Oxidative Stress in Down and Williams-Beuren Syndromes: An Overview.

Oxidative stress is the result of an imbalance in the redox state in a cell or a tissue. When the production of free radicals, which are physiologically essential for signaling, exceeds the antioxidant capability, pathological outcomes including oxidative damage to macromolecules, aberrant signaling, and inflammation can occur. Down syndrome (DS) and Williams-Beuren syndrome (WBS) are well-known and common genetic conditions with multi-systemic involvement. Their etiology is linked to oxidative stress with important causative genes, such as SOD-1 and NCF-1, respectively, of the diseases being primarily involved in the regulation of the redox state. Early aging, dementia, autoimmunity, and chronic inflammation are some of the main characteristics of these conditions that can be associated with oxidative stress. In recent decades, there has been a growing interest in the possible role of oxidative stress and inflammation in the pathology of these conditions. However, at present, few studies have investigated these correlations. We provide an overview of the current literature concerning the role of oxidative stress and oxidative damage in genetic syndromes with a focus on Down syndrome and WBS. We hope to provide new insights to improve the management of complications related to these diseases.

Executive functioning in children with epilepsy: Genes matter.

Pediatric epilepsy has emerged as a chronic medical disease with a characteristic behavioral and cognitive phenotype, which includes compromised executive functioning (EF) and attention-related deficits. However, considerable interindividual variability exists; children often display very different or even opposite outcomes, and some children are more likely than others to develop neurocognitive problems in the face of similar individual and disease-related problems. The factors responsible for this interindividual variability are still largely unknown, but we do know that some genetic factors render the developing brain more susceptible to damage or traumatic experiences than others. Dopamine availability has a neuromodulatory function in the prefrontal cortex (PFC) and especially affects EF. Dopamine availability relates to polymorphisms in the gene encoding catechol-O-methyltransferase (COMT Val158Met), which in turn is affected by the methylation state of its promoter. Allelic variation of the methylenetetrahydrofolate reductase (MTHFR C677T) gene, alters methylation and may influence the methylation state of the COMT promoter. Given this, we tested the hypothesis that these polymorphisms interact in children with epilepsy, and that variability in allelic expression is associated with variability in cognitive phenotype. Executive function was tested directly and indirectly (parent-rated) in 42 children between 5 and 12 years of age. The MTHFR T allele carriers performed worse than MTHFR homozygous CC carriers on indirect EF, and a significant decline was observed when T allele carriers had at least one met allele of the COMT gene, especially on Working Memory. Direct EF was significantly compromised in COMT Val/Val carriers where reduced dopamine availability seems to confer a higher risk in a test that requests a high degree of executive attention and planning. This finding suggests that in children with epilepsy, genes that influence methylation and dopamine availability affect PFC-related EF. Therefore, we should consider genetic vulnerability as a polygenic risk, which might predispose for a particular phenotype and include specific genetic signatures as part of each patient's behavioral and cognitive profile from the moment that we start to take care of the child.

Psychological Stress, Lung Function and Exacerbation Risk in COPD: Is an Increase of Cholinergic Tone a Possible Link?

at a glance: On the hypothesis that psychological distress might interfere with airway reactivity in patients suffering of mild to moderate COPD through a cholinergic-mediated-bronchial reflex.

IL-13 and idiopathic pulmonary fibrosis: Possible links and new therapeutic strategies.

The recent advances in the knowledge of immunological aspects of many pulmonary diseases, allowed to identify cells, biological functions, cytokines, and receptors that are preferentially involved in each disease. This is the case of asthma, where IL-13 (together with IL-4) is recognized as a central mediator. The role of IL-13 is strictly related, via complex signaling pathways, to eosinophil recruitment and activation, to mucus secretion, periostin generation and to fibrogenic processes (which are part of the remodeling process). These peculiar roles of IL-13 have suggested the hypothesis of its role in Idiopathic Pulmonary Fibrosis, and consequently of its antagonists in the treatment of such disease. We review herein the immunological roles of IL-13 in asthma and IPF, and the currently ongoing attempts to treat IPF by IL-13 antagonism strategies.

Asthma management in a specialist setting: Results of an Italian Respiratory Society survey.

