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Biomedical subjects

P Stewart

Publications and source records attributed to P Stewart.

At least 109 records · Page 6Linked to original sources
PubMed1991

Pretreatment of the primigravid uterine cervix with mifepristone 30 h prior to termination of pregnancy: a double blind study.

OBJECTIVE: To determine the effect of the antiprogestogen mifepristone (RU 486) on cervical resistance before first trimester termination of pregnancy. DESIGN: Prospective double blind randomized placebo controlled study. SETTING: Department of gynaecology in a university teaching hospital, Sheffield. SUBJECTS: 80 Primigravid women greater than 18 years of age, undergoing termination of pregnancy at between 7 and 13 weeks gestation. INTERVENTIONS: A single dose of 600 mg of mifepristone or placebo given orally 30 h before termination of pregnancy under general anaesthesia. MAIN OUTCOME MEASURES: Cervical resistance to dilatation. RESULTS: Pretreatment with mifepristone significantly reduced the amount of force required to dilate the cervix to 10 mm. In comparison with placebo, the mean sum of the peak forces obtained with dilators 4 to 10 mm was reduced from 84.3 N (SD 29.7) to 46.0 N (SD 26.7). Two women in the treated group had a cervical resistance of greater than 100 N compared with nine women in the placebo group (RR 0.18, 95% CI 0.04-0.89). The 8 mm dilator could be passed with less than 5 N force in 16 women (43%) in the treated group compared with none in the placebo group. Women in the active treatment group had more preoperative pelvic pain and vaginal bleeding but less postoperative pain. CONCLUSION: Mifepristone significantly reduces cervical resistance in the first trimester of pregnancy and produces minimal side effects.

Abortion, Therapeutic↗
PubMed1991

Dynorphin-induced depression of the dorsal root potential in rat spinal cord: a possible mechanism for potentiation of the C-fiber reflex.

Dynorphin A (1-13) acetate salt was applied to the exposed spinal cord of rats during electrophysiological recording of the dorsal root potential (DRP) and the DR III arising from dorsal root stimulation. Simultaneously, ventral root potentials indicative of monosynaptic and polysynaptic myelinated pathways were recorded. Amplitudes of the DRP and DR III were decreased for 30 to 60 min in a dose-dependent manner after dynorphin administration with ED50 values of 21 and 28 nmol, respectively. Amplitude of ventral root potentials was also decreased with a maximal effect at 5 min postdrug treatment. In contrast, we (Caudle and Isaac, J. Pharmacol. Exp. Ther. 246: 508-513, 1988b) showed that the polysynaptic unmyelinated pathway (C-fibers) was greatly enhanced by dynorphin treatment and that this pathway was the locus of excitotoxicity (Caudle and Isaac, Brain Res. 443: 329-332, 1988a). Because the DRP reflects gamma-aminobutyric acid-mediated presynaptic inhibition of primary afferent terminals, these data indicate that dynorphin suppresses gamma-aminobutyric acid-mediated inhibition thereby disinhibiting primary afferent transmission. This presynaptic disinhibition may be the mechanism for the selective potentiation of the C-fiber pathway which may account for the selective neuron toxicity, i.e., loss of the C-fiber pathway and sparing of the monosynaptic and polysynaptic myelinated pathways after dynorphin administration.

Action Potentials↗
PubMed1991

Prophylaxis of graft-versus-host disease by administration of the murine anti-IL-2 receptor antibody 2A3.

The efficacy of murine monoclonal IgG1 antibody 2A3 specific for the 55 kD chain of the human IL-2 receptor (CD25) was evaluated for prophylaxis of acute GVHD in patients with advanced leukemia transplanted with unmodified bone marrow from related HLA-haploidentical donors incompatible for two or three HLA loci of the nonshared haplotype. As GVHD prophylaxis, 36 patients (control) received standard cyclosporine and methotrexate (C + M) whereas 11 patients (study) received C + M plus antibody 2A3, 1.0 mg/kg on day -1, and 0.5 mg/kg daily from day 0 through day +19. Antibody administration was not associated with appreciable toxicity and did not adversely affect engraftment. During treatment, circulating CD25+ cells appeared saturated by the infused antibody. Patients receiving antibody 2A3 tolerated more cyclosporine than controls (p less than 0.001) with lower increase of serum creatinine (p less than 0.05) during the first month. Seven of 10 (70%) evaluable study patients developed acute GVHD of grade II-IV with onset at a median of 20 days compared to 27 of 31 (87%) control patients with onset at a median of 13 days (p = 0.11). Trough serum levels of antibody 2A3 ranged from 7.2 to 68.8 mg/l, and lower values correlated with occurrence of acute GVHD. A human anti-mouse immunoglobulin antibody response was detected in four patients but was not associated with lower levels of antibody 2A3 in the serum. Two study patients and two controls have survived more than 1 year (p = 0.92). These findings suggest that administration of antibody 2A3 suppressed and delayed activation of alloantigen-specific T cells but did not result in their elimination.

