瘦素和脂联素在老年结直肠腺瘤合并非酒精性脂肪肝患者中的表达及意义

目的:研究老年结直肠腺瘤合并非酒精性脂肪肝(non-alcoholic fatty liver disease,NAFLD)患者结直肠腺瘤的临床特征及探讨瘦素、脂联素的表达与有潜在恶变风险的结直肠腺瘤的关系.方法:82例老年结直肠腺瘤合并NAFLD患者为研究组,286例老年结直肠腺瘤非NAFLD患者为对照组.统计两组患者合并高血压、糖尿病情况,比较两组患者体质量指数(body mass index,BMI)、天门冬氨酸氨基转移酶(aspartate aminotransferase,AST)、丙氨酸氨基转移酶(alanine aminotransferase,ALT)、甘油三酯(triglyceride,TG)、总胆固醇(total cholesterol,TC)、高密度脂蛋白-胆固醇(highdensity lipoprotein-cholesterol,HDL-C)、低密度脂蛋白-胆固醇(low-density lipoproteincholesterol,LDL-C)、脂蛋白a(lipoprotein a,Lpa)及腺瘤发生部位、大小、数目、病理类型、上皮内瘤变.酶联免疫吸附试验法法检测两组患者瘦素和脂联素的表达.结果:老年结直肠腺瘤合并NAFLD组患者同非NAFLD组相比,吸烟、患有糖尿病、高血压、高甘油三酯血症、高低高密度脂蛋白患者更多(P0.05),且BMI明显高于非N A F L D结直肠腺瘤组(P0.05).结肠腺瘤合并NAFLD组老年患者腺瘤个数多于非NAFLD组(P0.05),绒毛状腺瘤比例也高于非NAFLD组结肠腺瘤患者(P0.05).脂联素在NAFLD组表达高于非NAFLD组(P0.05),而瘦素的表达与之相反(P0.05).脂联素在2个及其以上息肉数组的表达高于单个息肉组(P0.05),在绒毛状息肉组的表达低于非绒毛状息肉组(P0.05),在息肉有高级别瘤样变组的表达高于非高级别瘤样变组(P0.05).瘦素在绒毛状息肉组的表达高于非绒毛状息肉组(P0.05),在息肉有高级别瘤样变组的表达低于非高级别瘤样变组(P0.05).结论:老年结直肠腺瘤合并NAFLD患者腺瘤恶变风险更高,脂联素分泌减少及瘦素水平的升高是可能的原因之一.     

结直肠腺瘤上皮内瘤变高危因素657例分析

目的分析结直肠腺瘤临床、内镜及病理组织学特点,总结结直肠腺瘤发生上皮内瘤变的相关危险因素.方法回顾分析华中科技大学同济医学院附属协和医院2014-01/2016-04以电子结肠镜检出并经病理证实为结直肠腺瘤性息肉的657例患者的相关临床资料,依据是否存在上皮内瘤变分为上皮内瘤变组和非上皮内瘤变组,组间采用χ~2检验,腺瘤发生上皮内瘤变及其恶变程度的相关危险因素采用多因素Logistic回归分析.结果结直肠腺瘤多发生于左半结肠,上皮内瘤变总发生率为22.68%,年龄、息肉直径、蒂的长度、病理类型是腺瘤上皮内瘤变的危险因素,可纳入Logistic回归方程:logit P=-4.384+0.796X2(年龄)+0.324X3(息肉直径)+1.296X4(蒂部形态)+0.944X7(病理类型).性别、年龄、息肉大小是腺瘤高级别内瘤变的危险因素,可纳入Logistic回归方程:logit P=-2.939+1.036X1(性别)+0.853X2(年龄)+1.023X3(息肉直径).低级别及高级别上皮内瘤变组总胆固醇、甘油三酯水平均显著高于无上皮内瘤变组(P0.05).高级别上皮瘤变组在低密度脂蛋白、尿酸(uric acid,URIC)均显著高于无上皮内瘤变组(P0.05).而三组之间高密度脂蛋白、癌胚抗原无明显差异.结论年龄40岁、直径1 cm、有蒂及绒毛管状腺瘤更易发生上皮内瘤变,男性、息肉直径、年龄是结直肠腺瘤发生高级别上皮内瘤变的危险因素.结直肠腺瘤发生上皮内瘤变可能与血脂、URIC水平有关.     

