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Biomedical subjects

M R Price

Publications and source records attributed to M R Price.

At least 91 records · Page 5Linked to original sources
PubMed1992

Topographical investigations of human ovarian-carcinoma polymorphic epithelial mucin by scanning tunnelling microscopy.

Human polymorphic epithelial mucin is a high-molecular-mass glycoprotein that associates to provide protection to the epithelial-cell surface and may afford the malignant cell a selective advantage for growth. The scanning-tunnelling-microscopy micrographs obtained in the present study identify the purified human ovarian-carcinoma polymorphic epithelial mucin glycoproteins as rod-shaped molecules of mixed length. The dimensions of the individual molecules range from 25 to 45 nm in length and are 3-4 nm in width. The images further suggest that lateral association of the rods occurs.

Animals↗
PubMed1992

Monoclonal antibody binding to peptide epitopes conjugated to synthetic branched chain polypeptide carriers. Influence of the carrier upon antibody recognition.

The peptide C A P D T R P A P G has been linked covalently to defined branched polypeptides with a polylysine backbone and side chains of DL-alanine or D-leucine-DL-alanine oligopeptides. The peptide was coupled via its N terminal cysteine to the side chains of the macromolecular carrier to ensure uniform orientation. The compounds were subjected to compositional analyses to characterise the degrees of substitution and secondary structural studies were performed using circular dichroism spectroscopy. The peptide selected for investigation contains the immunodominant sequence P D T R P A P which is expressed in the protein core of epithelial mucins. It is to this region that many anti-mucin monoclonal antibodies bind (Burchell et al., 1989; Price et al., 1990a,b). With these characterised constructs, it has been possible to evaluate the influence of secondary structure upon the binding of monoclonal antibodies which recognise short linear sequences in the synthetic antigenic peptide. The findings are relevant to the design and construction of synthetic immunogens and vaccines as well as to the production of synthetic analogues of clinically relevant antigens (in this case, epithelial mucins associated with breast and ovarian carcinomas).

Amino Acid Sequence↗
PubMed1992

Mechanical forces contribute to neonatal lung growth: the influence of altered diaphragm function in piglets.

Neonatal lung growth is controlled in part by mechanical forces. Altered mechanical forces precipitated by phrenectomy or prosthetic replacement of the diaphragm result in altered thoracic volume relationships, which, in turn, change lung distending pressures and or thoracic volume. These effects might contribute to regional lung growth. We postulated a relationship between altered thoracic mechanical forces and changes in lung growth and asked if altered diaphragm function influenced regional lung growth. Piglets (28d, 7-8kg), were assigned to left transthoracic phrenectomy (P), prosthetic diaphragm replacement (PDR), or sham (S), (n = 6). After a mean 10 days, piglets were studied with tracheostomy and regional pleural pressure transducers. Integrated lung volumes (LV) were recorded with intrapleural pressure (Pip). Dynamic compliance (Cdyn) was calculated (dV/dP). After sacrifice continuous pressure volume (P/V) curves were generated. Lungs were then cut into 4 quadrants based on relationship to R/L bronchus and processed for DNA content and total protein indexes. Analysis of data were made within and between groups. Body weight and gain were similar in all. LV, Pip, Cdyn, and P/V were not significantly different in PDR and P compared with S. Pip differences between thoracic regions within each group were significant for PDR and showed LU less than RU, LL less than RL (P less than 0.05). RU and RL Pip in the PDR group were the same as S. Pip in the P group were decreased in the RU, LU, and LL but only the LL approached significance. Whole lung wet weights were decreased (P less than .05) in P compared to PDR and S.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Purification of anti-epithelial mucin monoclonal antibodies by epitope affinity chromatography.

