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Biomedical subjects

N L Jones

Publications and source records attributed to N L Jones.

At least 73 records · Page 4Linked to original sources
PubMed1995

Skeletal muscle pyruvate dehydrogenase activity during maximal exercise in humans.

The regulation of the active form of pyruvate dehydrogenase (PDHa) and related metabolic events were examined in human skeletal muscle during repeated bouts of maximum exercise. Seven subjects completed three consecutive 30-s bouts of maximum isokinetic cycling, separated by 4 min of recovery. Biopsies of the vastus lateralis were taken before and immediately after each bout. PDHa increased from 0.45 +/- 0.15 to 2.96 +/- 0.38, 1.10 +/- 0.11 to 2.91 +/- 0.11, and 1.28 +/- 0.18 to 2.82 +/- 0.32 mmol.min-1.kg wet wt-1 during bouts 1, 2, and 3, respectively. Glycolytic flux was 13-fold greater than PDHa in bouts 1 and 2 and 4-fold greater during bout 3. This discrepancy between the rate of pyruvate production and oxidation resulted in substantial lactate accumulation to 89.5 +/- 11.6 in bout 1, 130.8 +/- 13.8 in bout 2, and 106.6 +/- 10.1 mmol/kg dry wt in bout 3. These events coincided with an increase in the mitochondrial oxidation state, as reflected by a fall in mitochondrial NADH/NAD, indicating that muscle lactate production during exercise was not an O2-dependent process in our subjects. During exercise the primary factor regulating PDHa transformation was probably intracellular Ca2+. In contrast, the primary regulatory factors causing greater PDHa during recovery were lower ATP/ADP and NADH/NAD and increased concentrations of pyruvate and H+. Greater PDHa during recovery facilitated continued oxidation of the lactate load between exercise bouts.

Adenine Nucleotides↗
PubMed1995

Muscle strength, symptom intensity, and exercise capacity in patients with cardiorespiratory disorders.

The contribution of muscle strength to symptom intensity and work capacity was examined in normal individuals and patients with cardiorespiratory disorders. Respiratory muscle strengths (maximal inspiratory and expiratory pressures) and peripheral muscle strengths (leg extension, leg flexion, seated bench press, and seated row) were measured in 4,617 subjects referred for clinical exercise testing. Subjects then rated the intensity of leg effort, discomfort with breathing (dyspnea), and chest pain (Borg scale) during an incremental exercise task (100 kpm/min each minute) to capacity on a cycle ergometer. Subjects were classified into groups on the basis of pulmonary function, drug therapy for cardiac disorders, and the presence of chest pain during exercise with electrocardiographic changes indicative of myocardial ischemia. Respiratory and peripheral muscle strengths, normalized for differences in age, sex, and height, were significantly reduced in patients with cardiorespiratory disorders compared with normal individuals. Muscle strength was a significant contributor to symptom intensity and work capacity in both health and disease; a two-fold increase in muscle strength was associated with a 25 to 30% decrease in the intensity of both leg effort and dyspnea and a 1.4- to 1.6-fold increase in work capacity. These results emphasize the need for an integrative approach in the assessment and therapeutic management of exercise intolerance, which considers the contribution of muscle weakness to excessive symptoms and reduced work capacity, in addition to the contribution of ventilatory, gas exchange, and circulatory impairments.

Angina Pectoris↗
PubMed1995

Procoagulant activity after exposure of monocyte-derived macrophages to minimally oxidized low density lipoprotein. Co-localization of tissue factor antigen and nascent fibrin fibers at the cell surface.

