Mitochondrial DNA deletion in Pearson's marrow/pancreas syndrome.
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Anemia, Sideroblastic↗
Biomedical subjects
A Fischer
Publications and source records attributed to A Fischer.
The tumor-rejection antigens of the 1591 ultraviolet fibrosarcoma. Potential origin and evolutionary implications.
Previously, we cloned and sequenced the three novel MHC class I genes expressed by the C3H UV fibrosarcoma, 1591. We have extended the analysis of the polymorphic nature of these genes relative to the C3H strain. Scattered nucleotide differences among the tumor genes as compared with the C3H H-2 and Qa sequences make it highly unlikely that the novel tumor genes were generated by recombination between endogenous C3H sequences. Given that two of the tumor clones, A149 and A166, are remarkably similar in amino acid and DNA sequence to H-2Lq and H-2Dq, respectively, we also examined the 1591 RP2 and GUS loci for evidence of polymorphism. Compared with C3H and B10.AKM, 1591 appears to be heterozygous at each of these loci, consistent with an H-2q origin for the two novel 1591 class I genes. Interestingly, the third tumor gene, designated A216, shares certain characteristics with the H-2Ks antigen, reminiscent of the naturally occurring combination of H-2Ks, H-2Dq, and H-2Lq antigens found in some Swiss mouse strains. As a result, we propose that the non-C3H/HeN characteristics displayed by the 1591 tumor point to a non-C3H origin for the novel tumor class I genes of 1591.
Amino Acid Sequence↗
Hypoglycaemia induced by antibodies to insulin receptor following a bone marrow transplantation in an immunodeficient child.
Severe hypoglycaemia developed seven months after a bone marrow transplantation in a child with severe combined immunodeficiency. His serum exerted potent insulin-like activity: (a) it stimulated insulin receptor autophosphorylation and kinase activity in cell-free systems, this effect being additive to insulin; (b) it increased glucose transport in isolated soleus muscle. These insulin-like effects were due to immunoglobulins against the insulin receptor. Indeed, the patient serum immunoprecipitated human or murine insulin receptors from different tissues and inhibited insulin binding to receptor on human IM-9 lymphocytes. After corticoids and immunosuppressive therapy by azathioprine, the patient hypoglycaemic episodes disappeared, and concomitantly, the antibodies to insulin receptor were no longer detected, as judged by both immunoprecipitation of insulin receptor and stimulation of glucose transport.
Animals↗
Ultrastructure of calcitonin gene-related peptide- and substance P-like immunoreactive nerve fibres in the carotid body and carotid sinus of the guinea pig.
Previous studies have demonstrated that substance P- (SP) and calcitonin gene-related peptide-like immunoreactivities (CGRP-LI) coexist in sensory nerve fibres in the guinea-pig carotid body and carotid sinus. In the present study the ultrastructure of these nerve fibres was investigated by means of single- and double-labelling immunocytochemistry. In both, carotid body and carotid sinus immunoreactive fibres were unmyelinated axons of small diameter (0.12-0.56 microns). At the subcellular level, SP- and CGRP-LI were colocalized in intra-axonal dense core vesicles, suggesting corelease and simultaneous action of these two compounds. SP/CGRP-LI nerve fibres within the carotid body were mainly found in the interparenchymal connective tissue, but also occurred in relationship to blood vessels and nests of glomus cells. Neither in the carotid body not in the carotid sinus, SP/CGRP-LI axons corresponded to the large terminals which are generally considered to represent the main chemoreceptor and baroreceptor endings, respectively. Thus, SP/CGRP-LI fibres either belong to the chemo- and baroreceptors of the C-fibre class or constitute a fibre population not directly involved in conduction of baro- and chemoreflexes.
Animals↗
Effects of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) on the expression of LFA-1 in the moderate phenotype of leukocyte adhesion deficiency (LAD).
Leukocyte adhesion deficiency (LAD) is a recessive autosomal disease characterized by life-threatening recurrent bacterial infections, associated with defective functions of leukocytes due to deficient membrane expression of leukocyte adhesion glycoproteins. These proteins, LFA-1, Mac-1 (CR3), and p150,95 are alpha 1 beta 1 heterodimers composed of different alpha chains noncovalently associated with a common beta chain. Patients with the severe phenotype of the disease completely lack the three glycoproteins on leukocyte surfaces, while patients with the moderate phenotype can express low levels of leukocyte adhesion proteins (1-10%). We have studied a patient with the moderate phenotype of LAD. Polymorphonuclear functions such as chemotaxis and adherence were altered, natural killer activity was low, and cytotoxic T-lymphocyte activity was abolished. Previous biochemical studies showed a conserved synthesis of both the LFA-1 alpha-chain precursor and the beta-chain precursor with, occasionally, some amount of alpha-beta complexes in the cytosol. beta chain-specific mRNA transcripts of normal size were detected at normal levels in patients' cells. Attempts to increase the transcription of the beta gene by in vitro treatment with TNF-alpha or IFN-gamma were successful but did not result in increased membrane expression of the alpha-beta complexes.
