EtOH Abuse Research Articles

A Red Herring in a College Track and Field Thrower

HISTORY: 18 year old male track and field thrower, who was previously healthy, presented to the training room clinic 2 months after being diagnosed with mono by his PCP. The symptoms at the time of presentation to his PCP were fatigue and palpitations, and his labs showed elevated liver enzymes. The patient continued to have the same symptoms at the time of presentation to us. He had been on long term (>1 yr) Bactrim for acne, denied taking Tylenol regularly, but did occasionally drink ETOH. At the time of presentation to the training room, he had been scheduled for a stress treadmill and cardiac evaluation for work up of the palpitations. PHYSICAL EXAMINATION: Constitutional: Well developed. Eyes: B/L No injection. Neck: Inspection reveals symmetry. Respiratory: Lungs clear to auscultation. Normal effort Cardiovascular: No murmurs RRR No edema is present. Vascular: Pulses Capillary refill less than 2 sec. Abd: Symmetric - no distention. BS +, no bruits. NT, no RRG. No hepatic enlargement. Integumentary: No impressive skin lesions present. Ext: No edema. Neurological: Memory: Intact . Psychiatric: OA x 3 demonstrates the appropriate mood and affect. DIFFERENTIAL DIAGNOSIS: - Drug-induced hepatitis from multiple years of Bactrim use -ETOH abuse - Viral hepatitis - Gallbladder polyp/stones - Hemochromatosis - Mono TEST AND RESULTS: Hepatitis panel negative, CMP- Normal except for ALT 211 AST 87 Negative treadmill stress test FU lab 9 m later showed- Negative mono test, but ferritin was 5172, Total iron binding capacity 317, % of iron sat 91 %, iron 289, genetic testing for hemochromatosis was negative. FINAL WORKING DIAGNOSIS: Hemochromatosis TREATMENT AND OUTCOMES: Patient is doing much better at this time. Patient started out getting phlebotomies every 2 weeks and then was increased to twice weekly. His last ferritin was 750 and he continues now with once weekly phlebotomies. He is currently participating without restrictions in track and field at the NCAA level.

Relative fluid novelty differentially alters the time course of limited-access ethanol and water intake in selectively bred high-alcohol-preferring mice.

The influence of previous alcohol (ethanol [EtOH])-drinking experience on increasing the rate and amount of future EtOH consumption might be a genetically regulated phenomenon critical to the development and maintenance of repeated excessive EtOH abuse. We have recently found evidence supporting this view, wherein inbred C57BL/6J (B6) mice develop progressive increases in the rate of binge EtOH consumption over repeated drinking-in-the-dark (DID) EtOH access sessions (i.e., "front loading"). The primary goal of this study was to evaluate identical parameters in high-alcohol-preferring (HAP) mice to determine whether similar temporal alterations in limited-access EtOH drinking develop in a population selected for high EtOH preference/intake under continuous (24-hour) access conditions. Using specialized volumetric drinking devices, HAP mice received 14 daily 2-hour DID EtOH or water access sessions. A subset of these mice was then given 1day access to the opposite assigned fluid on day 15. Home cage locomotor activity was recorded concomitantly on each day of these studies. The possibility of behavioral/metabolic tolerance was evaluated on day 16 using experimenter-administered EtOH. The amount of EtOH consumed within the first 15minutes of access increased markedly over days. However, in contrast to previous observations in B6 mice, EtOH front loading was also observed on day 15 in mice that only had previous DID experience with water. Furthermore, a decrease in the amount of water consumed within the first 15minutes of access compared to animals given repeated water access was observed on day 15 in mice with 14 previous days of EtOH access. These data further illustrate the complexity and importance of the temporal aspects of limited-access EtOH consumption and suggest that previous procedural/fluid experience in HAP mice selectively alters the time course of EtOH and water consumption.

Abstract 19335: Not Your Typical Atrial Flutter

Case: Mr M. presented to the emergency room with two months of progressive shortness of breath and was found to be in atrial flutter with 2:1 conduction at a rate of 140 bpm. His medical history was significant for tobacco use, etoh abuse, and hypertension. Key objective findings included tachycardia, hypoxia an elevated JVP, bibasilar crackles, a summation gallop, and lower extremity edema. His work up included an echocardiogram that illustrated a globally depressed EF (15-20%) and a large “worm like” mass that was free floating and extended into the RV. Management: A heparin drip was already infusing as the initial plan included cardioversion. Since the patient remained hemodynamically stable and there was no evidence of concurrent deep vein thrombosis, a TEE was performed to fully evaluate the mass and to assess the intra-atrial septum for right to left shunting. The TEE with 3D renderings demonstrated a mobile 0.8 x 10 cm mass most consistent with a thrombus that intermittently prolapses through the tricuspid valve into the RV. CT surgery was consulted and discussed the options of thrombolysis vs surgical thrombectomy. Due to the size and apparent dense organization of the thrombus, surgical thrombectomy was performed. When the right atrium was opened after initiation of bypass, there was no visible clot. The main PA was explored and without evidence of the thrombus. As bypass flow decelerated, the clot proceeded into the RA from the IVC cannula. The attached picture illustrates the thrombus removed from the RA and associated echo images. Discussion: Right atrial or ventricular thrombi in transit in hypoxic patients create a challenging clinical dilemma, as distal embolization may be fatal. In this case we chose to surgically remove the thrombus instead of the more commonly employed thrombolytic therapy. The determining factors included clot organization, relative patient stability, and surgical candidacy.

