Nucleation of calcium oxalate crystals by albumin: involvement in the prevention of stone formation.
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BACKGROUND: Urine is supersaturated in calcium oxalate, which means that it will contain calcium oxalate crystals that form spontaneously. Their size must be controlled to prevent retention in ducts and the eventual development of a lithiasis. This is achieved, in part, by specific inhibitors of crystal growth. We investigated whether promoters of crystal nucleation could also participate in that control, because for the same amount of salt that will precipitate from a supersaturated solution, increasing the number of crystals will decrease their average size and facilitate their elimination. METHODS: Albumin was purified from commercial sources and from the urine of healthy subjects or idiopathic calcium stone formers. Its aggregation properties were characterized by biophysical and biochemical techniques. Albumin was then either attached to several supports or left free in solution and incubated in a metastable solution of calcium oxalate. Kinetics of calcium oxalate crystallization were determined by turbidimetry. The nature and efficiency of nucleation were measured by examining the type and number of neoformed crystals. RESULTS: Albumin, one of the most abundant proteins in urine, was a powerful nucleator of calcium oxalate crystals in vitro, with the polymers being more active than monomers. In addition, nucleation by albumin apparently led exclusively to the formation of calcium oxalate dihydrate crystals, whereas calcium oxalate monohydrate crystals were formed in the absence of albumin. An analysis of calcium oxalate crystals in urine showed that the dihydrate form was present in healthy subjects and stone formers, whereas the monohydrate, which is thermodynamically more stable and constitutes the core of most calcium oxalate stones, was present in stone formers only. Finally, urinary albumin purified from healthy subjects contained significantly more polymers and was a stronger promoter of calcium oxalate nucleation than albumin from idiopathic calcium stone formers. CONCLUSIONS: Promotion by albumin of calcium oxalate crystallization with specific formation of the dihydrate form might be protective, because with rapid nucleation of small crystals, the saturation levels fall; thus, larger crystal formation and aggregation with subsequent stone formation may be prevented. We believe that albumin may be an important factor of urine stability. (+info)
Overexpression of sialomucin complex, a rat homologue of MUC4, inhibits tumor killing by lymphokine-activated killer cells.
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Sialomucin complex (SMC) is a large heterodimeric glycoprotein complex composed of a mucin subunit ascites sialoglycoprotein-1 and a transmembrane subunit ascites sialoglycoprotein-2. It is a rat homologue of human mucin gene MUC4 and is abundantly expressed on the cell surface of highly metastatic ascites 13762 rat mammary adenocarcinoma cells. Because of their extended and rigid structures, mucin-type glycoproteins are suggested to have suppressing effects on cell-cell and cell-matrix interactions. During the metastatic process, these effects presumably cause tumor cell detachment from the primary tumor mass and facilitate escape of the tumor cells from immunosurveillance. Analyses of human breast cancer cells in solid tumors and tumor effusions showed that the more aggressive cells in effusions are stained with polyclonal antibodies against SMC more frequently than cells in solid tumors, suggesting a role for MUC4/SMC in tumor progression and metastasis. Previously, we generated recombinant cDNAs for SMC that vary in the number of mucin repeats to study the putative functions of SMC in tumor metastasis. These cDNAs were transfected into human cancer cell lines and tested for the effect of the expression of this gene. Here, using a tetracycline-responsive inducible expression system, we demonstrate that overexpression of SMC masks the surface antigens on target tumor cells and effectively suppresses tumor cell killing by cytotoxic lymphocytes. This effect results from the ability of SMC to block killer cell binding to the tumor cells and is dependent on both overexpression of the mucin and the number of mucin repeats in the expressed SMC. These results provide an explanation for the proposed role of SMC/MUC4 in tumor progression. (+info)
Transcranial Doppler pattern after intracarotid papaverine and prostaglandin E1 incorporated in lipid microsphere in patients with vasospasm.
