An eight country cross-sectional study of the psychosocial effects of COVID-19 induced quarantine and/or isolation during the pandemic.

Forced quarantine and nationwide lockdowns have been a primary response by many jurisdictions in their attempt at COVID-19 elimination or containment, yet the associated mental health burden is not fully understood. Using an eight country cross-sectional design, this study investigates the association between COVID-19 induced quarantine and/or isolation on probable generalized anxiety disorder (GAD) and major depressive episode (MDE) psychological outcomes approximately eight months after the pandemic was declared. Overall, 9027 adults participated, and 2937 (32.5%) were indicated with GAD and/or MDE. Reported quarantine and/or isolation was common, with 1199 (13.8%) confined for travel or health requirements, 566 (6.5%) for being close contact, 720 (8.3%) for having COVID-19 symptoms, and 457 (5.3%) for being COVID-19 positive. Compared to those not quarantining or isolating, the adjusted estimated relative risks of GAD and/or MDE associated with quarantine and/or isolation was significant (p < 0.001), ranging from 1.24 (95% confidence interval [CI]: 1.07, 1.43) for travel/health to 1.37 (95% CI 1.19, 1.59) for COVID-19 symptom isolation reasons. While almost universally employed, quarantine and/or isolation is associated with a heavy mental health toll. Preventive strategies are needed, such as minimizing time-limits imposed and providing clear rationale and information, together with additional treatment and rehabilitation resources.

Patterns of Suicide Ideation Across Eight Countries in Four Continents During the COVID-19 Pandemic Era: Repeated Cross-sectional Study.

BACKGROUND: The COVID-19 pandemic and countries' response measures have had a globally significant mental health impact. This mental health burden has also been fueled by an infodemic: an information overload that includes misinformation and disinformation. Suicide, the worst mental health outcome, is a serious public health problem that can be prevented with timely, evidence-based, and often low-cost interventions. Suicide ideation, one important risk factor for suicide, is thus important to measure and monitor, as are the factors that may impact on it. OBJECTIVE: This investigation had 2 primary aims: (1) to estimate and compare country-specific prevalence of suicide ideation at 2 different time points, overall and by gender and age groups, and (2) to investigate the influence of sociodemographic and infodemic variables on suicide ideation. METHODS: A repeated, online, 8-country (Canada, the United States, England, Switzerland, Belgium, Hong Kong, Philippines, and New Zealand), cross-sectional study was undertaken with adults aged ≥18 years, with measurement wave 1 conducted from May 29, 2020 to June 12, 2020 and measurement wave 2 conducted November 6-18, 2021. Self-reported suicide ideation was derived from item 9 of the Patient Health Questionnaire-9 (PHQ-9). Age-standardized suicide ideation rates were reported, a binomial regression model was used to estimate suicide ideation indication rates for each country and measurement wave, and logistic regression models were then employed to relate sociodemographic, pandemic, and infodemic variables to suicide ideation. RESULTS: The final sample totaled 17,833 adults: 8806 (49.4%) from measurement wave 1 and 9027 (50.6%) from wave 2. Overall, 24.2% (2131/8806) and 27.5% (2486/9027) of participants reported suicide ideation at measurement waves 1 and 2, respectively, a difference that was significant (P<.001). Considerable variability was observed in suicide ideation age-standardized rates between countries, ranging from 15.6% in Belgium (wave 1) to 42.9% in Hong Kong (wave 2). Frequent social media usage was associated with increased suicide ideation at wave 2 (adjusted odds ratio [AOR] 1.47, 95% CI 1.25-1.72; P<.001) but not wave 1 (AOR 1.11, 95% CI 0.96-1.23; P=.16). However, having a weaker sense of coherence (SOC; AOR 3.80, 95% CI 3.18-4.55 at wave 1 and AOR 4.39, 95% CI 3.66-5.27 at wave 2; both P<.001) had the largest overall effect size. CONCLUSIONS: Suicide ideation is prevalent and significantly increasing over time in this COVID-19 pandemic era, with considerable variability between countries. Younger adults and those residing in Hong Kong carried disproportionately higher rates. Social media appears to have an increasingly detrimental association with suicide ideation, although having a stronger SOC had a larger protective effect. Policies and promotion of SOC, together with disseminating health information that explicitly tackles the infodemic's misinformation and disinformation, may importantly reduce the rising mental health morbidity and mortality triggered by this pandemic.

