Vitamin D intoxication and the pathogenesis of vitamin D nephropathy in the dog.

Dogs given excess vitamin D (500 or 1,000 micrograms/kg of body weight each day for 1 to 3 weeks were observed for clinical and pathologic changes of increased blood pressure and of characteristic nephropathy associated with vitamin D toxicosis or hypercalcemia. Serum calcium and serum urea nitrogen (UN) increased throughout the treatment period, but serum phosphorus remained within the normal range. Plasma renin activity increased markedly. Blood pressure showed only insignificnat changes (P = greater than 0.05). Gross and microscopic examination of the kidneys suggested vascular-oriented changes with an ischemic basis. Glomerular vascular poles showed hypertrophy and hyperplasia of juxtaglomerular cells. Ultrastructually, an increase in the number of secretory granules was noticed in these cells. A hypothesis regarding the mechanism of renal injury during vitamin D toxicosis is presented.     

Examination of the effect of a naturally occurring mutation in glycoprotein L on Marek's disease virus pathogenesis

We recently reported a comparison of glycoprotein-encoding genes of different Marek's disease virus pathotypes (MDVs). One mutation found predominantly in very virulent (vv)+MDVs was a 12-bp (four-amino acid) deletion in the glycoprotein L (gL)-encoding gene in four of 23 MDV strains examined (three were vv+MDVs and one was a vvMDV). This mutation was noted in the gL of the TK (615K) strain, but not in the RL (615J) strain of MDV. These strains have identical mutations in the meq gene characteristic of vv+MDVs but can be distinguished by the mutation in the gL-encoding gene. The TK strain was originally isolated from vaccinated chickens and appeared to confer or enhance horizontal transmission of the vaccine virus, herpesvirus of turkeys (HVT). Because the molecular basis for increased virulence of MDV field strains is unknown, we hypothesized that one mechanism might be by coreplication of MDV-1 strains with HVT and that it could be mediated by the mutation of gL, an essential component of the glycoprotein H/L complex. In this study, we compared the pathogenicity of TK (615K) and RL (615J) strains of MDV in the presence and absence of simultaneous HVT coinfection. MDV infections were monitored at the levels of viremia (for both MDV-1 and HVT), clinical signs of MD, tumor incidence, and mortality in 1) inoculated chickens, 2) chickens exposed at 1 day of age, 3) chickens exposed at 2 wk of age, and 4) chickens exposed to both TK/HVT- and RL/HVT-infected chickens at 6 wk of age. We found high incidences of clinical MD signs in all inoculated treatment groups and all chickens exposed to TK and RL viruses, regardless of the presence of HVT. The median time to death of chickens exposed to TK1HVT-infected chickens, however, was lower than the other treatment groups for contact-exposed chickens. Although this difference was not considered to be statistically significant to a rigorously interpreted degree because of the removal of chickens for sampling from the test groups, these data suggest that replication of the TK strain and HVT, when coadministered, might incrementally affect the virulence of MDV-1 strains. The strict correlation of this enhancement of virulence with the mutation in gL, however, requires additional experiments with genetically identical MDV background strains.     

Spontaneous thyroiditis in BB Wistar diabetic rats

Spontaneous lymphocytic thyroiditis was observed at necropsy in 36 BB Wistar diabetic rats (63.2%) and in eight of their nondiabetic siblings (42.1%). The incidence of thyroiditis decreased both with age and with longer duration of diabetes. All rats with pancreatic insulitis (a manifestation of the onset of diabetes) also had thyroiditis. BB Wistar rats with insulitis had more severe lymphocytic thyroiditis, characterized by lymphocytic, plasmacytic, and macrophage infiltration of thyroid interstitium and follicles. A milder, mostly perivascular and interstitial lymphocytic thyroiditis was characteristic of lesions in rats which did not have insulitis. The histological appearance of the thyroiditis suggests that these rats may be subject to autoimmune disease at the onset of diabetes which involves sites other than just the pancreas.     

