Neighborhood Resources and Health Outcomes Among Stroke Survivors in a Population-Based Cohort.

BACKGROUND: Stroke survivors believe neighborhood resources such as community centers are beneficial; however, little is known about the influence of these resources on stroke outcomes. We evaluated whether residing in neighborhoods with greater resource density is associated with favorable post-stroke outcomes. METHODS AND RESULTS: We included Mexican American and non-Hispanic White stroke survivors from the Brain Attack Surveillance in Corpus Christi project (2009-2019). The exposure was density of neighborhood resources (eg, community centers, restaurants, stores) within a residential census tract at stroke onset. Outcomes included time to death and recurrence, and at 3 months following stroke: disability (activities of daily living/instrumental activities of daily living), cognition (Modified Mini-Mental State Exam), depression (Patient Health Questionnaire-8), and quality of life (abbreviated Stroke-Specific Quality of Life scale). We fit multivariable Cox regression and mixed linear models. We considered interactions with stroke severity, ethnicity, and sex. Among 1786 stroke survivors, median age was 64 years (interquartile range, 56-73), 55% men, and 62% Mexican American. Resource density was not associated with death, recurrence, or depression. Greater resource density (75th versus 25th percentile) was associated with more favorable cognition (Modified Mini-Mental State Exam mean difference=0.838, 95% CI=0.092, 1.584) and among moderate-severe stroke survivors, with more favorable functioning (activities of daily living/instrumental activities of daily living=-0.156 [95% CI, -0.284 to 0.027]) and quality of life (abbreviated Stroke-Specific Quality of Life scale=0.194 [95% CI, 0.029-0.359]). CONCLUSIONS: We observed associations between greater resource density and cognition overall and with functioning and quality of life among moderate-severe stroke survivors. Further research is needed to confirm these findings and determine if neighborhood resources may be a tool for recovery.

Association of Neighborhood Recreation Centers and Poststroke Outcomes in a Population-Based Cohort.

BACKGROUND: Higher neighborhood socioeconomic status has been favorably associated with stroke outcomes. This may be due to these areas having more beneficial resources such as recreational centers. We aimed to determine if neighborhood density of recreation centers is favorably associated with stroke outcomes. METHODS: We conducted analyses of data from the Brain Attack Surveillance in Corpus Christi project, a cohort of stroke survivors ≥45 years of age residing in Nueces County, TX (2009-2020). We included non-Hispanic White and Mexican American incident stroke survivors, who were not institutionalized prestroke and completed baseline and follow-up assessments (N=1392). We calculated the density of fitness and recreational sports centers within their residential census tract during the year of their stroke. Outcomes included function (self-ratings on activities of daily living and instrumental activities of daily living), cognition (modified mini-mental state exam), depression (Patient Health Questionnaire-8), and quality of life (abbreviated Stroke-Specific Quality of Life Scale). We fit confounder-adjusted gamma-distributed mixed generalized linear models with a log link for each outcome and considered interaction with stroke severity. RESULTS: On average, participants were 65 years old, 53% male, and 63% Mexican American. Median recreational centers were 1.60 per square mile (interquartile range, 0.41-3.06). Among moderate-severe stroke survivors, greater density of recreation centers (75th versus 25th percentile) was associated with more favorable function and possibly quality of life (activities of daily living/instrumental activities of daily living, 4.8% change [95% CI, -0.11% to -9.27%]; Stroke-Specific Quality of Life Scale, 3.7% change [95% CI, -0.7% to 8.2%]). Minimal nonsignificant differences were observed among the overall stroke population and those with mild stroke. CONCLUSIONS: The availability of recreation centers may be beneficial for poststroke function and quality of life among those with moderate-severe stroke. If further research confirms recreation centers to be beneficial, this could inform rehabilitation following stroke.

Outcomes in the Year After First-Ever Ischemic Stroke in a Bi-Ethnic Population.

