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Abstract. It is accepted that apoptosis is a gene-controlled process of cellular self-destruction. It occurs during physiological regulation and in pathological situations in the life of a cell. In the immune system, several different intracellular and extracellular factors have been associated with the induction of apoptosis, and the final responses depend on the cell system and the acquired signals. In lymphoid cells, dexamethasone-induced apoptosis is associated with c-myc downregulation in cells that remain in G0–G1 until the point of death. Ornithine decarboxylase (ODC), a key enzyme involved in polyamine biosynthesis, is regulated by c-myc, which is a transcriptional activator implicated not only in the control of cell proliferation and differentiation but also in programmed cell death. As dimethylsulphoxide (DMSO) induces apoptosis in the RPMI-8402 human pre-T cell line, the present study analysed the involvement of the c-myc proto-oncogene and polyamine pathway as mediators of apoptosis. Cell growth, programmed cell death, c-myc expression, ODC activity and intracellular polyamine content were detected after DMSO and difluoromethylornithine (DFMO) treatment. DMSO-treated cells exhibit a decrease in ODC activity and polyamine levels associated with cell growth arrest and programmed cell death induction. The expression of c-myc proto-oncogene, as its mRNA or protein, is specifically down-regulated. DFMO, a well defined polyamine biosynthesis inhibitor, completely blocks ODC activity, resulting in growth inhibition but not apoptosis. Moreover, in these samples no evidence of changes of c-myc expression were found. The results obtained suggest that, in RPMI-8402 cells, DMSO provokes a c-myc-dependent decrease of ODC activity followed by a depletion of intracellular polyamine levels, associated with programmed cell death and cell growth arrest. [ABSTRACT FROM AUTHOR]

IgE-mediated cow's milk protein allergy (CMPA) is one of the most prevalent food allergies in early childhood. Though the cornerstone of management involves the strict avoidance of milk products while awaiting natural tolerance, research increasingly shows that the rates of resolution are slowing down. Therefore, there is a need to explore alternative pathways to promote tolerance to cow's milk in pediatric populations. This review aims to combine and appraise the scientific literature regarding the three CMPA management methods: avoidance, the milk ladder, and oral immunotherapy (OIT) and their outcomes in terms of efficacy, safety, and immunological effects. Cow's milk (CM) avoidance virtually protects against allergic reaction until natural tolerance occurs, with hypoallergenic substitutes available in the market, but accidental ingestion represents the main issue for this strategy. Introduction to baked milk using the milk ladder was designed, with most CMPA patients successfully completing the ladder. Similar to baked milk treatment, many OIT protocols also demonstrated decreased IgE and increased IgG4 levels post protocol, as well as a reduction in wheal size diameter. Though these strategies are shown to be safe and effective in CMPA, future clinical trials should compare the safety and effectiveness of these three management strategies.

The fungus Austropuccinia psidii infects young tissues of Eucalyptus plants until they are two years old in the nursery and field, causing Myrtaceae rust. The characteristics making older eucalypt leaves resistant to A. psidii and the reason for the low levels of this pathogen in older plants need evaluations. The aim of this study was to evaluate the morphological differences between Eucalyptus grandis leaves of different growth stages and two plant ages to propose a visual phenological scale to classify E. grandis leaves according to their maturation stages and to evaluate the time of leaf maturation for young and adult plants. A scale, based on a morphological differentiation for E. grandis leaves, was made. The color, shape and size distinguished the leaves of the first five leaf pairs. Anatomical analysis showed a higher percentage of reinforced tissue, such as sclerenchyma-like tissue and collenchyma, greater leaf blade thickness, absence of lower palisade parenchyma in the mature leaves and a higher number of cavities with essential oils than in younger ones. Changes in anatomical characteristics that could reduce the susceptibility of older E. grandis leaves to A. psidii coincide with the time of developing leaf resistance. Reduced infection of this pathogen in older plants appears to be associated with a more rapid maturation of their leaf tissues.

