Hyperhomocysteinemia as a potential contributor of colorectal cancer development in inflammatory bowel diseases: A review

Homocysteine is an amino acid generated metabolically by the S-adenosylmethionine-dependent transmethylation pathway. In addition to being a well-known independent risk factor for coronary heart disease, is also a risk factor for cancer. Patients suffering from inflammatory bowel diseases(IBD) including ulcerative colitis and Crohn’s disease are at increased risk of developing colorectal cancer in comparison to healthy individuals. Furthermore, the risk of hyperhomocysteinaemia is significantly higher in IBD patients when compared with controls. In the present article, we review the mechanisms in which hyperhomocysteinemia may contribute to increased risk of colorectal cancer in IBD patients.     

自发性高血压大鼠一侧颈动脉去外膜后血管内膜增生及阿托伐他汀的干预作用

目的研究自发性高血压大鼠(SHR)一侧颈动脉外膜去除后血管内膜增生及阿托伐他汀的干预作用。方法24只13周龄雄性SHR去除右侧颈动脉外膜后,随机分为3组(每组8只),分别为SHR组、阿托伐他汀组、缬沙坦组;8只同周龄雄性WKY大鼠作为正常血压对照组(WKY组)。机械和化学方法去除大鼠右侧颈动脉外膜,左侧作假手术对照。4周后,放免法测定血浆及双侧颈动脉血管紧张素Ⅱ(AngⅡ)浓度,取双侧颈动脉制成光镜标本,病理图像分析系统测颈动脉管腔横截面积(LA)、内弹力层围绕面积(IELA)、外弹力层围绕面积(EELA),评价内膜和中膜增生程度。RT—PCR法检测颈动脉血管紧张素转换酶2 mRNA(ACE2 mRNA)表达,免疫组化法检测ACE2 mRNA、蛋白激酶C-ζ(PKC-ζ)和胞外信号调节激酶1／2(ERKl／2)蛋白表达。结果(1)与WKY组比较,SHR组双侧血管内膜明显增生(P<0．01),中膜面积显著增大[分别为(0．0240±0．0074)mm2和(0．0160±0．0052)mm2,P<0．05;(0．0250±0．0054)mM2和(0．0190±0．0035)mm2, P<0．01)],去外膜侧内膜增生较外膜完整侧显著(P<0．05);与SHR组比较,阿托伐他汀组内膜增生不显著(P<0．01);(2)与外膜完整侧比较,去外膜侧颈动脉AngⅡ浓度和PKC-ζ、ERK1／2蛋白表达均显著增高(P<0．01),ACE2 mRNA和蛋白表达均明显降低(P<0．01);与SHR组比较,阿托伐他汀组颈动脉AngⅡ浓度及PKC-ζ、ERK1／2蛋白表达显著降低(P<0．01),血浆AngⅡ浓度、ACE2 mRNA和蛋白表达显著升高(P<0．01)。结论SHR去除一侧颈动脉外膜后血管内膜增生明显,中膜面积增大,阿托伐他汀可显著改善这种改变。     

Effect of chronic alcohol consumption on total plasma homocysteine level in rats

BACKGROUND: Chronic alcoholism in humans is associated with the development of hyperhomocysteinemia, the mechanism of which remains unclear. Among the causes of hyperhomocysteinemia is depletion of folate, vitamin B12, or vitamin B6. Population-based studies indicate that folate is the strongest vitamin determinant of hyperhomocysteinemia and, in most settings, folate supplementation effectively lowers elevated homocysteine levels. However, it is not clear whether folate deficiency is the cause of alcohol-related hyperhomocysteinemia. METHODS: In the present study, 10 male Sprague Dawley rats were fed ethanol-containing Lieber-DeCarli diets with 13 mg of folic acid per kilogram of diet. This represents a folate intake more than 20 times the basal requirement. Ethanol represented 36% of total energy, which yielded a concentration of 6.2% (vol/vol). The same number of rats were pair-fed with isocaloric control diets that contained an identical level of folate in which ethanol was entirely replaced by maltodextrin. RESULTS: At the end of 4 weeks, alcohol-fed rats did not show any significant reduction in plasma or hepatic folate concentrations, plasma pyridoxal-5'-phosphate concentration, or plasma vitamin B12 concentration. On the other hand, alcohol-fed rats were significantly hyperhomocysteinemic (17.24 +/- 4.63 micromol/liter,p < 0.01) compared to the nonalcohol group (10.73 +/- 2.76 micromol/liter). Alcohol-fed rats also had a significantly lower hepatic S-adenosylmethionine and higher hepatic S-adenosylhomocysteine levels. CONCLUSIONS: Chronic alcohol consumption produces hyperhomocysteinemia by a mechanism that is related to interference with one-carbon metabolism, and not through vitamin depletion.     