The role of tissue factor (TF) as an initiator of the thrombotic complications secondary to atherosclerosis has been acknowledged, and in situ expression of TF activity by monocyte-derived macrophages and lesion-associated macrophage foam cells has been documented. Macrophages express TF activity upon exposure in vitro to either oxidized low density lipoprotein LDL (Ox-LDL) or endotoxin (lipopolysaccharide). This activity has been associated with membrane vesicles that apparently are shed after procoagulant expression. The present study based upon the correlative use of an enzyme-linked coagulant assay and three-dimensional multi-antigen, immunogold electron microscopy, reports the ultrastructural localization of TF antigen and spatially correlates TF with OX-LDL binding and the presence of nascent fibrin polymers on the plasma membrane of cultured macrophages. Pigeon monocyte/macrophages, after a 4-hour induction with lipopolysaccharide (2 micrograms/ml) or minimally oxidized LDL (50 micrograms/ml; thiobarbituric acid reducing substance, 5 to 8 nmol/mg protein) were incubated for 40 minutes in a Tris-buffered medium containing factors VII, V, X, II, and I before either assaying for coagulant activity or processing for gold-colloid cytochemistry. TF activity, as measured by enzyme-linked coagulant assay peaked 6 hours after agonist exposure with lipopolysaccharide and Ox-LDL giving, respectively, 115- and 60-fold stimulation as compared with control. This activity corresponded to the elaboration of membrane ruffles and microvilli on the cell surfaces. Through correlative immunogold cytochemistry (15-nm-diameter colloid) and gold-ligand cytochemistry (30-nm-diameter colloid), TF antigen (83%) and Ox-LDL (78%) were primarily associated with the membrane ruffles and microvilli. Multi-antigen immunogold cytochemistry when used in conjunction with ligand-gold cytochemistry documented co-localization of Ox-LDL (22-nm gold), TF antigen (15-nm gold) and a delicate three-dimensional network of short fibrin fibers that were decorated in a linear fashion with the immunogold probes (30-nm gold). These results provide evidence that TF antigen is located at selected regions on the cell surfaces. Furthermore, these same regions provide binding sites for agonist uptake and organization sites for fibrin polymerization. Hypothetically, the localized membrane regions could be shed from the cell surface as a means for regulating coagulation potential.

Animals↗
PubMed1994

Pathophysiology of the pancreatic defect in Johanson-Blizzard syndrome: a disorder of acinar development.

We compared pancreatic acinar and ductal secretion in two patients with Johanson-Blizzard syndrome, age-matched control subjects, and patients with other primary pancreatic diseases. Patients with Johanson-Blizzard syndrome had preservation of ductular output of fluid and electrolytes, as in patients with Shwachman syndrome but differing from those with cystic fibrosis, who have a primary ductular defect. They also had decreased acinar secretion of trypsin, colipase and total lipase, and low serum immunoreactive trypsinogen levels, consistent with a primary acinar cell defect.

Case-Control Studies↗
PubMed1994

Plasma volume and ion regulation during exercise after low- and high-carbohydrate diets.

This study compared plasma volume (PV) and ion regulation during prolonged exercise in control vs. glycogen-depleted (GD) conditions, with emphasis on the initial minutes of exercise. In two trials separated by 1-2 wk, four adult males cycled at 75% of peak oxygen consumption (VO2) until exhaustion (50 +/- 7 min for GD) or until the GD exhaustion time in the control trial. Blood was sampled from catheters placed in the brachial artery and retrograde in the femoral vein (fv). Arterial PV decreased rapidly and by 15 min PV was 83% (control) and 88% (GD) of initial. The decrease in PV was accompanied by a net osmotic flux of water from plasma and inactive tissues to contracting muscles. The significantly greater decrease in PV in control compared with GD was associated with a higher muscle lactate content (Lac-; 36 vs. 17 mumol/g dry wt, respectively). Increases in plasma [Cl-] and [Na+] were less than predicted from decreased PV, indicating net loss of these ions from the plasma compartment. Increases in arterial and fv [K+] were 50% greater than could be accounted for by decreased PV, corresponding with increased arterial and fv plasma K+ contents. The rapid net release of K+ and Lac- from contracting muscle during the first few minutes of exercise in both trials was abolished (control) or reversed (GD) within 15 min of beginning exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Effect of chronic acetazolamide administration on gas exchange and acid-base control after maximal exercise.