Lentiviral vector-mediated dopamine d3 receptor modulation in the rat brain impairs alcohol intake and ethanol-induced conditioned place preference.

It has been reported that dopamine D3 receptor (D3R) knockout mice display similar ethanol (EtOH) consumption compared to wild types. In addition, studies with D3R pharmacological targeting were inconclusive. In the current study, we used both gain- and loss-of-function approaches to test the effects of central D3R manipulation on voluntary alcohol intake and EtOH-induced conditioned place preference (CPP) in rats. To this aim, we developed a lentiviral-mediated gene transfer approach to examine whether D3R knockdown (LV-siD3R) or overexpression (LV-D3R) in the nucleus accumbens (NAcc) is sufficient to modulate voluntary alcohol consumption and EtOH-CPP. Using the standard 2-bottle choice drinking paradigm and an unbiased CPP procedure, our results indicated that, like the D3R selective antagonist SB-277011-A, LV-siD3R attenuated voluntary alcohol consumption. In contrast, LV-D3R increased EtOH intake with no effect on total fluid intake. Similarly, the D3R agonist 7-OH-DPAT also exacerbated EtOH intake. Interestingly, neither pharmacological nor genetic manipulation of D3R activity affected saccharin and quinine consumption and preference. More importantly, we report that LV-siD3R blocked, whereas LV-D3R exacerbated, EtOH-CPP. These results support the notion that the D3R plays an important role in alcohol reward in rats and suggest that a key threshold range of D3R levels is associated with impaired alcohol consumption. Taken together, these findings demonstrate that the D3R is an essential component of the molecular pathways underlying the reinforcing properties of alcohol. Thus, medications targeting the D3Rs may be beneficial to tackle EtOH abuse and alcoholism in humans.

Evaluation of the antidepressant, anxiolytic and memory-improving efficacy of aripiprazole and fluoxetine in ethanol-treated rats

Some study results indicate a positive effect of aripiprazole (ARI) on impaired cognitive functions caused by brain damage resulting from chronic EtOH abuse. However, other research shows that to manifest itself, an ARI antidepressant effect requires a combined therapy with another selective serotonin reuptake inhibitor antidepressant, namely, fluoxetine (FLX). The aim of this article was to assess antidepressant and anxiolytic effects of ARI as well as its effect on spatial memory in ethanol-treated (alcoholized) rats. On the basis of alcohol consumption pattern, groups of (1) ethanol-preferring rats, with mean ethanol intake above 50%, and (2) ethanol-nonpreferring rats (EtNPRs), with mean ethanol intake below 50% of total daily fluid intake, were formed. The group of EtNPRs was used for this study, subdivided further into three groups administered ARI, FLX and a combination of both, respectively. Behavioral tests such as Porsolt’s forced swimming test, the Morris water maze test and the two-compartment exploratory test were employed. Behavioral test results demonstrated (1) no antidepressant effect of ARI in EtNPRs in subchronic treatment and (2) no procognitive effect of ARI and FLX in EtNPRs in combined single administration. Combined administration of both drugs led to an anxiogenic effect and spatial memory deterioration in study animals. ARI had no antidepressant effect and failed to improve spatial memory in rats. However, potential antidepressant, anxiolytic and procognitive properties of the drug resulting from its mechanism of action encourage further research aimed at developing a dose of both ARI and FLX that will prove such effects in alcoholized EtNPRs.

Prenatal Ethanol (EtOH) Exposure Alters the Sensitivity of the Adult Dentate Gyrus to Acute EtOH Exposure

