Segmented silicon MZM for PAM-8 transmissions at 114 Gb/s with binary signaling.

We experimentally demonstrate PAM-8 generation from binary electrical signals driving a silicon multi-electrode Mach-Zehnder modulator acting as an optical digital-to-analog converter. Measured BER in back-to-back configuration is used to evaluate signal quality. We demonstrate 38 GBd PAM-8 transmission below the forward error correction (FEC) threshold using minimum mean square error (MMSE) equalization. The results show that modulators with segmented phase shifters can be advantageously used to eliminate the need for high bandwidth electronic digital-to-analog converters in the generation of multilevel signals. These modulators, that can be designed and fabricated with standard CMOS compatible tools and processes, are of high interest for short range high-speed data links.

Dual phase-shift Bragg grating silicon photonic modulator operating up to 60 Gb/s.

We demonstrate PAM-4 and OOK operation of a novel silicon photonic modulator. The modulator design is based on two phase-shifts in a Bragg Grating structure driven in a push pull configuration. Back-to-back PAM-4 modulation is demonstrated below the FEC threshold at up to 60 Gb/s. OOK modulation is also shown up to 55 Gb/s with MMSE equalization and up to 50 Gb/s without equalization. Eye diagrams and BER curves at different bit rates are provided for both PAM-4 and OOK modulations. To our knowledge, this structure is the fastest silicon photonic modulator based on Bragg gratings, reaching modulation speed comparable to the fastest Mach-Zehnder modulators and micro-ring modulators.

Chrysin attenuates experimental autoimmune neuritis by suppressing immuno-inflammatory responses.

Guillain-Barré syndrome (GBS) is an acute, post-infectious, immune-mediated, demyelinating disease of peripheral nerves and nerve roots. Experimental autoimmune neuritis (EAN) is an animal model of GBS. Chrysin, which is a naturally occurring flavonoid, exhibits various biological activities. This study was designed to investigate the anti-inflammatory and neuroprotective properties of preventative and therapeutic chrysin treatment in EAN rats. For preventative treatment, chrysin was administered orally from day 1 to day 16 (50mg/kg once daily) while, for therapeutic treatment, rats received chrysin from day 7 to day 16 at the same dose once daily. Control animals received the same volume of the vehicle (phosphate-buffered saline/2% dimethylsulfoxide). Regardless of the treatment regimen, chrysin attenuated the severity and duration of the clinical course of EAN and reduced inflammatory cell infiltration and demyelination of sciatic nerves. In the sciatic nerves, the expression of inducible nitric oxide synthase, cyclooxygenase-2 and nuclear factor kappa B was reduced. Furthermore, chrysin inhibited the splenic mononuclear cell secretion of interleukin-1ß, interleukin-2, interleukin-6, inteleukin-12, interferon γ and tumor necrosis factor α, and elevated the level of inteleukin-4. In summary, our data demonstrate that chrysin is a potentially useful agent for the treatment of EAN with its anti-inflammatory and neuroprotective effects.

Na+ appetite induced by depleting extracellular fluid volume activates the enkephalin/mu-opioid receptor system in the rat forebrain.

In Na(+) appetite neurobiology, it is essential to investigate whether endogenous opioids modulate the output of the neural substrates that are involved in both the detection and integration of Na(+) deficiency and the motivational aspect of Na(+) intake. Thus, evaluating the recruitment dynamics of enkephalin (ENK)-containing and/or mu-opioid receptor (µ-OR)-expressing neurons in close correlation with the hydromineral state of the rat might provide useful information regarding the role of the opioid system in regulating the central network that controls water and Na(+) intake. Furosemide was used to deplete both fluid volume and the Na(+) content of the extracellular fluid (ECF) compartment when combined with water repletion and a short-term Na(+)-free diet. Na(+) restoration in the ECF compartment was achieved by providing unrestricted access to both saline (0.3 M NaCl) and water. Combining in situ hybridization (against ENK and µ-OR mRNA) and immunohistochemistry (against Fos) revealed a specific pattern of hypovolemia-induced Fos expression in the enkephalinergic subpopulations of the central amygdala, in the oval nucleus of the bed nucleus of the stria terminalis and in the nucleus accumbens shell. Hypovolemia also induced transient Fos expression in µ-OR-expressing neurons in the same nuclei and in the median preoptic nucleus and subfornical organ. However, this specific hydromineral state did not activate the ENK and/or µ-OR-expressing neurons in the lateral parabrachial nucleus or in the medial nucleus of the solitary tract. These results implicate the ENK/µ-OR system as a putative facilitator of Na(+) intake in discrete regions of the forebrain, possibly by modulating the hedonic and reward value of Na(+) by increasing ENK release in these regions.

