Reversal of MYB-dependent suppression of MAFB expression overrides leukaemia phenotype in MLL-rearranged AML.

The transcription factor MYB plays a pivotal role in haematopoietic homoeostasis and its aberrant expression is involved in the genesis and maintenance of acute myeloid leukaemia (AML). We have previously demonstrated that not all AML subtypes display the same dependency on MYB expression and that such variability is dictated by the nature of the driver mutation. However, whether this difference in MYB dependency is a general trend in AML remains to be further elucidated. Here, we investigate the role of MYB in human leukaemia by performing siRNA-mediated knock-down in cell line models of AML with different driver lesions. We show that the characteristic reduction in proliferation and the concomitant induction of myeloid differentiation that is observed in MLL-rearranged and t(8;21) leukaemias upon MYB suppression is not seen in AML cells with a complex karyotype. Transcriptome analyses revealed that MYB ablation produces consensual increase of MAFB expression in MYB-dependent cells and, interestingly, the ectopic expression of MAFB could phenocopy the effect of MYB suppression. Accordingly, in silico stratification analyses of molecular data from AML patients revealed a reciprocal relationship between MYB and MAFB expression, highlighting a novel biological interconnection between these two factors in AML and supporting new rationales of MAFB targeting in MLL-rearranged leukaemias.

COVID-19 lockdown negatively impacted on adherence to denosumab therapy: incidence of non-traumatic fractures and role of telemedicine.

PURPOSE: Coronavirus disease (COVID-19) lockdowns have impacted on management of osteoporosis and the use of telemedicine is increasingly widespread albeit supported by little evidence so far. The aim of the study is to assess adherence to denosumab and incidence of non-traumatic fractures during the lockdown compared to the pre-COVID-19 year and to explore the effectiveness of telemedicine in the management of osteoporotic patients. METHODS: Retrospective, longitudinal, single-center study on patients receiving subcutaneous denosumab therapy every 6 months. Each patient was scheduled to undergo 2 visits: one during the pre-COVID-19 period (March 2019-March 2020) and another visit during the lockdown period (March 2020-March 2021). Data on new fractures, adherence, risk factors for osteoporosis and the modality of visit (telemedicine or face-to-face) were collected. RESULTS: The prevalence of non-adherent patients was higher during the lockdown (35 of 269 patients, 13.0%) than the pre-COVID-19 period (9 of 276 patients, 3.3%) (p < 0.0001). During the lockdown, the number of new non-traumatic fractures was higher than the pre-COVID-19 year (p < 0.0001): 10 patients out of 269 (3.7%) experienced a fragility fracture and 2 patients (0.7%) a probable rebound fracture during the lockdown period, whereas no patient had fragility/rebound fractures during the pre-COVID-19 period. No difference was found in the prevalence of non-adherence and new non-traumatic fractures comparing patients evaluated with tele-medicine to those evaluated with face-to-face visit. CONCLUSION: Non-adherent patients and new non-traumatic fractures (including rebound fractures) were more prevalent during the lockdown in comparison to the pre-COVID-19 period, regardless of the modality of medical evaluation.

Effects of acute and sub-acute hypobaric hypoxia on oxidative stress: a field study in the Alps.

PURPOSE: High altitude results in lower barometric pressure and hence partial pressure of O2 decrease can lead to several molecular and cellular changes, such as generation of reactive oxygen species (ROS). Electron Paramagnetic Resonance technique was adopted in the field, to evaluate the effects of acute and sub-acute hypobaric hypoxia (HH) on ROS production by micro-invasive method. Biological biomarkers, indicators of oxidative stress, renal function and inflammation were investigated too. METHODS: Fourteen lowlander subjects (mean age 27.3 ± 5.9 years) were exposed to HH at 3269 m s.l. ROS production, related oxidative damage to cellular components, systemic inflammatory response and renal function were determined through blood and urine profile performed at 1st, 2nd, 4th, 7th, and 14th days during sojourn. RESULTS: Kinetics of changes during HH exposition showed out significant (range p < 0.05-0.0001) increases that at max corresponds to 38% for ROS production rate, 140% for protein carbonyl, 44% for lipid peroxidation, 42% for DNA damage, 200% for inflammatory cytokines and modifications in renal function (assessed by neopterin concentration: 48%). Conversely, antioxidant capacity significantly (p < 0.0001) decreased - 17% at max. CONCLUSION: This 14 days in-field study describes changes of oxidative-stress biomarkers during HH exposure in lowlanders. The results show an overproduction of ROS and consequent oxidative damage to protein, lipids and DNA with a decrease in antioxidant capacity and the involvement of inflammatory status and a transient renal dysfunction. Exposure at high altitude induces a hypoxic condition during acute and sub-acute phases accompanied by molecular adaptation mechanism indicating acclimatization.

