Hypersensitivity to PACAP-38 in post-traumatic headache: a randomized clinical trial.

Pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38), known for its role in migraine pathogenesis, has been identified as a novel drug target. Given the clinical parallels between post-traumatic headache (PTH) and migraine, we explored the possible role of PACAP-38 in the pathogenesis of PTH. To this end, we conducted a randomized, double-blind, placebo-controlled, two-way crossover trial involving adult participants diagnosed with persistent PTH resulting from mild traumatic brain injury. Participants were randomly assigned to receive a 20-min continuous intravenous infusion of either PACAP-38 (10 pmol/kg/min) or placebo (isotonic saline) on two separate experimental days, with a 1-week washout period in between. The primary outcome was the difference in incidence of migraine-like headache between PACAP-38 and placebo during a 12-h observational period post-infusion. The secondary outcome was the difference in the area under the curve (AUC) for baseline-corrected median headache intensity scores during the same 12-h observational period. Of 49 individuals assessed for eligibility, 21 were enrolled and completed the trial. The participants had a mean age of 35.2 years, and 16 (76%) were female. Most [19 of 21 (90%)] had a migraine-like phenotype. During the 12-h observational period, 20 of 21 (95%) participants developed migraine-like headache after intravenous infusion of PACAP-38, compared with two (10%) participants after placebo (P < 0.001). Furthermore, the baseline-corrected AUC values for median headache intensity scores during the 12-h observational period was higher after PACAP-38 than placebo (P < 0.001). These compelling results demonstrate that PACAP-38 is potent inducer of migraine-like headache in people with persistent PTH. Thus, targeting PACAP-38 signalling might be a promising avenue for the treatment of PTH.

Non-vascular ATP-sensitive potassium channel activation does not trigger migraine attacks: A randomized clinical trial.

OBJECTIVE: To investigate the role of NN414, a selective KATP channel opener for the Kir6.2/SUR1 channel subtype found in neurons and ß-pancreatic cells, in inducing migraine attacks in individuals with migraine without aura. METHODS: Thirteen participants were randomly allocated to receive NN414 and placebo on two days separated by at least one week. The primary endpoint was the difference in the incidence of migraine attacks after NN414 compared with placebo. The secondary endpoints were the difference in the area under the curve for headache intensity scores, middle cerebral artery blood flow velocity (VMCA), superficial temporal artery diameter, heart rate and mean arterial pressure. RESULTS: Twelve participants completed the study, with two (16.6%) reporting migraine attacks after NN414 compared to one (8.3%) after placebo (p = 0.53). The area under the curve for headache intensity, VMCA, superficial temporal artery diameter, heart rate and mean arterial pressure did not differ between NN414 and placebo (p > 0.05, all comparisons). CONCLUSION: The lack of migraine induction upon activation of the Kir6.2/SUR1 channel subtype suggests it may not contribute to migraine pathogenesis. Our findings point to KATP channel blockers that target the Kir6.1/SUR2B subtype, found in cerebral vasculature, as potential candidates for innovative antimigraine treatments.Registration number: NCT04744129.

Premonitory symptoms in migraine: A REFORM Study.

BACKGROUND: Estimates of proportions of people with migraine who report premonitory symptoms vary greatly among previous studies. Our aims were to establish the proportion of patients reporting premonitory symptoms and its dependency on the enquiry method. Additionally, we investigated the impact of premonitory symptoms on disease burden using Headache Impact Test (HIT-6), Migraine Disability Assessment (MIDAS) and World Health Organization Disability Assessment 2.0 (WHODAS 2.0), whilst investigating how various clinical factors influenced the likelihood of reporting premonitory symptoms. METHODS: In a cross-sectional study, premonitory symptoms were assessed among 632 patients with migraine. Unprompted enquiry was used first, followed by a list of 17 items (prompted). Additionally, we obtained clinical characteristics through a semi-structured interview. RESULTS: Prompted enquiry resulted in a greater proportion reporting premonitory symptoms than unprompted (69.9% vs. 43.0%; p < 0.001) and with higher symptom counts (medians 2, interquartile range = 0-6 vs. 1, interquartile range = 0-1; p < 0.001). The number of symptoms correlated weakly with HIT-6 (ρ = 0.14; p < 0.001) and WHODAS scores (ρ = 0.09; p = 0.041). Reporting postdromal symptoms or triggers increased the probability of reporting premonitory symptoms, whereas monthly migraine days decreased it. CONCLUSIONS: The use of a standardized and optimized method for assessing premonitory symptoms is necessary to estimate their prevalence and to understand whether and how they contribute to disease burden.

