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Background: Neonates and infants are susceptible to hypoxaemia in the perioperative period. The aim of this study was to analyse interventions related to anaesthesia tracheal intubations in this European cohort and identify their clinical consequences. Methods: We performed a secondary analysis of tracheal intubations of the European multicentre observational trial (NEonate and Children audiT of Anaesthesia pRactice IN Europe [NECTARINE]) in neonates and small infants with difficult tracheal intubation. The primary endpoint was the incidence of difficult intubation and the related complications. The secondary endpoints were the risk factors for severe hypoxaemia attributed to difficult airway management, and 30 and 90 day outcomes. Results: Tracheal intubation was planned in 4683 procedures. Difficult tracheal intubation, defined as two failed attempts of direct laryngoscopy, occurred in 266 children (271 procedures) with an incidence (95% confidence interval [CI]) of 5.8% (95% CI, 5.1e6.5). Bradycardia occurred in 8% of the cases with difficult intubation, whereas a significant decrease in oxygen saturation (SpO2

Astrocytes are glial cells that are abundant in the central nervous system (CNS) and that have important homeostatic and disease-promoting functions1. However, little is known about the homeostatic anti-inflammatory activities of astrocytes and their regulation. Here, using high-throughput flow cytometry screening, single-cell RNA sequencing and CRISPR-Cas9-based cell-specific in vivo genetic perturbations in mice, we identify a subset of astrocytes that expresses the lysosomal protein LAMP12 and the death receptor ligand TRAIL3. LAMP1+TRAIL+ astrocytes limit inflammation in the CNS by inducing T cell apoptosis through TRAIL-DR5 signalling. In homeostatic conditions, the expression of TRAIL in astrocytes is driven by interferon-γ (IFNγ) produced by meningeal natural killer (NK) cells, in which IFNγ expression is modulated by the gut microbiome. TRAIL expression in astrocytes is repressed by molecules produced by T cells and microglia in the context of inflammation. Altogether, we show that LAMP1+TRAIL+ astrocytes limit CNS inflammation by inducing T cell apoptosis, and that this astrocyte subset is maintained by meningeal IFNγ+ NK cells that are licensed by the microbiome.

Background: Several studies on 18F-FDG-PET/CT have investigated the prognostic role of this imaging modality in different tumors after treatment. Nevertheless, its role in restaging patients with recurrent CM still needs to be defined. Objective: The aim of this retrospective multicenter study was to evaluate the clinical and prognostic impact of 18F-FDG-PET/CT on the restaging process of cutaneous melanoma (CM) after surgery in patients with suspected distant recurrent disease or suspected metastatic progression disease. Materials and Methods: 74 patients surgically treated for CM underwent 18F-FDG-PET/CT for suspected distant recurrent disease or suspected metastatic progression disease. The diagnostic accuracy of visually interpreted 18F-FDG-PET/CT was obtained by considering histology (n=21 patients), other diagnostic imaging modalities performed within 2 months of PET/CT (CT in 52/74 patients and Whole-Body MRI in 18/74 patients) and clinical follow-up (n=74 patients) for at least 24 months containing all the clinical and diagnostic information useful for the PET performance assessment and outcome. Progression-free survival (PFS) and overall survival (OS) were assessed by using the Kaplan- Meier method. The risk of progression (Hazard Ratio-HR) was computed by the Cox regression analysis. Results: Suspicion of recurrent CM was confirmed in 24/27 patients with a positive 18F-FDG-PET/CT scan. Overall, the sensitivity, specificity, positive predictive value, negative predictive value and accuracy of 18F-FDG-PET/CT were 82%, 93%, 88%, 89%, and 89%, respectively, with area under the curve being 0.87 (95%IC 0.78-0.97; p Conclusion: 18F-FDG-PET/CT showed a valuable diagnostic performance in patients with suspicion of recurrent CM. This imaging modality might have an important prognostic value in predicting the survival outcomes, assessing the risk of disease progression, and guiding treatment decision making.

