Clinical and experimental studies in idiopathic and Crohn's-related anal fistula

The factors leading to the creation and persistence of anal fistula in Crohn’s disease are poorly understood. As with luminal Crohn’s disease genetic, microbiological and immunological factors are implicated but the immunological and microbiological composition of Crohn’s and idiopathic anal fistulae have been obscure. My data demonstrate a lack of clinically relevant organisms within fistula tracts, a luminally driven immune response and subtle differences in this response between Crohn’s and idiopathic fistulae which may provide the basis for diagnostic tests, interventions and further research. Surgical treatment of anal fistula is characterised by a compromise between risk of recurrence and impairment of continence. In complex, recurrent and multiply operated anal fistulae, fistulotomy can still provide a high success rate with low additional risk of impairment of continence. Rectovaginal fistulae are also difficult to manage both surgically and medically. In the infliximab era, successful healing of Crohn’s RVF remains disappointingly rare. Surgery for RVF requires a variety of approaches but remains a valuable tool in the treatment of both Crohn’s and non-Crohn’s tracts. Medical treatment of Crohn’s anal fistulae with combination thiopurine and anti-TNFα agents has demonstrated good short term results. Clinical and radiological data to 3 years follow up demonstrate that around a third of patients maintain healing on infliximab, radiological healing lags behind clinical remission by around a year, and cessation may lead to recurrence in spite of a healed tract on MRI. A treatment for anal fistula with high success and low risk of impairment of continence in complex anal fistulae eludes colorectal surgeons and gastroenterologists. A treatment combining the best aspects of current fistula management with novel elements prompted by improved aetiological understanding must be the goal for fistula surgeons and is the inspiration behind this thesis

Dual targeting of mTOR/IL-17A and autophagy by fisetin alleviates psoriasis-like skin inflammation

Psoriasis is a chronic autoimmune inflammatory skin disorder characterized by epidermal hyperplasia and aberrant immune response. In addition to aberrant cytokine production, psoriasis is associated with activation of the Akt/mTOR pathway. mTOR/S6K1 regulates T-lymphocyte activation and migration, keratinocytes proliferation and is upregulated in psoriatic lesions. Several drugs that target Th1/Th17 cytokines or their receptors have been approved for treating psoriasis in humans with variable results necessitating improved therapies. Fisetin, a natural dietary polyphenol with anti-oxidant and anti-proliferative properties, covalently binds mTOR/S6K1. The effects of fisetin on psoriasis and its underlying mechanisms have not been clearly defined. Here, we evaluated the immunomodulatory effects of fisetin on Th1/Th17-cytokine-activated adult human epidermal keratinocytes (HEKa) and anti-CD3/CD28-stimulated inflammatory CD4+ T cells and compared these activities with those of rapamycin (an mTOR inhibitor). Transcriptomic analysis of HEKa revealed 12,713 differentially expressed genes (DEGs) in the fisetin-treated group compared to 7,374 DEGs in the rapamycin-treated group, both individually compared to a cytokine treated group. Gene ontology analysis revealed enriched functional groups related to PI3K/Akt/mTOR signaling pathways, psoriasis, and epidermal development. Using in silico molecular modeling, we observed a high binding affinity of fisetin to IL-17A. In vitro, fisetin significantly inhibited mTOR activity, increased the expression of autophagy markers LC3A/B and Atg5 in HEKa cells and suppressed the secretion of IL-17A by activated CD4+ T lymphocytes or T lymphocytes co-cultured with HEKa. Topical administration of fisetin in an imiquimod (IMQ)-induced mouse psoriasis model exhibited a better effect than rapamycin in reducing psoriasis-like inflammation and Akt/mTOR phosphorylation and promoting keratinocyte differentiation and autophagy in mice skin lesions. Fisetin also significantly inhibited T-lymphocytes and F4/80+ macrophage infiltration into skin. We conclude that fisetin potently inhibits IL-17A and the Akt/mTOR pathway and promotes keratinocyte differentiation and autophagy to alleviate IMQ-induced psoriasis-like disease in mice. Altogether, our findings suggest fisetin as a potential treatment for psoriasis and possibly other inflammatory skin diseases

Taurisolo®, a novel nutraceutical formulation based on grape pomace polyphenols, as a tool for the management of oxidative stress- and atherosclerosis-related diseases

The present PhD thesis summarises evidence from all the studies performed during the three-year PhD Course in Pharmaceutical Science, at the NutraPharmaLabs of the Department of Pharmacy, University of Naples Federico II, having as mail goal the evaluation of the nutraceutical potential of Taurisolo®, a novel nutraceutical formulation based on grape pomace polyphenolic extract. In particular, the present PhD project has been conducted in cooperation with both industrial (MBMed Company, Turin, Italy) and foreign University (University of Balearic Islands, Palma del Mallorca, Spain) partners. The entire project was planned with a dual view: design and formulate a novel nutraceutical product starting from re-use of agri-food by-products, following all the steps required by the nutraceutical industry, including preventive characterisation of the chemical profile, evaluation of bioaccessibility and bioavailability of bioactive compounds, optimisation of the productive processes and their translation in large-scale, marketing techniques evaluation of the biological activities, following a pharmacological approach including pre-clinical and clinical studies. More specifically, results herein presented refer to all the studies performed in our Labs and in collaboration with other Departments and Research Institutes. They include in vitro studies, animal-based studies and randomised clinical trials conducted on both healthy and pathological subjects. Further studies are still ongoing with the aim to clarify the main putative mechanisms of action for the cardioprotective role played by Taurisolo® or to provide novel insight regarding the observed clinical results. In summary, data so far collected allow concluding that Taurisolo® is a useful and valid polyphenol-based formulation with promising nutraceutical properties in reduction of risk factors related to both development and progression of cardiovascular diseases, in particular atherosclerosis

Medical-Data-Models.org:A collection of freely available forms (September 2016)

MDM-Portal (Medical Data-Models) is a meta-data repository for creating, analysing, sharing and reusing medical forms, developed by the Institute of Medical Informatics, University of Muenster in Germany. Electronic forms for documentation of patient data are an integral part within the workflow of physicians. A huge amount of data is collected either through routine documentation forms (EHRs) for electronic health records or as case report forms (CRFs) for clinical trials. This raises major scientific challenges for health care, since different health information systems are not necessarily compatible with each other and thus information exchange of structured data is hampered. Software vendors provide a variety of individual documentation forms according to their standard contracts, which function as isolated applications. Furthermore, free availability of those forms is rarely the case. Currently less than 5 % of medical forms are freely accessible. Based on this lack of transparency harmonization of data models in health care is extremely cumbersome, thus work and know-how of completed clinical trials and routine documentation in hospitals are hard to be re-used. The MDM-Portal serves as an infrastructure for academic (non-commercial) medical research to contribute a solution to this problem. It already contains more than 4,000 system-independent forms (CDISC ODM Format, www.cdisc.org, Operational Data Model) with more than 380,000 dataelements. This enables researchers to view, discuss, download and export forms in most common technical formats such as PDF, CSV, Excel, SQL, SPSS, R, etc. A growing user community will lead to a growing database of medical forms. In this matter, we would like to encourage all medical researchers to register and add forms and discuss existing forms