Prenatal ethanol (EtOH) exposure results in a spectrum of structural, cognitive, and behavioral abnormalities, collectively termed "fetal alcohol spectrum disorders" (FASDs). The hippocampal formation, an area of the brain strongly linked with learning and memory, is particularly vulnerable to the teratogenic effects of EtOH. Prenatal EtOH exposure can lead to long-lasting impairments in the ability to process spatial information, as well as produce long-lasting deficits in the ability of animals to exhibit long-term potentiation (LTP), a biological model of learning and memory processing. These deficits also have the ability to facilitate EtOH and/or other drug abuse later in life. This study sought to determine prenatal EtOH exposure altered the effects of acute EtOH application on synaptic plasticity. Prenatal EtOH exposure was modeled using a liquid diet where dams were given 1 of 3 diets: (i) a liquid diet containing EtOH (35.5% EtOH-derived calories), (ii) a liquid diet, isocaloric to the EtOH diet, but with maltose-dextrin substituting for the EtOH-derived calories, and (iii) an ad libitum diet of standard rat chow. Extracellular recordings from transverse brain slices (350μm) prepared from 50- to 70-day-old rats, following prenatal EtOH exposure (gestational day 1 to 21). LTP was examined in the dentate gyrus following acute EtOH exposure (0, 20, or 50mM) in these slices. Prenatal EtOH exposure attenuated LTP in the adult dentate gyrus. In control offspring, acute application of EtOH in adulthood attenuated (20mM) or blocked (50mM) LTP. Conversely, the effect of acute EtOH application on LTP was not as pronounced in prenatal EtOH offspring. Prenatal EtOH exposure alters the sensitivity of the adult dentate gyrus to acute EtOH application producing a long-lasting tolerance to the inhibitory effects of EtOH. This decreased sensitivity may provide a mechanism promoting the formation of drug-associated memories and help explain the increased likelihood of developing an alcohol dependency often observed in individuals with FASDs.

Female rats display enhanced rewarding effects of ethanol that are hormone dependent.

Ethanol (EtOH) abuse is a major health and economic concern, particularly for females who appear to be more sensitive to the rewarding effects of EtOH. This study compared sex differences to the rewarding and aversive effects of EtOH using place-conditioning procedures in rats. Separate groups of adult (male, female, ovariectomized [OVX] female) and adolescent (male and female) rats received EtOH (0, 0.5, 1.0, 2.0, or 2.5 g/kg, intraperitoneal) and were confined to their initially nonpreferred side of our conditioning apparatus for 30 minutes. On alternate days, they received saline and were confined to the other side. Following 5 drug pairings, the rats were retested for preference behavior. Separate cohorts of the same groups of rats were injected with a similar dose range of EtOH, and blood EtOH levels (BELs) were compared 30 minutes later. EtOH produced rewarding or aversive effects in a dose-dependent manner. An intermediate dose of EtOH (1.0 g/kg) produced rewarding effects in adult female, but not in male or OVX female rats, suggesting that ovarian hormones facilitate the rewarding effects of EtOH. Similarly, this intermediate dose of EtOH produced rewarding effects in adolescent female, but not in male rats. The highest dose of EtOH (2.5 g/kg) produced aversive effects that were similar across all adult groups. However, the aversive effects of EtOH were lower in adolescents than adults, suggesting that adolescents are less sensitive to the aversive effects of EtOH. The aversive effects of EtOH did not vary across the estrous cycle in intact adult females. There were also no group differences in BELs, suggesting that our results are not related to EtOH metabolism. Our results in rats suggest that human females may be more vulnerable to EtOH abuse due to enhanced rewarding effects of this drug that are mediated by the presence of ovarian hormones.

Ozone Oxidative Postconditioning Protects Against the Injury Associated with Alcohol Withdrawal Syndrome in Rats

Ethanol withdrawal (EW) increases acetaldehyde accumulation and reactive oxygen species formation that promote damage to the brain. It is necessary to emphasize that while EtOH abuse and dependence are widespread, treatment options are extremely limited. This study aimed at investigating the protective effects of Ozone Oxidative Postconditioning (OzoneOxPost) on brain injury induced by oxidative stress and behavioral changes after 2 weeks of EW in rats. Four groups of rats (n = 10 each one) were settled: (I) Control, (II) Ethanol; (III) Ethanol + Ozone, and (IV) Ethanol + Oxygen. At the end of EW, rats were subjected to behavioral tests followed by brain tissue collection to measure markers of oxidative damage. OzoneOxPost increased food consumption, maintained water intake at the same levels as the control group, and reestablished cellular redox status. Anxiety, locomotor activity, and memory/learning of the rats were improved. These results demonstrated that OzoneOxPost protected the brain against oxidative injury, improving important functions of the Central Nervous Systems (CNS). It is a novel finding that is evidence of ozone's effects on CNS.

Development of multi-route physiologically-based pharmacokinetic models for ethanol in the adult, pregnant, and neonatal rat

Biofuel blends of 10% ethanol (EtOH) and gasoline are common in the USA, and higher EtOH concentrations are being considered (15–85%). Currently, no physiologically-based pharmacokinetic (PBPK) models are available to describe the kinetics of EtOH-based biofuels. PBPK models were developed to describe life-stage differences in the kinetics of EtOH alone in adult, pregnant, and neonatal rats for inhalation, oral, and intravenous routes of exposure, using data available in the open literature. Whereas ample data exist from gavage and intravenous routes of exposure, kinetic data from inhalation exposures are limited, particularly at concentrations producing blood and target tissue concentrations associated with developmental neurotoxicity. Compared to available data, the three models reported in this paper accurately predicted the kinetics of EtOH, including the absorption, peak concentration, and clearance across multiple datasets. In general, model predictions for adult and pregnant animals matched inhalation and intravenous datasets better than gavage data. The adult model was initially better able to predict the time-course of blood concentrations than was the neonatal model. However, after accounting for age-related changes in gastric uptake using the calibrated neonate model, simulations consistently reproduced the early kinetic behavior in blood. This work provides comprehensive multi-route life-stage models of EtOH pharmacokinetics and represents a first step in development of models for use with gasoline-EtOH blends, with additional potential applicability in investigation of the pharmacokinetics of EtOH abuse, addiction, and toxicity.