OBJECTIVE: To investigate stroke outcomes at 3, 6, and 12 months post-stroke overall and by ethnicity in a population-based, longitudinal study. METHODS: First-ever ischemic strokes (2014-2019, n = 1,332) among Mexican American persons (n = 807) and non-Hispanic white persons (n = 525) were identified from the Brain Attack Surveillance in Corpus Christi Project. Data were collected from patient or proxy interviews (baseline, 3, 6, and 12 months post-stroke) and medical records, including functional (activities of daily living/instrumental activities of daily living score), neurological (National Institutes of Health Stroke Scale), cognitive (Modified Mini-Mental State Examination), and quality of life (QOL) outcomes (12-domain Stroke-specific Quality of Life scale). Outcome trajectories were analyzed using multivariable adjusted linear models, with generalized estimating equations to account for within-subject correlations; interactions between ethnicity and time were included to investigate ethnic differences in outcomes. RESULTS: The median age was 67 years (interquartile range 58,78), 48.5% were women, and 60.6% were Mexican American persons. For all outcomes, significant improvement was seen between 3 and 6 months (p < 0.05 for all), with stability between 6 and 12 months. Mexican American persons had significantly worse outcomes compared with non-Hispanic white persons at all time points (3, 6, and 12 months), with the exception of the National Institutes of Health Stroke Scale, which did not differ by ethnicity at 6 and 12 months, and the average change in outcomes did not vary significantly by ethnicity. INTERPRETATION: Outcomes were at their worst at 3 months post-stroke, and ethnic disparities were already present, suggesting the need for early assessment and strategies to improve outcomes and possibly reduce disparities. ANN NEUROL 2023;93:348-356.

Methods and early recruitment of the Brain Attack Surveillance in Corpus Christi-Post-acute Care (BASIC-PAC) Project.

OBJECTIVES: Compared with non-Hispanic whites (NHWs), Mexican Americans (MAs) have worse stroke outcomes. We report here the methods, background literature, and initial recruitment of the Brain Attack Surveillance in Corpus Christi-Post Acute Care (BASIC-PAC) Project which aims to explore PAC in MAs and NHWs from multiple perspectives: patients, caregivers, and community. MATERIALS AND METHODS: Rigorous active and passive stroke surveillance captures all strokes in Nueces County, Texas. Stroke patients are followed for 90 days to determine their care transitions and factors influencing their rehabilitation setting. Informal caregivers of the stroke patients are identified and interviewed at 90 days to determine aspects of their caregiving and caregiver outcomes. Available community resources are compared with stated needs among stroke patient and caregivers to determine unmet needs. RESULTS: Between October, 2019 and October, 2021, among the 629 stroke patients eligible, 413 were MA, 227 were NHW. Of the 629, all of the six follow-up calls were completed by 355 of the MAs (87%) and 191 of the NHWs (87%). During this same time period, we attempted to approach 621 potential caregivers. Of these, 458 (73.8%) potential caregivers participated in interviews to determine caregiver eligibility, and 373 (81.4%) of these participating potential caregivers met the eligibility criteria. CONCLUSIONS: BASIC-PAC has strong initial recruitment and is poised to provide valuable data on multiple aspects of PAC and how PAC differs by ethnicity and contributes to worse stroke outcomes in MAs. Based on the study findings, interventions can be developed that will improve stroke health equity.

Temporal Trends in Ischemic Stroke Rates by Ethnicity, Sex, and Age (2000-2017): The Brain Attack Surveillance in Corpus Christi Project.