Monoclonal antibodies against the protein core of epithelial mucins have been found to react with the immunodominant sequence P D T R P A P (Burchell et al., 1989; Price et al., 1990a). Two immunoadsorbent matrices were prepared by linking the peptide A P D T R P A P G to CNBr-activated Sepharose and by linking the peptide C A P D T R P A P G to activated thiol-Sepharose, so that each immunoadsorbent contained the immunodominant motif. Anti-epithelial mucin antibodies (anti-breast carcinoma antibodies, anti-purified mucin antibodies and anti-human milk fat globule antibodies) were examined for reactivity with these preparations. The initial tests indicated that the substituted CNBr-activated Sepharose displayed lower non-specific antibody binding and this matrix was selected for further investigation. The anti-mucin antibodies were shown to react specifically with this affinity matrix and irrelevant antibodies failed to bind. A Sepharose-peptide immunoadsorbent column was examined for its capacity to purify several of these anti-mucin antibodies and it was determined that this procedure was highly efficient--purified IgG and IgM antibodies could be isolated from either hybridoma tissue culture supernatants or ascitic fluids. The capacity of the column was in excess of 40 mg antibody protein per ml of gel for the IgG3 antibody, C595 (anti-urinary mucin) and at least 10 mg antibody protein per ml of gel for the IgM antibody, NCRC-11 (anti-breast carcinoma). The procedure described permits the efficient purification of anti-mucin antibodies and provides a product which would be suitable for further investigations requiring highly immunoreactive antibodies (e.g., for radioimmunotherapy or immunoscintigraphy in patients with malignant disease).

Amino Acid Sequence↗
PubMed1991

Endocytosis of immunotoxin-791T/36-RTA by tumor cells in relation to its cytotoxic action.

Ricin A chain immunotoxin constructed with monoclonal antibody 791T/36, which recognizes a tumor associated glycoprotein Mr 72,000 antigen present on sarcomas and colon and ovarian cancer cells, is cytotoxic for cell lines from tumors expressing this antigen. Incubation of sarcoma 791T cells with immunotoxin for only 5 min is sufficient to produce greater than 95% inhibition of tumor cell growth. Papain treatment of these cells to remove immunotoxin from the cell surface indicated that the cell surface acts as a reservoir for continued internalization of immunotoxin over several hours, but even so, 50% inhibition of cell survival was produced over a 2- to 3-h period. Analysis of the rate of endocytosis demonstrated that 30-50% of cell bound immunotoxin was internalized over a 180-min period. This was primarily dictated by the antibody moiety, regardless of the degree of conjugation to ricin A chain. This rate is much slower than that of other cell surface ligands such as transferrin. Cell cytosol acidification experiments were performed to determine whether this immunotoxin was internalized by clathrin coated pits, which is relatively rapid, or by smooth pits, which is slower, and the results indicated the latter mechanism is almost exclusively used. Intracellular trafficking of antibody 791T/36, conjugated to human serum albumin-tetramethylrhodamine was investigated by flow cytometry. The movement of the conjugate into the lysosomal compartment was delayed so that degradation products were only detected after a lag phase of 30-60 min. The lack of potentiator dependence of 791T/36 immunotoxin is in keeping with these findings.

Ammonium Chloride↗
PubMed1991

Prospective assessment of the role of five tumour markers in breast cancer.

Retrospective analysis previously identified significant elevation of five tumour markers, carcinoembryonic antigen (CEA), ferritin, orosomucoid. C-reactive protein and erythrocyte sedimentation rate (ESR), in patients with systemic breast cancer and showed that changes in each of these markers individually correlated significantly with therapeutic response. In this study we have prospectively tested these findings. None of the five markers was significantly elevated in primary breast cancer compared to normal control or benign breast disease groups. They therefore appear to have no role either in screening or in the differential diagnosis of breast cancer. There was a significant elevation of all five markers in patients with systemic breast cancer (P less than 0.0001: analysis of variance) but sequential changes in CEA and ESR only correlated significantly with the UICC-assessed response. Prospective confirmation of the correlation between changes in serum CEA and ESR provides the basis for using these markers in the assessment of response to therapy in patients with systemic breast cancer.

Adult↗
PubMed1991

Reactivity of an anti-(human gastric carcinoma) monoclonal antibody with core-related peptides of gastrointestinal mucin.

