Gene/Protein Disease Symptom Drug Enzyme Compound
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The aim of this study was to investigate the combined effect of DLA matching and immunosuppressive therapy on the survival of segmental small-bowel allografts in dogs. Orthotopic segmental small-bowel transplantations (25 to 30% of total small bowel length) were performed in two stages: first a heterotopic segmental small bowel transplantation, followed after 5 to 8 weeks by a second-stage operation during which the heterotopic graft was placed in an orthotopic position and the native small bowel was resected. All dogs received cyclosporine immunosuppression. Control dogs (n = 4), subjected to total enterectomy, survived 37.3 +/- 7.1 days (mean +/- SEM). Recipients of DLA-mismatched small bowel grafts (n = 6) survived 113.2 +/- 37.0 days, which was a significantly shorter time than dogs with a DLA-matched graft (n = 6, 211.5 +/- 38.8 days, P < 0.05). None of the matched allografts was rejected during CsA treatment, whereas four of six mismatched grafts were (P < 0.05). The control dogs uniformly showed progressive weight loss, steatorrhea, and hypoalbuminemia. The dogs with DLA-mismatched grafts did not regain initial body weight, whereas animals with DLA-matched grafts recovered preoperative weight after 20 weeks. Both transplanted groups showed near-normal fecal fat excretions and constant serum albumin, cholesterol, and triglyceride levels, whereas serum total protein levels increased during follow-up. We conclude that segmental small bowel transplantation between DLA-matched donor-recipient pairs results in long-term survivors with an adequate nutritional status. This may have important implications for future living-related small-bowel transplantation.
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PMID:Long-term survival of DLA-matched segmental small-bowel allografts in dogs. 824

Dietary supplementation with n-3 polyunsaturated fatty acids (n-3 PUFA) has been shown to reduce proteinuria in experimental models of renal diseases, but their potential role in the treatment of human renal disease is unknown. We administered n-3 PUFA in the form of triglycerides [with eicosapentaenoic (EPA)+docosahexaenoic (DHA) = 3 g/day into 4 patients] and of ethyl esters (EPA+DHA = 7.7 g/day) into 10 patients (one patient twice) with chronic glomerular disease (membranous glomerulonephritis and focal glomerular sclerosis), all diagnosed histologically. Serum albumin was > 2.4 g/dl and serum creatinine < 2.5 mg/dl in all patients. Treatment was given for periods of six weeks, followed by a prolonged follow-up for 27 weeks in 10 cases. Dietary supplementation with n-3 PUFA caused the expected reduction in platelet generation of thromboxane B2 (mean +/- SEM, from 490 +/- 70 ng/ml at baseline, to 342 +/- 147 ng/ml at 6 weeks, P < 0.05) of serum triglycerides (from 236 +/- 60 to 170 +/- 43, P < 0.01), and a prolongation of the bleeding time (from 5.8 +/- 0.4 min to 7.7 +/- 0.4 min, P < 0.01) in patients treated with ethyl esters. A modest but significant reduction in serum total cholesterol was noticed (from 275 +/- 27 to 252 +/- 24 mg/dl).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:n-3 fatty acids reduce proteinuria in patients with chronic glomerular disease. 825 59

We examined the role of ouabainlike compound in reduced renal mass-saline hypertension using a population of rats immunized with ouabain. To develop ouabain-immunized rats, ouabain-bovine serum albumin conjugates were injected subcutaneously three times at 4-week intervals. Titer determinations were made 2 weeks after the third immunization, and rats with high titers were used in the study. Immunoglobulin G fractions from ouabain-immunized rats effectively inhibited the contractile response of guinea pig aorta to exogenous ouabain (150 nmol). Fourteen ouabain-immunized and seven nonimmunized control rats underwent subtotal nephrectomy. An additional eight ouabain-immunized and six nonimmunized rats served as sham-operated rats. Four groups of rats drank 1% NaCl solution for 3 weeks, and systolic blood pressure was measured weekly by the tail-cuff method. Two groups of sham-operated rats remained normotensive. In contrast, two groups of subtotally nephrectomized rats developed hypertension. However, among these rats, systolic blood pressure was significantly lower in ouabain-immunized rats than in nonimmunized rats (161 +/- 5 versus 180 +/- 3 [+/- SEM) mm Hg, P < .01). The decrease in blood pressure was accompanied by a significant inhibition of aortic hypertrophy (P < .05). These results indicate that chronic blockade of circulating ouabainlike compound partly ameliorates reduced renal mass-saline hypertension and suggest that circulating ouabainlike compound may be involved in the pathophysiology in this model of hypertension.
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PMID:Participation of ouabainlike compound in reduced renal mass-saline hypertension. 828 41

