Osteopontin: A New Facilitating Factor in Alopecia Areata Pathogenesis?

Osteopontin (OPN) is a multifunctional glycophosphoprotein secreted by many cell types, including osteoblasts, lymphocites, macrophages, epithelial cells, and vascular smooth muscle cells. It has been implicated in many physiological and pathological processes, such as cell-mediated immunity, inflammation, cell survival, and tumor invasion and metastasis. Osteopontin has multiple emerging roles in cutaneous biology and pathology and OPN involvement has been emphasized in Th1-mediated diseases such as psoriasis. Alopecia areata (AA) is a form of non-scarring hair loss affecting anagen stage hair follicles with a multifactorial autoimmune pathogenesis characterized by a prevalent Th1 cytokine profile. Given the role of osteopontin in Th1-mediated inflammation, we have postulated that OPN may be involved in AA pathogenesis. The aim of our study was to investigate plasma OPN level in alopecia areata before and after DPCP treatment. Our results showed that OPN plasma levels in patients with alopecia areata were higher than in healthy controls, but patients achieving complete recovery after DPCP treatment did not show a statistically significant reduction of OPN plasma levels.</p

Skin morphology in double apoA-I/apoE knock-out mice: a structural and ultrastructural study

Apolipoprotein(apo)A-I, the main protein component of high density lipoproteins (HDLs), plays a major role in cholesterol removal from peripheral tissues and increasing evidence supports its function as an important regulator of the immune response (Annema et al., 2013). The aim of the study was to evaluate the effect of apoA-I deficiency in dyslipidemic mice, when fed a low-fat/low-cholesterol diet. Three lines of male mice were considered: wild-type mice as controls, apoE-KO mice as dyslipidemic model (Zhang et al.,1992) and apoA-I/apoE double KO mice (DKO mice). Whereas in wild-type mice cholesterol circulates almost exclusively in HDLs, apoE-KO mice are hypercholesterolemic and cholesterol mostly circulates in low-density lipoproteins. In DKO mice, cholesterol levels are comparable to wild-type mice, but HDLs are almost absent and cholesterol entirely accumulates in low-density lipoproteins. In the present study, all animals were maintained on a low-fat/low-cholesterol diet up to 30 weeks of age. At sacrifice, skin biopsies from two different anatomical areas (thoracic and abdominal regions) were harvested from each animal and processed for both light (LM) and transmission electron microscopy (TEM). Whereas the skin of apoE-KO mice was comparable to that of control mice, LM analysis in DKO mice revealed an increase in dermal thickness and a massive presence of foam cells and lymphocytes. TEM analysis showed the presence of cholesterol clefts in the papillary dermis and inside foam cells in the reticular dermis. In conclusion, our results demonstrate that in DKO mice fed a low-fat/low-cholesterol diet, the lack of apoA-I is responsible for an aberrant skin morphology, with an exacerbated inflammatory response, possibly caused by a local cholesterol accumulation

Oral drug therapy in elderly with dysphagia: between a rock and a hard place!

Demographic indicators forecast that by 2050, the elderly will account for about one-third of the global population. Geriatric patients require a large number of medicines, and in most cases, these products are administered as solid oral solid dosage forms, as they are by far the most common formulations on the market. However, this population tends to suffer difficulties with swallowing. Caregivers in hospital geriatric units routinely compound in solid oral dosage forms for dysphagic patients by crushing the tablets or opening the capsules to facilitate administration. The manipulation of a tablet or a capsule, if not clearly indicated in the product labeling, is an off-label use of the medicine, and must be supported by documented scientific evidence and requires the patient's informed consent. Compounding of marketed products has been recognized as being responsible for an increased number of adverse events and medical errors. Since extemporaneous compounding is the rule and not the exception in geriatrics departments, the seriousness and scope of issues caused by this daily practice are probably underestimated. In this article, the potential problems associated with the manipulation of authorized solid oral dosage forms are discussed

Tossicità cutanea da inibitori dell’Epidermal Growth Factor Receptor (EGFR): valutazione clinico-istologica ed approccio terapeutico

