Role of polymorphisms in the interleukin-10 gene in determining disease susceptibility and phenotype in inflamatory bowel disease

Interleukin-10 (IL-10) has a key role in regulating mucosal inflammation. The role of functional polymorphisms at positions –627 and –1117 in the IL-10 gene as candidate susceptibility loci in inflammatory bowel disease and their importance in determining disease extent were evaluated in 159 patients with ulcerative colitis (83 left-sided; 76 extensive), 90 patients with Crohn's disease (22 small bowel; 29 large bowel; 39 both), and 227 controls. Genotyping was performed either by PCR-RFLP assays (–627 site) or SSCP analysis (–1117 site). An excess of –627A allele was observed in patients with left-sided colitis (52%) compared with controls (33%; P = 0.004) suggesting that IL-10 may influence the extent of the disease. These results were not replicated in a newly recruited group (N = 100) of patients with UC. We conclude that polymorphisms at –627 and –1117 sites in the IL-10 gene do not contribute to the susceptibility to IBD or determining the extent of the disease in our population.     

Reduction in the response to coronary and iliac artery injury with photodynamic therapy using 5-aminolaevulinic acid

OBJECTIVE: Photodynamic therapy (PDT) uses red light (non-thermal, non-ionising) to activate a previously administered photosensitizing drug. This inhibits neointimal hyperplasia in injured arteries in small animals where it appears safe and well tolerated. Our aim was to develop a method for percutaneous application of PDT to iliac and coronary arteries in a large animal model and investigate its influence on the remodeling and intimal hyperplastic response to balloon injury. METHODS: Studies were undertaken on 13 juvenile Large White-Landrace crossbred pigs (15-20 kg). After intravenous administration of the photosensitizing agent 5-amino laevulinic acid (ALA), the arterial tree was accessed via the left common carotid artery and balloon injuries made by over-distension in both common iliacs (thirteen animals) and one or two main coronary arteries (eight animals). Half the injured sites were then illuminated with red laser light transmitted via the catheter. Animals were culled 28 days later and tissue harvested for histomorphometry. RESULTS: Compared with control injured vessels, PDT treated, balloon injured coronary arteries had a larger lumen (1.4 vs. 0.8 mm2, P = 0.002), larger area within the external elastic lamina (2.8 vs. 2.2 mm2, P = 0.006) and smaller area of neointimal hyperplasia (0.4 vs. 0.7 mm2, P = 0.06), 28 days after intervention. Less neointimal hyperplasia and the absence of negative remodeling resulted in the lumen of PDT-treated, injured segments being the same as that of adjacent reference segments (1.5 vs. 1.6 mm2). Similar trends, but with smaller differences, were seen in the iliac vessels. CONCLUSIONS: Intra-arterial, trans-catheter PDT favourably influences the arterial response to balloon injury in both the coronary and peripheral circulations. This technique offers a promising new approach to restenosis after endovascular procedures.     

Microangiopathic haemolytic anaemia and thrombocytopenia following lung volume reduction surgery in a single lung transplant recipient on maintenance tacrolimus (FK506) therapy

Microangiopathic haemolytic anaemia (MAHA) describes intravascular haemolysis due to mechanical destruction of red cells as a result of pathological changes in small blood vessels. It is well recognized as a complication of cyclosporin A therapy in solid organ transplantation but has been uncommonly reported in association with tacrolimus therapy and never before in the setting of lung transplantation. Discussed is a 54-year-old female recipient of a left single lung transplant who developed anaemia, thrombocytopenia and red blood cell fragmentation consistent with MAHA following lung volume reduction surgery (VRS) of the native right lung in the setting of high serum tacrolimus levels. Treatment with fresh frozen plasma and plasmapharesis plus supportive therapy with blood and platelet transfusions resulted in successful resolution of the haemolytic process. Cyclosporin A was substituted for tacrolimus and 18 months later there has been no evidence of recurrence. Tacrolimus therapy is a rare cause of MAHA in solid organ transplants but the diagnosis should be considered if there is an unexplained fall in haemoglobin and/or platelet count in the context of high serum tacrolimus levels.     

Condom use,pregnancy, and STDs in adolescent females with and without type 1 diabetes

PURPOSE: The purpose of this secondary analysis was to describe and compare adolescent females with and without diabetes in terms of use of condoms, pregnancy outcomes, and sexually transmitted disease (STD) outcomes. METHODS: Data from a multisite, case-controlled, telephone survey study were used in a secondary analysis to evaluate the parameters stated in the purpose. RESULTS: The 87 females with type 1 diabetes and 45 nondiabetic females who participated were 16 to 22 years old. Most were Caucasian, in high school, and lived with their parents. No demographic differences were noted between the groups. Of those sexually active, for both groups, the most common contraceptive method was male condoms. Four females with diabetes and 2 without diabetes reported an unplanned pregnancy. Three females with diabetes reported an STD infection (chlamydia or trichomonas). Five females with diabetes and 4 nondiabetic females had abnormal pap tests. CONCLUSIONS: Adolescent females with and without diabetes engaged in less than optimally protected sexual activity, which increased their risk for unplanned pregnancies and STD infections. Further research is needed of the incidence, treatment, and short-term and long-term complications of STDs in adolescent females with diabetes.     