The interaction between systems regulating acid-base balance (i.e., CO2, strong ions, week acids) was studied in six subjects for 10 min after 30 s of maximal isokinetic cycling during control conditions (CON) and after 3 days of chronic acetazolamide (ChACZ) administration (500 mg/8 h po) to inhibit carbonic anhydrase (CA). Gas exchange was measured; arterial and venous forearm blood was sampled for acid-base variables. Muscle power output was similar in ChACZ and CON, but peak O2 intake was lower in ChACZ; peak CO2 output was also lower in ChACZ (2,207 +/- 220 ml/min) than in CON (3,238 +/- 87 ml/min). Arterial PCO2 was lower at rest, and its fall after exercise was delayed in ChACZ. In ChACZ there was a higher arterial [Na+] and lower arterial [lactate-] ([La-]) accompanied by lower arterial [K+] and higher arterial [Cl-] during the first part of recovery, resulting in a higher arterial plasma strong ion difference (sigma [cations] - sigma [anions]). Venoarterial (v-a) differences across the forearm showed a similar uptake of Na+, K+, Cl-, and La- in ChACZ and CON. Arterial [H+] was higher and [HCO3-] was lower in ChACZ. Compared with CON, v-a [H+] was similar and v-a [HCO3-] was lower in ChACZ. Chronic CA inhibition impaired the efflux of CO2 from inactive muscle and its excretion by the lungs and also influenced the equilibration of strong ions.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetazolamide↗
PubMed1994

Mechanisms of exertional dyspnea.

To understand why someone is dyspneic during exercise, we need to follow the advice of Sir Francis Bacon: "No natural phenomenon can be adequately studied in itself alone, but to be understood must be considered as it stands connected with all of nature." In the present context, this implies the careful measurement of events related to metabolism, circulation, and respiration and of the associated sensory events as these systems adapt to the strain and stress of exercise.

Dyspnea↗
PubMed1994

Formation of cholesterol monohydrate crystals in macrophage-derived foam cells.

In a previous study using the J774 macrophage foam cells, we quantitated the accumulation of unesterified (free) cholesterol derived from cholesteryl ester hydrolysis in lysosomes, after phagocytic uptake of cholesteryl ester droplets. In the present study, we examined whether the accumulation of free cholesterol in lysosomes leads to the formation of cholesterol monohydrate crystals by analyzing the lipid composition of low density lysosome fractions isolated from cholesteryl ester-loaded macrophages after a 24-h incubation. Phase diagrams of the constituent lipids in the lipid-filled lysosomes predicted the formation of cholesterol monohydrate crystals. The formation of cholesterol monohydrate crystals was observed in cholesteryl ester-loaded macrophages after a 48-h incubation by polarizing light microscopy. The crystals had a density of 1.04 g/ml and the morphology of cholesterol monohydrate crystals with an acute edge angle of about 80 degrees. The crystals appeared as needles as well as plates and melted only when heated to greater than 85 degrees C. The physical properties of these crystals are characteristic of cholesterol monohydrate. In our studies, crystal formation was observed even when cells had active acyl-CoA:cholesterol acyltransferase or when cholesterol efflux was stimulated. Electron microscopy and acid phosphatase cytochemistry of lysosomes in cholesteryl ester-loaded cells confirmed that cholesterol crystal formation occurred within lipid-loaded lysosomes. Time-lapse video microscopic studies revealed that most of the cells containing cholesterol monohydrate crystals not only remain viable but also have the capacity to translocate single crystals within cells. The data demonstrate that lysosomal accumulation of free cholesterol in macrophages after phagocytic uptake and hydrolysis of cholesteryl ester droplets leads to the formation of cholesterol monohydrate crystals within lipid-filled lysosomes. Such a process may lead to deposition of free cholesterol and cholesterol monohydrate crystals in macrophage foam cells during the progression of atherosclerosis.

Animals↗
PubMed1993

Glycoprotein IIb/IIIa cross-reacting antigen in monocyte-derived macrophages from the pigeon.

