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Biomedical subjects

David Nelson

Publications and source records attributed to David Nelson.

At least 19 recordsLinked to original sources
PubMed2006

The urinary metabolite profile of the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine is predictive of colon DNA adducts after a low-dose exposure in humans.

Epidemiologic evidence indicates that exposure to heterocyclic amines in the diet is an important risk factor for the development of colon cancer. Well-done cooked meats contain significant levels of heterocyclic amines, which have been shown to cause cancer in laboratory animals. To better understand the mechanisms of heterocyclic amine bioactivation in humans, the most mass abundant heterocyclic amine, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), was used to assess the relationship between PhIP metabolism and DNA adduct formation. Ten human volunteers where administered a dietary relevant dose of [(14)C]PhIP 48 to 72 hours before surgery to remove colon tumors. Urine was collected for 24 hours after dosing for metabolite analysis, and DNA was extracted from colon tissue and analyzed by accelerator mass spectrometry for DNA adducts. All 10 subjects were phenotyped for cytochrome P4501A2 (CYP1A2), N-acetyltransferase 2, and sulfotransferase 1A1 enzyme activity. Twelve PhIP metabolites were detected in the urine samples. The most abundant metabolite in all volunteers was N-hydroxy-PhIP-N(2)-glucuronide. Metabolite levels varied significantly between the volunteers. Interindividual differences in colon DNA adducts levels were observed between each individual. The data showed that individuals with a rapid CYP1A2 phenotype and high levels of urinary N-hydroxy-PhIP-N(2)-glucuronide had the lowest level of colon PhIP-DNA adducts. This suggests that glucuronidation plays a significant role in detoxifying N-hydroxy-PhIP. The levels of urinary N-hydroxy-PhIP-N(2)-glucuronide were negatively correlated to colon DNA adduct levels. Although it is difficult to make definite conclusions from a small data set, the results from this pilot study have encouraged further investigations using a much larger study group.

Arylamine N-Acetyltransferase↗
PubMed2006

Kinase-mediated trapping of bi-functional conjugates of paclitaxel or vinblastine with thymidine in cancer cells.

In the present work, we explore the possibility of introducing selectivity to existing chemotherapeutics via the design of non-pro-drug, bi-functional molecules comprising a microtubule-binding agent and a substrate for a disease-associated kinase. The design, synthesis, and in vitro biological evaluation of paclitaxel-thymidine and vinblastine-thymidine bi-functional conjugates are reported here. This work provides the first account of 'kinase-mediated trapping' of cancer therapeutics.

Antineoplastic Agents↗
PubMed2006

Cognitive behavioral therapy for fibromyalgia.

Cognitive behavioral therapy (CBT) techniques offer short-term, goal-oriented psychotherapy. In this respect, it differs from classical psychoanalysis in emphasizing changes in thought patterns and behaviors rather than providing 'deep insight'. Importantly, the beneficial effects of CBT can be achieved in 10-20 sessions, compared with the many years required for classical psychoanalysis. Although CBT is often done on a one-to-one basis, it also lends itself to a group therapeutic setting. CBT was initially used in the treatment of mood disorders, but its use has subsequently been expanded to include various other medical conditions, including chronic pain states. Over the past 18 years, several chronic pain treatment programs have used CBT techniques in the management of fibromyalgia. In this review, the results from 13 programs using CBT, alone or in combination with other treatment modalities, are analyzed. In most studies, CBT provided worthwhile improvements in pain-related behavior, self-efficacy, coping strategies and overall physical function. Sustained improvements in pain were most evident when individualized CBT was used to treat patients with juvenile fibromyalgia. The current data indicate that CBT, as a single treatment modality, does not offer any distinct advantage over well-planned group programs of education or exercise, or both. Its role in the management of fibromyalgia patients needs further research.

Clinical Trials as Topic↗
PubMed2006

Who uses decision aids? Subgroup analyses from a randomized controlled effectiveness trial of two prostate cancer screening decision support interventions.

