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Biomedical subjects

M Harris

Publications and source records attributed to M Harris.

At least 487 records · Page 27Linked to original sources
PubMed1988

Maintenance chlorambucil after CVP in the management of advanced stage, low-grade histologic type non-Hodgkin's lymphoma. A randomized prospective study with an assessment of prognostic factors.

One hundred sixty-two patients with Stages III and IV non-Hodgkin's lymphoma of low-grade histologic type were treated with combination chemotherapy using cyclophosphamide, vincristine, and prednisolone (CVP) followed by radiotherapy to sites of previous bulk disease. The patients were randomized to receive either follow-up alone or "maintenance" chemotherapy with 2 years of intermittent chlorambucil. A complete remission was obtained in 56% of patients and the median survival was 64 months (median follow-up, 74 months). Multivariate analysis revealed stage (P less than 0.0001) and Karnofsky performance status (P = 0.021) to predict complete response (CR) and the achievement of a CR (P less than 0.0001), female sex (P = 0.008), the absence of bulk disease (P = 0.038) and low serum alkaline phosphatase (P = 0.002) to predict prolonged survival. The median relapse-free survival (RFS) of the complete responders was 41 months. A prolonged RFS was predicted by low stage (P = 0.014), low serum lactic dehydrogenase (LDH) (P = 0.045) levels, and by the administration of maintenance chlorambucil (P = 0.045). A prolonged survival of the complete responders was predicted by a low number of nodal sites of involvement with lymphoma at presentation (P = 0.022) and lack of liver involvement (P = 0.011). The administration of oral maintenance therapy with chlorambucil for a full 2 years was only possible in 38% of patients, mainly because of progression of disease and the induction of thrombocytopaenia, but despite this it prolonged the median RFS by 38 months and its use could be considered when future studies are being designed.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

Malignant disease in the mothers of children with Ewing's tumour.

Previous research has shown that mothers of children with soft tissue sarcoma, osteosarcoma, and chondrosarcoma are at excess risk of developing breast cancer. The occurrence of malignant disease in the mothers of a population-based series of children with Ewing's sarcoma was investigated in order to determine whether these mothers were at excess risk of cancer and of breast cancer in particular. Sixty-one mothers were traced; there were two cases of breast cancer and two other registrable neoplasms. Risk of malignancy in the mothers was not in excess of expectation.

Adult↗
PubMed1988

Deletion and hypermethylation of thymidine kinase gene in V79 Chinese hamster cells resistant to bromodeoxyuridine.

Previous studies on V79 Chinese hamster cells have shown that bromodeoxyuridine (BrdU) -resistant variants deficient in thymidine kinase (TK) activity arise by a multistep process which is initiated by a random event and progresses gradually during serial culture in the presence of the drug. In order to determine the molecular basis for the loss of TK activity in these cells, the TK gene was isolated from a lambda phage library of genomic V79 DNA, using a fragment of the human TK gene as a probe. One phage isolated contained the entire TK gene in a 15-kb insert, as demonstrated by the ability of the phage DNA to transform Ltk- mouse cells to the TK+ phenotype. Five fragments spanning the entire gene were then subcloned into the plasmid pUC12 for DNA methylation studies. With these probes it was shown by hybridization analysis that the copy number of the TK gene in V79 cells is about four times the copy number in CHO cells and Chinese hamster liver cells. Southern hybridization analysis of the DNA from first-stage variants partially resistant to BrdU indicated that partial resistance was accompanied by deletion of a number of copies of the TK gene in V79 cells. However, the subsequent gradual transition to full BrdU resistance and full loss of TK activity was correlated with a gradual hypermethylation of sites in the 5' region of the TK gene, with no further change in gene copy number.

Animals↗
PubMed1988

Heterogeneity of bone resorbing factors produced by unstimulated murine osteoblasts in vitro and in response to stimulation by parathyroid hormone and mononuclear cell factors.

