Clinical and laboratory characterization of patients with localized scleroderma and response to UVA-1 phototherapy: In vivo and in vitro skin models

Background/Purpose Localized scleroderma (LS) is a rare disease leading to progressive hardening and induration of the skin and subcutaneous tissues. LS is responsive to UVA-1 phototherapy, though its exact mechanism of action dermal fibrosis is yet to be fully elucidated. We aimed to investigate the molecular changes induced by UVA-1 rays in human primary fibroblasts cultures. Methods A total of 16 LS patients were treated with medium-dose UVA-1 phototherapy. At baseline, during and after therapy, Localized Scleroderma Assessment Tool, Dermatology Life Quality Index and lesions' staging and mapping were performed along with high-frequency ultrasound (HFUS) examination for dermal thickness assessment. Gene expression analysis for 23 mRNA transcripts, in vitro UVA-1 irradiation and viability tests were realized on lesional fibroblasts' primary cultures, before and 3 months after therapy. Results The dermal thickness, the LoSCAT and the DLQI progressively decreased starting from the last phototherapy session up to the 6 and 9 month follow-ups (-57% and -60%, respectively). Molecular gene analysis (rt-PCR) revealed that UVA-1 phototherapy exerts multiple effects: the activation of specific anti-fibrotic pathways (e.g., overexpression of CTHRC1 and metalloproteases 1, 2, 7, 8, 9, 12, suppression of TIMP-1), the downregulation of peculiar pro-fibrotic pathways (e.g., downregulation of TGF-ss, TGF-ssrII, Grb2, SMAD 2/3, TNRSF12A, CTGF) through a significant overexpression of IL-1ss; the stabilization of collagen synthesis acting on genes COL1A1, COL3A1, COL8A1, COL10A1, COL12A1. Conclusion UVA-1 phototherapy adds significant benefits in local tissue remodeling, rebalancing the alteration between pro-fibrotic and anti-fibrotic pathways; these changes can be well monitored by HFUS. © 2022 The Authors

The organic residues of lining in transport vessels from the Red Sea coast of Eritrea: a further element to understand past commercial relations

AbstractThe archaeological site of Adulis lays on the Red Sea Coast of Eritrea and during Late antiquity played a significant role in interregional commerce among the Mediterranean, the Red Sea and the Indian Ocean coasts. Contacts with the Eastern Mediterranean, Arabian Peninsula and the Sasanian world have been attested from different classes of pottery that were brought to light from on-going excavations at the site. Transport vessels have attracted particular attention as they testify the extent of trades and exchange networks. Transport vessels were coated by organic materials to seal porosity and make them suitable to transport different liquids and/or food. The characterisation of coating materials helped shedding light on their function, and support the attribution to different classes of transport vessels found in the Indian Ocean and Red Sea worlds. Here, the characterisation of the organic lining detected on a set of samples identified as Late Roman Amphora 1 is discussed. Results from the chemical analyses, performed preliminarily by FT-IR and then by GC–MS, revealed that bitumen was used for lining the jars, thus leading to set the classification of the amphorae within the wide class of the so- called Torpedo jars. By overcoming the question of typological complexity posed from macroscopic examination of the sherds, the chemical investigation contributed here crucial information for the interpretation of past trading in the Indian Ocean. The research gave clues to broaden the distribution of the Torpedo jars to Adulis, giving an unexpected insight into the trading routes of the past

