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Biomedical subjects

P Lee

Publications and source records attributed to P Lee.

At least 109 records · Page 6Linked to original sources
PubMed2000

Pharmacokinetic/pharmacodynamic modeling in drug research and development.

The two domains in clinical pharmacology dealing with optimizing dosing recommendations are pharmacokinetics and pharmacodynamics. However, the usefulness of these disciplines is limited if viewed in isolation. Pharmacokinetic/pharmacodynamic (PK/PD) relationships and modeling builds the bridge between these two classical disciplines of clinical pharmacology. It links the concentration-time profile as assessed by pharmacokinetics to the intensity of observed response as quantified by pharmacodynamics. Thus, the resulting so-called integrated PK/PD-models allow the description of the complete time course of the desired and/or undesired effects in response to a drug therapy. PK/PD-modeling can elucidate the causative relationship between drug exposure and response and provide a better understanding of the sequence of events that result in the observed drug effect. This information can then be used to streamline the drug development process and dose optimization. This consensus paper presents an update on the current state of PK/PD-modeling from an academic, industrial and regulatory perspective.

Drug Design↗
PubMed2000

Questionnaire survey on management of spontaneous pneumothorax.

INTRODUCTION: Management of spontaneous pneumothorax (SP) is variable and the initial management of SP is often undertaken by frontline junior medical staff. OBJECTIVES: To assess if medical education in the principles of SP management is adequate and to determine if practice variability exists among different disciplines. METHODS: A validated questionnaire survey on the knowledge and practice of the junior medical staff posted to a general hospital from May to December 1998 was performed. 138 doctors posted to the various departments: medical (n = S9), surgical (n = 46) and emergency (n = 33) were surveyed. RESULTS: The response rate was 95%. 73% surveyed had experience inserting chest tubes (CT). Of the 27% (n = 37) who had never inserted CT, 41% were medical officers. Our results showed adequate knowledge pertaining to initial management of primary SP (PSP). The preferred site and method for CT insertion was the 5th intercostal space, anterior axillary line and open method. There was significant practice variability in the CT size, method of insertion and CT removal sequence among the disciplines (p < 0.05). However a significant proportion of staff (49%) chose to observe or aspirate an acutely breathless patient with a 10% secondary SP (SSP) instead of CT insertion. CONCLUSION: While knowledge in PSP appears adequate, management of SSP and practical training in CT insertion must be emphasized as it is a simple procedure that is potentially life-saving.

Attitude of Health Personnel↗
PubMed1999

8-(4-Bromo-2,3-dioxobutylthio)guanosine 5'-triphosphate: a new affinity label for purine nucleotide sites in proteins.

A new affinity label, 8-(4-bromo-2,3-dioxobutylthio)guanosine 5'-triphosphate (8-BDB-TGTP), has been synthesized by initial reaction of GTP to form 8-Br-GTP, followed by its conversion to 8-thio-GTP, and finally coupling with 1,4-dibromobutanedione to produce 8-BDB-TGTP. 8-BDB-TGTP and its synthetic intermediates were characterized by thin-layer chromatography, UV, (31)P NMR spectroscopy, as well as by bromide and phosphorus analysis. Escherichia coli adenylosuccinate synthetase is inactivated by 8-BDB-TGTP at pH 7.0 at 25 degrees C. Pretreatment of the enzyme with N-ethylmaleimide (NEM) blocks the exposed Cys(291) and leads to simple pseudo-first-order kinetics of inactivation. The inactivation exhibits a nonlinear relationship of initial inactivation rate versus 8-BDB-TGTP concentration, indicating the reversible association of 8-BDB-TGTP with the enzyme prior to the formation of a covalent bond. The inactivation kinetics exhibit an apparent K(I) of 115 microM and a k(max) of 0.0262 min(-1). Reaction of the NEM-treated adenylosuccinate synthetase with 8-BDB-[(3)H]TGTP results in 1 mol of reagent incorporated/mol of enzyme subunit. Adenylosuccinate or IMP plus GTP completely protects the enzyme against 8-BDB-TGTP inactivation, whereas IMP or GTP alone provide partial protection against inactivation. AMP is much less effective in protection. The results of ligand protection studies suggest that E. coli adenylosuccinate synthetase may accommodate 8-BDB-TGTP as a GTP analog. The new affinity label may be useful for identifying catalytic amino acid residues of protein proximal to the guanosine ring.

