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Biomedical subjects

R J Cook

Publications and source records attributed to R J Cook.

At least 73 records · Page 4Linked to original sources
PubMed1998

von Willebrand disease and its management in oral and maxillofacial surgery.

von Willebrand disease (vWD) is the most common of the hereditary disorders of coagulation. We describe the pathophysiology, diagnosis and the new simplified classification of the disorder and discuss the management of patients about to undergo dental procedures and maxillofacial surgery. Close collaboration between oral and maxillofacial surgeons and haematologists in the management of patients with vWD is essential.

Blood Loss, Surgical↗
PubMed1998

Radiological assessment in psoriatic arthritis.

Our objective was to compare the reliability and responsiveness of the original Steinbrocker's (OS), our modified Steinbrocker's (MS) and Larsen's (L) radiological scoring methods for detecting radiological change in psoriatic arthritis over time. Two sets of radiographs of the hands and feet at least 2 yr apart were selected from 68 patients. Films were randomly presented and scored independently by a rheumatologist (DDG) and a radiologist (DS), in a blinded fashion using all methods. The index of reliability was the intraclass coefficient (ICC) and the responsiveness was assessed using plots and regression analyses. All three radiological scoring methods have excellent interobserver and good intra-observer reliability. L and MS are equally responsive and superior to OS in detecting change in joint damage over time. Thus, the L or MS radiological scoring methods can be used to monitor disease progression in psoriatic arthritis.

Adult↗
PubMed1998

A seven-gene locus for synthesis of phenazine-1-carboxylic acid by Pseudomonas fluorescens 2-79.

Pseudomonas fluorescens 2-79 produces the broad-spectrum antibiotic phenazine-1-carboxylic acid (PCA), which is active against a variety of fungal root pathogens. In this study, seven genes designated phzABCDEFG that are sufficient for synthesis of PCA were localized within a 6.8-kb BglII-XbaI fragment from the phenazine biosynthesis locus of strain 2-79. Polypeptides corresponding to all phz genes were identified by analysis of recombinant plasmids in a T7 promoter/polymerase expression system. Products of the phzC, phzD, and phzE genes have similarities to enzymes of shikimic acid and chorismic acid metabolism and, together with PhzF, are absolutely necessary for PCA production. PhzG is similar to pyridoxamine-5'-phosphate oxidases and probably is a source of cofactor for the PCA-synthesizing enzyme(s). Products of the phzA and phzB genes are highly homologous to each other and may be involved in stabilization of a putative PCA-synthesizing multienzyme complex. Two new genes, phzX and phzY, that are homologous to phzA and phzB, respectively, were cloned and sequenced from P. aureofaciens 30-84, which produces PCA, 2-hydroxyphenazine-1-carboxylic acid, and 2-hydroxyphenazine. Based on functional analysis of the phz genes from strains 2-79 and 30-84, we postulate that different species of fluorescent pseudomonads have similar genetic systems that confer the ability to synthesize PCA.

Amino Acid Sequence↗
PubMed1998

HLA markers and progression in psoriatic arthritis.

OBJECTIVE: To investigate whether the addition of all serologically defined HLA antigens to a baseline model further influences the predisposition to disease progression in psoriatic arthritis (PsA). METHODS: Patients with PsA followed prospectively over 19 years were studied. Clinical and laboratory assessments of both active inflammation and clinical damage were performed at 6 month intervals according to a standard protocol. Progression of damage was defined as transition to higher damage states defined by the number of damaged joints. A model that provides estimates of the ratio of transition rates for an individual with the antigen versus one without, and examines the antigen effect on each of the 3 transition rates, was used. HLA antigens were examined in groups by loci under the assumption of common effects across transitions when added to the basic model. The significance levels were examined in comparison with Bonferroni type corrections. Likelihood ratio chi-squared statistics were used as a basis for the significance levels. In total, 292 patients with PsA were included in the study. RESULTS: Only HLA-B22 was added to the original model, which includes HLA-B39, providing risk for progression in early stages, HLA-B27 in the presence of HLA-DR7 providing risk for progression through all states, and DQw3 providing increased risk in the absence of DR7, while in the presence of DR7 it provides "protection." HLA-B22 provides protection from disease progression through all states. CONCLUSION: This study extends our report that HLA antigens serve as markers for disease progression in PsA.

Adolescent↗
PubMed1998

The use of sulfasalazine in psoriatic arthritis: a clinic experience.

