Anti-CD25 mAb, anti-IL2 mAb, and IL2 block tolerance induction through anti-CD154 mAb and rapamycin in xenogeneic islet transplantation

BACKGROUND: We have used anti-CD154 monoclonal antibody (mAb; MR1) and rapamycin (rapa) to induce tolerance to islet xenografts. The aim of this study was to investigate whether classical anergy and/or regulation by interleukin (IL)2-dependent CD25+ T regulatory cells played roles in the induction and maintenance of tolerance in this model. METHODS: Streptozotocin-induced diabetic mice were transplanted with rat islets. We performed the following groups: control group, islet transplantation without therapy; rapamycin group, 0.2 mg/kg by oral gavage on days 0, 1, 2, and every other day to day 14; anti-CD154 mAb (MR1) group, 0.5 mg intraperitoneally on days 0, 2, and 4; combination therapy group with rapa and MR1. We then administered in addition to the combination therapy with early (from days 0 to 14 [for IL2] or to 28 [for anti-IL2 mAb and anti-CD25 mAb] post-transplantation) or late (from days 100 to 114 [for IL2] or to 128 [for anti-IL2 mAb and anti-CD25 mAb] posttransplantation) recombinant IL2 (2000 U, intraperitoneally twice a day), a neutralizing anti-IL2 mAb (S4B6-1, 0.3 mg intraperitoneally twice weekly), and a depleting anti-CD25 mAb (PC61, 0.3 mg intraperitoneally twice weekly), respectively. Histology was performed at time of rejection. RESULTS: Rapa and MR1 therapy alone significantly prolonged xenograft survival compared to the control group: median graft survival was 34 days versus 17 days (P<.05) and 98 days versus 17 days (P<.05), respectively, but rejection still occurred. Combination therapy with MR1 and rapa allowed indefinite graft survival (median graft survival [MGS]>200 days, P<.001). When exogenous IL2 was administered early with MR1 and rapa, rapid rejection developed in 18 of 18 mice (MGS 7 days), whereas when IL2 was given late, only 3 of 10 developed rejection. Early administration of anti-IL2 mAb led to rejection in 10 of 10 mice (MGS 42 days), whereas late administration led to rejection in only one of four mice. Early administration of anti-CD25 mAb led to rejection in eight of nine mice (MGS 49 days), whereas late administration led to rejection in only three of seven mice. CONCLUSIONS: Rapa and MR1 allowed indefinite graft survival of islet xenografts. Classical anergy and regulation by IL2-dependent CD25+ T regulatory cells were critical in the induction of tolerance in the immediate posttransplantation period and less important for maintenance of tolerance.     

Anaemia management in patients with chronic kidney disease: Taiwan practice guidelines

The introduction of erythropoiesis‐stimulating agents (ESAs) markedly improved the lives of many anaemic patients with chronic kidney disease (CKD). In Taiwan, the strategy of management of anaemia in patients with CKD was different from many other parts of the world. In 1996, the National Health Insurance Administration of Taiwan applied a more restrictive reimbursement criteria for ESA use in patients with CKD. ESA is to be initiated when non‐dialysis CKD patients have a serum creatinine >6 mg/dL and a hematocrit <28% to maintain a hematocrit level not exceeding 30%. The maximal dose of epoetin‐α or β was 20 000 U per month. The target haemoglobin range and dose limitation for ESAs were the same for dialysis CKD patients. Thus, long before randomized controlled trials showing an increased risk for cardiovascular events at nearly normal haemoglobin concentrations and higher ESA doses in CKD, nephrologists in Taiwan had avoided the use of disproportionately high dosages of ESAs to achieve a haemoglobin level of 10–11 g/dL. Moreover, intravenous iron supplementation was encouraged earlier in Taiwan in 1996, when we reached consensus on the diagnostic criteria for iron deficiency (serum ferritin <300 ng/mL and/or transferrin saturation <30%). The experience of CKD anaemia management in Taiwan demonstrated that a reasonable haemoglobin target can be achieved by using the lowest possible ESA dose and intravenous iron supplementation.     

The development of pediatric fluid resuscitation: an interview with Dr. Frederic A. ‘Fritz’ Berry

Dr. Frederic A. ‘Fritz’ Berry (1935), Professor Emeritus of Anesthesiology and Pediatrics at the University of Virginia, has played a pioneering role in the development of pediatric anesthesiology through training generations of anesthesiologists. He identifies his early advocacy of balanced electrolyte solution for perioperative fluid resuscitation as his defining contribution. Based on his clinical experiences, he pushed to extend the advances in adult fluid resuscitation into pediatric practice. He imparted these and other insights to his colleagues although textbooks, book chapters, original journal publications, and decades of Refresher Course Lectures at the American Society of Anesthesiologists' annual meetings. A model educator, clinician, and researcher, he shaped the careers of hundreds of physicians‐in‐training while advancing the field of pediatric anesthesiology.     