OBJECTIVE: To compare 18-year (2000-2017) temporal trends in ischemic stroke rates by ethnicity, sex, and age. METHODS: Data are from a population-based stroke surveillance study conducted in Nueces County, Texas, a geographically isolated, biethnic, urban community. Active (screening hospital admission logs, hospital wards, intensive care units) and passive (screening inpatient/emergency department discharge diagnosis codes) surveillance were used to identify cases aged ≥45 (n = 4,875) validated by stroke physicians using a consistent stroke definition over time. Ischemic stroke rates were derived from Poisson regression using annual population counts from the US Census to estimate the at-risk population. RESULTS: In those aged 45-59 years, rates increased in non-Hispanic Whites (104.3% relative increase; p < 0.001) but decreased in Mexican Americans (-21.9%; p = 0.03) such that rates were significantly higher in non-Hispanic Whites in 2016-2017 (p for ethnicity-time interaction < 0.001). In those age 60-74, rates declined in both groups but more so in Mexican Americans (non-Hispanic Whites -18.2%, p = 0.05; Mexican Americans -40.1%, p = 0.002), resulting in similar rates for the 2 groups in 2016-2017 (p for ethnicity-time interaction = 0.06). In those aged ≥75, trends did not vary by ethnicity, with declines noted in both groups (non-Hispanic Whites -33.7%, p = 0.002; Mexican Americans -26.9%, p = 0.02). Decreases in rates were observed in men (age 60-74, -25.7%, p = 0.009; age ≥75, -39.2%, p = 0.002) and women (age 60-74, -34.3%, p = 0.007; age ≥75, -24.0%, p = 0.02) in the 2 older age groups, while rates did not change in either sex in those age 45-59. CONCLUSION: Previously documented ethnic stroke incidence disparities have ended as a result of declining rates in Mexican Americans and increasing rates in non-Hispanic Whites, most notably in midlife.

Estrogen and Progesterone Integration in an in vitro Model of RP3V Kisspeptin Neurons.

Positive feedback on gonadotropin release requires not only estrogen but also progesterone to activate neural circuits. In rodents, ovarian estradiol (E2) stimulates progesterone synthesis in hypothalamic astrocytes (neuroP), needed for the luteinizing hormone (LH) surge. Kisspeptin (kiss) neurons are the principal stimulators of gonadotropin-releasing hormone neurons, and disruption of kiss signaling abrogates the LH surge. Similarly, blocking steroid synthesis in the hypothalamus or deleting classical progesterone receptor (PGR) selectively in kiss neurons prevents the LH surge. These results suggest a synergistic action of E2 and progesterone in kiss neurons to affect gonadotropin release. The mHypoA51, immortalized kiss-expressing neuronal cell line derived from adult female mice, is a tractable model for examining integration of steroid signaling underlying estrogen positive feedback. Here, we report that kiss neurons in vitro integrate E2 and progesterone signaling to increase levels of kiss translation and release. mHypoA51 neurons expressed nonclassical membrane progesterone receptors (mPRα and mPRß) and E2-inducible PGR, required for progesterone-augmentation of E2-induced kiss expression. With astrocyte-conditioned media or in mHypoA51-astrocyte co-culture, neuroP augmented stimulatory effects of E2 on kiss protein. Progesterone activation of classical, membrane-localized PGR led to activation of MAPK and Src kinases. Importantly, progesterone or Src activation induced release of kiss from E2-primed mHypoA51 neurons. Consistent with previous studies, the present results provide compelling evidence that the interaction of E2 and progesterone stimulates kiss expression and release. Further, these results demonstrate a mechanism though which peripheral E2 may prime kiss neurons to respond to neuroP, mediating estrogen positive feedback.

Sex differences in the impact of acute stroke treatment in a population-based study: a sex-specific propensity score approach.