Background: The impact of intrauterine growth restriction (IUGR) on lung function in very preterm children is largely unknown as current evidence is mainly based on studies in children born small for gestational age but not necessarily with IUGR., Methods: Spirometry, transfer factor of the lung for carbon monoxide (TLco), and lung clearance index (LCI) were cross-sectionally evaluated at 8.0-15.0 years of age in children born <32 weeks of gestation with IUGR (n = 28) and without IUGR (n = 67). Controls born at term (n = 67) were also included., Results: Very preterm children with IUGR had lower mean forced expired volume in the first second (FEV 1 ) z-score than those with normal fetal growth (∆ -0.66, 95% confidence interval (CI) -1.12, -0.19), but not significant differences in LCI (∆ +0.24, 95% CI -0.09, 0.56) and TLco z-score (∆ -0.11, 95% CI -0.44, 0.23). The frequency of bronchopulmonary dysplasia (BPD) in the two groups was, respectively, 43% and 10% (P = 0.003). IUGR was negatively associated with FEV 1 (B = -0.66; P = 0.004), but the association lost significance (P = 0.05) when adjusting for BPD., Conclusions: IUGR has an impact on conducting airways function of very preterm children at school age, with part of this effect being mediated by BPD. Ventilation inhomogeneity and diffusing capacity, instead, were not affected., Impact: IUGR does not necessarily imply a low birthweight for gestational age (and vice versa). While a low birthweight is associated with worse respiratory outcomes, the impact of IUGR on lung function in premature children is largely unknown. IUGR affects conducting airways function in school-age children born <32 weeks with IUGR, but not ventilation inhomogeneity and diffusing capacity. The impact of IUGR on FEV 1 seems mainly related to the higher risk of BPD in this group., (© 2020. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Objective: To determine provision of MRI for patients with cardiac implantable electronic devices (CIEDs; pacemakers and defibrillators) in England, to understand regional variation and assess the impact of guideline changes., Methods: Retrospective data related to MRI scans performed in patients with CIED over the preceding 12 months was collected using a structured survey tool distributed to every National Health Service Trust MRI unit in England. Data were compared with similar data from 2014/2015 and with demand (estimated from local CIED implantation rates and regional population data by sustainability and transformation partnerships (STPs))., Results: Responses were received from 212 of 223 (95%) hospitals in England. 112 (53%) MRI units' scan patients with MR-conditional CIEDs (10% also scan non-MR conditional devices), compared with 46% of sites in 2014/2015. Total annual scan volume increased over fourfold between 2014 and 2019 (1090 to 4896 scans). There was widespread geographical variation, with five STPs (total population >3·5 million representing approximately 25 000 patients with CIED) with no local provision. There was no correlation between local demand (CIED implantation rates) and MRI provision (scan volume). Complication rates were extremely low with three events nationally in 12 months (0·06% CIED-MRI scans)., Conclusions: Provision of MRI for patients with CIEDs in England increased over fourfold in 4 years, but an estimated 10-fold care gap remains. Almost half of hospitals and 1 in 10 STPs have no service, with no relationship between local supply and demand. Availability of MRI for patients with non-MR conditional devices, although demonstrably safe, remains limited., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Climate change (CC) is one of the main contributors to health emergencies worldwide. CC appears to be closely interrelated with air pollution, as some pollutants like carbon dioxide (CO 2 ), nitrogen oxides (NOx) and black carbon are naturally occurring greenhouse gases. Air pollution may enhance the allergenicity of some plants and, also, has an adverse effect on respiratory health. Children are a uniquely vulnerable group that suffers disproportionately from CC burden. The increasing global warming related to CC has a big impact on plants' lifecycles, with earlier and longer pollen seasons, as well as higher pollen production, putting children affected by asthma and allergic rhinitis at risk for exacerbations. Extreme weather events may play a role too, not only in the exacerbations of allergic respiratory diseases but, also, in favouring respiratory infections. Even though paediatricians are already seeing the impacts of CC on their patients, their knowledge about CC-related health outcomes with specific regards to children's respiratory health is incomplete. This advocates for paediatricians' increased awareness and a better understanding of the CC impact on children's respiratory health. Having a special responsibility for children, paediatricians should actively be involved in policies aimed to protect the next generation from CC-related adverse health effects. Hence, there is an urgent need for them to take action and successfully educate families about CC issues. This paper aims at reviewing the evidence of CC-related environmental factors such as temperature, humidity, rainfall and extreme events on respiratory allergic diseases and respiratory infections in children and proposing specific actionable items for paediatricians to deal with CC-related health issues in their clinical practice.

Objectives: We aimed to raise awareness among paediatricians and physicians about this often misunderstood condition., Methods: We discussed the clinical profiles associated with late or wrong diagnosis of mevalonate kinase deficency (MKD) in a single centre case series., Results: We analysed the most common challenges and pitfalls that a clinician might face during the diagnostic process. Five main clinical profiles were characterised., Conclusions: We propose a new perspective on MKD, suggesting that the presentation of this disease can vary from patient to patient.

Background: Periodic fever syndromes (PFS) are an emerging group of autoinflammatory disorders. Clinical overlap exists and multiple genetic analyses may be needed to assist diagnosis. We evaluated the diagnostic value of a 5-gene sequencing panel (5GP) in patients with undiagnosed PFS., Methods: Simultaneous double strand Sanger sequencing of MEFV, MVK, TNFRSF1A, NLRP3, NLRP12 genes was performed in 42 patients with unexplained PFS. Clinical features were correlated with genetic results., Results: None of 42 patients analyzed displayed a causative genotype. However, single or multiple genetic variants of uncertain significance were detected in 24 subjects. Only in 5 subjects a definite diagnosis was made by taking into account both genetic and clinical data (2 TRAPS syndrome; 2 FMF; 1 FCAS). Statistical analysis showed that patients carrying genetic variants in one or more of the five selected genes displayed a significantly lower response to glucocorticoids compared with subjects who had completely negative genetic results., Conclusions: The sequencing of multiple genes is of little help in the diagnostics of PFS and can often lead to results of uncertain interpretation, thus the clinically driven sequencing of single genes should remain the recommended approach. However, the presence of single or multiple genetic variants of uncertain significance, even if not allowing any specific diagnosis, correlated with a poorer response to glucocorticoids, possibly indicating a multifactorial subgroup of PFS with differential response to pharmacological treatment.