The effects of the preferential dopamine D3 receptor antagonist S33138 on ethanol binge drinking in C57BL/6J mice

The mesolimbic dopamine (DA) pathway plays an integral role in the reinforcing properties of many drugs of abuse, including alcohol (ethanol/EtOH). It has been reported that selective and acute blockade of the DA D3 receptor by SB-277011A will attenuate EtOH preference, intake, and lick responses in EtOH preferring rats. However, alcohol consumption that leads to abuse is often marked by binge drinking-which is characterized as bringing ones blood EtOH levels to ≥80 mg/dL within 2 hours of the initial drink. It is unclear if brain mechanisms implicated in EtOH reward are equally implicated in EtOH binge consumption and abuse. Therefore, in this study, we examined the effect of the preferential D3 receptor antagonist S33138 on ethanol (6% v/v) and water consumption in male C57BL/6J mice using a restricted-access binge-drinking model. Ethanol drinking was not significantly altered by the intraperitoneal (i.p.) administration of 0.16 mg/kg of S33138. In contrast, the i.p. administration of 0.64 or 2.5 mg/kg i.p. of S33138 produced a significant decrease in ethanol consumption on days 1 and 7 and days 7-14 compared to vehicle treated animals. However, the mean water consumption was significantly decreased by (1) 0.16 and 0.64 mg/kg i.p. of S33138 on Day 1 and (2) 2.5 mg/kg i.p. of S33138 at Days 1, 7, and 7-14. Our studies indicate that a low dose of S33138 significantly decreases binge drinking, and that it does not significantly alter the consumption of water. In addition, S33138 alone is not appetitive.

Combined Pre- and Postnatal Ethanol Exposure in Rats Disturbs the Myelination of Optic Axons†

To analyse myelination and outgrowth of the optic axons in relation to the neuro-ophthalmological manifestations of ethanol (EtOH) abuse during pregnancy. An experimental model of chronic EtOH exposure was developed in rats and their offspring by subjecting the dams to a liquid diet (35% of the daily total calories as either EtOH or maltose-dextrose nutritional controls (Con). Eyeballs and optic nerves were obtained at key developmental stages and processed for morphologic, immunocytochemical and immunoblotting procedures, using alternatively antibodies against myelin basic protein (MBP) or neurofilament (NF) protein, and image analysing. A significant delay in onset of optic axons myelination, as well as a significant reduction in optic nerve size (P < 0.001), optic axons number (P < 0.001), myelinated axons density (P < 0.001), number of myelin lamellae linked to axon diameter (P < 0.001) and optic axon cross-sectional area (P < 0.001) were detected in the global morphometric assessment of the EtOH nerves with respect to the Con. Expression of MBP and NF was noticeably reduced in the EtOH optic nerves when compared with the Con. Disturbed myelination of optic axons, caused by EtOH abuse, strongly disrupts the optic nerve development and the establishment of definitive retinal and optic nerve targets, and subsequently the visual patterns.

Neutrophil to Lymphocyte Ratio and Leukocyte Count as Predictors of Severity in Acute Pancreatitis: Is There a Difference Between Alcohol and Gallstone Associated Cases?

Purpose: To explore the usefulness of NLR & WBC as predictive tools of severity in alcohol versus gallstone induced acute pancreatitis. Methods: We used our database of 283 consecutive patients admitted between 2007 and 2009 with the diagnosis of acute pancreatitis. The clinical diagnosis was confirmed by significantly elevated levels of pancreatic enzymes and/or positive CT findings. Patients with the history of both ETOH abuse and gallstones were excluded. As markers of severity of illness we chose ICU admission, TPN management or mortality as a complex adverse primary outcome. Primary variables were total WBC, absolute neutrophil, lymphocyte counts and the NLR. We used the NLR of 4.7 and WBC of 11 as cutoff points for gallstone pancreatitis patients and NLR of 3.7 and WBC of 10 for alcohol induced cases. The decision to choose these cutoff points was based on literature review and statistical review of the preferable values from the receiver operator curves. Results: Out of 283 patients we had 67 patients with gallstone pancreatitis and 78 patients with ETOH pancreatitis. We excluded from our analysis those with combined ETOH abuse and gallstones as well as those with other etiologies. The WBC and NLR values were significantly elevated in gallstone pancreatitis versus alcohol induced (Table 1). There were 13 patients (19.4%) who had positive adverse outcomes (i.e., ICU or TPN management) in the gallstone group versus 9 (11.5%) in the alcohol induced group. NLR value above 3.7 in alcohol and 4.7 in the gallstone induced pancreatitis cases were 100% sensitive for predicting the above adverse outcomes; the respective specificities were 46% and 43%. The values of the total WBC of above 10,000 in the alcohol induced cases and 11,000 in the gallstone pancreatitis cases demonstrated low sensitivity (56% and 54%) and low specificity (54% and 41%) as predictors of the adverse outcomes. Figure 1 shows the superiority of NLR to WBC in predicting adverse outcomes in gallstone pancreatitis group. Conclusion: The NLR was superior to WBC in predicting adverse outcomes of either gallstone or alcohol induced pancreatitis. Patients with gallstone pancreatitis had higher values of the WBC and NLR than those with alcohol induced pancreatitis. We recommend using the specified NLRs rather than the total WBC in acute pancreatitis risk scoring systems.Figure: Gallstone acute pancreatitis patients according NLR and WBC.

