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1.
Feng-Cheng Chou Heng-Yi Chen Hsin-Hui Chen Gu-Jiun Lin Shih-Hua Lin Huey-Kang Sytwu 《Diabetologia》2017,60(12):2409-2417
Aims/hypothesis
The relative contribution of T helper (Th)1 and Th17 cells in graft rejection is inconclusive, on the basis of evidence provided by different T cell-related cytokine-deficient animal models and graft types.Methods
We used novel antigen-presenting-cell-specific Il-12p35 (also known as Il12a)-knockout (KO), IL-23p19-knockdown (KD) and IL-27p28-KD strategies to investigate T cell differentiation in islet graft rejection.Results
In vitro dendritic cell–T cell coculture experiments revealed that dendritic cells from Il-12p35-KO and IL-23p19-KD mice showed reduced ability to stimulate IFN-γ and IL-17 production in T cells, respectively. To further explore the T cell responses in islet graft rejection, we transplanted islets into streptozotocin-induced diabetic NOD/severe combined immunodeficiency (SCID) recipient mice with IL-12-, IL-23-, or IL-27-deficient backgrounds and then challenged them with NOD.BDC2.5 T cells. The survival of islet grafts was significantly prolonged in Il-12p35-KO and IL-23p19-KD recipients compared with the control recipients. T cell infiltrations and Th1 cell populations were also decreased in the grafts, correlating with prolonged graft survival.Conclusions/interpretation
Our results suggest that IL-12 and IL-23 promote and/or maintain Th1 cell-mediated islet graft rejection. Thus, blockade of IL-12 and IL-23 might act as therapeutic strategies for reducing rejection responses.2.
Mitsuaki Ishioka Kouichi Miura Shinichiro Minami Yoichiro Shimura Hirohide Ohnishi 《Digestive diseases and sciences》2017,62(2):396-406
Background
Although several types of diet have been used in experimental steatohepatitis models, comparison of gut microbiota and immunological alterations in the gut among diets has not yet been performed.Aim
We attempted to clarify the difference in the gut environment between mice administrated several experimental diets.Methods
Male wild-type mice were fed a high-fat (HF) diet, a choline-deficient amino acid-defined (CDAA) diet, and a methionine-choline-deficient (MCD) diet for 8 weeks. We compared the severity of steatohepatitis, the composition of gut microbiota, and the intestinal expression of interleukin (IL)-17, an immune modulator.Results
Steatohepatitis was most severe in the mice fed the CDAA diet, followed by the MCD diet, and the HF diet. Analysis of gut microbiota showed that the composition of the Firmicutes phylum differed markedly at order level between the mice fed the CDAA and HF diet. The CDAA diet increased the abundance of Clostridiales, while the HF diet increased that of lactate-producing bacteria. In addition, the CDAA diet decreased the abundance of lactate-producing bacteria and antiinflammatory bacterium Parabacteroides goldsteinii in the phylum Bacteroidetes. In CDAA-fed mice, IL-17 levels were increased in ileum as well as portal vein. In addition, the CDAA diet also elevated hepatic expression of chemokines, downstream targets of IL-17.Conclusions
The composition of gut microbiota and IL-17 expression varied considerably between mice administrated different experimental diets to induce steatohepatitis.3.
4.
Xiuli Xiao Wenbo Long Tingyu Huang Tian Xia Rupei Ye Yong Liu Hanan Long 《Digestive diseases and sciences》2018,63(11):2923-2929
Background
Multiple factors including host–microbiota interaction could contribute to the conversion of healthy mucosa to sporadic precancerous lesions. An imbalance of the gut microbiota may be a cause or consequence of this process.Aim
The goal was to investigate and analyze the composition of gut microbiota during the genesis of precancerous lesions of colorectal cancer.Methods
To analyze the composition of gut microbiota in the genesis of precancerous lesions, a rat model of 1, 2-dimethylhydrazine (DMH)-induced aberrant crypt foci (ACF) was established. The feces of these rats and healthy rats were collected for 16S rRNA sequencing.Results
The diversity and density of the rat intestinal microbiota were significantly different between ACF-bearing and non-bearing group. ACF were induced in rats treated with DMH and showed increased expression of the inflammatory cytokines IL-6, IL-8, and TNF-α. Firmicutes was the most predominant phylum in both ACF-bearing and non-bearing group, followed by Bacteroidetes. Interestingly, although the density of Bacteroidetes decreased from the fifth week to the 17th week in both groups, it was significantly reduced in ACF-bearing group at the 13th week (P?<?0.01). At the genus level, no significant difference was observed in the most predominant genus, Lactobacillus. Instead, Bacteroides and Prevotella were significantly less abundant (P?<?0.01), while Akkermansia was significantly more abundant (P?<?0.05) in ACF-bearing group at the 13th week.Conclusion
Imbalance of the intestinal microbiota existed between ACF-bearing and non-bearing rats, which could be used as biomarker to predict the genesis of precancerous lesions in the gut.5.
