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Biomedical subjects

A Fischer

Publications and source records attributed to A Fischer.

At least 235 records · Page 13Linked to original sources
PubMed1999

[Role of calcineurin-dependent drugs on the immunosuppressive effect induced by the anti-LFA-1 antibody in a fetal intestinal transplantation model in mice].

STUDY AIM: We have previously demonstrated that anti-LFA-1 monoclonal antibody (mAb) can efficiently protect against rejection of small bowel allograft in a mouse model. The aim of the present work was to determine, in the same model, the optimum conditions for utilisation of anti-LFA-1 mAb and the effects of calcineurin-dependent drugs on the immunosuppression induced by anti-LFA-1 mAb treatment. MATERIALS AND METHODS: Foetal small intestines of C57Bl/6 (H-2b) mice were transplanted into adult C3H/He (H-2k) mice. Recipients were treated with anti-LFA-1 mAb alone (with or without day-1 injection), or combined to cyclosporin (20 mg.kg-1.j-1 for 14 days), or to tacrolimus (1 mg.kg-1.j-1 from day 0 to day 7). Biopsies were performed after engraftment from day 5 to day 30. RESULTS: Administration of anti-LFA-1 mAb alone is sufficient to induce significant prolongation of intestinal allograft survival, provided that the treatment starts one day before engraftment. This tolerogenic effect is reversed by the transitory administration of tacrolimus (p = 0.008). CONCLUSION: Treatment with anti-LFA-1 mAb has to be started before the allogeneic response has begun. Calcineurin-dependent drugs can modulate the tolerogenic effect induced by anti-LFA-1. A transgenic mice model should give precise details about underlying mechanisms of these interactions, before a possible utilisation of anti-LFA-1 mAb in intestinal transplantation in humans.

Animals↗
PubMed1999

Cerebral microemboli during left heart catheterization.

BACKGROUND: The aim of this study was to describe the rate of microemboli signals (MES) during left heart catheterization (LHC). METHODS: A monitoring of both middle cerebral arteries using transcranial Doppler ultrasonography was performed to investigate cerebral microemboli during LHC. Seventy-two patients undergoing LHC and 29 patients with LHC followed by coronary intervention were studied. RESULTS: During a standardized LHC (n = 52), 95 +/- 45 MES were detected of which 67.5% occurred during injection of contrast media or saline solution, 30% during movements of wire and catheter, and 2% during catheter manipulation. During coronary interventions only, rotablation (n = 2) was followed by a massive increase in MES. The use of injection fluids prepared with minor gas content reduced the MES rate by 67% (P <.05). All MES were clinically silent. CONCLUSIONS: Cerebral microembolism is a current finding during LHC. The dependence of the MES rate during diagnostic LHC on the gas content of the injection fluids provides evidence that most of the MES are caused by microbubbles and not by solid emboli. The high rate of MES during coronary rotablation may be explained by the formation of cavitation bubbles. The clinical results of the MES during LHC appear to be benign.

Adult↗
PubMed1999

Abundant production of brain-derived neurotrophic factor by adult visceral epithelia. Implications for paracrine and target-derived Neurotrophic functions.

Brain-derived neurotrophic factor (BDNF) plays a crucial role for the survival of visceral sensory neurons during development. However, the physiological sources and the function of BDNF in the adult viscera are poorly described. We have investigated the cellular sources and the potential role of BDNF in adult murine viscera. We found markedly different amounts of BDNF protein in different organs. Surprisingly, BDNF levels in the urinary bladder, lung, and colon were higher than those found in the brain or skin. In situ hybridization experiments revealed that BDNF mRNA was made by visceral epithelial cells, several types of smooth muscle, and neurons of the myenteric plexus. Epithelia that expressed BDNF lacked both the high- and low-affinity receptors for BDNF, trkB and p75(NTR). In contrast, both receptors were present on neurons of the peripheral nervous system. Studies with BDNF-/-mice demonstrated that epithelial and smooth muscle cells developed normally in the absence of BDNF. These data provide evidence that visceral epithelia are a major source, but not a target, of BDNF in the adult viscera. The abundance of BDNF protein in certain internal organs suggests that this neurotrophin may regulate the function of adult visceral sensory and motor neurons.

