The Canadian Women's Heart Health Alliance Atlas on the Epidemiology, Diagnosis, and Management of Cardiovascular Disease in Women - Chapter 6: Sex- and Gender-Specific Diagnosis and Treatment.

This chapter summarizes the sex- and gender-specific diagnosis and treatment of acute/unstable presentations and nacute/stable presentations of cardiovascular disease in women. Guidelines, scientific statements, systematic reviews/meta-analyses, and primary research studies related to diagnosis and treatment of coronary artery disease, cerebrovascular disease (stroke), valvular heart disease, and heart failure in women were reviewed. The evidence is summarized as a narrative, and when available, sex- and gender-specific practice and research recommendations are provided. Acute coronary syndrome presentations and emergency department delays are different in women than they are in men. Coronary angiography remains the gold-standard test for diagnosis of obstructive coronary artery disease. Other diagnostic imaging modalities for ischemic heart disease detection (eg, positron emission tomography, echocardiography, single-photon emission computed tomography, cardiovascular magnetic resonance, coronary computed tomography angiography) have been shown to be useful in women, with their selection dependent upon both the goal of the individualized assessment and the testing resources available. Noncontrast computed tomography and computed tomography angiography are used to diagnose stroke in women. Although sex-specific differences appear to exist in the efficacy of standard treatments for diverse presentations of acute coronary syndrome, many cardiovascular drugs and interventions tested in clinical trials were not powered to detect sex-specific differences, and knowledge gaps remain. Similarly, although knowledge is evolving about sex-specific difference in the management of valvular heart disease, and heart failure with both reduced and preserved ejection fraction, current guidelines are lacking in sex-specific recommendations, and more research is needed.

Ce chapitre présente un résumé sur le diagnostic et le traitement des tableaux cliniques aigus/instables et non aigus/stables des maladies cardiovasculaires chez les femmes, et les différences propres à chacun des deux sexes. Les lignes directrices, les énoncés scientifiques, les revues systématiques/méta-analyses et les études de recherche originale sur le diagnostic et le traitement des coronaropathies, des maladies vasculaires cérébrales (AVC), des valvulopathies cardiaques et de l'insuffisance cardiaque chez les femmes ont été examinés. Les données probantes sont résumées sous forme narrative et, lorsqu'elles sont disponibles, des recommandations en matière de pratique et de recherche pour chacun des deux sexes sont présentées. Les tableaux cliniques du syndrome coronarien aigu et les délais d'attente à l'urgence sont différents selon qu'une femme ou un homme en est atteint. L'angiographie coronarienne reste l'examen de référence pour le diagnostic des coronaropathies obstructives. D'autres examens d'imagerie diagnostique (p. ex. la tomographie par émission de positons, l'échocardiographie, la tomographie d'émission à photon unique, la résonance magnétique cardiovasculaire, l'angiographie coronarienne par tomodensitométrie) se sont avérés utiles pour la détection des cardiopathies ischémiques chez les femmes. Le recours à ces modalités dépend de l'objectif de l'évaluation personnalisée et des ressources disponibles. La tomodensitométrie sans agent de contraste et l'angiographie par tomodensitométrie sont utilisées pour le diagnostic des AVC chez les femmes. Malgré les différences entre les sexes quant à l'efficacité des traitements de référence des divers tableaux cliniques du syndrome coronarien aigu, bon nombre des médicaments et des interventions cardiovasculaires qui ont fait l'objet d'essais cliniques n'avaient pas la puissance statistique nécessaire pour détecter des différences selon les sexes, de sorte que les connaissances restent fragmentaires sur ce sujet. De même, malgré l'évolution des connaissances sur les différences sexuelles quant à la prise en charge des valvulopathies cardiaques et de l'insuffisance cardiaque avec fraction d'éjection réduite ou préservée, on ne trouve pas de recommandations pour chaque sexe dans les lignes directrices actuelles, d'où la pertinence d'études supplémentaires portant sur cette question.

