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Biomedical subjects

C Redman

Publications and source records attributed to C Redman.

At least 55 records · Page 3Linked to original sources
PubMed1994

Theta class glutathione S-transferase GSTT1 genotypes and susceptibility to cervical neoplasia: interactions with GSTM1, CYP2D6 and smoking.

The factors that determine progression of cervical intra-epithelial neoplasia (CIN) to squamous cell carcinoma (SCC) are unknown. Cigarette smoking is a risk factor, suggesting polymorphism at loci that encode carcinogen-metabolizing enzymes such as glutathione S-transferase (GSTT1, GSTM1) and cytochrome P450 (CYP2D6) may determine susceptibility to these cancers. We have studied the frequency of the null genotype at the theta class GSTT1 locus in women with low-grade CIN, high-grade CIN and SCC. The control group comprised women with normal cervical pathology suffering menorrhagia. We found the frequency of GSTT1 null in the control and case groups was not significantly different, though frequency distributions of combinations of the genotype with smoking in mutually exclusive groups in the high-grade CIN group and the other case groups were significantly different. Interactive effects of GSTT1 null with the GSTM1 null and CYP2D6 EM genotypes, and cigarette smoking were also studied by comparing the multinomial frequency distributions of these factors over mutually exclusive categories. These showed no significant differences between the controls and SCC or low-grade CIN. Frequency distributions in high-grade CIN, however, were significantly different to the controls, and both SCC and low-grade CIN; frequency distributions of GSTT1 null with smoking and CYP2D6 EM, individually and in combination, were significantly different. However, inspection of our data does not indicate that GSTT1 null is a major factor mediating risk. Thus, comparison of chi 2 values for the differences between frequency distributions in high-grade CIN and other groups shows that values for combinations of GSTT1 null with other factors are lower than those for equivalent combinations with smoking and CYP2D6 EM. Interestingly, the combination GSTT1 null/GSTM1 null did not appear to influence susceptibility to CIN or SCC.

Adult↗
PubMed1994

Transient loss of proteins carrying Kell and Lutheran red cell antigens during consecutive relapses of autoimmune thrombocytopenia.

A patient is described in whom two consecutive relapses of autoimmune thrombocytopenic purpura (AITP) were associated with loss of red cell antigens of the Kell and Lutheran blood group systems respectively. During the second relapse the glycoprotein CD44 and to a lesser extent the LW antigen were also depressed. Both relapses were associated with concomitant production of IgG antibody recognizing high-frequency determinants on the corresponding antigen-carrying protein. Blocking of antigen sites by these antibodies was not the cause of reduced antigen expression, because immunoblotting studies showed absence of Kell protein during the first relapse, and Lutheran protein during the second. On both occasions the red cell changes reverted to normal with disappearance of the antibody as the AITP entered remission. There was no evidence of clonal lymphocyte expansion as demonstrated using immunoglobulin JH and T cell receptor beta chain probes.

Adult↗
PubMed1993

Iron(II)/hydroperoxide (Fenton reagent)-induced activation of dioxygen for (A) the direct ketonization of methylenic carbon and (B) the dioxygenation of cis-stilbene.

Several iron complexes [FeII(PA)2 (PA = picolinate), FeII(bpy)2(2+), FeII(OPPh3)4(2+), FeII(MeCN)4(2+), (Cl8TPP)FeII(py)2 (Cl8TPP = tetrakis(2,6-dichlorophenyl)porphyrin), and FeIIICl3] in combination with R'OOH (R' = H, t-Bu) catalytically activate O2 to oxygenate hydrocarbons [e.g., c-C6H12-->c-C6H10(O) [9 O2 turnovers per FeII(PA)2 or FeII(bpy)2(2+), and 13 per (Cl8TPP)-FeII(py)2]; PhCH2CH3-->PhC(O)CH3 (up to 25 O2 turnovers per FeIILx); c-C6H10-->c-C6H8(O) (up to 9 O2 turnovers per FeIILx); PhCH(Me)2-->PhC(O)Me, Ph(Me)2COH, and Ph(Me)C = CH2 (up to 5 O2 turnovers per FeIILx); and cis-PhCH = CHPh-->2PhCH(O) (up to 2 O2 turnovers per FeLx)]. With large R'OOH/FeLx ratios spontaneous decomposition occurs to give free O2 that is incorporated into the substrates. The product profiles for the various FeIILx/R'OOH, O2/RH systems and their electrochemical characterization during steady-state turnover confirm that the first-formed intermediate is a one-to-one R'OOH/FeIILx adduct (e.g., [(PA)2-FeIIOOR' + pyH+] (1)) (Fenton reagent), which reacts with (a) excess FeII(PA)2 to give (PA)2FeIIIOR', (b) excess c-C6H12 to give (c-C6H11)py (kinetic isotope effect, [KIE] = kc-C6H12/kc-C6D12, 4.6 with t-BuOOH and 1.7 with HOOH), (c) excess R'OOH to give [(PA)2FeIV(OH)(OOR')] (3), then [(PA)2FeIV(O2)] (7) and O2, and (d) O2 to form an adduct, [(PA)2-FeIII(O2)(OOR') + pyH+] (5), that reacts with c-C6H12 to form c-C6H10(O), [K] = 8.2 (t-BuOOH) and 2.1 (HOOH). When PhCH2CH3 or c-C6H10 are the substrates (RH), 5 reacts to form [(PA)2FeIV(OH)(OOR)] (6), which in turn reacts with RH and O2 in a catalytic cycle to give PhC(O)Me or c-C6H8(O) [up to 7 O2 turnovers per iron with FeII(OPPh3)4(2+)]. Species 7 reacts with cis-PhCH = CHPh to give PhCH(O).

