Preparedness of Practicing Nurses in the Care of Sexual and Gender Diverse People in the United States: A Scoping Review.

BACKGROUND: Sexual and gender diverse (SGD) people in the United States (US) experience health inequities due to societal stigma and marginalisation. The nursing workforce must provide evidence-based affirming, inclusive and culturally responsive care for SGD people to meet individual and community health needs and eliminate disparities. AIMS: The purpose of this scoping review was to synthesise what is known about (1) nurses' knowledge, skills and attitudes related to caring for SGD people in the US and (2) the existence, development and evaluation of SGD-related educational offerings available to practicing nurses in the US to develop the knowledge and skills needed to promote the health and wellbeing of SGD individuals, families and communities. METHODS: This review followed the scoping review methodology and PRISMA for Scoping Reviews (PRISMA-ScR). DATA SOURCES: In conjunction with a health librarian, an electronic literature search was conducted using PubMed, LGBT Health, CINAHL, ERIC and Health Source-Nursing. RESULTS: Thirty-two studies were included in this review, including quantitative and qualitative studies that sought to understand the knowledge, attitudes and clinical experiences of nurses related to the care of SGD people; studies that tested educational interventions and studies that identified educational barriers and facilitators. Major gaps in education, practice and research, as well as methodological limitations of existing studies, were noted. CONCLUSION: Nurses would benefit from expanded access to effective standardised foundational SGD-related health continuing education to help prepare them to care for diverse patient populations. Equity, inclusivity and dignity are key values of the nursing profession. It is imperative that nurses have the knowledge and skills to apply these values consistently in day-to-day professional practice across populations and settings. IMPACT: There is an urgent need to develop standardised, easily accessible evidence-based educational content to address nurses' knowledge of and attitudes towards caring for SGD people. REPORTING METHOD: This study adhered to the PRISMA-ScR reporting guidelines. PATIENT OR PUBLIC CONTRIBUTION: There was no patient or public contribution to this study.

Historic redlining and health outcomes: A systematic review.

OBJECTIVE: The purpose of this systematic review was to synthesize the existing literature on the associations between historic redlining and modern-day health outcomes across the lifespan. METHOD: This review searched PubMed and CINAHL for peer-reviewed, data-based articles examining the relationship between historic redlining and any health outcome. Articles were appraised using the JBI critical appraisal checklist. The results were synthesized using a narrative summary approach. RESULTS: Thirty-six articles were included and focused on various health outcomes, including cardiovascular outcomes, breast cancer incidence and mortality, firearm injury or death, birth-related outcomes, and asthma outcomes. Most of the included articles (n = 31; 86%) found significant associations between historic redlining and adverse health outcomes such as increased cardiovascular disease, higher rates of preterm births, increased cancer incidence, reduced survival time after breast cancer diagnosis, and increased firearm injury incidence. DISCUSSION: This review demonstrates the persistent effect of historic redlining on individuals' health. Public health nurses should recognize redlining as a form of structural racism when caring for affected communities and should advocate for policies and programs that advance health equity. Nurse researchers should develop and test multilevel interventions to address systemic racism and improve health outcomes in communities affected by redlining.

Socioeconomic correlates of health outcomes and mental health disparity in a sample of cancer patients during the COVID-19 pandemic.

AIMS AND OBJECTIVES: To investigate socioeconomic, behavioural and healthcare delivery factors that are associated with health outcomes of cancer patients during the COVID-19 pandemic, especially among underserved cancer patients. BACKGROUND: Cancer patients are at a higher risk of adverse physical and mental health outcomes during the pandemic than those without cancer. DESIGN: Cross-sectional online survey. We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines in this study. METHODS: The sample comprised 322 individuals diagnosed with incident cancer between January 2019 and January 2020. Demographically, 64% were female, 49% had a college degree, 12% were African American, and 88% were White (77% of the Whites were from metropolitan and 23% from nonmetropolitan areas). Descriptive analysis and multivariable regression analyses of global health status, depression and irritability were performed. RESULTS: After adjusting for demographic variables and comorbidity, the feelings of loneliness, crowded living space, lower confidence in taking preventive measures and less satisfaction with telehealth visits were significantly associated with poorer global health, depression and irritability. Daily exercise was associated with better global health, and difficulty in getting medicine was associated with depression and irritability. Moreover, African Americans who felt lonely reported more depression and irritability and those who had less confidence in taking preventive measures reported more irritability than Whites. Respondents having low income and feeling lonely reported more depression than others. CONCLUSIONS: In this study, socioeconomic factors (e.g. loneliness or crowded living conditions) were as important to health outcomes during the pandemic as behavioural (e.g. prevention and exercises) and quality-of-care factors (e.g. telehealth, access to medicine). Disparity was more pronounced in the mental health of African Americans and those with low incomes. RELEVANCE TO CLINICAL PRACTICE: Healthcare providers should promote social support and physical activity for improving health and reducing mental health disparities among cancer patients.