Long-term cardiac function and outcome in patients receiving primary angioplasty for AMI at a community hospital without on-site surgical back-up

BACKGROUND: Short- and long-term comparative follow-up studies of patients receiving primary angioplasty or thrombolytic therapy for acute myocardial infarction show higher 30-day survival, and sustained benefits in mortality, reinfarction and ejection fraction in patients treated with primary angioplasty. Long-term benefits of primary angioplasty on cardiac function performed in community hospitals without surgical back-up have not been fully assessed. METHODS: Sixty-one patients who underwent primary angioplasty were compared with patients receiving thrombolytic therapy who were matched for age, gender and location of acute myocardial infarction. Clinical information, reviewed through August 2000, was provided by retrospective analysis of healthcare databases and office and hospital charts. Mortality data were confirmed by the social security death index. RESULTS: Of the original 61 primary angioplasty patients, two died during initial hospitalization. Of the 59 surviving patients, fifty-four (92%) had complete follow-up averaging 57 months. Of the original 61 thrombolytic therapy patients, three died during initial hospitalization. Of the 58 surviving patients, fifty-two (90%) had complete follow-up averaging 46 months. At follow-up, averaging 57 months, ejection fraction was significantly higher in the primary angioplasty group, as compared with the thrombolytic therapy group (51.4% versus 45.8%, respectively; p = 0.038). There was no statistical difference between the two groups regarding reinfarction, revascularization at > or = 6 months after the initial presentation or cardiac death. CONCLUSIONS: Primary angioplasty performed in a community hospital without surgical back-up results in improved cardiac function when compared to thrombolytic therapy. These results are similar to those reported from large tertiary centers with on-site surgical back-up, and provide an explanation for the improved long-term outcome that is observed in patients with acute myocardial infarction treated with primary angioplasty.     

改性羟基磷灰石骨修复纳米复合材料的制备及生物学评价

目的:制备羟基磷灰石/聚乳酸聚乙醇酸骨修复材料,并对其进行生物学评价。方法:实验于2006-06/2007-02在中科院长春应用化学研究所完成材料制备,在吉林大学基础医学院实验动物中心完成动物实验。将低聚乳酸的羧基与羟基磷灰石表面的钙原子用化学键连接,得到表面接枝聚左旋乳酸的羟基磷灰石,将其与聚乳酸聚乙醇酸共混,得到复合材料PLLA-g-HA/PLGA。溶于氯仿后铺膜(厚0.2mm),用DMEM培养液浸泡材料膜制备浸提液。首先,进行材料生物安全性实验:①细胞毒性实验:将浸提液与培养液混合,接种兔成骨细胞,培养24h,MTT法检测细胞增殖,计算细胞增殖率和细胞毒性级(细胞毒性级0或1级为合格)。②全身毒性实验:小鼠以50mL/kg的剂量静脉注射浸提液,观察72h内小鼠中毒症状。③皮肤刺激实验:兔脊柱两侧皮内注射材料浸提液,观察72h内皮肤有无异常反应。④热原实验:自兔耳缘静脉注入浸提液(10mL/kg)。注射后每0.5h测肛温1次,共6次,以6次中最高的1次减去正常体温,计为升高度数。其次,对复合材料进行细胞黏附性检测:将复合材料制成1%氯仿溶液,涂于硅化的盖玻片上,置于6孔板,每孔接种1×105个成骨细胞,培养3d,在2,24,72h行FITC荧光染色,数码摄像系统拍摄细胞荧光照片。结果:制备了新型PLLA-g-HA/PLGA复合材料。①生物安全性实验结果:MTT实验检测复合材料细胞增殖率为94.8%,细胞毒性级为1级;全身毒性实验中动物无死亡、惊厥、瘫痪、呼吸抑制、腹泻和体质量下降等不良反应;热原实验中兔体温最大的变化值是0.25℃(国家标准为<0.6℃);皮肤刺激实验中未见任何刺激反应,无红斑、焦痂、水肿表现。②细胞黏附性实验结果:细胞接种后2h可见少量细胞开始贴壁;24h时可见贴壁细胞明显增多,并呈聚集生长;培养3d后可见细胞逐渐融合,细胞状态良好。结论:新型PLLA-g-HA/PLGA复合材料符合生物材料细胞毒性要求,按毒性剂量分级属无毒级,无致热原性、对皮肤无刺激作用,具有良好的生物相容性和细胞黏附性。     

