Differential effect of Coriolus versicolor (Yunzhi) extract on cytokine production by murine lymphocytes in vitro.

Being one of the commonly used Chinese medicinal herbs, Coriolus versicolor (CV), also named as Yunzhi, was known to possess both anti-tumor and immunopotentiating activities. The present study aimed to investigate the in vitro immunomodulatory effect of a standardized ethanol-water extract prepared from CV on the proliferation of murine splenic lymphocytes using the MTT assay, and the production of six T helper (Th)-related cytokines using the enzyme-linked immunosorbent assay (ELISA) technique. The results showed that the CV extract significantly augmented the proliferation of murine splenic lymphocytes in a time- and dose-dependent manner, maximally by 2.4-fold. Moreover, the production of two Th1-related cytokines, including interleukin (IL)-2 and IL-12, in culture supernatants from the CV extract-activated lymphocytes was prominently upregulated at 48 and 72 h. Positive correlations were found between the levels of these two cytokines and the MTT-based proliferative response. In contrast, the production of two other Th1-related cytokines, including interferon (IFN)-gamma and IL-18, was significantly augmented only at 24 h, but not at 48 and 72 h. On the other hand, the levels of two Th2-related cytokines such as IL-4 and IL-6 were undetectable in the culture supernatants of lymphocytes treated with the CV extract. The CV extract was suggested to be a lymphocyte mitogen by differentially enhancing the production of Th1-related cytokines.

Cytotoxic activities of Coriolus versicolor (Yunzhi) extract on human leukemia and lymphoma cells by induction of apoptosis.

Coriolus versicolor (CV), also known as Yunzhi, is one of the commonly used Chinese medicinal herbs. Although recent studies have demonstrated its antitumour activities on cancer cells in vitro and in vivo, the exact mechanism is not fully elucidated. Hence, the objective of this study was to examine the in vitro cytotoxic activities of a standardized aqueous ethanol extract prepared from Coriolus versicolor on a B-cell lymphoma (Raji) and two human promyelocytic leukemia (HL-60, NB-4) cell lines using a MTT cytotoxicity assay, and to test whether the mechanism involves induction of apoptosis. Cell death ELISA was employed to quantify the nucleosome production resulting from nuclear DNA fragmentation during apoptosis. The present results demonstrated that CV extract at 50 to 800 microg/ml dose-dependently suppressed the proliferation of Raji, NB-4, and HL-60 cells by more than 90% (p < 0.01), with ascending order of IC50 values: HL-60 (147.3 +/- 15.2 microg/ml), Raji (253.8 +/- 60.7 microg/ml) and NB-4 (269.3 +/- 12.4 microg/ml). The extract however did not exert any significant cytotoxic effect on normal liver cell line WRL (IC50 > 800 microg/ml) when compared with a chemotherapeutic anticancer drug, mitomycin C (MMC), confirming the tumour-selective cytotoxicity. Nucleosome productions in HL-60, NB-4 and Raji cells were significantly increased by 3.6-, 3.6- and 5.6-fold respectively upon the treatment of CV extract, while no significant nucleosome production was detected in extract-treated WRL cells. The CV extract was found to selectively and dose-dependently inhibit the proliferation of lymphoma and leukemic cells possibly via an apoptosis-dependent pathway.

Adrenal steroid secretion in girls with pseudoprecocious puberty due to autonomous ovarian cysts.