The Evolution in Anxiety and Depression with the Progression of the Pandemic in Adult Populations from Eight Countries and Four Continents.

Nearly a year after the classification of the COVID-19 outbreak as a global pandemic, it is clear that different factors have contributed to an increase in psychological disorders, including public health measures that infringe on personal freedoms, growing financial losses, and conflicting messages. This study examined the evolution of psychosocial impacts with the progression of the pandemic in adult populations from different countries and continents, and identified, among a wide range of individual and country-level factors, which ones are contributing to this evolving psychological response. An online survey was conducted in May/June 2020 and in November 2020, among a sample of 17,833 adults (Phase 1: 8806; Phase 2: 9027) from eight countries/regions (Canada, the United States, England, Switzerland, Belgium, Hong Kong, the Philippines, New Zealand). Probable generalized anxiety disorder (GAD) and major depressive episode (MDE) were assessed. The independent role of potential factors was examined using multilevel logistic regression. Probable GAD or MDE was indicated by 30.1% and 32.5% of the respondents during phases 1 and 2, respectively (a 7.9% increase over time), with an important variation according to countries/regions (range from 22.3% in Switzerland to 38.8% in the Philippines). This proportion exceeded 50% among young adults (18-24 years old) in all countries except for Switzerland. Beyond young age, several factors negatively influenced mental health in times of pandemic; important factors were found, including weak sense of coherence (adjusted odds ratio aOR = 3.89), false beliefs (aOR = 2.33), and self-isolation/quarantine (aOR = 2.01). The world has entered a new era dominated by psychological suffering and rising demand for mental health interventions, along a continuum from health promotion to specialized healthcare. More than ever, we need to innovate and build interventions aimed at strengthening key protective factors, such as sense of coherence, in the fight against the adversity caused by the concurrent pandemic and infodemic.

One Virus, Four Continents, Eight Countries: An Interdisciplinary and International Study on the Psychosocial Impacts of the COVID-19 Pandemic among Adults.

The novel coronavirus disease 2019 (COVID-19) pandemic brought about several features that increased the sense of fear and confusion, such as quarantine and financial losses among other stressors, which may have led to adverse psychosocial outcomes. The influence of such stressors took place within a broader sociocultural context that needs to be considered. The objective was to examine how the psychological response to the pandemic varied across countries and identify which risk/protective factors contributed to this response. An online survey was conducted from 29 May 2020-12 June 2020, among a multinational sample of 8806 adults from eight countries/regions (Canada, United States, England, Switzerland, Belgium, Hong Kong, Philippines, New Zealand). Probable generalized anxiety disorder (GAD) and major depression episode (MDE) were assessed. The independent role of a wide range of potential factors was examined using multilevel logistic regression. Probable GAD and MDE were indicated by 21.0% and 25.5% of the respondents, respectively, with an important variation according to countries/regions (GAD: 12.2-31.0%; MDE: 16.7-32.9%). When considered together, 30.2% of the participants indicated probable GAD or MDE. Several factors were positively associated with a probable GAD or MDE, including (in descending order of importance) weak sense of coherence (SOC), lower age, false beliefs, isolation, threat perceived for oneself/family, mistrust in authorities, stigma, threat perceived for country/world, financial losses, being a female, and having a high level of information about COVID-19. Having a weak SOC yielded the highest adjusted odds ratio for probable GAD or MDE (3.21; 95% confidence interval (CI): 2.73-3.77). This pandemic is having an impact on psychological health. In some places and under certain circumstances, however, people seem to be better protected psychologically. This is a unique opportunity to evaluate the psychosocial impacts across various sociocultural backgrounds, providing important lessons that could inform all phases of disaster risk management.

Health Consequences of an Armed Conflict in Zamboanga, Philippines Using a Syndromic Surveillance Database.

