Biomedical subjects

R B Armstrong

Publications and source records attributed to R B Armstrong.

At least 37 records · Page 2Linked to original sources

PubMed1996

Brain norepinephrine and metabolites after treadmill training and wheel running in rats.

Regional changes in concentrations of brain norepinephrine [NE] and its metabolites after chronic exercise have not been described for exercise protocols not confounded by other stressors. We examined levels of [NE], 3-methoxy-4-hydroxyphenylglycol [MHPG], and 3,4-dihydroxyphenylglycol [DHPG] in the frontal cortex, hippocampus, pons-medulla, and spinal cord after 8 wk of exercise. Male Sprague-Dawley rats (N = 36) were randomly assigned to three conditions: 1) 24-h access to activity wheel running (WR), 2) treadmill running (TR) at 0 degrees incline for 1 h.d-1 at 25-30 m.min-1, or 3) a sedentary control group (C). Levels (nmol.g-1) of [NE], [MHPG], and [DHPG] were assayed by high performance liquid chromatography with electrochemical detection. Planned contrasts (P < 0.05) indicated that exercise training increased succinate dehydrogenase activity (mmol cytochrome C reduced.min-1.g-1 wet weight) in soleus muscle for TR compared with WR or C. [NE] was higher in the pons-medulla and spinal cord for both TR and WR compared with C. [DHPG] was higher in the pons-medulla for TR compared with C, and [MHPG] was higher in the frontal cortex and in the hippocampus for TR compared with C. Our results suggest that treadmill exercise training is accompanied by brain noradrenergic adaptations consistent with increased metabolism of NE in areas containing NE cell bodies and ascending terminals, whereas treadmill running and wheel running are accompanied by increases in levels of NE in the areas of NE cell bodies and the spinal cord, independently of an exercise training effect.

Animals↗

PubMed1996

Differential effects of anesthetics on in vivo skeletal muscle contractile function in the mouse.

The purpose of this study was to evaluate the effects of four anesthetic regimens on in vivo contractile function of mouse ankle dorsiflexor muscles. The torque-frequency and torque-velocity relationships were determined for the following anesthetics: fentanyl-droperidol and diazepam (F-d/d); ketamine and xylazine (K/x); pentobarbital sodium (Ps); and methoxyflurane (Mf). Mf, Ps, and F-d/d regimens resulted in comparable contractile responses at low doses, whereas K/x produced a relative depression in isometric contractile function as shown by a decrease in the torque-time integral at the 300-Hz stimulation frequency (-13.9%; P < 0.05). Moreover, K/x caused a shift to the left in the torque-frequency curve as indicated by increases in torque-time integrals at 25 and 50 Hz. Both Ps and F-d/d regimens exhibited dose-dependent effects during the isovelocity contractions. Ps significantly reduced work (-28.7%) and average power (-28.9%) at 800 degrees/s at the high dose. In contrast, F-d/d anesthesia resulted in increases in peak torque (16-20%) and work (15-18%) output at all eccentric contraction velocities at the high dose, whereas average power was increased only at -800 (17%) and -1,000 degrees/s (17%). In conclusion, commonly used anesthetic regimens can affect the contractile response in vivo; K/x and Ps yield smaller torque outputs, whereas Mf and F-d/d consistently produce larger contractile responses. Mf and F-d/d are recommended for use in studying skeletal muscle function in mice in vivo.

Anesthesia↗

PubMed1996

Estradiol effect on anterior crural muscles-tibial bone relationship and susceptibility to injury.

