Pseudo-Wellens syndrome, acute pancreatitis, and an anomalous coronary artery: a case report.

BACKGROUND: Chest pain associated with transient electrocardiogram changes mimicking an acute myocardial infarction have been described in acute pancreatitis. These ischemic electrocardiogram changes can present a diagnostic dilemma, especially when patients present with concurrent angina pectoris and epigastric pain warranting noninvasive or invasive imaging studies. CASE PRESENTATION: A 45-year-old African-American man with a history of alcohol use disorder presented to the emergency department of our institution with 36 hours of concurrent epigastric pain and left-sided chest pain radiating to his left arm and associated with nausea and dyspnea. On physical examination, he was afebrile; his blood pressure was elevated; and he had epigastric tenderness. His laboratory test results were significant for hypokalemia, normal troponin, and elevated serum lipase and amylase levels. Serial electrocardiograms for persistent chest pain showed ST-segment elevations with dynamic T-wave changes in the right precordial electrocardiogram leads, consistent with Wellens syndrome. He was immediately taken to the cardiac catheterization laboratory, where selective coronary angiography showed normal coronary arteries with an anomalous origin of the right coronary artery from the opposite sinus. Given his elevated lipase and amylase levels, the patient was treated for acute alcohol-induced pancreatitis with intravenous fluids and pain control. His chest pain and ischemic electrocardiogram changes resolved within 24 hours of admission, and coronary computed tomography angiography showed an interarterial course of the right coronary artery without high-risk features. CONCLUSIONS: Clinicians may consider deferring immediate cardiac catheterization and attribute electrocardiogram changes to acute pancreatitis in patients presenting with angina pectoris and acute pancreatitis if confirmed by normal cardiac enzymes and elevated levels of lipase and amylase. However, when clinical signs and electrocardiogram findings are highly suggestive of myocardial ischemia/injury, immediate noninvasive coronary computed tomography angiography may be the best approach to make an early diagnosis.

Quantification of cell-free DNA in blood plasma and DNA damage degree in lymphocytes to evaluate dysregulation of apoptosis in schizophrenia patients.

Oxidative DNA damage has been proposed as one of the causes of schizophrenia (SZ), and post mortem data indicate a dysregulation of apoptosis in SZ patients. To evaluate apoptosis in vivo we quantified the concentration of plasma cell-free DNA (cfDNA index, determined using fluorescence), the levels of 8-oxodG in cfDNA (immunoassay) and lymphocytes (FL1-8-oxodG index, flow cytometry) of male patients with acute psychotic disorders: paranoid SZ (total N = 58), schizophreniform (N = 11) and alcohol-induced (N = 14) psychotic disorder, and 30 healthy males. CfDNA in SZ (N = 58) does not change compared with controls. In SZ patients. Elevated levels of 8-oxodG were found in cfDNA (N = 58) and lymphocytes (n = 45). The main sources of cfDNA are dying cells with oxidized DNA. Thus, the cfDNA/FL1-8-oxodG ratio shows the level of apoptosis in damaged cells. Two subgroups were identified among the SZ patients (n = 45). For SZ-1 (31%) and SZ-2 (69%) median values of cfDNA/FL1-8-oxodG index are related as 1:6 (p < 0.0000001). For the patients with other psychotic disorders and healthy controls, cfDNA/FL1-8-oxodG values were within the range of the values in SZ-2. Thus, apoptosis is impaired in approximately one-third of SZ patients. This leads to an increase in the number of cells with damaged DNA in the patient's body tissues and may be a contributing cause of acute psychotic disorder.

Association of testosterone and BDNF serum levels with craving during alcohol withdrawal.