Background: Neonates and infants requiring anaesthesia are at risk of physiological instability and complications, but triggers for peri-anaesthetic interventions and associations with subsequent outcome are unknown. Methods: This prospective, observational study recruited patients up to 60 weeks' postmenstrual age undergoing anaesthesia for surgical or diagnostic procedures from 165 centres in 31 European countries between March 2016 and January 2017. The primary aim was to identify thresholds of pre-determined physiological variables that triggered a medical intervention. The secondary aims were to evaluate morbidities, mortality at 30 and 90 days, or both, and associations with critical events. Results: Infants (n=5609) born at mean (standard deviation [SD]) 36.2 (4.4) weeks postmenstrual age (35.7% preterm) underwent 6542 procedures within 63 (48) days of birth. Critical event(s) requiring intervention occurred in 35.2% of cases, mainly hypotension (>30% decrease in blood pressure) or reduced oxygenation (SpO2

Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder characterized by prenatal and/or postnatal overgrowth, organomegaly, abdominal wall defects and tumor predisposition. CDKN1C is a maternally expressed gene of the 11p15.5 chromosomal region and is regulated by the imprinting control region IC2. It negatively controls cellular proliferation, and its expression or activity are frequently reduced in BWS. In particular, loss of IC2 methylation is associated with CDKN1C silencing in the majority of sporadic BWS cases, and maternally inherited loss-of-function variants of CDKN1C are the most frequent molecular defects of familial BWS. We have identified, using Sanger sequencing, novel CDKN1C variants in three families with recurrent cases of BWS, and a previously reported variant in a woman with recurrent miscarriages with exomphalos. Clinical evaluation of the patients showed variable manifestation of the disease. The frameshift and nonsense variants were consistently associated with exomphalos, while the missense variant caused a less severe phenotype. Pregnancy loss and perinatal lethality were found in the families segregating nonsense mutations. Intrafamilial variability of the clinical BWS features was observed, even between siblings. Our data are indicative of severe BWS phenotypes that, with variable expressivity, may be associated with both frameshift and nonsense variants of CDKN1C.

Natural products or nutraceuticals have been shown to elicit anti-aging, anti-cancer and other health-enhancing effects. A key target of the effects of natural products may be the regulation of microRNA (miR) expression which results in cell death or prevents aging, diabetes, cardiovascular and other diseases. This review will focus on a few natural products, especially on resveratrol (RES), curcumin (CUR) and berberine (BBR). RES is obtained from the skins of grapes and other fruits and berries. RES may extend human lifespan by activating the sirtuins and SIRT1 molecules. CUR is isolated from the root of turmeric (Curcuma longa). CUR is currently used in the tutreatment of many disorders, especially in those involving an inflammatory process. CUR and modified derivatives have been shown to have potent anti-cancer effects, especially on cancer stem cells (CSC). BBR is also isolated from various plants (e.g., Coptis chinensis) and has been used for centuries in traditional medicine to treat diseases such as adult- onset diabetes. Understanding the benefits of these and other nutraceuticals may result in approaches to improve human health.

In December 2019, in Wuhan (China), a highly pathogenic coronavirus, named SARS-CoV-2, dramatically emerged. This new virus, which causes severe pneumonia, is rapidly spreading around the world, hence it provoked the COVID-19 pandemic. This emergency launched by SARS-CoV-2 also had, and still has, devastating socio-economic aspects. Assessing the impact of COVID-19 on vulnerable groups of people is crucial for the adaptation of governments’ responses. Growing scientific evidence suggests that it is essential to keep the attention on people after acute SARS-CoV-2 infection; indeed, some clinical manifestations are frequently present even after recovery. There is consensus on the need to define which symptoms persist after the infection and which disabilities may arise after COVID-19. Recent reviews, case reports, and original contributions suggest that various organs may be affected, and neurological symptoms are present in about one third of patients with COVID-19. Neurological complications after severe COVID-19 infection might include delirium, brain inflammation, stroke, and nerve damage. In the recent pandemic, neurologists and neurobiologists have a chance to study key features of infection neurology. Furthermore, the psychological impact of the pandemic should not be underestimated, although there is currently no definition for this condition.