To evaluate the role of adrenal steroids in pseudoprecocious puberty due to large ovarian follicular cysts, we studied the serum 17-hydroxyprogesterone response to a combination of dexamethasone suppression followed by iv ACTH administration in two girls and compared the results to those in girls with premature thelarche, normal prepubertal girls, and a girl with true precocious puberty. Although basal serum 17-hydroxyprogesterone levels were normal in all subjects, there was incomplete suppression of 17-hydroxyprogesterone with dexamethasone in the two girls with pseudoprecocious puberty and large ovarian cysts. The 17-hydroxyprogesterone response to ACTH was much greater in these girls (360 and 540 ng/dl) than in the girls with other types of precocious puberty (mean +/- SD, 71 +/- 15 ng/dl) or in normal prepubertal girls (80 +/- 20 ng/dl). The girls with large ovarian cysts had decreased gonadotropin responses to GnRH, which were reversed subsequent to removal of the cyst. Removal of the ovarian cysts also restored the dexamethasone suppressibility of serum 17-hydroxyprogesterone and abolished the progression of pubertal development. However, 17-hydroxyprogesterone responses to ACTH were still elevated (160 and 350 ng/dl). Preoperatively, both girls had increased levels of dehydroepiandrosterone sulfate, 16-hydroxydehydroepiandrosterone sulfate, and another unidentified steroid sulfate. These steroid sulfates were also found in the cyst fluid from the one patient from whom the fluid was obtained. These results suggest that steroid production by the adrenal gland may stimulate the development of small ovarian cysts (which may be present in normal prepubertal girls) into large ovarian cysts capable of causing gonadotropin-independent precocious puberty.

Warfarin versus dipyridamole-aspirin and pentoxifylline-aspirin for the prevention of prosthetic heart valve thromboembolism: a prospective randomized clinical trial.

In a prospective, randomized, parallel study, two regimens of platelet-suppressant therapy (PST)--dipyridamole-aspirin and pentoxifylline-aspirin--were compared with standard oral anticoagulation with warfarin in the prevention of prosthetic heart valve thromboembolism. In the entire group of 254 patients followed for 395.6 patient-years, the thromboembolic rate was significantly less in the warfarin group (warfarin vs dipyridamole-aspirin, p less than .005; warfarin vs pentoxifylline-aspirin, p less than .05). Subgroup analysis disclosed that, in patients with isolated mitral valve replacement, warfarin was superior to both of the PSTs with respect to the prevention of thromboembolism (warfarin vs dipyridamole-aspirin, p = .005; warfarin vs pentoxifylline-aspirin, p less than .05). Furthermore, a significant number of our patients could not tolerate the antiplatelet agents. However, in the rare situation in which repeated significant bleeding occurs despite careful adjustment of the dosage of warfarin, PST may be an acceptable alternate method of thromboembolism prophylaxis.

The human sympathochromaffin system.

Hypoglycemia stimulates adrenomedullary epinephrine secretion; standing stimulates sympathetic neural norepinephrine release. In five bilaterally adrenalectomized persons plasma epinephrine, measured with a sensitive single-isotope derivative assay, rose from 15 +/- 2 to 35 +/- 7 pg/ml (P less than 0.02) during hypoglycemia but did not increase during standing. In contrast, plasma norepinephrine rose during standing but not during hypoglycemia. Thus, in humans 1) extra-adrenal epinephrine secretion is regulated and derived from innervated cells other than sympathetic postganglionic neurons; 2) because the plasma levels of epinephrine in adrenalectomized individuals even in response to the potent stimulus of hypoglycemia are below physiological thresholds, any biological actions of extra-adrenal epinephrine in adults must be paracrine rather than endocrine in nature; 3) hypoglycemia does not appear to stimulate the sympathetic nervous system. In view of these findings, we propose that extra-CNS catecholamine-producing tissues be termed the sympathochromaffin system consisting of two components: 1) the sympathetic nervous system that releases the neurotransmitter norepinephrine from its postganglionic neurons, and 2) the chromaffin tissues, including the adrenal medullae, that contain cells that secrete epinephrine, norepinephrine, or dopamine. The plasma epinephrine concentration is a valid measure of its chromaffin tissue (predominantly adrenomedullary) secretion, whereas the plasma norepinephrine concentration is an index of sympathetic neuronal activity under some but not all conditions.

Roles of glucagon and epinephrine in hypoglycemic and nonhypoglycemic glucose counterregulation in humans.

