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Biomedical subjects

J Peacock

Publications and source records attributed to J Peacock.

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

Doppler dynamics and their complex interrelation with fetal oxygen pressure, carbon dioxide pressure, and pH in growth-retarded fetuses.

OBJECTIVE: To evaluate the relation between fetal oxygen pressure (PO2), carbon dioxide pressure (PCO2), pH, and 19 fetomaternal Doppler indices that reflect the circulatory changes in growth-retarded fetuses. METHODS: In a cross-sectional study of 32 severely growth-retarded fetuses, the uteroplacental vessels, umbilical artery, middle cerebral artery, common carotid artery, thoracic aorta, abdominal aorta, and umbilical vein were assessed by Doppler ultrasound before funipuncture and measurement of umbilical venous PO2, PCO2, and pH. RESULTS: Compared to expected values, Doppler measurements from the middle cerebral and common carotid arteries were both decreased ("brain-sparing effect"), whereas thoracic and abdominal aortic Doppler indices were increased in association with increased uteroplacental and/or umbilical impedance. Carbon dioxide pressure and pH both correlated significantly with Doppler indices from the thoracic aorta, abdominal aorta, and common carotid artery. The middle cerebral and common carotid arteries were both significantly related to PO2 and PCO2. CONCLUSIONS: This investigation demonstrates circulatory redistribution in human fetal growth retardation and postulates that compensatory redistribution is regulated by more than one mechanism. Hypercapnia, acting alone or through acidemia, plays a role in the control of carotid and aortic vascular responses, whereas hypoxemia, alone or with hypercapnia and probably through local effects, is responsible for the cerebral vascular responses.

Blood Flow Velocity↗
PubMed1994

Mutant p53 increases radioresistance in rat embryo fibroblasts simultaneously transfected with HPV16-E7 and/or activated H-ras.

Recently, it has been suggested that abrogation of the wild type p53 protein function may alter the cellular response to DNA damaging agents, including ionizing radiation. This study was designed to compre the relative radiosensitivity and tumorigenicity of rat embryo fibroblast (REF) cell lines transfected with a mutant form of the p53 gene (plasmid MTp53pro193), alone, or in combination, with the H-ras (plasmid pEJ6.6) and HPV16-E7 (plasmid pJ4 omega 16.E7) oncogenes. Transfection of the mutant p53pro193 gene alone resulted in selected clones having increased radioresistance in culture which correlated with increased mutant p53 expression in these clones. However, the co-transfection of mutant p53 and H-ras genes or triple transfection of mutant p53, H-ras and E7 genes resulted in clones with high mutant p53 expression, significantly increased radioresistance and uniform tumorigenicity. There was no correlation between intrinsic radioresistance and spontaneous metastasis in the tumorigenic REF transfectant clones. Stepwise acquisition of radioresistance and an aggressive tumor cell phenotype is observed when the mutant p53 gene and HPV E7 co-operate with the ras oncogene in transfection assays, and can be correlated to increases in mutant p53 expression.

Animals↗
PubMed1993

Cell-cycle progression during continuous low dose rate irradiation of a human bladder carcinoma cell line.

At very low radiation dose rates, the proliferation of mammalian cells continues unaffected but as the dose rate is increased there comes a point at which it is interrupted. The dose rate at which this happens is often thought to be a significant factor in the effects of brachytherapy: it may determine the range from an implanted source at which cell-cycle redistribution and repopulation effects will occur. By means of mitotic counts and DNA flow cytometry, we have examined the dose rate effect in a human bladder carcinoma cell line (MGH-U1). Irradiation at dose rate 0.1 cGy/min had little or no effect on cell-cycle progression. Suppression of mitosis and arrest of cells in G2 was observed at 0.4 cGy/min and above. Surprisingly, the duration of mitotic arrest showed little dose rate dependence; it was followed by an overshoot of cells in mitosis after 24-39 h of irradiation. An even more pronounced overshoot of cells in G2 occurred and persisted throughout the irradiation period. The cell kinetic data indicate that after the temporary block in cell-cycle progression, cell proliferation continued at all dose rates up to 1.4 cGy/min. We have evaluated these results in the light of previous studies in this department of the dose rate effect for cell survival in the MGH-U1 cell line. After 24 h irradiation at 1.4 cGy/min the surviving fraction was below 10(-2), also after 30 h at 1.0 cGy/min. When cell-cycle blockade is considerable, so is the level of cell killing. Flow-cytometric data therefore are dominated by the properties of cells that are doomed to die.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Cycle↗
PubMed1993

Ataxia telangiectasia: an investigation of the repair defect in the cell line AT5BIVA by plasmid reconstitution.