The Canadian Women's Heart Health Alliance Atlas on the Epidemiology, Diagnosis, and Management of Cardiovascular Disease in Women-Chapter 3: Patient Perspectives.

In recent years, public awareness campaigns have targeted knowledge gaps and inequities in care while focusing on the unique female experience and heightened cardiovascular disease (CVD) risk profile. Recognizing and understanding the sex and gender constructs, barriers, facilitators, and factors that affect access, treatment, and recovery after an acute cardiac event from the unique patient perspective is a key step in transforming clinical practice and care patterns. The aim of this atlas chapter is to provide a knowledge review and to identify gaps regarding the experience of living with CVD from the perspective of the female survivor. The sections are as follows: (1) experiencing and living with CVD as a woman; (2) "stopped at the gate": barriers to accessing acute cardiovascular care; and (3) action items to "open the gate" to women: what our patients want and need. The final section culminates with targeted recommendations stemming from recent literature and most importantly, from women with the lived experience of CVD.

Depuis quelques années, des campagnes de sensibilisation du public ciblent les lacunes dans les connaissances et les iniquités en matière de soins, notamment l'expérience unique que vivent les femmes et leur profil de risque de maladie cardiovasculaire (MCV) accru. Pour transformer la pratique clinique et les modèles de soins, il est crucial de reconnaître et de comprendre les conceptions relatives au sexe et au genre, les obstacles, les éléments facilitateurs ainsi que les facteurs qui influent sur l'accès aux soins, le traitement et le rétablissement après une manifestation cardiaque aiguë, du point de vue unique des patientes. Ce nouveau chapitre de l'atlas dresse un bilan des connaissances et cerne les lacunes quant à l'expérience des femmes qui vivent avec une MCV, du point de vue de survivantes. Les thèmes suivants y sont abordés : 1) vivre avec une MCV quand on est une femme; 2) « arrêtées à la porte ¼ : les obstacles à l'accès aux soins cardiovasculaires aigus; et 3) les mesures à prendre pour « ouvrir la porte ¼ aux femmes : souhaits et besoins des patientes. Dans la dernière section sont formulées des recommandations ciblées fondées sur des données publiées récemment et, ce qui est encore plus important, sur les commentaires de femmes qui vivent avec une MCV.

The Avoiding Diabetes After Pregnancy Trial in Moms Program: Feasibility of a Diabetes Prevention Program for Women With Recent Gestational Diabetes Mellitus.

OBJECTIVE: Our aim in this study was to evaluate the feasibility of a home-based diabetes prevention program, delivered by interdisciplinary certified diabetes educators (CDEs), and customized for postpartum women with recent gestational diabetes mellitus (GDM). METHODS: This pilot randomized trial recruited women with GDM from 24 to 40 weeks gestation from 4 centres, and trained 10 CDEs in behaviour coaching, physical activity (PA) and low glycemic index education. Women were randomized after 3 months postpartum to standard care (1 visit) or 1 of 3 24-week coaching interventions (1 visit and 12 telephone calls): i) PA and diet, ii) PA only or iii) diet only. Feasibility outcomes included recruitment, retention, adherence and satisfaction. RESULTS: Of 1,342 eligible patients, 392 were actively invited (29.3%) and 227 (16.9%) consented. Of these, 149 (65.6%) were randomized postpartum, of whom 131 (87.9%) started the program and 105 (70.5%) attended the final assessment. Intervention arm participants completed a median 75% (interquartile range, 50% to 92%) of telephone calls. Visit and call duration were a mean 71.4 (standard deviation, 13.8) and 18.1 (standard deviation, 6.5) minutes, respectively. Participants reported excellent/very good satisfaction 73% of the time, and 87% would recommend the program to others. CONCLUSIONS: A home-based diabetes prevention program customized for postpartum women with GDM can be feasibly delivered by CDEs, and it is associated with >70% retention, adherence and satisfaction.

Determinants of health care utilisation: the case of Timor-Leste.

