Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE): Position Paper on Diagnosis, Prognosis and Treatment by the MNGIE International Network

Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE) is a rare autosomal recessive disease caused by TYMP mutations and thymidine phosphorylase (TP) deficiency. Thymidine and deoxyuridine accumulate impairing the mitochondrial DNA maintenance and integrity. Clinically, patients show severe and progressive gastrointestinal and neurological manifestations. The onset typically occurs in the second decade of life and mean age at death is 37 years. Signs and symptoms of MNGIE are heterogeneous and confirmatory diagnostic tests are not routinely performed by most laboratories, accounting for common misdiagnosis. Factors predictive of progression and appropriate tests for monitoring are still undefined. Several treatment options showed promising results in restoring the biochemical imbalance of MNGIE. The lack of controlled studies with appropriate follow‐up accounts for the limited evidence informing diagnostic and therapeutic choices. The International Consensus Conference (ICC) on MNGIE, held in Bologna, Italy, on March 30th‐31st, 2019, aimed at an evidence‐based consensus on diagnosis, prognosis and treatment of MNGIE among experts, patients, caregivers and other stakeholders involved in caring the condition. The conference was conducted according to the National Institute of Health Consensus Conference methodology. A consensus development panel formulated a set of statements and proposed a research agenda. Specifically, the ICC produced recommendations on: (1) diagnostic pathway; (2) prognosis and the main predictors of disease progression; (3) efficacy and safety of treatments; and (4) research priorities on diagnosis, prognosis and treatment. The Bologna ICC on diagnosis, management and treatment of MNGIE provided evidence‐based guidance for clinicians incorporating patients' values and preferences

Fattori di crescita e cellule staminali

La personalizzazione delle più moderne strategie di riabilitazione visiva è in grado di ottimizzare l’utilizzo del residuo visivo e/o delle capacità sensoriali non visive in un crescente numero di pazienti, realizzando un reale miglioramento della loro qualità di vita. Tuttavia, la maggior parte dei pazienti affetti da patologie oculari invalidanti o potenzialmente tali richiedono informazioni su possibili terapie in grado di farli tornare a vedere riferendosi, in particolare, alle cellule staminali ed a fattori di crescita quali, il fattore di crescita della cellula nervosa o Nerve Growth Factor (NGF) identificato da Rita Levi Montalcini negli Anni ‘50. I fattori di crescita sono proteine con molteplici funzioni di omeostasi tessutale tra cui la proliferazione, il differenziamento e la maturazione cellulare. Numerosi studi sperimentali sono in corso per valutare le potenzialità terapeutiche dei diversi fattori di crescita e per inquadrare il loro ruolo nella gestione dei pazienti con patologie disabilitanti le funzioni visive. Le cellule staminali sono cellule non mature e non specializzate, caratterizzate dalle capacità di auto-rinnovamento e di differenziamento eterogeneo (pluripotenza). L’auto-rinnovamento è la possibilità di compiere un numero illimitato di cicli replicativi mantenendo sempre il medesimo stadio differenziativo. La “potenza” è la capacità di generare una o più linee cellulari tramite il differenziamento. All'interno di quest’ultimo concetto è includibile anche quello di trans-differenziamento, cioè la capacità di una cellula staminale in fase di differenziamento di cambiare la propria linea cellulare modificando il suo programma di sviluppo. Il trans-differenziamento, evidenziato finora solo in animali da esperimento, permette a cellule staminali mesenchimali adulte o Mesenchimal Stem Cells (MSCs) di differenziarsi in cellule molto specifiche (come neuroni, cellule epiteliali, tipi cellulari ectodermici o endodermici) saltando da un cammino differenziativo ad un altro. Le tematiche riguardanti la “cura degli occhi” mediante fattori di crescita e cellule staminali devono essere affrontate in maniera del tutto diversa in relazione ai differenti tessuti oculari coinvolti dalla patologia causa di minorazione visiva. In base all’eterogenea derivazione embriogenetica delle diverse strutture oculari, sono distinguibili due principali ambiti applicativi: i. patologie del segmento anteriore, con particolare riferimento a quelle coinvolgenti le strutture corneali, quali l’epitelio (che origina dall’ectoderma), lo stroma (che origina dalla superficie anteriore della capsula di mesenchima indifferenziato che circonda il calice ottico) e l’endotelio (che origina da cellule della cresta neurale); ii. patologie del segmento posteriore, con particolare riferimento a quelle della retina / nervo ottico e dell’epitelio pigmentato retinico (EPR) che, rispettivamente, originano dalle pareti neuro-ectodermiche interna ed esterna dei calici ottici, derivanti dal tratto cefalico del tubo neurale come parti integranti del sistema nervoso centrale in formazione