Adolescent↗
PubMed1990

MK-801 blocks dynorphin A (1-13)-induced loss of the tail-flick reflex in the rat.

Dynorphin A (1-13) administered intrathecally to rats results in a dose-dependent loss of the tail-flick reflex. This effect is mediated, at least in part, by N-methyl-D-aspartate receptors. We examined the influence of pretreatment or post-treatment with MK-801 on this behavioral response. MK-801 administered i.p. 30 min prior to dynorphin provided dose-dependent protection against loss of the tail-flick reflex with an ED50 of 0.06 mg/kg. MK-801 administered after dynorphin had a dose- and time-dependent protective action. The dose of 0.06 mg/kg protected 63% of the animals from loss of the tail-flick reflex when injected 15 min after dynorphin. In contrast, 3 mg/kg did not protect animals when injected 15 min after dynorphin, but did protect 50% of the animals when injected 30 min post-dynorphin. Although we cannot exclude other effects mediated by MK-801, these data support our previous findings that dynorphin-induced loss of the tail-flick reflex involves the N-methyl-D-aspartate-receptor complex and support the contention that the process(es) initiated by dynorphin injection proceed rapidly (minutes rather than hours).

Animals↗
PubMed1990

What role for prednisone in prevention of acute graft-versus-host disease in patients undergoing marrow transplants?

One hundred forty-seven consecutive patients with leukemia, myelodysplastic syndrome, or aplastic anemia were treated by marrow grafts from genotypically HLA-identical siblings (n = 122) or HLA-haploidentical family members (n = 25). Haploidentical recipients differed from their donors for no more than one HLA locus on the nonshared haplotype. All were given postgrafting immunosuppression with a combination of methotrexate and cyclosporine. In a randomized study we explored whether prednisone administered from day 0 through 35 along with methotrexate/cyclosporine could improve prevention of acute graft-versus-host disease (GVHD). The GVHD incidence in patients not given prednisone was comparable with that previously reported with methotrexate/cyclosporine. Unexpectedly, significant increases in acute and also chronic GVHD were seen in HLA-identical recipients administered prednisone, but not in the small number of patients administered HLA-nonidentical grafts. However, the resultant increase in transplant-related mortality in patients administered prednisone was offset by an increase in leukemic relapse in patients not administered prednisone, presumably related to the absence of a graft-versus-leukemia effect. Therefore, overall disease-free survival of the two groups of patients was comparable, with slightly more than 50% of the patients being alive at more than 2 years after transplantation. We speculated that prednisone adversely affected GVHD prophylaxis, interfering with methotrexate's cell cycle-dependent suppression of donor lymphocyte proliferation in response to host antigens. In a pilot study we explored whether beginning prednisone on day 15, after completion of methotrexate administration, would avoid this adverse effect. The GVHD incidence in patients administered methotrexate/cyclosporine along with "late" prednisone was comparable with that in patients not administered prednisone. We conclude that methotrexate/cyclosporine is effective in decreasing the incidence of grade II through IV GVHD, and that the addition of prednisone to this regimen is not beneficial in recipients of HLA-identical marrow grafts.

Acute Disease↗
PubMed1990

Differences in the modulation of P450IA1 and epoxide hydratase expression by benz[a]anthracene and 2,3,7,8-tetrachlorodibenzo-p-dioxin in mouse embryo versus mouse hepatoma-derived cell lines.