The Zamboanga armed conflict was a 19-day long encounter in the Philippines in 2013 that displaced 119,000 people from their homes. This study describes the health consequences of this complex emergency in different age groups, time periods, and health facilities using data from Surveillance in Post Extreme Emergencies and Disasters (SPEED). This is a descriptive study of the SPEED database spanning 196 days of observation post-disaster and 1065 SPEED reports from 49 health facilities. Evacuation centers and village health centers, both primary care facilities, had the highest number of consults. Common infections and noncommunicable diseases were the most common reasons for consultations, namely, acute respiratory infections, fever, watery diarrhea, skin disease, and hypertension. Infections can be associated with environmental conditions in displaced populations, while hypertension has a high prevalence in the country and implies long-term care. Conflict-related injuries and deaths were not frequently observed due to the volatile situation that influenced health-seeking behavior as well as possible reporting gaps. In conclusion, in complex emergencies, as in natural disasters, wherein early alert and warning for potential outbreaks is crucial, SPEED can assist decision makers on response and recovery interventions. Linkages between SPEED and other surveillance and reporting systems need to be explored.

Relaxin Family Member Insulin-Like Peptide 6 Ameliorates Cardiac Fibrosis and Prevents Cardiac Remodeling in Murine Heart Failure Models.

BACKGROUND: The insulin/insulin-like growth factor/relaxin family represents a group of structurally related but functionally diverse proteins. The family member relaxin-2 has been evaluated in clinical trials for its efficacy in the treatment of acute heart failure. In this study, we assessed the role of insulin-like peptide 6 (INSL6), another member of this protein family, in murine heart failure models using genetic loss-of-function and protein delivery methods. METHODS AND RESULTS: Insl6-deficient and wild-type (C57BL/6N) mice were administered angiotensin II or isoproterenol via continuous infusion with an osmotic pump or via intraperitoneal injection once a day, respectively, for 2 weeks. In both models, Insl6-knockout mice exhibited greater cardiac systolic dysfunction and left ventricular dilatation. Cardiac dysfunction in the Insl6-knockout mice was associated with more extensive cardiac fibrosis and greater expression of fibrosis-associated genes. The continuous infusion of chemically synthesized INSL6 significantly attenuated left ventricular systolic dysfunction and cardiac fibrosis induced by isoproterenol infusion. Gene expression profiling suggests liver X receptor/retinoid X receptor signaling is activated in the isoproterenol-challenged hearts treated with INSL6 protein. CONCLUSIONS: Endogenous Insl6 protein inhibits cardiac systolic dysfunction and cardiac fibrosis in angiotensin II- and isoproterenol-induced cardiac stress models. The administration of recombinant INSL6 protein could have utility for the treatment of heart failure and cardiac fibrosis.

Health Consequences of Typhoon Haiyan in the Eastern Visayas Region Using a Syndromic Surveillance Database.

INTRODUCTION: Typhoon Haiyan was the strongest storm recorded in Philippine history. Surveillance in Post Extreme Emergencies and Disasters (SPEED) was activated during the typhoon response. This study analyzes the health impact of different diseases during different timeframes post-disaster during Typhoon Haiyan in 2013 using a syndromic surveillance database. METHODS: SPEED reports medical consultations based on 21 syndromes covering a range of conditions from three syndrome groups: communicable diseases, injuries, and non-communicable diseases (NCDs). We analyzed consultation rates for 150 days post-disaster by syndrome, syndrome group, time period, and health facility type for adults as well as for children under the age of five. RESULTS: Communicable diseases had the highest consultation rates followed by similar rates for both injuries and NCDs. While communicable diseases were the predominant syndrome group for children, wounds and hypertension were common syndromes observed in adults. Village health centers had the most consultations amongst health facilities, but also showed the highest variability. DISCUSSION: Children were more vulnerable to communicable diseases compared to adults. Community health centers showing consistently high consultation rates point out a need for their prioritization. The predominance of primary care conditions requires disaster managers to focus on basic health care and public health measures in community health centers that target the young, elderly and impoverished appropriate to the time period.

Developing the Philippines as a Global Hub for Disaster Risk Reduction - A Health Research Initiative as Presented at the 10th Philippine National Health Research System Week Celebration.

