Improved glucose tolerance and insulin sensitivity after electrical stimulation-assisted cycling in people with spinal cord injury.

DESIGN: Longitudinal training. OBJECTIVES: The purpose was to determine the effect of electrical stimulation (ES)-assisted cycling (30 min/day, 3 days/week for 8 weeks) on glucose tolerance and insulin sensitivity in people with spinal cord injury (SCI). SETTING: The Steadward Centre, Alberta, Canada. METHODS: Seven participants with motor complete SCI (five males and two females aged 30 to 53 years, injured 3-40 years, C5-T10) underwent 2-h oral glucose tolerance tests (OGTT, n=7) and hyperglycaemic clamp tests (n=3) before and after 8 weeks of training with ES-assisted cycling. RESULTS: Results indicated that subjects' glucose level were significantly lower at 2 h OGTT following 8 weeks of training (122.4+/-10 vs 139.9+/-16, P=0.014). Two-hour hyperglycaemic clamps tests showed improvement in all three people for glucose utilisation and in two of three people for insulin sensitivity. CONCLUSIONS: These results suggested that exercise with ES-assisted cycling is beneficial for the prevention and treatment of Type 2 diabetes mellitus in people with SCI. SPONSORSHIP: Supported by Alberta Paraplegic Foundation, Therapeutic Alliance.

Electrical stimulation: can it increase muscle strength and reverse osteopenia in spinal cord injured individuals?

OBJECTIVE: To study the extent to which atrophy of muscle and progressive weakening of the long bones after spinal cord injury (SCI) can be reversed by functional electrical stimulation (FES) and resistance training. DESIGN: A within-subject, contralateral limb, and matching design. SETTING: Research laboratories in university settings. PARTICIPANTS: Fourteen patients with SCI (C5 to T5) and 14 control subjects volunteered for this study. INTERVENTIONS: The left quadriceps were stimulated to contract against an isokinetic load (resisted) while the right quadriceps contracted against gravity (unresisted) for 1 hour a day, 5 days a week, for 24 weeks. MAIN OUTCOME MEASURES: Bone mineral density (BMD) of the distal femur, proximal tibia, and mid-tibia obtained by dual energy x-ray absorptiometry, and torque (strength). RESULTS: Initially, the BMD of SCI subjects was lower than that of controls. After training, the distal femur and proximal tibia had recovered nearly 30% of the bone lost, compared with the controls. There was no difference in the mid-tibia or between the sides at any level. There was a large strength gain, with the rate of increase being substantially greater on the resisted side. CONCLUSION: Osteopenia of the distal femur and proximal tibia and the loss of strength of the quadriceps can be partly reversed by regular FES-assisted training.

ADL-2-1294 (Adolor).

Adolor is developing various local and topical formulations of the antidiarrheal compound loperamide (ADL-2-1294), which acts as an opiate receptor agonist in the peripheral nervous system, for the potential treatment of pruritus and pain associated with burns, wounds, eye diseases and inflammation. Both the topical formulation and ophthalmic formulation are in phase II clinical trials. TOPICAL FORMULATION: A topical formulation is being developed for pain associated with cutaneous inflammatory lesions and other indications associated with inflammatory pain. Phase I trials were completed in spring 1997. The trials assessed the safety, tolerance, pharmacokinetics, and topical sensitivity of ADL-2-1294 in 35 burn patient volunteers. Following positive results, Adolor began two dose-ranging phase II trials in patients with minor burns, abrasions and sunburn in the first half of 1997. In July 1997, Adolor was to initiate the preclinical development of ADL-2-1294 for the potential treatment of hyperalgesia associated with surgical wounds. OPHTHALMIC FORMULATION: By July 1999, phase II clinical trials of ADL-2-1294 for the potential treatment of inflammatory corneal pain were underway. In June 1998, the FDA accepted an IND for ADL-2-1294 for the treatment of inflammatory pain associated with corneal abrasions, surgical and laser keratectomies and keratoconjunctivitis. By this time, a phase I study had been initiated to assess safety and efficacy parameters. By July 1997, an ophthalmic formulation was in preclinical development for the treatment of corneal hyperalgesia. In preclinical studies with the compound, efficacy was demonstrated in animal models of inflammatory pain. OTHER FORMULATIONS: By 1999, Adolor was also investigating mucosal, post-surgical and intra-articular indications for the compound. By 1996, Adolor had plans to carry out clinical development alone, up to and including phase II trials. Then, the company were to seek a corporate partner, probably from Japan, and hold on to US and European rights. Beyond phase III trials, Adolor had expected to sell the compound to a major US or European company. In 1997, Adolor licensed ADL-2-1294 to the South Korean OTC topically-administered epidermal analgesic. In July 1999, Adolor licensed worldwide (excluding Korea) prescription and OTC development and commercial rights to topical dermal ADL-2-1294, for use in the treatment of inflammatory pain, itching and other undisclosed indications, to SmithKline Beecham. The company was issued US-05849761 and US-05849762 in January 1999 covering the use of antidiarrheal opioid compounds for the treatment of inflammatory pain and the treatment of pruritus.

