Background
Opening of KATP channels by systemic levcromakalim treatment triggers attacks in migraine patients and hypersensitivity to von Frey stimulation in a mouse model. Blocking of these channels ...is effective in several preclinical migraine models. It is unknown in what tissue and cell type KATP-induced migraine attacks are initiated and which KATP channel subtype is targeted.
Methods
In mouse models, we administered levcromakalim intracerebroventricularly, intraperitoneally and intraplantarily and compared the nociceptive responses by von Frey and hotplate tests. Mice with a conditional loss-of-function mutation in the smooth muscle KATP channel subunit Kir6.1 were given levcromakalim and GTN and examined with von Frey filaments. Arteries were tested for their ability to dilate ex vivo. mRNA expression, western blotting and immunohistochemical stainings were made to identify relevant target tissue for migraine induced by KATP channel opening.
Results
Systemic administration of levcromakalim induced hypersensitivity but central and local administration provided antinociception respectively no effect. The Kir6.1 smooth muscle knockout mouse was protected from both GTN and levcromakalim induced hypersensitivity, and their arteries had impaired dilatory response to the latter. mRNA and protein expression studies showed that trigeminal ganglia did not have significant KATP channel expression of any subtype, whereas brain arteries and dura mater primarily expressed the Kir6.1 + SUR2B subtype.
Conclusion
Hypersensitivity provoked by GTN and levcromakalim in mice is dependent on functional smooth muscle KATP channels of extracerebral origin. These results suggest a vascular contribution to hypersensitivity induced by migraine triggers.
The most recent genome-wide association study of migraine increased the total number of known migraine risk loci to 38. Still, most of the heritability of migraine remains unexplained, and it has ...been suggested that rare gene dysregulatory variants play an important role in migraine etiology. Addressing the missing heritability of migraine, we aim to fine-map signals from the known migraine risk loci to regulatory mechanisms and associate these to downstream genic targets. We analyzed a large cohort of whole-genome sequenced patients from extended migraine pedigrees (1040 individuals from 155 families). We test for association between rare variants segregating in regulatory regions with migraine. The findings were replicated in an independent case-control cohort (2027 migraineurs, 1650 controls). We report an increased burden of rare variants in one CpG island and three polycomb group response elements near four migraine risk loci. We found that the association is independent of the common risk variants in the loci. The regulatory regions are suggested to affect different genes than those originally tagged by the index SNPs of the migraine loci. Families with familial clustering of migraine have an increased burden of rare variants in regulatory regions near known migraine risk loci, with effects that are independent of the variants in the loci. The possible regulatory targets suggest different genes than those originally tagged by the index SNPs of the migraine loci.
Boar taint (BT) is an offensive odour or taste observed in pork from a proportion of non-castrated male pigs. Surgical castration is effective in avoiding BT, but animal welfare issues have created ...an incentive for alternatives such as genomic selection. In order to find candidate biomarkers, gene expression profiles were analysed from tissues of non-castrated pigs grouped by their genetic merit of BT. Differential expression analysis revealed substantial changes with log-transformed fold changes of liver and testis from -3.39 to 2.96 and -7.51 to 3.53, respectively. Co-expression network analysis revealed one module with a correlation of -0.27 in liver and three modules with correlations of 0.31, -0.44 and -0.49 in testis. Differential expression and co-expression analysis revealed candidate biomarkers with varying biological functions: phase I (COQ3, COX6C, CYP2J2, CYP2B6, ACOX2) and phase II metabolism (GSTO1, GSR, FMO3) of skatole and androstenone in liver to steroidgenesis (HSD17B7, HSD17B8, CYP27A1), regulation of steroidgenesis (STARD10, CYB5R3) and GnRH signalling (MAPK3, MAP2K2, MAP3K2) in testis. Overrepresented pathways included "Ribosome", "Protein export" and "Oxidative phosphorylation" in liver and "Steroid hormone biosynthesis" and "Gap junction" in testis. Future work should evaluate the biomarkers in large populations to ensure their usefulness in genomic selection programs.
Background and purpose
Understanding migraine in a sex‐specific manner is crucial for improving clinical care, diagnosis and therapy for both females and males. Here, data on sex differences are ...provided in the presentation of migraine in a large European‐based population cohort, which is representative of the general population.
