Poor tolerability of thalidomide in end-stage oesophageal cancer.

Oesophageal cancer cachexia is a significant clinical problem, resulting in excessive morbidity and mortality. In a pilot study, 10 patients with cachexia due to advanced cancer of the oesophagus gained weight, including lean tissue, after 14-day treatment with thalidomide. Here, we present randomised placebo controlled trial data over a 6-week period to test the hypothesis that thalidomide is superior to placebo in terms of weight gain in patients with cachexia caused by oesophageal cancer. Thalidomide, 200 mg daily, or an identical placebo was given to patients with advanced oesophageal cancer. Total body weight and lean body mass were assessed in addition to drug tolerability and performance indices. Thirty-four patients were recruited. Of these, six given thalidomide and 16 given placebo completed the protocol; all withdrawals were due to adverse drug reactions or complications of disease. Thalidomide showed no benefit over placebo in participants who completed the protocol. These data suggest that thalidomide is poorly tolerated in patients with advanced cancer of the oesophagus and may not ameliorate the progression of cachexia. In the absence of hard supportive evidence, off-licence treatment with thalidomide should be used with great caution as an adjunct to nutritional support in patients with advanced cancer.

Facts, noise and wishful thinking: muscle protein turnover in aging and human disuse atrophy.

Surprisingly little is known about the mechanisms of muscle atrophy with aging and disuse in human beings, in contrast to rodents, from which much has been extrapolated to explain the human condition. However, this extrapolation is likely unwarranted because the time course, extent of wasting, muscle fiber involvement and alterations of muscle protein turnover are all quite different in rodent and human muscle. Furthermore, there is little evidence that static indices of protein turnover represent dynamic changes and may be misleading. With disuse there are reductions in the rate of muscle protein synthesis (MPS) large enough to explain the atrophic loss of muscle protein without a concomitant increase in proteolysis. In aging, there is no evidence that there are marked alterations in basal muscle protein turnover in healthy individuals but instead the ability to maintain muscle after feeding is compromised. This anabolic resistance is evident with physical inactivity, which exacerbates the inability to maintain muscle mass with aging. The main conclusion of this review is that in uncomplicated, non-inflammatory disuse atrophy, the facilitative change causing loss of muscle mass is a depression of MPS, exacerbated by anabolic resistance during feeding, with possible adaptive depressions, rather than increases, of muscle proteolysis.

Cyclic stretch reduces myofibrillar protein synthesis despite increases in FAK and anabolic signalling in L6 cells.

Muscle protein synthesis is increased after exercise, but evidence is now accruing that during muscular activity it is suppressed. In life, muscles are subjected to shortening forces due to contraction, but may also be subject to stretching forces during lengthening. It would be biologically inefficient if contraction and stretch have different effects on muscle protein turnover, but little is known about the metabolic effects of stretch. To investigate this, we assessed myofibrillar and sarcoplasmic protein synthesis (MPS, SPS, respectively) by incorporation of [1-13C]proline (using gas chromatography-mass spectrometry) and anabolic signalling (by phospho-immunoblotting and kinase assays) in cultured L6 skeletal muscle cells during 30 min of cyclic stretch and over 30 min intervals for up to 120 min afterwards. SPS was unaffected, whereas MPS was suppressed by 40 +/- 0.03% during stretch, before returning to basal rates by 90-20 min afterwards. Paradoxically, stretch stimulated anabolic signalling with peak values after 2-30 min: e.g. focal adhesion kinase (FAK Tyr576/577; +28 +/- 6%), protein kinase B activity (Akt; +113 +/- 31%), p70S6K1 (ribosomal S6 kinase Thr389; 25 +/- 5%), 4E binding protein 1 (4EBP1 Thr37/46; 14 +/- 3%), eukaryotic elongation factor 2 (eEF2 Thr56; -47 +/- 4%), extracellular regulated protein kinase 1/2 (ERK1/2 Tyr202/204; +65% +/- 9%), eukaryotic initiation factor 2alpha (eIF2alpha Ser51; -20 +/- 5%, P < 0.05) and eukaryotic initiation factor 4E (eIF4E Ser209; +33 +/- 10%, P < 0.05). After stretch, except for Akt activity, stimulatory phosphorylations were sustained: e.g. FAK (+26 +/- 11%) for > or =30 min, eEF2 for > or =60 min (peak -45 +/- 4%), 4EBP1 for > or =90 min (+33 +/- 5%), and p70S6K1 remained elevated throughout (peak +64 +/- 7%). Adenosine monophosphate-activated protein kinase (AMPK) phosphorylation was unchanged throughout. We report for the first time that acute cyclic stretch specifically suppresses MPS, despite increases in activity/phosphorylation of elements thought to increase anabolism.

