The sinusoidal barrier in alcoholic patients without liver fibrosis

Summary Alcohol induces morphological changes in the endothelial and perisinusoidal cells at the fibrotic stage of alcoholic liver diseases. Directly or indirectly, through hemodynamic disturbances linked to the enlargement of steatotic hepatocytes, alcohol may modify this barrier before the onset of fibrosis. Liver biopsies were obtained from control and from alcoholic patients and perfusion-fixed. Volume and surface densities of endothelial cells, perisinusoidal cells and their processes were measured. Liver histology was normal in the 2 groups except for steatosis in the alcoholics. Volume densities represented 8.2%, 4.7% and 3.2% of the sinusoid in controls for endothelial cells, perisinusoidal cells and their processes whereas surface densities represented respectively 0.5, 0.23, 0.21 m²/cm³ of sinusoid. Morphometric values were not significantly different in the alcoholic patients. In none of the alcoholic patients did fine morphological studies of sinusoidal cells give any indication of the possible evolution of the alcoholic disease towards fibrosis. These results indicate that in the group of patients studied, alcohol, before the fibrotic stage, did not significantly alter the sinusoidal barrier.     

Changed accumbal responsiveness to alcohol in rats pre-treated with nicotine or the cannabinoid receptor agonist WIN 55,212-2

Alcohol, nicotine, and cannabinoid acutely increase the activity of the mesolimbic dopamine (DA) pathway. Although polysubstance consumption is a common pattern of abuse in humans, little is known about dopamine release following pre-exposure to these drugs. The purpose of this study was to test whether alcohol-induced dopamine release into the nucleus accumbens (NAc) shell is modified by different pre-treatments: water (i.g.), alcohol (1 g/kg, i.g.), nicotine (0.4 mg/kg, s.c.), and WIN 55,212-2 (1 mg/kg, s.c.). Male Wistar rats were treated (i.g.) for 14 days with either water or alcohol. In the following 5 days rats were injected (s.c.) with vehicle, nicotine, or WIN 55,212-2. Finally, a cannula was surgically implanted into the NAc shell and alcohol-induced extracellular dopamine release was monitored in freely moving rats. Alcohol (1 g/kg; i.g.) only increased the release of dopamine when animals were previously treated with water. This DA increase was markedly inhibited by (subchronic) treatment (5 days) with nicotine or WIN 55-212-2 as well as by previous (chronic) exposure to alcohol (14 days). These data demonstrate that pre-treatment with nicotine and the cannabinoid agonist WIN 55,212-2 is able to change the sensitivity of the NAc shell in response to a moderate dose of alcohol. Therefore, cannabinoid and nicotine exposure may have important implications on the rewarding effects of alcohol, because these drugs lead to long-lasting changes in accumbal dopamine transmission.     

Behavioral Characterization of Alcohol-Tolerant and Alcohol-Nontolerant Rat Lines and an F2 Generation

The Alcohol Tolerant (AT) and Alcohol Nontolerant (ANT) rats, selectively bred for ethanol-induced ataxia on the inclined plane at ALKO in Finland, were moved to the University of Colorado in 1998. The selection phenotype was tested on generation 60 animals in Colorado. In week one, ataxia was measured on the inclined plane 30 minutes after an intraperitoneal dose of 2 g/kg 15% w/v ethanol. Differences in ethanol-induced ataxia between the AT and ANT lines at the University of Colorado were similar to those in the original lines in Finland. In week two, ataxia was measured on the inclined plane at 5 and 30 minutes, and tolerance was measured as the time to regain the original angle of sliding. The AT rats rapidly developed tolerance to 2 g/kg ethanol on the inclined plane; tolerance development was significantly slower in the ANT rats. In week three, the animals were tested for the duration of loss of righting reflex (LORR) and blood ethanol concentration at regain of the righting reflex (BEC_RRR) following a dose of 3.5 g/kg. The AT rats had a significantly higher BEC_RRR than did the ANT rats, but did not differ in LORR. A separate experiment with previously untreated rats demonstrated that naïve animals of the two lines did not differ in BEC_RRR or LORR. AT and ANT rats were genotyped for the mutation that occurs in the gene for the α6 subunit of the GABA_A receptor, a natural mutation that is known to affect benzodiazepine responses. All ANT animals tested carried the mutant allele, whereas some AT families carried the mutation and others were wild type. There was no effect of the mutation in AT rats for any of the phenotypes that were tested. After several generations of brother–sister mating, the AT and ANT lines were more than 90% inbred as determined by genotyping. One AT (wild-type) line and one ANT (mutant) line were selected for breeding an F₂ intercross generation of 1200 animals. They were phenotyped for sensitivity and tolerance to ethanol on each of three consecutive weeks. Order of testing had a modest effect on some of the phenotypes: when tested during the third week as compared to weeks one or two, BEC_RRR was increased, 30-minute sensitivity was increased, and development of acute tolerance was increased. Statistically significant correlations were found between tolerance and sensitivity at both 5 and 30 minutes, and between LORR and BEC_RRR. The smaller (or absence of) significant correlations between others of the phenotypes indicate(s) that they are most likely controlled by different sets of genes.     

