Biomedical subjects

R S Phillips

Publications and source records attributed to R S Phillips.

At least 73 records · Page 4Linked to original sources

PubMed1999

Patient age and decisions to withhold life-sustaining treatments from seriously ill, hospitalized adults. SUPPORT Investigators. Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatment.

BACKGROUND: Patient age may influence decisions to withhold life-sustaining treatments, independent of patients' preferences for or ability to benefit from such treatments. Controversy exists about the appropriateness of using age as a criterion for making treatment decisions. OBJECTIVE: To determine the effect of age on decisions to withhold life-sustaining therapies. DESIGN: Prospective cohort study. SETTING: Five medical centers participating in the Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments (SUPPORT). PATIENTS: 9105 hospitalized adults who had one of nine illnesses associated with an average 6-month mortality rate of 50%. MEASUREMENTS: Outcomes were the presence and timing of decisions to withhold ventilator support, surgery, and dialysis. Adjustment was made for sociodemographic characteristics, prognoses, baseline function, patients' preferences for life-extending care, and physicians' understanding of patients' preferences for life-extending care. RESULTS: The median patient age was 63 years; 44% of patients were women, and 53% survived to 180 days. In adjusted analyses, older age was associated with higher rates of withholding each of the three life-sustaining treatments studied. For ventilator support, the rate of decisions to withhold therapy increased 15% with each decade of age (hazard ratio, 1.15 [95% CI, 1.12 to 1.19]); for surgery, the increase per decade was 19% (hazard ratio, 1.19 [CI, 1.12 to 1.27]); and for dialysis, the increase per decade was 12% (hazard ratio, 1.12 [CI, 1.06 to 1.19]). Physicians underestimated older patients' preferences for life-extending care; adjustment for this underestimation resulted in an attenuation of the association between age and decisions to withhold treatments. CONCLUSION: Even after adjustment for differences in patients' prognoses and preferences, older age was associated with higher rates of decisions to withhold ventilator support, surgery, and dialysis.

Activities of Daily Living↗

PubMed1999

Health status versus quality of life in older patients: does the distinction matter?

PURPOSE: Although health-related quality of life in older people is generally assessed by measuring specific domains of health status, such as activities of daily living or pain, the association between health-status measures and patients' perceptions of their quality of life is not clear. Indeed, it is controversial whether these health-status measures should be considered measures of quality of life at all. Our objective was to determine the association between health-status measures and older patients' perceptions of their global quality of life. SUBJECTS AND METHODS: We performed a cross-sectional study of 493 cognitively intact patients 80 years of age and older, interviewed 2 months after a hospitalization. We measured patients' self-assessed global quality of life and four domains of health status: physical capacity, limitations in performing activities of daily living, psychological distress, and pain. RESULTS: Each of the four scales was significantly correlated with patients' global perceptions of their quality of life (P <0.001). The ability of the health-status scales to discriminate between patients with differing global quality of life was generally good, especially for the physical capacity (c statistic = 0.72) and psychological distress scales (c statistic = 0.70). However, for a substantial minority of patients, scores on the health-status scales did not accurately reflect their global quality of life. For example, global quality of life was described as fair or poor by 15% of patients with the highest (best tertile) physical capacity scores, 25% of patients who were independent in all activities of daily living, 21% of patients with the least psychological distress (best tertile), and by 30% with no pain symptoms. Similarly, global quality of life was described as good or better by 43% of patients with the worst physical capacity (worst tertile), 49% of patients who were dependent in at least two activities of daily living, 47% of patients with the most psychological distress (worst tertile), and 51% of patients with severe pain. CONCLUSION: On average, health status is a reasonable indicator of global quality of life for groups of older patients with recent illness. However, disagreement between patients' reported health status and their perceptions of their global quality of life was common. Therefore, assumptions about the overall quality of life of individual patients should not be based on measures of their health status alone.

Activities of Daily Living↗

PubMed1999

Stereospecificity of Pseudomonas fluorescens kynureninase for diastereomers of beta-methylkynurenine.