CDKL5 deficiency disorder: progressive brain atrophy may be part of the syndrome

The clinical phenotype of Cyclin-Dependent Kinase-Like 5 (CDKL5) deficiency disorder (CDD) has been delineated but neuroimaging features have not been systematically analyzed. We studied brain magnetic resonance imaging (MRI) scans in a cohort of CDD patients and reviewed age at seizure onset, seizure semiology, head circumference. Thirty-five brain MRI from 22 unrelated patients were included. The median age at study entry was 13.4 years. In 14/22 patients (85.7%), MRI in the first year of life was unremarkable in all but two. In 11/22, we performed MRI after 24 months of age (range 2.5-23 years). In 8 out of 11 (72.7%), MRI showed supratentorial atrophy and in six cerebellar atrophy. Quantitative analysis detected volumetric reduction of the whole brain (-17.7%, P-value = 0.014), including both white matter (-25.7%, P-value = 0.005) and cortical gray matter (-9.1%, P-value = 0.098), with a reduction of surface area (-18.0%, P-value = 0.032), mainly involving the temporal regions, correlated with the head circumference (& rho; = 0.79, P-value = 0.109). Both the qualitative structural assessment and the quantitative analysis detected brain volume reduction involving the gray and white matter. These neuroimaging findings may be related to either progressive changes due to CDD pathogenesis, or to the extreme severity of epilepsy, or both. Larger prospective studies are needed to clarify the bases for the structural changes we observed

On the occasion of the thirtieth anniversary of the journal Acta Stomatologica Croatica

Introduction: Opioid receptors are currently classified as Mu (\u3bc), Delta (\u3b4), Kappa (\u3ba) plus the opioid related nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP). Despite compelling evidence for interactions and benefits of targeting more than one receptor type in producing analgesia, clinical ligands are Mu agonists. In this study we have designed a Mu-NOP agonist named DeNo. The Mu agonist component is provided by dermorphin, a peptide isolated from the skin of Phyllomedusa frogs and the NOP component by the endogenous agonist N/OFQ. Methods: We have assessed receptor binding profile of DeNo and compared with dermorphin and N/OFQ. In a series of functional screens we have assessed the ability to (i) increase Ca2+ in cells coexpressing recombinant receptors and a the chimeric protein G\u3b1qi5, (ii) stimulate the binding of GTP\u3b3[35S], (iii) inhibit cAMP formation, (iv) activate MAPKinase, (v) stimulate receptor-G protein and arrestin interaction using BRET, (vi) electrically stimulated guinea pig ileum (gpI) assay and (vii) ability to produce analgesia via the intrathecal route in rats. Results: DeNo bound to Mu (pKi; 9.55) and NOP (pKi; 10.22) and with reasonable selectivity. This translated to increased Ca2+ in G\u3b1qi5 expressing cells (pEC50 Mu 7.17; NOP 9.69), increased binding of GTP\u3b3[35S] (pEC50 Mu 7.70; NOP 9.50) and receptor-G protein interaction in BRET (pEC50 Mu 8.01; NOP 9.02). cAMP formation was inhibited and arrestin was activated (pEC50 Mu 6.36; NOP 8.19). For MAPK DeNo activated p38 and ERK1/2 at Mu but only ERK1/2 at NOP. In the gpI DeNO inhibited electrically-evoked contractions (pEC50 8.63) that was sensitive to both Mu and NOP antagonists. DeNo was antinociceptive in rats. Conclusion: Collectively these data validate the strategy used to create a novel bivalent Mu-NOP peptide agonist by combining dermorphin (Mu) and N/OFQ (NOP). This molecule behaves essentially as the parent compounds in vitro. In the antonocicoeptive assays employed in this study DeNo displays only weak antinociceptive properties

Detection of Epileptogenic Focal Cortical Dysplasia Using Graph Neural Networks: A MELD Study

