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Biomedical subjects

R S Phillips

Publications and source records attributed to R S Phillips.

At least 19 recordsLinked to original sources
PubMed2001

Inhibition of tyrosine phenol-lyase from Citrobacter freundii by 2-azatyrosine and 3-azatyrosine.

The interactions of 2-azatyrosine and 3-azatyrosine with tyrosine phenol-lyase (TPL) from Citrobacter freundii have been examined. 2-Aza-DL-tyrosine and 3-aza-DL-tyrosine were synthesized by standard methods of amino acid synthesis, while the L-isomers were prepared from 3-hydroxypyridine and 2-hydroxypyridine, respectively, with TPL (Watkins, E. B., and Phillips, R. S. (2001) Bioorg. Med. Chem. Lett. 11, 2099-2100). 3-Azatyrosine was examined as a potential transition state analogue inhibitor of TPL. Both compounds were found to be competitive inhibitors of TPL, with K(i) values of 3.4 mM and 135 microM for 3- and 2-aza-L-tyrosine, respectively. Thus, 3-azatyrosine does not act as a transition state analogue, possibly due to the lack of tetrahedral geometry at C-1. However, 2-aza-L-tyrosine is the most potent competitive inhibitor of TPL found to date. The K(i) value of 2-aza-L-tyrosine is half that of 2-aza-DL-tyrosine, indicating that the D-enantiomer is inactive as an inhibitor. Neither azatyrosine isomer was shown to be a substrate for beta-elimination, based on coupled assays with lactate dehydrogenase and on HPLC measurements. Both isomers of azatyrosine form equilibrium mixtures of external aldimine and quinonoid intermediates when they bind to TPL. However, 2-azatyrosine reacts about 10-fold faster to form a quinonoid intermediate than does 3-azatyrosine. Since 2-azatyrosine is in the zwitterion or phenolate ion form at all the pH values examined, the strong binding of this compound suggests that L-tyrosine may be bound to the active site of TPL as the phenolate anion.

Alanine↗
PubMed2001

Enzymatic synthesis of aza-l-tyrosines.

Tyrosine phenol-lyase from Citrobacter freundii synthesizes 2-aza-L-tyrosine and 3-aza-L-tyrosine from 3-hydroxypyridine and 2-hydroxypyridine, respectively, and ammonium pyruvate.

Alanine↗
PubMed2001

Gene discovery in Plasmodium chabaudi by genome survey sequencing.

The first genome survey sequencing of the rodent malaria parasite Plasmodium chabaudi is presented here. In 766 sequences, 131 putative gene sequences have been identified by sequence similarity database searches. Further, 7 potential gene families, four of which have not previously been described, were discovered. These genes may be important in understanding the biology of malaria, as well as offering potential new drug targets. We have also identified a number of candidate minisatellite sequences that could be helpful in genetic studies. Genome survey sequencing in P. chabaudi is a productive strategy in further developing this in vivo model of malaria, in the context of the malaria genome projects.

Amino Acid Sequence↗
PubMed2001

Relationship between smoking and weight control efforts among adults in the united states.

BACKGROUND: The effect of weight control concerns on smoking among adults is unclear. We examined the association between smoking behavior and weight control efforts among US adults. METHODS: A total of 17 317 adults responded to the Year 2000 Supplement of the 1995 National Health Interview Survey (83% combined response rate). Respondents provided sociodemographic and health information, including their smoking history and whether they were trying to lose weight, maintain weight, or gain weight. RESULTS: Rates of smoking were lower among adults who were trying to lose or maintain weight than among those not trying to control weight (25% vs 31%; P<.001). After adjustment for sex, race, education, income, marital status, region of the country, and body mass index, the relationship between trying to lose weight and current smoking varied according to age. Among adults younger than 30 years, those trying to lose weight were more likely to smoke currently (odds ratio, 1.36 [95% confidence interval, 1.09-1.70]), whereas older adults trying to lose weight were as likely or less likely to smoke compared with adults not trying to control weight. After adjustment, smokers of all ages who were trying to lose weight were more likely to express a desire to quit smoking. Results were similar after stratification by sex and body mass index. CONCLUSIONS: Adults younger than 30 years are more likely to smoke if they are trying to lose weight. However, smokers of all ages who are trying to lose weight are more likely to want to stop smoking. Patients' weight control efforts should not discourage clinicians from counseling about smoking cessation. Education about smoking and healthy weight control methods should target young adults.

Adult↗
PubMed2001

Influence of financial productivity incentives on the use of preventive care.

