An immunohistochemical study of the human periodontal ligament during sperimental orthodontic movement

Orthodontic tooth movement is characterized by remodeling changes in dental and paradental tissues, including dental pulp, periodontal ligament (PDL), alveolar bone, and gingiva. These tissues, when exposed to varying degrees of magnitude, frequency, and duration of mechanical loading, express macroscopic and microscopic changes. The different modification of periodontal ligament during load deformation can be monitored by analysis of the expression of different collagen types, fibronectin and vascular endothelial growth factor. The aim of this study was to evalue PDL collagen types I and IV, fibronectin and vascular endothelial growth factor (VEGF) modification induced by application of a precalibrated and constant orthodontic strength at different stages of treatment. For the study we utilized a coilspring NiTi 50 gr. and in vivo samples of 20 maxillaries and mandibular premolars of patients aged from 13 to 18 years subject to orthodontic treatment. These teeth was extracted at 1, 7, 14, 21 and 28 days from application of force respectively. The extraction of the PDL was effectuated scarifying the radicular surface on the pressure and tension side. The results were compared with periodontal ligament samples of the normal homologous teeth (control). The periodontal ligament samples were fixed in 3% paraformaldehyde in a 0,2M phosphate buffer at pH 7,4. The following primary antibodies were used: anti collagen I, anti collagen IV, anti fibronectin and mouse monoclonal anti-VEGF. Section were then observed and photographed using Zeiss LSM 510 confocal microscope. Were analyzed fluorescence intensity and compared with the control side. The signal of type I collagen is negative in tension and pressure side after 1 day, showed an increased respect to control, in the tension and pressure side, until 7, 14 and 21 days. After this stage in both sides maintained the same values of the control. The immunofluorescence of type IV collagen is negative, in both sides, after 1 and 7 days. At 14, 21 and 28 days from treatment, increased gradually in pressure side and manteined the same values of the control in tension side. The observation of fibronectin showed strongly immunofluorescence at all stages of treatment. After 1, 7 and 14 days the immunofluorescence of VEGF is negative in pressure side, and positive in tension side. In the last observation periods at 21 and 28 days, VEGF signal showing, in both sides, significant increase when compared with the control group. These findings suggest that: the increase of collagen type I and fibronectin could indicate that the solicitation by orthodontic force could determinate an increase of metabolic activity in the periodontal ligament. The rapid modification after the start of tooth movement, suggest that VEGF may be involved in the early stages of periodontal remodeling during orthodontic tooth movement, when occur rapid changes in local blood circulation. The initial decrease of collagen type IV, indicate a loss of vascular component in the early stages of movement infact this protein is localized in perivessel zones

Etiology of intracerebral hemorrhage in children: cohort study, systematic review, and meta-analysis

International audienceOBJECTIVEUnderstanding the etiological spectrum of nontraumatic pediatric intracerebral hemorrhage (pICH) is key to the diagnostic workup and care pathway. The authors aimed to evaluate the etiological spectrum of diseases underlying pICH.METHODSChildren treated at the authors’ institution for a pICH were included in an inception cohort initiated in 2008 and retrospectively inclusive to 2000, which was analyzed in October 2019. They then conducted a systematic review of relevant articles in PubMed published between 1990 and 2019, identifying cohorts with pICH. Identified populations and patients from the authors’ cohort were pooled in a multicategory meta-analysis.RESULTSA total of 243 children with pICH were analyzed in the cohort study. The final primary diagnosis was an intracranial vascular lesion in 190 patients (78.2%), a complication of a cardiac disease in 17 (7.0%), and a coagulation disorder in 14 (5.8%). Hematological and cardiological etiologies were disproportionately more frequent in children younger than 2 years (p < 0.001). The systematic review identified 1309 children in 23 relevant records pooled in the meta-analysis. Overall, there was significant heterogeneity. The dominant etiology was vascular lesion, with an aggregate prevalence of 0.59 (95% CI 0.45–0.64; p < 0.001, Q = 302.8, I2 = 92%). In 18 studies reporting a detailed etiological spectrum, arteriovenous malformation was the dominant etiology (68.3% [95% CI 64.2%–70.9%] of all vascular causes), followed by cavernoma (15.7% [95% CI 13.0%–18.2%]).CONCLUSIONSThe most frequent etiology of pICH is brain arteriovenous malformation. The probability of an underlying vascular etiology increases with age, and, conversely, hematological and cardiac causes are dominant causes in children younger than 2 years