Antigens, Differentiation↗
Activation of genetically major histocompatibility complex (MHC) class II-deficient B lymphocytes.
It has been suggested that MHC class II molecules can transduce signals required for B-cell activation. Enhancement or inhibition of B-cell stimulation by anti-MHC class II molecule antibodies has likewise been reported. The study of B cells from patients with a combined immune deficiency due to a defective expression of MHC class II genes provides a useful tool for approaching the functional role of B-cell HLA class II molecules. We have thus analyzed the specific and nonspecific, cognate and noncognate B-cell activation of genetically HLA class II-deficient lymphocytes. B lymphocytes from 14 tested patients were able to synthesize RNA following stimulation with ionomycin and phorbol myristate acetate or anti-mu antibodies and with mannan, a T cell-independent polysaccharidic antigen. They were also able to synthetize DNA following the addition of ionomycin and PMA or of anti-mu antibodies in the presence of recombinant interleukin 2. Pokeweed mitogen failed to induce B-lymphocyte terminal differentiation into immunoglobulin-producing cells in the presence of normal T lymphocytes, while a combination of anti-CD2 antibodies were capable of triggering IgG synthesis. B-cell activation, whatever the condition used, did not induce HLA class II expression. Mannan-specific T cell-dependent antibody production (IgM) was detected in 6 of 14 patients. Anti-influenza virus antibody production was always found absent. These results are compatible with the hypothesis that B-cell activation events that do not require a cognate interaction with T cells can occur in the absence of HLA class II molecule expression, while the absence of HLA class II molecule expression prevents T-B cognate interaction.
Adolescent↗
Direct activation of human B lymphocytes by Candida albicans-derived mannan antigen.
We have studied the activation of human resting B cells by a carbohydrate antigen, mannan, with a polymannose branched repetitive structure. Mannan has been extracted from the cell wall of the Candida albicans yeast. For this purpose, dense G0 B lymphocytes were purified from tonsils. Mannan antigen was shown to trigger B cell activation, since an increase of cell volume and RNA synthesis occurred. B cell proliferation was observed following addition of recombinant interleukin 2, but not following addition of recombinant interleukin 4 or low-molecular-weight BCGF. The B cell activation appears to be mannan-specific since B cells obtained from mannan-sensitized subjects but not from unsensitized subjects were responsive. The observation that mannan antigen can directly activate specific dense B lymphocytes can be related to the previous observation that the in vitro anti-mannan antibody production does not require a cognate T-B cell interaction.
Antigens, Fungal↗
Combined immunodeficiency with abnormal expression of MHC class II genes.
The MHC class II CID represents an example of immunodeficiency in which the defect in expression of membrane glycoproteins leads to abnormal cell to cell interactions and thus to abnormal immune responses. It represents an interesting model which confirms the importance of MHC molecules in all immune responses to foreign antigens. It also underlines the complexity of regulatory mechanism which control the expression of MHC class II genes. To elucidate these mechanisms, it is essential to identify and characterize the genes involved in control of MHC class II expression.
Agammaglobulinemia↗
Unusual karyotypic evolution in subacute myelomonocytic leukemia in two monozygotic twins.
A subacute myelomonocytic leukemia was diagnosed in 28-month-old cotwins. At this age, their spontaneously dividing cells had a normal karyotype. A few months later, after treatment with 6-mercaptopurine, the following karyotypes were observed: 50,XX, +X, +13, +19, +21 in one and 51,XX, +X, +X, +10, +19, +21 in the other. After bone marrow transplantation, both relapsed although they had received high doses of chemo- and radiotherapy. One developed a clone 46,XX,del(20q), which acquired other clonal rearrangements. The other child developed two different abnormal clones, both with unbalanced rearrangement of chromosome 13. Some of these clones may correspond to immature erythroblasts. The gain of chromosomes, especially for #13, which occurred independently in the cotwins by various mechanisms and at different periods during the disease, is very striking. It may indicate the existence of a strong selective advantage for trisomic 13 cells and may be related to the genetic constitution of the patients.
Bone Marrow Transplantation↗
Cost of allogeneic bone marrow transplantation in four diseases.
