共查询到20条相似文献，搜索用时 31 毫秒
1.
Background
Coronary artery bypass graft (CABG) surgery is one of the major surgeries requiring long-term stay in hospital. This generally leads to the detrimental effects of bed-rest, including dependency in self-care, transfer, and locomotion. Our aim was to compare the effect of high-frequency and low-frequency exercise therapy in patients who had undergone CABG.Methods
Patients who had undergone CABG were recruited from PSG Medical College and Hospital, Coimbatore, India, between Jan 1 and March 31, 2006. Functional Independence Measure (FIM) and modified Borg Rating of Perceived Exertion (RPE) were used to assess functional outcome. In a quasi-experimental design, patients received either high-frequency exercise therapy (exercise three times a day for 10 days, group 1), or low-frequency exercise therapy (once a day for 10 days, group 2). Data were analysed with paired t tests.Findings
30 patients were recruited (15 in each group). Mean FIM was 75 (SD 1·77) in group 1 and 64 (1·65) in group 2. There was a significant difference between the pretest and post-test FIM values in group 1 patients (49·07 [2·43] vs 124·07 [1·75], p<0·0001) but not in group 2 patients. The RPE in group 1 and group 2 was 6·3 (0·62) and 4·2 (0·7), respectively.Interpretation
Patients given high-frequency exercise thearpy had a significant improvement in their physical activity, but low-frequency exercise did not lead to significantly improved changes. In conclusion, the high-frequency exercise therapy improves the functional ability of patients with CABG.Funding
None. 相似文献2.
Background
The annual number of newly licensed doctors is an important indicator of medical workforce supply, which can accurately reflect an inflow into the health-care market during a time period. Since the implementation of the Law on Practicing Doctors in 1999, the Chinese Government has established its medical licensure system to both regulate medical professions and improve the quality of health-care services. We aimed to analyse the trend and structure of newly licensed doctors since the establishment of its medical licensure system.Methods
We analysed a unique census dataset that provides the headcount of newly licensed doctors in China between 2005 and 2015. We also review a short history of medical licensing system reform in China since the 1990s.Findings
The annual number of first-time licensed doctors in China increased from 159?489 in 2005 to 221?639 in 2015. Until 2015, more than 50% of newly licensed doctors had not received equivalent medical education of a bachelor degree or higher. In 2005, about 51% of China's newly licensed doctors were women, whereas in 2015, 56% newly licensed doctors were women.Interpretation
Our findings could inform policy making in human resources for health in at least two aspects. First, the heterogeneity of medical education of entering doctors needs to draw more attention of policy makers. The second policy implication is, however, that the feminisation of physician in China is becoming more apparent, and the consequences still require more rigorous examinations.Funding
None. 相似文献3.
Background
Neuroblastoma is the commonest cancer in infants. Survival in high-risk groups is low (40–50%). Newer treatments are needed to improve survival and morbidity. Cytomegalovirus (CMV) is a common viral infection, which increases γδ T cells. We investigated the use of CMV-reactive γδ T cells as a potential new immunotherapy.Methods
Peripheral blood mononuclear cells from 30 paediatric haemato-oncology patients with or without CMV infection were analysed by flow cytometry. γδ T cells were expanded, and then co-cultured with CMV targets or neuroblastoma cells. T-cell activation, cytokine secretion, killing activity, and mechanisms were determined by ELISA, MTT colorimetric assay, and blocking assays. Novel γδ T cell receptors (TCR) were identified by sequencing.Findings
In paediatric haemato-oncology patients, acute CMV led to higher proportions of total γδ T cells (p=0·0002) with the dominant subtype Vδ1 (p=0·0035). CMV-reactive γδ T cells were of the effector memory phenotype and expanded to clinically significant numbers for adoptive transfer. When compared with γδ T cells from CMV-negative patients, CMV-reactive γδ T cells had statistically significantly higher interferon γ release (p<0·001) in co-cultures with CMV-infected fibroblasts and showed cytolytic activity against CMV-infected fibroblasts and neuroblastoma cells which was mediated by γδ TCR and the NKG2D receptor. Sequencing showed that the dominant γδ T-cell chains in CMV-infected patients were Vδ1 Vγ2. Within the TCRs, CDR3 sequences had minimal diversity, γ chains had wide variations, and we identified a novel subpopulation in some patients.Interpretation
We show that acute CMV infection in paediatric haemato-oncology patients leads to an increase in the Vδ1 Vγ2 subtype of γδ T cells. They can be expanded for adoptive transfer and are likely to retain killing ability post expansion. They recognise and kill CMV-infected targets and neuroblastoma cells via the γδ TCR and the NKG2D receptor. We have identified a novel TCR in a subpopulation of CMV-positive patients.Funding
Great Ormond Street Charity, National Institute for Health Research Biomedical Research Centre, Olivia Hodson Cancer Fund. 相似文献4.
