Proinflammatory-activated trigeminal satellite cells promote neuronal sensitization: relevance for migraine pathology.

BACKGROUND: Migraine is a complex, chronic, painful, neurovascular disorder characterized by episodic activation of the trigeminal system. Increased levels of calcitonin gene-related peptide (CGRP) are found at different levels during migraine attacks. Interestingly, CGRP is also released within the trigeminal ganglia suggesting possible local effects on satellite cells, a specialized type of glia that ensheaths trigeminal neurons. CGRP was shown to enhance satellite-cell production of interleukin 1beta (IL-1beta), while trigeminal neurons express an activity-dependent production of nitric oxide (NO). Thus, in the present study we tested the hypothesis that IL-1beta and NO induce trigeminal satellite cell activation, and that once activated these cells can influence neuronal responses. RESULTS: Primary cultures of rat trigeminal satellite cells isolated from neuronal cultures were characterized in vitro. Cyclooxygenase (COX) expression and activity were taken as a marker of glial pro-inflammatory activation. Most of the experiments were carried out to characterize satellite cell responses to the two different pro-inflammatory stimuli. Subsequently, medium harvested from activated satellite cells was used to test possible modulatory effects of glial factors on trigeminal neuronal activity. IL-1beta and the NO donor diethylenetriamine/nitric oxide (DETA/NO) elevated PGE2 release by satellite cells. The stimulatory effect of IL-1beta was mediated mainly by upregulation of the inducible form of COX enzyme (COX2), while NO increased the constitutive COX activity. Regardless of the activator used, it is relevant that short exposures of trigeminal satellite cells to both activators induced modifications within the cells which led to significant PGE2 production after removal of the pro-inflammatory stimuli. This effect allowed us to harvest medium from activated satellite cells (so-called 'conditioned medium') that did not contain any stimulus, and thus test the effects of glial factors on neuronal activation. Conditioned medium from satellite cells activated by either IL-1beta or NO augmented the evoked release of CGRP by trigeminal neurons. CONCLUSION: These findings indicate that satellite cells contribute to migraine-related neurochemical events and are induced to do so by autocrine/paracrine stimuli (such as IL-1beta and NO). The responsiveness of IL-1beta to CGRP creates the potential for a positive feedback loop and, thus, a plurality of targets for therapeutic intervention in migraine

Studio di fattibilità del progetto: Biennale del Design di Ascoli Piceno

Il rapporto raccoglie i principali risultati delle attività di ricerca e consulenza tecnicoscientifica per la redazione dello studio di fattibilità del progetto “Biennale del Design ad Ascoli Piceno”, condotte dal Dipartimento ProCAm, Progettazione e Costruzione dell’Ambiente, della Facoltà di Architettura dell’Università di Camerino, in collaborazione con il Consorzio Universitario Piceno (CUP). Obiettivo principale dello studio: delineare i fattori strutturali necessari e le condizioni contestuali più idonee per la realizzazione di una manifestazione biennale dedicata al design, cercando di evidenziarne le potenzialità e gli eventuali benefici, per quanto possibile, anche in termini socio-economici oltre che culturali

Influence of the Oral Dissolution Time on the Absorption Rate of Locally Administered Solid Formulations for Oromucosal Use: The Flurbiprofen Lozenges Paradigm

Flurbiprofen is a nonsteroidal anti-inflammatory agent preferentially used for local oromucosal treatment of painful and/or inflammatory conditions of the oropharynx such as gingivitis, stomatitis, periodontitis, pharyngitis and laryngitis. In this study, we have investigated the bioavailability of a new generic formulation of flurbiprofen lozenges developed by Epifarma Srl, compared to the originator Benactiv Gola® taken as reference. Within the framework of a formal bioequivalence study, we investigated in particular the putative influence of oral dissolution time (i.e. the time spent suckling the lozenge from its intake to complete dissolution) on the absorption rate, and the contribution of this factor to the total variability of plasma flurbiprofen during absorption. We found that the amount of flurbiprofen absorbed into the systemic circulation is not significantly higher for the test drug compared to that of the reference product. We observed that the length of oral dissolution time is inversely correlated to 10-min flurbiprofen plasma levels in the test but not in the reference formulation. We estimated that oral dissolution time accounts for about 14% of overall variability in flurbiprofen plasma 10 min after test drug administration. © 2014 S. Karger AG, Basel

