高血压合并糖尿病大鼠心肌毛细血管内皮细胞超微结构及eNOS的变化

目的:探讨高血压合并糖尿病(DM)对心肌毛细血管内皮细胞超微结构及内皮型一氧化氮合酶(eNOS)表达的影响。方法:自发性高血压大鼠(SHR)及SD大鼠腹腔注射链脲佐菌素(STZ)结合高能量饲料诱导DM模型。分为4组:正常SD大鼠组(SD组)、SHR组、单纯DM组(DM组)与自发性高血压合并DM大鼠组(SHDM组)。电镜观察各组心肌毛细血管内皮细胞超微结构,免疫组化法测定各组eNOS在毛细血管内皮细胞的表达。结果:SHR、DM和SHDM组心肌毛细血管超微结构明显改变,包括内皮细胞水肿,细胞膜向管腔内呈指状突起,管腔狭窄、不规则等,这些现象在DM组与SHDM组更明显。与SD组比较,SHR组基底膜稍有增厚,但无显著性差异(31.31±4.19nmvs28.64±3.62nm,P>0.05),而DM组(46.58±5.32nm)和SHDM(51.50±4.62nm)组基底膜显著增厚(与SD及SHR组比较,均P<0.01)。SHDM组心肌组织eNOS表达显著低于SHR组及DM组。结论:高血压与DM共存时对心肌毛细血管内皮细胞超微结构及功能有协同损害作用。     

氯沙坦对自发性高血压大鼠左心室肥厚和转化生长因子β_1的影响

目的 :探讨转化生长因子 β1 (TGFβ1 )在自发性高血压大鼠(SHR)左心室肥厚中的作用及氯沙坦对左心室肥厚和TGFβ1 水平的影响。方法 :2 0只SHR随机分成氯沙坦治疗组和未治疗组 ,每组10只 ,用免疫组织化学法检测SHR心肌TGFβ1 的表达及氯沙坦治疗后的改变 ,同时观察心肌肥厚的变化 ,并与正常WKY组对照。结果 :正常组心肌细胞胞浆内TGFβ1 表达呈弱阳性 ,SHR对照组呈强阳性 ,氯沙坦治疗组呈阳性反应。用图像分析仪计算其平均吸光度分别为 17.46± 2 .3 8、15 6.81± 2 1.75、67.19± 7.2 4,并且SHR左心室质量指数 (LVWI)高于WKY组 ,氯沙坦治疗组LVWI低于对照组。结论 :TGFβ1 在自发性高血压大鼠心肌中表达增强 ,而氯沙坦治疗可抑制其表达 ,从而可能延缓SHR左心室肥厚的病理学进展。     

Neuregulin-1在糖尿病大鼠心肌组织中的表达变化

目的: 探讨neuregulin-1(NRG-1)在糖尿病大鼠心肌组织中的表达。方法: 45只雄性SD大鼠随机分为4周、8周和12周糖尿病组(4th、8th 和12th DM组),4周、8周和12周对照组(4th 、8th 和12th C组)。腹腔注射链脲佐菌素诱导糖尿病模型。在诱导糖尿病后第4、8和12周用超声诊断仪评估大鼠心功能,计算心肌胶原容积分数(CVF),免疫组化观察NRG-1在心肌的表达部位,RT-PCR和Western blotting检测NRG-1 mRNA及蛋白的表达水平。结果: 4th DM组大鼠心功能指标、心肌CVF、NRG-1 mRNA及蛋白的表达与4thC组相比,差异无统计学意义(P>0.05);与8th C组相比,8th DM组左室收缩末内径(LVESD)和心肌CVF均增高,但左室短轴缩短率(LVFS)、左室射血分数(LVEF)、心肌NRG-1 mRNA及蛋白的表达仍未见明显改变(P>0.05)。与12th C组比较,12th DM组LVESD和心肌CVF均显著增高,而LVFS和LVEF显著降低(均P<0.01)。12th DM组心肌NRG-1 mRNA及蛋白的表达较同期对照组显著下调(0.073±0.008 vs 0.156±0.010,0.171±0.054 vs 0.324±0.039,均P<0.01)。结论: NRG-1在糖尿病大鼠心肌组织中的表达显著下调,这可能参与了糖尿病心肌病的发生和发展。     

