Alcohol, microbiome, life style influence alcohol and non-alcoholic organ damage.

This paper is based upon the "8th Charles Lieber's Satellite Symposium" organized by Manuela G. Neuman at the Research Society on Alcoholism Annual Meeting, on June 25, 2016 at New Orleans, Louisiana, USA. The integrative symposium investigated different aspects of alcohol-induced liver disease (ALD) as well as non-alcohol-induced liver disease (NAFLD) and possible repair. We revealed the basic aspects of alcohol metabolism that may be responsible for the development of liver disease as well as the factors that determine the amount, frequency and which type of alcohol misuse leads to liver and gastrointestinal diseases. We aimed to (1) describe the immuno-pathology of ALD, (2) examine the role of genetics in the development of alcoholic hepatitis (ASH) and NAFLD, (3) propose diagnostic markers of ASH and non-alcoholic steatohepatitis (NASH), (4) examine age and ethnic differences as well as analyze the validity of some models, (5) develop common research tools and biomarkers to study alcohol-induced effects, 6) examine the role of alcohol in oral health and colon and gastrointestinal cancer and (7) focus on factors that aggravate the severity of organ-damage. The present review includes pre-clinical, translational and clinical research that characterizes ALD and NAFLD. Strong clinical and experimental evidence lead to recognition of the key toxic role of alcohol in the pathogenesis of ALD with simple fatty infiltrations and chronic alcoholic hepatitis with hepatic fibrosis or cirrhosis. These latter stages may also be associated with a number of cellular and histological changes, including the presence of Mallory's hyaline, megamitochondria, or perivenular and perisinusoidal fibrosis. Genetic polymorphisms of ethanol metabolizing enzymes and cytochrome p450 (CYP) 2E1 activation may change the severity of ASH and NASH. Other risk factors such as its co-morbidities with chronic viral hepatitis in the presence or absence of human deficiency virus were discussed. Dysregulation of metabolism, as a result of ethanol exposure, in the intestine leads to colon carcinogenesis. The hepatotoxic effects of ethanol undermine the contribution of malnutrition to the liver injury. Dietary interventions such as micro and macronutrients, as well as changes to the microbiota have been suggested. The clinical aspects of NASH, as part of the metabolic syndrome in the aging population, have been presented. The symposium addressed mechanisms and biomarkers of alcohol induced damage to different organs, as well as the role of the microbiome in this dialog. The microbiota regulates and acts as a key element in harmonizing immune responses at intestinal mucosal surfaces. It is known that microbiota is an inducer of proinflammatory T helper 17 cells and regulatory T cells in the intestine. The signals at the sites of inflammation mediate recruitment and differentiation in order to remove inflammatory inducers and promote tissue homeostasis restoration. The change in the intestinal microbiota also influences the change in obesity and regresses the liver steatosis. Evidence on the positive role of moderate alcohol consumption on heart and metabolic diseases as well on reducing steatosis have been looked up. Moreover nutrition as a therapeutic intervention in alcoholic liver disease has been discussed. In addition to the original data, we searched the literature (2008-2016) for the latest publication on the described subjects. In order to obtain the updated data we used the usual engines (Pub Med and Google Scholar). The intention of the eighth symposia was to advance the international profile of the biological research on alcoholism. We also wish to further our mission of leading the forum to progress the science and practice of translational research in alcoholism.

Slow-release L-cysteine capsule prevents gastric mucosa exposure to carcinogenic acetaldehyde: results of a randomised single-blinded, cross-over study of Helicobacter-associated atrophic gastritis.