Background
Hepatitis B-related liver cirrhosis and hepatocellular carcinoma is a serious problem in China. Radiofrequency ablation had been considered a good option because it is minimally invasive. The aim of this study was to compare the perioperative outcomes of laparoscopic liver resection (LLR) with percutaneous radiofrequency ablation (RFA) for patients with hepatocellular carcinoma patients.Methods
A retrospective analysis of a prospective database for liver tumours identified patients with liver cirrhosis who underwent LLR and RFA of hepatocellular carcinoma in the University of Hong Kong, Queen Mary Hospital, Hong Kong between March 18, 2002, and Nov 23, 2015. The complications and-long term outcome after the operations were compared.Findings
We identified 217 patients who underwent laparoscopic treatment of hepatocellular carcinoma with liver cirrhosis in the University of Hong Kong, Queen Mary Hospital, between 2000 and 2015. 112 patients had undergone percutaneous RFA, and 105 patients who had undergone LLR with similar were selected for comparison. The patient baseline parameters, including age, sex, comorbidity, tumour size, number, and stage of hepatocellular carcinoma, did not differ between patients in the LLR and RFA groups. The median number of tumours was one tumour per patient in both treatment groups (range 1–3; p=0·517). Patients in the RFA group and LLR group had similar duration of hospital stay (2 days vs 4 days, p<0·0001), morbidity (4·5% vs 9·5%, p=0·142), and mortality (0% vs 0%). Intrahepatic recurrence was 70·5% in the RFA group versus 28·6% in the LLR group (p<0·0001). RFA was associated with the lowest overall survival (90·8 months in the RFA group vs >146·4 months in the LLR group, p=0·00019) and lowest disease-free survival (16·9 months vs 74·9 month; p<0·0001).Interpretation
LLR and RFA are well tolerated in patients with liver cirrhosis. A better survival outcome has been observed in the LLR group. We suggest LLR be considered as an option in selected patients who are deemed poor candidates for open hepatectomy.Funding
None. 相似文献5.
Background
In 2013, the authors of the World Alzheimer Report estimated that 44·35 million people had dementia worldwide, causing a substantial economic cost for the society. Objective, systematic economic costs caused by dementia are needed to track disease burden and inform health policy. We aimed to estimate the global economic burden of dementia by country and regions.Methods
We searched PubMed, Google Scholar, Web of Science, the China National Knowledge Infrastructure Database, and Wanfang databases for studies of the economic costs of Alzheimer's disease and other forms of dementia that were published between Jan 1, 2000, and April 1, 2017. On the basis of the scienti?c literature and regressions, we used the latest dementia prevalence estimates from the 2013 World Alzheimer's Disease Report and several other data sources to estimate the economic costs of dementia by setting for different countries and regions.Findings
Our global estimates suggest that the total economic costs caused by dementia increased from US$279·6 billion in 2000 to $948 billion in 2016, with an annual growth rate of 15·94%. This included costs of informal care at $95·1 billion in 2000 and $401·9 billion in 2016, with the annual growth rate of 21·50%. Regional differences in the economic burden of dementia exist, and the highest economic burden was found in Europe and North America.Interpretation
Our ?ndings suggest that dementia is a substantial economic burden worldwide. A global and regional strategic action plan for dementia will be important to reduce the future burden of dementia.Funding
Tsinghua University Education Foundation (Global Health Program, 16-263). 相似文献6.