Etiology of intracerebral hemorrhage in children: cohort study, systematic review, and meta-analysis

International audienceOBJECTIVEUnderstanding the etiological spectrum of nontraumatic pediatric intracerebral hemorrhage (pICH) is key to the diagnostic workup and care pathway. The authors aimed to evaluate the etiological spectrum of diseases underlying pICH.METHODSChildren treated at the authors’ institution for a pICH were included in an inception cohort initiated in 2008 and retrospectively inclusive to 2000, which was analyzed in October 2019. They then conducted a systematic review of relevant articles in PubMed published between 1990 and 2019, identifying cohorts with pICH. Identified populations and patients from the authors’ cohort were pooled in a multicategory meta-analysis.RESULTSA total of 243 children with pICH were analyzed in the cohort study. The final primary diagnosis was an intracranial vascular lesion in 190 patients (78.2%), a complication of a cardiac disease in 17 (7.0%), and a coagulation disorder in 14 (5.8%). Hematological and cardiological etiologies were disproportionately more frequent in children younger than 2 years (p < 0.001). The systematic review identified 1309 children in 23 relevant records pooled in the meta-analysis. Overall, there was significant heterogeneity. The dominant etiology was vascular lesion, with an aggregate prevalence of 0.59 (95% CI 0.45–0.64; p < 0.001, Q = 302.8, I2 = 92%). In 18 studies reporting a detailed etiological spectrum, arteriovenous malformation was the dominant etiology (68.3% [95% CI 64.2%–70.9%] of all vascular causes), followed by cavernoma (15.7% [95% CI 13.0%–18.2%]).CONCLUSIONSThe most frequent etiology of pICH is brain arteriovenous malformation. The probability of an underlying vascular etiology increases with age, and, conversely, hematological and cardiac causes are dominant causes in children younger than 2 years

The changing landscape of neonatal diabetes mellitus in Italy between 2003-2022

Context: In the last decade Sanger method of DNA sequencing has been replaced by next generation sequencing (NGS). NGS is valuable in conditions characterized by high genetic heterogeneity such as neonatal diabetes mellitus (NDM). Objective: To compare results of genetic analysis of patients with NDM and congenital severe insulin resistance (c.SIR) identified in Italy in 2003-2012 (Sanger) versus 2013-2022 (NGS). Methods: We reviewed clinical and genetic records of 104 cases with diabetes onset before 6 months of age (NDM+c.SIR) of the Italian dataset. Results: Fiftyfive patients (50 NDM + 5 c.SIR) were identified during 2003-2012 and 49 (46 NDM + 3 c.SIR) in 2013-2022. Twenty-year incidence was 1:103,340 (NDM) and 1:1,240,082 (c.SIR) live births. Frequent NDM/c.SIR genetic defects (KCNJ11, INS, ABCC8, 6q24, INSR) were detected in 41 and 34 probands during 2003-2012 and 2013-2022, respectively. We identified a pathogenic variant in rare genes in a single proband (GATA4) (1/42 or 2.4%) during 2003-2012 and in 8 infants (RFX6, PDX1, GATA6, HNF1B, FOXP3, IL2RA, LRBA, BSCL2) during 2013-2022 (8/42 or 19%, p= 0.034 vs 2003-2012). Notably, five among rare genes were recessive. Swift and accurate genetic diagnosis led to appropriate treatment: patients with autoimmune NDM (FOXP3, IL2RA, LRBA), were subjected to bone marrow transplant; patients with pancreas agenesis/hypoplasia (RFX6, PDX1) were supplemented with pancreatic enzymes and the individual with lipodystrophy caused by BSCL2 was started on metreleptin. Conclusions: NGS substantially improved diagnosis and precision therapy of monogenic forms of neonatal diabetes and congenital SIR in Italy

