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Paul Lee

Publications and source records attributed to Paul Lee.

At least 37 records · Page 2Linked to original sources
PubMed2004

Characterization of defective CD4-CD8- T cells in murine tumors generated independent of antigen specificity.

Immune-based therapy confers limited benefits to hosts bearing late-stage tumors. Mounting evidence points to local suppression of T cell function as the most substantial barrier to effective antitumor immunity in hosts with large tumor burdens. Despite this, events responsible for locally defective T cells and immune suppression in tumors remain unclear. We describe in this study a predominant T cell population localized within two murine tumors that is characterized by expression of apoptotic markers and TCRalphabeta/CD3, but not CD4, CD8, or NK-associated markers. These defective cells resembled double negative (DN) T cells in lpr mice, harbored defects in the expression of T cell signaling molecules, and produced the anti-inflammatory cytokine, IL-10. Conditions known to increase or decrease the accumulation of lpr DN T cells had corresponding effects on local DN tumor infiltrating lymphocyte (TIL) levels and inversely impacted host survival. Adoptive transfer into s.c. tumors demonstrated that naive CD8(+) T cells were highly susceptible to becoming DN TIL, and local supplementation of tumors with nontumor Ag-bearing MHC class I-expressing fibroblasts decreased both this susceptibility and endogenous DN TIL levels. These findings identify a major defective T cell population with suppressive potential within tumors. The data also suggest that local T cell defectiveness is controlled by the tumor environment independent of cognate Ag specificity per se. Decreasing defective DN TIL levels by increasing noncognate peptide MHC class I availability, or modulating TCR or cytokine signaling may facilitate host survival by bolstering endogenous immunity to late-stage tumors, and may help improve therapeutic tumor vaccines.

Adoptive Transfer↗
PubMed2004

Sti1 and Cdc37 can stabilize Hsp90 in chaperone complexes with a protein kinase.

Hsp90 functions in association with several cochaperones for folding of protein kinases and transcription factors, although the relative contribution of each to the overall reaction is unknown. We assayed the role of nine different cochaperones in the activation of Ste11, a Saccharomyces cerevisiae mitogen-activated protein kinase kinase kinase. Studies on signaling via this protein kinase pathway was measured by alpha-factor-stimulated induction of FIG1 or lacZ, and repression of HHF1. Several cochaperone mutants tested had reduced FIG1 induction or HHF1 repression, although to differing extents. The greatest defects were in cpr7Delta, sse1Delta, and ydj1Delta mutants. Assays of Ste11 kinase activity revealed a pattern of defects in the cochaperone mutant strains that were similar to the gene expression studies. Overexpression of CDC37, a chaperone required for protein kinase folding, suppressed defects the sti1Delta mutant back to wild-type levels. CDC37 overexpression also restored stable Hsp90 binding to the Ste11 protein kinase domain in the sti1Delta mutant strain. These data suggest that Cdc37 and Sti1 have functional overlap in stabilizing Hsp90:client complexes. Finally, we show that Cns1 functions in MAP kinase signaling in association with Cpr7.

Blotting, Western↗
PubMed2004

Correlation of postpercutaneous coronary intervention creatine kinase-MB and troponin I elevation in predicting mid-term mortality.