Adenylosuccinate Synthase↗
PubMed1999

Targeted expression of a dominant-negative K(v)4.2 K(+) channel subunit in the mouse heart.

Action potential duration is prolonged in many forms of heart disease, often as a result of reductions in Ca(2+)-independent transient outward K(+) currents (ie, I(to)). To examine the effects of a primary reduction in I(to) current in the heart, transgenic mice were generated that express a dominant-negative N-terminal fragment of the K(v)4.2 pore-forming potassium channel subunit under the control of the mouse alpha-myosin heavy chain promoter. Two of 6 founders died suddenly, and only 1 mouse successfully transmitted the transgene in mendelian fashion. Electrophysiological analysis at 2 to 4 weeks of age demonstrated that I(to) density was specifically reduced and action potential durations were prolonged in a subset of transgenic myocytes. The heterogeneous reduction in I(to) was accompanied by significant prolongation of monophasic action potentials. In vivo hemodynamic studies at this age revealed significant elevations in the mean arterial pressure, peak systolic ventricular pressures, and +/-dP/dt, indicative of enhanced contractility. Surprisingly, by 10 to 12 weeks of age, transgenic mice developed clinical and hemodynamic evidence of congestive heart failure. Failing transgenic hearts displayed molecular and cellular remodeling, with evidence of hypertrophy, chamber dilatation, and interstitial fibrosis, and individual myocytes showed sharp reductions in I(to) and I(K1) densities, action potential duration prolongation, and increased cell capacitance. Our results confirm that K(v)4.2 subunits contribute to I(to) in the mouse and demonstrate that manipulation of cardiac excitability may secondarily influence contractile performance.

Action Potentials↗
PubMed1999

Implication of arginine-131 and arginine-303 in the substrate site of adenylosuccinate synthetase of Escherichia coli by affinity labeling with 6-(4-bromo-2,3-dioxobutyl)thioadenosine 5'-monophosphate.

Adenylosuccinate synthetase from Escherichia coli is inactivated in a biphasic reaction by 6-(4-bromo-2,3-dioxobutyl)thioadenosine 5'-monophosphate (6-BDB-TAMP) at pH 7.0 and 25 degrees C. The initial fast-phase inactivation is not affected by the presence of active-site ligands and can be completely eliminated by blocking Cys291 of the enzyme with N-ethylmaleimide (NEM). Reaction of the NEM-treated enzyme with 6-BDB-[32P]TAMP results in 2 mol of reagent incorporated/mol of enzyme subunit. The inactivation kinetics of the slow-phase exhibit an apparent KI of 40.6 microM and kmax of 0.0228 min-1. Active-site ligands, either adenylosuccinate or IMP and GTP, completely prevent inactivation of the enzyme by 6-BDB-TAMP, whereas IMP or IMP and aspartate is much less effective in protection. 6-BDB-TAMP-inactivated enzyme has a 3-fold increase in Km for aspartate with no change in Km for IMP or GTP. Protease digestion of 6-BDB-[32P]TAMP inactivated enzyme reveals that both Arg131 and Arg303 are modified by the affinity-labeling reagent. The crystal structure [Poland, B. W., Fromm, H. J., and Honzatko, R. B. (1996) J. Mol. Biol. 264, 1013-1027] and site-directed mutagenesis [Kang, C., Sun, N., Poland, B. W., Gorrell, A., and Fromm, H. J. (1997) J. Biol. Chem. 272, 11881-11885] of E. coli adenylosuccinate synthetase show that Arg303 interacts with the carboxyl group of aspartate and the 2'-OH of the ribose of IMP and Arg131 is involved in stabilizing aspartate in the active site of the enzyme. We conclude that 6-BDB-TAMP functions as a reactive adenylosuccinate analogue in modifying both Arg131 and Arg303 in the active site of adenylosuccinate synthetase.

