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Biomedical subjects

C M Thomas

Publications and source records attributed to C M Thomas.

At least 19 recordsLinked to original sources
PubMed1992

Comparison of five immunoassay procedures for the ovarian carcinoma-associated antigenic determinant CA 125 in serum.

Interassay variability in CA 125 values was studied in 77 serum samples (covering a range of CA 125 values between 8.9 and 310 arb. U/ml as measured by the original Centocor RIA) using three 125I-labeled RIA kits (Centocor, Byk and Cis) and two enzyme-labeled immunoassays (Abbott and Roche). Taking the Centocor RIA as a reference, orthogonal regression equations resulted in slopes varying between 0.74 and 1.35, with y-axis intercepts varying between -6.5 and +6.2, and correlation coefficients ranging from 0.88 to 0.94. Compared with the results of the Centocor RIA, the EIAs of Abbott and Roche gave overall lower CA 125 values, whereas the Cis and the Byk RIAs gave higher assay results. At the 35 arb. U/ml Centocor cut-off, serum levels with the other assays varied between 23 and 53 arb. U/ml. The 65 arb. U/ml cut-off level corresponded with CA 125 serum levels between 45 and 94 arb. U/ml. When classifying CA 125 values in three clinically relevant categories based on Centocor RIA results, ('normal' < or = 35 arb. U/ml, 'slightly elevated' > 35- < or = 65 arb. U/ml and 'elevated' > 65 arb. U/ml), discordances ranged from 26% with the Cis RIA to 40% utilizing the Byk RIA. The five CA 125 assays tested do not give equal assay results. As a consequence, the interpretation of CA 125 serum concentrations should be done with caution in disease monitoring and in the assessment of ovarian masses, especially when using different serum assays.

Antigens, Tumor-Associated, Carbohydrate↗
PubMed1992

Beneficial effects on serum lipoproteins by 17 beta-oestradiol-dydrogesterone therapy in postmenopausal women; a prospective study.

STUDY OBJECTIVE: To study the possible changes of reproductive hormones, sex hormone binding globulin, serum lipids and lipoproteins, lipoprotein (a) included, coagulation and glucose in postmenopausal women treated with 17 beta-oestradiol and cyclic dydrogesterone for 14 days per 28 days treatment cycle. DESIGN: Open longitudinal prospective study. DURATION: Twelve 28 days treatment cycles. SETTING: Gynaecological department of university hospital. SUBJECTS: 27 healthy postmenopausal women. RESULTS: After treatment for six cycles serum concentrations of FSH and LH decreased significantly with 43.0% and 24.4%, respectively. Serum concentrations of 17 beta-oestradiol and oestrone increased significantly with 302% and 792%, respectively, and SHBG increased as well with 111% (P < 0.01). Serum total cholesterol decreased with 9.0% (P < 0.01). Serum VLDL-cholesterol did not change significantly. Serum LDL-cholesterol decreased with 16.3% (P < 0.01) and HDL-cholesterol increased with 8.0% (P < 0.01). This was accompanied with similar significant changes in the apolipoproteins: apolipoprotein A-I rose with 14.4% and apolipoprotein B decreased with 6.0%. Serum triglycerides and VLDL-triglycerides increased significantly with 14.4% and 17.9%, respectively. Lipoprotein (a) decreased with 17.5% (P < 0.01). These results more or less sustained at cycle 12 of treatment. Serum concentrations of antithrombin III and glucose did not change. Fibrinogen decreased slightly but significantly below the initial value. CONCLUSIONS: This combination replacement therapy gives beneficial changes in lipid-metabolism, indicating a reduced risk of developing coronary heart disease without unfavourably changing coagulation and glucose metabolism. The expected beneficial changes with oestradiol alone are not counteracted by the intermittent addition of dydrogesterone. Therefore this oestrogen/progestagen scheme can, indeed, be recommended for use in HRT.

