Sex differences in trends and outcomes of acute myocardial infarction with mechanical complications in the United States.

BACKGROUND: Mechanical complications (MC) are rare but significant sequelae of acute myocardial infarction (AMI). Current data on sex differences in AMI with MC is limited. METHODS: We queried the National Inpatient Sample database to identify adult patients with the primary diagnosis of AMI and MC. The main outcome of interest was sex difference in-hospital mortality. Secondary outcomes were sex differences in the incidence of acute kidney injury (AKI), major bleeding, use of inotropes, permanent pacemaker implantation (PPMI), performance of percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), surgery (VSD repair and MV surgery), pericardiocentesis, use of mechanical circulatory support (MCS), ischemic stroke, and mechanical ventilation. RESULTS: Among AMI-MC cohort, in-hospital mortality was higher among females compared to males (41.24% vs 28.13%: aOR 1.39. 95% CI 1.079-1.798; p = 0.01). Among those who had VSD, females also had higher in-hospital mortality compared to males (56.7% vs 43.1%: aOR 1.74, 95% CI 1.12-2.69; p = 0.01). Females were less likely to receive CABG compared to males (12.03% vs 20%: aOR 0.49 95% CI 0.345-0.690; p < 0.001). CONCLUSION: Despite the decreasing trend in AMI admission, females had higher risk of MC and associated mortality. Significant sex disparities still exist in AMI treatment.

Labile Coordination Interphase for Regulating Lean Ion Dynamics in Reversible Zn Batteries.

Rechargeability in zinc (Zn) batteries is limited by anode irreversibility. The practical lean electrolytes exacerbate the issue, compromising the cost benefits of zinc batteries for large-scale energy storage. In this study, a zinc-coordinated interphase is developed to avoid chemical corrosion and stabilize zinc anodes. The interphase promotes Zn2+ ions to selectively bind with histidine and carboxylate ligands, creating a coordination environment with high affinity and fast diffusion due to thermodynamic stability and kinetic lability. Experiments and simulations indicate that interphase regulates dendrite-free electrodeposition and reduces side reactions. Implementing such labile coordination interphase results in increased cycling at 20 mA cm-2 and high reversibility of dendrite-free zinc plating/stripping for over 200 hours. A Zn||LiMn2 O4 cell with 74.7 mWh g-1 energy density and 99.7% Coulombic efficiency after 500 cycles realized enhanced reversibility using the labile coordination interphase. A lean-electrolyte full cell using only 10 µL mAh-1 electrolyte is also demonstrated with an elongated lifespan of 100 cycles, five times longer than bare Zn anodes. The cell offers a higher energy density than most existing aqueous batteries. This study presents a proof-of-concept design for low-electrolyte, high-energy-density batteries by modulating coordination interphases on Zn anodes.

Chronically hypertensive transgenic mice expressing human AT1R haplotype-I exhibit increased susceptibility to Francisella tularensis.

Age-related illnesses, including hypertension and accompanying metabolic disorders, compromise immunity and exacerbate infection-associated fatalities. Renin-angiotensin system (RAS) is the key mechanism that controls blood pressure. Upregulation of RAS through angiotensin receptor type 1 (AT1R), a G-protein coupled receptor, contributes to the pathophysiological consequences leading to vascular remodeling, hypertension, and end-organ damage. Genetic variations that increase the expression of human AT1R may cause the above pathological outcomes associated with hypertension. Previously we have shown that our chronically hypertensive transgenic (TG) mice containing the haplotype-I variant (Hap-I, hypertensive genotype) of human AT1R (hAT1R) gene are more prone to develop the metabolic syndrome-related disorders as compared to the TG mice containing the haplotype-II variant (Hap-II, normotensive genotype). Since aging and an increased risk of hypertension can impact multiple organ systems in a complex manner, including susceptibility to various infections, the current study investigated the susceptibility and potential effect of acute bacterial infection using a Gram-negative intracellular bacterial pathogen, Francisella tularensis in our hAT1R TG mice. Our results show that compared to Hap-II, F. tularensis-infected aged Hap-I TG mice have significantly higher mortality post-infection, higher bacterial load and lung pathology, elevated inflammatory cytokines and altered gene expression profile favoring hypertension and inflammation. Consistent with worsened phenotype in aged Hap-I mice post-Francisella infection, gene expression profiles from their lungs revealed significantly altered expression of more than 1,400 genes. Furthermore, bioinformatics analysis identified genes associated with RAS and IFN-γ pathways regulating blood pressure and inflammation. These studies demonstrate that haplotype-dependent over-expression of the hAT1R gene leads to enhanced susceptibility and lethality due to F. tularensis LVS infection, which gets aggravated in aged animals. Clinically, these findings will help in exploring the role of AT1R-induced hypertension and enhanced susceptibility to infection-related respiratory diseases.

