Effects of streptozotocin-induced diabetes and of insulin treatment on homocysteine metabolism in the rat

An elevation in the concentration of total plasma homocysteine is known to be an independent risk factor for the development of vascular disease. Alterations in homocysteine metabolism have also been observed clinically in diabetic patients. Patients with either type 1 or type 2 diabetes who have signs of renal dysfunction tend to exhibit elevated total plasma homocysteine levels, whereas type 1 diabetic patients who have no clinical signs of renal dysfunction have lower than normal plasma homocysteine levels. The purpose of this study was to investigate homocysteine metabolism in a type 1 diabetic animal model and to examine whether insulin plays a role in its regulation. Diabetes was induced by intravenous administration of 100 mg/kg streptozotocin to Sprague-Dawley rats. We observed a 30% reduction in plasma homocysteine in the untreated diabetic rat. This decrease in homocysteine was prevented when diabetic rats received insulin. Transsulfuration and remethylation enzymes were measured in both the liver and the kidney. We observed an increase in the activities of the hepatic transsulfuration enzymes (cystathionine beta-synthase and cystathionine gamma-lyase) in the untreated diabetic rat. Insulin treatment normalized the activities of these enzymes. The renal activities of these enzymes were unchanged. These results suggest that insulin is involved in the regulation of plasma homocysteine concentrations by affecting the hepatic transsulfuration pathway, which is involved in the catabolism of homocysteine.     

Improved biochemical variables, nutrient intake, and hormonal factors in slow nocturnal hemodialysis: a pilot study

OBJECTIVE: To determine whether slow nocturnal hemodialysis (SNHD) can be safely performed in patients with end-stage renal disease to improve the biochemical and clinical outcome. MATERIAL AND METHODS: We conducted an 8-week pilot study in nondiabetic adult patients, who underwent dialysis 6 nights per week for 8 hours each night. A dialysate flow rate of 300 mL/min and a blood flow rate of 250 mL/min, through an internal jugular dual-lumen venous catheter, were used. The equipment used was a COBE Centry System 3 dialysis machine and Fresenius F-80 (1.8 m2) or Baxter CT 190 (1.9 m2) dialyzers. Five patients were enrolled in the study. RESULTS: Two patients did not complete the study because of catheter-related infections--one at day 7 and one after 4 weeks of SNHD. All patients had improved blood pressure control, and no intradialytic adverse events occurred. Dietary intake improved, urea and creatinine levels significantly decreased, and weekly delivery of dialysate increased on SNHD. Potassium, chloride, beta 2-microglobulin, phosphorus, calcium, and high-density lipoprotein cholesterol all improved on SNHD. Serum testosterone increased in the three men on SNHD, but parathyroid hormone, luteinizing hormone, and follicle-stimulating hormone remained unchanged. Erythropoietin levels increased on SNHD, despite no change in exogenous erythropoietin doses in three patients and discontinuation of administration of erythropoietin in one. The following biochemical factors did not change significantly: serum sodium, bicarbonate, vitamin B12, folate, alkaline phosphatase, total cholesterol, triglycerides, and albumin. CONCLUSION: Higher doses of hemodialysis benefit nutrition, improve biochemical variables, and may improve many hormonal systems.     

Serum endothelin and atrial natriuretic peptide in cirrhotic patients with ascites and hepatorenal syndrome

BACKGROUND: The pathogenesis of cirrhotic ascites and hepatorenal syndrome remains unresolved. The involvement of both endothelin-1 and atrial natriuretic peptide have recently been suggested. This study investigated the concentrations of serum endothelin and atrial natriuretic peptide in cirrhotic patients. METHODS: Seven healthy subjects and 31 cirrhotic patients were studied. Cirrhotic patients were divided into three groups: Group I, 16 cirrhotic patients without ascites; Group II, 10 cirrhotic patients with ascites, but without hepatorenal syndrome; and Group III, five cirrhotic patients with hepatorenal syndrome and ascites. Their sera were analyzed for endothelin-1 and atrial natriuretic peptide concentrations. RESULTS: Cirrhotic patients with ascites, Group II and Group III, had higher plasma endothelin-1 concentrations (15.9 +/- 2.3 pg/ml and 24 +/- 2.1 pg/ml, respectively) than normal subjects and compensated cirrhotics (3.8 +/- 0.7 pg/ml and 6.4 +/- 1.1 pg/ml, respectively); p < 0.001). Atrial natriuretic peptide concentrations were also significantly higher in cirrhotic patients than in normal subjects (p < 0.025). Plasma endothelin-1 concentration had a negative correlation with creatinine clearance (r = -0.65, p < 0.001), as did atrial natriuretic peptide concentrations (r = -0.44, p = 0.012). Plasma endothelin-1 correlated significantly with atrial natriuretic peptide concentrations (r = 0.38, p = 0.035). CONCLUSIONS: Both endothelin-1 and atrial natriuretic peptide concentrations were elevated in cirrhotic patients with ascites and hepatorenal syndrome. Endothelin-1 may have a negative impact on renal function. Our data also suggested that impaired responsiveness rather than impaired secretion of atrial natriuretic peptide is responsible for sodium retention in cirrhotic patients with ascites.     