Alterations of protein turnover underlying disuse atrophy in human skeletal muscle.

Unloading-induced atrophy is a relatively uncomplicated form of muscle loss, dependent almost solely on the loss of mechanical input, whereas in disease states associated with inflammation (cancer cachexia, AIDS, burns, sepsis, and uremia), there is a procatabolic hormonal and cytokine environment. It is therefore predictable that muscle loss mainly due to disuse alone would be governed by mechanisms somewhat differently from those in inflammatory states. We suggest that in vivo measurements made in human subjects using arterial-venous balance, tracer dilution, and tracer incorporation are dynamic and thus robust by comparison with static measurements of mRNA abundance and protein expression and/or phosphorylation in human muscle. In addition, measurements made with cultured cells or in animal models, all of which have often been used to infer alterations of protein turnover, appear to be different from results obtained in immobilized human muscle in vivo. In vivo measurements of human muscle protein turnover in disuse show that the primary variable that changes facilitating the loss of muscle mass is protein synthesis, which is reduced in both the postabsorptive and postprandial states; muscle proteolysis itself appears not to be elevated. The depressed postprandial protein synthetic response (a phenomenon we term "anabolic resistance") may even be accompanied by a diminished suppression of proteolysis. We therefore propose that most of the loss of muscle mass during disuse atrophy can be accounted for by a depression in the rate of protein synthesis. Thus the normal diurnal fasted-to-fed cycle of protein balance is disrupted and, by default, proteolysis becomes dominant but is not enhanced.

Regulation of leucine metabolism in man: a stable isotope study.

Leucine catabolism is regulated by either of the first two degradative steps: (reversible) transamination to the keto acid or subsequent decarboxylation. A method is described to measure rates of leucine transamination, reamination, and keto acid oxidation. The method is applied directly to humans by infusing the nonradioactive tracer, L-[15N,1-13C]leucine. Leucine transamination was found to be operating several times faster than the keto acid decarboxylation and to be of equal magnitude in adult human males under two different dietary conditions, postabsorptive and fed. These results indicate that decarboxylation, not transamination, is the rate-limiting step in normal human leucine metabolism.

Rheumatoid cachexia: a clinical perspective.

Rheumatoid cachexia is under-recognized in clinical practice. The loss of lean body tissue, which characterizes cachexia, is often compensated for by gain in body fat-so called 'cachectic obesity'-so that 85% or more RA patients have a normal BMI. Severe cachexia with loss of weight leads to increased morbidity and premature mortality but loss of muscle bulk with a normal BMI also associates with poor clinical outcomes. Increasing BMI, even into the obese range, is associated with less joint damage and reduced mortality. Measurement of body composition using DXA and other techniques is feasible but the results must be interpreted with care. Newer techniques such as whole-body MRI will help define with more confidence the mass and distribution of fat and muscle and help elucidate the relationships between body composition and outcomes. Cachexia shows little response to diet alone but progressive resistance training and anti-TNF therapies show promise in tackling this potentially disabling extra-articular feature of RA.

