AGE-TXNIP axis drives inflammation in Alzheimer's by targeting Aß to mitochondria in microglia.

Alzheimer's disease (AD) is the most common form of dementia characterized by progressive memory loss and cognitive decline. Although neuroinflammation and oxidative stress are well-recognized features of AD, their correlations with the early molecular events characterizing the pathology are not yet well clarified. Here, we characterize the role of RAGE-TXNIP axis in neuroinflammation in relation to amyloid-beta (Aß) burden in both in vivo and in vitro models. In the hippocampus of 5xFAD mice microglial activation, cytokine secretion, and glial fibrillary acidic protein-enhanced expression are paralleled with increased TXNIP expression. TXNIP silencing or its pharmacological inhibition prevents neuroinflammation in those mice. TXNIP is also associated with RAGE and Aß. In particular, RAGE-TXNIP axis is required for targeting Aß in mitochondria, leading to mitochondrial dysfunction and oxidative stress. Silencing of TXNIP or inhibition of RAGE activation reduces Aß transport from the cellular surface to mitochondria, restores mitochondrial functionality, and mitigates Aß toxicity. Furthermore, Aß shuttling into mitochondria promotes Drp1 activation and exacerbates mitochondrial dysfunction, which induces NLRP3 inflammasome activation, leading to secretion of IL-1ß and activation of the pyroptosis-associated protein Gasdermin D (GSDMD). Downregulation of RAGE-TXNIP axis inhibits Aß-induced mitochondria dysfunction, inflammation, and induction of GSDMD. Herein we unveil a new pathway driven by TXNIP that links the mitochondrial transport of Aß to the activation of Drp1 and the NLRP3 inflammasome, promoting the secretion of IL-1ß and the pyroptosis pathway associated with GSDMD cleavage. Altogether these data shed new light on a novel mechanism of action of RAGE-TXNIP axis in microglia, which is intertwined with Aß and ultimately causes mitochondria dysfunction and NLRP3 inflammasome cascade activation, suggesting TXNIP as a druggable target to be better deepened for AD.

"White-puncture": A simple technique to prevent tearing of the anterior capsule during capsulorhexis in intumescent white cataracts. / Blancopunción: una técnica simple para prevenir el desgarro de la cápsula anterior durante la capsulorrexis en cataratas blancas intumescentes.

In order to avoid radial tearing of the anterior capsule while performing continuous circular capsulorhexis (CCC) in a white intumescent cataract, called the "Argentinian flag sign" when CCC is associated with a previous capsular stain with trypan blue, an initial puncture of the anterior capsule is performed with a 30G needle as the first step of the surgical procedure, that means, prior to any previous aperture of the anterior chamber. This act seems to allow the pressure of the intracrystalline space and the pressure of the anterior chamber to be equalized, as the liquefied content of the intumescent white cataract is released into a presumably hermetic anterior chamber, avoiding the dreaded anterior capsular radial tear. This technique, called "white-puncture", has been used in 174 cases without any associated complications.

Safety and effectiveness of a somatropin biosimilar in children requiring growth hormone treatment: second analysis of the PATRO Children study Italian cohort.

PURPOSE: To investigate the long-term safety (primary endpoint) and effectiveness (secondary endpoint) of the somatropin biosimilar Omnitrope®. METHODS: PATRO Children is an ongoing, multicenter, observational, post-marketing surveillance study. Children who received Omnitrope® for any indication were included. Adverse events (AEs) were evaluated in all study participants. Auxological data, including height standard deviation scores (HSDS) and height velocity standard deviation scores (HVSDS), were used to assess effectiveness. In this snapshot analysis, data from the Italian subpopulation up to August 2017 were reported. RESULTS: A total of 291 patients (mean age 10.0 years, 56.0% male) were enrolled at 19 sites in Italy. The mean duration of Omnitrope® treatment was 33.1 ± 21.7 months. There were 48 AEs with a suspected relationship to the study drug (as reported by the investigator) that occurred in 35 (12.0%) patients, most commonly headache, pyrexia, arthralgia, insulin-like growth factor above normal range, abdominal pain, pain in extremity and acute gastroenteritis. There were no confirmed cases of type 1 or type 2 diabetes; however, two patients (0.7%) had impaired glucose tolerance that was considered Omnitrope® related. The mean HSDS increased from - 2.41 ± 0.73 at baseline (n = 238) to - 0.91 ± 0.68 at 6.5 years (n = 10). The mean HVSDS increased from - 1.77 ± 1.38 at baseline (n = 136) to 0.96 ± 1.13 at 6.5 years (n = 10). CONCLUSIONS: In this sub-analysis of PATRO Children, Omnitrope® appeared to have acceptable safety and effectiveness in the treatment of in Italian children, which was consistent with the earlier findings from controlled clinical trials.

