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Biomedical subjects

N L Jones

Publications and source records attributed to N L Jones.

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

Is there a conflict between minimizing effort and energy expenditure with increasing velocities of muscle contraction in humans?

1. The present study examined the possibility that minimizing effort conflicts with minimizing energy expenditure at different velocities of muscle contraction during cycling. 2. Six normal subjects underwent incremental exercise on an electrically stabilized cycle ergometer. Power output increased by 45 W every 3 min to exhaustion at pedalling frequencies of 40, 60, 80 and 100 r.p.m. on separate days. Energy expenditure (oxygen uptake), leg effort and dyspnoea (Borg 0-10 scale) were measured in parallel at the end of each minute. 3. All six subjects completed 10 min of exercise achieving 180 W for all four pedalling frequencies. Two-way analysis of variance indicated that oxygen uptake (P < 0.0001), leg effort (P < 0.0001) and dyspnoea (P < 0.0001) increased with duration of exercise and power output; oxygen uptake (P < 0.0001) and leg effort (P < 0.05) were significantly different between pedalling frequencies; the interactions were not significant. Oxygen uptake was minimal at 60 r.p.m., and increased at both higher and lower pedalling frequencies. Both leg effort and dyspnoea were minimal at 80 r.p.m.; leg effort intensified at higher and lower pedalling frequencies; and dyspnoea was most intense at 100 r.p.m. 4. There was a conflict between minimization of energy expenditure and leg effort at power outputs less than 180 W. Minimizing effort occurred at the expense of an increase in energy expenditure.

Adult↗
PubMed1999

Modified LDLs induce and bind to membrane ruffles on macrophages.

Macrophage foam cell formation in vitro requires uptake of modified low density lipoproteins (LDL) such as acetylated LDL (AcLDL) and moderately oxidized LDL (OxLDL), or beta-migrating very low density lipoprotein (betaVLDL), a naturally occurring lipoprotein. Incubation ofmacrophages with AcLDL and OxLDL resulted in stimulation of membrane ruffle formation, while betaVLDL primarily resulted in increased numbers of microvilli. Time-lapse Allen video enhanced contrast differential interference contrast (AVEC-DIC) light microscopy and correlative whole mount intermediate-voltage transmission electron microscopy (IVEM) was used to examine the dynamics ofAcLDL stimulated membrane ruffling and membrane ruffle ultrastructure. Stereo 3D surface replicas confirmed that AcLDL bound to these AcLDL-induced membrane ruffles. Quantification of the plasma membrane surface area after incubation with AcLDL, betaVLDL or LDL confirmed that AcLDL stimulated membrane ruffling, while betaVLDL and LDL stimulated microvilli formation. These studies suggest that modified LDLs induce circular membrane ruffles and modified LDLs bind to these ligand-induced membrane ruffles.

Animals↗
PubMed1999

Modified LDLs are internalized by macrophages in part via macropinocytosis.

Macrophage foam cell formation in vitro requires uptake of modified low density lipoproteins (LDL) such as acetylated LDL (AcLDL) and moderately oxidized LDL (OxLDL). Macrophages incubated with AcLDL and OxLDL, but not LDL, showed increased membrane ruffling as seen with time-lapse phase contrast video light microscopy. Modified LDLs stimulated circular membrane ruffles between 2 and 10 min after incubation. These membrane ruffles were readsorbed into the plasma membrane between 5 and 15 min later. Phase-bright macropinosomes formed at the base of the stimulated membrane ruffles. The fluid-phase marker lucifer yellow labeled the modified LDL stimulated macropinosomes. Modified LDLs stimulate fluid-phase uptake by 1.5-fold to threefold as measured with 14C-sucrose uptake. Transmission electron microscopy showed that gold conjugated AcLDL and OxLDL bound preferentially to membrane ruffles and were present in macropinosomes (diameter >0.2 pm) underneath these membrane ruffles. AcLDL and OxLDL were also present in clathrin-coated pits and endosomes. These studies suggest that modified lipoproteins stimulate macropinocytosis. AcLDL and OxLDL are partially internalized by macropinocytosis and partially internalized via clathrin-coated pit endocytosis.

