Dietary exposure to thyroid disrupting chemicals: a community-based study in Canada.

The marine ecosystem around the Island of Newfoundland is contaminated by thyroid disrupting chemicals (TDCs). Coastal inhabitants may be exposed to TDCs through consumption of contaminated local seafood products and affecting thyroid functions. The aim of this study was to explore: (1) consumption frequency of local seafood products consumed by rural residents, (2) thyroid hormones (THs) and TDCs concentrations in residents, (3) relationships between local seafood consumption, TDC concentrations, and THs. Participants (n = 80) were recruited from two rural Newfoundland communities. Seafood consumption was measured through a validated seafood consumption questionnaire. Blood samples were collected from all participants and tested for THs (thyroid stimulating hormone, free thyroxine, free triiodothyronine) and TDCs, including polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs), polybrominated biphenyls (PBBs), and dichlorodiphenyldichloroethylene (p,p'-DDE). Cod was the most frequently consumed local species, but there was a wide range of other local species consumed. Older participants (>50 years) had greater plasma concentrations of PBB-153, PCBs and p,p'-DDE, and males had higher concentrations of all TDCs than females. The consumption frequency of local cod was found to be positively associated with several PCB congeners, p,p'-DDE and ∑14TDCs. There was no significant relationship between TDCs and THs in either simple or multivariate linear regression analyses.

Sex differences in suicide mortality in Newfoundland and Labrador: An observational study with medical examiner data from 1997 to 2016.

Background: Globally, the suicide rate is two times higher for males than for females. Previous studies in Newfoundland and Labrador did not examine age-specific rates by sex. The objectives of this study were to determine suicide rates by sex and age group and to compare the demographic and clinical characteristics of males and females who died by suicide. Data and methods: This observational study analyzed a routinely collected dataset based on all medical examiner-determined suicide deaths among people aged 10 years and older in Newfoundland and Labrador, Canada, between 1997 and 2016. Age-standardized and age-specific suicide rates and rate ratios were calculated based on the number of deaths during the period, and descriptive statistics were used to compare demographic and clinical characteristics between males and females. Results: The age-standardized suicide rate was 4.6 times higher among males than females and was higher for males in most age groups. Rates were highest in the young adult age groups for males (20 to 24 years) and females (35 to 39 years). Males who died by suicide were more likely to be from a rural community and to have died by firearm; females were more likely to die by self-poisoning and to have had a mental illness or substance use history. Interpretation: The results are broadly consistent with previous research, though this is the first study to report age-specific suicide rates among females across the life course in Newfoundland and Labrador. The results underscore the need to design public health and clinical interventions that account for sex differences in suicide risks.

Polybrominated Diphenyl Ethers (PBDEs) in Marine Fish and Dietary Exposure in Newfoundland.

Presence of PBDEs tested in 127 liver samples from Atlantic Cod (Gadus morhua) and Turbot (Scophthalmus Maximus) and 80 adult participants from two rural Newfoundland communities. Seafood consumption was measured through a validated seafood consumption questionnaire. PBDEs (-28, -47, -99, -156, and -209) were found in all fish liver samples, and PBB-153 and PBDEs-28, -47, -99, -100, -153 were identified as the most prominent congeners from the participants' serum samples. Cod was the most frequently consumed species in the seafood consumption survey. PBB-153 was higher amongst older (> 50 years age) participants (p < 0.0001), however, no PBDE congeners were significantly different by age. PBB-153 (p = 0.001), PBDE-153 (p = 0.006), and 5PBDE (p = 0.008) levels were significantly higher in males. The study shows that the marine ecosystem around Newfoundland has been contaminated by PBDEs, and that rural coastal residents are potentially exposed to these contaminants through local seafood consumption.

Reducing maternal and child mortality in rural Ghana.

The lack of health infrastructure in developing countries to provide women with modern obstetric care and universal access to maternal and child health services has largely contributed to the existing high maternal and infant deaths. Access to basic obstetric care for pregnant women and their unborn babies is a key to reducing maternal and infants´ deaths, especially at the community-level. This calls for the strengthening of primary health care systems in all developing countries, including Ghana. Financial access and utilization of maternal and child health care services need action at the community-level across rural Ghana to avoid preventable deaths. Financial access and usage of maternal and child health services in rural Ghana is poor. Lack of financial access is a strong barrier to the use of maternal and child health services, particularly in rural Ghana. The sustainability of the national health insurance scheme is vital in ensuring full access to care in remote communities.

