lung diseases, such as asthma. Initial data suggest that the effects of ICS remain localized in the lung; however, recent studies demonstrate alteration to the peripheral immune system in patients with asthma. We sought to evaluate the effect of ICS on peripheral immune mediators and hypothalamic-pituitary-adrenal axis and their response to exercise in healthy men.MethodsEleven healthy males (18-30 yr old) were placed on 2 wk of fluticasone proprionate (440 μg) twice daily. A 30-min bout of exercise was performed on a cycle ergometer at approximately 70% of peak work rate before and after the start of ICS. Blood was sampled before and after exercise. Cytokines and hypothalamic-pituitary-adrenal axis mediators were measured by ELISA, and fluticasone was measured by liquid chromatography/tandem mass spectrometry.ResultsAfter ICS treatment, cortisol and adrenocorticotropin were decreased, and a blunted exercise response was observed for cortisol, adrenocorticotropin, and growth hormone. Peripheral leukocytes and neutrophils were significantly increased in response to exercise in both the untreated and the ICS-treated conditions and at baseline after ICS treatment. Interleukin-6 was elevated with ICS treatment, but the exercise response was blunted. Circulating median fluticasone levels were 0.15 ng·mL(-1) and were increased to 0.20 ng·mL(-1) in response to exercise.ConclusionsExercise revealed deficits in growth hormone production after ICS treatment not identified by static markers. Neutrophils were shown to be surrogate markers of the systemic effect of ICS. Exercise significantly increased circulating levels of fluticasone. Exercise challenge tests can be used to assess the physiological effect of exogenous corticosteroids.

Exercise leads to a rapid change in the profile of gene expression in circulating neutrophils. MicroRNAs (miRNAs) have been discovered to play important roles in immune function and often act to attenuate or silence gene translation. We hypothesized that miRNA expression in circulating neutrophils would be affected by brief exercise. Eleven healthy men (19-30 yr old) performed 10, 2-min bouts of cycle ergometer exercise interspersed with 1-min rest at a constant work equivalent to approximately 76% of maximal oxygen uptake (Vo(2 max)). We used the Agilent Human miRNA V2 Microarray. A conservative statistical approach was used to determine that exercise significantly altered 38 miRNAs (20 had lower expression). Using RT-PCR, we verified the expression level changes from before to after exercise of seven miRNAs. In silico analysis showed that collectively 36 miRNAs potentially targeted 4,724 genes (2 of the miRNAs had no apparent gene targets). Moreover, when we compared the gene expression changes (n = 458) in neutrophils that have been altered by exercise, as previously reported, with the miRNAs altered by exercise, we identified three pathways, Ubiquitin-mediated proteolysis, Jak-STAT signaling pathway, and Hedgehog signaling pathway, in which an interaction of miRNA and gene expression was plausible. Each of these pathways is known to play a role in key mechanisms of inflammation. Brief exercise alters miRNA profile in circulating neutrophils in humans. These data support the hypothesis that exercise-associated changes in neutrophil miRNA expression play a role in neutrophil gene expression in response to physical activity.

We evaluated the effect of cold ice-pack application following a brief sprint-interval training on the balance between anabolic mediators [growth hormone (GH), insulin-like growth factor-I (IGF-I), testosterone], catabolic markers (cortisol, IGFBP-1), and circulating pro [Interlukin-6 (IL-6) and IL-1β]- and anti-inflammatory cytokines [IL-1 receptor antagonist (IL-1ra)]. Twelve males, elite junior handball players performed 4 × 250 m treadmill run, at 80% of each individual’s maximal speed, followed by a rest period with and without local cold-pack application. Pre, immediately post, and 60-min post-exercise blood samples were drawn. Exercise was associated with a significant increase in IL-6, GH, IGFBP-3, and testosterone levels. Local cold-pack application was associated with significant decreases in IL-1β, IL-1ra, IGF-I, and IGFBP-3 and a greater increase of IGFBP-1 during recovery. Local ice therapy immediately following sprint-interval training was associated with greater decreases in both pro- and anti-inflammatory cytokines and anabolic hormones supporting some clinical evidence for possible negative effects on athletic performance.