Creatine kinase-MB (CK-MB) and troponin I elevations after successful percutaneous coronary intervention (PCI) are common, and different gradations have been correlated with mortality. To establish which of these 2 markers of myonecrosis, CK-MB and troponin I, accurately predicts mortality after successful PCI, we analyzed 2,873 patients without acute myocardial infarction who underwent PCI for in-hospital events and mid-term mortality. Patients were stratified into 4 groups based on peak post-PCI cardiac markers values: group I: normal CK-MB (<16 U/L) or troponin I (<2 ng/ml); group II: CK-MB or troponin I levels 1 to 3 times normal; group III: >3 to 5 times normal; and group IV: >5 times normal. CK-MB elevation occurred in 16.1% of patients, with 12.2%, 2.3%, and 1.6% in groups II to IV, respectively. Troponin I elevation was detected in 38.9% of patients, with 16.4%, 8.4%, and 14.1% in groups II to IV, respectively. There was poor correlation between postprocedural CK-MB and troponin I values (r = 0.10) and in their individual subgroups. Kaplan-Meier estimates of death for postprocedure CK-MB were 2.1%, 2.7%, 1.7%, and 10.3% (p = 0.002) for groups I to IV, respectively; for troponin I, these estimates were 2.2%, 2.3%, 2.9%, and 2.1% for groups I to IV, respectively (p = 0.58). A Cox proportional hazards model showed that CK-MB >5 times normal was the strongest predictor of mortality (hazard ratio 6.7, 95% confidence interval 1.9 to 22.9; p = 0.002), although heart failure, peripheral vascular disease, pre-PCI digoxin therapy, and post-PCI renal failure also predicted mortality. However, neither troponin I peak elevation nor any subgroup predicted mortality. Troponin I is frequently elevated after PCI, but does not predict mortality. Periprocedural CK-MB elevation >5 times normal remains an independent predictor of mid-term mortality and a valuable marker for PCI prognosis in low-to-medium risk patients.

Aged↗
PubMed2004

Outcome after colectomy for Clostridium difficile colitis.

PURPOSE: Clostridium difficile colitis is a relatively common entity, yet large series of patients with fulminant C. difficile colitis are infrequently reported. This study was designed to identify risk factors, clinical characteristics, and outcome of patients who required colectomy for fulminant C. difficile colitis. METHODS: A population-based study on all patients in 159 hospitals of the Department of Veterans Affairs from 1997 to 2001 was performed. Data were compiled from several national computerized Department of Veterans Affairs data sets. Supplementary information including demographic information, discharge summaries, operative reports, and pathology reports were obtained from local medical records. Patient variables were entered into a computerized database and analyzed using the Pearson chi-squared and Fisher's exact tests. Statistical significance was designated as P < 0.05. RESULTS: Sixty-seven patients (mean age, 69 (range, 40-86) years; 99 percent males) were identified. All 67 patients had C. difficile verified in the colectomy specimens. Thirty-six of 67 patients (54 percent) developed C. difficile colitis during a hospitalization for an unrelated illness, and 30 of 36 patients (87 percent) after a surgical procedure. Thirty-one of 67 (46 percent) developed C. difficile colitis at home. There was no history of diarrhea in 25 of 67 patients (37 percent). Thirty of 67 patients (45 percent) presented in shock (blood pressure, <90 mmHg). Forty-three of 67 patients (64 percent) presented with an acute surgical abdomen. Mean white blood cell count was 27.2; mean percent bands was 12. Twelve of 67 patients (18 percent) had a negative C difficile colitis stool assay. Abdominal computed tomography correctly diagnosed 45 of 46 patients (98 percent) who were imaged. Twenty-six of 67 patients (39 percent) underwent colonoscopy; all 26 were found to have severe inflammation or pseudomembranes. Fifty-three of 67 patients (80 percent) underwent total colectomy; 14 of 67 underwent segmental colonic resection. Perforation and infarction were found in 59 of 67 patients (58 percent) at surgery. Overall mortality was 48 percent (32/67). Mean hospitalization was 36 (range, 2-297) days. CONCLUSIONS: Patients with fulminant C. difficile colitis often present with an unexplained abdominal illness with a marked leukocytosis that rapidly progresses to shock and peritonitis. Although frequently developed during a hospitalization and often after a surgical procedure, it may develop outside of a hospital setting. Diarrhea may be absent and stool cytology may be negative for C. difficile toxin. Perforation and infarction are frequently found at surgery. In those patients who survive, a prolonged hospitalization is common. Mortality from fulminant C. difficile colitis remains high despite surgical intervention.

Adult↗
PubMed2004

Do routine eye exams improve vision?

