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Biomedical subjects

G J Ras

Publications and source records attributed to G J Ras.

At least 19 recordsLinked to original sources
PubMed2000

Value of estrogenic recruitment before chemotherapy: first randomized trial in primary breast cancer.

PURPOSE: Several preclinical studies showed that short-term pretreatment of breast cancer cells with estrogens can increase the antitumor efficacy of different cytotoxic drugs. Some early clinical studies in patients with advanced breast cancer did seem to support these findings. Therefore, the efficacy of estrogenic recruitment followed by chemotherapy was compared with that of chemotherapy alone in a randomized phase III study in women with lymph node-positive primary breast cancer. PATIENTS AND METHODS: Three hundred twenty-eight patients with stage II/IIIA breast cancer who were younger than 66 years of age were randomly allocated to chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide (FAC) or FAC plus pretreatment with ethinyl estradiol (EE(2)). FAC (500, 50, and 500 mg/m(2), respectively) was administered intravenously once every 4 weeks for four cycles. EE(2) (0.5 mg) was administered orally, both 24 hours and immediately preceding FAC chemotherapy. RESULTS: Patient and tumor characteristics and chemotherapy dosages were comparable in both treatment groups. Of 318 assessable patients, with a median follow-up of 6.8 years, 177 patients had a relapse and 127 died. No significant differences were observed between the two treatment groups with respect to relapse-free, local recurrence-free, and overall survival according to univariate and multivariate analyses adjusted for age, menopausal status, tumor size, grade, number of positive nodes, and steroid-receptor status. The power for the detection of an increase of 50% in the median relapse-free survival was 80%. CONCLUSION: Estrogenic recruitment of breast cancer cells before FAC chemotherapy did not influence the efficacy of adjuvant chemotherapy in stage II/IIIA breast cancer patients after a follow-up of 6.8 years.

Adult↗
PubMed1995

High-dose 5-fluorouracil and leucovorin as second-line chemotherapy in patients with platinum-resistant epithelial ovarian cancer.

A total of 14 patients with platinum-resistant advanced epithelial ovarian cancer were treated with a continuous infusion of high-dose 5-fluorouracil (5-FU, 1200 mg/m2 per day) for 2 consecutive days weekly for 4 weeks and, thereafter, every 2 weeks in combination with a push injection of folinic acid (20 mg/m2) given just before 5-FU and after 24 h. No objective response was documented, and only five patients showed stable disease. The median survival was 6.5 months. There was minimal toxicity. This schedule of 5-FU in combination with folinic acid is not effective as second-line chemotherapy in advanced ovarian cancer.

Aged↗
PubMed1994

Lung and respiratory muscle function in limb girdle muscular dystrophy.

BACKGROUND: Pulmonary involvement is frequently observed in patients with limb girdle muscular dystrophy and occurs early in the disease. The aim of this study was to establish the prevalence of pulmonary dysfunction; the type of dysfunction; and any correlation between patient age, disease duration, or limb weakness and lung or respiratory muscle dysfunction. METHODS: Twenty patients with strictly delineated limb girdle muscular dystrophy and 20 healthy controls were evaluated. Full inspiration chest radiographs were obtained. Standard lung and respiratory muscle function tests were performed and the data were statistically analysed. RESULTS: The mean age of the patients was 40.6 years, the mean disease duration was 18.9 years, and the mean average muscle score (a numerical expression of limb weakness) was 5.73 out of 10. Chest radiography showed unilateral paresis of the diaphragm in three patients. Increased residual volumes, with either increased or decreased total lung capacity, correlated inversely with disease duration. Respiratory muscle weakness was common but mild. Expiratory muscle function was more impaired than inspiratory muscle function and correlated positively with expiratory reserve volume. CONCLUSIONS: Respiratory muscle strength is commonly impaired in limb girdle muscle dystrophy. A dissociation of the limb and mild respiratory muscle involvement is observed; wheelchair restriction does not predict worsening of pulmonary function, and patient age, disease duration, or degree of limb weakness do not predict pulmonary morbidity. The diaphragm is not disproportionately affected by the dystrophic process compared with limb muscles.

Adult↗
PubMed1994

Respiratory manifestations of rigid spine syndrome.

