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Timothy Evans

Publications and source records attributed to Timothy Evans.

13 recordsLinked to original sources
PubMed2006

Resolution of chiral phosphate, phosphonate, and phosphinate esters by an enantioselective enzyme library.

An array of 16 enantiomeric pairs of chiral phosphate, phosphonate, and phosphinate esters was used to establish the breadth of the stereoselective discrimination inherent within the bacterial phosphotriesterase and 15 mutant enzymes. For each substrate, the leaving group was 4-hydroxyacetophenone while the other two groups attached to the phosphorus core consisted of an asymmetric mixture of methyl, methoxy, ethyl, ethoxy, isopropoxy, phenyl, phenoxy, cyclohexyl, and cyclohexoxy substituents. For the wild-type enzyme, the relative rates of hydrolysis for the two enantiomers ranged from 3 to 5.4 x 10(5). Various combinations of site-specific mutations within the active site were used to create modified enzymes with alterations in their enantioselective properties. For the single-site mutant enzyme, G60A, the stereoselectivity is enhanced relative to that of the wild-type enzyme by 1-3 orders of magnitude. Additional mutants were obtained where the stereoselectivity is inverted relative to the wild-type enzyme for 13 of the 16 pairs of enantiomers tested for this investigation. The most dramatic example was obtained for the hydrolysis of 4-acetylphenyl methyl phenyl phosphate. The G60A mutant preferentially hydrolyzes the SP-enantiomer by a factor of 3.7 x 10(5). The I106G/F132G/H257Y mutant preferentially hydrolyzes the RP-enantiomer by a factor of 9.7 x 10(2). This represents an enantioselective discrimination of 3.6 x 10(8) between these two mutants, with a total of only four amino acid changes. The rate differential between the two enantiomers for any given mutant enzyme is postulated to be governed by the degree of nonproductive binding within the enzyme active site and stabilization of the transition state. This hypothesis is supported by computational docking of the high-energy, pentavalent form of the substrates to modeled structures of the mutant enzyme; the energies of the docked transition-state analogues qualitatively capture the enantiomeric preferences of the various mutants for the different substrates. These results demonstrate that the catalytic properties of the wild-type phosphotriesterase can be exploited for the kinetic resolution of a wide range of phosphate, phosphonate, and phosphinate esters and that the active site of this enzyme is remarkably amenable to structural perturbations via amino acid substitution.

Amino Acid Substitution↗
PubMed2006

Reactivation histoplasmosis after treatment with anti-tumor necrosis factor alpha in a patient from a nonendemic area.

Histoplasma capsulatum (HC) is a thermally dimorphic ascomycete that is a significant cause of respiratory infections (>80%) in endemic areas (Midwest and southeast USA), but infections are rare in non-endemic areas. Most primary HC infections are subclinical or self-limited. While reactivation Histoplasmosis has been reported in the setting of immunosuppression, it remains unclear whether remote primary latent infection represents risk of endogenous reactivation after anti-tumor necrosis factor (TNF)-alpha therapy. We report a case of a patient who developed reactivation Histoplasmosis after receiving anti-TNF-alpha. To our knowledge, this is the first clear report of reactivation of "latent" Histoplasmosis after anti-TNF-alpha therapy.

Adult↗
PubMed2006

Intensive care and emergency medicine: progress over the past 25 years.

Over the last quarter of a century, intensive care medicine has developed into an established hospital specialty with its own unique identity and characteristics. Significant advances have occurred, mostly in a succession of small steps rather than any dramatic leap, with many being linked to advances in health care across other disciplines. In addition, many changes have resulted from the scientific identification of the detrimental effects of certain traditional practices once thought to be therapeutic. Here, in an attempt to learn from the past and offer guidance for future progress, we detail some of the key changes in various aspects of intensive care medicine including respiratory, cardiovascular, metabolic, and nutritional care, as well as sepsis, polytrauma, organization, and management.

Cardiovascular Diseases↗
PubMed2005

Identifying inaccuracies on emergency medicine residency applications.

BACKGROUND: Previous trials have showed a 10-30% rate of inaccuracies on applications to individual residency programs. No studies have attempted to corroborate this on a national level. Attempts by residency programs to diminish the frequency of inaccuracies on applications have not been reported. We seek to clarify the national incidence of inaccuracies on applications to emergency medicine residency programs. METHODS: This is a multi-center, single-blinded, randomized, cohort study of all applicants from LCME accredited schools to involved EM residency programs. Applications were randomly selected to investigate claims of AOA election, advanced degrees and publications. Errors were reported to applicants' deans and the NRMP. RESULTS: Nine residencies reviewed 493 applications (28.6% of all applicants who applied to any EM program). 56 applications (11.4%, 95%CI 8.6-14.2%) contained at least one error. Excluding "benign" errors, 9.8% (95% CI 7.2-12.4%), contained at least one error. 41% (95% CI 35.0-47.0%) of all publications contained an error. All AOA membership claims were verified, but 13.7% (95%CI 4.4-23.1%) of claimed advanced degrees were inaccurate. Inter-rater reliability of evaluations was good. Investigators were reluctant to notify applicants' dean's offices and the NRMP. CONCLUSION: This is the largest study to date of accuracy on application for residency and the first such multi-centered trial. High rates of incorrect data were found on applications. This data will serve as a baseline for future years of the project, with emphasis on reporting inaccuracies and warning applicants of the project's goals.