Background
Non-asthmatic eosinophilic bronchitis (NAEB) is one common cause of chronic cough which is characterized as airway eosinophilic inflammation like asthma but lack of airway hyper-responsiveness. Previous studies showed that Th2-pathway plays a role in NAEB, but the role of non-Th2 pathway in mechanism of NAEB remains unknown. Recently, IL-17A, a Th17-pathway cytokine, has been demonstrated to be involved in asthma development. However, the relationship between Th17-pathway and NAEB is unknown.Methods
We aim to assess the airway level of IL-17A in the subjects with NAEB. Relationships between the IL-17A level and airway function in NAEB or asthma are also observed. We measured IL-17A concentrations in the sputum supernatant from 12 subjects with EB, 16 subjects with asthma [9 eosinophilic asthmatic (EA) and 7 non-eosinophilic asthmatic (NEA) according to the sputum eosinophil ≥?3%], and 9 healthy control subjects.Results
Increasing IL-17A level was found in NAEB group (29.65?±?8.13 pg/ml), EA group (32.45?±?3.22 pg/ml), and NEA group (29.62?±?6.91 pg/ml) compared with the healthy control group (17.05?±?10.30 pg/ml) (P?<?0.05, P?<?0.01, P?<?0.05, respectively). The sputum IL-17A level was correlated with FENO (r?=?0.44, P?<?0.01), FEV1/FVC% (r?=???0.38, P?<?0.05), MMEF%pred (r?=???0.34, P?<?0.05), and sputum neutrophil% (r?=?0.33, P?<?0.05) in total.Conclusion
Th17-pathway may play a role not only in asthmatics, but also in subjects with NAEB, as reflected by increasing IL-17A concentrations in sputum supernatant.6.
Purpose of Review
The goal of this paper is to review the major adverse cutaneous reactions that have been reported to the most commonly used biologics.Recent Findings
Anti-TNF agents and immune checkpoint inhibitors have significant, immune-mediated cutaneous manifestations that can necessitate discontinuation. Anti-TNF agents, IL-6 inhibitors, and IL-12/23 inhibitors can paradoxically cause psoriasis flares or unmask previously undiagnosed psoriasis. IL-17 inhibitors are unique in increasing risk for Candida infections. Benign injection site reactions, non-specific rash, cellulitis, and hypersensitivity reactions are relatively common adverse events.Summary
A wide variety of cutaneous reactions caused by biologics have been reported, ranging from benign injection site reactions to life-threatening cutaneous reactions necessitating discontinuation of the implicated biologic agent.7.
Background
Disseminated nocardiosis is a rare disease mostly occurring in immunocompromised patients.Methods
We report a case of disseminated nocardiosis in a diabetic patient with both pulmonary and cutaneous involvement. Nocardia elegans was isolated and identified using the 16s ribosomal RNA gene sequence data.Results
Clinical improvement was observed within 3 months after initiation of antimicrobial treatment with oral doxycycline, trimethoprim-sulfamethoxazole and intravenous penicillin, but the patient died 5 months later after arbitrary discontinuation of the treatment.Conclusions
This is the first case report of disseminated nocardiosis caused by Nocardia elegans in China.8.