INTRODUCTION: Helicobacter-induced atrophic gastritis with a hypochlorhydric milieu is a risk factor for gastric cancer. Microbes colonising acid-free stomach oxidise ethanol to acetaldehyde, a recognised group 1 carcinogen. OBJECTIVE: To assess gastric production of acetaldehyde and its inert condensation product, non-toxic 2-methyl-1,3-thiazolidine-4-carboxylic acid (MTCA), after alcohol intake under treatment with slow-release L-cysteine or placebo. METHODS: Seven patients with biopsy-confirmed atrophic gastritis, low serum pepsinogen and high gastrin-17 were studied in a cross-over single-blinded design. On separate days, patients randomly received 200 mg slow-release L-cysteine or placebo with intragastric instillation of 15% (0.3 g/kg) ethanol. After intake, gastric concentrations of ethanol, acetaldehyde, L-cysteine and MTCA were analysed. RESULTS: Administration of L-cysteine increased MTCA (p < .0004) and decreased gastric acetaldehyde concentrations by 68% (p < .0001). The peak L-cysteine level was 7552 ± 2687 µmol/L at 40 min and peak MTCA level 196 ± 98 µmol/L at 80 min after intake. Gastric L-cysteine and MTCA concentrations were maintained for 3 h. The AUC for MTCA was 11-fold higher than acetaldehyde, indicating gastric first-pass metabolism of ethanol. With placebo, acetaldehyde remained elevated also at low ethanol concentrations representing 'non-alcoholic' beverages and food items. CONCLUSIONS: After gastric ethanol instillation, slow-release L-cysteine eliminates acetaldehyde to form inactive MTCA, which remains in gastric juice for up to 3 h. High acetaldehyde levels indicate a marked gastric first-pass metabolism of ethanol resulting in gastric accumulation of carcinogenic acetaldehyde. Local exposure of the gastric mucosa to acetaldehyde can be mitigated by slow-release L-cysteine capsules.

ALDH2-deficiency as genetic epidemiologic and biochemical model for the carcinogenicity of acetaldehyde.

Humans are cumulatively exposed to acetaldehyde from various sources including alcoholic beverages, tobacco smoke, foods and beverages. The genetic-epidemiologic and biochemical evidence in ALDH2-deficient humans provides strong evidence for the causal relationship between acetaldehyde-exposure due to alcohol consumption and cancer of the upper digestive tract. The risk assessment has so far relied on thresholds based on animal toxicology with lower one-sided confidence limit of the benchmark dose values (BMDL) typically ranging between 11 and 63 mg/kg bodyweight (bw)/day dependent on species and endpoint. The animal data is problematic for regulatory toxicology for various reasons (lack in study quality, problems in animal models and appropriateness of endpoints - especially cancer - for transfer to humans). In this study, data from genetic epidemiologic and biochemical studies are reviewed. The increase in the daily exposure dose to acetaldehyde in alcohol-consuming ALDH2-deficients vs. ALDH2-actives was about twofold. The acetaldehyde increase due to ALDH2 inactivity was calculated to be 6.7 µg/kg bw/day for heavy drinkers, which is associated with odds ratios of up to 7 for head and neck as well as oesophageal cancer. Previous animal toxicology based risk assessments may have underestimated the risk of acetaldehyde. Risk assessments of acetaldehyde need to be revised using this updated evidence.

ALDH2 Deficiency Promotes Ethanol-Induced Gut Barrier Dysfunction and Fatty Liver in Mice.

BACKGROUND: Acetaldehyde, the toxic ethanol (EtOH) metabolite, disrupts intestinal epithelial barrier function. Aldehyde dehydrogenase (ALDH) detoxifies acetaldehyde into acetate. Subpopulations of Asians and Native Americans show polymorphism with loss-of-function mutations in ALDH2. We evaluated the effect of ALDH2 deficiency on EtOH-induced disruption of intestinal epithelial tight junctions and adherens junctions, gut barrier dysfunction, and liver injury. METHODS: Wild-type and ALDH2-deficient mice were fed EtOH (1 to 6%) in Lieber-DeCarli diet for 4 weeks. Gut permeability in vivo was measured by plasma-to-luminal flux of FITC-inulin, tight junction and adherens junction integrity was analyzed by confocal microscopy, and liver injury was assessed by the analysis of plasma transaminase activity, histopathology, and liver triglyceride. RESULTS: EtOH feeding elevated colonic mucosal acetaldehyde, which was significantly greater in ALDH2-deficient mice. ALDH2(-/-) mice showed a drastic reduction in the EtOH diet intake. Therefore, this study was continued only in wild-type and ALDH2(+/-) mice. EtOH feeding elevated mucosal inulin permeability in distal colon, but not in proximal colon, ileum, or jejunum of wild-type mice. In ALDH2(+/-) mice, EtOH-induced inulin permeability in distal colon was not only higher than that in wild-type mice, but inulin permeability was also elevated in the proximal colon, ileum, and jejunum. Greater inulin permeability in distal colon of ALDH2(+/-) mice was associated with a more severe redistribution of tight junction and adherens junction proteins from the intercellular junctions. In ALDH2(+/-) mice, but not in wild-type mice, EtOH feeding caused a loss of junctional distribution of tight junction and adherens junction proteins in the ileum. Histopathology, plasma transaminases, and liver triglyceride analyses showed that EtOH-induced liver damage was significantly greater in ALDH2(+/-) mice compared to wild-type mice. CONCLUSIONS: These data demonstrate that ALDH2 deficiency enhances EtOH-induced disruption of intestinal epithelial tight junctions, barrier dysfunction, and liver damage.