Nursing pre-licensure and graduate education for LGBTQ health: A systematic review.

BACKGROUND: Lesbian, gay, bisexual, transgender, and queer plus (LGBTQ) people experience discrimination and health disparities compared to heterosexual cisgender people. Clinicians report discomfort and insufficient preparation for providing care to LGBTQ people and nursing has been slow to integrate LGBTQ health into curricula. PURPOSE: Conduct a systematic review to examine and critically appraise peer-reviewed literature on nursing student knowledge, skills, and attitudes (KSAs) regarding LGBTQ health and the development/evaluation of LGBTQ health content in nursing curricula. METHODS: A systematic review was conducted (N = 1275 articles from PubMed, LGBT Health, CINAHL, ERIC, and Health Source-Nursing/Academic Edition). FINDINGS: Twenty articles met inclusion criteria. Twelve studies described curricular interventions; however, there were few validated tools to evaluate content coverage or KSAs. Four themes emerged specific to LGBTQ health content inclusion. DISCUSSION: While an emerging science of LGBTQ nursing education has been identified, more work is needed to build and evaluate a comprehensive curricular approach for full programmatic integration of LGBTQ health. CONCLUSION: As nursing programs build LGBTQ content into nursing curricula, care must be taken to integrate this content fully with the depth of curricular content in population health, social determinants of health, social justice, intersectionality, cultural competence, and political advocacy. TWEETABLE ABSTRACT: Greater integration of LGBTQ health content into nursing education should be a priority for nursing education.

A systematic review of U.S. nursing faculty's knowledge, awareness, inclusion, and perceived importance of sexual and gender minority-related content in nursing curricula.

BACKGROUND: In the US, sexual and gender minority (SGM) individuals continue to experience health inequities, and nursing curricula content and nursing faculty with SGM health expertise in the US remain limited. Addressing health disparities begins with the preparation of future nurses-US nursing faculty must be supported to meet these growing needs. PURPOSE: To describe, appraise, and synthesize research from 2000-2020 on US nursing faculty knowledge, awareness, inclusion, and perceived importance of SGM health content. METHODS: Following PRISMA 2020 guidelines, we registered a systematic review and appraisal protocol in PROSPERO, and then executed the protocol and synthesized the literature. DISCUSSION: We found an empirical evidence base surrounding US nursing faculty and SGM health much more limited than expected. Only four cross-sectional, descriptive empirical articles fit the a priori inclusion criteria. The studies were of moderate quality at best and often relied on unvalidated or older measures. In general, the studies focused on examining characteristics of nursing programs, faculty comfort with content, faculty perceptions of content importance, and hours dedicated to content. CONCLUSION: Since the close of the review, new commentaries and editorials expanding the call for change in the US were published-the time for commentary has passed. It remains unclear whether US nursing faculty are adequately prepared to educate future nurses about SGM health issues-and an unprepared healthcare workforce is yet another barrier to SGM health equity. The evidence base supporting US nursing faculty development desperately needs more studies using rigorous methodologies.

Excess cancer prevalence in men with HIV: A nationwide analysis of Medicaid data.