Human Paraoxonase (PON1) is a High-Density Lipoprotein (HDL)-associated esterase that hydrolyses lipo-peroxides. PON1 has recently attracted attention as a protective factor against oxidative modification of LDL and may therefore play an important role in the prevention of the atherosclerotic process. Two polymorphisms have been extensively studied: a Leucine (L allele) to Methionine (M allele) substitution at codon 55, and a Glutamine (A allele) to Arginine (B allele) substitution at codon 192. We have examined these two aminoacidic changes in 579 people aged 20 to 65 years old, and 308 centenarians. We found that the percentage of carriers of the B allele at codon 192 (B+ individuals) is higher in centenarians than in controls (0.539 vs 0.447), moreover we found that among the B+ individuals, the phenomenon was due to an increase of people carrying M alleles at codon 55 locus. In conclusion, we propose that genetic variability at PON1 locus affects survival at extreme advanced age.

Melatonin is a small amino acid derivative hormone of the pineal gland. Melatonin quickly and reversibly blocked Kv1.3 channels, the predominant voltage-gated potassium channel in human T-lymphocytes, acting from the extracellular side. The block did not show state or voltage dependence and was associated with an increased inactivation rate of the current. A half-blocking concentration of 1.5 mM was obtained from the reduction of the peak current. We explored several models to describe the stoichiometry of melatonin-Kv1.3 interaction considering one or four independent binding sites per channel. The model in which the occupancy of one of four binding sites by melatonin is sufficient to block the channels gives the best fit to the dose-response relationship, although all four binding sites can be occupied by the drug. The dissociation constant for the individual binding sites is 8.11 mM. Parallel application of charybdotoxin and melatonin showed that both compounds can simultaneously bind to the channels, thereby localizing the melatonin binding site out of the pore region. However, binding of tetraethylammonium to its receptor decreases the melatonin affinity, and vice versa. Thus, the occupancy of the two separate receptor sites allosterically modulates each other.

It is accepted that apoptosis is a gene-controlled process of cellular self-destruction. It occurs during physiological regulation and in pathological situations in the life of a cell. In the immune system, several different intracellular and extracellular factors have been associated with the induction of apoptosis, and the final responses depend on the cell system and the acquired signals. In lymphoid cells, dexamethasone-induced apoptosis is associated with c-myc downregulation in cells that remain in G0-G1 until the point of death. Ornithine decarboxylase (ODC), a key enzyme involved in polyamine biosynthesis, is regulated by c-myc, which is a transcriptional activator implicated not only in the control of cell proliferation and differentiation but also in programmed cell death. As dimethylsulphoxide (DMSO) induces apoptosis in the RPMI-8402 human pre-T cell line, the present study analysed the involvement of the c-myc proto-oncogene and polyamine pathway as mediators of apoptosis. Cell growth, programmed cell death, c-myc expression, ODC activity and intracellular polyamine content were detected after DMSO and difluoromethylornithine (DFMO) treatment. DMSO-treated cells exhibit a decrease in ODC activity and polyamine levels associated with cell growth arrest and programmed cell death induction. The expression of c-myc proto-oncogene, as its mRNA or protein, is specifically down-regulated. DFMO, a well defined polyamine biosynthesis inhibitor, completely blocks ODC activity, resulting in growth inhibition but not apoptosis. Moreover, in these samples no evidence of changes of c-myc expression were found. The results obtained suggest that, in RPMI-8402 cells, DMSO provokes a c-myc-dependent decrease of ODC activity followed by a depletion of intracellular polyamine levels, associated with programmed cell death and cell growth arrest.

Major histocompatibility complex (MHC) class II molecules displayed clustered patterns at the surfaces of T (HUT-102B2) and B (JY) lymphoma cells characterized by interreceptor distances in the micrometer range as detected by scanning force microscopy of immunogold-labeled antigens. Electron microscopy revealed that a fraction of the MHC class II molecules was also heteroclustered with MHC class I antigens at the same hierarchical level as described by the scanning force microscopy data, after specifically and sequentially labeling the antigens with 30- and 15-nm immunogold beads. On JY cells the estimated fraction of co-clustered HLA II was 0.61, whereas that of the HLA I was 0.24. Clusterization of the antigens was detected by the deviation of their spatial distribution from the Poissonian distribution representing the random case. Fluorescence resonance energy transfer measurements also confirmed partial co-clustering of the HLA class I and II molecules at another hierarchical level characterized by the 2- to 10-nm Förster distance range and providing fine details of the molecular organization of receptors. The larger-scale topological organization of the MHC class I and II antigens may reflect underlying membrane lipid domains and may fulfill significant functions in cell-to-cell contacts and signal transduction.