The diastereomers of beta-methyl-L-kynurenine were prepared by preparative ozonolysis of the respective diastereomers of beta-methyl-L-tryptophan. A practical method for preparative enzymatic resolution of the diastereomers of beta-methyltryptophan was developed using carboxypeptidase A digestion of the N-trifluoroacetyl derivatives. The stereochemical assignment was confirmed by X-ray crystal structure determination of (2S, 3R)-threo-beta-methyl-L-tryptophan. (2S,3S)-erythro-beta-Methyl-L-kynurenine is a slow substrate for kynureninase from Pseudomonas fluorescens (k(cat)/K(m) = 0.1% that of L-kynurenine), producing anthranilic acid, while (2S,3R)-threo-L-kynurenine is about 390-fold less reactive than erythro. Rapid-scanning stopped-flow measurements show that beta-methyl substitution affects the rate of alpha-deprotonation of the L-kynurenine-pyridoxal-5'-phosphate Schiffs base. This is consistent with the stereoelectronic requirements of the reaction. These results are the first demonstration that beta-substituted kynurenines can be substrates for kynureninase, and may be useful in the design of mechanism-based inhibitors.

Hydrolases↗

PubMed1999

Does the Complications Screening Program flag cases with process of care problems? Using explicit criteria to judge processes.

BACKGROUND: The Complications Screening Program (CSP) aims to identify 28 potentially preventable complications of hospital care using computerized discharge abstracts, including demographic information, diagnosis and procedure codes. OBJECTIVE: To validate the CSP as a quality indicator by using explicit process of care criteria to determine whether hospital discharges flagged by the CSP experienced more process problems than unflagged discharges. METHODS: The (CSP was applied to computerized hospital discharge abstracts from Mledicare beneficiaries > 65 years old admitted in 1994 to hospitals in California and Connecticut for major surgery or medical treatment. ()f 28 CSP complications, 17 occurred sufficient frequently to study. Discharges flagged (cases) and unflagged (controls) by the (CSP were sampled and photocopied medical records were obtained. Physicians specified detailed, objective, explicit criteria, itemizing 'key steps' in processes of care that could potentially have prevented or caused complications. Trained nurses abstracted medical records using these explicit criteria. Process problem rates between cases and controls were compared. RESULTS: The final sample included 740 surgical and 416 medical discharges. Rates of process problems were high, ranging from 24.4 to 82.5% across CSP screens for surgical cases. Problems were lower for medical cases, ranging from 2.0 to 69.1% across CSP screens. Problem rates were 45.7% for surgical and 5.0% for medical controls. Rates of problems did not differ significantly across flagged and unflagged discharges. CONCLUSIONS: The CSP did not flag discharges with significantly higher rates of explicit process problems than unflagged discharges. Various initiatives throughout the USA use techniques similar to the CSP to identify complications of care. Based on these CSP findings, such approaches should be evaluated cautiously.

Aged↗

PubMed1999

Screening inpatient quality using post-discharge events.

BACKGROUND: Decreasing hospital lengths of stay (LOS) hamper efforts to detect and to definitively treat complications of care. Patients leave before some complications are identified. OBJECTIVES: To develop a computerized method to screen for hospital complications using readily available administrative data from outpatient and nonacute care within 90 days of discharge. DESIGN: We developed the Complications Screening Program for Outpatient data (CSP-O) by using diagnosis and procedure codes from Medicare Part A and B claims to define 50 complication screens. Seventeen apply to specific procedural cases, and 33 apply to all adult, acute, medical, or surgical hospitalizations. The CSP-O algorithm examined outpatient, physician office, home health agency, and hospice claims within 90 days following discharge. SUBJECTS: Seven hundred thirty nine thousand, two hundred and forty eight discharges of Medicare beneficiaries (age range, > or = 65 years) were admitted to 515 hospitals nationwide in 1994. RESULTS: Complete 90-day, post-discharge windows were present for 62.8% of all and 68.5% of procedural cases. The 33 general screens flagged 13.6% of all cases; only 1.8% of procedural cases were flagged by the 17 procedural screens. When we allowed the CSP-O algorithm to scan information from acute hospital readmissions, flag rates rose to 32.8% for general and 8.7% for procedural complications. Controlling for patient and hospital characteristics, flag rates were considerably higher among the very old and at small and for-profit institutions. CONCLUSIONS: Whereas several CSP-O findings have construct validity, limitations of claims raise concerns. Regardless of the CSPO's ultimate utility, examining post-discharge experiences to identify inpatient complications remains important as LOSs fall.

Aftercare↗

PubMed1999

Evidence that tristetraprolin binds to AU-rich elements and promotes the deadenylation and destabilization of tumor necrosis factor alpha mRNA.

