A pre-vertebrate endodermal origin of calcitonin-producing neuroendocrine cells.

Vertebrate calcitonin-producing cells (C-cells) are neuroendocrine cells that secrete the small peptide hormone calcitonin in response to elevated blood calcium levels. Whereas mouse C-cells reside within the thyroid gland and derive from pharyngeal endoderm, avian C-cells are located within ultimobranchial glands and have been reported to derive from the neural crest. We use a comparative cell lineage tracing approach in a range of vertebrate model systems to resolve the ancestral embryonic origin of vertebrate C-cells. We find, contrary to previous studies, that chick C-cells derive from pharyngeal endoderm, with neural crest-derived cells instead contributing to connective tissue intimately associated with C-cells in the ultimobranchial gland. This endodermal origin of C-cells is conserved in a ray-finned bony fish (zebrafish) and a cartilaginous fish (the little skate, Leucoraja erinacea). Furthermore, we discover putative C-cell homologs within the endodermally-derived pharyngeal epithelium of the ascidian Ciona intestinalis and the amphioxus Branchiostoma lanceolatum, two invertebrate chordates that lack neural crest cells. Our findings point to a conserved endodermal origin of C-cells across vertebrates and to a pre-vertebrate origin of this cell type along the chordate stem.

Defining the Functional Sensitivity for The Siemens Atellica Calcitonin Assay: Insight from A Single-center Study.

BACKGROUND: Detectable, and especially rising post-thyroidectomy serum calcitonin and Carcinoembryonic Antigen (CEA) levels, as per American Thyroid Association (ATA) guidelines, indicate potential disease presence, requiring frequent calcitonin measurement or imaging for early detection of persistent or recurrent Medullary Thyroid Carcinoma (MTC). Thus, defining the clinical cutoff value of detection of calcitonin assays relative to imaging and clinical status is crucial for patient care. This study aimed to evaluate postoperative calcitonin levels using the new Siemens Atellica assay system to determine the most appropriate levels for clinical decision-making. METHODS: A retrospective analysis was conducted using Siemens Atellica for calcitonin testing on 56 samples from 40 patients between 09/27/2022 and 08/11/2023. Only calcitonin results performed at least 3 months post-total thyroidectomy were included. Imaging studies, within 6 months of the calcitonin report, were assessed. CEA results were also reviewed. RESULTS: Precision analysis at 2.94 and 5.24 pg/mL revealed coefficients of variation (CVs) at 16.49% and 8.87%, respectively. For the evidence of post-total thyroidectomy persistent or recurrent MTC confirmed by imaging, using a 1.89 pg/mL cutoff for calcitonin yielded 43% sensitivity and 67% specificity. Using a 5.00 pg/mL cutoff resulted in 0% sensitivity and 100% specificity. CONCLUSIONS: Our findings indicate the potential suitability of a 5 pg/mL calcitonin cutoff on the Siemens Atellica platform for evaluating tumor persistence or recurrence in post-thyroidectomy patients in our institution. However, individual laboratories should establish their own clinical cutoff value when evaluating calcitonin levels for monitoring tumor recurrence post-thyroidectomy.

Brain-wide mapping of c-Fos expression in nitroglycerin-induced models of migraine.