A murine anti-(human gastric carcinoma) monoclonal antibody, GL-013 (IgG1), which reacts with a high-molecular-mass glycoprotein from colorectal tumour tissue [Yang and Price (1989) Anticancer Res 9: 1707], was examined for reactivity against a panel of purified and partially purified antigens associated with tumours of the gastrointestinal tract. These included carcinoembryonic antigen (CEA), normal cross-reacting antigen, Y-hapten glycoproteins, and perchloric acid extracts and glycolipid preparations from colorectal tumours. While the GL-013 antibody failed to bind to these antigens, it was found to react strongly with synthetic peptides with sequences based upon that reported for the protein core of a human gastrointestinal mucin [Barnd et al. (1989) Proc Natl Acad Sci USA 86: 7159; Gum et al. (1989) J Biol Chem 264: 6480]. In control tests, a series of other anti-(colorectal tumour) antibodies (IgG1 and IgG3), with broad reactivity towards gastrointestinal carcinomas, as well as an anti-CEA antibody, (IgG1) failed to react with the synthetic peptides. It is concluded that the anti-(gastric carcinoma) monoclonal antibody GL-013 binds to a threonine-rich peptide epitope expressed within the protein core of gastrointestinal mucins.

Adenocarcinoma↗
PubMed1991

Congenital diaphragmatic hernia, extracorporeal membrane oxygenation, and death: a spectrum of etiologies.

Extracorporeal Life Support Organization (ELSO) registry data show increased mortality in congenital diaphragmatic hernia (CDH) infants compared with other extracorporeal membrane oxygenation (ECMO) indications. To test the hypothesis that death might be related to various clinical parameters, retrospective data collection was solicited on 175 ECMO-related CDH deaths from 41 American ECMO centers (ELSO Registry 1980 through 1989). Data capture forms were received on 100 of 175 infants representing 29 of 41 centers. After review of all available material, a predominant cause of death was assigned. Other diagnoses were given secondary status. We analyzed arterial blood gas values at 6, 3, and 1 hour pre-ECMO, as well as at the time of highest recorded PO2 (preductal and postductal) and lowest recorded PCO2, and correlated these findings with predominant cause of death. The relationship between individual variables and cause of death was assessed by t test. Multivariate analysis was performed by using a stepwise discriminate procedure. The most common predominant causes of death were brain death (29%), pulmonary hypertension (25%), and pulmonary hypoplasia (17%). Correlation of arterial blood gas values at 6, 3, and 1 hour pre-ECMO with predominant causes of death established the following statistically significant associations (P less than .05): (1) pulmonary hypoplasia and low PO2 at 6 hours pre-ECMO; (2) brain death and low pH at 1 hour pre-ECMO; and (3) pulmonary hypertension and high HCO3- at 1 hour pre-ECMO.(ABSTRACT TRUNCATED AT 250 WORDS)

Bicarbonates↗
PubMed1991

Failure of CA19-9 to detect asymptomatic colorectal carcinoma.

Serum CA19-9 levels have been measured in 34 patients with asymptomatic colorectal cancer, 39 age and sex matched subjects with healthy colons (as assessed at full colonoscopy) and 55 patients known to have liver metastases from primary colorectal cancers. In subjects with asymptomatic cancer the median CA19-9 was 12.75 U ml-1 (0.0-280.7 U ml-1), in the healthy controls the median CA19-9 was 12.80 U ml-1 (0.0-88.9 U ml-1) and in those with liver metastases was 62.5 U ml-1 (4.8-458.0 U ml-1). Levels were significantly higher in patients with metastatic disease than in patients with asymptomatic tumours or the healthy controls, however there was no significant difference between the asymptomatic group and the controls. Using an upper limit of normal of 37 U ml-1, the sensitivity of CA19-9 was 60.3% for the detection of colorectal cancer with liver metastases but only 17.6% for asymptomatic cancer. Serum CA19-9 estimation is of no value as a means of screening for asymptomatic colorectal cancer.

Adult↗
PubMed1991

Objective measurement of therapeutic response in breast cancer using tumour markers.