L'inibizione del recettore del fattore di crescita epidermico (EGFR) rappresenta un importante traguardo raggiunto nella ricerca e nello sviluppo della terapia dei tumori solidi epiteliali. Si tratta di una classe di farmaci biologici che trovano attualmente ampio utilizzo nel trattamento di tumori del colon-retto, del pancreas, del polmone (NSCLC), della testa-collo e della mammella, metastatici e non responsivi alle chemioterapie convenzionali. L'EGFR, oltre ad essere sovraespresso in numerose neoplasie epiteliali, è costituzionalmente presente nei cheratinociti dello strato basale dell'epidermide, nella guaina esterna del follicolo pilifero, nelle ghiandole sebacee e sudoripare eccrine, nelle cellule dendritiche e in diverse cellule del tessuto connettivo. L'inibizione farmaco-indotta del recettore determina l'attivazione di un meccanismo trasduzionale responsabile di un'anormale maturazione e differenziazione cutanea, dell'aumento dell'apoptosi e dell'esacerbazione della risposta infiammatoria, con conseguente danno tissutale a carico delle strutture sopra menzionate. All'interazione EGF/EGFR fa seguito la fosforilazione del residui tirosino-chinasici del dominio intracellulare del recettore con conseguente attivazione di due distinte vie molecolari: la via RASMAPK e la via PI3K-Akt, attraverso le quali l'EGFR regola importanti processi cellulari, modulando, a livello nucleare, l'espressione di specifici fattori trascrizionali. La via MAPK (Mitogen-Activated Protein Kinase) è direttamente coinvolta nella regolazione del ciclo cellulare, promuovendo la proliferazione cellulare. La via PI3K (Phosphatidylinositol 3-Kinase)-Akt è invece responsabile dei segnali di sopravvivenza inviati alla cellula attraverso l'inibizione del meccanismo di morte cellulare programmata (apoptosi). Gli eventi avversi che più comunemente si riscontrano in corso di terapia con inibitori dell'EGFR sono a carico della cute e dei suoi annessi e consistono in: 1. rash cutaneo acneiforme prevalentemente del tronco e del volto, 2. xerosi cutanea, 3. prurito, 4. fissurazioni, paronichie, 5. iperpigmentazione, 6. alterazioni della crescita dei peli, 7. mucositi. La tossicità cutanea, oltre a causare una significativa alterazione dello stato di benessere fisico, psichico e sociale del paziente, è dose dipendente e può essere tale da indurre una riduzione della dose del farmaco somministrato o addirittura determinarne la sospensione, Numerosi dati di letteratura evidenziano una correlazione diretta tra lo sviluppo e la gravità della tossicità cutanea e la risposta alla terapia antitumorale. Pertanto è plausibile che l'effetto antineoplastico e la tossicità cutanea secondaria all'uso di questi farmaci condividano meccanismi fisiopatogenetici. Tutto questo è suggerito da recenti acquisizioni scientifiche. In particolare, l'incidenza e la gravità clinica della tossicità cutanea, correlano significativamente con la risposta clinica alla terapia antineoplastica. Inoltre dati preliminari su piccoli gruppi indicano che l'espressione cutanea di Akt è inversamente correlata con lo sviluppo della tossicità cutanea, e che pertanto potrebbe avere un significato predittivo. Al contrario l'attività tissutale cutanea della MAPK potrebbe correlare direttamente con la tossicità cutanea. La ricerca svolta nel triennio di Dottorato si è posta due obiettivi principali: valutare l'incidenza ed il polimorfismo clinico delle manifestazioni cutanee in corso di terapia con inibitori dell'EGFR ed eseguire indagini istologico-immunoistochimiche volte ad indagare l'aspetto morfologico delle lesioni cutanee e l'esistenza di biomarcatori tissutali cutanei predittivi di sviluppo della tossicità farmaco-indotta

Non-alcoholic fatty liver disease and psoriasis: So far, so near

Psoriasis is a chronic inflammatory immune-mediated skin diseases which is frequently associated to comorbidities. Non-alcoholic fatty liver disease (NAFLD) is defined as an excessive accumulation of triglycerides in hepatocytes and includes a wide spectrum of liver conditions ranging from relatively benign steatosis to non-alcoholic steatohepatitis with fatty infiltration and lobular inflammation and to cirrhosis and end-stage liver disease. Actually, psoriasis is considered a systemic diseases associated to comorbidities, as metabolic syndrome and NAFLD is seen the hepatic manifestation of the metabolic syndrome. The possible link between psoriasis, obesity and metabolic syndrome, which are known risk factors for NAFLD has been recently documented focusing in the crucial role of the adipose tissue in the development of the inflammatory background sharing by the above entities. According to recent data, patients with psoriasis show a greater prevalence of NAFLD and metabolic syndrome than the general population. Moreover, patients with NAFLD and psoriasis are at higher risk of severe liver fibrosis than those with NAFLD and without psoriasis. The link between these pathological conditions appears to be a chronic low-grade inflammatory status. The aim of this review is to focus on the multiple aspects linking NAFLD and psoriasis, only apparently far diseases

Psoriasis, non-alcoholic fatty liver disease, and cardiovascular disease: Three different diseases on a unique background

Psoriasis is a chronic inflammatory immune-mediated skin disease, frequently associated with systemic comorbidities. According to recent data, patients with psoriasis show a greater prevalence of metabolic syndrome, which confers a higher cardiovascular risk. The link between these pathological conditions appears to be a chronic low-grade inflammatory status. The aim of this review is to focus on the multiple epidemiological and physio-pathogenetic aspects linking non-alcoholic fatty liver disease, psoriasis, and cardiovascular disease