Response of brain protein kinase C isozymes to ethyl oleate, an alcohol metabolite

Rat brain protein kinase C (PKC) isozymes I, II and III were stimulated by fatty acids in the absence and presence of calcium. Ethyl oleate, which by itself has no effect on PKC activity, had a potentiating effect on fatty acid-induced activation of all 3 isozymes. Potentiation was observed predominantly in the presence of calcium. Interaction of ethyl oleate with a signalling mechanism involving PKC may underlie the cognitive disturbances noted after alcohol consumption.     

Low level of response to alcohol as associated with serotonin transporter genotype and high alcohol intake in adolescents.

BACKGROUND: A low level of response to alcohol has been associated with both the genetic constitution of the regulatory region (SLC6A4) of the human serotonin (5-hydroxytryptamine, 5-HT) transporter (5-HTT) and with future alcohol intake and an increased risk for alcoholism. To date, all studies of relevant polymorphisms have been carried out in populations in the United States. METHODS: Data were extracted from a subset (n = 243) of a cohort of children who have been observed since birth through evaluation of the family history of alcoholism and psychosocial risk influences. At age 16 years, the response to alcohol was assessed with the Self-Rating of the Effects of Alcohol (SRE) questionnaire, and the average amount of alcohol intake per month was assessed during the prior 6 months. Additional variables that were measured included the 5-HTT genotype, externalizing behavior, and sociodemographic variables, such as gender and age. RESULTS: The level of response to alcohol was significantly lower among carriers of two long alleles of the 5-HTT regulatory region compared with carriers of one or two short alleles (Mann-Whitney U = 5225.0, p = .005). In a multiple regression analysis, the level of response to alcohol and externalizing behavior but not psychosocial factors significantly predicted the average amount of alcohol intake per month. CONCLUSIONS: This study demonstrates that, independent of the assessed psychosocial variables, the 5-HTT genotype correlated with the level of response to alcohol and predicted alcohol intake among 16-year-old adolescents.     

Semiquantitative study of current coffee, caffeine, and ethanol intake in essential tremor cases and controls.

There are several reasons to study caffeine, coffee, and ethanol intake in essential tremor (ET) patients. ET patients also might modify their use of these beverages because of their effects on tremor. Intake of caffeine, coffee, and ethanol has not been quantified in a group of ET patients. Our objective is to use a semiquantitative food frequency questionnaire to compare current daily intake of coffee, caffeine, and ethanol in ET patients and controls. A total of 130 ET cases were patients at the Neurological Institute of New York, and 175 controls were ascertained by random digit dialing. Caffeine (in milligrams) and ethanol (in grams) intake were calculated from a semiquantitative food-frequency questionnaire. Mean daily caffeine intake in patients was 138.4 versus 246.6 mg in controls; medians were 101.1 versus 175.5 mg (P < 0.001). Mean daily ethanol intake in patients was 8.2 versus 6.2 gm in controls; medians were 2.4 versus 1.9 gm (P = 0.89). Cases drank less coffee than controls, but drank similar amounts of tea, soft drinks, fruit juices, and milk. Daily caffeine intake was not correlated with tremor severity or duration. ET patients consumed less caffeine than did controls, which is likely to be a dietary modification in response to tremor. The observation that caffeine consumption was not correlated with tremor severity raises the additional possibility that lower caffeine consumption in ET patients may not exclusively be a response to tremor. A prospective study is needed to explore whether decreased caffeine consumption is a risk factor for ET.     

Residual effects of ethanol and chlordiazepoxide treatments for alcohol withdrawal.

Eighteen male alcoholics were randomly assigned to one of two alcohol detoxification treatments. One group received a low dose ethanol treatment while the other group received a chlordiazepoxide treatment. This study compares recovery of sleep EEG and clinical symptomatology following these two detoxification treatments. Sleep EEG and clinical measures were obtained for the final medication day and during a 6-day postmedication "recovery" period. The chlordiazepoxide treatment produced suppression of rapid eye movement (REM) sleep lasting for about 4 days and virtually eliminated delta sleep (stages III and IV) during the recovery period. The low dose ethanol treatment regimen produced less disruption of REM and delta sleep during the recovery period. These findings suggest that under some circumstances an ethanol treatment regimen may prove more beneficial to the healthy alcoholic patient than current regimens which employ other psychoactive medication. In particular, the long lasting suppression of delta sleep during the recovery period in subjects treated with chlordiazepoxide suggests a vulnerability of the slow wave sleep mechanisms during early alcohol abstinence and raises the possibility that this regimen prolongs functional tolerance to alcohol effects. Continued clinical evaluation of low dose ethanol detoxification treatment is suggested.     