Omega-3 supplements in the prevention and treatment of youth depression and anxiety symptoms: A scoping review.

INTRODUCTION: Omega-3 supplements may be efficacious in reducing symptoms of depression and anxiety in adults, particularly as an adjunct to antidepressant medication. However, research in young people is limited. Thus, this scoping review aimed to summarise existing evidence on the efficacy of omega-3 supplementation in treating depression and anxiety symptoms in young people aged 14-24. A secondary aim was to determine whether grey literature intended for the general public accurately reflects the evidence. METHOD: Four databases (Cochrane CENTRAL, EmBASE, PsycINFO, PubMed) were searched from inception to 4th August 2021. Eligible peer-reviewed studies were empirical studies which examined the efficacy of omega-3 supplements in preventing/treating anxiety and/or depression symptoms in young people aged 14-24. Risk of bias was assessed for randomised studies using the Cochrane Risk of Bias Tool. Selected grey literature databases were also searched, with eligible sources assessed for quality. A stakeholder group including young people with lived experience of anxiety/depression, parents/carers and mental health professionals informed the research questions and data interpretation. Findings were summarised using narrative synthesis. RESULTS: 17 empirical studies (N = 1240 participants) meeting inclusion criteria were identified. Studies varied in treatment and participant characteristics. In general, the data did not support the view that omega-3 supplements were efficacious in improving symptoms of anxiety or depression in young people aged 14-24. In contrast, most grey literature sources recommended the use of omega-3 supplements in young people. DISCUSSION: Evidence for efficacy of omega-3 supplementation in reducing symptoms of depression and anxiety in young people was inconclusive. More research is needed to identify potential mechanisms and moderators of the effect of omega-3 supplements on depression and anxiety symptoms in young people.

Help-Seeking and Barriers to Service Use amongst Men with Past-Year Suicidal Ideation and not in Contact with Mental Health Services.

OBJECTIVE: Men are less likely than women to engage with formal mental health services for suicidality. We describe the sources of support, barriers to service use, and coping strategies of men with past-year suicidal ideation who are not receiving formal mental health services. METHOD: Australian men experiencing past-year suicidal ideation who also did not receive formal mental health services within the past year (n = 176) completed a survey that assessed help-seeking behaviors, coping strategies and styles, use of general services, barriers to service use, and individual-level characteristics. Analyses included descriptive statistics and bivariate analyses. RESULTS: The most common type of support was self-help resources, and self-reliance was the most common barrier to formal mental health service use. Most participants had seen a GP for non-mental-health-related reasons in the past year. Men who did not seek any help for their suicidality experienced lower instrumental barriers and perceived need for support, and lower levels of certain coping styles. Limitations included a cross-sectional design and small sample size. CONCLUSION: The current study provides insight into the help-seeking experiences of men with past-year suicidality and not receiving formal mental health services. The findings suggest it may be helpful to improve the linkage between online and informal sources of support and evidence-based interventions.HIGHLIGHTSOnline self-help, friends, and partners were the most commonly used sources of help.A subset of men (42%) with lower perceived need for help did not seek any support.Despite no past-year formal mental health service use, 80% of the men had seen a GP.

Oral health promotion and programming provided by Aboriginal Community Controlled Health Organisations in South Australia.

