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Obesity is linked to cognitive decline and metabolic dysregulation in the brain, yet the role of sex is relatively unexplored. We sought to explore the effects of obesity and sex on the brain metabolome. In male and female ob/ob and wild-type mice, we assessed whole brain untargeted metabolomics by liquid chromatography-mass spectrometry, behavior by open field test, and cognitive function by Y-maze and Morris water maze. The metabolic profiles of ob/ob and wild-type mice differed in both sexes. There were more obesity-altered brain metabolites in males than females. Thirty-nine metabolites were unique to males, 15 were unique to females, and five were common to both sexes. Two of the common metabolites were involved in nicotinamide adenine dinucleotide homeostasis. A key feature of the metabolites identified in males was an increase in free fatty acids. In females, a unique feature was the presence of the neuro-modulatory metabolites 2-linoleoyl glycerol and taurine. The behavioral effects of obesity were only seen in females. These results demonstrate that most impacts of obesity on the brain metabolomic profile are sex-specific. Our work has implications for understanding the role of obesity in brain metabolism and the differential contribution of obesity to cognitive decline in males and females.

Cardiovascular disease (CVD) is largely preventable, and the leading cause of death for men and women. Though women have increased life expectancy compared to men, there are marked sex disparities in prevalence and risk of CVD-associated mortality and dementia. Yet, the basis for these and female-male differences is not completely understood. It is increasingly recognized that heart and brain health represent a lifetime of exposures to shared risk factors (including obesity, hyperlipidemia, diabetes, and hypertension) that compromise cerebrovascular health. We describe the process and resources for establishing a new research Center for Women's Cardiovascular and Brain Health at the University of California, Davis as a model for: (1) use of the cy pres principle for funding science to improve health; (2) transdisciplinary collaboration to leapfrog progress in a convergence science approach that acknowledges and addresses social determinants of health; and (3) training the next generation of diverse researchers. This may serve as a blueprint for future Centers in academic health institutions, as the cy pres mechanism for funding research is a unique mechanism to leverage residual legal settlement funds to catalyze the pace of scientific discovery, maximize innovation, and promote health equity in addressing society's most vexing health problems.

Type 2 diabetes mellitus (T2DM) leads to the development of cardiovascular diseases, cognitive impairment, and dementia. There are sex differences in the presentation of T2DM and its associated complications. We sought to determine the impact of sex and T2DM on the brain metabolome to gain insights into the underlying mechanisms of T2DM-associated cognitive complications. Untargeted metabolomic analysis was performed, using liquid chromatography-mass spectrometry, on whole brain tissue from adult male and female db/db mice (a T2DM model) compared to wild-type (WT) C57Bl6/J mice. Regardless of sex, T2DM increased free fatty acids and decreased acylcarnitines in the brain. Sex impacted the number (103 versus 65 in males and females, respectively), and types of metabolites shifted by T2DM. Many choline-containing phospholipids were decreased by T2DM in males. Female-specific T2DM effects included changes in neuromodulatory metabolites (γ-aminobutyric acid, 2-linoleoyl glycerol, N-methylaspartic acid, and taurine). Further, there were more significantly different metabolites between sexes in the T2DM condition as compared to the WT controls (54 vs. 15 in T2DM and WT, respectively). T2DM alters the murine brain metabolome in both sex-independent and sex-dependent manners. This work extends our understanding of brain metabolic sex differences in T2DM, cognitive implications, and potential sex-specific metabolic therapeutic targets.

Oxylipins are the oxidation products of polyunsaturated fatty acids and have been implicated in neurodegenerative disorders, including dementia. Soluble epoxide hydrolase (sEH) converts epoxy-fatty acids to their corresponding diols, is found in the brain, and its inhibition is a treatment target for dementia. In this study, male and female C57Bl/6J mice were treated with an sEH inhibitor (sEHI), trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB), for 12 weeks to comprehensively study the effect of sEH inhibition on the brain oxylipin profile, and modulation by sex. Ultra-high-performance liquid chromatography-tandem mass spectrometry was used to measure the profile of 53 free oxylipins in the brain. More oxylipins were modified by the inhibitor in males than in females (19 versus 3, respectively) and favored a more neuroprotective profile. Most were downstream of lipoxygenase and cytochrome p450 in males, and cyclooxygenase and lipoxygenase in females. The inhibitor-associated oxylipin changes were unrelated to serum insulin, glucose, cholesterol, or female estrous cycle. The inhibitor affected behavior and cognitive function as measured by open field and Y-maze tests in males, but not females. These findings are novel and important to our understanding of sexual dimorphism in the brain's response to sEHI and may help inform sex-specific treatment targets.