Assessment of efficacy and safety of micropulse diode laser treatment in glaucoma: One year follow-up. / Evaluación de la eficacia y seguridad del diodo láser micropulsado en el tratamiento de glaucoma: un año de seguimiento.

OBJECTIVE: To determine the effectiveness and safety of the micropulse transscleral technique in lowering intraocular pressure in patients with glaucoma. MATERIALS AND METHODS: A retrospective cohort study was conducted on 143 eyes with various glaucoma subtypes between October 2016 and December 2018. Patients were grouped for analysis based on glaucoma subtypes, preoperative demographics, previous surgical procedures, and postoperative results. The data collected was based on intra- and post-operative complications, intraocular pressure, visual acuity, the need of micropulse re-treatment, incisional glaucoma surgery, and increasing the dose/quantity of medications. A logistic and Cox regression model was performed to determine predictors of therapeutic failure, in addition to building Kaplan-Meier curves. RESULTS: The mean follow-up was 268 days, and 63% of the patients completed one year. The micropulse procedure achieved a mean intraocular pressure decline of 7.3mmHg (excluding neovascular glaucoma), independent of the glaucoma subtype. The percentage of patients who achieved intraocular pressure less than 20mmHg at 24h was 78%, with 80% at 3 months, 77% at 6 months, and 78% at 12 months. During the follow-up, 29.6% of the patients required additional treatment or a dose increase. Only 2patients presented with minimal postoperative complications. CONCLUSION: The treatment with transscleral micropulse is a safe and efficient technique for use in glaucoma, attaining a reduction in intraocular pressure and decrease in need of antihypertensive medications within the first year following the procedure.

Precursory worldwide signatures of earthquake occurrences on Swarm satellite data.

The study of the preparation phase of large earthquakes is essential to understand the physical processes involved, and potentially useful also to develop a future reliable short-term warning system. Here we analyse electron density and magnetic field data measured by Swarm three-satellite constellation for 4.7 years, to look for possible in-situ ionospheric precursors of large earthquakes to study the interactions between the lithosphere and the above atmosphere and ionosphere, in what is called the Lithosphere-Atmosphere-Ionosphere Coupling (LAIC). We define these anomalies statistically in the whole space-time interval of interest and use a Worldwide Statistical Correlation (WSC) analysis through a superposed epoch approach to study the possible relation with the earthquakes. We find some clear concentrations of electron density and magnetic anomalies from more than two months to some days before the earthquake occurrences. Such anomaly clustering is, in general, statistically significant with respect to homogeneous random simulations, supporting a LAIC during the preparation phase of earthquakes. By investigating different earthquake magnitude ranges, not only do we confirm the well-known Rikitake empirical law between ionospheric anomaly precursor time and earthquake magnitude, but we also give more reliability to the seismic source origin for many of the identified anomalies.

Implementation of a mentored professional development programme in laboratory leadership and management in the Middle East and North Africa.

Laboratories need leaders who can effectively utilize the laboratories' resources, maximize the laboratories'capacity to detect disease, and advocate for laboratories in a fluctuating health care environment. To address this need, the University of Washington, USA, created the Certificate Program in Laboratory Leadership and Management in partnership with WHO Regional Office for the Eastern Mediterranean, and implemented it with 17 participants and 11 mentors from clinical and public health laboratories in 10 countries (Egypt, Iraq, Jordan, Lebanon, Morocco, Oman, Pakistan, Qatar, Saudi Arabia, and Yemen) in 2014. Designed to teach leadership and management skills to laboratory supervisors, the programme enabled participants to improve laboratory testing quality and operations. The programme was successful overall, with 80% of participants completing it and making impactful changes in their laboratories. This success is encouraging and could serve as a model to further strengthen laboratory capacity in the Region.