BACKGROUND: Aboriginal Community Controlled Health Organisations (ACCHOs) play a critical role in supporting Aboriginal and Torres Strait Islander health in Australia. This article aims to identify and describe oral health programming and promotion provided by ACCHOs in South Australia. METHODS: All ACCHOs in South Australia were identified through the Aboriginal Health Council of South Australia. A targeted search strategy was designed to include the websites and social media pages (Facebook, Twitter, Instagram) for each organisation. Program characteristics were extracted and summarised, and oral health promotion content was analysed utilising content analysis. RESULTS: Twelve programs were identified across the 12 ACCHOs in South Australia. Of these, seven focused on oral health and five focused on nutrition. Oral health and nutrition information shared online by ACCHOs was extracted and aggregated into oral health and nutrition categories, which included reminders about visiting services, advocacy statements, oral hygiene messaging, appointment availability, education resources, and upcoming community-based activities. CONCLUSIONS: The evidence explored highlights the integral role ACCHOs play in oral health promotion and service delivery. It is critically important that ACCHOs are involved in development and implementation of oral health services to ensure programming reflects community knowledges and is effective in improving oral health equity.

Scn1b expression in the adult mouse heart modulates Na+ influx in myocytes and reveals a mechanistic link between Na+ entry and diastolic function.

Voltage-gated sodium channels (VGSCs) are macromolecular assemblies composed of a number of proteins regulating channel conductance and properties. VGSCs generate Na+ current (INa) in myocytes and play fundamental roles in excitability and impulse conduction in the heart. Moreover, VGSCs condition mechanical properties of the myocardium, a process that appears to involve the late component of INa. Variants in the gene SCN1B, encoding the VGSC ß1- and ß1B-subunits, result in inherited neurological disorders and cardiac arrhythmias. But the precise contributions of ß1/ß1B-subunits and VGSC integrity to the overall function of the adult heart remain to be clarified. For this purpose, adult mice with cardiac-restricted, inducible deletion of Scn1b (conditional knockout, cKO) were studied. Myocytes from cKO mice had increased densities of fast (+20%)- and slow (+140%)-inactivating components of INa, with respect to control cells. By echocardiography and invasive hemodynamics, systolic function was preserved in cKO mice, but diastolic properties and ventricular compliance were compromised, with respect to control animals. Importantly, inhibition of late INa with GS967 normalized left ventricular filling pattern and isovolumic relaxation time in cKO mice. At the cellular level, cKO myocytes presented delayed kinetics of Ca2+ transients and cell mechanics, defects that were corrected by inhibition of INa. Collectively, these results document that VGSC ß1/ß1B-subunits modulate electrical and mechanical function of the heart by regulating, at least in part, Na+ influx in cardiomyocytes.NEW & NOTEWORTHY We have investigated the consequences of deletion of Scn1b, the gene encoding voltage-gated sodium channel ß1-subunits, on myocyte and cardiac function. Our findings support the notion that Scn1b expression controls properties of Na+ influx and Ca2+ cycling in cardiomyocytes affecting the modality of cell contraction and relaxation. These effects at the cellular level condition electrical recovery and diastolic function in vivo, substantiating the multifunctional role of ß1-subunits in the physiology of the heart.

Factors associated with professional mental health service use among adults with suicidal ideation.

BACKGROUND: The uptake of professional mental health services among people with suicidal ideation remains low, yet few community-based studies have characterised modifiable individual barriers to service use. Our aims were (1) to identify factors associated with use of professional mental health services among people experiencing suicidal ideation, and (2) to distinguish subgroups with varying levels of service use. METHODS: 1462 Australian adults (78.8% female) were recruited online to participate in a cross-sectional survey. Logistic regression analysis was used to identify factors associated with professional service use. A decision tree model was used to identify subgroups with varying rates of professional service use. RESULTS: Most participants (62%) had used professional services for mental health concerns in the past 12 months. Greater rates of service use were observed in participants who were middle aged, spoke English, disclosed to informal sources or helplines, met criteria for a mental health disorder, had higher levels of entrapment, psychological distress, and disinhibition, and lower levels of detachment and antagonism. At the terminal nodes of the decision tree analysis, service use ranged from 21% to 94%. The most important determinants of service use were meeting criteria for a mental disorder and disclosure of suicidal ideation to family/friends and helplines. CONCLUSION: These findings suggest that interventions to support the safe disclosure of suicidal ideation may assist in increasing service use. There is also the need for services that meet the needs of individuals who do not meet criteria for a mental health condition.

Neutrophil-Derived Myeloperoxidase and Hypochlorous Acid Critically Contribute to 20-Hydroxyeicosatetraenoic Acid Increases that Drive Postischemic Angiogenesis.

