Effect of alpha-trinositol on interstitial fluid pressure, oedema generation and albumin extravasation in experimental frostbite in the rat.
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1. The anti-inflammatory effect of alpha-trinositol (D-myo-inositol-1,2,6-trisphosphate) on oedema formation, microvascular protein leakage and interstitial fluid pressure (Pif) in rat skin after frostbite injury, was investigated. Alpha-trinositol (40 mg kg body weight(-1)) was administered intravenously as a bolus both before and/or in the interval between freezing and thawing of the tissue. 2. Pif was measured in rat paw skin with micropipettes connected to a servo-controlled counterpressure system. Oedema formation was estimated by measuring the increase in total tissue water content (wet weight minus dry weight divided by dry weight). Albumin extravasation (i.e., the difference between the plasma equivalent space for 125I- and 131I-human serum albumin (HSA) circulating for different time intervals) was used to estimate the microvascular leakage. 3. Compared to untreated animals, alpha-trinositol given pre- and/or post-freeze reduced total tissue water and albumin extravasation as well as the fall in Pif in injured tissue significantly (P<0.05). Alpha-trinositol given only post-freeze reduced total tissue water and albumin extravasation from 4.46+/-0.93 and 2.37+/-1.12 to 2.51+/-0.29 and 0.36+/-0.18 ml g dry weight(-1), respectively (P<0.05). 4. Pif fell from -0.8+/-0.2 mmHg pre-freeze to -3.4+/-1.0 mmHg (P<0.05) at 20 min after tissue injury (circulatory arrest) and was attenuated by treatment with alpha-trinositol. 5. We conclude that alpha-trinositol exerts its anti-oedematous effect by acting on the extracellular matrix, attenuating the lowering of Pif as well as on the microvascular wall, thereby decreasing the protein extravasation. (+info)
Cellular disposition of sulphamethoxazole and its metabolites: implications for hypersensitivity.
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1. Bioactivation of sulphamethoxazole (SMX) to chemically-reactive metabolites and subsequent protein conjugation is thought to be involved in SMX hypersensitivity. We have therefore examined the cellular metabolism, disposition and conjugation of SMX and its metabolites in vitro. 2. Flow cytometry revealed binding of N-hydroxy (SMX-NHOH) and nitroso (SMX-NO) metabolites of SMX, but not of SMX itself, to the surface of viable white blood cells. Cellular haptenation by SMX-NO was reduced by exogenous glutathione (GSH). 3. SMX-NHOH and SMX-NO were rapidly reduced back to the parent compound by cysteine (CYS), GSH, human peripheral blood cells and plasma, suggesting that this is an important and ubiquitous bioinactivation mechanism. 4. Fluorescence HPLC showed that SMX-NHOH and SMX-NO depleted CYS and GSH in buffer, and to a lesser extent, in cells and plasma. 5. Neutrophil apoptosis and inhibition of neutrophil function were induced at lower concentrations of SMX-NHOH and SMX-NO than those inducing loss of membrane viability, with SMX having no effect. Lymphocytes were significantly (P<0.05) more sensitive to the direct cytotoxic effects of SMX-NO than neutrophils. 6. Partitioning of SMX-NHOH into red blood cells was significantly (P<0.05) lower than with the hydroxylamine of dapsone. 7. Our results suggest that the balance between oxidation of SMX to its toxic metabolites and their reduction is an important protective cellular mechanism. If an imbalance exists, haptenation of the toxic metabolites to bodily proteins including the surface of viable cells can occur, and may result in drug hypersensitivity. (+info)
Granulocyte-macrophage colony-stimulating factor prevents the progression of atherosclerosis via changes in the cellular and extracellular composition of atherosclerotic lesions in watanabe heritable hyperlipidemic rabbits.
