Metabolic, inflammatory and haemostatic effects of a low-dose continuous combined HRT in women with type 2 diabetes: potentially safer with respect to vascular risk?

BACKGROUND Conventional hormone replacement therapy (HRT) containing conjugated equine oestrogen (CEE) and medroxyprogesterone acetate (MPA) increases triglyceride, C- reactive protein (CRP) and coagulation Factor VII concentrations, potentially explaining their increased coronary heart disease (CHD) and stroke risk. OBJECTIVE To assess the metabolic effects of a continuous combined HRT containing 1 mg oestradiol and 0.5 mg norethisterone or matching placebo. DESIGN Double-blind, randomized placebo-controlled trial. PATIENTS Fifty women with type 2 diabetes. MEASUREMENTS Classical and novel risk factors for vascular disease. RESULTS Triglyceride concentration was not altered (P = 0.31, change in active arm relative to placebo) and low-density lipoprotein (LDL) cholesterol concentration declined 13% (P = 0.018). IL-6 concentration (mean difference -1.42 pg/ml, 95% CI: -2.55 to - 0.29 IU/dl, P = 0.015), Factor VII (-32 IU/dl, -43 to -21 IU/l, P lt 0.001) and tissue plasminogen activator antigen (by 13%, P = 0.005) concentrations fell, but CRP was not significantly altered (P = 0.62). Fasting glucose (P = 0.026) also declined significantly, but there are no significant effects on HBA1c, Factor IX or APC resistance. CONCLUSIONS HRT containing 1 mg oestradiol and 0.5 mg norethisterone may avoid the adverse metabolic effects potentially implicated in the elevated CHD and stroke risk induced by conventional higher dose HRT. This type of preparation may therefore be more suitable than conventional HRT for women at elevated CHD risk such as those with type 2 diabetes. Large randomized controlled trials of such low dose preparations, powered for cardiovascular end points, are now needed

Risk Reducing Salpingectomy and Delayed Oophorectomy in high risk women: views of cancer geneticists, genetic counsellors and gynaecological oncologists in the UK

Risk-reducing-salpingectomy and Delayed-Oophorectomy (RRSDO) is being proposed as a two-staged approach in place of RRSO to reduce the risks associated with premature menopause in high-risk women. We report on the acceptability/attitude of UK health professionals towards RRSDO. An anonymised web-based survey was sent to UK Cancer Genetics Group (CGG) and British Gynaecological Cancer Society (BGCS) members to assess attitudes towards RRSDO. Baseline characteristics were described using descriptive statistics. A Chi square test was used to compare categorical, Kendal-tau-b test for ordinal and Mann–Whitney test for continuous variables between two groups. 173/708 (24.4 %) of invitees responded. 71 % respondents (CGG = 57 %/BGCS = 83 %, p = 0.005) agreed with the tubal hypothesis for OC, 55 % (CGG = 42 %/BGCS = 66 %, p = 0.003) had heard of RRSDO and 48 % (CGG = 46 %/BGCS = 50 %) felt evidence was not currently strong enough for introduction into clinical practice. However, 60 % respondents’ (CGG = 48 %/BGCS = 71 %, p = 0.009) favoured offering RRSDO to high-risk women declining RRSO, 77 % only supported RRSDO within a clinical trial (CGG = 78 %/BGCS = 76 %) and 81 % (CGG = 76 %/BGCS = 86 %) advocated a UK-wide registry. Vasomotor symptoms (72 %), impact on sexual function (63 %), osteoporosis (59 %), hormonal-therapy (55 %) and subfertility (48 %) related to premature menopause influenced their choice of RRSDO. Potential barriers to offering the two-stage procedure included lack of data on precise level of benefit (83 %), increased surgical morbidity (79 %), loss of breast cancer risk reduction associated with oophorectomy (68 %), need for long-term follow-up (61 %) and a proportion not undergoing DO (66 %). There were variations in perception between BGCS/CGG members which are probably attributable to differences in clinical focus/expertise between these two groups. Despite concerns, there is reasonable support amongst UK clinicians to offering RRSDO to premenopausal high-risk women wishing to avoid RRSO, within a prospective clinical trial.This work has not been directly funded by any commercial organisation, or charity

The effects of endogenous and exogenous androgens on cardiovascular disease risk factors and progression

