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Biomedical subjects

R A Seger

Publications and source records attributed to R A Seger.

At least 37 records · Page 2Linked to original sources
PubMed1995

Atypical Kawasaki disease with peripheral gangrene and myocardial infarction: therapeutic implications.

We describe a 2-month-old girl with atypical Kawasaki disease (KD) complicated by peripheral gangrene and myocardial infarction. Peripheral ischaemia leading to gangrene is a rare but serious complication of KD in infants younger than 7 months of age. Treatment has been targeted at reducing arterial inflammation, arteriospasm and thrombosis. We report the first patient with incomplete KD and peripheral ischaemia in whom therapy with prostaglandin E1 (PGE1) as vasodilating and antithrombotic agent appeared successful, restoring hand and foot perfusion without significant long-term sequelae. However, PGE1 could have supported development of myocardial infarction by shunting blood away from ischaemic areas distal to a giant coronary artery aneurysm with beginning thrombosis. CONCLUSION. Atypical KD with peripheral gangrene appears to react favourably to treatment with PGE1, but needs careful monitoring to detect early signs of cardiac ischaemia.

Alprostadil↗
PubMed1995

Persistent vacuoles in leukocytes: familial Jordans anomaly.

Multiple persistent vacuoles were seen in the neutrophils, monocytes and eosinophils of a 9 year old boy and his 10 year old sister. The siblings were both asymptomatic. In the bone marrow, the cytoplasmic vacuoles were also present in the promyelocytes, myelocytes and metamyelocytes, but not in the myeloblasts and they tended to be single and large in immature cells. The cytoplasmic vacuoles did not stain with PAS, Sudan Black or Oil Red O; Sudan III positivity of the vacuoles was found only in a very small number of granulocytes. The vacuoles appeared as round and bright bodies with phase contrast microscopy. By electron microscopy, the vacuoles contained material of low electron density and had no surrounding membrane. Granulocyte functions were unimpaired. Muscle biopsy showed normal morphology. This anomalous vacuolization of the leukocytes is consistent with familial Jordans anomaly.

Child↗
PubMed1994

156Pro-->Gln substitution in the light chain of cytochrome b558 of the human NADPH oxidase (p22-phox) leads to defective translocation of the cytosolic proteins p47-phox and p67-phox.

Src homology 3 (SH3) domains have been suggested to play an important role in the assembly of the superoxide-forming nicotinamide adenine dinucleotide phosphate (NADPH) oxidase upon activation of phagocytes, which involves the association of membrane-bound and cytosolic components. We studied the translocation of the cytosolic proteins to the plasma membrane in neutrophils of a patient with a point mutation in the gene encoding the light chain of cytochrome b558. This mutation leads to a substitution at residue 156 of a proline into a glutamine in a putative SH3 binding domain of p22-phox (Dinauer, M., E. A. Pierce, R. W. Erickson, T. Muhlebach, H. Messner, R. A. Seger, S. H. Orkin, and J. T. Curnutte. 1991. Proc. Natl. Acad. Sci. 88:11231). In PMA-stimulated neutrophils and in a cell-free translocation assay with neutrophil membranes and cytosol, association of the cytosolic proteins p47-phox and p67-phox with the membrane fraction of the patient's neutrophils was virtually absent. In contrast, when solubilized membranes of the patient's neutrophils were activated with phospholipids in the absence of cytosol (Koshkin, V., and E. Pick. 1993. FEBS [Fed. Eur. Biochem. Soc.] Lett. 327:57), the rate of NADPH-dependent oxygen uptake was observed at a rate similar to that of control membranes. We suggest that the binding of an SH3 domain of p47-phox to p22-phox, and thus activation of the oxidase, does not occur in the neutrophils of this patient, although under artificial conditions, electron flow from NADPH to oxygen in cytochrome b558 is possible.

Blotting, Western↗
PubMed1994

Non-Hodgkin's lymphoma in four children infected with the human immunodeficiency virus. Association with Epstein-Barr Virus and treatment.