盐酸莫索尼定对自发性高血压大鼠左室肥厚的影响

目的:研究国产盐酸莫索尼定对自发性高血压大鼠左室肥厚时心肌纤维化和冠状动脉微血管结构的影响。方法:20周龄的雄性自发性高血压大鼠30只随机分为①Mox+SHR组;②Cap+SHR组;③SHR组, 每组10只。另设性别周龄相配的SD大鼠10只为正常对照组(NC组)。观察13周后处死动物, 获取心脏。测量左心室重/体重, 左室胶原分数, 标准化血管周胶原面积和肌间动脉中膜厚度的变化。结果:Mox+SHR组不仅左心室重/体重明显低于SHR组, 而且左室胶原分数低于SHR组(0.086±0.018vs0.046±0.015, P＜0.01), 血管外膜胶原少于SHR组(0.69±0.11vs1.34±0.29, P＜0.01), 中膜薄于SHR组。结论:盐酸莫索尼定长期抗高血压治疗能够减轻左室肥厚时的心肌纤维化和改善受损的冠脉微血管结构。     

阿托伐他汀对自发性高血压大鼠心肌组织PPARs表达的影响

目的： 探讨阿托伐他汀对自发性高血压大鼠心肌组织PPARs（peroxisome proliferator-activated receptors, PPARs）表达的影响及其对心肌肥厚的逆转作用与可能机制。方法: 自发性高血压大鼠分为阿托伐他汀灌胃治疗组（SHR-A，30 mg·kg-1·d-1）及模型组（SHR），治疗8周，同周龄Wistar-Kyoto 鼠为正常血压对照组。治疗前及治疗后2、4、8周测量大鼠尾动脉血压。治疗后测血浆血脂水平，以心脏组织病理分析判断心肌肥厚，Western blotting 检测心肌组织PPARα、PPARγ的表达水平。结果: 经过8周治疗， SHR-A组及SHR组血压及血脂水平无明显差异（P＞0.05）。SHR-A组左室重量指数低于SHR组（P＜0.01）。在SHR-A组，PPARα及PPARγ表达高于SHR组（P＜0.01）。结论: 阿托伐他汀显著改善自发性高血压大鼠心肌组织PPARs表达，有效逆转左室肥厚，可能与其降压及降脂作用无关。     

伴有高血压的糖尿病大鼠主动脉的结构重建

目的 :观察伴有高血压的糖尿病 (SHRDM)主动脉结构重建的规律 ,并探讨高血糖、高血压对其影响。方法 :STZ诱导SHR大鼠建立SHRDM实验动物模型 ,。观测主动脉血管壁中膜结构成分的改变。结果 :SDDM(有高血压的糖尿病 )大鼠自 4周始主动脉中膜平滑肌相对含量和核密度、胶原纤维相对含量均大于SD组 ,弹性纤维相对含量少于SD组。SHRDM组主动脉平滑肌相对面积、C/E值大于SD和SHR组 ,但SMC核数少于SDDM ,多于SHR。结论 :糖尿病早期已出现主动脉结构重建 ,以平滑肌增生为主 ;高血压使平滑肌细胞肥大为主 ,因而SHRDM增生、肥大共存。高血压、高血糖均显著影响主动脉结构重建 ,高血压影响大于高血糖。     

自发性高血压大鼠第三脑室触液神经元内一氧化氮合酶与加压素的共表达

目的:观察自发性高血压大鼠(SHR)与SD大鼠第三脑室触液神经元(CSFCN)内一氧化氮合酶(NOS)与加压素(VP)的分布和共存。方法:应用还原型尼克酰胺嘌呤二核苷酸磷酸脱氢酶(NADPH-d)组织化学方法,结合ABC免疫组织化学技术。结果:在SHR视前区至室间核后大细胞亚核平面的第三脑室室壁均有NOS阳性CSFCN的分布;在SHR第三脑室室壁的CSFCN内NOS与VP具有共存性,且SHR组第三脑室的CSFCN内NOS与VP共存率较SD组高。结论:一氧化氮(NO)与VP在下丘脑的血压神经内分泌活动调节中起着重要的介导作用,也可能对高血压的发生发展有影响。     