Aravinthan Varatharaj Maria Liljeroth Stig Cramer Charlotte Stuart Elina Zotova Angela Darekar Henrik Larsson Ian Galea 《Lancet》2017
Background
Systemic inflammation can affect disease expression in multiple sclerosis. The mechanism might involve blood–brain barrier disruption. We aimed to assess the effects of systemic inflammation on disease progression in multiple sclerosis and the role of blood–brain barrier disruption.Methods
We recruited adults with relapsing–remitting multiple sclerosis and healthy controls from the general population. Three-dimensional dynamic-contrast enhanced MRI was used to measure blood–brain barrier permeability in the normal-appearing white matter (NAWM). Urinary neopterin, a product of activated macrophages, was measured to provide a readout of systemic inflammation. All study activities were performed in University Hospital Southampton after ethics approval (REC 12/SC/0176).Findings
12 patients with mutliple sclerosis and 12 healthy controls were recruited. Blood–brain barrier permeability in NAWM, measured as the constant Ktrans, was significantly higher in patients than in controls (mean 0·024 ml/100g per min [SD·0·018] vs 0·006 [0·004], p=0·015). Systemic inflammatory activity, measured as the urinary neopterin:creatinine ratio (UNCR), was also significantly higher (3·35 [1·98] vs 1·36 [0·29], p=0·002). Across all participants, there was a weak positive correlation between Ktrans and UNCR (r=0·40, p=0·031).Interpretation
Our findings support the hypothesis that the effects of systemic inflammation on expression of multiple sclerosis disease are mediated by blood–brain barrier disruption. Targeting this disruption and systemic inflammation might provide novel avenues for disease-modifying therapy.Funding
University of Southampton, National Institute for Health Research, Multiple Sclerosis Society. 相似文献7.
Background
Trachoma is the most common infectious cause of blindness worldwide. In-vivo confocal microscopy (IVCM) provides high-resolution images of the ocular surface. We have previously reported a grading system for the quantitative assessment of these images in scarring trachoma. We found that the presence of trachomatous scarring was strongly associated with the presence of dendritiform cells (DFCs). The present study assessed whether there is an association between DFCs and clinical progression in scarring.Methods
Participants with trachomatous scarring in northern Tanzania were examined at baseline and 24 months (clinical assessment, photography, and IVCM of the upper tarsal conjunctiva). IVCM images were graded according to a validated grading system. Two independent observers identified scarring progression by comparing photographs taken at baseline and 24 months.Findings
800 participants were assessed clinically at baseline and 617 of them were re-examined at 24 months. There were 465 individuals who had photographs that could be confidently graded as having either progression or scarring, or not having progression. Progression was found to occur in 113 (24%) of the 465 individuals. IVCM images were obtained in 344 of these participants at baseline and 24 months, and 29 (8·4%) had DFCs present at baseline. The presence of DFCs at baseline was significantly associated with scarring progression (p=0·01), including adjustment for age and sex (p=0·03).Interpretation
The presence of DFCs on IVCM images is associated with progressive trachomatous conjunctival scarring. DFCs are thought to represent dendritic cells, which have a central role in mediating the immune response and potentially in the pathogenesis of trachomatous scarring. The nature of these cells warrants further investigation, potentially as a novel antifibrotic therapeutic target.Funding
Wellcome Trust senior research fellowship (to MB). National Institute for Health and Research academic clinical fellowship (to JH). 相似文献8.
Background
Non-optimal blood lipid profiles are a major modifiable risk factor for cardiovascular diseases. We aimed to understand trends in blood lipid profiles for 12 middle-income and high-income countries in four continents.Methods
We pooled studies that had measured blood lipids in representative samples of the general population. For this analysis, we used data for individuals aged 30–59 years only. Studies were from Australia, Belgium, China, Czech Republic, Finland, Germany, Italy, Japan, Norway, South Korea, the UK, and the USA. Using weighted linear regression, we estimated trends in mean total cholesterol, HDL cholesterol, non-HDL cholesterol, and mean total-to-HDL cholesterol ratio by country, sex, and age-group from 1973 to 2013.Findings
We pooled 267 studies, with 2·3 million participants. Over four decades, mean total and non-HDL cholesterol levels decreased in high-income western countries from high levels, whereas they increased from low levels in China and Japan. Over the same period, changes in mean HDL cholesterol and mean total-to-HDL cholesterol ratio were more heterogeneous. Mean HDL cholesterol increased substantially in Belgium, Japan, and the UK; the increase of more than 0·1 mmol/L per decade in Japanese women led to a decrease in mean total-to-HDL cholesterol ratio despite increases in mean total cholesterol. By contrast, mean HDL cholesterol declined by about 0·05–0·1 mmol/L per decade in Germany and Norway, with stagnation or possible increases in mean total-to-HDL cholesterol ratio despite declines in both mean total and non-HDL cholesterol.Interpretation
Over the past 40 years, blood lipid profiles have changed in important ways. There has been convergence in mean total and non-HDL cholesterol in high-income western and East Asian countries, whereas mean HDL cholesterol and total-to-HDL cholesterol ratio show heterogeneous trends. This study underscores the importance of analysing entire lipid profiles.Funding
Wellcome Trust. 相似文献9.