The study's objective was to determine whether estradiol (E2) deficiency alters the functional relationship of muscle to bone and causes a differential increase in injury susceptibility. Ovariectomized 6-wk-old mice were administered E2 (40 micrograms. day-1. kg-1; n = 8) or the oil vehicle (n = 8) for 21 days. The anterior crural muscles of the left hindlimb were then stimulated to produce 150 maximal in vivo eccentric contractions. In vitro functional measurements were then made on the extensor digitorum longus (EDL) muscle and tibia from both the exercised and unexercised legs. The maximal isometric torque produced by the anterior crural muscles before the eccentric contraction protocol and the unexercised EDL maximal isometric tetanic force (P(0)) were higher in E2-treated mice by 18 and 14%, respectively (P < or = 0.03). Both ultimate load and stiffness for the unexercised tibia were higher by 16% in E2-treated mice (P < or = 0.03). The muscle-to-bone relationship of these measurements was unaffected by E2 status (P > or = 0.59). No evidence for increased injury susceptibility was found in either tissue from E2-deficient mice. In fact, the decrement in P(0) was only 36.9 +/- 3.8% in exercised EDL muscles from E2-deficient mice compared with 50.6 +/- 4.2% in exercised muscles from E2-treated mice (P = 0.03). Tibia stiffness was 3.9% higher in bones from exercised legs than in bones from unexercised legs (72.64 +/- 2.77 vs. 69.95 +/- 2.66 N/mm; P = 0.05) with ultimate load showing a similar trend (P = 0.07); no effect of E2 status was observed on these differences (P > or = 0.53). In conclusion, the functional relationship of bone to muscle and the susceptibility to injury in bone are not altered by the presence of E2 in ovariectomized mice; however, E2 does increase injury susceptibility in the EDL muscle.

Animals↗

PubMed1996

Decreased contraction economy in mouse EDL muscle injured by eccentric contractions.

The objective of this study was to find out whether basal and/or active energy metabolism are altered in isolated mouse extensor digitorum longus muscle injured by eccentric (Ecc) contractions. Measurements of basal O2 consumption and isometric tetanus O2 recovery cost were made at 25 degrees C on muscles that had done either 10 Ecc, 10 isometric (Iso), or no contractions (No). In parallel experiments, rates of lactate and pyruvate production were measured to estimate the anaerobic contribution. Basal O2 consumption was unaffected by the type of protocol performed (P = 0.07). However, the tetanus O2 cost per force-time integral was elevated by 30-36% for the Ecc protocol muscles over that for the Iso and No protocol muscles. When including the increased lactate production by the Ecc protocol muscles, the total energetic cost per force-time integral was 53% higher than that for the Iso protocol muscles [2.35 +/- 0.17 vs. 1.54 +/- 0.18 mumol O2/(N.m.s)]. The decreased economy was attributed to two factors. First, in skinned fibers isolated from the injured muscles, the ratio of maximal actomyosin adenosinetriphosphatase activity to force production was up by 37.5%, suggesting uncoupling of ATP hydrolysis from force production. Second, increased reliance on anaerobic metabolism along with the fluorescent microscopic study of mitochondrial membrane potential and histochemical study of ATP synthase suggested an uncoupling of oxidative phosphorylation in the injured muscles.

Animals↗

PubMed1995

Redistribution of cell membrane probes following contraction-induced injury of mouse soleus muscle.

Our aim was to study how mouse skeletal muscle membranes are altered by eccentric and isometric contractions. A fluorescent dialkyl carbocyanine dye (DiOC18(3)) was used to label muscle membranes, and the membranes accessible to the dye were observed by confocal laser scanning microscopy. Experiments were done on normal mouse soleus muscles and soleus muscles injured by 20 eccentric or 20 isometric contractions. Longitudinal optical sections of control muscle fibers revealed DiOC18(3) staining of the plasmalemma and regularly spaced transverse bands corresponding in location to the T-tubular system. Transverse optical sections showed an extensive reticular network with the DiOC18(3) staining. Injured muscle fibers showed distinctively different staining patterns in both longitudinal and transverse optical sections. Longitudinal optical sections of the injured fibers revealed staining in a longitudinally-oriented pattern. No correlations were found between the abnormal DiOC18(3) staining and the reductions in maximal isometric tetanic force or release of lactate dehydrogenase (P > or = 0.32). Additionally, no difference in the extent of abnormal staining was found between muscles performing eccentric contractions and those performing the less damaging isometric contractions. However, many fibers in muscles injured by eccentric contractions showed swollen regions with marked loss of membrane integrity and an elevated free cytosolic calcium concentration as observed in Fluo-3 images. In conclusion, a loss of cell membrane integrity results from contractile activity, enabling DiOC18(3) staining of internal membranes. The resulting staining pattern is striking and fibers with damaged cell membranes are easily distinguished from uninjured ones.