Genetic polymorphisms in NQO1 and SOD2: Interactions with smoking,schistosoma infection,and bladder cancer risk in Egypt

BackgroundBladder cancer is the most prevalent form of cancer in men among Egyptians, for whom tobacco smoke exposure and Schistosoma haematobium (SH) infection are the major risk factors. We hypothesized that functional polymorphisms in NAD(P)H:quinone oxidoreductase 1 (NQO1) and superoxide dismutase 2 (SOD2), modulators of the effects of reactive oxidative species, can influence an individual's susceptibility to these carcinogenic exposures and hence the risk of bladder cancer.MethodsWe assessed the effects of potential interactions between functional polymorphisms in the NQO1 and SOD2 genes and exposure to smoking and SH infection on bladder cancer risk among 902 cases and 804 population-based controls in Egypt. We used unconditional logistic regression to estimate the odds ratios (OR) and confidence intervals (CI) 95%.ResultsWater pipe and cigarette smoking were more strongly associated with cancer risk among individuals with the TT genotype for SOD2 (OR [CI 95%] = 4.41 [1.86–10.42]) as compared with those with the CC genotype (OR [CI 95%] = 2.26 [0.97–6.74]). Conversely, the risk associated with SH infection was higher among the latter (OR [CI 95%] = 3.59 [2.21–5.84]) than among the former (OR [CI 95%] = 1.86 [1.33–2.60]). Polymorphisms in NQO1 genotype showed a similar pattern, but to a much lesser extent. The highest odds for having bladder cancer following SH infection were observed among individuals with the CC genotypes for both NQO1 and SOD2 (OR [CI 95%] = 4.41 [2.32–8.38]).ConclusionOur findings suggest that genetic polymorphisms in NQO1 and SOD2 play important roles in the etiology of bladder cancer by modulating the effects of known contributing factors such as smoking and SH infection.     

NLR is predictive of upstaging at the time of radical cystectomy for patients with urothelial carcinoma of the bladder

ObjectiveTo evaluate the ability of preoperative neutrophil-lymphocyte ratio (NLR) to predict pathologic upstaging and nonorgan-confined (NOC) (≥pT3) disease.Methods and materialsAfter institutional review board approval, the records of consecutive patients undergoing radical cystectomy (RC) for urothelial carcinoma from 2002 to 2012 at the University of Wisconsin Hospital were reviewed. A total of 102 patients with NLR within 100 days of surgery were eligible for analysis. The primary outcome was difference in stage from preoperative assessment to time of RC. Differences in preoperative NLR between groups were evaluated with an unequal variance t test. A univariate analysis assessed whether NLR, preoperative stage, grade, associated lymphovascular invasion, preoperative hydronephrosis, gender, previous pelvic radiotherapy, previous intravesical bladder cancer treatments, or nodal stage were related to upstaging. Multivariate analyses were performed to evaluate the relationship of NLR to upstaging and relative organ-confined (≤pT2) and NOC disease.ResultsOf 390 consecutive patients undergoing RC, 102 patients met study criteria. Overall, 55 (53.9%) patients were upstaged, 25 (25.5%) were unchanged, and 21 (20.6%) were downstaged. Fifty-one patients (50%) were upstaged to more advanced disease (≥pT3). NLR and preoperative hydronephrosis were significantly related to pathologic tumor staging. NLR, preoperative hydronephrosis, and preoperative tumor stage were significantly related to upstaging to NOC disease. Patients who were upstaged to≥pT3 demonstrated statistically significant greater NLRs (4.33±0.87) compared with patients who remained at≤pT2 stage (2.66±0.29) (P<0.001).ConclusionsPreoperative NLR is a simple measurement that can be used to identify high-risk patients who may be upstaged at the time of RC and may benefit from neoadjuvant chemotherapy.     

Phylogenetic and Phylogeographic Analyses of Porcine Circovirus Type 2 Among Pig Farms in Vietnam

This study demonstrated the prevalence of Porcine circovirus type 2 (PCV2) among pig farms in Vietnam. Analyses of the genome, capsid protein and phylogeny classified all 30 Vietnamese PCV2 strains as the PCV2b genotype, belonging to the clusters of 1A, 1B, 1C and recombinant forms. Each viral genome was 1767 nucleotides long and shared 96.0–100% nucleotide sequence identity. The amino acid substitutions in the capsid protein of the Vietnamese PCV2 strains were in immunodominant regions, and the majority of strains (24/30) contained a lysine extension at the C‐terminus. Bayesian phylogeographic analysis revealed epidemic links of the PCV2 recombinant cluster within and among countries, which supports a circulating recombinant form of PCV2. Further analysis by the Jameson–Wolf antigenic index indicated antigenic alterations at important sites in the capsid protein (sites 131–133) among the recombinant cluster and the other clusters of PCV2b.     