Suicide in Newfoundland and Labrador, Canada: a time trend analysis from 1981 to 2018.

BACKGROUND: The suicide rate in Canada decreased by 24% during the past four decades. However, rates vary between provinces and territories, and not all jurisdictions experienced the same changes. This study examined suicide rates over time in the province of Newfoundland and Labrador. METHODS: We used cross-sectional surveillance data from the Canadian Vital Statistics Death Database to examine suicide rates in Newfoundland and Labrador from 1981 to 2018. We calculated annual age-standardized suicide mortality rates and used joinpoint regression to estimate the average annual percent change (AAPC) in suicide rates overall and by sex, age group, and means of suicide. RESULTS: From 1981 to 2018, 1759 deaths by suicide were recorded among people in Newfoundland and Labrador. The age-standardized suicide mortality rate increased more than threefold over the study period, from 4.6 to 15.4 deaths per 100,000. The suicide rate was higher among males than females, and accounted for 83.1% of suicide deaths (n = 1462); the male-to-female ratio of suicide deaths was 4.9 to 1. The average annual percent change in suicide rates was higher among females than males (6.3% versus 2.0%). Age-specific suicide rates increased significantly for all age groups, except seniors (aged 65 or older); the largest increase was among youth aged 10 to 24 years old (AAPC 3.5; 95% CI, 1.6 to 5.5). The predominant means of suicide was hanging/strangulation/suffocation, which accounted for 43.8% of all deaths by suicide. CONCLUSIONS: The suicide rate in Newfoundland and Labrador increased steadily between 1981 and 2018, which was in contrast to the national rate decline. The disparity between the provincial and national suicide rates and the variations by sex and age underscore the need for a public health approach to prevention that accounts for geographic and demographic differences in the epidemiology of suicide.

Rural-Urban Differences in Suicide Mortality: An Observational Study in Newfoundland and Labrador, Canada: Différences de la Mortalité Par Suicide en Milieu Rural-Urbain: Une Étude Observationnelle à Terre-Neuve et Labrador, Canada.

BACKGROUND: Suicide rates are higher in rural compared to urban areas. Although this pattern appears to be driven by higher rates among men, there is limited evidence about the characteristics of rural people who die by suicide in Canada. The objective of this study was to examine the demographics, manner of death, and social and clinical antecedents of people who died by suicide in rural areas compared to urban areas. METHODS: We conducted an observational study of all suicide deaths that occurred among Newfoundland and Labrador residents between 1997 and 2016 using a linked data set derived from a comprehensive review of provincial medical examiner records. We used t tests and χ2 to assess associations between rural/urban status and variables related to demographics, circumstances, and manner of death, as well as social and medical history. Logistic regression was utilized to assess the independent contribution of any variable found to be significant in univariate analysis. RESULTS: Rural people who died by suicide accounted for 54.8% of all deaths over a 20-year period. Overall, 81.6% of people who died were male. Compared to urban, rural people who died by suicide were younger, more likely to use firearms or hanging, and had a higher mean blood alcohol content at the time of death (27.69 vs. 22.95 mmol/L). Rural people were also less likely to have had a known history of a prior suicide attempt, psychiatric disorder, alcohol or substance abuse, or chronic pain. DISCUSSION: The demographic and clinical differences between rural and urban people who died by suicide underscore the need for suicide prevention approaches that account for place-based differences. A key challenge for suicide prevention in rural communities is to ensure that interventions are developed and implemented in a manner that fits local contexts.

Microaggression and everyday resistance in narratives of refugee resettlement.

The mental health of resettled refugees is not only affected by the trauma they experience before and while fleeing persecution, but also by experiences during the resettlement process. Drawing on a qualitative study of refugees' experiences of mental wellbeing in a small Canadian city this paper documents participants' experiences of microaggression and everyday resistance. In our analysis, we refer to the metaphor of uprooting that is often used to describe the totality of refugee displacement. In our expansion of the metaphor, microaggression re-uproots resettled refugees by challenging their right to be where they are. Using acts of everyday resistance, participants in our sample attempted to set down roots in the resettlement context despite microaggressions. Participants' acts of everyday resistance are captured under five themes: rejecting victimhood, rejecting burden narratives, ignorance as an explanation, the transience of vulnerability, and setting down roots. This study contributes to the literature that de-emphasizes the vulnerability narrative of refugee mental health by demonstrating the role of personal agency in refugees' experiences of their own wellbeing.