依那普利对自发性高血压大鼠心肌ACE和ACE2表达的影响

 目的 观察自发性高血压大鼠(spontaneously hypertensive rats, SHR)心肌的血管紧张素转换酶(angiotensin-converting enzyme, ACE)和ACE2的表达,以及依那普利干预的影响。方法 将15只SHR随机分为2组：SHR对照组(n=7)和依那普利组(n=8),分别给以安慰剂、依那普利15mg.kg-1.d-1灌胃干预4周。干预结束后处死大鼠,分离左心室,行RT-PCR、western blot蛋白质免疫印迹检测。同步取10只WKY大鼠作为正常血压对照组。结果SHR心肌的ACE的mRNA和蛋白质的表达都显著高于)WKY组(1.68±0.34 vs 0.33±0.12, P＜0.05;1.21±0.14 vs 0.71±0.11, P＜0.05),而ACE2 的mRNA和蛋白质表达皆明显低于WKY组(0.50±0.15 vs 1.16±0.24, P＜0.05; 0.71±0.24 vs 1.22±0.14, P＜0.05)。依那普利明显降低ACE的mRNA和蛋白质表达(0.44±0.19 vs 1.68±0.34, P＜0.01; 0.87±0.13 vs 1.21±0.14, P＜0.05),提升ACE2的mRNA表达(1.77±0.49 vs 0.50±0.15, P＜0.05),对ACE2的蛋白表达无明显影响(0.42±0.22 vs 0.71±0.24, P＞0.05)。结论 SHR心肌ACE明显升高,ACE2显著降低,有利于血压上调。依那普利能降低ACE,提升ACE2,可能是血管紧张素转换酶抑制剂(angiotensin-converting enzyme inhibitors, ACEI)的降压机制之一。     

苯那普利对高血压大鼠细胞外信号调节激酶和B型钠尿肽的影响

目的：研究苯那普利对自发性高血压大鼠（SHR）细胞外信号调节激酶（ERK）和B型钠尿肽（BNP）的影响。方法：选择Wistar Kyoto（WKY）大鼠作对照，将21只14周龄雄性SHR随机分成3组：未治疗组、肼苯哒嗪组和苯那普利组，每组7只。药物溶于载体（0.5%羧甲基纤维素钠）以灌胃法给予，肼苯哒嗪10 mg·kg-1·d-1，苯那普利10 mg·kg-1·d-1，SHR未治疗组及WKY组灌喂载体，共10周。以左心室重量与体重的比值反映心肌肥厚的程度；用袖带式尾动脉测压法测量大鼠尾动脉血压；分别用Western blotting方法和RT-PCR法半定量测定大鼠心肌中磷酸化ERK（p-ERK）的蛋白表达以及BNP mRNA的含量；酶联免疫吸附法检测大鼠血浆BNP水平。结果：（1） 治疗后SHR苯那普利组和SHR肼苯哒嗪组血压相似，均显著低于SHR未治疗组（P<0.01）。（2） SHR苯那普利组心肌肥厚指数显著低于SHR肼苯哒嗪组和SHR未治疗组(P<0.01) ，与WKY组无显著差异(P>0.05)；SHR肼苯哒嗪组和SHR未治疗组心肌肥厚指数无显著差异(P>0.05)。（3）SHR苯那普利组大鼠心肌p-ERK表达显著低于SHR肼苯哒嗪组和SHR未治疗组(P<0.05) ，与WKY组无显著差异(P>0.05)。SHR肼苯哒嗪组和SHR未治疗组大鼠心肌p-ERK表达无明显差异(P>0.05)。（4） SHR苯那普利组大鼠心肌BNP mRNA和血浆BNP水平显著低于SHR肼苯哒嗪组和SHR未治疗组(P<0.05)，与WKY组无显著差异(P>0.05)；SHR肼苯哒嗪组和SHR未治疗组大鼠心肌BNP mRNA和血浆BNP水平无明显差异(P>0.05)。结论：苯那普利能通过抑制ERK活性逆转心肌肥厚，伴随BNP水平下降；而降压效果相似的肼苯哒嗪不能抑制心肌肥厚，对p-ERK和BNP水平没有影响，提示BNP水平可以反映逆转心肌肥厚药物疗效。     

