Succinate Accumulation and Ischemia-Reperfusion Injury: Of Mice but Not Men, a Study in Renal Ischemia-Reperfusion.

A recent seminal paper implicated ischemia-related succinate accumulation followed by succinate-driven reactive oxygen species formation as a key driver of ischemia-reperfusion injury. Although the data show that the mechanism is universal for all organs tested (kidney, liver, heart, and brain), a remaining question is to what extent these observations in mice translate to humans. We showed in this study that succinate accumulation is not a universal event during ischemia and does not occur during renal graft procurement; in fact, tissue succinate content progressively decreased with increasing graft ischemia time (p < 0.007). Contrasting responses were also found with respect to mitochondrial susceptibility toward ischemia and reperfusion, with rodent mitochondria robustly resistant toward warm ischemia but human and pig mitochondria highly susceptible to warm ischemia (p < 0.05). These observations suggest that succinate-driven reactive oxygen formation does not occur in the context of kidney transplantation. Moreover, absent allantoin release from the reperfused grafts suggests minimal oxidative stress during clinical reperfusion.

Increasing temperature speeds intracellular PO2 kinetics during contractions in single Xenopus skeletal muscle fibers.

Precise determination of the effect of muscle temperature (T(m)) on mitochondrial oxygen consumption kinetics has proven difficult in humans, in part due to the complexities in controlling for T(m)-related variations in blood flow, fiber recruitment, muscle metabolism, and contractile properties. To address this issue, intracellular Po(2) (P(i)(O(2))) was measured continuously by phosphorescence quenching following the onset of contractions in single Xenopus myofibers (n = 24) while controlling extracellular temperature. Fibers were subjected to two identical contraction bouts, in random order, at 15°C (cold, C) and 20°C (normal, N; n = 12), or at N and 25°C (hot, H; n = 12). Contractile properties were determined for every contraction. The time delay of the P(i)(O(2)) response was significantly greater in C (59 ± 35 s) compared with N (35 ± 26 s, P = 0.01) and H (27 ± 14 s, P = 0.01). The time constant for the decline in P(i)(O(2)) was significantly greater in C (89 ± 34 s) compared with N (52 ± 15 s; P < 0.01) and H (37 ± 10 s; P < 0.01). There was a linear relationship between the rate constant for P(i)(O(2)) kinetics and T(m) (r = 0.322, P = 0.03). Estimated ATP turnover was significantly greater in H than in C (P < 0.01), but this increased energy requirement alone with increased T(m) could not account for the differences observed in P(i)(O(2)) kinetics among conditions. These results demonstrate that P(i)(O(2)) kinetics in single contracting myofibers are dependent on T(m), likely caused by temperature-induced differences in metabolic demand and by temperature-dependent processes underlying mitochondrial activation at the start of muscle contractions.

Region-specific adaptations in determinants of rat skeletal muscle oxygenation to chronic hypoxia.

Chronic exposure to hypoxia is associated with muscle atrophy (i.e., a reduction in muscle fiber cross-sectional area), reduced oxidative capacity, and capillary growth. It is controversial whether these changes are muscle and fiber type specific. We hypothesized that different regions of the same muscle would also respond differently to chronic hypoxia. To investigate this, we compared the deep (oxidative) and superficial (glycolytic) region of the plantaris muscle of eight male rats exposed to 4 wk of hypobaric hypoxia (410 mmHg, Po(2): 11.5 kPa) with those of nine normoxic rats. Hematocrit was higher in chronic hypoxic than control rats (59% vs. 50%, P < 0.001). Using histochemistry, we observed 10% fiber atrophy (P < 0.05) in both regions of the muscle but no shift in the fiber type composition and myoglobin concentration of the fibers. In hypoxic rats, succinate dehydrogenase (SDH) activity was elevated in fibers of each type in the superficial region (25%, P < 0.05) but not in the deep region, whereas in the deep region but not the superficial region the number of capillaries supplying a fiber was elevated (14%, P < 0.05). Model calculations showed that the region-specific alterations in fiber size, SDH activity, and capillary supply to a fiber prevented the occurrence of anoxic areas in the deep region but not in the superficial region. Inclusion of reported acclimatization-induced increases in mean capillary oxygen pressure attenuated the development of anoxic tissue areas in the superficial region of the muscle. We conclude that the determinants of tissue oxygenation show region-specific adaptations, resulting in a marked differential effect on tissue Po(2).