The effects of individual and community-level factors on maternal health outcomes in Ghana.

BACKGROUND: Utilization of maternal health care services is key to reducing the number of perinatal deaths and post-natal complications in sub-Saharan Africa. With a few exceptions, many studies that examine the use of maternal health services in sub-Saharan Africa have focused largely on individual-level explanations and have ignored the importance of contextual and community-level explanations. In Ghana, progress has been made in reducing maternal mortality ratio from 740/100,000 in the late 1990s to 319/100,000 in 2015 but these rates are still high. Our study focuses on impact of individual and community level-factors on maternal outcomes with the hope that it will inform public policy in Ghana. This approach highlights latent or unacknowledged aspects of fragility within health systems designed to improve maternal health and opportunities for improving uptake of services. METHODS AND FINDINGS: Using the 2014 Ghana Demographic and Health Survey, we examined the effects of individual and community-level factors on antenatal care, facility-based delivery, and post-natal care. Multilevel logistic regression models were used to examine the effects of individual and community-level factors on the outcome variables. Our analysis revealed that overall utilization of antenatal, facility-based delivery and post-natal care was substantial across the board; however, both individual and community-level factors were significant predictors of these maternal health outcomes. Wealthier and better educated women were more likely to use antenatal services and facility-based delivery; in contrast poor and uneducated women were more likely to use antenatal and postnatal care but not facility-based delivery. Additionally, use of National Health Insurance Scheme was statistically associated with the utilization of maternal health services. CONCLUSIONS: The findings point to areas where services can be better tailored to meet community-specific needs. Policy makers must consider factors such as educational levels and economic security at both individual and community-levels that shape women's preferences and uptake of maternal health care in Ghana.

Tracking progress in suicide prevention in Indigenous communities: a challenge for public health surveillance in Canada.

Indigenous peoples in Canada experience disproportionate rates of suicide compared to non-Indigenous populations. Indigenous communities and organizations have designed local and regional approaches to prevention, and the federal government has developed a national suicide prevention framework. However, public health systems continue to face challenges in monitoring the population burden of suicide and suicidal behaviour. National health data systems lack Indigenous identifiers, do not capture data from some regions, and do not routinely engage Indigenous communities in data governance. These challenges hamper efforts to detect changes in population-level outcomes and assess the impact of suicide prevention activities. Consequently, this limits the ability to achieve public health prevention goals and reduce suicide rates and rate inequities.This paper provides a critical analysis of the challenges related to suicide surveillance in Canada and assesses the strengths and limitations of existing data infrastructure for monitoring outcomes in Indigenous communities. To better understand these challenges, we discuss the policy context for suicide surveillance and examine the survey and administrative data sources that are commonly used in public health surveillance. We then review recent data on the epidemiology of suicide and suicidal behaviour among Indigenous populations, and identify challenges related to national surveillance.To enhance capacity for suicide surveillance, we propose strategies to better track progress in Indigenous suicide prevention. Specifically, we recommend establishing an independent community and scientific governing council, integrating Indigenous identifiers into population health datasets, increasing geographic coverage, improving suicide data quality, comprehensiveness, and timeliness, and developing a platform for making suicide data accessible to all stakeholders. Overall, the strategies we propose can build on the strengths of the existing national suicide surveillance system by adopting a collaborative and inclusive governance model that recognizes the stake Indigenous communities have in suicide prevention.

Global incidence of suicide among Indigenous peoples: a systematic review.

