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Biomedical subjects

M Shaw

Publications and source records attributed to M Shaw.

At least 109 records · Page 6Linked to original sources
PubMed1997

Bropirimine as neoadjuvant therapy decreases residual disease and expression of markers PCNA and TGF-beta 1 in a rat orthotopic prostate adenocarcinoma.

The role of bropirimine in prostate cancer remains unexplored. To address the efficacy of this immune modulator as neoadjuvant therapy we utilized the orthotopic placement of the Dunning AT-3 tumor. 2.4-2.6 x 10(6) Dunning AT-3 cells were injected into the ventral prostates of 50 Copenhagen X Fischer rats. Animals were then divided into 5 groups consisting of: 1) untreated controls; 2) those treated with ventral prostatectomy alone (performed 10-12 days following tumor cell inoculation); 3) those treated with ventral prostatectomy plus bropirimine (10 mg/kg) on postimplantation days 1, 3, 5, 10 and 11; 4) those treated with ventral prostatectomy plus bropirimine (100 mg/kg), at the same schedule; and 5) those treated with ventral prostatectomy plus bropirimine (500 mg/kg), at the same schedule. Animals were sacrificed 10 days after prostatectomy, autopsied, and residual disease was weighed. Prostate weights upon removal following neoadjuvant treatment and residual disease remaining after 20-22 days were expressed in grams (g). Following prostatectomy, mean prostate weights were: Group 2, 0.67 +/- 0.11; Group 3, 0.53 +/- 0.11; Group 4, 0.54 +/- 0.12; Group 5, 0.44 +/- 0.09. The effect of bropirimine was significant (p = 0.0001) by multiple regression analysis. In addition, mean residual tumor weights (expressed in grams) after 20-22 days were: Group 1, 12.7 +/- 1.9; Group 2, 6.7 +/- 4.8; Group 3, 5.2 +/- 5.9; Group 4, 3.8 +/- 3.5; and Group 5, 2.8 +/- 3.5. The effect of bropirimine was not significant (p = 0.07) by multiple regression analysis. However, prostatectomy alone, by Student's test, significantly (p = 0.04) reduced residual mean tumor weights by 47% and the additional effect of bropirimine upon residual disease was significant (p = 0.038) if a Chi-square analysis is applied. Finally, a multivariate analysis of the overall effect of bropirimine in rats treated with prostatectomy was significant (p = 0.002). The effect of bropirimine on expression of proliferating cell nuclear antigen (PCNA) and transforming growth factor beta 1 (TGF-beta 1) was also evaluated immunohistochemically and expression of both tumor markers was significantly reduced (p < 0.05). We conclude that bropirimine may have a role as a neoadjuvant therapy when combined with prostatectomy.

Adenocarcinoma↗
PubMed1996

Creation of a District Diabetes Register using the DIALOG system.

A District Diabetes Register has been created using the Family Health Services Computer Unit system, DIALOG, linked to the Family Health Services Authority (FHSA) population register. Initial informal discussions between the Diabetes Centre, Public Health, and the FHSA led to a formal proposal being accepted by the Local Diabetes Services Advisory Group to pilot the DIALOG software. Following installation of DIALOG on a separate computer, electronically linked to the main FHSA system, the register was compiled. This was approached in three ways. The existing Diabetes Centre Register was downloaded into DIALOG and patients matched with the FHSA register. A 'diabetes roadshow' was mounted, with Postgraduate Education Allowance approval, to individually visit every general practice in the district to explain the aims and objectives of creating a diabetes register and to enlist the support of these practices. Where practices already held their own diabetes register this was similarly transferred, if not, assistance was provided to identify their patients with diabetes. All patients were notified in writing that their names were being placed upon a diabetes register and that clinical data would be held against their entry. This notification included an opportunity to opt out. Additionally, a self registrations scheme was introduced whereby all retail pharmacists dispensing any diabetes related product and all optometrists seeing a person with diabetes, gave the patient a leaflet, describing the register and its purposes and inviting them to register themselves. A 'Data Ownership Committee' was established to control the use and interpretation of all clinical data held upon the register. The process of diabetes annual review is now being prompted across both primary and secondary care and clinical data is being returned to the register.