BACKGROUND: Cancer is one of the most common comorbidities in men living with HIV (MLWH). However, little is known about the MLWH subgroups with the highest cancer burden to which cancer prevention efforts should be targeted. Because Medicaid is the most important source of insurance for MLWH, we evaluated the excess cancer prevalence in MLWH on Medicaid relative to their non-HIV counterparts. METHODS: In this cross-sectional study using 2012 Medicaid Analytic eXtract data nationwide, we flagged the presence of HIV, 13 types of cancer, symptomatic HIV, and viral coinfections using codes from the International Classification of Diseases, Ninth Revision, Clinical Modification. The study population included individuals administratively noted to be of male sex (men), aged 18 to 64 years, with (n = 82,495) or without (n = 7,302,523) HIV. We developed log-binomial models with cancer as the outcome stratified by symptomatic status, age, and race/ethnicity. RESULTS: Cancer prevalence was higher in MLWH than in men without HIV (adjusted prevalence ratio [APR], 1.84; 95% confidence interval [CI], 1.78-1.90) and was higher among those with symptomatic HIV (APR, 2.74; 95% CI, 2.52-2.97) than among those with asymptomatic HIV (APR, 1.73; 95% CI, 1.67-1.79). The highest APRs were observed for anal cancer in younger men, both in the symptomatic and asymptomatic groups: APR, 312.97; 95% CI, 210.27-465.84, and APR, 482.26; 95% CI, 390.67-595.32, respectively. In race/ethnicity strata, the highest APRs were among Hispanic men for anal cancer (APR, 198.53; 95% CI, 144.54-272.68) and for lymphoma (APR, 9.10; 95% CI, 7.80-10.63). CONCLUSIONS: Given the Medicaid program's role in insuring MLWH, the current findings highlight the importance of the program's efforts to promote healthy behaviors and vaccination against human papillomavirus in all children and adolescents and to provide individualized cancer screening for MLWH.

Low initial in-hospital end-tidal carbon dioxide predicts poor patient outcomes and is a useful trauma bay adjunct.

INTRODUCTION: Appropriate triage of the trauma patient is critical. Low end-tidal carbon dioxide (ETCO2) is associated with mortality and hemorrhagic shock in trauma, but the relationship between low ETCO2 and important clinical variables is not known. This study investigates the association of initial in-hospital ETCO2 and patient outcomes, as well as the utility of ETCO2 as a predictive aid for blood transfusion. METHODS: Adult patients who presented to a Level One trauma center from 2019 to 2020 were eligible. Trauma bay ETCO2 measured by side-stream capnography was prospectively obtained for all trauma activations at time of initial evaluation. Using the Liu method of cut point estimation, patients were stratified as having low (≤29.5 mmHg) or normal ETCO2 (>29.5 mmHg). Multivariable regression was used to estimate the association of low ETCO2 with patient outcomes. RESULTS: A total of 955 patients underwent initial in-hospital ETCO2 measurement. Median time from arrival to ETCO2 measurement was 4 min. Among admitted patients (N = 493), 48.9% had low ETCO2. Compared to patients with normal ETCO2, those with low ETCO2 were older (median age 53 vs 46, p = 0.01) and more likely to have the highest trauma activation (27.4% vs 19.8%, p = 0.048). There was no difference in head injury. After adjustment, patients with low ETCO2 had greater odds of blood transfusion (OR 4.65, 95%CI 2.0-10.7), mortality (OR 5.10, 95%CI 1.1-24.9), inferior disposition (OR 1.64, 95%CI 1.1-2.6), and complications (OR 3.35, 95%CI 1.5-7.4). ETCO2 was more predictive of early blood transfusion than Shock Index (area under ROC = 67.6% vs 58.2%). CONCLUSIONS: Low trauma bay ETCO2 remains significantly associated with inferior clinical outcomes after adjustment. In comparison to other triage tools, low ETCO2 values may be more predictive of the need for blood transfusion. Further studies are needed to evaluate the role of ETCO2 as a decision making tool for early trauma management.

How can the nursing profession help reduce sexual and gender minority related health disparities: Recommendations from the National Nursing LGBTQ Health Summit.

BACKGROUND: Lesbian, gay, bisexual, transgender and queer (LGBTQ) people, also commonly referred to as sexual and gender minorities (SGMs), live in every part of the United States and encompass all races and/or ethnicities, religions, and social classes. Major reports from various sources document higher rates of health issues (e.g., substance abuse, depression, suicidality, cardiovascular disease) among SGMs than heterosexuals. Chronic stress related to marginalization and discrimination is a key contributor to these disparities. The nursing profession has paid relatively little attention to SGM health issues. PURPOSE AND METHODS: To address these gaps, the first National Nursing LGBTQ Health Summit brought together nursing deans, leaders of national nursing organizations, and other participants from across the United States. FINDINGS: Participants agreed that increasing SGM-specific content in nursing curricula, practice guidelines, faculty development, and research is necessary to improve the health of SGM people. DISCUSSION: The Summit ended with a call to action for the nursing profession to prioritize SGM health through innovations in education, research, and practice.