Objective: The aim of this study was (1) to investigate the application of texture analysis of choline PET/CT images in prostate cancer (PCa) patients and (2) to propose a machine-learning radiomics model able to select PET features predictive of disease progression in PCa patients with a same high-risk class at restaging. Material and methods: Ninety-four high-risk PCa patients who underwent restaging Cho-PET/CT were analyzed. Follow-up data were recorded for a minimum of 13 months after the PET/CT scan. PET images were imported in LIFEx toolbox to extract 51 features from each lesion. A statistical system based on correlation matrix and point-biserial-correlation coefficient has been implemented for features reduction and selection, while Discriminant analysis (DA) was used as a method for features classification in a whole sample and sub-groups for primary tumor or local relapse (T), nodal disease (N), and metastatic disease (M). Results: In the whole group, 2 feature (HISTO_Entropy_log10; HISTO_Energy_Uniformity) results were able to discriminate the occurrence of disease progression at follow-up, obtaining the best performance in DA classification (sensitivity 47.1%, specificity 76.5%, positive predictive value (PPV) 46.7%, and accuracy 67.6%). In the sub-group analysis, the best performance in DA classification for T was obtained by selecting 3 features (SUVmin; SHAPE_Sphericity; GLCM_Correlation) with a sensitivity of 91.6%, specificity 84.1%, PPV 79.1%, and accuracy 87%; for N by selecting 2 features (HISTO = _Energy Uniformity; GLZLM_SZLGE) with a sensitivity of 68.1%, specificity 91.4%, PPV 83%, and accuracy 82.6%; and for M by selecting 2 features (HISTO_Entropy_log10 - HISTO_Entropy_log2) with a sensitivity 64.4%, specificity 74.6%, PPV 40.6%, and accuracy 72.5%. Conclusion: This machine learning model demonstrated to be feasible and useful to select Cho-PET features for T, N, and M with valuable association with high-risk PCa patients’ outcomes. Key Points: • Artificial intelligence applications are feasible and useful to select Cho-PET features. • Our model demonstrated the presence of specific features for T, N, and M with valuable association with high-risk PCa patients’ outcomes. • Further prospective studies are necessary to confirm our results and to develop the application of artificial intelligence in PET imaging of PCa.

In the recent pandemic disease, called COVID-19, the role of neurologists and neurobiologists represents a chance to study key features of brain infection and deepen neurological manifestations of COVID-19 and other coronavirus infections. In fact, many studies suggest brain damage during infection and persistent neurological symptoms after COVID-19 infection. Reverse transcription PCR test, antibody tests, Computed Tomography (CT) of the lung, and Magnetic Resonance (MR) of the brain of the patient were periodically performed during this case report for eight months after infection. The aim of this article is to describe the prolonged neurological clinical consequences related to COVID-19. We believe it is clinically clear that we can define a post-acute COVID-19 neurological syndrome. Therefore, in patients after a severe clinical condition of COVID-19, a deepening of persistent neurological signs is necessary.

Silver-Russell syndrome is characterized by asymmetrical intrauterine growth retardation, with normal head circumference and small, pointed chin, which results in a triangular face. It can also include body asymmetry, among other characteristics. Its global incidence is estimated at 1 in 30 000-100 000 births, even though this figure may be underestimated. In approximately 60 % of cases, a molecular cause can be identified, and the main one is hypomethylation of the paternal allele at the imprinting control region 1 located at 11p15.5-p15.4. It is necessary to make the diagnosis of this entity, exclude differential diagnoses, and know (epi)genotype-phenotype correlations in order to ensure an adequate follow-up, provide available therapeutic options, and offer a timely family genetic counseling. The objective of this article is to describe the current status of the Silver-Russell syndrome, a model of genomic imprinting disorder.El síndrome de Silver-Russell se caracteriza por retraso del crecimiento intrauterino asimétrico, con circunferencia craneal normal, barbilla pequeña y puntiaguda, que proporciona un aspecto de rostro triangular. Puede, además, presentar asimetría corporal, entre otros. Tiene una incidencia mundial estimada de 1 en 30 000- 100 000 nacimientos, aunque este número es, probablemente, subestimado. En alrededor del 60 % de los casos, se puede identificar una causa molecular y la principal es la hipometilación del alelo paterno en la región de control de impresión 1 localizado en 11p15.5-p15.4. Realizar el diagnóstico de esta entidad, excluir los diagnósticos diferenciales y conocer las correlaciones (epi)genotipo-fenotipo son necesarios para realizar el adecuado seguimiento, brindar las opciones terapéuticas disponibles y el oportuno asesoramiento genético familiar. El objetivo del presente artículo es mostrar el estado actual del síndrome de Silver-Russell, un ejemplo de trastorno de impronta genómica.