BACKGROUND: Migraine is a neurological disorder characterized by complex, widespread, and sudden attacks with an unclear pathogenesis, particularly in chronic migraine (CM). Specific brain regions, including the insula, amygdala, thalamus, and cingulate, medial prefrontal, and anterior cingulate cortex, are commonly activated by pain stimuli in patients with CM and animal models. This study employs fluorescence microscopy optical sectioning tomography (fMOST) technology and AAV-PHP.eB whole-brain expression to map activation patterns of brain regions in CM mice, thus enhancing the understanding of CM pathogenesis and suggesting potential treatment targets. METHODS: By repeatedly administering nitroglycerin (NTG) to induce migraine-like pain in mice, a chronic migraine model (CMM) was established. Olcegepant (OLC) was then used as treatment and its effects on mechanical pain hypersensitivity and brain region activation were observed. All mice underwent mechanical withdrawal threshold, light-aversive, and elevated plus maze tests. Viral injections were administered to the mice one month prior to modelling, and brain samples were collected 2 h after the final NTG/vehicle control injection for whole-brain imaging using fMOST. RESULTS: In the NTG-induced CMM, mechanical pain threshold decreased, photophobia, and anxiety-like behavior were observed, and OLC was found to improve these manifestations. fMOST whole-brain imaging results suggest that the isocortex-cerebral cortex plate region, including somatomotor areas (MO), somatosensory areas (SS), and main olfactory bulb (MOB), appears to be the most sensitive area of activation in CM (P < 0.05). Other brain regions such as the inferior colliculus (IC) and intermediate reticular nucleus (IRN) were also exhibited significant activation (P < 0.05). The improvement in migraine-like symptoms observed with OLC treatment may be related to its effects on these brain regions, particularly SS, MO, ansiform lobule (AN), IC, spinal nucleus of the trigeminal, caudal part (Sp5c), IRN, and parvicellular reticular nucleus (PARN) (P < 0.05). CONCLUSIONS: fMOST whole-brain imaging reveals c-Fos + cells in numerous brain regions. OLC improves migraine-like symptoms by modulating brain activity in some brain regions. This study demonstrates the activation of the specific brain areas in NTG-induced CMM and suggests some regions as a potential treatment mechanism according to OLC.

Treatment patterns of patients with migraine eligible for anti-CGRP pathway monoclonal antibodies.

Introduction: Migraine is a debilitating neurological disorder, with a wide range of symptoms and disease burden, underscoring the heterogeneity of patients' disease characteristics and treatment needs. To characterize the profile of migraine patients in the US who may be eligible for preventive treatment with an anti-CGRP pathway mAb and to better understand treatment patterns and real-world use of acute and preventive medications for migraine, we conducted a retrospective cohort study of adult patients. Methods: These patients were identified as having migraine using diagnosis codes or migraine-specific medication use (first = index) in the IQVIA PharMetrics® Plus database. Patients were required to have ≥ 12 months of continuous enrollment in medical and pharmacy benefits prior to index (baseline) and after index (follow-up). Patients were stratified into chronic migraine (CM) and non-chronic migraine (non-CM) by diagnosis codes. Based on acute migraine-specific medication dispensing data in the follow-up period, non-CM patients were divided into 3 cohorts: highest, middle, and lowest tertile of total units of dispensed acute migraine-specific medication (gepants, ditans, ergot derivatives, and triptans). Migraine medication use was captured in the baseline and follow-up periods. Results: A total of 22,584 CM and 216,807 non-CM patients (72,269 patients in each tertile) were identified and included in the study. Over the follow-up, CM patients had a mean of 70 units of acute migraine-specific medications dispensed, while the highest, middle, and lowest tertile of non-CM patients had a mean of 92, 29, and 10 units, respectively. Anti-calcitonin gene-related peptide pathway mAbs were dispensed for 28.9% of CM patients, and for 6.9%, 4.1%, and 2.9% of non-CM patients in the highest, middle, and lowest tertiles, respectively. Conclusion: A lower proportion of non-CM patients had use of anti-calcitonin gene-related peptide pathway mAbs compared to CM patients, confirming the unmet need with appropriate preventive medication. There appears to be a persistent gap in management of patients without a diagnosis of CM who are dispensed high quantities of acute migraine-specific medications.

Assessing the immunogenicity risk of salmon calcitonin peptide impurities using in silico and in vitro methods.

