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Biomedical subjects

A Fischer

Publications and source records attributed to A Fischer.

At least 343 records · Page 19Linked to original sources
PubMed1997

Localization of cholinergic nerves in lower airways of guinea pigs using antisera to choline acetyltransferase.

Primary antiserum to choline acetyltransferase (ChAT), a specific marker for cholinergic nerves, was used to characterize the distribution of cholinergic nerve fibers and nerve cell bodies in guinea pig airways. ChAT immunoreactive nerve fibers were localized to the smooth muscle throughout the conducting airways and in the lamina propria of the trachea and large bronchi. Likewise, all nerve cell bodies in the ganglia intrinsic to the trachea and bronchi displayed a cholinergic phenotype. By contrast, ChAT immunoreactive nerve fibers were infrequently seen in the lamina propria of the peripheral airways and were absent in the airway epithelium. No evidence for colocalization of ChAT and the enzyme synthesizing the putative relaxant neurotransmitter nitric oxide was observed. These results provide further evidence for the key role played by cholinergic nerves in regulating airway smooth muscle tone and bronchial blood flow and provide further evidence that acetylcholine is not coreleased with the neurotransmitter(s) mediating relaxations of airway smooth muscle.

Animals↗
PubMed1997

In vivo infusion of anti-LFA-1 and anti-CD2 antibodies prevents graft failure after HLA partially incompatible bone marrow transplantation in children with high risk acute lymphoblastic leukaemia.

Bone marrow transplantation (BMT) from matched sibling donors is the therapy of choice for children with high-risk acute lymphoblastic leukaemia in children. It is however not available to more than two-thirds of patients who lack a matched donor. Here, we review the outcome of 28 patients with high-risk ALL who were transplanted in France with alternative marrow sources such as HLA-phenoidentical unrelated volunteers and HLA-partially incompatible relatives. For these patients, we tested the possibility to prevent T-depleted marrow graft rejection by infusing in vivo two monoclonal antibodies directed against adhesion receptors i.e., LFA-1 and CD2. Two previous multicenter trials in children transplanted with partially incompatible bone marrow for inborn errors of metabolism showed their efficacy in this setting. Twenty eight patients were enrolled in this study and followed for a median of 4.4 years. Bone marrow engraftment occurred in 81% of the evaluable patients. Post-transplantation leukaemic relapse was the most frequent cause of death in this group of patients, and occurred in 39% of patients. The second most frequent complication was infectious disease, while an EBV-induced B-lymphocyte proliferative disorder occurred in four patients. In conclusion, T-cell-depletion combined with infusion of anti-LFA-1 and anti-CD2 antibodies is efficient in preventing graft failure and GVHD in this group of children with high-risk leukaemia undergoing partially incompatible BMT. The overall DFS is not improved in contrast to what has been previously observed in patients with immunodeficiencies transplanted with a similar rejection prophylaxis. Other approaches are therefore needed aiming either at preserving donor T-cell mediated immunity or accelerating immune reconstitution.

Antibodies, Monoclonal↗
PubMed1997

Rapid retrieval of neonatal outcomes data: the Kaiser Permanente Neonatal Minimum Data Set.

Although neonatal intensive care units are known to be expensive, much of what happens inside such units in managed care organizations is not known. One reason for this lack of knowledge is that existing database systems were not designed to capture information in modern critical care units. This article describes the development of a dedicated outcomes database and wide area network linking six level III intensive care nurseries in the Kaiser Permanente Medical Care Program's Northern California Region. This database can be considered a hybrid, in that it combines attributes of research and operational systems.

California↗
PubMed1997

[Genetic anomalies of the human immune system].

The development of genetic tools in the recent years has made possible the characterization of the molecular basis from several genetic disorders of the human system. These findings lead to a better understanding of the physiology of the human system as well as to the definition of improved diagnosis tools offering new perspectives in genetic counseling and therapeutics. Recently, genetic disorders of the regulation of the immune system have been described both in men and mice. These diseases are characterized by a defective control of activation/proliferation of lymphocytes and macrophages. Their study opens a new field in immunological research. Understanding of their molecular basis showed help to define susceptibility factors to autoimmune disorders.

Animals↗
PubMed1997

PP60c-src expression in osteoclasts from osteopetrotic children and in giant tumor cells.