Biological sex and a high glycemic diet (HGD) contribute to dementia, yet little is known about the operative molecular mechanisms. Our goal was to understand the differences between males and females in the multi-genomic response of the hippocampal microvasculature to the HGD, and whether there was vasculoprotection via the inhibition of soluble epoxide hydrolase (sEHI). Adult wild type mice fed high or low glycemic diets for 12 weeks, with or without an sEHI inhibitor (t-AUCB), had hippocampal microvessels isolated by laser-capture microdissection. Differential gene expression was determined by microarray and integrated multi-omic bioinformatic analyses. The HGD induced opposite effects in males and females: the HGD-upregulated genes were involved in neurodegeneration or neuroinflammation in males, whereas in females they downregulated the same pathways, favoring neuroprotection. In males, the HGD was associated with a greater number of clinical diseases than in females, the sEHI downregulated genes involved in neurodegenerative diseases to a greater extent with the HGD and compared to females. In females, the sEHI downregulated genes involved in endothelial cell functions to a greater extent with the LGD and compared to males. Our work has potentially important implications for sex-specific therapeutic targets for vascular dementia and cardiovascular diseases in males and females.

Dysfunction of blood-brain barrier formed by endothelial cells of cerebral blood vessels, plays a key role in development of neurodegenerative disorders. Epicatechin exerts vasculo-protective effects through genomic modifications, however molecular mechanisms of action, particularly on brain endothelial cells, are largely unknow. This study aimed to use a multi-omic approach (transcriptomics of mRNA, miRNAs and lncRNAs, and proteomics), to provide novel in-depth insights into molecular mechanisms of how metabolites affect brain endothelial cells under lipid-stressed (as a model of BBB dysfunction) at physiological concentrations. We showed that metabolites can simultaneously modulate expression of protein-coding, non-coding genes and proteins. Integrative analysis revealed interactions between different types of RNAs and form functional groups of genes involved in regulation of processing like VEGF-related functions, cell signaling, cell adhesion and permeability. Molecular modeling of genomics data predicted that metabolites decrease endothelial cell permeability, increased by lipotoxic stress. Correlation analysis between genomic modifications observed and genomic signature of patients with vascular dementia and Alzheimer's diseases showed opposite gene expression changes. Taken together, this study describes for the first time a multi-omic mechanism of action by which (-)-epicatechin metabolites could preserve brain vascular endothelial cell integrity and reduce the risk of neurodegenerative diseases. SIGNIFICANCE: Dysfunction of the blood-brain barrier (BBB), characterized by dysfunction of endothelial cells of cerebral blood vessels, result in an increase in permeability and neuroinflammation which constitute a key factor in the development neurodegenerative disorders. Even though it is suggested that polyphenols can prevent or delay the development of these disorders, their impact on brain endothelial cells and underlying mechanisms of actions are unknow. This study aimed to use a multi-omic approach including analysis of expression of mRNA, microRNA, long non-coding RNAs, and proteins to provide novel global in-depth insights into molecular mechanisms of how (-)-epicatechin metabolites affect brain microvascular endothelial cells under lipid-stressed (as a model of BBB dysfunction) at physiological relevant conditions. The results provide basis of knowledge on the capacity of polyphenols to prevent brain endothelial dysfunction and consequently neurodegenerative disorders.

Background The mechanisms linking menopausal age and heart failure (HF) incidence are controversial. We investigated for heterogeneity by obesity on the relationship between menopausal age and HF incidence. Methods and Results Using postmenopausal women who attended the Atherosclerosis Risk in Communities Study Visit 4, we estimated hazard ratios of incident HF associated with menopausal age using Cox proportional hazards models, testing for effect modification by obesity and adjusting for HF risk factors. Women were categorized by menopausal age:

