β-Carbolines in Chronic Alcoholics Undergoing Elective Tumor Resection

The prevalence of chronic alcoholism in patients with carcinomas of the upper digestive tract exceeds 60%. The patient's history and laboratory markers, preoperatively, are often not sensitive or specific enough to detect alcohol-dependent patients, preoperatively, who are at risk of developing alcohol withdrawal syndrome (AWS) during their postoperative intensive care unit (ICU) stay. Previously, it was found that plasma norharman was elevated in chronic alcoholics, suggesting marker characteristics for chronic ethanol misuse and possibly alcohol dependence. We investigated whether β-carbolines (i.e., harman and norharman) were different between chronic alcoholics and nonalcoholics with carcinoma, and how the levels change in alcohol-dependent patients during their hospital stay. Ninety-seven patients with oral, pharyngeal, laryngeal, or esophageal carcinomas were evaluated regarding their drinking habits. Sixty patients were transferred to the ICU following tumor resection. Chronic alcoholics met the DSM-III-R and ICD-10 criteria for alcohol dependence or chronic alcohol abuse/harmful use. The daily ethanol intake in chronic alcoholics was ≥60 g. Blood samples were collected on admission to the hospital, preoperatively, on admission to the ICU and on days 2, 4, and 7 in the ICU. Harman and norharman were determined by HPLC. Elevated norharman was found in chronic alcoholics on admission to the hospital, whereas harman did not differ between groups. On admission, the area under the receiver operating characteristics curve was significantly larger for carbohydrate-deficient transferrin and preoperatively for norharman. The preoperative norharman levels were significantly correlated with the period of mechanical ventilation and the length of ICU stay. Postoperatively, norharman decreased in all patients, except a group of 11 alcohol-dependent patients who developed AWS during their ICU stay. The finding that elevated norharman levels were found in chronic alcoholics on admission to the hospital and preoperatively supports the view of a specific marker for alcoholism. Preoperative norharman was superior to carbohydrate-deficient transferrin and was associated with a prolonged ICU stay and a prolonged period of mechanical ventilation. Further studies are required to determine whether norhaman aids in the preoperative diagnosis of chronic alcohol misuse with respect to the prevention of postoperative complications.     

Excretion of β-Carbolines Harman and Norharman in 24-Hour Urine of Chronic Alcoholics During Withdrawal and Controlled Abstinence

Animal experiments suggest that endogenous substances that could result from the interaction between neurotransmitters (dopamine and indoleamines) and ethanol and its metabolite acetaldehyde might be involved in the pathogenesis and maintenance of alcohol dependence. Therefore, aromatic β-carbolines (norharman and harman) were investigated repeatedly in 24-hr urine of 13 male severe alcoholics without any psychiatric comorbidity during a controlled inpatient abstention program of up to 8 weeks. Harman excretion was ˜2-fold above levels in control subjects, with a steady decline after 3 weeks of abstinence and lower levels in patients with a longer duration of alcohol dependence. Severity of withdrawal symptoms and actual feelings of anxiety/depression were negatively associated with urinary harman excretion. Positive associations could be established with daily ethanol consumption the month before admission and the score on the scale "reward dependence" according to Cloninger's Tridimensional Personality Questionnaire. Moreover, patients without alcohol-dependent first-degree relatives and higher "reward dependence" exhibited an increased excretion of harman. Therefore, harman levels might characterize a distinct subgroup of alcoholic patients, who in part resemble the so-called type I alcoholics of Cloninger. However, this awaits further study in a larger number of individuals. In contrast, norharman excretion was elevated up to 6-fold, compared with nonalcoholics over 6 to 8 weeks of controlled abstention. No correlations to demographic or clinical variables could be observed. Therefore, increased norharman levels might be proposed as a "residual marker" or a trait variable. Whether the observed changes are specific markers of at least certain aspects of alcoholism or dependence remain to be elucidated.     