Animals↗
PubMed1999

Early and prolonged intravenous immunoglobulin replacement therapy in childhood agammaglobulinemia: a retrospective survey of 31 patients.

OBJECTIVE: To evaluate the outcome of children who received prolonged intravenous immunoglobulin (IVIg) replacement therapy early in life for X-linked agammaglobulinemia (XLA). STUDY DESIGN: We performed a retrospective study of the clinical features and outcome of patients with genetic and/or immunologic results consistent with XLA. Patients receiving IVIg replacement therapy within 3 months of the diagnosis and for at least 4 years between 1982 and 1997 were included. RESULTS: Thirty-one patients began receiving IVIg replacement therapy at a median age of 24 months and were followed up for a median time of 123 months. IVIg was given at doses >0.25 g/kg every 3 weeks, and mean individual residual IgG levels ranged from 500 to 1140 mg/dL (median, 700 mg/dL). During IVIg replacement, the incidence of bacterial infections requiring hospitalization fell from 0.40 to 0.06 per patient per year (P <. 001). However, viral or unidentified infections still developed, including enteroviral meningoencephalitis (n = 3) causing death in one patient, exudative enteropathy (n = 3), and aseptic arthritis (n = 1). At last follow-up, 30 patients were alive at a median age of 144 months (range, 58 to 253 months). Among 23 patients who were evaluated by respiratory function tests and computed tomography, 3 had an obstructive syndrome, 6 had bronchiectasis, and 20 had chronic sinusitis. CONCLUSION: Early IVIg replacement therapy achieving residual IgG levels >500 mg/dL is effective in preventing severe acute bacterial infections and pulmonary insufficiency. More intensive therapy may be required to fully prevent the onset of bronchiectasis, chronic sinusitis, and nonbacterial infections, particularly enteroviral infections, in all cases.

Agammaglobulinemia↗
PubMed1999

Influence of severe combined immunodeficiency phenotype on the outcome of HLA non-identical, T-cell-depleted bone marrow transplantation: a retrospective European survey from the European group for bone marrow transplantation and the european society for immunodeficiency.

We analyzed the outcomes of 214 HLA non-identical T-cell-depleted bone marrow transplantations (BMTs), performed in 178 consecutive patients for treatment of severe combined immunodeficiencies (SCID). Patients were treated in 18 European centers between 1981 and March 1995. SCID variants, that is, absence of T and B lymphocytes (B-) or absence of T cells with presence of B lymphocytes (B+) were found to have a major influence on outcome. The disease-free survival was significantly better for patients with B+ SCID (60%) as compared with patients with B- SCID (35%) (P =.002), with a median follow-up of 57 months and 52 months, respectively. Other factors associated with a poor prognosis were the presence of a lung infection before BMT (odds ratio = 2.47 [1.99-2.94]) and the use of monoclonal antibodies for T-cell depletion of the graft (odds ratio = 1.67 [1. 18-2.15]). Additional factors influencing outcome were age at BMT (<6 months) and period during which BMT was performed. Better results were achieved after 1991. Reduced survival of patients with B- SCID was associated with a higher incidence of early deaths from infection, a diminished rate of marrow engraftment, a trend to a higher incidence of chronic graft-versus-host disease, and slower kinetics of T/B immune function development. In both groups of patients, the use of busulfan (8 mg/kg total dose) and cyclophosphamide (200 mg/kg total dose) as a conditioning regimen provided the best cure rate (74% for patients with B+ SCID and 43% for patients with B- SCID, respectively), although results were not statistically significantly different from other regimens. This retrospective analysis should lead to the design of adapted measures to the performance of HLA non-identical BMT in patients with distinct SCID conditions.

Age Factors↗
PubMed1999

Thrombosis and coagulation abnormalities in the acute coronary syndromes.