OBJECTIVE: To assess the tolerability of sulfasalazine in a clinic setting and determine its longterm effectiveness with respect to articular disease and prevention of radiographic progression in patients with psoriatic arthritis (PsA). METHODS: Patients who were given sulfasalazine during their attendance at the University of Toronto Psoriatic Arthritis Clinic were enrolled in the study. For patients that were able to tolerate sulfasalazine for at least 3 months a matched control was identified who did not receive sulfasalazine. The primary outcome measures were the tolerability of sulfasalazine, clinical response of the actively inflamed joints at 6 and 12 months, and the change in radiographic score at 24 months. RESULTS: Thirty-six patients received sulfasalazine. Fourteen of 16 patients discontinued sulfasalazine due to one or more side effects occurring within 3 months of treatment initiation. For the remaining 20 patients, a 50% reduction in actively inflamed joint count was noted in 7/20 patients at 6 months and 11/15 patients at 12 months, compared to 7/19 patients in the control group at 6 months and 10/20 patients at 12 months. The mean change in the radiographic score at 24 months between the 2 groups was not statistically significant. CONCLUSION: Sulfasalazine was not well tolerated in patients with PsA in our clinic. For those able to tolerate sulfasalazine, there was no evidence of a treatment effect with respect to articular involvement. In addition, sulfasalazine does not appear to halt radiographic progression in PsA.

Adolescent↗
PubMed1998

Responsiveness of health status instruments to changes in articular status and perceived health in patients with psoriatic arthritis.

OBJECTIVE: To compare the responsiveness of the Health Assessment Questionnaire (HAQ), Arthritis Impact Measurement Scale 2 (AIMS2), and Medical Outcome Study Short Form Health Survey (SF-36) to changes in articular status and perceived health in outpatients with psoriatic arthritis (PsA). METHODS: The 3 health status instruments were administered in random order on 2 occasions, about 12-18 months apart, to 70 patients attending the University of Toronto psoriatic arthritis clinic. Standardized assessments of disease activity, disease severity, and general health perceptions were also performed at each clinic visit. To assess responsiveness we used: (1) linear regression analyses to relate change scores for perceived health, the number of actively inflamed, and damaged joints to change scores for selected dimensions of the HAQ, AIMS2, and SF-36; (2) logistic regression analyses to relate both improvement in disease activity and disease progression to health status change scores; and (3) standardized response means (SRM). RESULTS: There were 43 men and 27 women with a mean age of 46 years and arthritis duration of 13 years. Univariate regression analyses showed that the individual instruments were responsive to perceived changes in health, but relatively insensitive to detect changes in articular status. Multivariate regression analyses, in which the common dimensions of the instruments were jointly entered, indicated the SF-36 was equally or more responsive to changes in number of actively inflamed joints, clinical improvement in disease activity, and perceived health than the HAQ and AIMS2. The SRM analysis also suggested that the SF-36 was the most responsive. CONCLUSION: The SF-36 proved equally or more responsive to short term changes in perceived health and inflammatory disease activity; however, none of the instruments showed responsiveness to disease progression.

Adult↗
PubMed1997

Marginal analysis of recurrent events and a terminating event.

Chronic medical conditions are often manifested by the incidence of recurrent adverse clinical events. In clinical trials designed to investigate therapeutic interventions for such conditions it is natural to make treatment comparisons on the basis of event occurrence. However, when there is a more serious, possibly related, event that terminates the occurrence of the recurrent events, the problem of dependent censoring arises. Here, we consider robust modelling strategies for expressing covariate effects on the recurrent event process that address the possible dependence between the recurrent and terminal events. The various methods differ in the way the dependence is addressed, and hence in the interpretation of covariate effects. The methods are applied to a data set from a kidney transplant study and simulated data chosen for illustrative purposes.

Chronic Disease↗
PubMed1997

Expression, purification, and properties of the aldehyde dehydrogenase homologous carboxyl-terminal domain of rat 10-formyltetrahydrofolate dehydrogenase.