Neuroprotective role of the innate immune system by microglia.

Innate immunity is a rapid series of reactions to pathogens, cell injuries and toxic proteins. A key component of this natural response is the production of inflammatory mediators by resident microglia and infiltrating macrophages. There is accumulating evidence that inflammation contributes to acute injuries and more chronic CNS diseases, though other studies have shown that inhibition of microglia is, in contrast, associated with more damages or less repair. The controversies regarding the neuroprotective and neurodegenerative properties of microglia may depend on the experimental approaches. Neurotoxic substances are frequently used to produce animal models of acute injuries or diseases and they may activate microglia either directly or indirectly by their ability to cause neuronal death and demyelination. Whether microglia and the immune response play a direct role in such processes still remains an open question. On the other hand, there are data supporting the role of resident microglia and those derived from the bone marrow in the stimulation of myelin repair, removal of toxic proteins from the CNS and the prevention of neurodegeneration in chronic brain diseases. The ability of glucocorticoids to provide a negative feedback on nuclear factor kappa B pathways in microglia may be a determinant mechanism underlying the ultimate fate of the inflammatory response in the CNS. This review presents new concepts regarding the neuroprotective role of the innate immune response in the brain and how microglia can be directed to improve recovery after injuries and prevent/delay neurodegeneration.

Neuroprotective properties of the innate immune system and bone marrow stem cells in Alzheimer's disease.

The role of innate immunity and microglia in the brain is currently a matter of great debate and controversy. While several studies have provided evidence that they contribute to neurodegeneration in various animal models of brain diseases and traumas, others have shown that their inhibition may in contrast be associated with more damages or less repair. We have recently reported the existence of two different types of microglia, the resident and the newly differentiated microglia that derive from the bone marrow stem cells. Of great interest is the fact that blood-derived microglial cells are associated with amyloid plaques and these cells are able to prevent the formation or eliminate the presence of amyloid deposits in mice that develop the major hallmark of Alzheimer's disease (AD). These newly recruited cells are specifically attracted to the beta-amyloid 40/42 isoforms in vivo and they participate in the elimination of these proteins by phagocytosis. This review presents the mechanisms involved in the control of the innate immune response by microglia and the beneficial properties of such a response in brain diseases, such as AD.

Nerve activity-dependent modulation of calcineurin signaling in adult fast and slow skeletal muscle fibers.

This study tested the hypothesis that calcineurin signaling is modulated in skeletal muscle cells by fluctuations in nerve-mediated activity. We show that dephosphorylation of NFATc1, MEF2A, and MEF2D transcription factors by calcineurin in all muscle types is dependent on nerve activity and positively correlated with muscle usage under normal weightbearing conditions. With increased nerve-mediated activity, calcineurin dephosphorylation of these targets was found to be potentiated in a way that paralleled the higher muscle activation profiles associated with functional overload or nerve electrical stimulation conditions. We also establish that muscle activity must be sustained above native levels for calcineurin-dependent dephosphorylation of MEF2A and MEF2D to be transduced into an increase in MEF2 transcriptional function, suggesting that calcineurin cooperates with other activity-linked events to signal via these proteins. Finally, examination of individual fiber responses to overload and nerve electrical stimulation revealed that calcineurin-MEF2 signaling occurs in all fiber types but most readily in fibers that are normally least active (i.e. those expressing IIx and IIb myosin heavy chain (MHC)), suggesting that signaling via this phosphatase is also dependent upon the activation history of the muscle cell.

Hepatic uptake and metabolism of benzoate: a multiple indicator dilution, perfused rat liver study.

Multiple, noneliminated references ((51)Cr-labeled erythrocytes, (125)I-albumin, [(14)C]- or [(3)H]sucrose, and [(2)H](2)O), together with [(3)H]hippurate or [(14)C]benzoate, were injected simultaneously into the portal vein of the perfused rat liver during single-pass delivery of benzoate (5-1,000 microM) and hippurate (5 microM) to investigate hippurate formation kinetics and transport. The outflow dilution data best fit a space-distributed model comprising vascular and cellular pools for benzoate and hippurate; there was further need to segregate the cellular pool of benzoate into shallow (cytosolic) and deep (mitochondrial) pools. Fitted values of the membrane permeability-surface area products for sinusoidal entry of unbound benzoate were fast and concentration independent (0.89 +/- 0.17 ml. s(-1). g(-1)) and greatly exceeded the plasma flow rate (0.0169 +/- 0.0018 ml. s(-1). g(-1)), whereas both the influx of benzoate into the deep pool and the formation of hippurate occurring therein appeared to be saturable. Results of the fit to the dilution data suggest rapid uptake of benzoate, with glycination occurring within the deep and not the shallow pool as the rate-determining step.

