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While the harmful effects of alcohol abuse are well documented, experimental and clinical data support a potential benefit of light to moderate alcohol consumption. Cross-sectional studies have suggested an association between alcohol consumption and multiple sclerosis (MS) disability. In the absence of prospective, longitudinal studies, the causal nature of this relationship cannot be established. It remains possible that patients with increased disability progression reduce their alcohol intake. Even though there is substantial evidence for anti-inflammatory effects of low-to-moderate doses of alcohol, the associations need to be interpreted very cautiously. This study discusses the current state of knowledge about MS and alcohol consumption, and the limitations in conducting research with retrospective data in patients with MS.

Activity pacing (AP) is a concept that is central to many chronic pain theories and treatments, yet there remains confusion regarding its definition and effects.To review the current knowledge concerning AP and integrate this knowledge in a manner that allows for a clear definition and useful directions for future research.A narrative review of the major theoretical approaches to AP and of the empirical evidence regarding the effects of AP interventions, followed by an integrative discussion.The concept of AP is derived from 2 main traditions: operant and energy conservation. Although there are common elements across these traditions, significant conceptual and practical differences exist, which has led to confusion. Little empirical evidence exists concerning the efficacy of AP as a treatment for chronic pain.Future research on AP should be based on a clear theoretical foundation, consider the context in which the AP behavior occurs and the type of pacing problem ("underactivity" vs. "overactivity"), and should examine the impact of AP treatment on multiple clinical outcomes. We provide a provisional definition of AP and specific recommendations that we believe will move the field forward.

Systemic delivery of therapeutic agents remains ineffective against diffuse intrinsic pontine glioma (DIPG), possibly due to an intact blood-brain-barrier (BBB) and to dose-limiting toxicity of systemic chemotherapeutic agents. Convection-enhanced delivery (CED) into the brainstem may provide an effective local delivery alternative for DIPG patients.The aim of this study is to develop a method to perform CED into the murine brainstem and to test this method using the chemotherapeutic agent carmustine (BiCNU). To this end, a newly designed murine CED catheter was tested in vitro and in vivo. After determination of safety and distribution, mice bearing VUMC-DIPG-3 and E98FM-DIPG brainstem tumors were treated with carmustine dissolved in DW 5% or carmustine dissolved in 10% ethanol.Our results show that CED into the murine brainstem is feasible and well tolerated by mice with and without brainstem tumors. CED of carmustine dissolved in 5% DW increased median survival of mice with VUMC-DIPG-3 and E98FM-DIPG tumors with 35% and 25% respectively. Dissolving carmustine in 10% ethanol further improved survival to 45% in mice with E98FM-DIPG tumors.Since genetically engineered and primary DIPG models are currently only available in mice, murine CED studies have clear advantages over CED studies in other animals.CED in the murine brainstem can be performed safely, is well tolerated and can be used to study efficacy of chemotherapeutic agents orthotopically. These results set the foundation for more CED studies in murine DIPG models.

We compared the modulation of GABA (gamma-aminobutyric acid)-activated currents by benzodiazepines in recombinant GABAA receptors containing either one of two alpha subunits, alpha 1 or alpha 6. Lüddens et al. (Nature, 346 (1990) 648-651) have previously demonstrated that the alpha 6 subunit is part of a cerebellar receptor subtype which selectively binds Ro15-4513, an antagonist of alcohol-induced motor ataxia. Here we report that the imidazobenzodiazepine Ro15-4513 (ethyl 8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo-(1,5-a) (1,4)benzodiazepine-3-carboxylate) reduced GABA-activated currents in recombinant alpha 6 beta 2 gamma 2 and alpha 1 beta 2 gamma 2 receptors, thus acting consistently as an inverse agonist. Moreover, another well characterized negative modulator, DMCM (methyl-4-ethyl-6,7-dimethoxy-beta-carboline-3-carboxylate), also reduces GABA activated-currents in both receptors. In contrast, flunitrazepam (FNZM), a benzodiazepine agonist, increases GABA-activated currents in alpha 1 beta 2 gamma 2 receptors, but not in alpha 6 beta 2 gamma 2 receptors. This study lends further support to the hypothesis that the binding sites of full and partial inverse agonists are different.