breast screening axillary lymph node status of interval cancers by interval year

Abstract The aim of this study was to determine whether the excess risk of axillary lymph node metastases (N+) differs between interval breast cancers arising shortly after a negative mammography and those presenting later. In a registry-based series of pT1a–pT3 breast carcinoma patients aged 50–74years from the Italian screening programmes, the odds ratio (OR) for interval cancers ( n =791) versus the screen-detected (SD) cancers ( n =1211) having N+ was modelled using forward stepwise logistic regression analysis. The interscreening interval was divided into 1–12, 13–18, and 19–24months. The prevalence of N+ was 28% among SD cancers. With a prevalence of 38%, 42%, and 44%, the adjusted (demographics and N staging technique) OR of N+ for cancers diagnosed between 1–12, 13–18, and 19–24months of interval was 1.41 (95% confidence interval 1.06–1.87), 1.74 (1.31–2.31), and 1.91 (1.43–2.54), respectively. Histologic type, tumour grade, and tumour size were entered in turn into the model. Histologic type had modest effects. With adjustment for tumour grade, the ORs decreased to 1.23 (0.92–1.65), 1.58 (1.18–2.12), and 1.73 (1.29–2.32). Adjusting for tumour size decreased the ORs to 0.95 (0.70–1.29), 1.34 (0.99–1.81), and 1.37 (1.01–1.85). The strength of confounding by tumour size suggested that the excess risk of N+ for first-year interval cancers reflected only their higher chronological age, whereas the increased aggressiveness of second-year interval cancers was partly accounted for by intrinsic biological attributes

Switch to maraviroc with darunavir/r, both QD, in patients with suppressed HIV-1 was well tolerated but virologically inferior to standard antiretroviral therapy: 48-Week results of a randomized trial

Objectives Primary study outcome was absence of treatment failure (virological failure, VF, or treatment interruption) per protocol at week 48. Methods Patients on 3-drug ART with stable HIV-1 RNA <50 copies/mL and CCR5-tropic virus were randomized 1:1 to maraviroc with darunavir/ritonavir qd (study arm) or continue current ART (continuation arm).Results In June 2015, 115 patients were evaluable for the primary outcome (56 study, 59 continuation arm). The study was discontinued due to excess of VF in the study arm (7 cases, 12.5%, vs 0 in the continuation arm, p = 0.005). The proportion free of treatment failure was 73.2% in the study and 59.3% in the continuation arm. Two participants in the study and 10 in the continuation arm discontinued therapy due to adverse events (p = 0.030). At VF, no emergent drug resistance was detected. Co-receptor tropism switched to non-R5 in one patient. Patients with VF reported lower adherence and had lower plasma drug levels. Femoral bone mineral density was significantly improved in the study arm. Conclusion Switching to maraviroc with darunavir/ritonavir qd in virologically suppressed patients was associated with improved tolerability but was virologically inferior to 3-drug therap

Use of High-Dose Nebulized Colistimethate in Patients with Colistin-Only Susceptible Acinetobacter baumannii VAP: Clinical, Pharmacokinetic and Microbiome Features