Harman and Norharman in Alcoholism: Correlations with Psychopathology and Long-Term Changes

In the search for mechanisms specific for alcoholism, it has become evident that β-carbolines (BCs; e.g., harman and norharman) are compounds that may act on brain reward systems, thereby mediating an increase in voluntary ethanol (ETOH) drinking in animals. This study was undertaken to analyze relationships between these compounds and clinical variables (e.g., family history, personality data, and affect) in alcoholics and to trace the time course of blood concentrations in subjects abstaining from alcohol for at least 6 months. Nonalcoholics were investigated during sober and ETOH-loading conditions (1 g ETOH/kg body weight). Levels of harman were elevated in the chronically intoxicated alcoholics and correlated with the scores on the self-rating depression (SDS) and the self-rating anxiety (SAS) scales. The group of alcoholics with at least one alcoholic parent had higher levels than the group without such a history. Levels remained elevated for 6 months. Norharman levels were only slightly elevated on the day of admission. They were correlated to high harm avoidance and SDS scores. A family history of alcoholism and the severity of alcoholism as assessed by the number of ICD-10 criteria fulfilled were correlated with norharman levels. Long-term observation revealed elevated levels of norharman after 3 months of abstinence, but not after 6 months. The association of harman levels with anxiety and depression demonstrated in the present study suggests that alcoholics with high harman levels use alcoholic beverages as self-medication in an attempt to overcome possible anxiogenic/depressiogenic actions of harman. Norharman levels are less strongly associated with these mood states, but significantly correlated to harm avoidance tendencies. It has been suggested that the activity of the indolergic neurons is relatively high in individuals with a high harm avoidance score. Biosynthesis of norharman might be stimulated under these conditions (tryptamine serves as precursor).     

Effect of Alcohol on Blood Dolichol Concentration

Serum dolichol levels were studied in 95 active alcoholics and 16 abstinent alcoholics (at the time of blood sampling) and compared to those of 41 social drinkers. Active alcoholics had a significantly higher mean serum dolichol concentration (182.7 +/- 5.1 ng/ml, p less than 0.001 than either abstinent alcoholics (138.7 +/- 5.4 ng/ml) or social drinkers (142.1 +/- 4.1 ng/ml). During weekend (48 hr) heavy drinking (5.5 g of alcohol per kg b.w.) no significant changes were seen in mean serum dolichol concentrations in 10 healthy, nonalcoholic volunteers. Neither did moderate drinking for 10 days (60 g of alcohol daily)--preceded and followed by a period of abstinence--produce any significant changes in serum dolichol levels in 10 nonalcoholic subjects. During detoxification treatment of 12 alcoholics, mean serum dolichol concentration stayed constant for the first 7 days; on entering treatment it was 227.7 +/- 15.0 ng/ml, on the 3rd day 238.5 +/- 15.9 ng/ml, and on the 7th day of treatment 222.6 +/- 18.6 ng/ml. Our results show that as well as increasing urinary dolichol excretion, chronic alcohol abuse also produces increased serum dolichol concentrations. However, contrary to urinary dolichols, serum dolichol levels do not react significantly to heavy drinking lasting for 48 hr in nonalcoholic volunteers. Furthermore in alcoholics increased serum dolichol concentrations do not decrease as rapidly during abstinence as urinary dolichol concentrations do.     

Neuroendocrine, Fluid Balance, and Thirst Responses to Alcohol in Alcoholics

This study simultaneously evaluated multiple circulating neurohormones, osmolality, thirst, and fluid balance in eight actively drinking, alcoholic males and seven controls before and 12 hr after an ethanol challenge. Basal levels of serum osmolality and thirst were significantly higher in alcoholics compared with controls, yet actively drinking alcoholics at the start of the study had normal vasopressin (AVP) levels, plasma angiotensin II (Ang II), plasma renin activity, plasma aldosterone (Aldo), and plasma catecholamines. In response to ethanol, serum osmolalities rose significantly higher while plasma AVP levels became significantly suppressed in alcoholics. After the ethanol stimulus, plasma Ang II levels of alcoholics were significantly higher than those of controls at 11 AM (12.15 +/- 4.49 vs. 1.83 +/- 0.6 pg/ml, p less than 0.02) and 12 noon (14.93 +/- 6.81 vs. 1.37 +/- 0.17 pg/ml, p less than 0.04). Neither plasma renin activity nor Aldo changed in accordance with the elevated plasma Ang II in alcoholics. Diuresis in the alcoholics, assessed by the sum of urine output following the challenge dose, was significantly less than that of controls. Thirst scores and fluid intakes after the ethanol challenge did not differ between alcoholics and controls. The lack of an Ang II-mediated increase in plasma Aldo or thirst response suggests that ethanol may have a specific blunting effect on Ang II receptors. This study demonstrates that ethanol can be used as a provocative test in chronic alcoholics to uncover aberrant hormonal responses for two systems, namely, Ang II and AVP.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cerebrospinal fluid tau protein levels in demented and nondemented alcoholics

