Relation between liver amino acid-catabolizing enzymes and free amino acids of liver and plasma in adult cockerels fed diets containing graded levels of protein

Activities of liver amino acid-catabolizing enzymes and liver and plasma free amino acid concentrations in adult cockerels fed diets containing 3% to 21% casein were determined 2 hours after a meal. Liver tryptophan pyrrolase activity and liver tryptophan increased with an increase in dietary casein level, but plasma tryptophan decreased with the increase dietary casein level. As the dietary casein level increased, liver lysine-ketoglutarate reductase activity decreased, but liver and plasma lysine increased proportionally, and the rate of increase was larger in the plasma than in the liver. Liver phenylalanine hydroxylase activity increased with the increase in dietary casein level from 3% to 12%, and thereafter remained unchanged. Reflecting the change of this enzyme, phenylalanine increased in the liver and decreased in the plasma with the increase in dietary casein level from 3% to 12%, and thereafter the rate of increase in liver phenylalanine became small and plasms phenylalanine increased. Liver tyrosine was not influenced by the dietary casein level, whereas plasma tyrosine increased sharply from 3% to 12%, and thereafter the rate of increase decreased. Thus, the difference between liver and plasma free amino acid responses might be due to the changes in the activities of liver amino acid-catabolizing enzymes.     

A study of the relationship between home care services and hospital readmission of patients with congestive heart failure

Treatment of the alcohol withdrawal syndrome is best accomplished using pharmacologic agents that have minimal interaction with alcohol, have limited adverse effects, and are without abuse potential. The partial benzodiazepine receptor agonist beta-carboline compound, abecarnil, has been shown in animal and human studies to possess a number of these characteristics and to be useful in the reduction of alcohol withdrawal convulsions in mice. In this study, 49 alcohol-dependent inpatients who exhibited at least moderate symptoms of uncomplicated alcohol withdrawal were treated over a 5-day detoxification period with abecarnil or diazepam and rated daily for alcohol withdrawal symptoms and adverse events. Both the abecarnil and diazepam treatment groups exhibited a similar marked reduction in withdrawal symptoms over time. In addition, similar rates of successful treatment and improvement were observed after 1 day of treatment and at termination in alcoholics treated with either medication. Overall, rates of adverse events and changes in liver enzymes were similar in both treatment groups and were generally benign. Because of the unique pharmacologic profile of abecarnil in animal and in non-clinical human studies, including anticonvulsant action, low abuse liability, and a favorable side effect profile, further study of compounds of the partial benzodiazepine receptor agonist type in the treatment of alcohol withdrawal syndromes seems warranted.     

Elevated liver enzymes of unknown etiology

Elevated liver enzymes are a frequent clinical problem of varying significance. In otherwise healthy individuals the most frequent causes of elevated liver enzymes are toxins such as alcohol and drugs. In this situation, further studies are usually not needed; it is sufficient to control the relevant parameters after abstinence from alcohol or withdrawal of the drug(s). In patients with known, suspected or unknown nonhepatic diseases, elevated liver enzymes can be caused by cardiovascular diseases, obesity, endocrinopathies, infectious diseases, malignancies, collagen disorders, sarcoidosis and other diseases. In this situation, sonography or liver histology frequently will be diagnostic, revealing the cause of the underlying disease as well as of the elevated liver enzymes.     

Acute liver failure following tetrabamate

Tetrabamate (Atrium), a composite preparation of phenobarbital, difebarbamate and febarbamate, is widely used to reduce ethanol withdrawal symptoms such as tremor, agitation and anxiety. Generally this drug is well tolerated and a few cases of reversible hepatitis as well as clinically mild symptoms of asthenia have been described. We report on a 28-year-old female patient admitted to hospital with acute liver failure after treatment with tetrabamate because of alcohol withdrawal symptoms. Liver biopsy revealed a drug-induced toxic alteration with extensive panlobular necrosis without signs of alcoholic hepatitis. Under supportive therapy liver parameters normalized in 3 months. In view of this potentially lethal adverse effect of tetrabamate, it should not be used for ethanol withdrawal symptoms.     