Validity, reliability and minimum detectable change of COSMED K5 portable gas exchange system in breath-by-breath mode

Purpose This study aimed to examine the validity, reliability and minimum detectable change (MDC) of the Cosmed K5 in breath by breath (BxB) mode, against VacuMed metabolic simulator. Intra and inter-units reliability was also assessed. Methods Fourteen metabolic rates (from 0.9 to 4 L.min-1) were reproduced by a VacuMed system and pulmonary ventilation (VE), oxygen consumption (VO2) and carbon dioxide production (VCO2) were measured by two different K5 units. Validity was assessed by ordinary least products (OLP) regression analysis, Bland-Altman plots, intraclass correlation coefficients (ICC), mean percentage differences, technical errors (TE) and MDC for VE, VO2, and VCO2. Intra- and inter-K5 reliability was evaluated by absolute percentage differences between measurements (MAPE), ICCs, TE, and MDC. Results Validity analysis from OLP regression data and Bland- Altman plots indicated high agreement between K5 and simulator. ICC values were excellent for all variables (>0.99). Mean percentage differences in VE (-0.50%, p = 0.11), VO2 (-0.04%, p = 0.80), and VCO2 (-1.03%, p = 0.09) showed no significant bias. The technical error (TE) ranged from 0.73% to 1.34% (VE and VCO2 respectively). MDC were lower than 4% (VE = 2.0%, VO2 = 3.8%, VCO2 = 3.7%). The intra and inter K5 reliability assessment reveled excellent ICCs (>0.99), MAPE <2% (no significant differences between trials), TE < or around 1%, MDC <or around 3%. Conclusions K5 in BxB mode is a valid and reliable system for metabolic measurements. This is the first study assessing the MDC accounting only for technical variability reporting intra- and inter-units MDCs <3.3%

Impact of methylenetetrahydrofolate reductase C677T polymorphism on the efficacy of photodynamic therapy in patients with neovascular age-related macular degeneration

The most severe visual impairments due to age-related macular degeneration (AMD) are frequently caused by the occurrence of choroidal neovascularization (CNV). Although photodynamic therapy with verteporfin (PDT-V) is currently a second-line treatment for neovascular AMD, it can be conveniently combined with drugs acting against vascular endothelial growth factor (anti-VEGF) to reduce the healthcare burden associated with the growing necessity of anti-VEGF intravitreal re-injection. Because the common 677 C > T polymorphism of the methylenetetrahydrofolate reductase gene (MTHFR-C677T; rs1801133) has been described as predictor of satisfactory short-term responsiveness of AMD-related CNV to PDT-V, we retrospectively examined the outcomes of 371 Caucasian patients treated with standardized, pro-re-nata, photodynamic regimen for 24 months. Responder (R) and non-responder (NR) patients were distinguished on the basis of the total number of scheduled PDT-V (TN-PDT-V) and change of best-corrected visual acuity (∆-BCVA). The risk for both TN-PDT-V and ∆-BCVA to pass from R to NR group was strongly correlated with CT and TT genotypes of MTHFR-C677T variant resulting, respectively, in odd ratios of 0.19 [95% CI, 0.12-0.32] and 0.09 [95% CI, 0.04-0.21] (P < 0.001), and odd ratios of 0.24 [95% CI, 0.15-0.39] and 0.03 [95% CI, 0.01-0.11] (P < 0.001). These pharmacogenetic findings indicate a rational basis to optimize the future clinical application of PDT-V during the combined treatments of AMD-related CNV, highlighting the role of thrombophilia to be aware of the efficacy profile of photodynamic therapy

Photophysical Behaviour of Corrole and its Symmetrical and Unsymmetrical Dyads

The luminescence properties at room temperature and 77 K of octamethylcorrole are reported for the first time, together with the photophysical behaviour of corrole-corrole and porphyrin-corrole dyads covalently linked through the 10-position with a phenyl bridge. The photophysical properties of corroie free base are very similar to those of the porphyrin analogues, whereas the dimeric systems show luminescence bands different from those of the parent monomers, indicating an unexpectedly high degree of interaction between the chromophores. The porphyrin-corrole dyad undergoes photocatalysed ring opening of the corroie moiety to give the corresponding porphyrin-biliverdin species. Copyright © 1999 John Wiley & Sons, Ltd

Clinical Features and Prevalence of Spondyloarthritis in a Cohort of Italian Patients Presenting with Acute Nongranulomatous Anterior Uveitis