ObjectiveWhether or not individuals with allergy and asthma experience different patterns of change in the balance of both pro- and anti-inflammatory mediators with acute exercise is not known. We hypothesized that adolescent swimmers with a clinical diagnosis of respiratory allergy would have an exaggerated proinflammatory response to laboratory exercise relative to a no-allergy comparison group.MethodsAdolescent swimmers (17 with clinical symptoms of respiratory allergy (CSRA) and 17 in comparison group) completed the American Thoracic Society (ATS) exercise challenge on cycle ergometer. Blood was collected at baseline and immediately post-exercise. All study tests were conducted at the Institute for Clinical Translational Science at the University of California, Irvine. Circulating cytokines, growth factors, and adhesion molecules were measured using ELISAs including transforming growth factor-β1 (TGF-β1), tumor necrosis factor-α (TNF-α), interleukin-4 (IL-4), IL-6, IL-10, P-selectin, and immunoglobulin E (IgE).ResultsThere was a trend toward higher resting levels of TNF-α in the CSRA group (P = 0.076). Exercise induced a significant increase in P-selectin and TGF-β1 in both groups. TNF-α increased significantly (17%) in the comparison group (pre = 0.6, post = 0.7 pg/mL), but not in the CSRA group. IL-6 increased significantly in the CSRA group (pre = 0.7, post = 0.8 pg/mL), but not in the comparison group. Circulating levels of IL-4 and IL-10 were not altered immediately post-exercise in either group.ConclusionsA short bout of intense exercise increased inflammatory growth factors and adhesion molecules, namely TGF-β1 and P-selectin, both of which are known to be involved in allergic airway diseases. Differences in resting IL-6 and TNF-α and exercise alterations in these cytokines may also contribute to allergic disease in adolescent elite swimmers.

Brief high intensity exercise induces peripheral leukocytosis possibly leading to a higher incidence of allergic symptoms in athletes undergoing excessive training. We studied the exercise-induced alternation of circulating Tregs and FoxP3+ Tregs due to acute intense swim exercise in elite swimmers (n = 22, 12 males, age = 15.4 yrs). Twelve had prior or current rhinitis or asthma and 10 had no current or prior allergy or asthma. Circulating Tregs increased significantly (p < .001) following exercise (pre = 133 +/- 11.2, post = 196 +/- 17.6) as did FoxP3+ cells (pre = 44, post = 64 cells/microl). Increases in Tregs and FoxP3+ Tregs occurred to the same extent in both groups of adolescent swimmers.

The effect of a single exercise as well as exercise training on the growth hormone (GH)-insulin-like growth factor (IGF-I) axis and inflammatory cytokines was studied mainly in adults participating in individualized endurance-type sports. The gender-specific effect of exercise on these systems in adolescents is unknown. Therefore, the purpose of this study was to evaluate the effect of a typical volleyball practice on anabolic (GH, IGF-I, and testosterone) and catabolic hormones (cortisol) and inflammatory mediators (interleukin-6 [IL-6]) in elite, national team level, male (n = 14) and female (n = 13) adolescent volleyball players (13-18 years, Tanner stage 4-5). Exercise consisted of a typical 1-hour volleyball practice. Blood samples were collected before and immediately after the practice. Exercise led to significant increases in GH (0.2 +/- 0.1 to 2.7 +/- 0.7 and 1.7 +/- 0.5 to 6.4 +/- 1.4 ng x mL, in men and women, respectively, p < 0.05 for both), testosterone (6.1 +/- 0.9 to 7.3 +/- 1.0 and 2.4 +/- 0.6 to 3.3 +/- 0.7 ng x mL, in men and women, respectively, p < 0.05 for both), and IL-6 (1.1 +/- 0.6 to 3.1 +/- 1.5 and 1.2 +/- 0.5 to 2.5 +/- 1.1 pg x mL, in men and women, respectively, p < 0.002 for both). Exercise had no significant effect on IGF-I, insulin-like growth factor binding protein-3, and cortisol levels. There were no gender differences in the hormonal response to training. Changes in GH and testosterone after the volleyball practice suggest exercise-related anabolic adaptations. The increase in IL-6 may indicate its important role in muscle tissue repair. These changes may serve as an objective quantitative tool to monitor training intensity in unique occasions in team sports.