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We studied the effects of intracarotid papaverine and prostaglandin E1 incorporated in lipid microsphere (Lipo-PGE1) in relation with transcranial Doppler parameters such as mean flow velocity (MFV) and pulsatile index (PI) of the proximal segment of the middle cerebral artery. Eighty patients with subarachnoid hemorrhage (SAH) were included in this study. In the case of angiographic vasospasm, papaverine at 7 mg/min with total dose below 300 mg per artery and 10-20 micrograms of Lipo-PGE1 were injected in the supraclinoid portion of the internal carotid artery. Vasospasm was improved in 24 patients (63%), however, it was unchanged in 14 patients (37%). The former patients had more favorable outcomes than the latter patients (p < 0.005). After intracarotid injection therapy, the correlation between MFV and PI was classified into three types: type 1, both MFV and PI decreased; type 2, MFV decreased but PI increased; and type 3, both MFV and PI fluctuated. The Glasgow Outcome Scale 3 months after SAH was as follows: type 1 (n = 15), good in 14 (93%) and moderate disability in one (7%); type 2 (n = 9), good in eight (89%) and vegetative state in one (11%); and type 3 (n = 14), moderate disability in five (36%), severe disability in seven (50%), and death in two (14%). Chi-square analysis showed significant differences between type 1 and type 3 (p < 0.005), and type 2 and type 3 (p < 0.005). In conclusion, intracarotid papaverine combined with Lipo-PGE1 was effective for vasospasm but type 3 patients require a different treatment protocol. (+info)
Gastric emptying and intestinal transit of pancreatic enzyme supplements in cystic fibrosis.
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OBJECTIVE: To investigate gastric emptying and intestinal transit of pelleted pancreatin in relation to food boluses. METHODS: Dual isotope scintigraphy combined with breath hydrogen sampling was used to track the concurrent gastric emptying and intestinal transit of 111indium labelled microspheres and a 99mtechnetium labelled tin colloid test meal. Twelve pancreatic insufficient cystic fibrosis patients aged 5 to 38 years performed the study. RESULTS: 50% gastric emptying times showed patient to patient variation. The mean discrepancy in 50% gastric emptying times between the two labels was > 67 minutes. Mean small bowel transit time for the food bolus was prolonged at 3.6 minutes. A significant correlation was seen between weight standard deviation score and 50% emptying time for pancreatin (r = +0.73). CONCLUSION: Gastric mixing of food and pancreatin may be limited by rapid emptying of microspheres. Patients with high dosage requirements could benefit from changing the pattern of their pancreatin supplementation. (+info)
2-Deoxyglucose selectively inhibits Fc and complement receptor-mediated phagocytosis in mouse peritoneal macrophages. I. Description of the inhibitory effect.
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Incubation of normal or thioglycollate-elicited mouse peritoneal macrophages with 2-deoxy-D-glucose (2-dG) inhibits the capacity of these macrophages to phagocytize IgG- or complement-coated particles via their Fc and C3 receptors. 2-dG has no inhibitory effect on the capacity of these macrophages to phagocytize latex or zymosan particles, which are ingested in the absence of specific opsonins, and it does not inhibit binding of IgG- or C3-coated particles to their respective receptors on the macrophage's plasma membrane. 2-dG exerts its inhibitory effect on the macrophage and not on the opsonized particle. The inhibition is independent of particle size, occurs within 15-30 min of addition of this glucose analogue to the medium at 37 degrees C, cannot be overcome by supra-agglutinating amounts of opsonizing antibody, and is completely reversible by substitution of 5.5 mM glucose for 50 mM 2-dG in the medium. Addition of equimolar amounts of glucose or mannose, but not of fructose, galactose, fucose, or glucosamine, to medium containing 50 mM 2-dG results in substantial reversal of the inhibitory effect of 2-dG on Fc and C3 receptor mediated phagocytosis. (+info)
Experimental colitis increases blood-brain barrier permeability in rabbits.
