The immunosuppressive mode of action of mizoribine.

Mizoribine (MIZ) suppressed the mitogen response and mixed lymphocyte reaction (MLR) significantly at doses of 100 micrograms/ml and 10 micrograms/ml in a dose-response analysis. The 50% inhibition dose (ID50) was between 10 micrograms/ml and 1.0 microgram/ml, both in the mitogen response and MLR. In a kinetic study of the MLR, the degree of suppression with MIZ at a given dosage was essentially the same as the degree of suppression observed in the dose-response analysis when MIZ was added to MLR cultures from day 0 to day 4. In addition, MLR was more susceptible to the suppressive activity of MIZ at 100 micrograms/ml when MIZ was added near the peak of lymphocyte proliferation. This experiment also showed that MLR suppression induced by MIZ at 10 micrograms/ml was reversible and MLR activity had completely recovered 6-8 hr after its removal. MIZ had no inhibitory action on MLR-derived cytotoxic cells or the effector phase of cell mediated lymphocytotoxicity. These results clearly demonstrate that MIZ suppresses lymphoproliferation, but has no effect on the recognition phase or effector phase of cytotoxic lymphocytes.

Cutaneous vascular responses to heat simulated at a high altitude of 5,600 m.

Six healthy young men were studied in a high-altitude chamber during a 60-min heat exposure at a simulated altitude of 5,600 m or 0.5 atmosphere absolute (ATA). The heat load was provided by increasing the chamber temperature to 38 degrees C at the rate of 1 degree C/min after a 60-min equilibrium period at thermoneutrality (28 degrees C). Our question was whether or not hypoxia causes differential changes in regional cutaneous circulation during heat exposure. Skin blood flow in the forearm (FBF) and the finger (FiBF), temperatures of the esophagus (Tes) and of the skin, and cardiac output (CO) were measured during the heat exposure at 0.5 ATA and at the sea level (1 ATA). During the equilibrium period, hypoxia increased the mean skin temperature and mean heat transfer coefficient, as well as FBF and forearm vascular conductance. The increased blood flow in the cutaneous circulation during the hypoxic exposure may reflect cutaneous vasodilation and vasoconstriction in other regions of the body, since there was no alteration in CO and total peripheral resistance. During heat exposure, Tes rose faster at high altitude than at sea level. However, at the end of the 60-min heat exposure, all thermal as well as circulatory parameters showed no difference between the two altitudes, except for the FiBF. An attenuated vasodilation in the fingers during heat exposure at high altitude suggests differential vascular controls and possible impairment of thermoregulation when additional stress, such as heat, is imposed. The data suggest that cutaneous blood flow during heat exposure is not uniform throughout the entire skin in a hypoxic environment.

Esophageal and tympanic temperature responses to core blood temperature changes during hyperthermia.

Esophageal, rectal, tympanic, and central blood temperature, i.e., pulmonary artery and aortic arch, were recorded in three patients during iatrogenic whole-body hyperthermia for the treatment of advanced malignant metastatic cancer. Aortic temperature closely followed changes in pulmonary arterial temperature, with an average delay time of 27 s. Esophageal temperature reflected quantitatively and more quickly (avg lag time, 80 s) the temperature changes in the pulmonary artery than tympanic membrane temperature. Tympanic temperature was consistently lower than the blood temperature of the heart during steady state. Therefore it is suggested that esophageal temperature is a preferable index of central blood temperature. Additionally, measurement of esophageal temperature can be made more easily and safely than tympanic membrane temperature.

Water temperature and intensity of exercise in maintenance of thermal equilibrium.

