Methotrexate-mediated activation of an AMPK-CREB-dependent pathway: a novel mechanism for vascular protection in chronic systemic inflammation

Aims Premature cardiovascular events complicate chronic inflammatory conditions. Low-dose weekly methotrexate (MTX), the most widely used disease-modifying drug for rheumatoid arthritis (RA), reduces disease-associated cardiovascular mortality. MTX increases intracellular accumulation of adenosine monophosphate (AMP) and 5-aminoimidazole-4-carboxamide ribonucleotide which activates AMP-activated protein kinase (AMPK). We hypothesised that MTX specifically protects the vascular endothelium against inflammatory injury via induction of AMPK-regulated protective genes. Methods/results In the (NZW×BXSB)F1 murine model of inflammatory vasculopathy, MTX 1 mg/kg/week significantly reduced intramyocardial vasculopathy and attenuated end-organ damage. Studies of human umbilical vein endothelial cells (HUVEC) and arterial endothelial cells (HAEC) showed that therapeutically relevant concentrations of MTX phosphorylate AMPKαThr172, and induce cytoprotective genes including manganese superoxide dismutase (MnSOD) and haem oxygenase-1 (HO-1). These responses were preserved when HUVECs were pretreated with tumour necrosis factor-α to mimic dysfunctional endothelium. Furthermore, MTX protected against glucose deprivation-induced endothelial apoptosis. Mechanistically, MTX treatment led to cyclic AMP response element-binding protein (CREB)Ser133 phosphorylation, while AMPK depletion attenuated this response and the induction of MnSOD and HO-1. CREB siRNA inhibited upregulation of both cytoprotective genes by MTX, while chromatin immunoprecipitation demonstrated CREB binding to the MnSOD promoter in MTX-treated EC. Likewise, treatment of (NZW×BXSB)F1 mice with MTX enhanced AMPKαThr172 phosphorylation and MnSOD, and reduced aortic intercellular adhesion molecule-1 expression. Conclusions These data suggest that MTX therapeutically conditions vascular endothelium via activation of AMPK-CREB. We propose that this mechanism contributes to the protection against cardiovascular events seen in patients with RA treated with MTX

Women’s experiences of sexual harassment in hospitals in Riyadh: an exploratory study

This study, the first of its kind, explores women’s experiences of sexual harassment in hospitals in Saudi Arabia. Mixed methods were employed: a questionnaire distributed in three public hospitals and completed by 262 women, and semi-structured interviews with 25 women. The study found that that incidents of sexual harassment in Saudi Arabian hospitals are strikingly common, although there are ambiguities around the definition of this term. Sexual harassment was disproportionately experienced by women working at the administration level, as their occupations required frequent interactions with men. Other important factors were age, education level, marital status, job grade, the gender of supervisors and patients, and gender ratios and hierarchies in the workplace, as well as times of working. Sexual harassment in all its forms had a devastating impact on women’s quality of life in both personal and professional terms, and contributed to widening the gap between men and women in the Saudi community. The interview data gave an insight into the cultural and institutional factors shaping sexual harassment and responses to it. These include the gender-segregated and male dominated nature of Saudi society and a culture of honour and shame which produces prevalent victim-blaming. Also significant were a lack of institutional policies which meant that the size and community of the hospital became extremely relevant as a preventative factor: in smaller hospitals sexual harassment was more difficult to conceal, whereas in larger institutions men were harassing with impunity. The findings of this study suggest there is a need for more research into this phenomenon and an attempt to develop better institutional policies and procedures

Women’s experiences of sexual harassment in hospitals in Riyadh: an exploratory study

This study, the first of its kind, explores women’s experiences of sexual harassment in hospitals in Saudi Arabia. Mixed methods were employed: a questionnaire distributed in three public hospitals and completed by 262 women, and semi-structured interviews with 25 women. The study found that that incidents of sexual harassment in Saudi Arabian hospitals are strikingly common, although there are ambiguities around the definition of this term. Sexual harassment was disproportionately experienced by women working at the administration level, as their occupations required frequent interactions with men. Other important factors were age, education level, marital status, job grade, the gender of supervisors and patients, and gender ratios and hierarchies in the workplace, as well as times of working. Sexual harassment in all its forms had a devastating impact on women’s quality of life in both personal and professional terms, and contributed to widening the gap between men and women in the Saudi community. The interview data gave an insight into the cultural and institutional factors shaping sexual harassment and responses to it. These include the gender-segregated and male dominated nature of Saudi society and a culture of honour and shame which produces prevalent victim-blaming. Also significant were a lack of institutional policies which meant that the size and community of the hospital became extremely relevant as a preventative factor: in smaller hospitals sexual harassment was more difficult to conceal, whereas in larger institutions men were harassing with impunity. The findings of this study suggest there is a need for more research into this phenomenon and an attempt to develop better institutional policies and procedures