Recommendations for self-monitoring in pediatric diabetes: A consensus statement by the ISPED

none165noScaramuzza, Andrea; Cherubini, Valentino; Tumini, Stefano; Bonfanti, Riccardo; Buono, Pietro; Cardella, Francesca; D’Annunzio, Giuseppe; Frongia, Anna Paola; Lombardo, Fortunato; Monciotti, Anna Carla Maria; Rabbone, Ivana; Schiaffini, Riccardo; Toni, Sonia; Zucchini, Stefano; Frontino, Giulio; Iafusco, Dario; Arnaldi, Claudia; Banin, Patrizia; Barbetti, Fabrizio; Beccaria, Luciano; Benelli, Marzia; Berardi, Rosario; Biagioni, Martina; Bianchi, Giuliana; Bizzarri, Carla; Blasetti, Annalisa; Bobbio, Adriana; Boccato, Stefano; Bontempi, Franco; Bruzzese, Mariella; Cadario, Francesco; Calcaterra, Valeria; Cannatà, Alessandra; Cappa, Marco; Cardani, Roberta; Cardinale, Giuliana Marcella; Carloni, Ines; Castaldo, Vincenzo; Cauvin, Vittoria; Cerutti, Franco; Cester, Anna Maria; Chessa, Margherita; Chiarelli, Francesco; Chiari, Giovanni; Chiumello, Giuseppe; Cicchetti, Mario; Cirillo, Dante; Citriniti, Felice; Citro, Giuseppe; Coccioli, Maria Susanna; Cotellessa, Mario; Crinò, Antonino; De Berardinis, Fiorella; De Filippo, Gianpaolo; De Giorgi, Giovanni; De Luca, Filippo; De Marco, Rosaria; Delvecchio, Maurizio; Faleschini, Elena; Federico, Giovanni; Fifi, Anna Rita; Fontana, Franco; Franzese, Adriana; Frezza, Elda; Frongia, Annapaola; Gaiero, Alberto; Galderisi, Alfonso; Gallo, Francesco; Gargantini, Luigi; Ghione, Silvia; Giorgetti, Chiara; Gualtieri, Antonella; Guasti, Monica; Guerraggio, Lucia; Iannilli, Antonio; Ingletto, Dario; Iossa, Carmine; Iovene, Brunella; Iughetti, Lorenzo; Kaufmann, Peter; La Loggia, Alfonso; Lazzaro, Nicola; Lenzi, Lorenzo; Lera, Riccardo; Lia, Rosanna; Lo Presti, Donatella; Lorini, Renata; Lucchesi, Sonia; Luceri, Sergio; Madeo, Simona Filomena; Maffeis, Claudio; Mainetti, Benedetta; Mammi, Francesco; Manca Bitti, Maria Luisa; Marigliano, Marco; Marinari, Alessandra; Marinaro, Anna Maria; Meloni, Gianfranco; Marsciani, Alberto; Mastrangelo, Lisa; Mastrangelo, Costanzo; Meschi, Franco; Minasi, Domenico; Minenna, Adelaide; Minuto, Nicola; Monciotti, Carlamaria; Morganti, Gianfranco; Mozzillo, Enza; Nugnes, Rosa; Paradiso, Emanuela; Pardi, Daniela; Pasquino, Bruno; Patrizia Patera, Ippolita; Pennati, Cristina; Pepe, Rossella; Piccini, Barbara; Perrotta, Angelo; Piccinno, Elvira; Pinelli, Leonardo; Piredda, Gavina; Pocecco, Mauro; Ponzi, Giuseppe; Prandi, Elena; Predieri, Barbara; Prisco, Francesco; Quinci, Maria; Ricciardi, Maria Rossella; Rigamonti, Andrea; Ripoli, Carlo; Sabbion, Alberto; Salardi, Silvana; Salvatoni, Alessandro; Salvo, Caterina; Salzano, Giuseppina; Saporiti, Anna; Sardi, Rita; Schieven, Eleonardo; Scipione, Mirella; Soci, Cristina; Soro, Miriam; Spallino, Luisa; Stamati, Filomena; Suprani, Tosca; Savastio, Silvia; Taccardi, Rosa Anna; Tarchini, Luis; Tomaselli, Letizia; Tonini, Giorgio; Torelli, Cataldo; Tornese, Gianluca; Trada, Michela; Valerio, Giuliana; Vanelli, Maurizio; Vanini, Roberto; Vascotto, Marina; Vergerio, Amedeo; Viscardi, Matteo; Zaffani, Silvana; Zampolli, Maria; Zanatta, Manuela; Zanette, Giorgio; Zanfardino, Angela; Zecchino, Clara; Zedda, Maria