Recent studies show that brief exercise alters circulating neutrophil and peripheral blood mononuclear cell (PBMC) gene expression, ranging from cell growth to both pro-and anti-inflammatory processes. These initial observations were made solely in males, but whether PBMC gene expression is altered by exercise in females is not known. Ten early-pubertal girls (8-11 yr old) and 10 late-pubertal girls (15-17 yr old) performed ten 2-min bouts of cycle ergometry ( approximately 90% peak heart rate) interspersed with 1-min rest intervals. Blood was obtained at rest and after exercise, and microarrays were performed in each individual subject. RNA was hybridized to Affymetrix U133+2.0 Arrays. Exercise induced significant changes in PBMC gene expression in early (1,320 genes)- and late (877 genes)-pubertal girls. The expression of 622 genes changed similarly in both groups. Exercise influenced a variety of established gene pathways (EASE < 0.04) in both older (6 pathways) and younger girls (11 pathways). Five pathways were the same in both groups and were functionally related to inflammation, stress, and apoptosis, such as natural killer cell-mediated cytotoxicity, antigen processing and presentation, B cell receptor signaling, and apoptosis. In summary, brief exercise alters PBMC gene expression in early- and late-pubertal girls. The pattern of change involves diverse genetic pathways, consistent with a global danger-type response, perhaps readying PBMCs for a range of physiological functions from inflammation to tissue repair that would be useful following a bout of physical activity.

BackgroundNoninvasive detection of innate immune function such as the accumulation of neutrophils remains a challenge in many areas of clinical medicine. We hypothesized that granulocytes could generate volatile organic compounds.MethodsTo begin to test this, we developed a bioreactor and analytical GC-MS system to accurately identify and quantify gases in trace concentrations (parts per billion) emitted solely from cell/media culture. A human promyelocytic leukemia cell line, HL60, frequently used to assess neutrophil function, was grown in serum-free medium.ResultsHL60 cells released acetaldehyde and hexanaldehyde in a time-dependent manner. The mean ± SD concentration of acetaldehyde in the headspace above the cultured cells following 4-, 24- and 48-h incubation was 157 ± 13 ppbv, 490 ± 99 ppbv, 698 ± 87 ppbv. For hexanaldehyde these values were 1 ± 0.3 ppbv, 8 ± 2 ppbv, and 11 ± 2 ppbv. In addition, our experimental system permitted us to identify confounding trace gas contaminants such as styrene.ConclusionThis study demonstrates that human immune cells known to mimic the function of innate immune cells, like neutrophils, produce volatile gases that can be measured in vitro in trace amounts.

Peripheral blood mononuclear cells (PBMCs) are stimulated by exercise and contribute not only to host defense, but also to growth, repair, and disease pathogenesis. Whether PBMC gene expression is altered by exercise in children is not known. Ten early pubertal boys (8-12 y) and 10 late pubertal boys (15-18 y) performed ten 2-min bouts of strenuous, constant work rate exercise with 1-min rest intervals. PBMCs were isolated before and after exercise and microarray (Affymetrix U133 + 2 chips) analyzed. Statistical criterion to identify gene expression changes was less than 5% false discovery rate (FDR) with 95% confidence interval. One thousand two hundred forty-six genes were altered in older boys (517 up, 729 down), but only 109 were altered in the younger group (79 up, 30 down). In older boys, 13 gene pathways (using Expression Analysis Systematic Explorer, p < 0.05) were found (e.g. natural killer cell cytotoxicity, apoptosis). Epiregulin gene expression (EREG, a growth factor involved in wound healing) increased in older boys. In older boys exercise altered genes such as TBX21, GZMA, PGTDR, and CCL5 also play roles in pediatric inflammatory diseases like asthma. Sixty-six genes were changed significantly in both groups. The pattern of PBMC gene expression suggests the initiation of an immunologic "danger" signal associated with a sudden change in energy expenditure.