Rationale in diagnosis and screening of atrophic gastritis with stomach-specific plasma biomarkers.

BACKGROUND AND AIMS: Atrophic gastritis (AG) results most often from Helicobacter pylori (H. pylori) infection. AG is the most important single risk condition for gastric cancer that often leads to an acid-free or hypochlorhydric stomach. In the present paper, we suggest a rationale for noninvasive screening of AG with stomach-specific biomarkers. METHODS: The paper summarizes a set of data on application of the biomarkers and describes how the test results could be interpreted in practice. RESULTS: In AG of the gastric corpus and fundus, the plasma levels of pepsinogen I and/or the pepsinogen I/pepsinogen II ratio are always low. The fasting level of gastrin-17 is high in AG limited to the corpus and fundus, but low or non-elevated if the AG occurs in both antrum and corpus. A low fasting level of G-17 is a sign of antral AG or indicates high intragastric acidity. Differentiation between antral AG and high intragastric acidity can be done by assaying the plasma G-17 before and after protein stimulation, or before and after administration of the proton pump inhibitors (PPI). Amidated G-17 will rise if the antral mucosa is normal in structure. H. pylori antibodies are a reliable indicator of helicobacter infection, even in patients with AG and hypochlorhydria. CONCLUSIONS: Stomach-specific biomarkers provide information about the stomach health and about the function of stomach mucosa and are a noninvasive tool for diagnosis and screening of AG and acid-free stomach.

Interactions of alcohol and tobacco in gastrointestinal cancer.

Cancer prevention is based on the identification of specific etiologic factors. Acetaldehyde derived from the alcoholic beverage itself and formed from ethanol endogenously has recently been classified by the International Agency for Research on Cancer/World Health Organization as a group 1 carcinogen to humans. This is based on the uniform epidemiological and biochemical evidence derived from individuals carrying alcohol and aldehyde dehydrogenase gene mutations. After drinking alcohol, these mutations are associated with increased exposure of the upper digestive tract to acetaldehyde and as well with a remarkably increased risk for upper gastrointestinal (GI) tract cancers. Acetaldehyde is the key intermediate in alcoholic fermentation and ethanol oxidation. Therefore, it is widely present in our environment. Furthermore, it is the most abundant carcinogenic compound of tobacco smoke. Most of the known risk factors for upper digestive tract cancer appear to be associated with an enhanced exposure of GI mucosa to locally formed acetaldehyde. In these process microbes, salivary glands and even mucosal cells appear to play an essential role. Consequently, in the presence of ethanol mutagenic acetaldehyde concentrations are found in the saliva, achlorhydric stomach and colon. Equal acetaldehyde concentrations are seen in saliva also during active smoking. ALDH2-deficiency and high active ADH1C result in two- to threefold salivary acetaldehyde concentrations after a dose of alcohol and this prevails for as long as ethanol is present in the blood and saliva. Regarding cancer prevention, the good news is that acetaldehyde exposure can be markedly reduced. This can be achieved by giving high priority for regulatory measures and consumer guidance.

Xylitol inhibits carcinogenic acetaldehyde production by Candida species.