加压素在自发性高血压大鼠与正常大鼠下丘脑视上核、室旁核神经元内表达

目的观察加压素(AVP)在自发性高血压大鼠(SHR)与正常大鼠下丘脑视上核(SON)、室旁核(PVN)内的分布。方法应用光镜和免疫细胞化学技术。结果SHR的AVP阳性细胞内分泌颗粒密集呈棕黄色,正常大鼠组则染色较浅。SHR大鼠SON内AVP阳性神经元百分数(69.30±18.10%)明显多于正常大鼠(59.53±16.97%,P<0.05),而两组大鼠PVN内AVP的表达无明显差异。结论AVP在下丘脑的血压调节活动中起着重要的介导作用,中枢AVP含量的异常增加可能与高血压的发病有关。     

糖尿病早期大鼠视网膜毛细血管及视细胞超微结构变化规律

目的：探讨大糖尿病视网膜病变（糖网病）早期的视网膜毛细血管及视细胞的病变规律。材料与方法：选择健康成年Wistar大鼠,随机分成正常对照组,糖尿病1月,3月和6月组,一次性腹腔内注射链脲佐菌素STZ）诱导大鼠糖尿病,制备视网膜超薄切片,透镜观察并计算机图像分析。结果：病程1月,周细胞和内皮细胞核异染色质聚集靠边;视杆膜盘间隙略扩大。3月,毛细血管细胞异染色质聚集严重,基底膜增厚;膜盘间隙扩大明显,局灶性断裂,溶解。视杆细胞膜固缩,异染色质浓集,视杆内节线粒体肿胀,甚至空泡变性,病程6月,以上改变更加严重,毛细血管狭窄,变形,甚至闭塞。结论：糖网病早期大鼠视 膜毛细血管病变的同时,变出现视感受器超微结构的改变,随病程的进展病变逐渐加重。     

Morphological alterations in skeletal muscle of spontaneously hypertensive rats

The Extensor digitorum longus (EDL) and the soleus muscles of spontaneously hypertensive rats (SHR) were studied in comparison with those of their normal counterparts, the Wistar Kyoto (WKY) rats. Quantitative assessment of capillaries and muscle fibre typing was done with optical microscopy, while the study of capillary abnormalities was performed by ultrastructural observation. There were no differences in fibre type proportion or in capillarity indexes between the SHR and the control rats. A reduction in the area of IIB fibres was found in the EDL muscle of the hypertensive animals. The ultrastructural study showed abnormalities in the capillaries of both muscles in SHR, the cross section of the endothelial cells was enlarged; there was irregular distribution of caveolae and pinocytic vesicles, the capillary basement membrane showed irregular width, with parts engrossed and reduplicated. Some pericytes were prominent. There were macrophages present in the interstitial space. In some muscle fibres there was disorganization of the sarcomere structure, swelling of the sarcotubular system, abundant autophagic vacuoles, and proliferative satellite cells. There were abundant collagen fibrils. The presence of cellular rests, autophagic vacuoles and loss of sarcolemma indicated necrosis. It can be concluded, that in SHR, muscle capillaries showed alterations that may be the substrate of functional rarefaction, although anatomical rarefaction (number reduction) could not be demonstrated. In EDL and soleus muscles of SHR, signs of a mild myopathy with focal fibrosis were present.     

Renal medullary effects of transient prehypertensive treatment in young spontaneously hypertensive rats

Aim: Transient angiotensin II receptor blockade (ARB) leads to prolonged blood pressure (BP) lowering, but the underlying mechanism remains uncertain. Long‐term BP control is regulated by the medullary microcirculation with the pericyte as contractile cell. We hypothesize that the prolonged BP effect is caused by increased medullary blood flow (MBF) associated with structural alterations based on reduced medullary pericyte number. Methods: Four‐week‐old spontaneously hypertensive rats (SHR) were treated for 4 weeks with losartan (SHR‐Los: 20 mg kg^?1 day^?1), hydralazine (SHR‐Hyd: 15 mg kg^?1 day^?1), losartan and pan‐caspase inhibitor zVAD (SHR‐Los + 1 mg kg^?1 day^?1 zVAD), losartan and glycogen synthase kinase‐3β (GSK) inhibitor valproate (SHR‐Los + 10 mg kg^?1 day^?1 Val) or placebo. BP, MBF and pericyte number were determined under and after treatment (8 and 12 weeks). Apoptotic pericytes were determined with α‐actin and TUNEL double staining. Sodium concentration was determined in renal medulla and urine. Results: Antihypertensive treatment equipotently reduced BP at 8 weeks of age. After drug withdrawal (12 weeks of age) BP reduction was restricted to SHR‐Los (SHR‐Los: 153 ± 5, SHR‐Hyd: 177 ± 2, SHR: 184 ± 3 mmHg). Simultaneously, MBF was increased and pericyte number reduced, while medullary and urinary sodium concentration increased. Transient ARB in combination with zVAD or valproate resulted in more medullary pericytes and higher BP (SHR‐Los/zVAD: 164 ± 7; SHR‐Los/Val: 168 ± 6 mmHg) compared with transient ARB alone. Conclusion: After drug withdrawal, transient ARB leads to increased MBF and is associated with a reduction in medullary pericytes. This may be associated with pericyte apoptosis as anti‐apoptosis during transient ARB increases pericyte number and BP.     

