Antigen-specific immunotolerance limits the expansion of self-reactive T cells involved in autoimmune diseases. Here, we show that the E3 ubiquitin ligase Cbl-b is upregulated in T cells after tolerizing signals. Loss of Cbl-b in mice results in impaired induction of T cell tolerance both in vitro and in vivo. Importantly, rechallenge of Cbl-b mutant mice with the tolerizing antigen results in massive lethality. Moreover, ablation of Cbl-b resulted in exacerbated autoimmunity. Mechanistically, loss of Cbl-b rescues reduced calcium mobilization of anergic T cells, which was attributed to Cbl-b-mediated regulation of PLCgamma-1 phosphorylation. Our results show a critical role for Cbl-b in the regulation of peripheral tolerance and anergy of T cells. 相似文献
Obstetric fistula is a childbirth injury caused by prolonged obstructed labor that results in destruction of the tissue wall between the vagina and bladder. Although obstetric fistula is directly caused by prolonged obstructed labor, many other factors indirectly increase fistula risk. Some research suggests that many women in rural Malawi have limited autonomy and decision-making power in their households. We hypothesize that women’s limited autonomy may play a role in reinforcing childbirth practices that increase the risk of obstetric fistula in this setting by hindering access to emergency care and further prolonging obstructed labor.
Methods
A medical student at Baylor College of Medicine partnered with a Malawian research assistant in July 2015 to conduct in-depth qualitative interviews in Chichewa with 25 women living within the McGuire Wellness Centre’s catchment area (rural Central Lilongwe District) who had received obstetric fistula repair surgery.
Results
This study assessed whether women’s limited autonomy in rural Malawi reinforces childbearing practices that increase risk of obstetric fistula. We considered four dimensions of autonomy: sexual and reproductive decision-making, decision-making related to healthcare utilization, freedom of movement, and discretion over earned income. We found that participants had limited autonomy in these domains. For example, many women felt pressured by their husbands, families, and communities to become pregnant within three months of marriage; women often needed to seek permission from their husbands before leaving their homes to visit the clinic; and women were frequently prevented from delivering at the hospital by older women in the community.
Conclusions
Many of the obstetric fistula patients in our sample had limited autonomy in several or all of the aforementioned domains, and their limited autonomy often led both directly and indirectly to an increased risk of prolonged labor and fistula. Reducing the prevalence of fistula in Malawi requires a broad understanding of the causes of fistula, so we recommend that the relationship between women’s autonomy and fistula risk undergo further investigation.
Rixt F. Riemersma-van der Lek, MD; Dick F. Swaab, MD, PhD; Jos Twisk, PhD; Elly M. Hol, PhD; Witte J. G. Hoogendijk, MD, PhD; Eus J. W. Van Someren, PhD
JAMA. 2008;299(22):2642-2655.
Context Cognitive decline, mood, behavioral and sleepdisturbances, and limitations of activities of daily livingcommonly burden elderly patients with dementia and their caregivers.Circadian rhythm disturbances have been associated with thesesymptoms.
Objective To determine whether the progression of cognitiveand noncognitive symptoms may be ameliorated by individual orcombined long-term application of the 2 major synchronizersof the circadian timing system: bright light and melatonin.
Design, Setting, and Participants A long-term, double-blind,placebo-controlled, 2 x 2 factorial randomized trialperformed from 1999 to 2004 with 189 residents of 12 group carefacilities in the Netherlands; mean (SD) age, 85.8 (5.5) years;90% were female and 87% had dementia.
Interventions Random assignment by facility to long-termdaily treatment with whole-day bright (± 1000 lux)or dim (± 300 lux) light and by participant to eveningmelatonin (2.5 mg) or placebo for a mean (SD) of 15 (12) months(maximum period of 3.5 years).
Main Outcome Measures Standardized scales for cognitiveand noncognitive symptoms, limitations of activities of dailyliving, and adverse effects assessed every 6 months.
