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K Wasserman

Publications and source records attributed to K Wasserman.

At least 37 records · Page 2Linked to original sources
PubMed1999

Vascular endothelial growth factor and basic fibroblast growth factor induce expression of CXCR4 on human endothelial cells: In vivo neovascularization induced by stromal-derived factor-1alpha.

The contribution of chemokines toward angiogenesis is currently a focus of intensive investigation. Certain members of the CXC chemokine family can induce bovine capillary endothelial cell migration in vitro and corneal angiogenesis in vivo, and apparently act via binding to their receptors CXCR1 and CXCR2. We used an RNAse protection assay that permitted the simultaneous detection of mRNA for various CXC chemokine receptors in resting human umbilical vein endothelial cells (HUVECs) and detected low levels of only CXCR4 mRNA. Stimulation of HUVECs with vascular endothelial growth factor (VEGF) or basic fibroblast growth factor (bFGF) up-regulated levels of only CXCR4 mRNA. CXCR4 specifically binds the chemokine stromal-derived factor-1alpha (SDF-1alpha). Competitive binding studies using 125I-labeled SDF-1alpha with Scatchard analysis indicated that VEGF or bFGF induced an average number of approximately 16,600 CXCR4 molecules per endothelial cell, with a Kd = 1.23 x 10(-9) mol/L. These receptors were functional as HUVECs and human aorta endothelial cells (HAECs) migrated toward SDF-1alpha. Although SDF-1alpha-induced chemotaxis was inhibited by the addition of a neutralizing monoclonal CXCR4 antibody, endothelial chemotaxis toward VEGF was not altered; therefore, the angiogenic effect of VEGF is independent of SDF-1alpha. Furthermore, subcutaneous SDF-1alpha injections into mice induced formation of local small blood vessels that was accompanied by leukocytic infiltrates. To test whether these effects were dependent on circulating leukocytes, we successfully obtained SDF-1alpha-induced neovascularization from cross sections of leukocyte-free rat aorta. Taken together, our data indicate that SDF-1alpha acts as a potent chemoattractant for endothelial cells of different origins bearing CXCR4 and is a participant in angiogenesis that is regulated at the receptor level by VEGF and bFGF.

Animals↗
PubMed1999

RANTES and MCP-1 chemokine plasma levels in chronic renal transplant dysfunction and chronic renal failure.

OBJECTIVES: Procedures to diagnose renal allograft rejection depend on detection of graft dysfunction due to the presence of mononuclear leukocytic infiltrates. DESIGN AND METHODS: In our study, we pursued an immunodiagnostic approach utilizing an ELISA method on plasma samples to monitor patients waiting to undergo transplantation in order to evidence prognostic developments in renal transplantation and, at least, to diagnose renal chronic transplant dysfunction. We analyzed blood levels of two chemokines, RANTES and MCP-1, which are normally overexpressed locally in renal chronic rejection. RESULTS: Our results showed that patients affected by chronic renal failure (and waiting for kidney transplant), as well as kidney-grafted patients affected by chronic transplant dysfunction, had plasma levels of RANTES significantly higher than those of controls (patients without acute or chronic pathologies). CONCLUSIONS: Our data suggest a simple method to evaluate the plasmatic presence of RANTES, which could be involved in longterm kidney graft failure.

Adolescent↗
PubMed1999

Aerobically generated CO(2) stored during early exercise.