Animals↗
PubMed1999

Helicobacter pylori induces gastric epithelial cell apoptosis in association with increased Fas receptor expression.

The mechanisms involved in mediating the enhanced gastric epithelial cell apoptosis observed during infection with Helicobacter pylori in vivo are unknown. To determine whether H. pylori directly induces apoptosis of gastric epithelial cells in vitro and to define the role of the Fas-Fas ligand signal transduction cascade, human gastric epithelial cells were infected with H. pylori for up to 72 h under microaerophilic conditions. As assessed by both transmission electron microscopy and fluorescence microscopy, incubation with a cagA-positive, cagE-positive, VacA-positive clinical H. pylori isolate stimulated an increase in apoptosis compared to the apoptosis of untreated AGS cells (16.0% +/- 2.8% versus 5.9% +/- 1. 4%, P < 0.05) after 72 h. In contrast, apoptosis was not detected following infection with cagA-negative, cagE-negative, VacA-negative clinical isolates or a Campylobacter jejuni strain. In addition to stimulating apoptosis, infection with H. pylori enhanced Fas receptor expression in AGS cells to a degree comparable to that of treatment with a positive control, gamma interferon (12.5 ng/ml) (148% +/- 24% and 167% +/- 24% of control, respectively). The enhanced Fas receptor expression was associated with increased sensitivity to Fas-mediated cell death. Ligation of the Fas receptor with an agonistic monoclonal antibody resulted in an increase in apoptosis compared to the apoptosis of cells infected with the bacterium alone (38.5% +/- 7.1% versus 16.0% +/- 2.8%, P < 0.05). Incubation with neutralizing anti-Fas antibody did not prevent apoptosis of H. pylori-infected cells. Taken together, these findings demonstrate that the gastric pathogen H. pylori stimulates apoptosis of gastric epithelial cells in vitro in association with the enhanced expression of the Fas receptor. These data indicate a role for Fas-mediated signaling in the programmed cell death that occurs in response to H. pylori infection.

Apoptosis↗
PubMed1999

Pyruvate dehydrogenase activation in inactive muscle during and after maximal exercise in men.

Pyruvate dehydrogenase activity (PDHa) and acetyl-group accumulation were examined in the inactive deltoid muscle in response to maximal leg exercise in men. Seven subjects completed three consecutive 30-s bouts of maximal isokinetic cycling, with 4-min rest intervals between bouts. Biopsies of the deltoid were obtained before exercise, after bouts 1 and 3, and after 15 min of rest recovery. Inactive muscle lactate (LA) and pyruvate (PYR) contents increased more than twofold (P < 0.05) after exercise (bout 3) and remained elevated after 15 min of recovery (P < 0.05). Increased PYR accumulation secondary to LA uptake by the inactive deltoid was associated with greater PDHa, which progressively increased from 0.71 +/- 0.23 mmol. min-1. kg wet wt-1 at rest to a maximum of 1.83 +/- 0.30 mmol. min-1. kg wet wt-1 after bout 3 (P < 0.05) and remained elevated after 15 min of recovery (1.63 +/- 0.24 mmol. min-1. kg wet wt-1; P < 0.05). Acetyl-CoA and acetylcarnitine accumulations were unaltered. Increased PDHa allowed and did not limit the oxidation of LA and PYR in inactive human skeletal muscle after maximal exercise.

Acetyl Coenzyme A↗
PubMed1999

Effect of induced metabolic acidosis on human skeletal muscle metabolism during exercise.

