These data suggest that in UK primary care, depressive and anxious symptoms in COPD are related to age and high levels of symptoms. Depression is also associated with lower patient-reported generic health status. The data suggest that assessment and treatment for depression and anxiety should be considered for all COPD patients, not just those with more severe clinical levels of disease. The potential of the EQ-5D(VAS) as a screening tool for anxiety and depression in primary care COPD patients also merits study.
The rat has been explored in detail for its in utero susceptibility to male reproductive tract malformation following phthalate exposure. Few other species have been studied in detail, and it is important for both mechanistic and risk assessment purposes to understand the species specificity of this response. We investigated the response of the fetal mouse testis to phthalate exposure and compared these results with those previously obtained from the rat. Initial experiments using a variety of phthalate congeners (monobutyl phthalate, di-(n-butyl) phthalate, or mono (2-ethylhexyl) phthalate) and exposure paradigms did not reduce fetal mouse testis testosterone levels. Pharmacokinetic data after a single 500 mg/kg di-(n-butyl)-phthalate (DBP) exposure on mouse gestation day (gd) 18 demonstrated that the concentrations and kinetics of the active metabolite monobutyl phthalate (MBP) in fetal and maternal plasma were similar to the rat. After a single 500 mg/kg or multiple day 250 mg/kg fetal mouse DBP exposure, rapid and dynamic changes in testis gene expression were observed, including induction of immediate early genes. Unlike the rat, expression of genes involved in cholesterol homeostasis and steroidogenesis were not decreased and were increased in a few cases. Similar to the rat, however, a 250- or 500-mg DBP/kg/day mouse exposure from gd 16 through 18 significantly increased seminiferous cord diameter, the number of multinucleated gonocytes per cord, and the number of nuclei per multinucleated gonocyte. Together, these results demonstrate that fetal mouse and rat phthalate exposure both induce immediate early gene expression and disrupt seminiferous cord and gonocyte development. This response in the mouse occurs without a measurable decrease in testicular testosterone, suggesting that altered seminiferous cord formation and gonocyte multinucleation may not be mechanistically linked to lowered testosterone.
BackgroundPeople with cancer receive regular structured follow up after initial treatment, usually by a specialist in a cancer centre. Increasing numbers of cancer survivors prompts interest in alternative structured follow-up models. There is worldwide evidence of increasing interest in delivering cancer follow-up using technology. This review sough evidence supporting the use of technology in cancer follow-up from good quality randomised controlled trials.MethodA search strategy was developed to identify randomised controlled trials and reviews of randomised trials of interventions delivering some aspect of structured cancer follow-up using new technologies. Databases searched were: All EBM Reviews; Embase; Medline (No Revisions); Medline (Non-Indexed Citations), and CAB Abstracts. Included articles were published in English between 2000 and 2014. Key words were generated by the research question. Papers were read independently and appraised using a standardised checklist by two researchers, with differences being resolved by consensus [J Epidemiol Community Health, 52:377–384, 1998]. Information was collected on the purpose, process, results and limitations of each study. All outcomes were considered, but particular attention paid to areas under consideration in the review question.ResultsThe search strategy generated 22879 titles. Following removal of duplicates and abstract review 17 full papers pertaining to 13 randomised controlled studies were reviewed. Studies varied in technologies used and the elements of follow-up delivered, length of follow-up, tumour type and numbers participating. Most studies employed only standard telephone follow-up. Most studies involved women with breast cancer and included telephone follow-up. Together the results suggest that interventions comprising technology had not compromised patient satisfaction or safety, as measured by symptoms, health related quality of life or psychological distress. There was insufficient evidence to comment on the cost effectiveness of technological cancer follow-up interventions.ConclusionsModern technology could deliver cancer follow-up that is acceptable and safe. More research is required to develop cancer follow-up systems which exploit modern technology, which should be assessed using randomised trials, with consistent outcomes, so that evidence on the acceptability, safety, cost effectiveness and impact in quality of life of technological follow-up can accumulate and be made available to patients, professionals and policy makers.
Ubiquitin is encoded in mice by two polyubiquitin genes, Ubb and Ubc, that are considered to be stress inducible and two constitutively expressed monoubiquitin (Uba) genes. Here we report that targeted disruption of Ubb results in male and female infertility due to failure of germ cells to progress through meiosis I and hypogonadism. In the absence of Ubb, spermatocytes and oocytes arrest during meiotic prophase, before metaphase of the first meiotic division. Although cellular ubiquitin levels are believed to be maintained by a combination of functional redundancy among the four ubiquitin genes, stress inducibility of the two polyubiquitin genes, and ubiquitin recycling by proteasome-associated isopeptidases, our results indicate that ubiquitin is required for and consumed during meiotic progression. The striking similarity of the meiotic phenotype in Ubb ؊/؊ germ cells to the sporulation defect in fission yeast (Schizosaccharomyces pombe) lacking a polyubiquitin gene suggests that a meiotic role of the polyubiquitin gene has been conserved throughout eukaryotic evolution.