Acetaldehyde is a highly toxic and mutagenic product of alcohol fermentation and metabolism which has been classified as a Class I carcinogen for humans by the International Agency for Research on Cancer of the World Health Organisation (WHO). Many Candida species representing oral microbiota have been shown to be capable of marked acetaldehyde production. The aim of our study was to examine the effects of various sugar alcohols and sugars on microbial acetaldehyde production. The study hypothesis was that xylitol could reduce the amount of acetaldehyde produced by Candida. Laboratory and clinical isolates of seven Candida species were selected for the study. The isolates were incubated in 12 mM ethanol and 110 mM glucose, fructose or xylitol at 37°C for 30 min and the formed acetaldehyde was measured by gas chromatography. Xylitol significantly (p < 0.0001) reduced the amount of acetaldehyde produced from ethanol by 84%. In the absence of xylitol, the mean acetaldehyde production in ethanol incubation was 220.5 µM and in ethanol-xylitol incubation 32.8 µM. This was found to be mediated by inhibition of the alcohol dehydrogenase enzyme activity. Coincubation with glucose reduced the amount of produced acetaldehyde by 23% and coincubation with fructose by 29%. At concentrations that are representative of those found in the oral cavity during the intake of proprietary xylitol products, xylitol was found to reduce the production of carcinogenic acetaldehyde from ethanol by Candida below the mutagenic level of 40-100 µM.

Reducing carcinogenic acetaldehyde exposure in the achlorhydric stomach with cysteine.

BACKGROUND: Acetaldehyde, associated with alcohol consumption, has recently been classified as a group 1 carcinogen in humans. Achlorhydric atrophic gastritis is a well-known risk factor for gastric cancer. Achlorhydria leads to microbial colonization of the stomach. Several of these microbes are able to produce significant amounts of acetaldehyde by oxidation from alcohol. Acetaldehyde can be eliminated from saliva after alcohol intake and during smoking with a semi-essential amino acid, L-cysteine. The aim of this study was to determine whether cysteine can be used to bind acetaldehyde in the achlorhydric stomach after ethanol ingestion. METHODS: Seven volunteers with achlorhydric atrophic gastritis were given either slow-release L-cysteine or placebo capsules in a double-blinded randomized trial. Volunteers served as their own controls. A naso-gastric tube was inserted to each volunteer. The volunteers ingested placebo or 200 mg of L-cysteine capsules, and ethanol 0.3 g/kg body weight (15 vol%) was infused intragastrically through a naso-gastric tube. Five-milliliter samples of gastric contents were aspirated at 5-minute intervals. RESULTS: During the follow-up period, the mean acetaldehyde level of gastric juice was 2.6 times higher with placebo than with L-cysteine (13 vs. 4.7 µM, p < 0.05, n = 7). CONCLUSIONS: L-cysteine can be used to decrease acetaldehyde concentration in the achlorhydric stomach during alcohol exposure. Intervention studies with L-cysteine are needed on reducing acetaldehyde exposure in this important risk group for gastric cancer.

Effectiveness of buprenorphine maintenance treatment as compared to a syringe exchange program among buprenorphine misusing opioid-dependent patients.

AIMS: To investigate the effectiveness of buprenorphine maintenance treatment (BMT) among opioid dependents who are mainly misusing buprenorphine intravenously. METHODS: The study was a prospective naturalistic follow-up with a non-randomized control group. In Finland, 30 opioid dependents reporting previous misuse of buprenorphine and participating in the outpatient BMT and 30 matched controls participating in a syringe exchange program (SEP) were followed. Based on the evidence for the superiority of maintenance treatment, randomization was not done. The effectiveness was evaluated by retention rate, European Addiction Severity Index (EuropASI) interviews, Beck Depression Inventory (BDI), visual analogue scale for quality of life (VAS) during the 2-year follow-up and mortality rates during the 3-year follow-up. Because of drop-outs in the SEP group, only the BMT group was interviewed at 24 months. RESULTS: At 3 months, the retention rate of the BMT group was 100% and of the SEP group 47%. At 12 months, the corresponding percentages were 83% and 37%. The total EuropASI composite score improved significantly only in the BMT group. In the BMT group, the BDI total score and VAS scales for quality of life improved significantly more than they did in the SEP group. During 3-year follow-up, four patients in the SEP died and none in the BMT. CONCLUSIONS: BMT appears to be an effective treatment for opioid dependents using mainly buprenorphine intravenously. On the other hand, bare SEP appears to result in high drop-out, not significant improvements and deaths.