Yudai Torihata Kiyotaka Asanuma Katsunori Iijima Tetsuhiko Mikami Shin Hamada Naoki Asano Tomoyuki Koike Akira Imatani Atsushi Masamune Tooru Shimosegawa 《Digestive diseases and sciences》2018,63(2):345-355
Background
Gastroesophageal reflux disease is more common in males than in females. The enhanced antioxidative capacity of estrogen in females might account for the gender difference. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a pivotal role in the host defense mechanism against oxidative stress.Aims
This study aimed to clarify the role of Nrf2 in reflux-induced esophageal inflammation, focusing on the gender difference and nitric oxide.Methods
Gastroesophageal reflux was surgically induced in male and female rats. Nitrite and ascorbic acid were administered for 1 week to provoke nitric oxide in the esophageal lumen. Male rats with gastroesophageal reflux were supplemented with 17β-estradiol or tert-butylhydroquinone, an Nrf2-inducing reagent. Esophageal squamous cell carcinoma KYSE30 cells were treated with 17β-estradiol. Nrf2 expression was examined by Western blotting and quantitative real-time PCR. Antioxidant gene expression profiles were examined by a PCR array.Results
In the presence of nitric oxide, reflux-induced esophageal damage was less evident, whereas esophageal expression of Nrf2 and its target genes such as Nqo1 was more evident in female or male rats supplemented with 17β-estradiol than in male rats. 17β-Estradiol increased nuclear Nrf2 expression in KYSE30 cells. tert-Butylhydroquinone increased tissue Nqo1 mRNA expression, leading to a reduction in reflux-induced esophageal damage.Conclusions
Estrogen-dependent Nrf2 expression might contribute to protection against the development of gastroesophageal reflux disease in females.9.
YinHua Tang YingYing Chen Xi Wang Guang Song YongGuo Li LiJun Shi 《Digestive diseases and sciences》2015,60(7):1948-1957
Background
Bone marrow mesenchymal stem cells sometimes improve symptoms of inflammatory bowel disease.Aim
To test the effects of combined granulocyte colony-stimulating factor (G-CSF) and MSC therapy in a rat model of ulcerative colitis (UC).Methods
Seventy-two rats with TNBS-induced UC were divided into control or treatment groups: control (no disease and no treatment), no treatment (model), 5-aminosalicylate (5-ASA) enema, or MSCs (labeled with BrdU) with (MSC/GCSF) or without (MSC) G-CSF, and G-CSF alone (GCSF). On days 14 and 28 post-treatment, macroscopic and histological appearances were assessed and the disease activity index (DAI) scored to evaluate the severity of disease. BrdU-labeled MSCs were identified by immunofluorescence to confirm transplantation and their location. The inflammatory profile of each group was evaluated by measuring expression of nuclear NF-κB p65, serum TNF-α, and IL-10 and by activity of mucosal myeloperoxidase (MPO).Results
Rats receiving MSC and G-CSF combination therapy had increased recruitment of MSCs to the colonic mucosa compared with rats receiving MSC transplantation alone. On day 28, the DAI, MPO activity, serum TNF-α and IL-10 levels, and NF-κB p65 expression in the combination therapy group were significantly lower compared to animals receiving no treatment, MSCs alone, or G-CSF alone (P < 0.05).Conclusion
Intravenously transplanted MSCs migrate and distribute to the colon to effectively alleviate the symptoms of UC, while G-CSF enhances this effect via an anti-inflammatory effect and improvement in the pathologic features of UC. G-CSF may be a promising therapeutic regulator of MSCs that can improve therapeutic outcomes in patients with UC.10.
11.
Cornelia Lass-Flörl Astrid Mayr Maria Aigner Michaela Lackner Dorothea Orth-Höller 《Infection》2018,46(5):701-704
Purpose
To determine the burden of antifungal resistance in fungi over the last 10 years.Methods
Performance of a semi-nationwide surveillance on antifungal resistance.Results
We observed a low frequency of azole resistance in Aspergillus fumigatus, a moderate increase of echinocandin resistance in yeasts, and a stable amphotericin B activity in yeasts and molds. Posaconazole resistance in Aspergillus terreus occurred in a few isolates.Conclusion
The burden of resistance in fungi seems to be low in Tyrol, Austria.12.
