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Biomedical subjects

P Lee

Publications and source records attributed to P Lee.

At least 145 records · Page 8Linked to original sources
PubMed1999

Thrombotic thrombocytopenic purpura as an initial presentation of limited systemic sclerosis.

Thrombotic thrombocytopenic purpura (TTP) is a rare complication of scleroderma (systemic sclerosis, SSc). In the 5 reports documenting the association of TTP and SSc, the TTP syndrome developed on a background of well established SSc. We describe a 51-year-old woman with a 5 month history of an evolving connective tissue disease syndrome who presented initially with TTP, followed 4 months later by limited cutaneous SSc and Raynaud's phenomenon.

Brain↗
PubMed1999

Does strengthening the abdominal muscles prevent low back pain--a randomized controlled trial.

OBJECTIVE: To investigate the effects of abdominal muscle strengthening exercise on low back pain (LBP) risk reduction. METHODS: We compared the effects of abdominal muscle strength (AMS) exercise and back education with back education only on 402 asymptomatic subjects with weak AMS. The primary outcome was the percentage of subjects with at least one episode of LBP at 24 months. A diary was used to monitor compliance. RESULTS: There were no statistically significant differences between experimental (E) and control (C) subjects at 24 months for LBP episodes (E: 34.7%, C: 30.4%; C-E = 4.2%, P2 = 0.481; 95% CI -16.1%, 7.6%). The LBP episodes were also not statistically significantly different at 6 months (E: 13.2%, C: 16.1%; C-E: 2.9%, P2 = 0.493; 95% CI -5.3%, 11.0%) or at 12 months (E: 24.8%, C: 23.6%; C-E = -1.2%, P2 = 0.818; 95% CI -11.6%, 9.2%). Adjusting the data for strata and baseline AMS did not alter the findings. Imputed results for LBP episodes at 6 months (C-E: 4.8%, P2 = 0.191; 95% CI -2.4%, 12.0%), 12 months (C-E: -1.0%, P2 = 0.821; 95% CI -9.5%, 7.6%), and 24 months (C-E: -3.3%, P2 = 0.483; 95% CI -12.6%, 5.9%) were also not statistically significantly different. CONCLUSION: Back education and abdominal exercise instructions are similar to back education alone. There were no group differences in LBP episodes, possibly due to noncompliance with the exercise program. While the estimated benefit of 2.9% at 6 months from the complete data and 4.8% from the imputed data were not statistically significant, a larger study or future metaanalyses may be needed to confirm whether there is a clinical benefit or whether these results should be considered a chance finding.

Abdominal Muscles↗
PubMed1998

Conditional lineage ablation to model human diseases.

Cell loss contributes to the pathogenesis of many inherited and acquired human diseases. We have developed a system to conditionally ablate cells of any lineage and developmental stage in the mouse by regulated expression of the diphtheria toxin A (DTA) gene by using tetracycline-responsive promoters. As an example of this approach, we targeted expression of DTA to the hearts of adult mice to model structural abnormalities commonly observed in human cardiomyopathies. Induction of DTA expression resulted in cell loss, fibrosis, and chamber dilatation. As in many human cardiomyopathies, transgenic mice developed spontaneous arrhythmias in vivo, and programmed electrical stimulation of isolated-perfused transgenic hearts demonstrated a strikingly high incidence of spontaneous and inducible ventricular tachycardia. Affected mice showed marked perturbations of cardiac gap junction channel expression and localization, including a subset with disorganized epicardial activation patterns as revealed by optical action potential mapping. These studies provide important insights into mechanisms of arrhythmogenesis and suggest that conditional lineage ablation may have wide applicability for studies of disease pathogenesis.

Action Potentials↗
PubMed1998

Functional intracellular P-glycoprotein.

Efflux of chemotherapy drugs by P-glycoprotein (P-gp) at the plasma membrane is thought to be a major cause of cancer multidrug resistance. In this report, we show by flow cytometry that P-gp also concentrates large amounts of 2 different drugs, Hoechst 33342 and daunorubicin, within a cytoplasmic compartment of multidrug resistant CHRC5 cells. A quantitative assay of Hoechst 33342 revealed that cytoplasmic sequestration by P-gp in CHRC5 cells accounted for about half of the amount of Hoechst 33342 accumulated by the drug-sensitive parental Aux BI cells. Daunorubicin sequestered in the cytoplasm of CHRC5 cells could be released by inhibiting P-gp function with cyclosporin A, resulting in cell death. A likely site of drug sequestration is P-gp-containing cytoplasmic vesicles, in which the P-gp is oriented so that drugs are transported and concentrated in the interior of the vesicles. P-gp was detected in the membranes of cytoplasmic vesicles of CHRC5 cells by confocal immunofluorescence microscopy and immunoelectron microscopy with anti-P-gp monoclonal antibodies (MAbs). Vesicular localization of daunorubicin was observed by epifluorescence microscopy. The origin and nature of the P-gp-containing vesicles are unknown, but they do not correspond to endocytic vesicles. Our results directly demonstrate that chemosensitizer-induced release of drugs sequestered in cytoplasmic vesicles by P-gp can be used to overcome multidrug resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Cooperative ligand binding by bovine phenol sulfotransferase.

