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Biomedical subjects

R A Seger

Publications and source records attributed to R A Seger.

67 records · Page 4Linked to original sources
PubMed1984

Human IgG antibodies to carbohydrate and protein antigens in mouse protection tests with group B streptococci.

The protective effect of four commercial human gammaglobulin batches (I-IV) in mice was studied using six different strains of group B streptococci (GBS): types Ia; Ib; II, R-protein negative (R-); II, R+; III, R-; and III, R+. Each mouse received 1.0 ml gammaglobulin and 0.5 ml bacteria, 10(6)-10(8) colony forming units (CFU). There was a close correlation between antibody levels measured by the use of radiolabeled protein A and the mouse-protective effect of the gamma-globulins. The mouse-protection tests demonstrated that batch I protected against GBS types Ia and III, R- at low concentration (65 mg/kg mouse weight), against type Ib at medium (260 mg/kg) and against type III, R+ at high concentration. Batch IV protected against types Ia and Ib, although the doses were four times higher than those in batch I, but did not protect against type III, R+. There was no mouse protection by any of the batches against type II. Antibody levels against Ibc and R, protein antigens, were substantially lower in batch IV. Because the results of these mouse-protection studies indicate the importance of such antibodies against protein antigens, batches I-III might be more useful for therapy of neonatal GBS-septicemia.

Animals↗
PubMed1984

Cytosolic free calcium changes induced by chemotactic peptide in neutrophils from patients with chronic granulomatous disease.

Cytoplasmic free calcium concentration (Ca2+)i was measured in neutrophils from patients with the classical X-linked form of chronic granulomatous disease (CGD) by trapping the fluorescent calcium indicator Quin 2 in intact cells. CGD neutrophils do not produce superoxide and are only slightly depolarized upon stimulation by the chemotactic peptide. N-formyl-methionyl-leucyl-phenylalanine (FMLP). The resting levels, as well as (Ca2+)i changes induced by FMLP in CGD cells, were quantitatively and kinetically similar to those observed in normal cells. We conclude that the defect in CGD cells is distal to, or independent of, the changes in (Ca2+)i induced by FMLP stimulation and that normal membrane depolarization does not seem to be necessary for receptor-mediated rise in free cytosolic calcium in human neutrophils.

Calcium↗
PubMed1983

Chronic granulomatous disease, a heterogeneous syndrome.

Chronic granulomatous disease (CGD) is a clinical syndrome, the unifying characteristics of which are a severe predisposition to bacterial and fungal infections, an impaired ability of phagocytic leukocytes to kill certain microorganisms and the failure of these cells to produce microbicidal oxygen metabolites. In CGD the causal biochemical defect and the mechanism of genetic transmission vary from family to family. At least six different molecular defects have been found to underly the X-linked and at least three other the autosomal recessive form of CGD. Diagnosis of carriers is possible in most instances, and prenatal diagnosis by fetoscopic placental vessel puncture has become feasible.

Bone Diseases↗
PubMed1983

Granulocyte function in untreated pernicious anaemia.

Neutrophil granulocyte functions were evaluated in nine patients with pernicious anaemia (PA). Membrane potential, oxygen consumption, nitroblue tetrozolium reduction, and phagocytosis and killing of staphylococci were determined prior to the institution of vitamin B12 therapy. There were no significant alterations in these granulocyte functions as compared with normal controls, although in several patients low values were seen. We conclude that in PA the oxidative metabolism and microbicidal functions of granulocytes in general are normal, even in severely anaemic patients.

Aged↗
PubMed1983

Behavior of neutrophilic granulocytes in a case of Papillon-Lefèvre syndrome.

Recently we had the opportunity to examine and follow up over a period of 2 years an unusual case of Papillon-Lefèvre syndrome (PLS). A 10 year old boy exhibited all symptoms typical of PLS except periodontitis and premature loss of deciduous teeth. The present report aimed at studying the functional capacity of his neutrophilic granulocytes. It integrates clinical observations, histopathological findings and results of in vitro tests. The bioptic material examined included one gingival biopsy, extracted teeth, suppurative material discharged from periodontal pockets, pus emanating from a mucosal abscess, and peripheral blood leucocytes. The neutrophils were sampled on two separate occasions in two independent laboratories and tested for a variety of functions, i.e. motility, random and directional locomotion (chemotaxis), phagocytosis, membrane potential depolarization, oxygen consumption, NBT reduction, and intracellular killing of bacteria and fungi. Findings and test data indicated that in this case of PLS, neutrophilic granulocytes behaved normally with respect to all these functions including margination in blood vessels, emigration, phagocytosis of a broad range of bacteria, degranulation of lysosomes, and intracellular destruction. The data imply that factors other than neutrophil defects may be responsible for rapidly destructive periodontitis in cases where PLS is not associated with an increased susceptibility to infection.

Chemotaxis, Leukocyte↗
PubMed1983

Chronic granulomatous disease due to granulocytes with abnormal NADPH oxidase activity and deficient cytochrome-b.

A patient with an X-linked genetic disease resembling chronic granulomatous disease (CGD) but differing in several aspects from previously studied cases is described. The oxidase enzyme of the patient's granulocytes was normally activated, but had reduced activity as shown by an increased Michaelis constant and decreased maximum velocity of NADPH-dependent superoxide production. Cytochrome-b was undetectable in dithionite difference spectra. This CGD-like disease further implicates cytochrome-b as an important component of the microbicidal NADPH oxidase system and provides insight into its role in the enzyme complex.

Adolescent↗
PubMed1982

Chronic granulomatous disease: fatal septicemia caused by an unnamed gram-negative bacterium.