The effects of surface anaesthesia on the autonomic dysreflexia response during functional electrical stimulation.

Recently, increases in blood pressure (BP) and concomitant bradycardia, suggestive of autonomic dysreflexia (AD), have been documented during functional electrical stimulation (FES) in individuals with a high spinal cord injury (SCI). If uncontrolled, this response could preclude the safe use of FES among such individuals. FES induced pain is partly related to stimulation of skin nociceptors. Therefore, measures to reduce skin sensitivity may reduce the risk of AD during FES. The purpose of this study was to determine if topical anaesthetic applied over the site of electrical stimulation could minimize the AD cardiovascular and hormonal responses to FES in individuals with SCI above the T6 level. Seven subjects with a SCI above T6 received FES to the quadriceps muscle of each leg under two conditions on two different testing days. The two treatment conditions, topical anaesthetic and placebo creams, were double blinded and randomized. The cream was administered to an area the size of the electrode (10 x 10 cm) 1 h prior to stimulation. Stimulation began at 0 mAmps and increased by 16 mAmps every 2 min until an intensity of 160 mAmps was achieved. HR and BP were measured at each stimulation intensity level. Catecholamines were analyzed three times during the stimulation protocol (pre, mid and post stimulation intensities). At the end of the stimulation protocol, FES induced isometric quadriceps contraction force at 160 mAmps intensity was measured using a hand held dynamometer. As FES stimulation intensity increased, significant rises in systolic and diastolic BP were seen, with a concomitant progressive drop in HR. The AD response to stimulation was not significantly different between the topical anaesthetic and placebo conditions. Serum catecholamine (epinephrine and norepinephrine) levels tended to rise with increasing FES intensity levels but did not reach statistical significance. The two treatment conditions did not significantly affect serum catecholamine levels or FES-induced quadriceps contraction force. In summary, FES application to the quadriceps muscle in high level SCI subjects resulted in significant increases in BP, decreases in HR (AD-like response), a trend towards elevations in catecholamine levels, and no difference in quadriceps muscular strength. However, these responses were unaffected by the use of topical anaesthetic cream on the skin at the stimulation site. This suggests that other mechanisms than skin nociception are operative in FES-induced AD.

Hormonal responses to graded-resistance, FES-assisted strength training in spinal cord-injured.

Functional electrical stimulation (FES) assisted resistance training has been effective in increasing muscular strength and endurance in spinal cord injured men and women in preparation for FES-assisted cycle programs and for FES-assisted standing and walking. Increases in blood pressure and a concomitant bradycardia suggestive of autonomic dysreflexia have been reported during FES-assisted resistance training. Self-induced autonomic dysreflexia in athletes who use wheelchairs suppressed the normal exercise induced serum testosterone increase. We, therefore, examined the changes in hematocrit and circulating levels of testosterone, sex hormone binding globulin (SHBG), cortisol, prolactin, norepinephrine and epinephrine during FES assisted resistance exercise in five high spinal cord injured men (SCI) and comparable maximal exercise in five able bodied controls (AB). Mean serum testosterone levels significantly increased with FES-assisted resistance training in SCI and maximal resistance exercise in AB with no significant change in hematocrit or SHBG. Prolactin, cortisol and epinephrine levels were unchanged while norepinephrine levels were significantly increased in SCI and AB. These findings suggest that there is no concern over inadequate physiological androgen response to an exercise stimulus in SCI. The data do not support the previous findings that elevated levels of norepinephrine in autonomic dysreflexia suppress testosterone response to exercise.