PURPOSE: To describe the clinical features of acute nongranulomatous anterior uveitis (NGAU) patients and to estimate the prevalence of concomitant spondyloarthritis (SpA). METHODS: Retrospective study of consecutive patients affected by NGAU referred to the Ocular Immunology Unit of the AUSL-IRCCS di Reggio Emilia, Italy, between January 2016 and January 2019. All patients underwent ophthalmic evaluation and blood test with HLA-B27 typing and were referred to a rheumatologist to identify any undiagnosed SpA. SpA was classified according to the Assessment of SpondyloArthritis international Society (ASAS) criteria in axial or peripheral SpA. Patients were divided into two groups: NGAU with associated SpA (SpA+) and NGAU without SpA (SpA-). Clinical and demographic features of the two groups, including sex, HLA-B27, family history of rheumatic disease, uveitis laterality, course, and severity of ocular inflammation, complications, and treatment, were compared. RESULTS: Ninety-nine patients with NGAU were enrolled, of whom 36 (36%) with a diagnosis of SpA: 14 with peripheral SpA and 22 with axial SpA. The prevalence of SpA was higher in HLA-B27-positive patients than in HLA-B27-negative patients (50% vs. 15%, p < 0.0001). The multivariate logistic regression (R(2) = 0.28) for SpA diagnosis identified as significant predictive factors: age at diagnosis (odds ratio [OR] = 0.95, 95% confidence interval [CI]: 0.91-0.99) and HLA-B27+ (OR = 5.32, 95% CI: 1.80-15.70). CONCLUSIONS: Our results confirmed the high prevalence of undiagnosed SpA in patients with NGAU, suggesting that, regardless of HLA-B27 status, in the presence of IBP and/or peripheral arthritis, patients with NGAU must be referred to the rheumatologist to allow earlier diagnosis

Survival and Recurrence in Vitreoretinal Lymphoma Simulating Uveitis at Presentation: The Possible Role of Combined Chemotherapy

Purpose: To investigate the role of combined systemic and local chemotherapy in improving the survival of patients with vitreoretinal lymphoma (VRL). Methods: Patients with VRL consecutively seen from 2006 to 2020 were retrospectively reviewed; data on the presence and time of central nervous system (CNS) involvement and treatment regimen (systemic, local or combined chemotherapy) were collected. Overall survival (OS) and progression-free survival (PFS) were calculated for each group. Results: Forty-three eyes of 22 subjects with histology-proven VRL were included. Mean time of survival was 64.8 months (SE +/- 10.8). Twelve patients (57%) presented CNS involvement, which was significantly associated with progression (r = 0.48, P = .03) and death (r = 0.56, P = .009). The isolated primary VRL group had a 5-year OS of 80%. Combined systemic and local chemotherapy reduced the risk of death by 82% (hazard ratio 0.18[0.04- 0.85]) in the entire cohort. Conclusion: Combined systemic and local chemotherapy significantly improved OS but not PFS of patients affected by VRL

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): position paper on diagnosis, prognosis, and treatment by the MNGIE International Network

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disease caused by TYMP mutations and thymidine phosphorylase (TP) deficiency. Thymidine and deoxyuridine accumulate impairing the mitochondrial DNA maintenance and integrity. Clinically, patients show severe and progressive gastrointestinal and neurological manifestations. The onset typically occurs in the second decade of life and mean age at death is 37 years. Signs and symptoms of MNGIE are heterogeneous and confirmatory diagnostic tests are not routinely performed by most laboratories, accounting for common misdiagnosis. Factors predictive of progression and appropriate tests for monitoring are still undefined. Several treatment options showed promising results in restoring the biochemical imbalance of MNGIE. The lack of controlled studies with appropriate follow-up accounts for the limited evidence informing diagnostic and therapeutic choices. The International Consensus Conference (ICC) on MNGIE, held in Bologna, Italy, on 30 March to 31 March 2019, aimed at an evidence-based consensus on diagnosis, prognosis, and treatment of MNGIE among experts, patients, caregivers and other stakeholders involved in caring the condition. The conference was conducted according to the National Institute of Health Consensus Conference methodology. A consensus development panel formulated a set of statements and proposed a research agenda. Specifically, the ICC produced recommendations on: (a) diagnostic pathway; (b) prognosis and the main predictors of disease progression; (c) efficacy and safety of treatments; and (f) research priorities on diagnosis, prognosis, and treatment. The Bologna ICC on diagnosis, management and treatment of MNGIE provided evidence-based guidance for clinicians incorporating patients' values and preferences