BACKGROUND: Asthma considerably impairs patients' quality of life and increases healthcare costs. Severity, morbidity, and degree of disease control are the major drivers of its clinical and economic impact. National scientific societies are required to monitor the application of international guidelines and to adopt strategies to improve disease control and better allocate resources. AIM: to provide a detailed picture of the characteristics of asthma patients and modalities of asthma management by specialists in Italy and to develop recommendations for the daily management of asthma in a specialist setting. METHOD: A quantitative research program was implemented. Data were collected using an ad hoc questionnaire developed by a group of specialists selected by the Italian Pneumology Society/Italian Respiratory Society. RESULTS: The records of 557 patients were analyzed. In the next few years, specialists are expected to focus their activity patients with more severe disease and will be responsible for selection of patients for personalized biological therapy; however, only 20% of patients attending Italian specialist surgery can be considered severe. In 84.4% of cases, the visit was a follow-up visit requested in 82.2% of cases by the specialist him/herself. The Asthma Control Test is used only in 65% of patients. When available, a significant association has been observed between the test score and asthma control as judged by the physician, although concordance was only moderate (κ = 0.68). Asthma was considered uncontrolled by the specialist managing the case in 29.1% of patients; nevertheless, treatment was not stepped up in uncontrolled or partly controlled patients (modified in only 37.2% of patients). CONCLUSIONS: The results of this survey support re-evaluation of asthma management by Italian specialists. More resources should be made available for the initial visit and for more severely ill patients. In addition, more extensive use should be made of validated tools, and available drugs should be used more appropriately.

HLH as an additional warning sign of inborn errors of immunity beyond familial-HLH in children: a systematic review.

Background: Hemophagocytic Lymphohistiocytosis (HLH) is a rare and life-threatening condition characterized by a severe impairment of the immune homeostasis. While Familial-HLH (FHL) is a known cause, the involvement of other Inborn Errors of Immunity (IEI) in pediatric-HLH remains understudied. Objective: This systematic review aimed to assess the clinical features, triggers, laboratory data, treatment, and outcomes of pediatric HLH patients with IEI other than FHL (IEInotFHL), emphasizing the importance of accurate identification and management. Methods: A systematic search for studies meeting inclusion criteria was conducted in PubMed, EMBASE, MEDLINE, and Cochrane Central. Quality assessment was performed through JBI criteria. Results: A comprehensive search yielded 108 records meeting inclusion criteria, involving 178 patients. We identified 46 different IEI according to IUIS 2022 Classification. Combined immunodeficiencies, immune dysregulation disorders, and phagocyte defects were the IEI most frequently associated with HLH. In 75% of cases, HLH preceded the IEI diagnosis, often with an unrecognized history of severe infections. Triggers reflected the specific infection susceptibilities within IEI groups. Liver and central nervous system involvement were less common than in FHL cases. Treatment approaches and outcomes varied, with limited long-term follow-up data, limiting the assessment of therapeutic efficacy across IEI groups. Conclusion: A comprehensive evaluation encompassing immunological, infectious, and genetic aspects is essential in pediatric-HLH. Relying solely on FHL or EBV susceptibility disorders tests is insufficient, as diverse other IEI can contribute to HLH. Early recognition of HLH as a potential warning sign can guide timely diagnostic investigations and facilitate tailored therapeutic interventions for improved outcomes. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=371425, PROSPERO, CRD42022371425.

Corrigendum: HLH as an additional warning sign of inborn errors of immunity beyond familial-HLH in children: a systematic review.

[This corrects the article DOI: 10.3389/fimmu.2024.1282804.].

Worsening of Congenital Hypothyroidism After Start of Carob-bean Gum Thickened Formula: Is There a Link? A Case Report.