Efficacy of rowing, backward wheeling and isolated scapular retractor exercise as remedial strength activities for wheelchair users: application of electromyography.

Shoulder dysfunction due to regular wheelchair use is a common problem among people with spinal cord injuries. As a remedial measure, strengthening of the scapular retractor muscles has been suggested. Electromyographical analysis was utilized to examine scapular retraction muscle use during rowing, backward wheeling and a standardized scapular retraction exercise in seven people with spinal cord injuries and seven able bodied subjects. In addition, a pilot study using indwelling electrodes was completed to validate the use and placement of surface electrodes. Both rowing and the standardized scapular retraction exercise recruited higher levels of retractor involvement than backward wheeling. We suggest that rowing, because of its value as a cardiovascular exercise and high level of retractor recruitment, is an appropriate and effective means of remediating scapular retractor weakness.

Physiological correlates of simulated wheelchair racing in trained quadriplegics.

This study examined the physiological responses during a 7.5-km simulated wheelchair race (SR) performed on rollers by 8 male quadriplegic marathon racers and analyzed the factors associated with SR time. Cardiac output (Q) was estimated during the SR using carbon dioxide rebreathing, from which stroke volume (SV) and (alpha-v)O2 diff were calculated. Subjects raced at 90 and 93% of peak oxygen uptake (VO2) and peak heart rate, respectively. SR time was inversely related (p < 0.05) to peak VO2, and VO2, Q, and SV during the SR, but not (alpha-v)O2 diff, age, and lesion level. Multiple regression analysis included only absolute SR VO2 in the equation to predict SR time: Y = -29.7X + 65.9; SE = 5.8. SR VO2 was significantly (p < 0.05) related to Q and SV but not to (alpha-v)O2 diff. These descriptive data suggest that SR performance in trained male quadriplegics might be limited by central, as opposed to peripheral, factors that determine VO2.

Evidence of autonomic dysreflexia during functional electrical stimulation in individuals with spinal cord injuries.

The purpose of the investigation was to examine the safety and efficacy of functional electrical stimulation (FES)-assisted hydraulic resistance training in improving cardiovascular fitness in persons with spinal cord injuries. The cardiopulmonary responses of 10 high spinal cord injured (SCI) and five able bodied (AB) subjects were assessed during three bouts of FES-assisted leg extension exercise. The protocol involved three 30-minute tests: (1) unloaded leg extension, (2) hydraulically-resisted leg extension (loaded), and (3) a reproduction of the unloaded and loaded protocols to measure cardiac output (Q). Pre-measurements were made of body mass, mean limb weight, maximal force output and maximal oxygen uptake (incremental arm ergometry). Oxygen uptake (VO2), minute ventilation (Ve), respiratory exchange ratio (RER), heart rate (HR), blood pressure (BP) were recorded before, during and after tests. There was a significant difference in VO2 max between SCI and AB subjects. Cardiac output significantly increased between the loaded and unloaded tests. The significant increases from rest to unloaded and loaded exercise pointed to the potential value of adding resistance to a leg extension training regime. Heart rate and BP of the participants with SCI consistently demonstrated a response suggestive of autonomic dysreflexia. Upon stimulation an immediate increase in (predominantly systolic) BP was observed, followed by a fall in HR. On cessation of stimulation HR exhibited a substantial rebound effect and BP returned to normal levels. This response was highly reproducible and suggests caution be exercised in the use of FES for people with SCI with lesion levels above the major splanchnic outflow (T6).

Electrical stimulation-assisted rowing exercise in spinal cord injured people. A pilot study.

