The role of alcohol in oral and pharyngeal cancer in non-smokers, and of tobacco in non-drinkers.

Data from a hospital-based case-control study of oral and pharyngeal cancer conducted in Northern Italy were used to analyse the risk associated with alcohol in non-smokers and with tobacco in non-drinkers. Out of a total of 336 cases (291 males and 45 females) and 1,652 controls (1,272 males and 380 females) 27 cases and 572 controls described themselves as lifelong non-smokers. Odds ratios (ORs) were 1.5 for 14-55 vs. 0-13 alcoholic drinks per week and 2.2 for 56 or over; the trend in risk was statistically significant. Among 19 cases and 213 controls who described themselves as non-drinkers, the ORs were 3.8 and 12.9 for smokers of less than 15 and greater than or equal to 15 cigarettes per day, with a highly significant trend. This study therefore confirms that tobacco has an independent role in the aetiology of oral and pharyngeal cancer, and suggests that alcohol may have an independent role as well, even where, as in Northern Italy, wine is its predominant source. Indeed, ORs were similar to those for tobacco and alcohol individually, each adjusted for the other factor, in the overall data-set.

Diminished adrenocorticotropin response to insulin-induced hypoglycemia in nondepressed, actively drinking male alcoholics.

Although changes in hypothalamic-pituitary-adrenal axis function have frequently been reported in alcoholics, the majority of studies have used recently detoxified subjects in whom abstinence phenomena and clinical depression may contribute to observed stress axis alterations. To isolate the primary effects of alcohol dependence on the stress axis, the ACTH and cortisol responses to insulin-induced hypoglycemia were measured in seven actively drinking male alcoholics recruited from the general public through a newspaper advertisement along with eight age-matched male controls. The alcoholic subjects met current American Psychiatric Association diagnostic criteria for alcohol dependence, were stably employed, and had no concurrent psychiatric disorders, cognitive impairment, or psychometric evidence of depression. While relatively young (30.0 yr; range, 22-48 yr), they had lengthy histories of alcohol-related problems (11.9 yr; range, 5-30 yr). Insulin administration resulted in similar nadirs in blood sugar in both alcoholic and control groups. However, the plasma ACTH response was markedly blunted in the alcoholics (P = 0.040, by Mann-Whitney U test). There was a nonsignificant trend toward increased cortisol levels in the alcoholic group. The findings suggest that altered hypothalamic-pituitary-adrenal axis function in alcoholics is a primary results of chronic ethanol exposure rather than a confounding effect of clinical depression or recent detoxification.

Fetal and placental size and risk of hypertension in adult life.

OBJECTIVE: To study the effect of intrauterine growth and maternal physique on blood pressure in adult life. DESIGN: A follow up study of infants born 50 years previously whose measurements at birth were recorded in detail. SETTING: Preston, Lancashire. SUBJECTS: 449 Men and women born in hospital in Preston during 1935-43 and still living in Lancashire. MAIN OUTCOME MEASURES: Placental weight, birth weight, and blood pressure at age 46 to 54 years. RESULTS: In both sexes systolic and diastolic pressures were strongly related to placental weight and birth weight. Mean systolic pressure rose by 15 mm Hg as placental weight increased from less than or equal to 1 lb (0.45 kg) to greater than 1.5 lb and fell by 11 mm Hg as birth weight increased from less than or equal to 5.5 lb to greater than 7.5 lb. These relations were independent so that the highest blood pressures occurred in people who had been small babies with large placentas. Higher body mass index and alcohol consumption were also associated with higher blood pressure, but the relations of placental weight and birth weight to blood pressure and hypertension were independent of these influences. CONCLUSIONS: These findings show for the first time that the intrauterine environment has an important effect on blood pressure and hypertension in adults. The highest blood pressures occurred in men and women who had been small babies with large placentas. Such discordance between placental and fetal size may lead to circulatory adaptation in the fetus, altered arterial structure in the child, and hypertension in the adult. Prevention of hypertension may depend on improving the nutrition and health of mothers.

Moderate alcohol intake and spontaneous eating patterns of humans: evidence of unregulated supplementation.

Alcohol's effects on eating were investigated by paying 92 adult humans to maintain 7-d diaries of everything they ingested, the time of ingestion, their subjective state at the time of ingestion, and the number of people present at the time of ingestion. Total intakes, meal sizes, meal compositions, pre- and postmeal intervals, and deprivation and satiety ratios were compared between nondrinkers and drinkers and between meals associated with alcohol ingestion and those without. Univariate and multivariate prediction of meal size and of postmeal interval were also calculated to ascertain alcohol's contribution to the regulation. The results suggest that alcohol supplements rather than displaces macronutrient-supplied calories, that alcohol is associated with prolonged meal durations, and that alcohol calories may be unregulated. Other apparent changes in the meal pattern appear to be artifacts of time of day and meal duration.

