The influence of the schedule and the dose of gemcitabine on the anti-tumour efficacy in experimental human cancer.

The therapeutic efficacy of gemcitabine, a new nucleoside analogue, was assessed in a variety of well-established human soft tissue sarcoma and ovarian cancer xenografts grown s.c. in nude mice. Tumour lines selected had different histological subtypes, growth rates and sensitivities to conventional cytostatic agents. The three different doses and schedules designed on the basis of a mean weight loss between 5% and 15% were i.p. injections of daily 3.5 mg kg-1 x 4, every 3 days 120 mg kg-1 x 4, and weekly 240 mg kg-1 x 2, which ultimately resulted in 19%, 10% and 4% toxic deaths, respectively. The weekly schedule induced > or = 50% growth inhibition in 2/4 soft tissue sarcoma and 4/6 ovarian cancer lines, while in three ovarian cancer lines > or = 75% growth inhibition was obtained. The anti-tumour effects of gemcitabine appeared to be similar or even better than previous data with conventional drugs tested in the same tumour lines. In comparison with the every 3 days schedule, the weekly and the daily schedule were less effective in 5/7 and 3/3 tumour lines (P < 0.001), respectively. In another experiment in three human tumour lines selected for their differential sensitivity to gemcitabine, weekly injections of 240 mg kg-1 x 6 did not result in a significant increase in the percentages of growth inhibition when compared to lower doses of 120 mg kg-1 or 60 mg kg-1 in the same schedule. However, the 240 mg kg-1 weekly x 6 schedule showed superior effects in 2/3 tumour lines in comparison with the same dose given every 2 weeks x 3 (P < 0.05). The preclinical activity of gemcitabine suggests that the drug can induce responses in soft tissue sarcoma and ovarian cancer patients. Our results further indicate that clinical trials of gemcitabine in solid tumour types should be designed on the basis of a schedule rather than a dose dependence

Broken Symmetry in Density-Functional Theory: Analysis and Cure

We present a detailed analysis of the broken-symmetry mean-field solutions using a four-electron rectangular quantum dot as a model system. Comparisons of the density-functional theory predictions with the exact ones show that the symmetry breaking results from the single-configuration wave function used in the mean-field approach. As a general cure we present a scheme that systematically incorporates several configurations into the density-functional theory and restores the symmetry. This cure is easily applicable to any density-functional approach.Comment: 4 pages, 4 figures, submitted to PR

Targeting kidney mesangium by nanoparticles of defined size

Nanoparticles are being investigated for numerous medical applications and are showing potential as an emerging class of carriers for drug delivery. Investigations on how the physicochemical properties (e.g., size, surface charge, shape, and density of targeting ligands) of nanoparticles enable their ability to overcome biological barriers and reach designated cellular destinations in sufficient amounts to elicit biological efficacy are of interest. Despite proven success in nanoparticle accumulation at cellular locations and occurrence of downstream therapeutic effects (e.g., target gene inhibition) in a selected few organs such as tumor and liver, reports on effective delivery of engineered nanoparticles to other organs still remain scarce. Here, we show that nanoparticles of ~75 ± 25-nm diameters target the mesangium of the kidney. These data show the effects of particle diameter on targeting the mesangium of the kidney. Because many diseases originate from this area of the kidney, our findings establish design criteria for constructing nanoparticle-based therapeutics for targeting diseases that involve the mesangium of the kidney

Optical coherence tomography guided laser cochleostomy: towards the accuracy on tens of micrometer scale

Lasers have been proven to be precise tools for bone ablation. Applying no mechanical stress to the patient, they are potentially very suitable for microsurgery on fragile structures such as the inner ear. However, it remains challenging to control the laser-bone ablation without injuring embedded soft tissue. In this work, we demonstrate a closed-loop control of a short-pulsed CO2 laser to perform laser cochleostomy under the monitoring of an optical coherence tomography (OCT) system. A foresighted detection of the bone-endosteum-perilymph boundary several hundred micrometers before its exposure has been realized. Position and duration of the laser pulses are planned based on the residual bone thickness distribution. OCT itself is also used as a highly accurate tracking system for motion compensation between the target area and the optics. During ex vivo experimental evaluation on fresh porcine cochleae, the ablation process terminated automatically when the thickness of the residual tissue layer uniformly reached a predefined value. The shape of the resulting channel bottom converged to the natural curvature of the endosteal layer without injuring the critical structure. Preliminary measurements in OCT scans indicated that the mean absolute accuracy of the shape approximation was only around 20 μm

Reducing restrictive measures in complex long-term care for people with intellectual disabilities:Implementation interventions through the lens of normalisation process theory

