Varenicline effects on drinking,craving and neural reward processing among non-treatment-seeking alcohol-dependent individuals

Rationale

The α4β2 nicotinic acetylcholine receptor partial agonist varenicline has been reported to reduce drinking among both heavy-drinking smokers and primary alcoholics, and this effect may be related to varenicline-mediated reduction of alcohol craving. Among smokers, varenicline has been reported to modulate cigarette cue-elicited brain activation in several reward-related areas.

Objectives

This pilot study tested varenicline’s effects on drinking, alcohol craving, and alcohol cue-elicited activation of reward-related brain areas among non-treatment-seeking alcohol-dependent individuals.

Methods

Thirty-five such individuals (mean age?=?30, 57 % male, 76 % heavy drinking days in the past month, 15 smokers) were randomized to either varenicline (titrated to 2 mg) or placebo for 14 days, and were administered an alcohol cue reactivity fMRI task on day 14. A priori regions of interest (ROIs) were bilateral and medial orbitofrontal cortex (OFC), right ventral striatum (VS), and medial prefrontal cortex (mPFC).

Results

Despite good medication adherence, varenicline did not reduce heavy drinking days or other drinking parameters. It did, however, increase self-reported control over alcohol-related thoughts and reduced cue-elicited activation bilaterally in the OFC, but not in other brain areas.

Conclusions

These data indicate that varenicline reduces alcohol craving and some of the neural substrates of alcohol cue reactivity. However, varenicline effects on drinking mediated by cue-elicited brain activation and craving might be best observed among treatment-seekers motivated to reduce their alcohol consumption.     

Mitochondrial function and energy metabolism in neuronal HT22 cells resistant to oxidative stress

Background and Purpose

The hippocampal cell line HT22 is an excellent model for studying the consequences of endogenous oxidative stress. Extracellular glutamate depletes cellular glutathione by blocking the glutamate/cystine antiporter system xc−. Glutathione depletion induces a well-defined programme of cell death characterized by an increase in reactive oxygen species and mitochondrial dysfunction.

Experimental Approach

We compared the mitochondrial shape, the abundance of mitochondrial complexes and the mitochondrial respiration of HT22 cells, selected based on their resistance to glutamate, with those of the glutamate-sensitive parental cell line.

Key Results

Glutamate-resistant mitochondria were less fragmented and displayed seemingly contradictory features: mitochondrial calcium and superoxide were increased while high-resolution respirometry suggested a reduction in mitochondrial respiration. This was interpreted as a reverse activity of the ATP synthase under oxidative stress, leading to hydrolysis of ATP to maintain or even elevate the mitochondrial membrane potential, suggesting these cells endure ineffective energy metabolism to protect their membrane potential. Glutamate-resistant cells were also resistant to oligomycin, an inhibitor of the ATP synthase, but sensitive to deoxyglucose, an inhibitor of hexokinases. Exchanging glucose with galactose rendered resistant cells 1000-fold more sensitive to oligomycin. These results, together with a strong increase in cytosolic hexokinase 1 and 2, a reduced lactate production and an increased activity of glucose-6-phosphate dehydrogenase, suggest that glutamate-resistant HT22 cells shuttle most available glucose towards the hexose monophosphate shunt to increase glutathione recovery.

Conclusions and Implications

These results indicate that mitochondrial and metabolic adaptations play an important role in the resistance of cells to oxidative stress.

