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1. Combined unsupervised and semi-automated supervised analysis of flow cytometry data reveals cellular fingerprint associated with newly diagnosed pediatric type 1 diabetes

Author

Camillo Bechi Genzano, Eugenia Bezzecchi, Debora Carnovale, Alessandra Mandelli, Elisa Morotti, Valeria Castorani, Valeria Favalli, Angela Stabilini, Vittoria Insalaco, Francesca Ragogna, Valentina Codazzi, Giulia Maria Scotti, Stefania Del Rosso, Benedetta Allegra Mazzi, Maurizio De Pellegrin, Andrea Giustina, Lorenzo Piemonti, Emanuele Bosi, Manuela Battaglia, Marco J. Morelli, Riccardo Bonfanti, and Alessandra Petrelli

Subjects
type 1 diabetes, fingerprints, immune markers, pediatric diabetes, flow cytometry, computational biology, Immunologic diseases. Allergy, RC581-607
Abstract

An unbiased and replicable profiling of type 1 diabetes (T1D)-specific circulating immunome at disease onset has yet to be identified due to experimental and patient selection limitations. Multicolor flow cytometry was performed on whole blood from a pediatric cohort of 107 patients with new-onset T1D, 85 relatives of T1D patients with 0-1 islet autoantibodies (pre-T1D_LR), 58 patients with celiac disease or autoimmune thyroiditis (CD_THY) and 76 healthy controls (HC). Unsupervised clustering of flow cytometry data, validated by a semi-automated gating strategy, confirmed previous findings showing selective increase of naïve CD4 T cells and plasmacytoid DCs, and revealed a decrease in CD56brightNK cells in T1D. Furthermore, a non-selective decrease of CD3+CD56+ regulatory T cells was observed in T1D. The frequency of naïve CD4 T cells at disease onset was associated with partial remission, while it was found unaltered in the pre-symptomatic stages of the disease. Thanks to a broad cohort of pediatric individuals and the implementation of unbiased approaches for the analysis of flow cytometry data, here we determined the circulating immune fingerprint of newly diagnosed pediatric T1D and provide a reference dataset to be exploited for validation or discovery purposes to unravel the pathogenesis of T1D.

Published
2022
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2. Differences between Transient Neonatal Diabetes Mellitus Subtypes can Guide Diagnosis and Therapy

