TRYPTOPHAN METABOLISM IN MALE SARDINIAN ALCOHOL-PREFERRING (sP) AND -NON-PREFERRING (sNP) RATS

Parameters of tryptophan (Trp) and related metabolism were comparedin male Sardinian alcohol-preferring (sP) and -non-preferring(sNP) rats. Liver Trp pyrrolase activity was 38–58% higherin sP than in sNP rats, and this was associated with a greaterexpression of the enzyme mRNA as measured by multiprobe oligonucleotidesolution hybridization. Moderately (about 10–19%), butsignificantly, lower concentrations of free serum, total serum,and brain Trp were also observed in sP compared with sNP rats.Concentrations of whole brain 5-hydroxytryptamine (5-HT) andits major metabolite 5-hydroxyindol-3-yl-acetic acid (5-HIAA)were, however, 14–21% higher in sP rats. Serum corticosteroneconcentration was 18% higher in sP rats. We conclude that alcoholpreference in Sardinian rats is associated with increased liverTrp pyrrolase activity and mRNA expression leading to a decreasein Trp availability to the brain. Although a simple serotonindeficiency could not be demonstrated in the whole brain, thepossibility could not be ruled Out that a deficiency may bepresent in discrete areas of the brain of the sP rat.     

Rat liver tryptophan pyrrolase activity and gene expression during alcohol withdrawal

Rat liver tryptophan (Trp) pyrrolase activity and gene expression were studied in relation to the alcohol-withdrawal syndrome (AWS). Both activity and gene expression were enhanced after withdrawal of ethanol-containing liquid diets and the time-course of these changes mirrored that of development and intensity of the behavioural disturbances of the AWS. By contrast, no correlation was observed between the AWS-induced behaviour and changes in activity of another hepatic glucocorticoid-inducible enzyme, tyrosine aminotransferase, and a negative correlation was noted between behaviour and the gene expression of this latter enzyme and also of that of the hepatic glucocorticoid receptor. We suggest that the metabolic consequences of activation of liver Trp pyrrolase during alcohol withdrawal may play a role in the behavioural features of the AWS.     

EFFECTS OF CHRONIC ADMINISTRATION AND SUBSEQUENT WITHDRAWAL OF ETHANOL-CONTAINING LIQUID DIET ON RAT LIVER TRYPTOPHAN PYRROLASE AND TRYPTOPHAN METABOLISM

An investigation of the effects of chronic administration ofethanol by the liquid diet procedure and its subsequent withdrawalon tryptophan (Trp) metabolism and disposition was performedin rats. Treatment with the control liquid diet caused an enhancementof liver Trp pyrrolase activity and mRNA abundance. These effectsare not due to the starvation associated with this feeding procedure,because they occur in rats maintained on the liquid diet adlibitum. Chronic ethanol administration in the liquid diet didnot further influence the above increased expression of Trppyrrolase mRNA but caused inhibition of pyrrolase activity incompetition with the effects of the diet. The control liquiddiet decreased liver Trp concentration, but exerted no significanteffects on other aspects of Trp disposition. The most strikingand robust finding was a highly significant elevation in bothTrp pyrrolase activity and mRNA expression at 7 h followingdiscontinuation of ethanol availability, at which time therewere demonstrable behavioural signs of ethanol withdrawal. Theincrease in Trp pyrrolase mRNA during alcohol withdrawal maybe caused by corticosterone. whose circulating concentrationwas also increased. The changes in Trp pyrrolase activity duringethanol withdrawal were associated with significant alterationsin Trp disposition including decreased brain Trp concentrationand 5-hydroxy-tryptamine synthesis and turnover. These alterationsmay play a pivotal role in the behavioural manifestations ofethanol withdrawal including the hyperexcitement underlyingaudiogenic seizures. We suggest that rat Trp pyrrolase generegulation may be an important biological determinant of theethanol withdrawal syndrome and requires further study, andthat the use of the liquid diet procedure in Trp metabolic studiesrequires inclusion of adequate controls and special attentionto the effects of the liquid diet itself.     