Preclinical and clinical studies show associations between testosterone and brain-derived neurotrophic growth factor (BDNF) serum levels. BDNF and testosterone have been independently reported to influence alcohol consumption. Therefore, we aimed to investigate a possible interplay of testosterone and BDNF contributing to alcohol dependence. Regarding possible interplay of testosterone and BDNF and the activity of the hypothalamic pituitary axis (HPA), we included cortisol serum levels in our research. We investigated testosterone and BDNF serum levels in a sample of 99 male alcohol-dependent patients during alcohol withdrawal (day 1, 7, and 14) and compared them to a healthy male control group (n = 17). The testosterone serum levels were significantly (p < 0.001) higher in the patients' group than in the control group and decreased significantly during alcohol withdrawal (p < 0.001). The decrease of testosterone serum levels during alcohol withdrawal (days 1-7) was significantly associated with the BDNF serum levels (day 1: p = 0.008). In a subgroup of patients showing high cortisol serum levels (putatively mirroring high HPA activity), we found a significant association of BDNF and testosterone as well as with alcohol craving measured by the Obsessive and Compulsive Drinking Scale (OCDS). Our data suggest a possible association of BDNF and testosterone serum levels, which may be relevant for the symptomatology of alcohol dependence. Further studies are needed to clarify our results.

Alcohol Vapor Inhalation as a Model of Alcohol-Induced Organ Disease.

BACKGROUND: Chronic intermittent ethanol vapor (CIEV) exposure has been used extensively to produce rodent models of alcohol dependence, but unlike other models of alcohol abuse, CIEV has not been assessed as a model of end-organ damage. The purpose of this study was to characterize the effects of CIEV on peripheral organ systems affected by alcohol abuse, including the liver, lungs, and cardiovascular system. METHODS: Adult male Sprague-Dawley rats were exposed to daily CIEV for a period of 8 weeks (14HR ON/10HR OFF), producing blood alcohol levels of ~200 mg/dl. Controls were exposed to room air. After 8 weeks, echocardiography was performed to assess cardiac function. Indices of liver injury (alanine and aspartate aminotransferases [ALT and AST]; cytochrome p450 2E1 [CYP2E1]; alcohol dehydrogenase [ADH]; Oil Red O and triglyceride content; lipid peroxidation; inflammatory cytokine expression; and macrophage infiltration), and lung inflammatory cell count, proinflammatory cytokine expression, and lipid peroxidation were measured. RESULTS: Left ventricular posterior wall thickness was significantly decreased, and systolic blood pressure was significantly elevated by CIEV compared with air controls. CIEV led to a significant increase in plasma ALT and triglycerides compared with room air controls. CIEV did not affect liver triglyceride content, lipid staining or peroxidation, but increased CYP2E1 and chemokine (C-C motif) ligand 2 (CCL2) protein expression, while decreasing ADH expression. CIEV significantly increased numbers of both polymorphonuclear neutrophils and lymphocytes in the bronchoalveolar lavage fluid, indicative of pulmonary inflammation. However, CIEV did not produce significant changes in lung mass, pulmonary lipid peroxidation, inflammatory cytokine expression, or edema. CONCLUSIONS: These results show that CIEV produces hepatic, pulmonary, and cardiovascular effects in rats similar to those found in other models of chronic alcohol administration. Alcohol vapor administration is a novel method of alcohol-induced tissue injury with high potential for widespread use in alcohol toxicology research.

Nest building is a novel method for indexing severity of alcohol withdrawal in mice.

Withdrawal after chronic ethanol (EtOH) affects body temperature, goal-directed behavior and motor function in mice and increases general central nervous system excitability. Nest-building tests have been used to assay these states but to this point have not been employed as measures of EtOH withdrawal severity. We first refined nest-scoring methods using a genetically heterogeneous stock of mice (HS/Npt). Mice were then made physically dependent following three days of chronic EtOH vapor inhalation to produce average blood EtOH concentrations (BECs) of 1.89 mg/mL. EtOH withdrawal affected the progression of nest building over time when mice were tested 2-4 days after removal from three days of chronic exposure to EtOH. In a separate group of mice, chronic EtOH vapor inhalation (BECs 1.84 mg/mL) suppressed nest building over days 1-2 but not days 2-3 of withdrawal. In a following experiment, EtOH withdrawal dose-dependently slowed recovery of nest building for up to 32 h. Finally, we determined that long-lasting nest-building deficits extend to mice undergoing withdrawal from a high dose (4 g/kg) of acute EtOH. Sex differences for nest building were absent following EtOH exposure. In mice naïve to EtOH treatments, male mice had lower pre-test body temperatures and increased nest scores across a two-day testing period compared to females. These results suggest that nest building can be used to assess chronic and acute EtOH withdrawal severity in mice.