We use a longitudinal national sample of Medicare claims linked to the National Long-Term Care Survey (NLTCS) to assess the productivity of routine eye examinations. Although such exams are widely recommended by professional organizations for certain populations, there is limited empirical evidence on the productivity of such care. We measure two outcomes, the ability to continue reading, and no onset of blindness or low vision, accounting for potential endogeneity of frequency of eye exams. Using instrumental variables, we find a statistically significant and beneficial effect of routine eye exams for both outcomes. Marginal effects for reading ability are large, but decline in the number of years with eye exams. Effects for blindness/low vision are smaller for the general elderly population, but larger for persons with diabetes. Instrumental variables provide a useful approach for assessing the productivity of particular interventions, particularly in situations in which randomized controlled trials are expensive or perhaps unethical and difficult to conduct over a lengthy time period.

Cost-Benefit Analysis↗
PubMed2004

Bimanual coordination deficits in attention deficit/hyperactivity disorder (ADHD).

Although motor difficulties have been implicated in ADHD, studies investigating bimanual coordination have been few and their results inconsistent. This study examined the performance of 12 boys with ADHD combined type and their matched controls on a simple in-phase bimanual movement task (requiring symmetrical hand movements) and a complex out-of-phase bimanual movement task (requiring asymmetrical hand movements), at different designated speeds (1 and 2 Hz). Compared to controls, ADHD children were significantly more variable in both velocity and coordination, and less accurate in coordination, with the in-phase movements. For out-of-phase movements, the ADHD children were significantly more variable in velocity and coordination. These findings suggest a problem of bimanual coordination in the syndrome.

Aging↗
PubMed2004

Recent developments in tissue-type imaging (TTI) for planning and monitoring treatment of prostate cancer.

Because current methods of imaging prostate cancer are inadequate, biopsies cannot be effectively guided and treatment cannot be effectively planned and targeted. Therefore, our research is aimed at ultrasonically characterizing cancerous prostate tissue so that we can image it more effectively and thereby provide improved means of detecting, treating and monitoring prostate cancer. We base our characterization methods on spectrum analysis of radiofrequency (rf) echo signals combined with clinical variables such as prostate-specific antigen (PSA). Tissue typing using these parameters is performed by artificial neural networks. We employed and evaluated different approaches to data partitioning into training, validation, and test sets and different neural network configuration options. In this manner, we sought to determine what neural network configuration is optimal for these data and also to assess possible bias that might exist due to correlations among different data entries among the data for a given patient. The classification efficacy of each neural network configuration and data-partitioning method was measured using relative-operating-characteristic (ROC) methods. Neural network classification based on spectral parameters combined with clinical data generally produced ROC-curve areas of 0.80 compared to curve areas of 0.64 for conventional transrectal ultrasound imaging combined with clinical data. We then used the optimal neural network configuration to generate lookup tables that translate local spectral parameter values and global clinical-variable values into pixel values in tissue-type images (TTIs). TTIs continue to show cancerous regions successfully, and may prove to be particularly useful clinically in combination with other ultrasonic and nonultrasonic methods, e.g., magnetic-resonance spectroscopy.

Biopsy↗
PubMed2003

Postprocedure chest pain after coronary stenting: implications on clinical restenosis.

OBJECTIVES: The goal of this study was to analyze the incidence and predictors of postprocedure chest pain (PPCP) after percutaneous coronary intervention (PCI) and its correlation with clinical restenosis. BACKGROUND: Chest pain after PCI occurs frequently even in the absence of procedural events and is considered to be due to vasospasm or coronary artery stretch. The short- and long-term significance of PPCP after otherwise successful stenting is not clear. METHODS: We analyzed 1,362 patients undergoing coronary stenting for PPCP, procedural and in-hospital events, 30-day major adverse cardiac events, and target vessel revascularization (TVR) at 6 to 9 months. RESULTS: There were 488 patients with PPCP and, of these, 312 patients were excluded due to procedural events. The remaining 176 patients with PPCP were compared with 874 patients without PPCP. Creatine kinase-MB isoenzyme elevation occurred in 25.6% of the PPCP group versus 9.6% of the no PPCP group (p < 0.001). Despite similar reference vessel diameter, the PPCP group had larger postprocedure minimum lumen diameter, higher stent-to-vessel ratio, and higher inflation pressure versus the no PPCP group (p < 0.01). At 30 days, the emergency room visits and repeat catheterization (16% vs. 2.7%; p < 0.001) were higher in the PPCP group versus the no PPCP group, but repeat intervention was similar. At 6- to 9-month follow-up, the TVR was significantly higher in the PPCP group compared with the no PPCP group (29.5% vs. 16.6%; p < 0.01). CONCLUSIONS: Our analysis suggests micromyonecrosis and vessel stretch as causes of PPCP. Postprocedure chest pain is associated with similar short-term outcome as no PPCP, but has higher restenosis, perhaps mediated by deep vessel wall injury. Therefore, PPCP may identify patients at high risk for restenosis.