Importance: A leading cause of surgically remediable, drug-resistant focal epilepsy is focal cortical dysplasia (FCD). FCD is challenging to visualize and often considered magnetic resonance imaging (MRI) negative. Existing automated methods for FCD detection are limited by high numbers of false-positive predictions, hampering their clinical utility. // Objective: To evaluate the efficacy and interpretability of graph neural networks in automatically detecting FCD lesions on MRI scans. // Design, Setting, and Participants: In this multicenter diagnostic study, retrospective MRI data were collated from 23 epilepsy centers worldwide between 2018 and 2022, as part of the Multicenter Epilepsy Lesion Detection (MELD) Project, and analyzed in 2023. Data from 20 centers were split equally into training and testing cohorts, with data from 3 centers withheld for site-independent testing. A graph neural network (MELD Graph) was trained to identify FCD on surface-based features. Network performance was compared with an existing algorithm. Feature analysis, saliencies, and confidence scores were used to interpret network predictions. In total, 34 surface-based MRI features and manual lesion masks were collated from participants, 703 patients with FCD–related epilepsy and 482 controls, and 57 participants were excluded during MRI quality control. // Main Outcomes and Measures: Sensitivity, specificity, and positive predictive value (PPV) of automatically identified lesions. // Results: In the test dataset, the MELD Graph had a sensitivity of 81.6% in histopathologically confirmed patients seizure-free 1 year after surgery and 63.7% in MRI–negative patients with FCD. The PPV of putative lesions from the 260 patients in the test dataset (125 female [48%] and 135 male [52%]; mean age, 18.0 [IQR, 11.0-29.0] years) was 67% (70% sensitivity; 60% specificity), compared with 39% (67% sensitivity; 54% specificity) using an existing baseline algorithm. In the independent test cohort (116 patients; 62 female [53%] and 54 male [47%]; mean age, 22.5 [IQR, 13.5-27.5] years), the PPV was 76% (72% sensitivity; 56% specificity), compared with 46% (77% sensitivity; 47% specificity) using the baseline algorithm. Interpretable reports characterize lesion location, size, confidence, and salient features. // Conclusions and Relevance: In this study, the MELD Graph represented a state-of-the-art, openly available, and interpretable tool for FCD detection on MRI scans with significant improvements in PPV. Its clinical implementation holds promise for early diagnosis and improved management of focal epilepsy, potentially leading to better patient outcomes

Interpretable surface-based detection of focal cortical dysplasias:a Multi-centre Epilepsy Lesion Detection study

One outstanding challenge for machine learning in diagnostic biomedical imaging is algorithm interpretability. A key application is the identification of subtle epileptogenic focal cortical dysplasias (FCDs) from structural MRI. FCDs are difficult to visualize on structural MRI but are often amenable to surgical resection. We aimed to develop an open-source, interpretable, surface-based machine-learning algorithm to automatically identify FCDs on heterogeneous structural MRI data from epilepsy surgery centres worldwide. The Multi-centre Epilepsy Lesion Detection (MELD) Project collated and harmonized a retrospective MRI cohort of 1015 participants, 618 patients with focal FCD-related epilepsy and 397 controls, from 22 epilepsy centres worldwide. We created a neural network for FCD detection based on 33 surface-based features. The network was trained and cross-validated on 50% of the total cohort and tested on the remaining 50% as well as on 2 independent test sites. Multidimensional feature analysis and integrated gradient saliencies were used to interrogate network performance. Our pipeline outputs individual patient reports, which identify the location of predicted lesions, alongside their imaging features and relative saliency to the classifier. On a restricted 'gold-standard' subcohort of seizure-free patients with FCD type IIB who had T1 and fluid-attenuated inversion recovery MRI data, the MELD FCD surface-based algorithm had a sensitivity of 85%. Across the entire withheld test cohort the sensitivity was 59% and specificity was 54%. After including a border zone around lesions, to account for uncertainty around the borders of manually delineated lesion masks, the sensitivity was 67%. This multicentre, multinational study with open access protocols and code has developed a robust and interpretable machine-learning algorithm for automated detection of focal cortical dysplasias, giving physicians greater confidence in the identification of subtle MRI lesions in individuals with epilepsy

Rationale and design of an independent randomised controlled trial evaluating the effectiveness of aripiprazole or haloperidol in combination with clozapine for treatment-resistant schizophrenia