Behavior of alcohol-preferring AA and alcohol-avoiding ANA rat lines in tests of anxiety and aggression.

The present study examined whether behavior in the tests of aggression and anxiety differs between rat lines developed by selective outbreeding for differences in their voluntary alcohol consumption. The animals had either never had alcohol or had been given 10% alcohol solution as their only fluid for seven days followed by a choice between 10% alcohol and water for 30-37 days. The plus-maze test provided no clear evidence for differences in anxiety between the alcohol-preferring AA and alcohol-avoiding ANA rats. In the resident-intruder paradigm of aggressive behavior the AA rats showed more offensive and defensive behaviors than the ANA rats. The opportunity to consume alcohol influenced these behaviors, but did not produce differential responses in the AA and ANA rats.

Persistence of tolerance in the P line of alcohol-preferring rats does not require performance while intoxicated.

Persistence of tolerance was measured seven days after a single ethanol injection (2.5 g/kg b. wt.) in the alcohol-preferring P line of rats with and without testing in a shock-motivated jump task during the initial ethanol exposure. P rats were trained to jump 50 cm to avoid shock and were assigned to one of three groups. On day 0, group E/J (n = 8) was injected with ethanol and tested on the jump task until recovery to criterion (37.5 cm), while group S/J (n = 21) was injected with saline and was tested yoked to an E/J rat. Rats in the E/NJ group (n = 19) received ethanol but were not tested on day 0. Seven days later, all rats received 2.5 g ethanol/kg and were tested to criterion. Recovery times on day 7 were significantly longer (p less than 0.05) for rats in the S/J group (169 +/- 7 min) than for the E/J (141 +/- 11 min) and E/NJ (145 +/- 6 min) rats. Blood ethanol concentrations at recovery for the E/NJ group were higher than the S/J group on day 7 and higher than the E/J group on day 0 (p less than 0.05). The results indicate that the persistence of tolerance manifested by the P rats is an inherited behavioral trait that requires only ethanol exposure.

The effects of alpha-methyl-p-tyrosine pretreatment on ethanol-induced narcosis and hypothermia, as well as in the development of tolerance to these effects in UChA and UChB rats.

We have previously reported that UChA rats (genetically low ethanol consumer) develop tolerance to narcosis time easier than UChB rats (genetically high ethanol consumer). We also have reported that UChA rats develop tolerance to the hypothermic effect of ethanol, while in UChB rats the repeated administration of ethanol induces sensitization towards this effect. In the present paper the effects of alpha-methyl-p-tyrosine (AMPT)--a competitive inhibitor of norepinephrine synthesis--on ethanol-induced narcosis and hypothermia, as well as in the development of tolerance to these effects, were studied in both strains of rats. Results obtained show that AMPT pretreatment induced a significantly higher increase in narcosis time and hypothermia, as well as, greater susceptibility to ethanol toxicity in UChB than UChA rats. Furthermore, the simultaneous treatment with AMPT and ethanol did not change the development of tolerance to narcosis time in both strains and to hypothermia and sensitization in UChA and UChB rats respectively.

Voluntary consumption of beverage alcohol by vervet monkeys: population screening, descriptive behavior and biochemical measures.

Seventeen percent of 196 feral vervet monkeys (Cercopithecus aethiops) spontaneously drank appreciable quantities of beverage alcohol in 3% sucrose in preference to 3% sucrose alone. Ethanol consumption increased over time, as did the concentration of ethanol tolerated. Willingness to select ethanol was stable over a three-year period, as measured by periodic retesting. Individual patterns of drinking and behavioral responses to ethanol were quite variable. Upon occasion, some animals drank to ataxia and unconsciousness; signs of withdrawal, including tremulousness, pacing, irritability and increased aggression, followed the abrupt discontinuation of ethanol availability. A variety of changes in social interaction, including increased orientation to external stimulus, increased incidence of stereotyped aggression and of other stereotyped behaviors and decreased frequency of affiliative behaviors were observed during ethanol periods, as compared to baseline scoring periods. In a small number of alcohol-preferring animals, CSF amine metabolites (5-hydroxyindoleacetic acid and homovanillic acid) were raised by drinking alcohol. These studies suggest that the alcohol-selecting vervet monkey may be complementary to established primate models of alcoholism.