Although several phenol sulfotransferases (PSTs) that metabolize hormones and xenobiotics have been purified and examined by steady state kinetic methods, little is known about ligand binding and subunit interactions in these enzymes. Inhibition of a purified recombinant homodimeric bovine PST by 2,6-dichloro-4-nitrophenol (DCNP) and pentachlorophenol (PCP) displayed very sharp titration curves that required modeling with Hill equations with slope factors of 2 and 3, respectively. This observation suggested positive cooperative ligand binding during catalytic turnover. The binding of PCP was also monitored by intrinsic protein fluorescence, which was quenched up to 36% upon saturation with the inhibitor. In the absence of 3'-phosphoadenosine-5'-phosphosulfate (PAPS), quenching curves were fit with the Hill equation and an interaction factor of 1. In contrast, inclusion of PAPS increased the association of PCP and resulted in positive cooperative binding with an interaction factor of 1.6-1.9. Whereas adenosine-3',5'-diphosphate (PAP) also facilitated cooperative binding of PCP, adenosine-5'-monophosphate (AMP) was not effective. This correlated to inhibition of PST by PAP, whereas AMP was not inhibitory up to 1 mM. Therefore, occupation of the PST nucleotide binding site(s) facilitates a subunit interaction that can promote subsequent binding of phenolic ligands.

Animals↗
PubMed1998

Induced preference or conditioned aversion for sodium chloride in rats with chronic bile duct ligation.

We examined whether a learned aversion to saline could account for the reduction in saline intake produced by bile duct ligation (BDL) in rats and whether increased saline intake by BDL rats was associated with hypotension. In three experiments, rats were given continuous access to water in choice with saline after surgery. In Experiment 1, rats were deprived of food and fluid for 24 h and then given 2-h access to either 0.15 or 0.3 M saline. Rats received a BDL or sham-ligation immediately (paired) or 48 h after (nonpaired) the 2-h bout of saline ingestion. The results show that nonpaired BDL rats increased their daily saline intake relative to nonpaired sham-ligated or paired BDL rats approximately 1-4 weeks after surgery. In Experiment 2, when water and either cherry or grape Kool-Aid (0.05% w/v) dissolved in 0.15 M saline to distinguish the flavor of the solution was offered prior to surgery, BDL rats reduced their ingestion of grape-flavored saline after surgery regardless of whether they were exposed to grape- or cherry-flavored saline prior to surgery. In Experiment 3, when rats were offered water and 0.3 M saline 48 h after surgery, BDL rats ligated for 4 weeks increased their saline intake relative to sham-ligated controls and this elevation in saline intake by BDL rats was associated with hypotension. The results suggest that the symptoms associated with the BDL surgery can serve as effective unconditioned stimuli in the acquisition of learned flavor aversions, and that hypotension may play a role in the elevated intake of saline by BDL rats.

Animals↗
PubMed1998

Patterns of angiotensin-converting enzyme inhibitor prescriptions, educational interventions, and outcomes among hospitalized patients with heart failure.

BACKGROUND: Among hospitalized patients with heart failure, we describe characteristics associated with prescription of angiotensin-converting enzyme (ACE) inhibitors in the doses recommended by clinical practice guidelines. We also describe the impact of ACE inhibitor prescriptions, increases in ACE inhibitor dose, and nonpharmacologic educational interventions on readmission-free survival rates. HYPOTHESIS: We hypothesize that care by a cardiologist physician and higher mean arterial blood pressure on admission are associated with receipt of optimal ACE inhibitor doses. We hypothesize that receipt of an ACE inhibitor at discharge and an increase in ACE inhibitor dose during hospitalization are associated with superior readmission-free survival. METHODS: Between January 1, 1992, and December 31, 1993, medical records were reviewed for consecutively hospitalized patients with a principal diagnosis of heart failure at an academic medical center. Documented instructions and medications prescribed at discharge were abstracted. Deaths and readmissions through December 31, 1994, were identified with the National Death Index and the study institution's administrative data base, respectively. RESULTS: During 1992 and 1993, 387 patients were discharged alive from hospitalization for heart failure. Among patients discharged on enalapril or captopril, 18% received doses recommended by heart failure clinical practice guidelines. Patients discharged on a recommended ACE inhibitor dose were more likely to be African-American and had lower sodium levels and higher mean arterial pressures than patients discharged on lower ACE inhibitor doses. In survival analyses, an increase in ACE inhibitor dose was associated with improved readmission-free survival, independent of left ventricular systolic function type. Receipt of an ACE inhibitor at discharge was also associated with superior readmission-free survival, while nonpharmacologic educational instructions were not associated with improved outcomes. CONCLUSION: Interventions are needed to improve the frequency with which ACE inhibitors are prescribed at recommended doses to hospitalized patients with heart failure. We conclude that among these patients, receipt of an ACE inhibitor at discharge and an increase in ACE inhibitor dose during hospitalization are each associated with measurable effects on readmission-free survival, while provision of educational instructions as currently practiced is not associated with better outcomes.

