Publications

  • Lee Stoner, James Faulkner, Manning J Sabatier
    Journal of Hypertension 05/2013; 31(5):1057-8. · 4.22 Impact Factor
  • Lee Stoner, James Faulkner, Manning J Sabatier
    Atherosclerosis 02/2013; 228(1):280-281. · 3.71 Impact Factor
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    Lee Stoner, Manning J Sabatier
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    ABSTRACT: The pathological complications of atherosclerosis, namely heart attacks and strokes, remain the leading cause of mortality in the Western world. Preceding atherosclerosis is endothelial dysfunction. There is therefore interest in the application of non-invasive clinical tools to assess endothelial function. The flow-mediated dilation (FMD) test is the standard tool used to assess endothelial function. Reduced FMD is an early marker of atherosclerosis and has been noted for its capacity to predict future cardiovascular disease events. This review discusses the measurement of endothelial function using ultrasound, with a focus on the FMD technique.
    Journal of atherosclerosis and thrombosis 05/2012; 19(5):407-21. · 2.93 Impact Factor
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    Lee Stoner, Manning J. Sabatier
    Applied Aspects of Ultrasonography in Humans, 04/2012; , ISBN: 978-953-51-0522-0
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    Lee Stoner, Joanna M Young, Simon Fryer, Manning J Sabatier
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    ABSTRACT: The validity of the flow-mediated dilation test has been questioned due to the lack of normalization to the primary stimulus, shear stress. Shear stress can be calculated using Poiseuille's law. However, little attention has been given to the most appropriate blood velocity parameter(s) for calculating shear stress. The pulsatile nature of blood flow exposes the endothelial cells to two distinct shear stimuli during the cardiac cycle: a large rate of change in shear at the onset of flow (velocity acceleration), followed by a steady component. The parameter typically entered into the Poiseuille's law equation to determine shear stress is time-averaged blood velocity, with no regard for flow pulsatility. This paper will discuss (1) the limitations of using Posieuille's law to estimate shear stress and (2) the importance of the velocity profile-with emphasis on velocity acceleration-to endothelial function and vascular tone.
    International journal of vascular medicine 01/2012; 2012:589213.
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    ABSTRACT: Application of chondroitinase ABC (ChABC) to injured peripheral nerves improves axon regeneration, but it is not known whether functional recovery is also improved. Recordings of EMG activity [soleus (Sol) M response and H reflexes] evoked by nerve stimulation and of Sol and tibialis anterior (TA) EMG activity and hindlimb and foot kinematics during slope walking were made to determine whether ChABC treatment of the sciatic nerve at the time of transection improves functional recovery. Recovery of evoked EMG responses began as multiple small responses with a wide range of latencies that eventually coalesced into one or two more distinctive and consistent responses (the putative M response and the putative H reflex) in both groups. Both the initial evoked responses and the time course of their maturation returned sooner in the ChABC group than in the untreated (UT) group. The reinnervated Sol and TA were coactivated during treadmill locomotion during downslope, level, and upslope walking throughout the study period in both UT and ChABC-treated rats. By 10 wk after nerve transection and repair, locomotor activity in Sol, but not TA, had returned to its pretransection pattern. There was an increased reliance on central control of Sol activation across slopes for both groups as interpreted from elevated prestance Sol EMG activity that was no longer modulated with slope. Limb length and orientation during locomotion were similar to those observed prior to nerve injury during upslope walking only in the ChABC-treated rats. Thus treatment of cut nerves with ChABC leads to improvements in functional recovery.
    Journal of Neurophysiology 11/2011; 107(3):747-57. · 3.30 Impact Factor
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    ABSTRACT: Exercise in the form of daily treadmill training results in significant enhancement of axon regeneration following peripheral nerve injury. Because androgens are also linked to enhanced axon regeneration, we wanted to investigate whether sex differences in the effect of treadmill training might exist. The common fibular nerves of thy-1-YFP-H mice were cut and repaired with a graft of the same nerve from a strain-matched wild-type donor mouse. Animals were treated with one of two daily treadmill training paradigms: slow continuous walking for 1 h or four higher intensity intervals of 2 min duration separated by 5-min rest periods. Training was begun on the third day following nerve injury and continued 5 days per week for 2 weeks. Effects on regeneration were evaluated by measuring regenerating axon profile lengths in optical sections through the repair sites and grafts at the end of the training period. No sex differences were found in untrained control mice. Continuous training resulted in significant enhancement of axon regeneration only in males. No effect was found in females or in castrated males. Interval training was effective in enhancing axon regeneration only in females and not in intact males or castrated males. Untrained females treated with the aromatase inhibitor, anastrozole, had significant enhancement of axon regeneration without increasing serum testosterone levels. Two different mechanisms exist to promote axon regeneration in a sex-dependent manner. In males treadmill training uses testicular androgens. In females, a different cellular mechanism for the effect of treadmill training must exist.