新生大鼠缺氧缺血性脑病发病机理及其治疗的研究

缺氧缺血性脑病 (hypoxic- ischemic encephalopa-thy,HIE)是医学儿科临床上由于新生儿窒息引起的脑部合并症 ,是严重威胁新生儿生命和健康的疾病之一。但至今为止 ,国内外尚无统一、行之有效的治疗方案。所以 ,寻找治疗新生儿缺氧缺血性脑病更为有效的方法已成为围产医学中的重要课题。应用脑活素治疗 HIE虽然取得了一定效果 ,但其作用机制不明 ,仍需更深入的动物实验及临床研究。本项研究通过建立新生大鼠 HIE模型并应用脑活素予以治疗 ,旨在揭示新生大鼠缺氧缺血性脑病发病机理及脑活素的治疗作用 ,为医学儿科临床治疗缺氧缺血性脑病…     

Study on the pathogenesis of foreign body granulomatous inflammation in the livers of sprague-dawley rats

Focal granulomatous inflammation developed in the livers of five 10-week-old male Sprague-Dawley rats. The characteristic features of this lesion were the presence of foreign body multinucleated giant cells engulfing calcium deposits and site-specific development in a fissure formed in a sub-lobation in the left lobe or interlobar fissure of the medial lobe of the liver. To clarify the pathogenesis of this lesion, rat livers showing abnormal sub-lobation or lobar atrophy, rat livers in an acute dermal toxicity study and guinea pig livers in a skin sensitization test were also examined histologically. Consequently, the present lesion was considered to be a reactive change against calcium that was dystrophically deposited in the area of hepatocellular necrosis due to delayed circulatory disturbance caused by external pressure or extension force. Granulomatous lesions like in the present cases should be differentiated from those caused by evident exogenous pathogens such as chemicals or microorganisms.     

The importance of adrenocortical steroids in the pathogenesis of ketosis in diabetic guinea pigs (Caviae porcellus)

The roles of adrenocortical steroids in the pathogenesis of diabetic ketosis were investigated in guinea pigs. Groups of normal and Streptozotocin-induced diabetic animals were either given saline as a control, methylprednisilone as an exogenous steroid, or adrenocorticotrophin to stimulate endogenous steroid production. Plasma and urine ketone determinations were made daily for six days at which time animals were necropsied. The qualitative procedure used failed to detect ketonemia, and ketonuria was only found in diabetic guinea pigs treated with steroids. The results support the hypothesis that the absence of ketosis in spontaneously diabetic guinea pigs may be the result of a relative glucocorticoid insufficiency secondary to fatty degeneration of the adrenal glands, a common lesion in spontaneously diabetic guinea pigs.     

Examination of hemostatic parameters to detect hypercoagulability in dogs with severe protein‐losing nephropathy

Objective – To identify hemostatic abnormalities in dogs with protein‐losing nephropathies (PLN) that represent risk factors for pathologic thrombosis. Design – Cross‐sectional observational study of client‐owned dogs with PLN, nonprotein losing renal failure (RF), and systemic illness (SI) exclusive of primary renal disease. Setting – Urban University Referral Center. Animals – A total of 29 dogs (n=11 PLN, n=7 RF, n=11 SI) were enrolled between January 2001 and July 2002. Samples were also collected from 20 clinically normal dogs to serve as hemostasis assay controls. Interventions – None. Hemostasis Testing – Citrate anticoagulated blood was collected for point‐of‐care testing with a viscoelastic monitor (thromboelastograph [TEG]) and citrate plasma was prepared for coagulation screening tests and specific assay of the following hemostatic proteins: antiplasmin, antithrombin, D‐dimer, Factor VIII, fibrinogen, plasminogen, protein C, and von Willebrand factor. Results – Dogs with PLN and RF demonstrated TEG abnormalities consistent with hypercoagulability (eg, short clotting time, high clot amplitude) and both groups had significantly lower antithrombin than the SI group. The PLN dogs had significantly higher protein C than either the RF or SI group. Hyperfibrinogenemia was a consistent finding among all 3 disease groups, and the coagulation index a measure of hypercoagulability derived from TEG parameters, directly correlated with fibrinogen values of all study dogs. Conclusions – Hemostatic abnormalities consistent with systemic hypercoagulability are common in dogs with RF and PLN, however, no prothrombotic factors unique to PLN were identified in our study. The thrombotic tendency of PLN may therefore involve parameters we did not directly assess such as platelet reactivity, fibrinolysis, perturbations in blood flow, and/or endothelial dysfunction. High protein C is a novel finding in PLN dogs of unknown clinical relevance.     