In patients with cirrhosis and ascites decreased renal blood flow might be related to the severity of liver disease but the relationship between the severity of cirrhosis and renal perfusion has not yet been established. Thus we measured renal, systemic and splanchnic hemodynamics in 63 patients with ascites and in 28 without ascites. When compared to patients without ascites, patients with ascites had lower renal blood flow (1,170 +/- 100 vs. 935 +/- 55 ml/min/1.73 m2; mean +/- SEM, p < 0.05) and renal perfusion pressure (78 +/- 2 vs. 72 +/- 1 mm Hg, p < 0.05 and higher inferior vena cava pressure (6.5 +/- 0.7 vs. 10.7 +/- 0.7 mm Hg, p < 0.05). Patients with ascites had significantly higher serum bilirubin concentrations, hepatic venous pressure gradient and lower serum albumin concentrations, indocyanine green (ICG) extraction than patients without ascites. Renal vascular resistance, glomerular filtration rate, mean arterial pressure, cardiac index and systemic vascular resistance were not significantly different between the two groups. By multiple regression analysis no significant correlation was found between liver tests (i.e., prothrombin time, serum bilirubin and albumin concentrations, ICG extraction), hepatic venous pressure gradient, cardiac index and systemic vascular resistance on the one hand and renal blood flow on the other. No significant correlation was found between glomerular filtration rate and liver tests. In conclusion, in patients with cirrhosis and ascites, renal hypoperfusion is not related to the severity of liver disease.
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PMID:Renal hemodynamics in patients with cirrhosis: relationship with ascites and liver failure. 828 84

The high incidence of clinical remission after faecal diversion for Crohn's colitis suggests the faecal stream may play a part in the inflammatory mechanism. The effect of faecal diversion (n = 22) and restoration of intestinal continuity (n = 10) was assessed in patients with Crohn's colitis and compared with controls. Faecal diversion produced significant improvement in the disease activity index mean (SEM) (before 176 (9); after 114 (9), p < 0.01) and serum albumin concentrations (before 33 (3.0); after 38 (3.0), p < 0.05) in all patients with Crohn's colitis. The crypt cell production rate (CCPR) was maintained after faecal diversion for Crohn's colitis but fell in the control group (before = 3.6 (0.8)), at two (1.4 (0.4), p < 0.02), and six weeks (1.6 (0.4), p < 0.05). Mucosal glucosamine synthetase activity, reflecting glycoprotein synthesis, was significantly lower in patients with Crohn's colitis (analysis of variance p < 0.05) after diversion but was maintained in the control group. Restoration of intestinal continuity failed to produce reciprocal changes. The sustained cellular proliferation and fall in glycoprotein synthesis in Crohn's colitis after faecal diversion may represent the end of an exaggerated protective response and regenerative hyperplasia after exclusion of the faecal stream. This study suggests the faecal stream may participate in the inflammatory process in Crohn's colitis. The underlying mechanism is unknown.
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PMID:Faecal diversion for Crohn's colitis: a model to study the role of the faecal stream in the inflammatory process. 830 75