神经元自身抗体及其不同检测方法在自身免疫性脑炎中的价值研究进展

神经元自身抗体是自身免疫性脑炎诊断的关键,免疫组织化学法/间接免疫荧光法、啮齿类动物离体海马神经元的免疫细胞化学法、免疫印迹法等是目前常用的抗体检测方法,血清及脑脊液样本在不同亚型的自身免疫性脑炎中抗体检测的敏感性不同.神经元自身抗体滴度与肿瘤的发生相关,但与预后的相关性仍存在争议.近年来关于常见自身免疫性脑炎亚型相关...     

The value of drug and metabolite concentration in blood as a biomarker of psychopharmacological therapy

Abstract

Desirable and undesirable effects of a drug are related to its concentration at various sites of actions. For many psychotropic drugs, it has been shown that drug concentration in brain correlates with concentration in blood. The latter is also an available estimate of clearance and bioavailability. Its monitoring enables identification of multiple factors that have an impact on clinical outcomes, especially uncertain compliance and pharmacokinetic peculiarities. For this review we analysed for antidepressants if drug concentration in blood can be used as biomarker for psychopharmacological treatment. Systematic review of the literature revealed for new and old antidepressant drugs that drug and metabolite concentrations in blood are measures of the pharmacokinetic phenotype and related differentially to occupancy of primary target structures, therapeutic effects and unwanted anticholinergic, cardiac and other side effects. Drug concentration in blood can therefore be used as biomarker in clinical practice to guide psychopharmacological treatment with established antidepressant drugs. Monitoring of drug concentration is suitable to improve efficacy and safety of the pharmacotherapy, especially in elderly patients who require complex pharmacological therapies.     

Electrophysiological actions of acetate, a metabolite of ethanol, on hippocampal dentate granule neurons: interactions with adenosine.

Acetate is the primary breakdown product of ethanol metabolism in the liver and has been found in the brain following ethanol ingestion in rats. Systemically administered acetate has been shown to cause motor impairment, an effect which is blocked by the adenosine receptor blocker, 8-phenyltheophylline (8-PT). The effects of sodium acetate were investigated in this study using intracellular recording techniques in rat hippocampal dentate granule cells, and were compared to the actions of ethanol and adenosine individually and in conjunction with 8-PT. Acetate hyperpolarized the membrane at 0.4-0.8 mM. The amplitude and duration of the postspike train afterhyperpolarization (AHP) were increased by acetate when the cell was repolarized to the control resting membrane potential. Comparable results were seen in voltage clamp. Acetate also decreased spike frequency adaptation. The effects of acetate were mimicked by adenosine (50 microM) and ethanol (20 mM). The ethanol effects occluded those produced by acetate. All of the effects of acetate, adenosine and ethanol could be inhibited with prior perfusion of 8-PT (1-10 microM). These data suggest that the actions of the major metabolite of ethanol, acetate, may be mediated by adenosine receptor activation.     

Cerebral and peripheral neurotoxicity of chlorpromazine and ethanol interaction: implications for alcohol and aldehyde dehydrogenase.

The effects of certain experimental variables on rodents brain and liver alcohol--(ADH) and aldehyde-dehydrogenase (LALDH) were evaluated. The in vivo and in vitro effect of chlorpromazine on these enzymes was determined. Short-term housing under complete darkness differentially inhibited ADH and ALDH in distinct brain regions with ADH showing more sensitivity than ALDH. The hepatic enzymes studied were not affected by such housing conditions but a non-competitive inhibition of L-ALDH occurred as a consequence of exposure to UV lighting for 3 consecutive weeks. Short-term treatment with chlorpromazine inhibited striatal ADH which was not affected by experimentally-induced hypothermia. Likewise, both hepatic and testicular ADH were noncompetitively inhibited in vitro by chlorpromazine. The results suggest sensitivity of brain and hepatic ADH to environmental housing conditions and indicate a similarity between peripheral and cerebral ADH responses to chlorpromazine. The modulation of ADH and/or ALDH may facilitate the formation of endogenous biogenic amines derived alkaloids which have been implicated in alcohol and extrapyramidal side effects.     

Diagnostic value of quantitative electromyography. Its scope and limitations.