Effects of thirst-inducing stimuli on consumption of ethanol solutions by golden hamsters.

Two experiments were performed to examine the acute effects of thirst-inducing stimuli upon the intake of tap water and ethanol solutions by golden hamsters, a species which avidly consumes ethanol solutions. In Experiment 1, three groups of adult male hamsters (n = 6/group) were maintained on Purina chow and tap water; hamsters in two of the groups also had access to one of two ethanol solutions (15% or 30%, v/v). Animals were deprived at various times of either one or both fluids for 24 hr, and then either one or both fluids were presented during a 2-hr drinking test. Total water intake increased substantially following both selective water deprivation and total fluid deprivation whenever tap water was available during the drinking test, but no significant changes occurred when only the ethanol solution was available. Both total fluid deprivation and selective ethanol deprivation produced similar increases in ethanol consumption, but selective water deprivation did not, suggesting that the temporary removal of tap water has little direct effect upon ethanol intake in hamsters, at least at the ethanol concentration levels studied here. In Experiment 2, thirst was induced by a subcutaneous injection of 10% saline (1 ml/100 g). This procedure produced large increases in total water intake whenever tap water was available during the drinking test, but ethanol intake did not change under any circumstances. These results suggest that factors that acutely enhance water intake have little or no effect upon the ethanol consumption of golden hamsters.

Behavioral and subjective effects of ethanol: relationship to cerebral metabolism using PET.

This study examined the effects of ethanol on regional cerebral metabolic rate using positron emission tomography (PET). The study explored the relationship between the mood-altering effects of ethanol and its effects on regional cerebral glucose utilization (CMRglu) in eight healthy male volunteers. In the first phase of the study, the subjects participated in a behavioral preference procedure conducted in a recreational environment to determine their responses to ethanol (0.5 g/kg) in a naturalistic setting. They then participated in three PET sessions, receiving at three to seven day intervals, in counterbalanced order, placebo, 0.5 g/kg or 0.8 g/kg ethanol. PET scans were conducted using a PETT-VI scanner with F-18-2-fluoro-2-deoxyglucose (FDG) as the tracer. The mood-altering effects of ethanol were measured in both the naturalistic and the PET phases of the study. Ethanol produced comparable effects on mood in the naturalistic and the PET settings (i.e., increases in positive mood). The lower dose of ethanol produced variable effects on whole brain and regional CMRglu across subjects. There was some suggestion that certain regional metabolic changes after ethanol were correlated with subjective responses to the drug. The higher dose of ethanol decreased whole brain CMRglu in most subjects. All regions were affected about equally. It was concluded that the mood-altering effects of ethanol are not related in a simple manner to regional changes in CMRglu.

Both ethanol consumption and protein deficiency increase the fragility of pancreatic lysosomes.

Both ethanol abuse and protein deficiency result in pancreatic injury. Moreover, these two variables frequently coexist. As lysosomal enzymes may play a role in the initiation of pancreatic injury, the aim of this study was to determine the effects of ethanol consumption and protein deficiency on pancreatic lysosomal stability. For 3 weeks, male Sprague-Dawley rats were match-fed (in groups of four) isocaloric amounts of one of the following liquid diets: (1) protein-sufficient diet, (2) protein-sufficient diet containing ethanol as 36% of the total energy, (3) protein-deficient diet, and (4) protein-deficient diet containing ethanol as 36% of energy. Pancreatic lysosomal stability was assessed by determining (a) latency, as indicated by the percentage increase in lysosomal enzyme activity in pancreatic homogenate induced by Triton X-100, and (b) by the percentage of lysosomal enzyme remaining in the supernatant after sedimentation of the lysosomal pellet from the pancreatic homogenate. Protein deficiency was associated with a decrease in latency and an increase in supernatant enzyme. Ethanol administration was associated with a decreased latency. Both protein-deficient and ethanol-fed animals exhibited higher pancreatic activities of cathepsin B, a lysosomal protease capable of activating trypsinogen. In addition, protein-deficient animals exhibited higher pancreatic activities of acid phosphatase, N-acetyl-glucosaminidase, and beta-glucuronidase. As lysosomal enzymes are postulated to play a role in the initiation of pancreatitis, these results suggest that ethanol consumption and protein deficiency may at least partly exert their toxic effects on the pancreas by altering pancreatic lysosomal stability and increasing the glandular content of cathepsin B.

Alcohol consumption aggravates copper deficiency.