Previous studies have shown that a metabolic alkalosis develops in the muscle during early exercise. This has been linked to phosphocreatine hydrolysis. Over a similar time frame, the femoral vein blood pH and plasma K(+) and HCO(-)(3) concentrations increase without an increase in PCO(2). Thus CO(2) from aerobic metabolism is converted to HCO(-)(3) rather than being eliminated by the lungs. The purpose of this study was to quantify the increase in early CO(2) stores and the component due to the exercise-induced metabolic alkalosis (E-I Alk). To avoid masking the increase in CO(2) stores by CO(2) released as HCO(-)(3) buffers lactic acid, the transient increase in CO(2) stores was measured only for work rates (WRs) below the lactic acidosis threshold (LAT). The increase in CO(2) stores was evident at the airway starting at approximately 15 s; the increase reached a peak at approximately 60 s and was complete by approximately 3 min of exercise. The increase in CO(2) stores was greater, but the kinetics were unaffected at the higher WR. Three components of the change in aerobically generated CO(2) stores were considered relevant: the carbamate component of the Haldane effect, the increase in CO(2) stores due to increase in tissue PCO(2), and the E-I Alk. The Haldane effect was calculated to be approximately 5%. Physically dissolved CO(2) in the tissues was approximately 30% of the store increase. The remaining E-I Alk CO(2) stores averaged 61 and 68% for 60 and 80% LAT WRs, respectively. The kinetics of O(2) uptake correlated with the time course of the increase in CO(2) stores; the size of the O(2) deficit correlated with the size of the E-I Alk component of the CO(2) stores. We conclude that a major component of the aerobically generated increase in CO(2) stores is the new HCO(-)(3) generated as phosphocreatine is converted to creatine.

Adult↗
PubMed1998

Protection by L-2-oxothiazolidine-4-carboxylic acid of hydrogen peroxide-induced CD3zeta and CD16zeta chain down-regulation in human peripheral blood lymphocytes and lymphokine-activated killer cells.

We investigated whether L-2-oxothiazolidine-4-carboxylic acid (OTC) [in the form of Procysteine, kindly donated by Transcend Therapeutics] could protect peripheral blood lymphocytes (PBL) and lymphokine-activated killer (LAK) cells from CD3zeta and CD16zeta chain down-regulation induced by H2O2 produced by lipopolysaccharide (LPS)-activated autologous monocytes. OTC is known to enhance glutathione production in cells in which glutathione was depleted by reactive oxygen species. Our data showed that OTC induced a significant increase in CD3zeta and CD16zeta chain expression in peripheral blood lymphocytes and LAK cells, respectively, pretreated for 12 hr at 37 degrees. Moreover, OTC significantly protected peripheral blood lymphocytes and LAK against decreased zeta chain expression induced by lipopolysaccharide-activated monocytes or the addition of H2O2 to the culture medium. Our experiments thus suggested that alterations in signal-transducing molecules, such as decreased CD3zeta and CD16zeta expression observed in cytotoxic T lymphocytes and LAK cells in response to oxidative stress, could be prevented by the use of OTC.

CD3 Complex↗
PubMed1998

A four-minute submaximal constant work rate exercise test to assess cardiovascular functional class in chronic heart failure.

To develop a submaximal constant work rate exercise test able to grade cardiovascular dysfunction in patients with chronic heart failure, 80 patients and 59 control subjects performed a symptom-limited incremental exercise test and a constant work rate exercise test at a fixed work rate (50 W for 4 minutes). The time constant of VO2 at the start of constant work rate exercise and time for gas exchange ratio (respiratory exchange ratio) to equal 1 were independent predictors of cardiovascular functional class and correctly classified the functional class in 89 +/- 9% and 83 +/- 11% of patients, respectively.

Cardiac Output, Low↗
PubMed1998

Exercise tolerance in asymptomatic elderly men with fluoroscopically detected coronary artery calcification.