BACKGROUND The multi-disciplinarity of long-term care for people with intellectual disabilities makes organisations seek stability and predictability, complicating implementing innovations. Interventions to implement a method for reducing restrictive measures were analysed through the lens of Normalisation Process Theory to understand the social mechanisms at play. METHODS Process notes, collected during a trial in which a method to reduce restrictive measures was implemented, were analysed guided by implementation interventions defined by Cochrane Effective Practice and Organisation of Care Review Group. These interventions were mapped to social mechanisms of Normalisation Process Theory. RESULTS Implementation interventions were widely used in which clients’ perspectives were expressed (client-related-interventions), and consensus processes were held with care professionals. These interventions initiated NPT’s social mechanisms’ Coherence, Cognitive Participation and Collective Action. CONCLUSIONS The emphasis on consensus and clients’ perspectives when methodically reducing restrictive measures reflects some unique implementation challenges in long-term intellectual disability care

Анализ составляющих теплового баланса системы "прокатный стан - прокатываемая полоса" и пути снижения энергозатрат в процессе сортовой прокатки

Выполнен анализ составляющих теплового баланса системы «прокатный стан – прокатываемая полоса». Рассмотрены основные направления решения температурной задачи сортовой прокатки. Предложен ряд мероприятий, позволяющих снизить расход энергоресурсов на прокатку и уменьшить расходную часть теплового баланса системы «прокатный стан – прокатываемая полоса»

Health expenditure of employees versus self-employed individuals; a 5-year study.

It is unclear to what extent self‐employed choose to become self‐employed. This study aimed to compare the health care expenditures—as a proxy for health—of self‐employed individuals in the year before they started their business, to that of employees. Differences by sex, age, and industry were studied. In total, 5,741,457 individuals aged 25–65 years who were listed in the tax data between 2010 and 2015 with data on their health insurance claims were included. Self‐employed and employees were stratified according to sex, age, household position, personal income, region, and industry for each of the years covered. Weighted linear regression was used to compare health care expenditures in the preceding (year x–1) between self‐employed and employees (in year x). Compare

Hormone replacement therapy, mammography screening and changing age-specific incidence rates of breast cancer: an ecological study comparing two European populations

Background: In 2003, for the first time, US breast cancer incidence rates have fallen. Experts argue whether this is due to the reduced uptake of screening mammography or to lower use of Hormone Replacement Therapy (HRT). This study aims to disentangle the respective impact of screening and HRT on age-incidence rates and histology of breast cancer, by comparing two populations with comparably high levels of screening mammography, but with different prevalence of HRT. Methods: We included all invasive breast cancers recorded at the Geneva cancer registry (n=4,909) and the Netherlands Cancer Registry (n=152,428) between 1989-2003. We compared age-specific incidence rates and trends in histological subtyping between the two populations. Results: Between 1989-1991, incidence rates increased with age in both populations. In 2001-2003, women aged 60-64years showed highest incidence rates in Geneva, while in the Netherlands incidence rates continued to increase with age. The annual increase in ductal cancer incidence was similar in the Netherlands (2.3%) and Geneva (2.5%), but the annual increase in lobular cancer was sharper in Geneva (10%) than in the Netherlands (5%). Conclusion: The sharp differences in age distribution and histological subtyping of breast cancer between two European populations are not attributable to screening, since both populations have a high uptake of mammography screening. Since the prevalence of HRT use is very high in Geneva and rather low in the Netherlands, HRT may explain these discrepancies. However, other etiological factors and differences in histological assessment may also have played a rol

A Q-methodology study among caregivers of people with moderate intellectual disabilities on their clients’ health care:An example in oral health

Background: People with intellectual disabilities have less favourable outcomes in—among others—oral health variables, compared to their peers without intellectual disabilities. Before being able to develop target interventions for caregivers, all their prevailing viewpoints regarding oral hygiene need to be identified. Methods: This Q-methodology study—conducted among 40 caregivers of care-dependent Institutionalized living persons with moderate intellectual disability—used by-person factor analysis to reveal clusters of caregivers based on the way their statements were sorted. Results: A 4-factor solution was chosen based on both the Q-sorting and the interviews. The four factors identified were responsible and perseverant, motivated but aware of obstacles, social minded and knowledgeable and concerned and insecure. Conclusion: Q-methodology can be used to determine the different attitudes that caregivers have regarding oral health care. Developing a tool to determine into which factor caregivers should be categorized may be the next step in tailoring oral health instruction

The value of computed tomography in detecting distal radioulnar joint instability after a distal radius fracture

This study evaluated the value of computed tomography scans for the diagnosis of distal radioulnar joint instability. A total of 46 patients, conservatively treated for a unilateral distal radius fracture, were evaluated. Clinical instability was tested using the stress test and clunk test. A computed tomography scan of both wrists was performed in pronation and supination. Two independent observers reviewed the computed tomography scans using: the radioulnar line, subluxation ratio, epicentre and radioulnar ratio methods. Radiological distal radioulnar joint instability was assessed by comparing the measurements of the injured wrist with those of the contralateral uninjured wrists. A