Glycogen storage disease confined to the heart with deficient activity of cardiac phosphorylase kinase: a new type of glycogen storage disease.

The case of a male infant with marked deposition of glycogen, confined to the heart, is presented. Clinically, prominent cardiomegaly had been evident from immediately after birth until the infant's death due to heart failure. There were no significant clinical manifestations in other organs, including liver and skeletal muscle, during the clinical course. Autopsy revealed abnormal deposition of normally structured glycogen in the heart, but no deposition in the liver, skeletal muscle, or other systemic organs. This unusual pattern of glycogen deposition was also confirmed by measurement of the glycogen content of each organ. This is the first report of glycogen storage disease confined to the heart. Enzymatic analysis revealed no decrease in the activities of acid maltase, amylo-1,6-glucosidase, and phosphorylase in the heart or in the liver or skeletal muscle. However, phosphorylase kinase activity was not detectable in the heart, although high activity levels were observed in the liver and skeletal muscle. In this case the inborn error of metabolism responsible for the isolated deposition of glycogen in heart muscle may have been due to a deficiency of cardiac phosphorylase kinase.

Modulation of arterial baroreflex control of heart rate by skin cooling and heating in humans.

The purpose of this study was to examine the effects of skin cooling and heating on the heart rate (HR) control by the arterial baroreflex in humans. The subjects were 15 healthy men who underwent whole body thermal stress (esophageal temperatures, approximately 36.8 and approximately 37.0 degrees C; mean skin temperatures, approximately 26.4 and approximately 37.7 degrees C, in skin cooling and heating, respectively) produced by a cool or hot water-perfused suit during supine rest. The overall arterial baroreflex sensitivity in the HR control was calculated from spontaneous changes in beat-to-beat arterial pressure and HR during normothermic control and thermal stress periods. The carotid baroreflex sensitivity was evaluated from the maximum slope of the HR response to changes in carotid distending pressure, calculated as mean arterial pressure minus neck pressure. The overall arterial baroreflex sensitivity at existing arterial pressure increased during cooling (-1.32 +/- 0.25 vs. -2.13 +/- 0.20 beats. min(-1). mmHg(-1) in the control and cooling periods, respectively, P < 0.05), whereas it did not change significantly during heating (-1.39 +/- 0. 23 vs. -1.40 +/- 0.15 beats. min(-1). mmHg(-1) in the control and heating periods, respectively). Neither the cool nor heat loadings altered the carotid baroreflex sensitivity in the HR control. These results suggest that the sensitivity of HR control by the extracarotid (presumably aortic) baroreflex was augmented by whole body skin cooling, whereas the sensitivities of HR control by arterial baroreflex remain unchanged during mild whole body heating in humans.

Responses of sweating and body temperature to sinusoidal exercise.

This study determined the phase response and amplitude response (delta) of esophageal temperature (T(es)), mean skin temperature (Tsk), and forearm sweating rate (Msw) to sinusoidal work. Six healthy male subjects exercised on a cycle ergometer with a constant load (approximately 35% maximal O2 uptake) for a 30-min period; for the next 40 min they exercised with a sinusoidal load at 25 degrees C at 35% relative humidity. The sinusoidal load varied between approximately 10 and 60% maximal O2 uptake, and three different time periods (1.3, 4, and 8 min) were selected. Each subject performed three experiments that differed only in the timing of sinusoidal work. During the 4- and 8-min periods, T(es), Tsk, and Msw changed almost sinusoidally. The phase of Msw change significantly preceded those of T(es) and Tsk changes (P < 0.05). During the 1.3-min period, the level of T(es) and Tsk remained almost constant (delta T(es) 0.01 +/- 0.00 degrees C, delta Tsk 0.03 +/- 0.01 degrees C), whereas Msw showed a clear sinusoidal pattern. We conclude that the sweating response during sinusoidal work depends on both thermal and nonthermal factors, the latter being emotional, mental, or sensory stimulation. The contribution of the nonthermal factors to the general sweating response during exercise can be separated from that of the thermal factors by using sinusoidal work during a short period (e.g., 1.3 min).