结直肠息肉和结直肠癌中CD24和Lgr5的表达

目的检测肿瘤细胞表面标志物CD24和Lgr5在结直肠息肉和结直肠癌中的表达。方法选择行结肠镜检查或治疗患者100例,选择同期肠镜下活检,病理证实正常的结直肠黏膜20例作为对照组。通过免疫组化染色检测CD24和Lgr5的表达,所有病理切片由两名病理科医师独立阅片后统计分析。结果 CD24在正常肠黏膜和炎性增生性息肉组不表达,在腺瘤性息肉和腺癌中强表达,CD24在非腺瘤、管状腺瘤、绒毛状腺瘤、腺癌中阳性表达逐渐增高,CD24阳性率与息肉病理类型有相关性(r=0.627,P0.01);CD24阳性率随着息肉直径的增加而逐渐递增,CD24阳性表达与息肉大小有相关性(r=0.345,P0.05);CD24阳性率随着无异型增生、低级别上皮内瘤变、高级别上皮内瘤变及腺癌逐渐递增,两变量相关分析显示CD24阳性表达与异型增生程度呈显著相关(r=0.579,P0.05);年龄40岁的患者CD24阳性率明显低于≥40岁患者(χ~2=5.401,P0.05);CD24和Lgr5阳性率在男性和女性两组比较差异无统计学意义(P0.05)。Lgr5在正常肠黏膜和炎性增生性息肉组不表达或低表达,在腺瘤性息肉和腺癌中表达率高,且为强表达,Lgr5在正常结直肠黏膜、炎性息肉、管状腺瘤、绒毛状腺瘤、腺癌中的阳性表达逐渐增高,两变量相关分析显示Lgr5阳性表达与息肉病理类型呈相关性(r=0.563,P0.05);Lgr5阳性表达率随着息肉直径的增加而逐渐递增,但两变量相关分析显示Lgr5阳性率与息肉大小有相关性(r=0.419,P0.01),但是直径1.0 cm息肉组与1.0 cm两组比较差异有统计学意义(P0.01);Lgr5阳性率随着无异型增生、低级别上皮内瘤变、高级别上皮内瘤变及腺癌组逐渐递增,但两变量相关分析显示Lgr5阳性表达与异型增生程度有相关性(r=0.524,P0.01)。但无异型增生组与低级别上皮内瘤变组、高级别上皮内瘤变组和腺癌组之间两两比较,Lgr5阳性率差异有统计学意义(P0.01);Lgr5阳性率在40岁和≥40岁之间差异无统计学意义(χ~2=0.095,P0.05)。结论 CD24和Lgr5都是结直肠息肉恶变的重要参考指标,对它们的检测可以为结直肠癌的早期诊断提供帮助。     

MMP-7在大肠上皮不同病变中的表达及意义

目的 探讨MMP-7(基质溶解素)在结直肠上皮病变的恶性转变中的表达及意义。方法用免疫组化方法检测37例结直肠癌，23例结直肠腺瘤、10例非肿瘤性息肉及10例正常结直肠组织手术标本的石蜡切片中MMP-7的表达。结果 37例结直肠癌切片中25例MMP-7为阳性表达(阳性表达率67．6％)；23例腺瘤切片中，15例表达阳性，阳性表达率65．2％；10例非肿瘤性息肉中，1例阳性表达，阳性率10％；10例正常结直肠上皮对照均未见表达。结论MMP-7在结直肠上皮病变的恶性变中逐渐增强，在结直肠癌的发生发展中起重要作用。     