Advances in synthetic peptide synthesis have enabled rapid and cost-effective peptide drug manufacturing. For this reason, peptide drugs that were first produced using recombinant DNA (rDNA) technology are now being produced using solid- and liquid-phase peptide synthesis. While peptide synthesis has some advantages over rDNA expression methods, new peptide-related impurities that differ from the active pharmaceutical ingredient (API) may be generated during synthesis. These impurity byproducts of the original peptide sequence feature amino acid insertions, deletions, and side-chain modifications that may alter the immunogenicity risk profile of the drug product. Impurities resulting from synthesis have become the special focus of regulatory review and approval for human use, as outlined in the FDA's Center for Drug Evaluation and Research guidance document, "ANDAs for Certain Highly Purified Synthetic Peptide Drug Products That Refer to Listed Drugs of rDNA Origin," published in 2021. This case study illustrates how in silico and in vitro methods can be applied to assess the immunogenicity risk of impurities that may be present in synthetic generic versions of the salmon calcitonin (SCT) drug product. Sponsors of generic drug abbreviated new drug applications (ANDAs) should consider careful control of these impurities (for example, keeping the concentration of the immunogenic impurities below the cut-off recommended by FDA regulators). Twenty example SCT impurities were analyzed using in silico tools and assessed as having slightly more or less immunogenic risk potential relative to the SCT API peptide. Class II human leukocyte antigen (HLA)-binding assays provided independent confirmation that a 9-mer sequence present in the C-terminus of SCT binds promiscuously to multiple HLA DR alleles, while T-cell assays confirmed the expected T-cell responses to SCT and selected impurities. In silico analysis combined with in vitro assays that directly compare the API to each individual impurity peptide may be a useful approach for assessing the potential immunogenic risk posed by peptide impurities that are present in generic drug products.

Medullary Thyroid Carcinoma: A Unique Case Report.

Medullary thyroid carcinoma is a rare neuroendocrine tumor derived from parafollicular C-cells. It can be inherited as part of syndromes, such as familial medullary thyroid cancer (FMTC) and multiple endocrine neoplasia type 2 (MEN 2), or it can arise sporadically. We herein report a unique case of medullary thyroid carcinoma in a 50-year-old male who presented with a neck mass. Fine needle aspiration cytology (FNAC) of the thyroid and histopathological examination revealed a diagnosis of medullary thyroid carcinoma. Both carcinoembryonic antigen (CEA) and calcitonin are the key serum markers utilized in the diagnosis and monitoring of medullary thyroid cancer (MTC). Thorough evaluation, prompt identification, and efficient treatment constitute the pivotal measures for ensuring favorable survival outcomes.

miR-148b-5p regulates hypercalciuria and calcium-containing nephrolithiasis.

Calcium-containing stones represent the most common form of kidney calculi, frequently linked to idiopathic hypercalciuria, though their precise pathogenesis remains elusive. This research aimed to elucidate the molecular mechanisms involved by employing urinary exosomal microRNAs as proxies for renal tissue analysis. Elevated miR-148b-5p levels were observed in exosomes derived from patients with kidney stones. Systemic administration of miR-148b-5p in rat models resulted in heightened urinary calcium excretion, whereas its inhibition reduced stone formation. RNA immunoprecipitation combined with deep sequencing identified miR-148b-5p as a suppressor of calcitonin receptor (Calcr) expression, thereby promoting urinary calcium excretion and stone formation. Mice deficient in Calcr in distal epithelial cells demonstrated elevated urinary calcium excretion and renal calcification. Mechanistically, miR-148b-5p regulated Calcr through the circRNA-83536/miR-24-3p signaling pathway. Human kidney tissue samples corroborated these results. In summary, miR-148b-5p regulates the formation of calcium-containing kidney stones via the circRNA-83536/miR-24-3p/Calcr axis, presenting a potential target for novel therapeutic interventions to prevent calcium nephrolithiasis.

Biomarkers and Endophenotypes of Post-traumatic Headaches.

PURPOSE OF REVIEW: To review existing literature on biomarkers for post-traumatic headache (PTH). RECENT FINDINGS: Preclinical models and clinical findings have started to elucidate the biology that underlies PTH. Traumatic brain injury results in ionic flux, glutamatergic surge, and activation of the trigeminal cervical complex resulting in the release of pain neuropeptides. These neuropeptides, including calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP), play a key role in the pathophysiology of migraine and other primary headache disorders. Only two studies were identified that evaluated CGRP levels in PTH. Neither study found a consistent relationship between CGRP levels and PTH. One study did discover that nerve growth factor (NGF) was elevated in subjects with PTH. There is no conclusive evidence for reliable blood-based biomarkers for PTH. Limitations in assays, collection technique, and time since injury must be taken into account. There are multiple ideal candidates that have yet to be explored.