The tau protein levels in cerebrospinal fluid (CSF-tau) were examined in 27 patients with alcohol dependence (20 demented and 7 nondemented), 36 age and dementia severity-matched patients with Alzheimer's disease (AD), and 23 age-matched normal control subjects. The CSF-tau levels in the demented alcoholic group (alcohol-induced organic brain disorders, 25.4 +/- 10.2 pg/ml) was significantly lower (p < 0.0001) than that in the AD group (96.1 +/- 53.3 pg/ml), but not significantly different from that in the nondemented alcoholics (18.1 +/- 10.2 pg/ml) or the controls (19.2 +/- 12.9 pg/ml). Using a 44.9 pg/ml as a cut-off value (mean + 2 SD of the normal control group), only one patient with alcohol-induced organic brain disorders exceeded the value, whereas 3 of 36 of the AD group showed CSF-tau levels less than this level. These findings suggest that alcohol-induced organic brain disorders are a group of dementias that are characterized by normal CSF-tau levels, and that the CSF examination for tau in combination with other clinical findings may help in differentiating alcohol-induced organic brain disorders from AD.     

γ-Glutamyl Transpeptidase Activity in Liver of Alcoholics and Its Histochemical Localization

The activity and the histochemical localization of gamma-GTP in the liver of chronic alcoholics were investigated. Mean serum gamma-GTP activity in alcoholics was 542.5 +/- 337.9 milliunits/ml, and that of patients with nonalcoholic liver disease was 34.3 +/- 22.6 milliunits/ml. Hepatic gamma-GTP activity in alcoholics was significantly increased compared to that in control patients (15.62 +/- 9.29 versus 4.04 +/- 2.67 units/g of liver; p less than 0.001). A significant correlation was observed between hepatic and serum gamma-GTP activity. Light microscopically, a marked gamma-GTP activity was found in the bile canaliculi and a diffuse activity in the cytoplasm in alcoholic livers. By contrast, in the livers of nonalcoholic patients, only slight activity was observed in the bile canaliculi. The electron micrographs showed the enzyme was localized in the microvilli of both the bile canalicular and plasma membranes and the endoplasmic reticulum near the mitochondria in alcoholics. But a very low activity was demonstrated in the plasma membranes in the livers of nonalcoholic patients.     

Concentration of Vitamin B6 and Activities of Enzymes of B6 Metabolism in the Blood of Alcoholic and Nonalcoholic Men

The purpose of this study was to compare concentrations of vitamin B6 compounds and the activities of enzymes that synthesize or catabolize pyridoxal 5'-phosphate in the plasma and erythrocytes of nonalcoholic and alcoholic subjects. Blood was obtained from male nonalcoholics and chronic alcoholics with minimal liver damage and normal hematology. Plasma, erythrocyte, and urinary B6 compounds were analyzed by high performance liquid chromatography, and pyridoxal phosphate was also measured enzymatically. Erythrocyte pyridoxine kinase and pyridoxine phosphate oxidase and erythrocyte and plasma pyridoxine phosphate phosphatases were assayed. Plasma pyridoxal phosphate concentration was significantly lower in the alcoholics (31.3 +/- 3.6 nmol/liter) than in the nonalcoholics (58.7 +/- 7.5 nmol/liter). The concentrations of the other B6 compounds in plasma, erythrocytes, and urine were not different in the two groups. Plasma alkaline pyridoxine phosphate phosphatase activity was significantly higher in the alcoholics (4.05 +/- 0.36 nmol/(h.mg] than in the nonalcoholics (3.01 +/- 0.18 nmol/(h.mg]. The activities of erythrocyte kinase, oxidase, and phosphatases were not significantly different in the two groups. The relationship of plasma pyridoxal phosphate concentration to its metabolites and the activities of the enzymes involved in its metabolism was determined. Plasma pyridoxine phosphate phosphatase activity assayed at pH 9.0 or 7.4 correlated negatively with plasma pyridoxal phosphate concentration. The low pyridoxal phosphate concentration observed in the plasma of the alcoholic subjects may in part be related to increased plasma phosphatase activity.     