BACKGROUND: Reports on lymphoid malignancy and its treatment in children infected with human immunodeficiency virus (HIV) are limited. METHODS: Antibodies to Epstein-Barr virus (EBV) were detected by indirect immunofluorescence. DNA was extracted from peripheral blood lymphocytes or biopsy specimens. Polymerase chain reaction was run using primers for EBV. Reaction products underwent Southern blot analysis to confirm EBV specificity. Tumor clonality was assessed by immunohistochemistry and by Southern blot analysis of immunoglobulin heavy-chain and T-cell receptor beta-gene rearrangement. RESULTS: Within 1 year, non-Hodgkin's lymphoma (NHL) was diagnosed in four children infected with HIV. All four were EBV-seropositive and had detectable EBV DNA in peripheral blood lymphocytes. The EBV-linked disorders lymphoid interstitial pneumonia and recurrent parotid enlargement preceded NHL in three and two of the children, respectively. In all four patients, NHL involved at one time the central nervous system (CNS). All three tested NHL tissues were positive for EBV DNA: A 12-week course of chemotherapy given to two children resulted in rapid tumor regression. One of these children experienced meningeal relapse and died 16 months after diagnosis. The other child, who in addition received local irradiation of the affected eye and who underwent surgical removal of the involved ovaries, has been in continuous remission for 20 months. CONCLUSIONS: EBV-associated NHL may be seen more frequently in pediatric patients with HIV. Treatment protocols taking into account NHL propensity for the CNS in this age group need to be developed.

Abdominal Neoplasms↗
PubMed1994

Identification of allele-specific p22-phox mutations in a compound heterozygous patient with chronic granulomatous disease by mismatch PCR and restriction enzyme analysis.

A rare subgroup (approx. 5%) of all chronic granulomatous disease (CGD) patients suffers from mutations in the gene encoding the small p22-phox subunit of the flavocytochrome b558 heterodimer, the terminal redox component of the phagocyte NADPH oxidase. A male CGD patient with neutrophil granulocytes devoid of any spectrometrically detectable cytochrome b558 owing to autosomally inherited p22-phox deficiency (phenotype, A22-) is reported. The patient was identified as being compound heterozygous for two independent mutations of his p22-phox alleles. On the maternal allele a single base substitution (A186 to T) was found that predicts a nonconservative replacement of Glu 53 by Val. On his paternal p22-phox allele a G was found to be added to a G stretch between nucleotides G195 and G199 in the cDNA sequence. The resulting frame shift predicts an aberrant open reading frame, 16 amino acids longer than the normal p22-phox polypeptide. Genomic DNA was tested for the presence of the mutant allele by mismatch PCR (polymerase chain reaction). For this purpose, a single base mismatch was introduced at nucleotide position 189, leading to digestion of the normal allele by the restriction enzyme HinfI. The maternal allele was found to be present in 50% of the patient's DNA and in 50% of the DNA from his mother. The same mismatch PCR analysis with control DNA from 35 healthy individuals ruled out the possibility that the single base substitution (A186 to T) represents a common polymorphism. Inheritance of the second allelic mutation (G insertion) was verified by restriction enzyme analysis using BslI [CC(N)7GG] to digest PCR-amplified genomic DNA at the mutation site. PCR in combination with restriction enzyme analysis proved to be a powerful tool for verification of point mutations in the compound heterozygous CGD patient analyzed and may be used for prenatal diagnosis in this family.

Alleles↗
PubMed1994

A syndrome of primary combined immunodeficiency with microcephaly, cerebellar hypoplasia, growth failure and progressive pancytopenia.

A male infant with primary combined immunodeficiency, microcephaly with marked cerebellar hypoplasia, and growth failure of prenatal onset is presented. He developed progressive pancytopenia in the 3rd year of life and died at 42 months from disseminated aspergillosis. Laboratory studies and post mortem examination failed to reveal any known aetiology for his disorder. Hreidarsson et al. [3] previously described a syndrome of progressive pancytopenia with microcephaly, cerebellar hypoplasia and growth failure in three boys, with similar clinical and laboratory findings. Although extensive immunological investigations were not performed in those previous patients, recurrent infections in two of them are suggestive of immunodeficiency. In the light of the immunological findings in our patient, we propose that the condition of the four patients belongs to the same syndrome, which has to be considered as a primary combined immunodeficiency syndrome. This syndrome can be distinguished from the other known immunodeficiency syndromes by its associated characteristic features, namely microcephaly with cerebellar hypoplasia, growth failure of prenatal onset and progressive pancytopenia.

