Combining medical treatment and CBT in treating alcohol-dependent patients: effects on life quality and general well-being.

AIMS: The aim of the study was to examine how the combination of medication and a brief cognitive behavioral intervention for alcohol dependency can affect patients' quality of life (QL), symptoms of depression and smoking habits. METHODS: We conducted a randomized, open-label, multicenter naturalistic study for 243 voluntary-treatment-seeking alcohol-dependent adult outpatients in two phases: first, 12 weeks with continuous medication followed by targeted medication for up to 52 weeks, and second, a follow-up period of 67 weeks (altogether 2.5 years). The subjects were randomized 1:1:1 to receive supervised naltrexone, acamprosate or disulfiram, plus a brief manual-based cognitive behavioral intervention (CBT). RESULTS: All three study groups showed a significant reduction in drinking from baseline to the end of the study. In the QL test EQ-5D, patients exhibited significant positive changes in sleeping, action, pain and mood dimensions. Severity of depression decreased during the whole study. Smoking decreased more in the disulfiram group than in the naltrexone and acamprosate groups. CONCLUSION: A combination of medical treatment (naltrexone, acamprosate or disulfiram) with the CBT-booklet (patient guide) appears to help reduce patients' symptoms of depression and improve their QL. Treatment is also associated with success at quitting smoking, especially among patients using disulfiram.

Effect of opioid antagonists on sex hormone secretion.

BACKGROUND: Endogenous opioids have roles in various functions in different parts of the body, including intestinal motility, suppression of pain, reinforcement of behavior, and regulation of the hypothalamic-pituitary-gonadal axis. The endogenous opioid system is also recognized to be involved in the negative-feedback regulation of the release of LH and testosterone. AIM: The reviewed articles herein show the development of the current model of this regulation, the evidence supporting it, and also the observed effects of opioid antagonist (naloxone, naltrexone, and nalmefene) on the system. MATERIALS AND METHODS: Review of the studies published during the years 1979-1996 (no significant studies made after that). Search from databases Pubmed, SciFinder, and Medline with search words opioid antagonists, hormones, LH, testosterone, and GnRH, in different combinations. RESULTS/CONCLUSIONS: Opioid antagonists seem to increase the secretion of GnRH in the hypothalamus which then causes a pulsatile release of LH in the pituitary and secretion of testosterone. According to the experiments, the frequency of pulses and concentration of LH and testosterone in plasma seem to increase. These effects are seen in both men and women (at early follicular phase). More research is needed to investigate the consequences of these effects in general.

Predictors for the efficacy of naltrexone treatment in alcohol dependence: sweet preference.

AIMS: To analyse the possible associations between sweet preference and the efficacy of naltrexone treatment of alcohol dependence. METHODS: The preference for different concentrations of sucrose was evaluated in 78 participants diagnosed with alcohol dependence after treatment for 32 weeks with naltrexone or placebo without prior detoxification. RESULTS: A significant difference between naltrexone and placebo groups was found in the association between the preference for higher sucrose concentrations and relapses to heavy drinking. Higher sweet preference was significantly related to successful treatment measures in the naltrexone group but not in the placebo group. CONCLUSION: Sweet preference has a strong correlation to treatment outcomes with naltrexone, and sweet preference might be used as a predictor for better treatment results in alcoholics. Our study offers one possible new explanation of the clinical observation that naltrexone is not effective for every patient.

Diazepam-binding inhibitor: a neuropeptide located in selected neuronal populations of rat brain.

An endogenous polypeptide of rat brain has been identified that is capable of displacing 1,4-benzodiazepines and the esters of the 3-carboxylic acid derivatives of beta-carbolines from their specific synaptic binding sites. This polypeptide was termed diazepam-binding inhibitor (DBI). Previous studies have shown that DBI injected intraventricularly in rodents elicits "proconflict" responses and antagonizes the "anticonflict" action of benzodiazepines. An antiserum to this peptide, directed toward an immunodeterminant near its amino terminus, makes it possible to detect, measure, and study the neuronal location of this peptide in rat brain. In the rat cerebral cortex, DBI immunoreactivity is located in neurons that are not GABAergic (GABA, gamma-aminobutyric acid); in the cerebellum and hippocampus, however, it might be present also in GABAergic neurons.

Tissue-specific expression of the diazepam-binding inhibitor in Drosophila melanogaster: cloning, structure, and localization of the gene.