Sympathetic outflow to the skeletal muscle in humans increases during prolonged light exercise.

To investigate the effects of exercise duration on muscle sympathetic nerve activity (MSNA), heart rate, blood pressure (BP), tympanic temperature, blood lactate concentration, and thigh electromyogram were measured in eight volunteers during 30 min of cycling in the sitting position at an intensity of 40% of maximal oxygen uptake. MSNA burst frequency increased 18 min after exercise was begun (25 +/- 4 bursts/min at baseline and 36 +/- 5 bursts/min at 21 min of exercise), reaching 41 +/- 5 bursts/min at the end of exercise. Heart rate and systolic BP increased during exercise. Twenty minutes after commencement of exercise, however, both systolic and diastolic BP values tended to drop compared with the initial period of exercise. Tympanic temperature increased in a time-dependent manner, and the increment was significant 12 min after exercise was begun. Blood lactate concentration and integrated electromyogram showed no significant changes during exercise. The increased MSNA during prolonged light-intensity exercise may be a secondary effect of the drop in BP as a result of blood redistribution caused by thermoregulation rather than by metaboreflex.

Responses of sweating and body temperature to sinusoidal exercise in physically trained men.

The effect of physical training on the dynamic responses of sweating to transient exercise is still controversial. We determined the phase response and amplitude response (delta) of sweating rate and body temperature to sinusoidal exercise in physically trained and untrained subjects. Eight trained and seven untrained male subjects exercised on a cycle ergometer with a constant load for 30 min; for the next 28 min, they exercised with a sinusoidal load. The sinusoidal load variation ranged from approximately 10 to 60% of peak O2 uptake with a 4-min period. The ambient temperature and the relative humidity during exercise were 25 degrees C and 35%, respectively. There was no difference between the groups in the phase lags of esophageal temperature (Tes) and mean skin temperature (Tsk), whereas the phase lags of sweating rates for the chest and forearm were significantly shorter in the trained group (P < 0.05). The delta of Tes and Tsk per 1 W of exercise load in the trained group was significantly smaller than that in the untrained group (both, P < 0.05), whereas there was no difference between the groups in the delta of sweating rate for the chest and forearm. We conclude that subjects who have undergone long-term physical training show prompter dynamic characteristics of sweating response compared with untrained subjects and have a higher capacity to maintain constant body temperature during exercise at transient load.

Cardiovascular and humoral responses to sustained muscle metaboreflex activation in humans.

The cardiovascular and humoral responses to sustained muscle metaboreflex activation were examined in eight male volunteers while they performed two 24-min exercise protocols. Each of these consisted of six 1-min bouts of isometric handgrip exercise (the left and right hands being used alternately) at 50% of maximal voluntary contraction; after each bout, there was either 3-min postexercise occlusion (occlusion protocol) or 3-min rest (control protocol). In the occlusion protocol, mean arterial blood pressure was approximately 25 mmHg higher than during the control protocol, indicating that the muscle metaboreflex was activated during occlusion. During the control protocol, plasma renin activity, plasma vasopressin, and adrenocorticotropic hormone values were not significantly different from the values at rest. During the occlusion protocol, however, plasma renin activity, plasma vasopressin, and adrenocorticotropic hormone were all significantly increased at 25 min. These data demonstrate that, in humans, the sustained activation of the muscle metaboreflex causes the secretion of several hormones originating from different regions.

Involvement of central beta-adrenoceptors in the tachycardia induced by water immersion stress in rats.