Expression of p53 is associated with microbial acetaldehyde production in oralsquamous cell carcinoma.

OBJECTIVES: The objective of this study was to investigate the association between p53 expression and microbial acetaldehyde production in patients with oral squamous cell carcinoma (OSCC). STUDY DESIGN: Oral mucosal biopsies from 22 patients with OSCC and 24 healthy controls (HCs) were collected. p53 expression was analyzed by immunohistochemistry. Microbial samples were collected from the mucosa and microbial acetaldehyde production from ethanol was measured by gas chromatography. RESULTS: The majority of all OSCC (77%) and HC samples (67%) produced mutagenic levels of acetaldehyde (>100 µM). A significant positive correlation between microbial acetaldehyde production and p53 expression levels in OSCC samples was seen in the intermediate and superficial layers of the epithelium of the infiltrative zone (P = .0005 and P = .0004, respectively) and in the superficial layer of the healthy appearing mucosa next to the tumor (P = .0391). There was no significant correlation between acetaldehyde levels and p53 expression in HC samples. CONCLUSIONS: Our results show an association between microbial acetaldehyde production and immunostaining of p53 in OSCC samples.

Local Acetaldehyde: Its Key Role in Alcohol-Related Oropharyngeal Cancer.

BACKGROUND: Alcohol consumption and ethanol in alcoholic beverages are group 1 carcinogens, that is, carcinogenic to humans. However, ethanol itself is neither genotoxic nor mutagenic. Based on unique gene-epidemiologic and gene-biochemical evidence, the first metabolite of ethanol oxidation - acetaldehyde (ACH) - acts as a local carcinogen in the oropharynx. This review is focused on those facts, which highlight the importance of the oropharynx and local ACH in the pathogenesis of alcohol-related oropharyngeal cancer. SUMMARY: The strongest evidence for the local carcinogenicity of ACH in man provides a point mutation in the aldehyde dehydrogenase 2 (ALDH2) gene, which has randomized millions of alcohol consumers to markedly increased ACH exposure via saliva. This novel human cancer model is associated with manifold risk for oropharyngeal cancer and most importantly it is free from confounding factors markedly hampering epidemiological studies on alcohol-related cancer. The oropharynx is an ideal target organ for the cancer risk assessment of ACH. There is substantial epidemiological data on alcohol-related oropharyngeal cancer risk and also on salivary ACH concentrations among major risk groups for oropharyngeal cancer. Normal human saliva does not contain measurable levels of ACH. However, alcohol ingestion results within seconds in a concentration-dependent accumulation of ACH in saliva, which continues for up to 10-15 min after each sip of alcoholic beverage. This instant ACH exposure phase is followed by a long-term phase derived from ethanol diffused back to saliva from blood circulation. Microbes representing normal oral flora play a major role in local ACH formation from ethanol. In ALDH2-deficient subjects excess ACH during the long-term ACH exposure phase is most probably derived from salivary glands. KEY MESSAGE: ALDH2 gene mutation proves the causal relationship between local ACH exposure via saliva and oropharyngeal cancer and provides new means for the quantitative assessment of local ACH exposure in relation to oropharyngeal cancer risk. Instant ACH formation from ethanol represents approximately 70-100% of total local ACH exposure. Ethanol present in "non-alcoholic" beverages and food forms an epidemiological bias in studies on alcohol-related upper digestive tract cancer. RESPONSES: One should quit smoking, adopt sensible drinking habits, and maintain good oral hygiene. Genetic risk groups could be screened and educated. Consumption of beverages and foodstuffs containing low ethanol levels as well as alcoholic beverages containing high ACH levels should be minimized. To that aim, labelling of alcohol and ACH concentrations of all beverages and foodstuffs should be mandatory.