On the evidence of 951 cases of the 10,500 investigated with the aid of quantitative electromyography the author shows the value of the method for diagnosing muscle activity. Statistical analysis was applied to check the diagnostic value of EMG parameters separately and jointly in the identification of the pathology and its classification as either neurogenic or myogenic. Also surveyed are the sources of the discrepancies between the electromyographic and the histopathological results in very early and very advanced cases. Examples are given that show electromyographic findings as nosologically non-specific and the method as inferior to the morphological in this respect. On the other hand the method is stressed as one that permits it to (a) tell a malignant and rapid process from a slow one, (b) obtain evidence of repair and (c) prove generalization of processes considered to be local or the progressive character of processes considered to be non-progressive. The author also refers to the added scope given to electromyography by such developments as automatic recording, SFEMG, and determination of motor unit territory with the aid of multielectrodes.     

Dantrolene blockade of ryanodine receptor impairs ethanol-induced behavioral stimulation, ethanol intake and loss of righting reflex

Calcium has been characterized as one of the most ubiquitous, universal and versatile intracellular signals. Among other substances with the ability to alter intracellular calcium levels, ethanol has been described as particularly relevant because of its social and economic impact. Ethanol effects on calcium distribution and flux in vitro have been widely studied, showing that acute ethanol administration can modulate intracellular calcium concentrations in a dose dependent manner. Intracellular calcium released from the endoplasmic reticulum plays a determinant role in several cellular processes. In this study, we aim to assess the effect of dantrolene, a ryanodine receptor antagonist, on three different ethanol-elicited behaviors: locomotor activity, loss of righting reflex and ethanol intake. Mice were challenged with an injection of dantrolene (0-5 mg/kg, i.p.) 30 min before ethanol (0-4 g/kg, i.p.) administration. Animals were immediately placed in an open field cylinder to monitor distance travelled horizontally or in a V-shaped trough to measure righting reflex recovery time. For ethanol intake, dantrolene (0-5mg/kg, i.p.) was administered 30 min before ethanol (20%, v/v) exposure, following a drinking in the dark paradigm. Our results showed that dantrolene selectively reduces ethanol-induced stimulation, loss of righting reflex, and ethanol intake in a dose dependent manner. Together, these data suggest that intracellular calcium released from the endoplasmic reticulum may play a critical role in behavioral effects caused by ethanol, and point to a calcium-dependent pathway as a possible cellular mechanism of action for ethanol.     

Personality and the effects of acute alcohol intake. A contingent negative variation study in healthy subjects

This study investigates the relationship between blood alcohol concentrations (BACs) and contingent negative variation (CNV). Fourteen healthy subjects were divided on the basis of their personality profiles--the Minnesota Multiphasic Personality Inventory (Hs+Hy+D/3)--into a high score (HS) and low score (LS) subgroup. The CNV was recorded using a choice-reaction time (RT) task. CNV recording was performed in two conditions: inter-stimulus intervals (ISIs) of 1500 ms and 2500 ms at three different BACs (0.3, 0.5 and 0.8 g/L) after acute alcohol administration. At the high BAC (0.8 g/L), both subgroups showed a reduced CNV amplitude area and a longer RT (p<.05) in both ISI conditions. No effects either on the CNV or on the RT were observed at the low BAC (0.3 g/L). At the intermediate BAC (0.5 g/L), the HS subgroup displayed an increased CNV amplitude (p<.05), not accompanied by a significantly longer RT (short ISI condition), and a reduced late CNV (p<.05) with a longer RT (p<.05) (long ISI condition). In the LS group, only a longer RT was observed in the long ISI condition. CNV modifications point to an individual, apparently personality-related, threshold of sensitivity to different alcohol levels.     

Odor identification as an early marker for Alzheimer's disease: Impact of lexical functioning and detection sensitivity

Abstract

The impact of lexical functioning and detection sensitivity on the deficit of odor identification in Alzheimer's disease (AD) was studied in persons diagnosed with probable and questionable AD. Tests consisted of lexical-based odor identification, lexical-based picture identification, picture-based odor identification, and odor-detection threshold. Results suggest (1) that odor identification is poorer than picture identification in probable and questionable AD, (2) that odor identification continues to be poor even when lexical demands are eliminated, (3) that odor detection does contribute to the odor-identification deficit, but does not account for it completely, and (4) that odor identification tests have a correct classification rate of 83 – 100%. Odor identification tests can be very useful tools in diagnosing AD and should be considered an important addition to existing diagnostic test batteries.     

