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Biomedical subjects

P J Marsh

Publications and source records attributed to P J Marsh.

At least 19 recordsLinked to original sources
PubMed2001

ERKs regulate cyclic AMP-induced steroid synthesis through transcription of the steroidogenic acute regulatory (StAR) gene.

Cyclic AMP-dependent expression of the steroidogenic acute regulatory (StAR) protein is thought to be the controlling step for steroid production, but the mechanisms through which external signals are translated into increased transcription of the StAR gene are unknown. We demonstrate that cyclic AMP-induced steroid synthesis is dependent upon the phosphorylation and activation of ERKs and that ERK activation results in enhanced phosphorylation of SF-1 and increased steroid production through increased transcription of the StAR gene. Adenylate cyclase activation with forskolin (FSK) caused a time-dependent increase in ERK activity and translocation from cytoplasm to nucleus, which correlated with an increase in StAR mRNA levels, StAR protein accumulation, and steroidogenesis. Similarly, ERK inhibition led to a reduction in the levels of FSK-stimulated StAR mRNA, StAR protein, and steroid secretion. These effects were attributed to the finding that ERK activity is required for SF-1 phosphorylation, a transcription factor required for the regulation of StAR gene transcription. This conclusion was supported by our demonstration of an ERK-dependent increase in the binding of SF-1 from FSK-treated Y1 nuclei to three consensus double-stranded DNA sequences from the StAR promoter region. These observations suggest that the activation of ERK2/1 by increasing cAMP is an obligatory and regulated stage in the stimulation of steroid synthesis by cyclic AMP-generating stimuli.

Animals↗
PubMed2000

Crystal structure of bis(4-methylimidazole)tetraphenylporphyrinatoiron(III) chloride and related compounds. Correlation of ground state with Fe-N bond lengths.

The crystal structure of the title compound is presented and shown to be one of a class of low-spin iron porphyrin complexes having a ground-state electronic configuration of (dxy)2(dxz)2(dyz)1. If their Fe-N bond lengths (average N-porphyrin plotted against average N-axial) are considered, this class of low-spin iron(III) porphyrins of general formula [Fe(III)Por(L)2]+X- and of 2B ground state is shown to be distinctly different crystallographically from a similar class of compounds with the same general formula but with a 2E or a (dxy)2(dxz,dyz)3 ground state. A third group of compounds with the same general formula have a (dxz,dyz)4(d)1 ground state and again are in a different region of the plot. Compounds showing intermediate properties can be forecast from the simple relationship presented in this work. The electron paramagenetic resonance data are shown to be dependent on the ground state, and those of configuration (dxy)2(dxz,dyz)3 and the 2B ground state obey a correlation previously suggested in the literature.

Crystallography, X-Ray↗
PubMed1999

Comparison of IgE and IgG antibody-dependent cytotoxicity in vitro and in a SCID mouse xenograft model of ovarian carcinoma.

Allergic reactions are mediated by IgE antibodies bound to high-affinity receptors on mast cells in peripheral tissues and are characterized by their immediacy and hypersensitivity. These properties could also be advantageous in immunotherapy against cancer growth in peripheral tissues. We have constructed chimeric IgE and IgG1 antibodies with murine V regions and human C regions corresponding to the MOv18 monoclonal antibody against the human ovarian tumor-associated antigen, folate binding protein. The antibodies exhibited the expected binding affinities for antigen and Fc receptors, and effector activities with human basophils and platelets in vitro. The protective activities of MOv18-IgE and MOv18-IgG1 were compared in a SCID mouse xenograft model of ovarian carcinoma. The beneficial effects of MOv18-IgE were greater and of longer duration than those of MOv18-IgG1. Our results suggest that the allergic reaction could be harnessed for the suppression of ovarian tumors.

Animals↗
PubMed1999

Dysfunction in smooth pursuit eye movements and history of childhood trauma.