STUDY OBJECTIVE: The value of detecting coronary artery calcification (CAC), by cardiac imaging, for the diagnosis of coronary artery disease (CAD) in asymptomatic middle-aged men has been demonstrated. However, the incidence of CAC increases with age. The functional significance of CAC remains unknown in asymptomatic elderly men. The purpose of this study is to explore whether CAC in asymptomatic aging men signifies the presence of cardiovascular dysfunction during exercise. DESIGN: This study was designed to address whether elderly asymptomatic men, selected because they have CAC, have reduced exercise tolerance due to functionally significant CAD. PARTICIPANTS AND SETTING: Thirty-eight asymptomatic male volunteers (ages 50 to 75 years, mean [+/-SD] 64+/-7 years) with a normal resting ECG and at least one coronary risk factor, in a population study. Nineteen subjects had CAC detected by digital subtraction fluoroscopy in at least two major coronary arteries, and 19 subjects had no identifiable CAC. METHODS AND RESULTS: Each subject underwent a symptom-limited incremental exercise test with 12-lead ECG monitoring and respiratory gas analysis. Four indexes of exercise oxygen transport were evaluated: peak oxygen uptake (VO2), lactic acidosis threshold, peak VO2/heart rate ratio, and VO2 relative to a work rate increase. Eleven of 38 subjects (28%) were found to have reduced oxygen transport, which was defined as an abnormal reduction in more than two of the above four indexes of oxygen transport. Five of the 11 subjects with reduced oxygen transport had CAC, and 6 subjects did not (not significant). Only one subject with CAC had exercise ST depression. CONCLUSION: Significant CAC in asymptomatic men over age 50 does not signify exercise limitation due to CAD.

Aged↗
PubMed1997

Skeletal muscle oxygenation and oxygen uptake kinetics following constant work rate exercise in chronic congestive heart failure.

The aim of the present study was to determine the kinetics of recovery of muscle oxygenation (MO) from comparable levels of exercise in patients with chronic congestive heart failure (CHF) and in normal subjects, and to relate MO kinetics to the level of exercise intolerance. Ten patients with stable CHF secondary to ischemic cardiomyopathy (ejection fraction 34 +/- 6%) (mean age 47 +/- 10 years) and 8 healthy matched control subjects underwent an upright incremental cycle ergometer exercise test with gas exchange analysis and a 6-minute constant work rate protocol at 60% of peak oxygen consumption (VO2). Oxygenation of the vastus lateralis muscle was continuously monitored during exercise and recovery using near infrared spectroscopy. Recovery VO2 and MO mean response times for the constant work rate exercise test were longer in patients with CHF than in control subjects (p <0.05). Both VO2 and MO mean response times were inversely related to peak VO2 (r = -0.73 and -0.52, respectively; p <0.05 for both). Thus recovery of muscle and total body oxygenation from submaximal exercise is more delayed the greater the cardiac dysfunction, as assessed by peak VO2. This suggests that regeneration of phosphocreatine and/or resaturation of venous oxyhemoglobin take place more slowly the worse the cardiac function.

Adult↗
PubMed1997

Lung function and exercise gas exchange in chronic heart failure.

BACKGROUND: The ventilatory response to exercise in patients with chronic heart failure (HF) is greater than normal for a given metabolic rate. The objective of the present study was to determine the mechanism(s) for the high ventilatory output in patients with chronic HF. METHODS AND RESULTS: Centers in Germany, Italy, Japan, and the United States participated in this study. Each center contributed studies on patients and normal subjects of similar age and sex. One hundred thirty patients with chronic HF and 52 healthy subjects participated. Spirometric and breath-by-breath gas exchange measurements were made during rest and increasing cycle exercise. Arterial blood was sampled for measurement of pH, PaCO2, PaO2, and lactate during exercise in 85 patients. Resting forced expiratory volume in 1 second (FEV1) and vital capacity (VC) were proportionately reduced at all levels of impairment. Patients with more severe HF had greater tachypnea and a smaller tidal volume (VT) at a given exercise expired volume per unit time (VE). This was associated with an expiratory flow pattern characteristic of lung restriction. VE and VCO2 as a function of VO2 were increased during exercise in HF patients. The increases were greater the lower the peak VO2 per kilogram of body weight. The ratio of VD (physiological dead space) to VT and the difference between arterial and end tidal PCO2 at peak VO2 also increased inversely with peak VO2/kg. In contrast, the difference between alveolar and arterial PO2 and PaCO2 were both normal, on average, at peak VO2 regardless of the level of impairment. The more severe the exercise limitation, the higher the lactate and the lower the HCO3- at a given VO2, although pH was tightly regulated. CONCLUSIONS: The increase in VE in chronic HF patients is caused by an increase in VD/VT due to high ventilation/perfusion mismatching, an increase in VCO2 relative to VO2 resulting from HCO3- buffering of lactic acid, and a decrease in PaCO2 due to tight regulation of arterial pH. With regard to the excessive VE in HF patients, the increases in VD/VT and VCO2 relative to VO2 are more important as the patient becomes more exercise limited. Regional hypoperfusion but not hypoventilation typifies lung gas exchange in HF. This and other mechanisms might account for the restrictive changes leading to exercise tachypnea in HF patients.