BACKGROUND: Suicide is the second leading cause of death among adolescents worldwide, and is a major driver of health inequity among Indigenous people in high-income countries. However, little is known about the burden of suicide among Indigenous populations in low- and middle-income nations, and no synthesis of the global data is currently available. Our objective was to examine the global incidence of suicide among Indigenous peoples and assess disparities through comparisons with non-Indigenous populations. METHODS: We conducted a systematic review of suicide rates among Indigenous peoples worldwide and assessed disparities between Indigenous and non-Indigenous populations. We performed text word and Medical Subject Headings searches in PubMed, MEDLINE, Embase, Cumulative Index of Nursing and Allied Health (CINAHL), PsycINFO, Latin American and Caribbean Health Sciences Literature (LILACS), and Scientific Electronic Library Online (SciELO) for observational studies in any language, indexed from database inception until June 1, 2017. Eligible studies examined crude or standardized suicide rates in Indigenous populations at national, regional, or local levels, and examined rate ratios for comparisons to non-Indigenous populations. RESULTS: The search identified 13,736 papers and we included 99. Eligible studies examined suicide rates among Indigenous peoples in 30 countries and territories, though the majority focused on populations in high-income nations. Results showed that suicide rates are elevated in many Indigenous populations worldwide, though rate variation is common, and suicide incidence ranges from 0 to 187.5 suicide deaths per 100,000 population. We found evidence of suicide rate parity between Indigenous and non-Indigenous populations in some contexts, while elsewhere rates were more than 20 times higher among Indigenous peoples. CONCLUSIONS: This review showed that suicide rates in Indigenous populations vary globally, and that suicide rate disparities between Indigenous and non-Indigenous populations are substantial in some settings but not universal. Including Indigenous identifiers and disaggregating national suicide mortality data by geography and ethnicity will improve the quality and relevance of evidence that informs community, clinical, and public health practice in Indigenous suicide prevention.

The Impact of Access Barriers on Fertility Treatment Decision Making: A Qualitative Study From the Perspectives of Patients and Service Providers.

OBJECTIVE: The purpose of this study was to explore how barriers to accessing fertility services affect the treatment decisions made by fertility patients and service providers in Newfoundland and Labrador. METHODS: Semistructured, in-depth interviews were conducted with 11 patients across Newfoundland and with eight service providers from Newfoundland and Labrador Fertility Services (located in St. John's) to gather the perspectives of both patients and providers. The interview transcripts were analyzed thematically. RESULTS: Patients' responses to fertility service access barriers included choosing cheaper drugs, substituting intrauterine insemination (IUI) for IVF or not using IVF, delaying IVF, choosing more accessible IVF clinics, transferring multiple embryos, and stopping treatment altogether. Some patients, however, noted that the barriers would not stop them from continuing with treatment. Providers' responses to the barriers patients faced included changing drug protocols, manipulating ovulation, providing teleconsultations, and minimizing patients' clinic visits for those living some distance away from St. John's. CONCLUSION: Both patients and providers make treatment-related decisions to maximize the likelihood of a successful pregnancy and to reduce costs, which can result in less effective care and at times increased risk to the patient. Unlike with other types of care, responses to barriers to fertility treatment largely result in changes to individual patient treatment plans rather than changing models of care. As a result, many patients must continue to seek fertility services in large urban centres and incur substantial personal costs.

Inflammatory diet and risk for colorectal cancer: A population-based case-control study in Newfoundland, Canada.

OBJECTIVE: Chronic inflammation is implicated in causing cancer. Diet plays an important role in regulating chronic inflammation by altering circulating levels of inflammatory biomarkers. Effect of single food or nutrient on cancer often is inconclusive; perhaps due to dietary interactions and multicolinearity. The aim of this study was to determine prediagnostic inflammatory potential of overall diet in relation to risk for colorectal cancer (CRC). METHODS: In all, 547 patients with CRC from Newfoundland Familial Colorectal Cancer Registry and 685 controls from the general population were identified. Data on sociodemographic, medical history, lifestyle, and a 169-item food frequency questionnaire were collected retrospectively from both groups. Energy-adjusted Dietary Inflammatory Index (DII) score was calculated and used as both categorical and continuous variables for analysis. Odds ratio was estimated using multivariable logistic regression after adjusting potential confounders. A linear test for trend was performed using the median value in each quartile. RESULTS: Overall energy-adjusted mean DII score was -0.81 (range -5.19 to 6.93). Cases (-0.73 ± 1.5) had slightly higher DII scores than controls (-0.89 ± 1.6; P = 0.04). After adjusting the potential confounders, a statistically significant association was found between DII score and CRC risk. Using DII as a continuous variable (odds ratio [OR]continuous 1.10, 95% confidence interval [CI] 1.01-1.20) and categorical variable (ORquartile 1 versus 4 1.65, 95% CI 1.13-2.42; Ptrend = 0.02). CONCLUSION: Our findings indicate that proinflammatory diets are associated with an increased risk for CRC in the Newfoundland population.

Life in unexpected places: Employing visual thinking strategies in global health training.