Aged↗
PubMed2003

Associations of presbyopia with vision-targeted health-related quality of life.

OBJECTIVE: To evaluate the associations of presbyopia and its correction, particularly monovision optical correction, with vision-targeted health-related quality of life. METHODS: The National Eye Institute Refractive Error Quality of Life (NEI-RQL) Instrument was prospectively self-administered by subjects from 6 medical centers in the following age and correction categories: subjects with emmetropia younger than 45 years (n = 75), subjects with emmetropia aged 45 years or older (n = 38), and subjects with ametropia aged 45 years or older without monovision (n = 486) or corrected with monovision (n = 38). Differences in the 13 NEI-RQL Instrument subscale scores among subjects in the 4 groups were examined. The age of 45 years or older was used as a surrogate for presbyopia. RESULTS: A comparison of older (age > or =45 years) vs younger (age <45 years) persons with emmetropia suggests that presbyopia was associated with reduced scores in 7 of 13 subscales (P<.05). In those aged 45 years or older, correction of presbyopia with monovision was associated with statistically significantly better scores on 3 subscales (expectations, dependence on correction, and appearance) compared with single-vision correction. One subscale (dependence on correction) showed worsening scores with increasing age without adjustment for need or type of correction. Older persons with monovision correction had significantly worse scores than younger subjects with emmetropia on all subscales except suboptimal correction and appearance. CONCLUSIONS: Presbyopia is associated with worse vision-targeted health-related quality of life compared with younger subjects with emmetropia. Monovision correction of presbyopia is related to some improvements in health-related quality of life, but it is still worse than that for younger subjects with emmetropia in several areas.

Adult↗
PubMed2003

Responsiveness of the National Eye Institute Refractive Error Quality of Life instrument to surgical correction of refractive error.

OBJECTIVE: Refractive error and the means by which it is corrected may impact substantially on quality of vision and health-related quality of life in ways not captured adequately by standard measures of visual acuity. The goal of this analysis was to evaluate the responsiveness of the National Eye Institute Refractive Error Quality of Life (NEI-RQL) instrument to surgical correction of refractive error. DESIGN: Prospective, multicenter cohort study. PARTICIPANTS: The NEI-RQL, a 42-item measure with 13 scales, was self-administered by 185 patients before and after undergoing surgical correction of myopic or hyperopic refractive error. Preoperative and postoperative clinical information was collected, including refractive error and corrected visual acuity. METHODS: Differences between preoperative and postoperative NEI-RQL scores were examined. Responsiveness was assessed using the standardized response mean and the responsiveness statistic. We also compared scales using relative efficiency estimates. MAIN OUTCOME MEASURES: Changes in NEI-RQL scales (clarity of vision, expectations, near vision, far vision, diurnal fluctuations, activity limitations, glare, symptoms, dependence on correction, worry, suboptimal correction, appearance, and satisfaction with correction). RESULTS: For myopes and hyperopes combined, refractive surgical correction was associated with statistically significant (P<0.05) improvements in scores for 11 of 13 scales. The largest improvements, ranging from 26 to 58 points on the 0 to 100 possible score range, were seen in expectations, activity limitations, dependence on correction, appearance, and satisfaction with correction. Separate analysis of myopes and hyperopes revealed similar effects in the 2 groups. Baseline scores were found to be predictive of change after surgery. CONCLUSIONS: The NEI-RQL is responsive to changes in vision-targeted health-related quality of life resulting from keratorefractive surgery. This instrument may prove useful for evaluating the beneficial and adverse impacts of surgical and nonsurgical methods of refractive error correction.