The binding of fibrinogen to its receptor on mammalian platelets and avian thrombocytes has been extensively studied; and the receptors, composed of glycoproteins IIb and IIIa, have been characterized in both systems. Recently, monocytes have been implicated in the thrombotic complications of atherosclerosis, and in both the avian and human systems this appears to be through a procoagulant activity which leads to fibrinogen polymerization. Although fibrin polymerization by avian monocytes has been reported, the receptor for fibrinogen on these cells has not been reported previously. The present study describes the presence of glycoprotein IIb- and IIIa-like proteins in avian macrophages and correlates the localization of these glycoproteins with regions to which fibrinogen binds. Through the use of immunofluorescence light microscopy and immunogold electron microscopy in conjunction with monospecific, polyclonal antibodies, GPIIb and GPIIIa cross-reacting antigens were identified on membranes of monocyte/macrophages cultured from White Carneau pigeons. A specific concentration of the antigens was found on membrane ruffles and microvilli, sites to which FITC-labeled fibrinogen also bound. Interaction of the antibodies with pigeon macrophages was confirmed by enzyme-linked immunosorbent assays with cultured cells. Immunoblotting of membranes isolated from pigeon monocyte/macrophages identified a protein of 132,000 M(r) that was recognized by anti-GPIIb and a protein of 114,000 M(r) that was recognized by anti-GPIIIa. These pigeon monocyte glycoproteins comigrated with glycoproteins IIb and IIIa isolated from human platelets.

Animals↗
PubMed1993

Beta-very low density lipoprotein is sequestered in surface-connected tubules in mouse peritoneal macrophages.

beta-very low density lipoprotein (VLDL) is a large lipoprotein with multiple apoprotein E (apoE) molecules that bind to the LDL receptors on mouse macrophages. Even though they bind to the same receptor, the endocytic processing of beta-VLDL differs from low density lipoprotein (LDL). LDL is rapidly delivered to perinuclear lysosomes and degraded, but much of the beta-VLDL is retained in peripheral compartments for several minutes. We have investigated the properties of these peripheral compartments. Measurement of the pH was made using FITC-phosphatidylethanolamine incorporated into the beta-VLDL, and we found that the peripheral compartments were near neutral in pH. These peripheral, beta-VLDL containing compartments were poorly accessible to antibodies, but a low molecular weight fluorescence quencher (trypan blue) entered the compartments within a few seconds. Intermediate voltage EM of cells labeled with colloidal-gold-beta-VLDL revealed that the peripheral compartments are tubular, surface-connected invaginations. Kinetic studies with fluorescent beta-VLDL showed that the compartments become fully sealed with a half-time of 6 min, and the beta-VLDL is then delivered rapidly to perinuclear lysosomes. By monitoring fluorescence energy transfer between lipid analogs incorporated into the beta-VLDL, some processing of the lipoprotein in the peripheral tubular compartments is demonstrated. The novel mode of uptake of beta-VLDL may account for the high cholesterol ester accumulation induced by this lipoprotein.

Animals↗
PubMed1993

Maximal short-term exercise performance and ion regulation in cystic fibrosis.

Controversy exists over whether defects in electrolyte transport exist in erythrocytes from cystic fibrosis (CF) patients. We hypothesized that differences in ion regulation in CF would affect skeletal muscle performance during intense exercise. Seven well-nourished CF patients were compared with seven healthy age-matched control subjects. Skeletal muscle performance was assessed during a 30-s sprint on an isokinetic cycle ergometer. Ion regulation was evaluated from arterialized venous blood sampled at rest, at peak exercise, and after 5 min of recovery. There was no difference in sprint performance between the CF (total work, 93.7 +/- 30.02% predicted; endurance, 30.6 +/- 9.93% decline) and control (109.7 +/- 19.48%; 35.6 +/- 14.76%) groups. The changes in plasma and erythrocyte ions and blood gases did not differ between the groups. There was a suggestion that the CF group may have had an inadequate ventilatory response to the metabolic challenge of short-term maximal exercise. The contribution of decreases in the strong ion difference to increases in plasma hydrogen ion concentrations was less in the CF group. This may be due to alterations in ionic regulation in CF, but the influence of inadequate arterialization of the blood samples could not be ruled out.