Cerebellum↗
PubMed1993

Effective stimulation of donors for granulocyte transfusions with recombinant methionyl granulocyte colony-stimulating factor.

Effective granulocyte transfusion (GT) therapy has been hampered by the low yield of neutrophil granulocytes (PMN) obtainable from normal donors even by use of corticosteroid prestimulation, hydroxyethyl starch (HES), and modern leukapheresis (LA) techniques. To increase the PMN yield we performed LA in 22 healthy volunteer donors after a single subcutaneous administration of 300 micrograms of granulocyte colony-stimulating factor (G-CSF) 12 to 16 hours before LA. Five to 7 L of blood was processed within 1.9 to 3 hours using the standard CS-3000Plus (Baxter, Deerfield, IL) LA protocol including HES. The mean number of PMN harvested was 44.32 +/- 15.5 x 10(9), corresponding to 6.88 +/- 2.1 x 10(9)/L of blood processed. In the final product PMN functions (in vitro: chemotaxis, phagocytosis, chemiluminescence, superoxide anion production; in vivo: chemiluminescence, half-life) were at least normal. In all donors G-CSF induced a consistent increase of white blood cell (mean 16.46 +/- 3.8 x 10(9)/L) and PMN counts (15.94 +/- 3.6 x 10(9)/L). No G-CSF-related side effects were observed and LA was well tolerated. G-CSF prestimulation allows to harvest three to five times higher numbers of functionally normal PMN by LA compared with corticosteroid pretreatment. This may help to overcome one of the major limitations of an effective PMN support.

Blood Donors↗
PubMed1993

T cell activation and cytokine release in streptococcal toxic shock-like syndrome.

A 5-year-old girl with streptococcal toxic shock-like syndrome during varicella infection had high levels of tumor necrosis factor alpha and interleukin-6 but no interleukin-1 or interleukin-2 in the serum. Intravenous administration of gamma-globulin coincided with clinical improvement and with reduction of the levels of tumor necrosis factor alpha and interleukin-6. The data suggest that streptococcal pyrogenic exotoxins trigger synthesis of tumor necrosis factor alpha and interleukin-6 in vivo; intravenously administered gamma-globulin may down-regulate the cytokine response.

Arthritis, Infectious↗
PubMed1993

[Lupus erythematosus discoid-like dermatosis in a carrier of septic granulomatosis].

We present a clinically atypical case of discoid lupus erythematosus in the mother of a boy with chronic granulomatous disease. In this disorder, the phagocytes are unable to produce superoxide anion to degrade incorporated microorganisms. In addition to a discoid lupus erythematosus-like skin disease, recurrent stomatitis aphthosa, hidradenitis suppurativa and Raynaud phenomenon are markedly associated with heterozygote carriers of chronic granulomatous disease. Based on this conspicuous association, diverse models concerning the pathogenesis of lupus erythematosus are discussed.

Adult↗
PubMed1992

Chronic granulomatous disease with partial deficiency of cytochrome b558 and incomplete respiratory burst: variants of the X-linked, cytochrome b558-negative form of the disease.

Five male patients from four different families presented with a clinical record of chronic granulomatous disease (CGD): recurrent infections of the skin and/or respiratory tract with catalase-positive microorganisms, sometimes in combination with granulomata and/or abscesses in various organs. These patients differed from "classical" forms of the disease in that their neutrophils, although deficient in killing in vitro of Staphylococcus aureus, contained a decreased but measurable amount of cytochrome b558 (10-60% of normal on a heme basis), causing weak staining in the nitroblue tetrazolium dye test and a depressed respiratory burst after contact of the cells with fluid or particulate activators of the NADPH:O2 oxidoreductase. In the cell-free activation system, the defect in the patients' cells was localized in the membrane fraction. In each of the four families, the cellular abnormalities showed an X-linked inheritance. Fusion experiments performed with the monocytes from these patients and those from patients with classical X-linked, cytochrome b558-negative (Xb(0)) or autosomal, cytochrome b558-positive (Ab+) CGD showed complementation of NADPH:O2 oxidoreductase activity in the latter but not in the former combination. Thus, the unusual CGD patients represent variant forms of Xb(0) CGD, with mutations in the gene coding for the beta subunit of cytochrome b558 that do not cause complete loss of this protein.

