Switching to nevirapine-based HAART in virologically-suppressed patients: influence of a longer twice-daily induction period on once-a-day dosing

We are conducting a multicenter, randomized, controlled, prospective, open trial to evaluate both the efficacy and toxicity of nevirapine (NVP) (given twice [BID] or once daily [QD]) in virologically-suppressed patients on a PIbased HAART. NVP BID dosing is maintained for 2 months after the switch in both groups

CXCR1/2 pathways in paclitaxel-induced neuropathic pain

Chemotherapy-induced peripheral neuropathy (CIPN) is a type of neuropathic pain that represents a frequent and serious consequence of chemotherapy agents. Over the last years, significant progress has been achieved in elucidating the underlying pathogenesis of CIPN. The interference of taxanes with microtubule has been proposed as a mechanism that leads to altered axonal transport and to permanent neurological damages. The inflammatory process activated by chemotherapeutic agents has been considered as a potential trigger of nociceptive process in CIPN.In this study we investigated the effect of reparixin, an inhibitor of CXCR1/CXCR2, in suppressing the development of paclitaxel-induced nociception in rats. Moreover, reparixin activity in reversing the neurotoxic effects induced by paclitaxel or GRO/KC in F11 cells was also analyzed.Reparixin administered by continuous infusion ameliorated paclitaxel-induced mechanical and cold allodynia in rats. In F11 cells, reparixin was able to inhibit the increase of acetyladed α-tubulin induced both by paclitaxel and GRO/KC. The subsequent experiments were performed in order to dissect the signal transduction pathways under GRO/KC control, eventually modulated by paclitaxel and/or reparixin. To this aim we found that reparixin significantly counteracted p-FAK, p-JAK2/p-STAT3, and PI3K-p-cortactin activation induced either by paclitaxel or GRO/KC.Overall the present results have identified IL-8/CXCR1/2 pathway as a mechanism involved in paclitaxel-induced peripheral neuropathy. In particular, the obtained data suggest that the inhibition of CXCR1/2 combined with standard taxane therapy, in addition to potentiating the taxane anti-tumor activity can reduce chemotherapy-induced neurotoxicity, thus giving some insight for the development of novel treatments

Inflammation-Independent Antinociceptive Effects of DF2755A, a CXCR1/2 Selective Inhibitor: A New Potential Therapeutic Treatment for Peripheral Neuropathy Associated to Non-Ulcerative Interstitial Cystitis/Bladder Pain Syndrome

Interstitial cystitis (IC)/bladder pain syndrome (BPS) is a chronic bladder disease of unknown etiology characterized by urinary frequency and episodic and chronic pain. Analgesic treatments for IC/BPS are limited, especially for patients with non-Hunner (non-ulcerative) type IC who usually have poor overall outcomes. Here, we demonstrate that oral treatment with DF2755A, a potent and selective inhibitor of chemokine receptors CXCR1/2, can prevent and reverse peripheral neuropathy associated to non-Hunner IC/BPS by directly inhibiting chemokine-induced excitation of sensory neurons. We tested DF2755A antinociceptive effects in a cyclophosphamide (CYP)-induced non-ulcerative IC rat model characterized by severe peripheral neuropathy in the absence of bladder inflammatory infiltrate, urothelial hyperplasia, and hemorrhage. Treatment with DF2755A prevented the onset of peripheral neuropathy and reversed its development in CYP-induced IC rats, showing a strong and long-lasting anti-hyperalgesic effect. Ex vivo and in vitro studies showed that DF2755A treatment strongly inhibited the expression of CXCR2 agonists, CXCL1/KC, and CXCL5 and of transient receptor potential vanilloid 1 (TRPV1) compared to vehicle, suggesting that its effects can be due to the inhibition of the nociceptive signaling passing through the CXCL1/CXCR1-2 axis and TRPV1. In conclusion, our results highlight the key pathophysiological role played by the CXCL1/CXCR1-2 axis and TRPV1 in the onset and development of peripheral neuropathy in non-Hunner IC and propose DF2755A as a potential therapeutic approach for the treatment of not only inflammatory painful conditions but also neuropathic ones and in particular non-Hunner IC/BPS

