External-beam radiotherapy and brachytherapy, widely utilized as curative treatment modalities for prostate cancer, have undergone significant clinical and technological advances in recent decades. Contemporary radiotherapy treatment algorithms use pretreatment prognostic factors to stratify patients into low-, intermediate-, and high-risk groups that correlate with both pathologic stage of disease and risk of recurrence after treatment. The use of risk groups and additional prognostic factors guide selection of the optimal treatment modalities for individual patients. Here, the roles of external-beam radiotherapy, brachytherapy, and neoadjuvant or adjuvant androgen deprivation therapy are discussed in that context. Additional prognostic factors for recurrence in the post-prostatectomy setting and the role of adjuvant and salvage radiation therapy are also reviewed. The risk-adaptive approach in radiotherapy for prostate cancer aims to optimize cancer control outcomes while minimizing the morbidity of treatment.
Prostatic neoplasms; radiotherapy; brachytherapy; nomogram; adjuvant androgen deprivation therapy
There is great uncertainty about how Ireland attained its current fauna and flora. Long-distance human-mediated colonization from southwestern Europe has been seen as a possible way that Ireland obtained many of its species; however, Britain has (surprisingly) been neglected as a source area for Ireland. The pygmy shrew has long been considered an illustrative model species, such that the uncertainty of the Irish colonization process has been dubbed ‘the pygmy shrew syndrome'. Here, we used new genetic data consisting of 218 cytochrome (cyt) b sequences, 153 control region sequences, 17 Y-intron sequences and 335 microsatellite multilocus genotypes to distinguish between four possible hypotheses for the colonization of the British Isles, formulated in the context of previously published data. Cyt b sequences from western Europe were basal to those found in Ireland, but also to those found in the periphery of Britain and several offshore islands. Although the central cyt b haplotype in Ireland was found in northern Spain, we argue that it most likely occurred in Britain also, from where the pygmy shrew colonized Ireland as a human introduction during the Holocene. Y-intron and microsatellite data are consistent with this hypothesis, and the biological traits and distributional data of pygmy shrews argue against long-distance colonization from Spain. The compact starburst of the Irish cyt b expansion and the low genetic diversity across all markers strongly suggests a recent colonization. This detailed molecular study of the pygmy shrew provides a new perspective on an old colonization question.
British Isles; cytochrome b; human introduction; phylogeography; range expansion; Sorex minutus
Development of the cerebellum proceeds under the precise spatio-temporal control of several key developmental signalling pathways, including the Wnt/β-catenin pathway. We recently reported the activity of Wnt/β-catenin signalling in the perinatal cerebellar ventricular zone (VZ), a germinal centre in the developing cerebellum that gives rise to GABAergic and glial cells. In order to investigate the normal function of Wnt/β-catenin signalling in the VZ and the cell lineages it gives rise to, we used a combination of ex vivo cerebellar slice culture and in vivo genetic manipulation to dysregulate its activity during late embryonic development. Activation of the pathway at the cerebellar ventricular zone led to a reduction in the number of cells expressing the glial lineage markers Sox9 and GFAP and the interneuron marker Pax2, but had no consistent effect on either proliferation or apoptosis. Our findings suggest that activation of the Wnt/β-catenin pathway in the cerebellar ventricular zone causes a shift in the cell types produced, most likely due to disruption of normal differentiation. Thus, we propose that regulation of Wnt/β-catenin signalling levels are required for normal development of cells arising from the cerebellar ventricular zone during late embryogenesis.
The adult cerebellum is composed of several distinct cell types with well defined developmental origins. However, the molecular mechanisms that govern the generation of these cell types are only partially resolved. Wnt/β-catenin signalling has a wide variety of roles in generation of the central nervous system, though the specific activity of this pathway during cerebellum development is not well understood. Here, we present data that delineate the spatio-temporal specific pattern of Wnt/β-catenin signaling during mouse cerebellum development between E12.5 and P21. Using the BAT-gal Wnt/β-catenin reporter mouse, we found that Wnt/β-catenin activity is present transiently at the embryonic rhombic lip but not at later stages during the expansion of cell populations that arise from there. At late embryonic and early postnatal stages, Wnt/β-catenin activity shifts to the cerebellar ventricular zone and to cells arising from this germinal centre. Subsequently, the expression pattern becomes progressively restricted to Bergmann glial cells, which show expression of the reporter at P21. These results indicate a variety of potential functions for Wnt/β-catenin activity during cerebellum development.