Carbon Dioxide↗
PubMed1997

Endogenous fibronectin of blood polymorphonuclear leukocytes: stimulus-induced secretion and proteolysis by cell surface-bound elastase.

In an accompanying study, we described the presence of intact fibronectin, a large adhesive molecule, in the specific granules of blood PMNs. Secretion of fibronectin by blood PMNs is poorly understood, and the fate of this fibronectin is practically unknown. In the present study we demonstrate that nanomolar concentrations of phorbol ester or the chemoattractants fMLP, PAF, and LTB4 induce fibronectin secretion from blood PMNs. Phorbol ester induced secretion of approximately 85% of the total fibronectin content, as well as expression of small amounts on the cell surface of the activated PMNs. Secreted fibronectin was proteolytically cleaved and, after 20 min, four major fragments of 150, 120, 90, and 80 kDa containing a midchain epitope were identified by Western blot analysis. Kinetic studies indicated that fibronectin was rapidly secreted as an intact molecule and that proteolysis started within minutes and proceeded for at least 1 h. If cells were removed after 5 min TPA treatment, no further proteolysis of the secreted fibronectin was observed, indicating participation of cell-bound proteinases. From a cocktail of proteinase inhibitors, PMSF was the most active in suppressing fibronectin proteolysis. Studies with specific peptidyl inhibitors of human leukocyte elastase and cathepsin G, major serine proteinases of PMNs, demonstrated some inhibition with the cathepsin G inhibitor, while the human leukocyte elastase inhibitor almost completely abolished fibronectin proteolysis. A monoclonal antibody to the elastase had a similar effect. The results indicate that intact fibronectin is a secretory product of blood PMNs and that this endogenous adhesive molecule is within minutes extracellularly processed by cell surface-bound elastase.

Antibodies, Monoclonal↗
PubMed1997

Association between the anaerobic threshold and the break-point in the double product/work rate relationship.

A break point in the double product versus work rate relationship (DPBP) during incremental exercise has previously been reported. The aim of the current study was to investigate the frequency and degree of inter-observer agreement with which a DPBP could be detected. We also wished to determine its relationship, if any, to the lactic acidosis threshold (LATla). Ten normal volunteers performed continuous incremental bicycle ergometer exercise under three different concentrations of inspired oxygen (FiO2 = 0.21, 0.15 and 0.12). In addition, a group of patients with diseases expected to result in impaired exercise tolerance performed exercise under room air conditions. Gas exchange was measured continuously and double product was measured at 15-s intervals throughout exercise using an automated sphygmomanometer. Four observers, unaware of subject identity and test condition, analysed a total of 39 tests. All four observers detected a DPBP in 29 cases (74%) and an LAT in 35 cases (90%). The intra-class correlation coefficient was 0.76 for the DPBP and 0.93 for the LATla, indicating a reasonable level of agreement among observers for both break points. The DPBP was closely related to the LATla (r = 0.865, P < 0.0001), although it occurred at a slightly higher oxygen consumption (VO2, bias 0.137 1.min-1, 95% confidence intervals 0.041-0.233). We conclude that the DPBP is a common occurrence during incremental exercise. The close relationship between the DPBP and the LATla suggests that both may reflect similar events at the level of the skeletal muscle cell.

Acidosis, Lactic↗
PubMed1997

Nitric oxide production during exercise in chronic heart failure.