The effect of a high glycemic diet (HGD) on brain microvasculature is a crucial, yet understudied research topic, especially in females. This study aimed to determine the transcriptomic changes in female brain hippocampal microvasculature induced by a HGD and characterize the response to a soluble epoxide hydrolase inhibitor (sEHI) as a mechanism for increased epoxyeicosatrienoic acids (EETs) levels shown to be protective in prior models of brain injury. We fed mice a HGD or a low glycemic diet (LGD), with/without the sEHI (t-AUCB), for 12 weeks. Using microarray, we assessed differentially expressed protein-coding and noncoding genes, functional pathways, and transcription factors from laser-captured hippocampal microvessels. We demonstrated for the first time in females that the HGD had an opposite gene expression profile compared to the LGD and differentially expressed 506 genes, primarily downregulated, with functions related to cell signaling, cell adhesion, cellular metabolism, and neurodegenerative diseases. The sEHI modified the transcriptome of female mice consuming the LGD more than the HGD by modulating genes involved in metabolic pathways that synthesize neuroprotective EETs and associated with a higher EETs/dihydroxyeicosatrienoic acids (DHETs) ratio. Our findings have implications for sEHIs as promising therapeutic targets for the microvascular dysfunction that accompanies vascular dementia.

Diet is a modifiable risk factor for cardiovascular disease (CVD) and dementia, yet relatively little is known about the effect of a high glycemic diet (HGD) on the brain's microvasculature. The objective of our study was to determine the molecular effects of an HGD on hippocampal microvessels and cognitive function and determine if a soluble epoxide hydrolase (sEH) inhibitor (sEHI), known to be vasculoprotective and anti-inflammatory, modulates these effects. Wild type male mice were fed a low glycemic diet (LGD, 12% sucrose/weight) or an HGD (34% sucrose/weight) with/without the sEHI, trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB), for 12 weeks. Brain hippocampal microvascular gene expression was assessed by microarray and data analyzed using a multi-omic approach for differential expression of protein and non-protein-coding genes, gene networks, functional pathways, and transcription factors. Global hippocampal microvascular gene expression was fundamentally different for mice fed the HGD vs. the LGD. The HGD response was characterized by differential expression of 608 genes involved in cell signaling, neurodegeneration, metabolism, and cell adhesion/inflammation/oxidation effects reversible by t-AUCB and hence sEH inhibitor correlated with protection against Alzheimer's dementia. Ours is the first study to demonstrate that high dietary glycemia contributes to brain hippocampal microvascular inflammation through sEH.

Cerebral blood vessels are lined with endothelial cells and form the blood-brain barrier. Their dysfunction constitutes a crucial event in the physiopathology of neurodegenerative disorders and cognitive impairment. Epicatechin can improve cognitive functions and lower the risk for Alzheimer's disease or stroke. However, molecular mechanisms of epicatechin on brain vascular endothelium are still unexplored. The objective of this study was to investigate the biological effects of gut microbiome-derived metabolites of epicatechin, 5-(4'-Hydroxyphenyl)-γ-valerolactone-3'-sulfate and 5-(4'-Hydroxyphenyl)-γ-valerolactone-3'-O-glucuronide, in TNF-α-stimulated human brain microvascular endothelial cells at low (nM) concentrations by evaluating their multi-omic modification (expression of mRNA, microRNA, long non-coding RNAs, and proteins). We observed that metabolites are biologically active and can simultaneously modulate the expression of protein-coding and non-coding genes as well as proteins. Integrative bioinformatics analysis of obtained data revealed complex networks of genomics modifications by acting at different levels of regulation. Metabolites modulate cellular pathways including cell adhesion, cytoskeleton organization, focal adhesion, signaling pathways, pathways regulating endothelial permeability, and interaction with immune cells. This study demonstrates multimodal mechanisms of action by which epicatechin metabolites could preserve brain vascular endothelial cell integrity, presenting mechanisms of action underlying epicatechin neuroprotective properties.

The Western diet (WD) and hyperlipidemia are risk factors for vascular disease, dementia, and cognitive impairment. However, the molecular mechanisms are poorly understood. This pilot study investigated the genomic pathways by which the WD and hyperlipidemia regulate gene expression in brain microvessels. Five-week-old C57BL/6J wild type (WT) control and low-density lipoprotein receptor deficient (LDL-R-/-) male mice were fed the WD for eight weeks. Differential gene expression, gene networks and pathways, transcription factors, and non-protein coding RNAs were evaluated by a genome-wide microarray and bioinformatics analysis of laser-captured hippocampal microvessels. The WD resulted in the differential expression of 1972 genes. Much of the differentially expressed gene (DEG) was attributable to the differential regulation of cell signaling proteins and their transcription factors, approximately 4% was attributable to the differential expression of miRNAs, and 10% was due to other non-protein coding RNAs, primarily long non-coding RNAs (lncRNAs) and small nucleolar RNAs (snoRNAs) not previously described to be modified by the WD. Lipotoxic injury resulted in complex and multilevel molecular regulation of the hippocampal microvasculature involving transcriptional and post-transcriptional regulation and may provide a molecular basis for a better understanding of hyperlipidemia-associated dementia risk.

