Palmitoylethanolamide inhibits rMCP-5 expression by regulating MITF activation in rat chronic granulomatous inflammation

Chronic inflammation, a condition frequently associated with several pathologies, is characterized by angiogenic and fibrogenic responses that may account for the development of granulomatous tissue. We previously demonstrated that the chymase, rat mast cell protease-5 (rMCP-5), exhibits pro-inflammatory and pro-angiogenic properties in a model of chronic inflammation sustained by mast cells (MCs), granuloma induced by the subcutaneous carrageenan-soaked sponge implant in rat. In this study, we investigated the effects of palmitoylethanolamide (PEA), an anti-inflammatory and analgesic endogenous compound, on rMCP-5 mRNA expression and Microphtalmia-associated Transcription Factor (MITF) activation in the same model of chronic inflammation. The levels of rMCP-5 mRNA were detected using semi-quantitative RT-PCR; the protein expression of chymase and extracellular signal-regulated kinases (ERK) were analyzed by western blot; MITF/DNA binding activity and MITF phosphorylation were assessed by electrophoretic mobility shift assay (EMSA) and immunoprecipitation, respectively. The administration of PEA (200, 400 and 800 µg/ml) significantly decreased rMCP-5 mRNA and chymase protein expression induced by λ-carrageenan. These effects were associated with a significant decrease of MITF/DNA binding activity and phosphorylated MITF as well as phosphorylated ERK levels. In conclusion, our results, showing the ability of PEA to inhibit MITF activation and chymase expression in granulomatous tissue, may yield new insights into the understanding of the signaling pathways leading to MITF activation controlled by PEA

Diabetic ketoacidosis at the onset of disease during a national awareness campaign: a 2-year observational study in children aged 0-18 years

After a previous survey on the incidence of diabetic ketoacidosis (DKA) at onset of type 1 diabetes in children in 2013-2014 in Italy, we aimed to verify a possible decline in the incidence of DKA at onset during a national prevention campaign

An Unusual Retinal Vessel Modification in Patients Affected by JIA-Uveitis with a Follow-Up Longer Than 16 Years

Purpose. To report unusual and rare clinical changes of retinal vessel pattern in a series of patients affected by Juvenile Idiopathic Arthritis (JIA) uveitis with a follow-up longer than 16 years. Methods. A series of three patients with JIA-uveitis followed at the University of Rome “Sapienza” from 1998 to 2014 were reported. The retinal vessels were analyzed with fluorescein angiography using Heidelberg Retinal Angiogram-2 (HRA-2; Heidelberg Engineering GmBH, Dossenheim, Germany) and the Topcon TRC-50LX retinal camera (Topcon Europe, The Netherlands). A Spectralis Domain OCT (SD-OCT) (Spectralis Family Heidelberg, Germany) was performed to evaluate vessel anatomy. Results. Fundus photography showed sheathed vessels localized around the optic disc in every case. Angiography revealed a normal physiology of vessel walls and flow; no sheathing or leakage of dye was observed. SD-OCT demonstrated reflective vessel walls. Vessel lumen appeared patent, and the normal “hourglass configuration” was blurred, but identifiable. Conclusions. Vessel modifications observed in long-standing JIA-uveitis are not signs of vascular inflammation and are not associated to hypoperfusion. In these cases, ophthalmologists should avoid further invasive investigation and should consider introducing SD-OCT as a routine method to evaluate the vessel changes during the follow-up

The Interplay between miRNA-Related Variants and Age-Related Macular Degeneration: EVIDENCE of Association of <i>MIR146A</i> and <i>MIR27A</i>

The complex interplay among genetic, epigenetic, and environmental variables is the basis for the multifactorial origin of age-related macular degeneration (AMD). Previous results highlighted that single nucleotide polymorphisms (SNPs) of CFH, ARMS2, IL-8, TIMP3, SLC16A8, RAD51B, VEGFA, and COL8A1 were significantly associated with the risk of AMD in the Italian population. Given these data, this study aimed to investigate the impact of SNPs in genes coding for MIR146A, MIR31, MIR23A, MIR27A, MIR20A, and MIR150 on their susceptibility to AMD. Nine-hundred and seventy-six patients with exudative AMD and 1000 controls were subjected to an epigenotyping analysis through real-time PCR and direct sequencing. Biostatistical and bioinformatic analysis was performed to evaluate the association with susceptibility to AMD. These analyses reported that the SNPs rs11671784 (MIR27A, G/A) and rs2910164 (MIR146A, C/G) were significantly associated with AMD risk. Interestingly, the bioinformatic analysis showed that MIR27A and MIR146A take part in the angiogenic and inflammatory pathways underlying AMD etiopathogenesis. Thus, polymorphisms within the pre-miRNA sequences are likely to affect their functional activity, especially the interaction with specific targets. Therefore, our study represents a step forward in the comprehension of the mechanisms leading to AMD onset and progression, which certainly include the involvement of epigenetic modifications

Terapia combinata con fotodinamica-verterporfirina e ranibizumab intravitreale per il trattamento della Retinal Angiomatous Proliferation correlata alla degenerazione maculare senile.