Acetaldehyde as a common denominator and cumulative carcinogen in digestive tract cancers.

The key issue in cancer prevention is the identification of specific aetiologic factors. Acetaldehyde, the first metabolite of ethanol oxidation, is carcinogenic in animals. ADH and ALDH2 gene mutations provide an exceptional human model to estimate the long-term effects of acetaldehyde exposure in man. These models provide strong evidence for the local carcinogenic potential of acetaldehyde also in humans. Ethanol is metabolized to acetaldehyde by both mucosal and microbial enzymes. Many microbes produce acetaldehyde from ethanol, but their capacity to eliminate acetaldehyde is low, which leads to the accumulation of acetaldehyde in saliva during an alcohol challenge. Acetaldehyde is the most abundant carcinogen in tobacco smoke, and it readily dissolves into saliva during smoking. Fermented food and many alcoholic beverages can also contain significant amounts of acetaldehyde. Thus acetaldehyde, derived from mucosal or microbial oxidation of ethanol, tobacco smoke, and/or diet, appears to act as a cumulative carcinogen in the upper digestive tract of humans. The evidence strongly suggests the importance of world-wide screening of acetaldehyde and ethanol levels in many beverages and foodstuffs, as well as an urgent need for regulatory measures and consumer guidance. Screening of the risk groups with enhanced acetaldehyde exposure, e.g. people with ADH and ALDH2 gene polymorphisms and hypochlorhydric atrophic gastritis, should also be seriously considered. Most importantly, the GRAS (generally regarded as safe) status of acetaldehyde, which allows it to be used as a food additive, should be re-evaluated, and the classification of acetaldehyde as a carcinogen should be upgraded.

[Intoxicated patient at the emergency department and referral to treatment]. / Päihdepotilas päivystyksessä ja hoitoonohjaus.

An unconscious or delirious and aggressive, intoxicated emergency room patient causes frustration, fear and loathing among the treatment staff. An erroneous diagnosis and incorrect treatment may lead to patient's death or violent behavior. A clinical picture resembling psychosis or delirium can be caused by stimulant overdosage or beginning alcoholic delirium. Inconsciousness may be caused by alcohol, benzodiazepine or opiate intoxication. Of these, a specific antidote is available for the latter two. Correct information will decrease the anxiety, calm down the emergency situation and may save the patient's life.

Potential mechanism for Calvados-related oesophageal cancer.

The old Normandian habit of consumption of hot Calvados is associated with an increased risk of oesophageal cancer compared to other alcoholic beverages. The role of alcohol consumption in the risk of oesophageal cancer is well established. The first metabolite of alcohol, acetaldehyde is a potential local carcinogen in humans. Accordingly, different acetaldehyde concentrations in different beverages could account for some of the variations in cancer risk with regard to the type of alcoholic beverage. Eighteen samples of farm-made Calvados were collected in Normandy. Samples of commercially available beverages were purchased, including factory-made Calvados, other spirits, wines, beer and cider. The samples were analysed gas-chromatically for acetaldehyde and ethanol concentrations. All results are expressed as mean+/-SD. The mean acetaldehyde concentration of all Calvados samples (1781+/-861 microM, n =25) differed highly significantly (p<0.001) from that of all wine samples (275+/-236 microM), from all other spirits samples (1251+/-1155 microM, p<0.05), and from all beer and cider samples (233+/-281 microM, p<0.001). Farm-made Calvados and farm-made cognac had the highest mean acetaldehyde concentration of the measured beverages. The high concentration of acetaldehyde combined with possible effects of the high temperature at which Calvados is consumed could account for the increased risk of Calvados-related oesophageal cancer.

Local Acetaldehyde-An Essential Role in Alcohol-Related Upper Gastrointestinal Tract Carcinogenesis.