Apolipoproteins A↗
PubMed1992

Synthesis and evaluation of 2-pyridinone derivatives as HIV-1 specific reverse transcriptase inhibitors. 1. Phthalimidoalkyl and -alkylamino analogues.

A potent (IC50 = 30 nM), specific nonnucleoside HIV-1 reverse transcriptase (RT) inhibitor 3-[N-(phthalimidomethyl)amino]-5-ethyl-6-methylpyridin-2(1H) -one (1), was discovered through an in vitro screening program. This compound did not inhibit (IC50 > 300 microns) other DNA and RNA polymerases, including HIV-2 RT and SIV-RT. Unfortunately, hydrolytic instability of this (aminomethyl)phthalimide precluded use as an antiviral agent. In the first paper of this series, preliminary development efforts are described which produced ethylphthalimide 20, a hydrolytically stable compound with reduced (100-fold) HIV-1 RT inhibitory activity and weak (CIC95 = 40 microM) antiviral activity in H9 cells. Structure-activity studies demonstrated the importance of the 5-ethyl, 6-methyl substituent pattern on the pyridinone ring and the need for a flexible two-atom linker between the pyridinone and phthalimide heterocycles. These leads, 1 and 20, provided a basis for the further development of this structural class of inhibitors from which several compounds, the subject of accompanying reports, were selected for clinical evaluation.

Antiviral Agents↗
PubMed1992

Synthesis and evaluation of 2-pyridinone derivatives as HIV-1-specific reverse transcriptase inhibitors. 2. Analogues of 3-aminopyridin-2(1H)-one.

A series of nonnucleoside 3-aminopyridin-2(1H)-one derivatives was synthesized and evaluated for HIV-1 RT inhibitory properties. Several analogs proved to be potent and highly selective antagonists with in vitro IC50 values as low as 19 nM in the enzyme assay using rC.dG as template-primer. Two compounds from this series, 3-[[(4,7-dimethylbenzoxazol-2-yl)methyl]-amino]-5-ethyl-6-methy lpyridin-2(1H)-one (34, L-697,639) and the corresponding 4,7-dichloro analogue (37, L-697,661) inhibited the spread of HIV-1 IIIb infection by 95% in MT4 cell culture at concentrations of 25-50 nM and were selected for clinical trials as antiviral agents.

Aminopyridines↗
PubMed1992

Crosstalk between plasmid vegetative replication and conjugative transfer: repression of the trfA operon by trbA of broad host range plasmid RK2.

Previous deletion and complementation analysis has indicated that the region between trfA and kilBI (trbB) encodes trans-acting factor, designated trbA, required for conjugative transfer of broad host range plasmid RK2. In analysing the nucleotide sequence of this region we have discovered a gene encoding a 12 kDa polypeptide. The predicted amino acid sequence of this protein shows similarity at its C-terminal to KorA from the central control operon of RK2 and at its N-terminal to immunity repressor protein from phage phi 105 of Bacillus subtilis as well as the Sin protein of B. subtilis which regulates alternate developmental processes including sporulation, motility and competence. We show that TrbA represses transcription of both trfA (vegetative replication) and kilBI (trbB) (required for conjugative transfer and whose product has similarity to ComG, required for competence of B. subtilis) and may help to coordinate expression of both sets of functions. This region has similarities to some temperate bacteriophage immunity regions in modulating divergent transcription required for alternative means of propagation.

Amino Acid Sequence↗
PubMed1992

The relation between the soluble factor associated with H(+)-transhydrogenase of Rhodospirillum rubrum and the enzyme from mitochondria and Escherichia coli.