The recent Philippine National Health Research System (PNHRS) Week Celebration highlighted the growing commitment to Disaster Risk Reduction (DRR) in the Philippines. The event was lead by the Philippine Council for Health Research and Development of the Department of Science and Technology and the Department of Health, and saw the participation of national and international experts in DRR, and numerous research consortia from all over the Philippines. With a central focus on the Sendai Framework for Disaster Risk Reduction, the DRR related events recognised the significant disaster risks faced in the Philippines. They also illustrated the Philippine strengths and experience in DRR. Key innovations in science and technology showcased at the conference include the web-base hazard mapping applications 'Project NOAH' and 'FaultFinder'. Other notable innovations include 'Surveillance in Post Extreme Emergencies and Disasters' (SPEED) which monitors potential outbreaks through a syndromic reporting system. Three areas noted for further development in DRR science and technology included: integrated national hazard assessment, strengthened collaboration, and improved documentation. Finally, the event saw the proposal to develop the Philippines into a global hub for DRR. The combination of the risk profile of the Philippines, established national structures and experience in DRR, as well as scientific and technological innovation in this field are potential factors that could position the Philippines as a future global leader in DRR. The purpose of this article is to formally document the key messages of the DRR-related events of the PNHRS Week Celebration.

Post-disaster health impact of natural hazards in the Philippines in 2013.

BACKGROUND: In 2011, the Health Emergency Management Bureau (HEMB) created the Surveillance for Post Extreme Emergencies and Disasters (SPEED), a real-time syndromic surveillance system that allows the early detection and monitoring of post-disaster disease trends. SPEED can assist health leaders in making informed decisions on health systems affected by disasters. There is a need for further validation of current concepts in post-disaster disease patterns in respect to actual field data. This study aims to evaluate the temporal post-disaster patterns of selected diseases after a flood, an earthquake, and a typhoon in the Philippines in 2013. METHODOLOGY: We analyzed the 21 syndromes provided by SPEED both separately and grouped into injuries, communicable diseases, and non-communicable diseases (NCDs) by calculating daily post-disaster consultation rates for up to 150 days post-disaster. These were compared over time and juxtaposed according to the type of disaster. RESULTS: Communicable diseases were found to be the predominant syndrome group in all three disaster types. The top six syndromes found were: acute respiratory infections, open wounds, bruises and burns, high blood pressure, skin disease, fever, and acute watery diarrhea. DISCUSSION: Overall, the results aligned with the country's morbidity profile. Within 2 months, the clear gradation of increasing syndrome rates reflected the severity (flood

How to create innovation by building the translation bridge from basic research into medicinal drugs: an industrial perspective.

The global healthcare industry is undergoing substantial changes and adaptations to the constant decline of approved new medical entities. This decrease in internal research productivity is resulting in a major decline of patent-protected sales (patent cliff) of most of the pharmaceutical companies. Three major global adaptive trends as driving forces to cope with these challenges are evident: cut backs of internal research and development jobs in the western hemisphere (Europe and USA), following the market growth potential of Asia by building up internal or external research and development capabilities there and finally, 'early innovation hunting' with an increased focus on identifying and investing in very early innovation sources within academia and small start-up companies. Early innovation hunting can be done by different approaches: increased corporate funding, establishment of translational institutions to bridge innovation, increasing sponsored collaborations and formation of technology hunting groups for capturing very early scientific ideas and concepts. This emerging trend towards early innovation hunting demands special adaptations from both the pharmaceutical industry and basic researchers in academia to bridge the translation into new medicines which deliver innovative medicines that matters to the patient. This opinion article describes the different modalities of cross-fertilisation between basic university or publicly funded institutional research and the applied research and development activities within the pharmaceutical industry. Two key factors in this important translational bridge can be identified: preparation of both partnering organisations to open up for new and sometime disruptive ideas and creation of truly trust-based relationships between the different groups allowing long-term scientific collaborations while acknowledging that value-creating differences are an essential factor for successful collaboration building.

A Dominant-Negative PPARgamma Mutant Promotes Cell Cycle Progression and Cell Growth in Vascular Smooth Muscle Cells.