YB-1和P53蛋白在结直肠肿瘤中的表达及意义

目的:探讨YB-1和P53蛋白在结直肠肿瘤不同发展阶段表达水平的差异及其与结直肠癌临床病理特征的关系.方法:采用免疫组织化学方法检测结直肠20例正常组织、30例低级别上皮内瘤变组织、30例高级别上皮内瘤变组织和50例癌组织中YB-1和P53蛋白的表达.结果:YB-1蛋白在结直肠正常组织(NCM)、低级别上皮内瘤变组织(LGIN)、高级别上皮内瘤变组织(HGIN)和癌组织(CRC)中的强阳性率分别为0%、76.7%、80.0%、80.0%,低级别、高级别上皮内瘤变组织和癌组织中的强阳性表达率均与正常组织比较差异有统计学意义(P<0.05),且在癌组织中其强阳性表达与淋巴结转移和TNM分期有关(P<0.05);P53蛋白在结直肠正常组织、低级别上皮内瘤变组织、高级别上皮内瘤变组织、癌组织中表达分别为0%、6.7%、40.0%、60.0%,高级别上皮内瘤变组织和癌组织中其表达率均与正常组织和低级别上皮内瘤变组织比较差异有统计学意义(P<0.05),其在癌组织中的表达与分化程度、淋巴结转移和TNM分期有关(P<0.05).在癌组织中YB-1和P53的表达呈正相关性(r=0.306,P<0.05).结论:YB-1和P53蛋白在结直肠癌的发生发展、转移中起重要作用,YB-1和P53蛋白的联合检测可能为判断结直肠癌恶性程度和转移提供重要参考.     

XAF1基因与p53基因在结直肠肿瘤中的表达研究

目的观察两个相邻位置的抑癌基因XIAP相关因子1(XAF1)与p53基因在结直肠肿瘤中的表达。方法选取结肠癌细胞株Colo205、Colo320、LoVo、SW1116为体外研究对象,另取41例结直肠癌、28例结直肠腺瘤/息肉以及31例正常人结肠黏膜为体内研究对象。应用逆转录聚合酶链反应检测XAF1mRNA与p53mRNA在体内外的表达,应用免疫组化法检测P53蛋白在结直肠组织中的表达。结果4种细胞株中XAF1表达均较为低下,p53mRNA表达均较高。结直肠肿瘤组织中的XAF1mRNA表达显著低于正常组织(P<0.01),结直肠癌中的表达又显著低于良性肿瘤(P<0.05)。结直肠肿瘤组织中的p53mRNA表达显著高于正常组织(P<0.01),但在良、恶性肿瘤中的表达差异无统计学意义(P<0.05)。P53蛋白在正常组织中未见表达,良、恶性肿瘤组的组织P53蛋白表达之间差异无统计学意义(P>0.05)。结论XAF1基因在结直肠肿瘤中表达降低,且结直肠癌XAF1mRNA表达显著低于良性肿瘤,可作为判断良、恶性肿瘤的鉴别指标。     

PTTG在结直肠癌组织中的表达及意义

目的 探讨垂体瘤转化因子(PTTG)mRNA在结直肠癌发生、发展中的作用.方法 应用RT-PCR法检测PTTG mRNA在44份结直肠癌、12份正常结直肠黏膜、20份结直肠腺瘤组织中的表达.结果 PTTG mRNA在结直肠癌中的表达明显高于直肠腺瘤和正常直肠黏膜组织,结直肠癌Dukes C、D期者表达明显高于Dukes A、B期者,有淋巴结转移者明显高于无淋巴结转移者,P均＜0.05.提示PTTG可能参与了结直肠癌的发生、发展,并对肿瘤转移有促进作用.     

结直肠息肉的临床及病理特征分析180例

目的:了解结直肠息肉的临床资料,探究结直肠息肉的病理特征.方法:选择2014-03/2015-03右江民族医学院附属医院收治的90例腺瘤性结直息肉患者作为研究组,同时选择同一时期的90例非腺瘤性息肉患者作为对比组,分析两组患者病理方面的差别.结果:研究组患者大便带血的发生几率和平均年龄与对比组相比有明显差异,具有统计学意义(P0.05).研究组和对比组在大便性状改变、肛门坠胀、腹泻、腹部疼痛、体质量指数(body mass index,BMI)、性别等方面差异无统计学意义(P0.05).研究组在高级别上皮内瘤变、低级别上皮内瘤变、表面分叶、黏膜表面粗糙糜烂、广基息肉、息肉数量多发、息肉直径≥1 cm等方面均明显多于对比组,差异具有统计学意义(P0.05).结论:年龄较大、大便带血症状是腺瘤性息肉的主要危险因素,而腺瘤性息肉存在体积比较大、数量比较多、表面糜烂、容易出现分叶、高级别上皮内瘤变、低级别上皮内瘤变等病理特征时,可以提示患者具有结肠息肉癌变的可能性.     