MEF2 responds to multiple calcium-regulated signals in the control of skeletal muscle fiber type.

Different patterns of motor nerve activity drive distinctive programs of gene transcription in skeletal muscles, thereby establishing a high degree of metabolic and physiological specialization among myofiber subtypes. Recently, we proposed that the influence of motor nerve activity on skeletal muscle fiber type is transduced to the relevant genes by calcineurin, which controls the functional activity of NFAT (nuclear family of activated T cell) proteins. Here we demonstrate that calcineurin-dependent gene regulation in skeletal myocytes is mediated also by MEF2 transcription factors, and is integrated with additional calcium-regulated signaling inputs, specifically calmodulin-dependent protein kinase activity. In skeletal muscles of transgenic mice, both NFAT and MEF2 binding sites are necessary for properly regulated function of a slow fiber-specific enhancer, and either forced expression of activated calcineurin or motor nerve stimulation up-regulates a MEF2-dependent reporter gene. These results provide new insights into the molecular mechanisms by which specialized characteristics of skeletal myofiber subtypes are established and maintained.

Uptake of lactate by the liver: effect of red blood cell carriage.

Multiple-indicator dilution experiments with labeled lactate were performed in the livers of anesthetized dogs. A mixture of (51)Cr-labeled erythrocytes, [(3)H]sucrose, and L-[1-(14)C]lactate or a mixture of (51)Cr-labeled erythrocytes, [(14)C]sucrose, and L-[2-(3)H]lactate was injected into the portal vein, and samples were obtained from the hepatic vein. Data were evaluated using a model comprising flow along sinusoids, exchange of lactate between plasma and erythrocytes and between plasma and hepatocytes, and, in the case of L-[1-(14)C]lactate, metabolism to H[(14)C]O(-)(3) within hepatocytes. The coefficient for lactate efflux from erythrocytes was 0.62 +/- 0.24 s(-1), and those for influx into and efflux from hepatocytes were 0.44 +/- 0.13 and 0.14 +/- 0.07 s(-1), respectively. The influx permeability-surface area product of the hepatocyte membrane for lactate (P(in)S, in ml x s(-1) x g(-1)) varied with total flow rate (F, in ml s(-1) x g(-1)) according to P(in)S = (3.1 +/- 0.5)F + (0.021 +/- 0.014). Lactate in plasma, erythrocytes, and hepatocytes was close to equilibrium, whereas lactate metabolism was rate limiting.

[Redefining habitat and mental health of flood victims.]. / Redéfinition de l'habitat et santé mentale des sinistrés suite à une inondation.

During the July 1996 floods in the Saguenay area, many families lost everything : house, land and personal belongings. This disturbing situation forced many victims to let go of their home. A review of the literature has allowed to conclude that individuals develop profound feelings towards their homes and that its destruction entails disorganization as well as negative thoughts threatening their psychological equilibrium. With the objective of identifying the consequences of this disaster on the concept of home and mental health of victims, an exploratory study was realized during winter 1998 with 69 subjects having lost all their belongings. The data collected confirmed what has been raised in the scientific literature : many individuals have been profoundly scarred by this disaster on both levels of concept of home and psychosocial health. Two years following the disaster, nostalgia and disappointment are still present for most individuals who have been unable to find a new environment where they truly feel at home.

[Psychological and physical health of the July 1996 disaster victims: A comparative study between victims and non-victims.]. / L'état de santé psychologique et physique des sinistrés des inondations de juillet 1996 : étude comparative entre sinistrés et non sinistrés.

In July 1996, the Saguenay-Lac-St-Jean region suffered one of the greatest natural disasters in Québec's history. This article presents results of a study aiming at comparing, two years after the flood, the physical and psychological health condition of victims (n=177) to that of non-victims (n=168). The results indicate that victims, - regardless of their gender - present a psychological well-being as well as a post-disaster physical health that is different from non-victims. Disaster victims are much more numerous than non-victims in considering that their health is bad or average and in witnessing new health problems or the exacerbation of existing problems. Victims also present more manifestations of prosttraumatic stress and somatic complaints, have higher levels of depression, anxiety and social dysfunction than non-victims. However, no significant difference between subjects was revealed concerning severe depression. Results obtained corroborated that of other studies. After a natural or technological disaster involving important material damages to individual belongings, victims are more affected than non-victims concerning their psychological and physical health.

