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Objective To assess the efficacy at 12 months of an early psychosocial counselling and support programme for outpatients with mild Alzheimer’s disease and their primary care givers.Design Multicentre, randomised, controlled, rater blinded trial.Setting Primary care and memory clinics in five Danish districts.Participants 330 outpatients with mild Alzheimer’s disease and their 330 primary care givers.Interventions Participating dyads (patient and primary care giver) were randomised to control support during follow-up or to control support plus DAISY intervention (multifaceted and semi-tailored counselling, education, and support).Main outcome measures Primary outcomes at 12 months for patients were change from baseline in mini mental state examination (MMSE) score, Cornell depression scale score, and proxy rated European quality of life visual analogue scale (EQ-VAS) score. For care givers, outcomes were change from baseline in geriatric depression scale (GDS 30 items) score and EQ-VAS score.Results Because of multiple testing, statistical significance was set at an adjusted P limit of <0.0005. At 12 months there were no significant differences between the two allocation groups in changes from baseline in the primary and secondary outcomes. However, although non-significant with the adjusted P limit, a small difference was observed for one of the primary patient outcomes (Cornell depression scale score) in patients in favour of the DAISY intervention group before and after adjusting for attrition (P=0.0146 and P=0.0103 respectively).Conclusions The multifaceted, semi-tailored intervention with counselling, education, and support for patients with mild Alzheimer’s disease and their care givers did not have any significant effect beyond that with well structured follow-up support at 12 months after adjustment for multiple comparisons. The small positive effect found in the unadjusted primary outcome addressing depressive symptoms in patients may call for further research focusing on patients with Alzheimer’s disease and comorbid depression.Trial registration ISRCTN74848736.

Objectives To examine the long-term efficacy at the 36-month follow-up of an early psychosocial counselling and support programme lasting 8–12 months for community-dwelling patients with mild Alzheimer's disease and their caregivers. Design Multicentre, randomised, controlled, rater-blinded trial. Setting Primary care and memory clinics in five Danish districts. Participants 330 home-dwelling patients with mild Alzheimer's disease and their primary caregivers (dyads). Interventions Dyads were randomised to receive intervention during the first year after diagnosis. Both intervention and control groups had follow-up visits at 3, 6, 12 and 36 months. Main outcome measures Primary outcomes for the patients assessed at 36-month follow-up were changes from baseline in global cognitive function (Mini-Mental State Examination), depressive symptoms (Cornell Depression Scale) and proxy-rated EuroQoL quality of life on visual analogue scale. The primary outcomes for the caregivers were changes from baseline in depressive symptoms (Geriatric Depression Scale) and self-rated EuroQoL quality of life on a visual analogue scale. The secondary outcome measures for the patient were proxy-rated Quality of Life Scale for Alzheimer's disease (QoL-AD), Neuropsychiatric Inventory-Questionnaire, Alzheimer's disease Cooperative Study Activities of Daily Living Scale, all-cause mortality and nursing home placement. Results At a 36-month follow-up, 2 years after the completion of the Danish Alzheimer Intervention Study (DAISY), the unadjusted positive effects previously detected at the 12-month follow-up in one patient primary outcome (Cornell depression score) and one patient secondary outcome (proxy-rated QoL-AD) disappeared (Cornell depression score, p=0.93; proxy-rated QoL-AD, p=0.81). No long-term effect of DAISY intervention on any other primary and secondary outcomes was found at the 36-month follow-up. Conclusions For patients with very mild Alzheimer's disease and their caregivers, an intensive, multi-component, semitailored psychosocial intervention programme with counselling, education and support during the first year after diagnosis did not show any positive long-term effect on primary and secondary outcomes. Trial registration The study was registered in the Clinical Trial Database (http://www.controlled-trials.com/ISRCTN74848736).

Background: There is a lack of appropriately designed trials investigating the efficacy of psychosocial interventions for patients with mild dementia and their family caregivers. This paper reports the rationale and design of the Danish Alzheimer Disease Intervention Study and baseline characteristics of the cohort. Methods: The study was a 1-year multicentre randomized controlled rater-blinded trial with randomization to follow-up and a multifaceted semitailored intervention programme or to follow-up only (with extension of follow-up to 3 years). The intervention included a counselling programme, teaching courses, written information and logbooks. The outcomes included clinical efficacy parameters, patient satisfaction and health economic consequences. Results: A total of 330 patients and their 330 caregivers were included during a period of 18 months. The majority (65.2 %) of the caregivers were spouses. At inclusion the mean age of the patients and caregivers was 76.2 and 66.0 years, respectively. Conclusion: The study will explore the added value of a multifaceted intervention programme and contribute to the design of future interventions for patients with mild dementia and their caregivers.