The feasibility and cost of neonatal screening for prenatal alcohol exposure by measuring phosphatidylethanol in dried blood spots.

BACKGROUND: Accurate confirmation of prenatal alcohol exposure (PAE) is required as a diagnostic criterion for the majority of children adversely affected by PAE who do not manifest the physical features associated with fetal alcohol syndrome. A number of ethanol biomarkers have been used to assess PAE, often with suboptimal results. The purpose of this study was to evaluate the feasibility and cost of PAE screening in newborns by measuring phosphatidylethanol (PEth) in dried blood spot (DBS) cards. METHODS: The feasibility of collecting an additional DBS card during routine newborn screening and the background prevalence of PAE were evaluated in a de-identified sample of newborn children delivered at the University of New Mexico Hospital. Electronic orders to collect DBS cards from newborns who continue to bleed after the routine newborn screen, glucose, or hematocrit testing were initiated for all infants delivered during a 4-week time frame. Specimens were sent to a contract laboratory for PEth analysis by liquid chromatography-tandem mass spectrometry. A cost analysis was conducted to compare the cost of PAE screening by PEth in DBS versus PEth in conventional blood specimens and by meconium fatty acid ethyl esters. RESULTS: From 230 collected cards, 201 (87.4%) had at least 1 full blood spot (amount sufficient for PEth analysis), and 6.5% had PEth >20 ng/ml indicative of potential PAE in late pregnancy. PAE screening by PEth in DBS is logistically simpler and less expensive compared with 2 other screening approaches. CONCLUSIONS: These results indicate that screening for PAE in DBS cards is a feasible procedure and that a majority of infants have enough blood after the routine heel prick to fill an additional card. Moreover, screening by PEth analysis from DBS cards is cost-efficient. The acceptability of such screening by parents and corresponding ethical issues remain to be investigated.

Overexpression of serum response factor in astrocytes improves neuronal plasticity in a model of early alcohol exposure.

Neuronal plasticity deficits underlie many of the cognitive problems seen in fetal alcohol spectrum disorders (FASD). We have developed a ferret model showing that early alcohol exposure leads to a persistent disruption in ocular dominance (OD) plasticity. Recently, we showed that this deficit could be reversed by overexpression of serum response factor (SRF) in the primary visual cortex during the period of monocular deprivation (MD). Surprisingly, this restoration was observed throughout the extent of visual cortex and most of the cells transfected by the virus were positive for the astrocytic marker GFAP rather than the neuronal marker NeuN. Here we test whether overexpression of SRF exclusively in astrocytes is sufficient to restore OD plasticity in alcohol-exposed ferrets. To accomplish that, first we exposed cultured astrocytes to Sindbis viruses carrying either a constitutively active form of SRF (SRF+), a dominant negative (SRF-) or control Green Fluorescent Protein (GFP). After 24h, these astrocytes were implanted in the visual cortex of alcohol-exposed animals or saline controls one day before MD. Optical imaging of intrinsic signals showed that alcohol-exposed animals that were implanted with astrocytes expressing SRF, but not SRF- or GFP, showed robust restoration of OD plasticity in all visual cortex. These findings suggest that overexpression of SRF exclusively in astrocytes can improve neuronal plasticity in FASD.

Stopping insulin and achieving a good metabolic control in a heavy drinker five months after stopping alcohol.

