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Diazepam binding inhibitor-like immunoreactivity (DBI-LI) in normal and hypophysectomized (HPX) rat testis was studied by light and electron microscopic immunohistochemistry. In normal testis DBI-LI was observed in interstitial Leydig cells and Sertoli cells of most seminiferous tubules. At the electron microscopic level, DBI-LI was distributed throughout the cytoplasm of labeled cells; a concentration of the labeling product was observed in the smooth endoplasmic reticulum, Golgi apparati, and the outer membrane of the mitochondria. In the seminiferous epithelium, labeled processes of Sertoli cells could be traced among developing germ cells. After HPX a gradual disappearance of DBI-LI was observed in all Leydig cells. The number of labeled Sertoli cells was reduced in the majority of tubules after HPX, whereas in some tubules the staining was only slightly reduced. Replacement therapy of the HPX animals with human CG prevented the disappearance of DBI-LI from Leydig cells, whereas replacement with FSH did not prevent the disappearance of DBI-LI in Leydig cells. In Sertoli cells replacement therapies were not effective in restoring DBI-LI. In rat testis DBI and mitochondrial benzodiazepine binding sites are highly concentrated in the Leydig cells. Mitochondrial benzodiazepine binding sites and DBI are involved in the regulation of steroid production. As the expression of DBI-LI is under the control of pituitary hormones, DBI may play a role as an endogenous regulator of intracellular metabolic functions, such as steroidogenesis, in rat testis.

The effect of immobilization stress on the expression of the protooncogene c-fos in the rat pituitary and hypothalamus was investigated immunohistochemically using different polyclonal antibodies raised against the c-fos protein (Fos). After a 4 h immobilization, Fos-like immunoreactivity (Fos-LI) increased substantially in the parvocellular part of the paraventricular nucleus and in the intermediate and anterior lobe of the pituitary. The majority of the Fos-immunoreactive cells in the pituitary contained corticotropin, which was demonstrated by immunohistochemical double-staining. Since the paraventricular nucleus contains a large number of glucocorticoid receptor immunoreactive cells, the effect of a synthetic glucocorticoid, dexamethasone, on the induction of Fos-LI was studied. Dexamethasone treatment before immobilization considerably reduced the stress-induced expression of Fos-LI in the anterior and intermediate lobe of the pituitary but did not alter the induction of Fos-LI in the paraventricular nucleus. The present results demonstrate that immobilization stress induces Fos-LI both in the hypothalamus and in the pituitary, suggesting that Fos may be involved in regulating the synthesis of different mediators of stress response, such as CRF- and POMC-derived peptides. Apparently glucocorticoids do not directly repress c-fos expression, since dexamethasone did not affect the induction of Fos-LI in the paraventricular nucleus. The reduction of stress-induced Fos-LI in the pituitary by dexamethasone is possibly due to the diminished release of CRF factor from the paraventricular neurons.

The aim of this study was to determine whether the serotonin transporter gene polymorphism ( 5 - HTTLPR) is associated with the treatment outcomes of escitalopram for patients with comorbid major depression and alcohol dependence. Eighty treatment-seeking patients were randomly assigned to either receive 20mg of escitalopram or a control of 20mg of the non-serotonergically acting memantine. Depression was measured by the Montgomery–Asberg Depression Rating Scale (MADRS) and alcoholism by the Alcohol Use Disorders Identification Test (AUDIT). Twenty-nine participants in each treatment group completed the study, and from those DNA was given by 27 in the escitalopram group and 21 in the memantine group. In the escitalopram group linear regression showed that LL genotype predicted greater decrease in MADRS scores compared with the SS/SL genotypes ( p =0.04) after a 3month treatment period. Moreover, each L allele associated with MADRS score decrease by 15% ( p =0.04) in the escitalopram group. In the memantine group, however, no association between LL genotype and MADRS decrease was detected. AUDIT decrease was not associated with the 5 - HTTLPR genotype for either medication. This is the first study in the treatment of depression in dual diagnosis patients to report a significant association between outcomes with escitalopram and the 5 - HTTLPR gene polymorphism.

Approximately one third of problem gamblers in Finland suffer from pathological gambling. An essential factor affecting the genesis of pathological gambling is a dysfunction of the dopaminergic reward system. It may be associated with the pleasure arising from gambling along with the reward and expectance of reward. In Parkinsons's disease patients receiving dopaminergic medication, pathological gambling and disturbances of impulse control are more common than in the average population. Various psychosocial modes of treatment and medications have been developed for the treatment of pathological gambling, but based on current knowledge, none of them displays particular efficacy.

OBJECTIVE: The performance of the Alcohol Use Disorders Identification Test (AUDIT) in screening for heavy drinking among the elderly has been unsatisfactory. The aim of the present study was to determine whether tailoring the cut point improves the performance of the AUDIT and its derivatives in this age group. METHODS: From a stratified random sample of 804 Finns aged 65-74 years, 517 subjects (64.3%) completed the AUDIT and the Timeline Follow-back (TLFB) interview regarding alcohol consumption. A subject was defined as a heavy drinker if consumption of >/=8 drinks (approx. 12 g) on average in a week or >/=4 drinks at least in 1 day during the prior 28 days was reported. Combinations in which both sensitivity and specificity are >/=0.8 were defined as optimal. The elderly specific AUDIT-3 is a modification in which the binge drinking threshold is >/=4 drinks. RESULTS: Based on the TLFB, 118 subjects (22.8%) were heavy drinkers. The areas under receiving operating characteristics curves (AUROCs) were equivalent (>/=0.898) for all questionnaires. When using the standard cut point of >/=8 for the AUDIT, the sensitivity was 0.48. Lowering the cut point to >/=5 led to both a sensitivity and specificity over 0.85. The optimal cut point of the AUDIT-C was >/=4. The AUDIT-QF, AUDIT-3 and elderly specific AUDIT-3 did not provide optimal combinations of sensitivity and specificity with any cut point. CONCLUSIONS: The AUDIT and AUDIT-C are accurate in screening for heavy drinking among the elderly if the cut points are tailored to this age group. Language: en

Effective treatment choices for alcohol dependence have existed for long, but only a minor proportion of those dependent on alcohol seeks medical care and receives effective treatment. The biological mechanisms underlying the dependence and pharmacological means affecting them should be known in order to guarantee a successful pharmacological therapy of alcohol dependence. Therapy should be targeted depending on whether the goal is immediate total abstinence, gradual abstinence or maintaining of abstinence. The strongest scientific evidence for gradual abstinence exists for the opiate antagonist naltrexone. In attempting immediate total abstinence, a significant proportion of alcohol-dependent patients benefits from supervised disulfiram treatment.