Blood Bactericidal Activity↗
PubMed1992

Treatment of patients with chronic granulomatous disease with recombinant human interferon-gamma does not improve neutrophil oxidative metabolism, cytochrome b558 content or levels of four anti-microbial proteins.

Recombinant interferon-gamma (rIFN-gamma) has been described to enhance phagocyte functions in vitro and in vivo in several patients with chronic granulomatous disease (CGD). To demonstrate the clinical usefulness of this treatment, 128 patients were treated in a randomized, double-blind multi-centre study with a placebo preparation or with rIFN-gamma. We analysed parameters of neutrophil oxidative and non-oxidative metabolism in 16 patients enrolled in this study. No enhanced superoxide-release was observed in patients treated with rIFN-gamma compared to placebo-treated patients. Phagocyte cytochrome b558 content also remained unchanged. Levels of four non-oxidative antimicrobial proteins (cathepsin G, azurocidine, p29b, lactoferrin) rose, fell, or remained unchanged, irrespective of treatment with rIFN-gamma or placebo.

Blood Proteins↗
PubMed1991

Point mutation in the cytoplasmic domain of the neutrophil p22-phox cytochrome b subunit is associated with a nonfunctional NADPH oxidase and chronic granulomatous disease.

Chronic granulomatous disease (CGD) is a congenital disorder in which phagocytes cannot generate superoxide (O2-) and other microbial oxidants due to mutations in any one of four components of the O2(-)-generating complex, NADPH oxidase. We report here a female CGD patient in whom a missense mutation in one of these components, the p22-phox subunit of the neutrophil membrane cytochrome b [where phox indicates phagocyte oxidase (used to designate protein components of the phagocyte NADPH oxidase)] results in a nonfunctional oxidase and failure of neutrophils to produce O2- in response to phorbol 12-myristrate 13-acetate. Cytochrome b in the patient's neutrophils was normal in appearance and abundance as determined by visible spectroscopy and by immunoblots of the gp91 and p22 subunits. However, the neutrophil plasma membranes were devoid of activity in the cell-free oxidase activation system, whereas the cytosol functioned normally. We postulated that the patient was homozygous for a mutation in p22 that results in the synthesis of normal levels of a nonfunctional cytochrome b. A single-base substitution (C----A) was found in the patient's mononuclear cell p22-phox cDNA that predicts a nonconservative Pro----Gln substitution at residue 156. The same mutation was also identified in all clones sequenced from patient genomic DNA, demonstrating homozygosity for the mutant allele. An antipeptide antibody against p22 residues 153-164 was found to bind only to permeabilized neutrophils, indicating that the mutation occurs in a cytoplasmic domain. These studies establish that this domain of p22-phox is cytoplasmic and that mutations in this region can have profound effects on cytochrome b function.

Adult↗
PubMed1991

Granulocyte-macrophage colony stimulating factor does not improve neutrophil oxidative metabolism in a patient with variant X-linked chronic granulomatous disease.

Variant X-linked chronic granulomatous disease (CGD) is characterised by a decreased but still measurable respiratory burst and cytochrome b content of phagocytes resulting in a clinically milder form of the disease. We examined the in vivo effect of recombinant human granulocyte-macrophage colony stimulating factor (rh-GM-CSF) on the neutrophil functions of a patient treated for liver abscess. The number of white blood cells was markedly increased at the highest dose of GM-CSF injected (30 micrograms/kg per day). This was mainly due to a large increase in eosinophils and to a lesser extent in neutrophils. No change in the deficient neutrophil respiratory burst nitroblue tetrazolium (NBT)-reduction, superoxide (O2-)-production and cytochrome b content was observed during 6 weeks of therapy with increasing doses of GM-CSF. No significant clinical improvement of the liver abscess was observed during treatment with GM-CSF.

Adolescent↗