稳定型冠心病合并高同型半胱氨酸血症人群冠脉病变特点分析

目的 研究稳定型冠心病合并高同型半胱氨酸血症(Hcy)人群冠脉病变特点。方法 106例稳定型冠心病依据血浆Hcy水平分为高Hcy组、正常Hcy组。两组性别、年龄、血压、血脂等临床基础情况具可比性,将冠脉造影图像采用直径法分析血管狭窄程度,以血管支数法和Gensis评分评价冠脉病变程度。结果 与正常Hcy组相比,高Hcy组在冠脉病变血管支数和Gensis评分方面均存在差异,表现为高Hcy组冠脉三支血管病变比例增高(34.48% vs 8.33%)、Gensis评分增高(37.82±8.29 vs 30.06±4.94), P< 0.05,差异具有统计学意义。且Hcy水平与冠脉病变血管支数、Gensis评分存在正相关关系(P< 0.05)。结论 在稳定型冠心病患者,高血浆Hcy可进一步影响冠脉病变的范围和严重程度。     

Astragaloside IV attenuates carotid intimal hyperplasia by suppressing the basic fibroblast growth factor expression in rats

Bacground Percutaneous coronary intervention(PCI) has become one of the most effective treatments in coronary heart disease(CHD).However,the bottleneck problem of PCI is the in-stent restenosis(ISR).The aim of this study was to explore the effects of astragaloside IV(AST IV) on suppression of intimal hyperplasia modulation of the expression of basic fibroblast growth factor(b-FGF) in a rat carotid artery balloon injury model.Methods Fifty healthy male Sprague-Dawley(SD)rats were randomly divided into five groups:a sham-operation group(sham),a model group(model),and three astragaloside IV-treated groups.Three days before the surgery,1% carboxy methyl cellulose(CMC) or AST IV(20,40 or 60 mg·kg~(- 1)·d~(- 1)) was intragastrically administered into sham or 3 astragaloside-treated groups once a day for 17 days.Hematoxylin-elsin staining was carried out to determine the pathomorphological changes and the neointimal and media area ratio.Immunohistochemistry staining was performed to measure the expressions of proliferating cell nuclear antigen(PCNA)and basic fibrolast growth factor(b-FGF).PCNA and b-FGF were analyzed with Iamage-Pro Plus.Results(1) The carotid artery intimal hyperplasia in the rats of model was similar to lumen stenosis.Compared with the sham operation group,the area of the new intima and the ratio of the intima to media(I/M) were increased and the lumen area was decreased(P 0.01) in the model group.Astragaloside IV increased the lumen intimal dimension and decreased the area of new intima and the ratio of intima to media in a dose-dependent manner.(2) Compared with the sham-operation group,the expressions of PCNA and b-FGF in carotid artery of model group were significantly increased(P 0.01).AST IV decreased expressions of PCNA and b-FGF in the carotid artery of rats in a dosedependent manner.Conclusion Astragaloside IV significantly inhibits neointimal hyperplasia of rat carotid artery through down-regulating the expressions of PCNA and b-FGF.     

Hemodynamics and the development of anastomotic intimal hyperplasia of the polytetrafluoroethylene graft in dogs.