Studies of two models of human glucose counterregulation, glucose recovery from insulin-induced hypoglycemia and the transition from exogenous glucose delivery to endogenous glucose production late after glucose ingestion, indicate that the principles of rapid hypoglycemic and nonhypoglycemic glucose counterregulation in these models are the same. 1) Neither is solely explicable on the basis of dissipation of insulin; 2) glucagon plays a primary counterregulatory role in both; 3) epinephrine compensates largely for deficient glucagon secretion in both; and 4) counterregulation fails to occur only in the absence of both glucagon and epinephrine in both. Thus, prevention as well as correction of hypoglycemia is effectively accomplished by redundant glucose counterregulatory systems, primarily glucagon and secondarily epinephrine, coupled with dissipation of insulin in humans. Other hormones, neural mechanisms, or autoregulation may be involved but need not be invoked and are not sufficiently potent to prevent or correct hypoglycemia when both of the key glucose counterregulatory hormones, glucagon and epinephrine, are deficient. Although confirmed in that they predict the impact of disease-related deficiencies of glucagon, epinephrine, or both, the extent to which these principles can be generalized to additional models of glucose counterregulation remains to be established. However, they provide a basis for plausible, testable hypotheses concerning the physiology and pathophysiology of glucose counterregulation.

Oral propranolol and metoprolol both impair glucose recovery from insulin-induced hypoglycemia in insulin-dependent diabetes mellitus.

To the extent that they have deficient glucagon secretory responses to plasma glucose decrements, as they commonly do, patients with insulin-dependent diabetes mellitus (IDDM) are dependent on epinephrine-mediated beta-adrenergic mechanisms to promote recovery from hypoglycemia. Thus, they are at increased risk for prolonged hypoglycemia if treated with a nonselective beta-adrenergic antagonist such as propranolol. If the hyperglycemic actions of epinephrine are mediated through beta 2-adrenergic mechanisms, therapeutic efficacy (e.g., for hypertension or ischemic heart disease) could be accomplished without increased risk of hypoglycemia by selective beta 1-adrenergic blockade in such patients. However, oral administration of the relatively selective beta 1-adrenergic antagonist metoprolol (100 mg) and of the nonselective beta-adrenergic antagonist propranolol (80 mg) both impaired recovery from insulin-induced hypoglycemia in patients with IDDM. Thus, at a dose of 100 mg, oral metoprolol is not safer than oral propranolol with respect to recovery from hypoglycemia in patients with IDDM.

Pregnancy and Takayasu's arteritis.

Thirteen patients with Takayasu's arteritis had 30 pregnancies between 1970 and 1982. The 11 pregnancies occurring before the disease became clinically evident were uneventful. Eleven patients had 19 pregnancies after manifestation of the disease. Four ended in abortion, four in cesarean section, and 11 in uneventful vaginal delivery at term. There was no major obstetric problem apart from hypertension, and there was no maternal death directly related to the pregnancy per se. All 15 babies were born without asphyxia and congenital abnormality. The nine with some evidence of intrauterine growth retardation could be predicted by a prognostic score taking into account the timing of therapy, the severity of the hypertension, and the extent of arterial involvement.

Terbutaline infusion in cardiogenic shock: acute hemodynamic effects and clinical response.

The effect of terbutaline infusion was studied in six patients with cardiogenic shock due to acute myocardial infarction. Terbutaline was initiated at 3 micrograms/kg/min, and the subsequent infusion rate was adjusted according to heart rate and blood pressure. At 3 hours after infusion arterial pressure increased from 62 +/- 13 mm Hg (mean +/- S.D.) to 89 +/- 13 mm Hg (P less than 0.001), cardiac index increased from 1.38 +/- 0.29 liter/min/m2 to 2.68 +/- 0.47 liter/min/m2 (P less than 0.001), and heart rate increased from 92 +/- 32 beats/min to 112 +/- 29 beats/min (P less than 0.005). Pulmonary artery wedge pressure fell from 24 +/- 7 mm Hg to 17 +/- 3 mm Hg (P less than 0.01), right atrial pressure fell from 12 +/- 4 mm Hg to 6 +/- 3 mm Hg (P less than 0.005), and systemic vascular resistance fell from 1880 +/- 641 dyn-sec/cm5 to 1515 +/- 418 dyn-sec/cm5 (P less than 0.05). In addition, urine flow increased from 4 +/- 6 ml/hr to 314 +/- 237 ml/hr (P less than 0.05), and subjective improvement was noted in all subjects. Undesirable effects observed were hypokalemia (all subjects), supraventricular tachycardia (one subject), and ventricular ectopic beats (three subjects), which responded to potassium replacement and other treatments. All patients required prolonged maintenance infusion to maintain adequate hemodynamic and clinical response. Four patients were weaned off from maintenance therapy after a mean duration of 4.8 days and eventually were discharged from the hospital.(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial metabolic effects of intravenous terbutaline in patients with severe heart failure due to coronary artery disease.