The acute coronary syndromes, that include unstable angina, acute myocardial infarction, and many cases of sudden cardiac death, exact a considerable price on society in terms of mortality, morbidity, and health care costs. The coronary atherosclerotic lesion is often an indolent and progressive entity that can destabilize causing an acute syndrome with or without warning. The majority of acute coronary syndromes result from events such as rupture or disruption of the atherosclerotic plaque with intracoronary thrombosis and ischemia of the distal myocardium as a result. Advances in our understanding of the process underlying the acute coronary syndromes has allowed for the identification of targets and rational therapeutic strategies for the prevention and treatment of these syndromes. Many of these therapeutic strategies involve the reversal of prethrombotic forces that often coexist with coronary atherosclerosis. Even with recent advances in our approach to atherosclerosis, intracoronary thrombosis, and the resulting acute coronary syndromes, an unacceptably high event rate persists after these syndromes. Further advances in the prevention and treatment of coronary atherosclerosis and its thrombotic complications depends on a more thorough understanding of the biology of the atherosclerotic plaque and the factors which influence its stability.

Angina, Unstable↗
PubMed1999

Defective priming of the phagocyte oxidative burst in a child with recurrent intracellular infections.

Human phagocytes (polymorphonuclear neutrophils and monocytes) play a critical role in host defense against invading microorganisms. Recent studies reported that circulating phagocytes undergo a final maturation process, in particular in terms of oxidative burst, during extravasation and migration to local sites of inflammation. This process is known as priming. We report here on a nine-year-old boy with successive disseminated infections due to intracellular microorganisms (Mycobacterium bovis, BCG, and Salmonella typhimurium). No T- or B-cell quantitative or qualitative defects were found. Polymorphonuclear neutrophil (PMN) migration and NADPH oxidase in PMNs and monocytes stimulated with various agents at optimal concentrations were normal, ruling out a leukocyte adhesion deficiency syndrome, a Chediak Higashi syndrome, and a chronic granulomatous disease. Nevertheless, the patient's PMNs and monocytes showed defective priming capacity, as measured by H(2)O(2) production after pretreatment with LPS (5 microg/mL for 30 min), TNFalpha (100 units/mL for 30 min), or IL-8 (50 ng/mL for 30 min) in response to bacterial N-formyl peptides (fMLP 10(-6) M for 5 min). In these conditions, H(2)O(2) production of PMNs and monocytes from the patient did not exceed that of the samples treated with fMLP or LPS alone, while the controls strongly produced H(2)O(2). Moreover, monocytes from the patient showed an impaired capacity to kill S. typhimurium in vitro. Such an impairment could be related at least in part to the priming deficiency of phagocyte oxidative burst. This case suggests, for the first time, that in vivo priming processes are critical in host defence against intracellular pathogens.

Adult↗
PubMed1999

Effect of toluene diisocyanate and its corresponding amines on viability and growth of human lung fibroblasts in culture.

Toluene diisocyanate (TDI) is a highly volatile chemical known to cause occupational asthma in exposed workers. TDI-induced asthma is associated with airway epithelium injury and repair, and subepithelial fibrosis. We investigated the effect of TDI and its hydrolysis products, the 2,4- and 2,6-toluenediamines (TDA), on viability and growth of human lung fibroblasts (HLFs) in culture, using a tetrazolium-based cell viability assay. The effects of increasing concentrations of each of these chemicals were evaluated on quiescent cells seeded at two densities (2500 and 5000 cells/well) and treated for 24 or 48 h. TDI (10(-4)-10(-5) mol/L, as a mixture of 80% 2,4-TDI and 20% 2,6-TDI) exhibited a partial but significant cytotoxic effect (10-24%, p<0.05) on HLFs. This effect was observed at both cell densities, and was time- and concentration-dependent. 2,4-TDA, at lower concentrations (10(-8)-10(-6) mol/L) applied for 48 h, also partially reduced HLF viability (10-15%, p<0.05), whereas it tended to trigger cell growth at concentrations higher than 10(-5) mol/L. 2,6-TDA exhibited both a cytotoxic and a proliferative effect on HLFs that depended on concentration, time of exposure and cell culture density. Significant cytotoxicity was only observed after 24 h of treatment with 10(-7)-10(-6) mol/L 2,6-TDA, and reached greater intensity in cells cultured at the highest density. In contrast, 2,6-TDA stimulated HLF growth only after 48 h of incubation at 10(-4) mol/L on cells cultured at the lowest density. Taken together, our results showed that TDI and 2,4-TDA somewhat decreased HLF viability, whereas 2,6-TDA appeared to exhibit both a cytotoxic and a growth stimulatory effect on these cells. TDI and 2,4-TDA are thus suggested to contribute to airway epithelium damage associated with TDI-induced asthma, whereas 2,6-TDA might either trigger epithelial damage or induce cell proliferation that could contribute to epithelium repair or subepithelial fibrosis.