Activation of ATP-sensitive potassium channels triggers migraine attacks independent of calcitonin gene-related peptide receptors: a randomized placebo-controlled trial.

BACKGROUND: The present study aimed to investigate whether levcromakalim, a KATP channel opener, induces migraine attacks in people with migraine pre-treated with erenumab, a monoclonal CGRP receptor antibody. METHODS: In this double-blind, placebo-controlled, two-way cross-over study, adults with migraine without aura received a subcutaneous injection of 140 mg of erenumab on day 1. Subsequently, they were randomized to receive a 20-minute infusion of 0.05 mg/ml levcromakalim or placebo on two experimental days separated by at least one week (between days 8 and 21). The primary endpoint was the difference in the incidence of migraine attacks between levcromakalim and placebo during the 12-hour post-infusion period. RESULTS: In total, 16 participants completed the study. During the 12-hour observation period, 14 (88%) of 16 participants experienced migraine attacks after levcromakalim, compared to two (12%) after placebo (p < 0.001). The area under the curve for median headache intensity was greater after levcromakalim than placebo (p < 0.001). Levcromakalim elicited dilation of the superficial temporal artery during the first hour after infusion, a response absent following placebo (p < 0.001). CONCLUSIONS: The induction of migraine attacks via opening of KATP channels appears independent of CGRP receptor activation.Trial Registration: ClinicalTrials.gov, Identifier NCT05889442.

No wearing-off effect of erenumab or fremanezumab for chronic migraine prevention: a single-center, real-world, observational study.

BACKGROUND: The present study investigates the wearing-off effect in adults with chronic migraine treated with erenumab or fremanezumab. METHODS: This real-world observational study was based on pre-collected headache diaries from chronic migraine patients in treatment with either monthly injections of 140 mg of erenumab or 225 mg of fremanezumab. Consistent wearing-off was defined as an increase of ≥2 weekly migraine days in the last week compared to the second week over two consecutive 4-week treatment periods. The primary endpoint was wearing-off in the total population. The secondary endpoints were difference in wearing-off in (i) a subgroup of patients treated with erenumab and fremanezumab and (ii) consistent wearing-off in patients with a ≥30% reduction in monthly migraine days, compared to baseline, in the two consecutive treatment months. RESULTS: In total, 100 patients (erenumab: n = 60, fremanezumab: n = 40) were included. Sixty-two out of 100 (62%) patients had consistent ≥30% treatment response on antibody therapy in both months (erenumab: n = 36, fremanezumab: n = 26). There was no consistent wearing-off over the two consecutive months from week 2 to week 4 (3.04%, p = 0.558). There was no wearing-off within the erenumab (p = 0.194) or the fremanezumab (p = 0.581) groups. Among the ≥30% treatment responders, there was no consistent wearing-off over the two consecutive months (2.6%, p = 0.573). CONCLUSIONS: There was no wearing-off in treatment responders, which is in alignment with premarketing data from placebo-controlled phase III studies. These data suggest that patients should be informed upfront that no wearing-off effect is expected because anxiety for attacks at the end of the month per se may generate migraine attacks.

Hypersensitivity to CGRP as a predictive biomarker of migraine prevention with erenumab.