Advancing toward precision migraine treatment: Predicting responses to preventive medications with machine learning models based on patient and migraine features.

OBJECTIVE: To develop machine learning models using patient and migraine features that can predict treatment responses to commonly used migraine preventive medications. BACKGROUND: Currently, there is no accurate way to predict response to migraine preventive medications, and the standard trial-and-error approach is inefficient. METHODS: In this cohort study, we analyzed data from the Mayo Clinic Headache database prospectively collected from 2001 to December 2023. Adult patients with migraine completed questionnaires during their initial headache consultation to record detailed clinical features and then at each follow-up to track preventive medication changes and monthly headache days. We included patients treated with at least one of the following migraine preventive medications: topiramate, beta-blockers (propranolol, metoprolol, atenolol, nadolol, timolol), tricyclic antidepressants (amitriptyline, nortriptyline), verapamil, gabapentin, onabotulinumtoxinA, and calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) (erenumab, fremanezumab, galcanezumab, eptinezumab). We pre-trained a deep neural network, "TabNet," using 145 variables, then employed TabNet-embedded data to construct prediction models for each medication to predict binary outcomes (responder vs. non-responder). A treatment responder was defined as having at least a 30% reduction in monthly headache days from baseline. All model performances were evaluated, and metrics were reported in the held-out test set (train 85%, test 15%). SHapley Additive exPlanations (SHAP) were conducted to determine variable importance. RESULTS: Our final analysis included 4260 patients. The responder rate for each medication ranged from 28.7% to 34.9%, and the mean time to treatment outcome for each medication ranged from 151.3 to 209.5 days. The CGRP mAb prediction model achieved a high area under the receiver operating characteristics curve (AUC) of 0.825 (95% confidence interval [CI] 0.726, 0.920) and an accuracy of 0.80 (95% CI 0.70, 0.88). The AUCs of prediction models for beta-blockers, tricyclic antidepressants, topiramate, verapamil, gabapentin, and onabotulinumtoxinA were: 0.664 (95% CI 0.579, 0.745), 0.611 (95% CI 0.562, 0.682), 0.605 (95% CI 0.520, 0.688), 0.673 (95% CI 0.569, 0.724), 0.628 (0.533, 0.661), and 0.581 (95% CI 0.550, 0.632), respectively. Baseline monthly headache days, age, body mass index (BMI), duration of migraine attacks, responses to previous medication trials, cranial autonomic symptoms, family history of headache, and migraine attack triggers were among the most important variables across all models. A variable could have different contributions; for example, lower BMI predicts responsiveness to CGRP mAbs and beta-blockers, while higher BMI predicts responsiveness to onabotulinumtoxinA, topiramate, and gabapentin. CONCLUSION: We developed an accurate prediction model for CGRP mAbs treatment response, leveraging detailed migraine features gathered from a headache questionnaire before starting treatment. Employing the same methods, the model performances for other medications were less impressive, though similar to the machine learning models reported in the literature for other diseases. This may be due to CGRP mAbs being migraine-specific. Incorporating medical comorbidities, genomic, and imaging factors might enhance the model performance. We demonstrated that migraine characteristics are important in predicting treatment responses and identified the most crucial predictors for each of the seven types of preventive medications. Our results suggest that precision migraine treatment is feasible.

An overview of S100 proteins and their functions in skin homeostasis, interface dermatitis conditions and other skin pathologies.

