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Biomedical subjects

P Baker

Publications and source records attributed to P Baker.

At least 91 records · Page 5Linked to original sources
PubMed1996

Defects in human methionine synthase in cblG patients.

Inborn errors resulting in isolated functional methionine synthase deficiency fall into two complementation groups, cblG and cblE. Using biochemical approaches we demonstrate that one cblG patient has greatly reduced levels of methionine synthase while in another, the enzyme is specifically impaired in the reductive activation cycle. The biochemical data suggested that low levels of methionine synthase activity in the first patient may result from mutations in the catalytic domains of the enzyme, reduced transcription, or generation of unstable message or protein. Using Northern analysis, we demonstrate that the molecular basis for the biochemical phenotype in this patient is associated with greatly diminished steady-state levels of methionine synthase mRNA. The biochemical data on the second patient cell line implicated mutations specific to reductive activation, a function that is housed in the C-terminal AdoMet-binding domain and the intermediate B12-binding domain, in the highly homologous bacterial enzyme. We have detected two mutations in a compound heterozygous state, one that results in conversion of a conserved proline (1173) to a leucine residue and the other a deletion of an isoleucine residue (881). The crystal structure of the C-terminal domain of the Escherichia coli MS predicts that the Pro to Leu mutation could disrupt activation since it is embedded in a sequence that makes direct contacts with the bound AdoMet. Deletion of isoleucine in the B12-binding domain would result in shortening of a beta-sheet. Our data provide the first evidence for mutations in the methionine synthase gene being culpable for the cblG phenotype. In addition, they suggest directly that mutations in methionine synthase can lead to elevated homocysteine, implicated both in neural tube defects and in cardiovascular diseases.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1995

Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthritis. The Methotrexate-Cyclosporine Combination Study Group.

BACKGROUND: Patients with severe rheumatoid arthritis who are treated with methotrexate frequently have only partial improvement. METHODS: In a six-month randomized, double-blind trial, we compared combination therapy with cyclosporine (2.5 to 5 mg per kilogram of body weight per day in two divided doses at 12-hour intervals) and methotrexate (at the maximal tolerated dose) with methotrexate and placebo in 148 patients with rheumatoid arthritis who had residual inflammation and disability despite partial but substantial responses to prior methotrexate treatment. The primary outcome measure was the change in the number of tender joints. RESULTS: The mean (+/- SD) dose of cyclosporine at the final treatment was 2.97 +/- 1.02 mg per kilogram per day. As compared with the placebo group, the patients in the treatment group had a net improvement in the tender-joint count of 25 percent, or 4.8 joints (95 percent confidence interval, 0.7 to 8.9; P = 0.02), and in the swollen-joint count of 25 percent, or 3.8 joints (95 percent confidence interval, 1.3 to 6.3; P = 0.005); improvement in overall disease activity as assessed by the physician (19 percent, P < 0.001) and the patient (21 percent, P < 0.001); and improvement in joint pain (23 percent, P = 0.04) and in the degree of disability (26 percent, P < 0.001). The mean erythrocyte sedimentation rate increased by 4.2 mm per hour in the cyclosporine group and decreased by 4.8 mm per hour in the placebo group (P = 0.006). Thirty-six patients (48 percent) in the cyclosporine group and 12 patients (16 percent) in the placebo group (P < 0.001) met the 1993 criteria for improvement of the American College of Rheumatology (more than 20 percent improvement in the numbers of both swollen and tender joints and improvement in three of five other variables). Seventeen patients in the cyclosporine group and 12 patients in the placebo group were withdrawn from the study; 2 patients in the cyclosporine group died, 1 from viral pneumonia and the other in a motor vehicle accident. Serum creatinine concentrations increased by a mean of 0.14 +/- 0.27 mg per deciliter (12 +/- 24 mmol per liter) in the cyclosporine group and by 0.05 +/- 0.19 mg per deciliter (4 +/- 17 mmol per liter) in the placebo group (P = 0.02). CONCLUSIONS: In a six-month study, patients with severe rheumatoid arthritis and only partial responses to methotrexate had clinically important improvement after combination therapy with cyclosporine and methotrexate. Side effects were not substantially increased. Long-term follow-up of patients treated with this combination is needed.

Arthritis, Rheumatoid↗
PubMed1995

Crystallization and preliminary X-ray studies of recombinant horseradish peroxidase.

