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Current antimigraine drugs are believed, besides their direct vasoconstrictive effect, to inhibit calcitonin gene-related peptide (CGRP) release from trigeminal nerve endings during migraine. Objective The objective of this report is to establish a biomarker for the CGRP-interfering effect of antimigraine drugs. Methods We quantified the effect of sumatriptan on the trigeminal nerve-mediated rise in forehead dermal blood flow (DBF), induced by capsaicin application (0.6 mg/ml) and electrical stimulation (0.2-1.0 mA), in a randomised, double-blind, placebo-controlled, crossover study in healthy male ( n = 11, age ± SD: 29 ± 8 years) and female ( n = 11, 32 ± 7 years) individuals. Results DBF responses to capsaicin were attenuated by sumatriptan (ΔDBF, mean ± SEM: 82 ± 18 AU, p = 0.0002), but not by placebo (ΔDBF: 21 ± 12 AU, p = 0.1026). Conclusion We demonstrated that sumatriptan inhibits increases in DBF, induced by the release of, most likely, CGRP. Thus, our model may be used as a biomarker to establish the trigeminovascular effects of (potential) antimigraine drugs, such as CGRP receptor antagonists or antibodies directed against CGRP or its receptor. [ABSTRACT FROM AUTHOR]

Biochar is a soil amendment that can change soil's physical and hydraulic properties. However, biochar application is far from being a 'one size fits-all' approach. The impact of the management practices is dependent on biochar type (feedstock and production conditions), application depth and method, climate and site characteristics. Hence, this study aims to enrich the available inconclusive information on how biochar could affect clay loamy soil and to assess the potential impact of the induced change on water stress mitigation of rain-fed durum wheat under the specific condition of the semi-arid environment of North West of Tunisia. A field experiment was investigated in which three biochar rates 0 (B0), 10 (equivalent to 0.5% of weight) (B1) and 20 t/ha (equivalent to 1% of weight), (B2), were tested. Other laboratory analysis allowed the evaluation of soil water retention curve (SWRC), saturated hydraulic conductivity (Ks), dry density (ρ b ) and biostress biomarkers such as glutathione-S-transferase (GST), catalase activities (CAT) and malondialdehyde content (MDA) as well as yield attributes. Results showed that treatment B2 significantly decreased ρ b and Ks with relative change values of about -3.1% and -19%. Consequently, SWRC showed a better water retention capacity, mostly from saturation to matric potential value (h) of 33 kPa. Total (TAWC), plant (PAWC) and readily (RAWC) available water contents, significantly increased under B2 with relative changes of +6%, +44% and +44% respectively. Moreover, GST and CAT were also boosted under B2. Consequently, biological and grain yields as well as grain water use efficiency (GWUE) significantly increased. GWUE increased from 0.81 ± 0.04 in B0 to 1.09 ± 0.01 kg/m 3 in B2. The correlation analysis showed a significant and positive correlation, between GWUE and soil water parameters (θs, θfc and θmre) suggesting the indirect effect of biochar on water-use efficiency for grain yield of wheat. Therefore, among the tested rates 20 t/ha could be suggested to improve plant soil water availability and reduce the harmful impact of drought stress on rain-fed durum wheat., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Anomaly detection is one of the biggest issues of security in the Industrial Internet of Things (IIoT) due to the increase in cyber attack dangers for distributed devices and critical infrastructure networks. To face these challenges, the Intrusion Detection System (IDS) is suggested as a robust mechanism to protect and monitor malicious activities in IIoT networks. In this work, we suggest a new mechanism to improve the efficiency and robustness of the IDS system using Distributional Reinforcement Learning (DRL) and the Generative Adversarial Network (GAN). We aim to develop realistic and equilibrated distribution for a given feature set using artificial data in order to overcome the issue of data imbalance. We show how the GAN can efficiently assist the distributional RL-based-IDS in enhancing the detection of minority attacks. To assess the taxonomy of our approach, we verified the effectiveness of our algorithm by using the Distributed Smart Space Orchestration System (DS2OS) dataset. The performance of the normal DRL and DRL-GAN models in binary and multiclass classifications was evaluated based on anomaly detection datasets. The proposed models outperformed the normal DRL in the standard metrics of accuracy, precision, recall, and F1 score. We demonstrated that the GAN introduced in the training process of DRL with the aim of improving the detection of a specific class of data achieves the best results.

