Effect of the estrogen antagonist, tamoxifen, on development of glomerulosclerosis in the Cohen diabetic rat.

Long-term administration of the estrogen antagonist, tamoxifen, to female, Cohen diabetic rats caused a significant decrease in the incidence of glomerulosclerosis, 12.5% as compared with 58.3% in control, untreated, diabetic female rats. This change in incidence was correlated with a corresponding decrease in plasma estradiol and cholesterol levels, but not with changes in oral glucose tolerance or insulin response. A similar correlation between decreased incidence of glomerulosclerosis and a decrease in plasma estradiol was previously noted in ovariectomized animals.

Changes from high potassium (hk) to low potassium (lk) in bovine red cells.

Red cells of newborn calves contain 105-110 mmole K(+) and 1-5 mmole Na(+) per liter of cells. As the animals age the K(+) content decreases to a value of 25-30 mmole/liter of cells after about 60 days. At approximately the same time, the sodium content reaches a value of 60-70 mmole/liter. The time required for half change (t((1/2))) is 35-37 days for both Na(+) and K(+). The activity of (Na + K)-adenosine triphosphatase (ATPase) and the influx of K(42) and Rb(86) into the red cells are high at birth and are reduced to 5 and 15% of their original values, respectively, in mature animals. t((1/2)) for both is of the order of 30-35 days. The membrane Mg-ATPase activity is also high at birth and is reduced with a t((1/2)) of 28-32 days to a final value of about 20% of its activity at birth. Separation of red cells according to their age showed that, in animals at the age of transition, newly formed red cells contain a higher K/Na ratio and a higher active transport capacity than older red cells of the same animal. It is suggested that the changes observed are a reflection of the average age of the red cell population as the animal grows.

Renal pathologic findings associated with monoclonal gammopathies.

The myeloma kidney is characterized by casts in the distal and collecting tubules. The glomeruli are hardly affected unless amyloidosis is present. When the glomeruli are involved, the proteinuria is nonselective and, in some cases, the whole paraprotein is excreted in the urine. Nephrocalcinosis may be present and focal myeloma cell infiltration in the interstitium is a characteristic, but inconstant, finding. The nephrotic syndrome is extremely rare; if it exists, amyloidosis should be suspected. In contrast to multiple myeloma, the glomeruli are frequently involved in macroglobulinemia of Waldenstrom. Hyaline intracapillary deposits consisting of pure IgM are a characteristic finding as is infiltration of the kidney with lymphoid cells. No characteristic lesion of the kidney has been described in the heavy-chain diseases. Mixed cryoglobulinemia associated with an IgM paraprotein can produce glomerulonephritis that is due to the deposition in the glomeruli of an immune complex consisting of IgG, IgM, and complement.

Effects of enalapril, losartan, and verapamil on blood pressure and glucose metabolism in the Cohen-Rosenthal diabetic hypertensive rat.

We undertook the present study to examine the effect of the angiotensin-converting enzyme inhibitor enalapril, the angiotensin II antagonist losartan, and calcium antagonist verapamil on systolic pressure and spontaneous blood glucose levels in rats from the Cohen-Rosenthal diabetic hypertensive strain. Genetic hypertension and diabetes developed in this strain after crossbreeding of Cohen diabetic and spontaneously hypertensive rats. The new rat strain was fed their usual copper-poor sucrose diet, which is essential for the development of this model, and for 4 weeks received either enalapril, losartan, or verapamil. Systolic pressure was reduced significantly compared with controls in all treated groups. Chronic treatment with enalapril or verapamil, but not with losartan, succeeded in lowering spontaneous blood glucose, indicating improved diabetic control. Data suggest that angiotensin-converting enzyme inhibition by enalapril, but not angiotensin II antagonism by losartan, can improve glucose metabolism in addition to its hypotensive effect in a genetic diabetic hypertensive rat strain. This confirms that the drop in glucose with converting enzyme inhibition is highly dependent on bradykinin accumulation. Data further suggest that calcium channel blockade by verapamil can also improve glucose metabolism. The question remains whether the reduction in glucose by verapamil was a result of inhibition of glucogenesis.

Unilateral chronic pyelonephritis and hypertension: coincidental or causal relationship?

Three patients with well documented unilateral chronic pyelonephritis (UCP) of bacterial origin, one hypertensive and two normo-tensive, were presented. Removal of the contracted kidney in the hypertensive patient did not eradicate the hypertension. An attempt was made to define UCP as closely as possible. The clinical, roentgenologic, bacteriologic, functional and pathologic criteria of UCP was described. But, as other conditions may mimic the roentgenologic, functional and pathologic picture of UCP, a history of recurrent urinary tract infection accompanied by a documented unilateral renal bacteriuria is the basic requirement for a sustained diagnosis of UCP. In view of these more exacting criteria in the diagnosis of UCP, and its water and salt-losing functional pattern, UCP is a rare cause of hypertension, in the majority of cases the association of UCP with hypertension is merely coincidental.