Background: In utero exposure to endocrine-disrupting chemicals may contribute to testicular dysgenesis syndrome (TDS), a proposed constellation of increasingly common male reproductive tract abnormalities (including hypospadias, cryptorchidism, hypospermatogenesis, and testicular cancer). Male rats exposed in utero to certain phthalate plasticizers exhibit multinucleated germ cell (MNG) induction and suppressed steroidogenic gene expression and testosterone production in the fetal testis, causing TDS-consistent effects of hypospadias and cryptorchidism. Mice exposed to phthalates in utero exhibit MNG induction only. This disparity in response demonstrates a species-specific sensitivity to phthalate-induced suppression of fetal Leydig cell steroidogenesis. Importantly, ex vivo phthalate exposure of the fetal testis does not recapitulate the species-specific endocrine disruption, demonstrating the need for a new bioassay to assess the human response to phthalates.Objectives: In this study, we aimed to develop and validate a rat and mouse testis xenograft bioassay of phthalate exposure and examine the human fetal testis response.Methods: Fetal rat, mouse, and human testes were xenografted into immunodeficient rodent hosts, and hosts were gavaged with a range of phthalate doses over multiple days. Xenografts were harvested and assessed for histopathology and steroidogenic end points.Results: Consistent with the in utero response, phthalate exposure induced MNG formation in rat and mouse xenografts, but only rats exhibited suppressed steroidogenesis. Across a range of doses, human fetal testis xenografts exhibited MNG induction but were resistant to suppression of steroidogenic gene expression.Conclusions: Phthalate exposure of grafted human fetal testis altered fetal germ cells but did not reduce expression of genes that regulate fetal testosterone biosynthesis.
Sertoli cells are the primary cellular target for a number of pharmaceutical and environmental testicular toxicants, including 2,5-hexanedione, carbendazim, and mono-(2-ethylhexyl) phthalate. Exposure to these individual compounds can result in impaired Sertoli cell function and subsequent germ cell loss. The loss of testicular function is marked by histopathological changes in seminiferous tubule diameter, seminiferous epithelial sloughing, vacuolization, spermatid head retention, germ cell apoptosis, and altered microtubule assembly. The present study investigates dose-response relationships for these classic Sertoli cell toxicants using histopathology endpoints. Understanding the relationship between the Sertoli cell toxicant dose and its histopathologic manifestations will help establish the sensitivity of these endpoints as markers of testicular injury. The results indicate that no single histopathology endpoint was sensitive on its own in identifying altered testicular morphology resulting from toxicant exposure. However, when multiple endpoints were combined dose-response relationships could be associated with incremental alterations in histopathology. The data generated from these experiments will be useful in further investigating the effects of Sertoli cell toxicant exposure in animal toxicity studies. In addition, this work is fundamental to a planned investigation of the histopathologic and gene expression changes associated with testicular toxicant co-exposures, which may occur both occupationally and environmentally.
Background:People with colorectal cancer have impaired quality of life (QoL). We investigated what factors were most highly associated with it.Methods:Four hundred and ninety-six people with colorectal cancer completed questionnaires about QoL, functioning, symptoms, co-morbidity, cognitions and personal and social factors. Disease, treatment and co-morbidity data were abstracted from case notes. Multiple linear regression identified modifiable and unmodifiable factors independently predictive of global quality of life (EORTC-QLQ-C30).Results:Of unmodifiable factors, female sex (P<0.001), more self-reported co-morbidities (P=0.006) and metastases at diagnosis (P=0.036) significantly predicted poorer QoL, but explained little of the variability in the model (R2=0.064). Adding modifiable factors, poorer role (P<0.001) and social functioning (P=0.003), fatigue (P=0.001), dyspnoea (P=0.001), anorexia (P<0.001), depression (P<0.001) and worse perceived consequences (P=0.013) improved the model fit considerably (R2=0.574). Omitting functioning subscales resulted in recent diagnosis (P=0.002), lower perceived personal control (P=0.020) and travel difficulties (P<0.001) becoming significant predictors.Conclusion:Most factors affecting QoL are modifiable, especially symptoms (fatigue, anorexia, dyspnoea) and depression. Beliefs about illness are also important. Unmodifiable factors, including metastatic (or unstaged) disease at diagnosis, have less impact. There appears to be potential for interventions to improve QoL in patients with colorectal cancer.
BackgroundManagement of diabetes mellitus is complex and involves controlling multiple risk factors that may lead to complications. Given that patients provide most of their own diabetes care, patient self-management training is an important strategy for improving quality of care. Web-based interventions have the potential to bridge gaps in diabetes self-care and self-management. The objective of this study was to determine the effect of a web-based patient self-management intervention on psychological (self-efficacy, quality of life, self-care) and clinical (blood pressure, cholesterol, glycemic control, weight) outcomes.MethodsFor this cohort study we used repeated-measures modelling and qualitative individual interviews. We invited patients with type 2 diabetes to use a self-management website and asked them to complete questionnaires assessing self-efficacy (primary outcome) every three weeks for nine months before and nine months after they received access to the website. We collected clinical outcomes at three-month intervals over the same period. We conducted in-depth interviews at study conclusion to explore acceptability, strengths and weaknesses, and mediators of use of the website. We analyzed the data using a qualitative descriptive approach and inductive thematic analysis.ResultsEighty-one participants (mean age 57.2 years, standard deviation 12) were included in the analysis. The self-efficacy score did not improve significantly more than expected after nine months (absolute change 0.12; 95% confidence interval −0.028, 0.263; p = 0.11), nor did clinical outcomes. Website usage was limited (average 0.7 logins/month). Analysis of the interviews (n = 21) revealed four themes: 1) mediators of website use; 2) patterns of website use, including role of the blog in driving site traffic; 3) feedback on website; and 4) potential mechanisms for website effect.ConclusionsA self-management website for patients with type 2 diabetes did not improve self-efficacy. Website use was limited. Although its perceived reliability, availability of a blog and emailed reminders drew people to the website, participants’ struggles with type 2 diabetes, competing priorities in their lives, and website accessibility were barriers to its use. Future interventions should aim to integrate the intervention seamlessly into the daily routine of end users such that it is not seen as yet another chore.Electronic supplementary materialThe online version of this article (doi:10.1186/s12911-014-0117-3) contains supplementary material, which is available to authorized users.
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