PURPOSE: We investigated whether sex modifies the association of acute stroke treatment on functional outcome using propensity score (PS) methods to minimize confounding and to explore the differential effects of confounders by sex. METHODS: We included tissue plasminogen activator (tPA) treated (n = 84) and nontreated ischemic stroke cases (n = 143) from a population-based stroke study (2008-2013). The PS model that estimated the probability of receiving tPA included interactions between sex and treatment predictors. The outcome model included sex, tPA, and their interaction. In addition, sex-specific PS values were included as a continuous covariate and modeled using splines. We compared the results with conventional methods of statistical adjustment. RESULTS: Conventional methods of adjustment suggested that women receive greater benefit from tPA than men. After taking into consideration that the influence of confounders, specifically age and stroke severity, differed by sex, we found no sex difference in the tPA-functional outcome association (P = .94). CONCLUSIONS: Using PS methods that considered confounding of the sex × treatment interaction, we did not find that the association of tPA with functional outcome differed for women and men. Our findings may have implications for the methodologic approaches used to address confounding in studies that seek to compare stroke treatment effects by sex.

Synergism of Short-Term Air Pollution Exposures and Neighborhood Disadvantage on Initial Stroke Severity.

BACKGROUND AND PURPOSE: Little is known about the relation between environment and stroke severity. We investigated associations between environmental exposures, including neighborhood socioeconomic disadvantage and short-term exposure to airborne particulate matter <2.5 µm and ozone, and their interactions with initial stroke severity. METHODS: First-ever ischemic stroke cases were identified from the Brain Attack Surveillance in Corpus Christi project (2000-2012). Associations between pollutants, disadvantage, and National Institutes of Health Stroke Scale were modeled using linear and logistic regression with adjustment for demographics and risk factors. Pollutants and disadvantage were modeled individually, jointly, and with interactions. RESULTS: Higher disadvantage scores and previous-day ozone concentrations were associated with higher odds of severe stroke. Higher levels of particulate matter <2.5 µm were associated with higher odds of severe stroke among those in higher disadvantage areas (odds ratio, 1.24; 95% confidence interval, 1.00-1.55) but not in lower disadvantage areas (odds ratio, 0.82; 95% confidence interval, 0.56-1.22; P interaction =0.097). CONCLUSIONS: Air pollution exposures and neighborhood socioeconomic status may be important in understanding stroke severity. Future work should consider the multiple levels of influence on this important stroke outcome.

Rodent Models of Non-classical Progesterone Action Regulating Ovulation.

It is becoming clear that steroid hormones act not only by binding to nuclear receptors that associate with specific response elements in the nucleus but also by binding to receptors on the cell membrane. In this newly discovered manner, steroid hormones can initiate intracellular signaling cascades which elicit rapid effects such as release of internal calcium stores and activation of kinases. We have learned much about the translocation and signaling of steroid hormone receptors from investigations into estrogen receptor α, which can be trafficked to, and signal from, the cell membrane. It is now clear that progesterone (P4) can also elicit effects that cannot be exclusively explained by transcriptional changes. Similar to E2 and its receptors, P4 can initiate signaling at the cell membrane, both through progesterone receptor and via a host of newly discovered membrane receptors (e.g., membrane progesterone receptors, progesterone receptor membrane components). This review discusses the parallels between neurotransmitter-like E2 action and the more recently investigated non-classical P4 signaling, in the context of reproductive behaviors in the rodent.

Stroke Performance Measures Do Not Predict Functional Outcome.

BACKGROUND AND PURPOSE: Poststroke functional outcome is critical to stroke survivors. We sought to determine whether adherence to current stroke performance measures is associated with better functional outcome 90 days after an ischemic stroke. METHODS: Utilizing the Brain Attack Surveillance in Corpus Christi cohort, we examined adherence to 7 ischemic stroke performance measures from February 2009 to June 2012. Adherence to the measures was analyzed in aggregate using a binary defect-free score and an opportunity score, representing the proportion of eligible measures met. The opportunity score ranges from 0 to 1, with values closer to 1 implying better adherence. Functional outcome, defined by an activities of daily living and instrumental activities of daily living (ADL/IADL) score (range 1-4, higher scores worse), was ascertained at 90 days poststroke. Tobit regression models were fitted to examine the associations between the performance measures and functional outcome, adjusting for demographic and clinical characteristics, including stroke severity. RESULTS: There were 565 patients with ischemic stroke included in the analysis. The median ADL/IADL score was 2.32 (interquartile range [IQR]: 1.41-3.41). The median opportunity score was 1 (IQR: 0.8-1), and 58.4% of the patients received defect-free care. After adjustment, the opportunity score (P = .67) and defect-free care (P = .92) were not associated with functional outcome. CONCLUSION: In this population, adherence to a composite of current stroke performance measures was not associated with poststroke functional outcome after adjustment for other factors. Performance measures that are associated with improved functional outcome should be developed and incorporated into stroke quality measures.