Asthma↗
PubMed1999

Renal function one year after switching from Sandimmun to Neoral.

BACKGROUND: The replacement of Sandimmun by Neoral in 1995 was thought to cause subsequent renal function deterioration due to the better bioavailability of the new drug. We prospectively analyzed the effect of a dose-to-dose drug replacement on renal function over 12 months. METHODS AND RESULTS: The renal function of 47 consecutive heart transplanted patients was prospectively evaluated before (T0), at 1 (T1), 3 (T3), and 12 (T12) months after drug replacement. Mean serum creatinine was not significantly different at T0 and T12 (142 +/- 55 and 154 +/- 60 micromol/L, p = 0.1). We were able to reduce cyclosporine total and weight-indexed doses by, respectively, 11% and 14% between T0 and T12 (274 +/- 86 to 244 +/- 72 mg/d, p = 0.0003; and 3.7 +/- 1.4 to 3.2 +/- 1.2 mg/kg/d, respectively, p = 0.0005). CONCLUSIONS: This study demonstrates that the dose-to-dose replacement of Sandimmun by Neoral is feasible, with no direct influence on renal function over a 1-yr follow-up.

Cyclosporine↗
PubMed1999

A human IFNGR1 small deletion hotspot associated with dominant susceptibility to mycobacterial infection.

The immunogenetic basis of severe infections caused by bacille Calmette-Guérin vaccine and environmental mycobacteria in humans remains largely unknown. We describe 18 patients from several generations of 12 unrelated families who were heterozygous for 1 to 5 overlapping IFNGR1 frameshift small deletions and a wild-type IFNGR1 allele. There were 12 independent mutation events at a single mutation site, defining a small deletion hotspot. Neighbouring sequence analysis favours a small deletion model of slipped mispairing events during replication. The mutant alleles encode cell-surface IFNgamma receptors that lack the intra-cytoplasmic domain, which, through a combination of impaired recycling, abrogated signalling and normal binding to IFNgamma exert a dominant-negative effect. We thus report a hotspot for human IFNGR1 small deletions that confer dominant susceptibility to infections caused by poorly virulent mycobacteria.

Adolescent↗
PubMed1999

Naloxone blocks endomorphin-1 but not endomorphin-2 induced inhibition of tachykinergic contractions of guinea-pig isolated bronchus.

The recently identified endogenous agonists on the mu-opioid-receptor (mu OR), endomorphin-1 (EM-1) and endomorphin-2 (EM-2), induce a concentration dependent inhibition of electrical field stimulation (EFS)-induced tachykinin-mediated contractions of the guinea-pig bronchus (ED50s < 10 nM for both compounds). Surprisingly, only endomorphin-1 effects could be blocked by naloxone (10 microM), whereas endomorphin-2 effects were not affected by specific antagonists for the mu-, kappa-, and delta-opioid-receptor.

Analgesics, Opioid↗
PubMed1999

Chediak-Higashi syndrome associated with maternal uniparental isodisomy of chromosome 1.

Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disorder (incidence around 1 in 106 births), characterised by a complex immunologic defects, reduced pigmentation, and presence of giant granules in many different cell types. It most likely results from defective organellar trafficking or protein sorting. The causative gene (LYST) has recently been identified and shown to be homologous to the beige locus in the mouse. CHS has always been reported associated with premature-termination-codon mutations in both alleles of LYST. We report a unique patient with CHS, who was homozygous for a stop codon in the LYST gene on chromosome 1 and who had a normal 46,XY karyotype. The mother was found to be a carrier of the mutation, whereas the father had two normal LYST alleles. Non-paternity was excluded by the analysis of microsatellite markers from different chromosomes. The results of 13 informative microsatellite markers spanning the entire chromosome 1 revealed that the proband had a maternal isodisomy of chromosome 1 encompassing the LYST mutation. The proband's clinical presentation also confirms the absence of imprinted genes on chromosome 1.