Pancreatic secretion in chronic alcoholics

To gain further insight on the effects of alcohol on human pancreatic enzyme secretion, we tested the effects of a 12% (v/v) alcohol solution, wine, and a glucose sclution added to a meal on trypsin output in duodenal aspirate of nonalcoholic volunteers and compared the results to those of chronic alcoholics. Plasma concentrations of gastrin, cholecystokinin, and pancreatic polypeptide were monitored pre-and postprandially. Similar blood alcohol concentrations were determined in nonalcoholics and alcoholics following wine and the alcohol solution. Nonstimulated trypsin output (basal) was higher in alcoholics but not significantly so when compared to nonalcoholics. However postprandial trypsin output, 2014±301 mg/5 hr was significantly greater in alcoholics (P<0.05) compared to nonalcoholics 1271±118 mg/5 hr. Alcohol and wine when added to the meal significantly (P<0.05) inhibited trypsin output in both groups. Basal and postprandial levels of gastrin and cholecystokinin were similar in nonalcoholics and alcoholics. Basal plasma pancreatic polypeptide levels were similar in both groups, but the postprandial increments in pancreatic polypeptide levels observed in nonalcoholics were not observed in alcoholics. We conclude that chronic alcoholics have increased postprandial pancreatic enzyme secretion, and that this secretion, as that of nonalcoholics, can be affected by alcohol or wine. The postprandial hypersecretion of enzymes in alcoholics is not related to increased plasma levels of cholecystokinin or gastrin. It is possible that the impaired release of pancreatic polypeptide may participate in the mechanism for increased pancreatic enzyme secretion in chronic alcoholics.This work was supported by grant AA 07676-01A1 from the Alcohol, Drug Abuse and Mental Health Administration and in part by a grant (GCRC RR-43) from the General Clinical Research Centers Program of the Division of Research Resources, National Institute of Health.     

Exercise-related changes in serum catecholamines and potassium: effect of sustained exercise above and below lactate threshold

Plasma potassium and catecholamines exhibit rapid shifts during exercise testing, particularly when exercise intensity exceeds lactate threshold. To assess changes that may occur during sustained exercise, we studied 10 healthy men to determine the effect of 20 minutes of exercise at 25 W above lactate threshold (ALT) and 20 minutes of exercise at 25 W below lactate threshold (BLT). Both conditions showed elevation of catecholamines at end exercise compared to baseline, but catecholamine levels ALT were significantly higher than the levels BLT (2270 +/- 190 versus 900 +/- 230 pg/ml norepinephrine, p less than 0.001; 509 +/- 69 versus 150 +/- 18 pg/ml epinephrine, p less than 0.001). This difference persisted at 2 minutes of recovery (1620 +/- 130 versus 590 +/- 60 pg/ml norepinephrine, p less than 0.001; 216 +/- 31 versus 98 +/- 16 pg/ml epinephrine, p less than 0.001). Both conditions resulted in a significant elevation in potassium at end exercise compared to baseline, but the potassium levels ALT were significantly higher than the levels BLT (1.1 +/- 0.1 mEq/L versus 0.5 +/- 0.1 mEq/L, p less than 0.001. The fall in potassium in the immediate post-exercise period was significantly greater following exercise ALT (-0.8 +/- 0.1 mEq/L versus -0.2 +/- 0.1 mEq/L, p less than 0.001). Thus sustained exercise slightly ALT resulted in a significant potassium flux and very elevated catecholamine levels. Avoiding these metabolic stresses by exercising BLT may decrease chances for exercise-related arrhythmia or other cardiac dysfunction in susceptible patients.     