Short-term exposures to ambient air pollution and risk of recurrent ischemic stroke.

OBJECTIVE: To investigate the association between short-term changes in ambient pollution (particulate matter <2.5µm in aerodynamic diameter (PM2.5) and ozone (O3)) and the risk of recurrent ischemic stroke among individuals living in a bi-ethnic community. METHODS: We identified recurrent ischemic stroke cases from the population-based Brain Attack Surveillance in Corpus Christi (BASIC) project between 2000 and 2012. Associations between PM2.5 (mean 24-h) and O3 (maximal 8-h) levels, measured on the previous day, and odds of ischemic stroke were assessed using a time-stratified case-crossover design and modeled using conditional logistic regression. RESULTS: There were 317 recurrent ischemic strokes after excluding 41 strokes that occurred on days with missing air pollution data. Mean age was 72 years (SD=12) and median time to stroke recurrence was 1.1 years (IQR: 0.2-2.8 years). Median levels of PM2.5 and O3 over the study period were 7.7µg/m3 (IQR: 5.6-10.7µg/m3) and 35.2 ppb (IQR: 25.0-46.1 ppb), respectively. We observed no associations between previous-day PM2.5 and O3 and odds of recurrent stroke (OR=0.95 per 10µg/m3 of PM2.5, 95% CI: 0.71-1.28 and OR=0.97 per 10ppb of O3, 95% CI: 0.87-1.07) after adjusting for ambient temperature and relative humidity. Co-adjustment of both pollutants did not change the results. CONCLUSION: We found no evidence of associations between previous-day air pollution levels and recurrent ischemic stroke. Research on the influence of air pollutants on risk of stroke recurrence is still in its infancy, and more research is necessary in studies that are adequately powered to understand the relation.

Actions of Steroids: New Neurotransmitters.

Over the past two decades, the classical understanding of steroid action has been updated to include rapid, membrane-initiated, neurotransmitter-like functions. While steroids were known to function on very short time spans to induce physiological and behavioral changes, the mechanisms by which these changes occur are now becoming more clear. In avian systems, rapid estradiol effects can be mediated via local alterations in aromatase activity, which precisely regulates the temporal and spatial availability of estrogens. Acute regulation of brain-derived estrogens has been shown to rapidly affect sensorimotor function and sexual motivation in birds. In rodents, estrogens and progesterone are critical for reproduction, including preovulatory events and female sexual receptivity. Membrane progesterone receptor as well as classical progesterone receptor trafficked to the membrane mediate reproductive-related hypothalamic physiology, via second messenger systems with dopamine-induced cell signals. In addition to these relatively rapid actions, estrogen membrane-initiated signaling elicits changes in morphology. In the arcuate nucleus of the hypothalamus, these changes are needed for lordosis behavior. Recent evidence also demonstrates that membrane glucocorticoid receptor is present in numerous cell types and species, including mammals. Further, membrane glucocorticoid receptor influences glucocorticoid receptor translocation to the nucleus effecting transcriptional activity. The studies presented here underscore the evidence that steroids behave like neurotransmitters to regulate CNS functions. In the future, we hope to fully characterize steroid receptor-specific functions in the brain.

Ablation of KNDy Neurons Results in Hypogonadotropic Hypogonadism and Amplifies the Steroid-Induced LH Surge in Female Rats.