Adult↗
PubMed1993

Pyruvate dehydrogenase activity and acetyl group accumulation during exercise after different diets.

Pyruvate dehydrogenase activity (PDHa) and acetyl group accumulation were examined in human skeletal muscle at rest and during exercise after different diets. Five males cycled at 75% of maximal O2 uptake (VO2 max) to exhaustion after consuming a low-carbohydrate diet (LCD) for 3 days and again 1-2 wk later for the same duration after consuming a high-carbohydrate diet (HCD) for 3 days. Resting PDHa was lower after a LCD (0.20 +/- 0.04 vs. 0.69 +/- 0.05 mmol.min-1.kg wet wt-1; P < 0.05) and coincided with a greater intramuscular acetyl-CoA-to-CoASH ratio, acetyl-CoA content, and acetylcarnitine content. PDHa increased during exercise in both conditions but at a lower rate in the LCD condition compared with the HCD condition (1.46 +/- 0.25 vs. 2.65 +/- 0.23 mmol.min-1.kg wet wt-1 at 16 min and 1.88 +/- 0.20 vs. 3.11 +/- 0.14 at the end of exercise; P < 0.05). During exercise muscle acetyl-CoA and acetylcarnitine content and the acetyl-CoA-to-CoASH ratio decreased in the LCD condition but increased in the HCD condition. Under resting conditions PDHa was influenced by the availability of fat or carbohydrate fuels acting through changes in the acetyl-CoA-to-CoASH ratio. However, during exercise the activation of PDHa occurred independent of changes in the acetyl-CoA-to-CoASH ratio, suggesting that other factors are more important.

Acetyl Coenzyme A↗
PubMed1993

Comparison of three techniques for body composition analysis in cystic fibrosis.

Body composition analysis is an important component of nutritional assessment in cystic fibrosis (CF). No gold standard of measurement exists, and techniques applicable to healthy populations may be unsuitable for CF patients. We assessed lean body mass (LBM) in 12 children with CF by skinfold (SK) measurements, bioelectrical impedance analysis (BIA), and dual-photon absorptiometry (DPA) and repeated these measures in 10 subjects 6 mo later. SK and DPA measures in eight older CF patients and eight healthy controls were compared to evaluate any effect of disease on estimates of LBM by use of DPA. Good agreement between the measures was seen at baseline and 6 mo by use of concordance plots. However, the limits of agreement between measures ranged up to 19% of SK-derived LBM measures (baseline: SK and DPA, 2.63 to -3.93 kg; SK and BIA, 2.36 to -1.24 kg; BIA and DPA, 1.88 to -4.28 kg; 6 mo: SK and DPA, 2.10 to -3.58 kg; SK and BIA, 6.28 to -5.49 kg; BIA and DPA, 5.53 to -7.79 kg). The change in LBM over 6 mo did not correlate among the three measures. Only BIA change in LBM correlated with weight change (r = 0.716, P < 0.02), probably due to the inclusion of weight in the regression equations for determining LBM from impedance. The relationship between SK and DPA measures did not differ between the CF and control groups, suggesting that there was no effect of disease on the DPA measure. The results suggest that none of these methods is precise enough to follow short-term changes in the nutritional status of CF patients longitudinally.

Absorptiometry, Photon↗
PubMed1993

Respiratory and peripheral muscle function in cystic fibrosis.

