An alternative for rapid administration of medication and fluids in the emergency setting using a novel device.

Routes of administration for medications and fluids in the acute care setting have primarily focused on oral, intravenous, or intraosseous routes, but, in many patients, none of these routes is optimal. A novel device (Macy Catheter; Hospi Corp) that offers an easy route for administration of medications or fluids via rectal mucosal absorption (proctoclysis) has recently become available in the palliative care market; we describe here the first known uses of this device in the emergency setting. Three patients presenting to the hospital with conditions limiting more typical routes of medication or fluid administration were treated with this new device; patients were administered water for hydration, lorazepam for treatment of alcohol withdrawal, ondansetron for nausea, acetaminophen for fever, aspirin for antiplatelet effect, and methimazole for hyperthyroidism. Placement of the device was straightforward, absorption of administered medications (judged by immediacy of effects, where observable) was rapid, and use of the device was well tolerated by patients, suggesting that this device may be an appealing alternative route to medication and fluid administration for a variety of indications in acute and critical care settings.

Protective Effects of Tetramethylpyrazine on Cerebrovascular Regulations in Rats with Chronic Alcoholic Encephalopathy.

Recent studies showed that pathology of alcoholic encephalopathy was associated with cerebral vascular damage. TMP (tetramethyl- pyrazine) is widely used in the treatment of cerebrovascular diseases, however, it has not been reported whether TMP can relieve alcohol-induced cerebral vascular damages. The study was performed to investigate the learning and memory, cerebrovascular pathological changes and the expressions of vascular endothelial growth factor (VEGF) and serum levelsofendothelin-1 (ET-1) in the rat model of chronic alcoholic encephalopathy, and explore the effects of TMP intervention on alcoholic encephalopathy. In the present study, the rat model of chronic alcoholic encephalopathy was established by the gavage administration of alcohol; the learning and memory ability was tested by Morris water maze; the expression of VEGF was measured by RT-PCR and Western blot; and the serum levels of ET-1 was measured by radioimmunoassay. We found that alcohol intoxication impaired learning and memory, induced VEGF overexpression and increased ET 1 concentrations. TMP intervention improved learning abilities, increased the VEGF expression and reduced ET-1 level. These results indicate that TMP exhibits therapeutic effects on chronic alcoholic encephalopathy.

Dihydromyricetin as a novel anti-alcohol intoxication medication.

Alcohol use disorders (AUDs) constitute the most common form of substance abuse. The development of AUDs involves repeated alcohol use leading to tolerance, alcohol withdrawal syndrome, and physical and psychological dependence, with loss of ability to control excessive drinking. Currently there is no effective therapeutic agent for AUDs without major side effects. Dihydromyricetin (DHM; 1 mg/kg, i.p. injection), a flavonoid component of herbal medicines, counteracted acute alcohol (EtOH) intoxication, and also withdrawal signs in rats including tolerance, increased anxiety, and seizure susceptibility; DHM greatly reduced EtOH consumption in an intermittent voluntary EtOH intake paradigm in rats. GABA(A) receptors (GABA(A)Rs) are major targets of acute and chronic EtOH actions on the brain. At the cellular levels, DHM (1 µM) antagonized both acute EtOH-induced potentiation of GABA(A)Rs and EtOH exposure/withdrawal-induced GABA(A)R plasticity, including alterations in responsiveness of extrasynaptic and postsynaptic GABA(A)Rs to acute EtOH and, most importantly, increases in GABA(A)R α4 subunit expression in hippocampus and cultured neurons. DHM anti-alcohol effects on both behavior and CNS neurons were antagonized by flumazenil (10 mg/kg in vivo; 10 µM in vitro), the benzodiazepine (BZ) antagonist. DHM competitively inhibited BZ-site [(3)H]flunitrazepam binding (IC(50), 4.36 µM), suggesting DHM interaction with EtOH involves the BZ sites on GABA(A)Rs. In summary, we determined DHM anti-alcoholic effects on animal models and determined a major molecular target and cellular mechanism of DHM for counteracting alcohol intoxication and dependence. We demonstrated pharmacological properties of DHM consistent with those expected to underlie successful medical treatment of AUDs; therefore DHM is a therapeutic candidate.