To evaluate the relationships among measures of hot flushes, perceived hot flush interference, sleep disturbance, and measures of quality of life while controlling for potential covariates (patient and treatment variables).
Breast cancer survivors (n = 395) due to receive aromatase inhibitor therapy provided demographic information, physiological hot flush data via sternal skin conductance monitoring, hot flush frequency via written diary and electronic event marker, hot flush severity and bother via written diary, and questionnaire data via the Hot Flash Related Daily Interference Scale, Pittsburgh Sleep Quality Index, the EuroQOL, Hospital Anxiety and Depression Scale and the Center for Epidemiologic Studies Depression Scale.
Confirmatory factor analysis supported a two-factor model for hot flush symptoms (frequency and severity). Although there was strong convergence among self-reported hot flush measures, there was a high degree of unexplained variance associated with physiological measures. This suggests that self-report and physiological measures do not overlap substantially. The structural model showed that greater hot flush frequency and severity were directly related to greater perceived interference with daily life activities. Greater perceived interference, in turn, directly predicted greater sleep disruption, which predicted lower perceived health state and more symptoms of anxiety and depression.
Findings suggest hot flush interference may be the most appropriate single measure to include in clinical trials of vasomotor symptom therapies. Measuring and ameliorating patients' perceptions of hot flush interference with life activities and subjective sleep quality may be the most direct routes to improving quality of life.
Hot Flushes; Menopause; Breast Cancer; Quality of Life; Structural Model
Tamoxifen induces important changes in serum lipid profiles in some women; however, little information is available to predict which women will experience improved lipid profiles during tamoxifen therapy. As part of a multicenter prospective observational trial in 176 breast cancer patients, we tested the hypothesis that tamoxifen-induced lipid changes were associated with genetic variants in candidate target genes (CYP2D6, ESR1, and ESR2). Tamoxifen lowered low-density lipoprotein cholesterol (P<0.0001) by 23.5mg/dl (13.5–33.5mg/dl) and increased triglycerides (P=0.006). In postmenopausal women, the ESR1-XbaI and ESR2-02 genotypes were associated with tamoxifen-induced changes in total cholesterol (P=0.03; GG vs GA/AA) and triglycerides (P=0.01; gene–dose effect), respectively. In premenopausal women, the ESR1-XbaI genotypes were associated with tamoxifen-induced changes in triglycerides (P=0.002; gene–dose effect) and high-density lipoprotein (P=0.004; gene–dose effect). Our results suggest that estrogen receptor genotyping may be useful in predicting which women would benefit more from tamoxifen.
Numerous randomized trials have been published investigating the effectiveness of treatments for non-specific low-back pain (LBP) either by trials comparing interventions with a no-treatment group or comparing different interventions. In trials comparing two interventions, often no differences are found and it raises questions about the basic benefit of each treatment. To estimate the effect sizes of treatments for non-specific LBP compared to no-treatment comparison groups, we searched for randomized controlled trials from systematic reviews of treatment of non-specific LBP in the latest issue of the Cochrane Library, issue 2, 2005 and available databases until December 2005. Extracted data were effect sizes estimated as Standardized Mean Differences (SMD) and Relative Risk (RR) or data enabling calculation of effect sizes. For acute LBP, the effect size of non-steroidal anti-inflammatory drugs (NSAIDs) and manipulation were only modest (ES: 0.51 and 0.40, respectively) and there was no effect of exercise (ES: 0.07). For chronic LBP, acupuncture, behavioral therapy, exercise therapy, and NSAIDs had the largest effect sizes (SMD: 0.61, 0.57, and 0.52, and RR: 0.61, respectively), all with only a modest effect. Transcutaneous electric nerve stimulation and manipulation had small effect sizes (SMD: 0.22 and 0.35, respectively). As a conclusion, the effect of treatments for LBP is only small to moderate. Therefore, there is a dire need for developing more effective interventions.
Effect size; Low-back pain; Placebo; Systematic review; Randomized controlled trial
A fit young man sustained a ruptured diaphragm during a recreational scuba dive three months after undergoing an uncomplicated laparoscopic Nissen fundoplication for gastro-oesophageal reflux disease. It is proposed that this rare occurrence was attributable to gastrointestinal barotrauma. The injury was treated by laparotomy, mobilisation of herniated abdominal viscera back into the abdomen, repair of the crura and gastropexy. He made a full postoperative recovery. It is concluded that scuba diving should be avoided in patients who have undergone fundoplication.