Michael G. Usher Christine Fanning Vivian W. Fang Madeline Carroll Amay Parikh Anne Joseph Dana Herrigel 《Journal of general internal medicine》2018,33(12):2078-2084
Background
Patients transferred between hospitals are at high risk of adverse events and mortality. The relationship between insurance status, transfer practices, and outcomes has not been definitively characterized.Objective
To identify the association between insurance coverage and mortality of patients transferred between hospitals.Design
We conducted a single-institution observational study, and validated results using a national administrative database of inter-hospital transfers.Setting
Three ICUs at an academic tertiary care center validated by a nationally representative sample of inter-hospital transfers.Patients
The single-institution analysis included 652 consecutive patients transferred from 57 hospitals between 2011 and 2012. The administrative database included 353,018 patients transferred between 437 hospitals.Measurements
Adjusted inpatient mortality and 24-h mortality, stratified by insurance status.Results
Of 652 consecutive transfers to three ICUs, we observed that uninsured patients had higher adjusted inpatient mortality (OR 2.67, p?=?0.021) when controlling for age, race, gender, Apache-II, and whether the patient was transferred from an ED. Uninsured were more likely to be transferred from ED (OR 2.3, p?=?0.026), and earlier in their hospital course (3.9 vs 2.0 days, p?=?0.002). Using an administrative dataset, we validated these observations, finding that the uninsured had higher adjusted inpatient mortality (OR 1.24, 95% CI 1.13–1.36, p?<?0.001) and higher mortality within 24 h (OR 1.33 95% CI 1.11–1.60, p?<?0.002). The increase in mortality was independent of patient demographics, referral patterns, or diagnoses.Limitations
This is an observational study where transfer appropriateness cannot be directly assessed.Conclusions
Uninsured patients are more likely to be transferred from an ED and have higher mortality. These data suggest factors that drive inter-hospital transfer of uninsured patients have the potential to exacerbate outcome disparities.13.
Ning Liu Yuan-Yuan Sun Xiao-Wen Zhang Sheng Chen Ye Wang Zhao-Xiong Zhang Shao-Wei Song Guang-Bin Qiu Wei-Neng Fu 《Digestive diseases and sciences》2015,60(7):2000-2008
Background
miR-23a, which participates in invasion of pancreatic ductal adenocarcinoma cells into the mesothelial barrier, is a critical regulator in many cancers. It, however, is still unknown whether miR-23a regulates pancreatic cell proliferation and apoptosis or not.Aims
We sought to investigate the role of miR-23a in regulation of pancreatic cell proliferation and apoptosis.Methods
miRNA, mRNA, and protein expressions were determined by qRT-PCR and Western blot, respectively. Dual-luciferase reporter assay was used in detection for binding ability of miR-23a to APAF1. Ectopic miR-23a and APAF 1 were introduced to pancreatic cells, and their roles in proliferation and apoptosis were detected by MTT, colony formation, and apoptosis assays, respectively.Results
Up-regulation of miR-23a and down-regulation of APAF 1 were found in pancreatic ductal cancer, respectively. miR-23a significantly inhibited the luciferase activity by targeting APAF 1 3′UTR. Ectopic miR-23a significantly suppressed the APAF 1 gene expression in pancreatic cancer cells. Similar to siAPAF1, miR-23a significantly promoted pancreatic cancer cell proliferation and repressed apoptosis. Furthermore, miR-23a inhibitor and exogenous APAF 1 could recover the effects.Conclusions
It is suggested that miR-23a, acting as an oncogenic regulator by directly targeting APAF 1 in pancreatic cancer, is a useful potential biomarker in diagnosis and treatment of pancreatic cancer.14.
15.
Purpose
There is currently a paucity of published literature focused on the treatment of infections caused by NDM-producing organisms.Methods
We describe a case of a bacteraemia caused by an extensively drug-resistant (XDR) New Delhi metallo-β-lactamase (NDM)-producing Serratia marcescens and review the treatment options for XDR NDM-producing Enterobacteriaceae.Results
Infections caused by New Delhi beta-lactamase (NDM)-producing Enterobacteriaceae are becoming increasingly prevalent worldwide. The presence of the enzyme results in multidrug-resistant and extensively drug-resistant phenotypes which often pose a treatment challenge. Despite this challenge, case reports and series have demonstrated good clinical outcomes with numerous treatment options in comparison to infections due to KPC-producing Enterobacteriaceae.Conclusions
Further good-quality research focused on the treatment of NDM-producing Enterobacteriaceae is warranted.16.