Phenobarbital for acute alcohol withdrawal: a prospective randomized double-blind placebo-controlled study.

BACKGROUND: Acute alcohol withdrawal syndrome (AAWS) is encountered in patients presenting acutely to the Emergency Department (ED) and often requires pharmacologic management. OBJECTIVE: We investigated whether a single dose of intravenous (i.v.) phenobarbital combined with a standardized lorazepam-based alcohol withdrawal protocol decreases intensive care unit (ICU) admission in ED patients with acute alcohol withdrawal. METHODS: This was a prospective, randomized, double-blind, placebo-controlled study. Patients were randomized to receive either a single dose of i.v. phenobarbital (10 mg/kg in 100 mL normal saline) or placebo (100 mL normal saline). All patients were placed on the institutional symptom-guided lorazepam-based alcohol withdrawal protocol. The primary outcome was initial level of hospital admission (ICU vs. telemetry vs. floor ward). RESULTS: There were 198 patients enrolled in the study, and 102 met inclusion criteria for analysis. Fifty-one patients received phenobarbital and 51 received placebo. Baseline characteristics and severity were similar in both groups. Patients that received phenobarbital had fewer ICU admissions (8% vs. 25%, 95% confidence interval 4-32). There were no differences in adverse events. CONCLUSIONS: A single dose of i.v. phenobarbital combined with a symptom-guided lorazepam-based alcohol withdrawal protocol resulted in decreased ICU admission and did not cause increased adverse outcomes.

[Features of psychopharmacotherapeutic correction of alcohol dependence in the elderly].

The article is devoted to the actual in modern medicine problem as the study of the prevalence of alcohol dependence and its psyhofarmacological correction in the elderly. It is shown that elderly and old age as a result of reduction of the reserve capacity of the organism for clinical pathology becomes addictive specific psychopathological features that affect the course of disease and maintenance of preventive treatment. On the basis of empirical evidence the authors prove that at the border severity of alcohol withdrawal syndrome the drug "Cytoflavin" has a fairly pronounced psyhofarmacological activity for older people with alcohol dependence.

Impact of thiamine supplementation in the reversal of ethanol induced toxicity in rats.

One of the molecular mechanisms of alcohol induced toxicities is mediated by oxidative stress. Hence our studies were focused on the effect of thiamine (antioxidant) in the reversal of alcohol induced toxicity and comparison of the reversal with abstinence. Administration of ethanol at a dose of 4 g/kg body wt/day for 90 days to Sprague Dawley rats manifested chronic alcohol induced toxicity evidenced by decreased body weight, an increase in liver-body weight ratio, increase in activities of serum and liver aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transpeptidase (GGT); decrease in the activities of superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase in the liver and brain. The levels of inflammatory markers, fibrosis markers and DNA fragmentation were also elevated in the serum, liver and brain. After ethanol administration for 90 days, the reversal of the alcohol induced toxicity was studied by supplementing thiamine at a dose of 25 mg/100 g body wt/day. Duration of the reversal study was 30 days. The activities of AST, ALT, GGT, scavenging enzymes as well as markers of inflammation and fibrosis in serum, liver and brain were reversed to a certain extent by thiamine. Changes in neurotransmitter levels in brain were also reversed by thiamine supplementation. DNA damage was decreased and DNA content increased in thiamine supplemented group compared to abstinence group showing a faster regeneration. In short, histopathological and biochemical evaluations indicate that thiamine supplemented abstinent rats made a faster recovery of hepatic and neuronal damage than in the abstinence group.

Cyanidin-3-glucoside ameliorates ethanol neurotoxicity in the developing brain.

