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Biomedical subjects

M Pascual

Publications and source records attributed to M Pascual.

At least 19 recordsLinked to original sources
PubMed1997

Biological effects and fate of a soluble, dimeric, 80-kDa tumor necrosis factor receptor in renal transplant recipients who receive OKT3 therapy.

A preliminary clinical study of renal allograft recipients revealed that a dimeric form of the human 80 kDa soluble receptor (sTNFR:Fc) for tumor necrosis factor (TNF) is well tolerated and attenuates the OKT3-induced acute clinical syndrome. The current study determined the in vivo biological effects and fate of sTNFR:Fc in these patients. Serial assessment of both antigenic and biological activities of circulating TNF and sTNFR:Fc have led to the following observations. (1) Although control patients typically responded to the first OKT3 injection with a rapid increase of biologically active TNFalpha, patients on sTNFR:Fc therapy had markedly higher serum TNFalpha antigenic levels, but no detectable bioactivity. Thus, sTNFR:Fc functioned as a potent antagonist, despite its cytokine-carrier effect. (2) Peak sTNFR:Fc levels averaging 800 and 2500 ng/ml were routinely achieved in vivo, using the low-dose (0.05 mg/kg) and high-dose (0.15 mg/kg) protocols. (3) The half-life of circulating sTNFR:Fc was estimated to be approximately 4.4 days, and levels of p80 receptors in treated patients remained significantly above those in control patients for at least 20 days. (4) In vitro blocking studies demonstrated that circulating sTNFR:Fc remained biologically active for 2 weeks. These results demonstrate that under current protocols, significant serum levels of sTNFR:Fc, capable of effectively neutralizing TNF activity over prolonged periods, can be achieved. The persistent OKT3 side effects observed, despite sTNFR:Fc therapy, are therefore likely to be caused by factors other than TNF.

Dimerization↗
PubMed1997

Diagnosis of sibling species of Drosophila involved in the colonization of North America by D. subobscura.

To determine the effects of the recent colonization of the west coast of North America by the Palaearctic species Drosophila subobscura on the dynamics of the Drosophila populations, the sibling species D. athabasca and D. azteca must be classified unambiguously. We have characterized these two species using three molecular techniques: allozymes, mtDNA and RAPDs. All three techniques allow the classification of any individual as belonging to either species. The study of five localities in northern California and southern Oregon show that the area of overlap is larger than previously described.

Animals↗
PubMed1997

Acute renal failure: role of dialysis membrane biocompatibility.

Recent clinical studies of acute renal failure in adults have focused attention on the biocompatibility of the dialysis membrane as a possible factor influencing patient morbidity and mortality. In this article, we review the concept of dialysis membrane biocompatibility and highlight the difficulty of finding an ideal definition. We then expand on the possible roles of complement and neutrophil activation by dialysis membranes, which may prolong the recovery from acute renal failure. The results of several clinical studies analyzing the impact of dialysis membranes on the course and outcome of acute renal failure are discussed. Finally, the possible relevance of biocompatibility in continuous renal replacement therapies is emphasized.

Adult↗
PubMed1997

Paraproteins and complement depletion: pathogenesis and clinical syndromes.

Various clinical syndromes that associate paraproteinemia and complement depletion have been described in the last three decades. Among these, cryoglobulinemias, acquired Clq deficiency, and acquired deficiencies of the classical pathway of complement can be associated with B-cell lymphoproliferative disorders. Some specific symptoms should alert the clinician to suspect an underlying malignancy. In this report, we review the pathogenesis, symptomatology and therapeutic options of these clinical conditions.

Agammaglobulinemia↗
PubMed1996

Upregulation of BDNF mRNA expression in the barrel cortex of adult mice after sensory stimulation.