Nicotine dependence as comorbidity of alcohol dependence--epidemiology, etiology and therapy

There is a high association between alcohol and nicotine dependence. Compared to one particular dependence, associated nicotine and alcohol dependence are more severe and the course is more unfavourable for each dependence. This also applies to the sequels of dependence regarding physical health and cognitive functions. Possible biological causes for this high comorbidity are 1) an additive rewarding effect by combined consumption, 2) substance interaction with an impact on receptor activation and metabolism which results in reduction of adverse acute alcohol effects, and 3) a combined genetic disposition for both addictions. From a psychological point of view the association of both acts of use is learned. There is no evidence for the commonly presumed fundamental lack of interest, motivation, and ability for smoking cessation in alcohol dependent patients. The outcome of smoking cessation programs, however, is less successful compared to smokers without alcohol problems. Respective studies have used the common therapeutic strategies for nicotine addiction. Specifically adapted strategies for patients with a dual dependence are required.     

不同检测手段在脑梗死患者临床评估中的价值

目的 :探讨神经心理学量表、脑电生理及 MRI检查在脑梗死患者临床评估中的价值。方法 :对 5 5例脑梗死患者发病后一个月进行神经心理学上脑高级功能的评估 ,并进行了常规脑电图 ,P30 0及 MRI检查。其中神经心理学量表的检查包括 MMSE、韦氏智力及临床记忆量表检查。结果 :智商、临床记忆量表得分及 P30 0潜伏期检查患者组较对照组下降有明显差异。MRI所显示的病变大小与患者的认知功能和短时记忆明显相关。P30 0潜伏期不仅与认知功能明显相关 ,而且与韦氏智力有一定的相关性。结论 :合理的应用神经心理学量表检查可以全面地反映不同脑梗死患者脑功能障碍的不同侧面。脑梗死面积大小明显影响患者的认知功能和短时记忆。P30 0可以作为脑梗死患者认知功能评估的敏感指标。     

Beta-2-microglobulin levels in the cerebrospinal fluid: their value as a disease marker. A review of the recent literature

The usefulness of measuring beta 2-microglobulin levels in the cerebrospinal fluid (CSF) in neurological diseases is discussed and the relevant literature is reviewed in this article. An elevation of this protein in the CSF is particularly indicative of disease activity in multiple sclerosis, neuro-Beh?et's disease, sarcoidosis, acquired immunodeficiency syndrome-dementia complex and meningeal metastasis of malignant tumors, especially the meningeal dissemination of acute leukemia and malignant lymphoma.     

Reliability,sensitivity, and predictive value of fMRI during multiple object tracking as a marker of cognitive training gain in combination with tDCS in stroke survivors

Computerized cognitive training (CCT) combined with transcranial direct current stimulation (tDCS) has showed some promise in alleviating cognitive impairments in patients with brain disorders, but the robustness and possible mechanisms are unclear. In this prospective double‐blind randomized clinical trial, we investigated the feasibility and effectiveness of combining CCT and tDCS, and tested the predictive value of and training‐related changes in fMRI‐based brain activation during attentive performance (multiple object tracking) obtained at inclusion, before initiating training, and after the three‐weeks intervention in chronic stroke patients (>6 months since hospital admission). Patients were randomized to one of two groups, receiving CCT and either (a) tDCS targeting left dorsolateral prefrontal cortex (1 mA), or (b) sham tDCS, with 40s active stimulation (1 mA) before fade out of the current. Of note, 77 patients were enrolled in the study, 54 completed the cognitive training, and 48 completed all training and MRI sessions. We found significant improvement in performance across all trained tasks, but no additional gain of tDCS. fMRI‐based brain activation showed high reliability, and higher cognitive performance was associated with increased tracking‐related activation in the dorsal attention network and default mode network as well as anterior cingulate after compared to before the intervention. We found no significant associations between cognitive gain and brain activation measured before training or in the difference in activation after intervention. Combined, these results show significant training effects on trained cognitive tasks in stroke survivors, with no clear evidence of additional gain of concurrent tDCS.     

Direct ethanol injection for skull metastasis from hepatocellular carcinoma. The techniques and consequences of a therapeutic trial

Abstract

The frequency of skull metastasis from hepatocellular carcinoma (HCC) is increasing together with the recent progress in the management of the primary lesion. Cases are often complicated with poor general conditions or metastasis to the other organs, and not readily indicated for surgery. A direct injection of ethanol to the lesion could be one of the therapeutic options to cope with this complicated situation. To evaluate the feasibility of this technique, we planned a therapeutic trial in a patient with HCC associated with lumbar and skull metastasis, the latter metastasis repeated twice during the past one year. A total of 10 ml of ethanol was injected into the skull metastasis percutaneously under ultrasound (US) guidance. US guidance was very useful in determin.ing the sites of injections and the distribution of ethanol as well as monitoring the blood flow within the tumor vessels. The patient transiently.complained. of local.pan at the injection sites, but there were no other adverse effects. Four days after the injection the les of well as resected by surgery, which confirmed the pathologic diagnosis as well as the nearly-total necrosis: of the tumor This technique is simple, safe and repeatable with low cost. The technical details and the histologic effects are described. [Neural Res 1998; 20: 737-741]     

