Wegener's Granulomatosis: A Review of Three Cases

Clinical and autopsy features in three cases of Wegener''s granulomatosis are presented. The disease is characterized by the triad of necrotizing granulomatous lesions of the respiratory tract, segmental necrotizing angiitis of arteries and veins, and necrotizing glomerulitis commonly terminating in uremia. Correct antemortem diagnosis was made in two of the three cases-in one by recognition of the characteristic triad and in the other by a biopsy from the antrum. Pathological lesions were chiefly in respiratory tract, spleen, kidneys and blood vessels. Necrotizing granulomatous lesions were present in the lungs. Glomerular lesions were particularly severe and wide-spread in two of the three patients, leading to uremia. Trabeculitis of the spleen, an unusual lesion, was a noticeable feature in all three. Fibrinoid necrosis, with little or no inflammatory infiltration, was the prevailing type of vascular necrosis. The characteristics of the disease process suggest a hypersensitivity mechanism. Similarities to, but significant differences from, polyarteritis nodosa are recognized.     

The Case for Control in Diabetes Mellitus

In all diabetic animal models studied to date, microangiopathic complications develop which can be prevented by tight control and reversed by either islet cell transplantation or transplanting the diabetic kidney into a nondiabetic environment. In humans the prevalence of these complications in secondary diabetes mellitus is similar to the prevalence in genetic diabetes. Furthermore, mesangial basement membrane thickness is normal at the onset of the disease and increases shortly thereafter. These two facts strongly suggest that the microangiopathic complications are not an independent genetic component but rather are secondary to the metabolic derangements of uncontrolled diabetes. Normal kidneys transplanted into diabetic recipients developed the vascular lesions of diabetes. Conversely, two diabetic kidneys inadvertently transplanted into nondiabetic recipients showed clearing of the vascular lesions.Most retrospective studies support the conclusion that control is associated with lessened complications. The three prospective studies published to date also support this hypothesis. Because glucose concentrations cannot be brought to normal levels by present methods, the critical question is whether a major emphasis on restoring metabolism to as nearly normal as possible will help ameliorate the microangiopathic complications in our patients. The accumulated evidence would strongly favor an affirmative answer. Two daily injections of intermediate-acting insulin supplemented with small amounts of short-acting insulin as needed is one method to approach this goal.     

Defibrotide decreases cholesterol amount in hypercholesterolemic rabbit aorta, with no modification of plasma or lipoprotein cholesterol

Defibrotide, (D) an antithrombotic agent, when administered i.v. to cholesterol-fed rabbits decreased cholesterol in the aorta without changing total plasma cholesterol, triglyceride or phospholipid, nor the cholesterol, triglyceride, phospholipid and protein of plasma lipoproteins. Platelet aggregation was decreased in rabbits treated with D. There were fewer vascular lesions in the hearts and kidneys of animals treated with D than in animals fed cholesterol and treated with placebo. These data suggest that the antithrombotic activity of D and its ability to reduce platelet sensitivity could help to reduce the amount of cholesterol in the cardiovascular system in atherosclerosis-prone situations.     

A transgenic mouse model of autoimmune glomerulonephritis and necrotizing arteritis associated with cryoglobulinemia

Mice implanted with hybridoma secreting 6-19 IgG3 anti-IgG2a rheumatoid factor (RF) with cryoglobulin activity develop acute glomerulonephritis and cutaneous leukocytoclastic vasculitis. As the RF activity is implicated in the skin, but not glomerular lesions, it is still unclear whether the renal pathogenicity is determined by 6-19 H chains alone or their combination with L chains. To address this question, we have generated transgenic mice expressing only the H chain gene or both H and L chain genes of the 6-19 IgG3 anti-IgG2a RF and determined the development of glomerular and vascular lesions. H-single and H/L-double transgenic mice displayed comparable high amounts of IgG3 cryoglobulins, but only H/L-double transgenic mice having 10-fold higher levels of IgG3 anti-IgG2a RF progressively developed chronic, lethal glomerulonephritis. The severe glomerular lesions observed at 8-10 mo of age were very heterogeneous (membranoproliferative changes, crescents, and sclerosis); in addition, one-third of them had necrotizing arteritis in the kidneys and skeletal muscles. These renal and vascular changes were very different from those observed in the acute cryoglobulinemia, characterized by mainly "wire-loop" glomerular lesions and a cutaneous leukocytoclastic form of vasculitis. Thus, our data demonstrate the importance of a unique combination of the H and L chains for the expression of the pathogenic activity of IgG3 cryoglobulins and that a single autoantibody is able to induce different types of glomerular and vascular complications, depending on its production levels and kinetics.     