Mice deficient in tristetraprolin (TTP), the prototype of a family of CCCH zinc finger proteins, develop an inflammatory syndrome mediated by excess tumor necrosis factor alpha (TNF-alpha). Macrophages derived from these mice oversecrete TNF-alpha, by a mechanism that involves stabilization of TNF-alpha mRNA, and TTP can bind directly to the AU-rich element (ARE) in TNF-alpha mRNA (E. Carballo, W. S. Lai, and P. J. Blackshear, Science 281:1001-1005, 1998). We show here that TTP binding to the TNF-alpha ARE is dependent upon the integrity of both zinc fingers, since mutation of a single cysteine residue in either zinc finger to arginine severely attenuated the binding of TTP to the TNF-alpha ARE. In intact cells, TTP at low expression levels promoted a decrease in size of the TNF-alpha mRNA as well as a decrease in its amount; at higher expression levels, the shift to a smaller TNF-alpha mRNA size persisted, while the accumulation of this smaller species increased. RNase H experiments indicated that the shift to a smaller size was due to TTP-promoted deadenylation of TNF-alpha mRNA. This CCCH protein is likely to be important in the deadenylation and degradation of TNF-alpha mRNA and perhaps other ARE-containing mRNAs, both in normal physiology and in certain pathological conditions.

Base Sequence↗

PubMed1998

Risk for valvular heart disease among users of fenfluramine and dexfenfluramine who underwent echocardiography before use of medication.

BACKGROUND: Because uncontrolled echocardiographic surveys suggested that up to 30% to 38% of users of fenfluramine and dexfenfluramine had valvular disease, these drugs were withdrawn from the market. OBJECTIVE: To determine the risk for new or worsening valvular abnormalities among users of fenfluramine or dexfenfluramine who underwent echocardiography before they began to take these medications. DESIGN: Cohort study. SETTING: Academic primary care practices. PATIENTS: 46 patients who used fenfluramine or dexfenfluramine for 14 days or more and had echocardiograms obtained before therapy. MEASUREMENTS: Follow-up echocardiography. The primary outcome was new or worsening valvulopathy, defined as progression of either aortic or mitral regurgitation by at least one degree of severity and disease that met U.S. Food and Drug Administration criteria (at least mild aortic regurgitation or moderate mitral regurgitation). RESULTS: Two patients (4.3% [95% CI, 0.6% to 14.8%]) receiving fenfluramine-phentermine developed valvular heart disease. One had baseline bicuspid aortic valve and mild aortic regurgitation that progressed to moderate regurgitation. The second patient developed new moderate aortic insufficiency. CONCLUSION: Users of diet medications are at risk for valvular heart disease. However, the incidence may be lower than that reported previously.

Adult↗

PubMed1998

Patterns of use, expenditures, and perceived efficacy of complementary and alternative therapies in HIV-infected patients.

BACKGROUND: Complementary and alternative medicine (CAM) use is common in the general population, accounting for substantial expenditures. Among patients with human immunodeficiency virus (HIV) infection, few data are available on the prevalence, costs, and patterns of alternative therapy use. METHODS: We carried out detailed telephone surveys and medical chart reviews for 289 active patients with HIV in a general medicine practice at a university-based teaching hospital in Boston, Mass. Data were collected on prevalence and patterns of CAM use, out-of-pocket expenditures, associated outcomes, and correlates of CAM use. RESULTS: Of 180 patients who agreed to be interviewed, 122 (67.8%) used herbs, vitamins, or dietary supplements, 81 (45.0%) visited a CAM provider, and 43 (23.9%) reported using marijuana for medicinal purposes in the previous year. Patients who saw CAM providers made a median of 12 visits per year to these providers compared with 7 visits per year to their primary care physician and nurse practitioner. Mean yearly out-of-pocket expenditures for CAM users totaled $938 for all therapies. For the main reason CAM was used, respondents found therapies "extremely" or "quite a bit" helpful in 81 (81.0%) of 100 reports of supplement use, in 76 (65.5%) of 116 reports of CAM provider use, and in 27 (87%) of 31 reports of marijuana use. In multivariable models, college education (odds ratio [OR]=3.7, 95% confidence interval [CI]=1.9-7.1) and fatigue (OR=2.7, 95% CI=1.4-5.2) were associated with CAM provider use; memory loss (OR=2.3, 95% CI=1.1-4.8) and fatigue (OR=0.4, 95% CI=0.2-0.9) were associated with supplement use; and weight loss (OR=2.6, 95% CI=1.2-5.6) was associated with marijuana use. CONCLUSIONS: Patients with HIV infection use CAM, including marijuana, at a high rate; make frequent visits to CAM providers; incur substantial expenditures; and report considerable improvement with these treatments. Clinical trials of frequently used CAMs are needed to inform physicians and patients about therapies that may have measurable benefit or measurable risk.