Nephrotic syndrome: immunological mechanisms.

Nephrotic Syndrome (NS) is a rare diseases (around 2-7 cases per 100.000 children per year) characterized by proteinuria ≥50 mg/kg/day (or ≥40 mg/m2/h) or a proteinuria/creatininuria ratio >2 (mg/mg); hypoalbuminaemia less than 25 g/l and edema. The protein leakage, with the consequent hypoalbunaemia and edema, due to podocyte alterations may be caused by genetic diseases, immunological mechanisms, infections, toxins or malignancy. However, most commonly the exact etiology is unknow. The idiopathic NS may be classified based on response to corticosteroid therapy or the hytological appearance. The first classification identifies steroid-resistant NS (no response after 4 weeks of steroid therapy); frequently relapsing NS (≥ 2 relapses in first 6 months or ≥4 relapses in 1-year); steroid dependent NS (relapses during steroid decalage or within 2 weeks from steroid therapy interruption). The hystological classification is based on light and electron microscopy after renal biopsy, which is indicated in case of onset disease before 1 year or after 12 years of age. Macroscopic hematuria: persistent hypertension and/or microscopic hematuria and/or low plasma C3 renal failure not related to hypovolemia; steroid resistence: secondary or relatedsyndromes NS. Minimal change disease (MCD) is the most common form of idiopahtic NS in children, with good response to steroid treatment, and it is characterized by normal glomerular appearance on light microscopy and evidence of podocyte foot alterations on electron microscopy, due to immunological related damage. Focal segmental glomerulosclerosis (FSGS) is described inidiopahtic NS, particularly in steroiddependent or steroid-resistant forms, and is characterized by evidence of focal glomerular damage with secondary sclerosis and adhesion with Bowman's capsule; the electron appearance is the same of MCD one. Recent authors hypotizethat the FSGS is an evolution of MCD. These 2 idiopathic NS forms may be expression of the same immunological disease, with 2 different severity grades; so they may be considered different moments of the same disease spectrum. Less common idiopathic NS forms are membrano proliferative glomerulonephritis; membranous nephropathy; IgM-nephropathy; C1q nephropathy and thin basement membrane disease (1, 2, 3).

Pediatric urolithiasis.

Urolithiasis is a well-known condition that can affect any part of the urinary tract. With a rate of 3-5% the incidence of upper urinary tract for long has been higher in adults (1-3), but recently it has increased among children reaching 3,3% . Indeed, more than 1% of all urinary stones are seen in patients aged less than 18 years (4). Pediatric urolithiasis is endemic in Turkey and Far East and it is probably due to malnutrition and racial factors (5). The spontaneous stone passage is more likely in children than in adults, indeed ureteral calculi spontaneously pass into 41-63% of children (1). Rate of stone passage depends on size and stone location in the urinary system. Stones sized less than 5 mm have a passage rate ranging from 40% to 98%, whilst stones > 5 mm have between 55% and 50% (6). In the last decade, the use of alpha blockers has proven well efficacious in helping spontaneous passage of distal ureteric stones in adults (7-9). The latest EAU guidelines support their use in adults while remain vague about their use in children because of unclear safety and efficacy (4). In search of evidence supporting or not the use of medical expulsive therapy in children we reviewed the literature dealing with the management of urolithiasis in pediatric patients. The primary aim of the present study was to evaluate the efficacy of medical expulsive therapy (MET), defined as stone expulsion rate, with a-blockers compared to a control group. The secondary aim was to assess the safety, defined as side effects rate, of MET compared to a control group.

Monosymptomatic enuresis: the therapeutic weapons.

Nocturnal enuresis (NE) was defined by the World Health Organization (ICD-10) and the American Psychiatric Association (DSM-5) as bed-wetting in children aged >5 years. In cases of mental retardation, the developmental age may be equivalent to 5 years. In this review, we focus on the current knowledge about the etiology of enuresis and the most recent therapeutical options. Both non-pharmacological and pharmacological therapies are included, although the relative effectiveness of each remains uncertain. To date, motivational, alarm and drug therapies are the mainstay of treatment. Alarm therapy remains the first-line treatment modality for NE, while desmopressin is the most commonly used medical treatment.

Renal anomalies in newborns with vacterel association: case series and literature review.