Selective activation of AMPK-PGC-1alpha or PKB-TSC2-mTOR signaling can explain specific adaptive responses to endurance or resistance training-like electrical muscle stimulation.

Endurance training induces a partial fast-to-slow muscle phenotype transformation and mitochondrial biogenesis but no growth. In contrast, resistance training mainly stimulates muscle protein synthesis resulting in hypertrophy. The aim of this study was to identify signaling events that may mediate the specific adaptations to these types of exercise. Isolated rat muscles were electrically stimulated with either high frequency (HFS; 6x10 repetitions of 3 s-bursts at 100 Hz to mimic resistance training) or low frequency (LFS; 3 h at 10 Hz to mimic endurance training). HFS significantly increased myofibrillar and sarcoplasmic protein synthesis 3 h after stimulation 5.3- and 2.7-fold, respectively. LFS had no significant effect on protein synthesis 3 h after stimulation but increased UCP3 mRNA 11.7-fold, whereas HFS had no significant effect on UCP3 mRNA. Only LFS increased AMPK phosphorylation significantly at Thr172 by approximately 2-fold and increased PGC-1alpha protein to 1.3 times of control. LFS had no effect on PKB phosphorylation but reduced TSC2 phosphorylation at Thr1462 and deactivated translational regulators. In contrast, HFS acutely increased phosphorylation of PKB at Ser473 5.3-fold and the phosphorylation of TSC2, mTOR, GSK-3beta at PKB-sensitive sites. HFS also caused a prolonged activation of the translational regulators p70 S6k, 4E-BP1, eIF-2B, and eEF2. These data suggest that a specific signaling response to LFS is a specific activation of the AMPK-PGC-1alpha signaling pathway which may explain some endurance training adaptations. HFS selectively activates the PKB-TSC2-mTOR cascade causing a prolonged activation of translational regulators, which is consistent with increased protein synthesis and muscle growth. We term this behavior the "AMPK-PKB switch." We hypothesize that the AMPK-PKB switch is a mechanism that partially mediates specific adaptations to endurance and resistance training, respectively.

Protein synthesis measured in vivo in muscle and liver of cachectic tumor-bearing mice.

Protein synthesis has been measured in vivo in liver and muscle of mice bearing the XK1 tumor, an appropriate model for cancer cachexia. Two different methods were used involving measurement of tracer incorporation into tissue protein either at the end of a 4-hr constant infusion of [14C]tyrosine or 10 min after i.v. injection of a flooding dose of [3H]phenylalanine. Whole-body tyrosine flux was decreased by 60% in cachectic tumor-bearing mice, and protein synthesis was depressed by 70% in muscle and by 40% in liver. The depression of protein synthesis in muscle was due to a reduction in both RNA content (i.e., protein-synthesizing capacity) and RNA activity (i.e., protein synthesized per g of RNA per hr). In liver, the depression of protein synthesis was due entirely to a decrease in RNA activity. The results also suggest that the synthesis of export proteins was affected more than the synthesis of fixed liver protein. Restriction of food intake in normal mice by up to 50% caused a loss of body weight and reductions in protein synthesis in liver and muscle which were less severe than those caused by the presence of the tumor. It is concluded that the wasting which is associated with advanced malignant disease is brought about by a reduction in the rate of protein synthesis in the tissues, and that this cannot be explained by depression of food intake alone.

Efflux of 3-methylhistidine from the leg in cancer patients who experience weight loss.