Male weanling Sprague-Dawley rats were fed a copper-deficient (0.6 microgram Cu/g) diet containing either fructose or starch. Half of the animals fed the starch diet drank a 20% solution of ethanol in water. Ethanol was chosen as an agent to mimic fructose metabolism with the intention that ethanol will exacerbate the signs of copper deficiency and will negate the protective effect of dietary starch. The consumption of a 20% ethanol drink for 6 weeks by copper-deficient rats fed starch resulted in the exacerbation of the deficiency similar to that exerted by fructose. The signs associated with the deficiency in both alcohol and fructose consumption included anemia, heart hypertrophy with gross abnormalities, and mortality. In contrast, none of the copper-deficient control rats that drank water exhibited anemia or heart abnormalities, and none died of the deficiency. In addition, sorbitol pathway in the kidney and liver was stimulated by the consumption of alcohol and fructose. The data support the contention that the combination of certain metabolic pathways of carbohydrate metabolism with copper deficiency are responsible for the exacerbation of the deficiency.

Vagal mediation of the effect of alcohol on heart rate.

Alcohol (0.5 g/kg bodyweight) was administered in two sessions and placebo in a third session to normal, healthy social drinkers. A control group was administered a mixer (i.e., no alcohol) for each of the three sessions. The heart rate and vagal tone index (V) response patterns were different to alcohol than to the mixer or placebo. The treatments did not differentially influence pulse transit time. The results indicated that the acute effect of a moderate dose of alcohol on the heart is parasympathetically (i.e., vagally) mediated and has no significant direct sympathetic component.

Corticotropin-releasing factor is altered in brains of animals with high preference for ethanol.

Ethanol administered to rats has been shown to stimulate the hypothalamic-pituitary-adrenal axis. The present study describes alterations in brain CRF neuronal systems that accompanied the voluntary high consumption of ethanol by Wistar rats presented with a free choice between 6% ethanol and tap water. Hypothalamic CRF concentrations (outside median eminence) were significantly increased in animals with a high preference for ethanol whereas concentrations of CRF in neurointermediate pituitary and medulla-pons were significantly decreased. No changes of CRF levels were evident in median eminence, frontal cortex, midbrain, thalamus, or cerebellum. Brain CRF concentrations in two strains of mice with genetically determined differential alcohol preference were measured. In ethanol-naive mice, there were documented differences in CRF concentrations, with an increase in frontal cortex levels, and a decrease in medulla-pons levels in the ethanol-preferring strain (C57BL/6J) compared to the nonpreferring strain (C3H/CRGL/2). Thus, certain brain CRF neuronal systems are preferentially affected by high ethanol consumption, and pre-existing differences in these systems may even contribute to the development of a high preference for ethanol.

Lower serum thyroxine levels in rats following prenatal exposure to ethanol.

Fetal alcohol syndrome (FAS) is noted for poor growth, developmental delays, and mental retardation. In animals, prenatal alcohol exposure alters anatomical, physiological, and neurochemical maturation and produces behavioral changes similar to those in children. Since thyroid hormones are critical trophic factors for normal somatic and neural maturation, and since fetal thyroid hormones are profoundly affected by acute maternal ethanol administration, we hypothesized that postnatal effects of prenatal alcohol exposure may be related to abnormal thyroid hormone development. We report here that young rats exposed to alcohol in utero have significantly lower serum total thyroxine (T4) concentrations than normal and pair-fed control rats. The results suggest prenatal ethanol exposure may compromise thyroid development in ways not attributable to undernutrition or developmental delays alone. Lowered total T4 levels may be a teratogenic outcome of prenatal alcohol exposure, which could contribute to impaired growth, altered neural organization, and behavioral dysfunction.

Perinatal undernutrition reduced ethanol intake preference in adult recovered rats.

Adult female rats submitted to a protein deprivation schedule at perinatal age (from 14th day of fetal life until 50 days of age) were tested for alcohol intake in a preference test. When compared with control animals, experimental rats exhibited higher overall fluid intake. Nevertheless, in terms of ethanol preference these subjects evidenced lower preference to this drug. A test for assessing ethanol olfactory preference did not show any differences between control and experimental rats in basal conditions. However, after repeated exposure to alcohol, deprived rats showed an aversion to ethanol odor, while controls evidenced the opposite effect, i.e., heightened preference. Possible differences to the aversive effects of ethanol between control and experimental animals were assayed by means of two taste aversion tests, by associating alcohol to sucrose or NaCl. No differences were detected between both groups of rats. These results demonstrate that early undernutrition reduces ethanol preference in a free choice situation. Such an effect could be due, at least partially, to odor aversion developed by repeated exposure.