Chromatin-positive Klinefelter's syndrome with undetectable peripheral FSH levels.

An 18 year old phenotypic man is described with chromatin-positive Klinefelter's syndrome and undetectable peripheral human follicle stimulating hormone levels. The subject manifested chromosomal mosaicism consisting of three stem cell lines (45X; 46XY; and 47XXY). Testicular biopsy specimen showed germinal cell aplasia: the tubules were lined by Sertoli cells only, whereas the Leydig cells appeared normal. Serum human follicle stimulating hormone levels were undetectable and rose to only 5 mIU/ml after the administration of luteinizing hormone releasing hormone. Serum human luteinizing hormone varied between normal and moderately elevated values, and serum testosterone was in the low normal range. We discuss the features which distinguish this syndrome from isolated gonadotropin deficiency and from classic germinal cell aplasia. We suggest that the patient represents a new variant of Klinefelter's syndrome, with failure of human follicle stimulating hormone release secondary to prolonged hypersecretion.

Small bowel transplantation. The effect of intraportal donor-specific transfusion 24 hours pretransplant and low-dose cyclosporine.

We tested the synergy of donor-specific transfusion (DST) and cyclosporine (CsA) in small bowel transplantation by comparing the systemic versus portal route of DST administration in a fully allogeneic rat model. The protocol is relevant to cadaveric transplantation by conditioning only 24 hr before allografting. A 1 ml intraportal DST day -1 and low-dose CsA significantly prolonged survival (MST 53.7 +/- 17.5 days) when compared with systemic DST day -1 and low-dose CsA (MST 18.4 +/- 5.6 days). This suggests that intraportal DST can be beneficial in cadaveric SBT, as only a 24-hr induction period is necessary. We speculate that antigen trapping in the liver and interaction of the DST with Kupffer cells is central to the portal DST effect.

Successful renal transplantation from two donors with methanol intoxication.

Two patients with acute methanol intoxication are reported, one with acute renal failure. Both were declared brain-dead and kidneys were harvested at 80 and 130 hr after hospital admission. All four kidneys were transplanted and subsequently functioned well. In both donors who had received ethanol treatment, thrombocytopenia was present. The reluctance to use kidneys from such donors and from donors with acute renal failure before harvesting is discussed. Waiting lists for renal transplantation are growing and there is a world-wide shortage of cadaver organs. We were recently surprised to find reluctance to consider two local patients dying from methanol intoxication as suitable organ donors, and we report the outcome of four kidneys transplanted from these donors. We were unable to find any similar cases reported in the English literature.

Gonadotrophin, testosterone and prolactin interrelationships in cadmium-treated rats.

We have investigated the long-term effect of a single subcutaneous injection of cadmium chloride on plasma testosterone and gonadotrophin levels and the prolactin response to the dopaminergic antagonist metoclopramide in the rat. Twelve days after treatment with cadmium there was testicular necrosis, associated with a decrease in testosterone concentration and atrophy of the accessory sexual glands. By 185 days, partial recovery of the accessory sexual glands indicated by Leydig cell regeneration and a slight rise in testosterone levels had occurred. There was, however, persistent damage to the germinal epithelium. Concentrations of LH increased eightfold above controls by day 12, remained raised until 60 days and then decreased to threefold above controls at 280 days. In contrast, FSH levels reached a maximum between 60 and 130 days and remained persistently raised. The peak prolactin response to metoclopramide in cadmium-treated rats was depressed 12 days after cadmium administration and levels remained low at 19 and 75 days. Normal prolactin responses to metoclopramide were obtained 130 days after cadmium treatment using 1:0 mg metoclopramide/kg or 280 days after treatment using 0.25 mg/kg. When control and cadmium-treated rats were castrated at 280 days and then given metoclopramide 10 days later, the prolactin response was significantly reduced. It is concluded that the impaired prolactin response to metoclopramide in cadmium-treated rats is reversible. Prolactin returns to normal in parallel with regeneration of the Leydig cells, partial restoration of the accessory sex organ weight, slight increase in plasma testosterone and decrease in LH levels. These results suggest that testosterone is not solely responsible for the maintenance of normal prolactin secretion in the male rat.

Systemic lupus erythematosus associated with acute Epstein-Barr virus infection.

Systemic lupus erythematosus (SLE) is a multisystem disease of unknown origin, characterized by a variety of autoimmune phenomena. Viruses have long been postulated to play a role in its pathogenesis. Several observations suggested a link between Epstein-Barr virus (EBV) and SLE. We describe a 14-year-old girl who presented with acute onset of SLE concurrently with clinical and laboratory findings consistent with EBV-induced infectious mononucleosis (IM). Evidence for acute EBV infection was confirmed by serological studies and detection of specific EBV antigens on kidney biopsy. This close association between EBV and SLE suggests a possible role of the virus in the pathogenesis of SLE in this patient.