An improved method for measurement of 3-methylhistidine in blood samples has been used to assess efflux of 3-methylhistidine from the leg in cancer patients experiencing weight loss. Three control groups were studied: malnourished depleted patients without cancer; comparatively well-nourished but acutely ill patients; and well-nourished controls, hospitalized for elective surgery, who showed no symptoms of metabolic disease. Well-nourished controls and acutely ill patients had a statistically significant release of 3-methylhistidine [1.92 +/- 0.40 (S.E.) nmol/min/100 g leg tissue and 0.93 +/- 0.32 nmol/min/100 g, respectively], but cancer patients and malnourished noncancer patients had insignificant efflux. When nutritional support was provided, noncancer patients abolished their previously negative tyrosine balance and increased the efflux of 3-methylhistidine; however, cancer patients as a group continued to show a negative tyrosine balance, and the efflux of 3-methylhistidine continued to decrease further in them. The results in this study demonstrate that weight loss in clinical cancer is not dependent on increased skeletal muscle protein degradation, not even at an early stage of the disease. It seems likely that decreased protein synthesis is a more important factor.

L(+)-lactate transport in perfused rat skeletal muscle: kinetic characteristics and sensitivity to pH and transport inhibitors.

We have examined lactate uptake (as the rate of net muscle lactate accumulation) and unidirectional inward transport (measured by a paired-tracer dilution method) in muscle of the perfused skinned rat hindlimb. Inhibition of tracer influx (fractional uptake at 1 mM L(+)-lactate, 43.3 +/- 3.1% but only 32.9 +/- 1.8% at 50 mM lactate) suggested some competition between tracer and native forms of the carboxylate for transport. D(-)-lactate (50 mM) did not inhibit uptake of tracer L(+)-lactate. Pyruvate (25 mM), but none of five other monocarboxylates, inhibited uptake of tracer lactate, by 22% (P less than 0.01). Altering perfusate pH from 7.4 to 6.8 caused a 36% increase (P less than 0.001) in the unidirectional L(+)-lactate transport at 1 mM L(+)-lactate, whereas increasing pH to 7.7 reduced transport by 18% (P less than 0.01). Tracer lactate influx was inhibited by 500 microM 4-acetamido-4'-isothiocyanostilbene (SITS) (19%), 5 mM alpha-cyano-4-hydroxycinnamic acid (CIN) (20-30%), 1 mM amiloride (27%) and by a thiol group reagent p-chloromercuribenzenesulphonic acid (pCMBS) (26%). Overall the results indicate that at least two processes are involved in the transfer of lactate: one, saturable, with a Vmax of 0.84 mumol.min-1.g-1 and an apparent Km of 21 mM was sensitive to SITS, CIN, and a thiol group reagent; the other was non-saturable and insensitive to SITS and CIN with an apparent rate constant of 0.1 min-1.

Effects of corticosteroid on the transport and metabolism of glutamine in rat skeletal muscle.

Intramuscular glutamine falls with injury and disease in circumstances associated with increases in blood corticosteroids. We have investigated the effects of corticosteroid administration (0.44 mg/kg dexamethasone daily for 8 days, 200 g female rats) on intramuscular glutamine and Na+, muscle glutamine metabolism and sarcolemmal glutamine transport in the perfused hindlimb. After dexamethasone treatment intramuscular glutamine fell by 45% and Na+ rose by 25% (the respective muscle/plasma distribution ratios changed from 8.6 to 4.5 and 0.12 to 0.15); glutamine synthetase and glutaminase activities were unchanged at 475 +/- 75 and 60 +/- 19 nmol/g muscle per min. Glutamine output by the hindlimb of anaesthetized rats was increased from 31 to 85 nmol/g per min. Sarcolemmal glutamine transport was studied by paired-tracer dilution in the perfused hindlimb: the maximal capacity (Vmax) for glutamine transport into muscle (by Na(+)-glutamine symport) fell from 1058 +/- 310 to 395 +/- 110 nmol/g muscle per min after dexamethasone treatment, accompanied by a decrease in the Km (from 8.1 +/- 1.9 to 2.1 +/- 0.4 mM glutamine). At physiological plasma glutamine concentration (0.75 mM) dexamethasone appeared to cause a proportional increase in sarcolemmal glutamine efflux over influx. Addition of dexamethasone (200 nM) to the perfusate of control rat hindlimbs caused acute changes in Vmax and Km of glutamine transport similar to those resulting from 8-day dexamethasone treatment. The reduction in muscle glutamine concentration after dexamethasone treatment may be primarily due to a reduction in the driving force for intramuscular glutamine accumulation, i.e., in the Na+ electrochemical gradient. The prolonged increase in muscle glutamine output after dexamethasone treatment (which occurs despite a reduction in the size of the intramuscular glutamine pool) appears to be due to a combination of (a) accelerated sarcolemmal glutamine efflux and (b) increased intramuscular synthesis of glutamine.