Adenosine Monophosphate↗
PubMed1999

Delineation of a membrane-proximal beta-rich domain in the GABAA receptor by progressive deletions.

The type A gamma-aminobutyric acid (GABAA) receptor plays a major inhibitory role in the central nervous system. Structural elucidation of the GABAA receptor has been impeded by the large size of the receptor. We present here the delineation of a minimal structural domain as the first step of dissecting the receptor structure. This was achieved through prediction-assisted progressive deletions: the prediction of a candidate structural domain rich in beta-strands with no close similarity to known structures was tested by deleting putative secondary structure elements from the ends of the proposed domain, as well as mutations within the terminal secondary structures. Such progressive deletions revealed the limits of an integral domain, spanning Cys180 to Met293 (numbering of human alpha1 subunit). Below these limits the intact domain structure, as indicated by its circular dichroism, collapses. Based on its putative position, this domain is provisionally designated the membrane-proximal beta-rich domain of GABAA receptor. The inclusion of sequences from the first two out of four previously suggested transmembrane segments and one of the two conserved Cys residues in this domain defines important constraints to the receptor structure.

Amino Acid Sequence↗
PubMed1999

Dystonia in Huntington's disease: prevalence and clinical characteristics.

BACKGROUND: The prevalence and clinical characteristics of dystonia in Huntington's disease (HD) have not been formally assessed. OBJECTIVES: To study (1) the prevalence of dystonia in HD in a clinic population, (2) the clinical features of dystonia, and (3) clinical correlates of dystonia (for example, age, disease duration). METHODS: Patients with HD attending the HD Center at the New York State Psychiatric Center were administered the Unified HD Rating Scale and underwent a standardized 5.5-minute videotaped examination. Two neurologists reviewed the videotaped examination and rated the severity and constancy of dystonia, calculating a total dystonia score for each patient. RESULTS: Prevalence of dystonia of any severity was 95.2%. Twenty-four of 42 (57.1%) had dystonia in at least one body region that was moderate and present more than half of the time, and seven of 42 (16.7%) had dystonia that was severe and constant. The most prevalent types of dystonia were internal shoulder rotation (64.3%), sustained fist clenching (47.1%), excessive knee flexion (42.9%), and foot inversion (42.9%). In 37 of 42 (88.1%) patients, there were more than two types of dystonia, and in the average patient, three to four types of dystonia. The mean severity was between 1 (mild) and 2 (moderate), and the mean constancy was between 2 (present less than half of the time) and 3 (present more than half of the time). Multivariate linear regression revealed that disease duration (p = 0.0005) and taking an antidopaminergic agent (p = 0.03) were positively associated with the total dystonia score. CONCLUSIONS: The majority of patients in this HD clinic exhibited some dystonia. The dystonia was present in several body regions and manifested by a variety of movements and postures not typical of idiopathic torsion dystonia. The dystonia was not bothersome to most patients, and its severity was a function of disease duration and use of an antidopaminergic agent.

Adult↗
PubMed1999

Atrial fibrillation after coronary artery bypass surgery: association with changes in G protein levels in mononuclear leukocytes.