Background and Objectives: Migraine has consistently been associated with an increased risk of cardiovascular disease (CVD) events. It remains, however, unclear to what extent cardiovascular risk profiles might be linked with migraine activity status and how these profiles relate to the development of migraine., Methods: We used data from a cohort study of female health professionals (Women's Health Study, n = 27,539, age ≥45 years at baseline) without a history of CVD or other major diseases and who provided a blood sample at baseline. Framingham risk scores (FRSs) estimating the 10-year risk of coronary heart disease calculated at baseline were used to create vascular risk categories. The presence or development of self-reported migraine was assessed by questionnaires. Women were classified as having no migraine, history of migraine (experienced migraine in the past but did not experience any migraine attacks in the year before enrollment), active migraine at baseline (active), or incident migraine (first report of migraine during follow-up but not at baseline). We used multinomial logistic regression models to calculate ORs for the association between FRS categories and migraine status., Results: Of the 27,539 participants, a total of 21,927 women did not report migraine, 1,500 women reported a history of migraine, 3,579 had migraine at baseline, and 533 reported migraine for the first time during follow-up. The odds of the probability of having a history of migraine at baseline (vs never migraine) was 76% higher among those with FRS ≥10% compared with FRS ≤1% after adjustment (OR = 1.76, 95% CI 1.39-2.23). In contrast, having FRS ≥10% was associated with reduced odds of having active migraine at baseline (OR = 0.64, 95% CI 0.52-0.80) and with newly reported migraine during follow-up (OR = 0.42, 95% CI 0.22-0.81) when compared with women with FRS category ≤1% and those not reporting migraine. A similar association pattern was observed for FRS categories 5%-9% and 2%-4%., Discussion: High FRS categories were only observed among women with a history of migraine but not with active migraine at baseline or incident migraine after baseline. Our results suggest that the life course of migraine should be considered when studying associations with the vascular system. Our data further suggest that a relatively healthy vascular system, as assessed by the FRS, is associated with active migraine status or developing migraine in the future., (© 2022 American Academy of Neurology.)

Objective: Assess whether propranolol modulates the trigeminovascular system in both men and women., Methods: We investigated the effect of propranolol (80 mg, 90 min after oral administration, corresponding to T max ) on the increase in dermal blood flow of the forehead skin (innervated by the trigeminal nerve) by capsaicin application (0.6 mg/mL) and electrical stimulation (0.2-1.0 mA) before and after placebo (grapefruit juice) or propranolol (oral solution diluted in grapefruit juice) in a randomized, double-blind, placebo-controlled cross-over study, including healthy males (n = 10) and females on contraceptives (n = 11). Additionally, we compared our results with data from the Dutch IADB.nl prescription database by analyzing the change in triptan use after propranolol prescription in a population similar to our dermal blood flow study subjects (males and females, 20-39 years old)., Results: Dermal blood flow responses to capsaicin were significantly attenuated after propranolol, but not after placebo. When stratifying by sex, no significant changes in the capsaicin-induced dermal blood flow were observed in females after propranolol, whereas they remained significant in males. Dermal blood flow responses to electrical stimulation were not modified in any case. In our prescription database study, after propranolol, a more pronounced decrease in triptan use was observed in male patients than in female patients., Interpretation: Propranolol (80 mg) inhibits capsaicin-induced increases in dermal blood flow in a sex-dependent manner. In patients, a more pronounced decrease in triptan use is observed in males when compared with females, suggesting an interaction between propranolol and sex steroids in the modulation of the trigeminovascular system., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Cyclic hormonal fluctuations influence migraine incidence and severity. Previously, we described reduced menstrual cyclicity in estradiol levels and dermal blood flow reaction to capsaicin in female migraineurs. It is unclear whether pain perception in women with migraine is influenced by the menstrual cycle., Methods: Women with menstrually-related migraine (n = 14), healthy age-matched controls (n = 10) and postmenopausal women (n = 15) were asked to grade trigeminal and non-trigeminal painful stimuli on a numeric pain rating scale on menstrual cycle day 19-21 (mid-luteal) and day 1-2 (early follicular)., Results: In women with menstrually-related migraine, trigeminal pain remained low throughout the cycle. Controls showed increased trigeminal pain during the mid-luteal phase compared to the early follicular phase. Changes throughout the cycle were significantly different between women with MRM and controls., Conclusion: The compromised menstrual cyclicity of pain perception in women with menstrually-related migraine parallels our earlier findings on estradiol levels and dermal blood flow.

