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Biomedical subjects

James E Hansen

Publications and source records attributed to James E Hansen.

18 recordsLinked to original sources
PubMed2006

Ethnic- and sex-free formulae for detection of airway obstruction.

RATIONALE: Spirometric detection of airway obstruction in adults requires separate predictive formulae for each ethnicity and sex for percentage of FEV(1)/FVC (%FEV(1)/FVC) and percentage of FEV(3)/FVC (%FEV(3)/FVC), the major measurements for defining airway obstruction. OBJECTIVES: To eliminate the need for multiple formulae for black, Latin, and white men and women by developing single formulae with less variance than current formulae for %FEV(1)/FVC and %FEV(3)/FVC. METHODS: Data from nearly 6,000 healthy never-smokers 20.0-79.9 yr of age in the Third National Health and Nutrition Examination Survey were reevaluated mathematically and graphically based on the preliminary hypothesis that predictive normal FEV(1)/FVC and FEV(3)/FVC ratios could be calculated from the age and FVC alone, without considering ethnicity, sex, or height. Current and new formulae were evaluated, first considering the population as consisting of 36 equally weighted subgroups (6 decades x 3 ethnicities x 2 sexes) and then weighting each individual equally. MEASUREMENTS AND RESULTS: For each year of age, the slope of %FEV(1)/FVC versus FVC approximated -1.8%/l/yr; the slope of %FEV(3)/FVC versus FVC approximated -0.8%/l/yr. After trial and error iterations, the optimal formulae were %FEV(1)/FVC = 98.8 - 0.25 x years - 1.79 x FVC and %FEV(3)/FVC = 105.4 - 0.20 x years - 0.75 x FVC. CONCLUSIONS: These two new predicting formulae for %FEV(1)/FVC and %FEV(3)/FVC, which require only age and FVC as variables, approximate actual values closer than previously published separate formulae for each ethnicity and sex. With 95% confidence limits, they should allow better discrimination between normality and airway obstruction in adults of at least these three ethnicities.

Adult↗
PubMed2006

Antibody-mediated Hsp70 protein therapy.

Intracellular Hsp70 provides cytoprotection against a variety of stressful stimuli, and an effective means of increasing intracellular Hsp70 levels could prove beneficial in the prevention and treatment of a variety of human diseases. A novel protein transduction domain consisting of the single chain Fv fragment of an anti-DNA antibody known to penetrate into living cells and tissues, mAb 3E10, has recently been used to deliver functional proteins to cells. The ability of the single chain Fv fragment to deliver Hsp70 into living cells was tested by generating an Fv-Hsp70 fusion protein. Fv-Hsp70 was produced as a secreted protein in both COS-7 cells and the methylotropic yeast strain Pichia pastoris and was shown capable of penetrating into COS-7 cells and primary rat cortical neurons. Pre-treatment with Fv-Hsp70 protected both COS-7 cells and primary rat cortical neurons against subsequent exposure to hydrogen peroxide. These results provide the first evidence that the Fv fragment of mAb 3E10 is capable of delivering proteins to neurons and indicate its potential in the development of Hsp70 protein therapy.

Animals↗
PubMed2006

Role of p21-activated kinase pathway defects in the cognitive deficits of Alzheimer disease.

Defects in dendritic spines are common to several forms of cognitive deficits, including mental retardation and Alzheimer disease. Because mutation of p21-activated kinase (PAK) can lead to mental retardation and because PAK-cofilin signaling is critical in dendritic spine morphogenesis and actin dynamics, we hypothesized that the PAK pathway is involved in synaptic and cognitive deficits in Alzheimer disease. Here, we show that PAK and its activity are markedly reduced in Alzheimer disease and that this is accompanied by reduced and redistributed phosphoPAK, prominent cofilin pathology and downstream loss of the spine actin-regulatory protein drebrin, which cofilin removes from actin. We found that beta-amyloid (Abeta) was directly involved in PAK signaling deficits and drebrin loss in Abeta oligomer-treated hippocampal neurons and in the Appswe transgenic mouse model bearing a double mutation leading to higher Abeta production. In addition, pharmacological PAK inhibition in adult mice was sufficient to cause similar cofilin pathology, drebrin loss and memory impairment, consistent with a potential causal role of PAK defects in cognitive deficits in Alzheimer disease.

Actin Depolymerizing Factors↗
PubMed2006

Discriminating measures and normal values for expiratory obstruction.

