Potential Role of Aromatase over Estrogen Receptor Gene Polymorphisms in Migraine Susceptibility: A Case Control Study from North India

BACKGROUND: The present study was undertaken to find out the role of estrogen pathway related gene polymorphisms in susceptibility to migraine in Northern Indian population. Aromatase, CYP19A1 (rs10046 and rs4646); estrogen receptors, ESR1 (rs2234693, rs1801132, rs2228480 and rs9340799) and ESR2 (rs1271572 and rs1256049) polymorphisms were selected for the present study. METHODOLOGY/PRINCIPAL FINDINGS: The patients were recruited in two cohorts - primary (207) and replicative (127) along with 200 healthy controls and genotyped for various polymorphisms. Logistic regression analysis was applied for statistical analyses. The results were validated in the replicative cohort and pooled by meta analysis using Fisher's and Mantel-Haenszel test. Furthermore, Benjamini - Hochberg false discovery rate test was used to correct for multiple comparisons. CYP19A1 rs10046 and CYP19A1 rs4646 polymorphisms were found to confer risk and protective effect, respectively. Out of four ESR1 polymorphisms, only rs2234693 variant allele was significantly associated in migraine with aura. No significant associations were observed for ESR2 polymorphisms. Significant haplotypes were identified for CYP19A1 and ESR1 polymorphisms. Gene- gene interactions of genotypes as well as haplotypes were observed for CYP19A1- ESR1 showing both risk and protective combinations. CONCLUSION: We strongly suggest CYP19A1 polymorphisms to be the major contributing factors in migraine susceptibility instead of genetic variants of estrogen receptors

Clinical and radiographic spectrum of pathologically confirmed tumefactive multiple sclerosis

Atypical imaging features of multiple sclerosis lesions include size >2 cm, mass effect, oedema and/or ring enhancement. This constellation is often referred to as ‘tumefactive multiple sclerosis’. Previous series emphasize their unifocal and clinically isolated nature, however, evolution of these lesions is not well defined. Biopsy may be required for diagnosis. We describe clinical and radiographic features in 168 patients with biopsy confirmed CNS inflammatory demyelinating disease (IDD). Lesions were analysed on pre- and post-biopsy magnetic resonance imaging (MRI) for location, size, mass effect/oedema, enhancement, multifocality and fulfilment of Barkhof criteria. Clinical data were correlated to MRI. Female to male ratio was 1.2 : 1, median age at onset, 37 years, duration between symptom onset and biopsy, 7.1 weeks and total disease duration, 3.9 years. Clinical course prior to biopsy was a first neurological event in 61%, relapsing–remitting in 29% and progressive in 4%. Presentations were typically polysymptomatic, with motor, cognitive and sensory symptoms predominating. Aphasia, agnosia, seizures and visual field defects were observed. At follow-up, 70% developed definite multiple sclerosis, and 14% had an isolated demyelinating syndrome. Median time to second attack was 4.8 years, and median EDSS at follow-up was 3.0. Multiple lesions were present in 70% on pre-biopsy MRI, and in 83% by last MRI, with Barkhof criteria fulfilled in 46% prior to biopsy and 55% by follow-up. Only 17% of cases remained unifocal. Median largest lesion size on T2-weighted images was 4 cm (range 0.5–12), with a discernible size of 2.1 cm (range 0.5–7.5). Biopsied lesions demonstrated mass effect in 45% and oedema in 77%. A strong association was found between lesion size, and presence of mass effect and/or oedema (P < 0.001). Ring enhancement was frequent. Most tumefactive features did not correlate with gender, course or diagnosis. Although lesion size >5 cm was associated with a slightly higher EDSS at last follow-up, long-term prognosis in patients with disease duration >10 years was better (EDSS 1.5) compared with a population-based multiple sclerosis cohort matched for disease duration (EDSS 3.5; P < 0.001). Given the retrospective nature of the study, the precise reason for biopsy could not always be determined. This study underscores the diagnostically challenging nature of CNS IDDs that present with atypical clinical or radiographic features. Most have multifocal disease at onset, and develop RRMS by follow-up. Although increased awareness of this broad spectrum may obviate need for biopsy in many circumstances, an important role for diagnostic brain biopsy may be required in some cases

Secondary headaches: secondary or still primary?