Author

Riccardo Bonfanti, Dario Iafusco, Ivana Rabbone, Giacomo Diedenhofen, Carla Bizzarri, Patrizia Ippolita Patera, Petra Reinstadler, Francesco Costantino, Valeria Calcaterra, Lorenzo Iughetti, Silvia Savastio, Anna Favia, Francesca Cardella, Donatella Lo Presti, Ylenia Girtler, Sarah Rabbiosi, Giuseppe D’Annunzio, Angela Zanfardino, Alessia Piscopo, Francesca Casaburo, Letizia Pintomalli, Lucia Russo, Valeria Grasso, Nicola Minuto, Mafalda Mucciolo, Antonio Novelli, Antonella Marucci, Barbara Piccini, Sonia Toni, Francesca Silvestri, Paola Carrera, Andrea Rigamonti, Giulio Frontino, Michela Trada, Davide Tinti, Maurizio Delvecchio, Novella Rapini, Riccardo Schiaffini, Corrado Mammì, Fabrizio Barbetti, Monica Aloe, Simona Amadeo, Claudia Arnaldi, Marta Bassi, Luciano Beccaria, Marzia Benelli, Giulia Maria Berioloi, Enrica Bertelli, Martina Biagioni, Adriana Bobbio, Stefano Boccato, Oriana Bologna, Franco Bontempi, Clara Bonura, Giulia Bracciolini, Claudia Brufani, Patrizia Bruzzi, Pietro Buono, Roberta Cardani, Giuliana Cardinale, Alberto Casertano, Maria Cristina Castiglione, Vittoria Cauvin, Valentino Cherubini, Franco Chiarelli, Giovanni Chiari, Stefano Cianfarani, Dante Cirillo, Felice Citriniti, Susanna Coccioli, Anna Cogliardi, Santino Confetto, Giovanna Contreas, Anna Corò, Elisa Corsini, Nicoletta Cresta, Fiorella De Berardinis, Valeria De Donno, Giampaolo De Filippo, Rosaria De Marco, Annalisa Deodati, Elena Faleschini, Valentina Fattorusso, Valeria Favalli, Barbara Felappi, Lucia Ferrito, Graziella Fichera, Franco Fontana, Elena Fornari, Roberto Franceschi, Francesca Franco, Adriana Franzese, Anna Paola Frongia, Alberto Gaiero, Francesco Gallo, Luigi Gargantini, Elisa Giani, Chiara Giorgetti, Giulia Bianchi, Vanna Graziani, Antonella Gualtieri, Monica Guasti, Gennaro Iannicelli, Antonio Iannilli, Ignaccolo Giovanna, Dario Ingletto, Stefania Innaurato, Elena Inzaghi, Brunella Iovane, Peter Kaufmann, Alfonso La Loggia, Rosa Lapolla, Anna Lasagni, Nicola Lazzaro, Lorenzo Lenzi, Riccardo Lera, Gabriella Levantini, Fortunato Lombardo, Antonella Lonero, Silvia Longhi, Sonia Lucchesi, Lucia Paola Guerraggio, Sergio Lucieri, Patrizia Macellaro, Claudio Maffeis, Bendetta Mainetti, Giulio Maltoni, Chiara Mameli, Francesco Mammì, Maria Luisa Manca-Bitti, Melania Manco, Monica Marino, Matteo Mariano, Marco Marigliano, Alberto Marsciani, Costanzo Mastrangelo, Maria Cristina Matteoli, Elena Mazzali, Franco Meschi, Antonella MIgliaccio, Anita Morandi, Gianfranco Morganti, Enza Mozzillo, Gianluca Musolino, Rosa Nugnes, Federica Ortolani, Daniela Pardi, Filomena Pascarella, Stefano Passanisi, Annalisa Pedini, Cristina Pennati, Angelo Perrotta, Sonia Peruzzi, Paola Peverelli, Giulia Pezzino, Anita Claudia Piona, Gavina Piredda, Carmelo Pistone, Elena Prandi, Barbara Pedieri, Procolo Di Bonito, Anna Pulcina, Maria Quinci, Emioli Randazzo, Rossella Ricciardi, Carlo Ripoli, Rosanna Roppolo, Irene Rutigliano, Alberto Sabbio, Silvana salardi, Alessandro Salvatoni, Anna Saporiti, Rita Sardi, Mariapiera Scanu, Andrea Scaramuzza, Eleonardo Schiven, Andrea Secco, Linda Sessa, Paola Sogno Valin, Silvia Sordelli, Luisa Spallino, Stefano Stagi, Filomena Stamati, Tosca Suprani, Valentina Talarico, Tiziana Timapanaro, Antonella Tirendi, Letizia Tomaselli, Gianluca Tornese, Adolfo Andrea Trettene, Stefano Tumini, Giuliana Valerio, Claudia Ventrici, Matteo Viscardi, Silvana Zaffani, Maria Zampolli, Giorgio Zanette, Clara Zecchino, Maria Antonietta Zedda, Silvia Zonca, Stefano Zucchini, Bonfanti, R., Iafusco, D., Rabbone, I., Diedenhofen, G., Bizzarri, C., Patera, P. I., Reinstadler, P., Costantino, F., Calcaterra, V., Iughetti, L., Savastio, S., Favia, A., Cardella, F., Presti, D. L., Girtler, Y., Rabbiosi, S., D'Annunzio, G., Zanfardino, A., Piscopo, A., Casaburo, F., Pintomalli, L., Russo, L., Grasso, V., Minuto, N., Mucciolo, M., Novelli, A., Marucci, A., Piccini, B., Toni, S., Silvestri, F., Carrera, P., Rigamonti, A., Frontino, G., Trada, M., Tinti, D., Delvecchio, M., Rapini, N., Schiaffini, R., Mammi, C., and Barbetti, F.

Subjects
Proband, Male, Pediatrics, Potassium Channels, Endocrinology, Diabetes and Metabolism, Datasets as Topic, Diagnosis, Differential, Diagnostic Techniques, Endocrine, Female, Humans, Infant, Infant, Newborn, Italy, Mutation, Potassium Channels, Inwardly Rectifying, Remission Induction, Retrospective Studies, Sulfonylurea Receptors, Diabetes Mellitus, Infant, Newborn, Diseases, Diseases, Gastroenterology, Diabetes mellitus genetics, Endocrinology, Settore MED/13, Retrospective Studie, Diagnosis, Medicine, Endocrine pancreas, Transient Neonatal Diabetes Mellitus, 6q24 TNDM, KATP TNDM, Sulfonylureas, Sulfonylureas, Sulfonylurea Receptor, biology, Diabetes Mellitu, General Medicine, Metformin, Inwardly Rectifying, Settore MED/03, 6q24 TNDM, medicine.symptom, Endocrine, hormones, hormone substitutes, and hormone antagonists, medicine.drug, Human, endocrine system, medicine.medical_specialty, KATP TNDM, ABCC8, Transient Neonatal Diabetes Mellitus, Internal medicine, Diabetes mellitus, Macroglossia, Endocrine pancreas, business.industry, medicine.disease, Newborn, Diagnostic Techniques, Transient neonatal diabetes mellitus, Differential, biology.protein, Sulfonylurea receptor, business
Abstract