Malignant infantile osteopetrosis is a severe congenital disease characterized by impaired osteoclast activity. Among the multiple factors that influence bone resorption, the c-src protooncogene product pp60c-src plays an essential role, since mice which lack pp60c-src develop osteopetrosis. To gain insight into the possible role of pp60c-csrc in the pathogenesis of infantile osteopetrosis, we examined the osteoclasts of three children displaying the typical features of the disease, aged respectively one, four and seven months. pp60c-csrc expression and localization, together with the expression of a 80/85-kilodalton pp60c-src substrate, cortactin, were examined by immunoelectron microscopy. Osteoclasts from two giant cell tumors were used as controls. Bone and tumor samples were fixed in 4% paraformaldehyde, included in LR-White resin at -30 degrees C and the sections processed with mAb 327 or mAb anti p80/85 by an immunogold technique. pp60c-src was expressed in the cytoplasm, in nuclear membranes and in nuclei of the osteoclasts of the three osteopetrotic children. The subcellular localization of the kinase was not different from the localization in giant tumor cells. In both cases cortactin was abundant. In conclusion, in three children with malignant osteopetrosis, pp60c-src expression in osteoclasts does not appear to be involved in the pathogenesis of the disease. The presence of this protein, however, does not necessarily reflect normal c-src tyrosine kinase activity, nor normal c-src-dependent intracellular signaling pathways. Moreover the presence of the protein in nuclear membranes, and especially around nuclear pores supports the hypothesis that in osteoclasts, c-src may participate in the regulation of RNA processing.

Adolescent↗
PubMed1997

[Therapy outcome of patients with soft-tissue sarcoma: retrospective analysis for identifying independent prognostic factors].

The postoperative outcome of 108 patients with soft tissue sarcoma (STS) of the extremities, the retroperitoneum, or the trunk was investigated retrospectively to identify independent factors for the over all survival and local tumor control. Chi-square single factor analysis and a Cox model were used to identify independent postoperative risk factors. Single factor analysis revealed a significant correlation with negative effect on overall survival for the variables metastasis (p < 0.0001), chemotherapy (p < 0.0009), surgical procedures (0.001), tumor size > 10 cm (p < 0.003), localization (retroperitoneum, trunk) (p < 0.03), and grading (G3/G4) (p < 0.03). Local tumor control was significantly correlated with the variable tumor size > 10 cm (p < 0.01). The Cox model showed a significant negative impact on overall survival for the factors metastasis (p < 0.002), tumor size > 10 cm (p < 0.004), grading (G3/G4) (p < 0.005), and sex (male) (p < 0.008). For local tumor control the variables were age (p < 0.006), and surgical procedures (p < 0.01).

Adolescent↗
PubMed1996

Correlation of vasoactive intestinal peptide and nitric oxide synthase with choline acetyltransferase in the airway innervation.

Vasoactive intestinal peptide (VIP) and nitric oxide (NO) are potent mediators of neural airway smooth muscle relaxation. The major contractile mediator released by airway nerves under physiological conditions is acetylcholine (ACh). In the present study, we have correlated the immunohistochemical distribution of the relaxant mediators using antisera to VIP, to the marker enzyme of catecholamine synthesis tyrosine hydroxylase (TH) and to the NO-generating enzyme NO-synthase (NOS) with the distribution of the ACh-synthesizing enzyme, choline acetyltransferase (ChAT), and of substance P (SP), a neuropeptide present in sensory nerve fibers. In guinea-pig airways, VIP- and NOS-immunoreactivity (IR) were present in numerous nerve fibers in the airway smooth muscle and around submucosal glands; some fibers were also seen in the lamina propria and around blood vessels. The neuronal cell bodies in the intrinsic ganglia were devoid of both VIP- and NOS-IR. In contrast, all neuronal cell bodies in the intrinsic ganglia were immunoreactive for ChAT. In human airways, immunoreactivity for VIP, NOS, and ChAT was found in airway intrinsic neuronal perikarya. Whereas ChAT-IR appeared to be most frequent in the cell bodies, VIP-IR was seen in the largest number of nerve fibers in the airways. Therefore, in guinea pigs, a clear neuroanatomical and neurochemical separation of relaxant and of constrictor pathways is seen, whereas in human airways, both separate pathways as well as coexpression of VIP-/NOS- and of ChAT-IR are found.

Animals↗
PubMed1996

Expression and function of TrkB variants in developing sensory neurons.