Effects of sex and genotype in human APOE-targeted replacement mice on alcohol self-administration measured with the automated IntelliCage system before and after repeated mild traumatic brain injury.

BACKGROUND: Few studies have examined the association between APOE genotype and alcohol use. Although some of these studies have reported outcomes associated with a history of drinking, none have examined alcohol-seeking behavior. In addition, no preclinical studies have examined alcohol use as a function of APOE genotype with or without traumatic brain injury. METHODS: Male and female human APOE3- and APOE4-targeted replacement (TR) mice were used to assess voluntary alcohol seeking longitudinally using a 2-bottle choice paradigm conducted within the automated IntelliCage system prior to and following repeated mild TBI (rmTBI). Following an acquisition phase in which the concentration of ethanol (EtOH) was increased to 12%, a variety of drinking paradigms that included extended alcohol access (EAA1 and EAA2), alcohol deprivation effect (ADE), limited access drinking in the dark (DID), and progressive ratio (PR) were used to assess alcohol-seeking behavior. Additional behavioral tasks were performed to measure cognitive function and anxiety-like behavior. RESULTS: All groups readily consumed increasing concentrations of EtOH (4-12%) during the acquisition phase. During the EAA1 period (12% EtOH), there was a significant genotype effect in both males and females for EtOH preference. Following a 3-week abstinence period, mice received sham or rmTBI resulting in a genotype- and sex-independent main effect of rmTBI on the recovery of righting reflex and a main effect of rmTBI on spontaneous home-cage activity in females only. Reintroduction of 12% EtOH (EAA2) resulted in a significant effect genotype for alcohol preference in males with APOE4 mice displaying increased preference and motivation for alcohol compared with APOE3 mice independent of TBI while in females, there was a significant genotype × TBI interaction under the ADE and DID paradigms. Finally, there was a main effect of rmTBI on increased risk-seeking behavior in both sexes, but no effect on spatial learning or cognitive flexibility. CONCLUSION: These results suggest that sex and APOE genotype play a significant role in alcohol consumption and may subsequently influence long-term recovery following traumatic brain insults.

Toward effective river basin management (RBM): The politics of cooperation, sustainability, and collaboration in the Delaware River basin.

Creating institutions to manage shared waterways at the basin scale, instead of as a patchwork of fragmented political jurisdictions, has long held attraction for water managers and political scientists. Basin-scale planning, management, and governance, the scholarly consensus runs, can promote cooperative management of shared water resources, facilitate management on an ecological rather than political basis, and better engage a diverse set of stakeholders. Yet in practice, River Basin Management (RBM) has proven difficult to institute and often produced disappointing results, being either too weak to be effective or too technocratic. The case of the Delaware River basin in the United States is a noteworthy exception. RBM in the Delaware basin has taken the form of a capable but inclusive inter-jurisdictional commission that has almost eliminated previously widespread conflict between riparian states; generally improved water quality and ecosystem protection; and empowered civil society. Yet this effectiveness stemmed from a messy political process marked by tension and competition between central, state, and local levels of government. Harnessing this tension to forge a durable, adaptable institutional framework proved to be key to the relative success of RBM in the Delaware basin, providing lessons to inform the management of shared watersheds elsewhere.

Associations between COVID-19 perceptions, anxiety, and depressive symptoms among adults living in the United States.

BACKGROUND: Associations among illness perceptions of viruses, anxiety and depression symptoms, and self-management decisions, such as mask-wearing, are critical to informing public health practices to mitigate the short- and long-term consequences of the SARS-CoV-2 viral pandemic. PURPOSE: Guided by the common-sense model of self-regulation, this observational study examined associations among illness perceptions of COVID-19, anxiety, and depression symptoms among community-dwelling adults. METHOD: Data were collected from 1380 adults living in the United States early in the pandemic (03-23-2020 to 06-02-2020). Participants completed online surveys. Analyses were conducted using descriptive statistics and correlations. FINDINGS: While increased anxiety symptoms were associated with less perceived personal control, greater concern, and higher emotional responsiveness, increased depression symptoms were related to lower concern as well as greater emotional responsiveness and perceived consequences of the pandemic. DISCUSSION: Associations among illness perceptions, anxiety, and depression symptoms may impact viral spread mitigation behavior adoption.