Diabetes Mellitus↗
PubMed1996

Suramin as adjuvant therapy with radical prostatectomy.

Suramin is a newer agent employed in the management of prostate cancer. One suggested method of action is growth factor inhibition. While suramin has been employed to treat advanced disease its adjuvant role remains unexplored. To address this question we have employed a new model: the orthotopic placement of the Dunning AT-3 tumor. The purpose of this research was to assess the efficacy of adjuvant therapy in controlling residual disease. The method consisted of the injection of 2.4 to 2.6 x 10(6) AT-3 cells (harvested from flank tumors) into the ventral prostates of 29 Copenhagen X Fischer rats. The animals were then divided into four groups: 1) untreated controls (6 rats); 2) ventral prostatectomy only (10 rats); 3) ventral prostatectomy plus suramin (300mg/Kg) on post-op day 3 (5 rats); and 4) ventral prostatectomy plus cytoxan (50 mg/Kg) on post-op day 3 (8 rats). Prostatectomies were performed 10-12 days following AT-3 cell inoculation. Animals were sacrificed 10 days following prostatectomy, autopsied, and residual diseased weighed. All operating procedures: tumor cell inoculations, ventral prostatectomies, and necropsies were performed microsurgically employing a Zeiss operating microscope. The results (in mean tumor weights) were: Group 1, 20 +/- 1.4 gms; Group 2, 6.7 +/- 11.5 gms; Group 3, 2.7 +/- 3.8 gms; and Group 4, 2.2 +/- 2.5 gms. The differences between control and all treatment groups were significant: Group 1 vs. Group 2, P < 0.02; and Group 1 vs. Groups 3 and 4, P < 0.001. We conclude that prostatectomy resulted in a diminished weight of residual disease. Of more importance was the fact that adjuvant therapy further reduced residual disease. The orthotopic placement of the Dunning tumor may serve as a model to evaluate the place of suramin following radical prostatectomy.

Animals↗
PubMed1996

Inter-observer reliability of the Spondylitis Functional Index Instrument for assessing spondylarthropathies.

OBJECTIVE: To study the Spondylitis Functional Index (SFI) by having two physical therapists observe patients with spondylitis perform various tasks listed on the instrument. The physical therapists' observations were compared with each other and with the self-reported abilities of the patients. METHODS: Subjects (n = 30) were recruited from a cross-section of patients participating in a prospective randomized, multicenter, double-blind, parallel clinical trial of the efficacy of sulfasalazine on ankylosing spondylitis (n = 13), psoriatic arthritis (n = 13), and Reiter's syndrome (n = 4) conducted at the Veterans Affairs Medical Center in Salt Lake City. Percents of agreement and Cohen's kappa analysis were used to assess the reliability of the observations of the therapists and patients. RESULTS: The overall percent of agreement between the observers on the SFI was 93%. The overall percent of agreement between observer 1 and patients on the SFI was 66% and between observer 2 and patients was 67%. The overall inter-observer reliability measured by the Pearson coefficient was 0.91 and by Cohen's kappa was 0.86. Between observer 1 and the patients the Pearson was r = 0.53 and kappa = 0.39. For observer 2 the Pearson was r = 0.52 and kappa 0.39. CONCLUSIONS: We consider the agreement and reliability between observers to be high. The agreement and inter-observer reliability was poor between observers and patients. The SFI, as enhanced for use in this study to assess change in functional ability of patients with spondylitis, demonstrated high reliability when used by trained observers.

Activities of Daily Living↗
PubMed1996

Cell-type specificity of anti-CD45 autoantibodies in systemic lupus erythematosus.