In 65 patients with systemic breast cancer, a biochemical response index using three tumour markers in combination, carcinoembryonic antigen (CEA), carbohydrate antigen 15-3 (CA 15-3) and erythrocyte sedimentation rate (ESR), allowed objective biochemical assessment of response to endocrine therapy. Changes in these three markers at 2, 4 and 6 months showed a highly significant correlation with UICC assessed response at 6 months. At 4 months, changes in these three markers resulted in a selectivity of 93%, with a sensitivity of 92% and a specificity of 82%. Survival of groups of patients assessed biochemically or by UICC criteria for non-progression or progression showed no significant difference. The advantage of the biochemical assessment are that it is objective and reproducible. The assessment gives similar information to the UICC assessment but can be carried out earlier. Changes in the three markers appears to reflect the dynamics of change in tumour mass in response to systemic therapy in contrast to the UICC criteria which reflect structural change.

Adolescent↗
PubMed1991

Immune recognition of linear epitopes in peptide fragments of epithelial mucins.

Anti-human milk fat globule membrane monoclonal antibodies HMFG-1 and HMFG-2 recognize epitopes within the protein core of human polymorphic epithelial mucin (PEM). These have been identified as PDTR and DTR, respectively. Using the solid phase synthesis of immobilized tetrameric peptides, we have systematically investigated the contribution of each amino acid in the immune recognition of the PDTR domain by the antibodies HMFG-1 and HMFG-2. The findings obtained have been interpreted with respect to the presence of, and requirements for elements of secondary structure, which have been identified in this region of the PEM protein core.

Antibodies, Monoclonal↗
PubMed1990

Scanning tunneling microscopy imaging of the tumour associated antigenic 20 amino acid human polymorphic epithelial mucin core peptide fragment.

Human polymorphic epithelial mucins (PEM) are high molecular weight glycoproteins that are associated with breast cancer. Recent structural studies have identified that the protein core of PEM contains a 20 amino acid tandem repeat that has elements of secondary structure which coincide with the epitopes for a number of tumour reactive antibodies. In our continuing structural studies we have now investigated the use of the scanning tunneling microscope (STM) to directly image the conformation of the twenty amino acid PEM core peptide. High resolution STM images reveal that the peptide has an overall topography similar to that predicted by molecular modelling. The images identify directly that the free peptide is conformationally non-restricted and can adopt a number of discrete conformations in the solid state.

Amino Acid Sequence↗
PubMed1990

Emigration of doctors, military service and alternative service. Some proposals based on a survey of medical students.

In the face of a critical shortage of skilled medical personnel, especially in the rural areas of South Africa, and high rates of emigration of doctors, a survey was conducted in 1989 of white male medical students at the University of the Witwatersrand to assess their intentions to emigrate, their reasons for emigrating and their attitudes to alternative civilian service. Ninety-five per cent of respondents still had military service obligations; 39% said they were considering emigrating. Military service was ranked as the first or second most important reason by 59% of those intending to emigrate and 47% said they would remain in South Africa if alternative service were available. The majority of those willing to do alternative service were also willing to do this in rural areas. The introduction of the option of alternative service would reduce emigration, increase the provision of medical care in rural areas, and acknowledge the right of individuals to serve the country in a non-military capacity.

Attitude of Health Personnel↗
PubMed1990

The impact of the fee-for-service reimbursement system on the utilisation of health services. Part I. A review of the determinants of doctors' practice patterns.

The impact of different methods of reimbursement on the practice patterns of doctors has received little attention in the local literature. This series of three papers attempts to address this gap. Here the international evidence on this issue is reviewed. The 'information gap' between doctors and their patients allows doctors to induce demand for their services. This leads to the potential for doctors to increase the supply of services when they stand to gain financially from doing so, as is the case in the fee-for-service system. There is extensive international evidence, at both national and micro levels, of the link between increased utilisation and the fee-for-service payment system. This is in contrast with the pattern noted in the salary system, used in some health maintenance organisations (HMOs) in the USA, or in the capitation system, used in the British National Health Service. The 'practice setting' in which doctors operate also affects patterns of practice. In the local fee-for-service sector, 'third-party payment' means that both doctors and patients have little awareness of the direct costs of services. In other systems, such as HMOs, there is a strong cost consciousness on the part of practitioners. These differences in practice setting account in part for the different patterns of utilisation in these systems. The fee-for-service system, as it is structured in South Africa, thus leads to extreme inefficiency, and the development of alternatives is becoming an urgent necessity. All systems of reimbursement have certain problems, and some combination may be the best solution.