Platelet dysfunction and alteration of prostaglandin metabolism after chronic alcohol consumption

To study the effects of chronic alcohol consumption on platelet functions, the rate of arachidonate-induced platelet aggregation, the production of malondialdehyde in platelets, and plasma levels of prostaglandin endoperoxide metabolites were examined in 88 chronic alcoholics and 24 healthy controls. The rate of platelet aggregation and the production of malondialdehyde in platelets were greater in chronic alcoholics both on admission and 1 week after. However, these alterations returned to the level of healthy controls within 4 weeks of abstinence from alcohol and were independent of the number of circulating platelets. Furthermore, on admission, plasma levels of thromboxane B2 were significantly increased in chronic alcoholics when compared with those of healthy controls (400.8 +/- 36.5 versus 241.7 +/- 28.9 pg/ml plasma; p less than 0.025) and were also significantly correlated with malondialdehyde production in washed platelet debris (r = 0.6049; p less than 0.001). In contrast, plasma levels of 6-keto prostaglandin F1 alpha and prostaglandin E were not altered after chronic alcohol consumption. As a result, the ratio of 6-keto prostaglandin F1 alpha to thromboxane B2 was markedly decreased in chronic alcoholics (0.31 +/- 0.03 versus 0.62 +/- 0.13; p less than 0.001). These results strongly suggest that the imbalance in prostaglandin endoperoxide metabolites is produced by chronic alcohol ingestion. Moreover, a significant correlation was observed between platelet aggregation rate and malondialdehyde production during platelet aggregation (r = 0.559; p less than 0.005). Thus, we conclude that chronic alcohol consumption alters platelet thromboxane metabolism, which is likely associated with the increased ability of platelets to aggregate.     

Effect of exercise on circulating atrial natriuretic peptide and left ventricular ejection fraction in healthy persons and patients with coronary artery disease

Radionuclide angiographic measurements of left ventricular ejection fraction were performed at rest and during exercise in 10 normal persons and 11 patients with coronary artery disease. Exercise was continued on a supine bicycle exercise table up to a symptom-limited maximum. Plasma levels of atrial natriuretic peptide (ANP) were also determined at rest and during exercise. Ejection fraction in the normal volunteers was 59 +/- 3% (mean +/- SEM) at rest and increased significantly (p less than 0.01) to 69 +/- 3% during exercise. Ejection fraction in the patients was 47 +/- 5% at rest and did not change significantly during exercise (51 +/- 7%). Plasma ANP in the normals rose significantly (p less than 0.01) from 62 +/- 16 pg/ml at rest to 454 +/- 94 pg/ml during exercise. Plasma ANP in the patients also rose significantly (p less than 0.01) from 231 +/- 102 pg/ml to 794 +/- 170 pg/ml. The response of plasma ANP to exercise was enhanced significantly (p less than 0.05) in the patients as compared with the normals in relation to ejection fraction by analysis of covariance. In both the normals and the patients, plasma ANP was inversely and significantly correlated with ejection fraction during exercise (r = -0.46, p less than 0.05, n = 21), however, not at rest. Because it has been reported that plasma ANP is correlated positively with pulmonary artery wedge pressure, the estimation of plasma ANP during an exercise stress test might be used for the evaluation of cardiac reserve in coronary artery disease.     

TNF and sepsis

Recent experiments have demonstrated that TNF plays an important role in the pathogenesis of septic shock. To confirm the involvement of TNF in human septic shock, serum TNF levels were measured in 10 adult patients admitted to the intensive care unit for sepsis with or without shock. Septic shock was corroborated by hemodynamic data (right catheterization, measurement of cardiac output by thermodilution). For TNF measurement, venous blood samples were withdrawn, as soon as possible after the onset of sepsis, into a pyrogen--free tube. Serum TNF levels were determined using a radioimmunoenzymatic assay (IRE Medgenix). During septic shock (n = 7), TNF levels were significantly higher (m = 354 +/- 131 pg/ml) than during sepsis without shock (n = 8; m = 145 +/- 35 pg/ml) (p less than 0.0005). TNF levels were also significantly higher in non-survivors (m = 392 +/- 111 pg/ml) than in survivors (m = 167 +/- 81 pg/ml) (p less than 0.0005). The value of 250 pg/ml seems to be critical: no patient without shock had TNF levels above 250 and all the patients who died early during the first 24 h) had TNF levels above 250. The TNF level is negatively correlated with the platelet count (r = -0.70; p less than 0.05). These data favor a pathophysiological for TNF in human sepsis and septic shock.     

Secretion of growth hormone releasing hormone in obese children.