Compensatory angiogenesis is an important adaptation for recovery from critical ischemia. We recently identified 20-hydroxyeicosatetraenoic acid (20-HETE) as a novel contributor of ischemia-induced angiogenesis. However, the precise mechanisms by which ischemia promotes 20-HETE increases that drive angiogenesis are unknown. This study aims to address the hypothesis that inflammatory neutrophil-derived myeloperoxidase (MPO) and hypochlorous acid (HOCl) critically contribute to 20-HETE increases leading to ischemic angiogenesis. Using Liquid Chromatography-Mass Spectrometry/Mass Spectrometry, Laser Doppler Perfusion Imaging, and Microvascular Density analysis, we found that neutrophil depletion and MPO knockout mitigate angiogenesis and 20-HETE production in the gracilis muscles of mice subjected to hindlimb ischemia. Furthermore, we found MPO and HOCl to be elevated in these tissues postischemia as assessed by immunofluorescence microscopy and in vivo live imaging of HOCl. Next, we demonstrated that the additions of either HOCl or an enzymatic system for generating HOCl to endothelial cells increase the expression of CYP4A11 and its product, 20-HETE. Finally, pharmacological interference of hypoxia inducible factor (HIF) signaling results in ablation of HOCl-induced CYP4A11 transcript and significant reductions in CYP4A11 protein. Collectively, we conclude that neutrophil-derived MPO and its product HOCl activate HIF-1α and CYP4A11 leading to increased 20-HETE production that drives postischemic compensatory angiogenesis. SIGNIFICANCE STATEMENT: Traditionally, neutrophil derived MPO and HOCl are exclusively associated in the innate immunity as potent bactericidal/virucidal factors. The present study establishes a novel paradigm by proposing a unique function for MPO/HOCl as signaling agents that drive critical physiological angiogenesis by activating the CYP4A11-20-HETE signaling axis via a HIF-1α-dependent mechanism. The findings from this study potentially identify novel therapeutic targets for the treatment of ischemia and other diseases associated with abnormal angiogenesis.

Predictors of not receiving mental health services among people at risk of suicide: A systematic review.

BACKGROUND: The majority of people who die by suicide are unknown to formal mental health services. The current review identified predictors of non-receipt of mental health services among individuals experiencing suicidal thoughts or behaviours. Such data provides insight into the needs and preferences of these individuals and inform improvements to existing services. METHODS: PsycInfo, PubMed/Medline, CINAHL, and Web of Science were systematically searched from 1st January 1980 up to 20th September 2021. Included studies examined predictors of not receiving formal mental health services among people at risk of suicide. Study quality was assessed by adapting the Joanna-Briggs Institute Checklist for Analytical Cross-Sectional Studies. Findings were presented with narrative synthesis. PROSPERO registration: CRD42021256795. RESULTS: Included studies (n = 35, sample range = 46-19,243) were predominately conducted in the United States. Non-receipt of services in nationally representative studies was varied (25.7-91.8%). Results indicate that non-receipt of mental health services among people with suicidality is associated with minority ethnicity, better perceived general health, lower psychological distress, lower severity of suicidality, no mental health diagnosis, lower perceived need for treatment and lower use of medical services. LIMITATIONS: Limitations included few studies conducted in low-middle income countries, limited literature on key predictors of interest, and exclusion of informal sources of support. CONCLUSION: Individuals with suicidality who are unknown to mental health services have diverse attributes. For some, non-use of services may result from low suicidal distress and perceived need for treatment. Further research is needed to understand why these predictors are associated with service non-use.

A Qualitative Study on the Experiences of Women With Breast Implant Illness.

BACKGROUND: Breast implant illness (BII) is a term used to describe physical and psychological symptoms experienced by some women following breast implant surgery. Few studies have examined the experiences of women with BII-a poorly understood condition with no clear cause or treatment. OBJECTIVES: The aim of this study was to explore women's experiences of BII, including symptoms, healthcare encounters, social media, and explant surgery. METHODS: Employing an exploratory qualitative methodology, researchers undertook semistructured interviews with 29 women who self-identified as having BII. Interviews were audio-recorded and transcribed verbatim. Data were analyzed by inductive thematic analysis. RESULTS: Thematic analysis of the interviews identified 6 themes: (1) symptoms without explanation; (2) invalidation and invisibility; (3) making the BII connection; (4) implant toxicity; (5) explant surgery: solution to suffering?; and (6) concealed information. BII was described as distressing and debilitating across multiple domains including relationships, work, identity, and physical and mental health, and symptoms were attributed to implant toxicity and immune system rejection of foreign objects. When their experience was not validated by healthcare professionals, many looked to social media for information, support, and understanding, and saw explant as their only chance of recovery. CONCLUSIONS: BII is disabling mentally and physically. Women with BII require support, understanding, and validation, and proactive treatment to prevent disability. With unclear pathophysiology, future research should examine how biopsychosocial approaches can be used to guide treatment, and how to best support women with BII, focusing on early detection and evidence-based education and intervention.