In chronic heart failure (CHF), the ventilatory response is increased compared with normal. This response is, in part, caused by reduced perfusion to ventilated lung. Nitric oxide (NO) is a potent vasodilator and may have an important role in pulmonary vasodilatation during exercise. NO is present in exhaled air. The amount of NO in exhaled air, when breathing NO-free compressed air, is known to increase in normal subjects during exercise. In this study, we quantified NO output in exhaled air in patients with CHF during exercise. Six patients with CHF (New York Heart Association Class II and III; two with dilated cardiomyopathy, three with ischemic heart disease, and one with hypertensive heart disease) and six normal subjects were studied with a symptom-limited incremental exercise test on a cycle ergometer. Oxygen uptake (VO2), carbon dioxide output (VCO2), and minute ventilation (VE) were measured breath by breath with a mass spectrometer, flow meter, and computer. The NO concentration was continuously measured in mixed expired air by chemiluminescence. Peak exercise work rate was lower in patients with CHF than in normal subjects (71.3 +/- 41.6 W vs 257.0 +/- 49.7 W; p < 0.01). Patients with CHF showed a higher VE/VCO2 level at peak exercise than normal subjects (CHF, 47.0 +/- 10.7; normal subjects, 35.6 +/- 5.2; p < 0.01). NO concentration of exhaled air at rest was lower in CHF patients than in normal subjects (4.0 +/- 2.2 ppb vs 10.5 +/- 6.2 ppb, respectively; p < 0.05). NO output from the respiratory tract (VNO) was significantly lower in patients with CHF compared with normal subjects at rest (45.3 +/- 24.3 nl/min, 117.5 +/- 60.1 nl/min, respectively, p < 0.05), and although it increased during exercise, it did not increase in patients with CHF as much as in normal subjects (75.3 +/- 43.4 nl/min vs 512.9 +/- 253.6 nl/min, respectively; p < 0.01). The increase above rest (exercise/rest) was smaller in patients with CHF than in normal subjects (2.10 +/- 1.92 vs 4.81 +/- 2.67, p < 0.05). These data support the concept that the smaller increase in NO production (VNO) during exercise may be responsible for a blunted vasodilation in patients with CHF, resulting in a smaller reduction in dead space/tidal volume and VE/VCO2 at the lactic acidosis threshold than normal. This finding may play a role in the abnormally high ventilatory response to exercise in patients with CHF.

Adult↗
PubMed1997

Conversion of in vitro cultured human monocytes into effective presenters of an HER2/neu-encoded CTL peptide epitope.

Tumour-derived peptides have been surveyed, in a variety of systems, for their ability to elicit cytokine release from class I restricted T cells. Analogous studies on ovarian carcinoma have employed the antigen-processing defective T2 cell line, Purified dendritic cells (DC) have been reported to act as highly effective APC. A facile method was developed whereby DC-like cells were generated from monocyte precursors. Herein, evidence is presented suggesting DC-like cells are superior to T2 with respect to their ability to present a defined CTL epitope associated with ovarian carcinoma.

Antigen-Presenting Cells↗
PubMed1997

Cardiac output estimated noninvasively from oxygen uptake during exercise.

Because gas-exchange measurements during cardiopulmonary exercise testing allow noninvasive measurement of oxygen uptake (Vo2), which is equal to cardiac output (CO) x arteriovenous oxygen content difference [C(a-vDo2),] CO and stroke volume could theoretically be estimated if the C(a-vDo2) increased in a predictable fashion as a function of % maximum Vo2 (Vo2max) during exercise. To investigate the behavior of C(a-vDo2) during progressively increasing ramp pattern cycle ergometry exercise, 5 healthy subjects performed 10 studies to exhaustion while arterial and mixed venous blood were sampled. Samples were analyzed for blood gases (pH, Pco2, Po2) and oxyhemoglobin and hemoglobin concentration with a CO-oximeter. The C(a-vDo2) (ml/100 ml) could be estimated with a linear regression [C(a-vDo2) = 5.72 + 0.105 x % Vo2max; r = 0.94]. The CO estimated from the C(a-vDo2) by using the above linear regression was well correlated with the CO determined by the direct Fick method (r = 0.96). The coefficient of variation of the estimated CO was small (7-9%) between the lactic acidosis threshold and peak Vo2. The behavior of C(a-vDo2), as related to peak Vo2, was similar regardless of cardiac function compared with similar measurements from studies in the literature performed in normal and congestive heart failure patients. In summary, CO and stroke volume can be estimated during progressive work rate exercise testing from measured Vo2 (in normal subjects and patients with congestive heart failure), and the resultant linear regression equation provides a good estimate of C(a-vDo2).