Background Neuropsychological abnormalities have been proposed to contribute to the development and maintenance of Borderline Personality Disorder (BPD). Previous meta-analyses and reviews confirmed deficits in a broad range of cognitive domains, including attention, cognitive flexibility, memory, executive functions, planning, information processing, and visuospatial abilities, often suggested to underlie brain abnormalities. However, no study directly explored the structural neural correlates of these deficits in BPD, also accounting for the possible confounding effect of pharmacological treatments, often used as adjunctive symptom-targeted therapy in clinical setting. Methods In this study we compared the performance of 24 BPD patients to 24 healthy controls obtained at the neuropsychological battery “Brief Assessment and Cognition in Schizophrenia”, exploring the relationship between the cognitive impairments and current symptomatology, brain grey matter volumes and cortical thickness, controlling for medications load. Results Data revealed deficits in verbal memory and fluency, working memory, attention and speed of information processing and psychomotor speed and coordination when medication load was not in the model. Correcting for this variable, only the impairment in psychomotor abilities remained significant. A multiple regression confirmed the effect of this neuropsychological domain on the severity of BPD symptomatology (Borderline Evaluation of Severity Over Time). In BPD, the performance at psychomotor speed and coordination was also directly associated to cortical thickness in postcentral gyrus. Limitations Relatively small sample size, especially for neuroimaging. Conclusions Our study highlighted an influence of BPD neuropsychological impairments on symptomatology, and cortical thickness, prompting the potential clinical utility of a cognitive remediation program in BPD.

Aim The aim of this retrospective multicentre study was to evaluate the clinical and prognostic effect of fluorine-18-fluorodeoxyglucose (18F-FDG)-PET/computed tomography (CT) in the restaging process of pancreatic cancer (PC). Materials and methods Data from patients treated for primary PC, who underwent18F-FDG-PET/CT for suspicious of disease progression, were collected. Accuracy was assessed employing conventional diagnostic procedures, multidisciplinary team case notes, further18F-FDG-PET/CT scans and/or follow-up. Receiver operating characteristic curve and likelihood ratio (LR+/-) analyses were used for completion of accuracy definition. Progression-free survival (PFS) and overall survival were assessed by using Kaplan-Meier method. The Cox proportional hazards model was used to identify predictors of outcome. Results Fifty-two patients (33 males and 19 females, with mean age of 59 years and range: 42-78 years) with PC were finally included in our study. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of18F-FDG-PET were 85, 84, 90, 76, and 84%, respectively. Area under the curve was 0.84 (95% confidence intervals: 0.72-0.96; P6 h=4.2, P=0.02) and death (PET positivity hazard ratio=3.5, P=0.02; SUVmax>6 h=3.7, P=0.01). Conclusion18F-FDG-PET/CT showed high diagnostic accuracy for restaging process of PC, proving also its potential value in predicting clinical outcome after primary treatment.

Multiple sclerosis is a chronic inflammatory disease of the CNS(1). Astrocytes contribute to the pathogenesis of multiple sclerosis(2), but little is known about the heterogeneity of astrocytes and its regulation. Here we report the analysis of astrocytes in multiple sclerosis and its preclinical model experimental autoimmune encephalomyelitis (EAE) by single-cell RNA sequencing in combination with cell-specific Ribotag RNA profiling, assay for transposase-accessible chromatin with sequencing (ATAC–seq), chromatin immunoprecipitation with sequencing (ChIP–seq), genome-wide analysis of DNA methylation and in vivo CRISPR–Cas9-based genetic perturbations. We identified astrocytes in EAE and multiple sclerosis that were characterized by decreased expression of NRF2 and increased expression of MAFG, which cooperates with MAT2α to promote DNA methylation and represses antioxidant and anti-inflammatory transcriptional programs. Granulocyte–macrophage colony-stimulating factor (GM-CSF) signalling in astrocytes drives the expression of MAFG and MAT2α and pro-inflammatory transcriptional modules, contributing to CNS pathology in EAE and, potentially, multiple sclerosis. Our results identify candidate therapeutic targets in multiple sclerosis.