Chronic liver failure induced by long-term administration of tegafur: a case report

A 55 year-old man was admitted with massive ascites. Although the laboratory data on admission were compatible with hepatic cirrhosis and remarkable esophageal varices were observed during endoscopy, the imaging findings such as computed tomography and ultrasonographic examination did not confirm hepatic cirrhosis. The patient had no history of alcohol abuse, blood transfusions or acute hepatitis. Serological markers related to viral and autoimmune hepatitis were all negative. Seven years ago, the patient had undergone an operation for colon cancer and has been taking tegafur since then for a total of 55 months. Tegafur was suspected as the causative agent for the liver dysfunction of this patient and the administration of tegafur was stopped. His laboratory data improved gradually and the ascites vanished. The first liver biopsy performed 6 months after discontinuation of tegafur still revealed chronic active hepatitis. However, at the liver biopsy performed 18 months after withdrawal of tegafur, inflammatory activity had subsided and the third liver biopsy, performed 34 months thereafter, revealed further improvement of the pathological changes that had occurred in the liver. We therefore conclude that the administration of tegafur may have caused chronic active liver injury with portal hypertension manifested as ascites and esophageal varices.     

The effect of serotonin antibodies on the development of the alcohol abstinence syndrome in CBA mice

Experiments on CBA mice with alcohol withdrawal syndrome showed a reduction of abstinence after injection of serotonin antibodies in dose 5 and 10 mg intraperitoneally. One more result was a decrease of horizontal locomotory activity after injection of 5 mg of serotonin antibodies to mice with 24 hour withdrawal syndrome.     

The place of oral contraceptives and pregnancy in the aetiology of amenorrhoea, a study of 188 cases of secondary amenorrhoea lasting more than one year (author''s transl)

Platelet function was assessed before and one week after acute alcohol withdrawal in eighteen male alcoholics. Compared to normal male controls, the platelets of the alcoholics were slightly hypoaggregable on admission but became hyperaggregable one week after commencement of alcohol withdrawal therapy. The changes were most noticeable in those patients who were alcoholaemic on admission and when using ADP or adrenaline as aggregating agents. There was no consistent change in platelet counts or in platelet adenine nucleotide levels, both of which were normal.     

Vasopressin fragment, AVP-(4-8), improves long-term and short-term memory in the hole board search task

To investigate the neurotoxicity of acetaldehyde covalent adducts, immunohistochemical staining for acetaldehyde adducts using the antibody against acetaldehyde adducts, was performed in the cerebral cortex of ethanol-fed (withdrawal) mice. In the ethanol-fed mice, the degeneration in the cerebral cortex was found, while the protein epitope related to acetaldehyde was found in the cerebral cortex, liver and adrenal cortex. No histochemical and immunohistochemical changes in the tissues from the control mice were found. It is possible that acetaldehyde adducts may effect on the cerebral cortex as the neurotoxicity which cause psychosis such as delirium and hallucination after alcohol drinking.     

Role of Bcl-2 in alpha beta T cell development in mice deficient in the common cytokine receptor gamma-chain: the requirement for Bcl-2 differs depending on the TCR/MHC affinity