PURPOSE: We examined whether physician factors, particularly financial productivity incentives, affect the provision of preventive care. SUBJECTS AND METHODS: We surveyed and reviewed the charts of 4,473 patients who saw 1 of 169 internists from 11 academically affiliated primary care practices in Boston. We abstracted cancer risk factors, comorbid conditions, and the dates of the last Papanicolaou (Pap) smear, mammogram, cholesterol screening, and influenza vaccination. We obtained physician information including the method of financial compensation through a mailed physician survey. We used multivariable logistic regression to examine the association between physician factors and four outcomes based on Health Plan Employer Data and Information Set (HEDIS) measures: (1) Pap smear within the prior 3 years among women 20 to 75 years old; (2) mammogram in the prior 2 years among women 52 to 69 years old; (3) cholesterol screening within the prior 5 years among patients 40 to 64 years old; and (4) influenza vaccination among patients 65 years old and older. All analyses accounted for clus-tering by provider and site and were converted into adjusted rates. RESULTS: After adjustment for practice site, clinical, and physician factors, patients cared for by physicians with financial productivity incentives were significantly less likely than those cared for by physicians without this incentive to receive Pap smears (rate difference, 12%; 95% confidence interval [CI]: 5% to 18%) and cholesterol screening (rate difference, 4%; 95% CI: 0% to 8%). Financial incentives were not significantly associated with rates of mammography (rate difference, -3%; 95% CI: -15% to 10%) or influenza vaccination (rate difference, -13%; 95% CI: -28% to 2%). CONCLUSIONS: Our findings suggest that some financial productivity incentives may discourage the performance of certain forms of preventive care, specifically Pap smears and cholesterol screening. More studies are needed to examine the effects of financial incentives on the quality of care, and to examine whether quality improvement interventions or incentives based on quality improve the performance of preventive care.

Adult↗
PubMed2001

Mutation of cysteine-295 to alanine in secondary alcohol dehydrogenase from Thermoanaerobacter ethanolicus affects the enantioselectivity and substrate specificity of ketone reductions.

The mutation of Cys-295 to alanine in Thermoanaerobacter ethanolicus secondary alcohol dehydrogenase (SADH) was performed to give C295A SADH, on the basis of molecular modeling studies utilizing the X-ray crystal structure coordinates of the highly homologous T. brockii secondary alcohol dehydrogenase (1YKF.PDB). This mutant SADH has activity for 2-propanol comparable to wild-type SADH. However, the C295A mutation was found to cause a significant shift of enantioselectivity toward the (S)-configuration in the reduction of some ethynylketones to the corresponding chiral propargyl alcohols. This result confirms our prediction that Cys-295 is part of a small alkyl group binding pocket whose size determines the binding orientation of ketone substrates, and, hence, the stereochemical configuration of the product alcohol. Furthermore, C295A SADH has much higher activity towards t-butyl and some alpha-branched ketones than does wild-type SADH. The C295A mutation does not affect the thioester reductase activity of SADH. The broader substrate specificity and altered stereoselectivity for C295A SADH make it a potentially useful tool for asymmetric reductions.

Alanine↗
PubMed2001

Are aggressive treatment strategies less cost-effective for older patients? The case of ventilator support and aggressive care for patients with acute respiratory failure.

OBJECTIVES: A common assumption is that life-sustaining treatments are much less cost-effective for older patients than for younger patients. We estimated the incremental cost-effectiveness of providing mechanical ventilation and intensive care for patients of various ages who had acute respiratory failure. DESIGN: Retrospective analysis of data on acute respiratory failure from Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments (SUPPORT). SETTING: Acute hospital. PARTICIPANTS: 1,005 with acute respiratory failure; 963 received ventilator support and 42 had ventilator support withheld. MEASUREMENTS: We studied 1,005 patients enrolled in a five-center study of seriously ill patients (SUPPORT) with acute respiratory failure (pneumonia or acute respiratory distress syndrome and an Acute Physiology Score > or = 10) requiring ventilator support. For cost-effectiveness analyses, we estimated life expectancy based on long-term follow-up of SUPPORT patients and estimated utilities (quality-of-life weights) using time-tradeoff questions. We used hospital fiscal data and Medicare data to estimate healthcare costs. We divided patients into three age groups (< 65, 65-74, and > or = 75 years); for each age group, we performed separate analyses for patients with a < or = 50% probability of surviving at least 2 months (high-risk group) and those with a > 50% probability of surviving at least 2 months (low-risk group). RESULTS: Of the 963 patients who received ventilator support, 44% were female; 48% survived 6 months; and the median (25th, 75th percentile) age was 63 (46, 75) years. For the 42 patients for whom ventilator support was withheld, the median survival was 3 days. For low-risk patients (> 50% estimated 2-month survival), the incremental cost (1998 dollars) per quality-adjusted life-year (QALY) saved by providing ventilator support and aggressive care increased across the three age groups ($32,000 for patients age < 65, $44,000 for those age 65-74, and $46,000 for those age > or = 75). For high-risk patients, the incremental cost-effectiveness was much less favorable and was least favorable for younger patients ($130,000 for patients age < 65, $100,000 for those age 65-74, and $96,000 for those age > or = 75). When we varied our assumptions from 50% to 200% of our baseline estimates in sensitivity analyses, results were most sensitive to the costs of the index hospitalization. CONCLUSIONS: For patients with relatively good short-term prognoses, we found that ventilator support and aggressive care were economically worthwhile, even for patients 75 years and older. For patients with poor short-term prognoses, ventilator support and aggressive care were much less cost-effective for adults of all ages.