The ataxia telangiectasia cell line, AT5BIVA, exhibited low repair fidelity measured by the reconstitution of transfected linear plasmid. This assay involves transfecting a linear plasmid containing two selectable marker genes: one gene (neo) is undamaged and marks transfection and the other gene (gpt) is cleaved to test functional repair. The proportion of transfected cells which have a functionally intact gpt gene gives a measure of repair fidelity. Southern analysis of individual transfected clones showed that integrated plasmids in AT5BIVA had a high frequency of sequence rearrangement. Blunt or staggered-ended termini of a linear plasmid did not determine the type of misrepair. A variety of sizes of deletions and sequence insertions were found at and around the cleavage site. Loss of intact sequence occurred similarly following transfection by linear or circular plasmid (misrepair or rearrangement error). This suggests that the action of excess exonuclease activity upon, or lack of protection of, exposed DNA termini is not the sole mechanism of misrepair. Erroneous rearrangement of circular plasmid could involve any location along the plasmid. Rearrangement of transfected circular plasmid occurred in multiple copies of the same abnormal size, suggesting that error-prone recombination rather than degradation of presumed nicked circular plasmid was the underlying mechanism. It is hypothesized that misrepair in ataxia-telangiectasia arises by error-prone recombination.

Ataxia Telangiectasia↗
PubMed1993

A comparison of effects of fixed and tailored cardiopulmonary bypass flowrates on renal function.

Cardiopulmonary bypass may result in renal impairment but there is little investigative data on the effect of differing flowrates on postoperative renal function. One hundred and twenty-two patients presenting for cardiac surgery were randomly assigned to receive either a fixed CPB flow of 2.4 l.m-2 or a bypass flow tailored to maintain a venous return oxygen saturation of 75-80%. Vasoactive drugs were given to maintain a perfusion pressure of 50 to 80 mmHg. Patients were assessed by serum creatinine, creatinine clearance, arterial blood gases, serum lactates and electrolytes. The results show an overall decline in postoperative renal function compared with preoperative levels, with no significant differences between the two groups.

Aged↗
PubMed1993

Bilateral carcinoma of the breast.

In a retrospective review of 2820 patients with breast carcinoma seen at the Combined Breast Clinic of St George's Hospital over a 23-year period 101 cases were bilateral of which 52 (1.8%) presented synchronously and 49 (1.7%) metachronously. Twenty deaths occurred in the synchronous group after a mean follow-up of 56.2 months and 15 deaths in the metachronous group after a mean follow-up of 48.5 months following diagnosis of the second tumour. If timed from initial presentation patients with metachronous tumours fared better than those with unilateral disease (P < 0.01). There was no significant difference in survival between patients with metachronous (if timed from the second tumour), synchronous or unilateral breast carcinoma.

Breast Neoplasms↗
PubMed1992

Collateral resistance to photon and neutron irradiation is associated with acquired cis-platinum resistance in human ovarian tumour cells.

The melphalan resistant variant of the human ovarian OAW42 tumour cell line has previously been shown to be collaterally resistant to photon irradiation, but not to fast neutrons. In the present study, the "in vitro" photon and neutron radiosensitivity of human ovarian OAW42 tumour cells with acquired resistance to cis-platinum has been studied, to determine whether a similar pattern of cross-resistance exists between cis-platinum and these ionising radiations. Analysis of SF2 values suggests that resistance to cis-platinum conferred a 3-fold decrease in sensitivity to photons, primarily attributable to a 5-fold decrease in the magnitude of the initial slope (alpha). Depletion of GSH by BSO restored the magnitude of alpha to a value similar to that of the parental line. However, cis-platinum resistant OAW42/CP cells, in contrast to melphalan resistant cells, were 1.5-fold more resistant to "fast" neutrons (assessed at D0.1 survival level) than the parental OAW42 cell line. The mechanism for the collateral resistance between cis-platinum, and both photons and neutrons remains to be determined, but although GSH levels may be directly, or indirectly involved in the collateral resistance to photons, they would appear not to involved with the mechanisms responsible for collateral neutron resistance, in the cis-platinum resistant human ovarian cell lines used in this study.

Cell Survival↗
PubMed1992

BSO-induced reduction of glutathione levels increases the cellular radiosensitivity of drug-resistant human tumor cells.