A non-glycosylated form of horseradish peroxidase c extracted from Escherichia coli inclusion bodies and refolded in the presence of haem and Ca(2+) ions has been used to grow protein crystals suitable for X-ray diffraction analysis. The crystals are prisms in the trigonal space group P3(1)12 or P3(2)12 with a = b = 158.9 and c = 114.3 A, and diffract to 1.9 A. There are four molecules, each of 34 kDa, in the asymmetric unit. The molecules of the asymmetric unit are related by approximate translational symmetry, resulting in pseudo-centerings. Data to approximately 15 A can thus be described by a lattice of a' = b' = 91.7 A and c' = 57.1 A, alpha = beta = 90 degrees and gamma = 120 degrees, including four molecules.

Journal Article↗
PubMed1995

Guidelines for the use of cyclosporine in rheumatoid arthritis.

Cyclosporine has now been tested in over 10 clinical trials in Rheumatoid Arthritis. These show that it provides clinically important benefit in 30-50% of patients with severe rheumatoid arthritis with an acceptable side-effect profile. It should be offered to patients who fail to (or only partially respond to methotrexate. The use of Cyclosporine in combination with other slow acting agents shows promise and should be tested at different points in the natural history of the disease.

Arthritis, Rheumatoid↗
PubMed1995

Systemic and mucosal intestinal antibody response of sheep immunized with aromatic-dependent live or killed Salmonella typhimurium.

Following the development of a suitable formulation capable of inhibiting intestinal proteolytic activity, the total anti-lipopolysaccharide (LPS) and anti-flagellin (Fla) antibody response and isotype in the sera and intestinal washings of sheep, immunized with live aromatic-dependent (aro-) Salmonella typhimurium strain CS332 by the intramuscular (live i.m.) or oral (live oral) route or acetone-killed virulent S. typhimurium by the intramuscular route (killed i.m.), were determined at various intervals post-immunization. The serum or intestinal anti-lipopolysaccharide (LPS) or anti-flagellin (Fla) antibody titres of immunized sheep, regardless of the route of immunization, were significantly greater (P < 0.01) than those of non-immune control sheep. Although significant differences between the serum anti-LPS or anti-Fla antibody titres of sheep in various immunization regimes were observed, they were not consistent for different periods post-immunization. The predominant isotype contributing to serum anti-LPS antibody activity was IgM whereas the serum antiflagellar antibody activity was confined to IgM, IgG1 and IgG2. In either case, the contribution of the IgA antibody isotype was minimal. Antibody activity in the intestinal washings of immunized sheep, regardless of the route of immunization was significantly greater (P < 0.01) than that in non-immune control sheep. However, the titres in sheep immunized with the live S. typhimurium vaccines were significantly greater than those immunized with the killed vaccine. The major anti-LPS or anti-flagellin antibody isotype in the intestinal washings of sheep in the live i.m. or live oral groups was IgM at day 7 post-immunization followed by IgG1 and IgG2 at days 14 and 21 post-immunization, with only a minimal contribution by the IgA antibody isotype. On the other hand, the major antibody isotype in the intestinal washings of sheep immunized with the killed S. typhimurium was IgG1.

Administration, Oral↗
PubMed1995

A prospective randomized trial to evaluate different oral dose regimens of medroxyprogesterone acetate in women with advanced breast cancer.

A prospective randomized study was conducted to try to answer two questions: is a loading dose of medroxyprogesterone acetate (1000 mg p.o. q.d.s. for 48 h) superior to conventional dosing; and does an oral maintenance dose of 1000 mg daily offer any advantage over 500 mg daily in women with advanced breast cancer who have failed to respond to, or have relapsed after, tamoxifen? Of 211 patients randomized, 207 were evaluable. There was no improvement in response rates, time to response, response duration or overall survival as a result of the loading dose. When comparing high and low maintenance doses, there was a significant difference in response rates (48% versus 32%; chi 2 = 10.09, df = 2, P = 0.006) and survival (66% versus 41% alive at 12 months; chi 2 = 9.06, df = 1, P = 0.003) in favour of the higher dose regimen, although there was no significant difference in the duration of response. There was no additional toxicity attributable to the loading dose regimen, but side effects were more frequent with the high dose maintenance schedule (141 of 201 adverse effects occurring in these two groups) although the incidence of severe toxicity was similar with both high dose and low dose treatments.

Administration, Oral↗
PubMed1995

A cost-outcome description of the septic work-up for bacterial infection in neonates in a tertiary care hospital.