Respiratory muscle strength (RMS) and endurance are often preserved in cystic fibrosis (CF) despite malnutrition, chronic airflow limitation, and hyperinflation. Inspiratory muscle function may be relatively preserved due to a selective "training stimulus" from chronic lung disease. Respiratory and peripheral muscle function were evaluated in 14 stable CF patients and 16 healthy control subjects. RMS was measured using static maximal pressures performed at FRC. Respiratory fatigue (RF) was assessed using 18 repeated static efforts (10 s on/5 s off) over 4.5 min. Peripheral function was evaluated by leg strength (LS) and leg fatigue (LF) measured during sprint efforts on an isokinetic cycle ergometer. Despite a lower weight (mean +/- SD, 94 +/- 9.6% ideal wt for CF patients versus 107 +/- 14.6% for controls) and elevated residual volume (RV)/TLC ratio (38 +/- 13.0 versus 22 +/- 5.3), the CF group maintained RMS (inspiratory 96 +/- 23.2 versus 114 +/- 33.2; expiratory 105 +/- 28.3 versus 123 +/- 40.9 cm H2O) but had decreased LS (590 +/- 201.7 versus 813 +/- 167.1 W). There were no differences between the groups with respect to RF or LF. For the control group, inspiratory and expiratory RMS correlated with LS (p < 0.01) and lean body mass (p < 0.01). For the CF group, while expiratory RMS (p < 0.05) and LS (p < 0.01) correlated with lean body mass and each other (p < 0.01), inspiratory RMS was independent of lean body mass and LS (p > 0.1). Female CF patients appeared to have a better preservation of inspiratory RMS than males with CF.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Factors contributing to dyspnoea during bronchoconstriction and exercise in asthmatic subjects.

The purpose of the present study was to identify: 1) whether dyspnoea during bronchoconstriction and exercise is related, in asthmatic subjects; and 2) to what extent baseline pulmonary function and respiratory muscle strength contribute to dyspnoea under both conditions. One hundred and seventy five consecutive subjects, referred with suspected asthma, rated the intensity of dyspnoea (Borg scale 0-10): 1) during the administration of doubling concentrations of methacholine to 32 mg.ml-1 methacholine, or until the baseline forced expiratory volume in one second (FEV1) was reduced by 20%; and 2) during incremental cycle ergometry (100 kpm.min-1 each minute) to maximal capacity. 138/175 subjects achieved a 20% reduction in their baseline FEV1; 18 of the 138 were excluded, 2 children and 16 with complicating pulmonary disorders (diffusing capacity of the lung for carbon monoxide (DLCO) and/or total lung capacity (TLC) < 70% predicted). The remaining 120 out of 175 constituted the study population. Dyspnoea following a 20% reduction in the baseline FEV1 (Dys20%) was linearly interpolated, using the rating of dyspnoea and the FEV1 at the two final concentrations of methacholine. In the 120 asthmatic subjects, the mean intensity of dyspnoea was "moderate" (2.9, SD 1.91; Borg 0-10) and the intensity across subjects was not significantly related to baseline FEV1, vital capacity (VC), FEV1/VC, DLCO, TLC and maximal static inspiratory pressure (MIP), alone or in combination.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Beta very low density lipoprotein and clathrin-coated vesicles co-localize to microvilli in pigeon monocyte-derived macrophages.

Macrophages derived from blood monocytes are key in the development of atherosclerosis, as monocyte migration into the intima and accumulation of cholesterol leads to foam cell formation. To investigate the relationship between lipoprotein binding and the distribution of clathrin-coated endocytic vesicles, monocyte-derived macrophages were exposed in vitro to beta very low density lipoprotein (beta VLDL), conjugated to colloidal gold, and later were processed for immuno-electron microscopy to localize clathrin-coated vesicles. The immunolocalization was done in conjunction with either cryosectioning or whole mount intermediate voltage electron microscopy. Preferential binding of beta VLDL on small membrane ruffles and microvilli was quantitatively verified. Clathrin-coated vesicles were distributed throughout the cell; however, clusters of microvilli were associated with both a high concentration of coated vesicles and lipoprotein. Small membrane ruffles were not associated with clathrin-coated vesicles. These data support our hypothesis that endocytosis of beta VLDL near microvilli involves coated vesicles, whereas endocytosis of beta VLDL near ruffles is not mediated by coated endocytic vesicles. Furthermore, the association of coated vesicles with microvilli but not membrane ruffles may be important in understanding ligand trafficking within the cell. Given the distribution of coated vesicles within the cell, it is possible that the site of lipoprotein binding may determine the mechanism of entry into the cell and the metabolic effects of the internalized ligand.

Animals↗