Immunodeficiency associated with Dandy-Walker-like malformation, congenital heart defect, and craniofacial abnormalities.
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Child↗
Biomedical subjects
R Seger
Publications and source records attributed to R Seger.
Studying the structure of the intracellular moiety of the insulin receptor with a kinase-splitting membranal proteinase.
A kinase-splitting membranal proteinase specifically clips the cytoplasmic moiety of the insulin receptor beta-subunit (95 kd) to yield an 84-kd fragment. Using antibodies against different domains in the receptor, cleavage is shown to remove an 11-kd 'tail' (rooted at the C-terminal end of the kinase domain) which includes tyrosines 1316 and 1322. This cleavage impairs the ability of the clustered tyrosines 1146, 1150 and 1151 to undergo autophosphorylation. Nevertheless, the clipped beta-subunit is as active as the intact subunit if its kinase activity is measured at high exogenous substrate concentrations (greater than or equal to 2 mg/ml) indicating that autophosphorylation is not obligatory for insulin-dependent phosphotransferase activity. With low substrate concentrations (e.g. 0.2 mg/ml) a severe damage to the kinase activity is detected, which may reflect an important structural contribution of the 'tail' and/or the clustered phosphotyrosines in creating the preferential affinity of the kinase for its in vivo substrate(s). The membranal proteinase strictly recognizes the native conformation of the kinase domain, and fails to cleave it after denaturation. Since such a conformation-dependent cleavage occurs also in the case of the cytoplasmic moiety of the EGF receptor and the catalytic subunit of cAMP-dependent protein kinase, it is suggested that the similarity between these three kinase domains extends beyond their reported sequence homology to reflect a similarity in conformation.
Animals↗
Familial deficiency of the seventh component of complement associated with recurrent meningococcal infections.
We describe an 11-year-old girl suffering from recurrent meningitis with a complete absence of the seventh component of complement (C7). Diagnosis was established by haemolytic titration and western blotting. The patient's serum lacked the 85 kDa C7 chain. Haemolytic activity of serum was reconstituted with either pooled normal human serum or with purified C7. The relatives (parents and one sister) had half-normal levels of both immunochemically and functionally determined C7, indicating a heterozygous state for C7 deficiency.
Blotting, Western↗
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↗
Protective effect of aprotinin on ischemic hepatocellular damage.
During hepatic resection, occlusion of the hepatoduodenal ligament has been frequently applied to prevent intraoperative bleeding. To reduce hepatocellular ischemic damage in this procedure, we pretreated animals with Aprotinin. Three hours after an intravenous injection of 40,000 KIU Aprotinin in SD rats, we occluded the afferent hepatic vessels for 50-min and 60-min periods. 92% of occluded animals could sustain life after 60 min. Without premedication only 17 of 25 animals (68%) survived the 50-min occlusion, and 18 of 32 (56%) the 60-min occlusion. Biochemical analysis of sera was carried out 12 hr after a 40- and 60-min occlusion of the hepatoduodenal ligament with Aprotinin pretreatment. Furthermore we induced compensatory cirrhosis by application of CCL4 and biochemical analysis of sera was carried out after a 30-min occlusion. The elevation of SGOT and SGPT values was drastically reduced in the animals with Aprotinin medication in comparison with those without treatment. These observations suggest the highly protective effect of Aprotinin in the case of warm ischemic hepatic damage, especially in the cirrhotic liver. After pretreatment of LEW rats with Aprotinin (40,000 KIU i.v.), we perfused the livers with chilled Ringer solution containing 40,000 KIU Aprotinin/20 ml. We transplanted the livers orthotopically into LEW rats. With the application of Aprotinin liver preservation time increased to 10-15 hr. However, without Aprotinin the livers could be successfully preserved for only 4-6 hr. Our results indicated that premedication with high doses of Aprotinin provided highly protective effects against warm and cold ischemic damage of the liver.
Animals↗
Deficiency of the eighth component of complement. Evidence for linkage of C8 alpha-gamma pattern with C8 beta deficiency in sera of twelve patients.