A role for membrane transport in modulation of intramuscular free glutamine turnover in streptozotocin diabetic rats.

We wished to examine the effects of diabetes on muscle glutamine kinetics. Accordingly, female Wistar rats (200 g) were made diabetic by a single injection of streptozotocin (85 mg/kg) and studied 4 days later; control rats received saline. In diabetic rats, glutamine concentration of gastrocnemius muscle was 33% less than in control rats: 2.60 +/- 0.06 mumol/g vs. 3.84 +/- 0.13 mumol/g (P < 0.001). In gastrocnemius muscle, glutamine synthetase activity (Vmax) was unaltered by diabetes (approx. 235 nmol/min per g) but glutaminase Vmax increased from 146 +/- 29 to 401 +/- 94 nmol/min per g; substrate Km values of neither enzyme were affected by diabetes. Net glutamine efflux (A-V concentration difference x blood flow) from hindlimbs of diabetic rats in vivo was greater than control values (-30.0 +/- 3.2 vs. -1.9 +/- 2.6 nmol/min per g (P < 0.001)) and hindlimb NH3 uptake was concomitantly greater (about 27 nmol/min per g). The glutamine transport capacity (Vmax) of the Na-dependent System Nm in perfused hindlimb muscle was 29% lower in diabetic rats than in controls (820 +/- 50 vs. 1160 +/- 80 nmol/min per g (P < 0.01)), but transporter Km was the same in both groups (9.2 +/- 0.5 mM). The difference between inward and net glutamine fluxes indicated that glutamine efflux in perfused hindlimbs was stimulated in diabetes at physiological perfusate glutamine (0.5 mM); ammonia (1 mM in perfusate) had little effect on net glutamine flux in control and diabetic muscles. Intramuscular Na+ was 26% greater in diabetic (13.2 mumol/g) than control muscle, but muscle K+ (100 mumol/g) was similar. The accelerated rate of glutamine release from skeletal muscle and the lower muscle free glutamine concentration observed in diabetes may result from a combination of: (i), a diminished Na+ electrochemical gradient (i.e., the net driving force for glutamine accrual in muscle falls); (ii), a faster turnover of glutamine in muscle and (iii), an increased Vmax/Km for sarcolemmal glutamine efflux.

Effects of insulin and amino acids on leg protein turnover in IDDM patients.

To determine whether the responses of muscle protein metabolism to insulin and amino acids in patients with insulin-dependent diabetes mellitus (IDDM) were different from those in nondiabetic subjects, leg tissue kinetics of [15N]phenylalanine and [1-13C]leucine and its metabolites were measured in eight insulin-withdrawn IDDM patients and eight nondiabetic subjects during basal insulinemia and during infusion of insulin (0.29 nmol.min-1.m-2). The diabetic patients were studied in the absence of amino acids, and both groups were studied during infusion of a mixed-amino acid solution (AA). In the diabetic patients, insulin alone and combined with additional AA reduced leg tissue phenylalanine release by 42 and 41%, respectively (both P less than 0.05), but uptake was unchanged. Leg tissue leucine oxidation was unchanged by insulin alone but was increased (P = 0.012) fourfold during insulin infusion with additional AA. In the nondiabetic subjects, insulin with AA infusion increased leg tissue phenylalanine uptake (45.7 +/- 7.5 to 73.1 +/- 7.3 nmol.min-1.100 g-1, P less than 0.01). Insulin-stimulated glucose uptake in the diabetic patients (1.60 +/- 0.28 mumol.min-1.100 g-1, P = 0.04). These results suggest that, in IDDM patients, 1) infusion of insulin fails to stimulate muscle protein synthesis even when combined with a substantially increased provision of AA, and 2) compared with nondiabetic subjects, muscle protein synthesis as well as glucose uptake exhibit blunted responses to insulin.