The roles of pyruvate dehydrogenase (PDH), glycogen phosphorylase (Phos), and their regulators in lactate (Lac(-)) metabolism were examined during incremental exercise after ingestion of 0.3 g/kg of either NH(4)Cl [metabolic acidosis (ACID)] or CaCO(3) [control (CON)]. Subjects were studied at rest, at rest postingestion, and during continuous steady-state cycling at three stages (15 min each): 30, 60, and 75% of maximal oxygen uptake. Radial artery and femoral venous blood samples, leg blood flow, and biopsies of the vastus lateralis were obtained during each power output. ACID resulted in significantly lower intramuscular concentration of [Lac(-)] (ACID 40.8 vs. CON 56.9 mmol/kg dry wt), arterial whole blood [Lac(-)] (ACID 4.7 vs. CON 6.5 mmol/l), and leg Lac(-) efflux (ACID 3.05 vs. CON 6.98 mmol. l(-1). min(-1)). The reduced intramuscular [Lac(-)] resulted from decreases in pyruvate production due to inhibition of glycogenolysis, at the level of Phos a, and phosphofructokinase, together with an increase in the amount of pyruvate oxidized relative to the total produced. The reduction in Phos a activity was mediated through decreases in transformation, decreases in free inorganic phosphate concentration, and decreases in the posttransformational allosteric regulator free AMP. Reduced PDH activity occurred with ACID and may have resulted from alterations in the concentrations of acetyl-CoA, free ADP, pyruvate, NADH, and H(+), leading to greater relative activity of the kinase. The results demonstrate that imposed metabolic acidosis in skeletal muscle results in decreased Lac(-) production due to inhibition of glycogenolysis at the level of Phos and increased pyruvate oxidation at PDH.

Acidosis↗
PubMed1999

Regulation of skeletal muscle glycogen phosphorylase and PDH during maximal intermittent exercise.

The time course for the activation of glycogen phosphorylase (Phos) and pyruvate dehydrogenase (PDH) and their allosteric regulators was determined in human skeletal muscle during repeated bouts of maximal exercise. Six subjects completed three 30-s bouts of maximal isokinetic cycling separated by 4-min recovery periods. Muscle biopsies were taken at rest and at 6, 15, and 30 s of exercise during bouts 1 and 3. Phos was rapidly activated within the first 6 s of bout 1 from 12% at rest to 47% at 6 s. The activation of PDH increased from 14% at rest to 48% at 6 s and 95% at 15 s of bout 1. Phos reverted back to basal values at the end of the first bout, whereas PDH remained fully activated. In contrast, in the third bout, PDH was 42% at rest and was activated more rapidly and was nearly completely activated by 6 s, whereas Phos remained at basal levels (range 14-20%). Lactate accumulation was marked in the first bout and increased progressively from 2.7 to 76.1 mmol/kg dry wt with no further increase in bout 3. Glycogen utilization was also marked in the first bout and was negligible in bout 3. The rapid activation of Phos and slower activation of PDH in bout 1 was probably due to Ca(2+) release from the sarcoplasmic reticulum. Lactate accumulation appeared to be due to an imbalance of the relative activities of Phos and PDH. The increase in H(+) concentration may have served to reduce pyruvate production by inhibiting Phos transformation and may have simultaneously activated PDH in the third bout such that there was a better matching between pyruvate production and oxidation and minimal lactate accumulation. As each bout progressed and with successive bouts, there was a decreasing ability to stimulate substrate phosphorylation through phosphocreatine hydrolysis and glycolysis and a shift toward greater reliance on oxidative phosphorylation.

Acetylcarnitine↗
PubMed1999

Determinants of disease outcome following Helicobacter pylori infection in children.

Helicobacter pylori infection is primarily acquired during childhood, causes chronic, active gastritis and peptic ulcer disease, and is associated with the development of gastric malignancies. However, only a small number of infected individuals ever develop the more severe sequelae of peptic ulcer disease and gastric cancers. Therefore, the identification of bacterial and host factors that play a role in determining the outcomes and pathophysiology of infection is a major focus of current research. Recent advances in the understanding of disease pathogenesis are critically considered, with particular reference to the pediatric population.