Adult↗
PubMed2003

Perceptual asymmetries in normal children and children with attention deficit/hyperactivity disorder.

Perceptual asymmetries in normal right-handed children (7-12 years of age) and children with attention deficit/hyperactivity disorder (ADHD), combined type, were investigated using various chimeric stimuli in free-viewing conditions. In the face-matching task, participants indicated which of two symmetrical face chimeras more closely resembled the original; in the chimeric faces task, participants indicated which of a pair of faces appeared happier; and in the grey scales task participants indicated which of two shaded rectangles appeared to be darker overall. Leftward biases were found for normal children with no effects of age. Contrary to expectations, normal leftward biases were also found for ADHD children in the face-matching and the chimeric faces tasks; however, a significant leftward bias was not observed in the grey scales task. The absence of anomalous perceptual bias in ADHD children on these purely perceptual tasks, suggests that anomalous perceptual asymmetries observed in other tasks (line bisection and cancellation tasks) may have been confounded by the motor response, and/or the explicit spatial components of those tasks.

Attention Deficit Disorder with Hyperactivity↗
PubMed2003

Correlation among retinal thickness, optic disc, and visual field in glaucoma patients and suspects: a pilot study.

OBJECTIVE: To correlate losses of retinal thickness in the perifoveal area in glaucoma as measured by the Retinal Thickness Analyzer (Talia Technology Ltd, Israel) with optic nerve and visual field changes in glaucoma patients and suspects. METHODS: Observational case series of 55 consecutive patients from the Glaucoma Service who either presented with a diagnosis of glaucoma or were referred for evaluation of suspected glaucoma. The Retinal Thickness Analyzer (Talia Technology, Ltd.) was used to obtain retinal thickness maps. Retinal thickness analysis, visual field testing, and stereophotography of the optic nerve head were performed, and a glaucoma specialist who was masked to patient status and identity data randomly graded the level of severity of each parameter. Spearman rank correlations were used to assess the relationships among the three numerical measures. RESULTS: Retinal thickness losses correlated more strongly with severity of optic nerve head cupping (r = 0.75), whereas both of these measures correlated less strongly with the severity of visual field loss (r = 0.54). CONCLUSIONS: Retinal thickness measurements at the posterior pole provide another measure of neural loss in glaucoma, and may help in the clinical assessment of optic nerve cupping. However, there are limitations of the technology that must be considered.

Adult↗
PubMed2003

Effects of flaxseed oil on serum lipids and atherosclerosis in hypercholesterolemic rabbits.

OBJECTIVE: Flaxseed oil has very high content of alpha-linolenic acid (C18:3n-3, omega-3 [n-3] fatty acid). Based on the usefulness of n-3 fatty acid in fish oil against cardiovascular diseases, flaxseed oil is marketed as a health food. The n-3 fatty acid in flaxseed oil is different than that of fish oil. Indirect evidence suggests that the omega-3 fatty acid in flaxseed oil is not effective in lowering serum lipids and hypercholesterolemic atherosclerosis. The effects of flaxseed oil on serum lipids and hypercholesterolemic atherosclerosis are not known. An investigation, therefore, was made of flaxseed oil on high-cholesterol diet-induced atherosclerosis, serum lipids (triglycerides, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, risk ratio of total cholesterol to high-density lipoprotein cholesterol), serum and aortic malondialdehyde, an index of levels of reactive oxygen species, aortic chemiluminescence (a measure of antioxidant reserve), and reactive oxygen species-producing activity of white blood cell chemiluminescence in rabbits. METHODS: The rabbits were assigned to four groups: Group I, regular diet (control); Group II, 5% flaxseed oil in regular diet; Group III, 0.5% cholesterol diet; Group IV, diet containing 0.5% cholesterol and 5% flaxseed oil. Blood samples were collected before and after 4 and 8 weeks of experimental diets for measurement of serum lipids, serum malondialdehyde, and white blood cell chemiluminescence. At the end of 8 weeks of the experimental diet, aortas were removed for measurement of atherosclerotic plaques, aortic malondialdehyde, and antioxidant reserve. RESULTS: Serum total cholesterol, triglycerides, and low-density and high-density lipoprotein cholesterol, and risk ratio of total cholesterol to high-density lipoprotein cholesterol, were elevated to a similar extent in Groups III and IV compared to Groups I and II. The extent of atherosclerosis in Groups III and IV was similar (56.74% +/- 11.14% vs 58.01% +/- 10.95%). Groups III and IV both had similar increases in serum and aortic malondialdehyde and antioxidant reserve. Reactive oxygen species-producing activity of white blood cells increased in Group III, and flaxseed oil prevented the cholesterol-induced increase in white blood cell chemiluminescence in Group IV. CONCLUSION: These results suggest that flaxseed oil does not produce an alteration in serum lipids or in the extent of hypercholesterolemic atherosclerosis; however, it decreases white blood cell chemiluminescence. The ineffectiveness of flaxseed oil was associated with its ineffectiveness in altering the levels of oxidative stress.