Context: A recent meta-analysis (Bonora and coll.) reports benefits on death-risk for Italian diabetic patients mainly followed by the diabetic clinics of the National Health Service. Aims: A) to do a critical appraisal of the meta-analysis by Bonora and coll. B) to verify its results conducting a controlled cohort study based on clinical records of a primary care setting. Methods: (A) We evaluated the meta-analysis by Bonora through AMSTAR II checklist and the trials recruited in the review through ROBINS-I tool. (B) We analysed a cohort of diabetes 2 patients living in Veneto (Italy) and followed from 1/1/2009 to 12/31/2017 to compare the risk of death of a control group (i.e. never followed by specialists) with that of another two groups (i.e. respectively, followed by one specialist visit or by at least two visits in the last three years). We used a time-to-event approach (Cox model) for the main analysis; complementary designs were also tested (Restricted design and Matched design). Statistical adjustments were made both through Multivariate Cox regression and Propensity score. For the adjustments, the covariates considered were: age, sex, severity of diabetes, comorbidity, laboratory values, duration of diabetes and drugs use. Results: (A) The meta-analysis by Bonora shows to be affected by serious pitfalls (B) A cohort of 6530 diabetic patients (none visit: n=3441; one visit: n=947; two or more visits: n=2142) was followed for a mean of 7.32y. Main multivariate analysis was not able to demonstrate any difference in mortality between groups exposed or not exposed to specialist advice: one visit HR=1.01 (0.98-1.03); two or more visits HR=1.12 (0.88-1.43). These results were confirmed by all other analytical approaches. Conclusion: Mortality in diabetes2 is not influenced by specialist consultant. Our results differ by those reported by the meta-analysis because of our better adjustment for prognostic and confounding factors. Most of diabetes 2 patients should be entrusted with confidence to primary care facilities.

Thyroid cancer incidence is increased in volcanic areas where environment pollution biocontaminates residents. Tungsten (W) is the most increased heavy metal in drinking water of Mount Etna volcanic area where it exceeds the normal range in the urine of 27% inhabitants. The possible connection between increased tungsten and thyroid cancer has never been studied. We investigated in vitro the effect tungsten on both human thyrocytes in primary culture, thyrospheres (aggregates of stem/precursor thyroid cells) and thyrocytes differentiated from tungsten-exposed thyrospheres. Chronic exposure to low-dose (nanomolar range, as in the urines of volcanic area residents) soluble tungsten had major biological effects on thyroid stem/precursor cells, promoting growth with a biphasic (hormetic) dose-response and reducing apoptosis. No such effects were observed in mature thyrocytes. In addition, tungsten-exposed thyrospheres had abnormal expression of genes commonly altered also in thyroid cancer and increased activation of the DNA-repair proteins H2AX and 53BP1. Moreover, exposure to tungsten decreased thyrosphere differentiation, as indicated by the reduced expression of thyroid-specific genes in derived thyrocytes that also showed preneoplastic changes such as increased anchorage-independent growth, clonogenic growth and migration capacity. The mechanism of action of tungsten on thyroid stem/precursor cells is unclear but involves membrane G-proteins and activation of the ERK signaling pathway. These data indicate that chronic exposure to slightly increased tungsten, harmless for mature thyrocytes, importantly affects the biology of stem/precursor thyroid cells and of their progeny, inducing characteristics of preneoplastic transformation.

Although in recent years there has been intensification in the use of nanoparticles (NPs) for the production of many commercial products, few studies have been carried out to assess the risks associated with its use. Among the most used NPs, silver nanoparticles (AgNPs) have a preponderant position as they have various applications. In this study, 40 adult zebrafish were exposed to increasing concentrations of AgNPs (8, 45, and 70 mu g/L) for 30 days to evaluate the effects on eyes after chronic exposure to AgNPs with an average diameter of 50 nm. From the morphological and ultrastructural analysis performed, no alteration or lesions of the corneal epithelium were detected.