The diazepam-binding inhibitor (DBI; also called acyl coenzyme A-binding protein or endozepine) is a 10-kDa polypeptide found in organisms ranging from yeasts to mammals. It has been shown that DBI and its processing products are involved in various specific biological processes such as GABAA/benzodiazepine receptor modulation, acyl coenzyme A metabolism, steroidogenesis, and insulin secretion. We have cloned and sequenced the Drosophila melanogaster gene and cDNA encoding DBI. The Drosophila DBI gene encodes a protein of 86 amino acids that shows 51 to 56% identity with previously known DBI proteins. The gene is composed of one noncoding 5' and two coding exons and is localized on the chromosomal map at position 65E. Several transcription initiation sites were detected by RNase protection and primer extension experiments. Computer analysis of the promoter region revealed features typical of housekeeping genes, such as the lack of TATA and CCAAT elements. However, in its low GC content and lack of a CpG island, the region resembles promoters of tissue-specific genes. Northern (RNA) analysis revealed that the expression of the DBI gene occurred from the larval stage onwards throughout the adult stage. In adult flies, DBI mRNA and immunoreactivity were detected in the cardia, part of the Malpighian tubules, the fat body, and gametes of both sexes. Developmentally regulated expression, disappearing during metamorphosis, was detected in the larval and pupal brains. No expression was detected in the adult nervous system. On the basis of the expression of DBI in some but not all tissues with high energy consumption, we propose that in D. melanogaster, DBI is involved in energy metabolism in a manner that depends on the substrate used for energy production.

Tenascin is expressed in post-transplant obliterative bronchiolitis.

Tenascin is expressed in inflammatory and fibroproliferative processes, both contributing to posttransplant obliterative bronchiolitis (OB) in association with epithelial cell injury and airway obliteration. We studied bronchial allografts to elucidate the role of tenascin during this alloimmune response. Bronchial segments were subcutaneously implanted into eight pigs. Allografts and autograft controls were serially obtained until total obliteration in allografts and processed for histology and immunocytochemistry for CD4, CD8, and tenascin. Findings were graded on a scale from 0 to 3. In autografts the operative epithelial damage recovered and bronchi stayed patent with mild-graded fibrosis and inflammation. Partial recovery was observed in allografts on day 4, thereafter the epithelial loss gradually increased. Total recovery was achieved on day 11 (P < .001). Fibroblast proliferation resulted in total luminal obliteration on day 21 (P < .001). The number of inflammatory cells increased rapidly (P < .05) with numerous CD4+ and CD8+ cells on day 14 (P < .0001). Prior to total epithelial loss in allografts, tenascin expression was observed on day 7 in 69% of epithelial cells, whereas in only 5% of epithelial cells in recovered autografts. Paralleling the most intense fibroproliferation, tenascin-positive cells were observed in the bronchial wall on day 7 and day 11 (P < .001). Tenascin expression was demonstrated during the inflammatory response and fibroblast proliferation during the early stage of obliterative bronchiolitis showing that tenascin contributes to posttransplant obliterative bronchiolitis development.

Expression of peripheral-type benzodiazepine receptor and diazepam binding inhibitor in human astrocytomas: relationship to cell proliferation.

The expression of peripheral-type benzodiazepine receptor (PBR) and diazepam binding inhibitor (DBI) were studied in human astrocytic tumors using immunocytochemistry and in situ hybridization. Both PBR and DBI were prominently expressed in neoplastic cells, whereas in normal brain their amount was low or undetectable. Immunocytochemical double staining demonstrated that PBR and DBI were present in the same cells, suggesting that DBI may act in an autocrine manner in these cells. Analysis of 86 cases showed that PBR expression was statistically significantly associated with tumor malignancy grade (P = 0.004) and the proliferative index as determined by immunocytochemistry with the MIB-1 antibody (P = 0.004). Patients having tumors with high levels of PBR-immunoreactive cells had a shorter life expectancy than patients whose tumors showed lower PBR contents (P = 0.024). In conclusion, these results show that PBR expression is higher in neoplastic cells than in normal brain tissue. They also suggest that PBR immunocytochemistry might be useful in evaluating malignancy in brain tumors.

Expression of diazepam-binding inhibitor peptide in human skin: an immunohistochemical and ultrastructural study.