Background Opioid-substitution treatment (OST) for opioid dependence (OD) has proven effective in retaining patients in treatment and reducing illegal opiate abuse and crime. Consequently, the World Health Organization (WHO) has listed the opioid agonists methadone and buprenorphine as essential drugs for OD that should be available worldwide. In many areas of the world, OD is often associated with concomitant benzodiazepine (BZD) dependence and abuse, which complicates treatment. However, possible changes in the cognitive functioning of these patients are not well-known. The present study is the first to examine longitudinal stability of memory function in OST patients with BZD use, thus providing a new tool for health policy authorities in evaluating the usefulness of OST. Methods Within the first two months (T1) and between 6–9 months (T2) after OST admission, we followed the working memory, immediate verbal memory, and memory consolidation of 13 methadone- and 15 buprenorphine- or buprenorphine/naloxone-treated patients with BZD dependence or abuse disorder. The results were compared to those of fifteen normal comparison participants. All participants also completed a self-reported memory complaint questionnaire on both occasions. Results Both patient groups performed statistically significantly worse than normal comparison participants in working memory at time points T1 and T2. In immediate verbal memory, as measured by list learning at T1, patients scored lower than normal comparison participants. Both patient groups reported significantly more subjective memory problems than normal comparison participants. Patients with more memory complaints recalled fewer items at T2 from the verbal list they had learned at T1 than those patients with fewer memory complaints. The significance of the main analyses remained nearly the same when the statistical tests were performed without buprenorphine-only patients leaving 12 patients to buprenorphine/naloxone group. Conclusion Working memory may be persistently affected in OST patients with BZD use. A high number of memory complaints among OST patients with BZD use may indicate memory consolidation impairment. These findings show that recovery of memory function in OD patients treated along with BZDs takes time, and their memory complaints may have practical relevance.

Radiotherapy (RT) produces oxidative stress and local inflammation. This study aimed at clarifying the role of different cytokines (VEGF, TNFalpha, IL-1beta, IL-6, IL-8, IL-12 and IL-18) in bronchoalveolar lavage (BAL) fluid and in the serum of lung cancer patients at baseline and during RT. Bronchoscopy and BAL were performed on 36 lung cancer patients and 36 controls for diagnosis; patients receiving RT had a second bronchoscopy during RT. Serum samples were obtained during RT and three months after RT. In this study lung cancer patients had higher levels of serum and BAL fluid IL-6 and serum IL-8 compared to controls (p

The aim of the present study was to determine whether the alcohol biomarkers CDT, GGT, the biomarker γ-CDT index and previous drunken driving contributed significantly to the prediction of DUI recidivism. The subjects consisted of two different samples of drivers, viz. drivers who were found to have a positive breath alcohol concentration during random breath testing surveys ( n = 237), and drunken drivers who were apprehended during ordinary police work ( n = 193). The drunken driving events were monitored using a data-base both retrospectively and prospectively. It was found that the biomarker index, γ-CDT, emerged as a notable predictor of recidivism in the group of random breath tested drivers. Measurement of γ-CDT and its impact on DUI recidivism has not to our knowledge been applied to random breath tested drivers before. The apprehended drunken drivers, on the other hand, did not show a significant relationship between γ-CDT and DUI recidivism. However, in both groups of drivers it was found that a previous conviction for drunken driving strongly predicted DUI recidivism. More attention should be paid by both physicians and the police to the high risk of recidivism among those convicted of drunken driving.

AIMS: To estimate the gender-specific prevalences of alcohol consumption levels and to investigate the association between heavy drinking and all-cause mortality among elderly males. DESIGN: A cohort derived from a nationally representative sample of Finns aged >65 years was followed for six years. Number of subjects was 1569 (72.7% of the original sample, 65.3% females, weighted n=1357). MEASUREMENTS: Alcohol consumption was retrospectively measured by beverage-specific quantity and frequency over a 12-month period. Mortality data were obtained from the official Cause-of-Death Register. Cox proportional hazards models were used to analyse the relative risks (RRs) of death. FINDINGS: The prevalence of heavy drinking (>8 standard drinks per week) was 20.3% in males and 1.2% in females. Over one-tenth (11.4%) of males reported drinking >/=15 standard drinks per week. Relative death risks suggested a J-curved relationship between alcohol consumption levels and mortality. However, significant curvilinear relationship was not found, when using alcohol consumption as continuous variable. The multivariate adjusted RR of death among moderate drinkers (1-7 drinks per week) vs. abstinent subjects was 0.41 (95% CI=.23-.72). Males drinking >/=15 standard drinks per week had a two-fold multivariate adjusted risk of death (RR=2.11, 95% CI=1.19-3.75) compared with abstinent males. The level of alcohol consumption by females was too low for analysis. CONCLUSIONS: Heavy drinking is common among Finnish elderly males but not among females. The present study shows an increased all-cause mortality risk for males drinking, on average, more than two standard drinks per day. Language: en

