Variants in the CNR1 gene predispose to headache with nausea in the presence of life stress

One of the main effects of the endocannabinoid system in the brain is stress adaptation with presynaptic endocannabinoid receptor 1 (CB1 receptors) playing a major role. In the present study, we investigated whether the effect of the CB1 receptor coding CNR1 gene on migraine and its symptoms is conditional on life stress. In a cross-sectional European population (n = 2426), recruited from Manchester and Budapest, we used the ID-Migraine questionnaire for migraine screening, the Life Threatening Experiences questionnaire to measure recent negative life events (RLE), and covered the CNR1 gene with 11 SNPs. The main genetic effects and the CNR1 × RLE interaction with age and sex as covariates were tested. None of the SNPs showed main genetic effects on possible migraine or its symptoms, but 5 SNPs showed nominally significant interaction with RLE on headache with nausea using logistic regression models. The effect of rs806366 remained significant after correction for multiple testing and replicated in the subpopulations. This effect was independent from depression- and anxiety-related phenotypes. In addition, a Bayesian systems-based analysis demonstrated that in the development of headache with nausea all SNPs were more relevant with higher a posteriori probability in those who experienced recent life stress. In summary, the CNR1 gene in interaction with life stress increased the risk of headache with nausea suggesting a specific pathological mechanism to develop migraine, and indicating that a subgroup of migraine patients, who suffer from life stress triggered migraine with frequent nausea, may benefit from therapies that increase the endocannabinoid tone

Significance of risk polymorphisms for depression depends on stress exposure

Depression is a polygenic and multifactorial disorder where environmental effects exert a significant impact, yet most genetic studies do not consider the effect of stressors which may be one reason for the lack of replicable results in candidate gene studies, GWAS and between human studies and animal models. Relevance of functional polymorphisms in seven candidate genes previously implicated in animal and human studies on a depression-related phenotype given various recent stress exposure levels was assessed with Bayesian relevance analysis in 1682 subjects. This Bayesian analysis indicated a gene-environment interaction whose significance was also tested with a traditional multivariate analysis using general linear models. The investigated genetic factors were only relevant in the moderate and/or high stress exposure groups. Rank order of genes was GALR2 > BDNF > P2RX7 > HTR1A > SLC6A4 > CB1 > HTR2A, with strong relevance for the first four. Robust gene-gene-environment interaction was found between BDNF and HTR1A. Gene-environment interaction effect was confirmed, namely no main effect of genes, but a significant modulatory effect on environment-induced development of depression were found. Our data support the strong causative role of the environment modified by genetic factors, similar to animal models. Gene-environment interactions point to epigenetic factors associated with risk SNPs. Galanin-2 receptor, BDNF and X-type purin-7 receptor could be drug targets for new antidepressants

Increased activation of the pregenual anterior cingulate cortex to citalopram challenge in migraine: an fMRI study

Background: The anterior cingulate cortex (ACC) is a key structure of the pain processing network. Several structural and functional alterations of this brain area have been found in migraine. In addition, altered serotonergic neurotransmission has been repeatedly implicated in the pathophysiology of migraine, although the exact mechanism is not known. Thus, our aim was to investigate the relationship between acute increase of brain serotonin (5-HT) level and the activation changes of the ACC using pharmacological challenge MRI (phMRI) in migraine patients and healthy controls. Methods: Twenty-seven pain-free healthy controls and six migraine without aura patients participated in the study. All participant attended to two phMRI sessions during which intravenous citalopram, a selective serotonin reuptake inhibitor (SSRI), or placebo (normal saline) was administered. We used region of interest analysis of ACC to compere the citalopram evoked activation changes of this area between patients and healthy participants. Results: Significant difference in ACC activation was found between control and patient groups in the right pregenual ACC (pgACC) during and after citalopram infusion compared to placebo. The extracted time-series showed that pgACC activation increased in migraine patients compared to controls, especially in the first 8–10 min of citalopram infusion. Conclusions: Our results demonstrate that a small increase in 5-HT levels can lead to increased phMRI signal in the pregenual part of the ACC that is involved in processing emotional aspects of pain. This increased sensitivity of the pgACC to increased 5-HT in migraine may contribute to recurring headache attacks and increased stress-sensitivity in migraine