Although in mitochondria, Escherichia coli and Rhodobacter capsulatus the H(+)-transhydrogenases are intrinsic membrane proteins, in Rhodospirillum rubrum a water-soluble component (Ths) and a membrane-bound component are together required for activity. Ths was selectively removed from chromatophore membranes of Rhs. rubrum and was purified to homogeneity by precipitation with (NH4)2SO4 and ion-exchange, affinity dye and gel exclusion chromatography. The latter indicated an Mr of approx. 74,000 under non-denaturing conditions but analysis of the pure protein by SDS-PAGE revealed a single polypeptide, Mr 43,000. Antibodies against this polypeptide inhibited transhydrogenase activity of chromatophores and decreased the capacity of Ths to restore activity to depleted membranes. They reacted with a polypeptide of Mr 43,000 in crude cell extract, chromatophore membranes and chromatophore washings but not with transhydrogenase polypeptides from the membranes of E. coli, Rb. capsulatus or animal mitochondria. The N-terminal amino acid sequence of the 43,000 polypeptide was strongly homologous with the reported N-terminal regions of mitochondrial transhydrogenase and the alpha subunit of the E. coli protein. The break between the alpha and beta polypeptides of E. coli transhydrogenase is such that both components are membrane-associated. In contrast, these results suggest that in the Rhs. rubrum enzyme Ths has been formed by a break closer to the N-terminus, thus avoiding the putative trans-membrane helical segments and yielding a relatively hydrophilic subunit, which is water-soluble. There is a predicted similarity between Ths and the reported sequence of alanine dehydrogenase from Bacillus but Ths did not have any alanine dehydrogenase activity.

Amino Acid Sequence↗
PubMed1992

kfrA gene of broad host range plasmid RK2 encodes a novel DNA-binding protein.

The korABF operon of broad host range IncP plasmid RK2 encodes proteins that coordinate expression of many other operons and that aid plasmid stability by providing at least part of a partitioning apparatus. The kfrA gene lies downstream from this operon and its transcription is repressed by all except one of the proteins encoded by this operon (KorA, KorFI, KorFII and KorB). We report here that transcription from the kfrA promoter is autoregulated by the kfrA gene product. We have purified KfrA, which is an acidic polypeptide of 308 amino acid residues, and show that it is a site-specific DNA-binding protein whose operator overlaps the primary kfrA promoter. Deletion analysis suggests that this activity is critically dependent on the N-terminal section of KfrA, which appears to contain an alpha-helix-beta-turn-alpha-helix motif. Circular dichroism confirmed the structural prediction that KfrA is almost entirely alpha-helical. The position of predicted turns suggests that, while amino acid residues 1 to 80 may form a globular domain of four or five helices, residues 80 to 280 of KfrA may adopt an extended coiled-coil domain containing a heptad repeat segment, which is probably responsible for formation of the multimers detected by crosslinking. The possibility that this unusual structure serves a second function, for example in providing a bridge to host structures required for plasmid partitioning, is discussed.

Amino Acid Sequence↗
PubMed1992

Evaluation of seven tumor markers (CA 50, CA 19-9, CA 19-9 TruQuant, CA 72-4, CA 195, carcinoembryonic antigen, and tissue polypeptide antigen) in the pretreatment sera of patients with gastric carcinoma.

Preoperative serum levels of the tumor markers CA 50, CA 19-9, CA 19-9 TruQuant, CA 72-4, CA 195, carcinoembryonic antigen (CEA), and tissue polypeptide antigen (TPA) were measured in 94 patients with well-staged adenocarcinoma of the stomach and in 15 patients with benign gastric diseases. In all patients with carcinoma, a laparotomy was done. The serum levels were correlated with the stage of disease, the location of the primary tumor, and the resectability and grade of differentiation. The marker CA 50 was the best, with an overall positivity of 59.5%. For CA 19-9, this figure was 34%; for CA 19-9 TruQuant, 22%; for CA 72-4, 34%; for CA 195, 29%; for CEA, 33%; and for TPA, 50%. The best combination of two markers was CA 50 and TPA; this combination gave a positivity of 81%. There was no evident correlation with stage of disease and the percentage of positive serum levels or the median serum levels. The marker CA 50 gave the widest range of elevated serum levels between the cutoff level and the 90th percentile (54%). Patients with carcinoma of the cardia had higher preoperative serum levels than those with a tumor in other parts of the stomach. There was no correlation with the resectability of the tumor and the preoperative serum level. Patients with an undifferentiated tumors did not have significantly lower serum levels than those with more differentiated tumors. Currently, preoperative determination of serum tumor marker levels in patients with gastric carcinoma has no significant in clinical practice.