Alleles↗
PubMed1999

The mitosome, a novel organelle related to mitochondria in the amitochondrial parasite Entamoeba histolytica.

Ultrastructural analysis of Entamoeba histolytica reveals that this intestinal human pathogen lacks recognizable mitochondria, but the presence in its genome of genes encoding proteins of mitochondrial origin suggests the existence of a mitochondrially derived compartment. We have cloned the full-length E. histolytica gene encoding one such protein, chaperonin CPN60, and have characterized its structure and expression. Using an affinity-purified antibody raised against recombinant protein, we have localized native E. histolytica CPN60 to a previously undescribed organelle of putative mitochondrial origin, the mitosome. Most cells contain only one mitosome, as determined by immunofluorescence studies. Entamoeba histolytica CPN60 has an amino-terminal extension reminiscent of known mitochondrial and hydrogenosomal targeting signals. Deletion of the first 15 amino acids of CPN60 leads to an accumulation of the truncated protein in the cytoplasm. However, this mutant phenotype can be reversed by replacement of the deleted amino acids with a mitochondrial targeting signal from Trypanosoma cruzi HSP70. The observed functional conservation between mitochondrial import in trypanosomes and mitosome import in Entamoeba is strong evidence that the E. histolytica organelle housing chaperonin CPN60 represents a mitochondrial remnant.

Amino Acid Sequence↗
PubMed1999

The role of the fourth extracellular domain of the rat corticotropin-releasing factor receptor type 1 in ligand binding.

The role of the fourth extracellular loop (e4) of rat corticotropin-releasing factor (CRF) receptor, type 1, in ligand binding was investigated using chimeric receptor molecules. e4 of CRF receptor, type 1, was replaced by the corresponding domains of two other G protein-coupled receptors, the rat glucagon receptor or the human pituitary adenylate cyclase activating polypeptide (PACAP) receptor. Both chimeras were transported properly to the cell membranes of transfected chinese hamster ovary cells as indicated by immunocytochemical analysis. Ovine CRF (oCRF) was bound specifically, but with low affinity (Kd = 2-5 microm). Cyclic AMP was not accumulated intracellularly in response to increasing concentrations of oCRF. Based on these data, it is concluded that e4 of rat CRF receptor, type 1, is involved in ligand binding. To confirm the importance of e4 in binding CRF, three negatively charged amino acids of e4, Glu336, Asp337 and Glu338, were replaced by Gln, Asn and Gln, respectively. No effect on ligand binding and cyclic AMP accumulation was observed (Kd = 5 nm; EC50 = 1.5 nm). However, when Tyr346, Phe347 and Asn348 of e4 were changed to three alanine residues, ligand binding affinity as well as efficacy in cyclic AMP accumulation were significantly decreased (Kd = 64 nm; EC50 = 32 nm).

Animals↗
PubMed1999

Cervical esophagogastric anastomosis: results following esophagectomy for carcinoma.

We reviewed our experience with 262 consecutive two-layer, hand-sewn cervical esophageal anastomoses in patients undergoing surgery for esophageal carcinoma. Anastomotic leak rates were determined for the entire group and the frequency of post-operative esophageal dilatations was obtained for the first 101 patients. It was assumed that the frequency of dilatations would reflect the frequency of anastomotic strictures. The overall leak rate was 0.8% (two patients). Overall hospital mortality was 2.7%. No patient died as a result of anastomotic leakage. In our series, 26% of patients required at least one dilatation. If a dilatation was needed, the majority occurred within the first 6 months. We conclude that using a standardized, two-layer hand-sewn anastomotic technique cervical esophageal anastomoses may be performed safely with results similar to those reported using intrathoracic techniques.

Aged↗