Animals↗

PubMed1995

Muscle function and protein metabolism after initiation of eccentric contraction-induced injury.

This study was designed to determine the relationship between skeletal muscle function and protein metabolism after initiation of eccentric contraction-induced injury. Mouse anterior crural muscles were injured in vivo, and then either immediately or 3, 6, 24, 48, 72, 120, or 336 h after injury muscles were isolated and studied for indexes of muscle function, injury, phagocyte infiltration, and protein metabolism. A group of mice were administered anti-polymorphonuclear cell and anti-macrophage antisera in an attempt to reduce phagocytic infiltration into injured muscle. Force production in extensor digitorum longus muscles was reduced 55% immediately after injury induction and did not recover significantly until 120 h postinjury (28% below baseline). However, rates of protein degradation were not elevated until 48 h postinjury (60% above normal) and were not correlated with the changes in force production (r = -0.37; P = 0.24). Phagocytic infiltration was evident 24-120 h postinjury and was correlated with the elevated protein degradation rates (r = 0.75; P < 0.01). Protein synthesis rates began to increase approximately 48 h after injury was induced and were elevated by 83% 5 days postinjury. Fourteen days after injury, muscle protein degradation and synthesis rates had returned to normal, as well as specific force production, and phagocytic infiltration was not detected. However, muscle mass, protein content, and absolute force production were lower than normal. Antisera-treated mice were rendered neutropenic, but there was no difference in any variable measured between muscles from these mice and muscles from normal mice.

Animals↗

PubMed1994

Eccentric contraction-induced injury of mouse soleus muscle: effect of varying [Ca2+]o.

The objective of this study was to determine the effect of varying extracellular Ca2+ concentration ([Ca2+]o) on eccentric contraction-induced muscle injury. Isolated mouse soleus muscles (n = 64) performed either 20 eccentric or 20 isometric contractions over a 40-min period in a Krebs buffer containing 0.5, 1.25, or 5.0 mM Ca2+. Measurements of contractile function and lactate dehydrogenase accumulation in the buffer were then made every 15 min for 2 h. Prostaglandin E2, leukotriene B4, and tyrosine accumulation in the incubation medium and total muscle [Ca2+] were measured at the end of the experiment. Reductions in maximal isometric tetanic force for muscles immediately after performance of 20 eccentric and 20 isometric contractions were 21.1 +/- 1.4 and 1.2 +/- 0.7%, respectively. Total muscle [Ca2+] was 28-37% higher in muscles that performed eccentric contractions than in those that performed isometric contractions. However, estimates made with a confocal laser scanning microscope and fluo 3 do not indicate that there was a difference in free cytosolic [Ca2+] between fibers from injured and control muscles. Also, leukotriene B4, prostaglandin E2, and tyrosine accumulation in the buffer from muscles that performed eccentric contractions was not elevated over that from muscles that performed isometric contractions. Furthermore, lactate dehydrogenase accumulation and reductions of contractile function over the 2-h incubation period were not enhanced by higher [Ca2+]o or influenced by the type of contraction. These findings suggest that muscles that were injured by eccentric contractions were able to buffer the increased influx of extracellular Ca2+, maintain a normal free cytosolic [Ca2+], and avoid activation of Ca(2+)-sensitive degradative pathways.

Aniline Compounds↗

PubMed1994

Eccentric contraction-induced injury in normal and hindlimb-suspended mouse soleus and EDL muscles.