(1) Background: Colistin-only susceptible (COS) Acinetobacter baumannii (AB) ventilator-associated pneumonia (VAP) represents a clinical challenge in the Intensive Care Unit (ICU) due to the negligible lung diffusion of this molecule and the low-grade evidence on efficacy of its nebulization. (2) Methods: We conducted a prospective observational study on 134 ICU patients with COS-AB VAP to describe the 'real life' clinical use of high-dose (5 MIU q8) aerosolized colistin, using a vibrating mesh nebulizer. Lung pharmacokinetics and microbiome features were investigated. (3) Results: Patients were enrolled during the COVID-19 pandemic with the ICU presenting a SAPS II of 42 [32-57]. At VAP diagnosis, the median PaO2/FiO(2) was 120 [100-164], 40.3% were in septic shock, and 24.6% had secondary bacteremia. The twenty-eight day mortality was 50.7% with 60.4% and 40.3% rates of clinical cure and microbiological eradication, respectively. We did not observe any drug-related adverse events. Epithelial lining fluid colistin concentrations were far above the CRAB minimal-inhibitory concentration and the duration of nebulized therapy was an independent predictor of microbiological eradication (12 [9.75-14] vs. 7 [4-13] days, OR (95% CI): 1.069 (1.003-1.138), p = 0.039). (4) Conclusions: High-dose and prolonged colistin nebulization, using a vibrating mesh, was a safe adjunctive therapeutic strategy for COS-AB VAP. Its right place and efficacy in this setting warrant investigation in interventional studies

Novel sensitive, specific and rapid pharmacogenomic test for the prediction of abacavir hypersensitivity reaction: HLA-B*57:01 detection by real-time PCR.

Aim: International HIV treatment guidelines recommend HLA-B*57:01 typing before abacavir administration, in order to reduce the incidence of abacavir hypersensitivity reactions, the major cause of early therapy discontinuation. A fast, sensitive and specific test for HLA-B*57:01 detection has been developed in the present study. Materials & methods: Two sets of sequence-specific primers were designed, and amplification rapidly detected by real-time PCR. Results: A total of 108 samples were analyzed in a single-blind fashion, and 41 samples were identified as positive. Complete agreement, with k = 1 (standard error = 0.0962, p < 0.0001), was found, with a validated methodology used in the EPI109367 clinical trial funded by GlaxoSmithKline, and consisting of low-resolution sequence-specific oligonucleotide PCR, followed by high-resolution sequence-specific oligonucleotide PCR carried out on the HLA-B*57-positive samples. Conclusion: We provided a detailed characterization of a novel HLA-B*57:01 screening test, which can be easily implemented by those laboratories already involved in the detection of viral load and virus genotyping

Off-label use of combined antiretroviral therapy, analysis of data collected by the Italian Register for HIV-1 infection in paediatrics in a large cohort of children

Background: Early start of highly active antiretroviral therapy (HAART) in perinatally HIV-1 infected children is the optimal strategy to prevent immunological and clinical deterioration. To date, according to EMA, only 35% of antiretroviral drugs are licenced in children  25%. At last check, during the off label regimen, the 80% (40/50) of patients had an undetectable VL, and 90% (45/50) of them displayed CD4 + T lymphocyte percentage > 25%. The most widely used off-label drugs were: dolutegravir/abacavir/lamivudine (16%; 8/50), emtricitbine/tenofovir disoproxil (22%; 11/50), lopinavir/ritonavir (20%; 10/50) and elvitegravir/cobicistat/emtricitabine/ tenofovir alafenamide (10%; 10/50). At logistic regression analysis, detectable VL before starting the current HAART regimen was a risk factor for receiving an off-label therapy (OR: 2.41; 95% CI 1.13-5.19; p = 0.024). Moreover, children < 2 years of age were at increased risk for receiving off-label HAART with respect to older children (OR: 3.24; 95% CI 1063-7.3; p = 0.001). Even if our safety data regarding off-label regimens where poor, no adverse event was reported. Conclusion: The prescription of an off-label HAART regimen in perinatally HIV-1 infected children was common, in particular in children with detectable VL despite previous HAART and in younger children, especially those receiving their first regimen. Our data suggest similar proportions of virological and immunological successes at last check among children receiving off-label or on-label HAART. Larger studies are needed to better clarify efficacy and safety of off-label HAART regimens in children, in order to allow the enlargement of on-label prescription in children