Changes in quantitative profile of extracellular matrix components in the kidneys of rats with adriamycin-induced nephropathy

Extracellular matrix components (ECMs) in histological sections of the kidney cortex from the rats with adriamycin (ADR)-induced nephropathy (5 mg/kg, i.v.) were quantified by an immunohistochemical micromethod. Changes in kidney histopathology and urine and blood biochemistry were investigated. Enlarged kidneys were granular on the surface and pale in color in ADR-treated rats, and these rats had kidneys with glomeruli with expanded mesangial area and with capillary aneurysm. Severe albuminuria, hypoalbuminemia, hypercholesterolemia and disorders in other nephrotic parameters were observed in ADR-treated rats. Type I and IV collagens, fibronectin and laminin contents in the renal cortex of ADR-treated rats at 10 weeks were 329, 317, 263 and 295%, respectively, higher than in each vehicle control, and those at 28 weeks were 1,211, 930, 1,057 and 1,012%, respectively. The glomerular sclerotic abnormalities progressed in a time-dependent manner. Moreover, there was a strong correlation between the ECM levels and serum creatinine and blood urea nitrogen levels. In conclusion, microquantification provided useful information for accurate diagnosis and prognosis of nephrotic lesions and is a good tool to assess the advancement of renal disorders in patients with nephropathy.     

Comparison of gentamicin toxicity in normal and diabetic rats.

Gentamicin treatment caused an elevation in serum urea and creatinine concentrations and ALT activity, associated with pathological changes in the liver and kidney. The pathological and blood chemistry changes were more severe in diabetic gentamicin-treated than in non-diabetic gentamicin-treated rats. Alloxan-diabetic rats had lowered blood glutathione concentrations which may have been responsible for the enhancement of gentamicin toxicity in these rats.     

Endocrine cell populations in the pancreas of diabetic WBN/Kob rats.

Numerical changes of insulin-, glucagon- and somatostatin-positive cells in the pancreas of WBN/Kob male rats with spontaneously occurring diabetes were examined. The rats examined were divided into three different age groups: Groups I (12 weeks old) and II (33 weeks old) were clinically prediabetic and group III (60-90 weeks old) was diabetic. Serum glucose value was in the normal range in groups I and II, while it was much higher in group III. B and A cells were markedly decreased in number in groups II and III. In group II, the ratio of B to A cells was normally preserved, though the total endocrine cell number was markedly decreased as compared with that in group I. In group III, the percentage of B cells was decreased significantly. The normal ratio in group II seemed to keep serum glucose within the normal level. In addition to the total endocrine cell reduction, an altered ratio of B and A cells was considered to cause the diabetic condition.     

Effect of deoxycorticosterone acetate-salt-induced hypertension on diabetic peripheral neuropathy in alloxan-induced diabetic WBN/Kob rats

The relationship between hypertension and diabetic peripheral neuropathy (DPN) has recently been reported in clinical research, but it remains unclear whether hypertension is a risk factor for DPN. To investigate the effects of hypertension on DPN, we analyzed morphological features of peripheral nerves in diabetic rats with hypertension. Male WBN/Kob rats were divided into 2 groups: alloxan-induced diabetic rats with deoxycorticosterone acetate-salt (DOCA-salt) treatment (ADN group) and nondiabetic rats with DOCA-salt treatment (DN group). Sciatic, tibial (motor) and sural (sensory) nerves were subjected to qualitative and quantitative histomorphological analysis. Systolic blood pressure in the two groups exhibited a higher value (>140 mmHg), but there was no significant difference between the two groups. Endoneurial blood vessels in both groups presented endothelial hypertrophy and narrowing of the vascular lumen. Electron microscopically, duplication of basal lamina surrounding the endothelium and pericyte of the endoneurial vessels was observed, and this lesion appeared to be more frequent and severe in the ADN group than the DN group. Many nerve fibers of the ADN and DN groups showed an almost normal appearance, whereas morphometrical analysis of the tibial nerve showed a significant shift to smaller fiber and myelin sizes in the ADN group compared with DN group. In sural nerve, the fiber and axon-size significantly shifted to a smaller size in ADN group compared with the DN group. These results suggest that combined diabetes and hypertension could induce mild peripheral nerve lesions with vascular changes.     