大鼠心肌匀浆上清液对骨髓间质干细胞诱导分化的影响

目的：探讨心肌匀浆上清液对大鼠骨髓间质干细胞（MSCs）诱导分化的影响。 方法： 体外分离培养大鼠MSCs，检测纯度。于原代培养第3 d加入自体心肌匀浆上清液持续作用1周。3周后，观察细胞形态，采用免疫细胞化学检测肌球蛋白重链和心肌特异性肌钙蛋白-T，RT-PCR方法检测Nkx2.5、α-MHC和ANP基因的表达。 结果： 大鼠MSCs经诱导后，表达肌球蛋白重链、心肌特异性肌钙蛋白-T和Nkx2.5、α-MHC基因，但未表达ANP基因，也未观察到肌管和闰盘样结构。 结论： 心肌匀浆上清液对MSCs具有定向诱导分化作用，但诱导不完全，具体机制仍需深入研究。     

Ultrasonic vocalizations and maternal-infant interactions in a rat model of fetal alcohol syndrome

When isolated from their dams and littermates, rat pups emit ultrasonic vocalizations to elicit attention and retrieval from their dams. This study examined the effects of perinatal alcohol exposure on ultrasonic vocalizations and maternal-infant interactions. Alcohol was administered throughout gestation to the dams and during the early postnatal period to the pups. Control groups consisted of a nontreated control and an intubated, pair-fed control. Ultrasonic vocalizations were measured on postnatal day (PD) 5 under varying conditions of isolation. Maternal behaviors were examined on PD2, 4, 6, 8, and 10. Maternal behaviors were not significantly affected by prior alcohol administration to either the dams or the pups. However, ethanol-exposed rat pups vocalized more on PD5 than controls regardless of condition. The heightened vocalization response of the ethanol-exposed pups might be an underlying factor in the persistent effects of perinatal ethanol exposure on social behavior.     

Effects of ethanol and acetaldehyde on phagocytic functions

Summary Although a number of skin diseases are characterized by the presence of an increased number of phagocytes in their lesions, the effects of alcohol on phagocytic functions are not clearly understood. Therefore, we measured the influence of ethanol and acetaldehyde on the generation of oxygen radicals, chemotaxis and the release of lysosomal enzymes from human phagocytes. We added 0.03%–3% ethanol and 0.005%–0.25% acetaldehyde to cell cultures. We found that both ethanol and acetaldehyde suppressed the generation of oxygen radicals from granulocytes and monocytes; the ID₅₀ was achieved at concentrations of approximately 0.25% for ethanol and 0.03% for acetaldehyde. A significant inhibition of granulocyte chemotaxis was first noted with 0.063% ethanol and 0.016% acetaldehyde. Ethanol and acetaldehyde inhibited the release of the lysozyme of monocytes at concentrations of >0.75% and >0.03% respectively, but granulocytes were unaffected; the release of -glucuronidase and lactate dehydrogenase remained stable. Due to the high volatility of the agents, especially acetaldehyde, under the experimental procedures employed, the actual concentrations of the agents were probably lower and similar to those measured in vivo. Our results indicate that defined phagocytic functions are strongly inhibited by concentrations of ethanol and acetaldehyde which are associated with moderate to severe inebriation.In partial fulfillment of an M. D. thesis     