OBJECTIVE: To examine who reported using unsolicited prostate cancer screening decision aids distributed as part of a randomized controlled trial, whether reported use varied by type of aid (video or pamphlet), and what affect reported use had on study outcomes. METHODS: A total of 1,152 men aged 50 and older from four medical facilities in the United States were randomly assigned to pamphlet, video or usual care (control). Materials were mailed 2 weeks prior to clinic appointments in general internal medicine. Outcomes were assessed by phone survey 1 week after appointments. Analyses examined the reported use of materials by study group, the association between patient characteristics and reported use, and the impact of reported use (adjusting for patient characteristics) on a 10-item knowledge index. RESULTS: Fifty-six percent of those randomized to receive the video and 50% of those randomized to receive the pamphlet reported using the materials. Reported use of the video was higher for patients who had greater than a high school education (OR 1.73), were married (OR 2.20), and reported no prior abnormal prostate cancer screening test results (OR 3.39). Reported use of the pamphlet did not vary by patient characteristics. In intent-to-treat analyses (ignoring reported use), individuals randomized to the video and pamphlet groups had significantly higher knowledge scores relative to the control group (7.44, 7.26 and 6.90 respectively). Adjusting for reported use modestly increased the estimated differences across treatment groups but did not substantially change conclusions about the relative effects of these aids on knowledge. CONCLUSIONS: Only half of men receiving unsolicited prostate cancer screening decision aids before a visit reported using the aids, and who reported using them varied by type of aid. Efforts to broadly implement decision aids may need to offer a variety of approaches, and incorporate creative strategies to enhance reaching all population subgroups.

Aged↗
PubMed2005

High-Throughput GoMiner, an 'industrial-strength' integrative gene ontology tool for interpretation of multiple-microarray experiments, with application to studies of Common Variable Immune Deficiency (CVID).

BACKGROUND: We previously developed GoMiner, an application that organizes lists of 'interesting' genes (for example, under-and overexpressed genes from a microarray experiment) for biological interpretation in the context of the Gene Ontology. The original version of GoMiner was oriented toward visualization and interpretation of the results from a single microarray (or other high-throughput experimental platform), using a graphical user interface. Although that version can be used to examine the results from a number of microarrays one at a time, that is a rather tedious task, and original GoMiner includes no apparatus for obtaining a global picture of results from an experiment that consists of multiple microarrays. We wanted to provide a computational resource that automates the analysis of multiple microarrays and then integrates the results across all of them in useful exportable output files and visualizations. RESULTS: We now introduce a new tool, High-Throughput GoMiner, that has those capabilities and a number of others: It (i) efficiently performs the computationally-intensive task of automated batch processing of an arbitrary number of microarrays, (ii) produces a human-or computer-readable report that rank-orders the multiple microarray results according to the number of significant GO categories, (iii) integrates the multiple microarray results by providing organized, global clustered image map visualizations of the relationships of significant GO categories, (iv) provides a fast form of 'false discovery rate' multiple comparisons calculation, and (v) provides annotations and visualizations for relating transcription factor binding sites to genes and GO categories. CONCLUSION: High-Throughput GoMiner achieves the desired goal of providing a computational resource that automates the analysis of multiple microarrays and integrates results across all of the microarrays. For illustration, we show an application of this new tool to the interpretation of altered gene expression patterns in Common Variable Immune Deficiency (CVID). High-Throughput GoMiner will be useful in a wide range of applications, including the study of time-courses, evaluation of multiple drug treatments, comparison of multiple gene knock-outs or knock-downs, and screening of large numbers of chemical derivatives generated from a promising lead compound.

Binding Sites↗
PubMed2005

Temperature and gas-phase composition measurements in supersonic flows using tunable diode laser absorption spectroscopy: the effect of condensation on the boundary-layer thickness.

We used a tunable diode laser absorption spectrometer and a static-pressure probe to follow changes in temperature, vapor-phase concentration of D2O, and static pressure during condensation in a supersonic nozzle. Using the measured static-pressure ratio p/p0 and the mass fraction of the condensate g as inputs to the diabatic flow equations, we determined the area ratio (A/A*)wet and the corresponding centerline temperature of the flow during condensation. From (A/A*)wet we determined the boundary-layer displacement thickness during condensation (delta#)wet. We found that (delta#)wet first increases relative to the value of delta# in a dry expansion (delta#)Dry before becoming distinctly smaller than (delta#)Dry downstream of the condensation region. After correcting the temperature gradient across the boundary layers, the temperature determined from p/p0 and g agreed with the temperature determined by the laser-absorption measurements within our experimental error (+/-2 K), except when condensation occurred too close to the throat. The agreement between the two temperature measurements let us draw the following two conclusions. First, the differences in the temperature and mole fraction of D2O determined by the two experimental techniques, first observed in our previous study [P. Paci, Y. Zvinevich, S. Tanimura, B. E. Wyslouzil, M. Zahniser, J. Shorter, D. Nelson, and B. McManus, J. Chem. Phys. 121, 9964 (2004)], can be explained sufficiently by changes in delta# caused by the condensation of D2O, except when the phase transition occurs too close to the throat. Second, the extrapolation of the equation, which expresses the temperature dependence of the heat of vaporization of bulk D2O liquid, is a good estimate of the heat of condensation of supercooled D2O down to 210 K.