The relationship between screen time and mental health in young people: A systematic review of longitudinal studies.

An increase in time spent on screen-based technologies has been suggested to underlie recent increases in mental health problems among young people. However, this hypothesis has primarily been based on the findings of cross-sectional studies. The aim of the current review was to provide a comprehensive overview of longitudinal studies examining the relationship between screen time and internalising mental health symptoms. PsycINFO, PubMed/Medline and EMBASE were systematically searched for articles published up to August 2020. Thirty-five studies, with sample sizes ranging from 126 to 12,866 participants, met inclusion criteria. The association between screen time and subsequent depressive symptoms was found to be small to very small in size. There was limited evidence of any reverse association between depressive symptoms and subsequent screen time. The association between screen time and depressive symptoms varied between different devices and uses. In contrast to depressive symptoms, evidence to support longitudinal associations between screen time and other internalising mental health symptoms, including anxiety, self-esteem, and general internalising problems, was lacking. Together, these results suggest that the impact of increased screen time on the prevalence of mental health problems among young people is likely to be negligible or small. Further longitudinal studies that examine screen content and motivations underlying screen use are required to better discern any relationship between screen time and internalising mental health symptoms.

People Who Die by Suicide Without Receiving Mental Health Services: A Systematic Review.

INTRODUCTION: The majority of people who die by suicide have never seen a mental health professional or been diagnosed with a mental illness. To date, this majority group has largely been ignored, with most existing research focusing on predictors of suicide such as past suicide attempts. Identifying the characteristics of people who die by suicide without receiving services, often with a fatal first attempt, is crucial to reduce suicide rates through guiding improvements to service pathways and "just in time" interventions. METHODS: In this systematic review, PsycInfo, PubMed, CINAHL, and Web of Science were searched for peer-reviewed articles published from 1980 to 1st March 2021. Included studies examined predictors of non-receipt of formal mental health services among people who died by suicide. Data were extracted from published reports and the quality of included studies was assessed using a modified version of the Joanna Briggs Institute Checklist for Analytical Cross Sectional Studies. This review was registered with PROSPERO, CRD 42021226543. RESULTS: Sixty-seven studies met inclusion criteria, with sample sizes ranging from 39 to 193,152 individuals. Male sex, younger or older age, and rural location were consistently associated with non-receipt of mental health services. People not receiving mental health services were also less likely to have a psychiatric diagnosis, past suicidal behavior or contact with general health services, and more likely to use violent means of suicide. There was some evidence that minority ethnicity and psychosocial stressors were associated with service non-receipt. CONCLUSION: People who die by suicide without receiving mental health services are likely to have diverse profiles, indicating the need for multifaceted approaches to effectively support people at risk of suicide. Identifying the needs and preferences of individuals who are at risk of suicide is crucial in developing new support pathways and services, and improving the quality of existing services. SYSTEMATIC REVIEW REGISTRATION: http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42021226543.

Commentary on: Understanding Breast Implant Illness.

BACKGROUND: Breast implant surgery is the most common plastic surgery procedure performed globally. A subset of women with breast implants report experiencing a myriad of disabling and distressing physical and psychological symptoms attributed to their implants. Social media groups have coined the condition "breast implant illness" (BII). Little to no scientific research currently exists for BII. OBJECTIVES: The aim of this study was to investigate the experiences of women with BII (both those with implants still in place and those who have explanted) and compare them with those of a control group of women with implants who do not report BII. METHODS: Women with self-reported BII and implants still in place (n = 51), self-reported BII who had explanted (n = 60), and women with implants in place without BII (n = 58) completed online self-report questionnaires about their symptoms, physical and mental health, health service use patterns, and lifestyle factors (eg, exercise, smoking, alcohol consumption). RESULTS: Women with BII, regardless of whether they had undergone explant surgery, reported experiencing more severe somatic symptoms, higher depression, anxiety and health anxiety, and poorer physical health than women without BII. CONCLUSIONS: These findings highlight the need for further investigation into the causes, risk factors, long-term effects, and potential interventions for women who experience BII.