Background/Aim: To investigate the impact of early psychosocial intervention aimed at patients with Alzheimer's disease (AD) and their caregivers on resource use and costs from a societal perspective. Methods: Dyads of patients and their primary caregiver were randomised to intervention (n = 163) or control (n = 167) and followed for 3 years. Health care use was extracted from national registers, and the Resource Utilisation in Dementia questionnaire was used to measure informal care and productivity loss. Multiple imputation was used to replace missing data, and non-parametric bootstrapping was used to estimate standard errors. Results: Overall, there were no statistically significant differences because of large variation in the observations. The average additional cost of psychosocial intervention provision was estimated at EUR 3,401 per patient. This cost masked a reduced use of formal health care and an increased use of informal care. Conclusions: Early psychosocial intervention in AD could be cost-saving from a health care perspective, whereas the opposite seems to be true from a broader societal perspective.

Objective To assess the cost utility of early psychosocial intervention for patients with Alzheimer's disease and their primary caregivers. Design Cost utility evaluation alongside a multicentre, randomised controlled trial with 3 years of follow-up. Setting Primary care and memory clinics in five Danish districts. Participants 330 community-dwelling patients and their primary caregivers. Intervention Psychosocial counselling and support lasting 8–12 months after diagnosis and follow-up at 3, 6, 12 and 36 months in the intervention group or follow-up only in the control group. Main outcome measures The primary outcome measure was the cost of additional quality-adjusted life years (QALYs). Costs were measured from a societal perspective, including the costs of healthcare, social care, informal care and production loss. QALYs were estimated separately for the patient and the caregiver before aggregation for the main analysis. Results None of the observed cost and QALY measures were significantly different between the intervention and control groups, although a tendency was noted for psychosocial care leading to cost increases with informal care that was not outweighed by the tendency for cost savings with formal care. The probability of psychosocial intervention being cost-effective did not exceed 36% for any threshold value. The alternative scenario analysis showed that the probability of cost-effectiveness increased over the range of threshold values used if the cost perspective was restricted to formal healthcare. Conclusions A multifaceted, psychosocial intervention programme was found unlikely to be cost-effective from a societal perspective. The recommendation for practice in settings that are similar to the Danish setting is to provide follow-up with referral to available local support programmes when needed, and to restrict large multifaceted intervention programmes to patients and caregivers with special needs until further evidence for cost-effectiveness emerges. Trial registration The study was registered in the Clinical Trial Database as ISRCTN74848736.

Background Alzheimer's disease is the leading cause of dementia and affects about 25 million people worldwide. Recent studies have evaluated the effect of early interventions for dementia, but few studies have considered private time and transportation costs associated with the intervention. This study assessed the total economic costs associated with a multifaceted intervention for mild Alzheimer's disease, including an estimate of the ratio of public to private costs. Methods The study sample comprised 163 dyads of patients and caregivers who received a multifaceted intervention of counselling sessions, courses and informational packages. The typical duration of the intervention was 7 months. A micro-costing approach was applied using prospectively collected data on resource utilisation that included estimates of participant time and transportation. Precision estimates were calculated using a bootstrapping technique and structural uncertainty was assessed with sensitivity analysis. Results The direct intervention cost was estimated at EUR 1,070 (95% CI 1,029;1,109). The total cost (including private costs) was estimated at EUR 2,020 (95% CI 1,929;2,106) i.e. the ratio of private to public costs was almost 1:1. Conclusion Intervention for mild Alzheimer's disease can be undertaken at a relatively low cost to public funds. However, policy planners should pay attention to the significant private costs associated with an intervention, which may ultimately pose a threat to equity in access to health care. Trial registration Current Controlled Trials ISRCTN74848736.