Gas Chromatography-Mass Spectrometry↗
PubMed1992

Assembly and secretion of fibrinogen. Degradation of individual chains.

Hep G2 cells produce surplus A alpha and gamma fibrinogen chains. These excess chains, which are not secreted, exist primarily as free gamma chains and as an A alpha-gamma complex. We have determined the intracellular location and the degradative fate of these polypeptides by treatment with endoglycosidase-H and by inhibiting lysosomal enzyme activity, using NH4Cl, chloroquine, and leupeptin. Free gamma chain and the gamma component of A alpha-gamma are both cleaved by endoglycosidase-H, indicating that the gamma chains accumulate in a pre-Golgi compartment. Lysosomal enzyme inhibitors did not affect the disappearance of free gamma chains but inhibited A alpha-gamma by 50%, suggesting that A alpha-gamma is degraded in lysosomes. The degradative fate of individual chains was determined in transfected COS cells which express but do not secrete single chains. Leupeptin did not affect B beta chain degradation, had very little affect on gamma chain, but markedly inhibited A alpha chain degradation. Antibody to immunoglobulin heavy chain-binding protein (GRP 78) co-immunoprecipitated B beta but not A alpha or gamma chains. Preferential binding of heavy chain-binding protein to B beta was also noted in Hep G2 cells and in chicken hepatocytes. Taken together these studies indicate that B beta and gamma chains are degraded in the endoplasmic reticulum, but only B beta is bound to BiP. By contrast A alpha chains and the A alpha-gamma complex undergo lysosomal degradation.

Ammonium Chloride↗
PubMed1992

Glycoprotein glycosylation and the immunosuppressive effects of human pregnancy serum.

Pregnancy serum contains a factor or factors which suppress T lymphocyte proliferation, although the identity of the factor(s) is still unclear. We have demonstrated that the immunosuppressive activity of pregnancy sera can be destroyed by treatment with periodate which oxidises protein-linked oligosaccharides. Similar effects have been noted with uromodulin, a potent immunosuppressive glycoprotein initially isolated from pregnancy urine. We find, however, that uromodulin is present in both pregnancy and non-pregnancy sera, and that removal of uromodulin from pregnancy serum by lectin affinity chromatography is not associated with loss of activity, ruling out this glycoprotein as the immunosuppressive factor. The possible role of protein-linked oligosaccharides of other serum glycoproteins in causing the pregnancy-related immunosuppression is discussed.

Female↗
PubMed1992

Single agent high-dose cisplatin (200 mg m-2) treatment in ovarian carcinoma.

Twenty patients with epithelial ovarian carcinoma were treated with high-dose cisplatin 200mg m-2. Patients were to receive three cycles at 21 day intervals. Treatment was stopped if severe myelosuppression or any neurotoxicity occurred. Overall, eight (40%) of patients responded with a complete response in five (25%). Four of 16 (25%) previously treated patients responded. The median duration of response was 44 weeks (range 6-130). In patients previously treated there was a significant association (P < 0.002) between response and a remission free interval of 52 weeks or more from primary chemotherapy. Toxicity was assessable in 18 patients. Alopecia and nausea/vomiting were common. Myelosuppression was recorded in nine patients delaying planned administration in eight of 35 cycles. Five patients developed anaemia and six thrombocytopenia. Neurotoxicity affected seven patients and varying degrees of tinnitus six patients. Neurotoxicity and myelosuppression were indications for cessation of treatment in 8 patients receiving less than three cycles. Analysis revealed no significant association between toxicity and prior cisplatin exposure, age or the amount of high-dose cisplatin administered. This series reveals that it is possible to achieve good response rates using high-dose cisplatin without encountering debilitating neurotoxicity.