To clarify whether or not changes in wall shear stress play a determinant role in the induction of anastomotic intimal hyperplasia of polytetrafluoroethylene (PTFE) grafts, two experimental models were devised. Based on our previous study (J Vasc Surg, 1985), wall shear stress was defined by variation of wall shear stress (tau-variation) in one cardiac cycle. In experiment I, PTFE grafts were implanted into dogs under conditions of 85.2 +/- 36.2 ml/min of low flow rate with 66.7 +/- 31.1 dyne/cm2 of low tau-variation. In experiment II PTFE grafts were implanted under conditions of 10.1 +/- 4.6 ml/min of low flow rate with 120.4 +/- 37.2 dyne/cm2 of moderate tau-variation. The intimal thickness of 581 +/- 127 microns at one month and 1230 +/- 260 microns at three months implantation at the distal anastomosis under an abnormal flow condition in experiment I was statistically significant compared with findings in the case of 124 +/- 36 microns at 1 month and 171 +/- 74 microns at 3 months at the proximal anastomosis under an abnormal flow condition in experiment I, and with those of 164 +/- 68 microns at 1 month and 195 +/- 57 microns at three months at the distal anastomosis in experiment II (p less than 0.01). Under a normal flow condition, there was no evident intimal hyperplasia at proximal and distal anastomotic sites in experiment I. These observations are pertinent evidence that change in wall shear stress and not the rate of blood flow is the determinant factor related to development of intimal hyperplasia of PTFE grafts at the distal anastomosis.     

高同型半胱氨酸血症对血管损伤后新生内膜形成的作用及机制

目的研究饮食诱导的高同型半胱氨酸血症(Hcy)对血管损伤后新生内膜形成的作用及机制。方法采用1g(kg·d)L蛋氨酸灌胃制备Hcy大鼠模型。4周后行左颈动脉拉伤,第14天、第28天取材,检测新生内膜的形成、内皮覆盖和平滑肌细胞增殖情况。结果第14天、第28天高蛋氨酸饮食(HHCY)组比对照组新生内膜增生厚度分别增加36%和33%,新生内膜面积分别增加41%和30%,新生内膜面积与中膜面积之比分别增加36%和21%,管腔面积分别减少47%和61%,中膜面积无明显差别。第14天HHCY组内膜、中膜增殖细胞核抗体阳性颗粒百分比是对照组的1.7倍和2.3倍。第14天、第28天HHCY组血管内皮覆盖率比对照组减少52%和31%。结论高同型半胱氨酸血症促使血管损伤后新生内膜形成,促进平滑肌细胞增殖和抑制内皮修复是其致病机制,提示高同型半胱氨酸血症可能是血管成形术后再狭窄发生的重要的危险因素之一。     

中国农村地区血红蛋白与高同型半胱氨酸 血症相关性的横断面研究

目的 本研究旨在检查中国农村地区一般人群中血红蛋白（Hb）是否与高同型半胱氨酸血症（Hhcy）显著相关。方法 2012年1月至2013年8月在中国辽宁省农村地区采用多阶段、分层、随机集群抽样方案抽取具有代表性的≥35岁的个体样本,共纳入7141名参与者,收集参与者的一般资料,所有参与者禁食至少12小时后采集血样,并检测血红蛋白、血浆同型半胱氨酸等指标。Hhcy定义为血浆同型半胱氨酸≥15um/L。根据Hhcy的定义,将参与者分为Hhcy组（4208人）与非Hhcy组（2933人）。结果 多元线性回归分析显示Hb（0.120,P<0.001）和血小板分布宽度（PDW）（-0.089,P=0.012）与hhcy呈显著线性相关,而非血小板（PLT）（0.000,P=0.915）。但经过年龄、性别、教育程度、体育锻炼、吸烟、饮酒、睡眠时间、体重指数、舒张压、收缩压、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇、总胆固醇、三酰甘油和空腹血糖的调整后,发现血小板（PLT）（0.005,P=0.022）与hhcy具有显著的线性相关性,而不是Hb（0.010,P=0.311）和PDW（-0.001,P=0.988）。在对所有混杂因素进行调整之后,多元回归分析显示Hb（OR=1.007,95％CI：1.003-1.012; p=0.001）与hhcy显着相关,而不是PDW（OR=1.003,95％CI：0.989-1.017; p=0.676）和血小板（PLT）（OR=1.001,95％CI：1.000-1.002; p=0.141）。结论 Hb与中国农村地区的hhcy密切相关,而不是PDW和血小板（PLT）。     