Sequential alterations of glucocorticoid receptors in the hippocampus of STZ-treated type 1 diabetic rats

Type 1 diabetes is a common metabolic disorder accompanied by increased blood glucose levels along with glucocorticoid and cognitive deficits. The disease is also thought to be associated with environmental changes in brain and constantly induces oxidative stress in patients. Therefore, glucocorticoid-mediated negative feedback mechanisms involving the glucocorticoid receptor (GR) binding site are very important to understand the development of this disease. Many researchers have used streptozotocin (STZ)-treated diabetic animals to study changes in GR expression in the brain. However, few scientists have evaluated the hyperglycemic period following STZ exposure. In the present study, we found GR expression in the hippocampus varied based on the period after STZ administration for up to 4 weeks. We performed immunohistochemistry and Western blotting to validate the sequential alterations of GR expression in the hippocampus of STZ-treated type 1 diabetic rats. GR protein expression increased significantly until week 3 but decreased at week 4 following STZ administration. GR expression after 70 mg/kg STZ administration was highest at 3 weeks post-treatment and decreased thereafter. Although STZ-induced increase in GR expression in diabetic animals has been described, our data indicate that researchers should consider the sequential GR expression changes during the hyperglycemic period following STZ exposure.     

硒对STZ诱发糖尿病大鼠骨密度影响的研究初报

比较了在低硒饲料的基础上补充不同形态硒对糖尿病大鼠骨密度的影响。健康SD大鼠 1 2 8只 ,体重 50～ 60 g,随机分为 4组 ,每组 32只 ,雌雄各半 ,其中Ⅰ组为低硒对照组 (饲料含硒量 0 0 37mg/kg) ;Ⅱ组为补充亚硒酸钠组 (饲料含硒量 0 3mg/kg) ;Ⅲ组为补充富硒麦芽组(饲料含硒量 0 3mg/kg) ;Ⅳ组为补充富硒酵母组 (饲料含硒量 0 3mg/kg)。Ⅱ、Ⅲ、Ⅳ组的饲料均是在Ⅰ组低硒饲料的基础上分别添加适量的亚硒酸钠、富硒麦芽、富硒酵母后配制而成。喂饲 5周后 ,Ⅰ、Ⅱ、Ⅲ、Ⅳ组用链脲佐菌素 (streptozotocin ,STZ)按 60mg/kg腹腔注射诱发糖尿病 ,继续饲喂 6周。用单光子吸收法测定各组大鼠的肱骨、股骨、胫骨、桡骨的骨密度。结果表明 :①STZ致糖尿病大鼠的骨密度随时间的延长有逐渐下降的趋势。Ⅱ、Ⅲ、Ⅳ补硒组大鼠可以在一定时间内延缓STZ致糖尿病大鼠的骨密度下降。在此期间骨密度的下降以肱骨出现最早 ,股骨次之 ,桡骨、胫骨再次之。②饲料补硒组糖尿病大鼠的肱骨、股骨中硒的含量较饲料低硒组糖尿病大鼠的肱骨、股骨中硒的含量显著提高。③补充硒的形态 ,即有机硒 (富硒麦芽、富硒酵母 )或无机硒 (亚硒酸钠 )对糖尿病大鼠肱骨、股骨、胫骨、桡骨的骨密度影响差异不显著。     

Differential effects of treadmill exercise on calretinin immunoreactivity in type 2 diabetic rats in early and chronic diabetic stages

In this study, we investigated the effects of treadmill exercise on calretinin (CR), a marker of early postmitotic neurons, immunoreactivity in the dentate gyrus (DG) of Zucker diabetic fatty (ZDF) rats, before or after diabetes onset, and Zucker lean control (ZLC) rats. For this study, 6-week-old ZLC and prediabetic ZDF rats, and 22-week-old ZLC and ZDF rats were exercised on the treadmill. Sedentary ZLC and ZDF rats of the same age were used as exercise experiment controls. The exercised prediabetic ZDF rats did not show diabetes onset, while the sedentary prediabetic ZDF rats showed significantly increased blood glucose levels. The exercised diabetic ZDF rats exhibited a decrease in their blood glucose levels compared to the sedentary diabetic ZDF rats, but the levels were still above 20 mmol/l. ZLC rats of both ages were in the normoglycemic range. CR immunoreactivity was detected throughout the DG, including the subgranular zone and the polymorphic layer. Diabetic rats exhibited a significant decrease in the number of CR-immunoreactive cells and fibers in the DG. Exercise in the prediabetic ZDF rats significantly increased the number of CR-immunoreactive cells and fibers in the subgranular zone of the DG. In the ZLC and ZDF rats of chronic diabetic phase, exercise increased CR-immunoreactive neurons in the hilar region. These results suggest that diabetes significantly reduces the number of postmitotic CR-immunoreactive neurons and the intensity of immunoreactivity and that exercise increases these CR-related parameters in a diabetic stage-dependent manner.     