Background: Health financing and delivery reforms designed to achieve universal health coverage (UHC) need to be informed by an understanding of factors that both promote access to health care and undermine it. This study examines the level of health care utilisation in Timor-Leste and the factors that drive it. Methods: Data from a nationally representative cross-sectional survey of health care utilisation in 1712 households were used to develop multilevel models exploring how need and predisposing and enabling factors explain health care utilisation at both primary and secondary care facilities. Results: Need was found to be the key driver in seeking both primary care and hospital services. Rural households were less likely to go to hospital (odds ratio 0.7) than urban households. The poorest quintile was also less likely to use more expensive hospital services than other socio-economic groups. Conclusions: Understanding the determinants of seeking health care in Timor-Leste is of considerable policy significance, because health care is free at the point of use. Our findings indicate that the public resources for health care are subsidising the rich more than the poor. Health care reforms in Timor-Leste need to reduce the 'other' costs of health care, such as distance barriers, to address these inequities.

Gender matters in cardiac rehabilitation and diabetes: Using Bourdieu's concepts.

BACKGROUND: Habitual practices are challenged by chronic illness. Cardiac rehabilitation (CR) involves changes to habits of diet, activity and tobacco use, and although it is effective for people with diabetes and cardiovascular disease (CVD), some participants are reportedly less likely to complete programs and adopt new health related practices. Within the first three months of enrolling in CR, attrition rates are highest for women and for people with diabetes. Previous studies and reviews indicate that altering habits is very difficult, and the social significance of such change requires further study. PURPOSE: The purpose of the study was to use Bourdieu's concepts of habitus, capital and field to analyse the complexities of adopting new health practices within the first three months after enrolling in a CR program. We were particularly interested in gender issues. METHODS: Thirty-two men and women with diabetes and CVD were each interviewed twice within the first three months of their enrolment in one of three CR programs in Toronto, Canada. RESULTS: Attention to CR goals was not always the primary consideration for study participants. Instead, a central concern was to restore social dignity within other fields of activity, including family, friendships, and employment. Thus, study participants evolved improvised tactical approaches that combined both physical and social rehabilitation. These improvised tactics were socially embedded and blended new cultural capital with existing (often gendered) cultural capital and included: concealment, mobilizing cooperation, re-positioning, and push-back. CONCLUSIONS: Our findings suggest that success in CR requires certain baseline levels of capital - including embodied, often gendered, cultural capital - and that efforts to follow CR recommendations may alter social positioning.

"I go I die, I stay I die, better to stay and die in my house": understanding the barriers to accessing health care in Timor-Leste.

BACKGROUND: Despite public health care being free at the point of delivery in Timor-Leste, wealthier patients access hospital care at nearly twice the rate of poorer patients. This study seeks to understand the barriers driving inequitable utilisation of hospital services in Timor-Leste from the perspective of community members and health care managers. METHODS: This multisite qualitative study in Timor-Leste conducted gender segregated focus groups (n = 8) in eight districts, with 59 adults in urban and rural settings, and in-depth interviews (n = 8) with the Director of community health centres. Communication was in the local language, Tetum, using a pre-tested interview schedule. Approval was obtained from community and national stakeholders, with written consent from participants. RESULTS: Lack of patient transport is the critical cross-cutting issue preventing access to hospital care. Without it, many communities resort to carrying patients by porters or on horseback, walking or paying for (unaffordable) private arrangements to reach hospital, or opt for home-based care. Other significant out-of-pocket expenses for hospital visits were blood supplies from private suppliers; accommodation and food for the patient and family members; and repatriation of the deceased. Entrenched nepotism and hospital staff denigrating patients' hygiene and personal circumstances were also widely reported. Consequently, some respondents asserted they would never return to hospital, others delayed seeking treatment or interrupted their treatment to return home. Most considered traditional medicine provided an affordable, accessible and acceptable substitute to hospital care. Obtaining a referral for higher level care was not a significant barrier to gaining access to hospital care. CONCLUSIONS: Onerous physical, financial and socio-cultural barriers are preventing or discouraging people from accessing hospital care in Timor-Leste. Improving access to quality primary health care at the frontline is a key strategy for ensuring universal access to health care, pursued alongside initiatives to overcome the multi-faceted barriers to hospital care experienced by the vulnerable. Improving the availability and functioning of patient transport services, provision of travel subsidies to patients and their families and training hospital staff in standards of professional care are some options available to government and donors seeking faster progress towards universal health coverage in Timor-Leste.