S100 proteins comprise a family of structurally related proteins that are calcium-sensitive. S100 proteins have been found to play various roles in regulation of cell apoptosis, cell proliferation and differentiation, cell migration and invasion, energy metabolism, calcium homeostasis, protein phosphorylation, anti-microbial activity and inflammation in a variety of cell types. While the specific function of many S100 proteins remains unknown, some of the S100 proteins serve as disease biomarkers as well as possible therapeutic targets in skin diseases. Interface dermatitis (ID) is a histopathological term that covers many different skin conditions including cutaneous lupus erythematosus, lichen planus, and dermatomyositis. These pathologies share similar histological features, which include basal cell vacuolization and lymphocytic infiltration at the dermal-epidermal junction. In this review, we summarize how the S100 protein family contributes to both homeostatic and inflammatory processes in the skin. We also highlight the role of S100 proteins in neuronal signalling, describing how this might contribute to neuroimmune interactions in ID and other skin pathologies. Last, we discuss what is known about the S100 family proteins as both biomarkers and potential treatment targets in specific pathologies.

Medullary Thyroid Carcinoma in Patients with Graves' Disease-A Case Series and Literature Review.

INTRODUCTION: Graves' disease (GD) is an autoimmune disorder affecting the thyroid gland, leading to systemic manifestations such as hyperthyroidism, Graves' orbitopathy, and pretibial myxedema. Contrary to previous beliefs that hyperthyroidism protects against thyroid cancer, recent studies reveal an increased incidence of thyroid malignancies in GD patients, particularly differentiated thyroid carcinomas and, in rare cases, medullary thyroid carcinoma (MTC). CASE SERIES: This case series presents three female GD patients diagnosed with MTC, highlighting the complexities of diagnosis and management. All patients exhibited thyroid nodules with suspicious ultrasonographic features, elevated plasma calcitonin levels, and required total thyroidectomy. Histological examination confirmed MTC. DISCUSSION: These cases underscore the importance of routine calcitonin screening in GD patients with thyroid nodules to facilitate early detection and improve prognosis. Our findings suggest that while the coexistence of GD and MTC is likely incidental, vigilant monitoring and comprehensive evaluation are crucial for timely intervention. CONCLUSIONS: This study advocates for integrating calcitonin testing into the standard diagnostic protocol for GD patients presenting with thyroid abnormalities.

Erenumab versus topiramate: migraine-related disability, impact and health-related quality of life.

BACKGROUND AND PURPOSE: HER-MES was the first head-to-head study of erenumab against topiramate (standard of care). This post hoc analysis of the HER-MES study evaluated the effect of erenumab versus topiramate on patient-reported outcomes at week 24. METHODS: Adult patients with episodic or chronic migraine (n = 777) were randomized (1:1) to monthly subcutaneous erenumab (n = 389) or daily oral topiramate (n = 388). Migraine-related disability, as measured by the Headache Impact Test 6 (HIT-6) and Short Form 36 Health Survey version 2 (SF-36v2), was analysed in the entire study cohort and true completers. RESULTS: In the erenumab group (vs. topiramate), significant improvements were reported in Headache Impact Test 6 total scores (composite populations, -10.88 vs. -7.72; true completers, -11.92 vs. -10.61) and a higher proportion of patients achieved a ≥5-point reduction from baseline with erenumab (composite populations, 72.2% vs. 53.9%; true completers, 79.64% vs. 71.43%). The adjusted mean change from baseline in the SF-36v2 score was greater with erenumab for both physical component summary (composite population, 5.48 vs. 3.63; true completers, 5.95 vs. 5.23) and mental component summary (composite populations, 1.00 vs. -1.18; true completers, 1.74 vs. -0.33). A higher proportion of patients on erenumab versus topiramate had a ≥5-point improvement in SF-36v2 for the physical component summary (composite populations, 47.7% vs. 37.4%; true completers, 52.1% vs. 48.9%) and mental component summary (composite populations, 25.3% vs. 16.8%; true completers, 27.3% vs. 17.7%). CONCLUSIONS: This post hoc analysis demonstrated that patients treated with erenumab had significant improvements in headache impact and quality of life as measured by patient-reported outcomes versus patients treated with topiramate.

Evidence-based review and frontiers of migraine therapy.