The purpose of the present study was to investigate whether central beta-adrenoceptors are involved in stress-induced cardiovascular responses in rats. Using a biotelemetry system, blood pressure and heart rate were measured at rest and during stress induced by immersion in 1 cm-deep water. Intracerebroventricular (i.c.v.) injections of a nonselective beta-adrenoceptor antagonist, DL-propranolol (5 or 50 microg), significantly and dose dependently attenuated the tachycardia induced by water immersion stress (drug-induced reduction of tachycardia at 5 min after the start of stress: 61.4 +/- 13.2% for 5 microg, 72.5 +/- 8.2% for 50 microg). The same doses of DL-propranolol had no effect on the resting heart rate. Injection (i.c.v.) of a lower dose (5 microg) of D-propranolol--which has a lower potency as a beta-adrenoceptor antagonist than DL-propranolol, but a similar local anesthetic, membrane-stabilizing activity--did not attenuate the stress-induced tachycardia, although a higher dose (50 microg) did. Intravenous administration of DL-propranolol (5 or 50 microg) significantly attenuated the stress-induced tachycardia (drug-induced reduction of tachycardia at 5 min after the start of stress: 20.0 +/- 7.5% for 5 microg, 42.4 +/- 3.4% for 50 microg). However, the attenuation was much smaller than in the i.c.v. DL-propranolol-injected group. The i.c.v. injection of the 50 microg dose of DL-propranolol significantly augmented both the resting blood pressure and the pressor response to water immersion stress, whereas the lower dose (5 microg) had no effect. The i.c.v. injection of 50 microg D-propranolol also augmented, although not significantly, the resting blood pressure and the pressor response to stress. These results suggest that central beta-adrenoceptors are involved in the tachycardia induced by water immersion stress in rats.

Autonomic heart rate regulation during mild dynamic exercise in humans: insights from respiratory sinus arrhythmia.

To better understand the neural mechanism of heart rate (HR) regulation during dynamic exercise, the responses of HR and the magnitude of respiratory R-R interval variation were examined during exercise and recovery at mild intensities in humans. Eight subjects performed 3-min constant load cycle exercises in a semi-supine position at work rates of 25, 50, and 100 W. The respiratory interval was fixed at 4 s. Peak-to-valley variation in R-R interval caused by respiration was measured breath-by-breath and standardized for tidal volume (DeltaRRst, a noninvasive index of the degree of parasympathetic cardiac control). At all work rates the HR increased significantly from 2.5 s after the beginning of exercise (p <0.05) and decreased temporarily and slightly at around 15 s, and the DeltaRRst varied almost inversely. The HR and the DeltaRRst until 12.5 s after the beginning of exercise changed independently of work rate (ANOVA, p=0.27 and p=0.08). The HR-DeltaRRst relationship at the initial phase of exercise (for 12.5 s) was almost the same at all work rates. These results suggest that the initial HR response to exercise is strongly parasympathetically regulated independently of work rate. The HR recovered slower than the DeltaRRst at 50 and 100 W. On the HR-DeltaRRst relationship, the HR during recovery was significantly higher than during exercise at 1/3, 1/2, and 2/3 levels of pre-exercise DeltaRRst at 50 and 100 W and at the 1/3 level at 25 W (p < 0.05). At 25 W, the difference in HR at the 1/3 level was 5.5 beats.min(-1), and the HR increase to exercise was 21.2 beats.min(-1). We suggest that a HR regulatory system responds slower than a cardiac parasympathetic system to exercise, a cardiac sympathetic system, is activated even during mild exercise in humans.

An improved method for measurement of sweat expulsions during profuse sweating.

We present an improved ventilated-capsule method of recording for clear sweat expulsion patterns using nitrogen gas as a carrier gas heated to promote sweat evaporation. With this method, sweat expulsion patterns were more clearly recorded than with the conventional ventilated-capsule method. Taking the derivatives of these recordings of sweating expulsions could eliminate slow fluctuation components in the patterns of sweating. The results indicate that this method is useful in providing more-accurate measurements of sweat expulsion frequencies during profuse sweating.

Exercise-induced change in beta-adrenergic receptor number in lymphocytes from trained and untrained men.