Journal Article↗
PubMed2005

Acute and chronic effects of sildenafil in patients with pulmonary arterial hypertension.

Sildenafil and inhaled nitric oxide (iNO) relax smooth muscle by inhibiting the degradation and stimulating the production of cyclic guanosine monophosphate, respectively. We compared the acute pulmonary vasodilator effects of sildenafil, iNO, and epoprostenol and asked whether the combination of iNO with sildenafil had additive pulmonary vasodilator effects. We assessed the effects of extended use of sildenafil in a small cohort of patients. Twenty patients with pulmonary arterial hypertension underwent an acute vasodilator trial with sildenafil (all patients), iNO and iNO plus sildenafil (11), and epoprostenol (19). We also provided sildenafil to patients who were ineligible for, or had clinical deterioration on epoprostenol, treprostinil, or bosentan. Mean+/-se pulmonary artery pressure dropped by 13+/-3%, 19+/-4%, 14+/-3%, and 26+/-4% with epoprostenol, iNO, sildenafil, and iNO+sildenafil, respectively. Cardiac index increased with epoprostenol and sildenafil. A correlation was found between the effects of iNO and epoprostenol. Nine out of ten patients who were started on long-term sildenafil treatment alone or in combination with other vasodilators had symptomatic improvement. Three died of right heart failure. In conclusion, sildenafil is a potent acute pulmonary vasodilator, an effect that is potentiated by combination with iNO. Long-term therapy of pulmonary hypertension with sildenafil alone or in combination with other agents appears to be safe and well tolerated.

Administration, Inhalation↗
PubMed2005

Risk factors for carbamazepine elevation and toxicity following epilepsy surgery.

UNLABELLED: A proportion of patients undergoing epilepsy surgery, and receiving carbamazepine (CBZ), experience significant elevations in CBZ plasma concentrations, some with associated CBZ toxicity. The objective of this study was to identify significant risk factors for elevations (>12 microg/ml) in CBZ concentrations and CBZ-induced toxicity following epilepsy surgery. METHODS: We retrospectively examined charts of 74 inpatients (31 children and 43 adults) chronically receiving CBZ and undergoing epilepsy surgery between January 1996 and June 2000. Patient demographics, medications, type of surgery, seizure history, adverse events, CBZ doses and concentrations were evaluated. RESULTS: 51.2% of adults and 51.6% of pediatric patients had drug elevations. In the pediatric group, 12.9% had symptoms of toxicity compared to 9.3% in the adult group. Five risk factors-pre-operative CBZ dose, fentanyl dose, surgery day CBZ concentration, body weight, and blood loss-were related to post-operative CBZ concentrations. Three risk factors: age <18 years, pre-operative CBZ dose, and the surgery day CBZ (immediate pre-operative) concentration, were significantly related to the outcome measure of abnormal CBZ concentration (>12 microg/ml). Two variables significantly related to toxicity were average post-operative CBZ dose and the surgery day CBZ concentration. Increases in concentrations occurred at a mean 33+/-13.7 h (range: 11-74 h) after surgery. DISCUSSION: Based upon our results in patients with one or more risk factors, we suggest that reduction of post-operative CBZ doses be considered.

Adolescent↗
PubMed2005

The outcome consequences of defunding the Minnesota youth tobacco-use prevention program.

OBJECTIVE: To assess the immediate and intermediate outcome consequences of defunding a successful tobacco use prevention program. METHODS: A four-survey repeated cross-sectional design is employed. Two surveys were completed while the program was fully operational, one after program dismantling was initiated and another about 6 months after the campaign was completely dismantled. Survey to survey trends for five immediate and six intermediate outcomes are analyzed. Changes in measures are tested employing chi-square estimated using SAS 8. RESULTS: Each immediate outcome measure declined significantly from the third to the fourth survey except one, and this measure declined from the second to the third survey when it was eliminated. All intermediate outcomes showed significant change from the third or second to the fourth survey. These include two measures of openness to smoking, three attitude/belief scales and one measure of intention to smoke. CONCLUSIONS: Defunding a successful tobacco-use prevention campaign results in rapid erosion of program messages, parallel increases in susceptibility, a rapid and sharp re-emergence of pro-tobacco attitudes/beliefs and a marked rise in intentions to smoke.