Linked Articles

This article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2014.171.issue-8     

An essential review of Singapore’s response to out-of-hospital cardiac arrests: improvements over a ten-year period

Care for patients who experience out-of-hospital cardiac arrest (OHCA) has rapidly evolved in the past decade. Increased sophistication of care in the community, emergency medical services (EMS) and hospital setting is associated with improved patient-centred outcomes. Notably, Utstein survival doubled from 11.6% to 23.1% between 2011 and 2016. These achievements involved collaboration between policymakers, clinicians and researchers, and were made possible by a strategic interplay of policy, research and implementation. We review the development and current state of OHCA in Singapore using primary population-based data from the Pan-Asian Resuscitation Outcomes Study and an unstructured search of research databases. We discuss the roles of important milestones in policy, community, dispatch, EMS and hospital interventions. Finally, we relate these interventions to relevant processes and outcomes, such as the relationship between the strategic implementation of bystander cardiopulmonary resuscitation and placement of automated external defibrillator with return of spontaneous circulation, survival to discharge and survival with favourable neurological outcomes.     

小鼠耳蜗核因子-κB p50免疫组化定位

目的 了解核因子-κB(NF-κB)在耳蜗的表达情况.方法 小鼠皮下注射卡那霉素(KA),鼓室注射脂多糖(LPS),以注射等量生理盐水作为对照,用多克隆兔抗体NF-κB p50免疫组化染色,观察NF-κB p50在小鼠耳蜗的表达.结果 NF-κB p50主要定位在耳蜗的螺旋缘、盖膜、血管纹、螺旋韧带、螺旋神经节和神经纤维.整个耳蜗各圈均可观察到免疫反应,而螺旋韧带、盖膜、螺旋突、螺旋神经节和神经纤维均可观察到较强的免疫反应,Corti器的免疫反应比上述结构要弱一些.Corti器的内、外毛细胞,内、外柱细胞,Deiter细胞和Claudious细胞均可观察到NF-κB p50的免疫反应,这些免疫反应在内沟细胞、Hensen细胞和Claudious细胞较弱,而在螺旋神经节可观察到较强的免疫反应,内、外毛细胞核未见免疫反应.结论 注射脂多糖和卡那霉素可使NF-κB p50在小鼠耳蜗产生急性反应.     

Independent from muscle power and balance performance, a creatinine clearance below 65 ml/min is a significant and independent risk factor for falls and fall-related fractures in elderly men and women diagnosed with osteoporosis

Summary  

We assessed in a cross-sectional study in elderly men and women with osteoporosis, the association between the creatinine clearance (CrCl) and the performance in different balance and muscle power and function tests and found that a decreasing creatinine clearance was significantly associated with lower balance and muscle power.     

Osteoporosis in rheumatoid arthritis--significance of alfacalcidol in prevention and therapy

Besides localised osteopenia, patients with rheumatoid arthritis (RA) with or without corticosteroids develop in 30-50% osteoporosis induced by several factors and thus a higher risk of fractures. Bone loss appears very early and correlates directly with disease activity and also later with the negative effects of restrictive mobility. Corticosteroids reduce as a pathogenetic co-factor intestinal calcium absorption and increase renal calcium excretion resulting in compensatory increased PTH-release and increased sensitivity of bone to PTH. In addition, corticosteroids inhibit osteoblast function as well as the favourable effects of growth factors and sex hormones on bone. It has recently been recognised that the expression of D-hormone receptors (VDRs) is suppressed by these medications and that corticosteroids probably induce VDR disorders. The negative influence of corticosteroids on muscle strength (indirectly--via increased PTH-levels, lowered IGF-1-levels or reduced D-hormone activity) is a feature which has been underestimated. The demonstrated drop in 1,25(OH)2D3 (D-hormone) levels in patients with RA in correlation with C-reactive protein (CRP) is of significance in the pathogenesis of RA-induced osteoporosis and could further promote the process of inflammation. There is a general consensus that cytokines (e.g. IL-1, IL-6, IL-12, TNF-alpha) induce bone resorption in inflammatory rheumatic diseases. There are, however, new findings which show that cytokines like TNF-alpha also interfere with bone formation by promoting apoptosis of osteoblasts and reduce the muscle strength, too. D-hormone preparations (alfacalcidol, calcitriol) possess immunoregulatory effects in vitro and in vivo by inhibiting the cytokines IL-1, IL-6, TNF-alpha and particularly IL-12. At the cellular level, D-hormone reduces the expression of Th1 helper cells directly or indirectly by inhibition of IL-12 from monocytes. Therapy with alfacalcidol or calcitriol results in increased production of Th2 helper cells which produce bone protective cytokines like IL-4 and IL-10. It is important to know that D-hormone protects osteoblasts against TNF-alpha-induced cell death. After conversion to D-hormone in the liver and bone, alfacalcidol antagonises the above described pathogenetic factors of the corticosteroids. D-hormone is one of the body's own immunoregulators, which is produced in macrophages in cases of need to reduce immunological overreactions in a feed-back loop. Improved understanding of the pathogenesis of corticosteroid-induced osteoporosis and of the pharmacological effects of alfacalcidol in this type of iatrogenic bone loss as well as the results of specific animal models simulating bone loss in inflammatory diseases explain the favourable effects of alfacalcidol in this indication. Various clinical studies have demonstrated clearly that alfacalcidol retards corticosteroid-induced bone loss in contrast to plain vitamin D. Due to its immunomodulating properties, alfacalcidol is particularly suitable for RA-induced bone loss and for the prevention of transplantation osteoporosis, and an adjuvant contribution to the disease-modifying therapy of RA and to the immunosuppressive therapy after transplantation can not be excluded.     

