Prophylactic activity of increasing doses of intravenous histamine in refractory migraine: Retrospective observations of a series of patients with migraine without aura

Background: Histamine is thought to play a pivotal role in the modulation of peripheral and central pain. The administration of increasing doses of histamine may lead to desensitization of receptors of histamine types 1 and 2, causing meningeal vasodilation, and to depletion of neuropeptides in the trigeminal ganglion, thus inhibiting the initiation of migraine. Objective: In this study, the efficacy and tolerability of increasing doses of IV histamine in migraine prophylaxis were investigated. Methods: This single-center, open-label, retrospective, controlled study was conducted at the Headache Center (Department of Internal Medicine, University of Florence, Villa Monna Tessa, Italy). Patients included in the study had 3 to 6 migraines without aura per month that were refractory to common symptomatic and prophylactic agents in the 6 months preceding the study. Patients were treated with IV histamine hydrochloride for 21 days starting with a dosage of 0.5 mg/d and increasing to 4.0 mg/d. To assess the efficacy of the treatment, these patients were matched for age; sex; and frequency, duration, and severity of attacks with untreated migraineurs. Clinical benefit was defined as ⩽ 1 migraine of mild intensity per month. Tolerability was assessed during the hospitalization period, and patients were instructed to contact the Headache Center to report any adverse effects after hospital discharge. Results: The histamine group comprised 47 patients (40 women, 7 men; mean [SD] age, 42.0 [8.6] years) and the control group comprised 23 patients (20 women, 3 men; mean [SD] age, 38.8 [8.4] years). The histamine-treated patients showed a clinical benefit lasting for a mean of 10.4 (4.2) months, while the patients in the control group showed a clinical benefit of 3.8 (1.9) months. The difference in the duration of the clinical benefit between the 2 groups was 6.6 months (95% CI, 5.15-7.99). Adverse effects consisted of flushing, heat sensation during infusion, headache, and palpitations. Conclusions: In this study, histamine showed lasting prophylactic efficacy in migraineurs. If further research confirms this preliminary finding, histamine could be considered when established prophylactic drugs, such as betablockers, calcium antagonists, antidepressants, and antiepileptics, have not been effective

Circular RNAs in embryogenesis and cell differentiation with a focus on cancer development

In the recent years thousands of non-coding RNAs have been identified, also thanks to highthroughput sequencing technologies. Among them, circular RNAs (circRNAs) are a well-represented class characterized by the high sequence conservation and cell type specific expression in eukaryotes. They are covalently closed loops formed through back-splicing. Recently, circRNAs were shown to regulate a variety of cellular processes functioning as miRNA sponges, RBP binding molecules, transcriptional regulators, scaffold for protein translation, as well as immune regulators. A growing number of studies are showing that deregulated expression of circRNAs plays important and decisive actions during the development of several human diseases, including cancer. The research on their biogenesis and on the various molecular mechanisms in which they are involved is going very fast, however, there are still few studies that address their involvement in embryogenesis and eukaryotic development. This review has the intent to describe the most recent progress in the study of the biogenesis and molecular activities of circRNAs providing insightful information in the field of embryogenesis and cell differentiation. In addition, we describe the latest research on circRNAs as novel promising biomarkers in diverse types of tumors

p21(WAF1 )expression induced by MEK/ERK pathway activation or inhibition correlates with growth arrest, myogenic differentiation and onco-phenotype reversal in rhabdomyosarcoma cells

BACKGROUND: p21(WAF1), implicated in the cell cycle control of both normal and malignant cells, can be induced by p53-dependent and independent mechanisms. In some cells, MEKs/ERKs regulate p21(WAF1 )transcriptionally, while in others they also affect the post-transcriptional processes. In myogenic differentiation, p21(WAF1 )expression is also controlled by the myogenic transcription factor MyoD. We have previously demonstrated that the embryonal rhabdomyosarcoma cell line undergoes growth arrest and myogenic differentiation following treatments with TPA and the MEK inhibitor U0126, which respectively activate and inhibit the ERK pathway. In this paper we attempt to clarify the mechanism of ERK-mediated and ERK-independent growth arrest and myogenic differentiation of embryonal and alveolar rhabdomyosarcoma cell lines, particularly as regards the expression of the cell cycle inhibitor p21(WAF1). RESULTS: p21(WAF1 )expression and growth arrest are induced in both embryonal (RD) and alveolar (RH30) rhabdomyosarcoma cell lines following TPA or MEK/ERK inhibitor (U0126) treatments, whereas myogenic differentiation is induced in RD cells alone. Furthermore, the TPA-mediated post-transcriptional mechanism of p21(WAF1)-enhanced expression in RD cells is due to activation of the MEK/ERK pathway, as shown by transfections with constitutively active MEK1 or MEK2, which induces p21(WAF1 )expression, and with ERK1 and ERK2 siRNA, which prevents p21(WAF1 )expression. By contrast, U0126-mediated p21(WAF1 )expression is controlled transcriptionally by the p38 pathway. Similarly, myogenin and MyoD expression is induced both by U0126 and TPA and is prevented by p38 inhibition. Although MyoD and myogenin depletion by siRNA prevents U0126-mediated p21(WAF1) expression, the over-expression of these two transcription factors is insufficient to induce p21(WAF1). These data suggest that the transcriptional mechanism of p21(WAF1 )expression in RD cells is rescued when MEK/ERK inhibition relieves the functions of myogenic transcription factors. Notably, the forced expression of p21(WAF1 )in RD cells causes growth arrest and the reversion of anchorage-independent growth. CONCLUSION: Our data provide evidence of the key role played by the MEK/ERK pathway in the growth arrest of Rhabdomyosarcoma cells. The results of this study suggest that the targeting of MEK/ERKs to rescue p21(WAF1 )expression and myogenic transcription factor functions leads to the reversal of the Rhabdomyosarcoma phenotype