CXCL1-CXCR1/2 signaling is induced in human temporal lobe epilepsy and contributes to seizures in a murine model of acquired epilepsy

Abstract CXCL1, a functional murine orthologue of the human chemokine CXCL8 (IL-8), and its CXCR1 and CXCR2 receptors were investigated in a murine model of acquired epilepsy developing following status epilepticus (SE) induced by intra-amygdala kainate. CXCL8 and its receptors were also studied in human temporal lobe epilepsy (TLE). The functional involvement of the chemokine in seizure generation and neuronal cell loss was assessed in mice using reparixin (formerly referred to as repertaxin), a non-competitive allosteric inhibitor of CXCR1/2 receptors. We found a significant increase in hippocampal CXCL1 level within 24 h of SE onset that lasted for at least 1 week. No changes were measured in blood. In analogy with human TLE, immunohistochemistry in epileptic mice showed that CXCL1 and its two receptors were increased in hippocampal neuronal cells. Additional expression of these molecules was found in glia in human TLE. Mice were treated with reparixin or vehicle during SE and for additional 6 days thereafter, using subcutaneous osmotic minipumps. Drug-treated mice showed a faster SE decay, a reduced incidence of acute symptomatic seizures during 48 h post-SE, and a delayed time to spontaneous seizures onset compared to vehicle controls. Upon reparixin discontinuation, mice developed spontaneous seizures similar to vehicle mice, as shown by EEG monitoring at 14 days and 2.5 months post-SE. In the same epileptic mice, reparixin reduced neuronal cell loss in the hippocampus vs vehicle-injected mice, as assessed by Nissl staining at completion of EEG monitoring. Reparixin administration for 2 weeks in mice with established chronic seizures, reduced by 2-fold on average seizure number vs pre-treatment baseline, and this effect was reversible upon drug discontinuation. No significant changes in seizure number were measured in vehicle-injected epileptic mice that were EEG monitored in parallel. Data show that CXCL1-IL-8 signaling is activated in experimental and human epilepsy and contributes to acute and chronic seizures in mice, therefore representing a potential new target to attain anti-ictogenic effects

Molecular Approach for the Laboratory Diagnosis of Periprosthetic Joint Infections

The incidence of total joint arthroplasty is increasing over time since the last decade and expected to be more than 4 million by 2030. As a consequence, the detection of infections associated with surgical interventions is increasing and prosthetic joint infections are representing both a clinically and economically challenging problem. Many pathogens, from bacteria to fungi, elicit the immune system response and produce a polymeric matrix, the biofilm, that serves as their protection. In the last years, the implementation of diagnostic methodologies reduced the error rate and the turn-around time: polymerase chain reaction, targeted or broad-spectrum, and next-generation sequencing have been introduced and they represent a robust approach nowadays that frees laboratories from the unique approach based on culture-based techniques

Viral Population Heterogeneity and Fluctuating Mutational Pattern during a Persistent SARS‐CoV‐2 Infection in an Immunocompromised Patient

Literature offers plenty of cases of immunocompromised patients, who develop chronic and severe SARS‐CoV‐2 infections. The aim of this study is to provide further insight into SARS-CoV‐2 evolutionary dynamic taking into exam a subject suffering from follicular lymphoma, who developed a persistent infection for over 7 months. Eight nasopharyngeal swabs were obtained, and were analyses by qRT‐PCR for diagnostic purposes. All of them were considered eligible (Ct < 30) for NGS sequencing. Sequence analysis showed that all sequences matched the B.1.617.2 AY.122 lineage, but they differed by few mutations identifying three genetically similar subpopulations, which evolved during the course of infection, demonstrating that prolonged replication is paralleled with intra‐host virus evolution. These evidences support the hypothesis that SARS‐CoV‐2 adaptive capacities are able to shape a heterogeneous viral population in the context of immunocompromised patients. Spill‐over of viral variants with enhanced transmissibility or immune escape capacities from these subjects is plausible

SARS-CoV-2 vaccination modelling for safe surgery to save lives : data from an international prospective cohort study