A matrix metalloproteinase inhibitor, ONO-4817, suppresses the development of aortic intimal hyperplasia in experimental hyperlipidemic rabbit

Inhibition of matrix metalloproteinases (MMPs) would be expected to suppress atherosclerotic neointimal proliferation and thus limit atheromatous plaque progression, but this has not yet been demonstrated morphologically in atherosclerotic intimal hyperplasia induced by cholesterol loading in experimental animals. We therefore investigated whether a broad-spectrum MMP inhibitor (MMPi), ONO-4817, could inhibit the development of intimal hyperplasia in male hyperlipidemic rabbits (n = 6) fed laboratory chow supplemented with 1% cholesterol for 2 months followed by a 1% cholesterol diet plus 100 mg/kg ONO-4817 for another month (Chol + ONO group). Control animals (n = 6) received no ONO-4817. When the aortas were studied both histologically and immunohistochemically, intimal hyperplasia was inhibited in Chol + ONO rabbits. The distribution of macrophages and MMP-12 in the hyperplastic tissue of the Chol + ONO rabbits was limited to the luminal side of the lesions. No such limitation in the distribution of macrophages and MMP-12 was observed in the control group. The distribution of smooth muscle cells in the hyperplastic tissue was not different between the Chol + ONO and control groups. However, the distribution of MMP-2 and MMP-12 was limited to the luminal side of lesions in the Chol + ONO group. This is the first reported evidence that an MMPi can suppress the development of intimal hyperplasia in hyperlipidemic rabbits.     

高血压患者颈动脉粥样硬化病变与脑梗死关系的初步探讨

目的 初步探讨高血压及高血压伴糖尿病（DM）患者颈动脉病变与脑梗死的关系。方法 应用彩色多谱勒显像仪对48例非老年高血压患者、79例老年血压患者、37例老年高血压伴DM患者进行颈动脉检测,观察颈动脉病变与脑梗死及血脂、血凝的关系。结果 老年高血压组颈动脉斑块的检出率（63．3％）显著高于非老年高血压组（22．9％,P＜0．01）,老年高血压伴DM组与老年高血压组比较差异无显著性。老年高血压组中,颈动脉内膜增厚组脑梗死发生率（66．7％）较颈动脉正常组（25．0％）增高（P＜0．05）,与斑块组（36．0％）比较差异无显著性;老年高血压伴DM组中内膜增（66．7％）及斑块组（46．4％）脑梗死发生率均较颈动脉正常组（0．0％）高（P＜0．05）。老年高血压组及老年高血压伴DM组高血压病史与颈动脉病变呈正相关,血脂及纤维蛋白原（FIB）与颈动脉斑块呈正相关。结论 颈动脉超声对脑梗死的预测有一定的实用参考价值,应积极控制脑梗死的危险因素。     

Changes in basic fibroblast growth factor coincident with estradiol-induced hyperplasia of the anterior pituitaries of Fischer 344 and Sprague-Dawley rats