Adult↗
PubMed1999

Helicobacter pylori-epithelial cell interactions: from adhesion to apoptosis.

Studies suggest that host cell signal transduction cascades are manipulated during infection with microbes, including the gastric pathogen Helicobacter pylori. Several putative adhesins have been proposed to mediate the attachment of H pylori to gastric epithelial cells. Following bacterial binding, a series of signalling pathways are activated in the infected gastric epithelial cell. These signals include both cytoplasmic (such as vacuolization, tyrosine phosphorylation and elevation of cytosolic calcium) and nuclear (proliferation, apoptosis and chemokine transcription) events. Research aimed at elucidating the interactions that occur between the host cell and the bacterium during infection should improve the limited knowledge of disease pathogenesis.

Apoptosis↗
PubMed1998

Ketotifen therapy for acute ulcerative colitis in children: a pilot study.

Eosinophils contribute to the inflammatory process in a variety of chronic inflammatory bowel diseases. Ketotifen is beneficial in experimental models of colitis and in patients with eosinophilic gastroenteritis. Therefore, we investigated the efficacy of ketotifen therapy for the treatment of active ulcerative colitis. Children with newly or previously diagnosed ulcerative colitis with mild-moderate disease activity were treated with ketotifen at a dosage of 4 mg daily for eight weeks. Efficacy was determined by a physician disease severity index and by endoscopic and histologic examinations. Ten patients were enrolled. Symptoms improved in four patients and resolved completely in one patient. There was endoscopic improvement in three patients and histologic improvement in one. Increased eosinophils on rectal biopsy at entry were present in two of the responders. Five patients withdrew due to a lack of symptomatic improvement. No adverse events were identified. Low-dose ketotifen offers a limited therapeutic advantage in active ulcerative colitis that may be enhanced in the subgroup of patients with a high eosinophil count in the colonic mucosa. Further study of therapeutic efficacy with increased dosages of the mast cell stabilizer for acute and maintenance therapy is warranted.

Child↗
PubMed1998

Helicobacter pylori infection in children.

Helicobacter pylori causes chronic gastritis and peptic ulcer disease and is epidemiologically associated with the subsequent development of gastric malignancies. Knowledge regarding H. pylori is of particular relevance to pediatricians since acquisition of the infection occurs mainly during the childhood years and may be associated with the development of more severe disease manifestations such as gastric malignancies. Because only a minority of infected individuals will ever develop the sequelae of peptic ulcer disease or gastric cancer, the identification of bacteria factors that play a role in disease pathophysiology is a major focus of current research. This review highlights recent advances in our knowledge of disease pathogenesis, with particular emphasis on bacterial virulence. In addition, the recent literature addressing epidemiology, transmission, clinical features, treatment, and prevention of H. pylori infection is reviewed.

Child↗
PubMed1998

Short-term training increases human muscle MCT1 and femoral venous lactate in relation to muscle lactate.

We examined the effects of increasing a known lactate transporter protein, monocarboxylate transporter 1 (MCT1), on lactate extrusion from human skeletal muscle during exercise. Before and after short-term bicycle ergometry training [2 h/day, 7 days at 65% maximal oxygen consumption (VO2max)], subjects (n = 7) completed a continuous bicycle ergometer ride at 30% VO2max (15 min), 60% VO2max (15 min), and 75% VO2max (15 min). Muscle biopsy samples (vastus lateralis) and arterial and femoral venous blood samples were obtained before exercise and at the end of each workload. After 7 days of training the MCT1 content in muscle was increased (+18%; P < 0.05). The concentrations of both muscle lactate and femoral venous lactate were reduced during exercise (P < 0.05) that was performed after training. High correlations were observed between muscle lactate and venous lactate before training (r = 0.92, P < 0.05) and after training (r = 0.85, P < 0.05), but the slopes of the regression lines between these variables differed markedly. Before training, the slope was 0.12 +/- 0.01 mM lactate.mmol lactate-1.kg muscle dry wt-1, and this was increased by 33% after training to 0.18 +/- 0.02 mM lactate.mmol lactate-1.kg muscle dry wt-1. This indicated that after training the femoral venous lactate concentrations were increased for a given amount of muscle lactate. These results suggest that lactate extrusion from exercising muscles is increased after training, and this may be associated with the increase in skeletal muscle MCT1.