Gentamicin alters membrane structure as shown by freeze-fracture of liposomes

Freeze-fracture has been used to examine the effects of gentamicin on membrane structure in liposomes of different anionic phospholipids combined with a neutral phospholipid, phosphatidylcholine. The molar ratios of neutral: anionic lipid were 1:1 (high anionic lipid ratio) and 4:1 (low anionic lipid) and the liposomes were incubated with 0.1 mM (low) and 1 mM (high) gentamicin. With the anionic phospholipid phosphatidylinositol bisphosphate, an identifiable disruption of the membrane bilayer was observed as well as aggregation of liposomes leading to membrane fusion. These effects occurred both at low gentamicin concentration and low anionic lipid content of the liposomes; these responses were not inhibited by 1 mM Ca2+. With the other anionic lipids tested (phosphatidylserine, phosphatidylinositol and phosphatidylinositol monophosphate), only aggregation and fusion of liposomes was observed and this effect only occurred at high gentamicin concentration and high anionic lipid content. Further, 1 mM Ca2+ inhibited the responses of these other anionic lipids to gentamicin. The results demonstrate the unique character of the interaction between gentamicin and phosphatidylinositol bisphosphate and provide further support for the hypothesis that a specific binding to this lipid is a key step in the ototoxic action of aminoglycoside antibiotics. They also suggest that such an interaction in vivo might cause alterations to the structure and properties of cell membranes in the inner ear.     

The first report of a patient with interrupted inferior vena cava,multiple post-renal veins and azygos-hemiazygos continuation

The first case of a patient with interrupted inferior vena cava, four post-renal veins and an azygoshemiazygos continuation is presented. The complicated anomalies were omphalocele and atrial septal defect. Cine-magnetic resonance imaging and cardiac catheterization showed an anomalous retroaortic left innominate vein, azygos-hemiazygos continuation in the prerenal portion, arch formed renal vein in the renal portion and four embryonic vessels in the post-renal portion. Combination of these anomalies in the major venous system suggested that the inferior vena cava had failed to form and that the bilateral embryonic venous system, postcardinal and supracardinal veins persisted to be the systemic venous channels.     

Gamma-carboxyglutamate in normal and pathological human middle ear bones

Summary The presence of the amino acid -carboxyglutamate (GLA) was established in human middle ear bones. Proteins containing GLA have been described as being associated with normal as well as pathological calcifications. The GLA content of human incus, malleus, and stapes with 1–2 nmol/mg bone is in the range previously reported for a variety of bone. A limited number of samples with middle ear pathology, including otosclerosis, did not show altered GLA levels.