Adult female Fischer 344 (F344) and Sprague-Dawley (SD) rats were treated with estradiol via Silastic implants for 10 and 20 days. This treatment period in F344 rats is sufficient to produce dramatic hyperplasia of anterior pituitary lactotropes, activation of folliculo-stellate cells (FS) as phagocytes, and reorganization of the blood supply, i.e. hemorrhagic lakes and arteriogenesis from vessels in the adjacent meninges. Estradiol-treated SD rats do not demonstrate a comparable response. We now report intense focal concentrations of cells immunopositive for basic fibroblast growth factor (FGF) in estradiol-treated F344 rats predominantly near the posterolateral edge of the anterior pituitary, a zone rich in gonadotropes and lactotropes. Immunostaining for FGF, by both light and electron microscopy, revealed that the immunopositive cells were gonadotropes, and that the immunoprecipitate was cytosolic and was most abundant in the cytosol facing the capillaries. Immunostaining for extracellular matrix-associated FGF also revealed foci of positivity at the postero-lateral edge. Estradiol-treated SD rats did not reveal comparable localization for FGF. Morphological analysis and immunolocalization of S-100 protein, a marker for FS cells, revealed that the periphery of the anterior pituitary of estradiol-treated F344 rats included numerous disrupted gonadotropes and, furthermore, was largely devoid of FS cells. This zone was more intact in control F344 rats, but lacked FS cells. The peripheral parenchyma of control and estradiol-treated SD rats was intact compared to that of F344 rats and consistently included FS cells. These results suggest that disruptions of gonadotropes at the pituitary periphery may release FGF, which could then stimulate angiogenesis from blood vessels within the adjacent meninges. The resultant systemic blood supply would stimulate lactotrope hypertrophy and hyperplasia. Since FS cells are known phagocytes within the anterior pituitary, their absence from the periphery of F344 rats may intensify or prolong the effect of the peripherally released FGF.     

泛素及大鼠蛋白酶体第三亚基在大鼠颈总动脉球囊损伤后的表达

目的 研究泛素(ubiquitin)、大鼠蛋白酶体第三亚基(rat component 3 of proteasome,Re3)在大鼠颈总动脉球囊损伤后的动态表达及在内膜增生中的作用.方法 雄性SD大鼠56只,随机分为假手术组(8只)、单纯球囊损伤组(48只,包括1、4、7、14、21、28 d组),建立大鼠颈总动脉球囊损伤模型,苏木素-伊红(HE)染色光镜下观察血管内膜增生情况;应用逆转录聚合酶链反应(RTPCR)观察泛紊、RC3 mRNA表达情况,免疫组化方法 观察泛素蛋白表达情况.结果 球囊损伤后血管内膜增生明显,第28天内膜与中膜(Intima/Media,I/M)厚度比值最高[(2.31 ±0.43)比对照组(0.02±0.005),P＜0.01];泛素、RC3 mRNA表达升高,泛紊第7天达高峰[(1.33±0.26)比对照组(0.21±0.04),P＜0.01],RC3第14天达高峰[(1.35±0.26)比对照组0.31 ±0.06,P＜0.01];球囊损伤后泛素蛋白表达升高,第14天达高峰[(21.53±4.09)比对照组(4.21±0.78),P＜0.01].相关分析显示泛素蛋白表达与血管内膜增生呈正相关(r=0.827,P＜0.05).结论 大鼠颈总动脉球囊损伤后内膜增生明显,泛素、RC3 mRNA及泛素蛋白表达增高,球囊损伤后泛素蛋白表达与血管内膜增生呈正相关.     

Prevention of focal intimal hyperplasia in rat vein grafts by using a tissue engineering approach