The C8 alpha-gamma subunit of the eighth component of complement was analysed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and immunoblotting in sera from 68 normal individuals, 12 C8 beta-deficient patients (from seven unrelated families), and 10 of the parents of the latter. Three different forms of the C8 alpha-gamma subunit were observed: 34/68 normal individuals were found to have a C8 alpha-gamma triple band (termed C8 alpha-gamma 1, C8 alpha-gamma 2, C8 alpha-gamma 3 variants), 23/68 the C8 alpha-gamma 2 and C8 alpha-gamma 3 variants, and 11/68 the C8 alpha-gamma 1 and C8 alpha-gamma 3 variants. In contrast, all C8 beta-deficient patients had detectable C8 alpha-gamma 2 and C8 alpha-gamma 3 variants but lacked the C8 alpha-gamma 1 variant in addition to the C8 beta subunit. Three out of ten parents of the C8 beta-deficient patients were found to have the C8 alpha-gamma triple band, whereas 7/10, like their children, had the C8 alpha-gamma 2 and C8 alpha-gamma 3 variants only. We conclude that there is a linkage between the C8 alpha-gamma pattern and C8 beta deficiency. These data may support earlier findings that in humans the genes encoding for C8 alpha-gamma and C8 beta are closely linked on chromosome 1.
Adult↗
[Immunological basis of IgE-mediated allergies. A contribution to the understanding of new therapy forms].
The pathogenesis of IgE mediated allergies has been elucidated. We are dealing primarily with diseases of the T lymphocyte system. Due to overactivity of so-called T helper lymphocytes there is pathologic overproduction of IgE and inflammatory cells, mast cells and eosinophils, after antigen contact. Following exposure to nutrient and inhalant allergens in the presence of adjuvants, this atopic constitution manifests itself clinically. Mast cell mediators (e.g. histamine and leukotrienes) elicit immediate symptoms at the ports of entrance of allergens (at skin and mucosal surfaces); eosinophil mediators (e.g. platelet activating factor [PAF], eosinophil cationic protein [ECP], and major basic protein [MBP]) are responsible for late symptoms and hyperreactivity. Current antiinflammatory treatment tries to suppress this allergic inflammation (e.g. with cromoglycate and topical steroids). The regulatory immunotherapy of the near future attempts to regulate IgE synthesis by interleukins (e.g. gamma-Interferon) or antagonists of interleukins (e.g. anti-IL-4-antibodies).
Allergens↗
Immunoblot analysis of the eighth component of human complement. Demonstration of subunits and detection of C8 alpha-gamma double and triple bands.
Using SDS-PAGE/immunoblot analysis of the eighth component of human complement, C8, we have been able to demonstrate an 85 kDa C8 alpha-gamma and a 62 kDa C8 beta subunit in normal human serum. Serum from an undiagnosed patient who presented undetectable hemolytic C8 activity possessed only the 85 kDa subunit, suggesting a defect in the C8 beta subunit. Serum of a patient with known C8 alpha-gamma deficiency possessed only the complementary 62 kDa subunit. Both sera used together were able to lyse antibody-sensitized sheep erythrocytes, whereas individual sera could not. Optimum conditions for C8 immunoblotting were determined using small amounts of serum or plasma, during low voltage electrophoresis and a sensitive staining technique (nitrobluetetrazolium/bromochloroindoxylphosphate). Using these conditions, the C8 alpha-gamma subunit was found to be composed of up to three bands, termed C8 alpha-gamma 1, -2 and -3. All three bands were found in pooled normal sera. Individual sera had at least the C8 alpha-gamma 2 and C8 alpha-gamma 3 bands. Two C8 beta-deficient sera from two unrelated patients exhibited only the C8 alpha-gamma 2 and C8 alpha-gamma 3 bands. We conclude that immunoblotting of C8 permits a detailed analysis of the molecular composition of this component and helps to establish a precise diagnosis in inherited C8 deficiencies.
Collodion↗
The epidermal growth factor receptor as a substrate for a kinase-splitting membranal proteinase.
A brush-border membranal proteinase, which specifically clips the catalytic subunit of cAMP-dependent protein kinase, is shown to cleave the receptor for the epidermal growth factor (EGF) (Mr = 170,000) into two fragments of Mr = 140,000 and 30,000. The 140-kDa fragment retains its EGF-binding site and its EGF-dependent protein tyrosine kinase activity on exogenous substrates, but it loses its capacity to undergo self-phosphorylation. It is shown to be distinct from the 150-kDa fragment of the EGF receptor obtained by the Ca2+-activated neutral proteinase. The membranal proteinase strictly recognizes the native structure of the receptor and fails to cleave either the denatured receptor or its 150-kDa degradation product. Thus the membranal proteinase acts as a conformation-recognizing probe for both the protein-tyrosine kinase domain of the EGF receptor and the catalytic subunit of cAMP-dependent protein-Ser/Thr kinase, suggesting that the known sequence homology between these two kinases is also reflected in their conformation. The well defined 140-kDa fragment described here is useful for structure-function studies of the EGF receptor.