Failure of tryptophan deficiency to reduce specifically serum levels of transthyretin or albumin in rats

Because transthyretin (TTR) is a tryptophan-rich molecule and a sensitive nutritional marker, tryptophan deficiency might markedly influence the circulating level of TTR. The effect of severe tryptophan (Trp) deficiency on serum TTR, as well as on albumin and transferrin levels, was studied in growing rats for 8 d. The animals were then refed a control diet for 12 d. The Trp-deficient and control diets contained 0.008 and 0.34% Trp, respectively. A loss of body weight and a dramatic reduction in food intake were observed in the Trp-deficient rats. Although serum total Trp concentration was significantly less in these rats than in pair-fed controls, serum TTR declined to the same extent in both groups compared to control rats fed ad libitum. Albumin concentrations were not altered, but transferrin levels declined slightly in the Trp-deficient rats compared to both the pair-fed group and the controls fed ad libitum. Refeeding the control diet to Trp-deficient rats restored total and free Trp concentrations, as well as TTR and transferrin levels, but body weight and food intake remained lower than in the control group. To examine the effect of moderate Trp restriction, rats were fed for 2 wk a diet whose Trp content was 50% less than that of the control diet. Although total and free Trp concentrations were significantly lower in the rats fed the Trp-deficient diet than in the control group, body weight, food intake and TTR levels were similar in both groups. The results suggest that acute and severe Trp deficiency per se does not modify TTR and albumin levels.     

MR volumetry during acute alcohol withdrawal and abstinence: a descriptive study

AIMS: The brain volume of chronic drinkers is known to partially recover with abstinence from alcohol. To investigate the relative contribution of grey and white brain matter to this process, magnetic resonance imaging and brain tissue segmentation was used to study brain tissue in acute alcohol withdrawal and abstinence in seven alcohol-dependent men. METHODS: The patients were studied on three occasions; within 48 h after the last drink and approximately one month and two and a half months later. Total brain tissue class volumes [grey matter (GM) and white matter (WM) and cerebrospinal fluid (CSF)] were measured. Eleven healthy volunteers were scanned twice to serve as a control group. The alcohol-dependent patients were investigated with regard to drinking variables, neuropsychological performance and blood biochemistry. RESULTS: In the alcohol-dependent patients, intracranial volume and total GM volume did not change between scan occasions, except in a single patient who demonstrated a GM increase of 4.8% (4.2% relative volume) between scans 2 and 3. For all patients, the increase in total WM volume ranged between 1.9 and 22.4% (absolute volumes) and 2.1 and 21.2% (relative volumes). Between scans 2 and 3, the increase in total WM volume ranged between 0.3 and 13.2% (absolute volumes), and between 1.5 and 14.0% (relative volumes). One patient resumed drinking and was investigated a second time during acute withdrawal. In this patient, the measured decrease of 8.1 and 8.5% of absolute and relative WM volumes corresponded to the size of the volume increase between scans 1 and 2. CSF, GM and WM volumes in the healthy subjects were constant over time. CONCLUSIONS: The results demonstrate that changes in brain volume during short-term abstinence in chronic alcohol-dependent patients are confined to the WM. The time limit of WM volume restitution is variable and continues longer than 3 weeks after withdrawal.     

Platelet monoamine oxidase-B activity in type 1 alcohol-dependent subjects in sustained full remission

AIMS: The present study investigated platelet monoamine oxidase-B (MAO-B) activity in male alcohol-dependent subjects in sustained full remission (minimum 1 year), to exclude possible transient changes in platelet MAO-B activity, which occur up to several months after the end of alcohol intake. METHODS: MAO-B activity was examined in 16 alcohol-dependent subjects, characterized as type 1 alcoholics, with an abstinence period of 6 +/- 7 years (mean +/- SD) and in 12 healthy controls. RESULTS: The long-term abstinent alcohol-dependent subjects did not differ from controls in platelet MAO-B activity. CONCLUSIONS: Type 1 male alcohol-dependent subjects appear to have normal platelet MAO-B activity. The possibility, however, cannot be excluded that type 2 long-term abstinent alcoholics may have lower platelet MAO-B activity.     