In the human infundibular (arcuate) nucleus, a subpopulation of neurons coexpress kisspeptin and neurokinin B (NKB), 2 peptides required for normal reproductive function. A homologous group of neurons exists in the arcuate nucleus of rodents, termed KNDy neurons based on the coexpression of kisspeptin, NKB, and dynorphin. To study their function, we recently developed a method to selectively ablate KNDy neurons using NK3-SAP, a neurokinin 3 receptor agonist conjugated to saporin (SAP). Here, we ablated KNDy neurons in female rats to determine whether these neurons are required for estrous cyclicity and the steroid induced LH surge. NK3-SAP or Blank-SAP (control) was microinjected into the arcuate nucleus using stereotaxic surgery. After monitoring vaginal smears for 3-4 weeks, rats were ovariectomized and given 17ß-estradiol and progesterone in a regimen that induced an afternoon LH surge. Rats were killed at the time of peak LH levels, and brains were harvested for NKB and dual labeled GnRH/Fos immunohistochemistry. In ovary-intact rats, ablation of KNDy neurons resulted in hypogonadotropic hypogonadism, characterized by low levels of serum LH, constant diestrus, ovarian atrophy with increased follicular atresia, and uterine atrophy. Surprisingly, the 17ß-estradiol and progesterone-induced LH surge was 3 times higher in KNDy-ablated rats. Despite the marked increase in the magnitude of the LH surge, the number of GnRH or anterior ventral periventricular nucleus neurons expressing Fos was not significantly different between groups. Our studies show that KNDy neurons are essential for tonic levels of serum LH and estrous cyclicity and may play a role in limiting the magnitude of the LH surge.

Neighborhood Influences on Emergency Medical Services Use for Acute Stroke: A Population-Based Cross-sectional Study.

STUDY OBJECTIVE: Delay to hospital arrival limits acute stroke treatment. Use of emergency medical services (EMS) is key in ensuring timely stroke care. We aim to identify neighborhoods with low EMS use and to evaluate whether neighborhood-level factors are associated with EMS use. METHODS: We conducted a secondary analysis of data from the Brain Attack Surveillance in Corpus Christi project, a population-based stroke surveillance study of ischemic stroke and intracerebral hemorrhage cases presenting to emergency departments in Nueces County, TX. The primary outcome was arrival by EMS. The primary exposures were neighborhood resident age, poverty, and violent crime. We estimated the association of neighborhood-level factors with EMS use, using hierarchic logistic regression, controlling for individual factors (stroke severity, ethnicity, and age). RESULTS: During 2000 to 2009 there were 4,004 identified strokes, with EMS use data available for 3,474. Nearly half (49%) of stroke cases arrived by EMS. Adjusted stroke EMS use was lower in neighborhoods with higher family income (odds ratio [OR] 0.86; 95% confidence interval [CI] 0.75 to 0.97) and a larger percentage of older adults (OR 0.70; 95% CI 0.56 to 0.89). Individual factors associated with stroke EMS use included white race (OR 1.41; 95% CI 1.13 to 1.76) and older age (OR 1.36 per 10-year age increment; 95% CI 1.27 to 1.46). The proportion of neighborhood stroke cases arriving by EMS ranged from 17% to 71%. The fully adjusted model explained only 0.3% (95% CI 0% to 1.1%) of neighborhood EMS stroke use variance, indicating that individual factors are more strongly associated with stroke EMS use than neighborhood factors. CONCLUSION: Although some neighborhood-level factors were associated with EMS use, patient-level factors explained nearly all variability in stroke EMS use. In this community, strategies to increase EMS use should target individuals rather than specific neighborhoods.

Ethnic differences in ambient air pollution and risk of acute ischemic stroke.