Acute Disease↗
PubMed2001

Physician-reviewers' perceptions and judgments about quality of care.

OBJECTIVE: Although Peer Review Organizations (PROs) and researchers rely on physicians to assess quality of care, little is known about what physicians think about when they judge quality. We sought to identify features of individual cases that are associated with physicians' judgments. DESIGN: Using 1994 Medicare data, we selected hospitalizations for 1134 beneficiaries in 42 acute care hospitals in California and Connecticut. The sample was enriched with 17 surgical and six medical complications identified using diagnosis and procedure codes. PRO physicians confirmed quality problems using a structured implicit chart review instrument and provided written open-ended comments about each case. We coded physicians' comments for factors presumed to influence judgments about quality. RESULTS: In crude and adjusted comparisons, reviewers questioned quality more frequently in cases with serious or fatal outcomes, technical mishaps and inadequate documentation. Among surgical (but not medical) patients, they were less likely to record poor quality among patients presenting with an acute illness. CONCLUSION: Factors other than the adequacy of key processes of care are associated with physician-reviewers' judgments about quality.

Acute Disease↗
PubMed2001

Intention to discontinue care among primary care patients: influence of physician behavior and process of care.

BACKGROUND: Specific elements of health care process and physician behavior have been shown to influence disenrollment decisions in HMOs, but not in outpatient settings caring for patients with diverse types of insurance coverage. OBJECTIVE: To examine whether physician behavior and process of care affect patients' intention to return to their usual health care practice. DESIGN: Cross-sectional patient survey and medical record review. SETTING: Eleven academically affiliated primary care medicine practices in the Boston area. PATIENTS: 2,782 patients with at least one visit in the preceding year. MEASUREMENT: Unwillingness to return to the usual health care practice. RESULTS: Of the 2,782 patients interviewed, 160 (5.8%) indicated they would not be willing to return. Two variables correlated significantly with unwillingness to return after adjustment for demographics, health status, health care utilization, satisfaction with physician's technical skill, site of care, and clustering of patients by provider: dissatisfaction with visit duration (odds ratio [OR], 3.2; 95% confidence interval [CI], 1.4 to 7.4) and patient reports that the physician did not listen to what the patient had to say (OR, 8.8; 95% CI, 2.5 to 30.7). In subgroup analysis, patients who were prescribed medications at their last visit but who did not receive an explanation of the purpose of the medication were more likely to be unwilling to return (OR, 4.9; 95% CI, 1.8 to 13.3). CONCLUSION: Failure of physicians to acknowledge patient concerns, provide explanations of care, and spend sufficient time with patients may contribute to patients' decisions to discontinue care at their usual site of care.

Boston↗
PubMed2001

Physician views on caring for hospitalized patients and the hospitalist model of inpatient care.

We surveyed 241 board-certified internists affiliated with a large teaching hospital (Boston, Mass) before implementing a hospitalist service to determine attitudes towards providing inpatient care and the hospitalist model. Of physicians surveyed, 66% responded. Most disagreed that inpatient care is "an inefficient use of my time," only 10% felt a hospitalist service would improve patient satisfaction, and 54% felt it would hurt patient-doctor relationships. Multivariable analyses suggest that physicians physically furthest from their inpatient site were had more favorable attitudes toward the hospitalist model; more experienced and busier physicians were more negative. Future investigations should determine strategies for implementing the hospitalist model which address physicians' concerns.

Academic Medical Centers↗
PubMed2001

Current status of malaria and potential for control.