Polycyclic aromatic hydrocarbon (PAH)-induced C3H/10-T1/2/CL8 mouse embryo fibroblasts (10T1/2) and mouse hepatoma-derived Hepa 1c1c7 cells (Hepa-1), exhibit comparable total cytochrome P450 levels and total PAH-metabolizing activities but very different distributions of PAH metabolites. Based on anti-P450IA1-IgG inhibition data, P450IA1 contributes essentially all PAH metabolism in Hepa-1 microsomes but is not involved in PAH metabolism by 10T1/2 cells. In addition, the microsomal epoxide hydratase (EHm) in Hepa-1 cells is far less effective in dihydrodiol (diol) formation compared to that in 10T1/2 microsomes [Pottenger, L.H. and Jefcoate, C.R. Carcinogenesis, 11, 321-327 (1990)]. In the present study, the levels of expression of P450IA1 and EHm proteins and the corresponding mRNAs, both prior to and following exposure to benz[a]anthracene (BA) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), have been correlated with microsomal PAH metabolism by each cell type. In 10T1/2 cells, P450IA1 protein (56 kd) and mRNA (2.6 kb) were detectable at extremely low levels in only two of five cell preparations and then only after maximum induction by TCDD and BA. Thus although 10T1/2 cells contain functional Ah receptors, their capacity to induce P450IA1 is highly suppressed, representing at most 2% of the total P450. TCDD (10 nM) was 4-fold more effective than BA (10 microM) in inducing P450IA1 mRNA, while the levels of immunodetectable protein were comparable. An even greater discrepancy between P450IA1 mRNA and protein levels was seen in BA-induced Hepa-1 cells, where a 4-fold increase in mRNA was paralleled by a 20-fold increase in protein. This difference is probably due to the greater effect of BA depletion on mRNA compared to protein levels. In 10T1/2 cells, BA and TCDD were equally effective at increasing expression of an unidentified 1.9 kb mRNA sequence that blotted very weakly with the P450IA1 cDNA probe. The expression of this mRNA was independent from that of P450IA1. A similar band was visible in Hepa-1 cells less than 1% of the P450IA1 mRNA. EHm mRNA was almost 3-fold higher in 10T1/2 compared to Hepa-1 cells and was unaffected by cell treatments. In Hepa-1 cells, BA and TCDD elevated EHm protein and hydrating activity to levels comparable to those expressed in 10T1/2 cells. It is, therefore, suggested that the relative ineffectiveness of Hepa-1, compared to 10T1/2 EHm, to hydrate low levels of PAH-epoxides is due to differences between the two proteins or their disposition in the microsomal membrane.

Animals↗
PubMed1990

A phase I-II study evaluating the murine anti-IL-2 receptor antibody 2A3 for treatment of acute graft-versus-host disease.

A murine IgG1 antibody specific for the IL-2-binding site on the human lymphocyte IL-2 receptor beta chain (CD25) was evaluated in 11 patients who developed acute graft-versus-host disease following allogeneic marrow transplantation. All patients had received cyclosporine and methotrexate for prophylaxis of GVHD, either alone (4 cases), or in combination with antithymocyte globulin (4 cases) or with prednisone (3 cases). Patients had developed GVHD at 7-53 days (median 12) after transplantation and had failed treatment with corticosteroids for 3-44 days (median 19). Residual GVHD was of grade II severity in 4 patients, grade III in 5 patients, and grade IV in 2 patients. Sequential patients received monoclonal antibody in escalating doses from 0.1 mg/kg/day to 1.0 mg/kg/day for 7 days. Side effects were fever, respiratory distress, hypertension, hypotension, and chills occurring in 11 of 72 (14%) antibody infusions. Trough antibody levels greater than 6 micrograms/ml were achieved in patients treated with 0.5 or 1.0 mg/kg/day. Four of eight evaluable patients had an IgM antibody response, and one had an IgG response to the murine immunoglobulin. Clinical response of GVHD was evaluated in 10 patients who received the entire course of the antibody treatment. Among 7 patients treated within 40 days from transplantation, one patient had a complete response in the skin as the only involved organ, and 3 patients had a partial response, 2 in the skin and one in the gastrointestinal tract. No responses were achieved with liver disease at anytime or in any organ in patients treated beyond 40 days after transplantation. Since administration of this antibody was well tolerated and some efficacy was observed in patients with acute GVHD treated early after transplantation, there is a rationale for testing this antibody as an agent for prophylaxis of GVHD.

Acute Disease↗
PubMed1990

Brain damage from 125I brachytherapy evaluated by MR imaging, a blood-brain barrier tracer, and light and electron microscopy in a rat model.

Changes in normal rat brain were studied acutely, and at 3, 6, 9, and 12 months following interstitial brachytherapy with high-activity 125I seeds. An 80-Gy radiation dose was administered to an area with a 5.5-mm radius. Effects were measured with magnetic resonance (MR) imaging (with and without gadolinium enhancement), leakage of horseradish peroxidase (HRP), electron microscopy, and light microscopy. Significant histological damage was seen at radiation doses above 295 Gy, and breakdown of the blood-brain barrier was observed only in tissue receiving a dose of 165 Gy or greater. Blood-brain barrier breakdown increased up to the 6-month time point, and thereafter appeared to stabilize or decrease. The area of blood-brain barrier disruption indicated by gadolinium-enhanced MR imaging was greater than that indicated by leakage of HRP.