OBJECTIVES: To investigate the association between short-term changes in ambient pollution (particulate matter <2.5 µm in aerodynamic diameter (PM2.5) and ozone (O3)) and the risk of ischemic stroke among individuals living in a bi-ethnic community and whether this association is modified by ethnicity. METHODS: We identified incident ischemic stroke cases from the population-based Brain Attack Surveillance in Corpus Christi (BASIC) project between 2000 and 2012. Associations between PM2.5 (mean 24-h) and O3 (maximal 8-h) levels, measured on the same-day and lags of 1-3 days, and odds of ischemic stroke were assessed using a time-stratified case-crossover design and modeled using conditional logistic regression. We explored race/ethnicity (Mexican American versus non-Hispanic white) as a modifier by including interaction terms in the models. RESULTS: There were 2948 ischemic strokes with median age 71 years (IQR: 59-80). We observed no overall associations between the air pollutants and odds of ischemic stroke at any lag. When stratified by ethnicity, higher O3 was consistently associated with greater odds of ischemic stroke for non-Hispanic whites, but not for Mexican Americans. Higher PM2.5 was generally associated with lower odds of ischemic stroke for non-Hispanic whites but modestly greater odds for Mexican Americans. CONCLUSION: Ethnic differences in the associations between ischemic stroke and short-term exposures to O3 and PM2.5 were suggested indicating that further study in diverse populations may be warranted.

Neurokinin 3 Receptor-Expressing Neurons in the Median Preoptic Nucleus Modulate Heat-Dissipation Effectors in the Female Rat.

KNDy neurons facilitate tail skin vasodilation and modulate the effects of estradiol on thermoregulation. We hypothesize that KNDy neurons influence cutaneous vasodilation via projections to neurons in the median preoptic nucleus (MnPO) that express the neurokinin 3 receptor (NK3R). In support of this hypothesis, focal microinjections of senktide, an NK3R agonist, into the MnPO lowers core temperature (TCORE) in the female rat. To further study the role of MnPO NK3R neurons in thermoregulation, these neurons were specifically ablated using a conjugate of a selective NK3R agonist and saporin (NK3-SAP). NK3-SAP or blank-SAP (control) was injected into the MnPO/medial septum. Tail skin temperature (TSKIN) and TCORE were measured in ovariectomized rats exposed to 3 ambient temperatures (TAMBIENT) before and after estradiol-17ß (E2) treatment. Before killing, we injected senktide (sc), monitored TCORE for 70 minutes, and harvested brains for Fos immunohistochemistry. Ablation of MnPO NK3R neurons lowered TSKIN at neutral and subneutral TAMBIENT regardless of E2 treatment. However, ablation did not prevent the effects of E2 on TCORE and TSKIN. In control rats, senktide injections induced hypothermia with numerous Fos-immunoreactive cells in the MnPO. In contrast, in NK3-SAP rats, senktide did not alter TCORE and minimal Fos-immunoreactive neurons were identified in the MnPO. These data show that NK3R neurons in the MnPO are required for the hypothermic effects of senktide but not for the E2 modulation of thermoregulation. The lower TSKIN in NK3-SAP-injected rats suggests that MnPO NK3R neurons, like KNDy neurons, facilitate cutaneous vasodilation, an important heat-dissipation effector.

Residential ethnic segregation and stroke risk in Mexican Americans: the Brain Attack Surveillance in Corpus Christi project.