This study examined the thermal and metabolic responses of six men during exercise in water at critical temperature (Tcw, 31.2 +/- 0.5 degrees C), below Tcw (BTcw, 28.8 +/- 0.6 degrees C), at thermoneutrality (Ttn, 34 degrees C), and above Ttn (ATtn, 36 degrees C). At each water temperature (Tw) male volunteers wearing only swimming trunks completed four 1-h experiments while immersed up to the neck. During one experiment, subjects remained at rest (R), and the other three performed leg exercise (LE) at three different intensities (LE-1, 2 MET; LE-2, 3 MET; LE-3, 4 MET). In water warmer than Tcw, there was no difference in metabolic rate (M) during R. The M for each work load was independent of Tw. Esophageal temperature (Tes) remained unchanged during R in water of ATtn (36 degrees C). However, Tes significantly (P less than 0.05) declined over 1 h during R at Ttn (delta Tes = -0.39 degrees C), Tcw (delta Tes = -0.54 degrees C), and BTcw (delta Tes = -0.61 degrees C). All levels of underwater exercise elevated Tes and M compared with R at all Tw. In water colder than Tcw, the ratio of heat loss from limbs compared with the trunk became greater as LE intensity increased, indicating a preferential increase in heat loss from the limbs in cool water. Tissue insulation (Itissue) was lower during LE than at R and was inversely proportional to the increase in LE intensity. A linearly inverse relationship was established between Tw and M in maintaining thermal equilibrium.(ABSTRACT TRUNCATED AT 250 WORDS)

Critical water temperature during water immersion at various atmospheric pressures.

The present work was undertaken to determine the effect of atmospheric pressure [ranging from a high altitude of 4,300 m above sea level or 0.6 atmospheres absolute (ATA) to depths of 10 m deep or 2 ATA] on the critical water temperature (Tcw), defined as the lowest water temperature a subject can tolerate at rest for 2 h without shivering, of the unprotected subject during water immersion. Nine healthy males wearing only shorts were subjected to immersion to the neck in water at 0.6, 1, and 2 ATA while resting for 2 h. Continuous measurements included esophageal (Tes) and skin (Tsk) temperatures, direct heat loss from the skin (Htissue), and insulation of the tissue (Itissue). The Tcw was significantly higher at 0.6 ATA than 1 and 2 ATA: however, Tcw at 1 ATA was identical to that at 2 ATA. The metabolic heat production remained unchanged among the pressures. During the 2-h immersion in Tcw, Tes was identical among all atmospheric pressures: however, Tsk was significantly higher (P less than 0.05) at 0.6 ATA and was identical between 1 and 2 ATA. The overall mean Itissue was near maximal during immersion in Tcw in each pressure, and no difference was detected among the pressures. However, Itissue at the acral extremities (arm, hand, and foot) decreased significantly at 0.6 ATA, and subsequently heat loss from these parts was increased, which elevated an extremity-to-trunk heat loss ratio to 1.4 at 0.6 ATA from 1.1 at 1 and 2 ATA.(ABSTRACT TRUNCATED AT 250 WORDS)

Physiological responses of aged men to head-up tilt during heat exposure.

The effects of age on cardiovascular and thermoregulatory responses to passive tilting were investigated using six old (61-73 yr) and 10 young (21-39 yr) unacclimatized men. Experiments were carried out at 26 degrees C and after exposure to 40 degrees C and 40% relative humidity for 105 min. Continuous measurements of esophageal (Tes) and mean skin (Tsk) temperatures and heart rate (HR) were recorded. Other variables studied included blood pressure (BP), forearm blood flow (FBF), and cardiac output (CO), which were measured at 4- to 5-min intervals. Measurements were made in the supine position and after 70 degrees head-up tilt for 15 min. Cardioacceleration during the tilt test was greater in the young men than in the old. Other cardiovascular responses of the old men to orthostatism were qualitatively similar to that of the young except for FBF and forearm vascular conductance. The old men did not show significant changes in FBF during tilting, suggesting a deterioration in the sympathetic nervous reflex in the aged. However, other circulatory adaptations seemed to overcome this deficiency resulting in orthostatic tolerance similar to that of the young. During head-up tilt at 26 and 40 degrees C, Tes of both age groups increased. This may reflect a decrease in conductive heat transfer presumably due to diminished blood flow to the periphery.

Energetics of wet-suit diving in Japanese male breath-hold divers.