386: The Incidence of Hypoxia and Respiratory Depression During Emergency Department Chemical Restraint of Patients With Psychomotor Agitation

This is a prospective observational study to describe the incidence of hypoxia and respiratory depression in patients chemically restrained for psychomotor agitation in the emergency department (ED). Any patient over the age of 18 with psychomotor agitation who was to be chemically restrained with a benzodiazepine and/or a phenothiazine was eligible for enrollment. Routine management of these patients in our ED requires that they receive electronic monitoring of SpO2 and ETCO2. The ETCO2 monitor used recorded SpO2 and ETCO2 every 5 seconds, this data was saved and downloaded into Excel. A trained research associate recorded demographic data, history of drug or ETOH abuse, medical and psychiatric history. They also recorded HR and BP every 5 minutes, any physician intervention for hypoxia and/or respiratory depression, or adverse events. Hypoxia was defined as a SpO2 of <92% for >15 seconds, respiratory depression was defined as an ETCO2 of >50 mmHg, a change of 10% above or below baseline, or a loss of waveform for >15 seconds. 59 patients enrolled, 9 patients were excluded due to >35% data loss, leaving 50 patients for analysis. 21/50 patients developed hypoxia during their chemical restraint (42%). 28/50 developed respiratory depression during their chemical restraint (56%). 19/21 patients that developed hypoxia had an ETCO2 change. Of the 19 patients that developed hypoxia with a corresponding ETCO2 change. 15/19 had these changes before the onset of hypoxia. The mean length of time between the onset of an ETCO2 change to the onset of hypoxia was 5 minutes (SD +3.34 min). The average Ramsay sedation score was 4.36 (SD 0.57). The sensitivity of ETCO2 to predict the onset of a hypoxic event in this population is 90.48%, the sensitivity is 75.86%. 9 patients received an intervention for respiratory depression and hypoxia (5 verbal, 4 physical, 6 got supplemental O2). 37 pts had a history of concurrent drug or ETOH abuse; 24 patients had a concurrent psychiatric history. None of these patients had an adverse event. Almost half of the patients in this study exhibited hypoxia and/or respiratory depression. Most of the incidences of hypoxia were preceded by respiratory depression. Few of these events were recognized by their treating physicians. No adverse events were noted.

The First Case Report of APL (ACUTE PROMYELOCYTIC LEUKEMIA) in An HIV Positive Patient On (Highly Active Antiretroviral Therapy) Treated with ARSENIC TRIOXIDE.

