Changes in Dopamine Signalling Do Not Underlie Aberrant Hippocampal Plasticity in a Mouse Model of Huntington's Disease

Altered dopamine receptor labelling has been demonstrated in presymptomatic and symptomatic Huntington's disease (HD) gene carriers, indicating that alterations in dopaminergic signalling are an early event in HD. We have previously described early alterations in synaptic transmission and plasticity in both the cortex and hippocampus of the R6/1 mouse model of Huntington's disease. Deficits in cortical synaptic plasticity were associated with altered dopaminergic signalling and could be reversed by D1- or D2-like dopamine receptor activation. In light of these findings we here investigated whether defects in dopamine signalling could also contribute to the marked alteration in hippocampal synaptic function. To this end we performed dopamine receptor labelling and pharmacology in the R6/1 hippocampus and report a marked, age-dependent elevation of hippocampal D1 and D2 receptor labelling in R6/1 hippocampal subfields. Yet, pharmacological inhibition or activation of D1- or D2-like receptors did not modify the aberrant synaptic plasticity observed in R6/1 mice. These findings demonstrate that global perturbations to dopamine receptor expression do occur in HD transgenic mice, similarly in HD gene carriers and patients. However, the direction of change and the lack of effect of dopaminergic pharmacological agents on synaptic function demonstrate that the perturbations are heterogeneous and region-specific, a finding that may explain the mixed results of dopamine therapy in HD

Impact of generic alendronate cost on the cost-effectiveness of osteoporosis screening and treatment

Introduction: Since alendronate became available in generic form in the Unites States in 2008, its price has been decreasing. The objective of this study was to investigate the impact of alendronate cost on the cost-effectiveness of osteoporosis screening and treatment in postmenopausal women. Methods: Microsimulation cost-effectiveness model of osteoporosis screening and treatment for U.S. women age 65 and older. We assumed screening initiation at age 65 with central dual-energy x-ray absorptiometry (DXA), and alendronate treatment for individuals with osteoporosis; with a comparator of "no screening" and treatment only after fracture occurrence. We evaluated annual alendronate costs of $20 through$800; outcome measures included fractures; nursing home admission; medication adverse events; death; costs; quality-adjusted life-years (QALYs); and incremental cost-effectiveness ratios (ICERs) in 2010 U.S. dollars per QALY gained. A lifetime time horizon was used, and direct costs were included. Base-case and sensitivity analyses were performed. Results: Base-case analysis results showed that at annual alendronate costs of $200 or less, osteoporosis screening followed by treatment was cost-saving, resulting in lower total costs than no screening as well as more QALYs (10.6 additional quality-adjusted life-days). When assuming alendronate costs of$400 through $800, screening and treatment resulted in greater lifetime costs than no screening but was highly cost-effective, with ICERs ranging from$714 per QALY gained through $13,902 per QALY gained. Probabilistic sensitivity analyses revealed that the cost-effectiveness of osteoporosis screening followed by alendronate treatment was robust to joint input parameter estimate variation at a willingness-to-pay threshold of$50,000/QALY at all alendronate costs evaluated. Conclusions: Osteoporosis screening followed by alendronate treatment is effective and highly cost-effective for postmenopausal women across a range of alendronate costs, and may be cost-saving at annual alendronate costs of $200 or less. © 2012 Nayak et al

Use of a liquid nicotine delivery product to promote smoking cessation

<p>Abstract</p> <p>Background</p> <p>Despite access to various pharmacotherapies and counseling support to aid cessation, smokers typically demonstrate quit rates below 50%. This report describes the results of a Phase 2a study exploring the efficacy of a liquid nicotine delivery system as an aid to smoking cessation assessed after 12 weeks of therapy.</p> <p>Methods</p> <p>A single-arm Phase 2a study was conducted. Community-based smokers (ages 18+ years, smoking at least 10 cigarettes daily for the past year and interested in making a quit attempt) were recruited and completed clinic visits at 2 week intervals over the 12 week study period where carbon monoxide levels were assessed and the Smoke-Break product was rated on taste and overall satisfaction. Participants were provided with a supply of liquid nicotine cigarettes (e.g., Smoke-Break) at each clinic visit. A total of 69 smokers were enrolled and received the intervention product (intention to treat group, ITT) and 52 smokers verified participation (according to protocol group, ATP).</p> <p>Results</p> <p>The cessation rate at 12 weeks after the baseline visit, assessed as the bioverified point prevalence of abstinence, was 71.1% (95% confidence interval [CI] 58.8%-83.5%) in the ATP group and 53.6% (41.8%-65.4%) in the ITT group. Participants rated the liquid nicotine delivery system highly and also expressed general satisfaction. Few adverse events were identified with no serious adverse events.</p> <p>Conclusions</p> <p>These results support the efficacy of the liquid nicotine delivery system in smoking cessation. If this nicotine delivery product proves to be effective in larger trials, it could represent an inexpensive, readily accessible and well-tolerated agent to promote smoking cessation.</p> <p>Trial Registration</p> <p>This trial is registered at clinicaltrials.gov as study NCT00715871.</p

Fracture Risk Assessment in Chronic Kidney Disease, Prospective Testing Under Real World Environments (FRACTURE): a prospective study