Adult↗
PubMed1992

Disturbed reproductive performance in extreme folic acid deficient golden hamsters.

We studied the effects of folic acid-deficient diets on maternal red blood cell folate level and reproductive performance in golden hamsters (Mesocricetus auratus, Waterhouse). Animals on the same day of oestrous cycle were put together and finally divided into three groups. Each group comprised at least 12 mature female hamsters. The animals were given three different diets, which were commenced before mating. The feeding regimens comprised a standard diet (group 1), or a folic acid-deficient diet which started either 2 weeks (group 2) or 16 weeks (group 3) prior to mating. The regimens were continued until sacrifice of the animals on day 9 of pregnancy. Pregnancy was realized by caging a male with a selected female during the night of ovulation. Just prior to sacrifice, blood samples were drawn to measure maternal folic acid levels in red blood cells. The pregnant uteri were removed and the embryonic sacs were carefully dissected away from the uterus. The number of sacs per pregnant animal was noted. Extreme folic acid deficiencies were confirmed in the pregnant golden hamsters on a folic acid-deficient diet which started 16 weeks prior to mating as compared to those on a standard diet and on a folic acid-deficient diet which started 2 weeks prior to mating. This deficiency appears to interfere with normal reproductive performance. It caused early embryonic loss several days after mating and resulted, finally, in restoration of the oestrous cycle.

Animals↗
PubMed1992

Sugarbeet minicircular mitochondrial DNAs: high-resolution transcript mapping, transcript abundance and copy number determination.

Three minicircular mitochondrial DNAs have been studied to address several aspects of transcription in sugarbeet mitochondria. High-resolution transcript mapping experiments have shown that sequences at the 5' termini of minicircle transcripts are highly homologous and resemble sequences at the 5' termini of sugarbeet mainband mitochondrial genes (atpA, atp6). In addition, they show homology to transcript termini of mitochondrial genes from other dicotyledonous plants, suggesting they may function as promoter sequences. Conserved sequences, which most probably act as RNA processing signals, were also identified at the 3' termini of minicircle transcripts. An oligonucleotide probe to a 14 base conserved sequence was used to determine the relative copy numbers of the three minicircle components in male-fertile mitochondria. Copy numbers were roughly equivalent, suggesting minicircles are replicated and/or transmitted with nearly equal efficiency, at least in sugarbeet taproots. Mc.a and Mc.c transcript levels are equivalent, consistent with their template copy number, however; Mc.d transcript levels were significantly lower than expected, implicating additional factors such as promoter strength and/or transcript stability in determining transcript levels in sugarbeet mitochondria, as recently demonstrated in maize.

Base Sequence↗
PubMed1992

Effects of sub-50 oral contraceptives on homocysteine metabolism: a preliminary study.

The influence of a monophasic sub-50 oral contraceptive (OC), Marvelon, on fasting total homocysteine levels was investigated in OC users and controls. Homocysteine levels in serum of OC users were significantly higher (P less than .01) than in controls during the low-hormonal phase of the cycles and comparable with levels determined in heterozygotes for homocystinuria. Blood levels of pyridoxal phosphate (PLP) were significantly lower (P less than .05) in OC users both in the low and high hormonal phase. However, there were no significant differences in the levels of homocysteine nor in folate and vitamin B12 between both groups in the high-hormonal phase. In contrast to the control group, the homocysteine levels in OC users in the high-hormonal phase of the cycle were significantly decreased compared with those on a low-hormonal day (P less than .05). These data suggest that cyclically recurrent periods of hyperhomocysteinemia do occur during sub-50 OC use in normal women and might be considered a predisposition to the occurrence of vascular complications.