    Developmental Neurobiology 07/2011; 72(5):688-98. · 4.42 Impact Factor
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    ABSTRACT: The role of neurotrophin-4/5 (NT-4/5) in the enhancement of axon regeneration in peripheral nerves produced by treadmill training was studied in mice. Common fibular nerves of animals of the H strain of thy-1-YFP mice, in which a subset of axons in peripheral nerves is marked by the presence of yellow fluorescent protein, were cut and surgically repaired using nerve grafts from non-fluorescent mice. Lengths of profiles of fluorescent regenerating axons were measured using optical sections made through whole mounts of harvested nerves. Measurements from mice that had undergone 1 h of daily treadmill training at modest speed (10 m/min) were compared with those of untrained (control) mice. Modest treadmill training resulted in fluorescent axon profiles that were nearly twice as long as controls at 1, 2 and 4 week survival times. Similar enhanced regeneration was found when cut nerves of wild type mice were repaired with grafts from NT-4/5 knockout mice or grafts made acellular by repeated freezing/thawing. No enhancement was produced by treadmill training in NT-4/5 knockout mice, irrespective of the nature of the graft used to repair the cut nerve. Much as had been observed previously for the effects of brief electrical stimulation, the effects of treadmill training on axon regeneration in cut peripheral nerves are independent of changes produced in the distal segment of the cut nerve and depend on the promotion of axon regeneration by changes in NT-4/5 expression by cells in the proximal nerve segment.
    European Journal of Neuroscience 06/2011; 33(12):2265-71. · 3.75 Impact Factor
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    Arthur W English, Jennifer C Wilhelm, Manning J Sabatier
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    ABSTRACT: Full functional recovery after traumatic peripheral nerve injury is rare. We postulate three reasons for the poor functional outcome measures observed. Axon regeneration is slow and not all axons participate. Significant misdirection of regenerating axons to reinnervate inappropriate targets occurs. Seemingly permanent changes in neural circuitry in the central nervous system are found to accompany axotomy of peripheral axons. Exercise in the form of modest daily treadmill training impacts all three of these areas. Compared to untrained controls, regenerating axons elongate considerably farther in treadmill trained animals and do so via an autocrine/paracrine neurotrophin signaling pathway. This enhancement of axon regeneration takes place without an increase in the amount of misdirection of regenerating axons found without training. The enhancement also occurs in a sex-dependent manner. Slow continuous training is effective only in males, while more intense interval training is effective only in females. In treadmill trained, but not untrained mice the extent of coverage of axotomized motoneurons is maintained, thus preserving important elements of the spinal circuitry.
    Annals of anatomy = Anatomischer Anzeiger: official organ of the Anatomische Gesellschaft 03/2011; 193(4):354-61. · 1.96 Impact Factor
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    ABSTRACT: In this study, patterns of activity in the soleus (Sol) and tibialis anterior (TA) muscles and hindlimb kinematics were evaluated during slope walking in rats after transection and surgical repair either of the entire sciatic nerve (Sci group) or of its two branches separately, the tibial and common fibular nerves (T/CF group). With the latter method, axons from the tibial and common fibular nerves could not reinnervate targets of the other nerve branch after injury, reducing the opportunity for misdirection. Activity in the TA shifted from the swing phase in intact rats to nearly the entire step cycle in both injured groups. Since these changes occur without misdirection of regenerating axons, they are interpreted as centrally generated. Sol activity was changed from reciprocal to that of TA in intact rats to coactivate with TA, but only in the Sci group rats. In the T/CF group rats, Sol activity was not altered from that observed in intact rats. Despite effects of injury that limited foot movements, hindlimb kinematics were conserved during downslope walking in both injury groups and during level walking in the T/CF group. During level walking in the Sci group and during upslope walking in both groups of injured rats, the ability to compensate for the effects of the nerve injury was less effective and resulted in longer limb lengths held at more acute angles throughout the step cycle. Changes in limb movements occur irrespective of axon misdirection and reflect compensatory changes in the outputs of the neural circuits that drive locomotion.