Background Alcohol dependence comorbid with major depressive disorder poses a major challenge in the clinical setting. The results in the treatment with selective serotonin re-uptake inhibitors have been conflicting. Thus, we compared in alcohol-dependent patients with co-morbid major depressive disorder the selective serotonin re-uptake inhibitor escitalopram to a compound that acts on different transporter system and may reduce craving, the glutamate receptor antagonist memantine. Methods Eighty alcohol-dependent patients comorbid with major depressive disorder in municipal alcohol clinics were randomized 1:1 to receive memantine 20 mg or escitalopram 20 mg in a double-blind manner. During the 26-week study period patients continued their routine treatment at the clinics. Abstinence was not required but encouraged. The patients attended visits weekly during the first month, and then at 3 and at 6 months. Outcome measures were Alcohol Use Disorders Identification Test (AUDIT), Obsessive Compulsive Drinking Scale (OCDS) and Drinking Diary. Results The completion rate was high in both groups, especially among the patients who had been abstinent at the beginning of the study. However, among those patients who were not abstinent at baseline, 47% in both groups discontinued the study. Numbers of abstinent days were high in both groups throughout the study. Alcohol consumption measured by the AUDIT QF (quantity-frequency) score was significantly reduced in both groups, as was the craving for alcohol measured by the OCDS. Early age at first alcohol intoxication predicted poor treatment outcomes in patients treated with escitalopram, and the same was seen with the early onset of the first depressive episode. The same predictive effects were not found in patients treated with memantine. Conclusion Our results indicate that both memantine and escitalopram are useful adjunct medications for the treatment of alcohol dependence co-morbid with major depression. Memantine was at least as effective with regard to drinking as escitalopram. We believe that a direct comparison of memantine, with the commonly used escitalopram, can provide useful information for clinicians on the treatment of alcohol dependency co-morbid with MDD. Trial registration ClinicalTrials.gov Identifier # NCT00368862

Background In Finland, buprenorphine (Subutex) is the most abused opioid. In order to curb this problem, many treatment centres transferred ("forced transfer") their buprenorphine patients to the buprenorphine plus naloxone (Suboxone) combination product in late 2003. Methods Data from a retrospective study involving five different treatment centers, examining the effects of switching patients to Suboxone, were gathered from 64 opioid-dependent patients who had undergone the medication transfer. Results Most patients (90.6%) switched to Suboxone at the same dose of buprenorphine that they had been receiving as Subutex (average 22 mg). The majority of these patients (71.9%) were maintained at the same dose of Suboxone throughout the 4-week study period. During the first 4 weeks, 50% of the patients reported adverse events and at the four month time point, 26.6% reported adverse events. However, due to adverse events one patient only discontinued treatment with Suboxone during the 4-week study period, and five during the four month follow-up period. Of the 26 patients in the follow-up period, Suboxone was misused intravenously once each by 4 patients and twice by 1 patient. These 5 patients all reported that injecting Suboxone was like injecting "nothing" with any euphoria, or that it was a bad experience. Conclusion We conclude that when patients are transferred from high doses (> 22 mg) of buprenorphine to the combination product, dose adjustments may be necessary especially in the later phase of the treatment. We recommend that a transfer from Subutex to Suboxone should be carefully discussed and planned in advance with the patients and after the transfer adverse events should be regularly monitored. With regard of buprenorphine IV abuse, the combination product seems to have a less abuse potential than buprenorphine alone.

Resting electrical activity (EMG) in the frontalis, temporalis, trapezius and erector trunci muscles, as well as systolic and diastolic blood pressure (BP), were measured in boys in a community home, and in controls of the same age in an ordinary school. EMG in the community-home boys was significantly higher than in controls, whereas BP did not yield any difference. The community-home boys participated in a programme consisting of relaxation training and increased physical activity for 4 months. After this intervention, EMG in all muscle groups was decreased, and the level of EMG was also lower than the values measured in controls. Systolic and diastolic BP in the community-home boys was also lowered, but the decrease was not significant as compared to the control group. In conclusion, relaxation training and/or increased physical activity is effective in decreasing the elevated activation observed in community-home boys.

The cirdadian variation in the expression of Fos protein(s) in the rat brain was studied immunohistochemically. The number of Fos-immunoreactive nuclei was statistically increased in the hippocampus and caudate putamen after the onset of darkness. Unlike the cells of the hippocampus and putamen the cells in the suprachiasmatic nucleus displayed a circadian variation with the lowest values during the nighttime and the highest in the morning. As the circadian rhythm of Fos expression in the normal rat brain may correlate with that reported for ACTH and corticosteroids, the results suggest that the fos gene is involved in mediating physiological activation of specific neuron populations of intact rats.

The aim of this study was to determine predictors of the response to escitalopram, a selective serotonin re-uptake inhibitor antidepressant and memantine, a non-competitive glutamate NMDA receptor blocker, for the treatment of major depression comorbid with alcohol dependence. Eighty alcohol dependent treatment-seeking adult patients with comorbid major depressive disorder were randomized to receive either memantine 20 mg or escitalopram 20 mg for 26 weeks. In both treatment groups, depression was reduced significantly. Comparisons were made between patients in remission (final Montgomery-Asberg Depression Rating Scale (MADRS)