Antonietta; Zuccotti, Gian VincenzoScaramuzza, Andrea; Cherubini, Valentino; Tumini, Stefano; Bonfanti, Riccardo; Buono, Pietro; Cardella, Francesca; D’Annunzio, Giuseppe; Frongia, Anna Paola; Lombardo, Fortunato; Monciotti, Anna Carla Maria; Rabbone, Ivana; Schiaffini, Riccardo; Toni, Sonia; Zucchini, Stefano; Frontino, Giulio; Iafusco, Dario; Arnaldi, Claudia; Banin, Patrizia; Barbetti, Fabrizio; Beccaria, Luciano; Benelli, Marzia; Berardi, Rossana; Biagioni, Martina; Bianchi, Giuliana; Bizzarri, Carla; Blasetti, Annalisa; Bobbio, Adriana; Boccato, Stefano; Bontempi, Franco; Bruzzese, Mariella; Cadario, Francesco; Calcaterra, Valeria; Cannatà, Alessandra; Cappa, Marco; Cardani, Roberta; Cardinale, Giuliana Marcella; Carloni, Ines; Castaldo, Vincenzo; Cauvin, Vittoria; Cerutti, Franco; Cester, Anna Maria; Chessa, Margherita; Chiarelli, Francesco; Chiari, Giovanni; Chiumello, Giuseppe; Cicchetti, Mario; Cirillo, Dante; Citriniti, Felice; Citro, Giuseppe; Coccioli, Maria Susanna; Cotellessa, Mario; Crinò, Antonino; De Berardinis, Fiorella; De Filippo, Gianpaolo; De Giorgi, Giovanni; De Luca, Filippo; De Marco, Rosaria; Delvecchio, Maurizio; Faleschini, Elena; Federico, Giovanni; Fifi, Anna Rita; Fontana, Franco; Franzese, Adriana; Frezza, Elda; Frongia, Annapaola; Gaiero, Alberto; Galderisi, Alfonso; Gallo, Francesco; Gargantini, Luigi; Ghione, Silvia; Giorgetti, Chiara; Gualtieri, Antonella; Guasti, Monica; Guerraggio, Lucia; Iannilli, Antonio; Ingletto, Dario; Iossa, Carmine; Iovene, Brunella; Iughetti, Lorenzo; Kaufmann, Peter; La Loggia, Alfonso; Lazzaro, Nicola; Lenzi, Lorenzo; Lera, Riccardo; Lia, Rosanna; Lo Presti, Donatella; Lorini, Renata; Lucchesi, Sonia; Luceri, Sergio; Madeo, Simona Filomena; Maffeis, Claudio; Mainetti, Benedetta; Mammi, Francesco; Manca Bitti, Maria Luisa; Marigliano, Marco; Marinari, Alessandra; Marinaro, Anna Maria; Meloni, Gianfranco; Marsciani, Alberto; Mastrangelo, Lisa; Mastrangelo, Costanzo; Meschi, Franco; Minasi, Domenico; Minenna, Adelaide; Minuto, Nicola; Monciotti, Carlamaria; Morganti, Gianfranco; Mozzillo, Enza; Nugnes, Rosa; Paradiso, Emanuela; Pardi, Daniela; Pasquino, Bruno; Patrizia Patera, Ippolita; Pennati, Cristina; Pepe, Rossella; Piccini, Barbara; Perrotta, Angelo; Piccinno, Elvira; Pinelli, Leonardo; Piredda, Gavina; Pocecco, Mauro; Ponzi, Giuseppe; Prandi, Elena; Predieri, Barbara; Prisco, Francesco; Quinci, Maria; Ricciardi, Maria Rossella; Rigamonti, Andrea; Ripoli, Carlo; Sabbion, Alberto; Salardi, Silvana; Salvatoni, Alessandro; Salvo, Caterina; Salzano, Giuseppina; Saporiti, Anna; Sardi, Rita; Schieven, Eleonardo; Scipione, Mirella; Soci, Cristina; Soro, Miriam; Spallino, Luisa; Stamati, Filomena; Suprani, Tosca; Savastio, Silvia; Taccardi, Rosa Anna; Tarchini, Luis; Tomaselli, Letizia; Tonini, Giorgio; Torelli, Cataldo; Tornese, Gianluca; Trada, Michela; Valerio, Giuliana; Vanelli, Maurizio; Vanini, Roberto; Vascotto, Marina; Vergerio, Amedeo; Viscardi, Matteo; Zaffani, Silvana; Zampolli, Maria; Zanatta, Manuela; Zanette, Giorgio; Zanfardino, Angela; Zecchino, Clara; Zedda, Maria Antonietta; Zuccotti, Gian Vincenz