Animals↗
PubMed1989

Localization of dynorphin-induced neurotoxicity in rat spinal cord.

Intrathecally injected dynorphin A (1-13) in rats results in a reversible hindlimb paralysis and an irreversible loss of the tail-flick reflex. Histologic examination of the spinal cords of dynorphin treated rats demonstrated dead and/or dying neurons predominately localized in the central area which approximates Rexed lamina VII and X. In this area a maximum effect of the dynorphin-induced neurotoxicity is evident. Thus, the dynorphin-induced neuron death is suggestive of an anatomical selectivity.

Animals↗
PubMed1989

Acute renal failure following bone marrow transplantation: a retrospective study of 272 patients.

To assess the incidence, risk factors, and course of acute renal failure (ARF) following bone marrow transplantation (BMT), a retrospective analysis of 272 patients receiving transplants at the Fred Hutchinson Cancer Research Center during 1986 was undertaken. The patients were divided into three groups: group 1, hemodialysis requiring ARF; group 2, mild renal insufficiency (doubling of serum creatinine, Scr, but no dialysis); group 3, relatively normal post-BMT renal function (no doubling of Scr). Fifty-three percent of patients at least doubled their Scr (Groups 1 and 2), and 24% required dialysis. The degree of renal functional impairment had a dramatic impact on patient mortality rates (84%, 37%, and 17% in groups 1, 2, and 3, respectively). Jaundice (bilirubin greater than or equal to 2.0 mg/dL), weight gain (greater than or equal to 2.0 kg), amphotericin B use, and a pretransplant Scr greater than or equal to 0.7 mg/dL were independently associated with the subsequent development of dialysis-requiring ARF (P less than 0.001; relative risks, 3.0 to 7.7). Neither aminoglycoside/vancomycin/cyclosporine A use nor acute graft v host disease correlated with the development of ARF. A mismatched graft was a significant risk factor for ARF by univariate but not by multivariate analysis. Within 48 hours before doubling the Scr, 63% of group 1 patients had positive blood cultures and 39% developed hypotension. Of the 26 group 1 patients who had urine Na concentrations measured, 85% had values less than or equal to 40 mEq/L. Autopsy kidney specimens provided no clear explanation for ARF in the vast majority of patients in group 1.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Kidney Injury↗
PubMed1989

A randomized study of the sitting position for delivery using a newly designed obstetric chair.

A new obstetric chair has been designed to overcome some of the problems of those currently available commercially. The chair has been used to assess the effects of the sitting position in the second stage of labour on the outcome of delivery in 304 women randomly allocated to be delivered either in the chair or in the conventional dorsal position. Delivery in the chair conferred no benefits to mother or baby and resulted in greater mean blood loss and a higher rate of postpartum haemorrhage.

Delivery, Obstetric↗
PubMed1989

An evaluation of 6 dentifrice formulations for supragingival anticalculus and antiplaque activity.

A 4 week, double blind clinical trial was conducted to assess the antiplaque/anticalculus activity of test dentifrices containing varying levels of zinc citrate. Subjects were divided into 6 groups, 4 experimental, 1 positive control and a placebo group. All subjects only brushed at home using the placebo control during study weeks 1 and 3. Plaque and calculus were collected at the end of study weeks 2 and 4 on mylar strips worn on lower incisor teeth. Dentifrice efficacy was assessed by comparing group dry and ash weight decrements. While there were no significant differences between the test and control groups, there was a demonstrable trend toward greater inhibition with higher zinc citrate levels, especially among subjects with high levels of plaque and calculus at baseline.

Aluminum Oxide↗
PubMed1988

A critical investigation of the measurement of the force required to dilate the human uterine cervix.

A system for objectively analysing the forces of dilation of the human uterine cervix was devised using a force sensing device linked to a BBC microcomputer. The computer program allowed easy recording, storage and analysis of force/time curves obtained from the passage of tapered dilators through the cervix. A new design of dilator gave a smoother force/time curve. These force/time curves were analysed. Six indices: peak force, end force, area to peak, area to end the ratio of the peak and end forces recorded from the passage of the two largest and two smallest dilators, were compared. Area measurement was subject to artefact and rejected. Peak and end force measurements gave the best separation between parous and nulliparous patients. The peak force was judged to be the better as it was found to be easier to define than end force.

Biophysical Phenomena↗