In this case study, we describe a 25 year-old male who showed the symptoms of diabetes after a period of heavy drinking. (HbA1c=13%). Treatment was started with 120 units of insulin. After stopping alcohol consumption and taking an appropriate diet, insulin was tapered down. Five months after the start of treatment, insulin was stopped (HbA1c=5%). The results showed that he was in a good metabolic control after 18 months (HbA1c=5.9%).

Hypothalamic-pituitary-adrenal axis activity, dehydroepiandrosterone sulphate and their relationships with aggression in early and late alcohol withdrawal.

The study aims at investigating the relationship between hypothalamic-pituitary-adrenal (HPA) axis alterations and aggression level in alcoholic patients during early and late alcohol withdrawal. Serum levels of basal cortisol and dehydroepiandrosterone sulphate (DHEAS) were measured three times, and cortisol and DHEAS response to dexamethasone twice during the early and late withdrawal periods in alcohol dependent males (n=30) and once in healthy control males (n=20). Abnormal cortisol non-suppression response to dexamethasone in dexamethasone suppression test (DST) was observed in some proportion of the patients in early withdrawal, which normalized in late withdrawal. The study revealed reduced basal DHEAS levels and reduced DHEAS response to dexamethasone in late withdrawal. When the patients were assessed in two separate groups as high- and low-aggressives, in the high-aggression group abnormality in DST was observed during both early and late withdrawal periods, in the low-aggression group it was observed only in early withdrawal. While basal DHEAS levels were low in the high-aggression group only in early withdrawal, it was reduced in the low-aggression group during late withdrawal period. Some alterations of the HPA axis during alcohol withdrawal might be associated not only with alcohol use per se but also with aggressivity tendency of alcoholic patients.

Mean corpuscular volume and ADH1C genotype in white patients with alcohol-associated diseases.

BACKGROUND: Alcohol abuse is associated with several gastrointestinal diseases, such as esophageal carcinoma, chronic alcoholic pancreatitis, and liver cirrhosis. Increased mean corpuscular volume (MCV) has been recognized as a biomarker for alcohol abuse and heavy drinkers. Recent studies from Japan revealed that macrocytosis is related to ALDH-2/2 genotype, leading to increased acetaldehyde accumulation. It has also demonstrated that increased MCV values could also be an independent biomarker for esophageal cancer in Asians. Therefore, the aim of the current study was to investigate possible associations of MCV value with polymorphisms of ADH1C in white patients with alcohol-associated esophageal carcinoma, chronic alcoholic pancreatitis, and alcoholic cirrhosis as well as in heavy drinkers without organ damage. METHODS: In this study, a total of 510 alcoholic patients were enrolled with esophageal cancer (n = 98), chronic pancreatitis (n = 98), alcoholic liver cirrhosis (n = 151), and alcohol abuse without gastrointestinal disease (n = 163). ADH1C genotyping was performed by PCR-based restriction fragment length polymorphism (PCR-RFLP) analysis from whole blood. The relation between MCV and ADH1C gene polymorphisms (ADH1C*1 and 1C*2) controlled for the amount of drinking, smoking, and age were investigated using both univariate and multivariate analysis. RESULTS: In univariate analysis, higher alcohol consumption was associated with increased MCV. Other variables were not associated with macrocytosis. In multiple linear regression analysis, after adjustment for age and smoking, higher alcohol consumption and female sex were independently associated with higher MCV values. No other variables, including which alcohol-associated disease the patient had, had an independent effect. Adding ADH genotype rendered no independent significant effect on MCV value. CONCLUSIONS: In a white population, MCV values were not associated with genotype polymorphisms of ADH1C. In contrast to findings in Asians, macrocytosis does not seem to be an independent biomarker for esophageal cancer. The role of ADH1C polymorphism in increasing MCV and the potential use of MCV as a marker for esophageal carcinoma are still pending.