Crohn's disease patients' risk-benefit preferences: serious adverse event risks versus treatment efficacy

BACKGROUND & AIMS: Regulatory assessments of drug risks do not routinely consider patient preferences, despite evidence that some patients are willing to accept increased side-effect risk in exchange for therapeutic benefits. The aim of this study is to estimate the willingness of Crohn's disease (CD) patients to accept life-threatening adverse event risks in exchange for CD symptom relief. METHODS: Patients with CD completed choice-format conjoint trade-off tasks involving hypothetical treatments with varying efficacy and risk levels. The treatment features included daily symptoms and activity limitations, serious complications (fistulas, abscesses, bowel obstructions), time between flare-ups, oral steroid use and risk of 3 serious adverse events (SAEs) known to be associated with CD treatment (progressive multifocal leukoencephalopathy (PML), serious infections, and lymphoma). The mean maximum acceptable annual risk (MAR) for each of the SAEs was calculated for various levels of clinical benefit. RESULTS: Daily symptom severity was the most important factor in treatment preferences. Higher MAR was observed for trade-off tasks involving higher levels of clinical benefit. The MAR was similar across the 3 SAEs. For improvements from severe daily symptoms to remission and from moderate daily symptoms to remission, the MARs ranged from 0.69% to 0.81% and from 0.39% to 0.55%, respectively. CONCLUSIONS: Patients with CD have well-defined preferences among treatment attributes and are willing to accept tradeoffs among attributes. The patients indicated they are willing to accept elevated SAE risks in exchange for clinical efficacy. The perspective of the patients on the benefit versus risk balance can assist in making treatment and regulatory decisions.     

A nonsynonymous SNP in ATG16L1 predisposes to ileal Crohn's disease and is independent of CARD15 and IBD5

BACKGROUND & AIMS: A genome-wide association scan of nonsynonymous DNA polymorphisms identified association of a threonine-to-alanine substitution (T300A) in the autophagy-related 16-like gene ATG16L1 with Crohn's disease. We investigated this association in independent U.K. cohorts of Crohn's disease and ulcerative colitis. METHODS: The T300A variant (rs2241880) was genotyped in an independent sample of 727 Crohn's disease and 877 ulcerative colitis cases, and in 579 controls. We then performed an extension analysis combining these data with the U.K. data from the initial study to give a total of 1236 U.K. Crohn's disease cases and 1235 controls to estimate disease risk and test for interaction with the CARD15 and IBD5 risk loci and for association with disease subtypes. RESULTS: The association of T300A was replicated in the independent sample of 727 Crohn's disease cases (P = .001), and was strongly associated in the extended analysis of 1236 Crohn's cases (P = 2.4 x 10(-6)). The 300A/A genotype conferred a 1.65-fold risk of Crohn's disease, with a 2.2-fold risk of ileal disease. Analysis of the interaction of ATG16L1 with CARD15 and IBD5 indicated that all 3 loci contribute independently to disease risk. Homozygosity for the risk allele at all 3 loci conferred a combined risk of 20.4 (95% confidence interval: 8.71, 47.7) for Crohn's disease. The ATG16L1 risk genotype showed a modest but significant association with ulcerative colitis (P = .026). CONCLUSIONS: The association of ATG16L1 with Crohn's disease and possibly with ulcerative colitis supports a role for autophagy in the pathogenesis of inflammatory bowel disease.     

Wasting syndrome and disruption of the somatotropic axis in simian immunodeficiency virus-infected macaques with Mycobacterium avium complex infection

Mycobacterium avium is a common opportunistic infection of patients with acquired immunodeficiency syndrome (AIDS). We used the simian immunodeficiency virus (SIV)-infected rhesus macaque (Macaca mulatta) model to examine whether disseminated M. avium is associated with disruption of the somatotropic axis in AIDS. Macaques were followed prospectively, and body composition was determined by dual-energy x-ray absorption. Serum levels of insulin-like growth factor (IGF)-1, IGF binding protein-3, growth hormone (GH), and somatostatin were measured. SIV-infected macaques inoculated with mycobacteria had significant changes in body composition, perturbations of the somatotropic axis (characterized by increased GH/IGF-1 ratios) (day 0 [2.21] vs. day of death [DOD] [28.06]; P=.015, Mann-Whitney rank sum test), and increased serum somatostatin levels (day 0 [2.00 ng/mL] vs. DOD [8.58 ng/mL]; P=.026, Mann-Whitney rank sum test). These data document alterations in the somatotropic axis secondary to experimental disseminated M. avium infection and suggest that similar changes may contribute to alterations in body composition during AIDS.