老年胆囊切除患者结直肠腺瘤临床特点分析

目的了解老年胆囊切除患者结直肠腺瘤的临床特点,为老年结直肠癌的防治提供参考。方法纳入经肠镜检查发现息肉并行病理学检查提示为结直肠腺瘤的老年患者共1 272例,除外恶性肿瘤、家族性腺瘤性息肉病、炎症性肠病。根据既往有无行胆囊切除手术分为胆囊切除组和对照组,比较两组患者结直肠腺瘤的数量、大小、发生部位、病理类型,并比较胆囊切除时间不同亚组的结直肠腺瘤的特征。结果胆囊切除组女性患者比例明显高于对照组(P0.05);吸烟患者比例明显低于对照组(P0.05);腺瘤个数多于对照组(P0.05);绒毛状腺瘤比例高于对照组(P0.05)。恶变高风险息肉在胆囊切除时间不同的两个亚组中的比例差异无统计学意义(P0.05)。结论尽管与胆囊切除时间长短无关,老年胆囊切除患者结直肠腺瘤具有更高的恶变风险。     

胰岛素瘤的解剖分布特点分析

目的胰岛素瘤是最常见的胰腺神经内分泌肿瘤，因其临床表现多样，导致诊断困难。影像学诊断尤其是超声内镜(EUS)在胰岛素瘤的诊断中起着重要作用，拥有较高的敏感性和特异性。本研究拟通过明确胰岛素瘤的解剖分布特点，以期有助于提高影像学的诊断准确率和降低漏诊率，尤其是在教育和培训实践中对于EUS的学习者更具有指导价值。 方法回顾性分析解放军总医院第一医学中心病案资料数据库1993年1月至2019年11月经外科手术、病理确诊为胰岛素瘤的患者的临床资料，检索方法采取搜索术后病理诊断为"胰岛素瘤"的病例，通过查阅病例的方法，提取出胰岛素瘤的大小和解剖分布等数据，进一步分析其特点。 结果共检索到确诊为胰岛素瘤的患者116例，其中，男45例、女71例，年龄13～76岁，平均年龄(44.4±14.85)岁。胰岛素瘤单发110例(94.8%)、多发6例(5.2%)。位置分布：头颈部46例(39.7%)，单发45例、多发1例；体尾部68例(58.6%)，单发65例、多发3例；全胰腺多发2例(1.7%)。病变大小特点：最大径0.4～3.4 cm，平均大小(1.53±0.58)cm。≤1 cm 29例、>1 cm而≤1.5 cm41例、>1.5 cm而≤2.0 cm28例，≤3 cm 15例，>3 cm 3例。年龄与肿瘤的大小相关，≤44岁患者肿瘤平均大小为(1.36±0.51)cm、>44岁患者肿瘤平均大小为(1.70±0.60)cm，P<0.05。头颈部的肿瘤大于体尾部的肿瘤，头颈部肿瘤平均大小(1.66±0.63)cm，体尾部(1.42±0.52)cm，P<0.05。 结论胰岛素瘤在胰腺体尾部较头颈部更好发；绝大多数单发，但可以全胰腺多发；多数小于1.5 cm，肿瘤的大小与患者年龄和肿瘤的解剖分布相关。     

Pathogenesis of carcinoma of the papilla of Vater

Most adenomas and carcinomas of the small intestine and extrahepatic bile ducts arise in the region of the papilla of Vater. In familial adenomatous polyposis (FAP) it is the main location for carcinomas after proctocolectomy. In many cases symptoms due to stenosis lead to diagnosis at an early tumor stage. In about 80%, curative intended resection is possible. Operability is the most relevant prognostic factor. Most ampullary carcinomas resp. carcinomas of the papilla of Vater develop from adenomatous or flat dysplastic precursor lesions. They can be sited in the ampulloduodenal part of the papilla of Vater, which is lined by intestinal mucosa. They also can develop in deeper parts of the ampulla, which are lined by pancreaticobiliary duct mucosa. Intestinal-type adenocarcinoma and pancreaticobiliary-type adenocarcinoma represent the main histological types of ampullary carcinoma. Furthermore, there exist unusual types and undifferentiated carcinomas. Many carcinomas of intestinal type express the immunohistochemical marker profile of intestinal mucosa (keratin 7?, keratin 20+, MUC2+). Carcinomas of pancreaticobiliary type usually show the immunohistochemical profile of pancreaticobiliary duct mucosa (keratin 7+, keratin 20?, MUC2?). Even poorly differentiated carcinomas, as well as unusual histological types, may conserve the marker profile of the mucosa they developed from. These findings underline the concept of histogenetically different carcinomas of the papilla of Vater which develop either from intestinal- or from pancreaticobiliary-type mucosa of the papilla of Vater. Molecular alterations in ampullary carcinomas are similar to those of colorectal as well as pancreatic carcinomas, although they appear at different frequencies. In future studies, molecular alterations in ampullary carcinomas should be correlated closely with the different histologic tumor types. Consequently, the histologic classification should reflect the histogenesis of ampullary tumors from the two different types of papillary mucosa.     