Congenital hypothyroidism (CH), if not correctly treated with L-thyroxine (L-T4), may be responsible for a permanent intellectual disability. If patients treated with L-T4 do not achieve a good TSH control, the possibility of poor compliance and/or poor absorption of L- T4 should be investigated. We describe an infant with CH whose thyroid hormone levels worsened after she started a carob-bean gum thickened formula. A baby girl was diagnosed with CH by newborn screening (at confirmatory blood evaluation TSH was 496.0 µIU/mL and FT4 0.13 ng/dl). Five weeks after beginning L-T4 treatment TSH normalized (TSH 2.72 µIU/mL , FT4 2.08 ng/dl); nevertheless, only another 5 weeks later we noticed a new worsening of thyroid hormone levels (TSH 31.1 µIU/mL , FT4 1.27 ng/dl), which worsened further (TSH 44.8 µIU/mL, FT4 1.16 ng/dl) even if L-T4 dosage was increased. Anamnesis disclosed that she had been given a carob-bean gum thickened formula to combat gastroesophageal reflux disease (GERD) rather than regular type 1 formula milk. The anti-reflux milk formula was discontinued and after 14 days the patient's TSH level dropped to 0.38 µIU/mL and FT4 increased to 2.68 ng/dL, allowing the L-T4 dosage to be reduced. Carob-bean gum thickened formula may influence the absorption of L-T4. If such formulas are used, we recommend a more frequent evaluation of thyroid function. In CH infants, inexplicably high TSH levels could be caused by gastrointestinal disorders or the interference of drugs or other substances, including some types of milk formula, which impair L-T4 absorption.

Glycemic Control, Basal/Bolus Distribution, BMI and Meal Management in Children and Adolescents with Type 1 Diabetes and Advanced Hybrid Closed Loop.

Evidence about the impact of advanced hybrid closed loop (AHCL) on body mass index (BMI) and eating habits in children with type 1 diabetes (T1D) is lacking. This real-world study aimed at evaluating glycemic control, BMI, meals and basal/bolus distribution in young subjects with T1D treated by AHCL. Glycemic metrics, HbA1c, basal/bolus distribution, meals/day, BMI, total daily dose (TDD), and carbohydrates/kg (CHO/kg) have been evaluated in 83 subjects, aged 13 ± 4.5 years, in manual mode, 3 and 6 months after auto-mode. Time in range (TIR) increased after 3 months, exceeding the target of 70% and was maintained at 6 months. While coefficient of variation (CV) did not change, the glucose management indicator (GMI) decreased in auto-mode (6.7 ± 0.3 vs. 7.1 ± 0.5%; p < 0.001), as well as HbA1c. Basal proportion decreased in favor of boluses (38.3 ± 7.3 vs. 43.6 ± 10.9%; p < 0.001). Meals increased at 3 and 6 months (4.4 ± 1.2 vs. 5.0 ± 1.5, p 0.002 and 5.1 ± 1.7, p < 0.001), as well as TDD/kg, without changes in BMI and CHO consumed. No differences in meal composition have arisen from food diaries. In conclusion, AHCL ensured the achievement and maintenance of target TIR in young T1D subjects. The number of meals, TDD, and insulin bolus proportion increased over time, but BMI remained stable.

Prevalence of Long COVID Symptoms Related to SARS-CoV-2 Strains.

BACKGROUND: Few studies have assessed the differences of patterns of Long COVID (L-COVID) with regards to the pathogenetic SARS-CoV-2 strains. OBJECTIVES: To investigate the relationship between demographic and clinical characteristics of acute phase of infection and the persistence of L-COVID symptoms and clinical presentation across different SARS-CoV-2 strains. METHODS: In this observational-multicenter study we recorded all demographic and clinical characteristics, severity of infection, presence/persistence of symptoms of fatigue, dyspnoea and altered quality of life (QoL) at baseline and after 6 months, in a sample of Italian patients from Liguria between March 2020 and March 2022. RESULTS: 308 patients (mean age 63.2 years; 55.5% men) with previous COVID were enrolled. Obese patients were 21.2% with a significant difference in obesity prevalence across the second and third wave (p = 0.012). Treatment strategies differed between waves (p < 0.001): more patients required invasive mechanical ventilation in the first wave, more patients were treated with high-flow nasal cannula/non-invasive ventilation in the in the second and more patients were treated with oxygen-therapy in the fourth wave. At baseline, a high proportion of patients were symptomatic (dyspnoea and fatigue), with impairment in some QoL indicators. A higher prevalence of patients with pain, were seen in the first wave compared to later infections (p = 0.01). At follow-up, we observed improvement of dyspnoea, fatigue and some dimensions of QoL scale evaluation such as mobility, usual activities, pain evaluations; instead there was no improvement in remaining QoL scale indicators (usual care and anxiety-depression). CONCLUSIONS: There were no significant differences in the prevalence of the most frequent L-COVID symptoms, except for QoL pain domain that was especially associated with classical variant. Our results show substantial impact on social and professional life and usual care activities. These findings highlight the importance of multidisciplinary post COVID follow-up care including mental health support and rehabilitation program.