Boston↗

PubMed1998

Pyridoxal phosphate binding to wild type, W330F, and C298S mutants of Escherichia coli apotryptophanase: unraveling the cold inactivation.

The mechanism of pyridoxal phosphate (PLP) binding to apotryptophanase was investigated using stopped-flow kinetics with wild type (WT), W330F and C298S mutants. Based on the dependence of the rate constants on PLP concentrations for the fast and slow phases detected, two mechanistic schemes were proposed. For the WT and C298S mutant, the slow process is due to an isomerization of the aldimine complex after its formation, and not to the binding to an alternative conformation of the apoenzyme, which is the case proposed for the W330F mutant. It is suggested that during the cold inactivation process a conformational change precedes the aldimine bond cleavage. For the W330F apotryptophanase, another conformational change occurs subsequent to the aldimine bond cleavage.

Apoenzymes↗

PubMed1998

Resuscitation preferences among patients with severe congestive heart failure: results from the SUPPORT project. Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments.

BACKGROUND: We sought to describe the resuscitation preferences of patients hospitalized with an exacerbation of severe congestive heart failure, perceptions of those preferences by their physicians, and the stability of the preferences. METHODS AND RESULTS: Of 936 patients in this study, 215 (23%) explicitly stated that they did not want to be resuscitated. Significant correlates of not wanting to be resuscitated included older age, perception of a worse prognosis, poorer functional status, and higher income. The physician's perception of the patient's preference disagreed with the patient's actual preference in 24% of the cases overall. Only 25% of the patients reported discussing resuscitation preferences with their physician, but discussion of preferences was not significantly associated with higher agreement between the patient and physician. Of the 600 patients who responded to the resuscitation question again 2 months later, 19% had changed their preferences, including 14% of those who initially wanted resuscitation (69 of 480) and 40% of those who initially did not (48 of 120). The physician's perception of the patient's hospital resuscitation preference was correct for 84% of patients who had a stable preference and 68% of those who did not. CONCLUSIONS: Almost one quarter of patients hospitalized with severe heart failure expressed a preference not to be resuscitated. The physician's perception of the patient's preference was not accurate in about one quarter of the cases. but communication was not associated with greater agreement between the patient and the physician. A substantial proportion of patients who did not want to be resuscitated changed their minds within 2 months of discharge.

Adult↗

PubMed1998

Cleavage of Escherichia coli tryptophan indole-lyase by trypsin at Lys406 affects the transmission of conformational changes associated with monovalent cation activation.

Escherichia coli tryptophan indole-lyase (Trpase) is a pyridoxal 5'-phosphate(pyridoxal-P)-dependent enzyme which catalyzes the hydrolytic cleavage of L-tryptophan to indole and ammonium pyruvate. This enzyme is strongly activated by K+ and similar monovalent cations, and the spectrum of the pyridoxal-P cofactor is also affected by pH and cations. Treatment of Trpase with trypsin results in a 20-100-fold decrease in elimination activity, depending on the substrate, concomitant with a change in the relative amounts of the 337 nm and 420 nm forms of the bound pyridoxal-P, and a shift in the lambda(max) from 420 nm to 423 nm. In addition, the pH sensitivity of the pyridoxal-P cofactor is eliminated after trypsin treatment. Nicked Trpase exhibits only fourfold activation by K+, compared with about 50-fold for native enzyme, but the K(A) for K+ is unaffected. Both the native and trypsin-nicked Trpase react with amino acids to form equilibrating mixtures of external aldimine and quinonoid intermediates in rapid-scanning stopped-flow experiments. However, the rate constant for quinonoid intermediate formation from L-tryptophan is reduced by at least 400-fold by treatment with trypsin. In contrast, the rate constant for formation of quinonoid intermediates of L-alanine and S-ethyl-L-cysteine is affected only twofold or less by trypsin treatment. The site of trypsin cleavage was identified by electrospray-ionization mass spectrometry as Lys406, which is predicted to lie on a flexible surface loop. Some active-site residues, particularly Arg419, which is predicted by sequence similarity to be the substrate alpha-carboxylate-binding site, and His463, are located in the sequence between Lys406 and the C-terminus. Hence, cleavage of the peptide bond of E. coli Trpase at Lys406 probably affects the change from active to inactive conformations that normally takes place in the presence of activating monovalent cations.