Enhancement of maternal and fetal nephrotoxicity of salicylate by zinc deficiency. Morphological, enzyme histochemical and immunohistochemical studies

An oral dose of 700 mg/kg salicylic acid was given to normal and Zn-deficient rats at day 16 of gestation. Maternal and fetal kidneys were studied at day 19 of gestation. Zn-deficiency did not cause any lesions detectable by semi-thin section light microscopy, electron microscopy, enzyme histochemistry and immunohistochemistry. Salicylate may lead only to small morphological, enzymatic and cytoskeletal defects in the maternal and fetal kidney. However, enzyme activities decreased in plasma membranes, mitochondria, lysosomes, endoplasmic reticulum and peroxisomes in all segments of the tubular apparatus when salicylate was given to Zn-deficient rats. Cytoskeletal proteins such as keratin in the glomerular cells and epithelial lining of the collecting ducts and vimentin in vascular endothelial cells of the maternal kidney were also affected. In addition, the epithelial cells of the collecting ducts, which were comparatively less damaged, accumulated high amounts of fat. In severe cases, the enzymatic and cytoskeletal lesions were accompanied by hematuria and tubular necroses including and collecting ducts in the renal papilla. In less severe cases reduced activities of brush border hydrolases were the only sign of disturbed renal function in maternal rats indicating that membrane alteration and loss of membrane-bound enzymes are the primary defects. In the fetal kidneys, mitotic activity of the cells of the nephron anlagen and collecting ducts was reduced and enzymatic and morphological differentiation were disturbed. As a consequence less mature nephrons and collecting ducts occurred.     

Alloxan diabetes blocks noradrenergic tachyphylaxis in the isolated rabbit kidney--effects of insulin.

Normal and alloxan treated diabetic rabbit kidneys were perfused with Krebs-Henseleit solution in a non-recirculating system and the effects of norepinephrine (NOR) 10(-6)M were tested by infusion of this drug for three subsequent periods of 20 min each, with an interval of 10 min for drug wash-out. In the control kidneys the infusion of NOR promoted an intense vasoconstriction, which was less intense during the second and the third periods. This was known as tachyphylaxis. In contrast to the controls, kidneys from diabetic animals did not show tachyphylaxis to NOR, but when insulin was added to the perfusate, tachyphylaxis appeared. Normal kidneys perfused with hyperosmolar solutions show, as in controls, the same phenomenon. The data presented here demonstrate a defect of adrenergic vascular receptors in alloxan treated kidneys, which can be acutely reversed by insulin. These facts are of importance for the understanding of the vascular disease in diabetes.     

Enhancement of maternal and fetal nephrotoxicity of salicylate by zinc deficiency

Summary An oral dose of 700 mg/kg salicylic acid was given to normal and Zn-deficient rats at day 16 of gestation. Maternal and fetal kidneys were studied at day 19 of gestation. Zn-deficiency did not cause any lesions detectable by semi-thin section light microscopy, electron microscopy, enzyme histochemistry and immunohistochemistry. Salicylate may lead only to small morphological, enzymatic and cytoskeletal defects in the maternal and fetal kidney. However, enzyme activities decreased in plasma membranes, mitochondria, lysosomes, endoplasmic reticulum and peroxisomes in all segments of the tubular apparatus when salicylate was given to Zn-deficient rats. Cytoskeletal proteins such as keratin in the glomerular cells and epithelial lining of the collecting ducts and vimentin in vascular endothelial cells of the maternal kidney were also affected. In addition, the epithelial cells of the collecting ducts, which were comparatively less damaged, accumulated high amounts of fat. In severe cases, the enzymatic and cytoskeletal lesions were aecompanied by hematuria and tubular necroses including the collecting ducts in the renal papilla. In less severe cases reduced activities of brush border hydrolases were the only sign of disturbed renal function in maternal rats indicating that membrane alteration and loss of membrane-bound enzymes are the primary defects. In the fetal kidneys, mitotic activity of the cells of the nephron anlagen and collecting ducts was reduced and enzymatic and morphological differentiation were disturbed. As a consequence less mature nephrons and collecting ducts occurred.Dedicated to Professor Zdenek Lojda on the occasion of his 60th birthdaySupported by the German Research Foundation (Sfb 174)     

Cooling of rabbit kidneys permeated with glycerol to sub-zero temperatures.