PPARgamma ligands have been shown to have antiproliferative effects on many cell types. We herein report that a synthetic dominant-negative (DN) PPARgamma mutant functions like a growth factor to promote cell cycle progression and cell proliferation in human coronary artery smooth muscle cells (CASMCs). In quiescent CASMCs, adenovirus-expressed DN-PPARgamma promoted G1-->S cell cycle progression, enhanced BrdU incorporation, and increased cell proliferation. DN-PPARgamma expression also markedly enhanced positive regulators of the cell cycle, increasing Rb and CDC2 phosphorylation and the expression of cyclin A, B1, D1, and MCM7. Conversely, overexpression of wild-type (WT) or constitutively-active (CA) PPARgamma inhibited cell cycle progression and the activity and expression of positive regulators of the cell cycle. DN-PPARgamma expression, however, did not up-regulate positive cell cycle regulators in PPARgamma-deficient cells, strongly suggesting that DN-PPARgamma effects on cell cycle result from blocking the function of endogenous wild-type PPARgamma. DN-PPARgamma expression enhanced phosphorylation of ERK MAPKs. Furthermore, the ERK specific-inhibitor PD98059 blocked DN-PPARgamma-induced phosphorylation of Rb and expression of cyclin A and MCM7. Our data thus suggest that DN-PPARgamma promotes cell cycle progression and cell growth in CASMCs by modulating fundamental cell cycle regulatory proteins and MAPK mitogenic signaling pathways in vascular smooth muscle cells (VSMCs).

Vascular effects of TZDs: new implications.

The incidence of diabetes, now affecting more than 170 million individuals is growing rapidly. Type 2 diabetes, which accounts for 90% of all diabetes cases, is associated with increased cardiovascular morbidity and mortality. Thiazolidinediones (TZDs), used for the treatment of patients with type 2 diabetes improve insulin sensitivity and endothelial dysfunction and exert beneficial effects on the lipid profile by activating the peroxisome proliferator-activated receptor gamma (PPAR-gamma). Moreover, a large body of evidence indicates that TZDs exhibit antiatherogenic effects independent of their antidiabetic and lipid-lowering properties by modulating inflammatory processes. This review will focus on the role of PPAR-gamma agonists in the vessel wall and summarize their effects on C-reactive protein (CRP), plasminogen activator inhibitor type-1 (PAI-1), matrix metalloproteinase-9 (MMP-9), adiponectin and ATP-binding cassette transporter A1 (ABCA1) and their implications for treatment of advanced stages of atherosclerosis, particularly in a setting of type 2 diabetes.

Activation of peroxisome proliferator-activated receptor gamma suppresses telomerase activity in vascular smooth muscle cells.

Activation of the peroxisome proliferator-activated receptor (PPAR) gamma, the molecular target for insulin sensitizing thiazolidinediones used in patients with type 2 diabetes, inhibits vascular smooth muscle cell (VSMC) proliferation and prevents atherosclerosis and neointima formation. Emerging evidence indicates that telomerase controls key cellular functions including replicative lifespan, differentiation, and cell proliferation. In the present study, we demonstrate that ligand-induced and constitutive PPARgamma activation inhibits telomerase activity in VSMCs. Telomerase reverse transcriptase (TERT) confers the catalytic activity of telomerase, and PPARgamma ligands inhibit TERT expression through a receptor-dependent suppression of the TERT promoter. 5'-deletion analysis, site-directed mutagenesis, and transactivation studies using overexpression of Ets-1 revealed that suppression of TERT transcription by PPARgamma is mediated through negative cross-talk with Ets-1-dependent transactivation of the TERT promoter. Chromatin immunoprecipitation assays further demonstrated that PPARgamma ligands inhibit Ets-1 binding to the TERT promoter, which is mediated at least in part through an inhibition of Ets-1 expression by PPARgamma ligands. In VSMCs overexpressing TERT, the efficacy of PPARgamma ligands to inhibit cell proliferation is lost, indicating that TERT constitutes an important molecular target for the antiproliferative effects of PPARgamma ligands. Finally, we demonstrate that telomerase activation during the proliferative response after vascular injury is effectively inhibited by PPARgamma ligands. These findings provide a previously unrecognized mechanism for the antiproliferative effects of PPARgamma ligands and support the concept that PPARgamma ligands may constitute a novel therapeutic approach for the treatment of proliferative cardiovascular diseases.

Obesity, peroxisome proliferator-activated receptor, and atherosclerosis in type 2 diabetes.

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily. The 3 PPAR isotypes, PPAR-alpha, PPAR-gamma, and PPAR-delta, play a key role in the regulation of lipid and glucose metabolism. Obesity and the interrelated disorders of the metabolic syndrome have become a major worldwide health problem. In this review, we summarize the critical role of PPARs in regulating inflammation, lipoprotein metabolism, and glucose homeostasis and their potential implications for the treatment of obesity, diabetes, and atherosclerosis.