BACKGROUND: The present study aimed to investigate the predictive value of calcitonin gene-related peptide (CGRP)-induced migraine attacks for effectiveness to erenumab treatment in people with migraine. METHODS: In total, 139 participants with migraine underwent a single experimental day involving a 20-min infusion with CGRP. Following this, the participants entered a 24-week treatment period with erenumab. The primary endpoints were the predictive value of CGRP-induced migraine attacks on the effectiveness of erenumab, defined as ≥50% reduction in monthly migraine days, or ≥ 50% reduction in either monthly migraine or monthly headache days of moderate to severe intensity. RESULTS: Among participants with CGRP-induced migraine attacks, 60 of 99 (61%) achieved ≥50% reduction in monthly migraine days during weeks 13-24 with erenumab. Conversely, 13 of 25 (52%) where CGRP infusion did not induce a migraine achieved the same endpoint (p = 0.498). There were no significant differences between the ≥50% reduction in either monthly migraine or monthly headache days of moderate to severe intensity between CGRP-sensitive and non-sensitive participants (p = 0.625). CONCLUSIONS: Our findings suggest that the CGRP-provocation model cannot be used to predict erenumab's effectiveness. It remains uncertain whether this finding extends to other monoclonal antibodies targeting the CGRP ligand or to gepants.Trial Registration: The study was registered at ClinicalTrials.gov (NCT04592952).

Challenges in the management of new daily persistent headache at a tertiary headache center-A retrospective real-world evidence study.

OBJECTIVE: In this retrospective cross-sectional real-world evidence study from the Danish Headache Center (DHC), a national tertiary headache center in Denmark, we sought to identify potential pharmacological agents for the treatment of new daily persistent headache (NDPH). BACKGROUND: NDPH is an enigmatic headache disorder with abrupt onset and chronic duration for which evidence-based treatments are lacking. NDPH is a diagnosis of exclusion, for which secondary headaches must be ruled out and the etiology remains idiopathic. The sparse investigations of this disorder have not yielded a pathophysiological basis and no effective treatment for NDPH has been found. METHODS: All patients with an NDPH diagnosis at the DHC were enrolled (n = 64). First, we reviewed the records of all patients with an NDPH diagnosis to evaluate whether they fulfilled the diagnostic criteria. Next, we extracted all the trialled acute and prophylactic pharmacological interventions for the included patients. Then, pharmacological interventions that had been tried in ≥ 20 patients were analyzed post hoc with efficacy as the outcome, which was stratified in five effect categories ("no effect," "partial effect," "full effect," "partial effect and cessation due to adverse events," and "full effect and cessation due to adverse events"). Descriptive statistical analysis was performed, and the results were schematically presented (see Table 2). RESULTS: Fifty-one patients out of 64 were found to fulfill NDPH criteria and were included in the study. The drugs tried by ≥ 20 patients were amitriptyline (n = 34), candesartan (n = 27), and mirtazapine (n = 20). No patients experienced a complete effect with these drugs while 9% (3/34), 26% (7/27), and 15% (3/20) experienced a partial effect with no adverse events that led to treatment discontinuation, respectively. The remaining patients experienced either no effect or a partial effect with adverse events leading to treatment discontinuation. CONCLUSION: In this study we add real-world evidence to suggest that prophylactic drugs conventionally used for treating chronic migraine and chronic tension-type headache have limited utility for treating NDPH; however, a partial response in 26% of patients using candesartan and 15% of patients using mirtazapine warrants further investigation in randomized double-blinded placebo-controlled trials.

Epidemiology and clinical features of paroxysmal hemicrania: A systematic review and meta-analysis.