Mouse trigeminal neurons survive independently of neurotrophins when their axons are growing to their targets, and are then transiently supported by BDNF before becoming NGF dependent. During the stage of neurotrophin independence, transcripts encoding the BDNF receptor, TrkB, were expressed at very low levels. During the stage of BDNF dependence, high levels of a transcript encoding a receptor with the catalytic tyrosine kinase domain were expressed. Although the levels of this transcript fell as the neurons lost responsiveness to BDNF, there were concomitant increases in the expression of transcripts encoding TrkB variants lacking the kinase domain. Analysis of RNA from purified neurons showed that all of these transcripts were present in neurons. BDNF and NGF up-regulated the expression of these transcripts early in development but had little effect later on. To test whether truncated TrkB modulates BDNF signalling via catalytic TrkB, we injected TrkB expression plasmids into NGF-dependent sympathetic neurons. Whereas expression of catalytic TrkB alone conferred a BDNF survival response, co-expression of non-catalytic TrkB substantially reduced this response. Our results suggest that BDNF responsiveness in sensory neurons during development is modulated by the relative levels of catalytic and non-catalytic TrkB.

Animals↗
PubMed1996

Phosphatidylinositol 3-kinase participates in p56(lck)/CD4-dependent down-regulation of LFA-1-mediated T cell adhesion.

The mechanism inducing cell detachment in Ag-independent adhesion between lymphocytes is poorly understood. Different putative CD4 ligands, anti-CD4 Ab, a DR35-46 peptide mimicking residues 35 to 46 of HLA class II beta1, and a DR134-148 peptide mimicking residues 134 to 148 of HLA class II beta2, were previously found to down-regulate LFA-1-dependent adhesion between CD4+ T cells and HLA class II+ B cells. This down-regulation was shown to be p56(lck) dependent. Here we show that binding of these ligands to CD4 induced the activation of the tyrosine kinase p56(lck) associated with CD4 and also the lipid kinase phosphatidylinositol-3 kinase (PI3-kinase) associated with the CD4-p56(lck) complex in the HUT78 cell line. These events were not detected when p56(lck) was dissociated from CD4 in cell lines expressing mutated forms of CD4. It was also shown, using different inhibitors of the PI3-kinase (wortmannin, Ly294002, and antisense oligonucleotides), that this lipid kinase was necessary for the down-regulation of LFA-1-mediated adhesion induced by CD4 binding. These results strongly suggest that CD4-induced PI3-kinase activation, in the absence of concomitant TCR/CD3 triggering, leads to down-regulation of LFA-1-mediated T cell adhesion to B cells. The mechanism by which PI3-kinase could exert its effect remains unknown. Since PI3-kinase has previously been found to participate in the regulation of cytoskeleton structure, we propose that p56(lck)-associated PI3-kinase activation leads to a cytoskeleton organization unfavorable for LFA-1 function.

Amino Acid Sequence↗
PubMed1996

Induction of tachykinin gene and peptide expression in guinea pig nodose primary afferent neurons by allergic airway inflammation.

Substance P (SP), neurokinin A (NKA), and calcitonin gene-related peptide (CGRP) have potent proinflammatory effects in the airways. They are released from sensory nerve endings originating in jugular and dorsal root ganglia. However, the major sensory supply to the airways originates from the nodose ganglion. In this study, we evaluated changes in neuropeptide biosynthesis in the sensory airway innervation of ovalbumin-sensitized and -challenged guinea pigs at the mRNA and peptide level. In the airways, a three- to fourfold increase of SP, NKA, and CGRP, was seen 24 h following allergen challenge. Whereas no evidence of local tachykinin biosynthesis was found 12 h after challenge, increased levels of preprotachykinin (PPT)-A mRNA (encoding SP and NKA) were found in nodose ganglia. Quantitative in situ hybridization indicated that this increase could be accounted for by de novo induction of PPT-A mRNA in nodose ganglion neurons. Quantitative immunohistochemistry showed that 24 h after challenge, the number of tachykinin-immunoreactive nodose ganglion neurons had increased by 25%. Their projection to the airways was shown. Changes in other sensory ganglia innervating the airways were not evident. These findings suggest that an induction of sensory neuropeptides in nodose ganglion neurons is crucially involved in the increase of airway hyperreactivity in the late response to allergen challenge.

Animals↗
PubMed1996

Role of interleukin-2 (IL-2), IL-7, and IL-15 in natural killer cell differentiation from cord blood hematopoietic progenitor cells and from gamma c transduced severe combined immunodeficiency X1 bone marrow cells.