The cost of bone-marrow transplantation is compared in 4 diseases: acute myelogenous leukaemia, severe combined immunodeficiency, severe aplastic anaemia and chronic granulocytic leukaemia. Hospital cost components directly related to the clinical protocols applied are valorized. Results confirm the well-known fact that bone-marrow transplantation is a costly technique. The unit cost of a transplantation can vary from 1 to 2 between departments for the sole reason that patients treated are not suffering from the same illness. For one disease, the unit cost may vary from 1 to 2.7 when post-graft complications arise. Furthermore, in the health-care sector, as well as in every other economic sector, costs do not remain stable: they vary in time most especially when treatment protocols evolve. This type of cost information is the basis for management control systems without which physicians, hospital managers and health-care authorities cannot communicate effectively. In countries where health care is largely financed by the community, what is at stake is the future of advanced technologies in medicine.
Acquired Immunodeficiency Syndrome↗
Incidence, severity, and prevention of infections in chronic granulomatous disease.
We retrospectively analyzed the frequency and nature of infections occurring in 48 patients with chronic granulomatous disease. The long-term use of trimethoprim-sulfamethoxazole and ketoconazole as a preventive therapy for infections has also been evaluated. Lymphadenitis, lung infections, dermatitis, enteral infections, and hepatic abscesses were the most frequent infections. Staphylococcus aureus, Salmonella, and Aspergillus were the main microorganisms encountered. Twelve patients died: five from lung aspergillosis, three from hepatic abscesses, two from pneumonopathy of unknown origin, one from salmonellosis, and one from another probable infection that could not be proved. The actuarial survival rate was 50% at 10 years of age, with a prolonged plateau thereafter. There was no difference in survival rates between patients with X-linked and those with autosomal recessive chronic granulomatous disease. The 8-year actuarial survival rate was significantly higher for patients born in 1978 or afterward than for patients born before 1978 (92.9% vs 70.5%). A retrospective analysis of the occurrence of bacterial and fungal infections in patients who received trimethoprim-sulfamethoxazole and ketoconazole as infection prophylaxis indicated that the former was effective against bacterial infections but that ketoconazole provided no protection against Aspergillus infections.
Adolescent↗
Bone marrow transplantation following busulfan, cyclophosphamide and high dose cytosine-arabinoside as treatment for infants with translocation (4;11) acute leukaemia.
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Antineoplastic Combined Chemotherapy Protocols↗
Allogeneic bone marrow transplantation for children with acute lymphoblastic leukemia in first remission: a cooperative study of the Groupe d'Etude de la Greffe de Moelle Osseuse.
Thirty-two children ranging in age from 1.5 to 16 years with poor-prognosis acute lymphoblastic leukemia (ALL) were treated with myeloablative immunosuppressive therapy consisting of cyclophosphamide (CPM) and total body irradiation (TBI) followed by allogeneic bone marrow transplantation (BMT) while in first complete remission (CR). The main reasons for assignment to BMT were WBC count greater than 100,000/microL, structural chromosomal abnormalities, and resistance to initial induction therapy. All children were transplanted with marrow from histocompatible siblings. Twenty-seven patients are alive in first CR for 7 to 82 months post-transplantation (median, 30 months). The actuarial disease-free survival rate is 84.4% (confidence interval, 7.2% to 29%) and the actuarial relapse rate is 3.5% (confidence interval, 0.9% to 13%). Four patients died of transplant-related complications, 16 developed low-grade acute graft-v-host disease (GVHD), and six developed chronic GVHD. The very low incidence of relapse (one of 28 long-term survivors) precluded the determination of the prognostic significance of the different poor-outcome features. Moreover, two infants treated with busulfan, CPM, and cytarabine (Ara-C) relapsed promptly in the marrow. In summary, as a means of providing long-term disease-free survival and possible cure, BMT should be considered for children with ALL presenting poor-prognostic features, particularly certain chromosomal translocations [t(4;11), t(9;22)], very high WBC counts, notably if associated with a non-T immunophenotype, and, perhaps, a poor response to initial therapy with corticosteroids (CS), or infants less than 6 months of age.
Adolescent↗
Epstein-Barr virus-associated hemophagocytic syndrome: clinical presentation and treatment.
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Child, Preschool↗
Treatment of familial lymphohistiocytosis: chemotherapy or bone marrow transplant?
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Antineoplastic Combined Chemotherapy Protocols↗
Effect of cytokines on spontaneous and allergen-induced CD23 expression, sCD23 release and Ig(E,G) synthesis from peripheral blood lymphocytes.