Implementation of a mentored professional development programme in laboratory leadership and management in the Middle East and North Africa

Laboratories need leaders who can effectively utilize the laboratories' resources, maximize the laboratories'capacity to detect disease, and advocate for laboratories in a fluctuating health care environment. To address this need, the University of Washington, USA, created the Certificate Program in Laboratory Leadership and Management in partnership with WHO Regional Office for the Eastern Mediterranean, and implemented it with 17 participants and 11 mentors from clinical and public health laboratories in 10 countries [Egypt, Iraq, Jordan, Lebanon, Morocco, Oman, Pakistan, Qatar, Saudi Arabia, and Yemen] in 2014. Designed to teach leadership and management skills to laboratory supervisors, the programme enabled participants to improve laboratory testing quality and operations. The programme was successful overall, with 80% of participants completing it and making impactful changes in their laboratories. This success is encouraging and could serve as a model to further strengthen laboratory capacity in the Region

Les laboratoires ont besoin de directeurs à même d'utiliser les ressources internes de façon efficace, de maximiser leurs capacités à dépister les maladies, et d'oeuvrer pour le bien de ces établissements dans un environment de soins de santé en perpétuel changement. Pour répondre à ces besoins, l'Université de Washington [Etats-Unis], en partenariat avec le Bureau régional de l'OMS pour la Méditerranée orientale, a mis au point le Programme de certification en direction et gestion de laboratoire qui a été suivi par 17 participants et 11 mentors issus de laboratoires de santé clinique et publique dans 10 pays [Arabie saoudite, Egypte, Iraq, Jordanie, Liban, Maroc, Oman, Pakistan, Qatar et Yémen] au cours de l'année 2014. Conçu pour former les responsables de laboratoire aux compétences de direction et de gestion, le programme a permis aux participants de renforcer la qualité du dépistage et des opérations de leurs laboratoires. Le programme a été une réussite dans l'ensemble puisqu'il a été suivi jusqu'à son terme par 80% des participants et que ceux-ci ont ensuite pu mettre en place des changements réels dans leurs laboratoires. Ce succès est encourageant et pourrait servir de modèle afin de renforcer davantage encore les capacités des laboratoires dans la Région

Expanding the phenotype of RTTN variations: a new family with primary microcephaly, severe growth failure, brain malformations and dermatitis.

Primary autosomal recessive microcephaly (MCPH) is a developmental disorder characterized by prenatal onset of abnormal brain growth. MCPH occurs both alone and as part of a broad range of neurodevelopmental syndromes with or without cortical malformations and growth retardation. Here we report a consanguineous Moroccan family with two siblings affected by severe primary microcephaly, failure to thrive, congenital dermatitis and severe developmental delay. Brain magnetic resonance imaging showed lissencephaly of frontal lobes and periventricular heterotopia of the gray matter. We performed both Comparative Genomic Hybridization array and whole exome sequencing (WES) analyses of the kindred. No quantitative defects were detected. However, WES identified a new homozygous missense variation in the penultimate nucleotide of exon 23 of RTTN gene (c.2953A>G;pArg985Gly). cDNA sequencing revealed two abnormal spliced products, one lacking only exon 23 and the other lacking exons 22 and 23 (out-of-frame). RTTN is a protein involved in cilia structure and function. Homozygous mutations in RTTN gene have been described in bilateral diffuse isolated polymicrogyria and, more recently, in microcephalic primordial dwarfism (PD). We found a novel homozygous mutation in RTTN associated with microcephalic PD as well as complex brain malformations and congenital dermatitis, thus expanding the phenotypic spectrum of both RTTN-associated diseases and ciliary dysfunction.

TM6SF2 Glu167Lys polymorphism is associated with low levels of LDL-cholesterol and increased liver injury in obese children.