BACKGROUND: The desire to make meaning out of images, metaphor, and other representations indicates higher-order cognitive skills that can be difficult to teach, especially in the complex and unfamiliar environments like those encountered in many global health experiences. Because reflecting on art can help develop medical students' imaginative and interpretive skills, we used visual thinking strategies (VTS) during an immersive 4-week global health elective for medical students to help them construct new understanding of the social determinants of health in a low-resource setting. We were aware of no previous formal efforts to use art in global health training. METHODS: We assembled a group of eight medical students in front of a street mural in Kathmandu and used VTS methods to interpret the scene with respect to the social determinants of health. We recorded and transcribed the conversation and conducted a thematic analysis of student responses. RESULTS: Students shared observations about the mural in a supportive, nonjudgmental fashion. Two main themes emerged from their observations: those of human-environment interactions (specifically community dynamics, subsistence land use, resources, and health) and entrapment/control, particularly relating to expectations of, and demands on, women in traditional farming communities. They used the images as well as their experience in Nepali communities to consolidate complex community health concepts. DISCUSSION: VTS helped students articulate their deepening understanding of the social determinants of health in Nepal, suggesting that reflection on visual art can help learners apply, analyze, and evaluate complex concepts in global health. We demonstrate the relevance of drawing upon many aspects of cultural learning, regarding art as a kind of text that holds valuable information. These findings may help provide innovative opportunities for teaching and evaluating global health training in the future.

Suicide Rates in Aboriginal Communities in Labrador, Canada.

OBJECTIVES: To compare suicide rates in Aboriginal communities in Labrador, including Innu, Inuit, and Southern Inuit, with the general population of Newfoundland, Canada. METHODS: In partnership with Aboriginal governments, we conducted a population-based study to understand patterns of suicide mortality in Labrador. We analyzed suicide mortality data from 1993 to 2009 from the Vital Statistics Death Database. We combined this with community-based methods, including consultations with Elders, youths, mental health and community workers, primary care clinicians, and government decision-makers. RESULTS: The suicide rate was higher in Labrador than in Newfoundland. This trend persisted across all age groups; however, the disparity was greatest among those aged 10 to 19 years. Males accounted for the majority of deaths, although suicide rates were elevated among females in the Inuit communities. When comparing Aboriginal subregions, the Innu and Inuit communities had the highest age-standardized mortality rates of, respectively, 165.6 and 114.0 suicides per 100 000 person-years. CONCLUSIONS: Suicide disproportionately affects Innu and Inuit populations in Labrador. Suicide rates were high among male youths and Inuit females.

Two sides of the same coin: Factors that support and challenge the wellbeing of refugees resettled in a small urban center.

For refugees who undergo permanent resettlement, characteristics of the resettlement context influence their ability to heal from pre-migration persecution and achieve a sense of wellbeing. This ethnographic study examines the impact of place-related determinants on the sense of wellbeing experienced by refugees resettled in a small urban center. The paper reports on the results of in-depth interviews that were conducted with ten former refugees in St. John's, Canada. We found that challenges and coping resources both emerged from the same aspects of the city, including its built environment, natural environment, history, culture, and low ethnic diversity. Future research should attend to how aspects of the resettlement context can simultaneously challenge and support refugees' sense of wellbeing.

Skewed distribution of hypothyroidism in the coastal communities of Newfoundland, Canada.

Several studies published in the recent past have shown that rising levels of thyroid disrupting chemicals (TDCs) in the environment affect thyroid function in humans. These TDCs are the anthropogenic organic compounds that enter the human body mostly by ingestion and may trigger autoimmune thyroiditis, the most common cause of hypothyroidism. The studies also show the presence of high levels of TDCs in marine animals; therefore, consumption of contaminated seafood might trigger hypothyroidism. So far, there is no readily available population-based data, showing the regional distribution of hypothyroidism cases. We collected administrative data from the Newfoundland and Labrador Centre for Health Information on hospitalizations with hypothyroidism (from 1998 to 2012) in 41 coastal communities of Newfoundland and found that mean hypothyroidism rates of west and south coasts were significantly higher than in the east coast (1.8 and 1.9 times respectively). A one-way analysis of variance was used to test for regional differences in rates. A significant between-group difference in the rate of hypothyroidism was found (F2,38 = 8.309; p = 0.001). The St. Lawrence River, its estuary and the Gulf of St. Lawrence are heavily polluted with TDCs from industries, their effluents, and urbanization in the Great Lakes Watershed and along the river. Environment Canada has already identified this river along with the Great Lakes Watershed as one of the top TDCs polluted water sources in the country. The west and south coasts are in contact with the Gulf of St. Lawrence. Local marine products are a regular diet of the coastal communities of Newfoundland. Based on these available evidence, we hypothesize the role of TDCs in the rise of hypothyroidism on the western and southern coasts. However, further study will be needed to establish any association between abnormally high rates of hypothyroidism and exposure to TDCs.