OBJECTIVES: To develop mean and 95% confidence limits for the lower limit of normal (LLN) values for forced expiratory volume in 3 s (FEV3)/FVC ratio for Latin, black, and white adults; to ascertain comparative variability of the FEV1/FVC ratio, the FEV3/FVC ratio, and forced expiratory flow, midexpiratory phase (FEF(25-75)) in never-smoking adults; to evaluate their utility in measuring the effect of smoking on airflow limitation; and to develop and use the fraction of the FVC that had not been expired during the first 3 s of the FVC (1 - FEV3/FVC) to identify the growing fraction of long-time-constant lung units. DESIGN: Analysis of the Third National Health and Nutrition Examination Survey (NHANES III) database of never-smokers and current smokers. PARTICIPANTS: A total of 5,938 adult never-smokers and 3,570 current smokers from NHANES III with spirometric data meeting American Thoracic Society standards. MEASUREMENTS AND RESULTS: After establishing new databases for never-smokers and current smokers, we quantified the mean and LLN values of FEV3/FVC in never-smokers, and identified spirometric abnormalities in current smokers. When associated with older age, FEV3/FVC decreases and 1 - FEV3/FVC increases as FEV1/FVC decreases. On average, using these measurements, the condition of current smokers worsened about 20 years faster than that of never-smokers by middle age. If < 80% of the mean predicted FEF(25-75) was used to identify abnormality, over one quarter of all never-smokers would have been falsely identified as being abnormal. Using 95% confidence limits, 42% of 683 smokers with reduced FEV1/FVC and/or FEV3/FVC would have been judged as normal by FEF(25-75). CONCLUSIONS: FEV1/FVC, FEV3/FVC, and 1 - FEV3/FVC characterize expiratory obstruction well. In contrast, FEF(25-75) measurements can be misleading and can cause an unacceptably large number of probable false-negative results and probable false-positive results.

Adult↗
PubMed2005

Cardiopulmonary exercise testing and six-minute walk correlations in pulmonary arterial hypertension.

In a clinical trial of 178 patients with pulmonary arterial hypertension, treatment improved the 6-minute walk (6MW) distance but not the peak VO2. To clarify this discrepancy, we examined the exercise data from all study sites. Patients received either the endothelin receptor antagonist sitaxsentan or placebo and underwent serial 6MW and cardiopulmonary exercise testing (CPET). In 518 pairs of body weight-adjusted and unadjusted 6MW and CPET data, the correlation between 6MW and peak VO2 was 0.48. In the 4 sites with the highest overall correlation at baseline (r = 0.62 compared with 0.46 for the other 19 sites, p = 0.04), the correlations at baseline (0.66) and at week 12 (0.65) were similar (p = 0.90). However, the correlation increased significantly from baseline (0.34) to week 12 (0.54, p = 0.0005) for the other 19 sites. The correlations between weight-adjusted 6MW distance and peak VO2 for all centers (0.76) were significantly higher than the unadjusted correlations (0.48, p < 0.0001). Improvement in the correlations over time between the 6MW and CPET data at less-experienced sites was most consistent with improved technical skill with increasing experience. Weight adjustment of the 6MW improved its correlation with peak VO2. In conclusion, in future multicenter trials, CPET expertise should be validated at all sites before subject enrollment.

Adolescent↗
PubMed2005

Antibody mediated transduction of therapeutic proteins into living cells.

Protein therapy refers to the direct delivery of therapeutic proteins to cells and tissues with the goal of ameliorating or modifying a disease process. Current techniques for delivering proteins across cell membranes include taking advantage of receptor-mediated endocytosis or using protein transduction domains that penetrate directly into cells. The most commonly used protein transduction domains are small cell-penetrating peptides derived from such proteins as the HIV-1 Tat protein. A novel protein transduction domain developed as the single chain fragment (Fv) of a murine anti-DNA autoantibody, mAb 3E10, has recently been developed and used to deliver biologically active proteins to living cells in vitro. This review will provide a brief overview of the development of the Fv fragment and provide a summary of recent studies using Fv to deliver therapeutic peptides and proteins (such as a C-terminal p53 peptide, C-terminal p53 antibody fragment, full-length p53, and micro-dystrophin) to cells.

Animals↗
PubMed2005

An intracellular delivery vehicle for protein transduction of micro-dystrophin.