BACKGROUND: Cyclic vomiting syndrome (CVS) is identified as one of the "episodic syndromes that may be associated with migraine," along with benign paroxysmal torticollis, benign paroxysmal vertigo, and abdominal migraine. It has been proposed that CVS and migraine may share pathophysiologic mechanisms of hypothalamic activation and altered dopaminergic signaling, and impaired sensorimotor intrinsic connectivity. The past decade has brought groundbreaking advances in the treatment of migraine and other headache disorders. While many of these therapies have yet to be studied in episodic syndromes associated with migraine including CVS and abdominal migraine, the potential shared pathophysiology among these conditions suggests that use of migraine-specific treatments may have a beneficial role even in those for whom headache is not the primary symptom. PURPOSE: This manuscript highlights newer therapies in migraine. Calcitonin gene-related peptide (CGRP) and its relation to migraine pathophysiology and the therapies that target the CGRP pathway, as well as a 5HT1F receptor agonist and neuromodulation devices used to treat migraine are briefly discussed as they may potentially prove to be useful in the future treatment of CVS.

The dual amylin and calcitonin receptor agonist KBP-336 elicits a unique combination of weight loss, antinociception and bone protection - a novel disease-modifying osteoarthritis drug.

BACKGROUND: Despite the extensive research to provide a disease-modifying osteoarthritis drug (DMOAD), there is still no approved DMOAD. Dual amylin and calcitonin receptor agonists (DACRA) can provide metabolic benefits along with antinociceptive and potential structural preserving effects. In these studies, we tested a DACRA named KBP-336 on a metabolic model of OA in meniscectomised (MNX) rats. METHODS: We evaluated KBP-336's effect on pain-like symptoms in Sprague Dawley (SD) rats on high-fat diet (HFD) that underwent meniscectomy using the von Frey test to measure the 50% paw withdrawal threshold (PWT) and analyzed using one-way ANOVA. Short in vivo studies and in vitro cell receptor expression systems were used to illustrate receptor pharmacology. RESULTS: After 30 weeks on HFD, including an 8-week treatment, female MNX animals receiving KBP-336 4.5 nmol/Kg/72 h had lower body weight and smaller adipose tissues than their vehicle-treated counterparts. After 20 weeks on HFD, including an 8-week treatment, male rats receiving KBP-336 had lower body weight than the vehicle group. In both the female and male rats, the MNX groups on KBP-336 treatment had a higher PWT than the vehicle-treated MNX group. Aiming to identify the receptor influencing pain alleviation, KBP-336 was compared to the long-acting human calcitonin (hCTA). Single-dose studies on 12-week-old male rats showed that hCTA lowers CTX-I without affecting food intake, confirming its calcitonin receptor selectivity. On the metabolic OA model with 18 weeks of HFD, including 6-week treatment, hCTA at 100 nmol/Kg/24 h and KBP-336 at 0.5, 1.5, and 4.5 nmol/Kg/72 h produced significantly higher PWT in MNX animals compared to MNX animals on vehicle treatment. hCTA and KBP-336 at 0.5 nmol/Kg did not affect body weight and fat tissues. CONCLUSION: Overall, KBP-336 improved the pain observed in the metabolic OA model. Calcitonin receptor activation proved to be essential in this antinociceptive effect.

Impaired Tertiary Dentin Secretion after Shallow Injury in Tgfbr2-Deficient Dental Pulp Cells Is Rescued by Extended CGRP Signaling.

The transforming growth factor ß (TGFß) superfamily is a master regulator of development, adult homeostasis, and wound repair. Dysregulated TGFß signaling can lead to cancer, fibrosis, and musculoskeletal malformations. We previously demonstrated that TGFß receptor 2 (Tgfbr2) signaling regulates odontoblast differentiation, dentin mineralization, root elongation, and sensory innervation during tooth development. Sensory innervation also modulates the homeostasis and repair response in adult teeth. We hypothesized that Tgfbr2 regulates the neuro-pulpal responses to dentin injury. To test this, we performed a shallow dentin injury with a timed deletion of Tgfbr2 in the dental pulp mesenchyme of mice and analyzed the levels of tertiary dentin and calcitonin gene-related peptide (CGRP) axon sprouting. Microcomputed tomography imaging and histology indicated lower dentin volume in Tgfbr2cko M1s compared to WT M1s 21 days post-injury, but the volume was comparable by day 56. Immunofluorescent imaging of peptidergic afferents demonstrated that the duration of axon sprouting was longer in injured Tgfbr2cko compared to WT M1s. Thus, CGRP+ sensory afferents may provide Tgfbr2-deficient odontoblasts with compensatory signals for healing. Harnessing these neuro-pulpal signals has the potential to guide the development of treatments for enhanced dental healing and to help patients with TGFß-related diseases.