The resident microbiome plays a key role in exposure of the upper gastrointestinal (GI) tract mucosa to acetaldehyde (ACH), a carcinogenic metabolite of ethanol. Poor oral health is a significant risk factor for oral and esophageal carcinogenesis and is characterized by a dysbiotic microbiome. Dysbiosis leads to increased growth of opportunistic pathogens (such as Candida yeasts) and may cause an up to 100% increase in the local ACH production, which is further modified by organ-specific expression and gene polymorphisms of ethanol-metabolizing and ACH-metabolizing enzymes. A point mutation in the aldehyde dehydrogenase 2 gene has randomized millions of alcohol consumers to markedly increased local ACH exposure via saliva and gastric juice, which is associated with a manifold risk for upper GI tract cancers. This human cancer model proves conclusively the causal relationship between ACH and upper GI tract carcinogenesis and provides novel possibilities for the quantitative assessment of ACH carcinogenicity in the human oropharynx. ACH formed from ethanol present in "non-alcoholic" beverages, fermented food, or added during food preparation forms a significant epidemiologic bias in cancer epidemiology. The same also concerns "free" ACH present in mutagenic concentrations in multiple beverages and foodstuffs. Local exposure to ACH is cumulative and can be reduced markedly both at the population and individual level. At best, a person would never consume tobacco, alcohol, or both. However, even smoking cessation and moderation of alcohol consumption are associated with a marked decrease in local ACH exposure and cancer risk, especially among established risk groups.

Interrelationship between alcohol, smoking, acetaldehyde and cancer.

In industrialized countries alcohol and tobacco are the main risk factors of upper digestive tract cancer. With regard to the pathogenesis of these cancers, there is strong epidemiological, biochemical and genetic evidence supporting the role of the first metabolite of alcohol oxidation--acetaldehyde--as a common denominator. Alcohol is metabolized to acetaldehyde locally in the oral cavity by microbes representing normal oral flora. Poor oral hygiene, heavy drinking and chronic smoking modify oral flora to produce more acetaldehyde from ingested alcohol. Also, tobacco smoke contains acetaldehyde, which during smoking becomes dissolved in saliva. Via swallowing, salivary acetaldehyde of either origin is distributed from oral cavity to pharynx, oesophagus and stomach. Strongest evidence for the local carcinogenic action of acetaldehyde provides studies with ALDH2-deficient Asian drinkers, who form an exceptional human model for long-term acetaldehyde exposure. After drinking alcohol they have an increased concentration of acetaldehyde in their saliva and this is associated with over 10-fold risk of upper digestive tract cancers. In conclusion, acetaldehyde derived either from ethanol or tobacco appears to act in the upper digestive tract as a local carcinogen in a dose-dependent and synergistic way.

Acetaldehyde production from ethanol by oral streptococci.

Alcohol is a well documented risk factor for upper digestive tract cancers. It has been shown that acetaldehyde, the first metabolite of ethanol is carcinogenic. The role of microbes in the production of acetaldehyde to the oral cavity has previously been described in several studies. In the present study, the aim was to investigate the capability of viridans group streptococci of normal oral flora to produce acetaldehyde in vitro during ethanol incubation. Furthermore, the aim was to measure the alcohol dehydrogenase (ADH) activity of the bacteria. Eight clinical strains and eight American Type Culture Collection (ATCC) strains of viridans group streptococci were selected for the study. Bacterial suspensions were incubated in two different ethanol concentrations, 11 mM and 1100 mM and the acetaldehyde was measured by gas chromatography. ADH-activity was measured by using a sensitive spectroscopy. The results show significant differences between the bacterial strains regarding acetaldehyde production capability and the detected ADH-activity. In particular, clinical strain of Streptococcus salivarius, both clinical and culture collection strains of Streptococcus intermedius and culture collection strain of Streptococcus mitis produced high amounts of acetaldehyde in 11 mM and 1100 mM ethanol incubation. All these four bacterial strains also showed significant ADH-enzyme activity. Twelve other strains were found to be low acetaldehyde producers. Consequently, our study shows that viridans group streptococci may play a role in metabolizing ethanol to carcinogenic acetaldehyde in the mouth. The observation supports the concept of a novel mechanism in the pathogenesis of oral cancer.

Methadone vs. buprenorphine/naloxone during early opioid substitution treatment: a naturalistic comparison of cognitive performance relative to healthy controls.

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.