Kinetics of endothelin-1 binding in the dog liver microcirculation in vivo.

Endothelin-1 (ET-1) is a 21-amino acid peptide produced by vascular endothelial cells that acts as a potent constrictor of hepatic sinusoids. Hepatic binding of tracer (125)I-labeled ET-1 was investigated in anesthetized dogs with the multiple-indicator dilution technique with simultaneous measurements of unlabeled immunoreactive ET-1 plasma levels. Despite 80% binding to albumin, tracer (125)I-ET-1 was avidly extracted by the liver, with only 15 +/- 6% of the peptide surviving passage through the organ. Exchange of ET-1 between plasma and binding sites, probably located on the surface of liver cells, was quantitatively described by a barrier-limited, space-distributed variable transit time model. Reversible and irreversible parallel binding sites were found. Reversible and irreversible plasma clearances of unbound (125)I-ET-1 were 0.084 +/- 0.033 ml. s(-1). g liver(-1) and 0.17 +/- 0.09 ml. s(-1). g liver(-1), respectively, and the dissociation rate constant for reversible binding was 0.24 +/- 0.12 s(-1). The specific ET(A) receptor antagonist BMS-182874 did not modify binding to either site. The nonspecific ET(A)/ET(B) antagonist LU-224332 dose-dependently reduced irreversible binding only. ET-1 levels in the hepatic vein were significantly lower than in the portal vein but were not different from those in the hepatic artery. The ratio between hepatic vein and portal vein levels (0.64 +/- 0.31) was considerably higher than survival fractions, suggesting a substantial simultaneous release of newly synthesized or stored ET-1 by the liver. These results demonstrate both substantial clearance and production of ET-1 by the intact liver. Hepatic ET-1 clearance is mediated by the ET(B) receptor, with the presence of reversible, nonspecific ET-1 binding at the liver surface

Chronic obstructive pulmonary disease: capillarity and fiber-type characteristics of skeletal muscle.

BACKGROUND: The purpose of this investigation was to compare capillarity and fiber type proportions of the vastus lateralis muscle between patients with chronic obstructive pulmonary disease (COPD) and healthy subjects. METHODS: Fifteen male subjects were included in the study (8 COPD: 61.0 +/- 1.8 years [mean +/- SEM]; forced expiratory volume in 1 second 42.0 +/- 2.1% predicted; 7 N: age 54.0 +/- 1.1). Subjects were submitted to a symptom-limited maximal exercise test on ergocycle. After a transcutaneous biopsy of the vastus lateralis muscle, sections were cut 8 to 10 microns thick and stained with the Andersen method for capillarity and Stevens method for fiber typing. RESULTS: Patients with COPD had a decrease in peak oxygen consumption compared with healthy subjects (1.2 +/- 0.1 versus 3.0 +/- 0.2 L/min). Number of capillaries per square millimeter was lower in patients with COPD versus healthy subjects (92.6 +/- 16.1 and 213.3 +/- 33.5, P < 0.001); percentages of fiber types were 43.5 +/- 5.5% type I, 56.5 +/- 5.5% type II in COPD, and 56.7 +/- 3.4% type I, 43.2 +/- 3.4% type II in healthy subjects (P < 0.05). In addition, capillaries/fiber ratio was 0.83 +/- 0.05 in COPD, and 1.56 +/- 0.10 in healthy subjects (P < 0.001). CONCLUSION: As expected, patients with COPD showed a decrease in exercise capacity. The muscle analysis results indicate that patients with COPD have a greater proportion of type II fibers and a much lower capillaries/fiber ratio than normal subjects. We conclude that COPD adversely affects fiber type and capillarization of the lower limbs. This could be partly caused by deconditioning in these patients.

Endothelin-1 myocardial clearance, production, and effect on capillary permeability in vivo.