Metabolic activity and collagen turnover in human tendon in response to physical activity.

Connective tissue of the human tendon plays an important role in force transmission. The extracellular matrix turnover of tendon is influenced by physical activity. Blood flow, oxygen demand, and the level of collagen synthesis and matrix metalloproteinases increase with mechanical loading. Gene transcription and especially post-translational modifications of proteins of the extracellular matrix are enhanced following exercise. Conversely, inactivity markedly decreases collagen turnover. Training leads to a chronically increased collagen turnover, and dependent on the type of collagen also to some degree of net collagen synthesis. These changes modify the biomechanical properties of the tissue (for example, viscoelastic characteristics) as well as the structural properties of the in collagen (for example, cross-sectional area). Mechanical loading of human tendon does result in a marked interstitial increase in growth factors that are known potentially to stimulate synthesis of collagen and other extracellular matrix proteins. Taken together, human tendon tissue mounts a vigorous acute and chronic response to mechanical loading in terms of metabolic-circulatory changes as well as of extracellular matrix formation. These changes may contribute to training-induced adaptation of biomechanical properties consisting of altered resistance to loading and enhanced tolerance to strenuous exercise. Understanding of such changes is a pre-requisite in the development of measures aimed at prevention of overuse tendon injuries occurring during sport, work or leisure-related activities.

Perivenous localisation of Na-dependent glutamate transport in perfused rat liver.

Periportal and perivenous hepatocytes differ in their metabolism of blood glutamate (Glu). Uncertainty about the mechanisms of Glu blood-liver exchange led us to characterise, by paired-tracer dilution, a sodium-dependent dicarboxylate transporter (resembling system X-ag) in sinusoidal membranes of perfused rat liver (Vmax = 0.18 mumol Glu/g per min, Km = 0.29 mM Glu). Tracer Glu transport was depressed 65% after necrosis of perivenous hepatocytes by acute CCl4 treatment, indicating that X-ag transporter activity is located mainly in these cells, the sites of glutamine (Gln) synthesis from glutamate and ammonia. Modulation of Glu transport may influence the extent of hepatic Gln release.

A positive relationship between protein synthetic rate and intracellular glutamine concentration in perfused rat skeletal muscle.

During muscle-protein wasting associated with injury and disease the distribution ratio of free glutamine between muscle and blood falls. In pursuing possible consequences of this, we investigated the relationship between the rate of muscle protein synthesis and intramuscular glutamine concentration, manipulated acutely in the isolated perfused rat hindquarter. Increasing perfusate glutamine from 0.67 to 5.0 mM caused a 200% increase in intracellular glutamine and a 66% increase in protein synthesis in the absence of insulin; in the presence of insulin a 30% increase in intramuscular glutamine was accompanied by an 80% increase in protein synthesis. Analysis of variance of the results confirmed the existence of positive relationships between intramuscular glutamine and protein synthesis in the presence or absence of insulin. Control of the size of the intramuscular free pool of glutamine may be important in determining the muscle protein mass.

Involvement of integrins and the cytoskeleton in modulation of skeletal muscle glycogen synthesis by changes in cell volume.

