Endocrine disrupting chemicals: Friend or foe to brown and beige adipose tissue?

The effects of Endocrine Disrupting Chemicals (EDCs) on the current obesity epidemic is a growing field of interest. Numerous EDCs have shown the potential to alter energy metabolism, which may increase the risk of obesity, in part, through direct actions on adipose tissue. While white adipose tissue has historically been the primary focus of this work, evidence of the EDC-induced disruption of brown and beige adipose tissues continues to build. Both brown and beige fat are thermogenic adipose depots rich in mitochondria that dispense heat when activated. Due to these properties, brown and beige fat are implicated in metabolic diseases such as obesity, diabetes, and cachexia. This review delves into the current literature of different EDCs, including bisphenols, dioxins, air pollutants, phthalates, and phytochemicals. The possible implications that these EDCs have on thermogenic adipose tissues are covered. This review also introduces the possibility of using brown and beige fat as a therapeutic target organ by taking advantage of some of the properties of EDCs. Collectively, we provide a comprehensive discussion of the evidence of EDC disruption in white, brown, and beige fat and highlight gaps worthy of further exploration.

Calcineurin A-α suppression drives nuclear factor-κB-mediated NADPH oxidase-2 upregulation.

Calcineurin inhibitors (CNIs) are vital immunosuppressive therapies in the management of inflammatory conditions. A long-term consequence is nephrotoxicity. In the kidneys, the primary, catalytic calcineurin (CnA) isoforms are CnAα and CnAß. Although the renal phenotype of CnAα-/- mice substantially mirrors CNI-induced nephrotoxicity, the mechanisms downstream of CnAα are poorly understood. Since NADPH oxidase-2 (Nox2)-derived oxidative damage has been implicated in CNI-induced nephrotoxicity, we hypothesized that CnAα inhibition drives Nox2 upregulation and promotes oxidative stress. To test the hypothesis, Nox2 regulation was investigated in kidneys from CnAα-/-, CnAß-/-, and wild-type (WT) littermate mice. To identify the downstream mediator of CnAα, nuclear factor of activated T cells (NFAT) and NF-κB regulation was examined. To test if Nox2 is transcriptionally regulated via a NF-κB pathway, CnAα-/- and WT renal fibroblasts were treated with the NF-κB inhibitor caffeic acid phenethyl ester. Our findings showed that cyclosporine A treatment induced Nox2 upregulation and oxidative stress. Furthermore, Nox2 upregulation and elevated ROS generation occurred only in CnAα-/- mice. In these mice, NF-κB but not NFAT activity was increased. In CnAα-/- renal fibroblasts, NF-κB inhibition prevented Nox2 upregulation and reactive oxygen species (ROS) generation. In conclusion, these findings indicate that 1) CnAα loss stimulates Nox2 upregulation, 2) NF-κB is a novel CnAα-regulated transcription factor, and 3) NF-κB mediates CnAα-induced Nox2 and ROS regulation. Our results demonstrate that CnAα plays a key role in Nox2 and ROS generation. Furthermore, these novel findings provide evidence of divergent CnA isoform signaling pathways. Finally, this study advocates for CnAα-sparing CNIs, ultimately circumventing the CNI nephrotoxicity.NEW & NOTEWORTHY A long-term consequence of calcineurin inhibitors (CNIs) is oxidative damage and nephrotoxicity. This study indicates that NF-κB is a novel calcineurin-regulated transcription factor that is activated with calcineurin inhibition, thereby driving oxidative damage in CNI nephropathy. These findings provide additional evidence of divergent calcineurin signaling pathways and suggest that selective CNIs could improve the long-term outcomes of patients by mitigating renal side effects.

Differential expression of cyclosporine A-Induced calcineurin isoform-specific matrix metalloproteinase 9 (MMP-9) in renal fibroblasts.