    Cells Tissues Organs 03/2011; 193(5):298-309. · 1.96 Impact Factor
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    ABSTRACT: Slope-related differences in hindlimb movements and activation of the soleus and tibialis anterior muscles were studied during treadmill locomotion in intact rats and in rats 4 and 10 weeks following transection and surgical repair of the sciatic nerve. In intact rats, the tibialis anterior and soleus muscles were activated reciprocally at all slopes, and the overall intensity of activity in tibialis anterior and the mid-step activity in soleus increased with increasing slope. Based on the results of principal components analysis, the pattern of activation of soleus, but not of tibialis anterior, changed significantly with slope. Slope-related differences in hindlimb kinematics were found in intact rats, and these correlated well with the demands of walking up or down slopes. Following recovery from sciatic nerve injury, the soleus and tibialis anterior were co-activated throughout much of the step cycle and there was no difference in intensity or pattern of activation with slope for either muscle. Unlike intact rats, these animals walked with their feet flat on the treadmill belt through most of the stance phase. Even so, during downslope walking limb length and limb orientation throughout the step cycle were not significantly changed from values found in intact rats. This conservation of hindlimb kinematics was not observed during level or upslope walking. These findings are interpreted as evidence that the recovering animals adopt a novel locomotor strategy that involves stiffening of the ankle joint by antagonist co-activation and compensation at more proximal joints. Their movements are most suitable to the requirements of downslope walking but the recovering rats lack the ability to adapt to the demands of level or upslope walking.
    Journal of Experimental Biology 03/2011; 214(Pt 6):1007-16. · 3.24 Impact Factor
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    ABSTRACT: Poor functional recovery found after peripheral nerve injury has been attributed to the misdirection of regenerating axons to reinnervate functionally inappropriate muscles. We applied brief electrical stimulation (ES) to the common fibular (CF) but not the tibial (Tib) nerve just prior to transection and repair of the entire rat sciatic nerve, to attempt to influence the misdirection of its regenerating axons. The specificity with which regenerating axons reinnervated appropriate targets was evaluated physiologically using compound muscle action potentials (M responses) evoked from stimulation of the two nerve branches above the injury site. Functional recovery was assayed using the timing of electromyography (EMG) activity recorded from the tibialis anterior (TA) and soleus (Sol) muscles during treadmill locomotion and kinematic analysis of hindlimb locomotor movements. Selective ES of the CF nerve resulted in restored M-responses at earlier times than in unstimulated controls in both TA and Sol muscles. Stimulated CF axons reinnervated inappropriate targets to a greater extent than unstimulated Tib axons. During locomotion, functional antagonist muscles, TA and Sol, were coactivated both in stimulated rats and in unstimulated but injured rats. Hindlimb kinematics in stimulated rats were comparable to untreated rats, but significantly different from intact controls. Selective ES promotes enhanced axon regeneration but does so with decreased fidelity of muscle reinnervation. Functional recovery is neither improved nor degraded, suggesting that compensatory changes in the outputs of the spinal circuits driving locomotion may occur irrespective of the extent of misdirection of regenerating axons in the periphery.
    The Journal of Comparative Neurology 01/2011; 519(1):21-33. · 3.66 Impact Factor
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    Lee Stoner, manning Sabatier
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    ABSTRACT: The brachial artery flow-mediated dilation test (FMD) is the noninvasive gold standard used to test endothelial function. Reduced FMD is an early event in the development of atherosclerosis and provides a marker for predicting future cardiovascular disease events. However, the potential for this promising test is limited by poor reproducibility. Three major limitations associated with standard FMD methodology account for the majority of the poor reproducibility. Firstly, expressing FMD as a percentage limits statistical power. Secondly, studies often fail to account for the stimulus, i.e., shear stress. Lastly, peak diameters in response to reactive hyperaemia are short-lived and, therefore, hard to capture. To compensate for these limitations, we suggest t hat endothelial function be estimated using shear rate: diameter dose response curves. The use of dose-response curves could
    Journal of Cardiovascular Medicine 01/2011; 14(12):339-344. · 2.66 Impact Factor
  • Manning J. Sabatier, Mike Kaufman, Arthur W. English
    Medicine and Science in Sports and Exercise - MED SCI SPORT EXERCISE. 01/2010; 42.