OBJECTIVE: To assess the prevalence or relative frequency of paroxysmal hemicrania and its clinical features in the adult general population and among adult patients evaluated for headache in tertiary care. BACKGROUND: Paroxysmal hemicrania is a rare trigeminal autonomic cephalalgia with characteristic attacks of headache, associated cranial autonomic symptoms and signs, and an absolute response to indomethacin. Its epidemiological burden remains unknown in both the adult general population and among adult patients evaluated for headache in a tertiary care setting. Moreover, the frequencies of the clinical features associated with paroxysmal hemicrania have not been well established. METHODS: A literature search of PubMed and Embase was conducted from January 1, 1988, to January 20, 2023. Eligible for inclusion were observational studies reporting the point prevalence or relative frequency of paroxysmal hemicrania or its clinical features in the adult general population or among adult patients evaluated for headache in tertiary care. Two independent investigators (M.J.H. and J.G.L.) performed the title, abstract, and full-text article screening. Each included study's risk of bias was critically appraised using the Joanna Briggs Institute Critical Appraisal Checklist for Studies Reporting Prevalence Data. Estimates of prevalence or relative frequency were calculated using a random-effects meta-analysis. The between-study heterogeneity was assessed using the I2 statistic and further explored with meta-regression. This study was pre-registered on PROSPERO (identifier: CRD42023391127). RESULTS: A total of 17 clinic-based studies and one population-based study met the eligibility criteria. Importantly, an overall high risk of bias was observed across the eligible studies. The relative frequency of paroxysmal hemicrania was estimated to be 0.3% (95% CI, 0.2%-0.5%) among adult patients evaluated for headache in tertiary care with considerable heterogeneity (I2 = 76.4%). No cases with paroxysmal hemicrania were identified among 1,838 participants in a population-based sample. Moreover, the most prevalent cranial autonomic symptoms were lacrimation (77.3% [95% Cl, 62.7%-87.3%]), conjunctival injection (75.0% [95% Cl, 60.3%-85.6%]), and nasal congestion (47.7% [95% Cl, 33.6%-62.3%]). CONCLUSIONS: Our findings suggest that paroxysmal hemicrania is a rare disorder among adults evaluated for headache in tertiary care, while its prevalence in the general population remains unknown. Further studies focusing on the clinical features of paroxysmal hemicrania are warranted.

Silver nanoparticle-induced in vitro flowering in Dendrocalamus strictus (Roxb.) nees and genetic fidelity assessment of regenerants using molecular markers.

BACKGROUND: Dendrocalamus strictus (Roxb.) Nees, generally referred to as 'Male bamboo,' is a globally prevalent and highly significant species of bamboo. It is a versatile species and possesses notable industrial significance. However, despite its numerous applications, the production of this plant is insufficient to fulfill the worldwide demand. The challenges that impede the dissemination of D. strictus encompass the unpredictable blooming pattern (30-70 years), low seed production, and limited seed viability. Therefore, tissue culture presents a reliable and effective option for the mass production of standardized planting material. METHODOLOGY AND RESULTS: This study investigated the effects of silver nanoparticles (AgNPs) at a concentration of 6.0 mg L- 1 in the Murashige and Skoog (MS) nutrient medium fortified with pre-optimized plant growth regulators (3.0 mg L- 1 6-benzylaminopurine + 0.5 mg L- 1 α-naphthalene acetic acid) on the induction of flowering in a controlled environment in D. strictus. The use of AgNPs in the media induced a maximum of 14 inflorescences per culture vessel, 9 flowers per inflorescence, and improved the performance of the micropropagated plantlets during acclimatization in the greenhouse and field. The ISSR and SCoT amplified polymorphic DNA analysis of the regenerants resulted in the formation of 49 bands (300 to 2000 bp size) and 36 scorable bands (350 to 2000 bp) respectively. All the PCR amplicons produced by SCoT and ISSR were monomorphic confirming the genetic uniformity of the tissue cultured plants of D. strictus with the mother plant. CONCLUSIONS: It can be inferred that the incorporation of AgNPs during the shoot proliferation phase has the potential to stimulate in vitro flowering in D. strictus. This finding could provide valuable insights into innovative strategies for enhancing crop productivity and genetic manipulation for accelerated breeding and agricultural advancement.

Clinical features of migraine with aura: a REFORM study.