BACKGROUND: The Glu167Lys (E167K) transmembrane 6 superfamily member 2 (TM6SF2) variant has been associated with liver steatosis, high alanine transaminase (ALT) levels and reduced plasma levels of liver-derived triglyceride-rich lipoproteins. OBJECTIVES: The objectives of this study were to investigate in a group of obese children the association among the 167K allele of TM6SF2 gene and ALT, cholesterol and triglycerides levels, and hepatic steatosis, and to evaluate the potential interaction between this variant and the I148M patatin like phospholipase 3 gene (PNPLA3) polymorphism on liver enzymes. METHODS: We genotyped 1010 obese children for TM6SF2 E167K and PNPLA3 I148M polymorphisms. Anthropometrical and biochemical data were collected. Ultrasound imaging of the liver was performed. RESULTS: The 167K allele showed an association with steatosis (P < 0.0001), higher ALT levels (P < 0.001) and lower total cholesterol (P < 0.00001), low-density lipoprotein cholesterol (P < 0.0001), triglycerides (P = 0.02) and non-high-density lipoprotein cholesterol levels (P < 0.000001). The subjects homozygous for the PNPLA3 148M allele carrying the rare variant of TM6SF2 showed an odds ratio of 12.2 (confidence interval 3.8-39.6, P = 0.000001) to present hypertransaminasaemia compared with the remaining patients. CONCLUSION: Although the TMS6SF2 E167K variant predisposes the obese children to non-alcoholic fatty liver disease, there is an association between this variant and lower levels of cardiovascular risk factors. Overall, the data suggest differential effects of TMS6SF2 E167K variant on liver and heart health.

Association between cannabinoid receptor type 2 Q63R variant and oligo/polyarticular juvenile idiopathic arthritis.

OBJECTIVES: To investigate whether the functional variant Q63R of the cannabinoid 2 (CB2) receptor is associated with susceptibility to oligo/poly-articular juvenile idiopathic arthritis (JIA) and with its clinical features. METHOD: A total of 171 Italian children with oligoarticular/rheumatoid factor negative poly-articular JIA and 600 healthy controls were enrolled in the study and genotyped. RESULTS: A significant difference in genotype distribution of the CB2 Q63R variant (CNR2 rs35761398) between oligo/poly-articular JIA patients and controls was found (p = 0.001). The R63 variant was associated with increased rates of relapse (p = 0.0001). CONCLUSIONS: This study indicates that the CB2 receptor contributes to susceptibility to oligo/polyarticular JIA and to the severity of its clinical course.

[Health consequences of obesity in children and adolescents]. / Conseguenze dell'obesità sulla salute del bambino e dell' adolescente.

Obesity in childhood is associated with the presence of complications that can undermine health immediately or in the long term. Several conditions, such as pulmonary or orthopedic complications are strictly associated with the severity of overweight, since they are directly associated to the mechanic stress of fat tissue on the airways or on the bones. Other conditions, such as metabolic or liver complications, although increasing with the extent of overweight, are associated with insulin resistance, which can be modulated by different other factors (ethnicity, genetics, fat distribution) and can occur in overweight children as well. No less important are psychological correlates, such as depression and stigma, which can seriously affect the health related quality of life. Pediatric services for the care of childhood obesity need to be able to screen overweight and obese children for the presence of physical and psychological complications, which can be still reversed by weight loss. This article provides pediatricians a comprehensive update on the main complications in obese children and adolescents and their treatment.

Abdominal fat interacts with PNPLA3 I148M, but not with the APOC3 variant in the pathogenesis of liver steatosis in chronic hepatitis C.