Several commentators recently have advocated the view that a deficit in the performance of a smooth pursuit eye-movement task is a biological marker of the genetic predisposition to schizophrenia. This study considered the possibility that such an impairment is due in part to experiential or acquired characteristics, and specifically, to a history of childhood trauma. A sample of 100 Australian adults performed a visual tracking task and completed a self-report measure of childhood trauma. Although the effect size was small, a relationship was found between eye-tracking performance and a childhood history of physical and emotional abuse. This finding suggests that eye-tracking performance may not be governed entirely by genetic factors, a possibility that has implications for the use of indices of smooth pursuit eye movement as a purely genetic marker of proneness to schizophrenia. Further investigation is needed to clarify the basis of the association between these deficits and childhood abuse.

Adult↗
PubMed1998

The periodontopathogen Porphyromonas gingivalis binds iron protoporphyrin IX in the mu-oxo dimeric form: an oxidative buffer and possible pathogenic mechanism.

Mössbauer spectroscopy was used to re-evaluate iron protoporphyrin IX, FePPIX, binding and the chemical nature of the black iron porphyrin pigment of Porphyromonas gingivalis. We demonstrate that FePPIX is bound to the cell in the mu-oxo dimeric form, [Fe(III)PPIX]2O, and that the iron porphyrin pigment is also composed of this material. P. gingivalis also assimilated monomeric Fe(II)- and Fe(III)PPIX into mu-oxo dimers in vitro. Scatchard analysis revealed a greater binding maximum of cells for mu-oxo dimers than for monomeric Fe(III)-or Fe(II)PPIX, although the relative affinity constant for the dimers was lower. Formation of [Fe(III)PPIX]2O via reactions of Fe(II)PPIX with oxygen, and its toxic derivatives, would serve as an oxidative buffer and permit P. gingivalis and other black-pigmenting anaerobes to engender and maintain a local anaerobic environment. Tying up of free oxygen species with iron protoporphyrin IX would also reduce and limit Fe(II)PPIX-mediated oxygen-radical cell damage. More importantly, formation of a cell-surface mu-oxo dimer layer may function as a protective barrier against assault by reactive oxidants generated by neutrophils. Selective interference with these mechanisms would offer the possibility of attenuating the pathogenicity of P. gingivalis and other iron protoporphyrin IX-binding pathogens whose virulence is regulated by this reactive molecule.

Anaerobiosis↗
PubMed1996

The chemical mechanism of beta-haematin formation studied by Mössbauer spectroscopy.

Spontaneous formation of beta-haematin (malaria pigment) from haematin in acetate solution follows pseudo-zero-order and not autocatalytic kinetics. Acetate appears to facilitate the reaction by solubilizing the haematin and acting as a phase-transfer catalyst, a role which, in vivo, could be fulfilled by carboxylic acids or amino acids.

Acetates↗
PubMed1996

Ecthyma gangrenosum occurring at sites of iatrogenic trauma in pediatric oncology patients.

We report two cases of ecthyma gangrenosum which occurred at sites of iatrogenic trauma. The first case developed due to metastatic seeding with Pseudomonas aeruginosa during an episode of septicaemia and the second case occurred as a primary skin lesion. Both required prolonged courses of antibiotics and one patient died. The different pathogenic mechanisms and outcomes associated with this condition are discussed.

Anemia, Aplastic↗
PubMed1996

The iron environment in heme and heme-antimalarial complexes of pharmacological interest.

Mössbauer spectroscopy has been utilized to probe the electronic environment of iron in a number of Ferriprotoporphyrin IX complexes of relevance to malaria. The markedly different iron environments found for the complexes of hemin with quinine, chloroquine, and the Chinese herbal antimalarial artesunate suggest that these compounds act by protecting the heme from polymerization to insoluble hemozoin, and by facilitating the transport of the protected heme to the food vacuole membrane where it is able to exercise its cytotoxic redox catalytic activity. Mössbauer parameters determined here for purified malaria pigment and synthetic beta-hematin confirm the chemical identical-ness of these species. The Mössbauer spectra of the complexes are discussed in light of the proposed structures of the complexes.

Animals↗
PubMed1995

Definition of local recurrence after surgery for rectal carcinoma.