Adult↗
PubMed1992

On the origin and significance of serum CA-125 concentrations in 97 patients with endometriosis before, during, and after buserelin acetate, nafarelin, or danazol.

OBJECTIVE: To further elucidate the origin and significance of serum CA-125 in pelvic endometriosis. DESIGN: Retrospective. PATIENTS: Ninety-seven women with endometriosis who participated in two trials: (1) open-label study on buserelin acetate (n = 51) and (2) comparative, placebo-controlled study on nafarelin (n = 31) versus danazol (n = 15) (2:1 ratio). INTERVENTIONS: (1) Buserelin acetate 900 micrograms/d intranasally (IN); (2) nafarelin 400 micrograms/d IN versus danazol 400 mg/d orally during 6 months. MAIN OUTCOME MEASURE(S): Serum CA-125 and estradiol concentrations; severity of endometriosis-related symptoms; scores according to The American Fertility Society (AFS) classification for endometriosis and/or adhesions (before and on last day of therapy). RESULTS: Menstruation and adhesions appeared major factors influencing pretreatment serum CA-125 concentrations. Compared with nonmenstruating women without adhesions, both menses and adhesions induced a slight increase tending to significancy, whereas the elevating effect of adhesions and menses together was highly significant and more than expected. All three treatment regimens reduced CA-125 concentrations to the same extent; cessation of therapy was followed by restoration to pretreatment concentrations. Of the AFS scores for implants and/or adhesions, only pretreatment scores for adhesions correlated significantly with CA-125 concentrations. Severity scores for endometriosis-related complaints did not correlate. CONCLUSIONS: The findings indicate that adhesions play a major role in the presence of CA-125 in the systemic circulation and suggest that reductions of serum CA-125 concentrations during gonadotropin-releasing hormone agonist and danazol therapy are hormonally determined.

Antigens, Tumor-Associated, Carbohydrate↗
PubMed1992

Comparison of four serum tumour markers in the diagnosis of colorectal carcinoma.

The assessment of the diagnostic power of four serum tumour markers, CEA, CA 19-9, CA 50 and CA 195 for colorectal carcinoma is described, according to recently formulated guidelines. Preoperative serum concentrations of the four markers were determined in 198 colorectal cancer patients and 57 patients with a benign colorectal disorder. The cumulative frequency distributions of the malignant and benign group show strong overlap for all markers, which indicates low diagnostic ability. This is confirmed by the Receiver Operating Characteristic curves, which have areas under the curve of 0.65 (95% confidence interval (CI) 0.58-0.73) for CA 19-9, CA 50 and CA 195 and of 0.70 (95%) CI 0.63-0.77) for CEA. The new tumour markers appear to be of slightly less diagnostic value than CEA for the primary diagnosis of colorectal cancer, although the discrepancy is not statistically significant. The low diagnostic power of CA 19-9, CA 50 and CA 195 may be due to a high proportion of colorectal cancer patients having the Lewis(a-b-) phenotype, who cannot synthesise these markers.

Antigens, Tumor-Associated, Carbohydrate↗
PubMed1992

Nucleotide sequence of the structural gene encoding a 2-haloalkanoic acid dehalogenase of Pseudomonas putida strain AJ1 and purification of the encoded protein.

The nucleotide sequence of a gene encoding an L-2-haloalkanoic acid halidohydrolase from Pseudomonas putida strain AJ1 was determined. The ORF (hadL) codes for a polypeptide of 227 amino acids (Mr 25,687) which has significant homology to two other L-2-haloalkanoic acid halidohydrolases of Pseudomonas sp., DehcI and DehcII; these show 38% and 51% amino acid identity respectively to HadL. All three enzymes produce products of an opposite optical configuration to that of the substrates. Comparison of the three sequences shows several highly conserved motifs which indicate the possible position of the enzyme active site. The enzyme was purified to homogeneity and appears to exist as a tetramer.