Malnutrition and low serum albumin values predict increased mortality in uremic patients. Infrared interactance represents a novel approach to the estimation of body composition. We have examined total body fat, body water and fat-free weight in our male haemodialysis (n = 24) and peritoneal dialysis (n = 17) patients. There were no differences between the groups in a cross-sectional study. A longitudinal study showed a significant increase of total body fat (%) in the peritoneal dialysis patients after five months (mean values +/- SEM) (from 19.8 +/- 2.3 to 22.6 +/- 2.4, p < 0.05), and a significant decrease of body water (%) (from 59.9 +/- 1.5 to 58.2 +/- 1.6, p < 0.05). The difference in total body fat between the haemodialysis (n = 14) and peritoneal dialysis (n = 10) groups reached statistical significance (16.5 +/- 1.7 versus 22.6 +/- 2.4, p < 0.05). No difference was found in serum albumin. Infrared interactance has the capacity to characterize time-dependent differential changes of body composition in various dialysis modalities. Further studies are needed to describe the validity of the method for identification of patients with increasing malnutrition.
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PMID:[Estimation of body composition in patients on dialysis by means of near-infrared interaction ]. 833 49

Low dose infusion of alpha human atrial natriuretic peptide (ANP) has been shown to cause a shift of intravascular fluid to the interstitial space. No studies have been reported on the effect of ANP on capillary permeability to plasma proteins. We studied the effect of low dose ANP (2.5 pmol/kg.min) or equal volume of saline control when infused over 90 min, on plasma volume, transcapillary escape rate of intravascular albumin, and the rate of reentry of albumin to the vascular space in eight normal subjects. Intravenous injection of 125I-human serum albumin was used for measurement of plasma volume and intravascular albumin escape rate. A significant ANP-induced fall in plasma volume (P < 0.01) was observed. Transcapillary escape rate of intravascular albumin when corrected for concurrent plasma volume changes showed a significantly greater escape during ANP infusion than during saline control (P < 0.05). The mean +/- SEM changes in plasma albumin concentration were +0.36 +/- 0.22 g/L.h during ANP infusion and -0.46 +/- 0.50 g/L.h during placebo. Plasma sodium, red cell volume, and urinary albumin and radioactivity remained unchanged. The mass of albumin reentering the circulation per hour showed no significant difference between the 2 days. In summary, low dose ANP infusion in healthy subjects caused a shift of plasma water and electrolytes from the circulation, with albumin escape as a secondary phenomenon.
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PMID:The effect of alpha human atrial natriuretic peptide on plasma volume and vascular permeability in normotensive subjects. 843 76

Two experiments were conducted in cyclic beef heifers to determine whether active immunization against bovine inhibin alpha 1-26 Gly-Tyr (bINH) affected follicular dynamics, hormone concentration or ovulation rate. In Expt 1, heifers (n = 9) were actively immunized against bINH conjugated to human alpha globulins (HAG) using bis-diazotized benzidine in non-ulcerative Freund's adjuvant (NUFA; primary on day 0; booster injections on days 53, 84 and 116 using conjugated bINH and on days 176 and 366 using unconjugated bINH; ten heifers were used as controls). Ovaries were examined daily using ultrasound scanning (days 70-155 and 384-391) and corresponding blood samples were collected for bINH antibody titre, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and oestradiol determinations. Four treated and four control heifers were injected with 10 micrograms gonadotrophin-releasing hormone (GnRH) on day 386 (day 2 of the oestrous cycle). Although bINH-immunized heifers had variable antibody titres ranging from 4 to 50% I125-labelled bINH bound to serum diluted 1:2000, ovulation rate was unaffected. In oestrous cycles with three dominant follicles, the ovulatory follicles grew faster (2.5 +/- 0.2 versus 1.6 +/- 0.3 mm day-1; mean +/- SEM), had shorter durations of growth (5.7 +/- 0.8 versus 9.6 +/- 1.6 days) and duration of detection (7.5 +/- 0.8 versus 12.0 +/- 2.4 days) in immunized heifers. Mean concentrations of FSH, LH and oestradiol were unaltered in most cases during oestrous cycles in bINH-immunized compared with control heifers. There was no significant difference in the percentage increase in FSH or LH, after GnRH injection, between control and immunized heifers. As ovulation rate was unaltered in the first experiment, a second similar study was designed using a different immunization protocol. In Expt 2, heifers were immunized with bINH conjugated to human serum albumin using glutaraldehyde with the following doses: 0.0 (control; n = 7), 0.33 (n = 7), 1.0 (n = 8) and 3.0 (n = 7) mg. Three booster immunizations were given 33, 66 and 209 days after primary immunization. Immunization increased the number of oestrous cycles with multiple ovulations (42 of 132 (32%) oestrous cycles examined) compared with controls (1 of 30 (3.3%) oestrous cycles examined). Neither titre nor ovulation rate was affected by dose of bINH used. In summary, following bINH immunization, ovulation rate was not increased despite changes in follicular dynamics in Expt 1, but was increased in 32% of oestrous cycles in Expt 2.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Active immunization of heifers against a synthetic fragment of bovine inhibin. 846 14