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Extraintestinal manifestations of inflammatory bowel disease are numerous. This study examined the effects of two models of acute colitis on cerebral blood flow (CBF) and permeability of the blood-brain barrier in rabbits. CBF (measured with radiolabeled microspheres), or the extraction ratio or permeability-surface area (PS) product of the blood-brain barrier to fluorescein and FITC-dextran, was measured 48 h after colitis induction with acetic acid (HAc) or trinitrobenzene sulfonic acid (TNBS). PS product for fluorescein increased (P < 0.05) in TNBS colitis (1.33 x 10(-5) +/- 0.52 x 10(-5) ml/s and 0.48 x 10(-5) +/- 0.13 x 10(-5) ml/s (mean +/- SE) for treated (n = 14) and untreated (n = 10) animals, respectively. PS product for the larger FITC-dextran was not different in TNBS colitis (0.24 x 10(-5) +/- 0.09 x 10(-5) ml/s, n = 7) compared with untreated controls (0.19 x 10(-5) +/- 0.04 x 10(-5) ml/s, n = 8). PS product for fluorescein increased (P < 0.01) in HAc colitis compared with vehicle (2.66 x 10(-5) +/- 1.46 x 10(-5) ml/s and 0.33 x 10(-5) +/- 0.05 x 10(-5) ml/s, respectively; n = 6 in each group). The extraction of fluorescein from the blood to the brain increased by 75% during TNBS colitis when compared with vehicle (P < 0.05). CBF and cerebrovascular resistance did not change from the untreated control after TNBS colitis. Our data suggest that, irrespective of induction method, acute colitis increases the permeability of the blood-brain barrier to small molecules without changing CBF. (+info)
A new sample-processing unit for the fluorescent microsphere method.
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The use of fluorescent-labeled microspheres (FM) for measurement of regional blood flow is an attractive alternative to the use of radioactive-labeled microspheres. In the FM method the FM have to be completely recovered from the tissue samples in a time- and labor-intensive process. For this reason, a considerable loss of FM is possible. The aim of this study was to develop a filtration device that allows the tissue sample to remain in a single container throughout the procedure to make the process easier and to avoid the loss of FM. The core of the sample-processing unit (SPU) is a single-tube filtration device with a polyamide wire mesh. The protocol for processing tissue from different organs (heart, kidney, liver, spleen, intestine, muscle, bone, lung, brain) was modified and thus shortened significantly. Furthermore, the SPU allows direct filtration of the blood reference sample without previous digestion. Different experiments showed that the SPU in combination with the new protocol excludes the loss of 15-micrometers FM. The modifications of the whole procedure render it faster and highly standardized. (+info)
A pharmacokinetic/pharmacodynamic model for recombinant human growth hormone effects on induction of insulin-like growth factor I in monkeys.
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The pharmacokinetics of recombinant human growth hormone (rhGH) and its effects on the induction of insulin-like growth factor I (IGF-I) were studied in juvenile rhesus monkeys. Disposition profiles of rhGH from two short-term i.v. infusion studies were described by a two-compartment model yielding a clearance of 16.1 ml/min and T1/2 of 2.0 h. Four rhGH treatment groups were included in this study: group A, ProLease rhGH (24 mg), a sustained-release microsphere formulation; group B, a single s.c. injection plus an implanted osmotic pump (24.4 mg); group C, a single s.c. injection (25.9 mg); group D, daily 0.86-mg s.c. injection for 28 days. Their rhGH input profiles were analyzed by a numerical deconvolution method. ProLease and osmotic pump provided zero-order inputs of rhGH and maintained the serum rhGH concentrations around 9 to 13 ng/ml for 16 (group A) and 30 days (group B). For s.c. injections, rhGH underwent first-order absorption. An indirect response model was applied based on use of a Hill function for stimulation of IGF-I production. Parameter values obtained included Smax = 2.2, SC50 = 6.5 ng/ml, and gamma (slope coefficient) = 6.8, which were applicable to all treatments. The area under effect curve showed group B to be most effective for IGF-I induction, whereas group A produced the highest peak level in 16 days. Group C had the lowest induction among the four groups, despite being given the highest dose. Group D had modest IGF-I induction, but the pulsatile rhGH input is less effective than continuous input provided by ProLease. Our pharmacokinetic/pharmacodynamic model demonstrates that ProLease and osmotic pump delivery were best able to maintain rhGH level above the s.c.50 value, which provided more effective IGF-I induction compared with the single or daily subcutaneous injections in solution. (+info)