Results Light attenuated cognitive deterioration by amean of 0.9 points (95% confidence interval [CI], 0.04-1.71)on the Mini-Mental State Examination or a relative 5%. Lightalso ameliorated depressive symptoms by 1.5 points (95% CI,0.24-2.70) on the Cornell Scale for Depression in Dementia ora relative 19%, and attenuated the increase in functional limitationsover time by 1.8 points per year (95% CI, 0.61-2.92) on thenurse-informant activities of daily living scale or a relative53% difference. Melatonin shortened sleep onset latency by 8.2minutes (95% CI, 1.08-15.38) or 19% and increased sleep durationby 27 minutes (95% CI, 9-46) or 6%. However, melatonin adverselyaffected scores on the Philadelphia Geriatric Centre AffectRating Scale, both for positive affect (–0.5 points; 95%CI, –0.10 to –1.00) and negative affect (0.8 points;95% CI, 0.20-1.44). Melatonin also increased withdrawn behaviorby 1.02 points (95% CI, 0.18-1.86) on the Multi ObservationalScale for Elderly Subjects scale, although this effect was notseen if given in combination with light. Combined treatmentalso attenuated aggressive behavior by 3.9 points (95% CI, 0.88-6.92)on the Cohen-Mansfield Agitation Index or 9%, increased sleepefficiency by 3.5% (95% CI, 0.8%-6.1%), and improved nocturnalrestlessness by 1.00 minute per hour each year (95% CI, 0.26-1.78)or 9% (treatment x time effect).
Conclusions Light has a modest benefit in improving somecognitive and noncognitive symptoms of dementia. To counteractthe adverse effect of melatonin on mood, it is recommended onlyin combination with light.
Objective. The objective of this study was to determine to which degree travelers who received pretravel advice at a travel clinic have protected or unprotected sexual contact with a new partner and what factors influence this behavior. Method. An anonymous questionnaire was sent to travelers who came to a pretravel clinic between June 1 and August 31, 2005. Risk factors for casual travel sex and predictors of protected sex were studied in a multivariate model. Results. A total of 1,907 travelers were included (response rate 55%) in the study. Only 4.7% of the respondents had sexual contact with a new partner, and 63.1% of these new partners were from the country of destination. Of those who had casual travel sex, 52.4% did not expect this (women 75%), 30.9% did not always use condoms, and 41% were not protected against hepatitis B. Independent risk factors for casual travel sex were traveling without steady partner (OR 14.4), expecting casual travel sex (OR 9.2), having casual sexual contacts in the home country (OR 2.4), non-tourist journeys (OR 2.2), being male (OR 2.1), the fact that the information on sexually transmitted infections (STI) had been read (OR 2.0), and traveling to South and Central America (OR 2.0). Taking condoms along (OR 5.4) and reading the information on STI (OR 3.3) were identified as independent predictors of protected sex. Conclusions. Travelers have substantial sexual risk behavior. Casual sex is usually not expected, and the most important predictor is traveling without a steady partner. We would advice every client of a travel clinic who will travel without a steady partner to read the STI information, to take condoms along, and to be vaccinated against hepatitis B. 相似文献
Objective: To investigate the feasibility and validity of a proxy version of the EuroQol in children treated for imperforate anus. Methods: Patients included were between 1 and 51 years of age. Instruments included were the EuroQol, the TACQOL and a disease specific questionnaire, the Langemeijer Stool Questionnaire. Patients older than 15 years filled in all questionnaires themselves, in the age groups 5–10 and 11–15 a parent administered the questionnaires. Feasibility was judged on the number of missing values. In search of validity, EuroQol scores were compared with the prevalence of disease symptoms (convergent validity) and with the TACQOL (construct validity). Results: The number of missings was not related to age. The disease specific questionnaire correlated significantly with the EQvas from 11 years on and with the EQ-5Dindex from 5 years on. The mean correlation between contextual similar domains of the EuroQol and the TACQOL was –0.55. The correlation between different domains was –0.32. Conclusion: The results support the idea that the use of a proxy version of the EuroQol is feasible and valid. The convergent validity of the EQvas was supported from 11 years on. The EQ-5D showed good construct and convergent validity from 5 years on. 相似文献