BACKGROUND: About one-third of persons with migraine experience transient neurologic symptoms, referred to as aura. Despite its widespread prevalence, comprehensive clinical descriptions of migraine with aura remain sparse. Therefore, we aimed to provide an in-depth phenotypic analysis of aura symptoms and characteristics in a cross-sectional study of a large sample of adults diagnosed with migraine with aura. METHODS: Data were extracted from the baseline characteristics of participants in the Registry for Migraine (REFORM) study - a single-center, prospective, longitudinal cohort study. Participants were adults diagnosed with migraine aura, reporting ≥ 4 monthly migraine days in the preceding 3 months. Trained personnel conducted in-person semi-structured interviews, capturing details on the nature, duration, localization, and progression of individual aura symptoms. RESULTS: Of the 227 enrolled participants with migraine with aura, the mean age was 41.1 years, with a predominant female representation (n = 205 [90.3%]). Visual aura was present in 215 (94.7%) participants, somatosensory aura in 81 (35.7%), and speech and/or language aura in 31 (13.7%). A single type of aura was observed in 148 (65.2%) participants, whilst 79 (34.8%) reported multiple aura types. Most participants (n = 220 [96.9%]) described their aura symptoms as positive or gradually spreading. Headache in relation to aura was noted by 218 (96.0%) participants, with 177 (80.8%) stating that the onset of aura symptoms preceded the onset of headache. CONCLUSIONS: This study offers a detailed clinical depiction of persons with migraine with aura, who were predominantly enrolled from a tertiary care unit. The findings highlight potential gaps in the available literature on migraine with aura and should bolster clinicians' acumen in diagnosing migraine with aura in clinical settings.

Epidemiology and clinical features of hypnic headache: A systematic review and meta-analysis.

BACKGROUND: Hypnic headache is a neurological disorder characterized by recurrent headache attacks that occur exclusively during sleep, leading to awakening. Synthesizing the available epidemiological data might inform clinical decision-making. METHODS: We searched PubMed and Embase for observational studies on hypnic headache published between 1 May 2004, and 22 December 2022. Two investigators independently screened titles, abstracts, and full-text articles. We performed a random-effects meta-analysis with meta-regression to estimate the prevalence of hypnic headache and its clinical features based on epidemiologic data from population-based and clinic-based studies. RESULTS: Fourteen studies, one population-based and 13 clinic-based, met our eligibility criteria. The population-based study did not identify any people with hypnic headache. From 11 clinic-based studies, the pooled relative frequency of hypnic headache was 0.21% (95%CI, 0.13 to 0.35%; I2 = 87%) in adult patients evaluated for headache. The pooled mean age of onset was 60.5 years, with a slight female predisposition. Hypnic headache was typically bilateral (71%), pressing (73%), of moderate (38%) or severe (44%) pain intensity, and lasted about 115 minutes per attack. CONCLUSIONS: Our data should be cautiously interpreted due to between-study heterogeneity. The identified clinical presentation of hypnic headache can guide clinical diagnosis, in addition to the International Classification of Headache Disorders.

Prevalence and clinical features of hemicrania continua in clinic-based studies: A systematic review and meta-analysis.

OBJECTIVE: To estimate the relative frequencies of hemicrania continua and its clinical features in adult patients who were evaluated for headache in a clinic-based setting. METHODS: PubMed and Embase were searched for observational, clinic-based studies published between 1 January 2004 and 1 February 2022, that reported on the relative frequencies of hemicrania continua and its clinical features. Two independent investigators (HMA and SA-K) screened titles, abstracts, and full text-articles. A random-effects meta-analysis was conducted to estimate pooled relative frequencies of hemicrania continua and its clinical features across clinic-based studies. RESULTS: Eleven clinic-based studies were deemed eligible for inclusion. Of these, eight studies reported on the relative frequency of hemicrania continua among adult patients (n = 9854) who were evaluated for headache in a tertiary care unit. The pooled relative frequency of hemicrania continua was found to be 1.8% (95% CI; 1.0-3.3). Considerable heterogeneity was noted across studies (I2 = 89.8%). The three most common symptoms associated with hemicrania continua were lacrimation (72.3%), conjunctival injection (69.8%), and restlessness/agitation (60.2%). CONCLUSION: The findings of this meta-analysis suggest that there is limited epidemiologic data on the relative frequencies of hemicrania continua and its clinical features. Standardized data acquisition and reporting are needed to estimate prevalence rates more accurately and to better understand epidemiologic patterns. This, in turn, should increase awareness of the impact that hemicrania continua has in clinical practice.