Intravenous terbutaline, 0.3 mg/kg/min for 30 minutes followed by 0.15 mg/min for 60 minutes, was studied in nine patients with severe heart failure due to documented coronary artery disease. Hemodynamic and myocardial metabolic effects were measured during terbutaline infusion. Cardiac index and stroke index increased, whereas mean pulmonary artery wedge pressure and pulmonary vascular resistance decreased significantly. No significant alterations in aortic oxygen content, coronary sinus oxygen content, myocardial oxygen extraction, and myocardial lactate extraction were observed during terbutaline infusion. No patient developed angina or electrocardiographic changes suggestive of ischemia. These results indicate that intravenous terbutaline infusion, at the dosage employed, produces beneficial hemodynamic effects without a deterioration of myocardial metabolism in patients with heart failure due to coronary artery disease.

Neuroendocrine responses to glucose ingestion in man. Specificity, temporal relationships, and quantitative aspects.

The mechanisms of postprandial glucose counterregulation-those that blunt late decrements in plasma glucose, prevent hypoglycemia, and restore euglycemia-have not been fully defined. To begin to clarify these mechanisms, we measured neuroendocrine and metabolic responses to the ingestion of glucose (75 g), xylose (62.5 g), mannitol (20 g), and water in ten normal human subjects to determine for each response the magnitude, temporal relationships, and specificity for glucose ingestion. Measurements were made at 10-min intervals over 5 h. By multivariate analysis of variance, the plasma glucose (P < 0.0001), insulin (P < 0.0001), glucagon (P < 0.03), epinephrine (P < 0.0004), and growth hormone (P < 0.01) curves, as well as the blood lactate (P < 0.0001), glycerol (P < 0.001), and beta-hydroxybutyrate (P < 0.0001) curves following glucose ingestion differed significantly from those following water ingestion. However, the growth hormone curves did not differ after correction for differences at base line. In contrast, the plasma norepinephrine (P < 0.31) and cortisol (P < 0.24) curves were similar after ingestion of all four test solutions, although early and sustained increments in norepinephrine occurred after all four test solutions. Thus, among the potentially important glucose regulatory factors, only transient increments in insulin, transient decrements in glucagon, and late increments in epinephrine are specific for glucose ingestion. They do not follow ingestion of water, xylose, or mannitol. Following glucose ingestion, plasma glucose rose to peak levels of 156+/-6 mg/dl at 46+/-4 min, returned to base line at 177+/-4 min, reached nadirs of 63+/-3 mg/dl at 232+/-12 min, and rose to levels comparable to base line at 305 min, which was the final sampling point. Plasma insulin rose to peak levels of 150+/-17 muU/ml (P < 0.001) at 67+/-8 min. At the time glucose returned to base line, insulin levels (49+/-12 muU/ml) remained fourfold higher than base line (P < 0.01); thereafter they declined but never fell below base line. Plasma glucagon decreased from 95+/-14 pg/ml to nadirs of 67+/-11 pg/ml (P < 0.001) at 84+/-9 min and then rose progressively to peak levels of 114+/-17 pg/ml (P < 0.001 vs. nadirs) at 265+/-12 min. Plasma epinephrine, which was 18+/-4 pg/ml at base line, did not change initially and then rose to peak levels of 119+/-20 pg/ml (P < 0.001) at 271+/-13 min. These data indicate that the glucose counterregulatory process late after glucose ingestion is not solely due to the dissipation of insulin and that sympathetic neural norepinephrine, growth hormone, and cortisol do not play critical roles. They are consistent with, but do not establish, physiologic roles for the counterregulatory hormones-glucagon, epinephrine, or both-in that process.