Exercise training efficiency depends on the intensity, volume, duration, and frequency of training, as well as on the athlete's ability to tolerate it. Recent efforts to quantify the effects of aerobic exercise training on hormonal response have suggested that exercise leads to simultaneous changes of antagonistic mediators. The effects of anaerobic exercise on these mediators are not known. Therefore, the aim of the present study was to evaluate the effects of a brief sprint interval session on the balance between anabolic (growth hormone [GH]--> insulin-like growth factor [IGF]-I axis) and catabolic hormones (cortisol), and circulating inflammatory cytokines such as interleukin (IL)-6. Twelve healthy elite junior handball players (17-20 years) participated in the study. Exercise consisted of a 4 x 250-m run on a treadmill, at a constant intensity of 80% of the personal maximal speed. Each run was separated by 3 minutes of rest. Blood samples were collected before, immediately after each 250-m run, and 1 hour after the last run. Exercise led to significant increases in GH (0.3 +/- 0.2 to 5.1 +/- 2.2 ngxml, p < 0.05), IGF binding protein (IGFBP)-3 (4191 +/- 2.48 to 4875 +/- 301 ngxml, p < 0.05), IL-6 (1.3 +/- 0.2 to 2.1 +/- 0.3 pgxml, p < 0.002), testosterone, and testosterone/cortisol ratio, and to a significant decrease in IGFBP-1 levels. Levels of IL-6 remained elevated 1 hour after the end of exercise. Exercise had no significant effects on IGF-I and cortisol levels. Changes in the GH-IGF-I axis and testosterone/cortisol ratio after the brief sprint interval exercise suggested exercise-related anabolic adaptations. The increase in IL-6 may indicate its important role in muscle tissue repair after anaerobic exercise. Changes in the anabolic-catabolic hormonal balance and in inflammatory mediators can be used as an objective tool to gauge the training intensity of different types of anaerobic exercises and training periods.

ObjectiveTo compare ratings of perceived exertion (RPEs) during aerobic exercise in people with multiple sclerosis (MS) and control participants.DesignProspective experimental study.SettingAn exercise testing laboratory.ParticipantsSedentary adults (n=12) with mild MS (Expanded Disability Status Scale score < or = 3) aged 30 to 45 years and sedentary age-matched and sex-matched controls (n=12).InterventionsAll participants underwent a graded aerobic exercise test on a cycle ergometer with breath-by-breath gas measurements and continuous heart rate monitoring.Main outcome measuresAfter completing the Modified Fatigue Impact Scale, participants rated their effort sense every 30 seconds during exercise using the modified Borg 10-point scale.ResultsThe 2 study groups showed similar baseline characteristics except for higher fatigue scores in the MS group. There were no significant differences for any fitness measure, including oxygen cost slope (in VO(2) x min(-1) x W(-1)), VO(2), or work rate during exercise. Neither heart rate nor RPE--measured at 25%, 50%, 75%, and 100% of VO(2)peak--differed between groups.ConclusionsDespite greater reported fatigue levels, participants with MS showed similar RPE and physiologic responses to submaximal and maximal exercise compared with controls. In MS, the Borg 10-point scale may help improve evidence-based exercise prescriptions, which otherwise may be limited by fatigue, motor impairment, heat sensitivity, or autonomic dysfunction.

Relatively brief bouts of exercise alter gene expression in peripheral blood mononuclear cells (PBMCs), but whether exercise changes gene expression in circulating neutrophils (whose numbers, like PBMCs, increase) is not known. We hypothesized that exercise would activate neutrophil genes involved in apoptosis, inflammation, and cell growth and repair, since these functions in leukocytes are known to be influenced by exercise. Blood was sampled before and immediately after 30 min of constant, heavy ( approximately 80% peak O(2) uptake) cycle ergometer exercise in 12 healthy men (19-29 yr old) of average fitness. Neutrophils were isolated using density gradients; RNA was hybridized to Affymetrix U133+2 Genechip arrays. With false discovery rate (FDR)

Exercise affects t-cell cytokine production. Whether or not these effects are caused by circulating factors associated with physical activity (e.g., inflammatory mediators, acidosis) is unknown. To investigate this, we incubated sera (10%), obtained from 16 young-adults before (PRE) and after (END) 30-min of exercise, with commercially available Jurkat cells, a t-lymphocyte model, that, of course, had never been exposed to an exercise milieu. After 1 and 6h in culture, we measured in the supernatant four cytokines (each known to be altered by exercise and involved in disease pathophysiology): IL-2, TGF-beta1, TNF-alpha, and IL-1ra. Cell proliferation was assessed with proliferating nuclear cell antigen (PNCA). Statistical analysis consisted of a linear mixed model for repeated measurement. There was no effect of exercise on t-cell production of either TGF-beta1 or IL-1ra. In contrast, both IL-2 (p=0.025) and TNF-alpha (p=0.031) production was significantly suppressed in sera from the exercising participants. The suppression of these two cytokines occurred despite the fact that PNCA significantly increased (p=0.0004) in the END serum. In conclusion, exercise alters circulating factors that can, subsequently, influence t-cell cytokine production in vitro.