Cardiovascular risk factors and biologic sex play a role in vascular dementia which is characterized by progressive reduction in cognitive function and memory. Yet, we lack understanding about the role sex plays in the molecular mechanisms whereby lipid stress contributes to cognitive decline. Five-week-old low-density lipoprotein deficient (LDL-R -/-) male and female mice and C57BL/6J wild types (WT) were fed a control or Western Diet for 8 weeks. Differential expression of protein coding and non-protein coding genes (DEG) were determined in laser captured hippocampal microvessels using genome-wide microarray, followed by bioinformatic analysis of gene networks, pathways, transcription factors and sex/gender-based analysis (SGBA). Cognitive function was assessed by Y-maze. Bioinformatic analysis revealed more DEGs in females (2412) compared to males (1972). Hierarchical clusters revealed distinctly different sex-specific gene expression profiles irrespective of diet and genotype. There were also fewer and different biologic responses in males compared to females, as well as different cellular pathways and gene networks (favoring greater neuroprotection in females), together with sex-specific transcription factors and non-protein coding RNAs. Hyperlipidemic stress also resulted in less severe cognitive dysfunction in females. This sex-specific pattern of differential hippocampal microvascular RNA expression might provide therapeutic targets for dementia in males and females.

Hyperlipidemia is a risk factor for dementia, and chronic consumption of a Western Diet (WD) is associated with cognitive impairment. However, the molecular mechanisms underlying the development of microvascular disease in the memory centers of the brain are poorly understood. This pilot study investigated the nutrigenomic pathways by which the WD regulates gene expression in hippocampal brain microvessels of female mice. Five-week-old female low-density lipoprotein receptor deficient (LDL-R-/-) and C57BL/6J wild type (WT) mice were fed a chow or WD for 8 weeks. Metabolics for lipids, glucose and insulin were determined. Differential gene expression, gene networks and pathways, transcription factors, and non-protein coding RNAs were evaluated by genome-wide microarray and bioinformatics analysis of laser captured hippocampal microvessels. The WD resulted in differential expression of 2,412 genes. The majority of differential gene expression was attributable to differential regulation of cell signaling proteins and their transcription factors, approximately 7% was attributable to differential expression of miRNAs, and a lesser proportion was due to other non-protein coding RNAs, primarily long non-coding RNAs (lncRNAs) and small nucleolar RNAs (snoRNAs) not previously described to be modified by the WD in females. Our findings revealed that chronic consumption of the WD resulted in integrated multilevel molecular regulation of the hippocampal microvasculature of female mice and may provide one of the mechanisms underlying vascular dementia.

Type II diabetes mellitus (T2D) is a chronic metabolic disease and a risk factor for cardiovascular disease and cerebrovascular dysfunction including vascular dementia. Sex differences in the prevalence of T2D, dementia, and global genomic changes in the brain have been observed; however, most studies have been performed in males. Therefore, our aim was to evaluate the consequence of T2D on cognitive function and decipher the underlying molecular transcriptomic mechanisms of endothelial cells in an important brain memory center, the hippocampus, using a female murine diabetes model. We assessed cognitive function, metabolic parameters, and then performed hippocampal single-nuclei RNA sequencing (snRNA seq) in adult female db/db and control wild-type (WT) mice. db/db mice exhibited characteristic T2D metabolism with hyperglycemia, hyperinsulinemia, and hyperlipidemia when compared with WT mice. Female db/db mice presented cognitive decline compared with wild-type mice, as determined by open field and Morris water maze tests. snRNAseq showed that T2D induced significant changes in the global transcriptomic profile of hippocampal endothelial cells by modulating the expression of not only protein-coding genes but also long noncoding RNAs. These genes regulate cell-cell junctions, cell chemotaxis, actin cytoskeleton organization, and cell adhesion, suggesting that diabetes increases endothelial cell permeability. Observed genomic changes also correlated with the genetics of persons with clinical Alzheimer's disease and vascular dementia. In conclusion, T2D, by transcriptional and posttranscriptional regulation, regulates endothelial cell dysfunction predictive of increased vascular permeability, and negatively impacts cognitive function. Our work has implications for sex-specific molecular therapeutic targets for dementia in females. NEW & NOTEWORTHY: Female db/db mice presented cognitive decline as determined by open field and Morris water maze tests. snRNAseq showed that T2D induced changes in the global transcriptomic profile of hippocampal endothelial cells by modulating the expression of not only protein-coding genes but also long noncoding RNAs. These genes regulate cell-cell junctions, cell chemotaxis, or cell adhesion, suggesting increased endothelial permeability. Genomic changes correlated with the genetics of persons with clinical Alzheimer's disease and vascular dementia. [ABSTRACT FROM AUTHOR]