Upregulation of brain-derived neurotrophic factor (BDNF) mRNA expression by neuronal activity has been reported in cultured hippocampal cells and in different in vivo excitotoxic paradigms. The aim of the present study was to determine whether sensory stimulation of the whisker-to-barrel pathway alters BDNF mRNA expression in the cortex and, if so, to evaluate the specificity of this effect. To this end, a set of mystacial whiskers was unilaterally stimulated by mechanical deflection, and the expression of BDNF mRNA was analyzed in the barrel cortex by in situ hybridization (ISH) using a 35S-labeled antisense BDNF riboprobe and emulsion autoradiography. A clear-cut and specific upregulation of the BDNF mRNA expression was found at the level of the somatosensory cortex after the increased peripheral stimulation. In the barrel cortex of control mice, BDNF mRNA was present in a few cells in layers II/III and VI, whereas it was almost undetectable in layer IV. After 6 hr of whisker stimulation, increased levels of BDNF mRNA were found in layers II to VI of the contralateral barrel cortex. In layer IV, BDNF upregulation was confined to the barrels corresponding to the stimulated follicles. ISH combined with immunocytochemistry against the three calcium-binding proteins parvalbumin, calretinin, and calbindin-D28K revealed that BDNF mRNA-expressing cells do not belong to the GABAergic cell population of the barrel cortex. The present results support a role for BDNF in activity-dependent modifications of the adult cerebral cortex.

Animals↗
PubMed1996

Expression of NGF and NT3 mRNAs in hippocampal interneurons innervated by the GABAergic septohippocampal pathway.

We used in situ hybridization for the detection of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin 3 (NT3) mRNAs combined with immunocytochemistry against the calcium-binding proteins parvalbumin (PARV), calbindin 28k (CALB), and calretinin (CALR) to determine the expression of neurotrophins in functionally distinct subsets of hippocampal interneurons. Most PARV-immunoreactive neurons in the hippocampus were NGF mRNA-positive (82%), which corresponds to 71% of NGF-positive neurons in the hippocampus proper and in the dentate gyrus (excluding granule cells). In contrast, only a subset of CALB- and CALR-immunoreactive interneurons (24% and 23%, respectively) displayed hybridization signals for NGF. Small subsets of PARV- and CALR-positive cells expressed NT3 mRNA, but we did not find hippocampal interneurons expressing BDNF mRNA. These results show that NGF and NT3 genes are differentially regulated in distinct subsets of GABAergic cells, and these interneurons are a major source of NGF production in the hippocampus. We also addressed whether hippocampal interneurons expressing neurotrophins were targets of the GABAergic septohippocampal pathway. We developed a triple-labeling method that combines anterograde tracing of this pathway by means of Phaseolus vulgaris leucoagglutinin injections, with in situ hybridization for the detection of neurotrophins, and immunocytochemistry for calcium-binding proteins. Virtually every PARV-positive neuron innervated by GABAergic septohippocampal baskets expressed NGF mRNA (86%), whereas 39-59% of CALR- and CALB-positive interneurons that were contacted by GABAergic septohippocampal axons showed NGF gene expression. A small subset of NT3 mRNA-expressing interneurons was also innervated by septohippocampal baskets. These findings show that the GABAergic septohippocampal pathway preferentially terminates on interneurons expressing NGF mRNA, suggesting that this neurotrophic factor might be involved in the specification of this connection and in its maintenance and normal function in the adult brain.

Afferent Pathways↗
PubMed1996

New synthetic sulfated oligosaccharides prolong survival of cardiac xenografts by inhibiting release of heparan sulfate from endothelial cells.