Carbon monoxide inhalation reduces skeletal muscle fatigue resistance.

AIM: To determine whether inhalation of carbon monoxide (CO), resulting in carboxyhaemoglobin (COHb) levels observed in smokers, had an effect on muscle fatigue during electrically evoked and voluntary muscle contractions. METHODS: Young non-smoking males inspired CO from a Douglas bag until their COHb level reached 6%. During the control condition the same participants inspired ambient air from a Douglas bag for 6 min. Fatigue was assessed as the decline in torque in isometric knee extensions, during 2 min of electrically evoked contractions (30 Hz, 1 s on, 1 s off) and during 2 min of maximal isometric voluntary contractions (1 s on, 1 s off). A fatigue index (FI) was calculated as the ratio of final torque : initial torque. Time to peak torque (TPT) and half relaxation time ((1/2)RT) were also determined for the electrically evoked contractions. RESULTS: The FI during both the voluntary fatigue test (control: 0.80 +/- 0.09 vs. CO: 0.70 +/- 0.08; mean +/- SD) and that of the fatigue test with electrically evoked contractions (control: 0.61 +/- 0.09 vs. CO: 0.53 +/- 0.12) was significantly lower after CO inhalation than after inhalation of ambient air (P < 0.05). There was, however, no effect of CO on the changes in TPT or (1/2)RT during the fatigue test. CONCLUSION: Carbon monoxide inhalation resulting in COHb levels found in smokers has an acute impact on the ability of the muscle to resist fatigue.

Muscle fatigue resistance during stimulated contractions is reduced in young male smokers.

AIM: To determine whether muscle function is compromised in healthy smokers in comparison with activity-matched non-smokers. METHODS: Nine male smokers (aged 22.2 +/- 2.5 years: mean +/- SD) with a smoking history of 2.5 +/- 3.1 pack years, and ten male control participants (25.4 +/- 2.9 years) matched for physical activity level participated in this study. Knee extensor strength was measured using isometric maximal voluntary contractions. Voluntary activation of the quadriceps and co-activation of the biceps femoris were determined using interpolated twitches and surface electromyography respectively. The frequency-torque relationship and fatigue resistance were assessed with electrically evoked contractions. A fatigue index was determined as the ratio of final torque to initial torque during a series of isometric contractions (2 min; 30 Hz; 1 s contraction/1 s rest). Quadriceps anatomical cross sectional area was measured with MRI at 50% of femur length. RESULTS: Maximal voluntary contraction torque, quadriceps anatomical cross sectional area, knee extensor torque/quadriceps cross sectional area, activation, co-activation and force-frequency relationship were similar, whereas the fatigue index was 17% lower in smokers than non-smokers. CONCLUSION: In young men smoking does not significantly affect quadriceps muscle mass and contractile properties, but does reduce fatigue resistance of the quadriceps muscle, which was not attributable to differences in physical activity.

Visuomotor control of the relative movement of random-dot patterns.

A series of experiments were made on human performance in controlling optical relative movement. The aim was to test the influence of different kinds of relative movement on visually controlled steering tasks. Within adjacent displays on a computer screen random dot patterns moved in a fixed direction at continually changing speeds (Exp. 1) or at constant speed and in continually changing directions (Exp. 2). The subject was required to compensate for the unpredictable modulations of the pattern movement by means of an isometric joystick. The task was to adjust relative movements involving pure translation, symmetric convergence, divergence, or shear. Analysis indicated that the task performance was not dependent on the special kind of relative movement. However, performance was significantly higher in tasks where directionally disturbed relative movement had to be controlled compared to those situations in which relative movement varied with respect to speed.

Visually controlled matching of pattern movement.

Subjects were asked to match the speeds of two moving random-dot patterns seen through circular apertures. The speed of one pattern that moved horizontally toward the right of a computer screen changed continuously. The speed of this pattern represented the target. It was to be matched with the speed of the second pattern, which moved in the opposite direction. The subject controlled the speed of the second pattern by means of an isometric joystick. The distance between the apertures on the screen as well as the subject's distance from the screen served as experimental parameters. In this way, the effects of both spatial and temporal transients of pattern speed on human tracking performance were studied. To avoid anticipation by the subject, the amplitude and the frequency of the target pattern speed changed pseudorandomly. The accuracy with which the subject performed the matching task was influenced by the mean pattern speed and the parameters of the visual field. Within lower velocity ranges, the subject's sensitivity to the instantaneous speed differences varied according to Weber's law. The cross-correlation of the velocity time courses decreased when the mean speed of the target pattern was increased. Two stimulus parameters had a strong influence on the modulation of the correlation value: (1) the angular size of the stimulus on the retina and (2) the retinal eccentricity of the stimulus.