Ethanol exposure induces neurodegeneration in the developing central nervous system (CNS). Fetal alcohol spectrum disorders (FASD) are caused by ethanol exposure during pregnancy and are the most common nonhereditary cause of mental retardation. It is important to identify agents that provide neuroprotection against ethanol neurotoxicity. Multiple mechanisms have been proposed for ethanol-induced neurodegeneration, and oxidative stress is one of the most important mechanisms. Recent evidence indicates that glycogen synthase kinase 3ß (GSK3ß) is a potential mediator of ethanol-mediated neuronal death. Cyanidin-3-glucoside (C3G), a member of the anthocyanin family, is a potent natural antioxidant. Our previous study suggested that C3G inhibited GSK3ß activity in neurons. Using a third trimester equivalent mouse model of ethanol exposure, we tested the hypothesis that C3G can ameliorate ethanol-induced neuronal death in the developing brain. Intraperitoneal injection of C3G reduced ethanol-meditated caspase-3 activation, neurodegeneration, and microglial activation in the cerebral cortex of 7-day-old mice. C3G blocked ethanol-mediated GSK3ß activation by inducing phosphorylation at serine 9 while reducing the phosphorylation at tyrosine 216. C3G also inhibited ethanol-stimulated expression of malondialdehyde (MDA) and p47phox, indicating that C3G alleviated ethanol-induced oxidative stress. These results provide important insight into the therapeutic potential of C3G.

Comparison of two oral symptom-triggered pharmacological inpatient treatments of acute alcohol withdrawal: clomethiazole vs. clonazepam.

AIMS: To compare two inpatient symptom-triggered pharmacological treatments of acute alcohol withdrawal (AWS) (clomethiazole vs. clonazepam). METHODS: Prospective observational comparison within a quality improvement project. Because of a need for extra precautions against complications such as seizures and severe respiratory complaints, patients with a history of withdrawal seizures or complications with clomethiazole in their history were automatically assigned to the clonazepam group. The remaining patients were alternately assigned either to the clonazepam group (n = 38 altogether) or the clomethiazole group (n = 36). Rescue medication could consist of adding either extra clonazepam or clomethiazole. Effectiveness was measured by Clinical Global Impression Scale, Revised Clinical Institute Withdrawal Assessment for Alcohol Scale, Mainz Alcohol Withdrawal Scale, Essen Self-Assessment-Alcohol Withdrawal and attrition rate. Safety and tolerability was estimated from adverse clinical events. Secondary outcome values were heart rate, blood and pulse pressure. RESULTS: There were no significant differences between the treatments with respect to primary and secondary effectiveness measures, safety or tolerability or duration of medication treatment. Both reduced the severity of initial withdrawal symptoms below 20% up to the ending of withdrawal medications. No withdrawal seizure or delirium occurred. CONCLUSION: Both score-driven treatments were equally effective, safe and well tolerated in this setting. This is the first study demonstrating the utility of clonazepam in the treatment of AWS syndrome.

Neuroprotective effect of vitamin C against the ethanol and nicotine modulation of GABA(B) receptor and PKA-alpha expression in prenatal rat brain.

Prenatal ethanol exposure has various deleterious effects on neuronal development and can induce various defects in developing brain, resulting in fetal alcohol syndrome (FAS). gamma-Aminobutyric acid (GABA(B)) receptor (R) is known to play an important role during the development of the central nervous system (CNS). Our study was designed to investigate the effect of ethanol (100 mM), nicotine (50 microM) (for 30 min and 1 h), vitamin C (vitC, 0.5 mM), ethanol plus vitC, and nicotine plus vitC on expression level of GABA(B1), GABA(B2)R, and protein kinase A-alpha (PKA) in prenatal rat cortical and hippocampal neurons at gestational days (GD) 17.5. The results showed that, upon ethanol and nicotine exposure, GABA(B1) and GABA(B2)R protein expression increased significantly in the cortex and hippocampus for a short (30 min) and long term (1 h), whereas only GABA(B2)R subunit was decreased upon nicotine exposure for a long term in the cortex. Furthermore, PKA expression in cortex and hippocampus increased with ethanol exposure during short term, whereas long-term exposure results increased in cortex and decreased in hippocampus. Moreover, the cotreatment of vitC with ethanol and nicotine showed significantly decreased expression of GABA(B1), GABA(B2)R, and PKA in cortex and hippocampus for a long-term exposure. Mitochondrial membrane potential, Fluoro-jade-B, and propidium iodide staining were used to elucidate possible neurodegeneration. Our results suggest the involvement of GABA(B)R and PKA in nicotine and ethanol-mediated neurodevelopmental defects and the potential use of vitC as a effective protective agent for FAS-related deficits.