Development and validation of the ID-EC - The ITALIAN version of the identify chronic migraine

Background: Case-finding tools, such as the Identify Chronic Migraine (ID-CM) questionnaire, can improve detection of CM and alleviate its significant societal burden. We aimed to develop and validate the Italian version of the ID-CM (ID-EC) in paper and as a smart app version in a headache clinic-based setting. Methods: The study investigators translated and adapted to the Italian language the original ID-CM questionnaire (ID-EC) and further implemented it as a smart app. The ID-EC was tested in its paper and electronic version in consecutive patients referring to 9 Italian tertiary headache centers for their first in-person visit. The scoring algorithm of the ID-EC paper version was applied by the study investigators (case-finding) and by patients (self-diagnosis), while the smart app provided to patients automatically the diagnosis. Diagnostic accuracy of the ID-EC was assessed by matching the questionnaire results with the interview-based diagnoses performed by the headache specialists during the visit according to the criteria of International Classification of Headache Disorders, III edition, beta version. Results: We enrolled 531 patients in the test of the paper version of ID-EC and 427 in the validation study of the smart app. According to the clinical diagnosis 209 patients had CM in the paper version study and 202 had CM in the smart app study. 79.5% of patients returned valid paper questionnaires, while 100% of patients returned valid and complete smart app questionnaires. The paper questionnaire had a 81.5% sensitivity and a 81.1% specificity for case-finding and a 30.7% sensitivity and 90.7% specificity for self-diagnosis, while the smart app had a 64.9% sensitivity and 90.2% specificity. Conclusions: Our data suggest that the ID-EC, developed and validated in tertiary headache centers, is a valid case-finding tool for CM, with sensitivity and specificity values above 80% in paper form, while the ID-EC smart app is more useful to exclude CM diagnosis in case of a negative result. Further studies are warranted to assess the diagnostic accuracy of the ID-EC in general practice and population-based settings

Evaluation of effectiveness of an innovative semen extender (Formula®) comparing with a traditional extender (Lepus®) for artificial insemination in rabbits does

This study aimed to investigate the preservability and viability of the rabbit spermatozoa diluted in a new semen extender Formula® in comparison with Lepus® at 17 °C of storage. The main characteristic of the new extender formulation is the use of an enzymatic agent associated to a polysaccharide as energy source precursor, added with gentamycin. During eight trials, ejaculates from 70 bucks were collected and diluted at 1:10 ratio with both the extenders, after 24 h of storage the semen doses were used for the artificial insemination (AI). Aliquots of the semen doses for each trial were stored at 17 °C, the total and progressive motility were checked at 0, 4, 12, 18, 24, 36, 48, 60, 72, 84, 96, 108 h of storage. A total of 1267 and 1525 does were inseminated, respectively with Formula® and Lepus®. During storage the mean total and progressive motility (77.23% and 72.854%, respectively) were significantly higher for Formula® (p < .01) and the progressive motility at almost 70% was maintained for at least 60 h vs the 24 h of storage for Lepus® with significant differences after 12 h of storage (p < .05). The new extender reported a higher pregnancy rate (p < .05) and an average of 9.25 rabbits born per litter vs 8.83 for the traditional extender (p < .05), while the mean of the newborn alive was 9.08 using Formula® vs 8.51 with Lepus® (p < .05). In conclusion, the use of Formula® is recommended for rabbit semen AI programmes

La filosofia è un discorso pubblico? Medialità e mediaticità del discorso filosofico