Acquired resistance to cis-platinum and melphalan, in the human ovarian OAW42 tumor cell line, respectively, conferred a 3- and 1.5-fold decrease in photon sensitivity. Analysis of cell survival curves by the linear quadratic equation showed an accompanying 5- and 2-fold reduction in the magnitude of the initial slope (alpha). Treatment with the GSH depleting agent BSO restored the magnitude of alpha to a value similar to that of the parental line without evidence of dose modification in the high-dose region of the cell survival curve. This in conjunction with failure of alteration in GSH levels to affect parental OAW2 sensitivity and of the SER of BSO to reflect GSH levels suggest a possible GSH independent mechanism of action for BSO. If similar patterns occur in the clinic, the possibility exists of circumventing collateral resistance between chemotherapeutic agents and ionizing radiation, provided that tumor thiol levels can be preferentially depleted.

Buthionine Sulfoximine↗
PubMed1991

Ligand induced internalization of epidermal growth factor receptors by A431 cells decreases at high cell densities in culture.

Internalization of epidermal growth factor (EGF) receptors by human A431 epidermoid carcinoma cells was studied at various culture densities. The extent of EGF receptor internalization was measured by quantitation of internalized 125I-EGF during incubation at 37 degrees C for 30 min. When cell culture density was below 1 x 10(5) cells/cm2 receptor internalization was active; 30-40% excess moles of ligand over the moles of surface EGF receptors were internalized during this period. However, when culture density increased to above 1.5 x 10(5) cells/cm2 receptor internalization became less extensive, as only 30-50% of ligand bound to the cell surface underwent internalization during 30 min incubation. In parallel with this reduction in receptor internalization, the degradation rate of 35S-methionine labeled EGF receptors was reduced at a high culture density. In contrast with this regulation of receptor internalization, the affinity of EGF receptors for the ligand increased as culture density increased. The extent of EGF-dependent receptor phosphorylation was found to be constant at all culture densities tested. Thus, the observed low level of receptor internalization at high culture densities was not attributable to lower responsiveness of receptors to EGF. These data suggest the presence of an as yet unidentified cell density-dependent mechanism for regulating receptor internalization in cultured A431 cells.

Adenosine Triphosphate↗
PubMed1990

Endophthalmitis caused by exogenous nocardial infection in a patient with Sjögren's syndrome.

A 60-year-old woman receiving prednisolone therapy for Sjögren's syndrome presented with corneal perforation. Therapeutic penetrating keratoplasty was performed, but no causative organism was identified. Focal inflammatory infiltrates in both donor and host cornea and anterior uveitis developed postoperatively. Five months later the inflammation rapidly became much worse, with fulminating abscesses, and the eye was eviscerated because of severe endophthalmitis. Nocardia organisms were identified in the cornea, conjunctiva and vitreous by means of acridine orange and modified Ziehl-Neelsen stains. The infection produced both suppurative and granulomatous inflammation. Reexamination of the penetrating keratoplasty specimen with a modified Ziehl-Neelsen stain revealed a few Nocardia organisms, which suggested that infection had occurred at the time of corneal perforation.

Chloramphenicol↗
PubMed1988

Glucocorticoid receptor-mediated effects on rat fibrosarcoma growth.

Glucocorticoid receptors are present in most normal and malignant mammalian cells. To examine the hypothesis that the growth of methylcholanthrene-induced malignant sarcoma is glucocorticoid dependent, we evaluated the behavior of malignant fibrosarcoma (MCA) in adrenalectomized rats treated with either normal saline or deoxycorticosterone acetate and in intact rats treated with placebo or with the glucocorticoid receptor antagonist RU 486. Survival, tumor weight, and loss of body weight (an index of cachexia) were measured. In MCA-bearing rats, neither survival nor loss of body weight was affected by bilateral adrenalectomy or by treatment with RU 486. Tumor weight and time-integrated tumor volume, however, were significantly less in bilaterally adrenalectomized rats without deoxycorticosterone acetate replacement than in animals treated with deoxycorticosterone acetate. Similarly, tumor weight and time-integrated tumor volume were less in intact animals treated with RU 486 than in intact animals treated with placebo. The glucocorticoid receptors in the tumor cells had similar binding capacity (Ro) and equilibrium dissociation constant (Kd) as in control rat fibroblasts. These results suggest that the growth of MCA sarcoma cells is partially dependent upon glucocorticoids. This effect of glucocorticoids, however, was not of sufficient magnitude to improve survival and prevent cachexia. We conclude that glucocorticoids appear to influence MCA sarcoma growth in the rat, and that glucocorticoid receptor blockade, perhaps in combination with other antitumor agents, merits future study in the treatment of malignant tumors.