Spontaneously hypertensive rats develop pulmonary hypertension and hypertrophy of pulmonary venous sphincters.

This study explored the spontaneously hypertensive rat as an animal model of pulmonary hypertension and sought to identify anatomic changes in its pulmonary microvasculature, especially focal constrictions of pulmonary veins (sphincters). The average systemic and pulmonary artery blood pressures were 172/139 (+/- 9/9) and 36/14 (+/- 4/3), respectively, for spontaneously hypertensive Wistar Kyoto rats (SHR), and 134/83 (+/- 8/2) and 20/10 (+/- 2/2) for normotensive Wistar Kyoto rats (WKY) (P < 0.01 for both). Light microscopy of the lungs in SHR showed muscularization of both arteries and veins, but this was more pronounced in the small pulmonary veins. Perivascular edema was also present. There were 20 (+/- 4) leukocytes per 100 microns of capillary length in SHR and 9 (+/- 2) in WKY (P < 0.001). Transmission electron microscopy showed focal venous smooth muscle was greater in SHR than in WKY. Scanning electron microscopy of vascular casts showed the average maximal focal venous contraction (sphincter) was 54% (+/- 10) of its diameter in SHR, but was only 6% (+/- 4) in WKY (P < 0.01). Arterial contraction occurred in the hypertensive rats as bourglass narrowings of the casts, but was less conspicuous than venous constrictions. The mean alveolar capillary diameter was 8.1 microns (+/- 1.6) in SHR, compared with 6.3 microns (+/- 1.0) in WKY (P < 0.01). The central interspace between capillaries was 3.2 microns (+/- 1.6) in SHR and 6.0 microns (+/- 3.6) in WKY (P < 0.01). The venous contraction, capillary size, and capillary interspace distance correlated with the pulmonary blood pressure. The spontaneously hypertensive rat can be a model of pulmonary hypertension with its most notable structural change being increased muscularity in the small pulmonary veins.     

实验性糖尿病神经和微血管形态研究及黄腐酸钠早期干预

目的 :观察糖尿病大鼠神经和神经内膜毛细血管形态变化及黄腐酸钠早期干预效果。方法 :腹腔注射链脲佐菌素建立糖尿病大鼠模型。给予黄腐酸钠治疗 6个月。结果 :(1)糖尿病动物血糖明显增高。(2 )糖尿病组有髓神经纤维密度明显低于对照组。黄腐酸钠治疗组有髓神经纤维密度明显高于糖尿病组。(3)电镜下糖尿病组神经纤维、神经内膜毛细血管出现结构改变 ;黄腐酸钠治疗组上述改变较轻。结论 :提示糖尿病大鼠病程 6个月时出现早期糖尿病神经病变及神经内膜毛细血管结构改变 ,黄腐酸钠可一定程度地抑制其进展。     

Synergistic effects of diabetes mellitus and renovascular hypertension on the rat heart - stereological investigations on papillary muscles