Membrane fluidity matters: Hyperthermia from the aspects of lipids and membranes

Hyperthermia is a promising treatment modality for cancer in combination both with radio- and chemotherapy. In spite of its great therapeutic potential, the underlying molecular mechanisms still remain to be clarified. Due to lipid imbalances and 'membrane defects' most of the tumour cells possess elevated membrane fluidity. However, further increasing membrane fluidity to sensitise to chemo-or radiotherapy could have some other effects. In fact, hyperfluidisation of cell membrane induced by membrane fluidiser initiates a stress response as the heat shock protein response, which may modulate positively or negatively apoptotic cell death. Overviewing some recent findings based on a technology allowing direct imaging of lipid rafts in live cells and lipidomics, novel aspects of the intimate relationship between the 'membrane stress' of tumour cells and the cellular heat shock response will be highlighted. Our findings lend support to both the importance of membrane remodelling and the release of lipid signals initiating stress protein response, which can operate in tandem to control the extent of the ultimate cellular thermosensitivity. Overall, we suggest that the fluidity variable of membranes should be used as an independent factor for predicting the efficacy of combinational cancer therapies

Synchronized oscillations at alpha and theta frequencies in the lateral geniculate nucleus

In relaxed wakefulness, the EEG exhibits robust rhythms in the ? band (8–13 Hz), which decelerate to ? (2–7 Hz) frequencies during early sleep. In animal models, these rhythms occur coherently with synchronized activity in the thalamus. However, the mechanisms of this thalamic activity are unknown. Here we show that, in slices of the lateral geniculate nucleus maintained in vitro, activation of the metabotropic glutamate receptor (mGluR) mGluR1a induces synchronized oscillations at ? and ? frequencies that share similarities with thalamic ? and ? rhythms recorded in vivo. These in vitro oscillations are driven by an unusual form of burst firing that is present in a subset of thalamocortical neurons and are synchronized by gap junctions. We propose that mGluR1a-induced oscillations are a potential mechanism whereby the thalamus promotes EEG ? and ? rhythms in the intact brain

East Timor's pursuit of democratic independence

This thesis demonstrates how East Timor achieved statehood by linking independence with democracy. It argues that building a democracy was a consistent goal for some elements of East Timor’s independence movement throughout the transition to statehood. The independence movement committed a future East Timor state to establishing a liberal, multi-party, plural democracy with a particular emphasis on social justice and wealth re-distribution. This pursuit of the twin goals of independence and democracy enabled East Timor to become a sovereign state and this vision of statehood was important for how it instituted new political structures. The interplay between norms of self-determination and democracy is useful for understanding East Timor’s pursuit of sovereign independence. In contemporary International Relations, it has become increasingly recognised that there exists a democratic entitlement in which all people hold rights to internal self-determination and political participation. In essence, East Timor sought to attain the right of self-determination in order to achieve sovereign rights and establish a democracy. There were two key elements to their appeals for self-determination: first, that a unique and identifiable East Timorese ‘nation’ existed and held rights to self-determination under international law; and second, that an East Timorese state would establish a democracy and guarantee human rights. This commitment was important as individual rights to political participation have become international standards that all states are expected to uphold. International and domestic civil society organisations supported the East Timorese independence movement by pressuring governments,lobbying diplomats, holding protests, raising international awareness and providing information of the human rights situation and self-determination in East Timor. These international appeals for democracy, human rights and freedoms in East Timor ultimately led to the referendum on independence in 1999. The United Nations Transitional Administration in East Timor (UNTAET) was mandated to assist East Timor in establishing democracy following the referendum, and there has been considerable literature analysing and evaluating the roles of the UNTAET. However, there has been less attention on the roles of the East Timorese in constructing their political institutions and the relationship between the social and political realms during these processes. East Timorese leaders drafted the constitution, which established key political institutions such as electoral systems and the structure of government, and articulated the nature of citizenship rights and the relationship between the state and society. As such, East Timorese leaders played a considerable role in institutionally structuring the identity of their new state. East Timor’s Constitution outlined a vision of East Timor as a liberal, multi-party, social democracy that guarantees the civil, political and socio-economic rights of its people. The commitment to democracy and human rights demonstrated by political leaders prior and during East Timor’s transition is important for its capacities to consolidate its new political institutions and engender them with political legitimacy. A legitimate political order is one that is sanctioned by the population, thus a widespread, grassroots belief in the validity of democracy as a system of government has assisted East Timor in establishing and maintaining its democratic institutions