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    ABSTRACT: We investigated the extent of misdirection of regenerating axons when that regeneration was enhanced by using treadmill training. Retrograde fluorescent tracers were applied to the cut proximal stumps of the tibial and common fibular nerves 2 or 4 weeks after transection and surgical repair of the mouse sciatic nerve. The spatial locations of retrogradely labeled motoneurons were studied in untreated control mice and in mice receiving 2 weeks of treadmill training, according to either a continuous protocol (10 m/minute, 1 hour/day, 5 days/week) or an interval protocol (20 m/minute for 2 minutes, followed by a 5-minute rest, repeated four times, 5 days/week). More retrogradely labeled motoneurons were found in both treadmill-trained groups. The magnitude of this increase was as great as or greater than that found after using other enhancement strategies. In both treadmill-trained groups, the proportions of motoneurons labeled from tracer applied to the common fibular nerve that were found in spinal cord locations reserved for tibial motoneurons in intact mice were no greater than in untreated control mice and significantly less than those found after electrical stimulation or chondroitinase treatment. Treadmill training in the first 2 weeks following peripheral nerve injury produces a marked enhancement of motor axon regeneration without increasing the propensity of those axons to choose pathways leading to functionally inappropriate targets.
    The Journal of Comparative Neurology 08/2009; 517(2):245-55. · 3.66 Impact Factor
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    ABSTRACT: Animal studies have identified monocyte chemoattractive protein-1 (MCP-1) and vascular endothelial growth factor (VEGF) as critical mediators of arterial diameter enlargement in response to chronic increases in blood flow (arteriogenesis). Furthermore, cellular studies have shown that the shear stresses resulting from increased blood flow stimulate synthesis of MCP-1, which in turn stimulates synthesis of VEGF. The purpose of this study was to determine if these mechanisms are evident in healthy women. Resting femoral artery diameter and blood flow, lean leg mass, MCP-1 and VEGF concentrations, and aerobic capacity were measured in 34 healthy women along with plasma concentrations of lipids associated with cardiovascular disease risk. Femoral artery diameter was independently related to metabolically active (lean) leg mass (b=0.41, P=0.008) and aerobic capacity (b=0.45, P=0.004). Plasma MCP-1 correlated negatively with the ratio of femoral artery diameter to lean leg mass (b=-0.42, P=0.009) and positively with serum triglycerides (b=0.46, P=0.005). Plasma VEGF exhibited similar correlations and strongly correlated with MCP-1 (R=0.92, P<0.0001). The results indicate that circulating MCP-1 and VEGF concentrations are associated with both arteriogenic and atherogenic stimuli in healthy women.
    Vascular Pharmacology 12/2008; 50(3-4):104-9. · 3.21 Impact Factor
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    ABSTRACT: Cigarette smoking is associated with impaired arterial function as measured by reduced vasodilation in response to reactive hyperemia. However, previous studies did not account for potential differences in shear stimuli. The purpose of this study was to use young, occasional smokers to ethically evaluate the effects of acute and chronic smoking on shear rate-diameter dose-response slopes. Young (20 to 26-y-old) nonsmokers (n = 9) and occasional (<1 pack/week) smokers were tested (n = 9). Smokers were tested after abstaining for 2 or more d and then immediately after smoking two cigarettes. Shear rate was manipulated using five upstream ischemic durations (0.5, 1, 2, 5 and 10 min). Radial artery blood velocities and diameters were assessed using Doppler ultrasound. Hierarchical linear modeling (HLM) was used to estimate change in diameter using repeated measures of shear rate nested within each subject. The shear rate-diameter slope was reduced by 35.9% in occasional smokers compared with nonsmoking controls (beta = 2.78(10-4) versus 1.78(10-4), p = 0.004). Acute smoking further attenuated the shear rate-diameter slope (i.e., arterial function) by 23.8% (beta = 1.79(10-4) versus 1.36(10-4), p = 0.037). These results suggest that repeated bouts of occasional cigarette smoking can chronically attenuate arterial function in otherwise healthy, young persons.