Abstract 4166We report here for the first time the use of arsenic trioxide in the treatment of Acute Promyelocytic Leukemia in a patient with HIV on HAART (Highly Active Antiretroviral Therapy).A 37 year old man with a 7 year history of asymptomatic HIV infection, an undetectable viral load and a CD4 count of > 800 cells/mm3 presented with a furuncle and a new onset leukopenia. He denied constitutional symptoms or bleeding problems, but he did complain of fatigue and apthous ulcers. His medications included Epivir, Viramune, Videx EC, Viagra and Avelox. He denied smoking, ETOH abuse or intravenous drug abuse.On Physical Exam, he was afebrile and he did not have organomegaly or lymphadenopathy. Laboratory results revealed a white blood cell count of 1.6 K/uL with 7.9% neutrophils, 90.7% lymphocytes, 0.2% eosinophils, 0.3% basophils and 0.9% monocytes, hemoglobin of 12.4 g/dL, MCV of 96.3fL and platelet count of 112K/mL. Coagulation studies were normal. Bone marrow biopsy revealed a hypercellular marrow with immature myeloid cells (CD34 Positive and HLA-DR Negative). Peripheral blood PCR studies were positive for t (15:17) PML-RARA Translocation. The diagnosis of (APL) Acute Promyelocytic Leukemia (AML-M3 Subtype) was made and he was admitted to the hospital for induction chemotherapy with ATRA (All-Trans -Retinoic-Acid) 40 mg orally twice daily with Idarubicin 12mg/m2 followed by consolidation and maintenance treatment. He continued to take his HAART throughout his chemotherapy. Pt tolerated therapy well. On Day 68 Peripheral blood FISH for t 15:17 was done which was negative. On Day 77 a repeat Bone marrow biopsy revealed a complete remission with no evidence of leukemia and a normocellular marrow maturing trilineage hematopoiesis, and normal cytogenetics. He was non-compliant with maintenance ATRA because of nausea. He remained in remission for 1 year after which repeat labs on a routine visit showed leukopenia and thrombocytopenia. A bone Marrow biopsy done at that time showed recurrent APL with 80% infiltration with promyelocytes. Arsenic Trioxide 0.15 mg/kg/day therapy was begun. After 3 months of therapy the patient achieved complete remission with a normal bone marrow biopsy and a negative PCR for t (15:17) with no evidence of leukemia. Subsequently he underwent standard consolidation treatment 0.15 mg/kg/day 5 days a week for 4 weeks. Seventeen months later he is in Complete Remission and is doing well while still on Highly Active Antiretroviral Therapy.The occurrence of AML has been reported in HIV with a predominance of M2, M4 and M5 subtypes. Six cases of APL in HIV patients have been reported to date. In all of these cases ATRA and an anthracycline have been used to induce remission. Here we report the seventh case of APL/HIV and first successful use of arsenic trioxide with concomitant HAART. On the day of submitting the subtract, he presented with pancytopenia and is currently being worked up for possible relapse. Disclosures:No relevant conflicts of interest to declare.

Esophageal Variceal Bleed in a HIV Patient Secondary to Non-Cirrhotic Portal Hypertension After Didanosine Use

Purpose: We present a case of a HIV patient presenting with hematemesis secondary to esophageal varices, who was subsequently found to have noncirrhotic portal hypertension (NCPH) likely secondary to previous didanosine use. A 59 year old male with a history of HIV on ART since 1985, presented to our hospital with an episode of large volume hematemesis, and pre-syncopal symptoms. He was first diagnosed with HIV in 1985. He was initially started on monotherapy with zidovudine. In 1988, he entered a study for didanosine (ddI) and remained on this monotherapy till 1999. He then received stavudine monotherapy from 1999 until 2001, and then switched to his current therapy of abacavir, lamivudine, and efavirenz. With treatment he has had an undetectable viral load and CD4 count above 400. On presentation he had a Hct drop from 40 to 32. Emergent EGD demonstrated 3 large cords of esophageal varices with stigmata of recent bleeding. Banding ligation was performed with no further bleeding. He had no prior history of liver disease or ETOH abuse. His hepatitis serologies, BMI, LFT's, albumin, PT/INR were all normal. He had a mild thrombocytopenia. Abdominal US demonstrated patent hepatic and portal vasculature, normal appearing liver, and mild splenomegaly with small ascites. Transjugular liver biopsy was performed demonstrating a normal hepatic venous pressure gradient of 4 mmHg. Liver biopsy showed hepatocellular disarray, portal fibrosis, hepatoportal sclersosis with no steatosis, bridging fibrosis or cirrhosis. These findings are consistent with non-cirrhotic portal hypertension likely secondary from his previous prolonged exposure to didanosine. Chronic liver disease in HIV infected patients is increasing in occurrence, often secondary to co-infection with hepatitis B/C, alcohol abuse, fatty liver disease, or medication-induced hepatotoxicity. Non-cirrhotic portal hypertension can be due to portal vein thrombosis, nodular regenerative hyperplasia, incomplete septal cirrhosis, vasculitides, schistosomiasis, or idiopathic (hepatoportal sclerosis). Recent case series and case control studies have shown an association between HIV patients on ART and NCPH. Suspected causes in these patients include medication affect specifically long term ddI therapy versus direct affect from HIV. In HIV patients presenting with upper GI bleed, esophageal varices needs to be considered even in the absence of cirrhosis as NCPH is a potential complication of the ART treatment or HIV itself.

Intra-cornu ammonis 1 administration of the human immunodeficiency virus-1 protein trans-activator of transcription exacerbates the ethanol withdrawal syndrome in rodents and activates N-methyl- d-aspartate glutamate receptors to produce persisting spatial learning deficits