Transcriptional repression of ATP-binding cassette transporter A1 gene in macrophages: a novel atherosclerotic effect of angiotensin II.

Angiotensin II (Ang II) is a powerful accelerator of atherosclerosis. Herein, we describe a novel transcription mechanism through which Ang II inhibits macrophage expression of the ATP-binding cassette transporter A1 (ABCA1), a key regulator of reverse cholesterol transport. We demonstrate that chronic Ang II infusion substantially promotes macrophage infiltration, foam cell formation, and atherosclerosis in low-density lipoprotein receptor-deficient mice and significantly reduces ABCA1 expression in peripheral macrophages. Administration of the Ang II type 1 receptor blocker valsartan inhibited Ang II-induced ABCA1 mRNA repression, macrophage cholesterol accumulation, and atherosclerosis. Ang II treatment reduced ABCA1 promoter activity of in vitro cultured mouse peritoneal macrophages, inducing fos-related antigen 2 (Fra2) protein binding to an ABCA1 promoter E-box motif, a site known to negatively regulate macrophage ABCA1 transcription. Valsartan pretreatment blocked Fra2 binding to the ABCA1 promoter, and Fra2 small interfering RNA pretreatment attenuated Ang II-mediated ABCA1 transcriptional inhibition, confirming the role of Fra2 in this process. This new evidence suggests that Ang II, a well-known proinflammatory and pro-oxidative factor, alters macrophage cholesterol homeostasis by repressing ABCA1 to promote foam cell formation and atherosclerosis.

Liver x receptor agonists inhibit cytokine-induced osteopontin expression in macrophages through interference with activator protein-1 signaling pathways.

Osteopontin (OPN) is a proinflammatory cytokine and adhesion molecule implicated in the chemoattraction of monocytes and in cell-mediated immunity. We have recently reported that genetic OPN-deficiency attenuates the development of atherosclerosis in apoE-/- mice identifying OPN as potential target for pharmacological intervention in atherosclerosis. Synthetic agonists for the Liver X Receptor (LXR), members of the nuclear hormone receptor superfamily, prevent the development of atherosclerosis by regulating cholesterol homeostasis and suppressing inflammatory gene expression in macrophages. We demonstrate here that LXR ligands inhibit cytokine-induced OPN expression in macrophages. Two synthetic LXR ligands, T0901317 and GW3965, inhibited TNF-alpha, IL-1beta, INF-gamma and lipopolysaccharide induced OPN mRNA and protein expression in RAW 264.7 macrophages. Transient transfection experiments revealed that LXR ligands suppress cytokine-induced OPN promoter activity. Deletion analysis, heterologous promoter assays, and site-directed mutagenesis identified an activator protein-1 (AP-1) consensus site at -76 relative to the initiation site that supports OPN transcription in macrophages and mediates the effects of LXR ligands to inhibit OPN transcription. Electrophoretic mobility shift and chromatin immunoprecipitation assays indicated that LXR agonists inhibit cytokine-induced c-Fos and phospho-c-Jun binding to this AP-1 site. Cytokine-induced c-Fos and phospho-c-Jun protein expression was inhibited by LXR ligands and overexpression of c-Fos and c-Jun reversed the inhibitory effect of LXR ligands on OPN promoter activity in transactivation assays. Finally, treatment of C57BL/6J mice with LXR ligands inhibited OPN expression in peritoneal macrophages indicating that the observed effects of LXR ligands to inhibit OPN expression are applicable in vivo. These observations identify the regulation of macrophage OPN expression as a mechanism whereby LXR ligands may impact macrophage inflammatory responses and atherosclerosis. The full text of this article is available online at http://circres.ahajournals.org.

PPARgamma-mediated insulin sensitization: the importance of fat versus muscle.

Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a nuclear hormone receptor that functions as a transcriptional regulator in a variety of tissues. PPARgamma activation, e.g., through binding of the synthetic glitazones or thiazolidinediones (TZD), results in a marked improvement in type 2 diabetic patients of insulin and glucose parameters resulting from an improvement of whole body insulin sensitivity. The role of different metabolic tissues (fat, skeletal muscle, liver) in mediating PPARgamma function in glucose and insulin homeostasis is still unclear. Recently, the function of PPARgamma in adipose tissue and skeletal muscle has been intensively characterized by using targeted deletion of PPARgamma in those tissues. In those studies, adipose PPARgamma has been identified as an essential mediator for the maintainance of whole body insulin sensitivity. Two major mechanisms have been described. 1) Adipose PPARgamma protects nonadipose tissue against excessive lipid overload and maintains normal organ function (liver, skeletal muscle); and 2) adipose PPARgamma guarantees a balanced and adequate production of secretion from adipose tissue of adipocytokines such as adiponectin and leptin, which are important mediators of insulin action in peripheral tissues. In contrast to studies in adipose-specific PPARgamma-deficient mice, the data in muscle-specific PPARgamma(-/-) mice demonstrate that whole body insulin sensitivity is, at least in part, relying on an intact PPARgamma system in skeletal muscle. Finally, these early and elegant studies using tissue-specific PPARgamma knockout mouse models pinpoint adipose tissue as the major target of TZD-mediated improvement of hyperlipidemia and insulin sensitization.

Evaluating the cardiovascular effects of the thiazolidinediones and their place in the management of type 2 diabetes in relation to the metabolic syndrome.

BACKGROUND: The aim of this work was to review evidence on the contribution of the metabolic syndrome to diabetes and atherosclerosis, to evaluate the effects of the thiazolidinediones (TZDs) on cardiovascular risk, and to assess the clinical use of TZDs and their associated risks and benefits. METHODS: Participants were a multidisciplinary panel of experts in endocrinology, cardiology, and nephrology. Available studies on hyperglycemia, hyperinsulinemia, beta-cell function, dyslipidemia, obesity, hypertension, inflammation, endothelial dysfunction, and vascular reactivity were reviewed through presentations by the experts. Assessments were made regarding the associations between characteristics of the metabolic syndrome, type 2 diabetes, and cardiovascular disease, along with the place of TZDs in therapy and management of related adverse clinical events. A panel was convened in November 2002 to develop conclusions based on scientific evidence presented during the meeting. Summary statements were evaluated based on strength and clinical relevance of the data and approved by all panel members. RESULTS AND CONCLUSIONS: Many characteristics of the metabolic syndrome are present before diabetes develops that greatly contribute to the cardiovascular disease burden associated with the progression of diabetes, such as atherosclerosis and coronary artery disease. Insulin resistance is a fundamental component of the metabolic syndrome, and interventions to improve insulin sensitivity are associated with positive cardiovascular effects. From current experimental and clinical data, TZDs appear to reduce risk factors for future cardiovascular events in patients with type 2 diabetes. Study data up to 2 years have demonstrated that TZDs effectively maintain glycemic control in patients with type 2 diabetes, which is attributed to their insulin-sensitizing effects and preservation of beta-cell function. Potential adverse events of TZDs include weight gain and edema, which are generally manageable. Aside from improving insulin sensitivity, TZDs improve lipid profiles, favorably alter deposition of adipose tissue to the periphery rather than visceral areas, decrease markers of inflammation and endothelial dysfunction, and restore vascular reactivity. These pleiotropic effects have the potential to improve cardiovascular outcomes in patients with type 2 diabetes. Trials are underway to confirm this potentially beneficial addition to proven therapies for hypertension, dyslipidemia, and atherosclerosis.

Liver x receptors: potential novel targets in cardiovascular diseases.

The Liver X Receptors, LXRalpha and LXRbeta are members of the nuclear hormone receptor superfamily which have recently been implicated as novel pharmacological targets for the treatment of cardiovascular diseases. The identification of natural and synthetic ligands for LXRs and the generation of LXR-deficient mice have been crucial for our understanding of the function of these receptors and for the identification of LXR-regulated target genes, particularly with respect to the role of LXRs in regulating cholesterol homeostasis. Synthetic LXRalpha/beta agonists induce cholesterol efflux and reverse cholesterol transport, improve glucose metabolism, inhibit macrophage-derived inflammation, and suppress the proliferation of vascular smooth muscle cells. By regulating the expression of multiple genes involved in these pathways, LXR agonists prevent the development and progression of atherosclerosis and inhibit neointima formation following angioplasty of the arterial wall. In this review, we will summarize the important roles of LXR in metabolism and vascular biology and discuss its implications as potential molecular drug target for the treatment of cardiovascular diseases.