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

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

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

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods/Design</p> <p>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.</p> <p>Discussion</p> <p>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.</p> <p>Trial Registration</p> <p><b>Clincaltrials.gov Identifier</b>: NCT00395915</p

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

A diastereoselective synthesis of Cebranopadol, a novel analgesic showing NOP/mu mixed agonism.

A diastereoselective synthesis of the title compound as a single E diastereomer has been efficiently accomplished by assembling the featured pyrano-indole scaffold of the spiro[cyclohexanedihydropyrano[ 3,4-b]-indole]-amine framework through an oxa-Pictet-Spengler reaction, promoted by a cheap and green Zeolite catalyst. Basic pharmacological experiments demonstrate that Cebranopadol acts as a mixed nociception/orphanin FQ (NOP) and mu (MOP) opioid receptor agonist useful for treatment of chronic pain

A visual analytics gui for multigranular spatio-Temporal exploration and comparison of open mobility data

Recent technological developments in the fields of positioning and mobile communications gave rise to the availabilityof massive spatio-Temporal open datasets about cities. A proper exploitation of these big datasets by decision makers of smart cities could be very useful to analyse and understand mobility patterns, with the final goal of easing many transportation problems, like parking search and traffic. While many research efforts have been aimed at defining powerful visual analytics tools for exploring vehicular trajectory data, to date almost no specifically tailored tools are available to analyse (on-street) parking data and dynamics. To fill this gap, in this paper we present the current state of an on-going research on the development of a visual analytics tool, meant to support decision makers of smart cities in performing multigranular spatio-Temporal explorations of mobility open data, like those about parking. Moreover, the proposed GUI offers the possibility to overlay external spatio-Temporal datasets as well as to customize the way this data is rendered, to get a better insight on the parking dynamics and its influencing factors

Abdominal wall desmoid tumors: A proposal for US-guided resection

Background: Desmoid tumors (DTs) is a benign tumor with high tendency to infiltrative evolution and recurrence. Nowadays, in abdominal localization, the standard approach is surgery with R0 condition. The need to repair post-surgical wide wall defect requires conservative technique to decrease the incidence of incisional hernia and to obtain better quality of life (QoL). Methods: We perform an abdominal wall desmoid resection using ultrasound guide. This technique ensures to spare a wide wall area and to obtain a multilayer reconstruction minimizing postoperative risk. This approach allows good oncological results and better managing abdominal wall post-resection defect. Results: We use US guided surgery to get radical approach and wall tissue spare that allows us a multilayer reconstruction minimizing post-operative complications. No recurrences were observed in one year follow up period. Conclusion: Our experience represents first step to consider ultrasound mediated technique usefull to optimize wall resection surgery and to minimize following complications