The Contribution of Living Arrangements, Social Support, and Self-efficacy to Self-management Behaviors Among Individuals With Heart Failure: A Path Analysis.

BACKGROUND: Living arrangements, social support, and self-efficacy have significant implications for self-management science. Despite the theoretical linkages among the 3 concepts, there is limited empirical evidence about their interplay and the subsequent influence on heart failure (HF) self-management. OBJECTIVE: The aim of this study was to validate components of the Individual and Family Self-management Theory among individuals with HF. METHODS: This is a secondary analysis of cross-sectional data generated from a sample of 370 individuals with HF. A path analysis was conducted to examine the indirect and direct associations among social environment (living arrangements), social facilitation (social support) and belief (self-efficacy) processes, and self-management behaviors (HF self-care maintenance) while accounting for individual and condition-specific factors (age, sex, race, and HF disease severity). RESULTS: Three contextual factors (living arrangements, age, and HF disease severity) had direct associations with perceived social support and self-efficacy, which in turn were positively associated with HF self-management behaviors. Living alone (ß = -.164, P = .001) was associated with lower perceived social support, whereas being an older person (ß = .145, P = .004) was associated with better support. Moderate to severe HF status (ß = -.145, P = .004) or higher levels of perceived social support (ß = .153, P = .003) were associated with self-efficacy. CONCLUSIONS: Our results support the Individual and Family Self-management Theory, highlighting the importance of social support and self-efficacy to foster self-management behaviors for individuals with HF. Future research is needed to further explore relationships among living arrangements, perceived and received social support, self-efficacy, and HF self-management.

Mechanisms of increased hippocampal excitability in the Mashl+/- mouse model of Na+ /K+ -ATPase dysfunction.

OBJECTIVE: Na+ /K+ -ATPase dysfunction, primary (mutation) or secondary (energy crisis, neurodegenerative disease) increases neuronal excitability in the brain. To evaluate the mechanisms underlying such increased excitability we studied mice carrying the D801N mutation, the most common mutation causing human disease, specifically alternating hemiplegia of childhood (AHC) including epilepsy. Because the gene is expressed in all neurons, particularly γ-aminobutyric acid (GABA)ergic interneurons, we hypothesized that the pathophysiology would involve both pyramidal cells and interneurons and that fast-spiking interneurons, which have increased firing rates, would be most vulnerable. METHODS: We performed extracellular recordings, as well as whole-cell patch clamp recordings from pyramidal cells and interneurons, in the CA1 region on hippocampal slices. We also performed immunohistochemistry from hippocampal sections to count CA1 pyramidal cells as well as parvalbumin-positive interneurons. In addition, we performed video-electroencephalography (EEG) recordings from the dorsal hippocampal CA1 region. RESULTS: We observed that juvenile knock-in mice carrying the above mutation reproduce the human phenotype of AHC. We then demonstrated in the CA1 region of these mice the following findings as compared to wild type: (1) Increased number of spikes evoked by electrical stimulation of Schaffer collaterals; (2) equalization by bicuculline of the number of spikes induced by Schaffer collateral stimulation; (3) reduced miniature, spontaneous, and evoked inhibitory postsynaptic currents, but no change in excitatory postsynaptic currents; (4) robust action potential frequency adaptation in response to depolarizing current injection in CA1 fast-spiking interneurons; and (5) no change in the number of pyramidal cells, but reduced number of parvalbumin positive interneurons. SIGNIFICANCE: Our data indicate that, in our genetic model of Atp1α3 mutation, there is increased excitability and marked dysfunction in GABAergic inhibition. This supports the performance of further investigations to determine if selective expression of the mutation in GABAergic and or glutamatergic neurons is necessary and sufficient to result in the behavioral phenotype.

Behavioral Economics: A New Lens for Understanding Genomic Decision Making.