The patatin-like phospholipase domain-containing 3 gene (PNPLA3) and the apolipoprotein C3 gene (APOC3) have been studied in relation to liver steatosis and liver disease outcome. The aim of this study was to evaluate the influence of PNPLA3 p.I148M and APOC3 rs2854116 and rs2854117 polymorphisms on the clinical and histological presentation of chronic hepatitis C in an Italian population and their relationship with viral and anthropometric parameters. Patients with hepatitis C (n = 166) entered the study receiving a clinical, histological, virological and biochemical evaluation. APOC3 (rs2854116 and rs2854117) and PNPLA3 (p.I148M) variants were genotyped. PNPLA3 polymorphisms were associated with liver steatosis, which was significantly higher in patients with p.148I/M (P = 0.034) and p.148M/M (P = 0.004) variants than those homozygous for the PNPLA3 wild type. Excluding patients with HCV genotype 3, the association with liver steatosis and PNPLA3 variants was more marked (p.148I/I genotype vs p.148I/M, P = 0.02, and vs p.148M/M, P = 0.005). The APOC3 polymorphism was not associated with any of the evaluated parameters. Among the interacting factors, BMI and waist circumference correlated with liver steatosis (P = 0.008 and 0.004, respectively). Relationship between waist circumference and liver steatosis was analysed for the different PNPLA3 genotypes. Homozygous 148M patients showed a stronger correlation between waist circumference and steatosis than those carrying the other genotypes (P = 0.0047). In our hepatitis C-infected population, the PNPLA3 polymorphism influenced the development of liver steatosis, but not fibrosis progression. APOC3 polymorphisms had no effect on the development of steatosis and no influence on the PNPLA3 polymorphism. The amount of abdominal fat can increase the association of PNPLA3 p.I148M with liver steatosis.

LABAs in asthmatic children: highlights and new inside.

International asthma guidelines recommend increasing the dose of ICS or adding leukotriene modifiers or the use of long-acting inhaled beta2-agonists (LABAs) in combination with inhaled corticosteroids (ICS) when uncontrolled asthma occurs in adult and children in treatment with low-dose inhaled corticosteroids. However, in children, the effects of this last treatment option are unclear because there are few studies on the efficacy and safety of these drugs in pediatric age. Furthermore, salmeterol is licensed for use in children over 4 years and formoterol in children of more than 6 years. Finally, recent data provides evidence that repeated bronchoconstriction induces epithelial cell stress that may lead to remodeling and these findings may have potential implications for asthma management, particularly for LABAs treatment in the future.

Subclinical hypothyroidism and myocardial function in obese children.

BACKGROUND AND AIMS: Pediatric obesity is an important health problem representing a major public health concern worldwide in the last decades. An isolated elevation of Thyroid Stimulating Hormone (TSH) with normal levels of thyroid hormones is frequently found in obese children. It has been named Isolated Hyperthyreotropinemia or Subclinical Hypothyroidism (SCH) and may be considered a consequence of obesity. Evidence exists that SCH is related to impairment of both systolic and diastolic myocardial function in the adult population. The aim of our study is to establish if obesity-related SCH influences myocardial function in children. METHODS AND RESULTS: We examined 34 obese children and adolescents with SCH and 60 obese children with normal TSH levels who underwent Doppler echocardiographic to evaluate myocardial function. Global systolic function as assessed by Ejection Fraction (EF) was comparable between groups, however Right Ventricle pressure global systolic function and pressure were significantly reduced in SCH group. Mitral annulus peak systolic (MAPSE) excursion lateral and MAPSE septum resulted significantly reduced in SCH group. Tissue Doppler imaging peak systolic motion (TDI-S) was reduced in SCH group. Diastolic function also showed significant modifications in SCH group. CONCLUSION: These results suggest possible involvement of cardiac function in obese children with SCH resulting in both abnormal diastolic function and reduced longitudinal systolic function. This new insight into cardiovascular consequences of obesity-related SCH in children could influence clinical approach to such patients by pediatric endocrinologists.

Effectiveness of nebulized hypertonic saline and epinephrine in hospitalized infants with bronchiolitis.

The objective of the study is to verify effects of nebulized 3% saline hypertonic solution (HS) in comparison to normal saline (NS) in addition to epinephrine in hospitalized children with bronchiolitis. Infants were randomly assigned either to receive every 6 hours nebulized NS (group I) or 3% HS (group II) in addition to epinephrine (1.5 mg) and to conventional treatment. The main endpoints of this study were the length of stay (LOS) in hospital and the clinical response score (CSS). Patients presented a significant decrease in CSS from the first through the third day of treatment, present in the first group but even more evident in the second group (p=0.0001). Comparison between group I and II data shows significant decrease in CSS in the 3% HS-treated patients both at the second (p<0.005) and at the third day of treatment (p<0.005). Infants in the NS control group had a mean LOS of 5.6±1.6 days, whereas children treated with 3% HS were discharged with a LOS of 4.9±1.3 days, reaching a significant decrease in stay (p<0.05). In hospitalized patients bronchiolitis nebulized 3% HS and epinephrine significantly decreased symptoms and LOS as compared to 0.9% NS and epinephrine.