Adolescent↗
PubMed2005

Low-dose irradiation alters the transcript profiles of human lymphoblastoid cells including genes associated with cytogenetic radioadaptive response.

Low-dose ionizing radiation alters the gene expression profiles of mammalian cells, yet there is little understanding of the underlying cellular mechanisms responsible for these changes or of their consequences for genomic stability. We investigated the cytogenetic adaptive response of human lymphoblastoid cell lines exposed to 5 cGy (priming dose) followed by 2 Gy (challenge dose) compared to cells that received a single 2-Gy dose to (a) determine how the priming dose influences subsequent gene transcript expression in reproducibly adapting and non-adapting cell lines, and (b) identify gene transcripts that are associated with reductions in the magnitude of chromosomal damage after the challenge dose. The transcript profiles were evaluated using oligonucleotide arrays and RNA obtained 4 h after the challenge dose. A set of 145 genes (false discovery rate = 5%) with transcripts that were affected by the 5-cGy priming dose fell into two categories: (a) a set of common genes that were similarly modulated by the 5-cGy priming dose irrespective of whether the cells subsequently adapted or not and (b) genes with differential transcription in accordance with the cell lines that showed either adaptive or non-adaptive outcomes. The common priming-dose response genes showed up-regulation for protein synthesis genes and down-regulation of metabolic and signal transduction genes (>10-fold differences). The genes associated with subsequent adaptive and non-adaptive outcomes involved DNA repair, stress response, cell cycle control and apoptosis. Our findings support the importance of TP53-related functions in the control of the low-dose cytogenetic radioadaptive response and suggest that certain low-dose-induced alterations in cellular functions are predictive for the risk of subsequent genomic damage.

Adaptation, Physiological↗
PubMed2004

Spatially resolved gas phase composition measurements in supersonic flows using tunable diode laser absorption spectroscopy.

We used a tunable diode laser absorption spectrometer to follow the condensation of D(2)O in a supersonic Laval nozzle. We measured both the concentration of the condensible vapor and the spectroscopic temperature as a function of position and compared the results to those inferred from static pressure measurements. Upstream and in the early stages of condensation, the quantitative agreement between the different experimental techniques is good. Far downstream, the spectroscopic results predict a lower gas phase concentration, a higher condensate mass fraction, and a higher temperature than the pressure measurements. The difference between the two measurement techniques is consistent with a slight compression of the boundary layers along the nozzle walls during condensation.

Journal Article↗
PubMed2004

Effectiveness of statin therapy in adults with coronary heart disease.

BACKGROUND: We conducted a meta-analysis of patients with coronary heart disease (CHD) to determine the effectiveness of statin therapy; whether effectiveness varied according to patient characteristics, outcomes, or pretreatment low-density lipoprotein cholesterol (LDL-C) levels; and the optimal LDL-C goal and the level at which to initiate statin therapy. METHODS: Randomized trials or systematic reviews for secondary prevention of CHD with statin therapy published between January 1966 and December 2002 were identified through MEDLINE and the Cochrane Library. Studies were included if they randomly assigned adults with CHD to statin therapy or control, enrolled at least 100 individuals per arm, reported clinical outcomes and LDL-C levels, and were published as full studies in English. Two reviewers abstracted data using a prospectively designed protocol. RESULTS: Twenty-five studies enrolling 69 511 individuals were included. Participants in 19 placebo-controlled trials had a mean age of 63 years and a mean pretreatment LDL-C level of 149 mg/dL (3.85 mmol/L); 23% were women. Statin therapy reduced CHD mortality or nonfatal myocardial infarction 25% (relative risk [RR], 0.75; 95% confidence interval [CI], 0.71-0.79), all-cause mortality 16% (RR, 0.84; 95% CI, 0.79-0.89), and CHD mortality 23% (RR, 0.77; 95% CI, 0.71-0.83). Beneficial effects were seen in women and the elderly. There were no data to determine whether lowering the LDL-C level to less than 100 mg/dL (<2.59 mmol/L) was superior to lowering it to 100 to 130 mg/dL (2.59-3.36 mmol/L). Meta-regression analyses revealed risk reductions for CHD mortality or nonfatal myocardial infarction and major vascular events across available pretreatment LDL-C levels. CONCLUSION: Statin therapy reduces mortality and morbidity in adults with CHD, even at pretreatment LDL-C levels as low as 100 mg/dL (2.59 mmol/L).

Adult↗
PubMed2004

Effects of temperature on intracellular sodium, pH and cellular energy status in RIF-1 tumor cells.