Thoracic abnormalities and respiratory muscle function were investigated in nine patients with rigid spine syndrome. A severe restrictive chest wall defect and limited mobility of the spine associated with clinically significant respiratory muscle weakness were present in all patients. Respiratory muscle strength and endurance were less than 60% of control values. Slight to moderate scoliosis was present in five patients and absent in four. Scoliosis appeared to have only a minor additional effect on respiratory muscle function. Six patients were emaciated, and one patient was underweight, but no relationship was seen between body mass index and respiratory muscle strength. Respiratory muscle function was more impaired in patients with hypoventilation than in normocapnic patients. Respiratory muscle involvement appears to be a significant feature of rigid spine syndrome, terminating in hypercapnic ventilatory failure in some patients.

Adolescent↗
PubMed1992

Enhanced release of elastase and oxidative inactivation of alpha-1-protease inhibitor by stimulated human neutrophils exposed to Pseudomonas aeruginosa pigment 1-hydroxyphenazine.

The in vitro effects of the Pseudomonas aeruginosa-derived phenazine pigments pyocyanin and 1-hydroxyphenazine (1-hp) on neutrophil elastase release and myeloperoxidase-induced inactivation of alpha-1-protease inhibitor (alpha 1-PI) were investigated. 1-hp (6-25 microM), but not pyocyanin, caused a dose-dependent enhancement of elastase release by FMLP:cytochalasin B (CB)-activated human neutrophils. 1-hp (0.78-6.25 microM) also increased the oxidative inactivation of the elastase inhibitory capacity of alpha 1-PI exposed to FMLP:CB-activated neutrophils. Methionine, a scavenger of hypochlorous acid, completely protected alpha 1-PI from inactivation by stimulated neutrophils in the presence or absence of 1-hp. Similar protective effects were observed with sodium azide, an inhibitor of myeloperoxidase. P. aeruginosa-derived 1-hp may promote an elastase-antielastase imbalance in vivo by increasing the release of neutrophil elastase and by enhancing the oxidative inactivation of alpha 1-PI, thereby contributing to the development of tissue destruction in P. aeruginosa-infected patients.

Humans↗
PubMed1992

Clindamycin, erythromycin, and roxithromycin inhibit the proinflammatory interactions of Pseudomonas aeruginosa pigments with human neutrophils in vitro.

The Pseudomonas aeruginosa-derived phenazine pigments pyocyanin and 1-hydroxyphenazine (1-hp) prime human neutrophils for enhanced, stimulus-activated release of superoxide and myeloperoxidase (MPO), respectively. In the present study, the modulatory potentials of the antimicrobial agents clindamycin, erythromycin, and roxithromycin (10 and 20 micrograms/ml) on the prooxidative interactions of pyocyanin and 1-hp (12.5 microM) with human neutrophils have been investigated. Clindamycin, erythromycin, and especially roxithromycin caused dose-related inhibition of the generation of superoxide by both untreated and pyocyanin-treated neutrophils during activation with either the synthetic chemotactic tripeptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) or the calcium ionophore A23187. The antimicrobial agents also inhibited the generation of reactive oxidants by the MPO-H2O2-halide system during activation of both untreated and 1-hp-treated neutrophils by FMLP. These effects appeared to be due to drug-related interference with membrane-associated oxidative metabolism, since none of the antimicrobial agents inhibited the release of MPO by activated neutrophils, nor did they possess oxidant-scavenging properties. These data demonstrate that clindamycin, erythromycin, and especially roxithromycin antagonize the proinflammatory interactions of pyocyanin and 1-hp with neutrophils and indicate a possible therapeutic role for these antimicrobial agents in the prevention of tissue damage in diseases characterized by P. aeruginosa infection.

Clindamycin↗
PubMed1990

Proinflammatory interactions of pyocyanin and 1-hydroxyphenazine with human neutrophils in vitro.

The effects of the Pseudomonas aeruginosa-derived pigments, pyocyanin and 1-hydroxyphenazine (1-hp), on membrane-associated oxidative metabolism and release of lysozomal enzymes by human neutrophils were investigated in vitro. Pyocyanin, but not 1-hp, increased the generation of superoxide and the rate and duration of oxygen uptake by activated neutrophils. Both agents increased the myeloperoxidase-mediated iodinating activity of neutrophils, which in the case of 1-hp was due to stimulation of the release of myeloperoxidase by activated neutrophils. 1-hp also increased the release of lysozyme by activated neutrophils. Pyocyanin caused only slight enhancement of the release of myeloperoxidase and lysozyme by stimulated neutrophils but was more potent with respect to the release of the specific granule marker, vitamin B12-binding protein. These data indicate the existence of diverse, proinflammatory interactions of pyocyanin and 1-hp with human phagocytes, which may intensify neutrophil-mediated tissue damage during P. aeruginosa infections.