Binding Sites↗

PubMed1998

High-efficiency incorporation in vivo of tyrosine analogues with altered hydroxyl acidity in place of the catalytic tyrosine-14 of Delta 5-3-ketosteroid isomerase of Comamonas (Pseudomonas) testosteroni: effects of the modifications on isomerase kinetics.

Versions of the Y55F/Y88F modified form of Delta 5-3-ketosteroid isomerase in which the active-site tyrosine-14 is replaced by 2-fluorotyrosine, 3-fluorotyrosine, and 2,3-difluorotyrosine, amino acids having progressively greater acidity of their phenolic hydroxyls, have been expressed in an Escherichia coli host and purified to high homogeneity. The steady-state kinetic properties of Y55F/Y88F KSI and its fluorotyrosine modified forms have been determined. The mechanistic implications of the results are presented and discussed.

Amino Acid Substitution↗

PubMed1998

The catalytic mechanism of kynureninase from Pseudomonas fluorescens: evidence for transient quinonoid and ketimine intermediates from rapid-scanning stopped-flow spectrophotometry.

The reaction of Pseudomonas fluorescens kynureninase with L-kynurenine and L-alanine has been examined using rapid-scanning stopped-flow spectrophotometry. Mixing kynureninase with 0.5 mM L-kynurenine results in formation of a quinonoid intermediate, with lambdamax = 494 nm, within the dead time (ca. 2 ms) of the stopped-flow mixer. This intermediate then decays rapidly, with k = 743 s-1, and this rate constant is reduced to 347 s-1 in [2H]H2O, suggesting that protonation of this intermediate by a solvent exchangeable proton takes place. Rapid quench experiments demonstrate that covalent changes in the cofactor occur, as pyridoxal 5'-phosphate is converted to pyridoxamine 5'-phosphate in about 30 mol % within 5 ms after mixing. Under single turnover conditions in the reaction of kynureninase with l-kynurenine, a transient shoulder absorbing at 335 nm is observed that may be a pyruvate ketimine intermediate. In contrast, the reaction of kynureninase with 0.5 mM l-kynurenine in the presence of 10 mM benzaldehyde results in the formation of a quinonoid intermediate (k = 67.4 s-1) with a very strong absorbance peak at 496 nm. The reaction of L-alanine with kynureninase exhibits the rapid formation (386 s-1 at 0.1 M) of an external aldimine intermediate absorbing at 420 nm, followed by slower formation of a quinonoid intermediate with a peak at 500 nm (k = 2.5 s-1). The 420 nm peak then decays slowly with concomitant formation of a peak at 320 nm corresponding to a pyruvate ketimine. These data demonstrate that quinonoid and ketimine intermediates are catalytically competent in the reaction mechanism of kynureninase, and provide additional support for our proposed mechanism for kynureninase from steady-state kinetic studies [Koushik, S. V., Sundararaju, B., and Phillips, R. S. Biochemistry 1998, 37, 1376-1382].

Bacterial Proteins↗

PubMed1998

Relationship between cancer patients' predictions of prognosis and their treatment preferences.

CONTEXT: Previous studies have documented that cancer patients tend to overestimate the probability of long-term survival. If patient preferences about the trade-offs between the risks and benefits associated with alternative treatment strategies are based on inaccurate perceptions of prognosis, then treatment choices may not reflect each patient's true values. OBJECTIVE: To test the hypothesis that among terminally ill cancer patients an accurate understanding of prognosis is associated with a preference for therapy that focuses on comfort over attempts at life extension. DESIGN: Prospective cohort study. SETTING: Five teaching hospitals in the United States. PATIENTS: A total of 917 adults hospitalized with stage III or IV non-small cell lung cancer or colon cancer metastatic to liver in phases 1 and 2 of the Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments (SUPPORT). MAIN OUTCOME MEASURES: Proportion of patients favoring life-extending therapy over therapy focusing on relief of pain and discomfort, patient and physician estimates of the probability of 6-month survival, and actual 6-month survival. RESULTS: Patients who thought they were going to live for at least 6 months were more likely (odds ratio [OR], 2.6; 95% confidence interval [CI], 1.8-3.7) to favor life-extending therapy over comfort care compared with patients who thought there was at least a 10% chance that they would not live 6 months. This OR was highest (8.5; 95% CI, 3.0-24.0) among patients who estimated their 6-month survival probability at greater than 90% but whose physicians estimated it at 10% or less. Patients overestimated their chances of surviving 6 months, while physicians estimated prognosis quite accurately. Patients who preferred life-extending therapy were more likely to undergo aggressive treatment, but controlling for known prognostic factors, their 6-month survival was no better. CONCLUSIONS: Patients with metastatic colon and lung cancer overestimate their survival probabilities and these estimates may influence their preferences about medical therapies.