The present study was undertaken to investigate energy balance in professional male breath-hold divers in Tsushima Island, Japan. In 4 divers, rectal (Tre) and mean skin (Tsk) temperatures and rate of O2 consumption (VO2) were measured during diving work in summer (27 degrees C water) and winter (14 degrees C water). Thermal insulation and energy costs of diving work were estimated. In summer, comparisons were made of subjects clad either in wet suits (protected) or in swimming trunks (unprotected), and in winter, they wore wet suits. The average Tre in unprotected divers decreased to 36.4 +/- 0.2 degrees C at the end of 1-h diving work, but in protected divers it decreased to 37.2 +/- 0.3 degrees C in 2 h in summer and to 36.9 +/- 0.1 degree C in 1.5 h in winter. The average Tsk of unprotected divers decreased to 28.0 +/- 0.6 degrees C in summer and that of protected divers decreased to 32.9 +/- 0.5 degrees C in summer and 28.0 +/- 0.3 degrees C in winter. Average VO2 increased 190% (from 370 ml/min before diving to 1,070 ml/min) in unprotected divers in summer, but in protected divers it rose 120% (from 360 to 780 ml/min) in summer and 110% (from 330 to 690 ml/min) in winter. Overall thermal insulation (tissue and wet suit) calculated for protected divers was 0.065 +/- 0.006 degree C X kcal-1 X m-2 X h-1 in summer and 0.135 +/- 0.019 degree C X kcal-1 X m-2 X h-1 in winter.(ABSTRACT TRUNCATED AT 250 WORDS)

Independence of brain and tympanic temperatures in an unanesthetized human.

Temperature within the brain and the esophagus and at the tympanum were obtained in a 12-yr-old male in a series of experiments that began 8 days after surgery for implantation of a drainage catheter. Fanning the face did reduce tympanic temperature but not temperature in the brain; brain temperatures followed esophageal temperatures. In long-term monitoring, temperature in the lateral ventricle was 0.5 degree C above esophageal temperature and 0.2 degree C below that in white matter 1 cm above, with the offsets fixed throughout the overnight cycle. All temperatures went through similar excursions when the face was excluded from fanning applied to the body. These observations highlight the fact that in humans the defense against hyperthermia takes advantage of cooling distributed over the entire skin surface.

Changes in insulation of body tissue and wet suits during underwater exercise at various atmospheric pressures.

To clarify the independent changes of insulations of body tissues (Itissue) and wet suit (Isuit) in the wet-suited subject during underwater exercise, overall heat flow from the skin (Htissue) and wet suit (Hsuit) and esophageal (Tes), skin (Tsk), and wet suit temperatures were measured at 1, 2, and 2.5 atmospheres absolute (ATA) at critical water temperature (Tcw). The average Tcw in nine wet-suited men (23-38 yr) was 22.3 +/- 0.2, 26.3 +/- 0.2, and 28.0 +/- 0.4 degrees C (SE) at 1, 2, and 2.5 ATA, respectively. At Tcw of each pressure male volunteers wearing 5-mm neoprene wet suits completed three 2-h experiments while immersed up to the neck. During one experiment the subjects remained at rest, and in the other two they exercised on an underwater ergometer at two different intensities (2 and 3 met). Tes significantly declined (P less than 0.05) over 2 h from 37.1 to 36.5 degrees C during rest in each pressure. The 2-met exercise prevented Tes from falling in all pressures, and the 3-met exercise elevated Tes by 0.2-0.3 degrees C. There was no exercise-dependent difference in Isuit, but a pressure-dependent difference was remarkable. The Itissue at rest was identical for all pressures; however, it progressively decreased as a function of exercise intensity. It is concluded that overall Itissue is entirely determined by work intensity at Tcw, but not by atmospheric pressure. On the contrary, Isuit at Tcw is solely dependent on the pressure, but not on the work intensity.

Cardiorenal-endocrine responses to head-out immersion at night.