How to do (or not to do) translation of national health accounts data to evidence for policy making in a low resourced setting.

For more than a decade, the Organization for Economic Co-operation and Development (OECD), the World Health Organization (WHO) and the World Bank have promoted the international standardization of National Health Accounts (NHA) for reporting global statistics on public, private and donor health expenditure and improve the quality of evidence-based decision-making at country level. A 2010-2012 World Bank review of NHA activity in 50 countries found structural and technical constraints (rather than cost) were key impediments to institutionalizing NHA in many low- and middle-income countries (LMICs). Pilot projects focused resources on data production, neglecting longer-term capacity building for analysing the data, developing ownership among local stakeholders and establishing routine production, utilization and dissemination of NHA data. Hence, genuine institutionalization of NHA in most LMICs has been slow to materialize. International manuals focus on the production of NHA data and do not include practical, incremental and low-cost strategies to guide countries in translating the data into evidence for policy-making. The main aim of this article is to recommend strategies for bridging this divide between production and utilization of NHA data in low-resource settings. The article begins by discussing the origins and purpose of NHA, including factors currently undermining their uptake. The focus then turns to the development and application of strategies to assist LMICs in 'unlocking' the hidden value of their NHA. The article draws on the example of Fiji, a country currently attempting to integrate their NHA data into policy formulation, despite minimal resources, training and familiarity with economic analysis of health systems. Simple, low cost recommendations such as embedding health finance indicators in planning documents, a user-friendly NHA guide for evaluating local health priorities, and sharing NHA data for collaborative research have helped translate NHA from raw data to evidence for policymaking.

MicroRNA expression in mice infected with seasonal H1N1, swine H1N1 or highly pathogenic H5N1.

Influenza virus infections in humans remain a healthcare concern, and the need for vaccines, therapeutics and prophylactics remains a high priority. Understanding the molecular events associated with influenza-virus-induced pathology may lead to the identification of clinical disease biomarkers and novel antiviral targets. MicroRNAs (miRNAs) are well-conserved endogenous non-coding RNAs known to regulate post-transcriptional gene expression as well as play a major role in many biological processes and pathways. Animal studies have demonstrated that miRNAs are involved in viral disease and controlling inflammation. In this study, we examined the differences in the miRNA expression profiles associated with the lung in mice infected with influenza viruses that varied in virulence and pathogenicity. A statistical model was employed that utilized changes in miRNA expression to identify the virus that was used to infect the mice. This study identified a unique fingerprint of viral pathogenicity associated with seasonal H1N1, swine H1N1 and highly pathogenic H5N1 in the mouse model, and may lead to the identification of novel therapeutic and prophylactic targets.

Cardiac rehabilitation and the therapeutic environment: the importance of physical, social, and symbolic safety for programme participation among women.