This study was undertaken to clarify whether beta-adrenergic receptor (beta-AR) translocation from intracellular sites to the cell surface contributes to an increase in the number of beta-AR in lymphocytes from trained and untrained men after exercise. Nine trained and 9 untrained subjects performed exercise on a bicycle ergometer until exhaustion. The number of beta-AR in the cell surface (beta-AR(surface)) and intracellular sites (beta-AR(intra)) was determined at rest and after maximal exercise by measuring the binding of the radioligand 125I-iodocyanopindolol in the presence or absence of hydrophilic (CGP-12177A) or lipophilic (propranolol) unlabeled ligands. The number of beta-AR(surface) increased after exercise from 1,524.4 +/- 321.4 to 3,432.6 +/- 503.3 sites/cell (p < 0.01), whereas that of beta-AR(intra) decreased from 356.2 +/- 85.7 to 190.3 +/- 60.2 sites/cell (p < 0.05). The isoproterenol-stimulated cAMP production per 1 x 10(6) lymphocytes after exercise was significantly higher than that at rest. However, the cAMP production per single beta-AR(surface) tended to be lower after exercise. No differences between the trained and untrained subjects were found in beta-AR numbers or intracellular cAMP levels. These findings demonstrate that maximal exercise induces the translocation of beta-AR from intracellular sites to the cell surface in human lymphocytes. However, this translocation accounts for only 10% of the increase in total cellular beta-AR, suggesting that other mechanisms are predominant and contribute substantially to the increase in beta-AR(surface).

Cardiac and peripheral vascular responses to head-up tilt during whole body thermal stress.

During acute orthostatic stress, neurally mediated control of cardiac output (CO) and total peripheral vascular resistance (TPR) play an important role in the maintenance of systemic blood pressure. To examine the influence of thermal stress on the CO and TPR responses to orthostatic stress, 10 healthy male volunteers were exposed to normothermic control conditions followed by whole-body thermal stress produced by a cold or hot water-perfused suit during 5 min-70 degrees head-up tilt (HUT). HUT increased mean arterial pressure (MAP) by 3% of the pre-tilt value during normothermic control and cooling, whereas it decreased MAP by 4% of the pre-tilt value during heating. HUT decreased CO by 16-17% of the pre-tilt value under each thermal condition. The increase of TPR during HUT was exaggerated during cooling and inhibited during heating compared to normothermic control. Tilt-induced decrease of skin blood flow was greater during heating than cooling. These results suggest that the smaller increase of TPR rather than the CO change is responsible for the decreased MAP during acute orthostatic stress in hyperthermic humans. The contribution of skin vascular constriction to TPR changes during HUT is increased during heating and decreased during cooling.

[Pathological and immunohistochemical evaluation of keratoepithelioplasty in rats].

Keratoepithelioplasty was performed in the rat and epithelial rejection and epithelial regeneration were evaluated pathologically and immunohistochemically. A mechanical corneal epithelial defect was prepared in Lewis rats. Two lenticules, obtained from DA rats were grafted and postoperative observations were performed using a slit lamp microscope up to the 21st day. The same procedure was performed between Lewis rats only, as the control group (syngeneic model). Eyeballs were enucleated, and Hematoxylin-eosin (H-E) and Periodic Acid Shiff (PAS) staining were performed to allow observation by light microscopy. In addition, eyeballs were examined after staining by the Peroxidase-antiperoxidase (PAP) method using three kinds of monoclonal antibodies (W3/25, OX8 and OX6). Reepithelialization was completed by approximately postoperative day 6. Superficial keratitis occurred at postoperative day 10. Intense infiltration of helper T cells, cytotoxic T cells, Ia antigen positive cells, and neutrophils in the lenticules, regenerated epithelium, and beneath the regenerated epithelium was accompanied by rejection. On postoperative day 21, goblet cells were observed in the lenticules and its regenerated epithelial layer. There were no goblet cells in the lenticule and its regenerated epithelial layer of the control groups. Epithelial rejection began on the lenticular side, and rejected both the lenticules and the regenerated epithelium. The recovered corneal epithelium, migrated from the lenticules seemed to be replaced by regenerating conjunctival epithelium of the recipient.

Thermal stress modulates arterial pressure variability and arterial baroreflex response of heart rate during head-up tilt in humans.