Aim: To compare the effects in alcohol-dependent patients of three pharmacotherapies, disulfiram (DIS), naltrexone (NTX), and acamprosate (ACA), when used with a brief manual-based cognitive-behavioural intervention. Method: We conducted a randomized, open label, multicentre naturalistic study in two phases; first, a 12-week continuously supervised medication, followed by targeted medication (TM) up to 52 weeks in addition to a 67-week follow-up period; altogether 119 weeks (2.5 years), in 243 voluntary treatment-seeking alcohol-dependent adult outpatients. Subjects were randomized 1:1:1 to receive supervised NTX, ACA or DIS, 50, 1998, or 200 mg, respectively, per day, plus a brief manual-based cognitive-behavioural intervention. The patients were met in the second and sixth weeks, and then after 3, 6, and 12 months. The primary outcome measures were the time (days) to first heavy drinking day (HDD), and time during the first 3 months to the first drinking day after medication started. Secondary variables were abstinent days/week (0 drinks/day), average weekly alcohol intake, Alcohol Use Disorder Identification Test (AUDIT), Severity of Alcohol Dependence Data (SADD), and quality of life (QL) measures. Results: All three study groups showed marked reduction in drinking, from baseline to the end of the study. During the continuous medication phase, treatment with DIS was more effective in reducing HDDs and average weekly alcohol consumption, and increasing time to the first drink, as well as the number of abstinent days. During the TM period, there were no significant differences between the groups in time to first HDD and days to first drinking, but the abstinence days were significantly more frequent in the DIS group than ACA and NTX. There were no differences between the NTX and ACA groups in either phase of the study of drinking outcomes. However, SADD scores improved more in the NTX group than the ACA group. Conclusions: Patients allocated to ACA, NTX and DIS combined with brief manual-based cognitive behavioural intervention significantly reduce their alcohol consumption and report improved QL. Supervised DIS appeared superior, especially during the continuous medication period, to NTX and ACA.

Background Both methadone- and buprenorphine-treated opioid-dependent patients frequently show cognitive deficits in attention, working memory, and verbal memory. However, no study has compared these patient groups with each other during early opioid substitution treatment (OST). Therefore, we investigated attention, working memory, and verbal memory of opioid-dependent patients within six weeks after the introduction of OST in a naturalistic setting and compared to those of healthy controls. Methods The sample included 16 methadone-, 17 buprenorphine/naloxone-treated patients, and 17 healthy controls matched for sex and age. In both groups buprenorphine was the main opioid of abuse during the recent month. Benzodiazepine codependence, recent use, and comedication were also common in both patient groups. Analysis of variance was used to study the overall group effect in each cognitive test. Pair-wise group comparisons were made, when appropriate Results Methadone-treated patients, as a group, had significantly slower simple reaction time (RT) compared to buprenorphine/naloxone-treated patients. In Go/NoGo RT methadone patients were significantly slower than controls. Both patient groups were significantly debilitated compared to controls in working memory and verbal list learning. Only methadone patients were inferior to controls in story recall. In simple RT and delayed story recall buprenorphine/naloxone patients with current benzodiazepine medication (n = 13) were superior to methadone patients with current benzodiazepine medication (n = 13). When methadone patients were divided into two groups according to their mean dose, the patient group with a low dose (mean 40 mg, n = 8) showed significantly faster simple RT than the high dose group (mean 67 mg, n = 8). Conclusion Deficits in attention may only be present in methadone-treated early phase OST patients and may be dose-dependent. Working memory deficit is common in both patient groups. Verbal memory deficit may be more pronounced in methadone-treated patients than in buprenorphine/naloxone-treated patients. In sum, to preserve cognitive function in early OST, the use of buprenorphine/naloxone may be more preferable to methadone use of, at least if buprenorphine has been recently abused and when benzodiazepine comedication is used. Longitudinal studies are needed to investigate if the better performance of buprenorphine/naloxone-treated patients is a relatively permanent effect or reflects "only" transient opioid switching effect.

There is a multitude of data showing that coronary heart disease is affected by the quality of dietary fat. The fatty acid composition of serum lipids has been shown to reflect that of the diet. It is likely that, after myocardial infarction, both the health-care professionals and the patients themselves pay more attention to dietary guidelines. In order to assess the correctness of this assumption, we compared the composition of serum fatty acids in 40 male subjects with a history of myocardial infarction (MI) with that of 40 age-matched controls, both from the FINRISK study. The percentage composition of fatty acids of total serum lipids was analysed by gas chromatography. In comparison with the control group, the MI group had higher body mass index (BMI), a higher prevalence of diabetes, higher level of serum triglycerides and a lower level of serum high-density lipoprotein (HDL) cholesterol, all indicators of the metabolic syndrome. The MI group had higher proportions of serum palmitic (16:0) and oleic acids (18:1), and a lower proportion of linoleic (18:2 n-6) acid than the control group. The metabolic syndrome is accompanied by an elevated level of serum insulin, which is known to enhance the synthesis of saturated and monounsaturated fatty acids, such as 16:0 and 18:1, and to stimulate the activity delta-6 desaturase, decreasing the concentration of linoleic acid. Our results suggest that the observed serum fatty acid composition in subjects with coronary heart disease is dependent on metabolic factors in addition to dietary fatty acid composition.

The purpose of the present study was to compare and evaluate the new Helsinki Alcohol Use Test (HAUT) and Alcohol Use Disorders Identification Test (AUDIT) as screening instrument in the general working population. The relationship between the HAUT and serum gamma-glutamyl transferase (GGT), and carbohydrate-deficient transferrin (CDT) was also evaluated. Our results seem to indicate that the HAUT has good performance as screening instrument for alcohol-related problems in the general population.

— Aims: To ascertain the accuracy of a quantity–frequency questionnaire (QF) and a graduated frequency questionnaire (GF) as methods of obtaining self-reported alcohol intake in relation to a daily diary and biochemical tests. Methods: QF and GF data were obtained before and after a 1-month daily diary on alcohol intake in a sample of 52 volunteers aged 20–63 years, of whom 43 were female. A blood sample to measure serum aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), γ-glutamyltransferase (GGT) and % carbohydrate-deficient transferrin (CDT) was obtained at the outset. Results: Both QF and GF correlated closely with daily diary intake ( r > 0.90). Compared with a daily diary, the mean QF intake was slightly lower, whereas the mean GF intake was 2-fold. The apparent overestimation by GF was independent of the actual consumption level. Self-reported alcohol intake by each method correlated closely with serum ASAT, ALAT and GGT ( r = 0.41–0.67) but not with CDT. Conclusions: In adults motivated to recall alcohol intake, both QF and GF classify individuals in the correct rank order, but GF probably overestimates actual alcohol consumption.