PurposeAcademic medical and biomedical professionals need workplace flexibility to manage the demands of work and family roles and meet their commitments to both, but often fail to use the very programs and benefits that provide flexibility. This study investigated the reasons for faculty underutilization of work-life programs.MethodAs part of a National Institutes of Health-funded study, in 2010 the authors investigated attitudes of clinical and/or research biomedical faculty at the University of California, Davis, toward work-life policies, and the rationale behind their individual decisions regarding use of flexibility policies. The analysis used verbatim responses from 213 of 472 faculty (448 unstructured comments) to a series of open-ended survey questions. Questions elicited faculty members' self-reports of policy use, attitudes, and evaluations of the policies, and their perceptions of barriers that limited full benefit utilization. Data were coded and analyzed using a grounded theory approach.ResultsFaculty described how their utilization of workplace flexibility benefits was inhibited by organizational influences: the absence of reliable information about program eligibility and benefits, workplace norms and cultures that stigmatized program participation, influence of uninformed/unsupportive department heads, and concerns about how participation might burden coworkers, damage collegial relationships, or adversely affect workflow and grant funding.ConclusionsUnderstanding underuse of work-life programs is essential to maximize employee productivity and satisfaction, minimize turnover, and provide equal opportunities for career advancement to all faculty. The findings are discussed in relation to specific policy recommendations, implications for institutional change, and department chair leadership.

Cardiovascular disease (CVD) remains the number one cause of death in women. It is estimated that 44 million women in the United States are either living with or at risk for heart disease. This article highlights the recent significant progress made in improving care, clinical decision-making, and policy implications for women with CVD. We provide our perspective supported by evidence-based advances in cardiovascular research and clinical care guidelines in seven areas: (1) primary CVD prevention and community heart care, (2) secondary prevention of CVD, (3) stroke, (4) heart failure and cardiomyopathies, (5) ischemia with nonobstructive coronary artery disease, (6) spontaneous coronary artery dissection, and (7) arrhythmias and device therapies. Advances in these fields have improved the lives of women living with and at risk for heart disease. With increase awareness, partnership with national organizations, sex-specific research, and changes in policy, the morbidity and mortality of CVD in women can be further reduced.

ObjectiveWomen are under-represented in academia. Causative factors include challenges of career-family integration. We evaluated factors reflecting institutional culture (promotion, retention, hiring, and biasing language in promotion letters) as part of an intervention to help shift culture and raise awareness of flexibility policies at the University of California, Davis (UCD).Materials and methodsData on faculty use of family-friendly policies were obtained at baseline, and surveys for policy awareness were conducted pre(2010)/post(2013) an NIH-funded study educational intervention. Data on hires, separations, and promotions were obtained pre(2007-2009, 2234 person-year data points)/post(2010-2012, 2384 person-year data points) intervention and compared by logistic regression and for gender differences. Department promotion letters (53) were also analyzed for biasing language.ResultsPolicy use was overall low, highest for female assistant professors, and for maternity leave. Awareness significantly increased for all policies postintervention. Promotions decreased, likely because of increases in advancement deferrals or tenure clock extensions. Pre/postintervention, female and male hires were near parity for assistant professors, but female hires were substantially lower than males for associate (54% less likely, p = 0.03) and full professors (70% less likely, p = 0.002). Once hired, women were no more likely to separate than men. Fewer associate/full professors separated than assistant professors (p = 0.002, p

Background and purposeHeart disease is the leading killer of women and remains poorly recognized in high-risk groups. We assessed baseline knowledge gaps and efficacy of a survey-based educational intervention.MethodsFour hundred seventy-two women in clinical settings completed pre-/post-surveys for knowledge of: heart disease as the leading killer, risk factors (general and personal levels), heart attack/stroke symptoms, and taking appropriate emergency action. They received a clinic-based educational intervention delivered by healthcare professionals in the course of their clinical care. Change score analyses tested pre-/post-differences in knowledge after the educational intervention, comparing proportions by race, ethnicity, and urban/nonurban status.ResultsKnowledge and awareness was low in all groups, especially for American Indian women (p