A 2-year-old boy with proven X-linked chronic granulomatous disease was placed under continuous co-trimoxazole prophylaxis. He remained free of infection for 4 years. At age 6.25 years, he suddenly developed a fever with no localizing signs and died 16 days later in septic shock. A gram-negative, catalase-positive, halophilic, aerobic bacterium was cultured from blood, bone marrow, and ascitic fluid. This organism could not be identified in microbiological laboratories in Europe and the United States. Its biochemical features indicate that it may belong to a species which has not previously been described.

Bacteria↗
PubMed1982

The efficacy and tolerance of cefoxitin in the treatment of paediatric infections.

Eleven paediatric patients ranging in age from 7 weeks to 7 years were treated with intravenous cefoxitin for a variety of moderate or severe infections. All identifiable pathogens were sensitive to cefoxitin and the clinical outcome for every patient was regarded as a cure. Cefoxitin was well tolerated by all patients, the institution of therapy being associated in many cases with a rapid improvement in clinical condition.

Bacterial Infections↗
PubMed1981

Chronic granulomatous disease: mode of action of sulfamethoxazole/trimethoprim.

Four possible modes of action for the clinically observed effectiveness of sulfamethoxazole/trimethoprim in chronic granulomatous disease were evaluated: (1) inhibition of bacterial catalase, (2) improvement of granulocyte oxygen metabolism, (3) synergism of the antibiotic with nonoxygen-dependent granulocyte killing mechanisms, and (4) a purely antibiotic effect based on uptake and concentration of the antibiotic by and within granulocytes. While the first three mechanisms were excluded, the fourth mechanism is highly probable; sulfamethoxazole was found to reach granulocyte associated concentrations 1.7-fold and trimethoprim 4.1-fold of extracellular levels. Penicillin G, a known nonpenetrating antibiotic, reached 0.3-fold, and tetracycline, a known penetrating agent, 7.1-fold the extracellular level. These findings indicate that sulfamethoxazole/trimethoprim is an antibiotic combination uniquely suited for the long-term prophylaxis of infections in patients with defects of intracellular phagocyte killing.

Catalase↗
PubMed1981

Chronic granulomatous disease: effect of sulfamethoxazole/trimethoprim on neutrophil microbicidal function.

Normal and chronic granulomatous disease (CGD) neutrophils accumulated sulfamethoxazole (SMX) 3-fold and trimethoprim (TMP) 14-fold, possibly through a non-ionic diffusion and pH-partition mechanism. CGD neutrophils incubated with SMX/TMP after phagocytosis of S. aureus killed the bacteria. These findings explain the clinically observed beneficial effect of SMX/TMP in the treatment of infections in CGD and in other conditions characterized by impaired phagocyte microbicidal capacity.

Drug Therapy, Combination↗
PubMedDate not supplied

Lentivirus-mediated gene transfer of gp91phox corrects chronic granulomatous disease (CGD) phenotype in human X-CGD cells.

BACKGROUND: Chronic granulomatous diseases (CGD) are caused by impaired antimicrobial activity in phagocytes, due to the absence or malfunction of the respiratory burst NADPH oxidase. Two-thirds of the patients have mutations in their X-linked CGD gene encoding gp91phox, the largest subunit of the NADPH oxidase. METHODS: Aimed at gene therapy of X-CGD already at the level of resting pluripotent hematopoietic stem cells, we generated an advanced HIV-1-based vector with self-inactivating (SIN2) features containing the therapeutic gp91phox gene. In this vector an internal cytomegalovirus (CMV) promoter exclusively drives transgene expression. The green fluorescent protein (GFP) served as reporter for evaluation of gene transfer and expression in the human myeloid PLB985 X-CGD cell line. RESULTS: The X-CGD cells were efficiently transduced by the VSV-G pseudotyped lentivirus constructs (up to 74% GFP+ cells at 3 days post-transduction). CMV-driven GFP-expression was stable for at least 3 weeks after transduction and persisted after granulocytic differentiation of the target cells. Using the lentivector with the gp91phox transgene, 26% and 48% of the X-CGD cells expressed gp91phox at Days 2 and 20 after co-culture with 293T producer cells, respectively. Upon granulocytic differentiation of the transduced X-CGD cells with dimethylformamide (DMF), up to 63% (mean 49%, n = 7) of the cells were found to be functionally reconstituted with mean levels of superoxide production of 31% (n = 7) compared to wild-type PLB985 cells. CONCLUSION: Lentivirus vectors expressing gp91phox are able to at least partially correct human myeloid X-CGD cells.

Cell Differentiation↗
PubMedDate not supplied

Blockade of acute grade IV skin and eye graft-versus-host disease by anti-interleukin-2 receptor monoclonal antibody in genoidentical bone marrow transplantation setting.

A six-year-old boy with homozygous beta-thalassemia in the favorable class 1 risk group received a bone marrow transplant, from his histocompatible sister. He developed grade IV skin and eye graft-versus-host disease (GVHD) following varicella zoster reactivation. Despite the appropriate prophylactic use of cyclosporin A (CsA), methotrexate (MTX), and prompt treatment with high-dose steroids, GVHD progressed resulting in total body epidermal necrolysis. Anti-IL-2 receptor monoclonal antibodies (anti-IL-2R moAb) in combination with steroids were administered to selectively block the activated T cells. After 27 days of daily administration, followed by 17 doses of alternate-day therapy with anti-IL-2R moAb, the severe skin and eye GVHD resolved. The patient, at two years posttransplant, has full engraftment and immune reconstitution without chronic GVHD (cGVHD). In conclusion, we suggest that in the HLA-genoidentical bone marrow transplantation setting, very severe and steroid-resistant GVHD can be controlled through the use of anti-IL-2 receptor antibodies which specifically block the activated IL-2 receptor expressing T cells.

Acute Disease↗