Demonstration of the mechanism of action of biguanides

Summary Palmitic acid oxidation in rat diaphragm homogenate is depressed by biguanide concentrations that are still incapable of inhibiting oxidative phosphorylation. Glucose oxidation is not directly effected by the same biguanide concentrations: however, the inhibitory effect of palmitic acid on glucose oxidation is partly removed by biguanides. Inhibition of fatty acid oxidation, which accounts for most of the metabolic effects caused by these drugs, can be regarded as the fundamental mechanism of action of biguanides. There is some evidence suggesting that these drugs might interact with carnitine, thus preventing long-chain fatty acids from being transported across the mitochondrial membrane to the site of oxidation. Traduzione a cura degli AA.     

Lack of correlation of degree of villous atrophy with severity of clinical presentation of coeliac disease

BACKGROUND AND AIM: Both the clinical presentation and the degree of mucosal damage in coeliac disease vary greatly. In view of conflicting information as to whether the mode of presentation correlates with the degree of villous atrophy, we reviewed a large cohort of patients with coeliac disease. PATIENTS AND METHODS: We correlated mode of presentation (classical, diarrhoea predominant or atypical/silent) with histology of duodenal biopsies and examined their trends over time. RESULTS: The cohort consisted of 499 adults, mean age 44.1 years, 68% females. The majority had silent coeliac disease (56%) and total villous atrophy (65%). There was no correlation of mode of presentation with the degree of villous atrophy (p=0.25). Sixty-eight percent of females and 58% of males had a severe villous atrophy (p=0.052). There was a significant trend over time for a greater proportion of patients presenting as atypical/silent coeliac disease and having partial villous atrophy, though the majority still had total villous atrophy. CONCLUSIONS: Among our patients the degree of villous atrophy in duodenal biopsies did not correlate with the mode of presentation, indicating that factors other than the degree of villous atrophy must account for diarrhoea in coeliac disease.     

血吸虫童虫生长发育及其机制的研究进展

血吸虫童虫是宿主免疫系统攻击的重要靶标,包括皮肤型、肺型和肝门型童虫。宿主分子对童虫生长发育具有重要作用。童虫生长发育机制包括免疫调节、信号转导、性别发育及凋亡等。肌动蛋白、组织蛋白酶、烯醇化酶和葡萄糖基转移酶等分子为血吸虫童虫生长发育的重要分子。本文对血吸虫童虫生长发育及其机制的研究进展做一综述。     

氯硝柳胺悬浮剂的毒性评价

目的评价氯硝柳胺悬浮剂的毒性，为现场大规模应用灭螺提供依据。方法按照中华人民共和国国家标准GB 15670-1995《农药登记毒理学试验方法》和鱼类毒性试验方法进行。结果经口、经皮肤的LDso雌、雄性大鼠均>5 000 mg/kg，经呼吸道的LCso雌、雄性大鼠均>5 000mg/m3，该药经口、经皮肤、经呼吸道毒性均属微毒类药物；兔眼用药后，观察期内无不良反应，对眼无刺激性；皮肤用药后对皮肤无刺激性。与氯硝柳胺原药、氯硝柳胺乙醇胺盐原药和氯硝柳胺乙醇胺盐可湿性粉剂相比，氯硝柳胺悬浮剂对鱼急性毒性最低。结论氯硝柳胺悬浮剂属微毒类药物，对鱼的毒性低于其乙醇胺盐可湿性粉剂，适合于现场应用。     