Adenosine Triphosphate↗
Evaluation of diagnostic tests for HIV infection in infants born to HIV-infected mothers in Switzerland.
Children born to HIV-infected women in Switzerland were tested every 3 months for HIV-reactive serum immunoglobulin (Ig) G, IgM and IgA antibodies by Western blot, viral antigen, virus replicating in T-lymphocyte cultures, and immunologic and clinical parameters. At birth, 27% were isolation-positive, 68% had IgM, 48% IgA and 10% circulating antigen. The proportion of IgM and IgA declined to about 18 and 27%, respectively, during the first 2 years. Detection of circulating antigen was less frequently positive than virus isolation in all age and disease groups. Clinical symptoms were only seen in infants or children who were or had been positive for IgM and/or IgA, but only 39% of children positive for these markers have developed disease so far. Clinical symptoms combined with signs of immunodeficiency were seen only in children who were isolation-positive or had evidence of HIV-reactive IgA or child-produced IgG. Absorption studies showed that Western blot-detected IgM and IgA antibodies were of two types: 42% were directed against various HIV proteins, while the rest represented rheumatoid-factor-like IgM or IgA binding to HIV-specific IgG. HIV-specific IgG antibodies were detected in all samples up to the age of 12 months and were still found in 83% of infants 13-18 months old. We observed weak HIV-specific IgG above the age of 15 months with no other signs of HIV infection, suggesting that the demonstration of antibodies in children beyond this age does not necessarily indicate HIV infection.
AIDS Serodiagnosis↗
Gene deletion in a patient with chronic granulomatous disease and McLeod syndrome: fine mapping of the Xk gene locus.
In a patient suffering from X-linked chronic granulomatous disease (X-CGD)--a disorder of phagocytesuperoxide generation--and McLeod syndrome, characterized by the absence of the red cell Kell antigen, we identified a deletion of the entire X-CGD gene by means of DNA hybridization with a cDNA probe. Our findings suggest that the X-CGD and McLeod loci are physically close in the p21 region of the X chromosome proximal to the Duchenne muscular dystrophy locus.
Anemia, Hemolytic, Congenital↗
Neopterin in AIDs, other immunodeficiencies, and bacterial and viral infections.
An increase in total urinary neopterin was observed in 12 of 13 patients with acquired immunodeficiency syndrome (AIDS), seven of 13 patients with lymphadenopathy, one of six healthy homosexual males, seven of ten adult patients with staphylococcal pneumonia, 11 of 12 children with viral infections, four of seven children with bacterial infections, and 12 of 13 children with various immune defects. Extremely high values of total urinary neopterin and monapterin were observed in severely ill patients with AIDS and those with familial hemophagocytic lymphohistiocytosis. Neopterin excretion was normal in two AIDS patients with Kaposi's sarcoma, but without opportunistic infections at that time. On reexamination of one of these patients later on, elevated neopterin values were noted. Parallel increases in neopterin and monapterin were found, whereas biopterin was usually normal. The increase in total neopterin was mainly due to 7,8-dihydroneopterin and was accompanied by an increase in 3'-hydroxysepiapterin. Increased neopterin in urine is assumed to reflect the increase in GTP pool and GTP cyclohydrolase I activity as observed in stimulated monocytes. Thus, neopterin, as a measure of the activation of the nonspecific cellular immune system, may be used diagnostically to detect allograft rejection after transplantations and to follow-up HTLV-III positive patients.
Acquired Immunodeficiency Syndrome↗
[Suspected diagnosis of immunodeficiency. Study program in the evaluation of children with recurrent infections].
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Child↗
Uptake, intracellular activity, and influence of rifampin on normal function of polymorphonuclear leukocytes.
Quinone and hydroquinone forms of rifampin accumulated in normal polymorphonuclear leukocytes (PMN) (maximal cellular to extracellular concentration ratio [C/Emax] +/- standard error of the mean, 9.36 +/- 0.54 and 8.82 +/- 0.65, respectively, after 5 to 10 min) and chronic granulomatous disease PMN (C/Emax, 13.76 +/- 0.77 and 14.29, respectively). Uptake of rifampin was influenced by incubation temperature and extracellular pH but not by phorbol myristate acetate stimulation or metabolic inhibitors. At extracellular concentrations between 0.06 and 5.0 mg/liter, rifampin significantly reduced the number of staphylococci surviving inside chronic granulomatous disease PMN, thus compensating for the bactericidal defect inherent with this disease. Spontaneous migration and chemotaxis of normal PMN were unaffected by rifampin. However, phagocytosis of yeast particles and oxygen consumption of stimulated PMN were moderately depressed, and O2- production and chemiluminescence were significantly depressed in a dose-dependent manner. The bactericidal activity of normal PMN was not impaired. Inhibition of chemiluminescence and O2- release were also observed in a cell-free system. We conclude that rifampin possesses favorable characteristics for the effective elimination of intracellular microorganisms. Further studies are needed to evaluate the in vivo significance of ion scavenging by rifampin, which could be hazardous to immunocompromised patients.