Airways allergic inflammation and L. reuterii treatment in asthmatic children.

Recently, it has been hypothesized that the oral administration of specific live probiotic strains may have therapeutic potential in the treatment of allergic inflammation. The aim of this study was to evaluate the effect of the oral L. reuteri DSM 17938 administration (1X108CFU), in airways allergic inflammation in mild persistent asthmatic children. In this DBPC randomized study we selected 50 children (6-14 years old), affected by mild persistent asthma (GINA step 2) and allergic to HDM. At the run-in period (T-2), the children were submitted to medical examination, prick tests for the main respiratory allergens, spirometry and children asthma control test (C-ACT). We selected only the children with well controlled asthma (C-ACT >19 and FEV1> 80%). After two weeks (T0) the children were allocated into two groups, the FeNO was measured and the breath condensate was collected. Group A children were treated with the placebo (5 drops per day) and Group B children with L. reuteri (108CFU =5 drops per day) for 60 days. After the treatment period (T1), all patients were evaluated by medical examination, C-ACT, spirometry, FeNO measurement and exaled breath condensate analysis. The FeNO values showed a significant reduction (p=0,045) in L. reuteri group but not in the placebo group at the end of the treatment (T1). Furthermore, the cytokines exam showed an increase in IL-10 levels (p less than 0.05) and a significant reduction in IL-2 levels (p less than 0.05) only in L. reuteri group at T1. No significant differences in FEV1 values and C-ACT score were found in both groups. In conclusion, these data showed that L. reuteri (108 CFU) was effective in reducing bronchial inflammation in asthmatic children. No significant effect was found on FEV1 values and C-ACT score, probably because we selected children with well controlled asthma.

Could be a link between non atopic asthma and HP infection?

A potential role of Helicobater Pylori (HP) infection in several extra-intestinal pathologies has been recently suggested. The aim of our study was to assess the role of serology positive for HP in atopic and non atopic infants and children affected by atopic dermatitis, urticaria, rhinitis and asthma. We included 615 children affected by atopic diseases. According to prick test positivity and age, we divided the patients into two groups: atopic or non-atopic patients and infants (0-2 years) or children (2-12 years). The serum levels of antibodies for H. pylori immunoglobulin G were measured by using an ELISA test. We found a not significant difference between group 1 and group 2 about atopy. There was a significant higher frequency of HP positive serology in older children. As for infants, a higher significant prevalence of HP positive serology was found in non-atopic patients. HP positive serology was significantly higher only in non-atopic infants affected by atopic dermatitis and urticaria than in atopic. In group 2, non atopic children shown a significant increase in the prevalence of HP serum positivity than atopic children. As for asthma, there was an higher prevalence of HP serology positive in non atopic asthmatic children group than in atopic asthmatics. On the contrary, the prevalence of positive HP serology was not significantly different between atopic and non atopic children affected by dermatitis, urticaria, and rhinitis. The present data confirm an inverse association between HP positive serology and atopy in both groups. However, the higher prevalence of positive HP serology was observed in non atopic asthmatics children than in atopic asthmatics. We could speculate that HP infection can favour non-atopic asthma onset.

Atopy as a risk factor for thyroid autoimmunity in children.

Recently, there has been considerable interest in the relationship between allergic and autoimmune diseases. We evaluated the prevalence of thyroid autoimmunity in 566 children affected by atopic dermatitis (AD), urticaria, rhinitis, chronic cough, and asthma. Our results suggest that allergy and autoimmunity can be two potential outcomes of dysregulated immunity. It is tempting to speculate that NK Th2 cells can favour asthma onset and at the same time improve thyroid autoimmunity.