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BACKGROUND: A cytokine network is involved in atherogenesis. This study was conducted to investigate the effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) on the development and composition of atherosclerotic lesions in Watanabe heritable hyperlipidemic (WHHL) rabbits. METHODS AND RESULTS: GM-CSF (10 microg. kg-1. d-1) was administered to 4-month-old WHHL rabbits (n=9) 5 days a week for 7.5 months, whereas an equal dose of human serum albumin was administered to controls (n=9). The cholesterol levels were not changed significantly by the treatment. Age-matched 4-month-old rabbits (n=7) had atheromatous plaques over 30.7+/-5.7% of the inner surface area of the aortic arch. After treatment, the percentages of surface atheromatous plaques to total aortic arch area were 45.0+/-12.6% in the GM-CSF group and 74.3+/-11.0% in controls (P<0.0001). Histological examination demonstrated that GM-CSF reduced the ratio of intima to media (P<0.01) and cross-sectional areas of atherosclerotic lesions (P<0.0001). Quantitative analysis indicated a marked decrease in the areas of smooth muscle cells (P=0.0001), collagen (P=0.0001), and extracellular lipid deposits (P<0.05) of atheromatous plaques in GM-CSF-treated rabbits compared with controls. The terminal deoxynucleotidyltransferase-mediated dUTP-digoxigenin nick end-labeling (TUNEL) method and immunohistochemistry were performed to examine the relationship between decreased atherosclerotic lesions and apoptosis. The percentage of TUNEL-positive cells increased in the GM-CSF group (GM-CSF, 24.1+/-4.4% versus control, 11.6+/-3.2%; P<0.0001). GM-CSF enhanced the apoptosis of smooth muscle cells in the shoulder region and the fibrous cap (P<0.0001), suggesting one of the mechanisms for the antiatherogenic effect. CONCLUSIONS: GM-CSF altered the composition of atherosclerotic lesions and reduced the atherosclerosis in WHHL rabbits. (+info)
Albumin modifies the metabolism of hydroxyeicosatetraenoic acids via 12-lipoxygenase in human platelets.
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12-Lipoxygenase and cyclooxygenase 1 are the dominating enzymes that metabolize arachidonic acid in human platelets. In addition to the conversion of arachidonic acid to 12(S)-hydroxyeicosatetraenoic acid, 12-lipoxygenase can also utilize 5(S)-hydroxyeicosatetraenoic acid and 15(S)-hydroxyeicosatetraenoic acid to form 5(S), 12(S)-dihydroxyeicosatetraenoic acid and 14(R), 15(S)-dihydroxyeicosatetraenoic acid, respectively. Furthermore, 15(S)-hydroxyeicosatetraenoic acid works as an inhibitor for 12-lipoxygenase. In the present paper we have studied the influence of albumin on the in vitro metabolism of 5 - and 15 -hydroxyeicosatetraenoic acids, and 5,15 -dihydroxyeicosatetraenoic acid by the platelet 12-lipoxygenase. The presence of albumin reduced the formation of 5(S),12(S)- dihydroxyeicosatetraenoic acid from 5(S)-hydroxyeicosatetraenoic acid, however, it had no effect on the 12(S)-hydroxyeicosatetraenoic acid production from endogenous arachidonic acid. In contrast, when 15(S)-hydroxyeicosatetraenoic acid was incubated with activated platelets, the formation of 14(R), 15(S)- dihydroxyeicosatetraenoic acid was stimulated by the presence of albumin. Furthermore, albumin reduced the inhibitory action 15(S)-hydroxyeicosatetraenoic acid had on 12(S)-hydroxyeicosatetraenoic acid formation from endogenous arachidonic acid. However, addition of exogenous arachidonic acid (20 microm) to the incubations inverted the effects of albumin on the conversion of 15(S)-hydroxyeicosatetraenoic acid to 14(R),15(S)- dihydroxyeicosatetraenoic acid and the production of 12(S)-hydroxyeicosatetraenoic acid in these incubations. Based on the Scatchard equation, the estimates of the binding constants to albumin were 1.8 x 10(5) for 15 -HETE, 1.4 x 10(5) for 12-HETE, and 0.9 x 10(5) for 5 -HETE respectively. These results suggest an important role of albumin for the regulation of the availability of substrates for platelet 12-lipoxygenase. (+info)
Identification of a peptide from mammal albumins responsible for enhanced pigment production by group B streptococci.
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The peptide from peptones responsible for enhanced pigment production by Streptococcus agalactiae in culture media has been isolated from a peptic digest of human albumin and has been identified as Ile-Ala-Arg-Arg-His-Pro-Tyr-Phe. The related heptapeptide lacking the N-terminal Ile also had pigment-enhancing activity. A sequence similarity search showed that these sequences are present only in mammal albumins. (+info)
Association of morbidity with markers of nutrition and inflammation in chronic hemodialysis patients: a prospective study.