Background and Purpose- Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is an autosomal dominant small vessel disease caused by C-terminal frameshift mutations in the TREX1 gene that encodes the major mammalian 3' to 5' DNA exonuclease. RVCL-S is characterized by vasculopathy, especially in densely vascularized organs, progressive retinopathy, cerebral microvascular disease, white matter lesions, and migraine, but the underlying mechanisms are unknown. Methods- Homozygous transgenic RVCL-S knock-in mice expressing a truncated Trex1 (three prime repair exonuclease 1) protein (similar to what is seen in patients) and wild-type littermates, of various age groups, were subjected to (1) a survival analysis, (2) in vivo postocclusive reactive hyperemia and ex vivo Mulvany myograph studies to characterize the microvascular and macrovascular reactivity, and (3) experimental stroke after transient middle cerebral artery occlusion with neurological deficit assessment. Results- The mutant mice show increased mortality starting at midlife ( P =0.03 with hazard ratio, 3.14 [95% CI, 1.05-9.39]). The mutants also show a vascular phenotype as evidenced by attenuated postocclusive reactive hyperemia responses (across all age groups; F[1, 65]=5.7, P =0.02) and lower acetylcholine-induced relaxations in aortae (in 20- to 24-month-old mice; RVCL-S knock-in: E max : 37±8% versus WT: E max : 65±6%, P =0.01). A vascular phenotype is also suggested by the increased infarct volume seen in 12- to 14-month-old mutant mice at 24 hours after infarct onset (RVCL-S knock-in: 75.4±2.7 mm 3 versus WT: 52.9±5.6 mm 3 , P =0.01). Conclusions- Homozygous RVCL-S knock-in mice show increased mortality, signs of abnormal vascular function, and increased sensitivity to experimental stroke and can be instrumental to investigate the pathology seen in patients with RVCL-S.

Flow-mediated dilatation (FMD) is an established, but investigator-demanding method, used to non-invasively determine nitric oxide (NO)-dependent endothelial function in humans. Local thermal hyperemia (LTH) or post-occlusive reactive hyperemia (PORH) of the skin measured with a laser Doppler flow imager may be a less demanding alternative of FMD. We investigated the reproducibility of the different measures of vascular function, their interrelationship and the NO-dependency of LTH. Measurements were performed twice in 27 healthy men (8 smokers), one week apart. Local application of NG-monomethyl-l-arginine (L-NMMA) by means of iontophoresis was used to determine the NO-dependency of LTH. Using L-NMMA, the peak and plateau responses of LTH were reduced by 31% (p < .001) and 65% (<0.001), respectively. For all measurements the coefficient of variation (CV) was higher in smokers than in non-smokers. For non-smokers the CV of FMD was 12%, of LTH peak response 17%, of LTH plateau response 12%, of PORH peak response 14% and of PORH area under the curve response 11%. FMD correlated weakly with the PORH peak and area under the curve response (r = 0.39 and 0.43, p < .05), whereas the LTH-plateau response correlated with the PORH peak response (r = 0.68, p < .01) in non-smokers, but FMD and LTH peak or plateau responses were unrelated. In conclusion, the LTH plateau response is for two-third NO-dependent, but unrelated to FMD. Furthermore, despite easy to perform the LTH responses are not more reproducible than FMD. Given the weak associations, the different methods of vascular function assessment are not interchangeable., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background Migraine is much more common in females than in males, and occurrence is associated with changes in female sex hormones. Calcitonin gene-related peptide (CGRP) plays a key role in migraine, and variations in female sex hormones may affect CGRP sensitivity and/or production. Objectives Investigate repeatability, gender differences, influence of the menstrual cycle and of migraine on CGRP-dependent changes in dermal blood flow (DBF). Methods CGRP-dependent increases in DBF were assessed using laser Doppler perfusion imaging after topical application of 300 or 1000 µg capsaicin on the forearm of healthy subjects and migraine patients. Results In healthy males, DBF response did not vary over time and was comparable with DBF in male migraineurs. In healthy females, capsaicin-induced DBF responses to both doses of capsaicin were higher during menstruation compared to the late-secretory phase (p < 0.05); this menstrual cycle dependence was absent in female migraine patients. Compared to healthy subjects, female migraineurs displayed a higher DBF response both during menstruation and during the late-secretory phase (p < 0.05). Conclusions An increased capsaicin-induced, CGRP-mediated DBF response was observed during menstruation in healthy women, but in female migraine patients this increased response was not affected by the menstrual cycle.