Systematic review of interventions for children with Fetal Alcohol Spectrum Disorders.

BACKGROUND: Children with Fetal Alcohol Spectrum Disorders (FASD) may have significant neurobehavioural problems persisting into adulthood. Early diagnosis may decrease the risk of adverse life outcomes. However, little is known about effective interventions for children with FASD. Our aim is to conduct a systematic review of the literature to identify and evaluate the evidence for pharmacological and non-pharmacological interventions for children with FASD. METHODS: We did an electronic search of the Cochrane Library, MEDLINE, EMBASE, PsychINFO, CINAHL and ERIC for clinical studies (Randomized controlled trials (RCT), quasi RCT, controlled trials and pre- and post-intervention studies) which evaluated pharmacological, behavioural, speech therapy, occupational therapy, physiotherapy, psychosocial and educational interventions and early intervention programs. Participants were aged under 18 years with a diagnosis of a FASD. Selection of studies for inclusion and assessment of study quality was undertaken independently by two reviewers. Meta-analysis was not possible due to diversity in the interventions and outcome measures. RESULTS: Twelve studies met the inclusion criteria. Methodological weaknesses were common, including small sample sizes; inadequate study design and short term follow up. Pharmacological interventions, evaluated in two studies (both RCT) showed some benefit from stimulant medications. Educational and learning strategies (three RCT) were evaluated in seven studies. There was some evidence to suggest that virtual reality training, cognitive control therapy, language and literacy therapy, mathematics intervention and rehearsal training for memory may be beneficial strategies. Three studies evaluating social communication and behavioural strategies (two RCT) suggested that social skills training may improve social skills and behaviour at home and Attention Process Training may improve attention. CONCLUSION: There is limited good quality evidence for specific interventions for managing FASD, however seven randomized controlled trials that address specific functional deficits of children with FASD are underway or recently completed.

PARP inhibition in vivo blocks alcohol-induced brain neurodegeneration and neuroinflammatory cytosolic phospholipase A2 elevations.

Chronic alcoholism promotes brain damage that impairs memory and cognition. High binge alcohol levels in adult rats also cause substantial neurodamage to memory-linked regions, notably, the hippocampus (HC) and entorhinal cortex (ECX). Concurrent with neurodegeneration, alcohol elevates poly (ADP-ribose) polymerase-1 (PARP-1) and cytosolic phospholipase A2 (cPLA2) levels. PARP-1 triggers necrosis when excessively activated, while cPLA2 liberates neuroinflammatory ω-6 arachidonic acid. Inhibitors of PARP exert in vitro neuroprotection while suppressing cPLA2 elevations in alcohol-treated HC-ECX slice cultures. Here, we examined in vivo neuroprotection and cPLA2 suppression by the PARP inhibitor, veliparib, in a recognized adult rat model of alcohol-binging. Adult male rats received Vanilla Ensure containing alcohol (ethanol, 7.1 ±â€¯0.3 g/kg/day), or control (dextrose) ±â€¯veliparib (25 mg/kg/day), by gavage 3x daily for 4 days. Rats were sacrificed on the morning after the final binge. HC and ECX neurodegeneration was assessed in fixed sections by Fluoro-Jade B (FJB) staining. Dorsal HC, ventral HC, and ECX cPLA2 levels were quantified by immunoblotting. Like other studies using this model, alcohol binges elevated FJB staining in the HC (dentate gyrus) and ECX, indicating neurodegeneration. Veliparib co-treatment significantly reduced dentate gyrus and ECX neurodegeneration by 79% and 66%, respectively. Alcohol binges increased cPLA2 in the ventral HC by 34% and ECX by 72%, which veliparib co-treatment largely prevented. Dorsal HC cPLA2 levels remained unaffected by alcohol binges, consistent with negligible FJB staining in this brain region. These in vivo results support an emerging key role for PARP in binge alcohol-induced neurodegeneration and cPLA2-related neuroinflammation.