Adult↗
PubMed1992

Localization of tumour necrosis factor production in cells at the materno/fetal interface in human pregnancy.

Biologically active tumour necrosis factor (TNF) was detected in medium conditioned by incubation with explants of human pregnancy decidua or fetal chorionic villous tissue, taken in the first trimester and at term. Addition of endotoxin increased TNF release in most cases. ELISA assays gave similar results for TNF-alpha and also demonstrated low levels of TNF-beta. Using cell populations purified by flow cytometry, secretion of biologically active TNF was shown to be localized to the macrophages. Cytotrophoblast purified from term amniochorion produced no TNF. Both decidual and chorionic villous tissue at term contained mRNA for TNF-alpha and TNF-beta. TNF-alpha mRNA was confined to decidual macrophages in first trimester tissue, and was not present in chorionic cytotrophoblast. TNF-beta mRNA, in contrast, was detected in both macrophage and non-macrophage populations in term decidua.

Decidua↗
PubMed1991

Trophoblast deportation in pre-eclamptic pregnancy.

OBJECTIVES: To examine the deportation of trophoblast cells into the maternal blood in pre-eclamptic (gestational proteinuric hypertension) and normal pregnancy. DESIGN: The monoclonal anti-cytokeratin antibody JMB2 was used in the APAAP technique to label trophoblast cells in cell smears of uterine vein blood obtained at caesarean section. SUBJECTS: 10 women with proteinuric pre-eclampsia requiring caesarean section, 10 pregnant women requiring elective caesarean section for reasons other than pre-eclampsia and five control women who had never been pregnant. RESULTS: Three populations of trophoblast cells were identified; two mononuclear cytotrophoblast types with diameters varying from 11-14 microns and 19-25 microns respectively, and multinucleated syncytiotrophoblast cells varying in size from 23-88 microns. Women with pre-eclampsia had more trophoblast cells in uterine vein blood than were found in pregnant women without pre-eclampsia. There was no correlation between the numbers of trophoblast cells and the stage of gestation or severity of the pre-eclampsia, although an acute maternal or fetal event necessitating delivery was associated with increased deportation of trophoblast. Mononuclear cytotrophoblast cells were detected in the peripheral blood of only 1 of 5 pre-eclamptic patients, despite their presence in the uterine vein blood of all 5 women. CONCLUSIONS: Trophoblast deportation is increased in pre-eclamptic pregnancy, with both cytotrophoblast and syncytiotrophoblast present in the uterine vein blood, but there is no correlation with the severity of the disease. In some cases cytotrophoblast may also enter the peripheral circulation.

Antibodies, Monoclonal↗
PubMed1991

Umbilical artery resistance index as a screening test for fetal well-being. I: Prospective revealed evaluation.

Abnormalities of the human fetoplacental circulation, a common association with fetal morbidity and mortality, can be detected by Doppler ultrasound examination of the umbilical arterial blood flow. The value of this procedure as a screening test was assessed in 369 women whose fetuses were evaluated on 1354 occasions using both computerized antenatal fetal heart rate (FHR) analysis and continuous-wave Doppler ultrasound. The FHR analyses were used to guide management, but the results of the Doppler measurements were not made available to the clinical staff. The mean duration of each nonstress test (NST) was 27 minutes, compared with 6 minutes for the Doppler examination. Increased resistance indices in the umbilical artery identified those fetuses with an abnormal NST or a clinical diagnosis of antenatal distress with a high sensitivity and negative predictive value. The high rate of false-positive results with respect to these two end points was reduced when fetal distress in labor was included as a third end point. The value of the Doppler examination in predicting fetal distress was applicable to appropriately grown as well as small for gestational age fetuses.

Female↗
PubMed1990

Intracellular fate of fibrinogen B beta chain expressed in COS cells.

Full-length fibrinogen B beta cDNA was subcloned into an expression vector, pBC12BI, and transfected into COS cells. B beta chain expression was measured by pulse-labelling cells with L-[35S]methionine, immunoprecipitating the B beta chain with antibody to fibrinogen and separating the nascent radioactive protein by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). B beta chain was expressed in transfected COS cells but was not secreted into the medium. Treatment with endoglycosidase H showed that non-secreted B beta chain contains mannose-rich carbohydrates rather than the complex form of carbohydrate which occurs in plasma fibrinogen and indicates that B beta chain is not transported to the Golgi apparatus. In transfected COS cells, antibody to fibrinogen co-immunoprecipitated B beta chain and 78 kDa immunoglobulin-binding protein (BiP) and antibody to BiP immunoprecipitated BiP and nascent B beta chains. Non-secreted B beta chain was degraded intracellularly with a half-life of 5 h by enzymes which were not affected by incubating transfected cells with NH4Cl, which indicates a non-lysosomal pathway of degradation. These studies indicate that B beta chain by itself does not contain the signal for fibrinogen secretion and that non-secreted B beta chain is associated with BiP and degraded in the rough endoplasmic reticulum.