Mechanisms of postprandial glucose counterregulation in man. Physiologic roles of glucagon and epinephrine vis-a-vis insulin in the prevention of hypoglycemia late after glucose ingestion.

The transition from exogenous glucose delivery to endogenous glucose production late after glucose ingestion is not solely attributable to dissipation of insulin and, therefore, must also involve factors that actively raise the plasma glucose concentration--glucose counterregulatory factors. We have shown that the secretion of two of these, glucagon and epinephrine, is specific for glucose ingestion and temporally related to the glucose counterregulatory process. To determine the physiologic roles of glucagon and epinephrine in postprandial glucose counterregulation, we produced pharmacologic interventions that resulted in endogenous glucagon deficiency with and without exogenous glucagon replacement, adrenergic blockade, and adrenergic blockade coupled with glucagon deficiency starting 225 min after the ingestion of 75 g of glucose in normal subjects. Also, we assessed the effect of endogenous epinephrine deficiency alone and in combination with glucagon deficiency late after glucose ingestion in bilaterally adrenalectomized subjects. Glucagon deficiency resulted in nadir plasma glucose concentrations that were approximately 30% lower (P less than 0.01) than control values, but did not cause hypoglycemia late after glucose ingestion. This effect was prevented by glucagon replacement. Neither adrenergic blockade nor epinephrine deficiency alone impaired the glucose counterregulatory process. However, combined glucagon and epinephrine deficiencies resulted in a progressive fall in mean plasma glucose to a hypoglycemic level late after glucose ingestion; the final glucose concentration was 40% lower (P less than 0.02) than the control (epinephrine deficient) value in these patients, and was nearly 50% lower (P less than 0.001) than the control value and approximately 30% lower (P less than 0.05) than the glucagon-deficient value in normal subjects. We conclude (a) the transition from exogenous glucose delivery to endogenous glucose production late after glucose ingestion is the result of the coordinated diminution of insulin secretion and the resumption of glucagon secretion. (b) Epinephrine does not normally play a critical role in this process, but enhanced epinephrine secretion compensates largely and prevents hypoglycemia when glucagon secretion is deficient.

Beneficial hemodynamic effects of intravenous terbutaline in patients with severe heart failure.

The hemodynamic effects of terbutaline infusion at rates of 0.15, 0.3, and 0.45 micrograms/kg/min were studied and compared in eight patients with severe heart failure. Terbutaline infusion at 0.15 micrograms/kg/min infusion produced insignificant effects at 30 minutes. At 0.3 micrograms/kg/min infusion highly significant beneficial hemodynamic effects were observed: at 60 minutes cardiac index increased from 1.79 +/- 0.38 to 3.60 +/- 0.96 (mean +/- SD) L/min/m2 (p less than 0.0001) and stroke volume index increased from 20.1 +/- 6.2 to 36.7 +/- 13.1 ml/beat/m2 (p less than 0.0001); mean pulmonary artery wedge pressure fell from 27.5 +/0- 5.5 to 18.5 +/- 5.7 mm Hg (p less than 0.0001); systemic vascular resistance fell from 2624 +/- 586 to 1455 +/- 500 dynes . sec . cm-5/m2 (p less than 0.0001); and pulmonary vascular resistance fell from 248 +/- 84 to 150 +/- 70 dynes . sec . cm-5/m2 (p less than 0.0005). Mean arterial pressure and O2 uptake did not change significantly; however, mean heart rate increased from 93.4 +/- 22 to 103.1 +/- 26 bpm (p less than 0.005) and plasma potassium fell from 3.86 +/- 0.14 to 3.12 +/ 0.23 mEq/L (p less than 0.05). The 0.45 micrograms/kg/min infusion at 30 minutes produced no greater hemodynamic changes than that from 0.3 micrograms/kg/min. Our study suggests that intravenous terbutaline produces beneficial effects and may be useful in the acute management of severe heart failure.