The primary objective of this study was to compare the magnitude of injury in mouse extensor digitorum longus (EDL) and soleus muscles induced by high-force eccentric contractions. A second objective was to study the effect of altering the daily loading of the muscles through hindlimb suspension (HS) on the injury. One of two protocols was performed in vitro: 1) 15 eccentric contractions (n = 20: 10 EDL and 10 soleus muscles) or 2) 15 isometric contractions (n = 20: 10 EDL and 10 soleus muscles). After the protocol, the decrements in contractile performance and lactate dehydrogenase (LDH) release were measured at 15-min intervals over 1 h. Immediately after the eccentric contraction protocol, markedly greater decrements in maximal isometric tetanic force (Po) occurred in the normal EDL than in the normal soleus muscles (60.7 +/- 4.2 vs. 7.6 +/- 2.1%, P < or = 0.0001). LDH release immediately after the eccentric contraction protocol was 2.7-fold greater in the normal EDL than in the normal soleus muscles. To investigate the role of recent loading of the muscles in the injury, EDL (n = 9) and soleus (n = 10) muscles from mice subjected to HS for 14 days performed the eccentric contraction protocol. HS resulted in greater decrements in contractile performance for the soleus muscles (decreases in Po immediately after the protocol for HS and normal soleus muscles were 31.0 +/- 1.8 and 7.6 +/- 2.1%, respectively; P < or = 0.0001) but not for the EDL muscles.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Capillary blood transit time in muscles in relation to body size and aerobic capacity.

The mean minimal transit time for blood in muscle capillaries (tc) was estimated in six species, spanning two orders of magnitude in body mass and aerobic capacity: horse, steer, dog, goat, fox and agouti. Arterial (CaO2) and mixed venous (CvO2) blood O2 concentrations, blood hemoglobin concentrations ([Hb]) and oxygen uptake rates were measured while the animals ran on a treadmill at a speed that elicited the maximal oxygen consumption rate (VO2max) from each animal. Blood flow to the muscles (Qm) was assumed to be 85% of cardiac output, which was calculated using the Fick relationship. Total muscle capillary blood volume (Vc) and total muscle mitochondrial volume were estimated by morphometry, using a whole-body muscle sampling scheme. The tc was computed as Vc/Qm. The tc was 0.3-0.5 s in the 4 kg foxes and agoutis, 0.7-0.8 s in the 25 kg dogs and goats, and 0.8-1.0 s in the 400 kg horses and steers. The tc was positively correlated with body mass and negatively correlated with transcapillary O2 release rate per unit capillary length. Mitochondrial content was positively correlated with VO2max and with the product of Qm and [Hb]. These data suggested that Qm, Vc, maximal hemoglobin flux, and consequently tc, are co-adjusted to result in muscle O2 supply conditions that are matched to the O2 demands of the muscles at VO2max.

Aerobiosis↗

PubMed1993

Mechanical factors in the initiation of eccentric contraction-induced injury in rat soleus muscle.

1. Mechanical factor(s) associated with the initiation of eccentric contraction-induced muscle injury were investigated in isolated rat soleus muscles (n = 180; 42 protocols with 4-6 muscles per protocol). Five eccentric contractions were performed with 4 min between contractions. Three levels of peak eccentric contraction force (100, 125 and 150% of pre-injury maximal isometric tetanic tension, P0), length change (0.1, 0.2 and 0.3 muscle length, L0) and lengthening velocity (0.5, 1.0 and 1.5 L0/s) were utilized. Force was varied with stimulation frequency (10-150 Hz). The eccentric contractions were initiated at muscle lengths of 0.85 or 0.90 L0. Following the fifth eccentric contraction, the muscle was incubated in Krebs-Ringer buffer for 60 min. Peak isometric twitch tension (PT), P0, maximal rate of tension development (+ dP/dt), maximal rate of relaxation (-dP/dt), and creatine kinase (CK) release were measured prior to the five eccentric contractions and at 15 min intervals during the incubation period. Total muscle [Ca2+] was measured after 60 min incubation. 2. The mean (+/- S.E.M.) initial decline in P0 for the muscles performing the most injurious protocol was 13.6 +/- 4.8% (n = 6); P0 in control muscles immediately following performance of five isometric contractions was elevated 1.2 +/- 1.0% (n = 8). These means were different at probability, p = 0.005. Mean [ATP] in muscles immediately following the isometric control and most injurious protocols, respectively, were 16.30 +/- 1.49 and 19.84 +/- 1.38 mumol/g dry wt (p = 0.229). 3. Decrements in P0, PT, +dP/dt, and -dP/dt immediately after the injury protocol were related most closely to the peak forces produced during the eccentric contractions; greater initial declines in P0, +dP/dt and -dP/dt were also observed at higher lengthening velocities independent of peak force. Slow declines in P0 and -dP/dt during the 60 min incubation following the injury protocol were greatest for muscles performing contractions at the longer initial length. CK release was independent of all mechanical factors with the exception of lengthening velocity. CK activity at 45 and 60 min into the incubation period was greater for muscles lengthened at the highest velocity used (1.5 L0/s). Mean total muscle [Ca2+] for muscles performing the eccentric contractions was elevated by 38% over isometric control muscles but the elevation was unrelated to any of the four mechanical factors. 4. These data support the hypothesis that eccentric contraction-induced injury is initiated by mechanical factors, with muscle tension playing the dominant role.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1993