Chronic Alcohol Exposure Induced Neuroapoptosis: Diminishing Effect of Ethyl Acetate Fraction from Aralia elata.

An ethyl acetate fraction from Aralia elata (AEEF) was investigated to confirm its neuronal cell protective effect on ethanol-induced cytotoxicity in MC-IXC cells and its ameliorating effect on neurodegeneration in chronic alcohol-induced mice. The neuroprotective effect was examined by methylthiazolyldiphenyl-tetrazolium bromide (MTT) and 2',7'-dichlorodihydrofluorescein diacetate (DCF-DA) assays. As a result, AEEF reduced alcohol-induced cytotoxicity and oxidative stress. To evaluate the improvement of learning, memory ability, and spatial cognition, Y-maze, passive avoidance, and Morris water maze tests were conducted. The AEEF groups showed an alleviation of the decrease in cognitive function in alcohol-treated mice. Then, malondialdehyde (MDA) levels and the superoxide dismutase (SOD) content were measured to evaluate the antioxidant effect of AEEF in the brain tissue. Treatment with AEEF showed a considerable ameliorating effect on biomarkers such as SOD and MDA content in alcohol-induced mice. To assess the cerebral cholinergic system involved in neuronal signaling, acetylcholinesterase (AChE) activity and acetylcholine (ACh) content were measured. The AEEF groups showed increased ACh levels and decreased AChE activities. In addition, AEEF prevented alcohol-induced neuronal apoptosis via improvement of mitochondrial activity, including reactive oxygen species levels, mitochondrial membrane potential, and adenosine triphosphate content. AEEF inhibited apoptotic signals by regulating phosphorylated c-Jun N-terminal kinases (p-JNK), phosphorylated protein kinase B (p-Akt), Bcl-2-associated X protein (BAX), and phosphorylated Tau (p-Tau). Finally, the bioactive compounds of AEEF were identified as caffeoylquinic acid (CQA), 3,5-dicaffeoylquinic acid (3,5-diCQA), and chikusetsusaponin IVa using the UPLC-Q-TOF-MS system.

Altered water-maze search behavior in adult guinea pigs following chronic prenatal ethanol exposure: lack of mitigation by postnatal fluoxetine treatment.

Ingestion of ethanol during pregnancy can result in teratogenic effects in humans, including significant and long-lasting neurobehavioral deficits. Similar results are seen in guinea pigs with chronic prenatal ethanol exposure (CPEE) via maternal ethanol administration, which produces deficits in Morris water-maze performance and impaired hippocampal functioning (e.g., decreased long-term potentiation, LTP). In this study, we tested whether postnatal treatment with fluoxetine, a selective serotonin reuptake inhibitor, decreases some of the neurobehavioral impairments produced by CPEE. Timed, pregnant guinea pigs received oral administration of ethanol (4g/kg maternal body weight) or isocaloric sucrose pair feeding (control) for 5 days/week throughout gestation. Offspring of the CPEE and control groups were randomly assigned to receive either fluoxetine (10mg/kg body weight/day) or saline intraperitoneally from postnatal day 10 to 48. Subsequent behavioral tests in the Morris water-maze revealed a significant increase in thigmotaxic swimming in CPEE offspring without apparent signs of impairment in spatial mapping of the hidden escape platform. Measures of hippocampal short- and long-term plasticity (paired-pulse facilitation, frequency facilitation, and LTP) were unaffected by CPEE, consistent with the behavioral data indicating normal hippocampal functioning. Postnatal fluoxetine administration resulted in a significant loss of body weight, but did not affect the increased thigmotaxic swimming following CPEE. These results indicate that changes in search strategies in the water-maze might be a highly sensitive index of CPEE-induced neurobehavioral toxicity that can occur in the absence of significant hippocampal dysfunction. Further, these data demonstrate that fluoxetine, at the selected treatment regime, does not mitigate the thigmotaxic swimming response to CPEE in the guinea pig.

Baclofen does not counteract the acute effects of ethanol on flash-evoked potentials in Long-Evans rats.