OBJECTIVE: To determine the specificity of anti-CD45 autoantibodies in systemic lupus erythematosus (SLE) for native CD45 and for CD45 expressed by T cells and B cells, and at different stages of cellular activation. METHODS: CD45 purified from different types of lymphocytes was examined by immunoblotting with sera from patients with SLE. Indirect immunofluorescence experiments were performed with purified anti-CD45 autoantibodies. RESULTS: IgM anti-CD45 autoantibodies in SLE recognize native CD45 expressed on the surface membrane of viable lymphocytes and CD45 purified from activated peripheral T cells and certain T cell lines, but not CD45 purified from B cells or resting peripheral T cells. The presence or absence of reactivity is independent of the individual isoforms expressed. CONCLUSION: Recognition of CD45 by IgM antilymphocyte autoantibodies in SLE varies with the lineage and state of activation of the lymphocyte target. This pattern of reactivity is consistent with autoantibody specificities involving CD45 glycoforms, rather than CD45 isoforms.

Antibody Specificity↗
PubMed1996

Linkage of a fusion peptide to a CTL epitope from the nucleoprotein of measles virus enables incorporation into ISCOMs and induction of CTL responses following intranasal immunization.

The introduction of soluble protein antigens into the endogenous processing pathway is a prerequisite for the efficient induction of MHC class-1 restricted cytotoxic T-lymphocytes (CTLs). Antigens incorporated into immunostimulating complexes (ISCOMs) containing lipids and Quil-A are able to induce CD8+ CTL responses in vivo. Furthermore, lipopeptides have also been used to raise peptide-specific CTLs and bypass the requirement for the use of an adjuvant. Although conventional ISCOM technology is in general restricted to the use of hydrophobic proteins or fatty acid-derivitized proteins or peptides, we have demonstrated that the linkage of a conserved paramyxovirus fusion peptide to a CTL epitope NP29 (residues 281-290 of measles virus nucleoprotein) resulted in the incorporation of this hydrophilic CTL epitope into ISCOMs and the in vivo priming of peptide specific CTLs following intranasal immunization. In addition, the fusion peptide-CTL epitope chimera was able to efficiently sensitise P815 target cells for lysis by nucleoprotein specific CTLs induced following immunization of mice with recombinant RAd-68 adenovirus, suggesting the efficient introduction of the peptide into the class-1 restricted antigen processing pathway. Furthermore, immunization of mice with this fusion peptide chimera in saline was able to prime an NP29-specific CTL response despite the absence of adjuvant.

3T3 Cells↗
PubMed1996

Antitumor effect of CPT-11, a new derivative of camptothecin, against human prostate cancer (PC-3) in vitro and prostate rat tumor (AT-3) in vivo.

In an effort to evaluate the efficacy of CPT-11 on prostate cancer we utilized the PC-3 human prostate cancer cell line (in vitro), and the Dunning R3327 AT-3 rat prostate cancer tumor line (in vivo). PC-3 cells were initially seeded and cultured prior to the addition of CPT-11 at different concentrations 48 and 120 h later. After an additional 48 h the number of cells was determined using MTT dye uptake. CPT-11 at concentrations between 10 ng/ml and 50 micrograms/ml inhibited the growth of the PC-3 prostate human cancer cell line up < 0.001). AT-3 prostate rat cancer cells were injected into the right flank of 30 Copenhagen X Fischer rats, divided into treated and control groups. A total dose of CPT-11 (200 mg/kg) was given intraperitoneally, administered 1, 3 and 5 days postimplantation. We evaluated tumor growth by size and weight (5 and 10 days postimplantation). A total dose of 200 mg/kg inhibited the rapid growth of the prostate AT-3 tumor in vivo (p < 0.001).

Animals↗
PubMed1995

Pteroylpolyglutamate synthesis by lung- and culture-derived Pneumocystis carinii.