Adult↗
PubMed1998

Effects of short-term submaximal training in humans on muscle metabolism in exercise.

Muscle metabolism, including the role of pyruvate dehydrogenase (PDH) in muscle lactate (Lac-) production, was examined during incremental exercise before and after 7 days of submaximal training on a cycle ergometer [2 h daily at 60% peak O2 uptake (VO2 max)]. Subjects were studied at rest and during continuous steady-state cycling at three stages (15 min each): 30, 65, and 75% of the pretraining VO2 max. Blood was sampled from brachial artery and femoral vein, and leg blood flow was measured by thermodilution. Biopsies of the vastus lateralis were obtained at rest and during steady-state exercise at the end of each stage. VO2 max, leg O2 uptake, and the maximum activities of citrate synthase and PDH were not altered by training; muscle glycogen concentration was higher. During rest and cycling at 30% VO2 max, muscle Lac- concentration ([Lac-]) and leg efflux were similar. At 65% VO2 max, muscle [Lac-] was lower (11.9 +/- 3.2 vs. 20.0 +/- 5.8 mmol/kg dry wt) and Lac- efflux was less [-0.22 +/- 0.24 (one leg) vs. 1.42 +/- 0.33 mmol/min] after training. Similarly, at 75% VO2 max, lower muscle [Lac-] (17.2 +/- 4.4 vs. 45.2 +/- 6.6 mmol/kg dry wt) accompanied less release (0.41 +/- 0.53 vs. 1.32 +/- 0.65 mmol/min) after training. PDH in its active form (PDHa) was not different between conditions. Calculated pyruvate production at 75% VO2 max fell by 33%, pyruvate reduction to lactate fell by 59%, and pyruvate oxidation fell by 24% compared with before training. Muscle contents of coenzyme A and phosphocreatine were higher during exercise after training. Lower muscle lactate production after training resulted from improved matching of glycolytic and PDHa fluxes, independently of changes in muscle O2 consumption, and was associated with greater phosphorylation potential.

Adenine Nucleotides↗
PubMed1998

Regulation of skeletal muscle glycogen phosphorylase and PDH at varying exercise power outputs.

This study investigated the transformational and posttransformational control of skeletal muscle glycogen phosphorylase and pyruvate dehydrogenase (PDH) at three exercise power outputs [35, 65, and 90% of maximal oxygen uptake (VO2 max)]. Seven untrained subjects cycled at one power output for 10 min on three separate occasions, with muscle biopsies at rest and 1 and 10 min of exercise. Glycogen phosphorylase in the more active (a) form was not significantly different at any time across power outputs (21. 4-29.6%), with the exception of 90%, where it fell significantly to 15.3% at 10 min. PDH transformation increased significantly from rest (average 0.53 mmol . kg wet muscle-1 . min-1) to 1 min of exercise as a function of power output (1.60 +/- 0.26, 2.77 +/- 0.29, and 3.33 +/- 0.31 mmol . kg wet muscle-1 . min-1 at 35, 65, and 90%, respectively) with a further significant increase at 10 min (4.45 +/- 0.35) at 90% VO2 max. Muscle lactate, acetyl-CoA, acetylcarnitine, and free ADP, AMP, and Pi were unchanged from rest at 35% VO2 max but rose significantly at 65 and 90%, with accumulations at 90% being significantly higher than 65%. The results of this study indicate that glycogen phosphorylase transformation is independent of increasing power outputs, despite increasing glycogenolytic flux, suggesting that flux through glycogen phosphorylase is matched to the demand for energy by posttransformational factors, such as free Pi and AMP. Conversely, PDH transformation is directly related to the increasing power output and the calculated flux through the enzyme. The rise in PDH transformation is likely due to increased Ca2+ concentration and/or increased pyruvate. These results demonstrate that metabolic signals related to contraction and the energy state of the cell are sensitive to the exercise intensity and coordinate the increase in carbohydrate use with increasing power output.