Background
Tissue-resident macrophages and dendritic cells respond to immunological challenges within an organ. The kidney is a unique environment for these cells, with extreme but variable hypersalinity in the medulla, generated by urine concentration mechanisms. Lower urinary tract infections are one of the commonest human bacterial infections, yet renal involvement is rare. Mechanical forces, such as anterograde urine flow can be protective. We aimed to determine whether additional tissue-specific mechanisms protect the kidney.Methods
We characterised macrophages and dendritic cells (mononuclear phagocytes [MNP]) in human kidneys, and evaluated their role in defence against uropathogenic Escherichia coli (UPEC). We used murine models and mouse and human cells in culture to investigate the factors controlling MNP positioning in the medulla and, together with human epidemiological datasets, to determine the importance of the renal sodium gradient in defence against urinary tract infection.Findings
We found that physiological hypersalinity provided a cue to renal tubular epithelial cells, stimulating TonEBP-dependent production of chemokines (CCL2 and CX3CL1) that orchestrate the recruitment of CD14+ macrophages to the medulla. These CD14+ macrophages were adept at phagocytosis of UPEC, and their bactericidal and neutrophil chemotactic function was further enhanced by hypersalinity. In murine models, we confirmed that these macrophages were derived from monocytes and that their medullary localisation was CCR2-dependent. Finally, we demonstrated the relevance of these observations in vivo, showing that disruption of the renal sodium gradient in patients and mice led to aberrant chemokine expression and macrophage localisation, and susceptibility to pyelonephritis.Interpretation
We have shown a novel mechanism whereby changes in the tissue environment generated by the homoeostatic function of an organ stimulate epithelial–macrophage crosstalk to optimise defence against infection.Funding
Medical Research Council, Kidney Research UK. 相似文献10.
Sean Sylvia Hao Xue Chengchao Zhou Yaojiang Shi Hongmei Yi Huan Zhou Scott Rozelle Madhukar Pai Jishnu Das 《Lancet》2017
Background
Future progress against tuberculosis in China will likely rely on improved detection, particularly in rural areas where prevalence remains high. The ability of rural providers to correctly diagnose Tuberculosis is largely unknown, as are the potential effects on tuberculosis patients of health-system reforms promoting initial contact with grassroots providers.Methods
We employed unannounced standardised patients presenting with classic pulmonary tuberculosis symptoms in a representative survey of village, township, and county level providers in three provinces and assessed provider management of standardised patients against international and national standards of care. We then measured the gap between knowledge and practice by comparing doctor care of standardised patients to their performance in clinical vignettes of an identical presumptive tuberculosis case. Finally, we simulated the management of patients at the health-system level under alternative managed care policies accounting for provider referrals.Findings
In July, 2015, we successfully completed 274 standardised patient interactions. Of 46 interactions in village clinics, 13 (28%) were correctly managed (95% CI 17–43%), compared with 79 (38%) of 207 in township health centers (32–45%) and 19 (90%) of 21 in county hospitals (71–97%). The same providers were 45 percentage points (95% CI 37–53%) more likely to correctly manage the same case in vignettes. Under existing policy, which allows patients to freely choose initial providers, simulations suggest that 40% (95% CI 34–47%) of patients encountering the health system are correctly managed. This would reduce to 16% with gatekeeping from village clinics and to 37% from township centers.Interpretation
We uncovered important quality deficits among grassroots providers in the management of a case of presumptive tuberculosis and a large gap between provider knowledge and practice. In view of the current quality of care, reforms encouraging first contact in village clinics could reduce the rate of detection of patients with tuberculosis.Funding
Fundamental Research Funds for the Central Universities and the Research Funds of Renmin University of China (2015030245), the 111 Project (B16031), the National Science Foundation of China (71473152), and the Department of Science and Technology of Shandong Province (BS2012SF010). 相似文献11.
