Central nervous system cholesterol metabolism in health and disease.

Cholesterol is a ubiquitous and essential component of cellular membranes, as it regulates membrane structure and fluidity. Furthermore, cholesterol serves as a precursor for steroid hormones, oxysterol, and bile acids, that are essential for maintaining many of the body's metabolic processes. The biosynthesis and excretion of cholesterol is tightly regulated in order to maintain homeostasis. Although virtually all cells have the capacity to make cholesterol, the liver and brain are the two main organs producing cholesterol in mammals. Once produced, cholesterol is transported in the form of lipoprotein particles to other cell types and tissues. Upon formation of the blood-brain barrier (BBB) during embryonic development, lipoproteins cannot move between the central nervous system (CNS) and the rest of the body. As such, cholesterol biosynthesis and metabolism in the CNS operate autonomously without input from the circulation system in normal physiological conditions. Nevertheless, similar regulatory mechanisms for maintaining cholesterol homeostasis are utilized in both the CNS and peripheral systems. Here, we discuss the functions and metabolism of cholesterol in the CNS. We further focus on how different CNS cell types contribute to cholesterol metabolism, and how ApoE, the major CNS apolipoprotein, is involved in normal and pathophysiological functions. Understanding these basic mechanisms will aid our ability to elucidate how CNS cholesterol dysmetabolism contributes to neurogenerative diseases.

The role of single pill combination therapy in the prevention of ischaemic stroke.

BACKGROUND AND AIMS: The role of single pill combination therapy for stroke prevention remains to be established. We explored the perspectives of stroke survivors and healthcare professionals on single pill combination therapy for stroke prevention. METHODS: We conducted focus groups involving stroke survivors and healthcare professionals. RESULTS: We recruited six stroke survivors: four (67%) were female and mean age was 70 ± 12 years; and eight healthcare professionals (three Stroke Consultants, two Nurse Specialists, three General Practitioners). Improved adherence is the main perceived benefit of single pill combination therapy, although concerns exist surrounding less individualised care, unsuitability for use in the acute setting, reduced ability to titrate doses and difficulty identifying the cause of side effects. The clinical stability of patients, alongside single pill combination therapy efficacy, cost, side effect profile and evidence base for impact on risk factors and clinical outcomes are key factors influencing acceptability. Stroke survivors and healthcare professionals feel single pill combination therapy is most suitable for stable patients, although there is no evidence base for its use in this context. CONCLUSION: Stroke healthcare professionals and stroke survivors are most amenable to using single pill combination therapy for stable patients, although its role in this context should be evaluated in studies with risk factor targets and clinical outcomes as endpoints.

Aromatase inhibitors are associated with a higher fracture risk than tamoxifen: a systematic review and meta-analysis.

BACKGROUND: In this paper, our aim was to systematically evaluate published evidence of bone fracture risk associated with tamoxifen and aromatase inhibitors in women aged 65 and under, and diagnosed with nonmetastatic breast cancer. METHODS: We comprehensively searched MEDLINE, EMBASE and CINAHL databases from January 1997 through May 2015, and reference lists of the selected articles to identify English-language randomized controlled trials and cohort studies of fracture risk. Two independent reviewers screened articles and assessed methodological quality using Risk of Bias assessment for randomized controlled trials and the Newcastle-Ottawa Scale for cohort studies. Fracture risk was estimated as pooled risk ratios using a random-effects model and inverse variance method. RESULTS: Of 1926 identified articles, 21 independent studies fulfilled our selection criteria. Similar fracture risk was observed in women treated and not treated with tamoxifen [pooled risk ratio (RR) 0.95; 95% confidence interval (CI) 0.84-1.07]. A 35% (95% CI 1.21-1.51) higher fracture risk was observed in the aromatase inhibitor group compared with the tamoxifen group. A 17% (95% CI 1.07-1.28) higher fracture risk was observed in the aromatase inhibitor group than the no aromatase inhibitor group. Compared with the tamoxifen group, aromatase inhibitor-associated fracture risk increased by 33% (pooled RR 1.33; 95% CI 1.21-1.47) during the tamoxifen/aromatase inhibitor treatment period, but did not increase (pooled RR 0.99; 95% CI 0.72-1.37) during the post-tamoxifen/aromatase inhibitor treatment period. CONCLUSIONS: Fracture risk is significantly higher in women treated with aromatase inhibitors, especially during the treatment period. Tamoxifen is not associated with lower fracture risk while tamoxifen could potentially preserve bone mass. Better osteoporosis management programs, especially during the treatment period, are needed for this group of women.