Acute mental health responses during the COVID-19 pandemic in Australia.

The acute and long-term mental health impacts of the COVID-19 pandemic are unknown. The current study examined the acute mental health responses to the COVID-19 pandemic in 5070 adult participants in Australia, using an online survey administered during the peak of the outbreak in Australia (27th March to 7th April 2020). Self-report questionnaires examined COVID-19 fears and behavioural responses to COVID-19, as well as the severity of psychological distress (depression, anxiety and stress), health anxiety, contamination fears, alcohol use, and physical activity. 78% of respondents reported that their mental health had worsened since the outbreak, one quarter (25.9%) were very or extremely worried about contracting COVID-19, and half (52.7%) were worried about family and friends contracting COVID-19. Uncertainty, loneliness and financial worries (50%) were common. Rates of elevated psychological distress were higher than expected, with 62%, 50%, and 64% of respondents reporting elevated depression, anxiety and stress levels respectively, and one in four reporting elevated health anxiety in the past week. Participants with self-reported history of a mental health diagnosis had significantly higher distress, health anxiety, and COVID-19 fears than those without a prior mental health diagnosis. Demographic (e.g., non-binary or different gender identity; Aboriginal and Torres Strait Islander status), occupational (e.g., being a carer or stay at home parent), and psychological (e.g., perceived risk of contracting COVID-19) factors were associated with distress. Results revealed that precautionary behaviours (e.g., washing hands, using hand sanitiser, avoiding social events) were common, although in contrast to previous research, higher engagement in hygiene behaviours was associated with higher stress and anxiety levels. These results highlight the serious acute impact of COVID-19 on the mental health of respondents, and the need for proactive, accessible digital mental health services to address these mental health needs, particularly for those most vulnerable, including people with prior history of mental health problems. Longitudinal research is needed to explore long-term predictors of poor mental health from the COVID-19 pandemic.

The Role of Hormonal and Reproductive Status in the Treatment of Anxiety Disorders in Women.

Exposure therapy, a key treatment for anxiety disorders, can be modelled in the laboratory using Pavlovian fear extinction. Understanding the hormonal and neurobiological mechanisms underlying fear extinction in females, who are twice more likely than males to present with anxiety disorders, may aid in optimising exposure therapy outcomes in this population. This chapter will begin by discussing the role of the sex hormones, estradiol and progesterone, in fear extinction in females. We will also propose potential mechanisms by which these hormones may modulate fear extinction. The second half of this chapter will discuss the long-term hormonal, neurological and behavioural changes that arise from pregnancy and motherhood and how these changes may alter the features of fear extinction in females. Finally, we will discuss implications of this research for the treatment of anxiety disorders in women with and without prior reproductive experience.

Hormonal, reproductive, and behavioural predictors of fear extinction recall in female rats.

The prevalence, severity and chronicity of anxiety disorders is significantly higher in women compared to men. Exposure therapy, the gold-standard treatment for anxiety disorders, can be modelled in the laboratory through Pavlovian fear extinction. Understanding the factors that influence fear extinction in females may aid in optimising the treatment of anxiety disorders in this population. The aim of the current study was therefore to explore the hormonal, reproductive and behavioural predictors of fear extinction recall in female rats by analysing data from nine published experiments that examined fear extinction in female rats. A hierarchical multiple regression analysis revealed that estrous cycle effects on extinction recall may be modulated by reproductive status. While the estrous phase in which nulliparous (virgin) rats undergo extinction training was predictive of extinction recall, no relationship between estrous phase and extinction recall was found among primiparous (one prior reproductive experience) rats. Moreover, estrous cycle predicted the relationship between early extinction and extinction recall in nulliparous rats, but not primiparous rats. Although reproductive status did not predict extinction recall, primiparous rats exhibited poor extinction recall relative to nulliparous rats extinguished during proestrus, and better extinction recall than nulliparous rats extinguished during metestrus. A faster rate of extinction, and lower fear responses at the end of extinction training were predictive of lower levels of CS-elicited fear during extinction recall in both nulliparous and primiparous female rats, while the length of extinction training was not predictive of extinction recall. The potential theoretical and clinical implications of these findings are discussed.

d-Cycloserine and estradiol enhance fear extinction in nulliparous but not primiparous female rats.