Repeated treatment of rats with ethanol (1 g/kg, once daily for 15 days) enhanced the locomotor effect of morphine, 3 weeks post-treatment. This ethanol-induced long-term behavioural sensitization to morphine was associated with an increase in the electrically evoked release of [3H]dopamine (DA) and [14C]acetylcholine (ACh) from nucleus accumbens slices. A similar enhanced responsiveness of accumbal dopaminergic and cholinergic neurons to depolarization was apparent 3 weeks after repeated morphine, amphetamine or cocaine administration. Prior ethanol exposure also caused a long-term enhancement of electrically evoked release of [3H]DA and [14C]ACh from slices of the caudate-putamen. Unlike the locomotor effect of morphine, that of amphetamine was not enhanced in ethanol-pretreated rats. These data indicate that ethanol administration may cause long-term behavioural sensitization associated with adaptive changes in dopaminergic and cholinergic neurons of rat nucleus accumbens and caudate-putamen. Furthermore, an enhanced reactivity of nucleus accumbens dopaminergic nerve terminals and dopamine-sensitive cholinergic neurons appears to be a common long-term neuroadaptive effect of distinct types of addictive drugs. However, since repeated ethanol exposure did not cause a long-term increase in the locomotor effect of amphetamine, these neuroadaptations may not always be sufficient to cause long-lasting behavioural (cross-)sensitization.

To review new putative mechanisms involved in the pathophysiology of a disturbed energy balance in cancer cachexia, which can lead to novel targets for clinical cachexia management. In the context of rapid developments in tumour treatment with potential systemic consequences, this article reviews recent data on energy requirements. Furthermore, we focus on new insights in brown adipose tissue (BAT) activity and reward processing in the brain in relation to the cachexia process.Nearly no new data have been published on energy requirements of cancer patients in the light of comprehensive new therapies in oncology. New developments, such as the introduction of staging with 18F-fluorodeoxyglucose PET-computed tomography scanning, led to the observation that BAT activation may contribute to impaired energy balance in cancer cachexia. Animal and human data to date provide an indication that BAT activation indeed occurs, but its quantitative impact on the degree of cachexia is controversial. The peripheral and central nervous system is known to influence satiation, with a possible role for impaired food reward processing in the brain. To date, there are limited confirmatory data, but this is an interesting new area to explore for better understanding and treating cancer-induced anorexia.The multimodal approach to counteract cancer cachexia should expand its targets to BAT and food reward processing in the brain.

In this study, the suitability of amide proton transfer (APT) imaging as a biomarker for the characterization of high intensity focused ultrasound (HIFU)-treated tumor tissue was assessed.APT imaging was performed on tumor-bearing mice before (n = 15), directly after (n = 15) and at 3 days (n = 8) after HIFU treatment. A control group (n = 7) of nontreated animals was scanned at the same time points. Histogram analysis of the tumor APT-weighted signal distributions was performed to assess HIFU-induced changes in the tumor APT contrast.Distinct regions of decreased APT-weighted signal were observed at both time points after HIFU treatment. Analysis of the tumor APT-weighted signal distribution showed a pronounced shift toward lower APT-weighted signal values after HIFU treatment. A significantly increased fraction of pixels with an APT-weighted signal value between -10 and -2% was observed both directly (0.37 ± 0.16) and at 3 days (0.49 ± 0.16) after HIFU treatment as compared to baseline (0.22 ± 0.16).The presented results show that APT imaging is sensitive to HIFU-induced changes in tumor tissue and may thus serve as a new biomarker for monitoring the response of tumor tissue to HIFU treatment.

Maximal L-glutamate/glycine-evoked currents were inhibited by ethanol in Xenopus laevis oocytes expressing recombinant heteromeric NMDA receptors consisting of NR1-NR2A, NR1-NR2B, and NR1-NR2C subunit combinations. Concentration-dependent inhibition was observed at ethanol concentrations of > or = 50 mM both in Ca(2+)-containing and Ca(2+)-deficient, Ba(2+)-containing Mg(2+)-free media. The NR1-NR2C channels were slightly less sensitive to ethanol inhibition than the other heteromeric channels in Ca(2+)-deficient, Ba(2+)-containing medium. The inhibition was unaffected by the clamping-voltage and by a mutation [NR1-NR2A(N595Q)] that prevents the Mg(2+)-blockade of the channels, indicating that the mechanism of action of ethanol differs from that of Mg2+. The results are consistent with the hypothesis that the NMDA receptor subtypes can mediate many behavioural actions of ethanol.