The present study focused on the role of blood flow in the formation of focal intimal hyperplasia in vein grafts, as well as the development of an engineering approach that can be used to eliminate disturbed blood flow and prevent blood flow-related focal intimal hyperplasia. A rat vein graft model was constructed by interposing a jugular vein into the abdominal aorta with end-to-end anastomoses. Locally disturbed flow was identified by analyzing particle streak-lines in methyl salicylate-cleared and perfused vein grafts in vitro with a physiological Reynolds number. At day 10, 20, and 30 after surgery, focal intimal hyperplasia of the vein grafts was examined using a histological approach and the density of -actin positive cells was determined using immunohistological and fluorescent approaches. Results showed that apparent eddy blood flow formed at the proximal, but not at the distal, end of the vein grafts due to graft-host diameter mismatch and local geometric distortions, and was associated with apparent focal intimal hyperplasia. The thickness of the -actin positive layers of the proximal vein grafts was significantly higher than that of the distal grafts (192±27 vs. 94±18 μm, 278±55 vs. 124±20 μm, and 288±24 vs. 131 ±23 μm for day 10, 20, and 30, respectively). The density of the -actin positive cells, however, was similar between the proximal and the distal regions (3569±361 vs. 3285±343 cells/mm², 5540±650 vs. 5376±887 cells/mm², and 5465±791 vs. 5278±524 cells/mm² for day 10, 20, and 30, respectively). When eddy blood flow was eliminated by matching the graft-host diameters using a tissue engineering approach, the average thickness of the -actin positive layers of the proximal (71±15, 86±16, and 85±14 μm for day 10, 20, and 30, respectively) and the distal vein grafts (68±13, 80±14, and 79±13 μm for day 10, 20, and 30, respectively) was reduced significantly. The density of the -actin positive cells was also reduced significantly in the proximal (2946±359, 3261±295, 3472±599 cells/mm² for day 10, 20, and 30, respectively) and in the distal regions (3151±511, 3466±687, 3593±688 cells/mm² for day 10, 20, and 30, respectively). The thickness of the -actin positive layers and the density of the -actin positive cells were not significantly different between the proximal and distal regions of the engineered vein grafts at each observation time. These results suggest that eddy flow may develop in vein grafts and may facilitate the formation of focal intimal hyperplasia, and the vascular tissue engineering approach developed in this study may be used to prevent blood flow-related focal intimal hyperplasia in vein grafts.     

Sulfur-containing amino acids attenuate the development of liver fibrosis in rats through down-regulation of stellate cell activation

BACKGROUND/AIMS: We tested the pharmacological action of sulfur-containing amino acids on the development of liver fibrosis in rats and on the function of cultured stellate cells. METHODS: Liver fibrosis was induced in rats by thioacetamide administration or by ligating the common bile duct. DNA synthesis of cultured stellate cells was evaluated by BrdU incorporation. The expression of proteins and phospho-proteins was determined by western blot analysis. mRNA expression was evaluated by RT-PCR. RESULTS: Oral administration of l-cysteine or l-methionine attenuated the deposition of collagen in liver tissues in the two fibrotic models, accompanying a reduction in the expression of smooth muscle alpha-actin and platelet-derived growth factor receptor beta and mRNAs of collagens, transforming growth factor-betas and tissue inhibitors of matrix metalloproteinase. In cultured stellate cells, l-cysteine and l-methionine suppressed the DNA synthesis and the expression of growth factor receptors, smooth muscle alpha-actin and type I collagen. They hampered the phosphorylation of p44/42 MAPK and Akt under platelet-derived growth factor-BB stimulation. Stellate cells were found to express methionine adenosyltransferase 2A. CONCLUSIONS: l-Cysteine and l-methionine regulate the activation of stellate cells. Their oral supply aids the suppression of the progression of liver fibrosis.     

Intravascular ultrasonic comparative analysis of degree of intimal hyperplasia produced by four different stents in the coronary arteries

Intravascular ultrasound studies were performed at angiographic follow-up on 121 native coronary lesions treated with 1 bare metal stent (n = 50), high-dose dexamethasone-eluting stents (n = 18), non-polymer-based paclitaxel-eluting stents (n = 18), or sirolimus-eluting stents (n = 35). Paclitaxel- and sirolimus-eluting stents reduced mean intimal hyperplasia thickness compared with bare metal stents by 49% and 90% (p = 0.048 and p <0.001), respectively, whereas mean intimal hyperplasia thickness treated with dexamethasone-eluting stents was similar to those lesions treated with bare metal stents.     