PURPOSE: This article seeks to take the next step in examining the insights that nurses and other healthcare providers can derive from applying behavioral economic concepts to support genomic decision making. As genomic science continues to permeate clinical practice, nurses must continue to adapt practice to meet new challenges. Decisions associated with genomics are often not simple and dichotomous in nature. They can be complex and challenging for all involved. DESIGN: This article offers an introduction to behavioral economics as a possible tool to help support patients', families', and caregivers' decision making related to genomics. METHODS: Using current writings from nursing, ethics, behavioral economic, and other healthcare scholars, we review key concepts of behavioral economics and discuss their relevance to supporting genomic decision making. FINDINGS: Behavioral economic concepts-particularly relativity, deliberation, and choice architecture-are specifically examined as new ways to view the complexities of genomic decision making. Each concept is explored through patient decision making and clinical practice examples. This article also discusses next steps and practice implications for further development of the behavioral economic lens in nursing. CONCLUSIONS: Behavioral economics provides valuable insight into the unique nature of genetic decision-making practices. CLINICAL RELEVANCE: Nurses are often a source of information and support for patients during clinical decision making. This article seeks to offer behavioral economic concepts as a framework for understanding and examining the unique nature of genomic decision making. As genetic and genomic testing become more common in practice, it will continue to grow in importance for nurses to be able to support the autonomous decision making of patients, their families, and caregivers.

A method for evaluating the murine pulmonary vasculature using micro-computed tomography.

BACKGROUND: Significant mortality and morbidity are associated with alterations in the pulmonary vasculature. While techniques have been described for quantitative morphometry of whole-lung arterial trees in larger animals, no methods have been described in mice. We report a method for the quantitative assessment of murine pulmonary arterial vasculature using high-resolution computed tomography scanning. METHODS: Mice were harvested at 2 weeks, 4 weeks, and 3 months of age. The pulmonary artery vascular tree was pressure perfused to maximal dilation with a radio-opaque casting material with viscosity and pressure set to prevent capillary transit and venous filling. The lungs were fixed and scanned on a specimen computed tomography scanner at 8-µm resolution, and the vessels were segmented. Vessels were grouped into categories based on lumen diameter and branch generation. RESULTS: Robust high-resolution segmentation was achieved, permitting detailed quantitation of pulmonary vascular morphometrics. As expected, postnatal lung development was associated with progressive increase in small-vessel number and arterial branching complexity. CONCLUSIONS: These methods for quantitative analysis of the pulmonary vasculature in postnatal and adult mice provide a useful tool for the evaluation of mouse models of disease that affect the pulmonary vasculature.

Opposing effects of traumatic brain injury on excitatory synaptic function in the lateral amygdala in the absence and presence of preinjury stress.

Traumatic brain injury (TBI) is a leading cause of death and disability among young adults and is highly prevalent among recently deployed military personnel. Survivors of TBI often experience cognitive and emotional deficits, suggesting that long-term effects of injury may disrupt neuronal function in critical brain regions, including the amygdala, which is involved in emotion and fear memory. Amygdala hyperexcitability has been reported in both TBI and posttraumatic stress disorder patients, yet little is known regarding the effects of combined stress and TBI on amygdala structure and function at the neuronal level. The present study seeks to determine how the long-term effects of preinjury foot-shock stress and TBI interact to influence synaptic plasticity in the lateral amygdala (LA) of adult male C57BL/6J mice by using whole-cell patch clamp electrophysiology 2-3 months postinjury. In the absence of stress, TBI resulted in a significant increase in membrane excitability and spontaneous excitatory postsynaptic currents (sEPSCs) in LA pyramidal-like neurons. Foot-shock stress in the absence of TBI also resulted in increased sEPSC activity. In contrast, when preinjury stress and TBI occurred in combination, sEPSC activity was significantly decreased compared with either condition alone. There were no significant differences in inhibitory activity or total dendritic length among any of the treatment groups. These results demonstrate that stress and TBI may be contributing to amygdala hyperexcitability via different mechanisms and that these pathways may counterbalance each other with respect to long-term pathophysiology in the LA.

Congenic fine-mapping identifies a major causal locus for variation in the native collateral circulation and ischemic injury in brain and lower extremity.