Cardiovascular disease incidence rates have long been known to significantly differ between the two sexes. Estrogens alone fail to explain this phenomenon, bringing an increasing amount of attention to the role of androgens. Contrary to what was initially hypothesized, androgens seem to have an overall cardioprotective effect, especially in men. Recent studies and published data continue to support this notion displaying a consistent inverse correlation with atherosclerosis progression and cardiovascular disease both in regressive and prospective study models. Clinical studies have also revealed what seems to be a differential androgenic effect on various cardiovascular risk factors between men and women. Further insight indicates that in order to avoid confusion it may be also preferable to separately examine the effects of endogenous androgen levels from exogenous testosterone administration, as well as discern the differential results of low to normal and supraphysiological administration doses. This review summarizes old and recent data according to the above distinctions, in an attempt to further our understanding of the role of androgens in cardiovascular disease

Clinical practice: evidence-based recommendations for the treatment of cervical dystonia with botulinum toxin

Cervical dystonia (CD) is the most frequent form of focal dystonia. Symptoms often result in pain and functional disability. Local injections of botulinum neurotoxin are currently the treatment of choice for CD. Although this treatment has proven effective and is widely applied worldwide, many issues still remain open in the clinical practice. We performed a systematic review of the literature on botulinum toxin treatment for CD based on a question-oriented approach, with the aim to provide practical recommendations for the treating clinicians. Key questions from the clinical practice were explored. Results suggest that while the beneficial effect of botulinum toxin treatment on different aspects of CD is well established, robust evidence is still missing concerning some practical aspects, such as dose equivalence between different formulations, optimal treatment intervals, treatment approaches, and the use of supportive techniques including electromyography or ultrasounds. Established strategies to prevent or manage common side effects (including excessive muscle weakness, pain at injection site, dysphagia) and potential contraindications to this treatment (pregnancy and lactation, use of anticoagulants, neurological comorbidities) should also be further explored

Prescriptions for selective cyclooxygenase-2 inhibitors, non-selective non-steroidal anti-inflammatory drugs, and risk of breast cancer in a population-based case-control study

INTRODUCTION. Non-steroidal anti-inflammatory drugs (NSAIDs) prevent the growth of mammary tumours in animal models. Two population-based case-control studies suggest a reduced risk of breast cancer associated with selective cyclooxygenase-2 (sCox-2) inhibitor use, but data regarding the association between breast cancer occurrence and use of non-selective NSAIDs are conflicting. METHODS. We conducted a population-based case-control study using Danish healthcare databases to examine if use of NSAIDs, including sCox-2 inhibitors, was associated with a reduced risk of breast cancer. We included 8,195 incident breast cancer cases diagnosed in 1991 through 2006 and 81,950 population controls. RESULTS. Overall, we found no reduced breast cancer risk in ever users (>2 prescriptions) of sCox-2 inhibitors (odds ratio (OR) = 1.08, 95% confidence interval (95% CI) = 0.99, 1.18), aspirin (OR = 0.98, 95% CI = 0.90-1.07), or non-selective NSAIDs OR = 1.04, (95% CI = 0.98, 1.10)). Recent use (>2 prescriptions within two years of index date) of sCox-2 inhibitors, aspirin, or non-selective NSAIDs was likewise not associated with breast cancer risk (Ors = 1.06 (95% CI = 0.96, 1.18), 0.96 (95% CI = 0.87, 1.06) and 0.99 (95% CI = 0.85, 1.16), respectively). Risk estimates by duration (<10, 10 to 15, 15+ years) or intensity (low/medium/high) of NSAID use were also close to unity. Regardless of intensity, shorter or long-term NSAID use was not significantly associated with breast cancer risk. CONCLUSIONS. Overall, we found no compelling evidence of a reduced risk of breast cancer associated with use of sCox-2 inhibitors, aspirin, or non-selective NSAIDs.Karen Elise Jensen Foundatio

Menopausal hormone use and ovarian cancer risk: individual participant meta-analysis of 52 epidemiological studies