To examine the effects of thermal stress on the blood pressure variability and the arterial baroreceptor-cardiac reflex during orthostatic stress, 11 male volunteers underwent whole body thermal stress using a cool or hot water-perfused suit during 5 min of 70 degrees head-up tilt (HUT). The spontaneous variability in arterial pressure was quantified by power spectrum analysis. The sensitivity of the arterial baroreceptor-cardiac reflex was calculated from the spontaneous changes in beat-to-beat arterial pressure and heart rate (fc). During supine rest the variability of arterial pressure decreased during cooling, while it remained unchanged during heating. The variability increased with HUT; it was greater (P < 0.05) with heating than with cooling. In the supine condition, the arterial baroreflex sensitivity of fc increased during cooling, while it did not change during heating. The sensitivities decreased (P < 0.05) with HUT during both thermal stresses; the decreased rate of sensitivity from the pre-tilt value was greater during heating [mean 63 (SEM 4)%] and smaller during cooling [mean 11 (SEM 24)%] than during normothermia [mean 47 (SEM 4)%] (both, P < 0.05). There were significant negative correlations between the sensitivities and the amplitude of the arterial pressure variability during normothermia and heating (P < 0.0001). The results suggest that the spontaneous baroreflex response of fc is a modulatory factor for the changes of arterial pressure variability brought about by thermal stress during orthostatic stress.

Inhibitory effects of prostanoids on the proliferation of transformed human epidermal cells in culture.

The cytotoxic action of various prostanoids was examined on a transformed human epidermal cell line (HSC-1), and methyl(5S,6S,7Z)-5,6-diacetoxy-7-((2S)-4-chloro-2-hydroxy-2-((2 Z+ ++)-2-octenyl)-5-oxo-3-cyclopentenylidene)heptanoate (YM-11), which is a punaglandin compound, was found to be most active. YM-11 exerted a dose-dependent inhibition of HSC-1 cell growth over 0.03 microM (0.01 micrograms/ml), and at 0.3 microM (0.1 micrograms/ml) its growth was completely inhibited. The IC50 value of YM-11 on HSC-1 cell growth was calculated as 0.15 microM (0.05 micrograms/ml). Methyl(E)-7-(5-chloro-2-hydroxy-2-octyl-5-oxo-3-cyclopentenylidene )heptanoate (YM-3), which is also a punaglandin derivative, showed remarkable cytotoxicity on HSC-1 cells with an IC50 of 0.24 microM (0.08 micrograms/ml). Concerning other cytotoxic prostaglandins (PGs), the IC50 values of delta 7-PGA1, delta 12-PGJ2 and PGD2 were 1.5 microM (0.5 micrograms/ml), 2.1 microM (0.75 micrograms/ml) and 5.7 microM (2 micrograms/ml), respectively. On the basis of the present data and previous in vitro and in vivo evidence, punaglandin derivatives may be useful antineoplastic agents for skin cancer.

Mechanisms of potentiation in sweating induced by long-term physical training.

To evaluate the mechanism of potentiation of sweating after long-term physical training, we compared sweating function in trained and untrained subjects using the frequency of sweat expulsion (fsw) as an indicator of central sudomotor activity. Nine trained male subjects (trained group) and eight untrained male subjects (untrained group) performed 30-min cycle exercise at 35% maximal oxygen uptake at 25 degrees C ambient temperature and 35% relative humidity. Oesophageal temperature (T(oes)), mean body temperature (Tb), chest sweating rate (msw,chest), forearm sweating rate (msw,forearm), and fsw were measured. The slopes of the msw,chest versus body temperature (T(oes) and Tb) and versus fsw relationships in the trained group were significantly greater than those in the untrained group (both, P < 0.05), while there was no difference between the groups in the slopes of the msw,forearm versus body temperature or versus fsw relationships. Neither the body temperature threshold for initiation of chest or forearm sweating nor the slope of the fsw-Tb relationship differed between groups. We concluded that, during light exercise at moderate ambient temperature, the msw,chest in the subjects who had undergone long-term physical training was greater than that in the untrained subjects while the msw,forearm was not changed. The greater msw,chest in the trained subjects was concluded to be due to an increase of sensitivity of peripheral mechanisms.