<p>Abstract</p> <p>Background</p> <p>Chronic kidney disease (CKD) is associated with an increased risk of fracture. Decreased bone mass and disruption of microarchitecture occur early in the course of CKD and worsens with the progressive decline in renal function so that at the time of initiation of dialysis at least 50% of patients have had a fracture. Despite the excess fracture risk, and the associated increases in morbidity and mortality, little is known about the factors that are associated with an increase in fracture risk. Our study aims to identify prognostic factors for bone loss and fractures in patients with stages 3 to 5 CKD.</p> <p>Methods</p> <p>This prospective study aims to enroll two hundred and sixty men and women with stages 3 to 5 CKD. Subjects will be followed for 24 months and we will examine the ability of: 1) bone mineral density by dual x-ray absorptiometry at the spine, hip, and radius; 2) volumetric bone density by high resolution peripheral quantitated computed tomography at the radius and tibia; 3) serum markers of bone turnover; 4) bone formation rate by bone biopsy; and 5) muscle strength and balance to predict spine and non-spine fractures, identified by self-report and/or vertebral morphometry. All measurements will be obtained at baseline, at 12 and at 24 months with the exception of bone biopsy, which will be measured once at 12 months. Subjects will be contacted every 4 months to determine if there have been incident fractures or falls.</p> <p>Discussion</p> <p>This study is one of the first that aims to identify risk factors for fracture in early stage CKD patients. Ultimately, by identifying risk factors for fracture and targeting treatments in this group-before the initiation of renal replacement therapy - we will reduce the burden of disease due to fractures among patients with CKD.</p

Comparison of performance-based measures among native Japanese, Japanese-Americans in Hawaii and Caucasian women in the United States, ages 65 years and over: a cross-sectional study

BACKGROUND: Japanese (both in Japan and Hawaii) have a lower incidence of falls and of hip fracture than North American and European Caucasians, but the reasons for these differences are not clear. SUBJECTS AND METHODS: A cross-sectional study. We compared neuromuscular risk factors for falls using performance-based measures (chair stand time, usual and rapid walking speed, and grip strength) among 163 Japanese women in Japan, 681 Japanese-American women in Hawaii and 9403 Caucasian women in the United States aged 65 years and over. RESULTS: After adjusting for age, the Caucasian women required about 40% more time to complete 5 chair stands than either group of Japanese. Walking speed was about 10% slower among Caucasians than native Japanese, whereas Japanese-American women in Hawaii walked about 11% faster than native Japanese. Grip strength was greatest in Japan, which may reflect the rural farming district that this sample was drawn from. Additional adjustment for height, weight or body mass index increased the adjusted means of chair stand time and grip strength among Japanese, but the differences remained significant. CONCLUSIONS: Both native Japanese and Japanese-American women in Hawaii performed better than Caucasians on chair stand time and walking speed tests, and native Japanese had greater grip strength than Japanese in Hawaii and Caucasians. The biological implications of these differences in performance are uncertain, but may be useful in planning future comparisons between populations

Pilot case-control investigation of risk factors for hip fractures in the urban Indian population

<p>Abstract</p> <p>Background</p> <p>Despite the reported high prevalence of osteoporosis in India, there have been no previous studies examining the risk factors for hip fracture in the Indian population.</p> <p>Methods</p> <p>We carried out a case control investigation comprising 100 case subjects (57 women and 43 men) admitted with a first hip fracture into one of three hospitals across New Delhi. The 100 controls were age and sex matched subjects who were either healthy visitors not related to the case patients or hospital staff. Information from all subjects was obtained through a questionnaire based interview.</p> <p>Results</p> <p>There was a significant increase in the number of cases of hip fracture with increasing age. There were significantly more women (57%) than men (43%). Univariate analysis identified protective effects for increased activity, exercise, calcium and vitamin supplements, almonds, fish, paneer (cottage cheese), curd (plain yogurt), and milk. However, tea and other caffeinated beverages were significant risk factors. In women, hormone/estrogen therapy appeared to have a marginal protective effect. For all cases, decreased agility, visual impairment, long term medications, chronic illnesses increased the risk of hip fracture. The multivariate analysis confirmed a protective effect of increased activity and also showed a decrease in hip fracture risk with increasing body mass index (odds ratio (OR) 0.024, 95% confidence interval (CI) 0.006-0.10 & OR 0.81, 95% CI 0.68-0.97 respectively). Individuals who take calcium supplements have a decreased risk of hip fracture (OR 0.076; CI 0.017-0.340), as do individuals who eat fish (OR 0.094; CI 0.020-0.431), and those who eat paneer (OR 0.152; 0.031-0.741). Tea drinkers have a higher risk of hip fracture (OR 22.8; 95% CI 3.73-139.43). Difficulty in getting up from a chair also appears to be an important risk factor for hip fractures (OR 14.53; 95% CI 3.86-54.23).</p> <p>Conclusions</p> <p>In the urban Indian population, dietary calcium, vitamin D, increased body mass index, and higher activity levels have a significant protective effect on hip fracture. On the other hand, caffeine intake and decreased agility increase the risk of hip fracture. Future studies should be done in order to direct primary preventive programs for hip fracture in India.</p