大蒜阻断人体内N-亚硝基脯氨酸的合成

本文采用Ohshima以GC-TEA定量测定尿中N-亚硝基脯氨酸排出量的方法,以9名健康志愿者为对象,研究大蒜阻断人体内N-亚硝基脯氨酸的合成。受试者食生大蒜5g能完全阻断300mg硝酸钠与500mgL-脯氨酸在人体内合成N-亚硝基脯氨酸,平均阻断率为114.68％,为人群食大蒜预防内源性N-亚硝基化合物的合成及由此造成的致癌性危害提供科学依据。     

Menstrual cycle effects on the metabolism of tryptophan loads

The metabolism of tryptophan (Trp) was examined during the follicular and luteal phases of the human menstrual cycle. Eight healthy women were administered capsulated Trp (3 g) or placebo (3 g lactose) during two follicular and two luteal phases of their menstrual cycles. Trp loading resulted in increased plasma concentrations of Trp and kynurenine, in an increase in the ratio of Trp to neutral amino acids in plasma, and in an increase in urinary excretion of Trp and kynurenine at both phases of the menstrual cycle. However at 3 h after Trp ingestion, plasma kynurenine levels in the luteal phase (23.6 +/- 3.1 mumol/L) were 40% higher than in the follicular phase (16.7 +/- 1.1 mumol/L) (p less than 0.05). Urinary kynurenine excretion in the luteal phase (81.6 +/- 14.4 mumol/24 h) was 28% greater than in the follicular phase (63.9 +/- 13.0 mumol/24 h) (p less than 0.05). The results indicate that the catabolism of Trp via the kynurenine pathway is affected by the phase of the human menstrual cycle.     

Biological monitoring of occupational exposure to toluene diisocyanate: measurement of toluenediamine in hydrolysed urine and plasma by gas chromatography-mass spectrometry.

Exposure to toluene diisocyanate (TDI) was studied during 48 hours and biological samples from nine subjects were taken in a factory producing flexible polyurethane (PUR) foam. Five PUR workers, two white collar workers, and two volunteers were studied. The concentrations of TDI in air were determined by high performance liquid chromatography with the 9-(N-methylaminomethyl)-anthracene reagent. Urine and plasma samples were collected and the TDI related amines, 2,4-toluenediamine (2,4-TDA) and 2,6-toluenediamine (2,6-TDA), were determined (after hydrolysis) as pentafluoropropionic anhydride (PFPA) derivatives by capillary gas chromatography-mass spectrometry (GC-MS) with selected ion monitoring (SIM) in the negative chemical ionisation mode. The concentration of TDI in air was 1%-10% of the Swedish threshold limit value (TLV) of 40 micrograms/m3. The ratio between 2,4-TDI and 2,6-TDI varied in the air samples in the range of 60%:40%-5%:95%. Calibration plots for human urine spiked with 2,6-TDA and 2,4-TDA in the range of 0.2-12 micrograms/l were produced on eight different occasions during five weeks. The SDS of the calibration plot slopes (n = 8) were less than 4%. Urine and blood samples were taken on six occasions for eight of the studied subjects and on four occasions for one subject during a two day period. The five male PUR workers showed the highest average urinary elimination rate of TDA. Two PUR workers and the two white collar workers had an elimination rate of 20-70 ng on average for the sum of 2,6-TDA and 2,4-TDA per hour and three PUR workers had an average of 100-300 ng TDA per hour. The elimination rate curves for all the studied subjects had a linear relation with exposure to TDI. The concentrations of 2,4-TDA and 2,6-TDA in plasma for the PUR factory employees were virtually stable. No relation between the elimination rates of TDA in urine and plasma concentrations of TDA was found. The five PUR workers showed plasma concentrations of the sum of 2,4-TDA and 2,6-TDA in the range 1-8 ng per ml. The two white collar workers, present only on occasions in the factory, had 0.2- ng TDA per ml plasma. The two volunteers showed an increasing concentration of TDA in plasma with time. At the end of the study their plasma concentrations were 0.6 ng/ml and 0.2 ng/ml plasma. Three subjects had the same concentration of the two TDA isomers in plasma, two subjects had about double, and two subjects had 12 times higher concentrations of 2,6-TDA than 2,4-TDA. The presented study indicates that it is possible to monitor exposure to TDI by monitoring plasma concentrations of TDA.     