An exploratory analysis of clinical and sociodemographic factors in CGRP-induced migraine attacks: A REFORM study.

OBJECTIVE: To investigate whether clinical and sociodemographic factors are associated with calcitonin gene-related peptide (CGRP) induced migraine attacks. METHODS: A total of 139 participants with migraine received a 20-minute intravenous infusion of CGRP (1.5 µg/min) on a single experiment day. The incidence of CGRP-induced migraine attacks was recorded using a headache diary during the 12-hour observational period post-infusion. Univariable and multivariable regression analyses were conducted to examine potential predictors' relationship with CGRP-induced migraine attacks. RESULTS: CGRP-induced migraine attacks were reported in 110 (79%) of 139 participants. Univariable analysis revealed that participants with cutaneous allodynia had higher odds of developing CGRP-induced migraine attacks, compared with those without allodynia (OR, 2.97, 95% CI, 1.28 to 7.43). The subsequent multivariable analysis confirmed this association (OR, 3.26, 95% CI, 1.32 to 8.69) and also found that participants with migraine with aura had lower odds of developing CGRP-induced migraine attacks (OR, 0.32, 95% CI, 0.12 to 0.84). CONCLUSION: Our results suggest that cutaneous allodynia and aura play a role in CGRP-induced migraine attacks, while other clinical and sociodemographic factors do not seem to have any noticeable impact. This indicates that the CGRP provocation model is robust, as the CGRP hypersensitivity remained unaffected despite differences among a heterogeneous migraine population.Trial Registration: ClinicalTrials.gov Identifier: NCT04592952.

Real-world effectiveness of fremanezumab for the preventive treatment of migraine: Interim analysis of the pan-European, prospective, observational, phase 4 PEARL study.

BACKGROUND: The ongoing Pan-European Real Life (PEARL) phase 4 study is evaluating fremanezumab effectiveness and safety for the prevention of episodic and chronic migraine. This interim analysis reports primary, secondary and exploratory endpoints from when 500 participants completed at least six months of treatment. METHODS: Adults with episodic migraine or chronic migraine maintaining daily headache diaries were enrolled upon initiation of fremanezumab. Primary endpoint: proportion of participants with ≥50% reduction in monthly migraine days during the six-month period after fremanezumab initiation. Secondary endpoints: mean change from baseline across months 1-12 in monthly migraine days, acute migraine medication use, and headache-related disability. Exploratory endpoint: mean change in headache severity from baseline across months 1-12. Safety was assessed through adverse events reported. RESULTS: Overall, 897 participants were enrolled and 574 included in the effectiveness analyses (episodic migraine, 25.8%; chronic migraine, 74.2%). Of participants with data available, 175/313 (55.9%) achieved ≥50% monthly migraine days reduction during the six-month period post-initiation. Across months 1-12, there were sustained reductions in mean monthly migraine days, acute medication use, disability scores, and headache severity. Few adverse events were reported. CONCLUSION: PEARL interim results support the effectiveness and safety of fremanezumab for migraine prevention in a real-world population across several European countries.Trial registration: encepp.eu: EUPAS35111.

The increasing role of electronic media in headache.