Binding of recipient natural antibodies to the endothelium of the graft, complement activation, endothelial cell activation, and microvascular thrombosis are major events in the hyperacute rejection of organ xenografts. The aim of this study was to investigate the effects of two new synthetic sulfated oligosaccharides (A and B) on the survival of discordant cardiac xenografts in the guinea pig-to-rat model. In untreated recipients, hyperacute rejection occurred in 5 min (median; range, 4-6 min) and immunohistological analysis of all the grafts revealed deposition of IgM and C3 along the endothelium. Administration of oligosaccharides A and B prior to revascularization prolonged the survival of xenografts in a dose-dependent manner, up to 113 min (median; range, 42-145 min) and 86 min (median; range, 35-108 min), respectively, when doses of 20 mg/kg were used. There were no bleeding complications. Histological examination of the rejected grafts showed a picture of hyperacute rejection, with no difference in IgM and C3 deposition as compared with the untreated animals. In cell culture experiments, the release of heparan sulfate from guinea pig cardiac endothelial cells induced by rat serum was inhibited by both saccharides in a dose-dependent manner. The results indicate that these new synthetic sulfated oligosaccharides are effective for prolongation of discordant xenograft survival, possibly by interfering with endothelial cell activation. Such substances may be of value in other xenotransplant combinations.

Acute Disease↗
PubMed1996

Preliminary description of focal segmental glomerulosclerosis in patients with renovascular disease.

BACKGROUND: Primary and secondary forms of focal segmental glomerulosclerosis (FSGS) are common causes of glomerular proteinuria. Secondary forms of FSGS seem to be the result of adaptive changes that follow a reduction in renal mass. We saw an elderly patient with severe bilateral renal vascular disease (RVD) who had FSGS on percutaneous biopsy. To find out whether elderly patients with atherosclerotic RVD are predisposed to the development of FSGS, we reviewed all cases of FSGS at our institution between 1990 and 1995. METHODS: We identified 59 cases of biopsy-proven FSGS and examined clinical, histological, and radiographic records. FINDINGS: Of the 59 patients, 24 were older than 50 years; eight of these had RVD. No patient under the age of 50 had RVD. Seven of the eight patients with RVD and FSGS had substantial proteinuria at presentation. All had typical glomerular lesions with focal segmental tuft collapse and synechiae; other glomeruli were hypertrophic. All patients showed further decline in renal function on follow-up. INTERPRETATION: The association of FSGS and RVD may represent an under-recognised aetiology of significant proteinuria in elderly patients.

Aged↗
PubMed1996

Evaluation of recombinant human soluble dimeric tumor necrosis factor receptor for prevention of OKT3-associated acute clinical syndrome.

Tumor necrosis factor alpha (TNFa) has been shown to be the primary cytokine responsible for the OKT3-induced acute clinical syndrome (OKT3-ACS). Recombinant human soluble tumor necrosis factor receptor (TNFR:Fc) is a dimer of the p80 TNF receptor, which binds both TNFa and lymphotoxin (LT). Renal allograft recipients undergoing OKT3 therapy for steroid-resistant rejection were randomized to receive OKT3 alone or in combination with TNFR:Fc to determine its safety and efficacy in decreasing the severity of OKT3-ACS and in restoring renal function. Six of 12 patients were given TNFR:Fc prior to each of the first two injections of OKT3. All patients were monitored for manifestations of OKT3-ACS and changes in renal function. In addition, serial serum samples were assayed for TNFa and TNFR:Fc levels (ELISA) and TNFa bioactivity (L929). No adverse side effects were identified in patients receiving TNFR:Fc. Patients treated with TNFR:Fc had significantly fewer symptoms by day 2 of OKT3, and had a lower overall incidence of chills and arthralgias. Renal dysfunction reversed within 24 hr in the TNFR:Fc-treated group in contrast to the 48-72-hr delay in the control group. Antigenic TNFa levels increased in the control group from < 10 pg/ml pre OKT3 to a mean peak level of 30 +/- 13 pg/ml on day 1 and decreased to pretreatment levels by day 2. TNFR:Fc-treated patients had a mean peak TNFa level of 235 +/- 135 pg/ml, suggesting a carrier effect of TNFR:Fc. In contrast, bioactivity was barely detectable (mean 20 +/- 14 pg/ml) in the day 1 samples from TNFR:Fc-treated patients, whereas significant bioactivity (peak mean 60 +/- 35 pg/ml) was detected in sera from control patients. TNF receptor levels reached 600 ng/ml in treated patients and remained elevated for up to 18 days confirming the long half-life of TNFR:Fc. This phase 1 trial demonstrates that TNFR:Fc is well tolerated and may limit the severity of OKT3-ACS. The most significant observation was a more rapid improvement in renal function in the TNFR:Fc-treated patients. The absence of TNFa bioactivity indicates that TNFR:Fc functions as a TNF antagonist. Further evaluation of higher doses of TNFR:Fc in OKT3-treated patients is currently in progress.