Adult↗
PubMed1997

Mechanism of the exercise hyperkalemia: an alternate hypothesis.

A progressive hyperkalemia is observed as exercise intensity increases. The current most popular hypothesis for the hyperkalemia is that the Na+-K+ pump cannot keep pace with the K+ efflux from muscle during the depolarization-repolarization process of the sarcolemmal membrane during muscle contraction. In this report, we present data that suggest an alternate hypothesis to those previously described. Because phosphocreatine (PCr) is a highly dissociated acid and creatine is neutral at cell pH, the concentration of nondiffusible anions decreases, and an alkaline reaction takes place when PCr hydrolyzes. This creates a state of cation (K+) excess and H+ depletion in the cell. To examine the balance of K+ and H+ for exercising muscle during the early period of exercise when PCr changes most rapidly, catheters were inserted into the brachial artery and femoral vein (FV) in five healthy subjects who performed two 6-min cycle ergometer exercise tests at 40 and 85% of peak oxygen uptake. FV blood was sampled every 5 s during the first 2 min, then every 30 s for the remaining 4 min of exercise and the first 3 min of recovery, and then less frequently for the next 12 min. Arterial sampling was every 30 s during exercise and simultaneous with FV sampling during recovery. Arterial K+ concentration ([K+]) increase lagged FV [K+] increase. The hyperkalemia observed during early exercise results from K+ release from skeletal muscle. FV [K+] increased by 5 s of the start of exercise and followed the rate of H+ loss from the FV blood for the first 30 s of exercise. FV lactate and Na+ kinetics differed from K+ kinetics during exercise and recovery. As predicted from the PCr hydrolysis reaction, the exercising limb took up H+ and released K+ at the start of exercise (first 30 s) at both exercise intensities, resulting in a FV metabolic alkalosis. K+ release was essentially complete by 3 min, the time at which oxygen uptake (and, presumably, PCr) reached its asymptote. These findings lead us to hypothesize that the early K+ release by the cell takes place with H+ exchange and that the major mechanism for the exercise hyperkalemia is the reduction in nondiffusible intracellular anions in the myocyte as PCr hydrolyzes.

Adult↗
PubMed1997

Effect of hypoxia and carbon monoxide on muscle oxygenation during exercise.

We used near-infrared spectroscopy (NIRS) to test the hypothesis that reducing oxygen availability during exercise would affect the rate of muscle oxyhemoglobin (O2Hb) desaturation when performing work above the lactic acidosis threshold (LAT), but not below it. Seven healthy men each performed two constant work intensities (60%LAT and the LAT plus 40% of the difference between the LAT and VO2max [40%delta]) four times under the following conditions: (1) 10 min air; (2) 5 min 15%O2 + 5 min air; (3) 5 min air + 5 min 15%O2; (4) 5 min after carbon monoxide (CO) loading to increase the carboxyhemoglobin (COHb) saturation to 15%. During each test, cardiorespiratory parameters and muscle oxygenation measured with NIRS were continuously monitored. Forearm venous blood lactate was measured every 2 to 3 min. Hypoxia and CO accelerated muscle deoxygenation only for exercise above the LAT; for exercise below the LAT, neither progressive deoxygenation nor lactate accumulation occurred after initital, rapid muscle deoxygenation. The rate of decrease in muscle oxygenation between 3 to 5 min of exercise correlated with the increase in VO2 (r = 0.61, p < 0.01) and blood lactate (r = 0.70, p < 0.01) over the same period. These results support the hypothesis that progressive muscle deoxygenation occurs above the LAT and that the rate of deoxygenation is sensitive to oxygen delivery.

Adult↗