Reversion of chronic to episodic migraine in working age and botulinum toxin-resistant patients treated with fremanezumab: A real-life study.

OBJECTIVES: The objectives of this real-life study were to analyze the reversion of chronic migraine (CM) to episodic migraine (EM) with fremanezumab, evaluate its benefit on the symptomatology, and determine the influence of possible clinical features on the reversion. BACKGROUND: The clinical manifestations of CM have a high impact on the quality of life of patients, and monoclonal antibodies such as fremanezumab are used as prophylactic treatment. METHODS: Diagnosed CM patients treated for at least 3 months with monthly fremanezumab were interviewed. The data to assess efficacy were before treatment and at the time of the interview: monthly headache days (MHDs), daily headache hours (DHHs), monthly symptomatic medication days (MSMDs), percentage of patients with symptomatic medication overuse (SMO), and pain intensity with the numerical rating scale (NRS) score. Possible predictors of reversion were analyzed: percentage of patients treated for at least 12 months, hypertension, diabetes mellitus, depression, anxiety, symptomatic control with non-steroidal anti-inflammatory drugs (NSAIDs), triptans or both, and amitriptyline prophylaxis. RESULTS: A total of 54 patients were included, of whom 40 (74.1%) were converters to EM. There were significant improvements in converters compared to pre-treatment in MHDs (28.0 vs. 5.0 days), as well as on the variables DHHs, MSMDs, and SMO. The percentage of erenumab failures was significantly higher in non-converters than in converters, as was the percentage of patients with anxiety. CONCLUSIONS: High reversion from CM to EM was achieved with fremanezumab and notable symptomatological improvement, establishing previous failure to erenumab and anxiety as possible detrimental factors for reversion.

Clinical and epidemiologic characteristics of hospitalized oncological patients with hypercalcemia: a longitudinal, multicenter study.

BACKGROUND: There are few studies that have analyzed the characteristics of hypercalcemia in hospitalized oncological patients. Our objectives were to describe the clinical characteristics of hospitalized patients with paraneoplastic hypercalcemia and to identify prognostic variables for mortality. METHODS: This was an observational, longitudinal, retrospective, and bicentric study. It included adult patients admitted to two hospitals in Málaga, Spain (2014-2018). The minimum follow-up period was 2 years or until death. RESULTS: A total of 154 patients were included; the majority (71.4%) were admitted to the internal medicine department. The median follow-up was 3.5 weeks (interquartile range [IQR] 1.1-11.5). The mean (standard deviation) age was 67.6 (12.3) years, with a predominance of males (58.4%). The median (IQR) serum calcium at admission was 13.2 (11.8-14.6) mg/dl. The most common neoplasms were pulmonary (27.3%), hematologic (23.4%), urological (13%), and breast (12.3%). Furthermore, 56.5% of cases had a known history of neoplasia at the time of diagnosis. The parathyroid hormone (PTH) level was determined in 24%; of these, 10.8% had elevated levels. In all, 95.5% of patients died during follow-up. The median survival was 3.4 weeks (95% confidence interval 2.6-4.3). Factors associated with higher mortality were age, serum calcium at admission, previous history of neoplasia, etiology other than multiple myeloma, and noncorrection of hypercalcemia. CONCLUSIONS: In hospitalized patients, paraneoplastic hypercalcemia was associated with high short-term mortality. Several factors associated with a worse prognosis were identified in these patients.