Acute Disease↗
PubMed1996

Molecular basis of hereditary C1q deficiency associated with SLE and IgA nephropathy in a Turkish family.

Two siblings (case 1 and case 2) with homozygous C1q deficiency are described. Both presented with a photosensitive rash, and during follow-up case one developed SLE with nephrotic range proteinuria. Case 2 had microscopic hematuria with a past history of macroscopic hematuria. Renal biopsies revealed mesangioproliferative glomerulonephritis in case 1 and IgA nephropathy in case 2, a new finding in association with C1q deficiency. Since the classical pathway of complement plays a role in the development of antibody responses, the family was also evaluated for the immune response to hepatitis B vaccine. Antibody response to hepatitis B vaccine was normal in both affected members and the rest of the family. The A-, B- and C- chain genes of C1q were amplified by PCR and directly sequenced. A homozygous C to T point mutation was identified in genomic DNA isolated from the patients at codon 186 in the A chain that resulted in a premature stop codon. This mutation was present in both parents and both unaffected sibs in the heterozygous state. This mutation was identical to that previously described in a Slovakian family with C1q deficiency. Because of this finding, a series of 92 genomic DNA samples was screened from ethnically distinct patient groups with SLE to test the hypothesis that this mutation of C1q may be a widespread disease susceptibility gene. No further examples of this mutation were found.

Adolescent↗
PubMed1996

Complement depletion during haemofiltration with polyacrilonitrile membranes.

BACKGROUND: Polyacrylonitrile (PAN, AN69) dialysis membranes have been shown to improve the outcome of critically ill patients. Factor D is an essential enzyme of the alternative pathway of complement and is increased during renal failure. On the other hand the contact of blood with biomaterials activates the complement cascade through the alternative pathway. PAN filters adsorb factor D which looses its enzymatic activity whilst bound to the membrane [1]; the complement alternative pathway function of serum exposed to PAN filters is greatly diminished and restored after addition of purified factor D [1]. The aim of our study was to measure the time course of factor D adsorption and its blood concentration during CVVH in critically ill patients with acute renal failure. METHODS: We studied seven critically ill patients with ARF before, during and after continuous veno-venous haemofiltration (CVVH) with AN69. RESULTS: There was a rapid decrease of factor D levels to 62(+/-6%) of the pre-CVVH value during the first 2 h, which continued to 51(+/-7.3%) after 12 h; at 24 h there was a slight rise to 62 +/- 12%. Sequential use of Polyacrylonitrile (AN69) filters lowered factor D levels below the normal plasma concentration in three patients, thus producing a state of factor D depletion. CONCLUSION: The significant reduction of factor D levels during CVVH with PAN filters suggests that frequent changes of PAN filters may reduce alternative pathway function by lowering factor D levels. CVVH (as opposed to intermittent dialysis) with PAN membranes may further improve the outcome of critically ill patients.

Acrylic Resins↗
PubMed1995

Insulin-like growth factor I (IGF-I) affects plasma lipid profile and inhibits the lipolytic action of growth hormone (GH) in isolated adipocytes.

The actions of insulin-like growth factor I (IGF-I) and growth hormone (GH) on lipid metabolism have been investigated in hormonally intact rats. The subcutaneous injection of IGF-I (100 micrograms) and GH (100 micrograms) lowered total cholesterol plasma levels. The in vitro assays on isolated rat adipocytes showed an antilipolytic effect of IGF-I on GH induced lipolysis. All these data support an important role for IGF-I and GH on the regulation of lipid metabolism.

Adipocytes↗