Dysfunction of the cerebrovasculature plays an important role in vascular cognitive impairment (VCI). Lipotoxic injury of the systemic endothelium in response to hydrolyzed triglyceride-rich lipoproteins (TGRLs; TGRL lipolysis products) or a high-fat Western diet (WD) suggests similar mechanisms may be present in brain microvascular endothelium. We investigated the hypothesis that TGRL lipolysis products cause lipotoxic injury to brain microvascular endothelium by generating increased mitochondrial superoxide radical generation, upregulation of activating transcription factor 3 (ATF3)-dependent inflammatory pathways, and activation of cellular oxidative stress and apoptotic pathways. Human brain microvascular endothelial cells were treated with human TGRL lipolysis products that induced intracellular lipid droplet formation, mitochondrial superoxide generation, ATF3-dependent transcription of proinflammatory, stress response, and oxidative stress genes, as well as activation of proapoptotic cascades. Male apoE knockout mice were fed a high-fat/high-cholesterol WD for 2 months, and brain microvessels were isolated by laser capture microdissection. ATF3 gene transcription was elevated 8-fold in the hippocampus and cerebellar brain region of the WD-fed animals compared with chow-fed control animals. The microvascular injury phenotypes observed in vitro and in vivo were similar. ATF3 plays an important role in mediating brain microvascular responses to acute and chronic lipotoxic injury and may be an important preventative and therapeutic target for endothelial dysfunction in VCI.

Work-life balance is important to recruitment and retention of the younger generation of medical faculty, but medical school flexibility policies have not been fully effective. We have reported that our school's policies are underutilized due to faculty concerns about looking uncommitted to career or team. Since policies include leaves and accommodations that reduce physical presence, faculty may fear "face-time bias," which negatively affects evaluation of those not "seen" at work. Face-time bias is reported to negatively affect salary and career progress. We explored face-time bias on a leadership level and described development of compensation criteria intended to mitigate face-time bias, raise visibility, and reward commitment and contribution to team/group goals. Leaders from 6 partner departments participated in standardized interviews and group meetings. Ten compensation plans were analyzed, and published literature was reviewed. Leaders did not perceive face-time issues but saw team pressure and perception of availability as performance motivators. Compensation plans were multifactor productivity based with many quantifiable criteria; few addressed team contributions. Using these findings, novel compensation criteria were developed based on a published model to mitigate face-time bias associated with team perceptions. Criteria for organizational citizenship to raise visibility and reward group outcomes were included. We conclude that team pressure and perception of availability have the potential to lead to bias and may contribute to underuse of flexibility policies. Recognizing organizational citizenship and cooperative effort via specific criteria in a compensation plan may enhance a culture of flexibility. These novel criteria have been effective in one pilot department.

BackgroundBalancing career and family obligations poses challenges to medical school faculty and contributes to dissatisfaction and attrition from academics. We examined the relationship between family setting and responsibilities, rank, and career and work-life satisfaction for faculty in a large U.S. medical school.MethodsBaseline faculty surveys were analyzed from the first year of a 4-year National Institutes of Health-funded study to evaluate awareness, knowledge, attitudes, and use of family friendly policies and career satisfaction. The study focus was on the impact of family responsibilities and characteristics of the faculty position (rank, clinical vs. nonclinical, and academic series) in multivariate comparisons between primary predictors and outcomes of interest.ResultsBoth clinical and family responsibilities for children under 18 play a major and interacting role in satisfaction with career and work-life balance. Clinical faculty respondents without children at home reported significantly greater career satisfaction and better work-life balance than their nonclinical counterparts. Nonclinical faculty respondents with children reported greater satisfaction and better balance than counterparts without family responsibilities. However, the advantage in career satisfaction and work-life balance for clinical faculty respondents disappeared for those with responsibility for young children. No gender-based differences were noted in the results or across faculty rank for respondents; however, for women, reaching associate professor resulted in greater career satisfaction.ConclusionThis study suggests that both work-related factors and family responsibilities influence satisfaction with career and work-life balance, but the predictors appear to interact in complex and nuanced ways. Further research is needed to delineate more clearly these interactions and to explore other factors that may play important additional roles.