Summary To determine the effect of age and comorbid diseases on treatment choice and survival, the medical records of 300 breast cancer patients of 55 years and older were reviewed. All patients were admitted to the Netherlands Cancer Institute (NKI) for first treatment between 1980 and 1987. Patients were classified according to severity level of comorbid diseases. Physicians were found to treat women of 75 years and older less often with adjuvant radiotherapy after a mastectomy, and more often to employ only primary endocrine treatment for local stage disease, as compared with younger patients. According to the treatment guidelines of the institute, the study sample was divided into patients who received standard vs. non-standard treatment. The treatment of 38 women (13.1%) did not correspond with the guidelines. Of these, 84% were 75 years and older and 50% had a severe comorbidity status. Logistic regression analysis indicated that advanced age, per se, was a better indicator of the risk of not being treated according to protocol than the comorbidity status. Cox multivariate analyses demonstrated that neither the severity of the comorbidity status nor the differences in treatment between younger and older patients had a significant effect on the risk of dying from breast cancer or on the risk of developing recurrences. In this analysis, age 75 years or more proved to be a significant and independent predictor of a worse overall and disease-specific survival as compared to age between 65–74 years. 相似文献
Polycomb group (PcG) genes contribute to the maintenance of cell identity, cell cycle regulation, and oncogenesis. We describe the expression of five PcG genes (BMI-1, RING1, HPC1, HPC2, and EZH2) innormal breast tissues, invasive breast carcinomas, and their precursors. Members of the HPC-HPH/PRC1 PcG complex, including BMI-1, RING1, HPC1, and HPC2, were detected in normal resting and cycling breast cells. The EED-EZH/PRC2 PcG complex protein EZH2 was only found in rare cycling cells, whereas normal resting breast cells were negative for EZH2. PcG gene expression patterns in ductal hyperplasia (DH), well-differentiated ductal carcinoma in situ (DCIS), and well-differentiated invasive carcinomas closely resembled the pattern in healthy cells. However, poorly differentiated DCIS and invasive carcinomas frequently expressed EZH2 in combination with HPC-HPH/PRC1 proteins. Most BMI-1/EZH2 double-positive cells in poorly differentiated DCIS were resting. Poorly differentiated invasive carcinoma displayed an enhanced rate of cell division within BMI-1/EZH2 double-positive cells. We propose that the enhanced expression of EZH2 in BMI-1(+) cells contributes to the loss of cell identity in poorly differentiated breast carcinomas, and that increased EZH2 expression precedes high frequencies of proliferation. These observations suggest that deregulated expression of EZH2 is associated with loss of differentiation and development of poorly differentiated breast cancer in humans. 相似文献
Hirschsprung (HSCR) disease is a complex genetic disorder attributed to a failure of the enteric neural crest cells (ENCCs) to form ganglia in the hindgut. Hedgehog and Notch are implicated in mediating proliferation and differentiation of ENCCs. Nevertheless, how these signaling molecules may interact to mediate gut colonization by ENCCs and contribute to a primary etiology for HSCR are not known. Here, we report our pathway-based epistasis analysis of data generated by a genome-wide association study on HSCR disease, which indicates that specific genotype constellations of Patched (PTCH1) (which encodes a receptor for Hedgehog) and delta-like 3 (DLL3) (which encodes a receptor for Notch) SNPs confer higher risk to HSCR. Importantly, deletion of Ptch1 in mouse ENCCs induced robust Dll1 expression and activation of the Notch pathway, leading to premature gliogenesis and reduction of ENCC progenitors in mutant bowels. Dll1 integrated Hedgehog and Notch pathways to coordinate neuronal and glial cell differentiation during enteric nervous system development. In addition, Hedgehog-mediated gliogenesis was found to be highly conserved, such that Hedgehog was consistently able to promote gliogenesis of human neural crest-related precursors. Collectively, we defined PTCH1 and DLL3 as HSCR susceptibility genes and suggest that Hedgehog/Notch-induced premature gliogenesis may represent a new disease mechanism for HSCR. 相似文献