We have evaluated baseline and l-dopa-stimulated peripheral growth hormone releasing hormone (pGHRH) secretion in 6 obese pre-pubertal children and in 7 age-matched controls. Baseline pGHRH levels were no different between obese (36.6 +/- 9.8 pg/ml, mean +/- SE) and control children (40.6 +/- 10.1 pg/ml). Administration of l-dopa (500 mg po) caused a significant increase of pGHRH levels in both the obese (65.3 +/- 19.8 pg/ml, p less than 0.05) and the control children (84.1 +/- 10.0 pg/ml, p less than 0.003). Mean peak pGHRH levels after l-dopa were not significantly different between the two groups, whereas mean peak GH levels were significantly lower (p less than 0.05) in the obese (7.9 +/- 1.9 ng/ml) than in the control children (20.5 +/- 4.9 ng/ml). We conclude that despite reduced GH secretion, obese children have normal baseline and l-dopa stimulated pGHRH levels.     

Prevalence and mechanisms of hyperhomocysteinemia in chronic alcoholics

BACKGROUND: Homocysteine (Hcy) is formed as an intermediary in methionine metabolism. Impairment of Hcy remethylation or transulfuration leads to hyperhomocysteinemia, which is considered as a risk factor for atherosclerotic vascular disease and stroke in chronic alcoholics. The aim of the study was to investigate the prevalence of hyperhomocysteinemia in chronic alcoholics and the influence of alcohol consumption, vitamin deficiencies and liver damage on the plasma levels of Hcy. METHODS: 228 chronic alcoholic patients consecutively admitted for detoxication, classified according to clinical and biochemical data in normal liver (n = 117), and in mild to moderate liver disease (n = 111), and 49 healthy controls were studied. Blood levels of Hcy, vitamin B6, vitamin B12 and folate were measured. RESULTS: Plasma Hcy was significantly higher in chronic alcoholics than in controls (9.66 +/- 8.1 vs. 6.93 +/- 2.33 mumol/liter, p < 0.025). Furthermore, plasma Hcy levels were significantly higher in chronic alcoholics with liver injury (12.17 +/- 10.14 mumol/liter) than in those with normal liver and in controls (p < 0.001). The prevalence of hyperhomocysteinemia was also significantly higher in alcoholics with liver damage than in those with normal liver and in controls (29.7%, 5.1%, and 2%, respectively, p < 0.001). Serum folate values were lower in chronic alcoholics than in controls (4.7 +/- 2.6 vs. 7.6 +/- 2.4 nmol/liter, p < 0.001). The lowest values of folate were found in alcoholics with liver disease, especially in those with hyperhomocysteinemia, with a negative correlation between the two parameters. CONCLUSIONS: Moderate hyperhomocysteinemia is common in chronic alcoholics, mainly in those with liver damage, suggesting that, although folate deficiencies may have a contributory role, liver impairment, through changes in methionine metabolism, is the most important mechanism for the elevated plasma Hcy found in these patients.     

Variations in postprandial ghrelin status following ingestion of high-carbohydrate, high-fat, and high-protein meals in males

AIM: The purpose of this study was to investigate the response of postprandial acylated ghrelin to changes in macronutrient composition of meals in healthy adult males. METHODS: A randomized crossover study was performed. Ten healthy adult males were recruited. All subjects received, on separate occasions, a high-carbohydrate (HC), a high-fat (HF), and a high-protein (HP) meal. Blood samples were collected before and 15, 30, 60, 120, and 180 min following the ingestion of each meal. Plasma acylated ghrelin as well as serum insulin, glucose, and triglycerides were measured. RESULTS: The levels of acylated ghrelin fell significantly following the three meals. The HC meal induced the most significant decrease in postprandial ghrelin secretion (-15.5 +/- 2.53 pg/ml) as compared with HF (-8.4 +/- 2.17 pg/ml) and HP (-10.0 +/- 1.79 pg/ml) meals (p < 0.05). However, at 180 min, the HP meal maintained significantly lower mean ghrelin levels (29.7 +/- 3.56 pg/ml) than both HC (58.4 +/- 5.75 pg/ml) and HF (45.7 +/- 5.89 pg/ml) meals and lower levels than baseline (43.4 +/- 5.34 pg/ml) (p <0.01). The postprandial insulin levels increased to significantly higher levels following the HC meal (+80.6 +/- 11.14 microU/ml) than following both HF (37.3 +/- 4.82 microU/ml) and HP (51.4 +/- 6.00 microU/ml) meals (p < 0.001). However, at 180 min, the mean insulin levels were found to be significantly higher following the HP meal (56.4 +/- 10.80 microU/ml) as compared with both HC (30.9 +/- 4.31 microU/ml) and HF (33.7 +/- 4.42 microU/ml) meals (p < 0.05). Acylated ghrelin was also found to be negatively correlated with circulating insulin levels, across all meals. CONCLUSIONS: These results indicate that the nutrient composition of meals affects the extent of suppression of postprandial ghrelin levels and that partial substitution of dietary protein for carbohydrate or fat may promote longer-term postprandial ghrelin suppression and satiety. Our results also support the possible role of insulin in meal-induced ghrelin suppression.     