Human diazepam binding inhibitor (DBI) was originally isolated from the brain and subsequently found to be present in several peripheral tissues. The various physiologic effects recently attributed to DBI include acting as an endogenous ligand for the central and peripheral (mitochondrial) benzodiazepine receptors. The present work provides, for the first time, evidence of DBI immunoreactivity in skin. DBI immunoreactivity was found in the epidermis, in the eccrine sweat and in sebaceous glands. Ultrastructurally, DBI was distributed throughout the cytoplasm. Although the physiologic role of DBI in skin is unknown, our results indicate that DBI may serve as an endogenous ligand for mitochondrial benzodiazepine receptors. Its activity could be related to the regulation of lipid and cholesterol synthesis in keratinocytes and sebaceous glands and to the secretion of sweat in sweat glands.

Expression of diazepam binding inhibitor-like immunoreactivity in rat testis is dependent on pituitary hormones.

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.

Fos-like immunoreactivity in the rat hypothalamic-pituitary axis after immobilization stress.

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.

Neuropeptide Y in bovine adrenal glands: distribution and characterization.

Neuropeptide Y (NPY) distribution in bovine adrenal glands was studied by RIA and immunohistochemical technique. NPY content (picomoles per mg protein +/- SEM) of chromaffin cells, medulla, cortex, and whole glands was 4.2 +/- 0.16, 2.7 +/- 0.28, 0.19 +/- 0.02, and 0.94 +/- 0.14, respectively, while the chromaffin granule NPY content was 53. Immunohistochemically, NPY immunoreactivity was detected in norepinephrine containing chromaffin cells and also in nerve fibers crossing through adrenal cortex and medulla. NPY and enkephalin immunoreactivities were found in distinct chromaffin cells. Biochemical characterization by HPLC revealed two major NPY immunoreactive peptides. The most abundant molecular form was identified as authentic NPY.

Ubiquinol-10 and total peroxyl radical trapping capacity of LDL lipoproteins during aging: the effects of Q-10 supplementation.

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.

Is there an unidentified defence mechanism against infection in human plasma?

The total peroxyl radical scavenging capacity (TRAP) of human plasma was measured from pneumonia patients and controls. TRAP and its main components, ascorbic acid, alpha-tocopherol, uric acid or protein thiol groups, were unaltered, but the concentration of unidentified antioxidants in pneumonia patients was significantly reduced. Our results indicate that human plasma may contain so far unidentified antioxidants depleted in infection.

Biomarker evidence of DNA oxidation in lung cancer patients: association of urinary 8-hydroxy-2'-deoxyguanosine excretion with radiotherapy, chemotherapy, and response to treatment.

Ratios of urinary 8-hydroxy-2'-deoxyguanosine to urinary creatinine (8-OHdG/creatinine) have been considered as a good biological indicator of DNA oxidation. Urinary 8-OHdG/creatinine levels of lung cancer patients were evaluated by enzyme-linked immunosorbent assay using a monoclonal antibody N45.1 during radiotherapy and chemotherapy. An increase in urinary 8-OHdG/creatinine was found in non-small-cell carcinoma (non-SCC) patients during the course of radiotherapy. SCC patients showed higher levels of urinary 8-OHdG/creatinine than the controls. Furthermore, SCC patients with complete or partial response to the chemotherapy showed a significant decrease in urinary 8-OHdG/creatinine while patients with no change or progressive disease showed an increase.

Age-related changes in the peroxyl radical scavenging capacity of human plasma.

Aging and the diseases that typically follow with increasing age, notably atherosclerosis and cancer, are often proposed to be involved in increased oxidative stress. Animal studies, on the other hand, show no clear-cut pattern of age-related changes in enzymatic antioxidant defences. In this study we have demonstrated that total peroxyl radical scavenging antioxidant capacity (TRAP) in human plasma changes with age. We also found that among the antioxidants in human plasma there exists a major fraction of so far unidentified antioxidant(s). A chemiluminescent TRAP assay was used to determine the presence of peroxyl radical scavenging antioxidants in human plasma. The material consisted of 87 healthy volunteers, aged 20-96 years, who used no regular medication, vitamins, or trace elements. In females, total antioxidant capacity increased significantly during the life span. The increase in TRAP was mainly due to unidentified antioxidants. In males, TRAP increased until age 51-74, and then significantly decreased. The decrease observed among males was also due to the sharp decline in the concentration of unidentified antioxidants.