This experiment examined the separate and combined effects of baclofen (5.0 mg/kg, i.p.), a GABA B receptor agonist, and ethanol (2.0 g/kg, i.p.) on flash-evoked potentials (FEPs) recorded from both the visual cortex and superior colliculus (SC) of chronically implanted male Long-Evans rats. In the visual cortex, ethanol significantly decreased the amplitude of positive component P87, but increased P37 and P47. Other component amplitudes were not significantly altered. In contrast, baclofen reduced the amplitude of negative component N31 to such an extent that it became positive. Although P47 was also reduced by baclofen, the amplitude of most other components was increased. Only P24 and P87 were unchanged by baclofen. The combination of baclofen and ethanol resulted in amplitudes very similar to ethanol alone for secondary components P47, N62, and P87, but very similar to baclofen alone for primary component N31 and late components N147 and P230. In the SC, component amplitudes were generally decreased by ethanol, baclofen, and the combination treatment. Latencies of most components in both structures were increased by the drug treatments. Each drug treatment produced significant hypothermia. Locomotor behavior was also altered. These results demonstrate: (1) pharmacological differences between the primary and late components versus the secondary components of the cortical FEP, (2) that baclofen does not counteract significant effects of ethanol on cortical or collicular component amplitudes, and (3) that baclofen enhances N147-P230 amplitude, suggesting reduced cortical arousal.

Alcohol abuse in the critically ill patient.

Alcohol abuse and dependence disorders are common in the 10% of hospitalised patients who need admission to the intensive care unit (ICU), but these disorders are often undiagnosed. The systemic effects from the excessive use of alcohol increase susceptibility to, or directly cause various important disorders in the critically ill. Early recognition of alcohol abuse and dependence is necessary and should prompt consideration of several alcohol-specific diagnoses that have important prognostic and therapeutic implications for these patients. We discuss the use of screening tests to improve the identification of alcohol abuse and dependence disorders, the epidemiology and pathogenesis of important alcohol-related disorders, differences in the presentation of several common alcohol-related diagnoses in the ICU, and important alcohol-specific therapies.

Grape seed flavanols, but not Port wine, prevent ethanol-induced neuronal lipofuscin formation.

Lipofuscin is an end-product of lipid peroxidation which dramatically increases following ethanol consumption, as we have shown in hippocampal and cerebellar neurons. In this work, we corroborated observations indicating that supplementation of ethanol with 200 mg/l of grape seed flavanols prevents increased lipofuscin formation, an action that has been ascribed to the antioxidant properties of the flavanols. Because wine is an alcoholic beverage naturally rich in flavanols, we decided to study the effect of chronic ingestion of Port wine (PW), which also contains 20% ethanol and approximately 200 mg/l of flavanol oligomers, upon lipofuscin accumulation in the hippocampal CA1 and CA3 pyramidal neurons and in the cerebellar Purkinje cells. Six months old rats were fed with PW and results were compared with those obtained in ethanol-treated groups and pair-fed controls. After 6 months of treatment, the volume of lipofuscin per neuron was estimated using unbiased stereological methods. Treatment with PW resulted in an increase of lipofuscin in all neuronal populations studied when compared to controls and to rats treated with ethanol supplemented with flavanols. No differences were observed when comparisons were made with ethanol drinking rats. We conclude that PW, despite containing 20% ethanol and flavanols, does not prevent ethanol-induced lipofuscin formation as previously found in animals drinking ethanol plus flavanols. The reduced antioxidant capacity of PW might depend on the type and amount of flavanols present and on its content in sugars.

Anticonvulsive effects of kappa-opioid receptor modulation in an animal model of ethanol withdrawal.