Objective Transient neonatal diabetes mellitus (TNDM) is caused by activating mutations in ABCC8 and KCNJ11 genes (KATP/TNDM) or by chromosome 6q24 abnormalities (6q24/TNDM). We wanted to assess whether these different genetic aetiologies result in distinct clinical features. Design Retrospective analysis of the Italian data set of patients with TNDM. Methods Clinical features and treatment of 22 KATP/TNDM patients and 12 6q24/TNDM patients were compared. Results Fourteen KATP/TNDM probands had a carrier parent with abnormal glucose values, four patients with 6q24 showed macroglossia and/or umbilical hernia. Median age at diabetes onset and birth weight were lower in patients with 6q24 (1 week; −2.27 SD) than those with KATP mutations (4.0 weeks; −1.04 SD) (P = 0.009 and P = 0.007, respectively). Median time to remission was longer in KATP/TNDM than 6q24/TNDM (21.5 weeks vs 12 weeks) (P = 0.002). Two KATP/TNDM patients entered diabetes remission without pharmacological therapy. A proband with the ABCC8/L225P variant previously associated with permanent neonatal diabetes entered 7-year long remission after 1 year of sulfonylurea therapy. Seven diabetic individuals with KATP mutations were successfully treated with sulfonylurea monotherapy; four cases with relapsing 6q24/TNDM were treated with insulin, metformin or combination therapy. Conclusions If TNDM is suspected, KATP genes should be analyzed first with the exception of patients with macroglossia and/or umbilical hernia. Remission of diabetes without pharmacological therapy should not preclude genetic analysis. Early treatment with sulfonylurea may induce long-lasting remission of diabetes in patients with KATP mutations associated with PNDM. Adult patients carrying KATP/TNDM mutations respond favourably to sulfonylurea monotherapy.

Published
2021

4. Opportunities and Challenges of Telemedicine

Author

Giulio Frontino, Franco Meschi, Riccardo Bonfanti, Valeria Favalli, Andrea Rigamonti, Clara Bonura, Frontino, G., Meschi, F., Rigamonti, A., Favalli, V., Bonura, C., and Bonfanti, R.

Subjects
Telemedicine, business.industry, Endocrinology, Diabetes and Metabolism, 010401 analytical chemistry, 020206 networking & telecommunications, 02 engineering and technology, medicine.disease, 01 natural sciences, 0104 chemical sciences, Medical Laboratory Technology, Endocrinology, 0202 electrical engineering, electronic engineering, information engineering, medicine, Diabetes Mellitus, Humans, Medical emergency, business
Published
2016

5. Six cases with severe insulin resistance (SIR) associated with mutations of insulin receptor: Is a Bartter-like syndrome a feature of congenital SIR?

Author

Franco Cerutti, Franco Meschi, C. Monciotti, Ivana Rabbone, Valeria Favalli, Alfonso Galderisi, C. Colombo, Riccardo Bonfanti, Ornella Massa, Dario Iafusco, Fabrizio Barbetti, Enzo Bonora, Sara Gombos, Valeria Grasso, Grasso, V, Colombo, C, Favalli, V, Galderisi, A, Rabbone, I, Gombos, S, Bonora, E, Massa, O, Meschi, F, Cerutti, F, Iafusco, Dario, Bonfanti, R, Monciotti, C, and Barbetti, F.