Animals↗
PubMed2003

Suppression of oxidative stress as a mechanism of reduction of hypercholesterolemic atherosclerosis by aspirin.

BACKGROUND: Hypercholesterolemia increases the formation of arachidonic acid and thereby synthesis of prostaglandins and leukotrienes. During synthesis of these eicosanoids, oxyradicals are produced. Oxyradicals have been implicated in the development of hypercholes-terolemic atherosclerosis. Aspirin, an inhibitor of synthesis of prostaglandins, would prevent the generation of oxyradicals and hence would prevent the development of atherosclerosis. The purpose of the investigation was to determine if aspirin attenuates the development of hypercholesterolemic atherosclerosis, and if this attenuation is associated with a decrease in the oxidative stress. METHODS AND RESULTS: Three groups of rabbits were used for this study: Group I, control; Group II, 0.5% cholesterol; Group III, 0.5% cholesterol plus 0.068% aspirin. Blood samples were collected before and after 1 and 2 months of experimental diets for measurement of serum triglycerides, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, serum malondialdehyde, and white blood cell chemiluminescence, a measure of oxyradicals produced by white blood cells. Aortas were removed at the end of the protocol for the measurement of atherosclerotic plaques, malondialdehyde and aortic chemiluminescence, a measure of antioxidant reserve. Serum total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and ratio of total cholesterol to high-density lipoprotein cholesterol increased to a similar extent in Groups II and III compared to Group I. Serum triglycerides increased in both Groups II and III; however, the increase was greater in Group III than in Group II. Levels of serum and aortic malondialdehyde, and white blood cell-chemiluminescence were higher in Group II compared to Group I. Aspirin decreased the levels of these parameters. Antioxidant reserve increased in both Groups II and III, the increase being greater in the latter than the former. White blood cell-chemiluminescence increased in Group II compared to Group I, but remained unaltered in Group III compared to Group I. Aspirin treatment reduced the development of atherosclerosis by approximately 47%. CONCLUSION: These results suggest that aspirin, an inhibitor of cyclooxygenase, reduced the development of hypercholesterolemic atherosclerosis, and this effect was associated with a decrease in the oxidative stress.

Animals↗
PubMed2002

The Cdc37 protein kinase-binding domain is sufficient for protein kinase activity and cell viability.

Cdc37 is a molecular chaperone required for folding of protein kinases. It functions in association with Hsp90, although little is known of its mechanism of action or where it fits into a folding pathway involving other Hsp90 cochaperones. Using a genetic approach with Saccharomyces cerevisiae, we show that CDC37 overexpression suppressed a defect in v-Src folding in yeast deleted for STI1, which recruits Hsp90 to misfolded clients. Expression of CDC37 truncation mutants that were deleted for the Hsp90-binding site stabilized v-Src and led to some folding in both sti1Delta and hsc82Delta strains. The protein kinase-binding domain of Cdc37 was sufficient for yeast cell viability and permitted efficient signaling through the yeast MAP kinase-signaling pathway. We propose a model in which Cdc37 can function independently of Hsp90, although its ability to do so is restricted by its normally low expression levels. This may be a form of regulation by which cells restrict access to Cdc37 until it has passed through a triage involving other chaperones such as Hsp70 and Hsp90.

Binding Sites↗