AIM: To report an exploration of the multidimensionality of safety in cardiac rehabilitation programmes as perceived by women who were enrolled in the Women's Cardiovascular Health Initiative in Toronto, Canada. BACKGROUND: Cardiovascular disease is the leading cause of death among women. Although cardiac rehabilitation is clinically effective, significantly fewer women than men participate in available programmes. The literature identifies factors affecting women's cardiac rehabilitation participation, and provides possible explanations for this gender disparity. Although safety is mentioned among the barriers to women's cardiac rehabilitation participation, the extent to which safety contributes to programme participation, completion, and maintenance remains under-explored in the cardiac rehabilitation literature. DESIGN: We conducted an exploratory qualitative study to examine the role safety and place play for women engaged in cardiac prevention and rehabilitation at the Women's Cardiovascular Health Initiative. Methods. From 2005-2006, 14 participants engaged in semi-structured, qualitative interviews lasting 30-90 minutes. Discussions addressed women's experiences at the Women's Cardiovascular Health Initiative. Interview transcripts were analysed using thematic analysis. FINDINGS: Three themes were developed: 'Safety', which was sub-categorized according to physical, social, and symbolic interpretations of safety, 'searching for a sense of place', and 'confidence and empowerment'. CONCLUSION: Feeling physically, socially, and symbolically safe in one's cardiac rehabilitation environment may contribute to programme adherence and exercise maintenance for women. Focusing on comprehensive notions of safety in future cardiac rehabilitation research could offer insight into why many women do not maintain an exercise regimen in currently structured cardiac rehabilitation and community programmes.

Toxicogenomic analysis of chlorine vapor-induced porcine skin injury.

Chlorine is an industrial chemical that can cause cutaneous burns. Understanding the molecular mechanisms of tissue damage and wound healing is important for the selection and development of an effective post-exposure treatment. This study investigated the effect of cutaneous chlorine vapor exposure using a weanling swine burn model and microarray analysis. Ventral abdominal sites were exposed to a mean calculated chlorine vapor concentration of 2.9 g/L for 30 min. Skin samples were harvested at 1.5 h, 3 h, 6 h, and 24 h post-exposure and stored in RNAlater(®) until processing. Total RNA was isolated, processed, and hybridized to Affymetrix GeneChip(®) Porcine Genome Arrays. Differences in gene expression were observed with respect to sampling time. Ingenuity Pathways Analysis revealed seven common biological functions among the top ten functions of each time point, while canonical pathway analysis revealed 3 genes (IL-6, IL1A, and IL1B) were commonly shared among three significantly altered signaling pathways. The transcripts encoding all three genes were identified as common potential therapeutic targets for Phase II/III clinical trial, or FDA-approved drugs. The present study shows transcriptional profiling of cutaneous wounds induced by chlorine exposure identified potential targets for developing therapeutics against chlorine-induced skin injury.

Preliminary microRNA analysis in lung tissue to identify potential therapeutic targets against H5N1 infection.

Within the past decade, human infections with the highly pathogenic avian influenza H5N1 have resulted in approximately 60% mortality and increased the need for vaccines and therapeutics. Understanding the molecular events associated with pathology can aid this effort; therefore, this study was conducted to assess microRNA (miRNA) expression in mouse lungs infected with H5N1 A/Vietnam/1203/04. Intranasal administration of 1500 median tissue culture infectious dose of H5N1 promoted differences in the number and expression pattern of miRNA from lung tissue collected at 2, 4, 6, 24, and 96 h post-exposure that mapped to common biological functions. Informatics analysis identified miRNA-specific predicted genes known to be therapeutic drug targets in which Furin was common to all time periods. This study provides insight into the differential miRNA expression with respect to the host-pathogen relationship and identification of potential therapeutic drug targets.

An assessment of transcriptional changes in porcine skin exposed to bromine vapor.

Bromine is an industrial chemical that can cause severe cutaneous burns. This study was a preliminary investigation into the effect of cutaneous exposure to bromine vapor using a weanling swine burn model and microarray analysis. Ventral abdominal sites were exposed to a mean calculated bromine vapor concentration of 0.69 g L(-1) for 10 or 20 min. At 48 h postexposure, total RNA from skin samples was isolated, processed, and hybridized to Affymetrix GeneChip Porcine Genome Arrays. Expression analysis revealed that bromine vapor exposure for 10 or 20 min promoted similar transcriptional changes in the number of significantly modulated probe sets. A minimum of 83% of the probe sets was similar for both exposure times. Ingenuity pathways analysis revealed eight common biological functions among the top 10 functions of each experimental group, in which 30 genes were commonly shared among 19 significantly altered signaling pathways. Transcripts encoding heme oxygenase 1, interleukin-1ß, interleukin 2 receptor gamma chain, and plasminogen activator inhibitor-1 were identified as common potential therapeutic targets for Phase II/III clinical trial or FDA-approved drugs. The present study is an initial assessment of the transcriptional responses to cutaneous bromine vapor exposure identifying molecular networks and genes that could serve as targets for developing therapeutics for bromine-induced skin injury.