    Ultrasound in medicine & biology 10/2008; 34(12):1885-92. · 2.46 Impact Factor
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    ABSTRACT: It is currently unclear whether reductions in adiposity mediate the improvements in vascular health that occur with aerobic exercise. The purpose of this longitudinal study of 13 healthy women (33 +/- 4 years old) was to determine whether 14 weeks of aerobic exercise would alter functional measures of vascular health, namely resting aortic pulse wave velocity (aPWV, an index of arterial stiffness), femoral artery diameter (D(FA)), and femoral artery blood flow (BF(FA)) independent of changes in adiposity. Aerobic fitness was assessed as VO2peak normalized to fat-free mass, and adiposity (percent body fat) was determined by dual energy x-ray absorptiometry. Serum concentrations of proteins associated with risk for cardiovascular disease, including C-reactive protein (CRP), soluble intercellular adhesion molecule-1 (sICAM-1), and leptin, were also measured. Subjects cycled for 50 minutes, 3 times per week. Aerobic fitness normalized to fat-free mass increased 6% (P = 0.03) whereas adiposity did not change. Resting D(FA) increased 12% (P < 0.001) and resting shear rate decreased 28% (P = 0.007). Aortic PWV, and serum sICAM-1, CRP and leptin did not change with training. Significant reductions in adiposity were not necessary for aerobic exercise training to bring about improvements in aerobic fitness and arterial remodeling. Peripheral arterial remodeling occurred without changes in central arterial stiffness or markers of inflammation.
    Dynamic Medicine 09/2008; 7:13.
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    ABSTRACT: In animals, the adipocyte-derived hormone leptin induces increased blood pressure centrally via the hypothalamus, and one study has reported that exercise training decreases hypothalamic leptin receptor expression. In humans, high circulating leptin concentrations are associated with high blood pressure, but the possible influence of physical activity or aerobic capacity on this association is unknown. Forty-two healthy women, 25-40 years of age, with diverse ranges of body fatness and aerobic capacities, were studied under basal resting conditions. Blood pressure (sphygmomanometry), arterial stiffness (pulse wave velocity (PWV)), percent body fat (dual energy X-ray absorptiometry), circulating concentrations of leptin, soluble leptin receptor (sLR) (enzyme-linked immunoassay), and nitric oxide (Griess reaction) were measured. Serum leptin correlated with percent body fat (R(2) = 0.74, P < 0.0001) but was not significantly associated with aerobic capacity. Blood pressure correlated positively with serum leptin concentrations and had a negative interaction with aerobic capacity for both systolic (overall model: R(2) = 0.33, P = 0.002) and diastolic (R(2) = 0.48, P < 0.0001) pressure. The relation between leptin and blood pressure was attributable solely to women with below-median aerobic capacity even though their body fat percentages and leptin concentrations were similar to those of women above the median. The results could not be attributed to differences in peripheral factors such as sLR or nitric oxide concentrations or to differences in arterial stiffness determined by aortic PWV. Circulating leptin concentrations are related to body fatness, but the hypertensive influence of leptin is modified by physical fitness.
    American Journal of Hypertension 09/2008; 21(11):1245-50. · 3.67 Impact Factor
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    ABSTRACT: Physical activity after spinal cord injury promotes improvements in motor function, but its effects following peripheral nerve injury are less clear. Although axons in peripheral nerves are known to regenerate better than those in the CNS, methods of accelerating regeneration are needed due to the slow overall rate of growth. Therefore we studied the effect of two weeks of treadmill locomotion on the growth of regenerating axons in peripheral nerves following injury. The common fibular nerves of thy-1-YFP-H mice, in which a subset of axons in peripheral nerves express yellow fluorescent protein (YFP), were cut and repaired with allografts from non-fluorescent littermates, and then harvested two weeks later. Mice were divided into groups of low-intensity continuous training (CT, 60 min), low-intensity interval training (IT; one group, 10 reps, 20 min total), and high-intensity IT (three groups, 2, 4, and 10 reps). One repetition consisted of 2 min of running and 5 min of rest. Sixty minutes of CT resulted in the highest exercise volume, whereas 2 reps of IT resulted in the lowest volume of exercise. The lengths of regenerating YFP(+) axons were measured in images of longitudinal optical sections of nerves. Axon profiles were significantly longer than control in all exercise groups except the low-intensity IT group. In the CT group and the high-intensity IT groups that trained with 4 or 10 repetitions axons were more than twice as long as unexercised controls. The number of intervals did not impact axon elongation. Axon sprouting was enhanced in IT groups but not the CT group. Thus exercise, even in very small quantities, increases axon elongation in injured peripheral nerves whereas continuous exercise resulting in higher volume (total steps) may have no net impact on axon sprouting.
    Experimental Neurology 07/2008; 211(2):489-93. · 4.65 Impact Factor

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