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BACKGROUND: Numerous studies suggest a strong association between nutrition and clinical outcome in chronic hemodialysis (CHD) patients. Nevertheless, the pathophysiological link between malnutrition and morbidity remains to be clarified. In addition, recent evidence suggests that nutritional indices may reflect an inflammatory response, as well as protein-calorie malnutrition. In this study, we prospectively assessed the relative importance of markers of nutritional status and inflammatory response as determinants of hospitalization in CHD patients. METHODS: The study consisted of serial measurements of concentrations of serum albumin, creatinine, transferrin, prealbumin, C-reactive protein (CRP), and reactance values by bio-electrical impedance analysis (BIA) as an indirect measure of lean body mass every 3 months over a period of 15 months in 73 CHD patients. Outcome was determined by hospitalizations over the subsequent three months following each collection of data. RESULTS: Patients who required hospitalization in the three months following each of the measurement sets had significantly different values for all parameters than patients who were not hospitalized. Thus, serum albumin (3.93 +/- 0.39 vs. 3.74 +/- 0.39 g/dl), serum creatinine (11.0 +/- 3.7 vs. 9.1 +/- 3.5 mg/dl), serum transferrin (181 +/- 35 vs. 170 +/- 34 mg/dl), serum prealbumin (33.6 +/- 9.2 vs. 30.0 +/- 10.1 mg/dl), and reactance (50.4 +/- 15.6 vs. 43.0 +/- 13.0 ohms) were higher for patients not hospitalized, whereas CRP (0.78 +/- 0.89 vs. 2.25 +/- 2.72 mg/dl) was lower in patients who were not hospitalized. All differences were statistically significant (P < 0.05 for all parameters). When multivariate analysis was performed, serum CRP and reactance values were the only statistically significant predictors of hospitalization (P < 0.05 for both). When a serum CRP concentration of 0.12 mg/dl was considered as a reference range (relative risk 1.0), the relative risk for hospitalization was 7% higher (relative risk = 1.07) for a CRP concentration of 0.92 mg/dl and was 30% (relative risk = 1.30) higher for a CRP concentration of 3.4 mg/dl. When a reactance value of 70 ohms was considered as a reference range with a relative risk of 1.0, the relative risk of hospitalization increased to 1.09 for a reactance value of 43 ohms and further increased to 1.14 for a reactance value of 31 ohms. CONCLUSIONS: The results of this study strongly indicate that both nutritional status and inflammatory response are independent predictors of hospitalization in CHD patients. CRP and reactance values by BIA are reliable indicators of hospitalization. Visceral proteins such as serum albumin, prealbumin, and transferrin are influenced by inflammation when predicting hospitalization. When short-term clinical outcomes such as hospitalizations are considered, markers of both inflammation and nutrition should be evaluated. (+info)
Trends in clinical indicators of care for adult peritoneal dialysis patients in the United States from 1995 to 1997. ESRD Core Indicators Workgroup.
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BACKGROUND: This article describes the changes in four core indicator variables: dialysis adequacy, hematocrit, serum albumin, and blood pressure in peritoneal dialysis CAPD and cycler patients over a three-year period. METHODS: A national random sample of adult peritoneal dialysis patients in the United States was drawn each study period. Clinical data abstraction forms were completed by facility staff for patients selected for the sample, returned to the respective network, then forwarded to the Health Care Financing Administration for analysis. RESULTS: The mean weekly Kt/V urea for CAPD patients increased from 1.91 in 1995 to 2.12 in 1997 (P < 0.001) and for cycler patients, from 2.12 in 1996 to 2.24 in 1997 (P < 0.05). The mean weekly creatinine clearance for CAPD patients increased from 61.48 liter/week/1.73 m2 in 1995 to 65.84 liter/week/1.73 m2 in 1997 (P < 0.05). For cycler patients, it increased from 63.37 liter/week/1.73 m2 in 1996 to 67.45 liter/week/1.73 m2 in 1997 (P < 0.05). Despite this increase in adequacy values, less than 40% of peritoneal dialysis patients in 1997 had weekly Kt/V urea or creatinine clearance values that met subsequently published National Kidney Foundation's Dialysis Outcomes Quality Initiative (DOQI) guidelines. These data suggest that the dialysis prescription may not be adequately modified to compensate for increased body weight and for decreased residual renal function as years on dialysis increase. The average hematocrit value increased modestly in both CAPD and cycler patients from 1995 to 1997, and the number of patients with a hematocrit of less than 25% decreased from 6% in 1995 to 1.4% in 1997 (P < 0.001). Both serum albumin values and systolic and diastolic blood pressure values were essentially unchanged during the three-year period of observation. CONCLUSIONS: Despite improvements in dialysis adequacy and hematocrit values, there remains much room for improvement in these core indicator values. (+info)
Evidence for the genetic control of antibody affinity from breeding studies with inbred mouse strains producing high and low affinity antibody.
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The amount (Abt) and relative affinity (KR) of antibody produced in response to protein antigens injected in saline has been measured in the parents, F1 hybrids and backcross offspring of inbred mice which produce high and low KR antibody to these antigens. The results obtained support the view that antibody affinity is under polygenic control. Furthermore, strain related variation in Abt is independent of KR and the breeding experiments indicate that these two parameters are under independent genetic control. (+info)