"EEG abnormalities" may represent a confounding factor in celiac disease. A 4-year follow-up family report

Objective: The occurrence of celiac disease (CD), electroencephalographic (EEG) abnormalities (with "subtle" seizures or even without any clinical seizures), and neurological disorders has been reported since the 1980s, though there has been no definitive consensus about the possible causal relationship. This topic is further complicated by the occurrence in infancy of 'clinical-EEG pictures' called 'benign epilepsy of infancy'. Methods and results: Here, we report a 4-year follow-up on two siblings with newly diagnosed biopsy-proven celiac disease showing EEG abnormalities not responsive to a gluten-free diet. Conclusions: This family report indicates that in patients with neurologically asymptomatic CD and EEG abnormalities, it is advisable to make a differential diagnosis between EEG abnormalities associated with CD and an incidental association with cortical hyperexcitability, with "subtle" seizures or even without any clinical seizures. Practice implications: A long follow-up may sometimes be required, as it was in the family described here, to clarify the etiopathogenetic and therapeutic relationships between clinical and EEG features in CD

Age-related impairment in insulin release: the essential role of ϐ(2)-adrenergic receptor.

In this study, we investigated the significance of ϐ (2)-adrenergic receptor (ϐ (2)AR) in age-related impaired insulin secretion and glucose homeostasis. We characterized the metabolic phenotype of ϐ (2)AR-null C57Bl/6N mice (ϐ (2)AR(-/-)) by performing in vivo and ex vivo experiments. In vitro assays in cultured INS-1E ϐ-cells were carried out in order to clarify the mechanism by which ϐ (2)AR deficiency affects glucose metabolism. Adult ϐ (2)AR(-/-) mice featured glucose intolerance, and pancreatic islets isolated from these animals displayed impaired glucose-induced insulin release, accompanied by reduced expression of peroxisome proliferator-activated receptor (PPAR) γ, pancreatic duodenal homeobox-1 (PDX-1), and GLUT2. Adenovirus-mediated gene transfer of human ϐ (2)AR rescued these defects. Consistent effects were evoked in vitro both upon ϐ (2)AR knockdown and pharmacologic treatment. Interestingly, with aging, wild-type (ϐ (2)AR(+/+)) littermates developed impaired insulin secretion and glucose tolerance. Moreover, islets from 20-month-old ϐ (2)AR(+/+) mice exhibited reduced density of ϐ (2)AR compared with those from younger animals, paralleled by decreased levels of PPARγ, PDX-1, and GLUT2. Overexpression of ϐ (2)AR in aged mice rescued glucose intolerance and insulin release both in vivo and ex vivo, restoring PPARγ/PDX-1/GLUT2 levels. Our data indicate that reduced ϐ (2)AR expression contributes to the age-related decline of glucose tolerance in mice

Melanocortin-4 receptor gene: case-control study and transmission disequilibrium test confirm that functionally relevant mutations are compatible with a major gene effect for extreme obesity

We initially performed a mutation screen of the coding region of the MC4R in 808 extremely obese children and adolescents and 327 underweight or normal-weight controls allowing for a case-control study. A total of 16 different missense, nonsense, and frameshift mutations were found in the obese study group; five of these have not been observed previously. In vitro assays revealed that nine [the haplotype (Y35X; D37V) was counted as one mutation] of the 16 mutations led to impaired cAMP responses, compared with wild-type receptor constructs. In contrast, only one novel missense mutation was detected in the controls, which did not alter receptor function. The association test based on functionally relevant mutations was positive (P = 0.006, Fisher's exact test, one-sided). We proceeded by screening a total of 1040 parents of 520 of the aforementioned obese young index patients to perform transmission disequilibrium tests. The 11 parental carriers of functionally relevant mutations transmitted the mutation in 81.8% (P = 0.033; exact one-sided McNemar test). These results support the hypothesis that these MC4R mutations represent major gene effects for obesity