Myocardial metabolism of endothelin-1 (ET-1) and its effect on coronary microcirculatory exchanges were obtained in anesthetized dogs by combining the indicator-dilution technique with immunoreactive ET-1 measurements. The myocardium extracted 17.7 +/- 4.6% of tracer ET-1 (n = 12). Simultaneously measured ET-1 levels in the aorta (0.97 +/- 0.46 pg/ml) and coronary sinus (0.96 +/- 0.53 pg/ml) were not different, supporting a production of ET-1 by the heart that balances the amount extracted. Intracoronary infusion of ET-1 (5 ng.kg-1.min-1) increased coronary sinus ET-1 levels approximately 50-fold, decreased coronary blood flow per unit of interstitial space by approximately 30% (P = 0.006), and increased myocardial microcirculatory transit times (n = 6). Permeability to albumin was unaffected by ET-1, whereas the permeability-surface area product for sucrose decreased following derecruitment of myocardial capillaries. We conclude that there is a normal myocardial metabolic balance of ET-1 and that the heart marginally contributes to circulating ET-1. Pharmacological doses of ET-1 may adversely affect myocardial metabolism by reducing blood flow and the permeability-surface area product for small circulating substances.

Epidemiologic aspects of gallbladder cancer: a case-control study of the SEARCH Program of the International Agency for Research on Cancer.

BACKGROUND: There are few previous epidemiologic studies of gallbladder cancer, a rare but nearly always lethal gastrointestinal cancer with a demonstrated greater frequency in adult women and older subjects of both sexes, and also in the members of populations throughout central and eastern Europe and certain racial groups such as native American Indians. Unfortunately, the prospects for the prevention of this form of cancer are poor. PURPOSE: Our purpose in conducting this study was to investigate possible new risk factors for gallbladder cancer and to strengthen our understanding of established causal agents that may be involved in this disease. METHODS: A large, collaborative, multicenter, case-control study of cancer of the gallbladder was conducted in five centers located in Australia (Adelaide), Canada (Montreal and Toronto), The Netherlands (Utrecht), and Poland (Opole) from January 1983 through July 1988. Case subjects with gallbladder cancer were accrued by the centers from hospital pathology records and from reports to regional cancer registries. Cancer diagnosis was confirmed by either biopsy, cholecystectomy, or at the time of autopsy. Control subjects were randomly assigned at each center from the population. The pooled analysis included 196 case subjects and 1515 control subjects (who did not report previous cholecystectomy). Ninety-eight percent of the subjects were white. Personal interviews of case subjects, control subjects, and surrogates (spouse or next of kin) were conducted by trained personnel. RESULTS: After adjusting for potential confounding factors (age, sex, center, type of interview, years of schooling, alcohol intake, and lifetime cigarette smoking), a history of gallbladder symptoms requiring medical attention (e.g., reduced bile secretion from the gallbladder into the small intestine due to obstructions of the common bile or cystic ducts) was the major risk factor associated with this form of cancer (odds ratio [OR] = 4.4; 95% confidence interval [CI] = 2.6-7.5). This association was present even in subjects who had their first gallbladder examination because of symptoms present more than 20 years earlier (OR = 6.2; 95% CI = 2.8-13.4). Other variables associated with gallbladder cancer risk included an elevated body mass index, high total energy intake, high carbohydrate intake (after adjustment for total energy intake), and chronic diarrhea. All of these risk factors have been previously associated with gallstone disease. CONCLUSIONS: These findings are consistent with a major role of gallstones, or risk factors for gallstones, in the cause of gallbladder cancer. Additional information on whether or not screening high-risk subjects for gallstones or gallbladder cancer is needed.

Increased hepatocyte permeability surface area product for 86Rb with increase in blood flow.

Liver cell recruitment (the equivalent of capillary recruitment in other organs) was explored by carrying out multiple indicator dilution experiments with labeled rubidium across the liver of the anesthetized dog under basal conditions and after bleeding with saline replacement infusion, which increases liver blood flow. A mixture of 51Cr-labeled red blood cells (a vascular reference), 22Na (which immediately equilibrates in the extracellular space, the sum of the sinusoidal plasma and Disse or interstitial spaces, the expected distribution space for labeled rubidium in the absence of cellular entry), and 86Rb was injected into the portal vein, and normalized outflow patterns, expressed as outflowing fractions of each injected tracer per milliliter versus time, were obtained. In relation to the labeled red blood cell curve, the labeled sodium curve is displaced by flow-limited distribution into the Disse or interstitial space; it is lower on the upslope, reaches a lower and delayed peak, and decays more slowly. The early part of the labeled rubidium curve lies within the labeled sodium curve; it reaches a much reduced peak, and the later return of tracer entering cells is so slow that it is obscured by recirculation. Modeling of the concentrative cellular uptake of rubidium from the Disse space provided an influx permeability surface area product for labeled rubidium. This increases with flow over the observed flow range, demonstrating that sinusoidal recruitment occurs with increase in hepatic blood flow.