Methods
A population‐based study of 62,672 Danish blood donors (both present and previous donors), of whom 12,658 had migraine, was performed. All participants completed a 105‐item diagnostic migraine questionnaire sent via an electronic mailing system (e‐Boks) between May 2020 and August 2020. The questionnaire allowed for correct diagnosis of migraine according to the International Classification of Headache Disorders, third edition.
Results
The migraine questionnaire was in‐cohort validated and had a positive predictive value of 97% for any migraine, a specificity of 93% and a sensitivity of 93%. There were 9184 females (mean age 45.1 years) and 3434 males (mean age 48.0 years). The 3‐month prevalence of migraine without aura was 11% in females and 3.59% in males. The 3‐month prevalence of migraine with aura was 1.72% in females and 1.58% in males. In females, the age‐related 3‐month prevalence of migraine without aura increased markedly during childbearing age. In males, migraine both with and without aura showed less age variation. Females had a higher frequency of migraine attacks (odds ratio OR 1.22) but a lower frequency of non‐migraine headaches (OR = 0.35). Females also had a greater intensity of pain, more unilateral and pulsatile pain, and exacerbation by physical activity (OR = 1.40–1.49) as well as more associated symptoms (OR = 1.26–1.98). Females carried 79% of the total migraine disease burden, which was almost exclusively driven by migraine without aura (77%), whilst there was no sex difference in the disease burden of migraine with aura.
Conclusion
Females have more severe disease, resulting in a much higher migraine disease burden than indicated by prevalence alone.
•Transcriptome profiling of secondary sensory neurons: the trigeminal nucleus caudalis and spinal cord dorsal horn.•Genes involved in neural signal transmission and several migraine-associated genes ...are highly expressed.•There is a distinct transcriptomic profile of the two homologous tissues with 3591 differentially expressed genes.•Contributes to the understanding why several signalling molecules cause headache and no pain in the rest of the body.
The pain sensation system is highly conserved among species, thus animal models have been used to investigate relevant tissues. The focus for head-specific pain has been on the primary nociceptive neurons in the trigeminal pathway, i.e. trigeminal ganglia. The secondary nociceptive neurons of the trigeminal pathway, trigeminal nucleus caudalis (TNC), have not been assessed. We expect different gene expression profiles compared to the homologous spinal cord dorsal horn (SDH), as several signalling substances provoke head-specific pain but not peripheral pain. We aim to provide expression profiles of TNC and SDH, tissues highly relevant for pain- and migraine-studies. We extracted RNA from laser capture microdissected laminae I-V from TNC and SDH from six Wistar rats for RNA-Sequencing. We showed the expression profiles of genes involved in neural signal transmission and found that among all G protein-coupled receptors Gabbr1 was highest expressed in both tissues. Among the migraine-associated genes we showed that Cacna1a, where non-synonyms mutations can cause familial hemiplegic migraine, was highly expressed with a slightly lower expression in TNC than in SDH. To show the genetic differences between the two homologous systems we performed a differential expression analysis, revealing 1696 genes higher and 1895 genes lower expressed genes in TNC than in SDH, of which many were neuronal-related. The high number of differentially expressed genes shows the large genetic difference between the trigeminal and spinothalamic system. Our results contribute to the characterization of nociceptive pathways, which may help us understanding why several signalling molecules cause headache and no peripheral pain.
There is a need for better recognition and more extensive research into menstrual migraine (MM) in the general population, and a revision of the diagnostic criteria for MM is warranted to move the ...field forward. Increased understanding of MM is crucial for improving clinical care, diagnosis, and therapy for MM.
To assess the clinical characteristics of MM, including severity and treatment response, and to propose new diagnostic criteria for pure MM and menstrually related migraine.
This is a case-control study of Danish individuals with migraine. All individuals completed a 105-item validated diagnostic migraine questionnaire, sent via the Danish electronic mailing system (e-Boks) between May and August 2020, allowing diagnosis of pure MM and menstrually related migraine by the International Classification of Headache Disorders, Third Edition (ICHD-3). Data analysis was performed from September 2021 to November 2022.
Diagnosis of migraine.
Clinical characteristics of women with MM and women with nonmenstrual migraine (non-MM) were compared using the ICHD-3 diagnostic criteria. A simulation of the risk of randomly misclassifying MM was based on number of migraine attacks during 3 menstrual cycles (3 × 28 days), and simulation analyses were performed using 100 000 permutations of random migraine attacks in migraine patients.