Background Moderate alcohol consumption may reduce the risk of coronary heart disease (CHD), but excessive alcohol consumption is probably harmful to the heart. We analyzed the association of 2 commonly used markers of alcohol consumption—carbohydrate-deficient transferrin (CDT) and γ-glutamyltransferase (GGT)—and self-reported alcohol consumption with prevalent CHD. Methods The study included a random sample of 3666 Finnish men aged 25 to 74 years who participated in a risk factor survey in 1997. The cross-sectional association of CDT, GGT, and self-reported drinking with CHD was analyzed by means of logistic regression models. Results The CDT level was inversely and GGT level positively associated with CHD risk. The odds ratios (adjusted for age, smoking, total and high-density lipoprotein cholesterol levels, systolic blood pressure, and body mass index) of CHD among men in the fourth quartiles of CDT and GGT, as compared with the first quartiles, were 0.69 and 1.76, respectively. In a composite risk assessment, men with normal CDT levels (≤20 U/L) and elevated GGT levels (>80 U/L) had nearly 8-fold adjusted risk of CHD as compared with the men with normal GGT levels and elevated CDT levels. Self-reported alcohol consumption had an inverse association with CHD risk, which disappeared after adjustment for the other risk factors. Conclusions Levels of CDT and GGT may be indicators of factors behind the curvilinear association between alcohol consumption and CHD risk. The CDT level seems to be related to beneficial biological changes and GGT level with the changes that are detrimental to the cardiovascular system. The inverse association of CDT level with CHD risk will be examined further in a forthcoming prospective study.

Background: The susceptibility to alcoholism can be explained partially by genetic factors. Neuropeptide Y (NPY) has emerged as one potential factor contributing the development of alcoholism. A recent study indicated that the NPY gene variant producing a leucine-to-proline substitution (T to C at position 1128) was associated with 34% higher average alcohol consumption. Methods: The subjects consisted of 122 alcoholics classified as type 1 and type 2 subtypes by psychiatric evaluation. A random sample of 59 social drinkers was used as a control group to compare the distribution of NPY genotypes with those of alcoholics. Results: In a logistical regression model, there was a significantly lower frequency of the leucine(7)/proline(7) heterozygotes among well characterized type 2 alcoholics, compared with the controls (10.8 vs. 24.1%, p= 0.028). Conclusions: We speculate that the genetic polymorphism producing the proline(7) substitution of NPY might not predispose to alcoholism, but indeed retard the transition to alcoholism.

The relationships of carbohydrate-deficient transferrin (CDT), gamma-glutamyltransferase (GGT) and their mathematical combination (gamma-CDT) with self-reported diseases were evaluated in a large cross-sectional risk factor survey. Significant gender effects were observed in associations of the markers with several medical conditions as well as with general health care utilization. In men, CDT was associated with rheumatoid arthritis. In both genders, GGT was positively associated with hypertension and diabetes. gamma-CDT was positively associated with hypertension in males and with asthma in females. This general population study demonstrates that these markers, although most commonly used to assess alcohol misuse, might also serve as health risk indicators.

Several studies have shown the opioid antagonist naltrexone to be effective when combined with psychosocial therapies for the treatment of patients who are dependent on alcohol with fixed medication and time (12 weeks). In this study, 121 nonabstinent outpatients with alcohol dependence (DSM-IV) were treated with sessions of cognitive coping skills (N = 67) or supportive therapy (N = 54) and either naltrexone 50 mg/day (N = 63) or placebo (N = 58) daily for the first 12 weeks and thereafter for 20 weeks only when craving alcohol (i.e., targeted medication) in a prospective one-center, dual, double-blind, randomized clinical trial. The dropout rate for all subjects was 16.5% during the first 12-week period and approximately twice that level by the end of the study. There were no significant group differences in study completion and therapy participation rates. After the continuous medication (12 weeks), the coping/naltrexone group had the best outcome, and coping/placebo had the worst. This difference remained during the targeted medication period (the following 20 weeks). Naltrexone was not better than placebo in the supportive groups, but it had a significant effect in the coping groups: 27% of the coping/naltrexone patients had no relapses to heavy drinking throughout the 32 weeks, compared with only 3% of the coping/placebo patients. The authors' data confirm the original finding of the efficacy of naltrexone in conjunction with coping skills therapy. In addition, their data show that detoxification is not required and that targeted medication taken only when craving occurs is effective in maintaining the reduction in heavy drinking.

The aim of this research was to evaluate the effectiveness of long-term brief intervention in routine general practice. In five primary care out-patient clinics in a Finnish town, 296 male early-phase heavy drinkers consulting a general practitioner (GP) for various reasons were identified. Control group C (n = 88) was informed of the risks of drinking after the screening and were advised at the subsequent feedback about 2 weeks later to reduce their drinking. Groups A (n = 109) and B (n = 99) were offered in addition seven and three brief intervention sessions, respectively. All GPs took part, whether or not they indicated a special interest. The main outcome measures were differences between beginning and end-point at 3 years in self-reported alcohol consumption, mean corpuscular volume (MCV), and serum carbohydrate-deficient transferrin, aspartate aminotransferase, alanine aminotransferase and gamma-glutamyltransferase. There were no statistically significant differences between study groups A, B and C in mean changes in outcome measures. Within all the groups, MCV decreased. Depending on the outcome measure used and the study group analysed, clinically significant reduction of drinking was found in 25-53% of the subjects. In routine general practice, giving additional sessions of brief intervention may not be as effective as in special research conditions. Factors reducing the effectiveness of brief intervention programmes should be investigated, so that primary health care staff can be better supported in their efforts.