Malaria remains one of the world's worst health problems with 1.5 to 2.7 million deaths annually; these deaths are primarily among children under 5 years of age and pregnant women in sub-Saharan Africa. Of significance, more people are dying from malaria today than 30 years ago. This review considers the factors which have contributed to this gloomy picture, including those which relate to the vector, the female anopheline mosquito; to human activity such as creating new mosquito breeding sites, the impact of increased numbers of people, and how their migratory behavior can increase the incidence and spread of malaria; and the problems of drug resistance by the parasites to almost all currently available antimalarial drugs. In a selective manner, this review describes what is being done to ameliorate this situation both in terms of applying existing methods in a useful or even crucial role in control and prevention and in terms of new additions to the antimalarial armory that are being developed. Topics covered include biological control of mosquitoes, the use of insecticide-impregnated bed nets, transgenic mosquitoes manipulated for resistance to malaria parasites, old and new antimalarial drugs, drug resistance and how best to maintain the useful life of antimalarials, immunity to malaria and the search for antimalarial vaccines, and the malaria genome project and the potential benefits to accrue from it.

Africa South of the Sahara↗
PubMed2001

Health care paraprofessionals' awareness of the symptoms of geriatric depression.

1. Depression is not part of the normal aging process. 2. It is important to increase awareness of the symptoms of geriatric depression among health care paraprofessionals. 3. If depressed elderly people are identified and appropriate referrals are made, treatment for depression is available and effective. 4. Health care paraprofessionals can be taught to recognize geriatric depression.

Activities of Daily Living↗
PubMed2000

Outcomes and cost-effectiveness of ventilator support and aggressive care for patients with acute respiratory failure due to pneumonia or acute respiratory distress syndrome.

PURPOSE: Many patients with acute respiratory failure die despite prolonged and costly treatment. Our objective was to estimate the cost-effectiveness of providing rather than withholding mechanical ventilation and intensive care for patients with acute respiratory failure due to pneumonia or acute respiratory distress syndrome. SUBJECTS AND METHODS: We studied 1,005 patients enrolled in a five-center study of seriously ill patients (the Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments [SUPPORT]) with acute respiratory failure (pneumonia or acute respiratory distress syndrome and an Acute Physiology Score > or =10) who required ventilator support. We estimated life expectancy based on long-term follow-up of SUPPORT patients. Utilities were estimated using time-tradeoff questions. Costs (in 1998 dollars) were based on hospital fiscal data and Medicare data. RESULTS: Of the 963 patients who received ventilator support, 48% survived for at least 6 months. At 6 months, survivors reported a median of 1 dependence in activities of daily living, and 72% rated their quality of life as good, very good, or excellent. Among the 42 patients in whom ventilator support was withheld, the median survival was 3 days. Among patients whose estimated probability of surviving at least 2 months from the time of ventilator support ("prognostic estimate") was 70% or more, the incremental cost per quality-adjusted life-year (QALY) saved by providing rather than withholding ventilator support and aggressive care was $29,000. For medium-risk patients (prognostic estimate 51% to 70%), the incremental cost-effectiveness was $44,000 per QALY, and for high-risk patients (prognostic estimate < or =50%), it was $110,000 per QALY. When assumptions were varied from 50% to 200% of baseline estimates, the results ranged from $19,000 to $48,000 for low-risk patients, from $29,000 to $76, 000 for medium-risk patients, and from $67,000 to $200,000 for high-risk patients. CONCLUSIONS: Ventilator support and intensive care for acute respiratory failure due to pneumonia or acute respiratory distress syndrome are relatively cost-effective for patients with >50% probability of surviving 2 months. However, for patients with an expected 2-month survival < or =50%, the cost per QALY is more than threefold greater at >$100,000.

APACHE↗
PubMed2000

The role of glutamic acid-69 in the activation of Citrobacter freundii tyrosine phenol-lyase by monovalent cations.