Temporal effects in porcine skin following bromine vapor exposure.

Bromine is an industrial chemical that causes severe cutaneous burns. When selecting or developing effective treatments for bromine burns, it is important to understand the molecular mechanisms of tissue damage and wound healing. This study investigated the effect of cutaneous bromine vapor exposure on gene expression using a weanling swine burn model by microarray analysis. Ventral abdominal sites were exposed to a mean calculated bromine vapor concentration of 0.51 g/L for 7 or 17 min. At 6 h, 48 h, and 7 days post-exposure, total RNA from skin samples was isolated, processed, and analyzed with Affymetrix GeneChip® Porcine Genome Arrays (N = 3 per experimental group). Differences in gene expression were observed with respect to exposure duration and sampling time. Ingenuity Pathways Analysis (IPA) revealed four common biological functions (cancer, cellular movement, cell-to-cell signaling and interaction, and tissue development) among the top ten functions of each experimental group, while canonical pathway analysis revealed 9 genes (ARG2, CCR1, HMOX1, ATF2, IL-8, TIMP1, ESR1, HSPAIL, and SELE) that were commonly shared among four significantly altered signaling pathways. Among these, the transcripts encoding HMOX1 and ESR1 were identified using IPA as common potential therapeutic targets for Phase II/III clinical trial or FDA-approved drugs. The present study describes the transcriptional responses to cutaneous bromine vapor exposure identifying molecular networks and genes that could serve as targets for developing therapeutics for bromine-induced skin injury.

Women's experiences accessing a women-centered cardiac rehabilitation program: a qualitative study.

BACKGROUND AND RESEARCH OBJECTIVE: The health benefits of cardiac rehabilitation (CR) for women living with heart disease are well documented, yet women remain underrepresented in traditionally structured CR programs. This health service delivery gap has been attributed to a number of sex-related factors experienced by women, including lower rates of physician referral, travel-related barriers, competing work and caregiving responsibilities, greater cardiovascular disease severity, and number of comorbid health conditions. Whether a program specifically designed for women is able to address these barriers and facilitate women's participation is a question that has seldom been explored in the CR literature. As part of a larger study exploring whether 6 predefined principles of women's health (empowerment of women, accessible programs, broad definition of health care, high-quality of care, collaborative planning, and innovative and creative approaches) are reflected in the practices of the Women's Cardiovascular Health Initiative (WCHI) (a comprehensive CR and primary prevention program designed for women), the objective of this analysis was to explore how the principle of "accessible programs" is experienced by women participating in the WCHI. PARTICIPANTS AND METHOD: Fourteen women previously enrolled in the WCHI program participated in a single, in-person qualitative interview. Transcripts were analyzed using a constant-comparative approach to identify relevant themes related to program accessibility. RESULTS: Key themes identified included participants' experiences with acquiring physician referral, negotiating transportation issues, and navigating program schedules. Women discussed how peer support and staff members' willingness to address their health-related concerns facilitated their participation. CONCLUSION: While a women-centered CR/primary prevention program may facilitate and encourage women's participation by providing flexible program schedules as well as peer and professional support, efforts are still required to address persistent barriers for women related to physician referral and transportation to programs.

A review of transcriptomics in cutaneous chemical exposure.