Long-term treatment with the potent immunosuppressive drug cyclosporine A (CsA) results in chronic nephrotoxicity. Its immunosuppressive properties are due to the inhibition of the calcium- and calmodulin-dependent phosphatase protein calcineurin A (CnA) which has three catalytic isoforms. Of those, the CnAα and ß isoforms are ubiquitously expressed, particularly in the kidney. Additionally, chronic nephrotoxicity has been associated with an imbalance of extracellular matrix (ECM) synthesis and degradation resulting in an accumulation of ECM molecules. This study evaluates whether the expressions of matrix metalloproteinases (MMP-2 and MMP-9) induced by CsA are calcineurin isoform specific. Wild-type (WT), CnAα knockout (CnAα-/-) and CnAß knockout (CnAß-/-) kidney fibroblast cell lines (an in vitro innovative tool that was previously created in our lab) were treated with CsA at 10 ng/ml for 48 h. ELISA analysis demonstrated that the CsA-induced secretion profile of MMP-9 was highest in CnAα-/- cells and lowest in CnAß-/- cells vs. WT cells. In contrast, CsA did not induce an increase in MMP-2 protein levels in WT, CnAα-/- nor CnAß-/- renal fibroblasts. These results indicate that MMP-9 secretion is CnA-isoform specific, i.e. the CnAß isoform contributes to the CsA-induced upregulation of MMP-9 while the CnAα does not. As such, understanding the role of calcineurin A isoforms in the regulation of the homeostasis of ECM degradation in the kidney after long-term CsA treatment needs to be further investigated.

Cyclosporine A alters expression of renal microRNAs: New insights into calcineurin inhibitor nephrotoxicity.

Calcineurin inhibitors are powerful immunosuppressants that revolutionized organ transplantation. However, non-immune effects of the calcineurin inhibitor, such as cyclosporine A (CsA), have significantly hindered their use. Specifically, nephrotoxicity, which is associated with tubulointerstitial fibrosis, inflammation, and podocyte damage, affects up to half of all transplant patients. Calcineurin is involved in many aspects of kidney development and function; therefore, mechanisms of CsA-induced nephrotoxicity are complex and not yet fully understood. MicroRNAs are short non-coding RNAs that regulate protein-coding RNA expression through post-translational repression of target messenger RNAs. MicroRNA dysregulation is known to be involved in kidney diseases including fibrosis. In this study, we compared the renal microRNA expression profiles between mice that received CsA (20 mg/kg) or vehicle daily for six weeks. The results demonstrate that CsA induces significant changes in renal microRNA expression profile. We used combined criteria of False Discovery Rate (≤0.1), fold change (≥2) and median signal strength (≥50) and identified 76 differencially expressed microRNAs. This approach identified microRNAs previously linked to renal fibrosis that includes let-7d, miR-21, miR-29, miR-30, miR-130, miR-192, and miR-200 as well as microRNAs that have not been reported to be related to nephrotoxicity or immunosuppression. Pathway analysis of microRNA/mRNA changes highlights the Wnt, TGF-ß, mTOR, and VEGF pathways. The mRNA expression profiles were compared in the same samples. The change of mRNA and microRNA profiles showed close correlations. To validate that the observed microRNA and mRNA expression level changes in mice kidney tissue were directly related to CsA treatment, the expression change induced by CsA treatment of three microRNAs (miR-21, miR-186, and miR-709) and three mRNAs (BMPR1a, SMURF1 and SMAD7) were compared in HEK293 cell line. A similar trend of expression level change was induced by CsA treatment in all selected microRNAs and mRNAs in the in vitro cell model. These data provide a roadmap for future work to study the role of the known and novel candidate microRNAs in the mechanism of nephrotoxicity and their further therapeutic potential.

Does marriage explain murders in a society? In what way is divorce a public health concern?