p38MAPK抑制剂CBS3830对糖尿病大鼠自体静脉移植内膜增生的影响及机制探讨

目的观察p38MAPK抑制剂CBS3830对糖尿病大鼠自体移植静脉内膜增生的影响,并探讨机制。方法 SD雄性大鼠30只,采用腹腔注射链脲佐菌素法建立糖尿病动物模型;将造模成功的26只随机分为两组,采用改良cuff法建立自体静脉移植模型,造模前1 h药物组经胃管灌入0.3 mg/ml的CBS3830 10 ml/kg,对照组同法给予等体积的CBS3830溶媒1%甲基纤维素。分别于术前及术后1、3、7 d采用ELSIA法检测大鼠血清TNF-α;于第7天处死动物并获取移植静脉标本,HE染色观察大鼠移植静脉内膜及中膜厚度。结果术后7 d,药物组大鼠血清TNF-α水平显著低于对照组（P〈0.05）,药物组内膜增生程度明显低于对照组。药物组内膜厚度为（33.6±1.34）μm、内膜厚度/中膜厚度为1.23±0.08,对照组分别为（38.5±1.50）μm、1.7±0.12,两组相比,P均〈0.05。结论 p38MAPK抑制剂CBS3830对糖尿病大鼠自体移植静脉内膜的增生有抑制作用,可能与其降低血清TNF-α水平有关。     

Enhanced tumorigenicity of insulinoma by X-irradiation of the gastric regions in Sprague-Dawley male rats

BACKGROUND AND AIMS: There has been no suitable animal model for human insulinoma because incidence of pancreatic tumours induced by whole-body irradiation or chemicals has been very low. The purpose of this study was to establish an experimental model with a high incidence of insulinoma. The induction of islet cell tumour by X-irradiation was investigated. METHODS: Forty Sprague-Dawley male rats were used in this study. Twenty-eight rats were irradiated with two 10-Gy doses to the gastric region at a 3-day interval, and 12 rats not subjected to X-irradiation served as a control group. The rats were killed 16 months after the first irradiation. Expression of insulin mRNA and protein was examined by northern blot analysis and immunohistochemistry, respectively. Rat serum insulin and glucose levels were measured using enzyme-linked immunosorbent assay. RESULTS: Tumour incidence was 89.3% (25/28) in X-ray group and 8.3% (1/12) in the control group (P < 0.05). Pancreatic tumours, which appeared in all 25 rats with tumours, showed the highest incidence of all neoplasms detected. Tumour cells showed strong immunoreactivity for insulin in 20 of 25 pancreatic tumours (80%). Expression of insulin mRNA was confirmed by northern blot analysis. Furthermore, rats with pancreatic tumours had lower serum glucose levels and higher insulin levels than the control rats. CONCLUSION: X-irradiated SD rats may be considered a suitable model for insulinoma because of their high tumorigenicity.     

Influence of inflation pressure and balloon size on the development of intimal hyperplasia after balloon angioplasty. A study in the atherosclerotic rabbit

To evaluate the effect of balloon size and inflation pressure on acute and subsequent outcome following balloon angioplasty (BA), 70 New Zealand White rabbits with bilateral femoral atherosclerosis were assigned to four groups: group 1, oversized balloon, low inflation pressure (n = 35 vessels; balloon size, 3.0 mm/inflation pressure, 5 atm); group 2, oversized balloon, high inflation pressure (n = 36; 3.0 mm/10 atm); group 3, appropriate size, low inflation pressure (n = 17; 2.5 mm/5 atm); and group 4, appropriate size balloon, high inflation pressure (n = 19; 2.5 mm/10 atm). Angiograms were obtained before, 10 minutes after, and 28 days after BA and read by two blinded observers using electronic calipers. The in vivo balloon-to-vessel ratio was measured for each group. There were eight non-BA controls. Rabbits were sacrificed either immediately (n = 34) or at 28 days after BA (n = 36), with the femoral vessels pressure perfused for histologic and morphometric analysis. The latter was performed at 28 days only. Absolute angiographic diameters increased in all groups immediately after BA (p less than 0.01). Acute angiographic success, defined as greater than 20% increase in luminal diameter, was higher using high inflation pressure (group 2, 32/36 [89%] and group 4, 16/19 [84%] vs. group 1, 23/35 [66%] and group 3, 9/17 [53%]; p less than 0.05). A 3.0-mm balloon resulted in significant oversizing irrespective of inflation pressure (balloon-to-vessel ratio, 1.5 +/- 0.1 vs. 1.1 +/- 0.1 to 1, for the 2.5-mm balloon). Vessels exposed to high inflation pressure had a significantly higher incidence of mural thrombus, dissection (p less than 0.01), and medial necrosis versus low pressure (p less than 0.05). At 28 days, the rates of restenosis (defined as greater than 50% loss of initial gain) were 14/20 (70%), 11/16 (69%), 5/10 (50%), and 5/10 (50%) for groups 1 through 4 (p = NS; a trend in favor of the groups using an oversized balloon). There was an increase in the degree of intimal hyperplasia by morphometric analysis in all groups, being most marked in group 2 (oversized balloon and high inflation pressure, 1.7 +/- 0.9 vs. 0.5 +/- 0.2 mm for controls, p less than 0.001). We reached two conclusions. First, all protocols resulted in a significant increase in luminal diameter immediately after angioplasty with the highest success rate in vessels subjected to high pressure dilatation.(ABSTRACT TRUNCATED AT 400 WORDS)     