The liver cytosolic enzyme, 10-formyltetrahydrofolate dehydrogenase (FDH) (EC 1.5.1.6) catalyzes two reactions: the NADP+-dependent oxidation of 10-formyltetrahydrofolate to tetrahydrofolate and CO2 and the NADP+-independent hydrolysis of 10-formyltetrahydrofolate to tetrahydrofolate and formate. The COOH-terminal domain of the enzyme (residues 420-902) is about 48% identical to a family of NAD-dependent aldehyde dehydrogenases (EC 1.2.1.3), and FDH possesses aldehyde dehydrogenase activity. We expressed the COOH-terminal domain (residues 420-902) of FDH in insect cells using a baculovirus expression system. The recombinant protein was released from insect cells to the culture medium and was purified from the medium by a two-step procedure: precipitation with 35% saturated ammonium sulfate followed by chromatography on hydroxyapatite. The purified COOH-terminal domain displayed aldehyde dehydrogenase activity similar to that of native FDH but had neither dehydrogenase nor hydrolase activity toward folate substrates. Aldehyde dehydrogenase activity of the COOH-terminal domain and FDH was independent of the presence of 2-mercaptoethanol while 10-FDDF dehydrogenase activity of FDH occurred only in the presence of 2-mercaptoethanol. The COOH-terminal domain existed as a tetramer showing that the sites for oligomerization of subunits in native FDH resides in this domain. Using titration of tryptophan fluorescence, it was found that the COOH-terminal domain bound NADP+ to the same extent as FDH (Kd 0.2 and 0.3 microM, respectively) but did not bind folate. Both FDH and its COOH-terminal domain also bound NAD+ (Kd 11 and 16 microM, respectively) as measured by fluorescence titration. Both proteins were able to catalyze the aldehyde dehydrogenase reaction utilizing NADP+ or NAD+, but the Km for NAD+ was three orders higher than that for NADP+ (2 mM and 1.5-2.0 microM, respectively). The concentration of NAD+ required for the reaction was high compared with the physiological level of NAD+, suggesting that the reaction does not occur in vivo. NAD+ at physiological concentrations stimulated the aldehyde dehydrogenase reaction performed by FDH or its COOH-terminal domain using NADP+.

Aldehyde Dehydrogenase↗
PubMed1997

Domain structure of rat 10-formyltetrahydrofolate dehydrogenase. Resolution of the amino-terminal domain as 10-formyltetrahydrofolate hydrolase.

We expressed the NH2-terminal domain of the multidomain, multifunctional enzyme, 10-formyltetrahydrofolate dehydrogenase (FDH), using a baculovirus expression system in insect cells. Expression of the 203-amino acid NH2-terminal domain (residues 1-203), which is 24-30% identical to a group of glycinamide ribonucleotide transformylases (EC 2.1.2.2), resulted in the appearance of insoluble recombinant protein apparently due to incorrect folding. The longer NH2-terminal recombinant protein (residues 1-310), which shares 32% identity with Escherichia coli L-methionyl-tRNA formyltransferase (EC 2.1.2.9), was expressed as a soluble protein. During expression, this protein was released from cells to the culture medium and was purified from the culture medium by 5-formyltetrahydrofolate-Sepharose affinity chromatography followed by chromatography on a Mono-Q column. We found that the purified NH2-terminal domain bears a folate binding site, possesses 10-formyltetrahydrofolate hydrolase activity, and exists as a monomer. Titration of tryptophan fluorescence showed that native FDH bound both the substrate of the reaction, 10-formyl-5, 8-dideazafolate, and the product of the reaction, 5,8-dideazafolate, with the same affinities as its NH2-terminal domain did and that both proteins bound the substrate with a 50-fold higher affinity than the product. Neither the NH2-terminal domain nor its mixture with the previously purified COOH-terminal domain had 10-formyltetrahydrofolate dehydrogenase activity. Formation of complexes between the COOH- and NH2-terminal domains also was not observed. We conclude that the 10-formyltetrahydrofolate dehydrogenase activity of FDH is a result of the action of the aldehyde dehydrogenase catalytic center residing in the COOH-terminal domain on the substrate bound in the NH2-terminal domain and that the intermediate domain is necessary to bring the two functional domains together in the correct orientation.

Amidohydrolases↗
PubMed1997

Modeling two-state disease processes with random effects.

Many chronic medical conditions are manifested by alternating sojourns in symptom-free and symptomatic states. In many cases, in addition to their relapsing and remitting nature, these conditions lead to worsening disease patterns over time and may exhibit seasonal trends. We develop a mixed-effect two-state model for such disease processes in which covariate effects are modeled multiplicatively on transition intensities. The transition intensities, in turn, are functions of three time scales: the semi-Markov scale involving the backward recurrence time for the cyclical component, the Markov scale for the time trend component, and a seasonal time scale. Multiplicative bivariate log-normal random effects are introduced to accommodate heterogeneity in disease activity between subjects and to admit a possible negative correlation between the transition intensities. Maximum likelihood estimation is carried out using Gauss-Hermite integration and a standard Newton-Raphson procedure. Tests of homogeneity are presented based on score statistics. An application of the methodology to data from a multi-center clinical trial of chronic bronchitis is provided for illustrative purposes.

Anti-Infective Agents↗
PubMed1997

Pharmacokinetics and efficacy of long-term epidural ropivacaine infusion for postoperative analgesia.