Purpose : to evaluate the efficacy and safety of the combination of Photodynamic Therapy (PDT) with standard fluence verteporfin and Ranibizumab 0.5mg administered on the same day, in patients with the neovascolar AMD (Aged Macular Degeneration) known as RAP (Retinal angiomatous proliferation ). Type of study : open-label, monocentric, randomized case series trial. Methods: 6 eyes of 6 patients were consecutively enrolled and treated with combined therapy defined as standard fluence PDT and intravitreal Ranibizumab 0.5mg on the same day. More injection were administrated as needed.Best corrected visual acuity (BCVA), central macular thickness (CMT) on optical coherence tomography (OCT) and Fluorescein angiography (FA) were examined before and after treatment every 4 weeks. Patients were followed-up for twelve months. Results: the mean baseline BCVA (± standard deviation, SD) was 27,8 (LogMar 0,576)(±14,6) (p=), at 12 months after treatment mean BCVA was 33,3 (LogMar 0,466 )(±16,6) (p=). The mean CMT at baseline was 393,8µm (±82,4) (p=) at 12 months was 250,7 µm (±82,4) (p=). The mean reduction was 142,2 µm. At 12 months in 4 eyes (66,6%) there was the absence of leakage on FA . After 12 months, the rate of retreated eyes was 33,3 % (2 of 6 eyes). Discussion and Conclusion: In conclusion the treatment shows a functional and anatomical improvement since the first month after treatment. OCT shows this improvement as a great reduction of intraretinal edema. No ocular or systemic adverse effects from treatment were encountered

The synergistic effect of exposure to alcohol, tobacco smoke and other risk factors for age-related macular degeneration

[No abstract available

Azacitidine in Myelodysplastic Syndromes: Multicenter Retrospective Study of 34 Long-Responder Patients

Introduction.: Azacitidine (AZA) has proven effective in myelodysplastic syndromes (MDS). The duration of haematological response is limited (median 13. 6 months) (Fenaux, 2009), although some patients (pts) show a prolonged response. The French Group (Itzykson 2011) identified some clinical and haematologic parameters (poor ECOG performance status, IPSS intermediate and poor risk cytogenetics, circulating blasts, high transfusion need) independently associated with a a poorer outcome, and these 4 criteria were integrated in a 3-group prognostic score, validated in other cohorts (van der Helm 2011; Breccia 2012). Moreover, a complex karyotype was also predictive of a shorter duration of response. However long term survival was also observed in some of the pts with poor risk features (Itzykson 2012). Methods.: These data prompted us to retrospectively analyse our MDS pts treated with AZA who showed a favourable long-lasting response to AZA (i. e: duration of response 65 20 months), in order to enucleate the clinical and haematologic features of long-responder pts. The type of response was defined according to IWG criteria (Cheson 2006): Complete Remission (CR); Partial Remission (PR) and Hematologic Improvement (HI). The response duration was measured from the date of achievement of a first response (HI, PR or CR), (also in pts who subsequently achieved a higher response category) until the date of disease progression or death. Overall Survival (OS) was measured from the start of AZA treatment. Moreover, as some of us (Follo, 2009) demonstrated that phosphoinositide-phospholipase C (PI-PLC) beta1 may represent a target for AZA, in a subgroup of pts we quantified the degree of PI-PLCbeta1 methylation and gene expression before and during AZA administration. Results.: Thirty-four pts (M/F: 20/14), from eight Institutions, with a median age of 72 (range 52\u201384) yrs, showed a response duration 65 20 months. At AZA onset, WHO diagnosis was: refractory anemia (RA): 1 pt; refractory cytopenia with multilineage dysplasia (RCMD): 1 pt; RCMD with ringed sideroblasts (RCMD-RS): 1 pt; refractory anemia with excess blasts (RAEB)-1: 8 pts; RAEB-2: 15 pts; cronic myelomonocytic leukemia(CMML): 4 pts; AML with 20\u201330% blasts: 3 pts, MDS with fibrosis (MDS-F): 1 pt. Four pts had therapy-related MDS. IPSS risk was: low: 3 pts; intermediate-1: 6 pts; intermediate-2: 20 pts, high: 5 pts. IPSS cytogenetic risk was: low: 21 pts (61. 8%); intermediate: 8 pts (23. 5%); high: 5 pts (14. 7%) (3 with complex karyotypes and 2 with isolated -7 or 7q-). ECOG-PS was poor ( 65 2) in 2 pts (5. 8%) and 6 months in 13 pts. The pts received a median of 22 cycles of AZA (range: 8\u201352). The median number of cyles to any first response was 4 (range: 2\u201310). Twenty pts (58. 8%) showed an at least two-fold increase of platelets after the first cycle of AZA. The best response achieved was: CR in 23 pts (67. 7%), PR in 2 pts (5. 8%), and HI in 9 pts (26. 5%). Cytogenetic remission was achieved in 7 pts (20. 6%). The median duration of response was 24. 5 (range: 23\u201388) months. A significant toxicity (grade > 2) was observed in 5 (14. 7%) pts. Twenty-two pts (64. 8%) are still maintaining hematologic response, 6 pts (17. 6%) are still alive but discontinued treatment because of disease progression, and 6 pts died, for AML (2 pts), infection (1 pt), haemorrhage (1 pt), myocardial infarction (1 pt), cachexy (1 pt), respectively. Median OS from the start of AZA was 35. 5 (range: 22\u2013120) months. In a subgroup of pts, we observed an increase in PI-PLCbeta1 expression, that was maintained along with the hematologic response. Moreover, PI-PLCbeta1 early increase (during the cycles 1 to 3) was significantly associated with a higher duration of response. Conclusions.: Although our data confirm the finding of other Authors, as the majority of long-responder patients showed pre-treatment favourable prognostic factors, a long-lasting hematologic response can be achieved even in a significant fraction of pts presenting one or more poor risk features (IPSS intermediate or high risk cytogenetics, high transfusion need)