Adult↗

PubMed1998

Cold inactivation and dissociation into dimers of Escherichia coli tryptophanase and its W330F mutant form.

The kinetics and mechanism of reversible cold inactivation of the tetrameric enzyme tryptophanase have been studied. Cold inactivation is shown to occur slowly in the presence of K+ ions and much faster in their absence. The W330F mutant tryptophanase undergoes rapid cold inactivation even in the presence of K+ ions. In all cases the inactivation is accompanied by a decrease of the coenzyme 420-nm CD and absorption peaks and a shift of the latter peak to shorter wavelengths. The spectral changes and the NaBH4 test indicate that cooling of tryptophanase leads to breaking of the internal aldimine bond and release of the coenzyme. HPLC analysis showed that the ensuing apoenzyme dissociates into dimers. The dissociation depends on the nature and concentration of anions in the buffer solution. It readily occurs at low protein concentrations in the presence of salting-in anions Cl-, NO3- and I-, whereas salting-out anions, especially HPO4(2-), hinder the dissociation. K+ ions do not influence the dissociation of the apoenzyme, but partially protect holotryptophanase from cold inactivation. Thus, the two processes, cold inactivation of tryptophanase and dissociation of its apoform into dimers exhibit different dependencies on K+ ions and anions.

Bacterial Proteins↗

PubMed1998

Health values of hospitalized patients 80 years or older. HELP Investigators. Hospitalized Elderly Longitudinal Project.

CONTEXT: Health values (utilities or preferences for health states) are often incorporated into clinical decisions and health care policy when issues of quality vs length of life arise, but little is known about health values of the very old. OBJECTIVE: To assess health values of older hospitalized patients, compare their values with those of their surrogate decision makers, investigate possible determinants of health values, and determine whether health values change over time. DESIGN: A prospective, longitudinal, multicenter cohort study. SETTING: Four academic medical centers. PARTICIPANTS: Four hundred fourteen hospitalized patients aged 80 years or older and their surrogate decision makers who were interviewed and understood the task. MAIN OUTCOME MEASURES: Time-trade-off utilities, reflecting preferences for current health relative to a shorter but healthy life. RESULTS: On average, patients equated living 1 year in their current state of health with living 9.7 months in excellent health (mean [SD] utility, 0.81 [0.28]). Although only 126 patients (30.7%) rated their current quality of life as excellent or very good, 284 (68.6%) were willing to give up at most 1 month of 12 in exchange for excellent health (utility > or =0.92). At the other extreme, 25 (6.0%) were willing to live 2 weeks or less in excellent health rather than 1 year in their current state of health (utility < or =0.04). Patients were willing to trade significantly less time for a healthy life than their surrogates assumed they would (mean difference, 0.05; P=.007); 61 surrogates (20.3%) underestimated the patient's time-trade-off score by 0.25 (3 months of 12) or more. Patients willing to trade less time for better health were more likely to want resuscitation and other measures to extend life. Time-trade-off score correlated only modestly with quality-of-life rating (r=0.28) and inversely with depression score (r=-0.27), but there were few other clinical or demographic predictors of health values. When patients who survived were asked the time-trade-off question again at 1 year, they were willing to trade less time for better health than at baseline (mean difference, 0.04; P=.04). CONCLUSION: Very old hospitalized patients who could be interviewed were able, in most cases, to have their health values assessed using the time-trade-off technique. Most patients were unwilling to trade much time for excellent health, but preferences varied greatly. Because proxies and multivariable analyses cannot gauge health values of elderly hospitalized patients accurately, health values of the very old should be elicited directly from the patient.