Characteristics of a nationwide cohort of patients presenting with isolated hypogonadotropic hypogonadism (IHH)

Objective: Isolated hypogonadotropic hypogonadism (IHH) is a rare disorder with pubertal delay, normal (normoosmic-IHH, nIHH) or defective sense of smell (Kallmann syndrome, KS). Other reproductive and nonreproductive anomalies might be present although information on their frequency are scanty, particularly according to the age of presentation. Design: Observational cohort study carried out between January 2008 and June 2016 within a national network of academic or general hospitals. Methods: We performed a detailed phenotyping of 503 IHH patients with: (1) manifestations of hypogonadism with low sex steroid hormone and low/normal gonadotropins; (2) absence of expansive hypothalamic/pituitary lesions or multiple pituitary hormone defects. Cohort was divided on IHH onset (PPO, pre-pubertal onset or AO, adult onset) and olfactory function: PPO-nIHH (n = 275), KS (n = 184), AO-nIHH (n = 36) and AO-doIHH (AO-IHH with defective olfaction, n = 8). Results: 90% of patients were classifed as PPO and 10% as AO. Typical midline and olfactory defects, bimanual synkinesis and familiarity for pubertal delay were also found among the AO-IHH. Mean age at diagnosis was signifcantly earlier and more frequently associated with congenital hypogonadism stigmata in patients with Kallmann's syndrome (KS). Synkinesis, renal and male genital tract anomalies were enriched in KS. Overweight/obesity are signifcantly associated with AO-IHH rather than PPO-IHH. Conclusions: Patients with KS are more prone to develop a severe and complex phenotype than nIHH. The presence of typical extra-gonadal defects and familiarity for PPO-IHH among the AO-IHH patients indicates a common predisposition with variable clinical expression. Overall, these fndings improve the understanding of IHH and may have a positive impact on the management of patients and their families