ProblemAlthough more female physicians and scientists are choosing careers in academic medicine, women continue to be underrepresented as medical school faculty, particularly at the level of full professor and in leadership positions. Effective interventions to support women in academic medicine exist, but the nature and content of such programs varies widely.ApproachWomen in medicine programs can play a critical role in supporting women's careers and can improve recruitment and retention of women by providing opportunities for networking, sponsorship, mentorship, and career development. The University of California Davis School of Medicine established the Women in Medicine and Health Science (WIMHS) program in 2000 to ensure the full participation and success of women in all roles within academic medicine. The authors describe the components and evolution of the WIMHS program.OutcomesA steady increase in the number and percentage of female faculty and department chairs, as well as a relatively low departure rate for female faculty, strong and growing internal partnerships, and enthusiastic support from faculty and the school of medicine leadership, suggest that the WIMHS program has had a positive influence on recruitment and retention, career satisfaction, and institutional climate to provide a more inclusive and supportive culture for women.Next stepsGoing forward, the WIMHS program will continue to advocate for broader institutional change to support female faculty, like creating an on-site child care program. Other institutions seeking to address the challenges facing female faculty may consider using the WIMHS program as a model to guide their efforts.

BackgroundCardiovascular disease (CVD) is the leading cause of death in women, yet significant health disparities exist for high-risk groups, including Latinas, and comprehensive, culturally relevant, and effective prevention intervention models are lacking. We used a systems approach to develop, assess, and pilot a community-based education program for improving outcomes for knowledge/awareness of CVD, cardiometabolic risk, and health behaviors in Latinas.MethodsLatinas (n=35, mean age 50) participated in a 4-month community-based bilingual preventive cardiovascular education program. Pre/post analyses were for knowledge/awareness of CVD risk factors, symptoms, calling 911; personal risk factors (smoking, physical inactivity, family history of CVD); clinical parameters (weight, body mass index [BMI], waist, blood pressure, fasting lipids, and glucose); diagnosis of metabolic syndrome (MetS); and serum inflammatory markers (tumor necrosis factor [TNF]-α, high-sensitivity C reactive protein [hsCRP], and interleukin [IL]-12).ResultsBaseline knowledge/awareness was relatively low, risk factors and MetS prevalent, and serum inflammatory markers elevated. Postintervention, participants demonstrated significant (p

Maternal mainstream tobacco smoking is known to have adverse outcomes on fetal respiratory function; however, no data is currently available on the effects of passive exposure to tobacco smoking and environmental tobacco smoke (ETS) on fetal systemic arterial structure and function. Eight pregnant rhesus macaque monkeys were studied at the California Regional Primate Research Center breeding colony. The estimated gestational age for each dam was established by sonography performed before gestational day 40. Two inhalation chambers were used, each with an air capacity of 3.5 m3, and each housed two dams. Aged and diluted sidestream smoke was used as a surrogate for ETS. Exposure to ETS (1 mg/m3) occurred for 6 h/day, 5 days/week, beginning on gestational day 100. All dams were allowed to give birth spontaneously and then ETS exposure continued 70–80 days postnatally with the chamber containing both the mother and infant. Carotid arteries from four control (C) and four ETS-treated newborns were analyzed for mRNA by gene macroarray and for protein by Western blotting. A total of 588 cardiovascular genes were studied. Four genes were upregulated by ETS compared to C, and nine genes were downregulated (≥2-fold change). Three genes were selected for further study. Following ETS exposure, neonatal carotid arteries of non-human primates manifested evidence of inflammation with increased gene and protein expression of LFA-1 and RANTES, proteins that are recognized to be important in vascular adhesion and inflammation, and downregulation of expression for the receptor for VEGF, which has a key role in angiogenesis. Prenatal and postnatal exposure to ETS increases expression of pro-inflammatory genes and may be responsible for early arterial vascular remodeling that is predisposing to a subsequent vascular disease.

Estrogen is atheroprotective and a high-affinity ligand for both known estrogen receptors, ERα and ERβ. However, the role of the ERα in early-stage atherosclerosis has not been directly investigated and is incompletely understood. ERα-deficient (ERα−/−) and wild-type (ERα+/+) female mice consuming an atherogenic diet were studied concurrent with estrogen replacement to distinguish the actions of 17β-estradiol (E2) from those of ERα on the development of early atherosclerotic lesions. Mice were ovariectomized and implanted with subcutaneous slow-release pellets designed to deliver 6 or 8 μg/day of exogenous 17β-estradiol (E2) for a period of up to 4 months. Ovariectomized mice (OVX) with placebo pellets (E2-deficient controls) were compared to mice with endogenous E2 (intact ovaries) and exogenous E2. Aortas were analyzed for lesion area, number, and distribution. Lipid and hormone levels were also determined. Compared to OVX, early lesion development was significantly (p 90% reduction by exogenous E2. Compared to OVX, a decline in lesion number (2- to 4-fold) and lesser predilection (~4-fold) of lesion formation in the proximal aorta also occurred with E2. Lesion size, development, number, and distribution inversely correlated with circulating plasma E2 levels. However, atheroprotection was independent of ERα status, and E2 athero-protection in both genotypes was not explained by changes in plasma lipid levels (total cholesterol, triglyceride, and high-density lipoprotein cholesterol). The ERα is not essential for endogenous/exogenous E2-mediated protection against early-stage atherosclerosis. These observations have potentially significant implications for understanding the molecular and cellular mechanisms and timing of estrogen action in different estrogen receptor (ER) deletion murine models of atherosclerosis, as well as implications to human studies of ER polymorphisms and lipid metabolism. Our findings may contribute to future improved clinical decision-making concerning the use of hormone therapy.