Muscle glycogen synthesis is modulated by physiologically relevant changes in cell volume. We have investigated the possible involvement of integrin-extracellular matrix interactions in this process using primary cultures of rat skeletal muscle subject to hypo- or hyper-osmotic exposure with integrin binding peptide GRGDTP to disrupt integrin actions and the inactive analogue GRGESP as control. Osmotically induced increases (77%) and decreases (34%) in glycogen synthesis (D-[14C]glucose incorporation into glycogen) were prevented by GRGDTP (but not GRGESP) without affecting glucose transport. Cytoskeletal disruption with cytochalasin D or colchicine had similar effects to GRGDTP. Osmotically induced modulation of muscle glycogen synthesis involves integrin-extracellular matrix interactions and cytoskeletal elements, possibly as components of a cell-volume 'sensing' mechanism.

Inhibition of protein breakdown by glutamine in perfused rat skeletal muscle.

We have assessed the effects of glutamine (Gln) availability on protein breakdown in perfused rat hindlimb by measuring net phenylalanine (Phe) production (an index of protein balance), the dilution of [15N]Phe labelling (an index of mixed protein breakdown) and rate of production of 3-methylhistidine (3-MeH) (an index of myofibrillar breakdown). 15 mM Gln significantly inhibited net protein loss and protein breakdown compared to rates obtained in its absence (net protein loss, 200 +/- 230 vs 2080 +/- 200 nmol Phe/hindlimb per h; protein breakdown, 4566 +/- 480 vs 1614 +/- 180 nmol Phe/hindlimb per h; both p less than 0.01). Insulin (100 microU/ml) inhibited protein breakdown but less than Gln. The effects on protein breakdown of Gln and insulin together were not additive, suggesting a common mode of action. Production of 3-MeH (mean 20.3 +/- 2.8 nmol/hindlimb per h) was unaffected by Gln or insulin. Gln appears to inhibit protein breakdown of soluble rather than myofibrillar protein in muscle.

Plasma triglyceride lowering by exercise despite increased food intake in patients with type IV hyperlipoproteinemia.

Exercise can lower fasting triglyceride levels (TG). This study was undertaken to determine whether the exercise-induced decrease in TG is the result of a negative caloric balance. Five subjects with primary type IV hyperlipoproteinemia were given diets comparable in composition to their usual diets. During one experimental period the subjects exercised while maintaining their usual caloric intakes. During another experimental period their caloric intake was increased to compensate for the exercise-induced increase in energy expenditure. The exercise, which consisted of 30 min of treadmill walking per day for 4 days, resulted in a progressive decrease in TG. The reduction in TG, which averaged 120 mg/100 ml, occurred regardless of whether or not the increase in caloric expenditure was compensated for by an increase in food intake. The decrease in TG was limited to the very low density lipoprotein fraction. No significant changes occurred in total plasma cholesterol concentration or in the distribution of cholesterol between the lipoprotein fractions. Fasting plasma glucagon concentration was constant for each individual and was unaffected by the exercise. The finding that exercise induces a decrease in TG despite increased food intake indicates that the TG lowering effect of exercise is not mediated by a negative caloric balance.

Protein metabolism during treatment of chest infection in patients with cystic fibrosis.

Six cystic fibrosis patients with pulmonary exacerbations were studied to determine the effect of antibiotic treatment on protein nutritional status. Indirect calorimetry, nitrogen balance, protein turnover, urinary 3-methylhistidine, plasma albumin, prealbumin transferrin, and cortisol were measured before and after treatment. N loss averaged 16 and 17% on each balance. N in the sputum was up to 4.5% of absorbed N intake. At the peak of infection, protein synthesis, degradation, and urinary 3-methylhistidine were significantly higher than during recovery (31%, 28%, and 60%, respectively). On recovery a significant fall in blood sugar, albumin, morning cortisol and sputum N and a rise in prealbumin was found. Basal metabolic rate and N balance did not change. For patients in the fed state, active infection is associated with higher rates of protein synthesis and degradation. Antimicrobial treatment alters protein dynamics but does not alter measured N balance or the difference between measured protein synthesis and breakdown.