Monitoring gene expression profiles in the skin using microarrays has become a useful approach to enhance the understanding of dermal function, toxicologic mechanisms, and risk assessment. With respect to cutaneous chemical exposure, there are few transcriptomic studies in the published literature, and these often differ in experimental design and availability of raw data. An assessment of multiple microarray data sets could be advantageous for identifying potential redundant biological mechanisms or genes associated with dermal responses to chemical exposure. As in vivo cutaneous chemical exposure models can vary, extrapolations from analyzing multiple cross-species microarray data sets could aid in identifying a general set of pathways or genes that could guide future study direction and evaluation of dermal toxicologic assessments and potential therapeutic intervention. This review provides a summary of studies in the open literature that utilize transcriptomics in assessing the molecular responses in chemical-exposed skin with an intent of determining whether biomarkers could be identified and the potential for future meta-analyses.

Transcriptional changes in porcine skin at 7 days following sulfur mustard and thermal burn injury.

Severe cutaneous injuries continue to result from exposure to sulfur mustard [bis(2-chloroethyl)sulfide; HD] and thermal burns. Microarray analysis was utilized in this study to evaluate transcriptional changes in porcine skin assessing the underlying repair mechanisms of HD and thermal injury involved in wound healing. Four ventral abdominal sites on each of 4 weanling swine were exposed to 400 microL undiluted HD or a heated brass rod (70 degrees C) for 8 minutes and 45-60 seconds, respectively. At 7 days postexposure, skin samples were excised and total RNA was isolated, labeled, and hybridized to Affymetrix GeneChip (Santa Clara, CA, USA) Porcine Genome Arrays (containing 20,201 genes). Based on the gene expression patterns in HD- and thermal-exposed skin at 7 days, the transcriptional profiles do not differ greatly. HD and thermal exposures promoted similar changes in transcription, where 270 and 283 transcripts were increased with HD and thermal exposures, respectively. Both exposures promoted decreases in 317 and 414 transcripts, respectively. Of the significantly increased transcripts, at least 77% were commonly expressed in both HD- and thermal-exposed skin, whereas at least 67% of decreased transcripts were common between both exposure types. Six of the top 10 biological functions were common to HD and thermal injury in which 9 canonical pathways were shared. The present study illustrates the similarities found between HD and thermal injury with respect to transcriptional response and wound healing and identifies specific genes (CXCL2, CXCR4, FGFR2, HMOX1, IGF1, PF4, PLAU, PLAUR, S100A8, SPP1, and TNC) that may be useful as potential therapeutic targets to promote improved wound healing.

Transcriptional responses associated with sulfur mustard and thermal burns in porcine skin.

In military and civilian environments, serious cutaneous damage can result from thermal burns or exposure to the blistering agent sulfur mustard [bis (2-chloroethyl) sulfide; HD]. Similar therapies have historically been used to treat cutaneous thermal and HD injuries; however, the underlying molecular mechanisms of tissue damage and wound healing may differ between the types of burns. Using microarray analysis, this study assessed the transcriptional responses to cutaneous HD and thermal injury at 48 hours post-exposure to identify molecular networks and genes associated with each type of skin injury. Ventral abdominal sites on each of 4 weanling swine were exposed to 400 mul of undiluted HD or a heated brass rod (70 degrees C) for 8 minutes and 45-60 seconds, respectively. At 48 hours post-exposure, total RNA was isolated from excised skin samples and hybridized to Affymetrix GeneChip Porcine Genome Arrays (containing 20,201 genes). Both HD and thermal exposure promoted significant transcriptional changes where 290 and 267 transcripts were increased and 197 and 707 transcripts were decreased with HD and thermal exposure, respectively. HD- and thermal-injured skin expressed 149 increased and 148 decreased common transcripts. Comparison of the 10 most significantly changed biological functions for HD and thermal exposures identified 7 overlapping functional groups. Canonical pathways analysis revealed 15 separate signaling pathways containing transcripts associated with both HD and thermal exposure. Within these pathways, 5 transcripts (CXCR4, FGFR2, HMOX1, IL1R1, and TLR4) were identified as known targets for existing phase II/III clinical trial or Food and Drug Administration (FDA)-approved drugs. This study is the first to directly assess transcriptional changes in porcine skin subjected to HD or thermal injury over the same time period.

Gene expression analysis of bromine-induced burns in porcine skin.