Pneumocystis carinii synthesizes folates de novo from exogenous p-aminobenzoic acid (pABA). Lung-derived organisms take up [3H]pABA in vitro except in the presence of sulfamethoxazole. Supernatants from spinner-flask cultures take up [3H]pABA if they were inoculated with lungs from infected rats, but not if they were inoculated with lungs from uninfected rats. P. carinii folates consist primarily of pteroylpentaglutamates. Plasmodium falciparum, in contrast, contains primarily pteroyltetraglutamates. Culture-derived organisms synthesize folates at a four-fold higher specific activity than lung-derived organisms, possibly because they contain less contaminating lung debris. These data suggest that P. carinii remains metabolically active in culture for at least 4 days.

4-Aminobenzoic Acid↗
PubMed1995

Orthotopic placement of the Dunning R3327 AT-3 prostate tumor in the Copenhagen X Fischer rat.

Orthotopic placement of in vitro propagated Dunning R3327 AT-3 tumor cells resulted in a greater percentage of tumor takes and a two-fold shift in the exponential growth curve compared to flank implantation. The orthotopic tumor appeared to disseminate preferentially to regional lymph nodes, rather than to the lungs which is characteristic of flank tumors. The results suggest an important role of stromal-epithelial interactions in the growth of this tumor.

Adenocarcinoma, Papillary↗
PubMed1995

Is cimetidine associated with neutropenia?

BACKGROUND: Cimetidine is perceived as sufficiently safe that it is being considered for over-the-counter use. However, because of residual concerns about cimetidine-induced neutropenia, a study was conducted to evaluate this association. METHODS: A population-based, case-control study was undertaken using a large database with Medicaid data from six states. Cases were defined as patients hospitalized with a discharge diagnosis of neutropenia. Medical records were sought to validate the diagnoses of neutropenia and to characterize the severity of disease. Four controls were randomly selected for each case, matched for age, sex, state, and year of diagnosis. The frequency of exposures to cimetidine in the 30 days prior to hospital admission in the cases was compared to that in the identical time periods in the controls. RESULTS: When investigators simultaneously controlled for multiple, potentially confounding variables by using conditional logistic regression, the odds ratio associated with the use of cimetidine was 1.2 (P = 0.33), with a one-sided upper 95% confidence limit of 2.6 for all patients over 20 years of age, and 0.6 (P = 0.30) with a one-sided upper 95% confidence limit of 3.1 for validated cases over 12 years of age. Neither a dose-response relationship was evident (P = 0.899 and P = 0.716, respectively, when excluding the nonusers, or P = 0.245 and P = 0.215, respectively, when including the nonusers). From these data, one can exclude the occurrence of hospitalization with neutropenia or agranulocytosis due to cimetidine occurring more often than once in every 116,000 patients and once in every 573,000 patients receiving a 6-week course of the drug, respectively. CONCLUSION: If there is an association between cimetidine and neutropenia, it appears to be very small.

Adolescent↗
PubMed1995

Evaluation of potent inhibitors of dihydrofolate reductase in a culture model for growth of Pneumocystis carinii.

Many antifolates are known to inhibit dihydrofolate reductase from murine Pneumocystis carinii, with 50% inhibitory concentrations (IC50s) ranging from 10(-4) to 10(-11) M. The relationship of the potency against isolated enzyme to the potency against intact murine P. carinii cells was explored with 17 compounds that had proven selectivity for or potency against P. carinii dihydrofolate reductase. Pyrimethamine and one analog were inhibitory to P. carinii in culture at concentrations two to seven times the IC50s for the enzyme, suggesting that the compounds may enter P. carinii cells in culture. Methotrexate was a potent inhibitor of P. carinii dihydrofolate reductase, but the concentrations effective in culture were more than 1,000-fold higher than IC50s for the enzyme, since P. carinii lacks an uptake system for methotrexate. Analogs of methotrexate in which chlorine, bromine, or iodine was added to the phenyl ring had improved potency against the isolated enzyme but were markedly less effective in culture; polyglutamation also lowered the activity in culture but improved activity against the enzyme. Substitution of a naphthyl group for the phenyl group of methotrexate produced a compound with improved activity against the enzyme (IC50, 0.00019 microM) and excellent activity in culture (IC50, 0.1 microM). One trimetrexate analog in which an aspartate or a chlorine replaced two of the methoxy groups of trimetrexate was much more potent and was much more selective toward P. carinii dihydrofolate reductase than trimetrexate; this analog was also as active as trimetrexate in culture. These studies suggest that modifications of antifolate structures can be made that facilitate activity against intact organisms while maintaining the high degrees of potency and the selectivities of the agents can be made.