The Fv fragment of an antibody that selectively targets and penetrates skeletal muscle in vivo was produced as a fusion protein with a micro-dystrophin for use as a delivery vehicle to transport micro-dystrophin into muscle cells. Fv-micro-dystrophin was produced as a secreted protein by transient transfection of Fv-micro-dystrophin cDNA in COS-7 cells and as a non-secreted protein by permanent transfection in Pichia pastoris. Isolated Fv-micro-dystrophin was shown to be full-length by Western blot analysis. Fv-micro-dystrophin penetrated multiple cell lines in vitro, and it localized to the plasma membrane of a cell line with membrane beta-dystroglycan. In the absence of membrane beta-dystroglycan, it localized to the cytoplasm. Antibody-mediated transduction of micro-dystrophin into muscle cells is a potential therapy for dystrophin-deficient muscular dystrophies.

Animals↗
PubMed2005

End-tidal PCO2 abnormality and exercise limitation in patients with primary pulmonary hypertension.

OBJECTIVES: Primary pulmonary hypertension (PPH) is a pulmonary vasculopathy resulting in exercise intolerance, usually due to dyspnea. We hypothesized that ventilation is increased during exercise in PPH relative to normal because the ventilated lung is underperfused, cardiac output increase is restricted, and arterial hypoxemia may develop. Our aim was to determine the size of the reduction in end-tidal Pco(2) (Petco(2)) as a reflection of the abnormality in ventilatory efficiency and ventilatory drive in PPH patients. METHODS: We performed cardiopulmonary exercise testing (CPET) in 52 PPH patients. All had hemodynamic measurements to confirm the diagnosis of PPH. A subgroup of 29 patients who underwent right-heart catheterization within 50 days of CPET were studied to compare their CPET responses to resting hemodynamics. Nine healthy volunteers matched for age and gender served as CPET control subjects. RESULTS: In PPH patients, the percentage of predicted peak oxygen uptake (Vo(2)) correlated significantly with mean pulmonary artery pressure (mPAP) [r = - 0.59, p = 0.0007, n = 29]. Petco(2) values at rest, anaerobic threshold (AT), and peak Vo(2) were proportionately reduced as percentage of predicted peak Vo(2) decreased (r = 0.66 to 0.72, p < 0.0001, n = 52). Petco(2) values at rest, AT, and peak Vo(2) were also reduced as mPAP increased (r = - 0.51 to - 0.53, p < 0.005, n = 29). In contrast to normal subjects in whom Petco(2) increased from rest to AT, Petco(2) decreased in PPH patients, except for two patients with mild PPH in whom there was no change. Also, Petco(2) increased rather than decreased further at the start of recovery, in contrast to normal. Although usually normal at rest, oxyhemoglobin saturation decreased during exercise in most PPH patients. CONCLUSIONS: In patients with PPH, Petco(2) at rest and exercise is significantly reduced in proportion to physiologic disease severity. The range of values is unusually low. Furthermore, the directional changes of Petco(2) during exercise and early recovery are in the opposite direction of normal.

Adult↗
PubMed2004

Reproducibility of cardiopulmonary exercise measurements in patients with pulmonary arterial hypertension.

BACKGROUND AND OBJECTIVES: As part of a recent study, cardiopulmonary exercise tests (CPETs) were used to evaluate and follow up patients with pulmonary arterial hypertension (PAH). These patients were more impaired than those in other published series evaluating CPET reproducibility. We used these patient tests to assess patient performance variability and evaluate reading variability. To achieve this end, six independent evaluators graded key CPET measurements in patients with PAH who underwent duplicate CPETs within 3 days of each other. SETTING AND PATIENTS: Over a 15-month period at two tertiary-care teaching hospitals, 42 patients with PAH underwent repeated, paired CPETs using cycle ergometry. INTERVENTIONS AND MEASUREMENTS: Each patient underwent one to six pairs of cycle ergometry tests to maximal tolerance. Each pair of tests was separated by 3 months, with each test in the pair separated by 1 to 3 days. Specific guidelines were given to the independent evaluators for the key measurements assessed from each CPET study: peak O(2) uptake (Vo(2)), peak heart rate, peak O(2) pulse, anaerobic threshold (AT), and end-tidal Po(2), end-tidal Pco(2), and the ventilatory equivalent for CO(2) at the AT (Ve/Vco(2)@AT). RESULTS: There were no fatalities or complications occurring among the 242 tests performed on 42 patients. The mean peak Vo(2) was 722 mL/min or 41% of predicted; 34 patients were Weber class C or D. Using the specific guidelines to measure the variability of measurements made by the six independent evaluators, the coefficients of variation were < 2.2% for peak Vo(2), peak heart rate, peak O(2) pulse, end-tidal values at the AT, and Ve/Vco(2)@AT, while for the AT, it was 8.5%. There were no significant differences in these measurements between the first and second tests of any pair or between the earlier and later sets of pairs. CONCLUSIONS: Using specific guidelines, key CPET measurements can be safely, reliably, and reproducibly assessed even in patients with severe exercise intolerance.