Currently active and remitted alcohol dependence in a nationwide adult general population--results from the Finnish Health 2000 study

AIMS: To study the factors relating to remission from alcohol dependence in the general population. METHODS: Within a representative, cross-sectional general population sample aged 30 years or more, the characteristics of subjects remitted from alcohol dependence were examined by comparisons with actively alcohol-dependent subjects. RESULTS: The overall lifetime prevalence of alcohol dependence was 7.9%. Comorbid depressive and anxiety disorders were diagnosed in 22% of the actively alcohol-dependent and in 19% of the remitted subjects. There were few sociodemographic, clinical or childhood-related factors differentiating the two groups of subjects. Of comorbid mental disorders, social phobia (6% vs 1%) and dysthymia (7% vs 3%) were more common among the actively alcohol-dependent, whereas other common disorders were equally common for both active and remitted alcohol dependence. Health care or other service use for alcohol problems within the previous 12 months was more frequent among the actively dependent (16% vs 4%), and the same was true for health care use for mental health problems (17% vs 8%). Any service use in the previous year for either type of problem was more common among the actively dependent than the remitted (26% vs 13%). CONCLUSIONS: In an unselected setting, only comorbid social phobia and dysthymia differentiated active alcohol dependence from a remitted state, suggesting either that they are obstacles to remission from an active state, explaining why some alcohol-dependent individuals are unable to recover, or that their symptoms are maintained by excessive alcohol use. The actively alcohol-dependent used both substance use services and mental health services more often than the remitted subjects, possibly due to needs generated by their alcohol problem. Comorbid psychopathology should be considered when developing treatment options for alcohol dependence.     

NITRIC OXIDE IS NOT INCREASED IN ALCOHOLIC BRAIN

Nitric oxide (NO) metabolites nitrite and nitrate were measuredin the cerebrospinal fluid in 12 alcohol-dependent subjectsand in 16 healthy controls. The amounts of NO metabolites inalcoholics were not different from those in the controls. Theresults suggest that NO is not a major factor responsible forbrain damage in these patients.     

Erythrocyte thiamine (Th) esters: a major factor of the alcohol withdrawal syndrome or a candidate marker for alcoholism itself?

AIMS: Thiamine (Th) deficiency is a major problem in alcoholics. In this study, the relationship of alcohol withdrawal syndrome (AWS) to Th and its esters, as well as the diagnostic power of Th and its esters were investigated. PATIENTS AND METHODS: Th and its esters were assessed in a series of chronic alcoholics (and in controls) using an improved method. RESULTS: No association was found between AWS severity and Th and its esters, while the diagnostic power of thiamine diphosphate (TDP) and Th was very high. TDP was the most significant among the parameters under study, confirming that erythrocyte TDP is a suitable marker of alcoholism: TDP sensitivity across subjects was 84.1%, specificity 85.4%, positive predictive value 82.4%, and negative predictive value 88.0%.     

Extended effects of evening meal carbohydrate-to-fat ratio on fasting and postprandial substrate metabolism

BACKGROUND: High-fat and high-carbohydrate diets lead to insulin resistance, gastrointestinal adaptation, and high plasma triacylglycerol concentrations. It is unclear, however, how rapidly these changes occur. OBJECTIVE: We sought to determine the effects of both high-fat and high-carbohydrate evening meals on parameters of insulin resistance, hypertriglyceridemia, and gastrointestinal hormones. DESIGN: Twelve healthy men were studied on 4 separate occasions. On 2 occasions, the subjects received a high-fat evening meal (62% of energy from fat) and on the other 2 occasions the subjects received a low-fat evening meal (16% of energy from fat). The morning after each meal the subjects were administered either an oral-fat-tolerance test or an oral-glucose-tolerance test. Plasma samples were analyzed for glucose, insulin, fatty acids, 3-hydroxybutyrate, triacylglycerol, pancreatic polypeptide, peptide YY, and cholecystokinin. Postchallenge data were analyzed by two-way analysis of variance with interaction and fasting concentrations analyzed by repeated-measures analysis of variance. RESULTS: Fasting plasma concentrations of triacylglycerol were significantly elevated 12 h after each evening meal, but fatty acid and 3-hydroxybutyrate concentrations were reduced. No effects on glucose or insulin concentrations were detected. The high-fat evening meals elevated plasma cholecystokinin concentrations, reduced fasting concentrations of pancreatic polypeptide, and had no significant effect on peptide YY concentrations. The ratio of fat to carbohydrate in the evening meal produced significant effects on plasma triacylglycerol and fatty acids during both the oral-fat-tolerance and oral-glucose-tolerance tests. CONCLUSIONS: The present study showed that the effects of high-fat and high-carbohydrate evening meals persist at least overnight and suggests that knowledge of recent dietary history is essential to the effective design of metabolic studies.     