The aims of this study were to investigate if kidney preservation could be enhanced by cooling of the organs to high sub-zero temperatures after depression of their freezing points by addition of glycerol, and to study whether the added amounts of this compound would confer protection to the organs during freezing and thawing at slow rates.Glycerol was added and removed gradually by continuous, hypothermic perfusion, and the post-preservation viability was assessed by autotransplantation.Brief cooling to ?5 °C of kidneys perfused with 3 m glycerol was found to be compatible with life-sustaining posttransplant function, whereas no kidneys stored at that temperature for 5 days survived.Slow cooling af kidneys glycerolized to 3 m to ?80 °C was associated with a marked increase in vascular resistance after thawing, and none of such frozen kidneys functioned after transplantation. They showed immediately after revascularization severe impairment of the circulation, and vascular damage was observed by light microscopy. The use of 5 m glycerol for cryoprotection attenuated this rise in vascular resistance and reduced the release of the endocellular enzyme, lactate dehydrogenase after thawing, indicating less cellular damage although no kidneys functioned after grafting.It is suggested that the mechanical effect of interstitial and intravascular ice formation is a major factor in damage to intact organs during freezing, and that further injury is produced by incomplete removal of the cryoprotectant before transplantation.     

Effect of diabetes mellitus induced by streptozotocin on renal Superoxide dismutases in the rat

Two forms of superoxide dismutase, CuZn-SOD and MnSOD, have been investigated in the kidneys of streptozotocin-induced diabetic rats using both radio-immunoassay and immunoenzyme staining. The rats were killed 2, 8 and 12 weeks after the induction of diabetes mellitus and the kidneys excised. Two weeks after the induction of diabetes, the kidneys were hypertrophied because of the proliferation of renal tubular epithelium. However, the total CuZnSOD content of the kidneys did not increase and, because of the epithelial proliferation, the CuZnSOD concentration in each proximal tubular cell was decreased. Armanni-Ebstein lesions were found in the distal tubules 8 and 12 weeks after the induction of diabetes. The cells in these lesions were intensely stained for CuZnSOD, suggesting an adaptive response to the enhanced oxidative stress. The MnSOD staining in the thick ascending limbs of Henle's loops was enhanced in the diabetic kidneys, while that in the cortical tubules was unaltered. MnSOD was assumed to increase in response to hypermetabolism associated with the proliferation of renal tubules. This was most marked in the cells which were rich in mitochondria, again suggesting an adaptive response to enhanced oxidative stress induced by diabetes mellitus. The glomeruli of both the diabetic and control groups were not stained for SODs, and no significant microscopic change was found even 12 weeks after the induction of diabetes mellitus.     

Kidney lesions in pelagic seabirds with high tissue levels of cadmium and mercury

Light and electron microscopic techniques were employed to examine the kidneys of three species of pelagic seabird which had high tissue cadmium and mercury levels. Direct examination and comparison with the kidneys of cadmium and mercury dosed starlings showed that the seabirds had patchy nephrotoxic kidney lesions. It was suggested that these lesions were due to natural exposure of the animals to high levels of metals, particularly cadmium through their diet. Pathological features included necrosis and degeneration of the proximal tubular epithelium together with the direct observation of obstruction of the more distal neprhon segments by necrotic cellular debris. Abnormalities of the glomerular podocytes and Bowman's capsule cells were also observed. There was a high degree of similarity between the type and distribution of kidney lesions in the seabirds and the laboratory metal dosed starlings. The significance of this kidney damage and its possible effects on the birds survival prospects are discussed.     

Fluorocarbons as blood substitutes. Toxicity in the rat]

Liquid fluorocarbons, having high solubility for gases (O2, CO2...) have been used as artificial blood substitutes in animals with variable results. The great diversity of these products and the lack of reproductiveness in their composition have not permitted, up to now, a standardization of their utilisation norms. Our work was to study the toxicity, in the rat, of a new kind of fluorocarbon emulsion (E-66, Ugine-Kuhlmann, France) used as an artificial blood substitute during exchange-perfusion. The short survival of the rats is in opposition to the good in vitro results obtained in other experiments (high solubilities of oxygen and dioxide carbon). The toxicity of this fluorinated emulsion is demonstrated by histologic lesions in lungs, liver and kidneys and the great amount of fluor stored in these organs. The mechanism of this toxicity is still to be demonstrated. Hepatic lesions (hyperhemia with dilatation of central veins and sinusoids) and pulmonary lesions (vascular congestion, alveolar oedema) prove a circulatory disturbance leading to right-sided cardiac failure. However, cellular degenerescence lesions, observed in hepatocytes and renal tubular cells, do not permit to exclude formally a cellular toxicity of the E-66 emulsion.     