Preclinical studies have shown a larger inhibition of tumour growth when exercise begins prior to tumour implant (preventative setting) than when training begins after tumour implant (therapeutic setting). However, post-implantation exercise may alter the tumour microenvironment to make it more vulnerable to treatment by increasing tumour perfusion while reducing hypoxia. This has been shown most convincingly in breast and prostate cancer models to date and it is unclear whether other tumour types respond in a similar way. We aimed to determine whether tumour perfusion and hypoxia are altered with exercise in a melanoma model, and compared this with a breast cancer model. We hypothesised that post-implantation exercise would reduce tumour hypoxia and increase perfusion in these two models. Female, 6-10 week old C57BL/6 mice were inoculated with EO771 breast or B16-F10 melanoma tumour cells before randomisation to either exercise or non-exercising control. Exercising mice received a running wheel with a revolution counter. Mice were euthanised when tumours reached maximum ethical size and the tumours assessed for perfusion, hypoxia, blood vessel density and proliferation. We saw an increase in heart to body weight ratio in exercising compared with non-exercising mice (p = 0.0008), indicating that physiological changes occurred with this form of physical activity. However, exercise did not affect vascularity, perfusion, hypoxia or tumour growth rate in either tumour type. In addition, EO771 tumours had a more aggressive phenotype than B16-F10 tumours, as inferred from a higher rate of proliferation (p<0.0001), a higher level of tumour hypoxia (p = 0.0063) and a higher number of CD31+ vessels (p = 0.0005). Our results show that although a physiological training effect was seen with exercise, it did not affect tumour hypoxia, perfusion or growth rate. We suggest that exercise monotherapy is minimally effective and that future preclinical work should focus on the combination of exercise with standard cancer therapies.

Wildlife tuberculosis is a major economic and conservation concern globally. Bovine tuberculosis (bTB), caused by Mycobacterium bovis ( M. bovis ), is the most common form of wildlife tuberculosis. In South Africa, to date, M. bovis infection has been detected in 24 mammalian wildlife species. The identification of M. bovis infection in wildlife species is essential to limit the spread and to control the disease in these populations, sympatric wildlife species and neighboring livestock. The detection of M. bovis -infected individuals is challenging as only severely diseased animals show clinical disease manifestations and diagnostic tools to identify infection are limited. The emergence of novel reagents and technologies to identify M. bovis infection in wildlife species are instrumental in improving the diagnosis and control of bTB. This review provides an update on the diagnostic tools to detect M. bovis infection in South African wildlife but may be a useful guide for other wildlife species.

The 2 S 1 / 2 - 2 P 1 / 2 and 2 S 1 / 2 - 2 P 3 / 2 transitions in Li-like carbon ions stored and cooled at a velocity of β ≈ 0.47 in the experimental storage ring (ESR) at the GSI Helmholtz Centre in Darmstadt have been investigated in a laser spectroscopy experiment. Resonance wavelengths were obtained using a new continuous-wave UV laser system and a novel extreme UV (XUV) detection system to detect forward emitted fluorescence photons. The results obtained for the two transitions are compared to existing experimental and theoretical data. A discrepancy found in an earlier laser spectroscopy measurement at the ESR with results from plasma spectroscopy and interferometry has been resolved and agreement between experiment and theory is confirmed.

High-level amplification of the protein phosphatase PPM1D ( WIP1 ) is present in a subset of medulloblastomas (MBs) that have an expression profile consistent with active Sonic Hedgehog (SHH) signaling. We found that WIP1 overexpression increased expression of Shh target genes and cell proliferation in response to Shh stimulation in NIH3T3 and cerebellar granule neuron precursor cells in a p53-independent manner. Thus, we developed a mouse in which WIP1 is expressed in the developing brain under control of the Neurod2 promoter ( ND2:WIP1 ). The external granule layer (EGL) in early postnatal ND2:WIP1 mice exhibited increased proliferation and expression of Shh downstream targets. MB incidence increased and survival decreased when ND2:WIP1 mice were crossed with an Shh -activated MB mouse model. Conversely, Wip1 knockout significantly suppressed MB formation in two independent mouse models of Shh -activated MB. Furthermore, Wip1 knockdown or treatment with a WIP1 inhibitor suppressed the effects of Shh stimulation and potentiated the growth inhibitory effects of SHH pathway-inhibiting drugs in Shh- activated MB cells in vitro . This suggests an important cross-talk between SHH and WIP1 pathways that accelerates tumorigenesis and supports WIP1 inhibition as a potential treatment strategy for MB.