Adolescent↗
PubMed2004

Antibody-mediated transduction of p53 selectively kills cancer cells.

Some human cancers are caused by functional defects in p53 that are restored by gene therapy with wild-type p53. To circumvent the use of viral vectors, we reconstituted cancer cell lines with p53 by protein transduction. A fusion protein was produced from cDNA constructed from the Fv fragment of an antibody that penetrates living cells and wild-type p53 (Fv-p53). Fv-p53 penetrated and killed cancer cells that do not express p53. Additionally, Fv-p53 killed cancer cells that were malignant as a result of mutations within p53, nuclear exclusion of p53 and over-expression of MDM2. Non-specific toxicity was excluded by showing that Fv-p53 penetrated but did not kill primary cells and cancer cells unresponsive to p53. Fv fragments alone were not cytotoxic, indicating that killing was due to transduction of p53. Fv-p53 was shown to penetrate cancer cells engrafted in vivo. These results support continued efforts to evaluate the potential efficacy of Fv-p53 for the treatment of certain cancers in vivo.

Antibody Formation↗
PubMed2003

Pulmonary function in primary pulmonary hypertension.

OBJECTIVES: The study was done to ascertain the degree to which abnormalities in resting lung function correlate with the disease severity of patients with primary pulmonary hypertension (PPH). BACKGROUND: Patients with PPH are often difficult to diagnose until several years after the onset of symptoms. Despite the seriousness of the disorder, the diagnosis of PPH is often delayed because it is unsuspected and requires invasive measurements. Although PPH often causes abnormalities in resting lung function, these abnormalities have not been shown to be statistically significant when correlated with other measures of PPH severity. METHODS: Resting lung mechanics and diffusing capacity for carbon monoxide DL(CO) were assessed in 79 patients whose findings conformed to the classical diagnostic criteria of PPH and who had no evidence of secondary causes of pulmonary hypertension. These findings were correlated with severity of disease as assessed by cardiac catheterization, New York Heart Association (NYHA) class, and cardiopulmonary exercise testing. RESULTS: When PPH patients were first evaluated at our referral clinic, the DL(CO) and lung volumes were decreased in approximately three-quarters and one-half, respectively. The decreases in DL(CO), and to a lesser extent lung volumes, correlated significantly with decreases in peak oxygen uptake (reflecting maximum cardiac output), peak oxygen pulse (reflecting maximum stroke volume), and anaerobic threshold (reflecting sustainable exercise capacity) and higher NYHA class. CONCLUSIONS: Patients with PPH commonly have abnormalities in lung mechanics and DL(CO) levels that correlate significantly with disease severity. These measurements can be useful in evaluating patients with unexplained dyspnea and fatigue.

Adult↗
PubMed2002

Ventilatory efficiency during exercise in healthy subjects.

When evaluating dyspnea in patients with heart or lung disease it is useful to measure the quantity of ventilation needed to eliminate metabolically produced CO2 (i.e., the ventilatory efficiency). Mathematically, the relationship between ventilation (VE) and CO2 output is determined by the arterial CO2 pressure and the physiologic dead space-tidal volume ratio. We decided to determine how age, sex, size, fitness, and the type of ergometer influenced ventilatory efficiency in normal subjects. Three methods were compared for expressing this relationship: (1) the VE versus CO2 output slope below the ventilatory compensation point, commonly used by cardiologists for estimating the severity of heart failure; (2) the VE/CO2 output ratio at the anaerobic threshold, commonly used by pulmonologists; and (3) the lowest VE/CO2 output ratio during exercise, the latter parameter not previously reported. We studied 474 healthy adults, between 17 and 78 years of age during incremental cycle and treadmill cardiopulmonary exercise tests at three test sites, correcting the total VE for the equipment dead space. The lowest VE/CO2 output ratio was insignificantly different from the ratio at the anaerobic threshold, less variable than that for the slope relationship, and unaffected by the site, ergometer, and gas exchange measurement systems. The regression equation for the lowest VE/CO2 output ratio was 27.94 + 0.108 x age + (0.97 = F, 0.0 = M) - 0.0376 x height, where age is in years and height is in centimeters. We conclude that the lowest VE/CO2 output ratio is the preferred noninvasive method to estimate ventilatory inefficiency.