The bone resorbing activity of factors released from monolayer cultures of osteoblasts (OB) was examined by measurement of calcium released by neonatal mouse calvaria in vitro. Unstimulated conditioned media (CM) were found to contain significant bone resorbing activity, which was partially inhibited by indomethacin, dexamethasone and nordihydroguaiaretic acid. Ultrafiltration of CM (molecular weight cut-off of 5000) revealed bone resorbing activity in the filtrate and retentate. Fractionation of the CM by high-performance liquid chromatography revealed four major peaks of bone resorbing activity. Stimulation of the OB by mononuclear cell factor and parathyroid hormone significantly increased the synthesis and/or release of these factors with a relatively greater increase of lipid-soluble, low molecular-weight activity. These results suggested an important role for relatively small non-popular mediators in hormonally stimulated bone resorption.

Animals↗
PubMed1988

Crossing the midline by four to eight year old children.

In Experiment 1 children (Kinder, 4-5 yr; Prep, 5-6 yr; Grade 1, 6-7 yr; Grade 2, 7-8 yr) bisected horizontal lines placed to the left, right or across the midline. The youngest groups displayed symmetrical neglect, erring to the left with the left hand and to the right with the right, the adult pattern of leftwards error not appearing until about Grade 2. However, while Prep, Grade 1 and Grade 2 sinistrals showed bigger between-hand differences than dextrals, this was not, unlike an earlier study, true of the youngest Kinder group, and symmetrical neglect did not appear to be peculiar to young sinistrals. A timed peg-moving task in Experiment II showed that performance did not slow when crossing the midline; nor did young sinistrals perform better with centrifugal abductive movement. These and other findings were incompatible with the idea of callosal immaturity in young sinistrals.

Analysis of Variance↗
PubMed1988

Stimulation of bone resorption by lipoxygenase metabolites of arachidonic acid.

We have studied the effect of leukotrienes, (LT): B4, C4, D4 and E4 and the hydroxyeicosatetraenoic acids (HETEs) 5-HETE and 12-HETE on bone resorption in vitro. Resorption was measured by colorimetric assay of calcium released from neonatal mouse calvaria maintained in organ culture for 72h. All the LTs and HETEs stimulated bone resorption, with optimum responses at picomolar or nanomolar concentrations. The responses were biphasic, with a decreasing effect at higher concentrations. In contrast, prostaglandin E2 (PGE2) stimulated resorption only at 10nM and above. Indomethacin partially inhibited resorption by LTB4, LTC4 and LTD4, but did not affect resorption stimulated by LTE4, 5-HETE and 12-HETE. These results indicate that lipoxygenase products of arachidonic acid are highly potent bone resorbing factors and may play an important role in the localised bone loss associated with inflammatory lesions.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1988

Comparison of changes in serum androgen binding protein with germinal epithelial damage and infertility induced by di-n-pentyl phthalate.

Androgen binding protein (ABP), produced by Sertoli cells and released into seminiferous tubules and blood, was measured in the serum of di-n-pentyl phthalate (DPP)-treated rats as a potential index of germinal epithelial damage. A single oral dose of DPP (0, 0.25, 1.0, or 2.0 g/kg body wt in corn oil) was given to four groups of 110 Fischer 344 rats; 10 rats per group were killed weekly for 10 weeks. Effects of treatment on serum ABP were then compared with effects on other reproductive endpoints. Treatment did not produce any significant effect on body weight or weights of liver, kidney, prostate, and seminal vesicles. In high-dose rats, serum ABP values more than doubled 2 days after injection, remained significantly elevated for 3 weeks, then fell and remained significantly below control values from Week 4 through Week 10. Accordingly, 95% of the rats in this group showed greater than 50% of the seminiferous tubules degenerated, decreased epididymal sperm density, reduced testicular and epididymal weights, and up to 97% morphologically abnormal sperm. In medium-dose rats, serum ABP increased up to 48% during the first week, returned to control values by Week 2, and remained at control levels thereafter. Of these rats, 20% showed 20-50% degenerated tubules, decreased sperm density, reduced testicular and epididymal weights (which were not always statistically significant), and up to 23% abnormal sperm morphology. In low-dose rats, serum ABP levels were similar to those of controls, and the other parameters, except sperm density, also remained unchanged. To examine the effects of DPP on fertility, a second group of rats was exposed in an identical manner [gavaged once with DPP in corn oil (0, 0.25, 1.0, and 2.0 g/kg body wt)], then mated to untreated females at 3, 6, and 10 weeks postexposure. DPP at 2 (but not 1.0 or 0.25) g/kg caused a significant reduction in pregnancies and live pups and a significant increase in preimplantation loss. Histopathology of the testis in the first experiment suggested a very slow recovery. Therefore, controls and high-dose rats in the mating trial were killed 14, 18, and 30 weeks after dosing and the germinal epithelium was evaluated histologically. All high-dose animals showed testicular lesions typical of phthalate ester exposure and the epithelium did not recover within 30 weeks.(ABSTRACT TRUNCATED AT 400 WORDS)

Androgen-Binding Protein↗
PubMed1988

Prognostic factors in stage I and II high and intermediate grade non-Hodgkin's lymphoma.