Capitation Fee↗
PubMed1990

The impact of the fee-for-service reimbursement system on the utilisation of health services. Part II. Comparison of utilisation patterns in medical aid schemes and a local health maintenance organisation.

This study reports the results of a retrospective analysis of the use of a range of inpatient and outpatient services by the members of a health maintenance organisation (HMO), in which most providers are salaried, and by the members of three medical aid schemes in which providers are paid on a fee-for-services basis. The analysis shows significantly higher utilisation of all services by medical aid scheme members than by HMO members. Medical aid scheme patients saw all doctors 33% more often than their HMO counterparts. For general practitioners and specialists specifically, the differences were 36% and 18% respectively. Doctors looking after medical aid scheme beneficiaries ordered 133% more radiological procedures and 14% more pathological investigations than did those caring for HMO beneficiaries. Hospital utilisation was also higher for medical aid patients. While quality of care is difficult to measure, there are no reasons to suspect that significant differences in quality exist between the two systems described here. One factor that may contribute to the higher utilisation rates in the medical aid group is the higher average income of this group. However, these results also demonstrate that providers working in the fee-for-service system are likely to increase the supply of services compared with providers who are salaried. The different methods of reimbursement are compounded by the different practice settings in which these groups of doctors work; the HMO generates an awareness of costs that is absent from the independent practice, 'third-party payment' system of the medical aid schemes.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical Laboratory Techniques↗
PubMed1990

The impact of the fee-for-service reimbursement system on the utilisation of health services. Part III. A comparison of caesarean section rates in white nulliparous women in the private and public sectors.

The caesarean section (CS) rate among white women aged 20-35 years and having their first baby was examined, comparing the private fee-for-service medical aid sector with Johannesburg Hospital. The chance of having a CS in the private sector was 50% greater than in the public sector (28.7% v. 19.5%). Twice as many CSs were done on weekdays as over weekends, and it is argued that only a quarter of these are accounted for by elective procedures (planned before labour begins). We also found that in the private sector the daily frequency of non-caesarean deliveries was 56% higher during the week than on Saturdays or Sundays. Considering non-caesarean deliveries separately, it is inferred that the rate of induction of such deliveries was 28.7% in the private sector compared with 2.8% in Johannesburg Hospital. The evidence strongly confirms the international experience that the CS rate in a given population is not objectively determined by medical factors and is strongly influenced by individual doctors' decisions. Moreover, fee-for-service reimbursement of doctors leads to increased intervention in delivery, in the form of more frequent induction of labour and more CSs.

Adult↗
PubMed1990

The private health sector in South Africa--current trends and future developments.

The private health sector is experiencing a crisis of spiralling costs, with average annual cost increases of between 13% and 32% over the decade 1978-1988. This trend is partly explained by the high utilisation rates that result from the combination of the 'fee-for-service' system and the 'third-party' payment structure of the sector. Medical schemes have responded by promoting the idea of 'flexible packages', and have won the right to 'risk-rate' prospective members. It is argued that these measures will undermine the principle of equity in health care, and will not solve the problems of the private sector. Instead, a more significant restructuring of the sector is likely to emerge. This may take the form of 'managed care' structures, along the lines of the health maintenance organisation model from the USA. The principles, advantages and problems of 'managed care' structures are described. These are shown to be potentially more rational and efficient than the current structure of the private sector. Although some resistance to 'managed care' structures can be expected, the convergence of interests of large employers and trade unions in containing health care costs suggests that their emergence is a likely development.

Costs and Cost Analysis↗