Withdrawal seizure-prone (WSP) and withdrawal seizure-resistant (WSR) mice were selectively bred to have severe (WSP) or mild (WSR) handling-induced convulsions after chronic ethanol inhalation. The purpose of the present experiments was to determine whether seizure susceptibility differences between WSP and WSR mice during ethanol withdrawal were specific to agents acting at gamma-aminobutyric acidA or excitatory amino acid (EAA) receptors. Male WSP and WSR mice were exposed to ethanol vapor or air for 24 or 72 h. During peak withdrawal (i.e., between 6.5 and 8 h after removal from the inhalation chambers), separate groups of animals were administered pentylenetetrazol, (+)bicuculline, N-methyl-D-aspartate, kainic acid, or strychnine via timed tail vein infusion. Withdrawal from ethanol significantly increased sensitivity to pentylenetetrazol and (+)bicuculline versus air-exposed WSP and WSR mice. In contrast, sensitivity to N-methyl-D-aspartate-induced convulsions was significantly decreased in the ethanol-exposed WSR and unchanged in the ethanol-exposed WSP mice. Sensitivity to kainic acid was significantly increased in both ethanol-exposed WSR and WSP mice, although the magnitude of change in sensitivity was greater in the ethanol-withdrawing WSP line. Interestingly, sensitivity to strychnine was decreased similarly in the ethanol-exposed WSP and WSR mice, compared with their respective air-exposed animals. These results suggest that chronic ethanol increased sensitivity to convulsants active at gamma-aminobutyric acidA receptors similarly in WSP and WSR mice, but differentially changed sensitivity to convulsants active at EAA receptors in the lines. This supports a role for EAA systems in determining genetic susceptibility to alcohol withdrawal.     

Impact of age on the severity, course, and complications of alcohol withdrawal

BACKGROUND: Early identification of alcohol-dependent patients at increased risk for severe or complicated alcohol withdrawal would improve triage and treatment. However, the role of age in predicting alcohol withdrawal outcomes has not been well studied. OBJECTIVE: To assess the impact of age on the severity, course, and complications of alcohol withdrawal. METHODS: We performed a retrospective cohort study of 284 inpatients admitted for alcohol withdrawal between September 1992 and August 1994. Outcomes included alcohol withdrawal severity measured by the revised Clinical Institute Withdrawal Assessment for Alcohol scale, quantity and duration of benzodiazepine therapy, and complications during withdrawal. RESULTS: Initial and maximal withdrawal severity scores, amount of benzodiazepine administered, and duration of benzodiazepine treatment for elevated withdrawal severity scores did not change significantly with age. However, patients aged 60 years and older had increased risk for delirium (adjusted odds ratio [OR], 4.7; 95% confidence interval [CI], 1.5-15.0; P = .008), falls (OR, 3.1; 95% CI, 0.9-11.2; P = .08), and transient dependency in 2 or more activities of daily living (OR, 5.8; 95% CI, 2.9-11.7; P < .001). As age increased, there were significant increases in length of stay (P < .001) and frequency of discharge to an extended care facility (P < .001). CONCLUSIONS: Although alcohol withdrawal severity scores and benzodiazepine requirements were similar across age groups, patients aged 60 years and older were at increased risk for cognitive and functional impairment during withdrawal. These findings support recommendations that older patients with alcohol withdrawal are best treated in closely supervised settings.     

Research progress on the glia cell line-derived neurotrophic factor

The therapy of the alcohol withdrawal syndrome is very heterogeneous with more than 100 drug combinations. This results from differently qualified physicians and from insufficient pharmacostudies concerning evaluation and psychopathological methodology of the alcohol withdrawal syndrome. The following advices can be given: Physical withdrawal should take place under the conditions of an appropriate hospital with a qualified team. The application of electrolytes and vitamines (B1) may be necessary in alcohol addicts. Less severe alcohol withdrawal syndromes are treated sufficiently with carbamazepine, sometimes it can be necessary to combine it with neuroleptics or benzodiazepines. A secure prevention from delirium tremens and its treatment is only guaranteed by clomethiazole or benzodiazepines. To reduce the doses of those drugs, combinations with neuroleptics are possible. In general voluntary physical withdrawal proves only to be successful if longtime abstinence is planned and a motivation program is setup the for withdrawal treatment.     