Between 1975 and 1986, the Manchester Lymphoma Group treated 127 patients with localized (Stages I/II) high and intermediate grade non-Hodgkin's lymphoma (NHL) on one of three protocols of combined involved field radiotherapy and chemotherapy. The study included patients with widespread bulky abdominal disease providing there was no apparent spread outside the abdomen and the liver was not involved with metastatic disease. The median duration of follow-up was 70 months. The complete response rate was 86% and the overall 5-year survival was 70%. The 5-year relapse-free survival of the complete responders was 80%. Cox model multivariate analysis showed that bulk disease (greater than 5 cm), low serum albumin and gut involvement were the pretreatment factors associated with shorter survival. When remission status was included in the model the attainment of a complete response was the major determinant of long-term survival but bulk disease and gut involvement were still significant adverse predictors for survival. These factors need to be assessed when analysing results of therapy in NHL and in the design of future treatment strategies.

Adult↗
PubMed1988

Applications of the in vitro aryl hydrocarbon hydroxylase induction assay for determining "2,3,7,8-tetrachlorodibenzo-p-dioxin equivalents": pyrolyzed brominated flame retardants.

The pyrolysis of brominated flame retardants FR 300 BA (decabromobiphenyl) ether, FireMaster BP-6 (polybrominated biphenyls), Bromkal 70-5-DE (primarily pentabromodiphenylether), Bromkal 70-DE (primarily penta and tetrabromodiphenylether) and Bromkal G1 (pentabromodiphenylether) resulted in the formation of relatively high levels of polybrominated dibenzofurans (PBDFs) and dibenzo-p-dioxins (PBDDs as determined by gas chromatography-mass spectrometric analysis. The dose response EC50 values for the induction of aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin O-deethylase (EROD) by the flame retardant pyrolysates was determined in rat hepatoma H-4-II E cells and compared to the relative induction activities of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and the concentrations of "2,3,7,8-TCDD equivalents" were calculated. The range of "2,3,7,8-TCDD equivalents" levels (micrograms/g or ppm) derived from values obtained from the AHH and EROD bioassays for each of the pyrolyzed flame retardant samples was: 174-194, 480-1400, 2140-4680, 6740-8780 and 3920-5260 ppm for FR 300 BA, FireMaster BP-6, Bromkal 70 DE, Bromkal 70-5 DE and Bromkal G1, respectively. The in vivo dose-response effects of 2 pyrolyzed flame retardants were determined in immature male Wistar rats and compared to the dose-response activities of 2,3,7,8-TCDD. The in vivo responses which were measured included hepatic microsomal AHH and EROD induction, body weight loss and thymic atrophy. For the pyrolyzed FireMaster BP-6 and Bromkal 70-5 DE samples, the range of calculated in vivo "2,3,7,8-TCDD equivalents" (ppm in sample) for the 4 in vivo bioassays was 520-1780 ppm and 3860-8960 ppm, respectively. The excellent overlap between the in vivo and in vitro 2,3,7,8-TCDD equivalents for the 2 flame retardant pyrolysate extracts supports the utility of the in vitro induction bioassay for quantitatively determining "2,3,7,8-TCDD equivalents" for mixtures containing toxic halogenated aryl hydrocarbons.

Animals↗
PubMed1988

Endurance testing for evaluation of antianginal therapy with amlodipine, a calcium channel blocking agent.