Adult↗
Deficiency of the adhesive protein complex lymphocyte function antigen 1, complement receptor type 3, glycoprotein p150,95 in a girl with recurrent bacterial infections. Effects on phagocytic cells and lymphocyte functions.
A patient presenting delayed umbilical cord detachment, severe recurrent bacterial infections, and inability to form pus exhibited a profound defect in the expression of alpha- and beta-chains of the receptor for the C3bi fragment of C3 (CR3), lymphocyte function antigen 1 (LFA-1) molecule, and the p150,95 molecule found on neutrophils, monocytes, and lymphocyte membranes. This was shown by immunofluorescence studies using specific monoclonal antibodies, rosette formation with C3bi-coated erythrocytes, and immunoprecipitation for the LFA-1 complex. These membrane defects were responsible for abnormal phagocytic cell functions including adherence to nylon wool, cell movement, phagocytosis, and opsonized particle-induced oxidative response and for defective natural killer cell activity. In addition, lymphocyte function deficiencies previously unobserved in this disease were found. Cytolytic T lymphocyte activity was profoundly reduced; alpha- and gamma-interferon production were impaired. Finally, there was no antibody production to vaccinal antigens whereas the antibody responses to polysaccharides and to cytomegalovirus were found to be normal. The cytotoxic T cell deficiency could be expected from previous blocking experiments of this function with monoclonal antibodies to LFA-1 and is probably related to an extremely severe deficiency in LFA-1 expression in this patient. Anomalies in interferon and in antibody production suggest additional role(s) of the LFA-1 complex in monocyte/T lymphocyte/B lymphocyte cell interactions that have not yet been envisaged.
Antibodies, Monoclonal↗
Congenital acatalasemia: a study of neutrophil functions after provocation with hydrogen peroxide.
Five Swiss subjects with hereditary acatalasemia (4 homo-, 1 heterozygous) were studied by a series of neutrophil function tests. H2O2 was added to a polymorphonuclear neutrophil leukocyte-suspension to produce a metabolic stress; neutrophil functions related to membrane deformation were subsequently found to be depressed, i.e., chemotaxis, membrane potential, and chemiluminescence. This mechanism might be one pathogenetic factor in the formation of mucosal ulcers in acatalasemic individuals.
Adult↗
Surgery and granulocyte transfusions for life-threatening infections in chronic granulomatous disease.
We report two patients with chronic granulomatous disease (CGD) and life-threatening infections: a 10 10/12-year-old boy had Aspergillus fumigatus spondylitis with destruction of the 11th vertebral body and paravertebral abscess formation, and an 8 5/12-year-old boy had multiple Staphylococcus aureus hepatic abscesses with subphrenic abscess formation. Both patients failed to respond to intense antimicrobial therapy but showed a remarkable recovery following surgical drainage combined with granulocyte transfusions. These results suggest that antimicrobial therapy and surgical drainage followed by granulocyte transfusions may be the ideal mode of treatment for severe infections in patients with CGD.
Amphotericin B↗
[Acanthocytosis in chronic septic granulomatosis: the McLeod syndrome].
Acanthocytosis was observed in a boy suffering from Chronic Granulomatous Disease (CGD). Further investigations revealed weak Kell-antigen-expression on the patient's erythrocytes. This so-called "McLeod-Syndrome" is due to the absence of Kx, the Kell antigen precursor substance. So far, 8 cases of an association between McLeod-Syndrome and CGD have been reported. Both genetic defects are closely linked on the X-chromosome and may therefore be inherited together. In female carriers, the variable inactivation of one X-chromosome according to the Lyon-hypothesis is the reason for the appearance of both normal and McLeod-erythrocytes at the same time. This was observed in the mother and sister of our patient too. Blood transfusions should be avoided, because McLeod-patients are at risk to form antibodies against the precursor substance Kx common to the erythrocytes of virtually all people. These patients should therefore be encouraged to donate blood which can be stored frozen and used either as autotransfusion (for the patient himself) or for other McLeod-patients.
Acanthocytes↗