Alcoholic liver disease. Treatment strategies for the potentially reversible stages

Even modest alcohol ingestion can increase the risk of steatosis, and long-term, excessive consumption can lead to alcoholic hepatitis and eventually cirrhosis. Most patients with clinically significant alcoholic liver disease have histologic findings typical of all three conditions. The only clearly beneficial treatment is abstinence from alcohol. Abstinence in combination with proper nutrition and general supportive care is state of the art. Steatosis is reversible upon withdrawal of alcohol, but alcoholic hepatitis can persist even with abstinence and may progress to cirrhosis. Corticosteroid therapy may reduce short-term mortality rates in patients with moderate or severe alcoholic hepatitis who have hepatic encephalopathy but no evidence of infection or gastrointestinal bleeding. Treatment with colchicine may decrease the risk of cirrhosis; however, once cirrhosis has developed, the liver damage is irreversible. The prognosis is improved with abstinence, but complications (e.g., ascites, gastrointestinal bleeding) often occur. Liver transplantation may be considered in patients with severe complications.     

Effects of chronic ethanol consumption and withdrawal on the neuroactive steroid 3alpha-hydroxy-5alpha-pregnan-20-one in male and female rats

Prolonged alcohol (ethanol) consumption leads to the development of alcohol tolerance and cross-tolerance to some benzodiazepines and barbiturates. In contrast, rats undergoing alcohol withdrawal are sensitized to the anticonvulsant effects of the endogenous GABA(A) receptor modulator, 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP). Alterations in endogenous, cerebral cortical levels of 3alpha,5alpha-THP during alcohol withdrawal could contribute to the observed sensitization to 3alpha,5alpha-THP. Therefore, this study investigated plasma and brain levels of 3alpha,5alpha-THP, progesterone, and corticosterone during alcohol dependence and withdrawal in the rat. Plasma corticosterone, progesterone (a precursor of 3alpha,5alpha-THP) and 3alpha,5alpha-THP levels were unchanged in alcohol-dependent animals. Cerebral cortical levels of 3alpha,5alpha-THP decreased in dependent male animals, but not in dependent female rats. During alcohol withdrawal, plasma corticosterone and progesterone levels increased in male, but not female rats. However, neither plasma nor cerebral cortical 3alpha,5alpha-THP levels were altered from control levels in male or female rats during alcohol withdrawal. Plasma and brain levels of 3alpha,5alpha-THP were markedly higher in female compared with male rats. Cerebral cortical levels of 3alpha,5alpha-THP during the diestrus phase of the estrus cycle were approximately 4 to 6 ng/g, a concentration that may approach physiological relevance. These findings suggest that sensitization to 3alpha,5alpha-THP during alcohol withdrawal is not mediated by elevations in brain levels of endogenous 3alpha,5alpha-THP in male or female rats. However, elevations in circulating corticosterone and progesterone levels during ethanol withdrawal in male rats may underlie gender differences in allopregnanolone sensitivity during ethanol withdrawal.     

Protein fluorescence and electronic energy transfer in the determination of molecular dimensions and rotational relaxation times of native and coenzyme-bound horse liver alcohol dehydrogenase

The intrinsic fluorescence lifetimes of horse liver alcohol dehydrogenase (EC 1.1.1.1) and pig heart isocitrate dehydrogenase (EC 1.1.1.42) have been determined to be 5.36 ns and 4.84 ns, respectively. When reduced coenzyme is bound, the fluorescence lifetime of alcohol dehydrogenase is reduced to 4.98 ns while that of isocitrate dehydrogenase remains unchanged. Oxidized coenzymes have no effect on fluorescence lifetimes of alcohol and isocitrate dehydrogenases. This virtual constancy of protein fluorescence lifetimes has allowed the conclusion to be reached that in protein-ligand complexes with equilibrium constants in the range of 10(4)-10(6) M(-1), the static mode of quenching is substantial. The observation of resonance energy transfer in alcohol dehydrogenase-NADH complex facilitates the determination of the distance between tryptophan and the reduced nicotinamide ring involved in the transfer as 30.6 A, compared to the effective molecular radius of 36.2 A for alcohol dehydrogenase. The increased rotational relaxation times of coenzyme-bound alcohol dehydrogenase relative to the unliganded form (sigmah = 72 ns) indicate in this protein structural fluctuations occurring in the time range of nanoseconds.     