Background: Moderate consumption of alcohol may reduce mortality from vascular diseases. The beneficial effects of alcohol may partly be mediated by its effects on lipoprotein metabolism. We studied the connection between alcohol consumption and the serum lipid profile from a well-documented national health program study. Methods and results: Carbohydrate-deficient transferrin (CDT) and gamma-glutamyl-transferase (GGT) were used as biochemical markers for alcohol consumption. The laboratory analyses were carried out on 5675 subjects (3097 males and 2578 females). The subjects were divided into quartiles on the basis of CDT or GGT value. The highest CDT quartile and the lowest GGT quartile seemed to be associated with a favorable lipid profile and the lowest CDT quartile and the highest GGT quartile were associated with an unfavorable lipid profile. Serum high density lipoprotein (HDL) cholesterol values were significantly higher and triglycerides lower with increasing serum CDT concentrations for both men and women. Increasing serum GGT was associated with higher serum total cholesterol and higher triglycerides in both men and women and lower HDL cholesterol in men. Conclusions: CDT and GGT seem to detect different populations of subjects in regard to lipid metabolism. These observations may lead to a better understanding of the effects of alcohol consumption on lipids as well as mechanisms behind favorable and detrimental effects of alcohol on vascular diseases. Condensed abstract: Carbohydrate-deficient transferrin (CDT) and gamma-glutamyl-transferase (GGT) were used as biochemical markers for alcohol consumption. A total of 3097 males and 2578 females were divided into quartiles on the basis of their CDT or GGT values. The highest CDT quartiles had higher HDL and lower triglycerides, whereas the highest GGT quartiles appeared to be associated with higher total cholesterol and triglycerides in both genders and lower HDL in men. CDT and GGT seem to detect different populations of subjects in regard to lipid metabolism. These observations may have important clinical and public health implications.

The dose response to alcohol use of carbohydrate-deficient transferrin (CDT), gamma-glutamyltransferase (GGT), and their combination (gamma-CDT) was studied in an age- and gender-stratified, random sample from Finland in 1997. A linear association with a threshold between alcohol consumption and the three markers was observed. Body mass index was negatively associated with CDT and positively with GGT Age was positively associated with GGT and gamma-CDT In conclusion, CDT appears to be an early phase marker of alcohol consumption. The combined marker, gamma-CDT, was less associated with factors such as body mass index but more strongly correlated with alcohol consumption than were the two markers separately.

Background: Carbohydrate-deficient transferrin (CDT) and γ-glutamyltransferase (GGT) are the most commonly used markers for alcohol abuse, but their sensitivity and specificity are lower and have different reference values among females compared with males. In the present study, we evaluated the effect of women's hormone balance on these two alcohol markers, as well as on their mathematical combination, named γ-CDT. Methods: An age-stratified random sample of 3962 women, between 25–74 years old, was drawn from the normal population. Pregnancy, the use of oral contraceptives, intrauterine device for contraception, hormone replacement therapy, and hormone treatment for infertility were considered. A comparison between fertile, peri- and postmenopausal women was also done. Results: Existing pregnancy increased CDT levels but decreased GGT values. Lower CDT and higher GGT levels were observed among those women using oral contraceptives and in postmenopausal women compared with women at the fertile stage. γ-CDT was not influenced by hormone balance. Conclusions: The different hormonal status had an opposite effect on CDT and GGT. Women who were close to late menopause had levels of both markers closer to the values of men. It must be pointed out that the findings presented here are based on measurements of absolute CDT values and that no measurements of total transferrin were done. γ-CDT, not influenced by hormone balance, indicates promising clinical utility among women.

Background: The use of a combination of markers to detect excessive alcohol consumption has been reported to provide better sensitivity in the diagnosis of alcohol abuse than single markers. However, the optimal combination of markers for the diagnosis of alcohol abuse has not yet been found. The aim of this study was to compare the diagnostic value of carbohydrate-deficient transferrin (CDT) and γ-glutamyltransferase (GGT) to discriminate among heavy drinkers (>280 g/week), moderate drinkers (105–280 g/week), and light drinkers (

Furosemide increases the basal tert-[35S]butylbicyclophosphorothionate ([35S]TBPS) binding and reverses the inhibition of the binding by gamma-aminobutyric acid (GABA) in the cerebellar GABA(A) receptors containing the alpha6 and beta2/beta3 subunits. These effects are less pronounced in the alcohol-sensitive (ANT) than in the alcohol-insensitive (AT) rat line. The difference between the rat lines in the increase of basal [35S]TBPS binding was removed after a longer preincubation with ethylendiaminetetraacetic acid (EDTA) containing buffer, but long preincubation did not reduce the GABA content of the incubation fluid or remove the difference in GABA antagonism by furosemide. The GABA sensitivity of the [35S]TBPS binding did not differ between the rat lines. There was no nucleotide sequence difference in the beta2 or beta3 subunits between the rat lines and similar beta2/3 subunit-dependent agonistic actions by methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) in the rat lines were detected. The data suggest that there are still unknown structural alterations in the cerebellar GABA(A) receptors between the AT and ANT rat lines, possibly associated with differential alcohol sensitivity.