Subjects
Male, Pediatrics, medicine.medical_specialty, Adolescent, Endocrinology, Diabetes and Metabolism, Gene mutation, Bartter syndrome, Extreme insulin resistance, Severity of Illness Index, Endocrinology, Internal medicine, Bartter's syndrome, Insulin receptor, Mutation, Acanthosis Nigricans, Bartter Syndrome, Child, Preschool, Donohue Syndrome, Female, Humans, Infant, Infant, Newborn, Insulin Resistance, Nephrocalcinosis, Receptor, Insulin, Internal Medicine, medicine, Insulin, Child, Preschool, Acanthosis nigricans, business.industry, General Medicine, medicine.disease, Newborn, Hyperaldosteronism, Diabetes and Metabolism, Bartter’s syndrome, Donohue syndrome, business, Hyperinsulinism, Receptor
Abstract

Biallelic insulin receptor (INSR) gene mutations cause congenital syndromes of severe insulin resistance (SIR) known as Donohue syndrome (DS) and Rabson-Mendenhall syndrome (RMS). At presentation, DS and RMS are difficult to differentiate since they share many clinical features; however, while patients with DS usually die within 1 year of birth, individuals classified as RMS can reach adult age. INSR mutations can be also found in pubertal females with hyperinsulinism, hyperandrogenism, and acanthosis nigricans (type A SIR). We studied the INSR gene in five subjects with congenital SIR and in a patient with type A SIR. Nine biallelic INSR gene mutations (eight novels, including an in-frame deletion of INSR signal peptide) were identified in patients with congenital SIR; a heterozygous, spontaneous INSR mutation was detected in the patient with type A SIR. Two probands, presenting severe hirsutism at birth, died at the age of 3 months and were classified as DS, while other 2, currently 2 and 3 years old, were diagnosed with RMS (patients 3 and 4). The fifth patient with congenital SIR died when 14 months old. Nephrocalcinosis, hyperaldosteronism, hyperreninemia, and hypokalemia, in the absence of hypertension, were discovered in patients 3 and 5 when 24 and 4 months old, respectively. Patient 3, now 3 years/3 months old, still shows hyperreninemic hyperaldosteronism requiring potassium supplementation. We conclude that renal abnormalities resembling antenatal Bartter's syndrome type II, recently reported also by others, is a common observation in patients with congenital SIR.

Published
2013

6. Sensor-augmented pump therapy in very young children with type 1 diabetes: an efficacy and feasibility observational study

Author

Giuseppe Chiumello, Giulio Frontino, Ivana Rabbone, Franco Meschi, Riccardo Bonfanti, Elisa Gioia, Gian Vincenzo Zuccotti, Sabrina Sicignano, Franco Cerutti, Clara Bonura, Roseila Battaglino, Andrea Scaramuzza, Valeria Favalli, Andrea Rigamonti, Frontino, G, Bonfanti, R, Scaramuzza, A, Rabbone, I, Meschi, F, Rigamonti, A, Battaglino, R, Favalli, V, Bonura, C, Sicignano, S, Gioia, E, Zuccotti, Gv, Cerutti, F, Chiumello, G., Frontino, G., Bonfanti, R., Scaramuzza, A., Rabbone, I., Meschi, F., Rigamonti, A., Battaglino, R., Favalli, V., Bonura, C., Sicignano, S., Gioia, E., Zuccotti, G. V., and Cerutti, F.

Subjects
Blood Glucose, Male, Insulin pump, medicine.medical_specialty, endocrine system diseases, Endocrinology, Diabetes and Metabolism, Biosensing Techniques, Hypoglycemia, Drug Administration Schedule, Insulin Infusion Systems, Endocrinology, Rating scale, Internal medicine, Diabetes mellitus, medicine, Humans, Hypoglycemic Agents, In patient, Child, Retrospective Studies, Glycated Hemoglobin, Type 1 diabetes, Dose-Response Relationship, Drug, business.industry, nutritional and metabolic diseases, Mean age, medicine.disease, Medical Laboratory Technology, Diabetes Mellitus, Type 1, Treatment Outcome, Italy, Child, Preschool, Physical therapy, Feasibility Studies, Female, Observational study, business
Abstract

Background: Efficacy and feasibility of sensor-augmented pump (SAP) therapy were evaluated in very young children with type 1 diabetes (T1D). Subjects and Methods: SAP (Dexcom [San Diego, CA] Seven Plus™ usage combined with insulin pump) therapy was retrospectively evaluated in 28 children (15 boys) younger than 7 years (mean age, 5.8±1.2 years; range, 3–7 years), with T1D. Glycosylated hemoglobin (HbA1c) was evaluated at baseline and at the end of the study, as were efficacy and feasibility of the system, using a rating scale (with 3 being the most positive). Results: SAP has been used for at least 6 months by 85% of patients, with an overall good satisfaction (92%). The greatest perceived benefit was the reduced fear of hypoglycemia (score of 3, 81%). HbA1c significantly improved only in patients with baseline HbA1c >7.5% (P=0.026). Conclusions: SAP therapy is effective and feasible in preschool children with T1D. In patients with high HbA1c at baseline it provide a 0.9% decrease, sustained for...

Published
2012

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