Local recurrence rates of rectal carcinoma have been analysed among 284 patients in a prospective randomized multicentre trial of adjuvant preoperative radiotherapy for locally advanced rectal carcinoma. Wide variations in local recurrence rates are demonstrated depending on the definition of local recurrence employed and the subgroup studied. Thus after surgical operation alone, rates as high as 43.3 per cent or as low as 12.7 per cent can be calculated. After both adjuvant preoperative radiotherapy and operation the overall local recurrence rate is 12.8 per cent, although the local recurrence rate inside the radiotherapy field (true recurrence) may be as low as 2.3 per cent. It is recommended that local recurrence after operation for rectal carcinoma be defined as any detectable local disease at follow-up, occurring either alone or in conjunction with generalized recurrence, in patients who have undergone resection. A rate should be given both for all patients and for those operated on for cure, but not for the latter group alone as this could introduce bias.

Humans↗
PubMed1995

Anterior chamber aspirate cultures in small incision cataract surgery.

BACKGROUND: Anterior chamber aspirates on completion of extracapsular cataract surgery contain significant numbers of organisms, particularly coagulase negative staphylococci, an important cause of endophthalmitis. METHODS: Culture rates were compared in 50 patients after phacoemulsification surgery, which allows the possible benefits of a small, self sealing wound and maintenance of positive intraocular pressure, with a similar number of extracapsular cases. RESULTS: A culture positive rate of 20% and 24% respectively was found, an insignificant difference. CONCLUSION: Small incision surgery has no proved advantage over extracapsular surgery in terms of reducing the intraoperative bacterial inoculum. The significance of this result in terms of causation of endophthalmitis is discussed.

Anterior Chamber↗
PubMed1994

conformation and phasing of dystrophin structural repeats.

The presumptive rod domain of dystrophin contains a series of degenerate repeating sequences with homology to those of spectrin. To determine the relation of the implied structural repeating units to the sequence repeat (the phasing), recombinant fragments of the domain of dystrophin were prepared by expression in Escherichia coli. The phasing was established by identifying the minimum sequence element that would form a stable fold of high (approx. 75%) alpha-helicity: by contrast, incorrectly phased fragments had labile structure with an average alpha-helicity of about 40%. The isolated folded structural repeat showed high stability towards proteolysis and a urea-denaturation profile with a plateau at low denaturant concentration, indicative of a unique folded conformation. The phasing is consistent with a structure inferred from analysis of the amino acid sequence and also found in spectrin, in which each structural repeat comprises a three-stranded coiled-coil, made up of one short helix (approx. 30 residues) and the N and C-terminal halves of two separate long helices, such that each long helix participates in the formation of two contiguous structural units.

Amino Acid Sequence↗
PubMed1994

Adjuvant preoperative radiotherapy for locally advanced rectal carcinoma. Results of a prospective, randomized trial.

PURPOSE: A prospective, randomized clinical trial was conducted by the Northwest Rectal Cancer Group to study the effects of preoperative radiotherapy given one week before surgery in locally advanced (tethered or fixed) rectal carcinoma. METHODS: A total of 284 patients were entered into the trial between 1982 and 1986; 141 were allocated to receive surgical treatment alone, and 143 were allocated to receive preoperative radiotherapy. A 10 x 10 x 10 cm volume in the posterior pelvis, centered on the tumor, was irradiated at a dose of 20 Gy, divided into four daily fractions of 5 Gy each. RESULTS: No differences were observed in any of the clinicopathologic variables in the two arms of the trial; there were no striking down-staging effects in the irradiated tumors. After a minimum follow-up period of 96 months, the overall and cancer-related mortality rates were similar in both arms of the study (P = 0.21 and P = 0.09, respectively). There was a highly significant reduction in local recurrences in the irradiated group (12.8 percent x-ray therapy vs. 36.5 percent surgery; P = 0.0001). The majority of local recurrences after preoperative radiotherapy occurred inside the radiotherapy field (10 cases; 7 percent), with only six cases (5 percent) outside the field. No significant difference was observed in the rates of distant metastasis between the two treatment groups (P = 0.73). CONCLUSIONS: Although there is no statistically significant survival benefit in the whole series, there is a survival benefit for the subset of patients considered by the surgeon to have undergone a curative operation. We recommend that this form of adjuvant therapy should be offered to all patients with locally advanced rectal cancer who are to undergo radical surgery.