Although the neurochemical mechanisms contributing to alcohol withdrawal seizures are poorly understood, withdrawal seizures probably reflect neuronal hyperexcitability resulting from adaptation to chronic alcohol. Altered kappa-Opioid receptor (KOP-R) signaling has been observed in multiple seizure types; however, a role for this system in ethanol withdrawal seizures has not been systematically characterized. We hypothesized that pharmacological manipulations of the KOP-R would alter withdrawal in mice selectively bred for differences in ethanol withdrawal severity. Withdrawal Seizure-Prone (WSP) and Withdrawal Seizure-Resistant (WSR) mice were made physically dependent using chronic ethanol vapor inhalation, and the effects of the KOP-R antagonist nor-binaltorphimine or agonist U-50,488H on withdrawal severity were examined. Pretreatment with nor-binaltorphimine significantly increased handling-induced convulsion (HIC) severity in withdrawing WSR mice, with no observable effects in withdrawing WSP mice. In contrast, U-50,488H significantly decreased HIC severity in WSP mice, with no effects in WSR mice. During extended withdrawal (i.e. hours 12+), a rebound hyperexcitability was observed in WSP mice given agonist. Thus, administration of a KOP-R antagonist increased withdrawal severity in mice normally resistant to withdrawal seizures, while a KOP-R agonist reduced convulsion severity in animals susceptible to withdrawal seizures. These observations are consistent with differences in the KOP-R system observed in these lines at the molecular level, and suggest the KOP-R system may be a promising therapeutic target for management of ethanol withdrawal seizures. Finally, these findings underscore the importance of determining the potential for rebound increases in withdrawal severity during later withdrawal episodes.

Glial-derived neurotrophic factor (GDNF) prevents ethanol (EtOH) induced B92 glial cell death by both PI3K/AKT and MEK/ERK signaling pathways.

We investigated the neuroprotective effect of glial-derived neurotrophic factor (GDNF) upon alcohol-exposed B92 cultures, as well as the role of the cytoskeleton and mitogen-activated protein kinase (MAPK) pathways in this effect. Ethanol (EtOH) was added to cultures, either alone or in combination with 30 ng/ml GDNF. Exposure to EtOH (86 and 172 mM; 60 and 120 min) increased the frequency of apoptotic cells identified by nuclear DNA staining with 4,6-diamidino-2-phenylindole (DAPI). Cultures treated with GDNF showed a decrease in ethanol-induced apoptosis. A jun N-terminal kinase (JNK) pathway is activated by EtOH and their pharmacological inhibition (by SP600125) neutralized ethanol-induced apoptosis, suggesting a role for JNK in EtOH neurotoxicity. Immunocytochemically detected phospho-JNK (p-JNK) showed an unusual filamental expression, and localized together with actin stress fibers. Examination of the cytoskeleton showed that EtOH depolymerized actin filaments, inducing p-JNK dissociation and translocation to the nucleus, which suggests that released p-JNK may contribute to glial cell death after EtOH exposure. Treatment with GDNF, in turn, may neutralize the ethanol-induced cell death pathway. Either a phosphatidylinositol 3-kinase (PI3K)/AKT pathway inhibitor (LY294002) or an inhibitor of the extracellular signal-regulated kinase (ERK) 1, 2 pathways (UO126) failed to neutralize GDNF protective effects. However, the simultaneous use of both inhibitors blocked the protective effect of GDNF, suggesting a role for both signaling cascades in the GDNF protection. These findings provide further insight into the mechanism involved in ethanol-induced apoptosis and the neurotrophic protection of glial cells.

[Reversible demyelinisation of corpus callosum in the course of Marchiafava-Bignami disease]. / Odwracalna demielinizacja ciala modzelowatego w przebiegu choroby Marchiafavy-Bignamiego.

Marchiafava-Bignami disease is a rare disorder of an unknown aetiology that is marked by focal demyelinisation in the corpus callosum. Chronic alcohol abuse plays an important role in its development. Its course is unfavourable, although rare cases of clinical improvement confirmed in MRI have been reported. Until now, no case of Marchiafava-Bignami disease diagnosed intra vitam was so far described on the territory of Poland. The authors present such a case with favourable course. A 52-year-old male with chronic alcoholism was hospitalised due to altered consciousness which developed subacutely prior to admission. The first MRI scans yielded demyelinating lesions in the corpus callosum. The clinical and radiological findings were consistent with the diagnosis of Marchiafava-Bignami disease. Thiamine, vitamin B12, folic acid and amantadine were administered, which resulted in an improvement in both motor and cognitive functions. Control MRI scans revealed remyelinisation of the corpus callosum. Hence, this technique proved itself to be useful in monitoring the course of the disease.