Human genetics of plasma dopamine beta-hydroxylase activity: applications to research in psychiatry and neurology.

RATIONALE: Norepinephrine (NE) is a key neurotransmitter in the central and peripheral nervous systems. Dopamine beta-hydroxylase (DbetaH) catalyzes the synthesis of NE from dopamine (DA) and occurs in the plasma as a stable heritable trait. Studies of this trait have been useful in psychiatric and neurological research. OBJECTIVE: To selectively and critically review the literature on plasma DbetaH, and on recent progress understanding the molecular genetic basis for its inheritance. Based on this review, directions for future research in psychiatry and neurology will be suggested. METHODS: We selectively review the literature on the biochemical and molecular genetics of plasma DbetaH activity, as well as research on plasma and cerebrospinal fluid (CSF) DbetaH in psychiatric and neurological disorders. RESULTS: Strong evidence implicates DBH, the structural locus encoding DbetaH enzyme, as the major quantitative trait locus influencing plasma DbetaH activity, with one single nucleotide polymorphism (SNP) accounting for up to 50% of the variance. Mutations at DBH appear to be responsible for the rare syndrome of DbetaH deficiency. Some biochemical and genetic studies suggest associations between low plasma or CSF DbetaH and psychotic symptoms in several psychiatric disorders. Studies combining genotyping at DBH with biochemical measurement of plasma DbetaH have proven useful in studies of schizophrenia, cocaine-induced paranoia (CIP), depression, attention deficit hyperactivity disorder, and alcoholism. Such studies may also elucidate the contribution of noradrenergic dysfunction to a variety of symptoms in Parkinson's disease and other degenerative neurological disorders. CONCLUSIONS: A model is proposed, in which lower levels of DbetaH protein may lead to elevated ratios of DA to NE. This model may explain associations between lower plasma DbetaH activity and vulnerability to psychotic symptoms. Genotype-controlled analysis of plasma DbetaH holds promise for promoting further progress in research on psychiatric and neurological disorders.

[Pathomorphological manifestations of various forms of alcohol disease]. / Patomorfologicheskie proiavleniia razlichnykh form alkogol'noi bolezni.

In acute poisoning with ethanol a cardiac variant of tanatogenesis prevails. Signs for ethanol surrogates of DIC syndrome are more characteristic. Alcohol cardiomyopathy and liver cirrhosis are typical as causes of death for chronic forms of alcoholic disease. Histochemical features in the brain are found characteristic for some forms of alcoholic disease.

The potential beneficial effect of leptin on an experimental model of hyperlipidemia, induced by chronic ethanol treatment.

BACKGROUND: Obesity is known to predispose individuals to liver disease by increasing hepatic sensitivity to endotoxin. The aim of the present study was to determine the effect of mouse recombinant leptin on food intake, body weight, hepatic and plasma lipids and lipoproteins in alcohol-induced liver injury. METHOD: Male Swiss mice weighing 28-32 g were administered ethanol (6.32 g x kg(-1) body weight, p.o.) for the first 30 days. Subsequently, ethanol-fed mice were given intraperitoneal injections of exogenous leptin (230 microg x kg(-1) body weight, i.p.) every alternate day for 15 days. At the end of the total experimental period of 45 days, plasma concentrations of total cholesterol, free fatty acids, triglycerides, lipoprotein lipase and lipoproteins were measured. RESULTS: Exogenous leptin injections to alcohol-fed mice significantly (P<0.05) inhibited the rise in hepatic and plasma lipid and lipoprotein concentrations as compared with those of the unsupplemented ethanol fed mice. Food intake and average body weight at the end of the experimental period was significantly decreased on leptin administration. CONCLUSION: Chronic administration of exogenous mouse recombinant leptin prevents the rise in lipids and lipoprotein concentrations significantly in an animal model of alcohol-induced hyperlipidemia.

Changes in plasma noradrenaline and serotonin levels and craving during alcohol withdrawal.