Advance Directives↗

PubMed1998

The catalytic mechanism of kynureninase from Pseudomonas fluorescens: insights from the effects of pH and isotopic substitution on steady-state and pre-steady-state kinetics.

The effects of pH and isotopic substitution of substrate and solvent on the reaction of kynureninase from Pseudomonas fluorescens have been determined. The pH dependence of kcat/Km for L-kynurenine is bell-shaped, with apparent pKa's of 6.25 +/- 0.05 on the acidic limb and 8.9 +/- 0.1 on the basic limb, and with a pH-dependent value of kcat/Km of 2 x 10(5) M-1 s-1. The pH dependence of kcat/Km for 3-hydroxykynurenine is also bell-shaped, with apparent pKa's of 6.49 +/- 0.07 and 8.55 +/- 0.09, and with a pH-dependent value of 2.5 x 10(3) M-1 s-1. The kcat for L-kynurenine decreases at acidic pH values, with an apparent pKa of 6.43 +/- 0.06 and a pH-dependent value of 7 s-1. The solvent kinetic isotope effect on kcat for the reaction of kynurenine in [2H]H2O is 6.56 +/- 0.59, whereas there is no normal kinetic isotope effect on kcat/Km, at pH 8.1. The proton inventory of kcat fits very well to the Gross-Butler equation, with x = 0.825 +/- 0.08, suggesting that only a single proton is transferred in the rate-determining step. In contrast, there is no significant kinetic isotope effect on either kcat or kcat/Km with alpha-[2H]-L-kynurenine as the substrate. There is a "burst" of anthranilate (0.7 mol/mol of enzyme) formed in the pre steady state of the reaction of kynureninase, with a rate constant of 54 s-1 which is not affected by [2H]H2O. The partition ratio of alanine to pyruvate formation is 2.3 x 10(4) in H2O and 6.9 x 10(3) in [2H]H2O. Taken together, these data indicate that the rate-limiting step in the reaction of kynureninase occurs subsequent to the first irreversible step, which is anthranilate release, is general base catalyzed, and involves transfer of only a single proton. On the basis of these observations, we propose that the rate-limiting step in the reaction of kynureninase is C-4' deprotonation of the pyruvate pyridoxamine 5'-phosphate ketimine intermediate.

Catalysis↗

PubMed1998

Outcomes, preferences for resuscitation, and physician-patient communication among patients with metastatic colorectal cancer. SUPPORT Investigators. Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments.

PURPOSE: To describe characteristics, outcomes, and decision making in patients with colorectal cancer metastatic to the liver, and to examine the relationship of doctor-patient communication with patient understanding of prognosis and physician understanding of patients' treatment preferences. PATIENTS AND METHODS: The Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments (SUPPORT) was a prospective cohort study conducted at five teaching hospitals in the United States between 1989 and 1994. Participants in this study were hospitalized patients 18 years of age or older with known liver metastases who had been diagnosed with colorectal cancer at least 1 month earlier. Data were collected by patient interview and chart review at study entry; patients were interviewed again at 2 and 6 months. Data collected by physician interview included estimates of survival and impressions of patients' preferences for cardiopulmonary resuscitation (CPR). Patients and physicians were also asked about discussions about prognosis and resuscitation preferences. RESULTS: We studied 520 patients with metastatic colorectal cancer (median age 64, 56% male, 80% white, 2-month survival 78%, 6-month survival 56%). Quality of life (62% "good" to "excellent") and functional status (median number of disabilities = 0) were high at study entry and remained so among interviewed survivors at 2 and 6 months. Of 339 patients with available information, 212 (63%) of 339 wanted CPR in the event of a cardiopulmonary arrest. Factors independently associated with preference for resuscitation included younger age, better quality of life, absence of lung metastases, and greater patient estimate of 2-month prognosis. Of the patients who preferred not to receive CPR, less than half had a do-not-resuscitate note or order written. Patients' self-assessed prognoses were less accurate than those of their physicians. Physicians incorrectly identified patient CPR preferences in 30% of cases. Neither patient prognostication nor physician understanding of preferences were significantly better when discussions were reported between doctors and patients. CONCLUSIONS: A majority of patients with colorectal cancer have preferences regarding end of life care. The substantial misunderstanding between patients and their physicians about prognosis and treatment preferences appears not to be improved by direct communication. Future research focused on enhancing the effectiveness of communication between patients and physicians about end of life issues is needed.

Cardiopulmonary Resuscitation↗