124例耐多药结核分枝杆菌基因突变特征分析

目的对临床分离的耐多药结核分枝杆菌相关基因的突变特征进行分析。方法对124例耐多药结核分枝杆菌以及50株敏感株的耐药相关基因(包括异烟肼inh A、kat G、oxyR-ahp C间隔区以及利福平rpo B)进行序列测定,分析其基因突变情况。结果异烟肼耐药inh A基因突变率为14.5%;kat G基因突变率为70.2%(87/124),主要位于315位;oxyR-ahp C间隔区突变率为15.3%;inh A、kat G两种基因同时突变率75.0%,三种基因同时突变率为89.5%。利福平rpo B基因突变的检出率高达95.2%,突变主要发生在531、526、516位点。结论我省耐多药菌异烟肼耐药相关基因最常见突变为kat G 315、inh A C-T(-15)、axyR-ahp C间隔区(-10)C-T,利福平为rpo B531、526、516。结合MDR-TB耐药相关基因的特征分析,可以建立一种快速、准确、特异的适合于我省的检测结核菌耐多药性的新方法。     

Assessment of quality of life of parents of children with juvenile chronic arthritis

The aim of the study was to assess the quality of life (QOL) and the psychological status of parents of children with juvenile chronic arthritis (JCA). The QOL, anxiety and depression of the parents of 28 children with JCA were evaluated and compared to those of the parents of 28 healthy children. Mothers of JCA children and mothers of healthy children reported similar QOL. The reported anxiety and depression levels were similar for mothers and fathers in both groups. The parents of children with pauciarticular-type JCA reported lower QOL and higher levels of anxiety and depression than the parents of children with other types, namely polyarticular and systemic JCA. These findings may be explained by the fact that the pauciarticular patients had shorter disease duration and were less frequently seen in the outpatient clinic. The QOL of mothers of children with JCA was found to be slightly impaired in the group of children with pauciarticular JCA. Future larger studies are needed to confirm these results, as the number of subjects in the three groups was rather low. Received: 26 September 2001 / Accepted: 8 February 2002     

Numerical Simulation of the Effect of Rate of Change of Glucose on Measurement Error of Continuous Glucose Monitors

Background

A 5-day in-patient study designed to assess the accuracy of the FreeStyle Navigator® Continuous Glucose Monitoring System revealed that the level of accuracy of the continuous sensor measurements was dependent on the rate of glucose change. When the absolute rate of change was less than 1 mg•dl⁻¹•min⁻¹ (75% of the time), the median absolute relative difference (ARD) was 8.5%, with 85% of all points falling within the A zone of the Clarke error grid. When the absolute rate of change was greater than 2 mg•dl⁻¹•min⁻¹ (8% of the time), the median ARD was 17.5%, with 59% of all points falling within the Clarke A zone.

Method

Numerical simulations were performed to investigate effects of the rate of change of glucose on sensor measurement error. This approach enabled physiologically relevant distributions of glucose values to be reordered to explore the effect of different glucose rate-of-change distributions on apparent sensor accuracy.

Results

The physiological lag between blood and interstitial fluid glucose levels is sufficient to account for the observed difference in sensor accuracy between periods of stable glucose and periods of rapidly changing glucose.

Conclusions

The role of physiological lag on the apparent decrease in sensor accuracy at high glucose rates of change has implications for clinical study design, regulatory review of continuous glucose sensors, and development of performance standards for this new technology. This work demonstrates the difficulty in comparing accuracy measures between different clinical studies and highlights the need for studies to include both relevant glucose distributions and relevant glucose rate-of-change distributions.     

Study of constancy of hydrogen-consuming flora of human colon

The constancy of the hydrogen consuming flora of the human colon was studied in 15 healthy subjects via two measurements obtained 18 to 36 months apart. Hydrogen disappearance rate and the major products of H₂-consuming bacteria, methane and sulfide, were measured during incubation of fecal homogenates with excess hydrogen and sulfate. In 11/15, the hydrogen consumption rate and the predominant hydrogen-consuming pathway (methanogenesis, sulfate reduction, or neither) remained constant. However, major shifts in these pathways were observed in four subjects, with two losing and two gaining the ability to produce methane. Methanogenesis was associated with the highest hydrogen consumption rate. This study demonstrates that clinically unrecognizable, major alterations of the colonic flora occur in healthy subjects. Understanding of the factors responsible for these alterations might allow for therapeutic manipulation of the colonic flora.Supported in part by the Department of Veterans Affairs and NIDDKD RO1 DK 13309-25.