Materials fatigue initiates eccentric contraction-induced injury in rat soleus muscle.

1. The initiation of exercise-induced muscle injury is thought to be the result of high tensile stresses produced in the muscle during eccentric contractions. Materials science theory suggests that high tensile stresses could initiate the injury during the first eccentric contraction (normal stress theory) or after multiple eccentric contractions (materials fatigue). It was the objective of this study to investigate the two possibilities. 2. Rat soleus muscles (n = 66; 11 protocols with 6 muscles per protocol) were isolated, placed in an oxygenated Krebs-Ringer buffer at 37 degrees C, and baseline measurements were made. The muscle then performed an injury protocol which consisted of between zero and ten eccentric contractions (muscle starting length = 0.90 soleus muscle length, L0; length change = 0.25 L0; velocity = 1.5 L0/s; peak force = 180% maximal isometric tetanic tension (P0); time between contractions = 4 min; total duration of the injury protocol = 40 min). At the end of the injury protocol, the muscle was incubated in buffer for 1 h; every 15 min, an isometric twitch and tetanus were performed and lactate dehydrogenase (LDH) release was measured. Total muscle [Ca2+] was measured at the end of the incubation. 3. Change-point regression analysis indicates that at 0 min into the incubation, declines in P0, maximal rate of tension development (+dP/dt), maximal rate of relaxation (-dP/dt), and muscle stiffness (dP/dx) became significantly greater after eight eccentric contractions (p < or = 0.05). No relation was found between the number of eccentric contractions performed and the LDH activity at 0 min into the incubation, although after 60 min of incubation, LDH activity in the buffer was linearly related to eccentric contraction number (p = 0.01). There was no relationship between total muscle [Ca2+] and eccentric contraction number. These findings support the materials fatigue hypothesis of exercise-induced muscle injury.

Animals↗

PubMed1993

Excitation failure in eccentric contraction-induced injury of mouse soleus muscle.

1. Histological evidence suggests that the force deficit associated with eccentric contraction-induced muscle injury is due to structural damage to contractile elements within the muscle fibre. Alternatively, the force deficit could be explained by an inability to activate the contractile proteins. It was the objective of this study to investigate the latter possibility. 2. Mouse soleus muscles were isolated, placed in an oxygenated Krebs-Ringer buffer at 37 degrees C, and baseline measurements were made. The muscle then performed one of three contraction protocols: (1) twenty eccentric (n = 10 muscles); (2) ten eccentric (n = 12); or (3) twenty isometric (n = 10) contractions. At the end of the injury protocol, measurements were made during performance of a passive stretch, twitch and tetanus. Next, force was recorded during exposure of the muscle to buffer containing 50 mM caffeine. 3. Decrements in maximal isometric tetanic force (P0) observed for muscles in the twenty eccentric, ten eccentric, and twenty isometric contraction protocols were 42.6 +/- 4.2, 20.0 +/- 2.3 and 3.9 +/- 2.4%, respectively. However, the caffeine-elicited forces in muscles from the three protocols were not different when corrected for initial differences in P0 (64.9 +/- 1.3, 64.2 +/- 2.1 and 68.9 +/- 2.5% of pre-injury P0). The peak caffeine-elicited force was 118.4 +/- 8.6% of post-injury P0 for the muscles in the twenty eccentric contraction protocol, which was significantly different from that observed for the other protocols (71.8-80.2% post-injury P0). These findings indicate that the force deficit in this muscle injury model results from a failure of the excitation process at some step prior to calcium (Ca2+) release by the sarcoplasmic reticulum. 4. In an attempt to locate the site of failure, intracellular measurements were made in injured muscles to test whether injury to the sarcolemma might have resulted in a shift of the resting membrane potential of the muscle fibre. However, microelectrode measurements of resting membrane potential for muscles in the twenty eccentric contraction protocol (-74.4 +/- 0.6 mV) were not different from muscles in the twenty isometric contraction protocol (-73.4 +/- 1.0 mV). These data suggest that membrane resting conductances were normal and are compatible with the idea that the ability of the injured fibres to conduct action potentials was probably not impaired.