Streptococcus pneumoniae colonisation in children and adolescents with asthma: Impact of the heptavalent pneumococcal conjugate vaccine and evaluation of potential effect of thirteen-valent pneumococcal conjugate vaccine

none14noBackground: The main aim of this study was to evaluate Streptococcus pneumoniae carriage in a group of school-aged children and adolescents with asthma because these results might indicate the theoretical risk of invasive pneumococcal disease (IPD) of such patients and the potential protective efficacy of the 13-valent pneumococcal conjugate vaccine (PCV13). Methods: Oropharyngeal samples were obtained from 423 children with documented asthma (300 males, 70.9 %), and tested for the autolysin-A-encoding (lytA) and the wzg (cpsA) gene of S. pneumoniae by means of real-time polymerase chain reaction. Results: S. pneumoniae was identified in the swabs of 192 subjects (45.4 %): 48.4 % of whom were aged = 15 years (p < 0.001). Carriage was significantly less frequent among the children who had received recent antibiotic therapy (odds ratio [OR 0.41]; 95 % confidence interval [95 % CI] 0.22-0.76). Multivariate analyses showed no association between carriage and vaccination status, with ORs of 1.05 (95 % CI 0.70-1.58) for carriers of any pneumococcal serotype, 1.08 (95 % CI 0.72-1.62) for carriers of any of the serotypes included in 7-valent pneumococcal conjugate vaccine (PCV7), and 0.76 (95 % CI 0.45-1.28) for carriers of any of the six additional serotypes of PCV13. Serotypes 19 F, 4 and 9 V were the most frequently identified serotypes in vaccinated subjects. Conclusions: These results showed that carriage of S. pneumoniae is relatively common in all school-aged children and adolescents with asthma, regardless of the severity of disease and the administration of PCV7 in the first years of life. This highlights the problem of the duration of the protection against colonisation provided by pneumococcal conjugate vaccine, and the importance of re-colonization by the same pneumococcal serotypes included in the previously used vaccine.Esposito, Susanna; Terranova, Leonardo; Patria, Maria Francesca; Marseglia, Gian Luigi; Miraglia del Giudice, Michele; Bodini, Alessandro; Martelli, Alberto; Baraldi, Eugenio; Mazzina, Oscar; Tagliabue, Claudia; Licari, Amelia; Ierardi, Valentina; Lelii, Mara; Principi, NicolaEsposito, Susanna; Terranova, Leonardo; Patria, Maria Francesca; Marseglia, GIAN LUIGI; Miraglia del Giudice, Michele; Bodini, Alessandro; Martelli, Alberto; Baraldi, Eugenio; Mazzina, Oscar; Tagliabue, Claudia; Licari, Amelia; Ierardi, Valentina; Lelii, Mara; Principi, Nicol

Human glioblastoma multiforme: p53 reactivation by a novel MDM2 inhibitor

Cancer development and chemo-resistance are often due to impaired functioning of the p53 tumor suppressor through genetic mutation or sequestration by other proteins. In glioblastoma multiforme (GBM), p53 availability is frequently reduced because it binds to the Murine Double Minute-2 (MDM2) oncoprotein, which accumulates at high concentrations in tumor cells. The use of MDM2 inhibitors that interfere with the binding of p53 and MDM2 has become a valid approach to inhibit cell growth in a number of cancers; however little is known about the efficacy of these inhibitors in GBM. We report that a new small-molecule inhibitor of MDM2 with a spirooxoindolepyrrolidine core structure, named ISA27, effectively reactivated p53 function and inhibited human GBM cell growth in vitro by inducing cell cycle arrest and apoptosis. In immunoincompetent BALB/c nude mice bearing a human GBM xenograft, the administration of ISA27 in vivo activated p53, inhibited cell proliferation and induced apoptosis in tumor tissue. Significantly, ISA27 was non-toxic in an in vitro normal human cell model and an in vivo mouse model. ISA27 administration in combination with temozolomide (TMZ) produced a synergistic inhibitory effect on GBM cell viability in vitro, suggesting the possibility of lowering the dose of TMZ used in the treatment of GBM. In conclusion, our data show that ISA27 releases the powerful antitumor capacities of p53 in GBM cells. The use of this MDM2 inhibitor could become a novel therapy for the treatment of GBM patients

