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).

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.

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.

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.

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.

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.

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.

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.

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.

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.

Role of disorder in the thermodynamics and atomic dynamics of glasses.

We measured the density of vibrational states (DOS) and the specific heat of various glassy and crystalline polymorphs of SiO2. The typical (ambient) glass shows a well-known excess of specific heat relative to the typical crystal (α-quartz). This, however, holds when comparing a lower-density glass to a higher-density crystal. For glassy and crystalline polymorphs with matched densities, the DOS of the glass appears as the smoothed counterpart of the DOS of the corresponding crystal; it reveals the same number of the excess states relative to the Debye model, the same number of all states in the low-energy region, and it provides the same specific heat. This shows that glasses have higher specific heat than crystals not due to disorder, but because the typical glass has lower density than the typical crystal.

Nickel free-diet enhances the Helicobacter pylori eradication rate: a pilot study.

BACKGROUND: The Helicobacter pylori eradication rate with standard triple therapy is very low. H. pylori is known to require the nickel-containing metalloenzymes urease and NiFe-hydrogenase to survive at the low pH environment in the stomach. AIM: To compare the H. pylori eradication rate of a nickel free-diet associated with standard triple therapy and standard triple therapy alone as the first-line regimen. METHODS: Fifty-two sex- and age-matched patients at the first diagnosis of H. pylori infection were randomized 1:1 into two different therapeutic schemes: (1) standard LCA (26 patients): lansoprazole 15 mg bid, clarithromycin 500 mg bid and amoxicillin 1,000 mg bid for 7 days with a common diet; (2) standard LCA plus a nickel free-diet (NFD-LCA) (26 patients). Patients followed 30 days of a nickel-free diet plus a week of lansoprazole 15 mg bid, clarithromycin 500 mg bid and amoxicillin 1,000 mg bid starting from day 15 of the diet. RESULTS: All patients completed the study. A significantly higher eradication rate was observed in the NFD-LCA group (22/26) versus LCA group (12/26) (p < 0.01). Only a few patients (9 of 52) reported the occurrence of mild therapy-related side effects, without any significant differences between the two groups. CONCLUSIONS: The addition of a nickel-free diet to standard triple therapy significantly increases the H. pylori eradication rate. The reduction of H. pylori urease activity due to the nickel-free diet could expose the bacterium to gastric acid and increase H. pylori's susceptibility to amoxicillin. Further studies are necessary to confirm this preliminary result.

Multi-component modeling of quasielastic neutron scattering from phospholipid membranes.

We investigated molecular motions in the 0.3-350 ps time range of D2O-hydrated bilayers of 1-palmitoyl-oleoyl-sn-glycero-phosphocholine and 1,2-dimyristoyl-sn-glycero-phosphocholine in the liquid phase by quasielastic neutron scattering. Model analysis of sets of spectra covering scale lengths from 4.8 to 30 Å revealed the presence of three types of motion taking place on well-separated time scales: (i) slow diffusion of the whole phospholipid molecules in a confined cylindrical region; (ii) conformational motion of the phospholipid chains; and (iii) fast uniaxial rotation of the hydrogen atoms around their carbon atoms. Based on theoretical models for the hydrogen dynamics in phospholipids, the spatial extent of these motions was analysed in detail and the results were compared with existing literature data. The complex dynamics of protons was described in terms of elemental dynamical processes involving different parts of the phospholipid chain on whose motions the hydrogen atoms ride.

Methane intestinal production and poor metabolic control in type I diabetes complicated by autonomic neuropathy.

AIM: At the state of art it's unknown the correlation between diabetes and lower gastrointestinal disorders. Some studies show a significantly higher prevalence of small intestinal bacterial overgrowth in patients with type I diabetes in particular complicated by autonomic neuropathy. No data exists about gastrointestinal methane production in patients with diabetes and autonomic diabetic neuropathy. The aim of this paper was to evaluate the correlation of small intestinal bacterial overgrowth and gastrointestinal methane production with metabolic control and daily insulin requirements in patients with type 1 diabetes and. autonomic diabetic neuropathy. METHODS: Thirty subjects with type 1 diabetes and autonomic diabetic neuropathy were underwent hydrogen and methane lactulose breath test (LBT) to evaluate the presence of small intestinal bacterial overgrowth (double peak of hydrogen) and methane production. The metabolic control was evaluated through the glycated hemoglobin and the daily insulin requirement (calculated as ratio between total insulin units in a day and body weight). Methane producers were treated with metronidazole (500 mg bid for 10 days) and perform a LBT 8 weeks after the end of therapy RESULTS: Eight over thirty patients (26.6%) met the diagnostic criteria for small intestinal bacterial overgrowth. 11/30 patients (36%) were methane-producers (mean baseline value 16.37 ± 13.01 ppm; mean peak 26.62 ± 11.41 ppm); interestingly this subset of patients showed a worse glycemic control (mean HbA1c 8.16 ± 0.9% vs. 7.49 ± 0.8%, P<0.05). After metronidazole therapy 7/11 (63.3%) reduced CH4 production and they showed a mean HbA1c significantly lower than corresponding value before antibiotic therapy (7.63 ± 0.7% vs. 8.25 ± 0.8%). CONCLUSION: Our study showed for the first time a possible role of CH4 production in metabolic control. In particular, the most interesting data is that an increased values of HbA1c seems to be related to a gut CH4 production as confirmed by its significant improvement after eradication therapy. We are not yet able to determine whether poor glycemic control is the cause or the consequence of the selection of methanogenic flora.