Culture Media↗
PubMed1995

Characterization of an insect cell-derived Theileria parva sporozoite vaccine antigen and immunogenicity in cattle.

Previous data showed that six out of a group of nine cattle inoculated with NS1-p67, a recombinant form of a 67-kDa Theileria parva sporozoite surface protein, were immune to East Coast fever. This bacterially expressed antigen encoded all 709 amino acid residues of p67 fused to the C-terminal end of 87 residues derived from NS1, a structural protein of influenza virus, and a linker DNA sequence. NS1-p67 lacked reactivity with TpM 12, a monoclonal antibody to native p67, and had an estimated molecular mass of 110 kDa, as opposed to the calculated mass of 85,000 Da. We have used the baculovirus expression system in an attempt to express this parasite protein in a native form and thereby increase the protective capacity of the antigen. However, Spodoptera frugiperda SF21AE cells infected with recombinant virus expressed p67 as a 100-kDa molecule. The host cells exhibited a limited capacity to glycosylate this molecule to a 110-kDa form, and p67 was not exported to the surface membrane. TpM 12 did not bind to these recombinant forms but, at time points late during viral infection, reacted with a molecule of about 70 kDa. Since the bulk of insect cell-derived p67 was not expressed in an appropriate form, we tested the immunogenicity of these partially processed recombinant p67 forms in cattle. Two groups of three cattle were inoculated with antigen formulated either with saponin or Freund's adjuvant. As seen previously with NS1-p67, all animals developed high levels of anti-p67 antibodies that neutralized sporozoite infectivity in vitro, but antigen-specific T-cell proliferative responses were not detected in peripheral blood. Given the caveat of the small number of cattle analyzed, insect cell-derived p67 does not appear to be superior to NS1-p67 as an immunogen, and the latter remains the molecule of choice for the development of vaccines against East Coast fever.

Animals↗
PubMed1995

Long-term weight cycling reduces body weight and fat free mass, but not fat mass in female Wistar rats.

OBJECTIVE: The effects of repeated weight gain and loss, the weight cycling (WC) phenomenon, on body composition have been controversial. WC history and age are two confounding factors which may contribute to this inconsistency. In the present investigation, we examined the effects of WC on body weight regulation, body composition and feeding efficiency in a long-term study when WC history was controlled. METHOD: Six groups of female Wistar rats were used in this study. Five of these six groups were made obese by feeding a high fat (HF) diet for 11 weeks and then divided into five groups: non-cycling control group (HFCON); one group which cycled three times (HFCYC); and three one-cycle groups which cycled only once corresponding to each of the three cycles in the HFCYC group. The sixth group was fed the low fat diet without cycling (LFCON). Weight cycling (WC) was produced by feeding 50% of a HF diet with extra protein, vitamin and mineral mixture until body weight of the cycled groups reached the level of the LFCON group. After three cycles (52-56 weeks), all rats were killed. RESULTS: Results showed that repeated WC reduced final body weight and fat free mass, but not body fat mass in the HFCYC group. Repeated WC also reduced rate of weight regain. During the third cycle, the amount of fat regained during refeeding was more than the fat mass lost during restricted feeding in the HFCYC group. For the three one-cycle groups, the rate of weight regain was slower but rate of weight loss was the same in older rats as in the younger rats. CONCLUSION: Thus repeated WC may favor more body fat retention in later cycles. Aging affected rate of weight regain but not rate of weight loss, nor body composition, while repeated WC affected both rate of weight loss and regain.

Animals↗