糖尿病病人和健康人的血铬、尿铬含量

对83名非胰岛素依赖型糖尿病病人及24名健康人进行了血、尿铬测定。结果显示糖尿病病人的空腹血铬(39.9±17.4ppb)和血铬面积(128.6±48.5ppb/b)明显低于健康人(80.9±28.5ppb、270.6±88.4ppb/h)(P<<0.001),提示糖尿病病人可能缺铬。健康男性于馒头试验后60、120、180分钟时的血铬值明显高于空腹血铬值,而健康女性和糖尿病病人无明显波动,提示健康男性对铬的反应力较好。血铬和尿铬值随年令增大而增加,表现出老年人体内铬库对铬的释放、排泄增快。糖尿病病人的血铬与病程成反比,尿铬与病情成正比。     

Proposal of a comprehensive clinical typology of alcohol withdrawal--a cluster analysis approach

AIMS: To characterize the various courses of alcohol withdrawal. METHODS: The Alcohol Withdrawal Scale (AWS) was applied to 217 alcohol-dependent patients every 4 h till the symptoms of withdrawal had passed (until each of four consecutive scores were <3). Patients were medicated by a standardized treatment scheme according to AWS-scores. Hierarchical cluster analysis and discriminant analysis were applied. RESULTS: We found five clusters representing increasing severity of alcohol withdrawal. Each cluster is characterized by a combination of the two maximum subscores (vegetative and psychopathological subscore) and three additional psychopathological symptoms (anxiety, disorientation, and hallucination). In 18.4% of the patients, relevant symptoms were not observed (cluster 1), 18.9% developed mild or moderate vegetative symptoms only (cluster 2), and 40.6% additional anxiety (cluster 3). In cluster 4 (11.1%) the most frequent psychopathological symptoms were disorientation and anxiety but no hallucinations, which could be observed only in cluster 5 (11.1%). Discriminant analysis using the maximum subscores at the first day of treatment as independent variables correctly predicted 89.9% of the five clusters. CONCLUSIONS: Our findings support a model of alcohol withdrawal clustering along the two dimensions of vegetative and psychopathological severity. Furthermore, the AWS may be useful to predict the course of alcohol withdrawal already at the first day of treatment.     

Mechanisms of action of beta-glucan in postprandial glucose metabolism in healthy men

OBJECTIVE: To assess whether beta-glucan (which is fermented in the colon) lowers postprandial glucose concentrations through mechanisms distinct from a delayed carbohydrate absorption and inhibits de novo lipogenesis. DESIGN: Administration of frequent small meals each hour over 9 h allows a rate of intestinal absorption to be reached which is independent of a delayed absorption. A group of 10 healthy men received either an isoenergetic diet containing 8.9 g/day beta-glucan or without beta-glucan for 3 days. On the third day, the diet was administered as fractioned meals ingested every hour for 9 h. SETTING: Laboratory for human metabolic investigations. SUBJECTS: Ten healthy male volunteers. MAIN OUTCOME MEASURES: Plasma glucose and insulin concentrations, glucose kinetics, glucose oxidation, de novo lipogenesis. RESULTS: On the third day, plasma glucose and free fatty acid concentrations, carbohydrate and lipid oxidation, and energy expenditure were identical with beta-glucan and cellulose. Plasma insulin concentrations were, however, 26% lower with beta-glucan during the last 2 h of the 9 h meal ingestion. Glucose rate of appearance at steady state was 12% lower with beta-glucan. This corresponded to a 21% reduction in the systemic appearance rate of exogenous carbohydrate with beta-glucan, while endogenous glucose production was similar with both diets. De novo lipogenesis was similar with and without beta-glucan. CONCLUSION: Administration of frequent meals with or without beta-glucan results in similar carbohydrate and lipid metabolism. This suggests that the lowered postprandial glucose concentrations which are observed after ingestion of a single meal containing beta-glucan are essentially due to a delayed and somewhat reduced carbohydrate absorption from the gut and do not result from the effects of fermentation products in the colon.     