Morphoquantitative aspects of NADH-diaphorase myenteric neurons in the ileum of diabetic rats treated with acetyl-L-carnitine

In this work, we investigated the effect of the acetyl-L-carnitine (ALC) supplementation (200 mg/kg/day) on the myenteric neurons of the ileum of rats made diabetic by streptozotocin (35 mg/kg, i.v.). Four groups were used: diabetic (D), diabetic supplemented with ALC (DC), control (C) and control supplemented with ALC (CC). After 15 weeks of diabetes induction the animals were killed and the ileum was collected and subjected to whole-mount preparation to evidence the myenteric neurons through the histochemical technique of the NADH-diaphorase. The density of neurons seen in 12.72 mm2 of ileum showed no difference among the groups, although in group D it was 22% smaller than in group C, while group DC was 9% smaller to group CC. The profiles of the cell bodies (PC) of 1000 neurons per group were analysed. The neurons PC in group D decreased (P < 0.0001) when compared with other groups and increased (P < 0.0001) when compared with group DC. The incidence of neurons with a PC inferior to 200 microm2 was larger in group D. The frequency of neurons with a PC higher than 200 microm2 in group DC was close to those seen in groups C and CC. We concluded that ALC eases the loss of neurons and makes the incidence of myenteric neurons with a PC higher than 200 microm2 similar to the control rats.     

Membranous nephropathy in the dog

Membranous nephropathy, a disease syndrome characterized by severe proteinuria and often accompanied by the nephrotic syndrome, was identified in 29% of a population of 46 proteinuric dogs. Renal lesions were characterized by the presence of subepithelial immunoglobulin deposits distributed diffusely along the glomerular capillary wall. Advanced stages were associated with progressive thickening of capillary basement membranes and incorporation of the immune deposits. These changes were followed by either glomerulosclerosis or recovery. Characteristic morphologic stages were correlated with clinical pathologic findings which showed that the level of proteinuria, hypoalbuminemia, and consequent nephrotic syndrome was most severe in the initial stages of membranous nephropathy while the level of azotemia increased in the more advanced stages of the syndrome.     

Obstructive nephropathy induced with DL-potassium hydrogen tartrate in F344 rats

We experienced obstructive nephropathy in F344 rats treated with DL-potassium hydrogen tartrate (PHT) in a 13-week oral repeated dose toxicity study. Six-week-old male and female F344/DuCrj rats were fed a diet containing up to 2.0% PHT for 13 weeks. Microscopical findings including irregular dilation of the distal tubule lumen, foreign body giant cells, inflammatory cell infiltration, and regeneration of renal tubules were observed focally or multifocally in the renal cortex and/or medulla in the 0.5% and higher dosage groups of both sexes. The severity of these lesions increased in a dose-dependent manner. In the urinalysis, an increase in protein and white blood cells or the concentration of tartaric acid was detected in the 0.5% PHT and higher dosage groups of both sexes or males, respectively, though conventional blood biochemical analysis did not indicate failure of renal function. These results indicate that the PHT induces obstructive nephropathy in rats. There were no other treatment-related changes in other organs.     

菊糖对糖尿病大鼠的抗氧化系统和血脂的影响

糖尿病(diabetes mellitus,DM)是由于胰岛素分泌绝对不足或相对不足而引起的糖、脂肪、蛋白质代谢紊乱为特征的疾病.菊糖(dahlin),义名菊粉(inulin)是一种天然多聚糖.菊糖具有多种生物功能,如提高机体免疫力,调节血糖、血脂,改善能量代谢等.本文旨在观察菊糖对实验性糖尿病大鼠的抗氧化系统和血脂的影响.     

Changes in cyclooxygenase-2 immunoreactivity in the hippocampus in a model of streptozotocin-induced type 1 diabetic rats

In this study, we investigated diabetic stage dependent cyclooxygenase-2 (COX-2) immunoreactivity in the dentate gyrus in streptozotocin (STZ)-induced type 1 diabetic rats. The animals were sacrificed at 2, 3 and 4 weeks after STZ treatment. Blood glucose levels were increased after STZ treatment. COX-2 immunoreactivity in dentate gyrus was significantly increased in these regions 3 weeks after STZ treatment and restored to its basal level to 4 weeks after STZ treatment. In contrast, COX-2 immunoreactivity was not changed in CA3 region in all groups. These results suggest that STZ-induced type 1 diabetes transiently, but not permanently, decreased synaptic transmission and plasticity 3 weeks after STZ treatment in the dentate gyrus.