RATIONALE: Severity of tissue injury in occlusive disease is dependent on the extent (number and diameter) of collateral vessels, which varies widely among healthy mice and humans. However, the causative genetic elements are unknown. Recently, much of the variation among different mouse strains, including C57Bl/6J (B6, high extent) and BALB/cByJ (Bc, low extent), was linked to a quantitative trait locus on chromosome 7 (Candq1). OBJECTIVE: We used congenic mapping to refine Candq1 and its candidate genes to create an isogenic strain set with large differences in collateral extent to assess their impact and the impact of Candq1, alone, on ischemic injury. METHODS AND RESULTS: Six congenic strains possessing portions of Candq1 introgressed from B6 into Bc were generated and phenotyped. Candq1 was refined from 27 to 0.737 Mb with full retention of effect, that is, return or rescue of phenotypes from the poor values in Bc to nearly those of wild-type B6 in the B6/B6 congenic mice as follows: 83% rescue of low pial collateral extent and 4.5-fold increase in blood flow and 85% reduction of infarct volume after middle cerebral artery occlusion; 54% rescue of low skeletal muscle collaterals and augmented recovery of perfusion (83%) and function after femoral artery ligation. Gene deletion and in silico analysis further delineated the candidate genes. CONCLUSIONS: We have significantly refined Candq1 (now designated determinant of collateral extent 1; Dce1), demonstrated that genetic background-dependent variation in collaterals is a major factor underlying differences in ischemic tissue injury, and generated a congenic strain set with wide allele dose-dependent variation in collateral extent for use in investigations of the collateral circulation.

Presynaptic BK channels modulate ethanol-induced enhancement of GABAergic transmission in the rat central amygdala nucleus.

Large-conductance calcium-activated potassium BK channels are widely expressed in the brain and are involved in the regulation of neuronal functions such as neurotransmitter release. However, their possible role in mediating ethanol-induced GABA release is still unknown. We assessed the role of BK channels in modulating the action of ethanol on inhibitory synaptic transmission mediated via GABAA receptors in the rat central nucleus of the amygdala (CeA). Evoked IPSCs (eIPSCs) mediated by GABAA receptors were isolated from CeA neurons under whole-cell voltage clamp, and their response to selective BK channel antagonists, channel activators, or ethanol was analyzed. Blocking BK channels with the specific BK channel antagonist paxilline significantly increased the mean amplitude of eIPSCs, whereas the activation of BK channels with the channel opener NS1619 reversibly attenuated the mean amplitude of eIPSCs. Ethanol (50 mM) alone enhanced the amplitude of eIPSCs but failed to further enhance eIPSCs in the slices pretreated with paxilline. Bath application of either BK channel blockers significantly increased the frequency of miniature IPSCs (mIPSCs). Similarly, 50 mM ethanol alone also enhanced mIPSC frequency. Increases in mIPSC frequency by either selective BK channel antagonists or ethanol were not accompanied with changes in the amplitude of mIPSCs. Furthermore, following bath application of BK channel blockers for 10 min, ethanol failed to further increase mIPSC frequency. Together, these results suggest that blocking BK channels mimics the effects of ethanol on GABA release and that presynaptic BK channels could serve as a target for ethanol effects in CeA.

Cardiovascular risk factors cause premature rarefaction of the collateral circulation and greater ischemic tissue injury.

RATIONALE: Collaterals lessen tissue injury in occlusive disease. However, aging causes progressive decline in their number and smaller diameters in those that remain (collateral rarefaction), beginning at 16 months of age in mice (i.e., middle age), and worse ischemic injury-effects that are accelerated in even 3-month-old eNOS(-/-) mice. These findings have found indirect support in recent human studies. OBJECTIVE: We sought to determine whether other cardiovascular risk factors (CVRFs) associated with endothelial dysfunction cause collateral rarefaction, investigate possible mechanisms, and test strategies for prevention. METHODS AND RESULTS: Mice with nine different models of CVRFs of 4-12 months of age were assessed for number and diameter of native collaterals in skeletal muscle and brain and for collateral-dependent perfusion and ischemic injury after arterial occlusion. Hypertension caused collateral rarefaction whose severity increased with duration and level of hypertension, accompanied by greater hindlimb ischemia and cerebral infarct volume. Chronic treatment of wild-type mice with L-N (G)-nitro-arginine methylester caused similar rarefaction and worse ischemic injury which were not prevented by lowering arterial pressure with hydralazine. Metabolic syndrome, hypercholesterolemia, diabetes mellitus, and obesity also caused collateral rarefaction. Neither chronic statin treatment nor exercise training lessened hypertension-induced rarefaction. CONCLUSION: Chronic CVRF presence caused collateral rarefaction and worse ischemic injury, even at relatively young ages. Rarefaction was associated with increased proliferation rate of collateral endothelial cells, effects that may promote accelerated endothelial cell senescence.