The TRPA1 Ion Channel Mediates Oxidative Stress-Related Migraine Pathogenesis.

Although the introduction of drugs targeting calcitonin gene-related peptide (CGRP) revolutionized migraine treatment, still a substantial proportion of migraine patients do not respond satisfactorily to such a treatment, and new therapeutic targets are needed. Therefore, molecular studies on migraine pathogenesis are justified. Oxidative stress is implicated in migraine pathogenesis, as many migraine triggers are related to the production of reactive oxygen and nitrogen species (RONS). Migraine has been proposed as a superior mechanism of the brain to face oxidative stress resulting from energetic imbalance. However, the precise mechanism behind the link between migraine and oxidative stress is not known. Nociceptive primary afferent nerve fiber endings express ion channel receptors that change harmful stimuli into electric pain signals. Transient receptor potential cation channel subfamily A member 1 (TRPA1) is an ion channel that can be activated by oxidative stress products and stimulate the release of CGRP from nerve endings. It is a transmembrane protein with ankyrin repeats and conserved cysteines in its N-terminus embedded in the cytosol. TRPA1 may be a central element of the signaling pathway from oxidative stress and NO production to CGRP release, which may play a critical role in headache induction. In this narrative review, we present information on the role of oxidative stress in migraine pathogenesis and provide arguments that TRPA1 may be "a missing link" between oxidative stress and migraine and therefore a druggable target in this disease.

A Vestibular Challenge Combined with Calcitonin Gene-Related Peptide (CGRP) Promotes Anxiety-Like Behaviors.

Motion-induced anxiety and agoraphobia are more frequent symptoms in patients with vestibular migraine (VM) than migraine without vertigo. The neuropeptide calcitonin gene-related peptide (CGRP) is a therapeutic target for migraine and VM, but the link between motion hypersensitivity, anxiety, and CGRP is relatively unexplored, especially in preclinical mouse models. To further examine this link, we tested the effects of systemic CGRP and off-vertical axis rotation (OVAR) on elevated plus maze (EPM) and rotarod performance in male and female C57BL/6J mice. Rotarod ability was assessed using two different dowel diameters: mouse dowel (r = 1.5 cm) versus rat dowel (r = 3.5 cm). EPM results indicate that CGRP alone or OVAR alone did not increase anxiety indices. However, the combination of CGRP and OVAR did elicit anxiety-like behavior. On the rotarod, CGRP reduced performance in both sexes on a mouse dowel but had no effect on a rat dowel, whereas OVAR had a significant effect on the rat dowel. These results suggest that only the combination of CGRP with vestibular stimulation induces anxiety-like behavior and that CGRP affects the dynamic balance function in mice depending on the type of challenge presented. These findings suggest that anxiety-like behaviors can be teased out from imbalance behaviors in a mouse model of "migraine." Future studies are aimed to determine if CGRP receptor antagonists that have been effective treating migraineurs and mouse "migraine" models may also reduce the anxiety observed in migraine.

Role of Gubernaculum testis inervation during the process of testicular migration in human fetuses.

PURPOSE: The gubernaculum seems to be the most important anatomical structure in the testicular migration process. The objective of this paper is to review current literature regarding the role of gubernaculum testis nerves in testicular migration. We conducted a comprehensive literature review about the gubernaculum testis innervation. A PubMed database search was performed in April 2024, focusing on gubernaculum testis and cryptorchidism and genitofemoral nerve (GFN) and calcitonin gene-related peptide (CGRP) gene. The gubernaculum has its own nerve supply, the GFN, descending on the anteromedial surface of the psoas muscle from L1-L2 segments. The second phase of testicular descent is regulated by androgens and CGRP, released from the sensory nucleus of the GFN. The GFN doesn't directly play a role in testicular migration but there is a theory that shows a regulatory function of this nerve in hormonal action during this process. The gubernaculum testis has important structural alterations during the testicular migration and the genitofemoral nerve and CGRP gene are of great importance in this process. The genitofemoral nerve provides motor innervation to the cremaster muscle and gubernaculum, which helps regulate the position of the testes within the scrotum.