Most perfused tumor cell experiments are performed at 37 degrees C, the normal healthy body temperature. However, the temperature of subcutaneously implanted tumors in small animals is generally 29-33 degrees C when the rectal temperature of the animal is maintained at 37 degrees C. We have investigated the acute effects of increasing the temperature of perfused radiation-induced-fibrosarcoma (RIF-1) tumor cells from 33 to 37 degrees C (30 min) on intracellular sodium (Na(i)+) , intracellular pH (pH(i)), and bioenergetic status. Heating the cells by 4 degrees C produced a reversible increase in Na(i)+, slight acidification and no change in nucleotide triphosphate to inorganic phosphate ratio (NTP/P(i)) as measured by shift-reagent-aided (23)Na and (31)P NMR spectroscopy. In the presence of 3 microM 5-(N-ethyl-N-isopropyl) amiloride (EIPA), a potent and specific inhibitor of Na(+)/H(+) antiporter, the increase in Na(i)+ during the heating was completely abolished suggesting that the heat induced increase in Na(i)+ was caused by an increase in Na(+)/H(+) antiporter activity. However, the changes in pH(i) with the heating were identical with or without EIPA, indicating that pH(i) is controlled by other ion exchange mechanisms in addition to Na(+)/H(+) antiporter. NTP/P(i) was significantly higher in presence of EIPA for some time points during the heating suggesting that both NTP production and consumption rates may be altered during the heating. These results indicate that a slight increase in temperature from 33 to 37 degrees C induces significant changes in Na(+) physiology largely because of activation of Na(+)/H(+) antiporter but other ion exchange mechanisms are also involved in maintaining pH(i) in the RIF-1 tumor cells. Thus, care must be taken in choosing the temperature for perfused cell studies.

Animals↗
PubMed2004

Measuring patient knowledge of the risks and benefits of prostate cancer screening.

This manuscript describes the development and validation of measures assessing patient knowledge about the risks and benefits of prostate cancer (CaP) screening. The measures described include a 10-item knowledge index and four single-item measures, used in previous studies, that assess knowledge of: CaP natural history and treatment efficacy, expert disagreement over the value of CaP screening, and the accuracy of the prostate specific antigen (PSA) test for CaP. We assessed the validity and reliability of these measures on a sample of 1152 male veteran patients age 50 and older. All knowledge index items had acceptable levels of discrimination, difficulty, and reliability. The index demonstrated strong evidence for construct and criterion validity. Much weaker validity evidence was found for the four single-item knowledge questions. The 10-item index developed in this study provides a valid and reliable tool for assessing patient knowledge of the risks and benefits of CaP screening.

Aged↗
PubMed2004

Outcomes of patients with do-not-intubate orders treated with noninvasive ventilation.

OBJECTIVE: To determine whether diagnosis and bedside observations predict outcomes of patients who have declined intubation but accept noninvasive positive pressure ventilation (NPPV) to treat their respiratory failure. DESIGN: Prospective multiple-center cohort trial. SETTING: Two teaching hospitals and two community-based hospitals in southeastern New England from January through October 1999. PATIENTS: All patients receiving NPPV for acute respiratory failure were screened and enrolled if they had a written do-not-intubate (DNI) order. INTERVENTIONS: Patients were begun on NPPV with mean inspiratory and expiratory pressures of 13.4 +/- 0.3 and 5.0 +/- 1 cm H2O, respectively. Respiratory therapists recorded demographic information, blood gases, and ventilator type and settings, and they made bedside assessments of cough strength, presence of airway secretions, awake state, and agitation. Patients were followed until discharge for duration of NPPV, survival status, and disposition. MEASUREMENTS AND MAIN RESULTS: Of 1,211 screened patients, 114 had a DNI status and were enrolled into the study. Of these, 49 (43%) survived to discharge. Age, gender, location in a community vs. teaching hospital, and initial pH and PaO2 did not affect survival, but a higher baseline PaCO2 was associated with a favorable odds ratios for survival to discharge. Diagnosis was an important determinant of survival, with congestive heart failure patients having significantly better survival rates than those with chronic obstructive pulmonary disease, cancer, pneumonia, or other diagnoses. A stronger cough and being awake were also associated with increased probability of survival. CONCLUSION: Patients with respiratory failure and a DNI status have a high overall mortality rate when treated with NPPV, but those with diagnoses such as congestive heart failure or chronic obstructive pulmonary disease, who have a strong cough, or who are awake have better prognoses. These data should be useful when counseling DNI patients and their families on use of NPPV.

Aged↗