A total of 12 618 individuals, including 9184 women, with migraine participated in the study. Among the women with migraine, the prevalence of MM was 16.6% (1532 women), and the prevalence of non-MM was 45.9% (4216 women). The mean (SD) age was 38.7 (8.7) years for women with MM and 37.0 (9.2) years for women with non-MM. Of the 1532 women with MM, 410 (26.8%) fulfilled ICHD-3 diagnostic criteria for pure MM, 1037 (67.7%) fulfilled ICHD-3 diagnostic criteria for menstrually related migraine, and 152 (9.9%) fulfilled proposed diagnostic criteria for rare pure MM. MM was associated with a higher frequency of migraine-accompanying symptoms (odds ratio OR, 1.98; 95% CI, 1.71-2.29), more frequent (OR, 7.21; 95% CI, 5.77-9.03) and more severe (OR, 1.17; 95% CI, 1.13-1.21) migraine attacks, lower frequency of nonmigraine headache (OR, 0.31; 95% CI, 0.18-0.49), an overall greater response to treatment with triptans (OR, 1.66; 95% CI, 1.24-2.24), better improvement of migraine attacks during late pregnancy (OR, 5.10; 95% CI, 2.17-14.00), and faster reappearance of migraine attacks post partum (OR, 3.19; 95% CI, 2.40-4.25). Hormonal contraceptive-related MM was associated with a higher prevalence of migraine without aura than migraine related to spontaneous menstruation (OR, 1.82; 95% CI, 1.62-2.06). Otherwise, no differences between hormonal and spontaneous MM were observed. The risk of random diagnostic misclassification of ICHD-3 menstrually related migraine in women with high frequency episodic migraine was 43%. This risk was reduced to 3% when applying the proposed criteria for menstrually related migraine.
In this case-control study, MM in the general population had clinical characteristics that were quantitively different from those of non-MM. Detailed descriptive data and suggested improved diagnostic criteria for pure MM and menstrually related migraine were provided.
Background
It is unknown whether clinical parameters differ between migraineurs with and without first‐degree family members with migraine.
Objectives
The present cross‐sectional study describes ...differences between familial and sporadic migraine with a focus on migraine characteristics, migraine severity, comorbidities, and treatment.
Method
From the Danish Headache Center we recruited 358 patients with familial migraine and 1727 patients with sporadic migraine. Each participant was assessed using a validated semi‐structured interview.
Results
No differences in age (Mean = 44 and 44 SD = 12.28 and 12.58 for familial and sporadic migraineurs, respectively; P = .900) or sex (295/358 (82.4%) and 1413/1727 (81.8%) women in familial and sporadic migraineurs, respectively; P = .853) were found. Familial migraineurs had more aphasic aura than sporadic migraineurs (41% vs 27%, P = .001). Sporadic migraineurs had more lifetime attacks ie, >100 attacks (45% vs 70%, P < .001) and prolonged attacks ie, lasting >72 hours (5% vs 12%, P < .001) than familial migraineurs. Further, sporadic migraineurs had a higher incidence of concussions (37% vs 41%, P = .001) compared to familial migraineurs. In agreement with a previous study, there was no difference between familial and sporadic migraine regarding triptan response (84% vs 81%, P = .440).
Conclusion
Headache characteristics, triptan response, and comorbidities where similar in individulas with and without inherited migraine, suggesting that migraine are to be considered a hmogenoues disease. The difference in the clinical presentation of migraine with aura symptoms among patients with familial migraine should be considered in future studies. Further, more severe migraine among patients with sporadic migraine with aura could suggest that sporadic migraineurs have been exposed to stronger or multiple environmental factors and indicate that an early intervention in migraine treatment could lessen the severity of migraine.
Background
Migraine with cranial autonomic symptoms is well described in the literature, but its prevalence in previous studies varies enormously. A precise estimate of the prevalence in a ...population-based material is important because migraine with cranial autonomic symptoms might represent an endophenotype, in which genetic and pathophysiological features differ from those without cranial autonomic features. The aim of the present study, therefore, was to estimate the prevalence in a big population-based sample using both questionnaire-based diagnosis (N = 12,620) and interview-based diagnosis (N = 302). We validate questionnaire-based diagnosis of migraine with cranial autonomic symptoms and develop the first diagnostic criteria for future research of this possible endophenotype.