Aged↗
PubMed1994

Enterococcal bacteraemia: a prospective study of 125 episodes.

One hundred and twenty-five episodes of enterococcal bacteraemia occurring over a 50-month period were studied prospectively. Enterococcus faecium was the commonest species, accounting for 76 (59.8%) of the 127 isolates. Overall, 33.1% of isolates were resistant to ampicillin and one isolate (0.8%) to vancomycin; high-level gentamicin resistance was detected in 4.3% of 93 isolates tested. The percentage of nosocomial episodes was 70.4, and 95.2% of the patients had significant underlying illness. Central venous catheters (CVCs) were the commonest source of infection. Eighty-four per cent of episodes were ultimately treated with appropriate antibiotics. The overall mortality rate was 17.6%, and that directly attributable to infection was 8.0%. An increased mortality rate was observed in intensive care and neonatal unit patients, and in patients who had received antimicrobial therapy in the 2 weeks prior to enterococcemia. CVC-related infections were associated with a reduced mortality. No other clinical or microbiological factors were found to influence outcome.

Ampicillin Resistance↗
PubMed1994

Prognostic significance of 5T4 oncofetal antigen expression in colorectal carcinoma.

The 5T4 oncofetal antigen is a 72 kDa glycoprotein defined by a monoclonal antibody raised against human placental trophoblast and is expressed in many different carcinomas but detected only at low levels in some normal epithelia. Immunohistochemical analysis of the patterns of expression in colorectal carcinomas has indicated a significant association between the presence of the antigen in tumour cells and metastatic spread. The 5T4 antigen phenotype of 72 colorectal cancers has been compared with the clinical outcome of the patients in order to assess its relationship with prognosis. Forty per cent of tumours were 5T4 positive; the remainder were either unlabelled or exhibited stroma-associated labelling only. There was a significant correlation between 5T4 expression in the malignant cells and unfavourable course of disease (P < 0.001). The 5 year survival with 5T4-positive tumours was 22% compared with 75% for patients with 5T4-negative tumours; median survival was 24 versus > 90 months respectively. Stratified analysis showed that 5T4 antigen tumour positivity was acting independently of each of stage, site of tumour, age or sex. There were significant differences in survival for patients with Dukes' B and C stage carcinomas (P = 0.001 and P = 0.034). The results suggest that in colorectal cancer immunohistochemical assessment of 5T4 expression may be useful in identifying patients at high risk for tumour recurrence and for whom additional treatment strategies might be most appropriate.

Adult↗
PubMed1993

p53 overexpression as a marker of malignancy in gastric biopsies.

Inactivation of the p53 tumour-suppressor gene is the commonest genetic abnormality in human cancers. This results in a conformational change in the p53 protein, and a consequent prolongation in its half-life; thereby permitting the identification of p53 immunoreactivity in malignant cells. Such reactivity is observed in up to 57% of gastric carcinomas, and is a proven indicator of poor prognosis. We have investigated the use of p53 immunohistochemistry in the diagnosis of malignancy in pre-operative gastric biopsy specimens. Using a three-stage immunoperoxidase technique, p53 expression was examined in 117 gastric biopsies obtained during flexible upper gastrointestinal endoscopy: 80 of these biopsies were from known gastric carcinomas, 20 from benign gastric disorders and 17 from normal gastric mucosa. Of the gastric cancers 40% (n = 32) exhibited overexpression of p53. No reactivity was observed in any of the biopsies of gastric ulcers, polyps or normal mucosa. The expression of p53 by gastric carcinomas improved the diagnostic accuracy of conventional histopathology from 86% to 92.5%; with 5% of biopsies incorrectly diagnosed and 2.5% of an equivocal appearance. These results demonstrate that the detection of p53 is a highly specific marker of gastric malignancy, and that such a technique can easily be performed on biopsies obtained at endoscopy.

Adenocarcinoma↗