Characterization of sports by the VO2 dynamics of athletes in response to sinusoidal work load.

The purpose of this study was to evaluate the specificity of maximal oxygen uptake (VO2max) and the dynamic response of oxygen uptake (VO2) to sinusoidal work load in distance runners and in American-football players. Sinusoidal work load during ergometer cycling was carried from 30 W to 60% to VO2max (60% VO2max) for a 2 min period. VO2 was measured by the breath-by-breath method. The subjects were 10 distance runners (DRs), 10 American-football players (AFPs), and 11 untrained men (UTM). Mean VO2max was 64.4 mL kg-1 min-1 in the DRs, 53.1 mL kg-1 min-1 in the AFPs and 47.3 mL kg-1 min-1 in the UTM. The fundamental amplitudes of the VO2 response, normalized by dividing by steady state VO2 at 60% VO2max, were similar in the AFPs (20.3%) and the UTM (19.5%), and both were significantly less than in the DRs (25.5%). Phase shift to work load expressed in degrees was similar in the AFPs (87.7 degrees) and UTM (88.0 degrees), but significantly greater than in the DRs (80.4 degrees). HR dynamics in all three groups were similar to a dynamic VO2 response. These findings suggest that development of the dynamic VO2 response and higher VO2max is achieved in the DRs. They also suggest that despite the higher VO2max in the AFPs there is no improvement in the dynamic VO2 response. The results of the present study demonstrate that athletes participating in different sports have characteristic dynamic VO2 responses during cycling exercise.

A comparison of sweating responses during exercise and recovery in terms of sweating rate and body temperature.

Based on the hypothesis that the relation between sweating rate and body temperature should be different during exercise and rest after exercise, we compared the sweating response during exercise and recovery at a similar body temperature. Healthy male subjects performed submaximal exercise (Experiment 1) and maximal exercise (Experiment 2) in a room at 27 degrees C and 35% relative humidity. During exercise and recovery of 20 min after exercise, esophageal temperature (Tes), mean skin temperature, mean body temperature (Tb), chest sweating rate (msw), and the frequency of sweat expulsion (Fsw) were measured. In both experiments, msw and Fsw were clearly higher during exercise than recovery at a similar body temperature (Tes, Tb). msw was similar during exercise and recovery, or a little less during the former, at a similar Fsw. It is concluded that the sweating rate during exercise is greater than that during recovery at the same body temperature, due to greater central sudomotor activity during exercise. The difference between the two values is thought to be related to non-thermal factors and the rate of change in mean skin temperature.

[Response of respiratory exchange ratio (R) to sinusoidal work load in humans].

An examination was made of the response of respiratory exchange ratio (R), carbon dioxide output (VCO2) and oxygen uptake (VO2) to sinusoidal work load with periods (T) of 1-16 min in six healthy men to determine whether R response is sinusoidal. The influence of the ratio of the amplitude of VCO2 to that of VO2 and the phase lag between them on R response was also studied by computer simulation. The results and conclusions obtained are as follows: 1) With decrease in the period, the amplitudes of VO2 and VCO2 dropped exponentially, becoming least at T of 1 min (T = 1 min). In contrast, the amplitude of R was largest at T = 4 min and subsequently decreased progressively. 2) The peak amplitude of R at T = 4 min can be explained by the larger phase lag and relatively low of amplitude of VCO2 to VO2. 3) The smallest amplitude of R at T = 1 min was due not to the ratio of amplitude or phase lag, but to remarkably smaller amplitudes of VO2 and VCO2. 4) The phase lag of VO2 to sinusoidal work load was smaller than that of VCO2. Phase lag of R was considerably larger than that of VO2 or VCO2. 5) The response curve of VO2 and VCO2 is a sinusoidal curve with the same period as exercise. However, the response of R is not a real sinusoidal but a deformed biphasic curve with a high crest and low trough. The deformity is determined by the phase lag between VO2 and VCO2 response and also the ratio of amplitude of VCO2 to that of VO2.