Judith K. Ockene Rashelle B. Hayes Linda C. Churchill Sybil L. Crawford Denise G. Jolicoeur David M. Murray Abigail B. Shoben Sean P. David Kristi J. Ferguson Kathryn N. Huggett Michael Adams Catherine A. Okuliar Robin L. Gross Pat F. BassIII Ruth B. Greenberg Frank T. Leone Kola S. Okuyemi David W. Rudy Jonathan B. Waugh Alan C. Geller 《Journal of general internal medicine》2016,31(2):172-181
Background
Early in medical education, physicians must develop competencies needed for tobacco dependence treatment.Objective
To assess the effect of a multi-modal tobacco dependence treatment curriculum on medical students’ counseling skills.Design
A group-randomized controlled trial (2010–2014) included ten U.S. medical schools that were randomized to receive either multi-modal tobacco treatment education (MME) or traditional tobacco treatment education (TE).Setting/Participants
Students from the classes of 2012 and 2014 at ten medical schools participated. Students from the class of 2012 (N?=?1345) completed objective structured clinical examinations (OSCEs), and 50 % (N?=?660) were randomly selected for pre-intervention evaluation. A total of 72.9 % of eligible students (N?=?1096) from the class of 2014 completed an OSCE and 69.7 % (N?=?1047) completed pre and post surveys.Interventions
The MME included a Web-based course, a role-play classroom demonstration, and a clerkship booster session. Clerkship preceptors in MME schools participated in an academic detailing module and were encouraged to be role models for third-year students.Measurements
The primary outcome was student tobacco treatment skills using the 5As measured by an objective structured clinical examination (OSCE) scored on a 33-item behavior checklist. Secondary outcomes were student self-reported skills for performing 5As and pharmacotherapy counseling.Results
Although the difference was not statistically significant, MME students completed more tobacco counseling behaviors on the OSCE checklist (mean 8.7 [SE 0.6] vs. mean?8.0 [SE 0.6], p?=?0.52) than TE students. Several of the individual Assist and Arrange items were significantly more likely to have been completed by MME students, including suggesting behavioral strategies (11.8 % vs. 4.5 %, p?<?0.001) and providing information regarding quitline (21.0 % vs. 3.8 %, p?<?0.001). MME students reported higher self-efficacy for Assist, Arrange, and Pharmacotherapy counseling items (ps?≤0.05).Limitations
Inclusion of only ten schools limits generalizability.Conclusions
Subsequent interventions should incorporate lessons learned from this first randomized controlled trial of a multi-modal longitudinal tobacco treatment curriculum in multiple U.S. medical schools.NIH Trial Registry Number: NCT0190561817.
Giorgia Montrucchio Silvia Corcione Monica Vaj Teresa Zaccaria Cristina Costa Luca Brazzi Rossana Cavallo Giovanni Di Perri Francesco G. De Rosa 《Infection》2018,46(1):123-125
Introduction
Elizabethkingia meningoseptica can frequently colonizes the respiratory tract, but its pathogenetic role and its clinical significance are frequently questioned. However, recent data reported E. meningoseptica outbreaks in particular settings, as hospitalized patients.Case Report
We report here the first case of Elizabethkingia meningoseptica infection in Italy in a patient with necrotic-hemorrhagic pancreatitis. E. meningoseptica was isolated from respiratory tract and treated with combination antibiotic therapy.Conclusion
We discuss here the role of isolation of E. meningoseptica in hospitalized patients as a sign of patient’s frailty.18.