Sense of smell in chronic rhinosinusitis: A multicentric study on 811 patients

Introduction: The impairment of the sense of smell is often related to chronic rhinosinusitis (CRS) with or without nasal polyps (CRSwNP, CRSsNP). CRSwNP is a frequent condition that drastically worsens the quality of life of those affected; it has a higher prevalence than CRSsNP. CRSwNP patients experience severe loss of smell with earlier presentation and are more likely to experience recurrence of their symptoms, often requiring revision surgery. Methods: The present study performed a multicentric data collection, enrolling 811 patients with CRS divided according to the inflammatory endotype (Type 2 and non-Type 2). All patients were referred for nasal endoscopy for the assessment of nasal polyposis using nasal polyp score (NPS); Sniffin' Sticks olfactory test were performed to measure olfactory function, and SNOT-22 (22-item sinonasal outcome test) questionnaire was used to assess patients' quality of life; allergic status was evaluated with skin prick test and nasal cytology completed the evaluation when available. Results: Data showed that Type 2 inflammation is more common than non-type 2 (656 patients versus 155) and patients suffer from worse quality of life and nasal polyp score. Moreover, 86.1% of patients with Type 2 CRSwNP were affected by a dysfunction of the sense of smell while it involved a lesser percentage of non-Type 2 patients. Indeed, these data give us new information about type-2 inflammation patients' characteristics. Discussion: The present study confirms that olfactory function weights on patients' QoL and it represents an important therapeutic goal that can also improve patients' compliance when achieved. In a future - and present - perspective of rhinological precision medicine, an impairment of the sense of smell could help the clinician to characterize patients better and to choose the best treatment available

Development and Implementation of the AIDA International Registry for Patients with Non-Infectious Uveitis

Introduction: The aim of this paper is to point out the design, development and deployment of the AutoInflammatory Disease Alliance (AIDA) International Registry for paediatric and adult patients with non-infectious uveitis (NIU). Methods: This is a physician-driven, population- and electronic-based registry implemented for both retrospective and prospective collection of real-world demographics, clinical, laboratory, instrumental and socioeconomic data of patients with uveitis and other non-infectious inflammatory ocular diseases recruited through the AIDA Network. Data recruitment, based on the Research Electronic Data Capture (REDCap) tool, is thought to collect standardised information for real-life research and has been developed to change over time according to future scientific acquisitions and potentially communicate with other similar instruments. Security, data quality and data governance are cornerstones of this platform. Results: Ninety-five centres have been involved from 19 countries and four continents from 24&nbsp;March to 16&nbsp;November 2021. Forty-eight out of 95 have already obtained the approval from their local ethics committees. At present, the platform counts 259 users (95 principal investigators, 160 site investigators, 2 lead investigators, and 2 data managers). The AIDA Registry collects baseline and follow-up data using 3943 fields organised into 13 instruments, including patient's demographics, history, symptoms, trigger/risk factors, therapies and healthcare utilization for patients with NIU. Conclusions: The development of the AIDA Registry for patients with NIU will facilitate the collection of standardised data leading to real-world evidence and enabling international multicentre collaborative research through inclusion of patients and their families worldwide

Las damas del mar. Viajeras, emigrantes, literatas y artistas desde y hacia el cono Sur en los siglos XIX y XX

Este proyecto se desarrolla en forma conjunta entre investigadores argentinos e italianos. Se analizan obras de escritoras y artistas de los siglos XIX y XX, de sendas nacionalidades, en relación con la problemática inmigratoria y la construcción de una identidad femenina cimentada a lo largo del diálogo entre dos riberas: la mediterránea y la rioplatense. Las investigadoras argentinas se ocupan de la obra de Eduarda Mansilla, viajera y nómade, que inició un derrotero continuado por otras mujeres argentinas destacadas en la literatura y en las artes. Entre ellas se distinguen Victoria Ocampo y Sara Gallardo en las letras, y Lola Mora, en las artes plásticas. Por su parte, los investigadores italianos, se centran en los mecanismos de elaboración de la experiencia migratoria en la narrativa italiana y argentina escrita por mujeres desde los años cincuenta del siglo XX hasta nuestros días, según dos líneas principales: narrativas de segundo grado directo (S. Poletti, G. Gambaro, M. T. Andruetto), escritas por narradoras de segunda generación, que escriben desde un locus diferente del originario (suyo o de sus antepasados inmigrantes); narrativas de segundo grado indirecto (M. Sedda, R. Mambelli, R. Petri), que tematizan historias de vida entre Italia y Argentina, sin que sus autoras tengan experiencia propia o familiar de la migración. Estudian el diálogo simbólico que estas narrativas entrelazan y su aporte a la construcción de un imaginario migratorio memorable y memorializable.This project is developed by Argentine and Italian researchers jointly. There are analyze the works of women writers as well as visual artists from 19th and 20th centuries, coming from diverse nationalities, regarding to the immigration problems and the construction of and feminine identity, consolidated through the dialogue between two banks: the Mediterranean’s and the Río de La Plata’s sides. On the one hand, Argentine researchers study Eduarda Mansilla’s work, traveller and nomad,who prepared the way for others argentines women outstanded at Literature (Victoria Ocampo andSara Gallardo) and at Arts (Lola Mora). On the other hand, Italian researchers focus on the elaborationprocess of migratory experience at the Italian and Argentine narrative, written by women,since 1950s till nowadays, according to two main groups: direct narratives of second degree (S.Poletti, G. Gambaro, M. T. Andruetto), written by second generation narrators, who build their storiesfrom a locus different to the original one (hers or her immigrant ancestors); indirect narrativesof second degree (M. Sedda, R. Mambelli, R. Petri), which thematize life stories between Italy andArgentina, even when their authors haven’t experienced their own or family migration. All of themstudy the symbolic dialogue set up among these narratives and its contribution to the consolidationof a migratory imaginary, memorable and memoralizable