两种内镜下术式治疗胆总管结石的临床效果与安全性比较

目的比较两种内镜下术式治疗胆总管结石的临床效果与安全性。 方法对2015年3月至2017年5月90例胆总管结石患者进行前瞻性对照研究,使用随机数字表法将其分为A组、B组,各45例,A组接受内镜下十二指肠乳头括约肌切开术(EST)联合腹腔镜下胆囊切开术(LC)治疗,B组接受经皮经胆囊十二指肠乳头肌球囊扩张排石术治疗。数据采用SPSS 22.0进行分析,术中术后指标及实验室指标以( ±s)表示,并采用独立t检验;临床预后及术后并发症采用χ²检验,以P<0.05为差异有统计学意义。 结果B组术后近期急性胰腺炎发生率及远期结石复发率低于A组(P<0.05)。两组患者术后1周、术后1个月CA19－9、总胆红素、直接胆红素、ALT、AST均较术前降低,术后1周B组上述指标低于A组(P<0.05)。 结论两种内镜下术式治疗胆总管结石的临床效果相当,经皮经胆囊十二指肠乳头肌球囊扩张排石术的安全性更为理想,值得推荐。     

CD146在聚乙二醇诱导的小鼠脉络膜新生血管模型中的表达及意义

目的：探讨在聚乙二醇（polyethylene glycol,PEG）诱导的小鼠脉络膜新生血管（choroidal neovascularization,CNV）模型中CD146的表达及意义。方法：将60只8周龄雄性C57BL/6J小鼠采用随机数字表法,将小鼠随机分为第5、10和15天组,每组各20只。设定每组小鼠左眼为正常对照眼,右眼为实验眼,采用在视网膜下注射PEG诱导形成脉络膜新生血管模型。造模后摘取各组小鼠眼球,制作视网膜组织切片及HE染色,鉴定CNV模型。通过比较各组视网膜HE染色切片外核层（outer nuclear layer,ONL）厚度,观察PEG的视网膜毒性作用。采用实时荧光定量PCR法检测小鼠神经视网膜和RPE/脉络膜复合体中CD146、血管内皮生长因子（vascular endothelial growth factor,VEGF）、血管内皮生长因子受体2（vascular endothelial growth factor receptor 2,VEGFR2）的mRNA水平变化。免疫组化染色法检测小鼠眼内CD146、VEGF和VEGFR2的表达。结果：HE染色和ONL层厚度比较均证实,视网膜下注射PEG造模成功且模型可靠,视网膜下注射后第5和10天均有CNV形成。实验组小鼠神经视网膜和脉络膜中CD146、VEGF、VEGFR2的mRNA表达水平与对照组相比明显升高,差异有统计学意义（F=30.412,P=0.000;F=84.974,P=0.000;F=117.423,P=0.000;F=918.786,P=0.000;F=319.110,P=0.000;F=113.896,P=0.000）。Person相关性分析提示在视网膜下注射PEG后,小鼠RPE/脉络膜复合体中CD146与VEGF和VEGFR2的表达量呈正相关（r=0.940,P=0.000;r=0.940,P=0.000;r=0.769,P=0.045;r=0.910,P=0.003;r=0.910,P=0.003;r=0.777,P=0.042）。免疫组化染色的结果显示,在造模第10天后,造模组与正常对照组相比较CD146、VEGFR2在神经节细胞层、内核层、外从状层、外核层的阳性表达均有不同程度增强（P=0.000,P=0.000,P=0.000）。结论：CD146伴随着CNV的形成表达上调,且与VEGF的表达量和VEGFR2的表达量呈正相关性,由此推断CD146可能在CNV形成的病理过程中起到至关重要的作用。     

男性精神分裂症患者睾酮水平及与认知功能的相关性研究*

目的 探讨男性精神分裂症患者与健康男性血清睾酮水平表达差异及其与患者认知功能的相关性。方法 选取中国人民解放军102医院男性首发精神分裂症患者64例为研究组,同期健康体检男性57例为对照组。检测两组研究对象的血清睾酮水平,评估认知功能,对检测结果进行相关性分析。结果 研究组血清睾酮水平与对照组比较,差异无统计学意义（P?>0.05）。研究组认知功能测试中,数字划销时间、连线A测试结果高于对照组（P?<0.05）,范畴流畅、空间广度、木块图、连续定步调听觉正确数、连续定步调听觉尝试数低于对照组（P?<0.05）。Pearson相关性分析显示,健康男性睾酮水平与数字划销时间、连线A、空间广度、木块图、连续定步调听觉正确数、连续定步调听觉尝试数无相关（P?>0.05）,男性精神分裂症患者睾酮水平与数字划销时间、连线A呈正相关（P?<0.05）,与空间广度、木块图、连续定步调听觉正确数、连续定步调听觉尝试数呈负相关（P?<0.05）,与范畴流畅无相关（P?>0.05）。结论 首发男性精神分裂症患者血清睾酮水平与健康男性无差异。男性精神分裂症患者血清睾酮水平与空间记忆、注意功能呈负相关,可通过调节患者睾酮水平的方法改善其认知功能。