Atrial fibrillation (AFib) is a frequent complication of coronary artery bypass grafting (CABG). Its cause, however, is unknown. As the adrenergic system is involved in some types of AFib, we hypothesized that a change in guanine nucleotide-binding protein (G protein) expression plays a role in the development of post-CABG AFib. In 28 patients undergoing CABG surgery, the G(s alpha)/G(i alpha) ratio (stimulatory/inhibitory G protein alpha) at the protein (Western blotting) and mRNA (reverse transcription polymerase chain reaction) levels was measured before and after surgery. As a suitable test system allowing multiple analysis mononuclear leukocytes (MNL) were chosen. The perioperative change of the G(s alpha)/G(i alpha) ratio of protein and mRNA was significantly different in patients who subsequently developed AFib (eight patients) and in patients who did not (20 patients; P<0.01 and <0.001, respectively). On average, the protein G(s alpha)/G(i alpha) ratio decreased from 1.79+/-1.13 (mean+/-SD) to 1.32+/-0.69 in patients without AFib (P=0.1, n.s.) whereas a significant increase from 0.86+/-0.44 to 1.62+/-0.65 (P<0.01) was observed in patients subsequently developing AFib. The mRNA G(s alpha)/G(i alpha) ratio decreased significantly from 0.53+/-0.24 to 0.36+/-0.11 in patients without AFib (P<0.01) whereas a significant increase from 0.31+/-0.14 to 0.47+/-0.13 was observed in those who subsequently developed AFib (P<0.05). These results indicate that an increase of the G(s alpha)/G(i alpha) ratio in MNL is associated with AFib after CABG surgery and possibly may be used as a prognostic indicator of this complication.

Adult↗
PubMed1999

The relationship of self-rated vision and hearing to functional status and well-being among seniors 70 years and older.

PURPOSE: To describe the relationship between self-reported visual and hearing impairment and an index of global functional status among seniors age 70 years or older. METHODS: A total of 7,320 United States community-dwelling persons aged 70 years or older participating in the 1993 Assets and Health Dynamics of the Oldest Old Survey (AHEAD) completed detailed questionnaires about their demographic, socioeconomic, and health status. Multivariate analyses of functional status (using a global index of functional status based on self-reported limitations in 11 activities) were conducted, controlling for demographic and socioeconomic status and common medical conditions, as well as independently for hearing and vision. RESULTS: Of the respondents, 27% rated their vision as fair or poor, whereas 25% rated their hearing as fair or poor. Controlling for demographic factors, socioeconomic status, medical conditions, and general health status, limitations in both vision and hearing correlated independently with worsened functional status. Controlling for income, wealth, and education did not greatly reduce the strength of the association between visual and hearing impairment and function. CONCLUSIONS: Visual and hearing impairment appear to have a significant relationship to overall functioning in the oldest old, regardless of income or wealth. By confirming these findings across income and household wealth groups, adjusted for medical conditions and general health status, in a nationally representative population of Americans age 70 years or older, this study provides a powerful added impetus to efforts for improving vision and hearing for all other Americans, including the oldest old.

Aged↗
PubMed1999

Effects of endorectal ultrasonography in the surgical management of rectal adenomas and carcinomas.

BACKGROUND: Accurate preoperative staging of rectal lesions can help select patients for treatment options. This prospective study examines the effects of endorectal ultrasonography (ERUS) in the management of resectable adenomas and adenocarcinomas. METHODS: Between November 1995 and August 1998, 34 patients had resection of their rectal lesions (28 adenocarcinomas, 6 adenomas). Preoperative clinical stage and surgical and adjuvant therapy plans were specified before ERUS staging; then comparisons were made to postoperative pathologic stage and actual treatment. RESULTS: ERUS helped select 7 of 11 patients (64%) for preoperative chemoradiation therapy. Treatments of adenocarcinomas were altered by ERUS to local excision (LOC) in 4 of 9 patients (45%) planned for low anterior resection (LAR), and 2 of 10 patients (20%) planned for abdominoperineal resection (APR). ERUS helped spare 2 patients with adenoma from APR. CONCLUSION: ERUS is a useful modality in the surgical management of patients with rectal adenomas and carcinomas.

Adenocarcinoma↗
PubMed1999

Transhiatal esophagectomy in a patient with aberrant right subclavian artery.

During transhiatal esophagectomy, the esophagus is generally safely and easily dissected posteriorly. However, in 1% to 2% of patients, an aberrant right subclavian artery passes between the esophagus and spine. We demonstrate that transhiatal esophagectomy may be safely performed in these patients when recognition and careful dissection are performed. Thoracic surgeons must be aware of this anomaly in order to prevent laceration of the aberrant right subclavian artery with catastrophic hemorrhage.

Aged↗