Neuropsychological status of alcohol-dependent patients: increased performance through goal-setting instructions

AIMS: The effects of goal-setting instructions on neuropsychological performance of alcohol-dependent patients and control subjects were assessed. METHODS: 57 alcohol-dependent patients and 59 carefully age- and education-matched healthy control subjects underwent standard neuropsychological investigation. In addition, the goal-setting paradigm was used to systematically manipulate motivation. Participants were requested to calculate simple mathematical problems repeatedly within phases of a 2-min duration receiving normal or goal setting-instructions (to increase performance in the next phase by 20%). RESULTS: The patients demonstrated deficits in standard neuropsychological tests. Patients under goal-setting instructions demonstrated significantly higher improvement (correct responses: P = 0.016) relative to patients with standard instructions. Control subjects with goal-setting instructions demonstrated tendencies for higher improvement relative to control subjects with normal instructions. However, the differences were not significant. Interaction of group (patients vs. control subjects) and instructions (goal setting vs. normal) remained insignificant (P = 0.489) indicating that the increase through goal setting for the patients was not significantly higher than that for the control subjects. CONCLUSIONS: Despite of neuropsychological deficits in reasoning and psychomotor functioning, alcohol-dependent patients early in recovery are responsive to goal setting and able to increase neuropsychological performance. Therefore, goal-setting strategies might possibly be used in cognitive rehabilitation and therapy of alcohol-dependent patients. As there was no significant interaction in increase between patients and control subjects, our results do not support the hypothesis that the neuropsychological deficits are affected by or even caused by motivational limitations of the alcohol-dependent patients.     

ALCOHOLICS WITH REDUCED DOPAMINE D2 RECEPTOR FUNCTION POSSESS NORMAL PLATELET MONOAMINE OXIDASE ACTIVITY

Platelet monoamine oxidase (MAO) activity, proposed to be amarker for central 5- hydroxytryptamine (5-HT) capacity, wasinvestigated in 14 severely alcohol-dependent subjects withreduced dopamine (DA) D₂ receptor function, as assessed by thegrowth hormone responses to apomorphine. Twelve healthy menwere used as controls. Platelet MAO activity in the alcohol-dependent subjects was not different from that in controls.The finding from this preliminary study suggests that severelyalcohol-dependent subjects with reduced DA D₂ receptor functionhave normal 5-HT capacity.     

高血压病心率变异性与临床心血管事件发生的关系的研究

目的:探讨原发性高血压病(EH)伴左室肥厚(LVH)和非左室肥厚(NLVH)的心率变异性(HVR)与临床心血管事件发生之间的关系。方法:90例高血压患者,分为有或无左室肥厚两组及45例正常人作为对照组,分别检测24h动态心电图R-R间期的心率变异性(HRV)时域指标:24h内正常R-R间期的标准差(SDANN);24h内连续5min节段平均正常R-R间期的标准差(SDANN);两个相邻R-R间期差>50ms的心跳数占正常心跳次数的百分比(PNN50);连续R-R间期平方根均值(rMSSD)。随访上述患者心血管事件(CVE)的发生情况。结果:EH伴LVH组的HRV时域指标SDNN、SDANN、rMSSD明显低于EH伴NLVH组及对照组(P<0.01),PNN50明显高于EH伴NLVH组及对照组(P<0.01),随访发现心血管事件发生率在LVH组为51.1%,在NLVH组为26.7%,而健康组为0;发生CVE患者HRV明显低于无CVE者。以SDNN低于70ms及PNN50高于55%为界定值,预测心血管事件发生的敏感性为80%,特异性为71%,阳性预测值为84%。结论:EH伴LVH的发生可能与HRV的减低有关,HRV的减低增加了心血管事件的发生率,对预测心血管事件的发生有一定的临床价值。