Animals↗
PubMed1990

Feasibility and outcome of complete secondary tumor resection for patients with advanced ovarian cancer.

From November 1981 to July 1985, 124 women with International Federation of Gynecology and Obstetrics (FIGO) stage III ovarian cancer were treated in prospective studies of surgery and chemotherapy in our institution. Patients with no macroscopic cancer after primary surgery (n = 16) received five cycles of adjuvant cis-platinum; those with residual cancer after primary laparotomy (n = 108) underwent a second surgical debulking after three or five cycles of cis-platinum-based cytoreductive chemotherapy. Total macroscopic tumor clearance was achieved in 26 of these 108 patients. Fourteen patients with total tumor excision at primary laparotomy remain in complete clinical remission a minimum of 36 months after diagnosis, but the median progression-free interval for the other two groups was 9 and 17 months, respectively. The survival for women who have total tumor clearance only at secondary surgery after chemotherapy is inferior to that for women with primary macroscopic tumor excision followed by chemotherapy.

Adult↗
PubMed1990

The value of Doppler assessment of the uteroplacental circulation in predicting preeclampsia or intrauterine growth retardation.

Flow velocity waveforms of the uteroplacental arteries were analyzed at 20 and 24 weeks of gestation, by means of duplex pulsed Doppler ultrasonography, in 93 women at risk for preeclampsia or intrauterine growth retardation. The ability of an elevated resistance index to predict these conditions was tested. At 20 and 24 weeks an abnormal resistance index was significantly associated with intrauterine growth retardation but not with preeclampsia, with or without proteinuria. A low fetal abdominal circumference at 20 or 24 weeks or an increasing maternal plasma uric acid concentration at 24 weeks was as predictive as an elevated resistance index. In a second group of 43 women, screened in the same way, the only association was of an elevated resistance index at 20 weeks with intrauterine growth retardation. Although elevated resistance indices occur more commonly in women who develop intrauterine growth retardation and/or preeclampsia, the correlation is not close enough to be clinically useful as a screening test.

Blood Flow Velocity↗
PubMed1989

Phase II study of combination 4'-epidoxorubicin and mitomycin C in recurrent epithelial ovarian cancer.

Thirty-three evaluable patients who had epithelial ovarian cancer that had not responded to treatment were entered into a phase II study of combination epirubicin and mitomycin C. Epirubicin (65 mg/m2) and mitomycin C (4 mg/m2) were administered separately, each as an i.v. bolus every 4 weeks. Ten patients (30%) had a complete or partial responses. The median duration of response was 20 weeks (range, 9-53). The regimen was well tolerated. Myelotoxicity occurred in four patients requiring hospitalization for septicaemia. Eleven patients had a blood transfusion. Alopecia was common, and nausea and vomiting, though frequent, usually mild. Cardiological toxicity was observed in one patient only. She developed congestive cardiac failure after an acute myocardial infarction. This regimen is active in advanced ovarian cancer that has not responded to prior treatment and warrants further study combination with other active drugs as a first-line regimen for ovarian cancer.

Adult↗
PubMed1989

Response of patients in phase II studies of chemotherapy in ovarian cancer: implications for patient treatment and the design of phase II trials.

Results using the same drug in phase II studies of treatment in ovarian cancer vary widely. An analysis of five phase II studies with a total of 93 patients was carried out to determine whether factors other than the efficacy of the drug affect response. The drugs for the phase II studies were chosen on the basis of in vitro activity or previous activity in humans. Univariate analysis showed that several factors were of significance in predicting response. The most significant was interval from the end of previous treatment to entry into a phase II study. Others were the original presenting stage of the patient, the second line treatment given and the best previous response to therapy. In multivariate analysis, however, only two factors were shown to be of importance which were interval and the FIGO stage of the patient. Using these two variables the discriminant analysis predicted 89% of those who did not respond and 75% of those who did, with an overall correct prediction of 85%. The importance of interval is emphasised by the observation that the response rate for those patients who progressed on treatment or who relapsed within 3-6 months of primary therapy had a response rate of less than 10%. Future phase II studies should probably exclude patients in this category, since the chance of their responding is very low.

Antineoplastic Combined Chemotherapy Protocols↗