The effect of ascorbate and ubiquinone supplementation on plasma and CSF total antioxidant capacity.

Free radicals are thought to be involved in the onset of neuronal disturbances such as Alzheimer's disease, Parkinson's disease, and neuronal ceroid lipofuscinosis. It is also assumed that they play a role in cerebral injury caused by ischemia or trauma. Plasma and cerebrospinal fluid (CSF), Total (peroxyl) Radical-trapping Antioxidant Parameter (TRAP), and the known antioxidant components of TRAP, for instance, ascorbic acid, uric acid, protein sulfhydryl groups, tocopherol, and ubiquinol were analyzed and the remaining unidentified fragment was calculated in five healthy volunteers before and after 4 weeks of ascorbate and ubiquinone (Q-10) supplementation. In CSF, TRAP was significantly lower than in plasma. The major contributor to plasma's antioxidant capacity was uric acid (UA), whereas in CSF it was ascorbic acid (AA). In CSF, AA concentrations were four times higher than in plasma. Oral supplementation of AA (500 mg/d first 2 weeks, 1,000 mg/d following 2 weeks) and Q-10 (100 mg/d first 2 weeks, 300 mg/d following 2 weeks) induced a significant increase in plasma AA and Q-10. Surprisingly, in spite of the high lipophilicity of Q-10, its concentration did not change in CSF. The supplementation of AA increased its concentration in CSF by 28% (p < .05). However, the increase in AA did not result in an increase in CSF TRAP. This indicates that AA had lost one-third of its radical trapping capacity as compared to that in plasma. The facts that AA is the highest contributor to CSF TRAP and its effect on TRAP is concentration dependent could indicate that the peroxyl radical-trapping capacity of CSF is buffered by AA.

New biomarker evidence of oxidative DNA damage in patients with non-insulin-dependent diabetes mellitus.

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.

Effect of vitamin E and selenium supplement on the aging peripheral neurons of the male Sprague-Dawley rat.

The effect of life-long diets containing different concentrations of selenium and vitamin E on the age pigment accumulation in the rat superior cervical ganglion, vagal ganglion and dorsal root ganglion, was studied using microspectrofluorometry. All types of ganglia showed unchanged amounts of age pigments at low or high concentrations of selenium, whereas dietary concentration of vitamin E regulated age pigment content in the dorsal root ganglion, but not in the superior cervical and vagal ganglion. Vitamin E deficiency induced a three-fold increase in age pigment content in dorsal root ganglion at 8 months of age, whereas high vitamin E concentration was associated with a lesser amount of pigments at 18 months of age. Emission spectra of age pigment recorded from the dorsal root ganglion and vagal ganglion were different from that from the superior cervical ganglion, but were independent of dietary concentrations of selenium or vitamin E. The results suggest that exogenous antioxidants may play a more crucial role in lipid peroxidation and accumulation of age pigment in dorsal root ganglion than in autonomic ganglia.

Microspectrofluorometric quantitation of autofluorescent lipopigment in the human sympathetic ganglia.

The age-related changes in lipopigment autofluorescence were studied by microspectrofluorometry in three different types of human neurons: the sympathetic neurons of the stellate and superior mesenteric ganglion and pyramidal neurons of the frontal cortex. The age-related increase in lipopigment autofluorescence was more rapid in stellate ganglion but similar linear increases were found also in superior mesenteric ganglion and frontal cortex. There was an age-related shift in the autofluorescence from yellow to orange in the ganglia. This may be due to the accumulation of neuromelanin in noradrenergic neurons. Lipopigments were identified in sympathetic neurons at the age of 4 months and all neurons carried pigment granules after the age of 64 years. It is concluded that lipopigment autofluorescence is a useful marker for cellular ageing in both the peripheral and the central nervous system.

Age related heterogeneity of lipopigments in human sympathetic ganglia.

The histochemical, autofluorescence and morphological characteristics of lipopigments accumulating with age in the human sympathetic neurons were studied. The spectral characteristics of the lipopigment autofluorescence change with age suggesting the accumulation of additional components in the residual bodies. This component is electron microscopically highly osmiophilic and stains also with silver staining. These changes may indicate the gradual melanization of the lipopigments due to auto-oxidation of catecholamines. The accumulation of the melanized form of lipopigment may be a sign of more advanced cellular trauma.