Background Half the epidemiological studies with information about menopausal hormone therapy and ovarian cancer risk remain unpublished, and some retrospective studies could have been biased by selective participation or recall. We aimed to assess with minimal bias the effects of hormone therapy on ovarian cancer risk. Methods Individual participant datasets from 52 epidemiological studies were analysed centrally. The principal analyses involved the prospective studies (with last hormone therapy use extrapolated forwards for up to 4 years). Sensitivity analyses included the retrospective studies. Adjusted Poisson regressions yielded relative risks (RRs) versus never-use. Findings During prospective follow-up, 12 110 postmenopausal women, 55% (6601) of whom had used hormone therapy, developed ovarian cancer. Among women last recorded as current users, risk was increased even with <5 years of use (RR 1·43, 95% CI 1·31–1·56; p<0·0001). Combining current-or-recent use (any duration, but stopped <5 years before diagnosis) resulted in an RR of 1·37 (95% CI 1·29–1·46; p<0·0001); this risk was similar in European and American prospective studies and for oestrogen-only and oestrogen-progestagen preparations, but differed across the four main tumour types (heterogeneity p<0·0001), being definitely increased only for the two most common types, serous (RR 1·53, 95% CI 1·40–1·66; p<0·0001) and endometrioid (1·42, 1·20–1·67; p<0·0001). Risk declined the longer ago use had ceased, although about 10 years after stopping long-duration hormone therapy use there was still an excess of serous or endometrioid tumours (RR 1·25, 95% CI 1·07–1·46, p=0·005). Interpretation The increased risk may well be largely or wholly causal; if it is, women who use hormone therapy for 5 years from around age 50 years have about one extra ovarian cancer per 1000 users and, if its prognosis is typical, about one extra ovarian cancer death per 1700 users

Altered sensorimotor activation patterns in idiopathic dystonia - an activation likelihood estimation meta-analysis of functional brain imaging studies

Dystonia is characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements or postures. Functional neuroimaging studies have yielded abnormal task-related sensorimotor activation in dystonia, but the results appear to be rather variable across studies. Further, study size was usually small including different types of dystonia. Here we performed an activation likelihood estimation (ALE) meta-analysis of functional neuroimaging studies in patients with primary dystonia to test for convergence of dystonia-related alterations in task-related activity across studies. Activation likelihood estimates were based on previously reported regional maxima of task-related increases or decreases in dystonia patients compared to healthy controls. The meta-analyses encompassed data from 179 patients with dystonia reported in 18 functional neuroimaging studies using a range of sensorimotor tasks. Patients with dystonia showed bilateral increases in task-related activation in the parietal operculum and ventral postcentral gyrus as well as right middle temporal gyrus. Decreases in task-related activation converged in left supplementary motor area and left postcentral gyrus, right superior temporal gyrus and dorsal midbrain. Apart from the midbrain cluster, all between-group differences in task-related activity were retrieved in a sub-analysis including only the 14 studies on patients with focal dystonia. For focal dystonia, an additional cluster of increased sensorimotor activation emerged in the caudal cingulate motor zone. The results show that dystonia is consistently associated with abnormal somatosensory processing in the primary and secondary somatosensory cortex along with abnormal sensorimotor activation of mesial premotor and right lateral temporal cortex

Functional neuroimaging of motor control in Parkinson's disease: A meta-analysis

Functional neuroimaging has been widely used to study the activation patterns of the motor network in patients with Parkinson's disease (PD), but these studies have yielded conflicting results. This meta-analysis of previous neuroimaging studies was performed to identify patterns of abnormal movement-related activation in PD that were consistent across studies. We applied activation likelihood estimation (ALE) of functional neuroimaging studies probing motor function in patients with PD. The meta-analysis encompassed data from 283 patients with PD reported in 24 functional neuroimaging studies and yielded consistent alterations in neural activity in patients with PD. Differences in cortical activation between PD patients and healthy controls converged in a left-lateralized fronto-parietal network comprising the presupplementary motor area, primary motor cortex, inferior parietal cortex, and superior parietal lobule. Both, increases as well as decreases in motor cortical activity, which were related to differences in movement timing and selection in the applied motor tasks, were reported in these cortical areas. In the basal ganglia, PD patients expressed a decrease of motor activation in the posterior motor putamen, which improved with dopaminergic medication. The likelihood of detecting a decrease in putaminal activity increased with motor impairment. This reduced motor activation of the posterior putamen across previous neuroimaging studies indicates that nigrostriatal dopaminergic denervation affects neural processing in the denervated striatal motor territory. In contrast, fronto-parietal motor areas display both increases as well as decreases in movement related activation. This points to a more complex relationship between altered cortical physiology and nigrostriatal dopaminergic denervation in P