Today, in talking about public sphere and the possible role of philosophy in it, one can not but refer to information technology. However, in order to investigate the relationship of the philosophical discourse with the environments of the digital age, seems appropriate to start from the more general question of the status of philosophy itself, as well as from its relationship with persuasion and the rhetorical dimension. The basic question to which this essay is intended to answer is the following: in what sense is philosophy a public discourse? In what terms, moreover, does the reconfiguration of the public/private distinction determined by digi-tal media influence the nature of the philosophical debate, its internal dynam-ics, its objectives and its diffusion? First of all, the article will reconstruct, in particular through an analysis of the Platonic Phaedrus, the common origins and a certain consubstantiality of philosophical thought and its rhetorical manifestation. Starting from this assumption the thesis according to which philosophy has always been and, in a certain sense, must be philosophy of communication will be supported. The specificity of the relationship between philosophy and communication lies in its being always mediology in the sense of a discourse in, of, and on the medium, medium and medium. Finally, this retrospective redefinition of the status of philosophy will be applied to the context of Computer-Mediated Communication (CMC) in order to understand how reflection can recover its role of taking a critical distance in the current public context

La cultura della normativa antisismica e la sua evoluzione.

Il centenario dell’evento sismico che ha interessato lo Stretto è stato colto come occasione di riflessioni sulle attività antisismiche sviluppatesi nell’arco del secolo XX. In particolare il contributo al libro e al convegno ha trattato l’evoluzione della normativa antisismica italiana che origina proprio nel periodo successivo alla calamità che colpì Reggio e Messina. A queste riflessioni se ne aggiungono altre sulle tecniche tradizionali e sulle moderne applicazioni tecnologiche per il loro consolidamento e rinforzo. In particolare sono state evidenziate quelle tipologie di murature armate (con ferro e legno) che spesso sono state adottate nell’area mediterranea e che con la loro reiterazione e permanenza nel tempo assumono caratteri di tradizionalità costruttiva. / The following study wants to underline the evolution of the knowledge and the constructive procedures in relationship to the seismic action and the normative production of the last three/four centuries. It is possible to find out in the ancient framework constructions, in a way alternative to the blocks structures or to the masonry building, a common matrix in the Mediterranean area, developed in the last century, when the elastic framework started to be considered as a valid answer to seismic possibility. Through the examination of the norms, it is possible to track a first phase in which the technical-normative devices come after the events – as the occasion of the seism of Calabria – Sicily and the Abruzzo regions (where the event was influenced by similar cultural context) – with local characteristic and constructive directions. There is a second phase in which the technical-normative set of rules, extended to the whole national territory, including project indications based on the numerical verification, precedes the event with a pre-caution attitude. At the same time, in the development of the reinforced concrete technique it is found a parable that is sorted out among its own technical identity and the application in the field of consolidation of historical and monumental constructions. In this contest, we can witness at first to the one ‘triumphal’ and ‘aggressive’ phase of great successes and expectations – regularly recorded by essays and publications of that time – so to give way to a reflection in which – apart from the positive effects in safety terms – incompatibility and lacks were also recognized, especially in terms of duration. At the same time, with an evident causal connection, a recovery of the structural values of the masonries occurred until, in the actual phase, particular ‘guidelines’ are developed with maximum respect for the existing structures, in the order to preserve their historical and documentary capability and also their ‘material part’. At the same time, the techniques and the cares of the historical construction tradition are also recovered through their employment

Emerging Pharmacological Treatments for Migraine in the Pediatric Population

Headaches in children and adolescents have high incidence and prevalence rates, with consequent elevated disability costs to individuals and the community. Pediatric migraine is a disorder with substantial clinical differences compared to the adult form. Few clinical trials have been performed specifically on primary headache in pediatric populations using acute and preventative treatments, often with conflicting findings. The limited high-quality data on the effectiveness of treatments are also due to the high placebo effect, in terms of reductions in both the frequency and intensity of migraine attacks in the pediatric population. The recent introduction of calcitonin gene-related peptide (CGRP) pathway inhibitors and ditans is changing the treatment of migraine, but the majority of the data are still limited to adulthood. Thus, few drugs have indications for migraine treatment in the pediatric age group, and limited evidence gives guidance as to the choice of pharmacotherapy. Herein, we review the current evidence of pharmacological treatments and ongoing clinical trials on acute and preventative treatments in the pediatric population with migraine

Emerging Pharmacological Treatments for Migraine in the Pediatric Population

Headaches in children and adolescents have high incidence and prevalence rates, with consequent elevated disability costs to individuals and the community. Pediatric migraine is a disorder with substantial clinical differences compared to the adult form. Few clinical trials have been performed specifically on primary headache in pediatric populations using acute and preventative treatments, often with conflicting findings. The limited high-quality data on the effectiveness of treatments are also due to the high placebo effect, in terms of reductions in both the frequency and intensity of migraine attacks in the pediatric population. The recent introduction of calcitonin gene-related peptide (CGRP) pathway inhibitors and ditans is changing the treatment of migraine, but the majority of the data are still limited to adulthood. Thus, few drugs have indications for migraine treatment in the pediatric age group, and limited evidence gives guidance as to the choice of pharmacotherapy. Herein, we review the current evidence of pharmacological treatments and ongoing clinical trials on acute and preventative treatments in the pediatric population with migraine