Action Potentials↗

PubMed1993

Elevations in rat soleus muscle [Ca2+] with passive stretch.

Previous work has demonstrated that muscular injury in rat soleus muscles resulting from eccentric contractions (downhill walking) is accompanied by elevations in mitochondrial [Ca2+] (MCC). Muscles are stretched during eccentric contractions, and there is evidence in the literature that stretch of the cell membrane induces Ca2+ influx in various tissues, including skeletal muscle. The purpose of this study was to determine if passive stretch of rat soleus muscles will induce increases in total muscle [Ca2+] (TCC) and MCC. Soleus muscles from female rats (51-122 g) were isolated and incubated in vitro for 2 h at resting length (Lo) or at the maximal in situ length (S). TCC (+62%) and MCC (+56%) were elevated in the S muscles. Also, there was a 63% reduction in maximal twitch tension in the S muscles. ATP concentration, phosphocreatine concentration, and lactate release between Lo and S muscles were the same, indicating that impaired metabolism was not responsible for the observed differences in [Ca2+] and force production between Lo and S muscles. Increases in TCC in the S condition indicate that stretch results in Ca2+ influx from the extracellular space, which is supported by the observation that when S muscles were incubated in Ca(2+)-free buffer, TCC and MCC did not increase. High concentrations of verapamil (0.25-0.75 mM) blocked the elevations in TCC and MCC in the S muscles, but the magnitude of the drug concentration required makes it questionable whether the effect resulted from specific blockade of slow voltage-sensitive Ca2+ channels.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Glycogen loss in rat muscles during locomotion on different inclines.

Running downhill causes structural damage in deep slow-twitch extensor muscles of the limbs. Both mechanical and metabolic hypotheses have been proposed to explain the damage. The purpose of this study was to use measurements of glycogen loss in the muscles and metabolic rates of rats running on the level and up and down 16 degrees inclines at 26 m min-1 to try to distinguish between these hypotheses. Glycogen loss in the soleus and medial head to the triceps brachii muscles during running on the three inclines was proportional to whole-animal oxygen consumption, indicating that there were no unusual metabolic demands on these muscles during the downhill exercise. The minimum area of these muscles showing glycogen loss was smaller during downhill than during uphill running. Average forces in the muscles are similar during locomotion on different inclines at the same speed, suggesting that stresses in the active motor units were greater during downhill running. Thus, the results are more consistent with a mechanical than with a metabolic etiology for the muscle injury resulting from downhill running.

Animals↗

PubMed1992

Estimating transit time for capillary blood in selected muscles of exercising animals.

The mean minimal capillary transit time was estimated in muscles of various animals using a combination of physiological and morphometric methods. Radioactive microspheres were injected intravascularly in various animals running on a treadmill at maximum oxygen consumption rate (VO2,max) to label blood flow to individual muscles. The muscles were then removed and preserved by standard methods for electron microscopy. The volume density of mitochondria was measured to assess muscle oxidative capacity. Capillary densities in muscle cross-sections, capillary diameters and tortuosities were incorporated into an estimate of capillary volume per unit muscle mass. Mean capillary transit time (tc) in the exercising muscles was estimated by dividing mass-specific capillary volume by mass-specific blood flow. Estimates of tc ranged from values near 1 s in horse heart and thigh muscles to 0.2 s in duck gastrocnemius. The relationship between muscle blood flow and tc was hyperbolic. The experimental data indicate a limiting value of 0.2 s for transit times at very high blood flows. There was no correlation between tc and body-mass-specific VO2,max.

