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Rasopathies, including Noonan Syndrome (NS) and Neurofibromatosis type 1 (NF1), are developmental disorders caused by germline mutations in genes of the RAS/mitogen-activated protein kinase pathway (RAS-MAPK). This study investigates irritability, a highly prevalent transdiagnostic construct, in children with Rasopathies and the impact of Rasopathy status on the associations between irritability, emotional dysregulation-related disorders, and social skills impairments. The sample comprise 174 children aged 4-17 (age mean = 9.49; 98 females), including 113 children with Rasopathies (NS n = 85, NF1 n = 28) and 61 age-sex-matched typically developed (TD) children. We used parent questionnaires (CBCL, SRS) to assess irritability, symptoms of ADHD, defiance, anxiety/depression, and social skills impairments while controlling for cognitive measures (IQ). Children with Rasopathies exhibited higher irritability than TD children (mean difference = 1.09; p < 0.001). Children with NS showed a weaker association between irritability and ADHD symptoms compared to TD children ( p  = .032, η p 2  = .03) and a stronger association between irritability and social skills impairments compared to both TD ( p  = .033, η p 2  = .03), and NF1 groups ( p  = .009, η p 2  = .06). We present novel and clinically significant findings showing high irritability in children with Rasopathies. Our study provides syndrome-specific results, suggesting differences in the mechanisms involved in irritability, ADHD, and social processes in children with NS and NF1. In essence, children with Rasopathies showed a highly irritable profile associated with ADHD symptoms and social skills impairments, with a significantly stronger association between irritability and social processes in NS. Our results suggest that developing prevention and treatments targeting irritability can distinctly affect the trajectories of neurodevelopmental disorders in children with Rasopathies.

Background and Aims: Insulin resistance (IR) is a major risk factor for cardiovascular disease. Recently, a novel index (triglyceride-glucose index-TyG) has been proposed as a surrogate marker of IR and a better expression of IR than the Homeostatic Model Assessment of IR (HOMA-IR) index. Few and heterogeneous data are so far available on the relationship between vascular damage and this novel index. Therefore, we aimed to estimate the predictive role of TyG, in comparison with the HOMA-IR, on the development of arterial stiffening (AS), defined as a pulse pressure>60 mmHg, in an 8-year follow-up observation of a sample of non-diabetic adult men (the Olivetti Heart Study)., Methods and Results: The analysis included 527 non-diabetic men, with normal arterial elasticity at baseline and not on antihypertensive or hypolipidemic treatment. TyG was significantly greater in those who developed AS than those who did not (p = 0.006). On the contrary, the HOMA-IR index was not different between the two groups (p = 0.24). Similar trends were shown by logistic regression analysis adjusting for main confounders. After the stratification by the optimal cut-off point, values of TyG >4.70 were significantly associated with the development of AS, also after adjustment for main confounders. On the contrary, the HOMA-IR index >1.90 was not associated with the risk of AS development in multivariate models., Conclusion: The results of this study indicate a predictive role of TyG on AS, independently of the main potential confounders. Moreover, the predictive power of TyG seems to be greater than that of the HOMA-IR index., Competing Interests: Declaration of competing interest All the authors declare that they have no conflict of interest. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients to be included in the study. No animal studies were carried out by the authors for this article., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Metabolic syndrome (MetS) and its components are directly associated with cardiovascular risk. Insulin resistance (IR) is the most common pathophysiological feature of MetS. A novel index, the triglyceride-glucose index (TyG), is considered a surrogate marker of IR. Hence, we estimated the ability of TyG to predict the risk to develop MetS over a follow-up period of 8 years. In addition, we compared the predictive role of TyG and that of the HOmeostatis Model Assessment (HOMA) of IR index (a widely used tool to evaluate IR)., Methods: The analysis included 440 adult men (The Olivetti Heart Study) without MetS at baseline. The optimal cut-off point of the association of continuous TyG or HOMA-IR with MetS was identified by ROC analysis., Results: During the follow-up period, 21.6% of participants developed MetS. Baseline TyG and HOMA-IR were both significantly greater in those who developed MetS than in those who did not. These results were confirmed upon adjustment for the main confounders. After stratification by the optimal cut-off point, TyG >4.78 was a significant predictor of MetS, also after adjustment for main confounders. Likewise, HOMA-IR >2.14 was associated with the risk of MetS development in multivariate models., Conclusions: The results of this prospective study indicate a significant predictive role of TyG on the risk of MetS, independently of the main confounders. They suggest that TyG may serve as a low-cost and simple non-invasive marker for cardio-metabolic risk stratification, with respect to more complex and expensive assays of IR requiring the insulin measurement.

A number of evidence showed an emerging role of leptin on immune system, involving inflammation, and innate and adaptive immunity. Few observational studies have evaluated the relationship between leptin and immunity, albeit with low statistical power and methodological differences. Therefore, the aim of this study was to evaluate the potential role of leptin on the immunity, expressed as white blood cells (WBC)-and its subpopulations, by comprehensive multivariate models in a sample of adult men. A cross-sectional evaluation of a general population comprised 939 subjects participating in the Olivetti Heart Study, with available leptin levels and WBC-and its subpopulations. WBC were significantly and positively associated with leptin, C-reactive protein and HOMA index (p < 0.05), but not with age and anthropometric indices (p > 0.05). The multivariate analysis confirmed the association between leptin and WBC, after accounting for main confounders (p < 0.05). Additional analysis on WBC subpopulations showed a positive and significant correlation between leptin and lymphocytes, monocytes and eosinophils (p < 0.05), but not with neutrophils and basophils (p > 0.05). After stratification by body weight, the positive and significant association between leptin and WBC-and its subpopulations-was found in excess body weight participants. The results of this study indicate a direct relationship between leptin levels and WBC-and its subpopulations-in excess body weight participants. These results support the hypothesis that leptin has modulatory functions on immunity and role in the pathophysiology of immune-related diseases, in particular in those associated with excess body weight., (© 2023. The Author(s).)