A unique patient with coexisting cerebrotendinous xanthomatosis and beta-sitosterolemia.

An adult Chinese man presented with tendinous and tuberous xanthomatosis and severe atheromatous changes in the coronary arteries. In addition, he had chronic hemolytic anemia, with spherostomatocytic erythrocytes. Cerebrotendinous xanthomatosis was diagnosed on the basis of increased cholestanol levels in his plasma, red cells and xanthoma, changes in bile acid composition due to the defective synthesis of chenodeoxycholic acid. Coexisting beta-sitosterolemia was confirmed by the finding of large amounts of the plant sterols such as beta-sitosterol and campesterol. This is the first report of these two rare lipid storage disorders in the same patient.

Haemodynamic responses to intravenous cimetidine in subjects with normal lung function and in subjects with chronic airway obstruction.

1 The haemodynamic responses to a bolus intravenous injection of 400 mg cimetidine were studied in eight subjects with normal lung function and sixteen with chronic obstructive airway disease (COAD), under continuous systemic and pulmonary arterial monitoring. In all subjects there were significant immediate but transient (less than 10 min) drops in the systemic and pulmonary arterial pressures (both systolic and diastolic), the systemic vascular resistance and total pulmonary resistance. The percentage drops were significant more marked in the COAD group in the following: systemic arterial pressures (systolic and diastolic), systemic vascular resistance and total pulmonary resistance. The cardiac output showed no significant change in the group with normal lung function but rose significantly in the COAD group. None of the subjects had any symptoms associated with the haemodynamic changes. 2 These results can be explained by a generalized vasodilatory effect of cimetidine, but the relationship to its H2-receptor blocking effect is undetermined. Hypoxia and/or hypercapnia may sensitize an individual to the vasodilatory effect of cimetidine.

Comparison of the metabolic and antihypertensive properties of tienilic acid and hydrochlorothiazide.

Tienilic acid (2,3-dichloro-4-(2-thienylcarbonyl) phenoxyacetic acid) is a new diuretic with uricosuric properties. Eighteen patients, aged between 37 and 67 years, with moderate arterial hypertension underwent a double-blind, within-patient, crossover study to compare the effects of tienilic acid (TNCF) and hydrochlorothiazide (HCTZ) on blood pressure, renal function, serum levels of uric acid and electrolytes, and liver function. Blood pressure was lowered similarly by TNCF and HCTZ. The prime advantage of TCNF over HCTZ was its profound hypouricaemic effect. Despite the possibility of hepatotoxicity of TNCF, it may still have a place in the treatment of hypertensive hyperuricaemic patients when the mechanism of hepatotoxicity of TNCF is elucidated.

Hepatic microvascular effects of terbutaline in experimental cardiogenic shock in rats.

1. Experimental myocardial infarction was produced in rats by direct electrical cauterization of the myocardium of left ventricle. This produced cardiogenic shock with the accompanying haemodynamic changes of low cardiac output, low mean arterial pressure, raised central venous pressure and an absence of cardiac arrhythmias. 2. The liver microcirculation was observed using in vivo television microscope method. The diameter and erythrocyte flow velocity in the liver sinusoids were measured quantitatively. 3. During experimental cardiogenic shock 80% of the liver sinusoids were constricted; the remaining 20% showed dilatation. In all these liver sinusoids the erythrocyte flow velocity was only 50% of the pre-shock level. 4. Intravenous injection of the selective beta 2-adrenoceptor agonist terbutaline (0.15 mg/kg) restored the systemic arterial pressure to pre-shcok levels and partially raised the cardiac output. In the liver microcirculation terbutaline restored both constricted and dilated liver sinusoids to pre-shock calibres, but only partially raised erythrocyte flow velocity. 5. It is proposed that during experimental cardiogenic shock, terbutaline produces dilatation in the terminal liver microcirculation by opening sphincters of liver sinusoids and restores sinusoid diameters to pre-shock calibres. Therefore, terbutaline has the capacity to decrease peripheral resistance and unload the circulation during cardiogenic shock.