Adult↗
PubMed2004

Background concentrations of dioxins, furans, and PCBs in Sprague-Dawley rats and juvenile swine.

In preparation for a study of the relative oral bioavailability of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) in soils (typically containing less than 1 ppb 2,3,7,8-tetrachlo-rodibenzo-p-dioxin [TCDD] toxic equivalents [TEQ]), the background concentrations of PCDD/Fs and selected polychlorinated biphenyls (PCBs) were measured in liver and adipose tissue from female Sprague-Dawley rats and juvenile swine after 30 d of ingesting laboratory chow. The measured concentrations of TCDD and other PCDD/Fs in rat livers were severalfold less than previously reported in the literature for control (unexposed) laboratory rodents. The concentrations of PCDD/Fs and selected PCBs in livers of swine were three- to fourfold lower than those reported for rats. The lower concentrations found in this study compared to previous findings may be due to inadvertent laboratory contamination in previous studies or to declining levels of PCDD/Fs in laboratory feed, which parallel the declines in emissions, general environmental levels, and human food and tissue levels of PCDD/Fs.

Adipose Tissue↗
PubMed2004

Responding to the global human resources crisis.

The global community is in the midst of a growing response to health crises in developing countries, which is focused on mobilising financial resources and increasing access to essential medicines. However, the response has yet to tackle the most important aspect of health-care systems--the people that make them work. Human resources for health--the personnel that deliver public-health, clinical, and environmental services--are in disarray and decline in much of the developing world, particularly in sub-Saharan Africa. The reasons behind this disorder are complex. For decades, efforts have focused on building training institutions. What is becoming increasingly clear, however, is that issues of supply, demand, and mobility (transnational, regional, and local) are central to the human-resource problem. Without substantial improvements in workforces, newly mobilised funds and commodities will not deliver on their promise. The global community needs to engage in four core strategies: raise the profile of the issue of human resources; improve the conceptual base and statistical evidence available to decision makers; collect, share, and learn from country experiences; and begin to formulate and enact policies at the country level that affect all aspects of the crisis.

Africa South of the Sahara↗
PubMed2003

Ventilator-associated lung injury.

Mechanical ventilation is indispensable in support of patients with respiratory failure who are critically ill. However, use of this technique has adverse effects, including increased risk of pneumonia, impaired cardiac performance, and difficulties associated with sedation and paralysis. Moreover, application of pressure to the lung, whether positive or negative, can cause damage known as ventilator-associated lung injury (VALI). Despite difficulties in distinguishing the effects of mechanical ventilation from those of the underlying disorder, VALI greatly assists patients with the most severe form of lung injury, acute respiratory distress syndrome (ARDS). Moreover, modification of mechanical ventilation so that VALI is kept to a minimum improves survival of patients with ARDS. Here, we outline the effects of mechanical ventilation on injured lungs and explore the underlying mechanisms.

Humans↗
PubMedDate not supplied

Overcoming health-systems constraints to achieve the Millennium Development Goals.

Effective interventions exist for many priority health problems in low income countries; prices are falling, and funds are increasing. However, progress towards agreed health goals remains slow. There is increasing consensus that stronger health systems are key to achieving improved health outcomes. There is much less agreement on quite how to strengthen them. Part of the challenge is to get existing and emerging knowledge about more (and less) effective strategies into practice. The evidence base also remains remarkably weak, partly because health-systems research has an image problem. The forthcoming Ministerial Summit on Health Research seeks to help define a learning agenda for health systems, so that by 2015, substantial progress will have been made to reducing the system constraints to achieving the MDGs.

Delivery of Health Care↗
PubMedDate not supplied

Human resources for health: overcoming the crisis.

In this analysis of the global workforce, the Joint Learning Initiative-a consortium of more than 100 health leaders-proposes that mobilisation and strengthening of human resources for health, neglected yet critical, is central to combating health crises in some of the world's poorest countries and for building sustainable health systems in all countries. Nearly all countries are challenged by worker shortage, skill mix imbalance, maldistribution, negative work environment, and weak knowledge base. Especially in the poorest countries, the workforce is under assault by HIV/AIDS, out-migration, and inadequate investment. Effective country strategies should be backed by international reinforcement. Ultimately, the crisis in human resources is a shared problem requiring shared responsibility for cooperative action. Alliances for action are recommended to strengthen the performance of all existing actors while expanding space and energy for fresh actors.

Africa↗