INTRODUCTION: Like medicine, public health practitioners seek to understand causes of mortality, practices of humans and issues that can change population conditions, in order to preserve and care for life. The murder pandemic has been such in Jamaica that the World Bank sponsored a qualitative study on crime in urban areas in Jamaica in the late 1990s to provide a platform to guide policy intervention and programmes. As a result this study will fill the gap in the literature by providing the evidence to support that divorce and marriage are public health concerns from the perspective of murders. OBJECTIVE: To evaluate the role of divorce and marital relationships on murders. MATERIALS AND METHODS: The data for this study are taken from various Jamaica Government Publications. The period for this work is from 1950 through 2013. Data were recorded, stored and retrieved using the Statistical Packages for the Social Sciences (SPSS) for Windows, Version 21.0. The level of significance that is used to determine statistical significance is less than 5% (0.05). Ordinary least square (OLS) regression analyses and curve estimations were used to determine models and best fitted models. RESULTS: On average, annually, 523 Jamaicans are murdered (± 484), with there being 9,531 marriages (± 22,747) and 904 divorces (± 468). Logged marriage rate and divorce rate are factors of murder rate, with both independent factors accounting for 82.2% of the variability in the murder rate. Both factors are positively correlated with the murder rate, with the divorce rate accounting for most of the variance in the murder rate (R2 = 79.2%). CONCLUSION: Death can be extremely devasting to families, however, murder among married couples can severely disrupt the lives of both families along with any children from such relationship.

Knowledge, attitude and practices of adults of the reproductive years on reproductive health matters, with emphasis on HIV infected people in a Caribbean society.

BACKGROUND: South and Southeast Asia represent the largest number of new HIV infections, while Sub-Saharan Africa represents the highest rate of new infections, followed by Latin America and the Caribbean. Yet no study that has emerged in the Caribbean has comprehensively examined young people's sexual and reproductive health attitudes, knowledge and practices, comparing the result with those who are HIV infected. AIM: The present study examines core issues of sexual and reproductive health among youths, particularly with respect to HIV. MATERIAL AND METHODS: The sample was 1,800 respondents ages 15-49 years. Multivariate logistic regressions were fitted using one outcome measure: self-reported confirmed positive HIV test results. RESULTS: Almost 34% of the sample had been tested for HIV, and 16.9% had done this in the past 12 months. Only 0.2% of the sample knew that they were HIV positive and 4% had positive HIV test results when they did the test. Of those with a positive HIV test result, 58.1% were females. Approximately 16% of those with HIV have had an STI infection in the past, and 61% were actively practicing religion. The mean age of first sexual relations for the sample was 15.4 years (SD = 3.2 years), and 15.6 years for those infected with HIV. Four variables emerged as statistically significant factors of Jamaicans' willingness to do an HIV test in the future. CONCLUSION: The findings of this research are far-reaching and can be used to guide public health policy formulation.

Perception, attitude and practices of women towards pelvic examination and Pap smear in Jamaica.

BACKGROUND: Studies have shown that women's ability to access contraceptive methods depend on their socio-economic, educational, professional status, and the health and well-being of their families and themselves. Therefore, the embarking of the Governments of the Caribbean on important initiatives relating to gynecological matters is very important and timely. AIMS: This study aims to examine the perception, attitude and practice of Jamaican women towards the matter of pelvic examination. PATIENTS AND METHODS: The current study used an extracted sample of 7,168 women in their reproductive years (15-49 yrs) from a study which was undertaken by the National Family Planning Board in 2002 on Reproductive Health. Data was analyzed using SPSS for Windows, Version 16.0 (SPSS Inc.; Chicago, Ill. USA). Logistic regression was used to analyze factors/variables pertaining to Pelvic examination. RESULTS: The findings revealed that older women are more likely to have done a Pelvic examination compared to younger women (χ(2) = 675.29, P < 0.001). Age, number of pregnancies that resulted in miscarriages, number of pregnancies that resulted in induced abortion, age of first sexual intercourse, number of years of schooling, area of residence and socio-economic class are statistically significant factors of Pelvic examinations in Jamaica. Therefore, the model had significant predictive power where (χ(2) = 1022.79, P < 0.001). CONCLUSION: The multidimensional nature of the variables, which emerged in the current study, indicate that a multisectoral approach should be used to address low pelvic and Pap smear examination among Jamaican women.

The changing faces of diabetes, hypertension and arthritis in a Caribbean population.