Aged↗
PubMed1998

A pharmacokinetic study of intravenous itraconazole followed by oral administration of itraconazole capsules in patients with advanced human immunodeficiency virus infection.

A randomized, open-label, comparative study was conducted in 30 male patients with moderately advanced human immunodeficiency virus (HIV) infection to examine the pharmacokinetics of an investigational intravenous preparation of itraconazole compared with pharmacokinetics after administration of itraconazole capsules. The study also assessed whether adequate plasma concentrations of itraconazole could be rapidly achieved with the intravenous formulation and then maintained after cessation of intravenous therapy with itraconazole capsules. All patients received 200 mg intravenous itraconazole as a 1-hour infusion in 40% hydroxypropyl-beta-cyclodextrin (HP-beta-CD) vehicle twice daily for 2 days, and then 200 mg intravenously once daily for 5 days. Patients then received itraconazole capsules, either 200 mg twice daily or 200 mg once daily for 28 days. Steady-state plasma concentrations of itraconazole were reached by day 3 with intravenous infusion, a much shorter time than observed with administration of itraconazole capsules. Steady-state concentrations of itraconazole and hydroxyitraconazole were effectively maintained during the rest of the intravenous infusions of itraconazole. Oral follow-up with administration of 200-mg capsules once daily could not maintain the plasma concentrations of itraconazole and hydroxyitraconazole obtained at the end of the intravenous treatment, whereas twice-daily oral administration maintained or increased these concentrations. Mean plasma concentrations of itraconazole and hydroxyitraconazole on day 7 were similar to those on day 36 in the twice-daily group. Mean renal clearance was comparable to mean total body clearance, and approximately 93% to 101% of the HP-beta-CD was excreted unchanged in urine within 12 hours of administration. The HP-beta-CD was essentially eliminated through the kidney, and little accumulation in the body was observed in this patient population. Adverse events during the intravenous phase were most commonly associated with intravenous administration. Intravenous infusion of itraconazole for 7 days followed by administration of itraconazole capsules twice daily for 28 days is an effective dose regimen in patients with advanced HIV infection.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1998

Fragment of GABA(A) receptor containing key ligand-binding residues overexpressed in Escherichia coli.

GABA(A) receptor plays a major role in inhibitory synaptic transmission in the central nervous system and is the target of drugs such as the benzodiazepine tranquilizers. The polymeric membrane protein nature of GABA(A) receptor has rendered structural elucidation of the receptor a formidable task, greatly hampering structure-based drug design. We report here the first expression in Escherichia coli of a fragment of GABA(A) receptor. This 131-residue fragment, spanning Cys166 to Leu296 of human GABAA receptor alpha1 subunit, contains residues previously suggested to be involved in benzodiazepine binding. The overexpressed non-fusion recombinant protein was purified to near homogeneity and characterized by circular dichroism (CD), which showed that the recombinant protein has well defined secondary structures where beta-strands are dominant. The stability of the secondary structures was demonstrated by CD spectra at high pH and elevated temperature. Excluding part of the sequences from the carboxyl terminal of the fragment resulted in dramatic changes in the secondary structures comparable to the effects caused by SDS denaturation. Our results therefore suggest that the 131-residue fragment harbors an integral structural domain of the receptor. The overexpression of the recombinant protein fragment thus opens the way to the biochemical and structural studies of a functionally important region of the receptor, and exemplifies an effective approach of expression and characterization that potentially may be extended to other members of the ligand gated channel receptor superfamily, to which the GABA(A) receptor belongs.

Binding Sites↗
PubMed1998

An analysis and evaluation of Casey's conceptual framework.