Alcoholism and Epilepsy

There is a scarcity of population-based epidemiological investigations concerning the prevalence of epilepsy among alcoholics, and of alcoholism among epileptic patients. Available data seem to suggest that the prevalence of epilepsy among alcoholics is at least triple that in the general population, and that alcoholism may be more prevalent among epileptic patients than in the general population. The term "alcoholic epilepsy" has been used with varying definitions in different investigations. It is suggested that a uniform definition be adopted so as to minimize confusion when comparing data from different laboratories. Although there is general agreement that excessive alcohol intake can increase the frequency of seizures in epileptic patients, limited available data suggest that light to moderate social alcohol drinking may not affect seizure frequency. However, epileptic patients should be warned about the possible adverse effects of alcohol, especially those who have refractory forms of epilepsy. Except for a few anomalous cases, evidence for the direct seizure-provoking effect of alcohol is not strong. This is because it is difficult to pinpoint alcohol as the only etiology; more likely, alcohol is only one factor among others (e.g., head trauma, cerebral infarct, alcohol withdrawal, and metabolic effects of alcohol) in provoking seizures. Because seizures are a symptom and not a disease, it is often difficult to distinguish epileptic seizures from alcohol-withdrawal seizures. Patients with only the latter kind of seizures should not need chronic antiepileptic medication.     

Alcohol and obesity: A new look at high blood pressure and stroke

Summary An investigation of the staff of a car assembly plant (3,351 persons) revealed a similarity between the change in relative body weight and diastolic blood pressure with age. There is a good temporal correlation between the course of alcohol consumption during life and the change of the relative body weight. German women had significantly less blood pressure for the same relative body weight than German men, and foreign employees had lower blood pressure than Germans In both cases the main cause is the difference in alcohol consumption. Besides obesity and hereditary factors, alcohol is the main cause of essential hypertension today. Epidemiological and experimental data indicate that there are two ways from alcohol to high blood pressure, a more direct one and an indirect one via obesity. Alcohol causes obesity via a change in metabolism (hyperinsulinism) rather than by higher caloric intake. In both ways alcohol is an important cause of stroke. To reduce body weight and blood pressure, a reduction of alcohol consumption should be recommended in addition to reduced caloric intake and increased physical activity as means of preventive neurology.     

Dexamethasone suppression and multiple hormonal responses (TSH,prolactin and growth hormone) to TRH in some psychiatric disorders

Summary Baseline and TRH-induced changes of thyroid stimulating hormone (TSH), prolactin (PRL), and growth hormone (GH) were measured in 15 healthy control subjects and 63 psychiatric inpatients with DSM-III diagnoses of major depression (n = 19), schizophrenic disorder (n = 20), alcohol dependence (n = 10), and adjustment disorder (n = 14); baseline and postdexamethasone cortisol (CS) were also determined 3–6 days after the TRH-challenge. All patients and controls were women of similar mean age, weight, height, and they were free from interfering illness or drugs.Baseline TSH and PRL were lower in depression, TRH-induced TSH and PRL responses were lower in the whole patient group, but most markedly in depression and alcohol dependence. Postdexamethasone CS was significantly higher in depression, schizophrenia and alcohol dependence. Basal GH did not differentiate the subgroups; TRH-induced pathological GH responses were sometimes found in the patient groups. The differences were most marked quantitatively in major depression: a multivariate analysis of variance showed that TSH, postdexamethasone CS and PRL were the most important variables in separating patients from controls. A discriminant function derived from these variables classified all controls and 18 of 19 depressed patients correctly; however, 25 of the 44 other patients were also classified with depression.It was confirmed that psychiatric patients show significantly more endocrine disturbances than controls, and this was seen not only in major depression but also in at least three other conditions. Further work is needed to identify other neuroendocrine patterns more specific to depressive disorder.     

Bladder cancer and the consumption of alcoholic beverages in Spain

The relationship between bladder cancer and alcohol consumption was investigated in a case-control study conducted in 546 patients (453 males and 53 females) with diagnoses of papillary urothelial carcinoma during 1978–1982 at La Paz hospital (Madrid), and an equal number of controls matched for age, sex and date of admission to the hospital. The results showed that the risk of bladder cancer does not increase with the intake of beer, wine and spirit beverages. However, a high risk of bladder cancer was associated with consumption of wine mixed with gaseosa (a refreshment beverage consisiting of carbonated water plus artificial sweeteners).