Migraine is responsible for high rates of disability. In addition, it is associated with an increased risk of cardiovascular disease. This association is not limited to the brain in the form of stroke, but includes cardiac ischemia. The increased risk is most consistently described in the female population and in particular for migraine with aura. This article reviews the current knowledge on migraine and the associated risk of cardiovascular disease, with a focus on female-specific factors., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Angiotensin-induced vasodilation, involving type 2 receptor (AT2R)-induced generation of nitric oxide (NO; by endothelial NO synthase) and endothelium-derived hyperpolarizing factors, may be limited to women. To distinguish the contribution of female sex hormones and chromosomes to AT2R function and endothelium-derived hyperpolarizing factor-mediated vasodilation, we made use of the four-core genotype model, where the testis-determining Sry gene has been deleted (Y(-)) from the Y chromosome, allowing XY(-) mice to develop a female gonadal phenotype. Simultaneously, by incorporating the Sry gene onto an autosome, XY(-)Sry and XXSry transgenic mice develop into gonadal male mice. Four-core genotype mice underwent a sham or gonadectomy (GDX) operation, and after 8 weeks, iliac arteries were collected to assess vascular function. XY(-)Sry male mice responded more strongly to angiotensin than XX female mice, and the AT2R antagonist PD123319 revealed that this was because of a dilator AT2R-mediated effect occurring exclusively in XX female mice. The latter could not be demonstrated in XXSry male and XY(-) female mice nor in XX female mice after GDX, suggesting that it depends on both sex hormones and chromosomes. Indeed, treating C57bl/6 GDX male mice with estrogen could not restore angiotensin-mediated, AT2R-dependent relaxation. To block acetylcholine-induced relaxation of iliac arteries obtained from four-core genotype XX mice, both endothelial NO synthase and endothelium-derived hyperpolarizing factor inhibition were required, whereas in four-core genotype XY animals, endothelial NO synthase inhibition alone was sufficient. These findings were independent of gonadal sex and unaltered after GDX. In conclusion, AT2R-induced relaxation requires both estrogen and the XX chromosome sex complement, whereas only the latter is required for endothelium-derived hyperpolarizing factors., (© 2015 American Heart Association, Inc.)

Objective: A case-control study to investigate the effect of the menstrual cycle on trigeminal nerve-induced vasodilation in healthy women and patients with menstrually related migraine (MRM)., Methods: Using a laser-Doppler imager, we compared the vasodilator effects of capsaicin application and electrical stimulation (ES) on the forehead skin, a trigeminal nerve-innervated dermatome, in premenopausal patients with MRM (n = 22), healthy controls (n = 20), and postmenopausal women without migraine (n = 22). Blood samples were collected for female sex hormone measurements., Results: Dermal blood flow (DBF) responses to capsaicin were higher in controls during days 1-2 than during days 19-21 of their menstruation cycle (mean Emax ± SEM: 203 ± 28 AU vs 156 ± 27 AU [p = 0.031] for 0.06 mg/mL capsaicin and 497 ± 25 AU vs 456 ± 24 AU [p = 0.009] for 6.0 mg/mL capsaicin). In contrast, patients with MRM demonstrated DBF responses without significant cycle-dependent variability (days 1-2 vs days 19-21: Emax 148 ± 20 AU vs 154 ± 20 AU [p = 0.788] for 0.06 mg/mL capsaicin and 470 ± 17 AU vs 465 ± 20 AU [p = 0.679] for 6.0 mg/mL capsaicin). DBF responses to ES were not different between either patients with MRM or controls, at either occasion. Estradiol levels on days 19-21 of the menstrual cycle were higher in healthy controls (mean ± SEM: 75 ± 8 pg/mL) than in patients with MRM (52 ± 4 pg/mL, p = 0.014). In postmenopausal women, DBF responses to capsaicin and ES, as well as estradiol levels at both visits, were all significantly reduced compared to patients with MRM and controls (in all cases, p < 0.05)., Conclusions: Our study provides evidence for a reduced menstrual cyclicity of both estradiol levels and the trigeminovascular vasodilator system in patients with MRM., (© 2014 American Academy of Neurology.)

Perimenopause and migraine are closely linked. The hormonal instability during the perimenopausal period not only causes vasomotor symptoms and mood disturbances, but also increases migraine incidence. Women do report new onset migraine during this period, but the increased incidence is reported by women with menstrually related migraine (MRM). The hormonal fluctuations can be stabilized with hormone replacement therapy (HRT), while simultaneously improving the migraine in some patients. The increased stroke risk in women with migraine with aura (MA) should be taken into consideration when intending to treat perimenopausal women with migraine with HRT., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Calcitonin gene-related peptide (CGRP) exerts a key function in migraine pathophysiology through the trigeminovascular system. Influencing this system via CGRP receptor antagonists seems to be an important new option in treating migraine attacks. To characterize new compounds, models are used to study the vascular effects as well as their effects on the central nervous system., Areas Covered: The authors review the clinical trials and many different in vitro and in vivo experimental models that have been used to investigate the effects and side effects in animals, healthy subjects and patients. These experimental models are essential, not only in characterizing new CGRP receptor antagonists, but also in gaining more insight into the pathophysiological mechanisms behind migraines., Expert Opinion: Although triptans were a major breakthrough in migraine treatment, they are not effective for every patient and contraindicated in patients with cardiovascular disease. There is still a demand for other acute antimigraine acting drugs with CGRP receptor antagonists being the most promising candidates. CGRP plays a role in protection against ischemia, but CGRP receptor antagonists do not seem to affect this protection to a harmfull extent, when used incidentally as acute antimigraine treatment. In order for drug specificity to be increased, the site of action needs to be identified; this consequently may lead to a decrease in dosing with fewer side effects.