The LUCK study: Laxative Usage in patients with GP-diagnosed Constipation in the UK, within the general population and in pregnancy. An epidemiological study using the General Practice Research Database (GPRD).

BACKGROUND: Despite the high prevalence of constipation and its related public health implications, there is relatively little research available on the condition from large epidemiological studies. The aim of this study was to investigate the epidemiology of general practitioner (GP)-diagnosed constipation and the prescribing trends for laxatives in the UK, within the general population and during pregnancy. METHODS: A cohort study for the period from 2005 to 2009 was performed using the UK primary care database (General Practice Research Database), which contains information on over 3 million individuals. RESULTS: The prevalence of GP-diagnosed constipation ranged from 12 per 1000 persons in 2005 (0.012 per person year) to 12.8 per 1000 in 2009 (0.013 per person year). The prevalence was almost twice as high in women as in men, and was higher in older patients. In 2005 the most commonly prescribed laxatives were lactulose (37%), senna (26%), macrogol (19%), ispaghula (6%), docusate sodium (5%), bisacodyl (4%) and glycerol suppositories (2%). By 2009, this pattern had changed: macrogol (31%), lactulose (29%), senna (22%), ispaghula (5%), docusate sodium (6%), bisacodyl (3%) and glycerol suppositories (3%). In pregnancy, lactulose accounted for 81% of laxative use in 2005, falling to 64% by 2009. In contrast, macrogol use in pregnancy rose from 13% in 2005 to 32% in 2009. CONCLUSIONS: GP-diagnosed constipation is common, accounting for a large number of consultations. Laxative prescribing trends have changed over the 5-year study period, prescriptions for macrogol becoming increasingly common and prescriptions for lactulose and senna less common. Macrogol also appears to have been replacing lactulose for treating constipation in pregnant women.

UK stroke incidence, mortality and cardiovascular risk management 1999-2008: time-trend analysis from the General Practice Research Database.

OBJECTIVES: Stroke is a major cause of morbidity and mortality. This study aimed to investigate secular trends in stroke across the UK. DESIGN: This study aimed to investigate recent trends in the epidemiology of stroke in the UK. The study was a time-trend analysis from 1999 to 2008 within the UK General Practice Research Database. Outcome measures were incidence and prevalence of stroke, stroke mortality, rate of secondary cardiovascular events, and prescribing of pharmacological therapy for primary and secondary prevention of cardiovascular disease. RESULTS: The study cohort included 32,151 patients with a first stroke. Stroke incidence fell by 30%, from 1.48/1000 person-years in 1999 to 1.04/1000 person-years in 2008 (p<0.001). Stroke prevalence increased by 12.5%, from 6.40/1000 in 1999 to 7.20/1000 in 2008 (p<0.001). 56-day mortality after first stroke reduced from 21% in 1999 to 12% in 2008 (p<0.0001). Prescribing of drugs to control cardiovascular risk factors increased consistently over the study period, particularly for lipid lowering agents and antihypertensive agents. In patients with atrial fibrillation, use of anticoagulants prior to first stroke did not increase with increasing stroke risk. CONCLUSION: Stroke incidence in the UK has decreased and survival after stroke has improved in the past 10 years. Improved drug treatment in primary care is likely to be a major contributor to this, with better control of risk factors both before and after incident stroke. There is, however, scope for further improvement in risk factor reduction in high-risk patients with atrial fibrillation.

Development of an siRNA-based method for repressing specific genes in renal organ culture and its use to show that the Wt1 tumour suppressor is required for nephron differentiation.

Wt1 is a tumour suppressor gene, mutation of which is a cause of Wilms' tumour, a childhood renal nephroblastoma. Wt1 is expressed in a rich pattern during renal development suggesting that it acts at three stages: determination of the kidney area, the differentiation of nephrons and maturation of glomeruli. Wt1-/- mice confirm that Wt1 is essential for the inception of kidney development; cells that ought to form kidneys die by apoptosis instead. Specific human WT1 mutations cause defects of glomerular maturation (Denys-Drash and Frasier syndromes), providing circumstantial evidence for action of Wt1 during glomerular maturation. There is, however, no genetic evidence for a function during nephron differentiation because this stage is never reached in Wt1-/- mice. We have therefore developed a novel technique, based on small interfering RNA (siRNA), to repress the expression of Wt1 and other specific genes at different stages of kidney development in culture. We find that early repression of Wt1 phenocopies the Wt1-/- mouse, but later repression prevents cells differentiating into nephrons and causes them instead to proliferate abnormally, possibly mimicking aspects of Wilms' tumour. In line with established hypotheses about genetic pathways that control kidney development, we find that repressing Pax2 using siRNAs represses Wt1 expression and blocks both bud growth and nephron differentiation, but that repressing Wnt4 blocks nephron differentiation without affecting Wt1 expression. As well as illuminating previously inaccessible aspects of Wt1 biology, our results suggest that siRNA in organ culture will be a powerful method for analyzing other developmental pathways and testing the effects of stage-specific loss of tumour suppressor genes.