BACKGROUND: While much has been published about the career outcomes of doctors who completed general practice vocational training prior to 1990, no evidence is currently available about those who have qualified since that time. AIM: To obtain information about the career paths of doctors who had completed general practice vocational training since 1990, and to compare the results with previously published data. METHOD: Postal questionnaire survey of all doctors completing vocational training during the period 1990-1995 in three regions of the United Kingdom. The study examined current work status, career path since completion of training, desire for and experience of part-time training, degree of difficulty in choosing and following a career, and the degree to which certain factors impeded career choice. RESULTS: The overall response rate was 64.8%, although there was a significant difference between the response rates for men and women. While virtually all responders were employed, with the majority working in general practice, women were significantly less likely than men to be working as principals in general practice, for all cohorts. These results were very similar to those cohorts described in earlier studies. The career paths of doctors only became stable after about four years. Of those working in general practice, about 20% found it difficult to choose their career, and about 10% found it difficult to follow their career. Out-of-hours work was the major factor impeding career choice. CONCLUSION: Although they are taking longer to reach, the final career destinations of doctors completing vocational training since 1990 are no different from those of earlier cohorts.
Written evidence of the ability to carry out audit and performance review looks likely to be one of the four components of a summative assessment package for the end of vocational training. This paper seeks to raise the issues involved in this process. The features of audit which lend themselves to assessment of the attributes of a general practitioner are discussed. The criteria which might be used to assess a written submission are presented. A possible mechanism for marking and grading is suggested, and strategies for optimizing the validity and reliability of that assessment discussed. A timescale for implementation is also suggested. These issues need to be discussed and a process piloted if a credible mechanism is to be in place by August 1996.
OBJECTIVE: Develop standard terms and codes for recording nursing care information in patient records to permit relevant data to be abstracted into a shared database for effectiveness research. DESIGN: A collaborative effort by the University of Virginia, Thomas Jefferson University Hospital, and the University Hospital Consortium to develop a set of terms to represent specific examples of nursing diagnoses/patient care problems, nursing interventions/patient care activities, and patient outcomes. Terms found in standards of care are being compiled, classified, and coded. RESULTS: Standard terminology and codes have been developed for 209 nursing diagnoses/patient care problems, 122 expected patient outcomes, and 545 interventions/patient care activities. The terms come from five nursing units in one hospital and from two units in a second hospital. Preliminary findings suggest that in the specialty areas for which terms have been developed, the terms are adequate to capture these types of nursing data in the patient record.
We have studied respiratory symptoms, smoking habits, chest radiographs, sickness absence, and pulmonary function among 258 welders and an equal number of matched control subjects in three engineering factories. Welders who smoked had a higher frequency of chronic phlegm production than control subjects but there was no difference in cough or dyspnoea. The frequency of abnormality on chest radiographs was low and similar in welders and controls. Upper respiratory infections were a more frequent cause of sickness absence in welders than in controls but no difference was found in other respiratory diseases. FEV1 and peak expiratory flow rate were similar in welders and controls. In a subset of 186 subjects the maximum expiratory flow rate at low lung volumes was significantly less in welders who smoked than in control subjects who smoked, but there was no difference in non-smokers. Welders working under these conditions in the engineering industry appear to have no increased risk of chronic obstructive lung disease.
Mammary teat removal (thelectomy) was performed unilaterally in female Sprague-Dawley rats at 35 days of age. They were given 7,12-dimethylbenz(a)anthracene (DMBA) when aged either 55 days or 79 days. One third were unmated; one third were mated one week and one third mated more than 3 weeks after DMBA administration. Animals were killed when tumour-positive or after one year, when mammary lesions had developed in 99% of rats. The mean latent period for adenocarcinomas was 18.9 +/- 2.0 weeks. Benign mammary tumours, mainly secretory adenomas, developed significantly later (39.2 +/- 1.7 weeks). The rapid unilateral involution of the thelectomized glands at parturition had no effect on the localization of either adenocarcinomas or benign mammary tumours. Pregnancy and delayed DMBA administration markedly reduced the incidence of adenocarcinomas; lactation had no significant effect. In a separate experiment, precocious puberty induced with pregnant-mare-serum gonadotrophin in 30-day-old female Sprague-Dawley rats enabled their first pregnancy and lactation to be completed by 80 days of age. Parity before carcinogen administration significantly delayed the development of adenocarcinomas.