Analysis of the septic work-up of 194 neonates at Women's College Hospital, Toronto, showed that the only antepartum condition predicting neonatal sepsis was the mother being on antibiotics. The only postnatal condition predicting sepsis was a maternal postpartum white blood cell count over 11,000. The average cost for tests for a septic work-up in these 194 mother-neonate pairs was $71.48 (Canadian dollars), and the average cost of tests to find a septic case was $1,066.77.

Adult↗
PubMed1995

Early genital stimulation of rats lowers limbic seizure latencies for females but increases latencies for males.

The genitals of male and female rats were tactilely stimulated (glass rod) for 10 successive days beginning on postnatal Days 5, 15, 35; handled but nonstimulated litter mates served as the reference groups. Limbic seizures were induced by a single systemic injection of lithium and pilocarpine when the rats were adults. The genitally stimulated female rats displayed a lower seizure threshold (as inferred from shorter seizure-onset times) relative to their cage mates. The single largest effect occurred for those females which had been stimulated after the vagina had opened (postnatal 35-45 days).

Animals↗
PubMed1995

Effect of carbon dioxide on the temperature dependence of anion exchange in human red cells.

Anion exchange across the red cell membrane was studied by measuring the rate of shrinkage of cells when transferred from a medium of low pH to one of higher pH. Removal of trace amounts of CO2/bicarbonate from the media by degassing and the inhibition of carbonic anhydrase with 5 microM ethoxzolamide slowed the shrinkage rate. Arrhenius plots were linear over a temperature range of 40 degrees C, both in the presence of trace amounts of CO2/bicarbonate and in their absence, and gave an apparent activation energy for Cl- exchange of 73.9 +/- 8.9 kJ mole-1 when CO2 was present but this increased to 135.8 +/- 7.7 kJ mole-1 in its absence. From the results it is concluded that the lower value for the activation energy is determined by the rate of formation of bicarbonate ions while the high value represents hydroxyl:anion exchange and is a truer measure of the activation energy of the exchange process.

Anions↗
PubMed1995

Interactive conference voting. The OMERACT II Committee. Outcome Measures in Rheumatoid Arthritis Clinical Trial Conference.

We describe and analyze opinion polling results from interactive voting procedures undertaken before and after presentations during the Outcome Measures in Rheumatoid Arthritis Clinical Trials Conference (OMERACT II) in Ottawa, Canada, June 30-July 2, 1994. The scoring procedure was a matched voting design; when a participant used the same keypad at the beginning and end of voting, change within a participant could be estimated. Participants, experienced in the rheumatic diseases included clinicians, researchers, methodologists, regulators, and representatives of the pharmaceutical industry. Patients under consideration were those with any rheumatic diseases. Questions were constructed to evaluate the change in voting behavior expected from the content of the presentation. Statistically significant and substantively important changes were evident in most questions.

Arthritis, Rheumatoid↗
PubMed1994

Clozapine treatment of polydipsia.

A patient with refractory chronic schizophrenia having severe polydipsia and hyponatremia was treated with clozapine. There followed a dramatic improvement in the polydipsia and correction of the hyponatremia. This improvement has been sustained throughout a 6-month follow-up.

Adult↗
PubMed1994

The acceleration of pH volume changes in human red cells by bicarbonate and the role of carbonic anhydrase.

The red cell shrinkage rate due to bicarbonate in media of high pH (ca 9.4) has been compared with the hydroxyl shrinkage rate on a per mM basis. The shrinkage rate due to bicarbonate was only half that due to OH-/Cl- exchanges. It was therefore deduced that the Jacobs-Stewart cycle was limited by the carbonic anhydrase step and not by the rate of transport on the anion exchanger protein. To explain this and other anomalies the hypothesis is made that carbonic anhydrase has evolved as a pH-dependent catalyst with specific physiological functions in pH regulation and in other cellular mechanisms. The kinetic theory and some physiological implications of the hypothesis are discussed.

Anion Exchange Protein 1, Erythrocyte↗
PubMed1994

Monocyte procoagulant activity: development of a microtitre plate chromogenic assay.

A monocyte procoagulant assay was developed based on the original method of Surprenant and Zuckerman, which quantitates a factor Xa-specific chromogenic substrate (at 405 nm) activated via the extrinsic coagulation pathway. Normal tissue factor initiation of the pathway is replaced by tissue factor generated from monocytes, stimulated by various agents including bacterial lipopolysaccharide, and antibody/antigen complexes. Hydrolysis of the chromogenic substrate is therefore directly proportional to the degree of monocyte activation. Using a chromogenic substrate as an end-point the assay was performed in a standard microtitre plate.

Blood Coagulation Tests↗