Targeted ablation of the chromogranin a (Chga) gene: normal neuroendocrine dense-core secretory granules and increased expression of other granins.

Chromogranin A (CgA), originally identified in adrenal chromaffin cells, is a member of the granin family of acidic secretory glycoproteins that are expressed in endocrine cells and neurons. CgA has been proposed to play multiple roles in the secretory process. Intracellularly, CgA may control secretory granule biogenesis and target neurotransmitters and peptide hormones to granules of the regulated pathway. Extracellularly, peptides formed as a result of proteolytic processing of CgA may regulate hormone secretion. To investigate the role of CgA in the whole animal, we created a mouse mutant null for the Chga gene. These mice are viable and fertile and have no obvious developmental abnormalities, and their neural and endocrine functions are not grossly impaired. Their adrenal glands were structurally unremarkable, and morphometric analyses of chromaffin cells showed vesicle size and number to be normal. However, the excretion of epinephrine, norepinephrine, and dopamine was significantly elevated in the Chga null mutants. Adrenal medullary mRNA and protein levels of other dense-core secretory granule proteins including chromogranin B, and secretogranins II to VI were up-regulated 2- to 3-fold in the Chga null mutant mice. Hence, the increased expression of the other granin family members is likely to compensate for the Chga deficiency.

Field stimulation-induced tetrodotoxin-resistant vasorelaxation is mediated by sodium hypochlorite.

This study was done to determine the mechanism of field stimulation-induced tetrodotoxin (TTX)- and NG- nitro-l-arginine (LNA)-resistant vasorelaxation. Field stimulation with platinum and carbon, but not with silver, electrodes (30 V, 30 HZ, 2-5 ms pulse width) as well as electrically stimulated salt (0.9% NaCl) solution (ESSS) or Krebs solution caused 100% relaxation of phenylephrine-contracted rat aortic strips, which was TTX and LNA resistant and endothelium independent. ESSS also relaxed other vascular preparations (rabbit aorta and renal artery, dog coronary artery, pig ductus arteriosus, and rat portal vein). The electric current generated hypochlorite (OCl-) and H2O2 from the salt solution; however, vasorelaxation was caused by NaOCl and not by H2O2. ESSS and NaOCl caused contraction failure of spontaneously beating right atria of rats and did not affect uterine contractions, vascular cAMP, cGMP, or the pH of the tissue bath. Field stimulation, ESSS, and NaOCl did not relax aortic preparations contracted by 32 mmol/L potassium and their vasorelaxant effects on phenylephrine-contracted rat aortic strips and rings were completely reversed by tetraethylammonium and partially by glibenclamide and iberiotoxin. We conclude that electric pulses generate the oxidant OCl- from the salt solution, which causes vasorelaxation by increasing K+ conductance.

Mechanism of the negative inotropic effects of alpha 1-adrenoceptor agonists on mouse myocardium.

This study was done to identify the mechanism of the alpha1-adrenoceptor (AR) mediated negative inotropic effects of phenylephrine (PE) on adult mouse myocardium. As reported by others, we also found that the nonselective alpha1AR agonist PE produced a negative inotropic effect on ventricular strips from adult mice that was inhibited by the alpha1AAR antagonist 5-methylurapidil (5MU) but not by the alpha1BAR antagonist chloroethylclonidine (CEC) or the alpha1DAR antagonist BMY 7378. The selective alpha1AAR agonist A61603 also produced a negative inotropic effect, which was antagonized by 5MU. Phorbol 12,13-dibutyrate (activator of all PKC isoforms) mimicked the negative inotropic responses to PE and A61603. The negative inotropic effects of PE were inhibited by bisindolylmaleimide (inhibitor of all PKC isoforms) but not by Gö 6976 (inhibitor of Ca2+-dependent PKC). Rottlerin, an inhibitor of Ca2+-independent PKCdelta, antagonized the negative inotropic effects of PE and A61603. PE and A61603 increased the translocation of PKCdelta, which was prevented by rottlerin. These data suggest that the alpha1AR-mediated negative inotropy on adult mouse myocardium is signaled by Ca2+-independent PKCdelta.