Animals↗

PubMed1992

Topical isotretinoin for photodamaged skin.

Photodamaged skin is characterized clinically by coarseness, telangiectasia, wrinkling, discrete hyperpigmented and hypopigmented macules, atrophy, and ultimately the development of neoplasms. Studies on the UVB-irradiated hairless mouse indicate that topical application of tretinoin or isotretinoin induces structural modifications at the dermal level. Clinical trials indicate that tretinoin improves skin appearance in patients who have photodamage. This double-blind, vehicle-controlled clinical trial was conducted to determine whether 36 weeks of treatment with topical isotretinoin improves mildly to moderately photodamaged facial skin. After they gave written informed consent 776 patients were randomly assigned to 36 weeks of treatment with either vehicle cream or isotretinoin cream, applied once nightly. Efficacy was evaluated by means of physician and patient assessment and a blinded analysis of standardized photographs taken before and after treatment. When compared with vehicle, treatment with isotretinoin resulted in statistically significant improvement in overall appearance, fine wrinkling, discrete pigmentation, sallowness, and texture. Isotretinoin cream was well tolerated.

Administration, Cutaneous↗

PubMed1992

Retinoids for the future: investigational approaches for the identification of new compounds.

One desired goal for future retinoid development is the dissociation of therapeutic benefit from teratogenic risk. It is not known if this result can be achieved, but increasing our understanding of the molecular mechanisms of retinoid action offers rational approaches to the attainment of this goal. The basis for these new approaches is the recent discovery of nuclear receptors for all-trans-retinoic acid and for the 9-cis form of retinoic acid. These receptors, like the steroid hormone receptors, are ligand-dependent transcription factors. Retinoids act by binding to these receptors and modulating specific gene pathways that ultimately control cell differentiation and development. Retinoic acid is required for normal embryonic development, and retinoic acid concentrations are regulated in the developing embryo. The malformations associated with in utero exposure to retinoids might be the result of inappropriate activation of specific receptors and inappropriate modulation of specific gene pathways. At least three nuclear receptors for all-trans-retinoic acid and three nuclear receptors for the 9-cis form of retinoic acid are known to exist, with the two receptor subfamilies interacting to form heterodimers. This multiplicity of receptors and receptor interactions suggests that differences may exist among receptors in the biologic effects they mediate. Although some retinoid ligands are not specific, others are highly selective for one particular receptor. Contrasting the effects of ligands with different specificities should increase understanding of the biologic responses associated with specific receptors and efforts to dissociate therapeutic activity from undesired effects.

Animals↗

PubMed1992

Elevated muscle vitamin E does not attenuate eccentric exercise-induced muscle injury.

The purpose of this study was to evaluate the effect of elevated muscle vitamin E content on skeletal muscle damage from eccentric exercise. Sixty Sprague-Dawley rats were put on a normal (40 IU vitamin E/kg food) or supplemented (10,000 IU vitamin E/kg food) diet for 5 wk. Injury in soleus muscle was determined using several criteria: reductions in maximal tetanic force and number of intact fibers per square millimeter and elevations in muscle glucose 6-phosphate dehydrogenase activity and plasma creatine kinase activity, either immediately (0 h) or 2 days (48 h) after a downhill walking protocol. Sedentary animals were also tested but did not exercise. Muscle vitamin E levels were significantly elevated (approximately 3- to 4-fold), and susceptibility of the muscles to oxidant stress was decreased, after supplementation. However, vitamin E supplementation did not attenuate injury by any of the criteria employed. Maximal tetanic force decreased approximately 20% at 0 and 48 h after exercise in both groups. The number of intact fibers per square millimeter decreased approximately 30-35% in both groups at 0 and 48 h. Glucose 6-phosphate dehydrogenase activity increased approximately 50-100% in both groups at 48 h, and plasma creatine kinase activity was elevated approximately 2- to 2.5-fold at 0 h in both groups. These findings do not support a major role for free radical damage to muscle membranes in the initiation of injury from eccentric exercise, although they do not disprove free radical involvement in the etiology.

Animals↗