UNLABELLED: The aim of this study was to evaluate the pharmacokinetics and efficacy of the new local anesthetic ropivacaine when used for epidural infusion for up to 72 h after major orthopedic surgery. Immediately after surgery, an epidural infusion of ropivacaine 2 mg/mL was begun at a rate of 6 mL/h in 11 patients. The infusion rate was then adjusted according to patient analgesic needs or side effects. Blood samples were taken during and after the infusion to determine total and unbound ropivacaine and alpha1-acid glycoprotein (AAG) concentrations. Patients were assessed regularly for sensory and motor block and pain using a visual analog scale (VAS) score (0-100 mm). Ten patients received 63-72 h of infusion. Total plasma concentrations of ropivacaine and binding protein (AAG) increased during the infusion such that free concentrations plateaued or began to fall over time. VAS values during mobilization were less than 40 mm in 93% of patients. The majority of patients had no measurable motor block once the surgical block had regressed. When epidural ropivacaine was titrated to achieve a stable sensory block, there was a low incidence of motor block, and free plasma ropivacaine levels were well below the toxic range. IMPLICATIONS: The pharmacokinetics of continuous epidural infusions of ropivacaine are described in patients for up to 72 h postoperatively. Clinical efficacy and side effects are also reported. An understanding of the plasma concentrations obtained and modes of elimination during prolonged epidural infusion is important for safe, routine clinical use in postoperative analgesia.

Adolescent↗
PubMed1997

Localization of language cortices by functional MR imaging compared with intracarotid amobarbital hemispheric sedation.

OBJECTIVE: We undertook this study to investigate functional MR imaging as a new clinical method for determining hemispheric language dominance. Seven patients undergoing surgical evaluation for chronic intractable epilepsy were studied. Intracarotid amobarbital injection was also performed and the findings compared with the functional MR imaging results. CONCLUSION: Functional MR imaging studies enabled localization of the frontal and temporal lobe language cortices. The results of functional MR imaging and intracarotid amobarbital testing of hemispheric language dominance agreed in all seven patients, including two right-handed patients with right-hemisphere language dominance. These preliminary results show that functional MR imaging is an accurate noninvasive method of determining language dominance that may replace the amobarbital test for some purposes if confirmed by additional research.

Adult↗
PubMed1997

Covalent binding of acetaminophen to N-10-formyltetrahydrofolate dehydrogenase in mice.

The analgesic acetaminophen is frequently used as a model chemical to study hepatotoxicity; however, the critical mechanisms by which it produces toxicity within the cell are unknown. It has been postulated that covalent binding of a toxic metabolite to crucial proteins may inhibit vital cellular functions and may be responsible for, or contribute to, the hepatotoxicity. To further understand the importance of covalent binding in the toxicity, a major cytosolic acetaminophen-protein adduct of 100 kDa has been purified by a combination of anion exchange chromatography and preparative electrophoresis. N-Terminal and internal amino acid sequences of peptides from the purified 100-kDa acetaminophen-protein adduct were found to be homologous with the deduced amino amino acid sequence from the cDNA of N-10-formyltetrahydrofolate dehydrogenase. Antiserum specific for N-10-formyltetrahydrofolate dehydrogenase and acetaminophen react in a Western blot with the purified 100-kDa acetaminophen-protein adduct. Administration of a toxic dose of acetaminophen (400 mg/kg) to mice resulted in a 25% decrease in cytosolic N-10-formyltetrahydrofolate dehydrogenase activity at 2 hr. The covalent binding of acetaminophen to proteins such as N-10-formyltetrahydrofolate dehydrogenase and the subsequent decreases in their enzyme activity may play a role in acetaminophen hepatotoxicity.

Acetaminophen↗
PubMed1997

Validating the SF-36 health survey questionnaire in patients with psoriatic arthritis.

OBJECTIVE: To assess the reliability and validity of the SF-36 in patients with psoriatic arthritis (PsA). METHODS: The SF-36 was administered to all patients attending the University of Toronto Psoriatic Arthritis Clinic between January and December 1994. Clinical and radiological assessments were performed during the clinic visits. RESULTS: We studied 113 patients, 43 women and 70 men, with a mean age of 50.5 years and a mean arthritis duration of 14.2 years. The reliability of the SF-36 was high, with the Cronbach alpha coefficient exceeding 0.90 for all the 8 health scales. The SF-36 was able to detect meaningful differences in health status between patients with PsA and individuals from the general population. As predicted, patients with PsA reported substantially lower scores on the physical functioning, role limitations due to physical problems, and pain scales. They also reported significantly lower scores on the role limitations due to emotional problems and general health perception scale. In general all scales were moderately to highly correlated with measures of function and pain (r = 0.33-0.67), while the physical functioning, pain, and vitality scales were also moderately correlated with disease activity (r = 0.34-0.42). With one exception the scales were unrelated to disease severity. CONCLUSION: The SF-36 questionnaire is reliable and valid for use in PsA, supporting its use as an adjunct outcome measure for clinical trials in PsA. Because the SF-36 can be used to compare health status across different patient populations, its application can also help to clarify the disease burden associated with PsA.

Adult↗