Cell Degranulation↗
PubMed1988

Ascorbic acid neutralizes reactive oxidants released by hyperactive phagocytes from cigarette smokers.

During exposure to the leukoattractant FMLP (N-formyl-L-methionyl-L-leucyl-L-phenylalanine) human polymorphonuclear leukocytes (PMNL) exhibit a bimodal pattern of luminol-enhanced chemiluminescence (LECL) with distinct early extracellular and later-occurring intracellular membrane-associated oxidative responses [4, 7, 14]. With the primary objective of measuring the effects of oral administration of the antioxidant ascorbate on the generation of reactive oxidants by circulating phagocytes from cigarette smokers and nonsmokers, we have developed a method for the measurement of FMLP-activated LECL in whole blood. With this method definite bimodal LECL responses, similar to those obtained with pure PMNL, were observed with FMLP-activated whole blood. No LECL responses were observed when whole blood from 3 children with chronic granulomatous disease was stimulated with FMLP, which shows that the FMLP-activated LECL responses are exclusively phagocyte-derived in blood from normal individuals. The whole blood method was used to compare the FMLP-activated LECL responses in blood from 30 asymptomatic smokers and 30 nonsmokers and to investigate the effects of co-incubation of whole blood from smokers and nonsmokers with ascorbate (2.5 X 10(-5) M-2.5 X 10(-4)M), as well as the effects of oral administration of the antioxidant on FMLP-activated LECL. Increased generation of both extracellular (58% mean increase, P less than 0.005) and intracellular (75% mean increase, P less than 0.005) phagocyte-derived oxidants was observed with FMLP-activated blood from smokers relative to nonsmokers. Co-incubation of blood with ascorbate in vitro caused a dose-dependent selective neutralization of extracellular oxidants. Similar effects were observed following the oral administration of a single dose of ascorbate (1 g). The whole blood method may be useful in identifying smokers at risk for smoking-related diseases.

Adolescent↗
PubMed1987

Regulation by the antioxidants ascorbate, cysteine, and dapsone of the increased extracellular and intracellular generation of reactive oxidants by activated phagocytes from cigarette smokers.

The bimodal pattern of N-formyl-methionyl-leucyl-phenylalanine (FMLP)-activated luminol-enhanced chemiluminescence with distinct early (occurring within 1 min) extracellular and late intracellular oxidative responses was compared in polymorphonuclear leukocytes (PMNL) from asymptomatic cigarette smokers and nonsmoking control subjects. Relative to control PMNL, the PMNL from smokers were hyperreactive to FMLP stimulation with increased generation of both extracellular (p less than 0.025) and intracellular (p less than 0.025) reactive oxidants. Smokers' PMNL also showed increased PMNL-activated superoxide generation and increased apparent receptors for FMLP. The water-soluble antioxidants ascorbate and cysteine (2.5 X 10(-5) M to 2.5 X 10(-4) M) selectively neutralized the extracellular activity of PMNL-derived reactive oxidants. The lipid-soluble antioxidant dapsone (1.25 to 30 micrograms/ml), on the other hand, inhibited both the extracellular and intracellular FMLP-activated chemiluminescence responses in PMNL from smokers and nonsmoking control subjects. Regulation of the increased extracellular and intracellular membrane-associated oxidative responses in PMNL from cigarette smokers is probably an important function of water-soluble and lipid-soluble antioxidants in vivo.

Adult↗
PubMed1986

An in-vitro study of oral therapeutic doses of co-trimoxazole and erythromycin stearate on abnormal polymorphonuclear leucocyte migration.

The effects of administration for four days of co-trimoxazole (2 X 500 mg tablets daily) and erythromycin stearate (3 X 500 mg tablets daily) on persistently abnormal polymorphonuclear leucocyte (PMNL) migration in six individuals with a history of chronic or recurrent bacterial infections were studied. The effects of co-incubation of PMNL in vitro with both antimicrobial agents at concentrations of 12(-5) and 10(-4) M were also investigated. Two different leucoattractants were used, autologous serum activated with bacterial endotoxin (EAS) and the synthetic chemotactic tripeptide FMLP. In three homosexual males with the acquired immunodeficiency syndrome (AIDS) abnormal PMNL motility was associated with the presence of serum inhibitor(s) of cell migration. In a fourth female subject, with recurrent episodes of acute periodontitis, and intrinsic cellular defect of PMNL migration associated with markedly impaired FMLP-induced degranulation and binding to PMNL was observed. In the remaining two subjects with chronic osteomyelitis, the precise abnormality of PMNL movement was not defined but appeared to be of the cellular intrinsic type. Co-incubation of PMNL with erythromycin, but not cotrimoxazole, at both concentrations tested (10(-5) and 10(-4) M) significantly improved cell migration to EAS, Likewise administration of erythromycin, but not cotrimoxazole, significantly improved PMNL migration to EAS. Improvement or correction of abnormal PMNL motility during antimicrobial chemotherapy with erythromycin may be a useful property of this antimicrobial agent.