Human immunodeficiency virus-1 (HIV-1) infection may produce neurological deficits, such as cognitive decline, that may be worsened by concurrent ethanol (EtOH) abuse. Among the many biochemical cascades likely mediating HIV-1-associated neuronal injury is enhancement of N-methyl- d-aspartate (NMDA) receptor function and progression to excitotoxicity, an effect that may be directly or indirectly related to accumulation in brain of the HIV-1 trans-activator of transcription (Tat) factor. The present studies were designed to examine the hypothesis that binge-like EtOH pre-exposure would enhance effects of Tat on NMDA receptor function. These studies employed a modified in vivo binge EtOH exposure regimen designed to produce peak blood EtOH levels (BEL) of <200 mg/dl in adult male rats and were designed to examine effects of intra-hippocampal injection of Tat (0.5 μl/500 pM/2 min) on EtOH withdrawal-related behavior, spatial learning, and histological measures. Unilateral cannulae were implanted into the cornu ammonis 1 (CA1) pyramidal cell layer of animals prior to beginning a 4-day binge EtOH regimen. EtOH was administered via intragastric intubation (∼3.0–5.0 g/kg) with dose determined by behavioral ratings of intoxication daily for 4 days (at 08:00, 16:00, and 24:00 h). EtOH withdrawal behaviors were monitored 12 h after the last administration of EtOH. Morris water maze learning was assessed during the following 4 days, at which times brains were harvested for autoradiographic measurement of NMDA receptor density and neuroinflammation. Maximal BELs of 187.69 mg/dl were observed 60 min after EtOH administration on day 2 of the regimen. In contrast, peak BELs of approximately 100 mg/dl were observed 60 min after EtOH administration on day 4 of the regimen, suggesting development of metabolic tolerance. Significant behavioral abnormalities were observed in EtOH withdrawn animals, including tremor and seizures. Intra-CA1 region injection of Tat significantly potentiated EtOH withdrawal behavioral abnormalities, an effect that was reduced by MK-801 pre-exposure. While EtOH withdrawn animals showed learning similar to control animals, EtOH withdrawn animals that received intra-CA1 Tat injection demonstrated persisting deficits in spatial learning on days 3 and 4 of training, effects that were markedly reduced by administration of the competitive NMDA receptor antagonist MK-801 30 min prior to Tat injection. No changes in [ 3H]MK-801 binding were observed. Binding density of [ 3H]PK11195, a ligand for peripheral benzodiazepine receptors expressed on activated microglia, was elevated proximal to cannula tracks in all animals, but was not altered by EtOH or Tat exposure. These findings suggest that EtOH abuse and/or dependence in HIV-positive individuals may promote HIV-1-associated cognitive deficits by altering NMDA receptor function in the absence of microglial activation or neuroinflammation.

S1004 Month 4 Post-OLT Liver Biopsy Accurately Predicts Subsequent Fibrosis in Those Undergoing Orthotopic Liver Transplantation for HCV-Related Cirrhosis

HCVrelated end stage liver disease is the most common indication for OLT in the US. There is evidence that HCV-related fibrosis is accelerated post OLT leading to poorer survival compared to other etiologies. Our AIM was to identify factors in hepatitis C patients undergoing OLT that predict accelerated fibrosis 1 year post OLT. METHODS: Retrospective single center review of patients undergoing OLT due to HCVrelated cirrhosis from 2001 to 2008. Donor variables included age,gender,BMI,race,ETOH use,positive toxicology screen,presence of anti-HCV or anti-HBV, graft steatosis/fibrosis,CMV status,perfusion solution,organ procurement location, cold and warm ischemia time,sodium,creatinine,total bilirubin,aminotransferase levels. Recipient variables included age,race,gender,BMI,post OLT ICU duration,MELD score,prior ETOH abuse, presence of HCC,immunosuppression regimen,HCV genotype/viral load,lack of SVR,CMV status,pre-OLT TIPS,pre-OLT encephalopathy stage III-IV, pre-OLT ascites, post-OLT prolonged mechanical ventilation, post-OLT hypotension requiring pressors,ALT,Alk Phos,TB, ERCP post OLT,hyperglycemia post OLT,creatinine post OLT, rejection episodes, tacrolimus levels, and liver biopsy fibrosis stage scored by Metavir at month 4,and years 1-4 post OLT. Data were analyzed using Chi Square test, Fisher's Exact test and t-tests. The probit-normal model for correlated data and ordinal outcome was used to analyze repeated measures of fibrosis stage as the dependent variable with patient as a random effect. In both sets of analyses, adjustment for year 1 through 4 was also performed and year effect was evaluated.RESULTS: 114 HCV patients (mean ± SEM) age 52 ± 0.3 yrs, BMI 28 ± 0.5, MELD 16 ± 1, 77% male, 87% Caucasian underwent OLT with follow up liver biopsies available for review. Immunosuppression: ATG induction and tacrolimus monotherapy. Only the presence of month 4 fibrosis predicted fibrosis progression during years 1-4 post OLT by probit-normal (estimate 0.911 fibrosis units; p=0.004) and cumulative ordinal logistic regression (estimate 0.864 fibrosis units; p= 0.002). Specific year post OLT was not a predictor of later fibrosis. The interaction between month 4 fibrosis and year fibrosis was not significant. Conclusions:In HCV patients undergoing OLT, month 4 liver biopsy fibrosis level accurately predicts subsequent fibrosis. Those with stage 1-2 fibrosis at month 4 may be candidates for treatment of HCV to prevent further fibrosis progression.