A hydrodynamic model of cerebrospinal fluid flow in man.

A hydrodynamic bi-compartmental model for the cerebrospinal fluid (CSF) flow in humans is presented which combines anatomical and physiological conditions in the central nervous system with results of special radioisotope diagnostic techniques. Normal and disturbed conditions, the diagnostic methods and the results are explained. A differential equation for the time behaviour of regional radioisotope concentrations is derived by applying to the model mathematical procedures which are familiar from the description of radioactive decay series, or reaction kinetics of chemical or pharmaceutical processes. The solutions are analysed and discussed with respect to findings of isotope diagnostics, and parameters for the complete and quantitative evaluation of CSF flow systems are derived. A system factor is introduced for classification purposes and, in conjunction with basic principles of hydrodynamics, is used to postulate a similarity law of CSF flow systems. The diagnostical and therapeutical value of the model for analysis and simulation of CSF flow systems is discussed. Practical applications to other disciplines are proposed.

Mechanical loading of peripheral nerves during remobilisation of the affected member after end-to-end anastomosis.

Our study involved simulating end-to-end neurorrhaphy of the sciatic nerve in a number of rabbits and analysing in vivo the mechanical loads acting on the nerve while the affected member was being remobilised. We found both the suture and mobilisation loads to be related to the size of the nerve defect. In each case, traction force, strain, and stress were proportional. The effect which these experimental findings may have on the future use of flexing neighbouring joints as a "manipulative" measure to achieve a tension-free nerve suture will be discussed.

New aspects of cerebrospinal fluid dynamics in humans investigated by sequential gamma camera cisternography, with data evaluation by the digital multichannel analyzer. Part 4: A unifying criterion of the development of hydrocephalic syndrome. Its dynamic basis.

In the final part of this series we present all of the clinical material, and the patients are classified by different cisternographic syndromes on the dynamic basis offered for our method: dynamic disconnection between ventricular system and basal cisterns, brain atrophy, initial dynamic decompensation or prehydrocephalus, communicating hydrocephalus with and without epicortical fluid circulation. A nomogram method for clinical estimation of CSF production based on the mathematical properties of our analysis of the ventricular reflux is proposed. The different normal and pathological characteristics of fluid movements in the spinal canal are given, and their importance as signs of turbulence in the posterior fossa are emphasized. Different aspects of the dynamics of CSF production are shown and discussed, and an evolving conception of hydrocephalus development is presented.

New aspects of cerebrospinal fluid dynamics in humans investigated by sequential gammacamera cisternography, with data evaluation by the digital multichannel analyzer. Part 3: Physiopathology of the ventricular reflux.

Although well described and intensively used for diagnostic purposes, the ventricular reflux as a gammacisternographic phenomen has not yet been satisfactorily explained, and its physiopathology is a subject of controversy. Based on our method of quantitative gammacisternography and gammaventriculography we study the evolution of the tracer concentrations in two main chambers:--the basal cisterns together with the upper cervical canal, considered as a functional unity (the distribution area) and--the ventricular system. We propose the mathematical analysis of a theoretical model which represents the normal and pathological situations of these two chambers, as a method for measuring ventricular volume and ventricular tracer clearance. From the correlation in results with patients and models, we suggest turbulence as the main factor in generating backmixing or total mixing, the appearance of which is called ventricular reflux. We deny the existence of a real inversion of CSF flow. The spinal canal velocity of isotope flow is proposed as additional evidence of turbulence. The normal general dynamics of CSF are delineated, and we propose the following factors that lead to ventricular reflux:--partial obstruction to epicortical CSF flow;--total obstruction to epicortical CSF flow. Their principal characteristics are given, and the importance of using their quantitative parameters in descriptions of patients is stressed. Different aspects in the evolution of hydrocephalus, transependymal resorption, and factors involved in hydrodynamic changes etc. are discussed.