Role of substance P in the pathogenesis of spider angiomas in patients with nonalcoholic liver cirrhosis

OBJECTIVE: Cutaneous spider angioma is a common sign observed in patients with liver cirrhosis, but its pathogenesis is still unclear. Increased plasma levels of estrogen, vascular dilation, and neovascularization are possible etiologies. This study was designed to investigate the relationship of spider angiomas in patients with nonalcoholic liver cirrhosis to the plasma levels of sex hormones and various vasodilators and hemodynamic parameters. METHODS: A total of 60 patients with nonalcoholic liver cirrhosis and 20 healthy subjects were included in this study. The number, size, and location of the spider angiomas were recorded. Plasma levels of estradiol, testosterone, substance P, calcitonin gene-related peptide, and nitrate/nitrite and forearm hemodynamics were measured. RESULTS: Cirrhotic patients showed higher plasma estradiol/testosterone ratios (28.3+/-47.2 x 10(-3), median 10.5 x 10(-3) vs 8.2+/-8.3 x 10(-3), median 5.7 x 10(-3), p = 0.003) and levels of nitrate/ nitrite (29.9+/-17.5, median 23.8 vs 21.4+/-10.0, median 20.6 micromol/L, p = 0.01) and substance P (47.5+/-62.5, median 29.2 vs 15.2+/-7.7, median 12.3 pg/ml, p < 0.001) than healthy controls. Sixteen (27%) of the 60 cirrhotic patients had spider angiomas. Cirrhotic patients with spider angiomas disclosed higher plasma levels of substance P (84.7+/-105.3, median 53.1 vs 34.5+/-30.7, median 25.8 pg/ml, p = 0.006) and serum levels of bilirubin (3.9+/-3.8, median 1.9 vs 1.9+/-1.9, median 1.2 mg/dl, p = 0.02) than those without. Stepwise logistic regression showed substance P was the only significant and independent predictor associated with the presence of spider angiomas in cirrhotic patients (odds ratio = 3.0, 95% confidence interval = 1.4-6.6, p = 0.01). CONCLUSION: Plasma levels of substance P are elevated in patients with nonalcoholic cirrhosis and may play an important role in the pathogenesis of spider angiomas.     

Activity of CYP2E1 and CYP3A enzymes in adults with moderate alcohol consumption: a comparison with nonalcoholics

Alcohol consumption is known to induce hepatic CYP2E1 activity, but its effect on hepatic and intestinal CYP3A in humans is not known. We have conducted a study to compare the CYP2E1 and CYP3A activities in 20 individuals with moderate alcohol consumption and 20 gender-, race-. and body mass index (BMI)-matched nonalcoholics. Intravenous and oral midazolam (MDZ) clearances were used to measure the in vivo CYP3A activity, and chlorzoxazone (CHZ) oral clearance was used to assess in vivo CYP2E1 activity. Furthermore, we assessed the relationship between hepatic CYP2E1 and CYP3A activities and their messenger RNA (mRNA) expression in the peripheral lymphocytes. The systemic clearance (CL) of MDZ was not different between alcoholics (36.9 +/- 12 L/hr) and nonalcoholics (36.6 +/- 14.1; P = .9). The oral availability of MDZ was significantly lower in alcoholics than in the nonalcoholics (0.28 +/- .09 vs. 0.38 +/- .17, respectively, P = .03). The maximum serum concentration after oral midazolam dosing was significantly different between the 2 groups. CHZ CL was significantly higher in alcoholics than in nonalcoholics (31.5 +/- 11.9 vs. 23.4 +/- 8.7 L/hr, P < 0.05). CYP3A4 and CYP2E1 mRNA levels were not significantly different between the groups, and no correlation was observed between lymphocyte CYP mRNA and in vivo CYP activity. In conclusion, in individuals with moderate alcohol consumption, there was no alteration in the hepatic CYP3A activity, but the reduced midazolam oral bioavailability suggests that moderate alcohol consumption may cause intestinal CYP3A induction. Lymphocyte CYP2E1 and CYP3A4 mRNA levels did not correlate with CYP2E1 and CYP3A activities.     