Nocturnal enuresis (NE) was defined by the World Health Organization (ICD-10) and the American Psychiatric Association (DSM-5) as bed-wetting in children aged >5 years. In cases of mental retardation, the developmental age may be equivalent to 5 years. In this review, we focus on the current knowledge about the etiology of enuresis and the most recent therapeutical options. Both non-pharmacological and pharmacological therapies are included, although the relative effectiveness of each remains uncertain. To date, motivational, alarm and drug therapies are the mainstay of treatment. Alarm therapy remains the first-line treatment modality for NE, while desmopressin is the most commonly used medical treatment.

Renal involvement in paediatric Fabry disease.

Anderson-Fabry Disease (AFD) is a rare, X-linked inborn error of glycosphingolipid catabolism caused by a deficient or absent activity of the lysosomal enzyme, α-galactosidase A, resulting in the progressive multisystem lysosomal accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3). Among the wide spectrum of clinical signs and symptoms and the life-threatening complications of Fabry disease, renal failure causes significant morbidity and mortality. Various evidence shows that the accumulation of Gb3 in different renal cells is present since the first years of life, many years and usually decades before manifest symptoms and signs of renal involvement. Early renal damage can be demonstrated by clinical signs as microalbuminuria and proteinuria, developing as early as in the second decade of life. A decline in GFR is uncommon at paediatric ages but may be seen as early as adolescence. Renal biopsy is rarely used in paediatric patients with Fabry disease although evidence shows that it may be considered a valid tool for the diagnosis of early and potentially reversible nephropathy, as well as for the evaluation of the effectiveness of enzyme replacement therapy (ERT). Although there is consensus in considering the early initiation of ERT as the only tool able to prevent the progression of nephropathy, the issue on the correct timing for the onset of ERT in pediatric age remains open in the management of this chronic and progressive disease.

Decay pathways for protonated and deprotonated adenine molecules.

We have measured fragment mass spectra and total destruction cross sections for protonated and deprotonated adenine following collisions with He at center-of-mass energies in the 20-240 eV range. Classical and ab initio molecular dynamics simulations are used to provide detailed information on the fragmentation pathways and suggest a range of alternative routes compared to those reported in earlier studies. These new pathways involve, for instance, losses of HNC molecules from protonated adenine and losses of NH2 or C3H2N2 from deprotonated adenine. The present results may be important to advance the understanding of how biomolecules may be formed and processed in various astrophysical environments.

Microplastics occurrence in the Tyrrhenian waters and in the gastrointestinal tract of two congener species of seabreams.

In this work it is reported for the first time the characterization of microplastics from sea water samples and in two congener species of seabreams: Pagellus erythrinus and P. bogaraveo, Mediterranean fish species of great commercial importance. An experimental survey was conducted on May-June 2017 in the southernmost part of the Tyrrhenian Sea. Microplastics found in the sea water and in the grastrointestinal tract of two teleosts were characterized by Raman and IR spectroscopies. Microplastics found in sea water samples appeared in the form of fragments made of plastics of low and high density (PVC and LPDE). All the microplastics found in fish belonged to Nylon 66, typical fibers used in industry and in fisheries. Our findings highlighted the importance of further studies along the food web chain for a better understanding of the diffusion and possible consequences of this terrible threat.

Different concentration of human cord blood HMGB1 according to delivery and labour: A pilot study.

OBJECTIVE: Oxidative stress is involved in several maternal conditions characterized both by an increase in free radicals synthesis and a parallel decrease in the antioxidant activity. Parturition induces considerable oxidative stress and many inflammatory mediators, among which HMGB1, are involved from the beginning of pregnancy to the birth of the infant. We evaluated serum cord blood HMGB1 levels in a population of neonates to investigate correlation with mode of delivery, as well as the influence of labour. SETTING AND PATIENTS: The study subjects were 325 neonates delivered at University Hospital "G. Martino" of Messina over an 18-month period. Following cord separation, venous blood sampling was performed on umbelical cords. RESULTS: In the cord venous blood, we found HMGB1 values significantly more elevated in spontaneous vaginal group when compared to elective or emergency caesarean section group. Regarding labour, umbilical cord venous blood HMGB1 levels were significantly higher in the spontaneous and induced labour group, compared to non-labouring women. CONCLUSION: These results could highlight a possible role of HMGB1 during birth time related to mode of delivery and labour.

Why many polymers are so fragile: A new perspective.