Localization of glycogen in the placenta of diabetic rats: a light and electron microscopic study.

The ultrastructure of the placentae on day 20 of gestation was studied in rats made diabetic by streptozotocin injection on day 13 of gestation. In the placentae of control rats most of the glycogen was found in the glycogen cells, while some of it was localized to the labyrinth trophoblastic layers. In the diabetic rats a marked increase in glycogen content, together with higher numbers of glycogen cells in the junctional zone, was seen. Glycogen was also stored in other cell types of this zone, as well as in all cell types of the placental labyrinth of the diabetic animals.

The 56 kDa androgen-binding protein in human genital skin fibroblasts: its relation to the human androgen receptor.

We have recently described in genital skin fibroblasts (GSF) a relatively abundant 56 kDa protein with androgen-binding activity. This protein is missing in GSF of most patients with complete androgen insensitivity syndrome (CAI). The protein has many characteristics compatible with the androgen receptor; it has in fact been tentatively considered as a precursor or degradation form of the prototypic (approximately 100 kDa) human androgen receptor. We have prepared an antiserum to this protein, which allowed us to detect it as a direct product by in vitro translation of mRNA from GSF. It is thus very unlikely to be a degradation product of a larger precursor. Furthermore, covalent photolytic labeling of this protein with the androgen analogue [3H]mibolerone revealed a much lower affinity for this protein than is known for the androgen receptor. Finally, the GSF of two exceptional patients with complete androgen insensitivity syndrome due to negligible androgen receptor-binding activity express this protein normally, as determined on two-dimensional gels by Western blot analysis with the antiserum and by photolytic covalent labeling with androgen analogues. These data indicate that the protein is not a precursor or a degradation product of the receptor; nor is it androgen-induced. They are more compatible with the idea that the protein is another member of the steroid/thyroid/retinoic acid receptor supergene family, perhaps as an unorthodox product of the human androgen receptor gene.

Rectal mucosal biopsy in aganglionosis and allied conditions.

Rectal mucosal biopsies were performed in 146 patients suspected of having Hirschsprung's disease. The biopsies were serially sectioned and screened for the presence of ganglion cells. In the 101 cases in which ganglion cells were found, the diagnosis of Hirschsprung's disease was ruled out. In 45 patients, histologic examination revealed the typical features of Hirschsprung's disease, i.e., the absence of ganglion cells and the presence of numerous hypertrophied nerve bundles. The varied morphologic features of Meissner's plexus in patients of different ages and the diagnostic pitfalls are described in detail. Serial frozen sections stained with hematoxylin-eosin were examined in eight cases of neonatal intestinal obstruction and enterocolitis. This method was found to be useful and reliable in emergencies. In three of these cases ganglion cells were found and major surgical procedures were avoided. In 73 cases, staining for acetylcholinesterase activity was performed. The results matched the microscopic findings in all but three false-positive cases.

Crohn's disease isolated to the appendix: truths and fallacies.

Twenty-five cases of Crohn's disease confined to the appendix were reported in eight hospitals in Israel during a 15-year period. Review of the histologic slides confirmed the diagnosis in 22 cases. Re-evaluation of these 22 patients included physical examination and radiologic studies of the small and large bowel. Rectosigmoidoscopy was performed in 16 patients. Signs and symptoms of Crohn's disease at other sites in the gastrointestinal tract did not occur during follow-up periods of two to 15 years (mean, 6.4 years) after appendectomy. This study and a review of the literature indicate that in most cases (93 per cent) Crohn's disease initially limited to the appendix is not a predictor of subsequent involvement of another portion of the bowel. It is concluded that the so-called Crohn's disease isolated to the appendix is a form of chronic granulomatous and follicular appendicitis of unknown etiology that is unrelated nosologically in the majority of the cases to Crohn's disease proper.

The role of hypovolemic stress in the production of fat embolism in rabbits. 2. Changes in arterial blood gas levels and static compliance.

The purpose of this study was to assess the possible role of hypovolemia as a factor in the production of impaired pulmonary function in pulmonary fat embolizaiton. Iv vivo static lung compliance was measured by inflating the lungs with known volumes of air and recording the transpulmonary pressure, monitoring intraesophageal pressure as an index of intrapleural pressure. Arterial blood was drawn from the central artery of the ear. Embolization was produced by the intravenous injection of homologous fat cells either as the sole experimental procedure or in conjunction with hypovolemic shock. Two types of shock were studied. In one, 20 percent of the blood volume was removed, producing hypovolemia associated with hemodilution, and in the other a tourniquet was applied to induce hypovolemia and hemoconcentration. The results indicate that embolization is associated with significantly greater impairment of pulmonary function if it develops on a background of shock than if it occurs in an otherwise healthy animal. These pathophysiologic findings parallel the results of a morphologic study.