Cigarette smoking in hypertensive patients. Blood pressure and endocrine responses

The blood pressure and endocrine responses to cigarette smoking were studied in 19 hypertensive patients to determine whether smoking activates the renin-aldosterone axis. Blood pressure rose from 140 +/- 7/99 +/- 3 (mean +/- SEM) to 151 +/- 5/108 +/- 2 mm Hg (p less than 0.01) within 10 minutes after smoking, and pulse rate also increased significantly (69 +/- 2 to 96 +/- 4 beats per minute). Plasma renin activity did not change but rose 15 minutes after ambulation. In contrast, plasma aldosterone and plasma cortisol levels increased significantly after smoking and peaked at 20 minutes: 13.9 +/- 0.9 to 20.2 +/- 2.0 ng/dl (p less than 0.01) and 10.2 +/- 1.0 to 22.0 +/- 2.2 micrograms/dl (p less than 0.01), respectively. These responses were closely correlated (r = 0.6467, p less than 0.01), suggesting a pituitary-adrenal mechanism is activated during smoking. Plasma ACTH levels rose from 58 +/- 6 to 87 +/- 10 pg/ml in 10 minutes (p less than 0.001) and to 90 +/- 14 pg/ml at 20 minutes (p less than 0.01). Total plasma catecholamine levels also rose from 468 +/- 60 to 624 +/- 73 pg/ml 10 minutes after smoking (p less than 0.01) and to 724 +/- 69 pg/ml (p less than 0.01) 15 minutes after ambulation. In hypertensive smokers, cigarette smoking is associated with an increase in blood pressure, pulse rate, and plasma ACTH, cortisol, aldosterone, and plasma catecholamine levels. The long-term significance of these acute hormonal changes in regard to blood pressure homeostasis and vascular disease in cigarette smokers remains to be determined. Smoking should be avoided prior to blood pressure and endocrine determinations.     

Effect of AV synchronization and rate increase on hemodynamics and on atrial natriuretic peptide in patients with total AV block

We studied nine patients (56 +/- 7 years) with complete AV-block and permanent dual-chamber pacemaker (DDD) under different pacing modes: ventricle pacing (VVI) 70 bpm, DDD 106 +/- 4 bpm, rate adaptive pacing (VVI-FA) 108 +/- 3 bpm. Exercise was performed supine on the bicycle ergometer at 50 watts for 5 min at each setting. DDD-paced patients showed significantly higher mixed venous oxygen saturation, being 45 +/- 2% after the fourth minute, (VVI 38 +/- 2%, p less than 0.01 and VVI-FA paced patients 40 +/- 1%, p less than 0.01). Pressures were normal under DDD pacing during exercise (RAP 7 +/- 2 mm Hg; PCP 14 +/- 3 mm Hg) and showed further increase to abnormal levels during VVI (RAP 13 +/- 2 mm Hg, p less than 0.01; PCP 21 +/- 3 mm Hg, p less than 0.02) and VVI-FA pacing (RAP 10 +/- 2 mm Hg, p less than 0.05; PCP 20 +/- 3 mm Hg, p less than 0.01). Stroke volume increased from 71 +/- 5 ml to 105 +/- 7 ml during VVI and from 64 +/- 7 ml to 81 +/- 7 ml during DDD pacing. Stroke volume remained unchanged (69 +/- 5 ml) during VVI-FA pacing. The peak levels of ANP during and after exercise were significantly higher under VVI (951 +/- 248 pg/ml) than under DDD pacing (650 +/- 140 pg/ml, p less than 0.01) and were not different between DDD and VVI-FA pacing (677 +/- 97 pg/ml). These results show that VVI pacing effects a more pronounced increase of ANP level than other pacing modes. Under moderate exercise, rate-responsive pacing compared to VVI pacing showed no differences in mixed venous oxygen saturation and in atrial pressures. Only DDD pacing showed higher oxygen saturation and a normalization of atrial pressures when compared to other types of single chamber pacing.