Bromine is an industrial chemical that is irritating to the skin and causes cutaneous burns. An important factor in selecting or developing an effective treatment is to understand the underlying molecular mechanisms of tissue damage and wound healing. This study used a weanling swine burn model and microarray analysis to evaluate the effect of exposure length and sampling times on the transcriptional changes in response to cutaneous bromine injury. Ventral abdominal sites (N=4/treatment group) were exposed to 600microL undiluted bromine for 45 s or 8 min. At 24 h and 7d post-exposure, total RNA from skin samples was isolated, processed, and hybridized to Affymetrix GeneChip Porcine Genome Arrays. Expression analysis revealed that bromine exposure duration appeared to have less effect on the transcript changes than the sampling time. The percent transcripts changed at 24h were similar (30%) whether having a 45 s or 8 min bromine exposure; percent transcripts changed at 7d were also similar (62%) regardless of exposure length. However, only 13-14% of the transcripts were similar when comparing samples analyzed at 24h and 7d. Ingenuity Pathways Analysis (IPA) revealed six common biological functions among the top 10 functions of each experimental group, while canonical pathway analysis revealed 11 genes that were commonly shared among 24 significantly altered signaling pathways. Additionally, there were 11 signaling pathways in which there were no commonly shared transcripts. The present study is an initial assessment of the transcriptional responses to cutaneous bromine exposure identifying molecular networks and genes that could serve as targets for developing therapeutics for bromine-induced skin injury.

Evaluation of Acute Immunotoxicity of Aerosolized Aflatoxin B(1) in Female C57BL/6N Mice.

There is evidence for immunotoxicity of aflatoxin B1 (AFB(1)) in chronic animal feeding studies; however, little information is available as to the effects of inhalation exposure. This study evaluated the acute affects of aerosolized AFB(1) on systemic immune function of female C57BL/6N mice following a single aerosol exposure. Mice were exposed in nose-only inhalation tubes to 0, 2.86, 6.59 and 10 mug AFB(1) aerosol/L air for 90 minutes. A negative control group of untreated mice and a positive control group of cyclophosphamide-treated mice were included to account for day to day variation. Three days following exposure, mice were sacrificed and body, liver, lung, thymus and spleen weights, and complete blood counts and white blood cell differentials were measured. Splenocytes were isolated for flow cytometric analysis of CD4(+) and CD8(+) lymphocytes, CD19(+) B-cells and natural killer cells (NK 1.1(+)). The effect of AFB(1) on humoral immunity was assessed by measuring serum anti-keyhole limpet hemocyanin (KLH) IgM levels. Of the tissues examined, only the thymus weight of AFB(1) exposed mice decreased significantly compared to naive mice; however, the decrease was not dose related and was also observed in the 0 AFB(1) aerosol control group. A decrease in the mean white blood cell count of treated vs. naive mice was observed at all dose levels but was clearly not dose related and was statistically significant only in the 0 and 2.86 mug/L groups. Red blood cell and platelet counts and white blood cell differentials were not significantly affected by AFB(1). The number of CD4(+) (helper T-cells), CD8(+) (cytotoxic T-cells) and CD19(+) (B-cells) decreased in spleens of AFB(1) aerosol exposed mice compared to naive mice; however, the decrease was not dose-related and was also observed in the 0 AFB(1) exposure group. Dose-related changes in the CD4(+)/CD8(+) T-lymphocyte ratios were not observed. The IgM response to KLH was not significantly different in AFB(1) compared to naive mice, suggesting that AFB(1) did not effect antigen-specific antibody production. Based on the results of this study, a single AFB(1) inhalation exposure up to 10 mug/L for 90 minutes (CxT = 900 mug .min/L) did not significantly alter the immune parameters measured in this study. The aerosol vehicle (ethanol) and/or stress could have masked subtle AFB(1)-dependent changes in thymus and spleen weights, and in splenic lymphocyte subpopulations. However, for other immunological parameters, such as the IgM response to KLH, there was clearly no significant effect of AFB(1) aerosol exposure.