BACKGROUND: Globally, chronic illnesses are the leading cause of mortality, and this is no different in developing countries, particularly in the Caribbean. Little information emerged in the literature on the changing faces of particular self-reported chronic diseases. AIMS: This study examines the transitions in the demographic characteristics of those with diabetes, hypertension and arthritis, as we hypothesized that there are changing faces of those with these illnesses. MATERIALS AND METHODS: A sample of 592 respondents from the 2002 and 2007 Jamaica Survey of Living Conditions. Only respondents who indicated that they were diagnosed with these particular chronic conditions were used for the analysis. RESULTS: The prevalence of particular chronic diseases increased from 8 per 1,000 in 2002 to 56 per 1,000 in 2007. The average annual increase in particular chronic diseases was 17.2%. Diabetes mellitus showed an exponential average annual increase of 185% compared to hypertension (+ 12.7%) and arthritis (- 3.8%). Almost 5 percent of diabetics were less than 30 years of age (2.4% less than 15 years), and 41% less than 59 years. Three percent of hypertensive respondents were 30 years and under as well as 2% of arthritics. CONCLUSION: The demographic transition in particular chronic conditions now demands that data collection on those illnesses be lowered to < 15 years. This research highlights the urgent need for a diabetes campaign that extends beyond parents to include vendors, confectionary manufacturers and government, in order to address the tsunami of chronic diseases facing the nation.

Patient care: Is interpersonal trust missing?

BACKGROUND: Health statistics and studies in the Caribbean have omitted interpersonal trust in their investigations. AIMS: This study will examine the effect of interpersonal trust and other conditions on psychosocial subjective wellbeing and self-reported health, in order to assess the significance of interpersonal trust, as well as other socio-demographic factors on health. MATERIALS AND METHOD: The current study utilized primary data commissioned by the Centre of Leadership and Governance, Department of Government, the University of West Indies, Mona, Jamaica, between July and August 2006. It was a nationally representative probability sampling survey. A sample of 1,338 respondents was interviewed with a detailed 166-item questionnaire. RESULTS: Generally, the psychosocial subjective wellbeing of Jamaicans was high (mean = 6.8 ± 1.8), and self-reported health was moderately high (mean = 6.3 ± 2.6). The current study has revealed that income, political system, subjective social class, employment status, and interpersonal trust determine psychosocial subjective wellbeing as well as self-reported health. Interpersonal trust accounted for between 9.4 to 10.4% of the explanatory power of the wellbeing and self-reported health of Jamaicans. CONCLUSION: The current study highlights that the determinants of health include interpersonal trust. It is critical to point out here that trust must be taken into consideration in any evaluation of health statistics, as it is a factor of subjective wellbeing and health. It is within this context that clinicians need to incorporate interpersonal trust along with other conditions, as it is a part of the psychosocial determinants of health, subjective wellbeing, and health treatment.

The image of health status and quality of life in a Caribbean society.

BACKGROUND: Health is defined as the presence or absence of illness. This conceptualization of health status is dominant in health treatment and in fashioning the health care system. However, very little research has been done on how Jamaicans view health status and quality of life (QoL). AIMS: This article seeks to understand how Jamaicans conceptualize health status and QoL because definitional content has implications for their health. MATERIAL AND METHODS: The current study utilized two national cross-sectional probability surveys from the Centre for Leadership and Governance (CLG) which looked at QoL among other variables and the Jamaican Survey of Living Conditions (JSLC) which measured living standards including health status. The sample in both surveys was 8,120 participants. RESULTS: The majority of the respondents in the CLG (54%) and the JSLC (82.2%) surveys reported good health status. There was a strong statistical relationship between area of residence and health status (P < 0.0001) unlike the relationship between area of residence and quality of life (P < 0.137). The respondents dichotomized health status and QoL and a significant relationship was found between both variables (P < 0.0001). The respondents' dichotomization of health status and QoL is explained by the significant relationship between health status and self reported illness (P < 0.0001) where respondents view health status as the absence or presence of illness, excluding QoL. CONCLUSION: Health status means the presence or absence of illness and excludes QoL which is not in keeping with previous findings. This distinction is culturally determined.