Biomedical subjects
R J Cook
Publications and source records attributed to R J Cook.
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.
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+.
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.
Dietary calcium and blood pressure.
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Use of 10-formyl-5,8-dideazafolate as substrate for rat 10-formyltetrahydrofolate dehydrogenase.
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State accountability for wife-beating: the Indian challenge.
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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.
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.
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.
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.
A logistic model for trend in 2 x 2 x kappa tables with applications to meta-analyses.
There recently has been an increased interest in examining the relationship between the baseline (control) risk of an adverse outcome and the magnitude of the treatment effect (Brand and Kragt, 1992, Statistics in Medicine 11, 2077-2082; Davey Smith, Song, and Sheldon, 1993, The British Medical Journal 306, 1367-1373; Senn, 1994, Statistics in Medicine 13, 293-294). To facilitate such an examination, we propose a logistic model in which the relationship between the treatment effect, as measured by the log odds ratio, and the baseline risk is specified parametrically. This procedure is founded on a product-binomial likelihood and generates maximum likelihood estimates of the baseline event rates and two parameters characterizing the trend in the treatment effect. We fit this model to data from a meta-analysis involving the treatment of women at risk of preterm labor and contrast our findings with those of an earlier analysis.
A logistic-bivariate normal model for overdispersed two-state Markov processes.
We describe a logistic-bivariate normal mixture model for a two-state Markov chain in which each individual makes transitions between states according to a subject-specific transition probability matrix. The use of the bivariate normal mixing distribution facilitates inferences regarding the correlation of the random effects and hence provides insight as to the nature of the subject-to-subject variability in the transition probabilities. Tests regarding the correlation can be based on likelihood ratio, score, or Wald statistics. Estimates of the transition intensities of a latent continuous time conditionally Markov process may also be computed. We illustrate this methodology by application to a parasitic infection field study and contrast our findings with those previously published on this data set.
Reproductive health law: where next, after Cairo and Beijing?
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Methodology for clinical trials in rheumatology: logical foundations.
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Effect of calcium supplementation on pregnancy-induced hypertension and preeclampsia: a meta-analysis of randomized controlled trials.
OBJECTIVE: To review the effect of calcium supplementation during pregnancy on blood pressure, preeclampsia, and adverse outcomes of pregnancy. DATA SOURCE: We searched MEDLINE and EMBASE for 1966 to May 1994. We contacted authors of eligible trials to ensure accuracy and completeness of data and to identify unpublished trials. STUDY SELECTION: Fourteen randomized trials involving 2459 women were eligible. DATA EXTRACTION: Reviewers working independently in pairs abstracted data and assessed validity according to six quality criteria. DATA SYNTHESIS: Each trial yielded differences in blood pressure change between calcium supplementation and control groups that we weighted by the inverse of the variance. The pooled analysis showed a reduction in systolic blood pressure of -5.40 mm Hg (95% confidence interval [CI], -7.81 to -3.00 mm Hg; P<.001) and in diastolic blood pressure of -3.44 mm Hg (95% CI, -5.20 to -1.68 mm Hg; P<.001). The odds ratio for preeclampsia in women with calcium supplementation compared with placebo was 0.38 (95% CI, 0.22 to 0.65). CONCLUSIONS: Calcium supplementation during pregnancy leads to an important reduction in systolic and diastolic blood pressure and preeclampsia. While pregnant women at risk of preeclampsia should consider taking calcium, many more patient events are needed to confirm calcium's impact on maternal and fetal morbidity.
Effects of dietary calcium supplementation on blood pressure. A meta-analysis of randomized controlled trials.
OBJECTIVE: To review the effect of supplemental calcium on blood pressure. DATA SOURCE: We searched MEDLINE and EMBASE for 1996 to May 1994. We contacted authors of eligible trials to ensure accuracy and completeness of data and to identify unpublished trials. STUDY SELECTION: We included any study in which investigators randomized people to calcium supplementation or placebo and measured blood pressure for at least 2 weeks. Fifty-six articles met the inclusion criteria, and 33 were eligible for analysis, involving a total of 2412 patients. DATA EXTRACTION: Two pairs of independent reviewers abstracted data and assessed validity according to six quality criteria. DATA SYNTHESIS: We calculated the differences in blood pressure change between the calcium supplementation group and the control group and pooled the estimates, with each trial weighted with the inverse of the variance using a random-effects model. Predictors of blood pressure reduction that we examined included method of supplementation, baseline blood pressure, and the methodological quality of the studies. The pooled analysis showed a reduction in systolic blood pressure of -1.27 mm Hg (95% confidence interval [CI], -2.25 to -0.29 mm Hg; P=.01) and in diastolic blood pressure of -0.24 mm Hg (95% CI, -0.92 to 0.44 mm Hg; P=.49). None of the possible mediators of blood pressure reduction explained differences in treatment effects. CONCLUSIONS: Calcium supplementation may lead to a small reduction in systolic but not diastolic blood pressure. The results do not exclude a larger, important effect of calcium on blood pressure in subpopulations. In particular, further studies should address the hypothesis that inadequate calcium intake is associated with increased blood pressure that can be corrected with calcium supplementation.
Criteria for the evaluation of treatment planning systems.
Radiation treatment planning systems (RTPS) are evolving on a rapid and continual basis. After the evaluation of several commercial systems, we have developed a list of features we consider desirable in a product. The goal in the compilation of these criteria was a comprehensive worksheet which categorized the characteristics of RTPS into hardware (computer and peripheral devices), 2-D planning tools, 3-D planning tools, irregular field planning tools, and brachytherapy planning. With these distinctions, one can evaluate a system conforming to the specific planning needs, e.g., conformal therapy, dynamic therapy capabilities, or optimized remote afterloading brachytherapy, of a department. The rationales of the special requirements are provided for justification.