Many polymers exhibit much steeper temperature dependence of their structural relaxation time (higher fragility) than liquids of small molecules, and the mechanism of this unusually high fragility in polymers remains a puzzle. To reveal additional hints for understanding the underlying mechanism, we analyzed correlation of many properties of polymers to their fragility on example of model polymer polystyrene with various molecular weights (MWs). We demonstrate that these correlations work for short chains (oligomers), but fail progressively with increase in MW. Our surprising discovery is that the steepness of the temperature dependence (fragility) of the viscosity that is determined by chain relaxation follows the correlations at all molecular weights. These results suggest that the molecular level relaxation still follows the behavior usual for small molecules even in polymers, and its fragility (chain fragility) falls in the range usual for molecular liquids. It is the segmental relaxation that has this unusually high fragility. We speculate that many polymers cannot reach an ergodic state on the time scale of segmental dynamics due to chain connectivity and rigidity. This leads to sharper decrease in accessible configurational entropy upon cooling and results in steeper temperature dependence of segmental relaxation. The proposed scenario provides a new important insight into the specifics of polymer dynamics: the role of ergodicity time and length scale. At the end, we suggest that a similar scenario can be applicable also to other molecular systems with slow intra-molecular degrees of freedom and to chemically complex systems where the time scale of chemical fluctuations can be longer than the time scale of structural relaxation.

Human herpesviruses-6 and -7 encephalitis in immunocompetent infants: are they really so uncommon?

Human herpesviruses-6 and -7 (HHV-6 and 7) are considered uncommon causes of central nervous system infection and may occasionally cause encephalitis in young infants, however, the clinical syndrome and incidence are not well defined. In immunosuppressed hosts, reactivation is associated with a worse outcome such as encephalitis, hepatitis, or graft rejection. In immunocompetent hosts, this persistent infection is generally of no consequence. We report 4 cases of immunocompetent critically ill children, affected by HHV-6 and -7 encephalitis, admitted to our Pediatric Intensive Care Unit. In three patients, herpesvirus polymerase chain reaction in blood and cerebrospinal fluid was positive for HHV- 6, while one patient was positive for HHV-7. In our cases, a typical clinical picture of viral infection was not present but neurological symptoms were predominant. In all 4 children, neurological involvement rapidly regressed after acyclovir therapy. In this report, we offer evidence that HHV-6 and -7 primary infections can cause several clinical manifestations, such as encephalitis, also in immunocompetent hosts. In our experience, children with neurological symptoms suggestive of viral encephalitis should be fully investigated for these two viruses.

P260Right cardiac chambers remodeling in marathon and ultra-trail athletes detected by speckle-tracking echocardiography.

BACKGROUND: Strenuous and chronic exercise training can have detrimental effects on cardiac morphology and function. Our aim was to evaluate the cardiac adaptation between 2 different specialties' endurance athletes: marathon runners (M) and ultra-trailers (UT). METHODS: 47 M (age 45±7, men 32; training: 18 (9-53) years*days/week), 41 UT (age 42±9, men 38, training: 30 (15-66) years*days/week) were submitted in rest condition to conventional 2D echocardiography and Speckle-Tracking echo (STE) (Beyond Diogenes 2.0, AMID) during agonistic season and compared with 15 age matched sedentary individuals (S) (age 43±6, men 10). RESULTS: Left ventricle (LV) global longitudinal strain (GLS) and global radial strain (GRS) were increased in M and UT compared to S (see table) without differences in LV anatomy and function. Right ventricle (RV) end-diastolic area (p=0.026), fractional area changing (p=0.008) and RV GLS were increased in UT compared to M. Moreover UT showed larger right atrium (RA) volume compared to M (p=0.03) and S (p=0.003). RA GLS was reduced in UT compared to M while the RA Global Circumferential Strain was significantly increased in UT. After adjusted for age, sex and HR as covariates, UT showed a reduced RA GLS (OR 0.907; CI 0.856-0.961) and increased RV FAC (OR 1.172; CI: 1.044-1.317) compared to M; while when compared to S subjects, UT showed increased RA volume (OR 1.048; CI 1.002-1.096) and RV GLS (OR 0.667; CI 0.490-0.907). CONCLUSION: UT showed higher RV and RA morphological and functional remodeling in comparison with M. 2D-STE is a useful tool to investigate the deformation dynamic in different sport specialties. Further studies will be necessary to clarify the long-term consequences for cardiac health due to myocardial perturbations.MUTSpLV GLS-28.59±3.43*-27.64±4.18*-24.82±4.53<0.05LV GRS69.85±8.94*66.59±11.19*56.27±16.25<0.001RV GLS-25.60±10.54-30.41±4.38*-27.10±4.64<0.05RA GLS37.15±13.4931.65±9.60*35.37±9.99<0.05RA GCS17.46±6.4222.28±8.97*23.37±6.47<0.01.

ATOPIC DERMATITIS: MELATONIN AS POTENTIAL TREATMENT.