Cardiorenal-endocrine responses to 3-h head-out immersion (HOI) (water temperature = 34.5 +/- 0.5 degrees C) were studied during day (0900-1400 h) and night (2300-0400 h) in six hydropenic male human subjects. Although HOI induced a reversible increase in urine flow in all subjects, the response was faster and greater in magnitude during the day compared with night (P less than 0.05). Na excretion and osmolal clearance (Cosm) also followed the identical response pattern as urine flow, and in fact, the HOI-induced diuresis was entirely accounted for by the increased Cosm. Endogenous creatinine clearance was not different between the day and the night and remained unchanged during HOI. Both plasma renin activity and aldosterone concentration and urinary aldosterone excretion were nearly twofold greater during the day compared with night before HOI but decreased to the same level during HOI in both daytime and the nighttime series (P less than 0.05). There was no correlation between the Na excretion rate and renin-aldosterone levels either before or during HOI. Plasma antidiuretic hormone (ADH) level was comparable between day and night before HOI and decreased to a similar level during HOI in both daytime and nighttime series (P less than 0.05 for nighttime HOI). Cardiac output increased from 3.3 1/min before HOI to 5-6 1/min during HOI without showing any significant circadian difference. Hematocrit, hemoglobin, and plasma concentrations remained unchanged under all conditions. It is concluded that the renal response to HOI is subject to nocturnal inhibition, which cannot be attributed to circadian differences in the degree of HOI-induced central blood pooling, renin-aldosterone, or ADH responses.

Effect of dehydration on thirst and drinking during immersion in men.

The mechanism for reduced voluntary water intake during water immersion was studied in eight men (19-25 yr of age) immersed to the neck while sitting for 3 h at 34.5 degrees C or in air at 28 degrees C when euhydrated (Eu-H2O and Eu-air, respectively) and hypohydrated (Hypo-H2O and Hypo-air) by 3.6% body weight loss. Thirst sensations (degree of thirst, mouth dryness and taste, drinking desirability, and stomach fullness) were similar at the beginning of Hypo-air and Hypo-H2O test periods. Initial drinking of tap water (15 degrees C) was 216 +/- 30 ml/7 min (P less than 0.05) with Hypo-air, decreased to 108 +/- 28 ml/7 min (P less than 0.05) with Hypo-H2O, and was 10-50 ml/10-30 min thereafter. Intake was less than 10 ml/10-30 min in Eu-air, and there was no drinking in Eu-H2O. Within the first 10 min of immersion, compared with Hypo-air findings, the significant reduction in drinking in the Hypo-H2O experiment was associated with unchanged plasma Na+, plasma osmolality, heart rates, and mean arterial pressures; the different responses were increased cardiac output, plasma volume, and atrial natriuretic peptides and decreased plasma renin activity and arginine vasopressin. Thus the extracellular pathway, as opposed to the osmotic pathway, appears to be the major mechanism for immersion-induced suppression of drinking.

Effect of water temperature on diuresis-natriuresis: AVP, ANP, and urodilatin during immersion in men.

Effects of water temperature on diuresis, natriuresis, and associated endocrine responses during head-out immersion were studied in eight men (23.4 +/- 0.3 yr) during four 5-h experimental conditions: air control at 28 degrees C and immersion at 34.5 degrees C [thermoneutral (Tnt)], 36 degrees C [above Tnt (aTnt)], and 32 degrees C [below Tnt (bTnt)]. Esophageal temperature decreased by approximately 0.4 degrees C in bTnt and increased by approximately 0.5 degrees C in aTnt. Cardiac output increased by approximately 80% in aTnt and approximately 40% in bTnt while thoracic impedance, an index of central blood pooling, decreased by 7.5 omega in bTnt (NS vs. Tnt) and 8.8 omega in aTnt (P < 0.05 vs. Tnt and bTnt). Total peripheral resistance decreased at all temperatures (50% in aTnt, 20% in bTnt). Urine flow and Na+ excretion increased by sixfold in bTnt and Tnt but by only threefold in aTnt. Creatinine clearance was unchanged while osmolal clearance (but not free water clearance) increased two-fold with all immersions. Plasma atrial natriuretic peptide (ANP), urinary urodilatin, and urinary guanosine 3',5'-cyclic monophosphate increased while plasma renin activity, aldosterone, and arginine vasopressin (AVP) decreased similarly at all temperatures. bTnt did not potentiate diuresis by selective attenuation of AVP. The overall natriuretic response exhibited a higher correlation with urodilatin (r = 0.45, P < 0.001) than with ANP (r = 0.26, P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Remarkable effect of endocrine therapy on brain metastasis from prostatic carcinoma.