Acetyl Coenzyme A↗
PubMed1997

Sprint training enhances ionic regulation during intense exercise in men.

1. This study investigated the effects of 7 weeks of sprint training on changes in electrolyte concentrations and acid-base status in arterial and femoral venous blood, during and following maximal exercise for 30 s on an isokinetic cycle ergometer. 2. Six healthy males performed maximal exercise, before and after training. Blood samples were drawn simultaneously from brachial arterial and femoral venous catheters, at rest, during the final 10 s of exercise and during 10 min of recovery, and analysed for whole blood and plasma ions and acid-base variables. 3. Maximal exercise performance was enhanced after training, with a 13% increase in total work output and a 14% less decline in power output during maximal cycling. 4. The acute changes in plasma volume, ions and acid-base variables during maximal exercise were similar to previous observations. Sprint training did not influence the decline in plasma volume during or following maximal exercise. After training, maximal exercise was accompanied by lower arterial and femoral venous plasma [K+] and [Na+] across all measurement times (P < 0.05). Arterial plasma lactate concentration ([Lac-]) was greater (P < 0.05), but femoral venous plasma [Lac-] was unchanged by training. 5. Net release into, or uptake of ions from plasma passing through the exercising muscle was assessed by arteriovenous concentration differences, corrected for fluid movements. K+ release into plasma during exercise, and a small net K+ uptake from plasma 1 min post-exercise (P < 0.05), were unchanged by training. A net Na+ loss from plasma during exercise (P < 0.05) tended to be reduced after training (P < 0.06). Release of Lac- into plasma during and after exercise (P < 0.05) was unchanged by training. 6. Arterial and venous plasma strong ion difference ([SID]; [SID] = [Na+] + [K+] - [Lac-] - [Cl-]) were lower after training (mean differences) by 2.7 and 1.8 mmol l-1, respectively (P < 0.05). Arterial and femoral venous CO2 tensions and arterial plasma [HCO3-] were lower after training (mean differences) by 1.7 mmHg, 4.5 mmHg and 1.2 mmol l-1, respectively (P < 0.05), with arterial plasma [H+] being greater after training by 2.2 nmol l-1 (P < 0.05). 7. The acute changes in whole blood volume and ion concentrations during maximal exercise were similar to previous observations: Arterial and femoral whole blood [K+] and [Cl-] were increased, whilst [Na+] was lower, across all observation times after training (P < 0.05). 8. Net uptake or release of ions by exercising muscle was assessed by arteriovenous whole blood concentration differences, corrected for fluid movements. A net K+ uptake by muscle occurred at all times, including exercise, but this was not significantly different after training. An increased net Na+ uptake by muscle occurred during exercise (P < 0.05) with greater Na+ uptake after training (P < 0.05). Net muscle Lac- release and Cl- uptake occurred at all times (P < 0.05) and were unchanged by training. 9. Sprint training improved muscle ion regulation, associated with increased intense exercise performance, at the expense of a greater systemic acidosis. Increased muscle Na+ and K+ uptake by muscle during the final seconds of exercise after training are consistent with a greater activation of the muscle Na(+) - K+ pump, reduced cellular K+ loss and the observed lesser rate of fatigue. The greater plasma acidosis found after sprint training was caused by a lower arterial plasma [SID] due to lower plasma [K+] and [Na+], and higher plasma [Lac-].

Acid-Base Equilibrium↗