We studied the expression of the CD23 antigen as well as the release of soluble CD23 from peripheral blood lymphocytes (PBL) of atopic donors. PBL were stimulated with allergen (Dermatophagoides pteronyssinus; Der.p.), cytokines (interleukin-4, interferon-gamma; IL-4, IFN-gamma) or combinations of stimuli. CD23 levels were enhanced after the addition of allergen or IL-4 (10 U/ml) up to 10-fold compared to spontaneous expression. Soluble CD23 (sCD23) release was enhanced in a dose-dependent manner by allergen or IL-4. The combined addition of IL-4 and allergen resulted in an expression of CD23 as well as sCD23 release from PBL that was higher compared to the effects obtained with a single component. The production of Ig(E,G) increased in the presence of IL-4 (10 U/ml). This effect was enhanced after the addition of allergen. In contrast, the addition of allergen alone did not modulate IgE synthesis but revealed an enhanced IgG synthesis. Spontaneous as well as allergen- or IL-4-induced CD23 expression was significantly reduced in the presence of IFN-gamma, whereas the concomitant sCD23 release was enhanced in a dose-dependent fashion. IgE synthesis (spontaneous, IL-4 induced) was suppressed in the presence of IFN-gamma. IFN-gamma also reduced the IL-4-enhanced IgG secretion, whereas the spontaneous IgG production was not affected.
Allergens↗
Cell-cell interactions for CD23 expression and soluble CD23 release from peripheral lymphocytes of atopic donors.
The cell-cell interactions for CD23 expression and soluble (s)CD23 release from peripheral blood lymphocytes (PBL), as well as purified cells (B, T cells, monocytes) of atopic donors, were studied. Cells either stimulated combined and subsequently separated or stimulated after separation were analysed. IL-4, IL-2, phytohaemagglutinin (PHA), interferon-gamma (IFN-gamma) and the combined interaction of IL-4 and IFN-gamma as well as PHA and IFN-gamma were used as stimuli. sCD23 release in the cell supernatant was determined from cells separated before stimulation. CD23 expression induced by IL-4 on cells stimulated and subsequently separated was significantly lower compared with amounts on separated cells which were subsequently stimulated. Major expression of CD23 was obtained on B cells and monocytes. Stimulation with PHA led to an increased expression on T cells compared to the control. When cells were stimulated, combined and separated, the combined stimuli of IL-4 and IFN-gamma showed a reduced CD23 expression for both experimental procedures and an enhanced release of sCD23. The data suggest an important role for cell-cell interactions. These results were supported by experiments in which separated cells were either co-cultured or cultured in Transwells. Co-culture of T cells with B cells and monocytes suggested that T cells are responsible for suppressed CD23 expression. No or only slight enhancement was obtained for sCD23 release. Our data indicate that cell-cell interactions and cytokines regulate CD23 expression, while sCD23 release is apparently solely regulated by soluble mediators (e.g. cytokines).
Antigens, Differentiation, B-Lymphocyte↗
Nephrotoxicity of high and low osmolar contrast media: case control studies following digital subtraction angiography in potential risk patients.
The urinary excretion of kidney-specific marker proteins before and 120 hours after intravenous injection of either high- or low-osmolar contrast media (CM; diatrizoate, iopamidol 370) was monitored in patients after digital vascular imaging. Inclusion criteria for the randomized clinical study in a total of 40 patients (15 women, 25 men; mean age, 64.5 years) were at least 50 years of age or diabetes mellitus with normal creatinine concentration in serum. Compared with the control period, the elimination of tubular indicator enzymes alanine aminopeptidase, gamma-glutamyltranspeptidase, alkaline phosphatase, as well as of glomerular localized angiotensinase A was significantly higher in all patients after injection of the CM. The most significant differences were observed after 48 hours. In contrast, lysosomal N-acetyl-beta-D-glucosaminidase activity in urine specimens reacted less clearly and appears to be a less sensitive parameter in assessing CM nephrotoxicity. Elimination of brush border as well as of glomerular marker proteins was significantly lower after intravenous injection of low-osmolar CM iopamidol 370 (832 mOsm/kg) than after meglumine diatrizoate 76 (2100 mOsm/kg). In all 40 patients a significant decrease in creatinine clearance was observed; however, patients receiving diatrizoate had a significant decrease in creatinine clearance (period 0 versus 24 to 48 hours after CM), whereas patients after administration of iopamidol had not. No difference was found between creatinine clearance after 48 hours of CM injection within both groups of CM. Due to noninvasive parameters of kidney damage nonionic, low-osmolar CM are less nephrotoxic in potential risk patients, and should be preferred to conventional CM.
Aged↗