The brain metastasis of prostatic carcinoma is rare and is distinguished by its poor prognosis in cases which are not surgically resectable. Herein we report on a case of brain metastasis of prostatic carcinoma which showed a dramatic regression through bilateral orchiectomy and doses of diethylstilbestrol diphosphate and estramustine phosphate. Neurologic and psychiatric symptoms diminished within three months, and the patient is alive and well without any subjective symptoms after twelve months.

Predictability of renal allograft prognosis during rejection crisis by ultrasonic Doppler flow technique.

Using the ultrasonic Doppler technique, renal blood flow was measured in 67 patients who underwent living related renal transplantation from January, 1976 to December, 1979. In 58 of 67 cases, 81 acute and 9 chronic rejection episodes occurred. In the initial stage of acute rejection, there are no particular changes in the pattern of systolic blood flow and by contrast marked changes of diastolic flow. The disappearance of the diastolic phase is indicative of an advanced stage of rejection, the reappearance indicative of recovery from rejection, and persistent loss accompanied by changes of systolic flow indicative of an unfavorable prognosis of rejection. In chronic rejection, there are rapid changes of neither systolic nor diastolic flow though the acceleration time in the systolic phase lengthens gradually. The ultrasonic Doppler flow technique for blood flowmetry of a transplanted kidney is a useful means of knowing the prognosis of rejection and provides an index for corticosteroid bolus therapy.

Hypovolemic intolerance to lower body negative pressure in female runners.

PURPOSE: An attenuated baroreflex response and orthostatic intolerance have been reported in endurance-trained male athletes; however, it is still unknown whether this occurs also in females. The purpose of the present study was to examine whether endurance exercise-trained women had a predisposition to orthostatic compromise, and if so, what causative factor(s) may induce orthostatic intolerance. METHODS: We studied cardiovascular and hormonal responses to graded lower body negative pressure (LBNP) (0 to -60 mm Hg) in 26 middle-distance female runners (18.6 +/- 0.1 yr) as the exercise-trained (ET) subjects and 23 age-matched untrained (UT) control subjects. On the basis of the occurrence of syncope episodes during LBNP, ET and UT subjects were further allocated to two groups; ET with presyncope (ET+syncope) and without presyncope (ET-syncope) and UT with presyncope (UT+syncope) and without presyncope (UT-syncope). RESULTS: Occurrence of presyncope episodes during LBNP was higher in ET (65.4%, P < 0.05) than that for UT (34.8%). Leg compliance was higher (P < 0.05) in ET than in UT. LBNP reduced stroke volume (SV) more (P < 0.05), increased heart rate (HR) higher (P < 0.05), and increased forearm vascular resistance (FVR) more in ET+syncope as compared with the other groups. Response of vasoactive hormones to LBNP was higher in ET+syncope (P < 0.05) than that of the other groups except for norepinephrine (NE); high in both ET+syncope and UT+syncope. The relationship between SV and NE, an index of sympathetic neuronal response, had no training-related changes during LBNP. CONCLUSION: We conclude that exercise-trained females have a high incidence of orthostatic intolerance during LBNP, with a greater reduction of SV independent of changes in baroreflex and neurohumoral function. A lower incidence of LBNP intolerance in UT may be accounted for by a lower reduction of SV during LBNP. An increase in leg compliance in the exercise-trained females may play an important role in inducing pronounced reduction of SV and hence the intolerance to LBNP.

Use of the hematocrit for estimating changes in plasma and red cell volumes in the rat.

Methods to quantitate changes in plasma volume based on changes in the hematocrit, which have been widely used in human subjects and large animals, were tested in small animals, such as rats. A modified equation was derived for application of the hematocrit method to small animals.

Changes of osmotic fragility of red blood cells due to repletion or depletion of cholesterol in human and rat red cells in vitro.

The relation of membrane lipids and osmotic fragility of red cells of human and rat were studied in vitro by repletion and depletion of cell cholesterol. A decrease in the red cell cholesterol corresponded to an increase in osmotic fragility. Conversely, a repletion of red cell cholesterol decreased the osmotic fragility, but the procedure did not significantly change the phospholipid contents of red cells. Accordingly, osmotic fragility of the red cells correlated highly with the cholesterol content of the cell membrane (r = -0.922, p < 0.001) and with the molar ratio of cholesterol to phospholipid in the red cells (r = -0.887, p < 0.001). Red cells incubated with plasma had decreased membrane cholesterol and increased osmotic fragility, but the change was prevented by the inactivation of lecithin cholesterol acyltransferase (LCAT) in the plasma. The above results confirm that membrane cholesterol stabilizes human and rat red cells in vitro as well as in vivo, and the content of red cell cholesterol is regulated by the exchange of plasma free cholesterol in vitro. LCAT activity in the plasma is an influential factor in controlling the cholesterol content of red cells.