OBJECTIVE: Residential ethnic segregation may operate through multiple mechanisms to increase stroke risk. The current study evaluated if residential ethnic segregation was associated with stroke risk in a bi-ethnic population. DESIGN: Incident strokes were identified in Nueces County, Texas from 2000 to 2010. Residential ethnic segregation (range: 0-1) was derived for each census tract in the county (n=64) using 2000 US Census data, and categorized into: predominantly non-Hispanic White (NHW, <.3); ethnically mixed (.3-.7); predominantly Mexican American (MA, >.7). Multilevel Poisson regression models were fitted separately for NHWs and MAs to assess the association between residential ethnic segregation (predominantly NHW referent) and relative risk for stroke, adjusted for age category, sex and census tract-level median per capita income. Effect modification by age was also examined. RESULTS: In adjusted models, residential ethnic segregation was not associated with stroke risk in either ethnic group. Effect modification by age was significant in both groups. Young MAs and NHWs living in predominantly MA census tracts were at greater relative risk for stroke than those living in predominantly NHW census tracts, but this association was only significant for MAs (MAs: RR = 2.38 [95% CI: 1.31-4.31]; NHWs: RR = 1.53 [95% CI: .92-2.52]). CONCLUSION: Our findings demonstrate that residential ethnic segregation may influence downstream stroke risk in young MAs. Pathways between residential ethnic segregation and stroke in young MAs should be explored.

Classical and membrane-initiated estrogen signaling in an in vitro model of anterior hypothalamic kisspeptin neurons.

The neuropeptide kisspeptin is essential for sexual maturation and reproductive function. In particular, kisspeptin-expressing neurons in the anterior rostral periventricular area of the third ventricle are generally recognized as mediators of estrogen positive feedback for the surge release of LH, which stimulates ovulation. Estradiol induces kisspeptin expression in the neurons of the rostral periventricular area of the third ventricle but suppresses kisspeptin expression in neurons of the arcuate nucleus that regulate estrogen-negative feedback. To focus on the intracellular signaling and response to estradiol underlying positive feedback, we used mHypoA51 cells, an immortalized line of kisspeptin neurons derived from adult female mouse hypothalamus. mHypoA51 neurons express estrogen receptor (ER)-α, classical progesterone receptor (PR), and kisspeptin, all key elements of estrogen-positive feedback. As with kisspeptin neurons in vivo, 17ß-estradiol (E2) induced kisspeptin and PR in mHypoA51s. The ERα agonist, 1,3,5-Tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole, produced similar increases in expression, indicating that these events were mediated by ERα. However, E2-induced PR up-regulation required an intracellular ER, whereas kisspeptin expression was stimulated through a membrane ER activated by E2 coupled to BSA. These data suggest that anterior hypothalamic kisspeptin neurons integrate both membrane-initiated and classical nuclear estrogen signaling to up-regulate kisspeptin and PR, which are essential for the LH surge.

Factors influencing sex differences in poststroke functional outcome.

BACKGROUND AND PURPOSE: Our objective was to identify factors that contribute to or modify the sex difference in poststroke functional outcome. METHODS: Ischemic strokes (n=439) were identified from the Brain Attack Surveillance in Corpus Christi (BASIC) Project (2008-2011). Data were ascertained from interviews (baseline and 90 days post stroke) and medical records. Functional outcome was measured as an average of 22 activities of daily living (ADL)/instrumental ADL items (range, 1-4; higher scores worse function). Tobit regression was used to estimate sex differences and to identify confounding and modifying factors. RESULTS: Fifty-one percent were women. Median age was 71 (interquartile range, 59-80) years in women and 64 (interquartile range, 56-77) years in men. Median ADL/instrumental ADL score at 90 days was 2.7 (interquartile range, 1.8-3.6) in women and 2.0 (interquartile range, 1.3-3.1) in men (P<0.01); this difference remained after age-adjustment (P<0.001). Factors contributing to higher ADL/instrumental ADL scores in women included prestroke function, marital status, prestroke cognition, nursing home residence, stroke severity, history of stroke/transient ischemic attack, and body mass index; prestroke function was the largest contributor. Stroke severity modified the sex difference in outcome such that differences were apparent for mild to moderate but not severe strokes. After adjustment, women still had significantly worse functional outcome than men. CONCLUSIONS: These findings yield insight into possible strategies and subgroups to target to reduce the sex disparity in stroke outcome; demographics and prestroke and clinical factors explained only 41% of the sex difference in stroke outcome highlighting the need for future research to identify modifiable factors that contribute to sex differences.