Recent evidence suggests that sulfhydryl species can react with oxides of nitrogen under physiologic conditions and thereby stabilize endothelium-derived relaxing factor (EDRF) activity, but the presence of a specific in vivo thiol carrier for nitric oxide (NO) remains controversial. The single free sulfhydryl of serum albumin is the most abundant thiol species in plasma (approximately 0.5 mM) and is particularly reactive towards NO. To examine the potential role of serum albumin in endogenous nitric oxide metabolism, we synthesized S-nitroso-BSA (S-NO-BSA), a model S-nitroso-protein, and examined its effects on platelet function and coronary and systemic vascular tone in 16 mongrel dogs. Intravenous bolus S-NO-BSA markedly reduced mean arterial pressure in a dose-dependent manner and proved seven and a half-fold less potent than intravenous nitroglycerin and 10-fold less potent than intravenous S-nitroso-cysteine (half-maximal response of 75 nmol/kg compared to 10 and 7.5 nmol/kg, respectively; P < 0.05); when given by intravenous infusion (half-maximal response = 10 nmol/kg per min), however, S-NO-BSA and nitroglycerin were equipotent. Intravenous bolus S-NO-BSA had a greater duration of action than either nitroglycerin or S-nitroso-cysteine and produced marked prolongation of the template bleeding time associated with dose-dependent inhibition of ex vivo platelet aggregation (half-maximal response approximately 70 nmol/kg). Intracoronary S-NO-BSA increased coronary blood flow (mean +/- SEM) less effectively than nitroprusside, acetylcholine, or S-nitroso-cysteine (165% +/- 24% vs. 315% +/- 82%, 483% +/- 55%, or 475% +/- 66%, respectively; P < 0.05) although with much longer duration of action. On a molar basis, S-nitroso-cysteine proved more effective than S-nitroso-BSA, nitroprusside, or acetylcholine as an epicardial coronary vasodilator. Thus, serum albumin reacts with oxides of nitrogen to form a stable S-nitroso-thiol with properties reminiscent of authentic EDRF supporting the view that protein associated thiol may participate in the action and metabolism of EDRF.
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PMID:NO forms an adduct with serum albumin that has endothelium-derived relaxing factor-like properties. 847 1

We measured ivermectin in plasma, urine, and saliva of nine patients with onchocerciasis. The aim was to establish pharmacokinetic parameters and to assess the most facile medium for use in monitoring compliance. Binding of ivermectin to plasma proteins in vitro was also investigated. The mean (+/- SEM) plasma values for the nine subjects were as follows: weight, 66.3 +/- 2.8 kg; dose, 11.11 +/- 0.4 mg; half-life, 56.50 +/- 7.01 hours; clearance, 142.5 +/- 22.6 L/kg; volume of distribution, 9.91 +/- 2.67 L/kg; area under the plasma concentration-time curve, 1545.3 +/- 190.5 ng/ml.hr; time to reach maximum concentration, 4.7 +/- 0.5 hours; and maximum concentration, 38.2 +/- 5.8 ng/ml. Ivermectin was not detected in the urine of any of the nine subjects. Low levels were found in saliva. Blood specimens remain the only reliable biologic fluid for assessment of compliance after ivermectin oral administration. Ivermectin binds specifically to human serum albumin.
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PMID:Protein binding and ivermectin estimations in patients with onchocerciasis. 847 58


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