Shishir Shetty Daniel Patten Pia Rantakari Chris Weston Sirpa Jalkanen Marko Salmi David Adams 《Lancet》2017
Background
Organ fibrosis is a major cause of global mortality. Few medical therapies are available to treat this condition. We have previously demonstrated increased expression of stabilin-1 at sites of chronic liver disease. Using models of chronic liver injury, we aimed to elucidate the role of stabilin-1 during fibrosis and repair.Methods
We used full knockout and cell specific knockouts of stabilin-1 in murine models of chronic liver injury including carbon tetrachloride treatment and a methionine and choline deficient diet. A resolution phase after carbon tetrachloride treatment was used to study tissue repair. Tissue was analysed for fibrosis by confocal microscopy, collagen quantification, and immune cell infiltrate analysis. RNA sequencing and cell transfer experiments were done to elucidate underlying mechanisms. Human tissue was also analysed for stabilin-1 expression in chronic liver injury.Findings
We detected a subset of stabilin-1 macrophages that were induced at sites of cellular injury close to the hepatic scar in mouse models of liver fibrosis and in human liver disease. Stabilin-1 deficiency abrogated malondialdehyde-LDL uptake by hepatic macrophages and was associated with excess collagen III deposition. Mechanistically, the lack of stabilin-1 led to elevated intrahepatic levels of the profibrogenic chemokine CCL3 and an increase in GFAP+ fibrogenic cells. Stabilin-1 knockout macrophages demonstrated a proinflammatory phenotype during liver injury and this led to delayed wound healing.Interpretation
We have demonstrated a pathway in which the evolutionarily conserved receptor stabilin-1 on tissue-infiltrating macrophages promotes the uptake of products of lipid peroxidation and thus prevents excess scarring. We propose that macrophage stabilin-1 is a crucial defence against oxidative tissue damage and thereby maintains tissue homoeostasis.Funding
Wellcome Trust. 相似文献12.
13.
Jonathan Wan Suzanne Murphy Davina Gale James Morris Florent C Mouliere Francesco Marass Katrin Heider Dineika Chandrananda Graham Bignell Christine Parkinson Amer Durrani Ultan McDermott Charles Massie Pippa Corrie Nitzan Rosenfeld 《Lancet》2017
Background
Circulating tumour DNA (ctDNA) is released by cancer cells into the bloodstream, which can be analysed via liquid biopsy. Analysis of liquid biopsy samples provides a real-time snapshot of tumour burden. After treatment, ctDNA concentrations can be low, making detection challenging. To study clonal evolution during treatment in patients with melanoma with high sensitivity, we sought to maximise the number of mutations targeted through individualised next-generation sequencing panel design.Methods
72 patients with stage III or IV melanoma were recruited to MelResist, a translational, multicentre research study. Serial plasma samples were taken from patients at monthly intervals during treatment (median 6·7 samples per patient). Clinical events were scored according to Response Evaluation Criteria In Solid Tumors (RECIST) (version 1.1) criteria. Exome and targeted sequencing were carried out on tumour samples at baseline and progression for nine patients, whose identified mutations were used to design an individualised targeted sequencing panel.Findings
Multiple mutations per patient were tracked to monitor response to therapy. The percentage change in ctDNA mutant allele fraction after treatment initiation agreed with RECIST response for seven out of eight evaluable patients. ctDNA concentration strongly correlated with lactate dehydrogenase (LDH) concentration, a currently used measure of melanoma tumour burden (r2=0·64, p=9·93?×?10?7). ctDNA dynamics were compared against rising LDH, which showed a median lead-time to biochemical progression (rising LDH) of 70 days (IQR 28–152·3). Targeting multiple mutations could improve sensitivity compared with individual mutations.Interpretation
In this study, we applied an individualised targeted sequencing panel on ctDNA from patients with melanoma. As tumour sequencing becomes more routine, individualised sequencing panel design might become more feasible, facilitating a more sensitive approach for ctDNA analysis than targeting individual loci. Tracking clonal evolution during therapy non-invasively may facilitate personalised treatment decisions with molecularly targeted agents.Funding
Cancer Research UK, Lewis Family Charitable Trust, Addenbrooke's Charitable Trust, Cambridge Cancer Trials Centre, NIHR Cambridge Biomedical Research Centre and Human Research Tissue Bank. 相似文献14.