Age-related non-tumorous lesions in SPF C57BL/6 mice with special reference to amyloidosis]

Non-tumorous pathological changes in C57BL/6 CrSlc mice, which were reared under a barrier system and died spontaneously, were examined. At 3 months intervals 125 to 209 mice were purchased at 4 weeks of age and raised for the supply of aged animals. A large portion of the mice were used for various experiments between 3 and 30 months of age, while not a small number died spontaneously and were autopsied. The major non-neoplastic lesion was amyloidosis, with incidence of 55.5% and 74.4% for the autopsied female and male, respectively. The organs involved were the liver, kidneys, spleen, adrenal glands, ileum, heart and lungs. Skin ulceration and its scar, cerebral vascular calcification, glomerulosclerosis and sepsis in both sexes, distension of the seminal vesicles in males, fibroblast growth of the adrenal glands in females were commonly found. Incidence of spontaneous neoplastic lesions was 69.7% and 55.1% for the female and male, respectively.     

Modulating biochemical perturbations during 72-hour machine perfusion of kidneys: role of preservation solution

This study documents renal biochemistry during hypothermic machine perfusion of kidneys. It is intended to demonstrate that a comprehensive evaluation of organ viability during ex-vivo preservation is needed to increase the number of organs available for transplantation and to reduce the current renal discard rate. Porcine kidneys were hypothermically machine perfused for 72 h with either Unisol-UHK or Belzer-Machine Perfusion Solution, (Belzer-MPS). Renal perfusate samples were periodically collected and biochemically analyzed. Significant differences were measured in the renal metabolic activity between the two experimental groups while similar values for traditional parameters such as renal flow rate and vascular resistance values were recorded. The effluent of UHK perfused kidneys showed strong metabolites and NH(4)(+) dynamics (P<0.05 vs. baseline), while the Belzer-MPS kidneys metabolic activity led to little or no change of the effluent biochemistry relative to baseline.     

Impaired blood flow autoregulation in nonfiltering kidneys: effects of theophylline administration

To investigate blood flow autoregulation in filtering and nonfiltering kidneys, renal blood flow was determined during graded reductions in renal perfusion pressure in seven anesthetized dogs containing both a filtering and nonfiltering kidney. In each dog, one kidney was made nonfiltering by the method of EH Blaine, JO Davis, and RT Witty (Circ Res 27:1081-1089, 1970). Renal perfusion pressure was decreased from 129 to 115, 99, and 83 mm Hg by stepwise constriction of the suprarenal aorta. In filtering kidneys, the maximum decrease in renal perfusion pressure reduced renal blood flow only 20.1% of control whereas renal blood flow of nonfiltering kidneys decreased by 41.0% of control. During aortic constriction, renal vascular resistance of nonfiltering kidneys remained unchanged or slightly increased. These hemodynamic changes were associated with significantly greater autoregulation indices in nonfiltering kidneys. In eight dogs with nonfiltering kidneys, competitive inhibition of adenosine with theophylline (9 mg/kg iv) restored autoregulation of renal blood flow as shown by significant decreases in renal vascular resistance. These data indicate that in the nonfiltering kidney model, autoregulation of renal blood flow is impaired. It is suggested that this impaired autoregulatory response may result from renal ischemia and the vasoconstrictor influence of elevated intrarenal adenosine concentration.     

Pathogenicity and Neurological Effects of Oidiodendron kalrai for Mice

An experimental infection was induced in mice by intravenous and intraperitoneal inoculation with Oidiodendron kalrai. The infected mice developed a complex neurological syndrome consisting of hyperirritability, jumping, circling, and ataxia, followed by coma and death or by apparent recovery. Visible lesions accompanied by inflammatory reaction and fungal elements were seen only in kidneys, but organisms were also identified in and isolated from the liver, spleen, lungs, and brain. Cortisone alone or in combination with streptomycin rendered the mice highly susceptible to infection with O. kalrai, and lesions were found in the brains as well as in the kidneys of these mice. Treatment of infected mice with streptomycin alone increased the severity and duration of the neurological syndrome, but such treatment did not increase the mortality rate.     