Atopic dermatitis (AD) is a chronic relapsing-remitting inflammatory skin disorder, characterized by a skin barrier dysfunction resulting in epidermal damage and altered permeability to allergens and microbes. Traditionally, the immunological mechanism involving the Th1-Th2 paradigm is considered central in the pathogenesis of AD. However, oxidative stress is, currently, recognized as a fundamental predisposing stimulus for AD. Several therapeutic approaches have been proposed as treatment, including the use of melatonin. This indolamine, through widespread expression and pleiotropic activity of the cutaneous melatoninergic system, may counteract environmental and endogenous stressors, regulate the immune response, decrease oxidative stress, and, finally, promote skin integrity. In the light of its pleiotropic effects, melatonin could represent a potential and alternative therapeutic approach in patients with AD.

Evaluation of the main coagulation tests in the presence of hemolysis in healthy subjects and patients on oral anticoagulant therapy.

INTRODUCTION: Our study was designed to evaluate, on healthy subjects and patients on oral anticoagulant therapy vitamin K antagonist (OAT-vka), the possible interference caused by hemolysis on the main coagulation tests. METHODS: To obtain hemolyzed samples, two methods were used: heat shock and mechanical system. The coagulation tests on hemolyzed samples were performed employing optical automated analyser BCSxp (Siemens Healthcare(®)). Moreover, the prothrombin time (PT) and activated partial thromboplastin time (aPTT) tests were also carried out manually using an electromechanical device (KC4 - Amelung). RESULTS: The PT test, on healthy subjects, in case of moderate hemolysis can be performed without significant interference on automatic instrument. On manual instrument, the PT test can be performed even in case of marked hemolysis. For patients on OAT-vka, the PT test in case of marked hemolysis can be performed both on automatic and manual instrument. For the aPTT test, it can be carried out manually, because also in case of marked hemolysis a statistically significant difference was not observed. For the fibrinogen test, a dramatic concentration decrease was already clear for weak hemolysis. A decreased function on antithrombin test was statistically significant for mild-moderate hemolysis. The D-dimer test showed increased values for mild hemolysis. CONCLUSIONS: The rejection of hemolyzed sample and/or the request of a second sample are not always the proper attitudes to take for performing clotting tests. The rational management of the hemolyzed samples decreases the employment of both nursing and technical staff significantly, the turnaround time and, consequently, does not lead to additional costs for each patient involved.

POTENTIAL USE OF MELATONIN IN PROCEDURAL ANXIETY AND PAIN IN CHILDREN UNDERGOING BLOOD WITHDRAWAL.

The recognition of the value of pain, especially in the pediatric population, has increased over the last decade. It is known that pain-related anxiety can increase perceived pain intensity. There are several different approaches to the treatment of pre-procedural anxiety and procedural pain in children. Melatonin, a neurohormone with the profile of a novel hypnotic-anaesthetic agent, plays an important role in anxiolysis and analgesia. This study investigated the effects of oral melatonin premedication to reduce anxiety and pain in children having blood samples taken. The investigations were carried out on 60 children, aged 1-14 years, divided into 2 equal groups. Using a computer-generated randomization schedule, patients were given either melatonin orally (0.5 mg/kg BW, max 5 mg) or placebo 30 min before blood draw. Pre-procedural anxiety was assessed using the scale from the Children’s Anxiety and Pain Scales, while procedural pain used the Face, Legs, Activity, Cry and Consolability assessment tool for children under the age of 3 years, Faces Pain Scale-Revised for children aged 3-8 years and Numeric Rating Scale for children over the age of 8 years. Oral administration of melatonin before the blood withdrawal procedure significantly reduced both anxiety (p<0.0005) and pain levels than placebo (p<0.0002 for children under 3 years and p<0.0039 for children over 3 years). These data support the use of melatonin for taking blood samples due to its anxiolytic and analgesic properties. Further studies are needed to support the routine use of melatonin to alleviate anxiety and pain in pediatric patients having blood samples taken.

Colonic stenosis post-necrotizing enterocolitis in term newborn with acquired cytomegalovirus infection.

Necrotizing enterocolitis is a gastrointestinal emergency typical of premature infants. Intestinal strictures infrequently complicate medical or surgical treatment of necrotizing enterocolitis. Postnatal cytomegalovirus infection with gastrointestinal linvolvement has occasionally been described in subjects with necrotizing enterocolitis. We report the case of a full term infant presenting necrotizing enterocolitis, acquired cytomegalovirus infection and post necrotizing enterocolitis colonic stricture.List of abbreviations: necrotizing enterocolitis = NEC,cytomegalovirus = CMV.