Female reproductive experience has been shown to alter the hormonal, neurobiological and behavioural features of fear extinction, which is the laboratory basis of exposure therapy. This raises uncertainties as to whether pharmacological agents that enhance fear extinction in reproductively inexperienced females are equally effective in reproductively experienced females. The aim of the current study was therefore to compare the effects of two pharmacological enhancers of fear extinction, d-cycloserine (DCS) and estradiol, between nulliparous (virgin) and primiparous (reproductively experienced) female rats. In Experiment 1, nulliparous and primiparous females received systemic administration of either DCS or saline immediately after extinction training, and were tested for extinction recall the following day. DCS enhanced extinction recall in nulliparous females that showed low levels of freezing at the end of extinction training, but not among those that showed high levels of freezing at the end of extinction training. DCS did not enhance fear extinction in primiparous females, regardless of their level of freezing at the end of extinction training. In Experiment 2, nulliparous and primiparous female rats received systemic administration of either estradiol or vehicle prior to extinction training. Estradiol enhanced extinction recall among nulliparous females, but not primiparous females. Increasing the dose of estradiol administered prior to extinction training did not alter the outcomes in primiparous females (Experiment 3). Together, these findings suggest that reproductive status may be an important individual difference factor associated with the response to pharmacological modulators of extinction in rats. The implications of these findings for the pharmacological augmentation of exposure therapy in clinical populations are discussed.

CYP4A/20-HETE regulates ischemia-induced neovascularization via its actions on endothelial progenitor and preexisting endothelial cells.

20-Hydroxyeicosatetraenoic acid (20-HETE) was recently identified as a novel contributor of ischemia-induced neovascularization based on the key observation that pharmacological interferences of CYP4A/20-HETE decrease ischemic neovascularization. The objective of the present study is to examine whether the underlying cellular mechanisms involve endothelial progenitor cells (EPCs) and preexisting endothelial cells (ECs). We found that ischemia leads to a time-dependent increase of cyp4a12 expression and 20-HETE production, which are endothelial in origin, using immunofluorescent microscopy, Western blot analysis, and LC-MS/MS. This is accompanied by increases in the tissue stromal cell-derived factor-1α (SDF-1α) expressions as well as SDF-1α plasma levels, EPC mobilization from bone marrow, and subsequent homing to ischemic tissues. Pharmacological interferences of CYP4A/20-HETE with a 20-HETE synthesis inhibitor, dibromo-dodecenyl-methylsulfimide (DDMS), or a 20-HETE antagonist, N-(20-hydroxyeicosa-6(Z), 15(Z)-dienoyl) glycine (6, 15-20-HEDGE), significantly attenuated these increases. Importantly, we also determined that 20-HETE plays a novel role in maintaining EPC functions and increasing the expression of Oct4, Sox2, and Nanog, which are indicative of increased progenitor cell stemness. Flow cytometric analysis revealed that pharmacological interferences of CYP4A/20-HETE decrease the EPC population in culture, whereas 20-HETE increases the cultured EPC population. Furthermore, ischemia also markedly increased the proliferation, oxidative stress, and ICAM-1 expression in the preexisting EC in the hindlimb gracilis muscles. We found that these increases were markedly negated by DDMS and 6, 15-20-HEDGE. Taken together, CYP4A/20-HETE regulates ischemia-induced compensatory neovascularization via its combined actions on promoting EPC and local preexisting EC responses that are associated with increased neovascularization. NEW & NOTEWORTHY CYP4A/20-hydroxyeicosatetraenoic acid (20-HETE) was recently discovered as a novel contributor of ischemia-induced neovascularization. However, the underlying molecular and cellular mechanisms are completely unknown. Here, we show that CYP4A/20-HETE regulates the ischemic neovascularization process via its combined actions on both endothelial progenitor cells (EPCs) and preexisting endothelial cells. Moreover, this is the first study, to the best of our knowledge, that associates CYP4A/20-HETE with EPC differentiation and stemness.