Acquired Immunodeficiency Syndrome↗
PubMed1985

An objective filter-based, enzymatic method for the in vivo measurement of the migration of human polymorphonuclear leucocytes.

Incorporation of control valves into a previously described device enabled us to regulate the formation of 8 suction blisters on the upper surface of the forearm in adult human volunteers. After the removal of the raised epidermis and blister fluid, uniform areas of denuded dermis were obtained by placing hollow adhesive ring reinforcers onto each of the regions of exposed dermis. Single or double nitrocellulose filters were then placed onto each of the areas of moistened, exposed dermis. The chemotactic tripeptide FMLP was incorporated into 1% agarose containing 0.1% bovine serum albumin (BSA) to give a concentration range of 10(-8) M to 10(-6) M FMLP. In control systems the FMLP was omitted. Cylindrical agarose blocks +/- FMLP were then placed onto the filters and encased in individual perspex cups glued firmly onto the skin. The filter(s) and agarose blocks were replaced at 2 h intervals and polymorphonuclear leucocyte (PMNL) migration onto (single filter) and into (double filter) the filters was measured by microscopic enumeration or according to the amount of myeloperoxidase (MPO) and lysozyme in the supernatants of filters immersed in 0.1% Triton-X for 10 min to lyse the PMNL. Microscopic enumeration was found to be unsuitable but the method based on MPO and lysozyme release from filter-associated PMNL was rapid, accurate and reproducible. Detectable PMNL migration (greater than 90%) occurred at 3-4 h and was maximal at 8-10 h. This pattern was observed for both the control and FMLP-containing systems. However, PMNL migration was significantly greater in FMLP-exposed dermis. FMLP at 10(-6) M was found to promote maximal PMNL migration. Significantly greater MPO and lysozyme activities were observed with the double filter system. This method is suitable for the objective quantitation of PMNL migration in vivo.

Adult↗
PubMed1984

Mononuclear and polymorphonuclear leucocyte dysfunction in male homosexuals with the acquired immunodeficiency syndrome (AIDS).

In addition to the well-documented abnormalities of cell-mediated immunity we have observed that both polymorphonuclear leucocytes (PMNLs) and mononuclear leucocytes (MNLs) from 3 patients with the acquired immunodeficiency syndrome (AIDS) showed markedly defective migratory responsiveness to leuko-attractants in vitro. Reduced PMNL and MNL chemotaxis is attributable, at least in part, to a serum inhibitor of leucocyte migration, since co-incubation of PMNLs from healthy control subjects with 10% AIDS serum inhibited the migration to leuko-attractants of these cells. This serum-inhibitory effect on leucocyte migration was not due to the presence in AIDS serum of increased levels of prostaglandin E2, cytomegalo-virus or anti-leukocyte antibodies. However, elevated serum immunoglobulin A (IgA) levels were observed in all 3 patients. IgA is a potent inhibitor of PMNL and MNL migration. It is possible that serum inhibitors of leucocyte migration perpetuate the profound immunosuppression characteristic of AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1983

Primary ciliary dyskinesia in association with Marfan's syndrome. A case report.

Marfan's syndrome and primary ciliary dyskinesia are both disease entities with specific criteria for diagnosis. Pulmonary manifestations of Marfan's syndrome, including bronchiectasis, are well documented, but the association with ciliary dyskinesia is unknown. A case in which criteria for both diagnoses were satisfied is discussed.

Adult↗
PubMed1983

Acquired immunodeficiency syndrome. A report of 2 South African cases.

This report documents the first 2 cases of the acquired immunodeficiency syndrome in male homosexuals identified in South Africa. Both patients died of Pneumocystis carinii pneumonia and both had cytomegalovirus infection. Neither had peripheral lymphadenopathy and in both cases the lymph nodes showed cortical and paracortical atrophy with marked plasma cell and histiocytic infiltration. It is suggested that this lymph node pattern represents the morphological expression of the immunological defect in this syndrome.

Acquired Immunodeficiency Syndrome↗