Methods
The Danish Blood Donor Study included 127,802 persons who all received a migraine diagnostic questionnaire. Participants who had answered the diagnostic questionnaire constituted the Danish Migraine Population Cohort (N = 62,677) of whom 12,620 had migraine. The diagnostic migraine questionnaire included questions about the following cranial autonomic symptoms: Facial/forehead sweating, lacrimation, ptosis, conjunctival injection, rhinorrhea, nasal congestion, and miosis. Validation was performed by a follow-up semi-structured, purpose-built interview of 302 participants with migraine, where detailed questions were asked to ascertain the validity of the symptoms.
Results
The questionnaire-based prevalences of one, respectively two cranial autonomic symptoms were 57% and 31%. The semi-structured interview-based prevalences of one, respectively two symptoms were 44% and 22%. The most common symptoms were facial/forehead sweating (39%) and lacrimation (24%). The specificity of the questionnaire was 80% and the sensitivity was 68%. Correlation analysis showed a weak correlation between symptoms ranging from 0.07 – 0.41, and no clear clustering of symptoms was detected. We suggest the first diagnostic appendix criteria for genetic and epidemiological studies and tighter criteria for clinical and pathophysiological studies. We encourage further studies of severity and consistency of symptoms.
Conclusion
Migraine with cranial autonomic symptoms is prevalent in the general population. Suggested diagnostic appendix criteria are important for future studies of this possible migraine endophenotype.
Background
Migraine mechanisms are
*These authors contributed equally to this work.
only partly known. Some studies have previously described genes differentially expressed between blood from ...migraineurs and controls. The objective of this study was to describe gene expression in subtypes of migraine outside of attack and in healthy controls.
Methods
We extensively phenotyped 17 migraine without aura and nine migraine with aura female patients, and 20 age-matched female controls. Cubital venous blood was RNA sequenced. Genes differentially expressed between migraineurs (migraine without aura and migraine with aura) and controls, and between migraine without aura and migraine with aura were identified using a case-control design. A co-expression network was constructed to investigate the difference between migraineurs and healthy controls at the network level.
Results
We found two differentially expressed genes: NMNAT2 and RETN. Both were differentially expressed between migraine with aura and controls, but they could not be replicated in an independent cohort. Co-expression network analysis resulted in one cluster of highly interconnected genes that was nominally significantly associated with migraine; however, no pathways or gene ontology terms were detected.
Conclusions
We showed no clear distinct difference in gene expression profiles of peripheral blood of migraineurs and controls and were not able to replicate findings from previous studies. A larger sample size may be needed to detect minor differences.
In livestock populations the genetic contribution to muscling is intensively monitored in the progeny of industry sires and used as a tool in selective breeding programs. The genes and pathways ...conferring this genetic merit are largely undefined. Genetic variation within a population has potential, amongst other mechanisms, to alter gene expression via cis- or trans-acting mechanisms in a manner that impacts the functional activities of specific pathways that contribute to muscling traits. By integrating sire-based genetic merit information for a muscling trait with progeny-based gene expression data we directly tested the hypothesis that there is genetic structure in the gene expression program in ovine skeletal muscle.
The genetic performance of six sires for a well defined muscling trait, longissimus lumborum muscle depth, was measured using extensive progeny testing and expressed as an Estimated Breeding Value by comparison with contemporary sires. Microarray gene expression data were obtained for longissimus lumborum samples taken from forty progeny of the six sires (4-8 progeny/sire). Initial unsupervised hierarchical clustering analysis revealed strong genetic architecture to the gene expression data, which also discriminated the sire-based Estimated Breeding Value for the trait. An integrated systems biology approach was then used to identify the major functional pathways contributing to the genetics of enhanced muscling by using both Estimated Breeding Value weighted gene co-expression network analysis and a differential gene co-expression network analysis. The modules of genes revealed by these analyses were enriched for a number of functional terms summarised as muscle sarcomere organisation and development, protein catabolism (proteosome), RNA processing, mitochondrial function and transcriptional regulation.
This study has revealed strong genetic structure in the gene expression program within ovine longissimus lumborum muscle. The balance between muscle protein synthesis, at the levels of both transcription and translation control, and protein catabolism mediated by regulated proteolysis is likely to be the primary determinant of the genetic merit for the muscling trait in this sheep population. There is also evidence that high genetic merit for muscling is associated with a fibre type shift toward fast glycolytic fibres. This study provides insight into mechanisms, presumably subject to strong artificial selection, that underpin enhanced muscling in sheep populations.
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