Induction of malignant tumors in Wistar and Sprague-Dawley rats by single doses of n-butyl-nitrosourea in perinatal and juvenile phases of development

n-butyl-nitrosourea (BNU), which is highly leukemogenic in adult rats and in young mice, was applied in a single dose of 120 mg/kg body weight to pregnant Wistar rats on day 22 post conceptionem (p.c.). In another group the same dose was injected directly to fetuses of Wistar rats on day 22 p.c. after surgical delivery with subsequent feeding by nurses. The same single dose was given to 1 and 2 days old Wistar rats as well as to 10 and 30 days old Sprague-Dawley rats. In about 50% of the progeny tumors (predominantly neurogenic) developed both after diaplacental and after direct application of the substance on day 22 p.c. After neonatal application, almost exclusively neurogenic tumors were found in greater than 85% of the treated juvenile animals. Comparison of survival time and tumor rates between the rats treated diaplacentally or directly on day 22 p.c. and the rats treated neonatally revealed significant differences. This shows that the nervous tissue of the rat is less sensitive to BNU prenatally than in the neonatal phase of development. After application of BNU on day 10 post partum (p.p.) in Sprague-Dawley rats greater than 95% of the animals developed almost exclusively neurogenic tumors with a high percentage of brain tumors. After a single dose on day 30 p.p. a significant increase in survival time and a significant decrease in the total tumor yield is observed in comparison to the animals treated on day 10. Additionally a decrease in the rate of neurogenic tumors is accompanied by an increase of tumors outside the nervous system. Aftertreatment with single doses of BNU perinatally and on day 10 p.p. only 2 rats out of 154 animals were found to have leukemia. After application of BNU to 30 days old rats, leukemia was diagnosed in 7 out of 40 animals.     

Inhibition of proteinuria development in aging Sprague-Dawley rats and C57BL/6 mice by long-term treatment with dehydroepiandrosterone

Dehydroepiandrosterone (DHEA) is an adrenal steroid that previously has been shown to produce antiobesity, antidiabetic, cancer preventive, and antiautoimmune effects in laboratory rodents. DHEA, when administered in the diet to male Sprague-Dawley rats beginning at 2 months of age, inhibited the development of proteinuria at 19 months. The nontreated rats excreted 6.5 times as much urinary protein as the group treated with DHEA. Part of the effect of DHEA is apparently a result of reduced food intake in the treated rats (14% reduction), but this alone could not account for its action as a pair-fed group excreted significantly more urinary protein than the DHEA treated rats (2.3 times as much). A similar inhibition of proteinuria in 17-month-old male C57BL/6 mice was produced by DHEA treatment initiated at 10 months of age (5.8 times as much urinary protein excreted by non-DHEA treated mice). DHEA treatment reduced food intake by 11% in the C57BL/6 mice. This reduction in food intake had no apparent effect on proteinuria since a pair-fed group was found to excrete 6.5 times the amount of urinary protein as the DHEA-treated mice.