The peripheral benzodiazepine receptor system triggers intracellular metabolic events and has been associated with cell proliferation. Its endogenous ligand, the diazepam binding inhibitor, contributes to steroidogenesis by promoting cholesterol delivery to the inner mitochondrial membrane. The present study was undertaken to verify whether this system is altered in tumors sited in the liver. Peripheral benzodiazepine receptors and diazepam binding inhibitor were studied using immunocytochemistry and in situ hybridization in 9 human tumors sited in the liver, in liver hyperplasia, cirrhotic nodular regeneration, intestinal adenocarcinoma and in surrounding non-tumoral tissue. Immunocytochemical staining and in situ hybridization demonstrated that peripheral benzodiazepine receptors and diazepam binding inhibitor were more prominently expressed in neoplastic cells than in non-tumoral tissue. They were present in the same cells, suggesting that diazepam binding inhibitor may act in an intracrine manner in these cells. Higher peripheral benzodiazepine receptors and diazepam binding inhibitor expression in tumor cells suggest an implication of this system in the metabolism of neoplastic cells. Furthermore the evaluation of peripheral benzodiazepine receptor and diazepam binding inhibitor expression might be useful in evaluating malignancy and in diagnostic approaches of tumors in liver tissue.

Background and Methods: Recently, sialic acid has been suggested as a potential marker for alcohol abuse. In this study, social drinkers and alcoholics were analyzed with a modified version of Warren's method for sialic acid and traditional markers of alcohol abuse in serum (n= 38; n= 87), saliva (n= 36; n= 29), and urine (n= 37; n= 83), respectively. The alcoholics were participating in an alcohol dependency treatment program and were followed in this study for 5 weeks. Results: The sialic acid concentrations in female and male alcoholics were significantly higher in serum (p < 0.001; p < 0.001 respectively) and saliva (p < 0.05; p < 0.05) but not in urine, compared with social drinkers. The diagnostic efficiency of serum sialic acid was higher than that for traditional markers: 77% for female subjects and 64% for male subjects. The corresponding results for saliva were 72% and 53%. The sialic acid concentrations were significantly decreased during the alcohol dependency treatment program (after 5 weeks of treatment) in both females and males. Conclusions: This study confirms that serum sialic acid is a valuable marker for detecting and monitoring alcohol abuse. This work also indicates that sialic acid in saliva could be used possibly as a noninvasive marker for alcohol abuse.

Publisher Summary This chapter presents detailed protocols for the measurement of chemiluminescence-enhanced total peroxyl radical-trapping potential (TRAP) of both plasma and low-density lipoprotein (LDL). The chemiluminescence-enhanced TRAP method has proven to be a reliable tool for evaluating the total activity of chain-breaking antioxidants in biological fluids. Chemiluminescence-enhanced TRAP has revealed important information in evaluating the antioxidant status of human plasma. Plasma antioxidant defenses seem to respond to needs related to the basic metabolic rate and to the challenges caused by physiological or pathological stress. According to the study, an important, possibly endogenous, antioxidant remains to be identified. However, the total antioxidative potential cannot be evaluated reliably by measuring only TRAP because of its dependence on uric acid. TRAP combined with its main components is likely to give more valid information in determining the total antioxidant status.

Oxidative stress may be an important pathogenetic factor in the development of diabetic vascular complications. The total antioxidative potential of plasma reflects the ability of an individual to resist oxidative stress. We measured the plasma total peroxyl radical-trapping potential (TRAP) and the concentrations of four plasma chain-breaking antioxidants in 81 patients with non-insulin-dependent diabetes mellitus (NIDDM) nine years after diagnosis and in 102 well-matched non-diabetic control subjects. The association between the total antioxidative potential and the presence of coronary heart disease (CHD) and diabetic kidney disease were also studied. There were no significant differences in plasma TRAP between NIDDM patients and control subjects (1250+/-199 vs. 1224+/-198 microM). Nor were there any significant differences in the concentrations of plasma uric acid, ascorbic acid, alpha-tocopherol, and protein thiols between NIDDM patients and control subjects. Patients with a low glomerular filtration rate and/or high urinary albumin excretion had elevated plasma uric acid. Plasma TRAP was not, however, associated with renal dysfunction. The plasma of NIDDM patients with CHD had a significantly higher value of unidentified antioxidative potential than that of patients without CHD. This relation was strongly dependent upon smoking. In conclusion, these data demonstrate that there are no major defects in the antioxidative potential of plasma caused by NIDDM per se. CHD and diabetic renal dysfunction were not associated with changes in plasma TRAP.

Evidence suggests that free oxygen radicals are involved in the destruction of islet beta-cells in insulin-dependent diabetes mellitus (IDDM). Therefore, we determined the plasma antioxidant activity in 51 healthy unaffected children and adolescents randomly chosen from a study of beta-cell autoimmunity in schoolchildren in northern Finland. Twenty-two subjects tested positive for one or more IDDM-associated autoantibodies and 9 subjects had at least two of the three antibodies tested (antibodies against islet cells, ICA; glutamic acid decarboxylase, GADA; insulin, IAA). There was no significant association of total plasma antioxidant potential, plasma concentrations of alpha-tocopherol, ascorbic acid, protein thiols, or uric acid with the presence of ICA, GADA, or IAA. A reduced first-phase insulin response to intravenous glucose was also not associated with reduced plasma antioxidant activity. These results indicate that the plasma antioxidant activity is not decreased in subjects at increased risk for IDDM. Furthermore, the results suggest that the clinical onset of IDDM is not preceded by signs of increased systemic oxidative stress in plasma.

Oxidation of low-density lipoprotein (LDL) may be an important factor in the development of diabetic macrovascular and renal complications. The level of autoantibodies against oxidized LDL (oxLDL-Ab) can be used as an index of LDL oxidation in vivo. The purpose of this study was to investigate the association between the level of oxLDL-Ab and the presence of coronary heart disease and renal dysfunction in patients with non-insulin-dependent diabetes mellitus (NIDDM). We determined the plasma levels of oxLDL-Ab in 46 NIDDM patients and 48 well matched nondiabetic control subjects. NIDDM patients had a moderately higher level of oxLDL-Ab than control subjects (0.083 +/- 0.051 vs. 0.062 +/- 0.045, p = 0.04). However, there was no difference in the level of oxLDL-Ab between subjects with and without coronary heart disease, and the level of oxLDL-Ab was not associated with indices of glomerular filtration rate or urinary albumin excretion.