Most individuals with access to the internet use social media platforms. These platforms represent an excellent opportunity to disseminate knowledge about management and treatment to the benefit of patients. The International Headache Society, The European Headache Federation, and The American Headache Society have electronic media committees to promote and highlight the organizations' expertise and disseminate research findings. A growing mistrust in science has made dealing with infodemics (i.e., sudden access to excessive unvetted information) an increasing part of clinical management. An increasing role of these committees will be to address this challenge. As an example, recent studies have demonstrated that the most popular online content on migraine management is not evidence-based and is disseminated by for-profit organizations. As healthcare professionals and members of professional headache organizations, we are obliged to prioritize knowledge dissemination. A progressive social media strategy is associated not only with increased online visibility and outreach, but also with a higher scientific interest. To identify gaps and barriers, future research should assess the range of available information on headache disorders in electronic media, characterize direct and indirect consequences on clinical management, and recognize best practice and strategies to improve our communication on internet-based communication platforms. In turn, these efforts will reduce the burden of headache disorders by facilitating improved education of both patients and providers.

Numerical Analysis of Highly Sensitive Twin-Core, Gold-Coated, D-Shaped Photonic Crystal Fiber Based on Surface Plasmon Resonance Sensor.

This research article proposes and numerically investigates a photonic crystal fiber (PCF) based on a surface plasmon resonance (SPR) sensor for the detecting refractive index (RI) of unknown analytes. The plasmonic material (gold) layer is placed outside of the PCF by removing two air holes from the main structure, and a D-shaped PCF-SPR sensor is formed. The purpose of using a plasmonic material (gold) layer in a PCF structure is to introduce an SPR phenomenon. The structure of the PCF is likely enclosed by the analyte to be detected, and an external sensing system is used to measure changes in the SPR signal. Moreover, a perfectly matched layer (PML) is also placed outside of the PCF to absorb unwanted light signals towards the surface. The numerical investigation of all guiding properties of the PCF-SPR sensor is completed using a fully vectorial-based finite element method (FEM) to achieve the finest sensing performance. The design of the PCF-SPR sensor is completed using COMSOL Multiphysics software, version 1.4.50. According to the simulation results, the proposed PCF-SPR sensor has a maximum wavelength sensitivity of 9000 nm/RIU, an amplitude sensitivity of 3746 RIU-1, a sensor resolution of 1 × 10-5 RIU, and a figure of merit (FOM) of 900 RIU-1 in the x-polarized direction light signal. The miniaturized structure and high sensitivity of the proposed PCF-SPR sensor make it a promising candidate for detecting RI of analytes ranging from 1.28 to 1.42.

Effectiveness of Nonfunctionalized Graphene Oxide Nanolayers as Nanomedicine against Colon, Cervical, and Breast Cancer Cells.

Recent studies in nanomedicine have intensively explored the prospective applications of surface-tailored graphene oxide (GO) as anticancer entity. However, the efficacy of nonfunctionalized graphene oxide nanolayers (GRO-NLs) as an anticancer agent is less explored. In this study, we report the synthesis of GRO-NLs and their in vitro anticancer potential in breast (MCF-7), colon (HT-29), and cervical (HeLa) cancer cells. GRO-NLs-treated HT-29, HeLa, and MCF-7 cells showed cytotoxicity in the MTT and NRU assays via defects in mitochondrial functions and lysosomal activity. HT-29, HeLa, and MCF-7 cells treated with GRO-NLs exhibited substantial elevations in ROS, disturbances of the mitochondrial membrane potential, an influx of Ca2+, and apoptosis. The qPCR quantification showed the upregulation of caspase 3, caspase 9, bax, and SOD1 genes in GRO-NLs-treated cells. Western blotting showed the depletion of P21, P53, and CDC25C proteins in the above cancer cell lines after GRO-NLs treatment, indicating its function as a mutagen to induce mutation in the P53 gene, thereby affecting P53 protein and downstream effectors P21 and CDC25C. In addition, there may be a mechanism other than P53 mutation that controls P53 dysfunction. We conclude that nonfunctionalized GRO-NLs exhibit prospective biomedical application as a putative anticancer entity against colon, cervical, and breast cancers.

Marine Natural Compound (Neviotin A) Displays Anticancer Efficacy by Triggering Transcriptomic Alterations and Cell Death in MCF-7 Cells.

