SummaryBackgroundResults of small trials indicate that fluoxetine might improve functional outcomes after stroke. The FOCUS trial aimed to provide a precise estimate of these effects.MethodsFOCUS was a pragmatic, multicentre, parallel group, double-blind, randomised, placebo-controlled trial done at 103 hospitals in the UK. Patients were eligible if they were aged 18 years or older, had a clinical stroke diagnosis, were enrolled and randomly assigned between 2 days and 15 days after onset, and had focal neurological deficits. Patients were randomly allocated fluoxetine 20 mg or matching placebo orally once daily for 6 months via a web-based system by use of a minimisation algorithm. The primary outcome was functional status, measured with the modified Rankin Scale (mRS), at 6 months. Patients, carers, health-care staff, and the trial team were masked to treatment allocation. Functional status was assessed at 6 months and 12 months after randomisation. Patients were analysed according to their treatment allocation. This trial is registered with the ISRCTN registry, number ISRCTN83290762.FindingsBetween Sept 10, 2012, and March 31, 2017, 3127 patients were recruited. 1564 patients were allocated fluoxetine and 1563 allocated placebo. mRS data at 6 months were available for 1553 (99·3%) patients in each treatment group. The distribution across mRS categories at 6 months was similar in the fluoxetine and placebo groups (common odds ratio adjusted for minimisation variables 0·951 [95% CI 0·839–1·079]; p=0·439). Patients allocated fluoxetine were less likely than those allocated placebo to develop new depression by 6 months (210 [13·43%] patients vs 269 [17·21%]; difference 3·78% [95% CI 1·26–6·30]; p=0·0033), but they had more bone fractures (45 [2·88%] vs 23 [1·47%]; difference 1·41% [95% CI 0·38–2·43]; p=0·0070). There were no significant differences in any other event at 6 or 12 months.InterpretationFluoxetine 20 mg given daily for 6 months after acute stroke does not seem to improve functional outcomes. Although the treatment reduced the occurrence of depression, it increased the frequency of bone fractures. These results do not support the routine use of fluoxetine either for the prevention of post-stroke depression or to promote recovery of function.FundingUK Stroke Association and NIHR Health Technology Assessment Programme.

In this preliminary study, we observed a persistent, strong pro-inflammatory cytokine milieu in pSLE patients which reflects ongoing inflammatory damage in different organs. The gene expression profile of these cytokines may be used for assessing organ involvement in pSLE. IL-17 may also serve as a prognostic marker in pSLE. However, longitudinal studies on treatment of naïve patients are required to corroborate these findings.

Background: AT 1 R activation induces oxidative stress, promotes inflammation, and increases blood pressure. Results: SNPs in AT 1 R promoter occur in linkage disequilibrium, forming two haplotypes. Transgenic mice with haplotype I have USF2-dependent AT 1 R overexpression, increased oxidative stress, and increased blood pressure. Conclusion: Haplotype I leads to enhanced expression and pathophysiological effects of AT 1 R. Significance: Polymorphisms in AT 1 R provide for genetic predisposition to hypertension.

Background Aldosterone, synthesized in the adrenal cortex by the enzyme CYP11B2, induces positive sodium balance and predisposes to hypertension. Various investigators, using genomic DNA analyses, have linked −344T polymorphism in the hCYP11B2 gene to human hypertension. Human CYP11B2 gene promoter has three SNPs in linkage disequilibrium: T/A at −663, T/C at −470 and C/T at −344. Variants ACT occur together and form the haplotype-I while variants TTC constitute haplotype-II. We hypothesize that these SNPs, when present together, will lead to haplotype-dependent differences in the transcriptional regulation of the hCYP11B2 gene and affect blood pressure regulation. Methods and Results We evaluated differences in tissue expression, in vivo, and consequential effects on blood pressure stemming from the two haplotypes. Novel transgenic (TG) mice with the hCYP11B2 gene, targeted to the mouse HPRT locus, with either haplotype-II or I variant are used in the study. Our results show increased adrenal and renal expression of hCYP11B2 in TG mice with haplotype-I, as compared to mice with haplotype-II. Importantly, we observed increased baseline blood pressure in haplotype-I TG mice, an effect accentuated by a high-salt diet. Pathophysiological impact of elevated aldosterone was corroborated by our results showing up-regulation of proinflammatory markers in renal tissues from the TG mice with haplotype-I. Conclusions These findings characterize haplotype-dependent regulation of the hCYP11B2 gene where −344T serves as a reporter polymorphism and show that haplotype-I leads to increased expression of hCYP11B2, with permissive effects on blood pressure and inflammatory milieu.