Recently a FES (functional electrical stimulation)-assisted rowing machine was developed to enhance cardiovascular training in people with spinal cord injuries. The machine was assessed in terms of its efficacy as a training tool. Six patients who were quadriplegic (C6-T1) and 2 who were paraplegic (T3-6) completed a series of three tests in succession: (1) leg stimulation only (quadriceps and hamstring groups)--'Stim', (2) arm row only--'Row' and (3) simultaneous row and stimulation--'R & S'. Measurements recorded included oxygen uptake (VO2), minute ventilation (Ve), respiratory exchange ratio (RER), heart rate (HR) and blood pressure (BP). In addition, 6 out of the 8 subjects took part in a qualitative assessment comprising a guided interview exploring the subject's perception of the machine and test. Significant increases in VO2 were demonstrated between the three tests with R & S producing mean steady-state values of 16.34 nm (+/- 0.74) ml/kg/min (83% of maximum). These values represented a 12% increase over Row alone. Of interest was the qualitative assessment which revealed that subjects perceived R & S to be easier than Row despite the higher levels of VO2 observed. The results suggest that the rowing machine represents a potentially valuable hybrid training device that may significantly reduce risk factors for cardiovascular disease and improve the quality of life of people with SCI.

Bone mass measurements in the distal forearm using dual-energy x-ray absorptiometry and gamma-ray computed tomography: a longitudinal, in vivo comparative study.

Indices of bone mass were measured in 23 volunteers weekly over 14-16 weeks using dual-energy x-ray absorptiometry (DEXA) and special-purpose computed tomography (gamma-CT). In vitro, the precision for both systems was excellent (coefficient of variation less than 0.5%). Over 4 months, the precision in vivo (average CV for all subjects) for DEXA measures (BMD, g/cm2, and BMC, g/cm) varied between 0.6 and 1.1%; with gamma-CT it varied from 1.1% for TBD (g/cm3) to 2.2% for CBD (g/cm3). Correlation between the indices of bone mass measured using DEXA and gamma-CT at the ultradistal site was moderate, but these indices were not correlated at the distal third site. When BMD and BMC were derived from the CT index IBD, however, the correlation between these gamma-CT indices and the corresponding DEXA indices was high for both ultradistal and proximal radial sites.

Endurance training decreases serum testosterone levels in men without change in luteinizing hormone pulsatile release.

Cross-sectional studies have suggested that total and bioavailable testosterone levels are reduced in some male athletes. Such changes may be related to loss of body weight, increased serum cortisol, and/or alterations in LH pulsatile release. To determine how endurance training may affect androgen levels, we measured serum total testosterone, sex hormone-binding globulin, free androgen index, LH, FSH, PRL, cortisol, and weight in 15 previously sedentary males. We also examined pulsatile LH release in a subset of 5 subjects. Over 6 months of training, the men increased weekly running mileage to an average of 56 km/week. Total testosterone and free androgen index levels decreased significantly. PRL and cortisol also decreased, while single sample LH and FSH remained unchanged. There was a significant reduction in weight, which did not correlate with changes in serum testosterone levels. LH pulsatile release was not altered by training in the subset of 5 runners. These data confirm previous findings of physiological reduction in serum testosterone and PRL levels and suggest that the testosterone decrease is not related to changes in LH pulsatile release, weight, or increased serum cortisol levels.

The effects of acute exercise on pulsatile LH release in high-mileage male runners.

Evidence suggests that acute exercise and endurance training has a suppressive effect on the hypothalamic-pituitary-gonadal (HPG) axis in men and women. To determine if training and acute exercise influence the neuroendocrine regulation of the HPG axis in men we examined pulsatile LH release in six male endurance runners with a training volume of at least 80 km per week, and compared this with values in six age-matched sedentary controls. Blood samples were obtained through an indwelling i.v. cannula from the subjects at 15-min intervals for 6 h following 24 h without significant physical activity and again in the runners, following 60 min of running at a speed equivalent to 5% below the anaerobic threshold. Mean LH pulse frequency and amplitude, as well as areas under the LH pulses and total LH curve, were calculated but only the mean post-exercise area under the total LH curve area was significantly lower than basal values (P less than 0.05) following exercise compared with the resting values in runners. Other measures of LH release did not change with acute exercise. Basal and pre-exercise testosterone levels were also measured and found to be at the lower end of normal men. The mean pre-exercise serum testosterone levels were significantly higher than basal levels. Mean testosterone levels, mean pulse amplitude, and mean area under the LH curve were significantly lower in resting runners than in the controls. The data suggest that exercise induces a general lowering of LH levels but does not inhibit LH pulsatile release. An anticipatory increase in serum testosterone occurred before exercise.

The effects of exercise on reproductive function in men.