We investigated the anticancer mechanism of a chloroform extract of marine sponge (Haliclona fascigera) (sample C) in human breast adenocarcinoma (MCF-7) cells. Viability analysis using MTT and neutral red uptake (NRU) assays showed that sample C exposure decreased the proliferation of cells. Flow cytometric data exhibited reactive oxygen species (ROS), nitric oxide (NO), dysfunction of mitochondrial potential, and apoptosis in sample C-treated MCF-7 cells. A qPCR array of sample C-treated MCF-7 cells showed crosstalk between different pathways of apoptosis, especially BIRC5, BCL2L2, and TNFRSF1A genes. Immunofluorescence analysis affirmed the localization of p53, bax, bcl2, MAPKPK2, PARP-1, and caspase-3 proteins in exposed cells. Bioassay-guided fractionation of sample C revealed Neviotin A as the most active compound triggering maximum cell death in MCF-7, indicating its pharmacological potency for the development of a drug for the treatment of human breast cancer.

Migraine attacks are of peripheral origin: the debate goes on.

BACKGROUND: Despite the pervasiveness of migraine, the underlying pathophysiological mechanisms initiating migraine attacks are far from well understood and are matter of scientific debate. OBJECTIVE: In this narrative review, we discuss key evidence for that suggest a peripheral origin or central origin and provide directions for future studies that may provide further clarification. DISCUSSION: Migraine pathogenesis is considered to involve the trigeminovascular system, a term that encompasses the trigeminal nerve and its axonal projections to the intracranial blood vessels. Beyond any doubt both peripheral and central mechanisms are involved in migraine pathogenesis, but an unresolved question is the how the initial activation occurs in a migraine attack. Evidence favoring a peripheral origin of migraine attacks, i.e., initial events occur outside of the blood-brain barrier, include the importance of sensitization of perivascular sensory afferents early on in a migraine attack. Evidence favoring a central origin include the occurrence of prodromal symptoms, migraine aura, and activation of structures within the central nervous system early in and during a migraine attack. CONCLUSIONS: Both peripheral and central mechanisms are likely involved in a migraine attack, e.g., peripheral nociceptive input is necessary for pain transmission and cortical activity is necessary for pain perception. Yet, the debate of whether migraine attacks are initiated a peripheral or central site remains unresolved. The increased focus on prodromal symptoms and on the development of a human model of migraine aura will possibly provide key arguments needed to answer this question in the near future. Until then, we cannot draw firm conclusions and the debate goes on. VIDEO LINK: Video recording of the debate held at the 1st International Conference on Advances in Migraine Sciences (ICAMS 2022, Copenhagen, Denmark) is available at: https://www.youtube.com/watch?v=NC0nlcKohz0 .

Menstrual migraine is caused by estrogen withdrawal: revisiting the evidence.

OBJECTIVE: To explore and critically appraise the evidence supporting the role of estrogen withdrawal in menstrual migraine. MAIN BODY: Menstrual migraine, impacting about 6% of reproductive-age women, manifests as migraine attacks closely related to the menstrual cycle. The estrogen withdrawal hypothesis posits that the premenstrual drop in estrogen levels serves as a trigger of migraine attacks. Despite its wide acceptance, the current body of evidence supporting this hypothesis remains limited, warranting further validation. Estrogen is believed to exert a modulatory effect on pain, particularly within the trigeminovascular system - the anatomic and physiologic substrate of migraine pathogenesis. Nevertheless, existing studies are limited by methodologic inconsistencies, small sample sizes, and variable case definitions, precluding definitive conclusions. To improve our understanding of menstrual migraine, future research should concentrate on untangling the intricate interplay between estrogen, the trigeminovascular system, and migraine itself. This necessitates the use of robust methods, larger sample sizes, and standardized case definitions to surmount the limitations encountered in previous investigations. CONCLUSION: Further research is thus needed to ascertain the involvement of estrogen withdrawal in menstrual migraine and advance the development of effective management strategies to address unmet treatment needs.