Pathological evaluation of Polystichum squarrosum (D. Don) fern in laboratory rats

Polystichum squarrosum fern fed (30% w/w) rats showed moderate mortality, decrease in body weight, less body fat and splenomegaly. On post-mortem examination, significant gross lesions were not seen in sacrificed animals. Histopathologically, Polystichum fed rats showed dilated Virchow Robin's space in brain, mild to moderate vascular changes likeoedema, engorgement of blood vessels and haemorrhages in most of the visceral organs, interstitial pneumonia in lungs, focal necrosis and generalised vacuolative degenerative changes in liver, more haemosiderin deposition and presence of higher number of megakaryocytes in spleen, shrunken glomeruli, more peri-glomerular space and more number of glomeruli per microscopic field in kidneys, focal hyperplasia of urinary bladder and moderate to marked depletion of germinal epithelium and spermatids in seminiferous tubules of testes. Pathologically, progressive changes were observed only in liver, urinary bladder and testes on 180 days post feeding (DPF). One fern fed rat sacrificed on 135 DPF showed hepatic tumour which was diagnosed as hepatocellular carcinoma. The results showed that P. squarrosum produced almost comparable pathological changes/preneoplastic lesions as reported in bracken fern fed animals. Long term exposure studies (i.e. 2 yrs) are desired.     

2型糖尿病患者血糖波动与心律失常和下肢血管病变的关系及其影响因素分析

目的:探讨2型糖尿病(T2DM)患者血糖波动与心律失常和下肢血管病变的关系,分析影响T2DM心律失常和下肢血管病变的因素。方法:选择2019年7月到2020年6月我院收治的82例T2DM患者,根据是否合并心律失常分为心律失常组28例和无心律失常组54例,根据是否合并下肢血管病变分为下肢血管病变组31例和无下肢血管病变组51例。所有患者均通过72 h监测血糖获得日内平均血糖波动幅度(MAGE)、日间血糖平均绝对差(MODD)、全天血糖标准差(SDBG)、全天血糖波动次数(NGE)。比较组间差异,分析影响T2DM患者心律失常和下肢血管病变的因素。结果:心律失常组MAGE、MODD、SDBG、NGE、糖化血红蛋白(HbA1c)、胰岛素抵抗指数(HOMA-IR)、T2DM病程、同型半胱氨酸(Hcy)、丙二醛(MDA)高于无心律失常组(P<0.05)。下肢血管病变组T2DM病程、Hcy、MDA、HOMA-IR、MAGE、MODD、SDBG、NGE均高于无下肢血管病变组(P<0.05)。Logistic回归分析结果显示MDA、HOMA-IR、MAGE、MODD是T2DM患者心律失常的危险因素(P<0.001),MAGE、MODD、SDBG是T2DM患者下肢血管病变的危险因素(P<0.001)。结论:T2DM患者血糖波动与心律失常和下肢血管病变均有关,血糖波动增加是T2DM心律失常和下肢血管病变的危险因素。     

Distribution and removal of glycerol by vascular albumin perfusion in rabbit kidneys.

A simple perfusion circuit for gradual glycerolization and deglycerolization of rabbit kidneys is described; it has been used to study vascular resistance and glycerol distribution during perfusion at +10 °C with a perfusate of extracellular composition.An attempt was made to diminish the dramatic rise in vascular resistance during deglycerolization of rabbit kidneys, seen in previous experiments, by increasing the perfusate colloid osmotic pressure and decreasing the rate of change of cryoprotectant concentration during the last third of removal. These modifications of the method did not improve perfusion characteristics or post-transplant function.Melting points of perfusates and different parts of the kidney were determined by differential thermal analysis before glycerolization, after glycerolization to 3 m and after subsequent deglycerolization. The variations of tissue melting temperatures were found to be identical with variations in the perfusate, thus indicating a complete distribution and removal of cryoprotective concentrations of glycerol.     

Histopathology of Mycotoxicosis produced in Swiss albino mice by metabolites of some fungal isolates.

Of 199 fungal cultures isolated from some of the common cereals collected from different parts of Uttar Pradesh and Madhya Pradesh, 70 produced toxic metabolites. Of the 70 fungi isolated, 59 produced toxins which caused visible lesions in livers, kidneys, and spleens but did not cause mortality. Toxicity, graded in terms of the mortality rate and the extent of lesions in livers, kidneys, and spleens, was found to be highest in various species of Aspergillus (40%), followed by Chaetomium spp. (31%).