15.
Nicolas Orsi Tathagata Dasgupta Michele Cummings Julius Adebayo Vinay Sharma Jeremy Gunawardena Sarah Field 《Lancet》2017
Background
Conception assisted by intracytoplasmic sperm injection (ICSI) requires oocyte stripping for morphological evaluation of maturity status. However, this approach prevents further maturation and poorly predicts fertilisability, so more robust assessment strategies are needed. Given that cytokines orchestrate oocyte development, we aimed to assess the association of follicular fluid cytokine profiles with maturation stage and develop predictive machine learning-based methods to identify those with the greatest fertilisation potential.Methods
In this retrospective study, follicular fluid was collected at oocyte retrieval from 64 women and linked to oocyte maturity status or fate—namely, germinal vesicle (n=26), metaphase I (51), metaphase II not fertilised (51), and metaphase II fertilised (84). 51 follicular fluid cytokines were profiled by multiplex immunoassay. Machine learning-based classifiers to predict oocyte fertilisability were subjected to iterative feature reduction to a threshold suitable for developing a clinically viable assessment of oocyte maturity. Women gave written, informed consent.Findings
Cytokine profiles varied dynamically throughout maturation. When applied to naive samples with known outcome, classifiers developed using tumour necrosis factor-related apoptosis-inducing ligand and interleukin 18 profiles alone correctly discriminated 89% of metaphase II not fertilised oocytes (ie, those with the highest fertilisability) with high confidence from all other maturation stages.Interpretation
These classifiers offer the prospect of cost-effective, point-of-care testing, and streamlined ICSI-based workflows. This assessment circumvents stripping such that immature or low fertilisability oocytes could benefit from in-vitro maturation and increase the pool of usable oocytes. Further studies will confirm the robustness of these classifiers in women with a broader morbidity spectrum and their translational value across a range of clinical settings.Funding
Infertility Research Trust. 相似文献16.
17.
Lu Yang Shi Qiu Linghui Deng Haiyang Bian Ian Charles Tobias Chengyi Huang Liangren Liu Zhenhua Liu Yige Bao Qiang Wei 《Lancet》2017
Background
The introduction of three kinds of MRI-guided prostate biopsies (MRI-PB) has changed the model of practice regarding prostate biopsies. The most appropriate strategy is still unknown, we therefore aimed to compare and rank prostate biopsies strategies.Methods
We did a network meta-analysis to incorporate both direct and indirect evidence from relevant trials. We searched PubMed, the Cochrane Library Central Register of Controlled Trials, Scopus, Embase, and the reference lists of relevant articles for randomised controlled trials published up to Sept 1, 2016, of different strategies for prostate biopsy. Involved studies were full text reports of randomised trials that compared different biopsy strategies, and reported efficacy endpoints. The primary outcome was overall prostate cancer detection rate. We did pairwise meta-analyses by random effects model and network meta-analysis by Bayesian random effects model. We assessed the quality of evidence contributing to each network estimate using the GRADE framework. This study is registered with PROSPERO, number CRD42016044011.Findings
From a total of 3616 citations, 24 randomised trials with a total of 6497 participants were included in this network meta-analysis. We considered 11 strategies of prostate biopsy published between 2000 and 2016. Cognitive MRI prostate biopsy was significantly better (relative risk [RR] 2·66, 95% credible interval [CrI] 1·44–4·72) than TRUS (10-12; PCa detection from 10–12 needle core transrectal ultrasound prostate biopsy) prostate biopsy considering overall prostate cancer detection rate. Detection rates of clinically significant and insignificant prostate cancers suggested no significant difference between any group of all biopsy techniques.Interpretation
Although cognitive MRI prostate biopsy obtained better detection rates of overall prostate cancer than did TRUS (10-12) prostate biopsy, it had no remarkable advantages in detection of clinically significant and insignificant prostate cancers. Nevertheless, these results should be considered together with all known safety and economy information when selecting the strategy for individual patients.Funding
This study was supported by the Prostate Cancer Foundation Young Investigator Award 2013, the National Natural Science Foundation of China (81300627, 81370855) and Programs from Science and Technology Department of Sichuan Province (2013SZ0006, 2014JY0219). 相似文献18.