Effects of moderate alcohol consumption on platelet function, tissue-type plasminogen activator and plasminogen activator inhibitor.

Short-term effects of moderate alcohol consumption on platelet function, tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI) were studied in two age groups of volunteers (20-30 and 45-55 years), each consisting of eight healthy males. The alcohol (30 g in red port and wine) was consumed during a standard dinner. Two blood samples were drawn: one in the postprandial phase, and one the next morning after fasting overnight. Alcohol consumption tended to increase platelet aggregation and production of hydroxy fatty acids, reduced plasma t-PA activity and increased PAI activity in the postprandial phase. After the overnight fast the effects on t-PA and PAI had disappeared whereas at that time alcohol consumption tended to decrease platelet function. The effects of alcohol on t-PA and PAI activity appeared mainly in the older age group, whereas the t-PA activity in this group was already much lower, irrespective of alcohol consumption.

[General practice trial with breath alcohol analysis]. / Praxiserprobung der Atemalkoholanalyse.

Breath- (BrAC) and blood-alcohol concentrations (BAC) of 42 persons are compared in a drinking experiment under conditions which approach the situation in practice. Breath-alcohol determinations consisted in double measurements and included the determination of temperature of expired air. The measured BrAC was related to a temperature of 34 degrees C and was interpolated to the time when the blood sample was taken. According to the fact that in most cases the resorption of alcohol was not yet finished, the BrAC converted by a factor 2.1 to blood equivalent values were remarkably higher than the corresponding BAC values. If only these values are taken into consideration which are measured in the period of more than 20 minutes after drinking was stopped, the converted BrAC values differ not more than +20% from BAC values.

The role of the gastric and hepatic vagus in voluntary alcohol intake.

The present study investigated a possible role for neural signals sent from the liver and stomach to the brain in the regulation of alcohol intake. Experiment 1 showed that gastric vagotomy (GVX) reduced the intake of 3% alcohol and 6% alcohol, while water intake was increased. This effect was not due to an alteration in pharmacokinetics, although an alteration in taste function could not be ruled out. Angiotensin II reduced the intake of 6% alcohol and stimulated the intake of water similarly in both GVX and sham groups. In Experiment 2 rats were subjected to hepatic vagotomy or sham laparotomy and then offered a choice between an alcohol solution and tap water for 40 min each day. Although hepatic vagotomy (HVX) did not alter the intake of 3% alcohol or water, 6% alcohol intake was significantly reduced. Angiotensin II decreased 6% alcohol intake and increased water intake similarly in both groups. These experiments indicated that interrupting information from the liver and stomach to the brain by selective gastric and hepatic vagotomy can decrease voluntary alcohol intake. Since vagal afferent nerves are thought to participate in the control of food intake, the present findings support the hypothesis that the "food-like" qualities of alcohol, i.e., calories and taste, can contribute to the regulation of alcohol intake.

Does alcohol promote reactive hypoglycemia in the rat?

Alcohol induces a reactive hypoglycemia in man, but divergent results have been reported, in man and rats, on the effects of ethanol plus a carbohydrate load. The interactions between ethanol and glucose metabolism are complex. In the present study isocaloric solutions of glucose alone (A) or glucose plus alcohol (B) were administered in rats at the beginning of nighttime. Their effects were compared on blood glucose (BG) levels. Since rats don't drink alcohol spontaneously, glucose was given by mouth and alcohol through an intragastric catheter (IG); in the case of glucose alone half the load was ingested by mouth, and half IG. After administration, BG level was continuously determined in freely moving rats. It was shown that the latency to eat after the ingestion of glucose plus alcohol was significantly shorter and the size of the meal smaller. The postabsorptive hyperglycemia was significantly decreased in B as compared to A. The following hypoglycemia was more severe in B and it appeared earlier. In addition, a stress was applied after both A and B. It is well known that stress are potent stimuli of the sympathetic nervous system which inhibits insulin secretion. In both situations (A and B) with stress, the small preabsorptive hypoglycemia which appeared 4 min after the ingestion was suppressed. The hyperglycemia was higher in situation A with, than without, stress. The subsequent hypoglycemia was significantly lower. After stress in B, there was no difference in the peak of hyperglycemia but it appeared later. So, in rat the ingestion of alcohol together with an oral glucose load could trigger a reactive hypoglycemia. Stress greatly enhanced the phenomenon.