Adrenalectomy↗
PubMed1987

Early-stage developmental abnormalities induced by murine cytomegalovirus.

The onset of the effects of murine cytomegalovirus (MCMV) infection on an early stage of embryonic development (nine days) in a mouse model was studied with the aid of scanning electron microscopy. MCMV was injected into the endometrial lumina of pregnant mice at the time of implantation. The mice were later killed, and sites of embryonic implantation were examined. Compared with uninfected mice and mice inoculated with heat-inactivated virus, litter sizes were reduced, and the incidence of abnormal fetuses was significantly increased among MCMV-infected animals. Scanning electron microscopy also revealed maldeveloped cranial regions characterized by an unclosed neural tube and severely underdeveloped head. Ectodermal abnormalities, including poxlike formations and ballooning cells, were observed in several embryos. Thus, early cytomegalovirus infection may not only result in fetal loss, but may also interfere with the process of morphogenesis.

Animals↗
PubMed1987

Deletion of 5'-coding sequences of the cellular p53 gene in mouse erythroleukemia: a novel mechanism of oncogene regulation.

The p53 gene is rearranged in an erythroleukemic cell line (DP15-2) transformed by Friend retrovirus. Here, we characterize the mutation and identify a deletion of approximately equal to 3.0 kilobases that removes exon 2 coding sequences. The gene is expressed in DP15-2 cells and results in synthesis of a 44,000-dalton protein that is missing the N-terminal amino acid residues of p53. The truncated protein is unusually stable and accumulates to high levels intracellularly. Moreover, it appears to have undergone a change in conformation as revealed by epitope mapping studies. This study represents the first description of an altered p53 gene product arising by mutation during neoplastic progression and identifies a region in the p53 protein molecule that plays a role in determining p53 stability in vivo.

Animals↗
PubMed1986

Epidemiology of colonization by nontypable Haemophilus influenzae in children: a longitudinal study.

Eighty-six nasopharyngeal isolates of Haemophilus influenzae were prospectively obtained from three children who attended a day care center from infancy until early childhood (five to seven years). A majority of the strains were nontypable. We analyzed strains by comparing their biotypes and by performing electrophoresis of outer membrane proteins on polyacrylamide gels. Profiles of outer membrane proteins were very heterogeneous and could not be used as the basis for the development of a subtyping scheme. The children characteristically carried a nasopharyngeal strain defined by a unique outer membrane pattern for a period of months, lost it, and then acquired a new strain. We probed the outer membrane proteins of a child's strains by the western blot technique with serum obtained serially from the child. Isolates whose outer membrane proteins appeared identical on stained gels generally had similar antigenic bands on western blots but were occasionally immunologically distinct. Serum immunoglobulins of the IgG class that reacted with the outer membrane proteins did not appear to change greatly over time or to play a role in preventing or terminating colonization. We conclude that nasopharyngeal colonization in children by nontypable H. influenzae is a dynamic process and that factors that cause loss and acquisition of strains remain to be determined.

Antigens, Bacterial↗
PubMed1986

Diagnosis of cerebral toxoplasmosis using fluorescein-labeled antitoxoplasma monoclonal antibodies.

The direct immunofluorescence technique using monoclonal antitoxoplasma antibodies was used to detect Toxoplasma organisms in 13 brain touch preparations and six smears of cerebrospinal fluid. For comparison, Giemsa-stained smears and histologic sections of the same cases were also studied. Positive results were obtained from two cases of acquired immunodeficiency syndrome (AIDS) with all three methods. Toxoplasma cysts, pseudocysts, and tachyzoites were easily identified by the immunofluorescence technique, and no false-positive results were encountered in nine cases of AIDS with different kinds of encephalitides. It was difficult to identify tachyzoites in histologic sections and time-consuming to search for pseudocysts and cysts. The parasite was even more difficult to recognize in Giemsa-stained brain touch preparations due to the easy distortion of the organisms. In the present study, immunofluorescence technique was more sensitive than hematoxylin--eosin or Giemsa staining in terms of the number and range of forms demonstrated in tissue. Therefore, immunofluorescence technique using monoclonal antibodies appears to be the preferred method for a rapid diagnosis of cerebral toxoplasmosis as compared to Giemsa staining and histology.

Antibodies, Monoclonal↗