Amino Acid Sequence↗
PubMed1992

Conjugative transfer functions of broad-host-range plasmid RK2 are coregulated with vegetative replication.

The kilB locus (which is unclonable in the absence of korB) of broad-host-range plasmid RK2 (60 kb) lies between the trfA operon (co-ordinates 16.4 to 18.2 kb), which encodes a protein essential for vegetative replication, and the Tra2 block of conjugative transfer genes (co-ordinates 20.0 to 27.0 kb). Promoter probe studies indicated that kilB is transcribed clockwise from a region containing closely spaced divergent promoters, one of which is the trfA promoter. The repression of both promoters by korB suggested that kilB may also play a role in stable maintenance of RK2. We have sequenced the region containing kilB and analysed it by deletion and insertion mutagenesis. Loss of the KilB+ phenotype does not result in decreased stability of mini RK2 plasmids. However insertion in ORFI (kilBI) of the region analysed results in a Tra- phenotype in plasmids which are otherwise competent for transfer, demonstrating that this locus is essential for transfer and is probably the first gene of the Tra2 region. From the kilBI DNA sequence KilBI is predicted to be 34995 Da, in line with M(r) = 36,000 observed by sodium dodecyl sulphate/polyacrylamide gel electrophoresis, and contains a type I ATP-binding motif. The purified product was used to raise antibody which allowed the level of KilBI produced from RK2 to be estimated at approximately 2000 molecules per bacterium. Protein sequence comparisons showed the highest homology score with VirB11, which is essential for the transfer of the Agrobacterium tumefaciens Ti plasmid DNA from bacteria to plant cells. The sequence similarity of both KilBI and VirB11 to a family of protein export functions suggested that KilBI may be involved in assembly of the surface-associated Tra functions. The data presented in this paper provide the first demonstration of coregulation of genes required for vegetative replication and conjugative transfer on a bacterial plasmid.

Agrobacterium tumefaciens↗
PubMed1992

Streptokinase morbidity--more common than previously recognised.

Streptokinase is the thrombolytic agent most commonly used for the treatment of acute myocardial infarction. We report eight patients who developed late uncommon adverse reactions to streptokinase probably due to immune complex disease. The clinical manifestations included vasculitic rashes, abnormal renal and liver function tests and a syndrome resembling adult respiratory distress syndrome. Major adverse events with streptokinase such as stroke, bleeding and other allergic reactions, have been previously documented but the morbidity related to delayed reactions has not been widely recognised. These reactions produced significant morbidity resulting in prolonged hospital stay and may need to be considered in the decision to use streptokinase.

Adult↗
PubMed1992

Use of serum tumor markers in the differential diagnosis between ovarian and colorectal adenocarcinomas.

In the search for a method to facilitate the preoperative discrimination of ovarian carcinomas from colorectal carcinomas serum levels of 6 tumor markers were measured in 47 patients presenting with ovarian cancer and compared to levels found in 24 female patients with advanced, untreated colorectal cancer. The markers studied were CA 125, CA 15.3, CA 19.9, CEA and two recently developed mucin markers, CA M29 and CA M26. Levels of CA 125, CA 15.3, CEA and CA M29 showed significant differences between both groups. In predicting ovarian cancer, sensitivity was highest for CA 125 at 94% (35 U/ml cutoff level). However, the specificity of CA 125 was at 71% low. Specificity increased significantly by using a combination of a CA 125-positive score (greater than 35 U/ml) and a simultaneous negative CEA score (less than or equal to 5 ng/ml) (specificity 100%, sensitivity 81%). A CA 125/CEA serum ratio greater than 25 resulted in the highest discriminative power with a specificity of 100% and a sensitivity of 91% resulting in an overall test accuracy of 94%. It is concluded that the serum tumor markers used, especially a combination of CA 125 and CEA, are helpful in the preoperative differential diagnosis between adenocarcinomas of ovarian and colorectal origin.

Adenocarcinoma↗