Background: Preoperative SARS-CoV-2 vaccination could support safer elective surgery. Vaccine numbers are limited so this study aimed to inform their prioritization by modelling. Methods: The primary outcome was the number needed to vaccinate (NNV) to prevent one COVID-19-related death in 1 year. NNVs were based on postoperative SARS-CoV-2 rates and mortality in an international cohort study (surgical patients), and community SARS-CoV-2 incidence and case fatality data (general population). NNV estimates were stratified by age (18-49, 50-69, 70 or more years) and type of surgery. Best- and worst-case scenarios were used to describe uncertainty. Results: NNVs were more favourable in surgical patients than the general population. The most favourable NNVs were in patients aged 70 years or more needing cancer surgery (351; best case 196, worst case 816) or non-cancer surgery (733; best case 407, worst case 1664). Both exceeded the NNV in the general population (1840; best case 1196, worst case 3066). NNVs for surgical patients remained favourable at a range of SARS-CoV-2 incidence rates in sensitivity analysis modelling. Globally, prioritizing preoperative vaccination of patients needing elective surgery ahead of the general population could prevent an additional 58 687 (best case 115 007, worst case 20 177) COVID-19-related deaths in 1 year. Conclusion: As global roll out of SARS-CoV-2 vaccination proceeds, patients needing elective surgery should be prioritized ahead of the general population.Peer reviewe

Implicazioni del COVID-19 per il Supply Chain Management e progettazione del new normal: il caso IMA S.p.A.

L'interesse nei confronti del tema analizzato all'interno dell'elaborato sorge dalla necessità individuale di una maggiore comprensione del contesto storico che stiamo vivendo e vede, in primo luogo, una contestualizzazione a livello geopolitico e socioeconomico dello scenario di riferimento. Da qui la scelta di intrecciare tali tematiche con discipline che permettessero di coglierne gli impatti ad ampio raggio e di valutare le scelte strategiche in risposta allo shock. Il seguente elaborato si pone l'obiettivo di individuare gli effetti che la pandemia ha generato sulle filiere, riscontrando differenze consistenti nell'impatto sulla base di alcune variabili. A fronte delle nuove consapevolezze, verranno evidenziati i cambiamenti strutturali che caratterizzeranno le supply chain del futuro. Per avvalorare la ricerca, è stata condotta un'analisi sul caso di studio della società IMA S.p.A., realtà con una supply chain innovativa che si è trovata ad affrontare sfide interessanti durante il periodo pandemico. La logica portata avanti per la stesura dei capitoli di letteratura è stata utilizzata anche nel caso empirico. Sono stati in primo luogo individuati gli impatti della crisi su una filiera cruciale per l'autosufficienza nazionale, per poi valutare in maniera critica le strategie di mitigazione messe in atto dall'azienda, identificando prospettive in un new normal post-COVID

Molecular markers for the discrimination of Triticum turgidum L. subsp. dicoccum (Schrank ex Schübl.) Thell. and Triticum timopheevii (Zhuk.) Zhuk. subsp. timopheevii

The persistent uncertainty on the classification of the "new" glume wheat found in Neolithic and Bronze Age sites from Greece and other European settlements might be resolved only through analysis of its ancient DNA. Tools able to discriminate among different Triticum species on the basis of scarce, very damaged DNA, are therefore essential. While current attempts concentrate on DNA fragments sequencing and comparison, in some instances PCR-based selective amplification techniques might offer a cheaper and quicker alternative. The purpose of this research was therefore the identification of species-specific primers, able to distinguish caryopses of Triticum timopheevii subsp. timopheevii from those of Triticum turgidum subsp. dicoccum. Primers and their working conditions were defined and optimized using DNA from modern accessions. The ribosomal primers ITS1 tim and ITS2 tim, and the nuclear primer acetyl-coenzyme A tim clearly discriminated the sequences of Triticum timopheevii from other species. Finally, Neolithic charred wheat grains found in the sites of Sammardenchia (Pozzuolo del Friuli, Udine) and La Marmotta (Lago di Bracciano, Roma), belonging to the "new" wheat type or to emmer, were tested with the three selected primers. However, the results were not conclusive, because the samples analysed were apparently too degraded to yield useful DNA

Contaminazione da micotossine in alimenti di produzione biologica.

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