Adult↗
PubMed2002

Gas exchange detection of exercise-induced right-to-left shunt in patients with primary pulmonary hypertension.

BACKGROUND: Because of high pulmonary vascular resistance in patients with primary pulmonary hypertension (PPH), right atrial pressure may exceed left atrial pressure during exercise, resulting in a right-to-left shunt via a patent foramen ovale (PFO). This shunting would disturb arterial PCO2 and H+ homeostasis if the pulmonary blood were not simultaneously hyperventilated to compensate for the high CO2 and H+ in the shunted blood. This article first hypothesizes and then describes unique changes in gas exchange when right-to-left exercise-induced shunting (EIS) occurs. METHODS AND RESULTS: Retrospectively, the cardiopulmonary exercise tests of 71 PPH patients were studied. Criteria postulated to document hyperventilation of the pulmonary blood flow due to a right-to-left EIS were (1) an abrupt and sustained increase in end-tidal O2 with a simultaneous sustained decrease in end-tidal CO2; (2) an abrupt and sustained increase in the respiratory exchange ratio; and (3) usually, an associated decline in pulse oximetry saturation. Each patient was evaluated for a PFO with resting echocardiography. The investigators interpreting the gas exchange evidence of EIS were blinded to the echocardiographic readings. Forty-five percent of the patients had demonstrable EIS by gas exchange criteria. Almost all were also positive for a PFO by echocardiography. Using the resting echocardiograph as the reference, the sensitivity, specificity, positive and negative predictive values, and accuracy were all between 90% to 96%. CONCLUSIONS: Exercise-induced right-to-left shunting can be detected by noninvasive, cardiopulmonary exercise testing in patients with PPH.

Adult↗
PubMed2002

Muscle deoxygenation as related to work rate.

PURPOSE: The kinetics of the decrease in venous O(2) content in response to constant work rate exercise below the lactic acidosis threshold (LAT) is very rapid, reaching a constant value by approximately 1 min. However, for work rates above the LAT, a slow further decrease in venous O(2) content takes place that is attributable to the Bohr effect rather than further decrease in end capillary PO. We hypothesized that similar differences, with respect to the LAT, will be observed in muscle deoxygenation kinetics when studied with near-infrared spectroscopy (NIRS). METHODS: Twelve normal subjects performed three constant work rate tests from unloaded cycling at 60% of LAT, 80% LAT, each with four repetitions, and above LAT (LAT + 35% between LAT and VO(2max) three times, on a cycle ergometer for 6 min. We measured tissue deoxygenation with NIRS, with the probe over the vastus lateralis muscle, time-averaging the repetitions. Gas exchange and heart rate (HR) were measured breath-by-breath and beat-by-beat. RESULTS: Tissue deoxygenation kinetics were significantly faster than VO(2) and HR at 60%- and 80%-LAT work rates. By 1 min of exercise, deoxygenation was constant for the work rate below the LAT. At 30 s, tissue deoxygenation was 70-95% complete, whereas VO(2) and HR were only 30-60% complete. For the work rate above the LAT, a steady state for muscle deoxygenation was not reached during the 6 min of exercise. After 1 min of above-LAT exercise, either one of two patterns of slow change in tissue oxygenation developed, deoxygenation or reoxygenation. It is postulated that these different responses might be due to effects of the exercise lactic acidosis. H accompanying lactate increase might cause further deoxygenation due to the Bohr effect, and acidosis-induced vasodilatation might cause reoxygenation after the initial deoxygenation. CONCLUSION: 1) The kinetics of tissue deoxygenation are significantly more rapid than VO(2) and HR kinetics at all work rates studied, and 2) steady-state in tissue deoxygenation is seen by 1 min of constant work rate exercise below the LAT, but this is much delayed for work rates above the LAT.

Acidosis, Lactic↗