Abstract BACKGROUND: One third to two thirds of people with schizophrenia have persistent psychotic symptoms despite clozapine treatment. Under real-world circumstances, the need to provide effective therapeutic interventions to patients who do not have an optimal response to clozapine has been cited as the most common reason for simultaneously prescribing a second antipsychotic drug in combination treatment strategies. In a clinical area where the pressing need of providing therapeutic answers has progressively increased the occurrence of antipsychotic polypharmacy, despite the lack of robust evidence of its efficacy, we sought to implement a pre-planned protocol where two alternative therapeutic answers are systematically provided and evaluated within the context of a pragmatic, multicentre, independent randomised study. METHODS/DESIGN: The principal clinical question to be answered by the present project is the relative efficacy and tolerability of combination treatment with clozapine plus aripiprazole compared with combination treatment with clozapine plus haloperidol in patients with an incomplete response to treatment with clozapine over an appropriate period of time. This project is a prospective, multicentre, randomized, parallel-group, superiority trial that follow patients over a period of 12 months. Withdrawal from allocated treatment within 3 months is the primary outcome. DISCUSSION: The implementation of the protocol presented here shows that it is possible to create a network of community psychiatric services that accept the idea of using their everyday clinical practice to produce randomised knowledge. The employed pragmatic attitude allowed to randomly allocate more than 100 individuals, which means that this study is the largest antipsychotic combination trial conducted so far in Western countries. We expect that the current project, by generating evidence on whether it is clinically useful to combine clozapine with aripiprazole rather than with haloperidol, provides physicians with a solid evidence base to be directly applied in the routine care of patients with schizophrenia

Studio dei reperti archeologici egizi partendo dall’analisi VOCs con una nuova tecnica di massa in situ e con la cromatografia liquida ad alta prestazione

In the present study, we evaluated the potential of Selected Ion-Flow Tube with Mass Spectrometry (SIFT-MS) and Liquid Chromatography coupled to Mass Spectrometry (HPLC-MS / MS) for the characterization and the study of organic materials such as constituents of archaeological finds . The SIFT-MS, a non-destructive technique to be carried out in situ, was chosen in order to evaluate its potentials in the study of the volatile organic components (VOCs) of very ancient artifacts such as Egyptian vases. The HPLC-MS/MS, on the other hand, was used for the characterization of the lipid materials and, after an appropriate optimization of the analitic procedure, for the realization of a database composed by waxes of different nature

Pianosa accessibile. Opportunità e limiti

LAUREA MAGISTRALELa tesi affronta il tema della riqualificazione dell’isola di Pianosa, ex colonia penale agricola e carcere di massima sicurezza, per il suo rilancio sia dal punto di vista turistico che insediativo. L’approccio al tema è stato affrontato inizialmente tramite uno studio approfondito della documentazione reperita in modo da delineare l’evoluzione storica che ha interessato l’Isola e la situazione territoriale ed amministrativa attuale. In seguito al sopralluogo, abbiamo elaborato un’approfondita analisi dello stato di fatto dei luoghi, da cui sono emerse numerose opportunità progettuali che vedono nell’accessibilità un limite ma al contempo l’elemento conduttore per lo sviluppo dell’Isola; in quanto la fruizione è soggetta a forti restrizioni dovute all’Ente Parco e all’inadeguata rete di collegamento marittimo. Ulteriori limitazioni si prospettano in merito ai costi elevati per il riutilizzo delle strutture degradate e l’attivazione di servizi basilari; inoltre la presenza dell’attività carceraria come realtà protetta, che vede oggi sull’Isola una trentina di detenuti in semilibertà e regime di lavoro all’esterno, porta con se il problema di gestione delle interazioni. Il presupposto fondamentale, su cui si fonda l’approfondimento oggetto di tesi, è che l’isola di Pianosa sia raggiungile e fruibile da tutti in maniera libera e costante, fatte salve alcune attenzioni e limitazioni connesse alla tutela di alcune risorse indicate dal Parco e all’attività carceraria. Per questo motivo il nostro intervento propone la sistemazione del porto in modo da permettere un attracco libero, il recupero di manufatti dismessi destinandoli a servizi, strutture ricettive e commerciali, e la riqualificazione dei percorsi al fine di consentire una fruizione dei diversi scenari che l’isola offre in quanto sito di elevato valore naturalistico, storico e archeologico, sempre nel rispetto delle caratteristiche ambientali e paesaggistiche. Queste proposte sono da vedersi come primo intervento di un progetto più complesso e articolato che permetterebbe di ripristinare le antiche funzioni dell’isola. L’obiettivo del nostro progetto è quindi incrementare l’offerta turistica in modo da attrarre un bacino di utenza più vasto e destagionalizzare le affluenze; questo processo porterebbe ad una richiesta di servizi tale da incentivare la residenza stabile e di conseguenza far rivivere l’isola di Pianosa