Tyrosine phenol-lyase (TPL) from Citrobacter freundii is activated about 30-fold by monovalent cations, the most effective being K(+), NH(4)(+), and Rb(+). Previous X-ray crystal structure analysis has demonstrated that the monovalent cation binding site is located at the interface between subunits, with ligands contributed by the carbonyl oxygens of Gly52 and Asn262 from one chain and monodentate ligation by one of the epsilon-oxygens of Glu69 from another chain [Antson, A. A., Demidkina, T. V., Gollnick, P., Dauter, Z., Von Tersch, R. L., Long, J., Berezhnoy, S. N., Phillips, R. S., Harutyunyan, E. H., and Wilson, K. S. (1993) Biochemistry 32, 4195]. We have studied the effect of mutation of Glu69 to glutamine (E69Q) and aspartate (E69D) to determine the role of Glu69 in the activation of TPL. E69Q TPL is activated by K(+), NH(4)(+), and Rb(+), with K(D) values similar to wild-type TPL, indicating that the negative charge on Glu69 is not necessary for cation binding and activation. In contrast, E69D TPL exhibits very low basal activity and only weak activation by monovalent cations, even though monovalent cations are capable of binding, indicating that the geometry of the monovalent cation binding site is critical for activation. Rapid-scanning stopped-flow kinetic studies of wild-type TPL show that the activating effect of the cation is seen in an acceleration of rates of quinonoid intermediate formation (30-50-fold) and of phenol elimination. Similar rapid-scanning stopped-flow results were obtained with E69Q TPL; however, E69D TPL shows only a 4-fold increase in the rate of quinonoid intermediate formation with K(+). Preincubation of TPL with monovalent cations is necessary to observe the rate acceleration in stopped flow kinetic experiments, suggesting that the activation of TPL by monovalent cations is a slow process. In agreement with this conclusion, a slow increase (k < 0.5 s(-)(1)) in fluorescence intensity (lambda(ex) = 420 nm, lambda(em) = 505 nm) is observed when wild-type and E69Q TPL are mixed with K(+), Rb(+), and NH(4)(+) but not Li(+) or Na(+). E69D TPL shows no change in fluorescence under these conditions. High concentrations (>100 mM) of all monovalent cations result in inhibition of wild-type TPL. This inhibition is probably due to cation binding to the ES complex to form a complex that releases pyruvate slowly.

Alanine Racemase↗
PubMed2000

The O(2) binding pocket of myohemerythrin: role of a conserved leucine.

A conserved O(2) binding pocket residue in Phascolopsis gouldii myohemerythrin (myoHr), namely, L104, was mutated to several other residues, and the effects on O(2) association and dissociation rates, O(2) affinity, and autoxidation were examined. The L104V, -F, and -Y myoHrs formed stable O(2) adducts whose UV-vis and resonance Raman spectra closely matched those of wild-type oxymyoHr. The L104V mutation produced only minimal effects on either O(2) association or dissociation, whereas the L104F and -Y mutations resulted in 100-300-fold decreases in both O(2) association and dissociation rates. These decreases are attributed to introduction of steric restrictions into the O(2) binding pocket, which are not present in either wild-type or L104V myoHrs. The failure to observe increased O(2) association or dissociation rates for L104V indicates that the side chain of leucine at position 104 does not sterically "gate" O(2) entry into or exit from the binding pocket in the rate-determining step(s). L104V myoHr autoxidized approximately 3 times faster than did wild type, whereas L104T autoxidized >10(6) times faster than did wild type. The latter large increase is attributed to increased side chain polarity, thereby increasing water occupancy in the oxymyoHr binding pocket. These results indicate that L104 contributes a hydrophobic barrier that restricts water entry into the oxymyoHr binding pocket. Thus, a leucine at position 104 in myoHr appears to have the optimal combination of size and hydrophobicity to facilitate O(2) binding while simultaneously inhibiting autoxidation.

Amino Acid Sequence↗
PubMed2000

A leucine residue "Gates" solvent but not O2 access to the binding pocket of phascolopsis gouldii hemerythrin.

A leucine residue, Leu-98, lines the O(2)-binding pocket in all known hemerythrins. Leu-98 in recombinant Phascolopsis gouldii hemerythrin, was mutated to several other residues of varying sizes (Ala, Val), polarities (Thr, Asp, Asn), and aromaticities (Phe, Tyr, Trp). UV-visible and resonance Raman spectra showed that the di-iron sites in these L98X Hrs are very similar to those in the wild type protein, and several of the L98X hemerythrins formed stable oxy adducts. Despite the apparently tight packing in the pocket, all of the L98X Hrs except for L98W, had second order O(2) association rate constants within a factor of 3 of the wild type value. Similarly, the O(2) dissociation rate constant was essentially unaffected by substitutions of larger (Phe) or smaller (Val, Thr) residues for Leu-98. L98Y Hr showed a 170-fold decrease in the O(2) dissociation rate constant and a large D(2)O effect on this rate, which are attributed to a hydrogen-bonding interaction between the Tyr-98 hydroxyl and the bound O(2). Significant increases in autoxidation rates were observed for all of the L98X Hrs other than X = Tyr. These increases in autoxidation rates are attributed to increased solvent access to the binding pocket caused by inefficient packing (Phe), smaller size (Val, Ala), or increased polarity (Thr, Asp, Asn) of the residue 98 side chain. A leucine at position 98 appears to have the optimal size, shape, and hydrophobicity for inhibition of solvent access. Thus, "gating" of small molecule access to the binding pocket of Hr by Leu-98 is not evident for O(2), but is evident for solvent.

Animals↗