FXR agonist INT-747 upregulates DDAH expression and enhances insulin sensitivity in high-salt fed Dahl rats.

AIMS: Genetic and pharmacological studies have shown that impairment of the nitric oxide (NO) synthase (NOS) pathway is associated with hypertension and insulin-resistance (IR). In addition, inhibition of NOS by the endogenous inhibitor, asymmetric dimethylarginine (ADMA), may also result in hypertension and IR. On the other hand, overexpression of dimethylarginine dimethylaminohydrolase (DDAH), an enzyme that metabolizes ADMA, in mice is associated with lower ADMA, increased NO and enhanced insulin sensitivity. Since DDAH carries a farnesoid X receptor (FXR)-responsive element, we aimed to upregulate its expression by an FXR-agonist, INT-747, and evaluate its effect on blood pressure and insulin sensitivity. METHODS AND RESULTS: In this study, we evaluated the in vivo effect of INT-747 on tissue DDAH expression and insulin sensitivity in the Dahl rat model of salt-sensitive hypertension and IR (Dahl-SS). Our data indicates that high salt (HS) diet significantly increased systemic blood pressure. In addition, HS diet downregulated tissue DDAH expression while INT-747 protected the loss in DDAH expression and enhanced insulin sensitivity compared to vehicle controls. CONCLUSION: Our study may provide the basis for a new therapeutic approach for IR by modulating DDAH expression and/or activity using small molecules.

A multi-institutional medical educational collaborative: advocacy training in California pediatric residency programs.

Educational collaboratives offer a promising approach to disseminate educational resources and provide faculty development to advance residents' training, especially in areas of novel curricular content; however, their impact has not been clearly described. Advocacy training is a recently mandated requirement of the Accreditation Council for Graduate Medical Education that many programs struggle to meet.The authors describe the formation (in 2007) and impact (from 2008 to 2010) of 13 California pediatric residency programs working in an educational collaboration ("the Collaborative") to improve advocacy training. The Collaborative defined an overarching mission, assessed the needs of the programs, and mapped their strengths. The infrastructure required to build the collaboration among programs included a social networking site, frequent conference calls, and face-to-face semiannual meetings. An evaluation of the Collaborative's activities showed that programs demonstrated increased uptake of curricular components and an increase in advocacy activities. The themes extracted from semistructured interviews of lead faculty at each program revealed that the Collaborative (1) reduced faculty isolation, increased motivation, and strengthened faculty academic development, (2) enhanced identification of curricular areas of weakness and provided curricular development from new resources, (3) helped to address barriers of limited resident time and program resources, and (4) sustained the Collaborative's impact even after formal funding of the program had ceased through curricular enhancement, the need for further resources, and a shared desire to expand the collaborative network.

Mercury in the environment: sources, toxicities, and prevention of exposure.

Acute and chronic exposure to mercury can significantly affect the health of a population, specifically the children. Methylmercury may pose the highest threat, as it is ubiquitous in the environment and it is a potent neurotoxicant. Methylmercury easily passes through the placenta to the developing fetus. Elemental mercury, or quicksilver, also poses a threat to children because it may be found readily in schools, hospitals, and medicine cabinets, and its intriguing liquid nature may be enticing to children. Pediatricians must be diligent in informing patients of possible exposure sources, and alerting them to new government advisories and recommendations. They should also be knowledgeable regarding classic clinical presentations of mercury toxicity. It is only in cases involving a knowledge of mercury that appropriate historical information is obtained and correct diagnoses are made. Preventing mercury exposure and consequent toxicity is of importance because therapies are controversial and long-term consequences may be significant.