Iron-related indexes in chronic alcoholics. Effect of alcohol withdrawal

BACKGROUND: Increased serum transferrin saturation and ferritin levels have been reported in chronic alcoholics. AIM: To evaluate modifications in serum iron-related indexes in chronic alcohol abusers with and without cirrhosis, at enrolment and after complete alcohol withdrawal. PATIENTS: Fifty-one consecutive chronic alcohol abusers, 33 without and 18 with cirrhosis. METHODS: Liver function tests were performed and transferrin saturation percent and serum ferritin levels measured at time 0 and after 7 and 14 days of complete alcohol withdrawal. RESULTS: Duration of alcohol abuse was significantly longer in patients with cirrhosis than in those without (24 +/- 13 SD vs 18 +/- 13 SD years, p < 0.01). A concomitant increase in transferrin saturation percent and serum ferritin was found in 60% of the cirrhotics and 45% of the non cirrhotic group. During the observation period, transferrin saturation percent and serum ferritin fell significantly in both groups (from 59 +/- 33 SD to 36 +/- 22% SD, p < 0.05, and from 900 +/- 933 SD to 469 +/- 457 SD ng/ml, p < 0.01, in cirrhotics, and from 46 +/- 30 SD to 27 +/- 12% SD, p < 0.01, and from 702 +/- 602 SD to 340 +/- 29 SD ng/ml, p < 0.01, in non cirrhotics). CONCLUSIONS: Iron-related indexes increase with chronic alcohol abuse and return to normal rapidly after complete alcohol withdrawal. In chronic alcoholics the timing of determinations of iron-related indexes is crucial, and screening for possible concomitant genetic haemochromatosis must be postponed.     

Distribution of peripheral blood lymphoid subsets in alcoholic liver cirrhosis: influence of ethanol intake

The aim of the present study was to investigate the effect of chronic ethanol (EtOH) consumption on the immune system in patients with alcoholic liver cirrhosis (ALC), as analyzed by the distribution of peripheral blood (PB-) T, B, and NK lymphoid subsets using multiple stainings with monoclonal antibodies and flow cytometry. For that purpose, we have analyzed a group of patients with ALC and active EtOH intake (ALCET group) which were re-evaluated 3 months after alcohol withdrawal. As controls, both ALC patients with at least 1 year of alcohol withdrawal (ALCAW group) and healthy subjects were used. Regarding the alcohol intake period, the most relevant findings were a significant activation of the PB T-cell compartment, and specifically of the TCR alpha beta + subset, as reflected by an increased expression of both the HLA DR and CD11c antigens as well as a significant increase of both the PB NK cells (CD3-/CD56+) and the cytotoxic T cells coexpressing the CD3 and CD56 molecules. In addition, a decrease of both the numbers of total B cells and their CD5+/CD19+ subset were observed. After a relatively short withdrawal period (3 months), the abnormalities of T, P, and NK cells disappeared. These findings suggest the existence of a close relationship between EtOH consumption and the abnormalities of the immune system observed during active alcoholism. Nevertheless, ALCAW individuals displayed marked alterations on the immunophenotypic profile, as reflected by a significantly decreased number of total T cells, due to reduced levels of the CD3+/TCR alpha beta+, CD4+, CD8+, and CD4+/CD45RA+ T-cell subsets. In addition, a significantly decreased number of total PB B cells was observed in this group of patients. Our results show that in patients suffering from ALC, the abnormalities of the immune system due to a direct effect of EtOH intake (or its metabolites) should be distinguished from the immunological alterations related to the liver disease itself.     

Role of tryptophan in the elevated serotonin-turnover in hepatic encephalopathy

The increase of the brain levels of 5-hydroxyindoleacetic acid (5-HIAA) in hepatic encephalopathy (HE) suggests an increased turnover of serotonin (5-HT). To study the role of tryptophan on the increased brain 5-HT metabolism in HE, we attempted to monitor brain levels of tryptophan in rats with thioacetamide-induced acute liver failure by intravenous infusion of branched-chain amino acids (BCAA). The effect of this treatment on 5-HT synthesis and metabolism was investigated in five brain areas. BCAA-infusions (1 and 2 gm/kg/24 h) increased the ratio BCAA/aromatic amino acids in plasma two- and fourfold, respectively, and lowered both plasma and brain levels of tryptophan. At the higher BCAA-dose all parameters suggesting an altered brain 5-HT metabolism (increased brain levels of 5-HT and 5-HIAA, increased 5-HIAA/5-HT ratio) were almost completely normalized. These results provide further evidence for the role of tryptophan in the elevation of brain 5-HT metabolism and for a potential role of BCAA in the treatment of HE.     