Endobronchial actinomycosis simulating bronchogenic carcinoma. Diagnosis by bronchial biopsy.

Five cases of actinomycosis of the main bronchi or trachea which were suggestive clinically of bronchogenic carcinoma are described. In four patients the correct diagnosis was made by a bronchial biopsy or wash, or both. Three of them recovered following antibiotic treatment, and one died a few days after bronchoscopy. In one case the Actinomyces were found in the bronchial wash retrospectively following diagnosis of pulmonary actinomycosis in the lobectomy specimen. A concomitant endobronchial lipoma was found in one of the patients. The diagnosis of pulmonary actinomycosis by bronchial biopsy may save the patient major surgical intervention.

The role of hypovolemic stress in the production of fat embolism in rabbits. 1. Morphologic alterations of the lungs.

In rabbits, an experimental model of fat embolism was produced that simulates the course of events in the clinical situation. Small doses of fat-cell suspension (0.075 ml/kg of body weight), prepared by collagenase treatment of homologous adipose tissue, were injected intravenously. Concomitantly, hypovolemia was produced in two animal groups by either withdrawing 20 percent of the estimated blood volume or by application of a hind-limb ischemic tourniquet for 90 minutes. The presence of pathoanatomic characteristics typical of fat embolism was evaluated by recording lung/body weights, macroscopic appearance, and semiquantitative microscopic estimation in the lungs of edema, hemorrhage, atelectasis, intravascular coagulation, and leukocytic thrombi. Mean indices of lung/body weight were higher in all animals receiving injections of fat-cell suspension, as compared to controls. The score for microscopic generalized pulmonary damage was significantly higher in rabbits exposed to both fat-cell injections and hypovolemia than in controls or after fat-cell injections alone. It is concluded that hypovolemia enhances the development of fat embolism in rabbits subjected to small doses of fat-cell suspension.

Prolonged pyrexia and lung metastases. A rare presentation of an occult epithelioid sarcoma.

A 31-year-old patient presenting with fever of unknown origin, night sweats and weight loss, associated later with pulmonary nodules, is described. Multiple invasive diagnostic procedures, including exploratory laparotomy and open-lung biopsy, suggested a benign inflammatory granulomatous disease. Metastatic epithelioid sarcoma was ultimately diagnosed after biopsy of an enlarging groin mass. Epithelioid sarcoma should be considered in the differential diagnosis of prolonged fever, associated with granulomas of obscure etiology.

Prevention of clot formation in cat retinal vein by systemic and subconjunctival urokinase.

The thrombolytic effect of urokinase was tested on cat retinal vein thrombus induced by argon laser photocoagulation. At various time intervals after thrombosis, intravenous infusion or subconjunctival injections were given. Subconjunctival normal saline injections were used for controls. In vitro subconjunctival urokinase prevented thrombus organization if given within six hours of thrombosis. Subconjunctival injections of urokinase vs normal saline were also studied in vivo in a masked fashion. At intervals of three to 24 hours following thrombosis, 11 cats were treated with subconjunctival urokinase in one eye and normal saline in the 11 fellow eyes. Within ten days after thrombosis, the vein was patent in eight (72%) of the 11 eyes treated with urokinase and in one (9%) of the 11 control eyes.

The Cohen diabetic (non-insulin-dependent) hypertensive rat model. Description of the model and pathologic findings.

The available diabetic hypertensive models are of type I chemically induced diabetes in one-clip Goldblatt rat or in the spontaneously hypertensive (SHR) rat. We describe here a genetic type II diabetic hypertensive model (CDHM) developed by cross breeding the Cohen diabetic rat (CDR) and the SHR. In the succeeding generations, sibling pairs with the highest spontaneous blood glucose (SBG) and blood pressure (BP) were selected and mated. In the sixth selected generation, non-insulin-dependent overt diabetes and hypertension were evident. Blood pressure was 171 +/- 1.2 mm Hg, spontaneous blood glucose 340 +/- 22 mg/dL, and plasma insulin at 60 min following intragastric (IG) glucose load 83.3 +/- 10.2 microU/mL. In the CDHM there was severe diffuse diabetic glomerulosclerosis and severe hypertensive changes in arteries and arterioles, characterized by fibrinoid necrosis and/or "onion skin" lesions, as well as by smooth muscle cell hyperplasia. Such vascular changes were not observed in the CDR or in the SHR. Myocardial changes were prominent, with foci of ischemic necrosis and hyperplastic vascular changes. This model may be useful in probing the mechanisms potentiating cardiovascular and renal morbid events in the setting of spontaneous hypertension and diabetes.