Suppressor of Cytokine Signaling-3 (SOCS-3) induces Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) expression in hepatic HepG2 cell line

The suppressor of cytokine signaling (SOCS) proteins are negative regulators of the JAK/STAT pathway activated by proinflammatory cytokines, including the tumor necrosis factor (TNF-\u3b1). SOCS3 is also implicated in hypertriglyceridemia associated to insulin resistance. Proprotein convertase subtilisin kexin type 9 (PCSK9) levels are frequently found to be positively correlated to insulin resistance and plasma very low density lipoprotein (VLDL) triglycerides concentrations. The present study aimed to investigate the possible role of TNF-\u3b1 and JAK/STAT pathway on de novo lipogenesis and PCSK9 expression in HepG2 cells. TNF-\u3b1 induced both SOCS3 and PCSK9 in a concentration-dependent manner. This effect was inhibited by transfection with siRNA anti-STAT3, suggesting the involvement of the JAK/STAT pathway. Retroviral overexpression of SOCS3 in HepG2 cells (HepG2SOCS3) strongly inhibited STAT3 phosphorylation and induced PCSK9 mRNA and protein, with no effect on its promoter activity and mRNA stability. Consistently, siRNA anti-SOCS3 reduced PCSK9 mRNA levels, whereas an opposite effect was observed with siRNA anti- STAT3. In addition, HepG2SOCS3 express higher mRNA levels of key enzymes involved in the de novo lipogenesis, such as fattyacid synthase, stearoyl-CoA desaturase (SCD)-1, and apoB. These responses were associated with a significant increase of SCD-1 protein, activation of sterol regulatory element-binding protein-1c (SREBP-1), accumulation of cellular triglycerides, and secretion of apoB. HepG2SOCS3 show lower phosphorylation levels of insulin receptor substrate 1 (IRS-1) Tyr896 and Akt Ser473 in response to insulin. Finally, insulin stimulation produced an additive effect with SOCS3 overexpression, further inducing PCSK9, SREBP-1, fatty acid synthase, and apoB mRNA. In conclusion, our data candidate PCSK9 as a gene involved in lipid metabolism regulated by proinflammatory cytokine TNF- in a SOCS3-dependent manner

The Role of Executive Functions in the Development of Empathy and Its Association with Externalizing Behaviors in Children with Neurodevelopmental Disorders and Other Psychiatric Comorbidities

: Executive functions have been previously shown to correlate with empathic attitudes and prosocial behaviors. People with higher levels of executive functions, as a whole, may better regulate their emotions and reduce perceived distress during the empathetic processes. Our goal was to explore the relationship between empathy and executive functioning in a sample of children and adolescents diagnosed with Attention Deficit and Hyperactivity Disorder alone or associated with comorbid Disruptive Behavior Disorders and/or Autism Spectrum Disorder. We also aimed to examine the role of empathic dimensions and executive skills in regulating externalizing behaviors. The 151 participants with ADHD were assigned to four groups according to their psychiatric comorbidity (either "pure" or with ASD and/or ODD/CD) and assessed by means of either parent- or self-reported questionnaires, namely the BRIEF-2, the BES, and the IRI. No questionnaire was found to discriminate between the four groups. Affective Empathy was found to positively correlate with Emotional and Behavioral Regulation competences. Furthermore, Aggressiveness and Oppositional Defiant Problems were positively associated with Executive Emotional and Behavioral Regulation competences. On the other hand, Rule-Breaking Behaviors and Conduct Problems were negatively associated with Affective Empathy and with Behavioral skills. Our study provides an additional contribution for a better understanding of the complex relationship between empathic competence and executive functions, showing that executive functioning and empathic attitudes interact with each other to regulate aggressive behaviors. This study further corroborates developmental models of empathy and their clinical implications, for which externalizing behaviors could be attenuated by enhancing executive functioning skills

Enhancing DLG2 Implications in Neuropsychiatric Disorders: Analysis of a Cohort of Eight Patients with 11q14.1 Imbalances

Neurodevelopmental disorders (NDDs) are considered synaptopathies, as they are due to anomalies in neuronal connectivity during development. DLG2 is a gene involved insynaptic function; the phenotypic effect of itsalterations in NDDs has been underestimated since few cases have been thoroughly described.We report on eight patients with 11q14.1 imbalances involving DLG2, underlining its potential effects on clinical presentation and its contribution to NDD comorbidity by accurate neuropsychiatric data collection. DLG2 is a very large gene in 11q14.1, extending over 2.172 Mb, with alternative splicing that gives rise to numerous isoforms differentially expressed in brain tissues. A thorough bioinformatic analysis of the altered transcripts was conducted for each patient. The different expression profiles of the isoforms of this gene and their influence on the excitatory–inhibitory balance in crucial brain structures could contribute to the phenotypic variability related to DLG2 alterations. Further studies on patients would be helpful to enrich clinical and neurodevelopmental findings and elucidate the molecular mechanisms subtended to NDDs

Callous–Unemotional Traits and Intelligence in Children with Externalizing Behavioral Problems

Research on the association between callous–unemotional (CU) traits and intelligence yielded contradictory results. Moreover, several previous studies focused on global intelligence scores or verbal vs. nonverbal/performance abilities usually evaluated with short/abbreviated instruments. The current study builds on these previous works and explores the link between CU traits and intelligence using the full version of the Wechsler Intelligence Scale for Children—4th Edition (WISC-IV), which provides four different verbal and nonverbal abilities scores. This guarantees a more detailed evaluation of children’s intelligence and its relation to CU traits. The sample included children (N = 149; age 6–14 years old) with severe behavioral problems. Clinicians administered the WISC-IV, and parents completed questionnaires evaluating the child’s externalizing problems and CU traits. Findings showed that CU traits were associated with lower verbal comprehension scores after also controlling for gender, age, externalizing problems, and the other WISC-IV indexes. In addition, CU traits and externalizing problems did not interact in predicting the WISC-IV indexes, and there were no significant differences in the WISC-IV indexes between children with CU traits and high vs. low externalizing problems. The current study suggests the relevance of assessing and addressing verbal abilities in children with behavioral problems and CU traits