Administration of MDMA to ethanol-deprived rats increases ethanol operant self-administration and dopamine release during reinstatement

Recreational use of (±)-3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is often associated with other drugs, among which ethanol (EtOH) is one of the most common. However, little is known about how neurochemical sensitization produced by MDMA can modulate EtOH abuse. In this study we used EtOH operant self-administration tasks to investigate the effect of several low doses (0.33, 1.0 and 3.0 mg/kg) of MDMA in Dark Agouti rats. Motor activity was recorded after each MDMA administration. Changes in extracellular dopamine in the nucleus accumbens following a single EtOH injection (1.5 g/kg i.p.) were measured using intracerebral microdialysis in vivo after 1 wk of abstinence from EtOH, in order to mimic the dopaminergic response associated with reinstatement into EtOH consumption. Animals exposed to higher doses of MDMA (1.0 and 3.0 mg/kg) showed significantly enhanced EtOH self-administration during reinstatement and an increased EtOH-induced dopamine efflux. MDMA treatment acutely elevated motor activity after each administration in a dose-dependent manner. These findings suggest that repeated administration of MDMA, a relatively common drug of abuse, even at low doses, can alter subsequent vulnerability to EtOH consumption.

Dissociation Between Acute Alcohol (EtOH) Intoxication‐Induced Increases in Atrogin‐1 and MuRF1 mRNA and Rates of Proteolysis in Skeletal Muscle

EtOH abuse causes skeletal muscle wasting resulting, in part, from a reduction in protein synthesis. However, whether alcohol enhances muscle proteolysis remains controversial. The current study determined whether acute EtOH stimulated muscle protein breakdown by measuring the mRNA content for the muscle‐specific ubiquitin E3 ligases atrogin‐1 and MuRF1 (aka atrogenes) and assessing the in vitro rate of proteolysis. IP injection of EtOH in rats increased atrogene mRNA in a time‐dependent manner, peaking at 8 h (4‐fold) and returning to baseline by 24 h. The EtOH‐induced rise in atrogenes was dose‐dependent, with increases observed in rats with blood alcohol levels &gt;150 mg/dL. In contrast, there was no EtOH‐induced change in atrogene mRNA in heart or soleus under these conditions. Elevated atrogene expression appears mediated indirectly because neither perfusion of an EtOH‐containing buffer into the isolated hindlimb of control rats nor incubation of C2C12 myocytes with EtOH increased atrogene mRNA. Finally, IP injection of a maximally effective dose of EtOH showed no change in proteolysis determined in the isolated epitrochlearis muscle. These data demonstrate EtOH selectively increases atrogene mRNA in fast‐twitch skeletal muscle, most likely via production of a secondary mediator, but this change was not associated with a concomitant stimulation of muscle protein breakdown. (AA11290 and AA12814).

Liver Abscess as a Complication of Esophgeal Balloon Dilation

Purpose: Despite the increase use of upper endoscopy, the complication rate has remained low. Infectious complications of EGD include transmission of infection by contaminated endoscopes or ancillary equipment, bacteremia and aspiration pneumonia. Here, we are reporting a liver abscess followed a routine upper endoscopy dilation in patient with gastric bypass. Methods: A 59 year old patient with history of gastric bypass 19 years ago presented with intermittent dysphagia has been going on for the last few months. Her upper endoscopy was remarkable for schatzki ring and gastric pouch contained undigested food. The gastrointestinal anastomosis was patent. The schatzki ring was dilated using CRE balloon 15–18 mm with evidence of breaking the mucosa at 16.5 and 18 mm. Her other past medical history was significant otherwise for thyroid cancer, thyroidectomy 20 years ago, tobacco and ETOH abuse. Patient presented with right upper quadrant pain 2 days after the EGD to outside facility. She was treated symptomatically. Pain returned and patient developed fever and chills. CT scan of the abdomen performed at our facility 2 weeks after the EGD showed left hepatic lobe abscess. US guided drainage grew Candida Albicans, streptococcus Solivarius, and Beta Hemolytic Strep Group B. Esophagogram failed to show any leak or perforation. The abscess resolved with IV antibiotic and percutaneous drainage without the need for surgery. Results: The timing between the onset of her symptoms and the EGD suggest causal relationship. This is most likely related to transient bacteremia secondary to the dilation. Her altered anatomy, gastroparesis and ETOH intake, probably predisposed her for the bacteremia and the immune suppression status. Conclusion: Esophageal dilation has the highest incidence of bacteremia of all gastrointestinal endoscopic procedures, occurring in approximately 45 percent of cases. In spite of this, complications of bacteremia such as endocarditis are rare. The most common reported complication is endocarditis, and less frequently meningitis. Antibiotic prophylaxis is not warranted in most patients undergoing esophageal dilation except for those at high risk. People with immunosupressed status or altered anatomy might need to be considered for prophylaxis.