The utility of using an endurance test as well as a maximal exercise test to assess the effect of amlodipine, a dihydropyridine calcium antagonist, was evaluated in 16 patients with angina pectoris. Amlodipine, 10 mg/day, was compared with placebo in a double blind crossover study. After a 2 week single blind placebo period, patients entered a double blind crossover phase alternating between 4 weeks of placebo and 4 weeks of amlodipine. The two 4 week periods were separated by a 1 week single blind placebo washout period. The efficacy of drug therapy was assessed by frequency of angina, nitroglycerin consumption, peak oxygen consumption during a maximal treadmill exercise test and endurance time during a separate exercise test performed at 70% of the peak work capacity determined before randomization. There was a reduction in angina frequency during the double blind placebo and amlodipine studies (single blind placebo 14 +/- 2 episodes/2 weeks, double blind placebo 7 +/- 2 episodes/2 weeks [p less than 0.005], amlodipine 6 +/- 3 episodes/2 weeks, [p less than 0.005]), whereas nitroglycerin consumption was reduced with amlodipine (single blind placebo 12 +/- 4 tablets/2 weeks, double blind placebo 8 +/- 3 tablets/2 weeks, amlodipine 5 +/- 3 tablets/2 weeks [p less than 0.01]). Amlodipine produced a significant increase in peak oxygen consumption (single blind placebo 18.7 +/- 1.1 ml/kg per min, double blind placebo 18.2 +/- 1.8 ml/kg per min, amlodipine 20.4 +/- 1.6 ml/kg per min [p less than 0.05]) and endurance time (single blind placebo 15.2 +/- 1.5 min, double blind placebo 15.8 +/- 2.1 min, amlodipine 20.2 +/- 2.5 min [p less than 0.005]).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1988

Macromolecular osteolytic factor synthesised by squamous carcinoma cell lines from the head and neck in vitro is interleukin 1.

Three human cell lines derived from oro-pharyngeal squamous cell carcinomas of the head were investigated for bone-resorbing activity in vitro. Culture media from all three spontaneously produced a non-dialysable osteolytic factor with activity in three in vitro assays for interleukin 1 (IL1), viz. the lymphocyte activating factor (LAF) assay, stimulation of collagenase synthesis by articular chondrocytes, and stimulation of prostaglandin E2 synthesis by fibroblasts. Addition of anti-human IL1 antibody to the culture media abolished all the bone-resorbing activity. Fractionation of the cell culture media by high performance liquid chromatography (HPLC) showed a single peak of activity in the chondrocyte assay with an apparent mol.wt of 15-17,000. This co-eluted with activity in a preparation of IL1 from rat peritoneal macrophage cultures. These results indicate that IL1 is responsible for the prostaglandin-independent bone resorbing activity synthesised by these cells in vitro, and may contribute to the bone destruction associated with the tumour.

Bone Resorption↗
PubMed1988

The effect of age and menstrual cycle upon proliferative activity of the normal human breast.

The aim of this study was to determine the proliferative activity within the epithelial cells of the normal human breast in 122 patients (6 reduction mammoplasties and 116 fibroadenoma excisions) in relation to age and the phase of the menstrual cycle. Thirty three of the patients were on oral contraceptives and 33 were parous. Thin tissue slices were incubated with tritiated thymidine and processed for autoradiography. Other samples were fixed directly and prepared for histology. The labelling, mitotic and apoptotic indices (LI, MI and AI) were determined and all illustrated considerable variability. The labelling indices are significantly (P less than 0.05) influenced by both patient age and stage during the menstrual cycle and ranged from 0-11.5%. Maximum LI values were obtained on the 20.8th day of the cycle. A square root transformation of the data was used to reduce the skewness of the data to a more normal distribution. The square root of the LI declined by 0.22 per decade. The mitotic data showed similar significant (P less than 0.05) correlations against age and day of cycle with a peak on the 21.5th day of the cycle, a decline by 0.072 per decade and a range from 0-0.6%. The data for apoptotic cells were less clearly influenced by the stage of the menstrual cycle but showed a significant (P less than 0.5) decline with age. The AI in parous patients was significantly higher than that in non-parous patients. There was no significant effect of oral contraceptives on any of the parameters measured when age and stage of cycle were taken into account. The considerable variability in the data could not be fully accounted for by either technical factors, the age of the patients, or the day of the cycle. We conclude that proliferation is negatively related to age and is influenced by the menstrual cycle but that additional as yet unknown factors must account for a large part of the variability seen in the data.

Adolescent↗