The purpose of this study was to reduce cardiovascular disease (CVD) risk in women by implementing a cardiovascular prevention health promotion program in faith- and community-based sites. The primary outcomes were reducing obesity and increasing physical activity. A longitudinal cohort of high-risk (age > 40, ethnic minority) women (n = 1,052) was enrolled at 32 sites across the USA. The pre- or post-educational intervention consisted of eight biweekly counseling sessions conducted over 4 months each addressing one of six of the major CVD risk factors (smoking, diabetes, hypertension, cholesterol, obesity, and physical inactivity) as well as signs and symptoms of a heart attack and stroke; plus 4–6 maintenance sessions over three additional months. A multifaceted approach delivered by lay and medically trained personnel involving medical screenings, health behavior counseling, risk behavior modification, and stage of change were determined at baseline and end of counseling or maintenance. Following list-wise deletion, data were analyzed on 423 women who completed all follow-up time-points. Overall, significant improvement was attained in most of 28 secondary outcomes but not in the primary outcomes. Knowledge and awareness of heart disease as the leading killer or women, all of the signs and symptoms of a heart attack, calling 911, and CVD risk factors increased significantly (p

The overall goal of this project was to examine the interactions of hyperglycemia and loss of ovarian hormones on the artery wall in a type I diabetic mouse model. Intact or ovariectomized (OVX) female BALB/C mice were fed a high-cholesterol diet. Half the animals were treated with steptozotocin to induce insulin-deficient diabetes mellitus, generating four treatment groups: control, intact; control, ovariectomized; diabetic, intact; diabetic, ovariectomized (DOVX). We examined arterial structure and function and found that 1) diabetes and ovariectomy additively increased endothelial layer permeability, 2) arterial stiffening was increased in DOVX, 3) DOVX synergistically increased atheroma formation, and 4) ultrastructural evaluation revealed that the basal lamina was often multilayered and formed convoluted aggregates separating endothelium from the internal elastic lamina in diabetic, but not control arteries or arteries from OVX mice. Endothelium overlying these regions formed thin cytoplasmic extensions between these aggregates and was often separated from the basal lamina by electron lucent spaces. Our studies showed that diabetes and loss of ovarian function have additive and synergistic effects to worsen arterial pathophysiology by disrupting the arterial endothelial layer with increased permeability and increased atheroma formation. diabetes; vascular; atherosclerosis; postmenopause; pathophysiology

While regulation of receptor function is known to occur at many levels (e.g. transcriptional, post-translational), it is generally perceived that a tissue either expresses or does not express a particular receptor in an all-ornone fashion. Many pathological (e.g. tissue injury) and physiological (e.g. angiogenesis) processes have, however, been shown to be associated with the transcriptional induction of specific receptors. Induced receptors are not confined to any particular class, but range from G protein-coupled receptors to receptor tyrosine kinases. The potential implications of de novo receptor expression are profound with respect to potential novel therapeutic targets in specific disease states. Further, this observation may explain unexpected side-effects in the pharmacotherapy of existing disease states. In this article Lucy Donaldson, Michael Hanley and Amparo Villablanca discuss circumstances under which de novo receptor induction has been described, potential mechanisms of induction and the implications for pharmacology.

Studies conducted on individually perfused in situ frog capillaries show that the substance P, a tachykinin neuropeptide, increases the permeability of the microvessels and this effect persists as long as substance P is present in the perfusate. Formation of nitric oxide and the activation of the neurokinin receptor, NK1, is necessary for substance P-induced permeability which does not depend on changes in vasomotor tone. The transport of albumin is by water-filled connective pathways between the endothelial cells.