Cigarette smoking and pancreas cancer: a case control study of the search programme of the IARC.

A multi-centre case-control study of pancreas cancer, designed to be population-based, to use a random sample of local populations as controls and to use a common protocol and core questionnaire, was conducted as the first study of the SEARCH programme of the International Agency for Research on Cancer. "Ever-smokers" were found to be at increased risk for pancreas cancer compared with "never-smokers" consistently in all strata of gender, response status and centre. Risk of pancreas cancer was found to increase with increasing lifetime consumption of cigarettes, the relative risk rising to 2.70 (95% C.I. 1.95 to 3.74) in the highest intake category. The overall trend in risk was highly significant and the association was found consistently in each stratum of gender, response status and centre. Fifteen years had to pass from quitting cigarette smoking until the risk fell to a level compatible with that in never-smokers among the heaviest group of smokers; among the 2 lowest tertiles this happened within 5 years. Further, reported smoking habits more than 15 years before diagnosis appeared to have no influence on pancreas-cancer risk, irrespective of amount smoked. The results are consistent with a causal role for cigarette smoking in the aetiology of pancreas cancer and illustrate that ceasing to smoke cigarettes can lead to reductions in the elevated risk of pancreas cancer produced by this habit.

Oleate uptake by isolated hepatocytes and the perfused rat liver is competitively inhibited by palmitate.

Competition for uptake between long-chain free fatty acids has been difficult to document, because there has been no algorithm for computing unbound concentrations of two fatty acids simultaneously in solution with albumin. We modified an iterative procedure to permit this computation and studied initial [3H]oleate uptake by isolated hepatocytes and steady-state uptake by the single-pass perfused rat liver from 600 microM bovine serum albumin solutions containing various concentrations of oleate in the presence and absence of palmitate. In both systems, the Michaelis-Menten constant was significantly higher in the presence of palmitate than in its absence, whereas the maximal reaction velocity was unaltered, indicating competitive inhibition. In additional experiments employing the multiple transhepatic indicator-dilution technique, the influx rate constant and permeability-surface area product for oleate influx were significantly reduced by palmitate, confirming that the competition observed in the conventional perfused liver studies was at the influx step. Long-chain fatty acid uptake has now been shown to exhibit all the kinetic properties of facilitated transport and cannot be attributed solely to passive diffusion.

Oxidative capacity of the skeletal muscle and lactic acid kinetics during exercise in normal subjects and in patients with COPD.

Early lactic acidosis during exercise and abnormal skeletal muscle function have been reported in chronic obstructive pulmonary disease (COPD) but a possible relationship between these two abnormalities has not been evaluated. The purpose of this study was to compare and correlate the increase in arterial lactic acid (La) during exercise and the oxidative capacity of the skeletal muscle in nine COPD patients (age = 62 +/- 5 yr, mean +/- SD, FEV1 40 +/- 9% of predicted) and in nine normal subjects of similar age (54 +/- 3 yr). Following a transcutaneous biopsy of the vastus laterialis, each subject performed a stepwise exercise test on an ergocycle up to his or her maximal capacity during which 5-breath averages of oxygen consumption (Vo2), and serial La concentration measurements were obtained. From the muscle biopsy specimen, the activity of two oxidative enzymes, citrate synthase (CS) and 3-hydroxyacyl CoA dehydrogenase (HADH), and of three glycolytic enzymes, lactate dehydrogenase, hexokinase, and phosphofructokinase were determined. The La/Vo2 relationship during exercise was fitted by an exponential function in the form La = a + bvo2, where be represents the shape of the relationship. The activity of the oxidative enzymes was significantly lower in COPD than in control subjects (22.8 +/- 3.3 versus 36.8 +/- 8.6 mumol/min/g muscle for CS, and 3.1 +/- 1.1 versus 5.5 +/- 1.4 mumol/min/g for HADH, p < 0.0005) and the increase in lactic acid was steeper in COPD (b = 4.3 +/- 2.0 versus 2.1 +/- 0.2 for normal subjects, p = 0.0005). A significant inverse relationship was found between CS, HADH, and b. No difference was found between the two groups for the glycolytic enzymes. We conclude that in COPD the increase in arterial La during exercise is excessive, the oxidative capacity of the skeletal muscle is reduced, and that these two results are interrelated.