Focus on the Involvement of the Nose and Paranasal Sinuses in Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss Syndrome): Nasal Cytology Reveals Infiltration of Eosinophils as a Very Common Feature

Background: Eosinophilic granulomatosis with polyangiitis (EGPA) is a necrotizing vasculitis that predominantly affects small- to medium-sized vessels. It is characterized by a wide spectrum of extrapulmonary symptoms, including sinonasal and paranasal sinus abnormalities. These are the most common features of this disease, constituting diagnostic criteria for EGPA. However, the actual clinical features, cellular mechanisms and impact on patientsâ\u80\u99 quality of life (QoL) are still a matter of study. Methods: Thirty-nine EGPA patients underwent multidimensional rhinological evaluations, including rhinofibroscopy, nasal cytology, and QoL questionnaires. This was coupled with respiratory and rheumatological assessments. Results: Twenty-eight patients were diagnosed with chronic rhinosinusitis (CRS). Of these, 18 had nasal polyposis (NP). Chronic rhinitis was diagnosed in 10 patients. Of these, 3 had allergic rhinitis (AR) and seven had non-AR (NAR). Overall, only 1 patient (2.6%) was normal. Nasal cytology showed that hypereosinophilia was present in 17/28 patients with CRS, 4/7 patients with NAR and all patients with AR. SNOT-22 and SF-36 showed a severe impact of nasal symptoms on QoL. No differences in asthma control or rheumatological patterns for EGPA were observed among patients with or without NP. Conclusions: Even when the rheumatological assessment scored EGPA â\u80\u9cunder controlâ\u80\u9d according to the Birmingham Vasculitis Activity Score and Vasculitis Damage Index, sinonasal diseases and related nasal inflammatory processes were not controlled. Therefore, there is a need for clinical monitoring and targeted treatment to control the inflammatory processes and improve the QoL of EGPA patients

Sleep disturbances in specific learning disorders: a qualitative and quantitative investigation

Background: The literature reports a significant association between sleep disorders and learning disabilities. Nevertheless, not all children with learning disorders have sleep alterations, and which sleep characteristics are associated with which learning difficulty is still unknown. The study aimed at acquiring new information on the relation between sleep disturbances or habits and the learning profiles of children with a specific learning disorder (SLD). Methods: The Sleep Disturbance Scale for Children (SDSC) and an actigraph (the FitBit-Flex, FB-F) were used in 26 and 16 SLD children respectively; all children were also assessed for learning skills. Results: Although parents' reports at the SDSC did not differentiate SLD from typical readers, the awakening, respiratory and arousal disturbances at the SDSC correlated with sleep duration at the FB-F. Sleep alterations at the FB-F actigraph characterize SLD with literacy difficulties: children with reading decoding difficulties showed shorter minimum amount of sleep than typical children, and severe SLDs showed shorter maximum sleep duration and a higher number of awakenings in comparison to SLDs with mild learning deficits. Conclusions: Mild alterations in the amount, duration and quality of sleep may characterize children with learning disorders and actigraphy proves to be a useful tool in starting the individual monitoring of sleep in these populations

Hemispheric language organization after congenital left brain lesions: A comparison between functional transcranial Doppler and functional MRI

This study investigated whether functional transcranial Doppler ultrasound (fTCD) is a suitable tool for studying hemispheric lateralization of language in patients with pre-perinatal left hemisphere (LH) lesions and right hemiparesis. Eighteen left-hemisphere-damaged children and young adults and 18 healthy controls were assessed by fTCD and fMRI to evaluate hemispheric activation during two language tasks: a fTCD animation description task and a fMRI covert rhyme generation task. Lateralization indices (LIs), measured by the two methods, differed significantly between the two groups, for a clear LH dominance in healthy participants and a prevalent activation of right hemisphere in more than 80% of brain-damaged patients. Distribution of participants in terms of left, right, and bilateral lateralization was highly concordant between fTCD and fMRI values. Moreover, right hemisphere language dominance in patients with left hemispheric lesions was significantly associated with severity of cortical and subcortical damage in LH. This study suggests that fTCD is an easily applicable tool that might be a valid alternative to fMRI for large-scale studies of patients with congenital brain lesions

Hemispheric language organization after congenital left brain lesions: A comparison between functional transcranial Doppler and functional MRI

This study investigated whether functional transcranial Doppler ultrasound (fTCD) is a suitable tool for studying hemispheric lateralization of language in patients with pre-perinatal left hemisphere (LH) lesions and right hemiparesis. Eighteen left-hemisphere-damaged children and young adults and 18 healthy controls were assessed by fTCD and fMRI to evaluate hemispheric activation during two language tasks: a fTCD animation description task and a fMRI covert rhyme generation task. Lateralization indices (LIs), measured by the two methods, differed significantly between the two groups, for a clear LH dominance in healthy participants and a prevalent activation of right hemisphere in more than 80% of brain-damaged patients. Distribution of participants in terms of left, right, and bilateral lateralization was highly concordant between fTCD and fMRI values. Moreover, right hemisphere language dominance in patients with left hemispheric lesions was significantly associated with severity of cortical and subcortical damage in LH. This study suggests that fTCD is an easily applicable tool that might be a valid alternative to fMRI for large-scale studies of patients with congenital brain lesions