Summary The effects of combined renovascular hypertension and diabetes mellitus on the rat heart were investigated in order to detect possible synergistic effects of the two conditions. Hypertensive diabetic and hypertensive nondiabetic young male Wistar rats were compared with diabetic and nondiabetic controls. Since the normal body weight increase of the diabetic animals was markedly suppressed a weight-matched nondiabetic control group was introduced in addition. Hypertension was established for eight weeks by a surgical stenosis of the left renal artery, diabetes mellitus was maintained for four weeks after a single intraperitoneal injection of 75 mg/kg streptozotocin. Light and electron microscopic stereological parameters were obtained for the left ventricular papillary muscles. The whole hearts were also investigated histologically. Qualitative morphology failed to substantiate synergistic effects in the hypertensive diabetic rats. Vascular abnormalities were not observed. The stereological parameters, however, revealed microstructural reactions which were observed exclusively in the hypertensive diabetic group: the volume ratio of mitochondria-to-myofibrils was decreased, the surface-to-volume ratio of mitochondria was increased (reduction of mitochondrial size) and the mean cross sectional area of capillaries was decreased. Similar quantitative mitochondrial changes have been frequently described in long-standing hypertension, but in the present investigation, they were not found in the nondiabetic hypertensive group. It is therefore concluded that diabetes mellitus potentiates the effects of chronic pressure overload on myocardial cells. However, the myocardial fibrosis which has been found by other groups at later stages of hypertension and/or diabetes mellitus was not detected in the present study. The reduced mean cross sectional area of capillaries in hypertensive-diabetic rats may be correlated with early molecular changes of the myocardial interstitium or with early abnormalities of small arteries. Thus our stereological results support the hypothesis that a non-coronary hypertensive diabetic cardiomyopathy occurs in mammalian hearts.The results were presented in part at the Erwin Riesch Symposium,The results were presented in part at the Erwin Riesch Symposium,Dedicated to Prof. Dr. Drs.h.c.mult. G. Schettler on theDedicated to Prof. Dr. Drs.h.c.mult. G. Schettler on the     

氯沙坦逆转高血压大鼠心肌重塑的实验研究

目的探讨氯沙坦对自发性高血压大鼠(SHR)心肌重塑的影响。方法16周龄雄性SHR20只,随机分为氯沙坦治疗组和SHR对照组。同龄雄性WKY鼠10只作为正常对照组。给予氯沙坦每天30mg/kg溶于饮水灌胃治疗17周。测定动脉收缩压、左心室壁的厚度、左心室重量与体重之比(LVW/BW)。透射电镜评估左心室肥厚(LVH)的程度。用真彩色图像分析系统计算左心室胶原容积分数。结果氯沙坦治疗组血压、LVW/BW、左室壁厚度与SHR对照组相比明显降低,但与WKY相比有所升高。透射电镜下氯沙坦治疗组心肌的超微结构与WKY相似,SHR的结构有异常改变。与SHR对照组相比,氯沙坦治疗组左心室胶原容积分数下降。结论氯沙坦能有效地降低SHR的血压、逆转高血压左室重塑。     

The retinal capillaries of the rat in deoxycorticosterone hypertension. An ultrastructural study with the diffusion tracer lanthanum.

Unilaterally nephrectomized rats treated with deoxycorticosterone and 1% sodium chloride in their drinking water developed severe systemic hypertension with marked cardiac and renal lesions. No pathologic changes could be detected in the retinal vasculature by light microscopy, but electron microscopy revealed inconstant alterations in the pericytes of retinal capillaries: these cells showed hyaloplasmic edema, margination of chromatin, dilatation of rough endoplasmic reticulum, and swelling of mitochondria. Injection of lanthanum into control rats confirmed that this 40-A tracer cannot pass the interendothelial tight junctions. In hypertensive animals, however, it penetrated these junctions and could be visualized in capillary basement membranes and between cells of the retina. The results indicate that an increase in permeability is probably the first pathologic change to occur in the retinal capillaries of hypertensive rats.     

Early sucrose-induced retinal vascular lesions in spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY)

Retinal capillary basement membrane damage was demonstrated over a relatively short time period (two to three months) by feeding a diet containing high amounts of sucrose to spontaneously hypertensive rats (SHR) and their normotensive controls, Wistar Kyoto rats (WKY). Similar changes did not occur in SHR and WKY on a high starch diet. The early damage to the capillaries consisted of thickening of capillary basement membranes, loss of homogeneity, and inclusions containing debris. Previous studies on sucrose-induced eye lesions have reported chronic pathological changes only after prolonged periods of heavy sucrose ingestion, usually exceeding one year. Accordingly, the temporally foreshortened experimental pathogenesis offered by the SHR/WKY model allowed us to examine early changes in sucrose-induced vascular eye lesions.