Color Doppler ultrasonography of soft-tissue masses

Procaine penicillin G was administered by intramuscular (i.m.) injection to groups of healthy 100 kg market pigs at the approved label dose (15,000 IU/kg body weight), once daily for three consecutive days; or an extra-label dose (66,000 IU/kg body weight), once daily for five consecutive days. Penicillin G residue depletion was followed in plasma, tissue and injection sites using a liquid chromatographic method. Groups of pigs were killed 1, 2, 3, 4, 5 and 8 days after the last injection with the label dose. Penicillin G was not detected in liver after 1 day of withdrawal, in muscle and fat after 2 days of withdrawal, in plasma after 4 days of withdrawal, in skin after 5 days of withdrawal, or in kidney and the injection sites after 8 days of withdrawal. Other groups of pigs were killed 1, 2, 3, 5 and 7 days after injection with the extra-label dose. In these pigs penicillin G was not found in liver after 2 days of withdrawal, in fat after 3 days of withdrawal, or in the muscle, skin, plasma and injection sites after 7 days of withdrawal. Penicillin G was found at all times in the kidneys of the groups of pigs that received the high dose. The technique used for neck injections was critical to obtain intramuscular rather than intermuscular injections. The Bureau of Veterinary Drugs, Health Protection Branch, Health Canada calculated that the appropriate withdrawal period for pigs was 8 days for a dose of 15,000 IU procaine penicillin G/kg body weight and 15 days for a dose of 66,000 IU/kg.     

Alcohol withdrawal-induced change in lipoprotein(a): association with the growth hormone/insulin-like growth factor-I (IGF-I)/IGF-binding protein-1 (IGFBP-1) axis

Lipoprotein(a) [Lp(a)] is an important risk factor for cardiovascular disease. Alcohol is one of the few nongenetic factors that lower Lp(a) levels, but the metabolic mechanisms of this action are unknown. Alcohol inhibits the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis. Alcohol might also affect IGF-binding protein-1 (IGFBP-1), which is an acute inhibitor of IGF-I. We studied how alcohol withdrawal affects Lp(a) levels and the GH/IGF-I/IGFBP-1 axis. Male alcohol abusers (n=27; 20 to 64 years old) were monitored immediately after alcohol withdrawal for 4 days. Twenty-six healthy men, mainly moderate drinkers, served as control subjects. Fasting blood samples were drawn to determine Lp(a), IGF-I, and IGFBP-1 (by ELISA, RIA, and immunoenzymometric assay, respectively). Nocturnal (12 hours) urine collection was performed in 9 alcoholics and 11 control subjects for GH analyses (RIA). The groups were similar in age and body mass index. Lp(a), GH, and IGF-I tended to be lower and IGFBP-1 higher in the alcoholics immediately after alcohol withdrawal than in the control subjects. During the 4-day observation in alcoholics, Lp(a) levels increased by 64% and IGF-I levels by 41%, whereas IGFBP-1 levels decreased by 59% (P<.001 after ANOVA for all comparisons). Urinary GH levels tended to decline. The increase in Lp(a) correlated inversely with the changes in IGFBP-1 (r= -.63, P<.001, n=27) and GH (r=-.70, P<.05, n=9), but not with IGF-I. In multiple regression analysis, the main predictors for the increase in Lp(a) were IGFBP-1 and urinary GH. In conclusion, alcohol withdrawal induces interrelated and potentially atherogenic changes in Lp(a) and IGFBP-1 levels.