AIMS: Despite substantial preclinical evidence that supports the involvement of noradrenergic (NA) and serotonergic (5-HT) mechanisms in alcohol withdrawal, human data remain inconsistent. We examined whether plasma levels of NA and 5-HT were altered during alcohol withdrawal and whether these measures were related to craving. We also explored whether alterations in NA and 5-HT activity differ between type I and type II alcohol-dependent patients during withdrawal. METHODS: Plasma measurements of NA and 5-HT and assessments of craving were performed longitudinally in 26 Caucasian alcohol-dependent men who were hospitalized for detoxification, at baseline (day 0), and on the 1st, 7th and 14th days of withdrawal. These measures were compared with NA and 5-HT levels obtained in 28 controls. RESULTS: During withdrawal, NA levels declined significantly from day 1 through day 14, whereas 5-HT levels and craving declined significantly from day 0 through day 14. The NA levels on days 0 and 1 of withdrawal were significantly higher than those in controls; however, by day 7 the NA levels were similar to the control values. In contrast, the 5-HT levels on day 0 of withdrawal resembled control values; however, the 5-HT concentrations on days 1, 7 and 14 were significantly lower than those in controls. There were no significant correlations between NA and 5-HT levels or between craving and the biological measures during withdrawal. Type I and type II patients did not differ in NA or 5-HT levels during withdrawal. CONCLUSIONS: These findings indicate that both plasma NA and 5-HT levels change during withdrawal; however, the pattern of change is different for the two measures. Also, while alterations in NA activity appear to normalize by late withdrawal, 5-HT changes seem to be more persistent. Neither craving nor subtypes of alcoholism seem to be related to alterations in NA or 5-HT during withdrawal.

Serotonin, impulsivity, and alcohol use disorders in the older adolescent: a psychobiological study.

BACKGROUND: Alcohol use disorders (AUDs) among adolescents are associated with a high prevalence of conduct disorder (CD), much as type II alcoholism in adults is associated with impulsive-aggressive behavior and antisocial personality traits. Adults with impulsive personality disorders and AUD demonstrate diminished central serotonergic responsiveness to serotonergic agonists. Dysregulation of central serotonergic function may contribute to a vulnerability to impulsive-aggressive behavior, CD, and AUD. We studied older adolescents, both male and female, to examine the relationships between sex, dispositional impulsivity, aggressivity, CD, and responsiveness to serotonergic challenge with d,l fenfluramine (FEN) early in the development of AUD. METHODS: Thirty-six adolescents between the ages of 16 and 21 years were assessed for DSM-IV AUD and other Axis I disorders by using the Psychoactive Substance Use Disorders section of the Structured Clinical Interview for DSM III-R, the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version, and CD interviews. Impulsivity and aggressivity were assessed by the Barratt Impulsiveness Scale, Lifetime History of Aggression, Buss-Durkee Hostility Inventory, Eysenck Impulsiveness Questionnaire, Youth Self Report, and Multidimensional Personality Questionnaires. FEN was administered as 0.8 mg/kg to a maximum of 60 mg, and blood was sampled at fixed intervals for prolactin, cortisol, fenfluramine, and norfenfluramine levels. RESULTS: Eighteen adolescents (12 male, 6 female) with AUD scored significantly higher on all measures of impulsivity and aggressivity compared with 18 healthy controls (12 male, 6 female). There were no significant differences between groups in peak prolactin or cortisol responses (minus baseline), or area-under-the-curve determinations (AUC); however, 9 subjects with AUD and comorbid CD had significantly elevated cortisol AUC levels compared with subjects with AUD and no CD or with normal controls. In the total sample, cortisol AUC was associated positively with measures of aggression. CONCLUSIONS: Adolescents with early-onset AUD are characterized by impulsivity and aggressivity compared with healthy peers but do not demonstrate the diminished prolactin or cortisol responses to FEN characteristic of adult alcoholics with impulsive-aggression.