Delayed protection by MK-801 and tetrodotoxin in a rat organotypic hippocampal culture model of ischemia

BACKGROUND AND PURPOSE: The hippocampus demonstrates a regional pattern of vulnerability to ischemic injury that depends on its characteristic differentiation and intrinsic connections. We now describe a model of ischemic injury using organotypic hippocampal culture, which preserves the anatomic differentiation of the hippocampus in long-term tissue culture. METHODS: Ischemic conditions were modeled by metabolic inhibition. Cultures were briefly exposed to potassium cyanide to block oxidative phosphorylation and 2-deoxyglucose to block glycolysis. The fluorescent dye propidium iodide was used to observe membrane damage in living cultures during recovery. RESULTS: 2-Deoxyglucose/potassium cyanide incubation resulted in dose-dependent, regionally selective neuronal injury in CA1 and the dentate hilus, which began slowly after 2 to 6 hours of recovery. Subsequent histological examination of cultures after 1 to 7 days of recovery demonstrated neuronal pyknosis that was correlated with the early, direct observation of membrane damage with propidium. Both propidium staining and histological degeneration were prevented by the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 when administered 30 minutes after the end of the exposure to 2-deoxyglucose and potassium cyanide. Tetrodotoxin, which blocks voltage-dependent sodium channels, had protective effects that were greatest during the period of 2-deoxyglucose and potassium cyanide incubation but also produced protection against the mildest conditions of metabolic inhibition when administered after 30 minutes of recovery. CONCLUSIONS: This in vitro model reproduced elements of the time course, regional vulnerability, and pharmacologic sensitivities of in vivo ischemic hippocampal injury. Inhibition of metabolism in organotypic culture provides a rapid, easily controlled injury and reproduces the in vitro pattern of hippocampal regional vulnerability to ischemia. It is the first in vitro model of ischemia to exhibit complete protection by delayed administration of an NMDA receptor antagonist during recovery from a brief insult. The protective effects of tetrodotoxin suggest that an early period of sodium entry into cells during and after ATP depletion may be responsible for the more prolonged period of toxic NMDA receptor activation.     

Virtual colonoscopy: imaging features with colonoscopic correlation

BACKGROUND: We determined whether activation of the nitric oxide/cyclic guanosine monophosphate pathway by sodium nitroprusside (SNP) protects hearts subjected to cardioplegic arrest and prolonged hypothermic storage. METHODS: Isolated rat hearts arrested with St. Thomas' II cardioplegia and stored at 3 degrees +/- 1 degree C for 8 hours were reperfused at 37 degrees C in Langendorff (10 minutes) and working (60 minutes) modes. RESULTS: During reperfusion, left ventricular work was depressed in stored hearts relative to fresh hearts. When present during arrest, storage, and both reperfusion phases, SNP (200 mumol/L) improved work to values close to those in fresh hearts. When added only during the 10-minute period of Langendorff reperfusion, SNP also improved the subsequent recovery of work. This effect was antagonized by the soluble guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). Poststorage coronary perfusion was not increased by SNP. CONCLUSIONS: The ability of SNP to enhance recovery independent of changes in coronary perfusion and in an ODQ-sensitive manner suggests that SNP-induced protection is due to activation of the myocardial nitric oxide/cyclic guanisine monophosphate pathway. These results suggest that supplementing cardioplegic solutions with SNP, administering SNP during early reperfusion, or both may offer additional means to improve donor heart preservation.     

Teaching smoking-cessation counseling to medical students using simulated patients

The controversy continues over the appropriate use of vaginal hysterectomy for many indications that were previously treated only with abdominal or laparoscopic methods. Current outcomes data have pointed up the need for established guidelines to ensure that patients receive appropriate surgical treatment that is most cost-effective and that meets the standard of quality care. Dr Kovac reviews recent data regarding the various surgical options for hysterectomy and offers guidelines based on objective pathologic criteria.     

Characterization of a human papillomavirus type 16 variant-dependent neutralizing epitope

We have determined that three type-specific and conformationally dependent monoclonal antibodies, H16.E70, H16.U4, and H16.V5, neutralize pseudotype human papillomavirus type 16 (HPV16) virions in vitro. H16.U4 and H16.V5 neutralized pseudotype virions derived from the German HPV16 variant 114K and the Zairian variant Z-1194 with equal efficiency. In contrast, neutralization of Z-1194 pseudotype virions by H16.E70 was two orders of magnitude weaker than neutralization of 114K pseudotype virions. This difference correlated with enzyme-linked immunosorbent assay reactivity of H16.E70 to L1 virus-like particles of the two variants. A substitution at residue 282 of L1 was responsible for this differential reactivity, suggesting that this residue constitutes part of the H16.E70 epitope.