Background
While early evidence suggests that Medicare accountable care organizations (ACOs) may reduce post-acute care (PAC) utilization for attributed beneficiaries, whether these effects spill over to all beneficiaries admitted to hospitals participating in ACOs stray is unknown.Objective
The objective of this study was to evaluate whether changes in PAC use and Medicare spending spill over to all beneficiaries admitted to hospitals participating in the Medicare Shared Savings Program (MSSP).Design
Observational study using a difference-in-differences design comparing changes in PAC utilization and spending among beneficiaries admitted to ACO-participating hospitals before and after the start of the ACO contracts, compared to those admitted to non-ACO hospitals.Setting
A total of 233 hospitals participate in MSSP ACOs and 3103 non-ACO hospitals.Participants
A national sample of 11,683,573 Medicare beneficiaries experiencing 26,503,086 hospital admissions from 2010 to 2013.Exposure
Admission to a hospital participating in an MSSP ACO.Main Measures
The probability of discharge and Medicare payments to inpatient rehabilitation facilities (IRF), skilled nursing facilities (SNF), and home health agencies (HHA).Key Results
For beneficiaries admitted to hospitals that joined an ACO, the likelihood of being discharged to PAC did not change after the hospital joined the ACO compared with non-ACO hospitals over the same period (differential change in probability of discharge to any PAC was 0.000 (P?=?0.89), SNF was 0.000 (P?=?0.73), IRF was 0.000 (P?=?0.96), and HHA was 0.001 (P?=?0.57)). Payments reduced significantly for PAC overall (??$130.41, P?=?0.03), but not for any individual PAC type alone. These results were consistent in samples that were conditional on discharge to any PAC, across conditions with high PAC use nationally, and among ACO-participating hospitals that also had a PAC participant.Conclusions
Hospital participation in an ACO did not result in spillovers in PAC utilization or payments to all beneficiaries, even when considering high PAC-use conditions and ACO hospitals that also have an ACO-participating PAC.19.
Takeshi Kimura Atsushi Uda Tomoyuki Sakaue Kazuhiko Yamashita Tatsuya Nishioka Sho Nishimura Kei Ebisawa Manabu Nagata Goh Ohji Tatsuya Nakamura Chihiro Koike Mari Kusuki Takeshi Ioroi Akira Mukai Yasuhisa Abe Hiroyuki Yoshida Midori Hirai Soichi Arakawa Ikuko Yano Kentaro Iwata Issei Tokimatsu 《Infection》2018,46(2):215-224
Objective
To evaluate the long-term effects of comprehensive antibiotic stewardship programs (ASPs) on antibiotic use, antimicrobial-resistant bacteria, and clinical outcomes.Design
Before–after study.Setting
National university hospital with 934 beds.Intervention
Implementation in March 2010 of a comprehensive ASPs including, among other strategies, weekly prospective audit and feedback with multidisciplinary collaboration.Methods
The primary outcome was the use of antipseudomonal antibiotics as measured by the monthly mean days of therapy per 1000 patient days each year. Secondary outcomes included overall antibiotic use and that of each antibiotic class, susceptibility of Pseudomonas aeruginosa, the proportion of patients isolated methicillin-resistant Staphylococcus aureus (MRSA) among all patients isolated S. aureus, the incidence of MRSA, and the 30-day mortality attributable to bacteremia.Results
The mean monthly use of antipseudomonal antibiotics significantly decreased in 2011 and after as compared with 2009. Susceptibility to levofloxacin was significantly increased from 2009 to 2016 (P = 0.01 for trend). Its susceptibility to other antibiotics remained over 84% and did not change significantly during the study period. The proportion of patients isolated MRSA and the incidence of MRSA decreased significantly from 2009 to 2016 (P < 0.001 and = 0.02 for trend, respectively). There were no significant changes in the 30-day mortality attributable to bacteremia during the study period (P = 0.57 for trend).Conclusion
The comprehensive ASPs had long-term efficacy for reducing the use of the targeted broad-spectrum antibiotics, maintaining the antibiotic susceptibility of P. aeruginosa, and decreasing the prevalence of MRSA, without adversely affecting clinical outcome.20.
Angela Sheu Yixian Chan Angela Ferguson Mohammad B. Bakhtyari Wendy Hawke Chris White Yuk Fun Chan Patrick J. Bertolino Heng G. Woon Umaimainthan Palendira Frederic Sierro Sue Mei Lau 《Diabetologia》2018,61(7):1633-1643