Validity of carbohydrate deficient transferrin and other markers as diagnostic aids in the detection of alcohol related seizures

OBJECTIVE: The role of alcohol misuse in the genesis of seizures is probably often undetected. The aim was to investigate the utility of carbohydrate deficient transferrin (CDT) compared with other biomarkers and clinical examination in the diagnosis of alcohol related seizures. METHODS: The study included consecutively 158 seizure patients-83 men and 75 women-with mean age 45 (16-79) years. Seizures related to alcohol use were identified by a score > or =8 in the alcohol use disorders identification test (AUDIT positive). AUDIT was applied as the gold standard to which sensitivity and specificity of the various markers were related. Blood samples were obtained from 150 patients on admission and analysed for ethanol, liver enzymes, and CDT, using AXIS Biochemicals' %CDT-TIA kit. RESULTS: 53 patients (34%) were AUDIT positive. Using the commonly applied decision value for %CDT of 5.0%, a sensitivity of 41% and a specificity of 84% were obtained. Analysis of receiver operator characteristics (ROC) curves disclosed an optimal cut off value for %CDT of 5.4%, which yielded a sensitivity of 39% and a specificity of 88%. At a specificity of 80%, the sensitivity was 43% for %CDT and 26% for GGT. The %CDT sensitivity was markedly higher for men than for women. Compared with GGT, ASAT, ALAT, and ASAT/ALAT ratio, CDT was the best single biomarker for alcohol related seizures. However, even in the subgroup of withdrawal seizures, the sensitivity level barely exceeded 50%. Clinicians scored alcohol as the main cause of the seizure in only 19 cases (12%). In 38 (24%) cases, clinicians suspected that alcohol had a role (sensitivity of 62% at a specificity of 89%). Their ability to identify AUDIT positive patients was better than that of any biomarker, but many cases were missed. Agreement of clinicians' scores to CDT was only fair (kappa=0.28). CDT concentrations were significantly increased among alcohol abstaining patients on enzyme-inducing antiepileptic drugs. Six out of 16 patients with false positive CDT results were exposed to such drugs. CONCLUSIONS: CDT is not recommended as a stand alone marker for alcohol related seizures, but may provide a useful contribution to the overall diagnostic investigation of seizures. Confirmatory studies are needed as to the apparent vulnerability of CDT to antiepileptic drugs.     

Platelets, alcohol consumption, and onset of brain infarction.

OBJECTIVES: Previous investigations have suggested that recurrent rebound thrombocytosis after alcohol misuse may be a factor in the pathogenesis of thromboembolic disease. Alcohol consumption, platelet count, and platelet function were examined among patients of working age with brain infarction. METHODS: Platelet count and risk factors for stroke were studied in 426 stroke patients and 157 control patients in hospital. The measures were platelet count obtained within four days after the stroke onset, in vitro adenosine diphosphate induced platelet aggregation, associated thromboxane B2 formation, and urinary excretion of 11-dehydrothromboxane B2. RESULTS: After adjustment for sex, age, cardiac disease, diabetes, and alcohol intake, hypertension (OR 3.4, 95% confidence interval (95% CI) 2.0-6.0) and current smoking (OR 2.1, 95% CI 1.4-3.3) were associated with an increased risk for brain infarction. Platelet count shortly after the onset of disease was higher in the stroke patients than in the controls (OR 1.05/10(10)/1 platelets; 95% CI 1.02-1.09). The patients with brain infarction who were heavy alcohol drinkers (n = 144) showed both thrombocytosis (OR 2.30, 95% CI 0.82-6.44) and thrombocytopenia (OR 3.20, 95% CI 1.19 to 8.59) more often at the onset of the stroke than the other patients with brain infarction. The thromboxane variables showed inconsistent associations with the onset of stroke. There was no consistent platelet abnormality among alcohol misusers at the onset of ischaemic brain infarction. CONCLUSIONS: Alcohol induced thrombocytopenia and rebound thrombocytosis were both often seen at the onset of brain infarction in patients who were heavy alcohol drinkers. Therefore, other mechanisms which could contribute to the high frequency of recurrences of ischaemic stroke among heavy drinkers should be investigated.