Natural killer (NK) cells are characterized by their ability to mediate spontaneous cytotoxicity against susceptible tumor cells and infected cells. They differentiate from hematopoietic progenitor cells. Patients with X-linked severe combined immunodeficiency (SCID X1) carry mutations in the gamma c cytokine receptor gene that result in lack of both T and NK cells. To assess the role of interleukin-2 (IL-2), IL-7, and IL-15 cytokines, which share gamma c receptor subunit, in NK cell differentiation, we have studied NK cell differentiation from cord blood CD34 (+) cells in the presence of either stem cell factor (SCF), IL-2, and IL-7 or SCF and IL-15. The former cytokine combination efficiently induced CD34 (+) CD7 (+) cord blood cells to proliferate and mature into NK cells, while the latter was also able to induce NK cell differentiation from more immature CD34 (+) CD7 (-) cord blood cells. NK cells expressed CD56 and efficiently killed K562 target cells. These results show that IL-15 could play an important role in the maturation of NK cell from cord blood progenitors. Following retroviral-mediated gene transfer of gamma c into SCID X1 bone marrow progenitors, it was possible to reproduce a similar pattern of NK cell differentiation in two SCID-X1 patients with SCF + IL-2 + IL-7 and more efficiently in one of them with SCF + IL-15. These results strongly suggest that the gamma c chain transduces major signal(s) involved in NK cell differentiation from hematopoietic progenitor cells and that IL-15 interaction with gamma c is involved in this process at an earlier step than IL-2/IL-7 interactions of gamma c are. It also shows that gene transfer into hematopoietic progenitor cells could potentially restore NK cell differentiation in SCID X1 patients.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1996

A human non-XLA immunodeficiency disease characterized by blockage of B cell development at an early proB cell stage.

We report a detailed analysis of a B cell defect affecting a patient girl born from first cousin parents, characterized by a severe non-X-linked agammaglobulinemia with a total absence of CD19- cells in the periphery. In the bone marrow, CD19 expression was also highly impaired, resulting in the absence of both B and preB compartments. By contrast, CD34+CD10+, CD34psiL+, and some CD19+CD10+ mostly CD34+ early proB cells were present, although diminished. Semiquantitative RT-PCR analysis performed on mononuclear bone marrow cells indicated that lambda-like, VpreB, Rag-1, Rag-2, and TdT transcripts expressed during proB cell stages were found at normal levels whereas E2A, CD10, Syk, Pax-5, CD19, Igalpha, Igbeta, VH-Cmu, and Vkappa-Ckappa transcripts characteristic of later stages were severely depressed. This phenotype resembles that of Pax-5 knock-out mice, but since the coding sequence of the patient Pax-5 cDNA was shown to be normal, the defect might rather result from an altered regulation of this gene. All these data indicate that the patient suffers from a new genetic defect that results in an arrest of differentiation within the proB cell compartment, i.e., earlier than X-linked agammaglobulinemia, before the onset of Ig gene rearrangements.

Agammaglobulinemia↗
PubMed1996

Clinical, immunological, and pathological consequences of Fas-deficient conditions.

BACKGROUND: The surface molecule named Fas/CD95, which is expressed on activated lymphocytes, can trigger cell death following interaction with its ligand (Fas L). This Fas-Fas-L interaction is thought to be a major regulatory mechanism for controlling the life span of peripheral lymphocytes, and therefore autoimmunity. METHODS: We assessed clinical, immunological and pathological features in three children who inherited mutations of the Fas-encoding gene. One infant had a genomic homozygous deletion, while two siblings had a heterozygous mutation in the fas gene. FINDINGS: The patient with a complete lack of Fas protein expression had prenatal onset of massive lymphoproliferation, which involved the spleen, the liver, and the intrathoracic and abdominal lymph nodes. Lymphoproliferation mainly involved T cells negative for the CD4 and CD8 receptors. These cells, which had a high mitotic index, were essentially found in the T cell zones of lymphoid organs. Active cell division was indicated by a rapid rise in the lymphocyte count following a chemotherapy-induced reduction in the lymphocyte burden. Despite the total Fas protein deficiency, limited autoimmunity was found in this child at age 1 year. A lymphoproliferative syndrome with similar characteristics--but less intense than in the patient with complete Fas deficiency--also occurred from a young age in the siblings with a fas gene mutation on one allele only. One sibling developed neutropoenia, autoimmune haemolytic anaemia, and severe recurrent thrombocytopoenia. INTERPRETATION: Fas-deficiency causes a non-malignant syndrome characterised by the accumulation of dividing lymphocytes. Severity of disease is probably related to the degree of functional Fas deficiency. Heterozygous fas gene mutations, like homozygous deletions, can also be expressed in various cells and tissues and may predispose towards autoimmune disorders. Fas deficiency should be considered in children with enlarged peripheral lymphoid organs and hyperimmunoglobulinaemia, and sometimes the occurrence of autoimmune manifestations towards blood cells.

Anemia, Hemolytic↗