Role of lipids in stabilizing red cells in rats.

The causes of osmotic fragility of red cells were studied in rats. Osmotic fragility of red cells in vivo changed after removal of the spleen or induction of experimental splenomegaly by repeated intraperitoneal injections of methyl cellulose (MC): in splenectomized rats, the red cells showed reduced osmotic fragility and an increase in diameter as well as in contents of phospholipids and cholesterol. Conversely in rats with splenomegaly, the cells showed increased osmotic fragility and a decrease in diameter and in lipid contents. Results confirmed that increase in the phospholipid content resulted in decreased fragility and that increase in the cholesterol content brought about decreased spherocytosis. The activity of lecithin cholesterol acyltransferase (LCAT) in the plasma varied inversely with the cholesterol content of the red cells. The above results show that the fragility of red cells is influenced by their lipid content and shape, and that LCAT activity in the plasma influences the membrane content of cholesterol and spherocytosis.

Influence of dietary protein on the properties of the red cell membrane in intact and splenectomized rats.

The possibility that there is some common factor in protein deprivation and splenectomy affecting the properties of red cells was examined by measuring the lipid contents of the plasma and red cells, the surgace area and spherical index of red cells, and the lecithin cholesterol acyltransferase (LCAT) activity of the plasma in intact and splenectomized rats on diets with various levels of protein. Results showed that splenectomy markedly reduced the osmotic fragility and increased the lipid content and surface area of the red cells of all dietary groups, and that decrease in the protein content of the diet gradually reduced the osmotic fragility and increased the lipid content of the red cells. A significant linear correlation was observed between osmotic fragility and the lipid content of red cells. LCAT did not influence the cholesterol level in red cell membranes because its activity in the plasma was not affected by either splenectomy or the protein content of the diet. A protein-free diet induced normaocytic anemia, but increased the lipid content and reduced the osmotic fragility of red cells. Therefore, the effect of cholesterol in increasing the surface area of red cells was not proportional in the red cells of rats on a protein-free diet. The present studies suggest that the mechanism of accumulation of cholesterol in red cells is different in protein deprivation and splenectomy. That is, in protein deprivation, increase in red cell cholesterol may result from decreased esterification of cholesterol in the plasma because of the low concentration of the substrate of LCAT, high density lipoprotein; and in splenectomized rats, the cholesterol level of the cells may not be reduced because the red cells are not exposed to the red pulp of the spleen where the pH is very low. These possibilities are supported by the finding that the osmotic fragility of the red cells decreased most and the lipid content of the cells increased most in splenectomized rats on a protein-free diet.

The influence of increased hepatic sequestration after splenectomy on the survival and osmotic fragility of red cells in rats, with reference to protein levels in diets.

The sequestration of erythrocytes in rats was studied using an isologous 51Cr-labeled population of either normal or N-ethyl-maleimide (NEM) treated red cells. The spleen sequestered the damaged red cells selectively, while the liver compensated and overshot the sequestration for spleen after splenectomy. The sequestering response in liver increased gradually reaching a maximum level around 8 weeks after splenectomy and then declining toward the control level. These compensatory responses in liver were not observed in rats fed a low-protein diet, which indicated that the proliferative response imposed on liver by an extra work after splenectomy was not stimulated in the rats fed a low-protein diet. Splenectomy prolonged erythrocyte survival and reduced the osmotic fragility of normal red cells, but the compensatory increase in sequestration of damaged red cells in liver did not alter the survival and osmotic fragility of normal red cells of the rat. This fact indicates that the increased sequestration of reticuloendothelial cells in liver is basically reparative, and it is impossible to compensate for the absence of the spleen because of an inability to duplicate certain anatomic features peculiary to the spleen.