Increased number of peripheral benzodiazepine receptors (PBRs) have been found in some tumors outside the liver. The present study was to verify whether the PBR system is altered in hepatocellular carcinoma (HCC). The levels of endogenous benzodiazepine-like compounds (BZDs). measured by radioreceptor binding technique after HPLC purification and the endogenous ligand for PBRs. termed diazepam binding inhibitor (DBI). measured by radioimmunoassay utilizing a specific antibody for human DBI, were studied in the blood of 15 normal subjects, 12 liver cirrhosis and 10 patients with HCC. The levels of BZDs in serum were increased hundred fold in liver cirrhosis patients and slightly elevated in HCC patients. DBI was found to be increased in HCC patients. The binding recognition sites for PBRs (Bmax) were increased 4 to 7 fold in HCC tissue in comparison with that found in non-tumoral liver tissue (NTLT). On the contrary the concentrations of DBI were found to be significantly decreased in HCC tissue in comparison with the respective NTLT. These results seem to suggest an implication of PBRs and of their putative endogenous ligands in the metabolism of these neoplastic cells and possibly in their proliferation. The up-regulation of PBRs found in HCC tissue seems to indicate an increased functional activity of these receptors and opens up the possibility of new pharmacological and diagnostic approaches while the changes in the circulating endogenous ligands for the above receptors might be envisaged as early markers of tumorigenesis in liver cirrhosis.

The polypeptide diazepam binding inhibitor (DBI) displays epileptogenic activity by binding to benzodiazepine receptors. We analyzed DBI concentrations in the plasma of pediatric and adult epileptic patients, as a possible peripheral marker in epilepsy. DBI plasma concentrations are significantly higher (+ 62%, P0.001) in adult patients and slightly but significantly higher (+15%, P0.01) in pediatric patients, compared to age-related controls. Strikingly, plasma DBI is much higher (+81%, P0.001) in generalized epilepsy in adults and in drug-resistant pediatric and adult patients. Based on these findings, plasma DBI may be considered as a peripheral biological marker of epilepsy and, in association with lymphocyte benzodiazepine receptor density, of anticonvulsant drug responsiveness.

Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) has been reported to serve as a sensitive biomarker of oxidative DNA damage and also of oxidative stress. We have investigated oxidative DNA damage in patients with non-insulin-dependent diabetes mellitus (NIDDM) by urinary 8-OHdG assessments. We determined the total urinary excretion of 8-OHdG from 24 h urine samples of 81 NIDDM patients 9 years after the initial diagnosis and of 100 non-diabetic control subjects matched for age and gender. The total 24 h urinary excretion of 8-OHdG was markedly higher in NIDDM patients than in control subjects (68.2 +/- 39.4 microg vs. 49.6 +/- 37.7 microg, P = 0.001). High glycosylated hemoglobin was associated with a high level of urinary 8-OHdG. The increased excretion of urinary 8-OHdG is seen as indicating an increased systemic level of oxidative DNA damage in NIDDM patients.

The diazepam binding inhibitor [DBI, also known as acyl-CoA-binding protein, (ACBP), or endozepine] is a 10-kD protein that has been suggested to be involved in the regulation of several biological processes such as acyl-CoA metabolism, steroidogenesis, insulin secretion, and gamma-aminobutyric acid type A (GABA(A))/benzodiazepine receptor modulation. DBI has been cloned from vertebrates, insects, plants, and yeasts. In mammals, DBI is expressed in almost all the tissues studied. Nevertheless, DBI expression is restricted to specific cell types. Here we have studied DBI gene expression in the germ-line cells of rat testis. The DBI gene was intensively transcribed in postmeiotic round spermatids from stages VI to VIII of the seminiferous epithelial cycle. A prominent, spermatid-specific upstream transcription initiation site was identified in addition to the multiple common transcriptional initiation sites found in the somatic tissues. However, no DBI protein was detected in round spermatids, suggesting that the DBI transcripts were translationally arrested. The DBI protein was detected in the late spermatogenic stages starting from elongating spermatids from step 18 (stage VI) onward. The DBI protein was also detected in mature spermatozoa and in ejaculated human sperms. The majority of DBI was located at the middle piece of the spermatozoons tail enriched with mitochondria. On the basis of this observation and the well-established role of DBI in acyl-CoA metabolism, we propose that DBI expression in spermatozoa reflects the usage of fatty acids as a primary energy source by spermatozoa. The biological function of DBI in spermatozoa could thus be related to the motility function of sperm.

Evidence is rapidly accumulating that oxidative modification of low density lipoprotein (LDL) may play an important role in the pathogenesis of atherosclerosis. In this study we measured the total peroxyl radical trapping capacity of human plasma LDL phospholipids (TRAPLDL) with a luminescent method. The study was carried out with 70 healthy volunteers, aged 28-77. In males an age-related decrease in TRAPLDL was observed. In the age group under 50 years the mean TRAPLDL was 31.36 +/- 1.45 pmol peroxyl radicals/nmol Pi; among those over 50 years it was significantly lower at 26.67 0.94 pmol/nmol Pi. As regards the components of TRAPLDL, the concentration of LDL-ubiquinol did not change and a non-significant decrease in the LDL-tocopherol concentration was detected with age. In females, the mean TRAPLDL, LDL-ubiquinol-10 and tocopherol concentrations did not differ between the age groups. When 17 of the participants were given coenzyme Q10 (Q10) supplementation, 100 mg/day, a highly significant increase in LDL-ubiquinol concentration was detected. Our results indicate that LDL antioxidant defenses tend to decrease with age in the Finnish male population. The decline is most significant in males under 50 years; in older age groups the values remain stable at a low level. Q10 supplementation doubles the number of ubiquinol-10-containing LDL molecules and may therefore have an inhibitory effect on LDL oxidation.