The second edition of the International Classification of Headache Disorders makes a distinction between primary and secondary headaches. The diagnosis of a secondary headache is made if the underlying disease is thought to cause headache or if a close temporal relationship is present together with the occurrence of the headache. At first glance, this may allow clearly secondary headaches to be distinguished from primary headaches. However, by reviewing the available literature concerning several selected secondary headaches, we will discuss the hypothesis that some secondary headaches can also be understood as a variation of primary headaches in the sense that the underlying cause (e.g. infusion of glyceryl trinitrate [ICHD-II 8.1.1], epilepsy [7.6.2], brain tumours [7.4], craniotomy [5.7], etc.) triggers the same neurophysiologic mechanisms that are responsible for the pain in primary headache attacks

Large-Scale Mass Spectrometry Imaging Investigation of Consequences of Cortical Spreading Depression in a Transgenic Mouse Model of Migraine

Cortical spreading depression (CSD) is the electrophysiological correlate of migraine aura. Transgenic mice carrying the R192Q missense mutation in the Cacna1a gene, which in patients causes familial hemiplegic migraine type 1 (FHM1), exhibit increased propensity to CSD. Herein, mass spectrometry imaging (MSI) was applied for the first time to an animal cohort of transgenic and wild type mice to study the biomolecular changes following CSD in the brain. Ninety-six coronal brain sections from 32 mice were analyzed by MALDI-MSI. All MSI datasets were registered to the Allen Brain Atlas reference atlas of the mouse brain so that the molecular signatures of distinct brain regions could be compared. A number of metabolites and peptides showed substantial changes in the brain associated with CSD. Among those, different mass spectral features showed significant (t-test, P < 0.05) changes in the cortex, 146 and 377 Da, and in the thalamus, 1820 and 1834 Da, of the CSD-affected hemisphere of FHM1 R192Q mice. Our findings reveal CSD- and genotype-specific molecular changes in the brain of FHM1 transgenic mice that may further our understanding about the role of CSD in migraine pathophysiology. The results also demonstrate the utility of aligning MSI datasets to a common reference atlas for large-scale MSI investigations. [Figure: see text] ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s13361-015-1136-8) contains supplementary material, which is available to authorized users

Virus genomes reveal factors that spread and sustained the Ebola epidemic.

The 2013-2016 West African epidemic caused by the Ebola virus was of unprecedented magnitude, duration and impact. Here we reconstruct the dispersal, proliferation and decline of Ebola virus throughout the region by analysing 1,610 Ebola virus genomes, which represent over 5% of the known cases. We test the association of geography, climate and demography with viral movement among administrative regions, inferring a classic 'gravity' model, with intense dispersal between larger and closer populations. Despite attenuation of international dispersal after border closures, cross-border transmission had already sown the seeds for an international epidemic, rendering these measures ineffective at curbing the epidemic. We address why the epidemic did not spread into neighbouring countries, showing that these countries were susceptible to substantial outbreaks but at lower risk of introductions. Finally, we reveal that this large epidemic was a heterogeneous and spatially dissociated collection of transmission clusters of varying size, duration and connectivity. These insights will help to inform interventions in future epidemics

Function of MAPK and downstream transcription factors in monomer-induced apoptosis.

The resin monomer triethylene glycol dimethacrylate (TEGDMA) disrupts vital cell functions, and the production of oxidative stress is considered a common underlying mechanism. The precise signaling pathways, however, that initiate monomer-induced effects, which disturb responses of the innate immune system, inhibit dentin mineralization processes, or induce apoptosis in target cells in vitro are still unknown. The present study provides insight into the causal relationship between TEGDMA-induced apoptosis and the activation of MAPK and transcription factors downstream using pharmacological inhibitors of the ERK1/2, p38 and JNK pathways. The endotoxin lipopolysaccharide (LPS; 0.1 μg/ml) was included as an inducer of MAPK activity in RAW264.7 mouse macrophages. Cell viability was decreased from 95\% in untreated cultures to about 43\% after a 24 h exposure to 3 mM TEGDMA. Inhibition of the ERK1/2 pathway by the MEK1/2 inhibitor PD98059 reduced cell viability to 84\%. While apoptosis induced by TEGDMA remained unchanged, Western blot analyses revealed that the activation of ERK1/2 in the presence of TEGDMA was inhibited by PD98059. LPS-induced expression of activated transcription factors c-Jun, ATF-2, ATF-3 and phospho-Elk1 was decreased in cells co-treated with TEGDMA. This inhibition was more intense in the presence of PD98059, indicating that the MEK/ERK pathway is involved in the inhibition of the LPS-induced activation of transcription factors by TEGDMA. No clear effects of the p38 inhibitor SB203580 and the JNK inhibitor SP600125 on TEGDMA-induced apoptosis were detected. The antioxidant N-acetylcysteine (NAC) protected cells from TEGDMA-induced cell death, and inhibited the activation of ERK1/2, p38 and JNK by TEGDMA. Moreover, the TEGDMA-induced downregulation of the expression of the transcription factors c-Jun and ATF-2 was prevented as well. In conclusion, physiologically relevant concentrations of inhibitors differentially modified the expression of MAPK and transcription factors in cell cultures exposed to LPS and the monomer TEGDMA. The absence of a drastic effect of the MAPK pathway inhibitors on TEGDMA-induced apoptosis on the one hand, and the protective effect of NAC and PD98059 in particular on TEGDMA-induced MAPK activation and apoptosis on the other hand, leads to a new model for the role of MAPK in the regulation of cell homeostasis in monomer-exposed cells and tissues