Physical activity has a range of effects on male reproductive function depending upon the intensity and duration of the activity and the fitness of the individual. In general, it appears that relatively short, intense exercise increases serum testosterone levels, but there is debate to what degree haemoconcentration, decreased clearance and/or increased synthesis are involved. It is clear from the promptness of the testosterone increment that the mechanism does not involve gonadotrophin stimulation of the testes. There is suppression of serum testosterone levels during and subsequent to more prolonged exercise (and to some extent in the hours following intense short term exercise). Again the mechanisms are not clear: a variety of systems could influence the decrease of testosterone synthesis, including decreased gonadotrophin, increased cortisol, catecholamine or prolactin levels, or perhaps even an accumulation of metabolic waste materials. Endurance training induces changes in the function of the reproductive axis in men in a manner which appears similar to the changes in women. As in women, there is a subclinical inhibition of normal reproductive function but it is unclear whether clinical expression of reproductive suppression is common in men. The long term, physiological suppression of the hypothalamic-pituitary-gonadal axis in men is probably not of major significance but it is clear that further investigation in several areas is essential to provide continuing reassurance that 'exercise is good for you'.

Immunocytochemical and enzyme histochemical localization of kallikrein-like enzymes in colon, intestine, and stomach of rat and cat.

Kallikrein was localized in goblet (or mucous) cells of rat colon and in rat and cat small intestine and stomach by two immunocytochemical techniques. A kallikrein-like enzyme was also localized by enzyme histochemistry in mast cells of colon, intestine, and stomach of the cat, where they appeared to be associated with blood vessels in the lamina propria. The mast cell enzyme, however, was not detected by immunocytochemistry using antibodies to kallikrein. Modification in the enzyme histochemical procedure (pH, fixation) yielded positive results for a kallikrein-like protease in goblet cells of the intestine and colon. The possible physiological and pathological significance of kallikrein-like enzyme in the gastrointestinal tract and elsewhere is discussed.

Are anorexic tendencies prevalent in the habitual runner?

To investigate whether runners displayed any of the abnormalities characteristic of patients with anorexia nervosa, we conducted a cross sectional study of 31 high mileage, 18 low mileage runners and 18 non-running controls. Subjects completed a personal data questionnaire, the Jackson Personality Inventory (JPI) and the Eating Attitudes Questionnaire (EAT), underwent a body image test and a blood sample was obtained for measurement of reproductive, thyroid and adrenal hormones. High mileage runners scored significantly higher infrequency scores on the JPI than sedentary controls but there was no evidence of psychopathology. The high mileage runners also significantly overestimated waist width and there were small but statistically significant differences in EAT scores between controls and the runner groups. Ten of 49 runners had EAT scores beyond two standard deviations above the mean of non-running controls. Serum total, free and non-specifically bound testosterone and prolactin levels were significantly lower in high mileage runners than controls. LH, FSH, cortisol and thyroid hormones were not significantly different. There were no significant differences in any hormone between low mileage runners and controls. displayed no clear abnormalities characteristic of patients with anorexia The results suggested that running may have a chronic effect on serum testosterone and prolactin levels in high mileage but not low mileage runners. Although there was no significant evidence of anorexia nervosa on testing the runners with EAT, the overestimation of waist size provided some evidence of a distortion of body image in the high mileage runners. Runners displayed no clear abnormalities characteristic of patients with anorexia nervosa.

Reduced serum testosterone and prolactin levels in male distance runners.

To investigate whether endurance running in men produced basal hormonal changes similar to those reported in women, we obtained blood samples from 31 men running at least 64 km each week and 18 sedentary controls for measurement of levels of total testosterone, non-sex hormone-binding globulin-bound and free testosterone, luteinizing hormone, follicle-stimulating hormone, prolactin, and cortisol. The mean levels of total and nonspecifically bound testosterone as well as prolactin were significantly lower than in controls, although levels remained within the physiological range. Other hormone levels were similar in both groups. The lowered testosterone and prolactin levels parallel the changes reported in women runners.

Immunolocalization of the protease kallikrein in the colon.

Colon kallikrein was localized in the goblet cells of cat and man by a variety of immunocytochemical techniques. No evidence of this enzyme was found in other sites in this organ. The possible physiological significance of kallikrein in the gastrointestinal tract and of the many related serine proteases is discussed.