Ester Coutinho David Menassa Leslie Jacobson Steven West Joana Domingos Teresa Moloney Marianne G Pedersen Michael E Benros Bethan Lang David Bennett Paul J Harrison Preben B Mortensen Bent Nørgaard-Pedersen David Bannerman Angela Vincent 《Lancet》2017
Background
CNS disorders can be caused by IgG antibodies to neuronal surface proteins, and these antibodies have the potential to cross the placenta. Since some of them target proteins involved in neurodevelopment, such as contactin-associated protein-2 (CASPR2), we hypothesised that they could alter developing neuronal circuits in utero and lead to neurodevelopmental disorders in the children.Methods
A dual approach to the study was undertaken. First, we studied pregnancy serum samples from two population-based Danish cohorts: a cohort of women with postpartum psychosis and a cohort of mothers of children with mental retardation and other disorders of psychological development (MR–DPD), each with individually matched controls. We screened them for the presence of antibodies to CASPR2. Then, we assessed the effects of in-utero exposure to the antibodies in a mouse maternal-to-fetal model.Findings
The combined results from these two cohorts showed that maternal antibodies to CASPR2 were associated with an increased risk of MR–DPD in the children: eight (4·4%) of 182 mothers of MR–DPD children had CASPR2 antibodies compared with only three (0·9%) of 347 mothers of children without this diagnosis (p=0·01). This association was explored by injection of mouse dams with IgG purified from CASPR2-antibody-positive patients, or from healthy controls. The mouse offspring had long-term behavioural sequelae, manifested as deficits in social interaction and social activities, and increased repetitive, non-social behaviours. When they were culled at 12 months, their brains showed abnormal migration of cortical projection neurons, increased microglial activation, and reduction in the number of glutamatergic synapses, confirming that there had been long-term changes in neurodevelopment.Interpretation
CASPR2 was identified as a specific target for maternal antibodies that can alter brain development in utero, resulting in long-term behavioural deficits and permanent abnormalities at the cellular and synaptic level. These results should encourage further epidemiological and experimental studies to confirm and explore further how CASPR2 and other maternal antibodies can lead to neurodevelopmental disorders in children.Funding
EC was funded by the Programme for Advanced Medical Education at the Calouste Gulbenkian Foundation. This work was also supported by the Stanley Medical Research Institute. Resources were provided by the Nuffield Department of Clinical Neurosciences. 相似文献19.
Background
Epigallocathechin-3-gallate (EGCG), the major bioactive polyphenol in green tea, has anticarcinogenic properties in vitro and in vivo. Several recent reports have shown that EGCG affects the expression of human papillomavirus (HPV)-encoded E6 and E7, two oncoproteins required for HPV-driven oncogenesis. Here, we aimed to explore the effects of EGCG on keratinocyte proliferation and differentiation, in addition to HPV18 replication, in a three-dimensional organotypic raft culture system.Methods
Organotypic raft cultures of HPV18-infected keratinocytes cultured at the air–liquid interface for 10 days were treated with EGCG for an additional 10 days before fixation and processing. Raft sections were stained with antibodies specific for various cell proliferation and keratinocyte differentiation markers in addition to tumour suppressor genes. Western blotting was performed on EGCG-treated cells to measure the level of HPV18 E6 and E7 protein expression.Findings
EGCG treatment blocked the ability of HPV18-positive keratinocytes to generate hyperplastic epithelium in raft culture. EGCG reduced cell proliferation as assessed by bromodeoxyuridine label incorporation and Ki67 staining; it upregulated expression of several tumour suppressor genes (p53 [TP53], p21, pRb), and impaired productive viral replication (as assessed by HPV18 E4 protein expression), but did not have an effect on keratinocyte differentiation. In culture, EGCG treatment promoted degradation of the E6 and E7 proteins and restored tumour suppressor gene expression.Interpretation
The results of our preclinical study suggest that EGCG inhibits the proliferation of HPV18-infected keratinocytes by enhancing the turnover and degradation of the E6 and E7 proteins, resulting in re-expression of several key tumour suppressor genes. These findings suggest that EGCG could potentially reverse the dysplastic changes induced by oncogenic HPV strains and could be used clinically to treat HPV-induced neoplasia.Funding
Cancer Research UK. 相似文献20.
Roslyn Simms Desmond Ryan Peter Metherall Peter Wright Nicolas Gruel Wendy Tindale Albert Ong 《Lancet》2017