In the United Kingdom a nursing model has been developed specifically to assist children's nurses to work in partnership with children and their families [Casey, A., 1988. A partnership with child and family. Senior Nurse 8(4), 8-9.]. This model has been accepted and adopted widely in children's units throughout the UK. However, the model has not undergone rigorous testing to determine its contribution to nursing theory, although other authors have since defined the concept of partnership in both scholarly and measurable ways. Analysis and evaluation of the Partnership Model of nursing reveals that the work is not a nursing model but is actually middle range theory according to Fawcett's analysis [Fawcett, J., 1995. Analysis and Evaluation of Conceptual Models of Nursing, 3rd ed. F. A. Davis, Philadelphia.] and evaluation of nursing models. Suggestions are offered regarding the future development of the work.

Humans↗
PubMed1998

HMG-CoA reductase and ACAT inhibitors act synergistically to lower plasma cholesterol and limit atherosclerotic lesion development in the cholesterol-fed rabbit.

Given the beneficial effects of HMG-CoA reductase and ACAT inhibitors on hypercholesterolemia and atherosclerosis, we hypothesized that coadministration would improve the hypolipidemic response and not only limit lesion development but also alter the cellular composition of atherosclerotic lesions so as to induce a stable atherosclerotic lesion morphology. Plasma total cholesterol exposure was reduced 29 and 39% with atorvastatin (2.5 mg/kg) and CI-976 (5 mg/kg), respectively, and 60% upon coadministration due primarily to reductions in VLDL-cholesterol. Modest changes in liver cholesterol ester (CE) content were observed with atorvastatin or CI-976; however, a striking 48% reduction was noted upon coadministration. Liver HMG-CoA reductase mRNA levels were reduced 73% by cholesterol feeding and drug treatment did not prevent the reduction; however, atorvastatin alone and upon coadministration blunted the decrease in LDL receptor mRNA levels. The CE content of the iliac-femoral was unaffected by atorvastatin but was reduced 35% by CI-976 and 53% upon coadministration. Thoracic aortic CE content was reduced 38% by atorvastatin, 48% by CI-976 and 80% upon coadministration. Iliac-femoral lesion and macrophage area were reduced 48 and 67% by atorvastatin, respectively, and 68 and 81% by CI-976 but upon coadministration only an 85% reduction in macrophage area was noted. Aortic arch cross-sectional lesion and macrophage area were unaffected by atorvastatin, decreased 72-80% by CI-976 and reduced 87-92% upon coadministration. We conclude that inhibition of HMG-CoA reductase and ACAT acts synergistically to lower plasma total and lipoprotein cholesterol levels and to limit the development of atherosclerotic lesions in the cholesterol-fed rabbit by presumably regulating cholesterol trafficking pathways within liver and vascular cells.

Animals↗
PubMed1998

Visual function impairments in relation to gender, age, and visual acuity in patients who undergo cataract surgery.

PURPOSE: This study aimed to determine the relationship between visual function impairment in 776 patients who had extracapsular cataract extraction with posterior chamber intraocular lens implantation and gender, age, preoperative visual acuity (VA) of both the operative and the contralateral eye, and presence of other ocular disease in the operative eye. DESIGN: Retrospective cross-sectional study. PARTICIPANTS: 1139 patients whose medical records were abstracted and who had cataract surgery performed at 1 of 10 participating academic medical centers in 1990. MAIN OUTCOME MEASURE: In the 776 patients who had explicit statements about impairment of visual function documented in their medical records, univariate and multivariable logistic analyses were used to assess the above relationship. RESULTS: The most severe visual functional deficit that justified the cataract operation varied in relation to gender, age, and VA. On bivariate analysis, men were more likely to have impairment with employment, driving, and glare, whereas women were more likely to have impairment with activities of daily living and recreational activities. Significant findings between visual impairment and the independent variables from the logistic regression models included: (1) employment limitation and male gender (odds ratio [OR], 1.92; 95% confidence interval [CI], 1.08-3.40); (2) employment limitation and younger age (OR, 0.12; 95% CI, 0.050-0.28 for ages 70-79); (3) recreational impairment and older age (OR, 2.77; 95% CI, 1.64-4.70 for ages 80+); (4) impairment in performing activities of daily living and female gender (OR, 0.72; 95% CI, 0.53-0.98 for male gender); (5) impairment in performing activities of daily living and worse VA in the operative eye (OR, 5.13; 95% CI, 2.93-9.00 for VA < 20/100); (6) glare-associated impairment and younger age (OR, 0.40; 95% CI, 0.24-0.69 for age 80+); and (7) glare-associated impairment and better VA (OR, 0.16; 95% CI, 0.067-0.38 for VA < 20/100). CONCLUSION: When deciding whether to perform cataract surgery, functional impairment must be considered in relation to the age and the gender of the patient, for the type of functional impairment varies in association with age and gender.

Activities of Daily Living↗