Poly (diglycerol adipate) variants as enhanced nanocarrier replacements in drug delivery applications

Sustainably derived poly(glycerol adipate) (PGA) has been deemed to deliver all the desirable features expected in a polymeric scaffold for drug-delivery, including biodegradability, biocompatibility, self-assembly into nanoparticles (NPs) and a functionalisable pendant group. Despite showing these advantages over commercial alkyl polyesters, PGA suffers from a series of key drawbacks caused by poor amphiphilic balance. This leads to weak drug-polymer interactions and subsequent low drug-loading in NPs, as well as low NPs stability. To overcome this, in the present work, we applied a more significant variation of the polyester backbone while maintaining mild and sustainable polymerisation conditions. We have investigated the effect of the variation of both hydrophilic and hydrophobic segments upon physical properties and drug interactions as well as self-assembly and NPs stability. For the first time we have replaced glycerol with the more hydrophilic diglycerol, as well as adjusting the final amphiphilic balance of the polyester repetitive units by incorporating the more hydrophobic 1,6-n-hexanediol (Hex). The properties of the novel poly(diglycerol adipate) (PDGA) variants have been compared against known polyglycerol-based polyesters. Interestingly, while the bare PDGA showed improved water solubility and diminished self-assembling ability, the Hex variation demonstrated enhanced features as a nanocarrier. In this regard, PDGAHex NPs were tested for their stability in different environments and for their ability to encode enhanced drug loading. Moreover, the novel materials have shown good biocompatibility in both in vitro and in vivo (whole organism) experiments

Poly (diglycerol adipate) variants as enhanced nanocarrier replacements in drug delivery applications.

Sustainably derived poly(glycerol adipate) (PGA) has been deemed to deliver all the desirable features expected in a polymeric scaffold for drug-delivery, including biodegradability, biocompatibility, self-assembly into nanoparticles (NPs) and a functionalisable pendant group. Despite showing these advantages over commercial alkyl polyesters, PGA suffers from a series of key drawbacks caused by poor amphiphilic balance. This leads to weak drug-polymer interactions and subsequent low drug-loading in NPs, as well as low NPs stability. To overcome this, in the present work, we applied a more significant variation of the polyester backbone while maintaining mild and sustainable polymerisation conditions. We have investigated the effect of the variation of both hydrophilic and hydrophobic segments upon physical properties and drug interactions as well as self-assembly and NPs stability. For the first time we have replaced glycerol with the more hydrophilic diglycerol, as well as adjusting the final amphiphilic balance of the polyester repetitive units by incorporating the more hydrophobic 1,6-n-hexanediol (Hex). The properties of the novel poly(diglycerol adipate) (PDGA) variants have been compared against known polyglycerol-based polyesters. Interestingly, while the bare PDGA showed improved water solubility and diminished self-assembling ability, the Hex variation demonstrated enhanced features as a nanocarrier. In this regard, PDGAHex NPs were tested for their stability in different environments and for their ability to encode enhanced drug loading. Moreover, the novel materials have shown good biocompatibility in both in vitro and in vivo (whole organism) experiments