Spondylometaphyseal dysplasia Algerian type (MIM no.: 184253) is an uncommon autosomal dominant skeletal dysplasia caused by heterozygous mutations in the COL2A1 gene (MIM no.: 120140). In this case based review, we reported a 5-year-old boy with short stature, severe dorsolumbar scoliosis, lumbar hyperlordosis, short trunk, and severe genu valgum. Radiological examination showed platyspondyly, irregular metaphyseal radiolucencies intermingled with radiodensities, and corner fractures. The patient has a c.3275G > A; p.Gly1092Asp mutation in exon 47 of the COL2A1 gene and a variant of unknown significance in c.1366–13C > A in intron 21. This latter sequence variant could partially or completely disrupt the natural splice acceptor site of intron 21/exon 22 in the COL2A1 gene leading to a potential modification of the phenotypic severity.

Introduction The effectiveness of bowel cleansing is a key element for high-quality colonoscopy. Recently, a 1 L polyethylene glycol plus ascorbate (PEG-ASC) solution has been introduced, but effectiveness and safety of this preparation have not been assessed in IBD patients. This study aims to evaluate effectiveness and safety of 1 L PEG-ASC solution in patients with IBD compared to controls. Methods We retrospectively analysed prospectively collected data on a cohort of 411 patients performing a colonoscopy after preparation with 1 L PEG-ASC, consecutively enrolled in 5 Italian centres. Results Overall, 185/411 (45%) were patients with IBD and 226/411 (55%) served as controls. A significantly higher cleansing success was achieved in IBD patients (92.9% vs 85.4%, p = 0.02). The multiple regression model showed that presence of IBD (OR=2.514, 95%CI=1.165–5.426; P = 0.019), lower age (OR=0.981, 95%CI=0.967–0.996; P = 0.014), split preparation (OR=2.430, 95%CI=1.076–5.492; P = 0.033), absence of diabetes (OR=2.848, 95%CI=1.228–6.605; P = 0.015), and of chronic constipation (OR=3.350, 95%CI=1.429–7.852; P = 0.005), were independently associated with cleansing success. The number of treatment-emergent adverse events (TEAEs) (51 vs 62%, p = 0.821), and of patients with TEAEs (22.2% vs 21.2%, p = 0.821), were similar in IBD patients and in controls, respectively. Conclusions Results from this study support the effectiveness and safety of 1 L PEG-ASC solution in IBD patients, which may improve the definition of endoscopic outcomes both in Crohn’s disease and ulcerative colitis.

Background: The presence of residual disease after initial treatment in small cell lung cancer (SCLC) influences prognosis and impacts patient management. To date, few data exist on the value of fluorine-18-fluorodeoxyglucose ([F]FDG)-PET/computed tomography (CT) in SCLC at restaging. Therefore, in restaging patients with SCLC, we aimed to (a) evaluate the prognostic value yielded by [F]FDG-PET/CT and (b) assess the diagnostic agreement between [F]FDG-PET/CT and contrast-enhanced computed tomography (ceCT). Patients and methods: From a multicenter database, we evaluated 164 patients with SCLC who underwent [F]FDG-PET/CT for restaging purposes. PET scans were evaluated visually to identify the presence of recurrence. For each patient, the maximum and the mean standardized uptake value (SUVmax and SUVmean, respectively), metabolic tumor volume, and total lesion glycolysis were calculated, taking into account the lesion with the highest [F]FDG uptake (namely, the index lesion) in the local recurrences, lymph node involvement, and distant metastasis categories. Kaplan-Meier curves were computed to assess the effects of [F]FDG-PET/CT findings on overall survival (OS) and progression-free survival. Furthermore, the agreement between PET/CT and ceCT in detecting metastases was evaluated in 119 patients on a patient-based analysis (Cohen's κ; P < 0.05). Results: The presence of metastatic lesions at [F]FDG-PET/CT was associated with a significantly shorter OS (P = 0.039) and progression-free survival (P < 0.001). Higher SUVmax showed a trend toward a shorter OS (P = 0.065). The K-agreement between ceCT and PET/CT in recurrent SCLC was 0.37 (P < 0.001). PET/CT and ceCT showed the same number of lesions in 52 (43.7%) patients, whereas PET/CT detected additional lesions in 35 (29.4%) patients. Conclusion: Detection of metastatic lesions at restaging by [F]FDG-PET/CT can predict a higher rate of progression and negatively influence OS in patients with SCLC. [F]FDG-PET/CT and ceCT seem to be complementary imaging modalities in patients with metastatic SCLC.

BACKGROUND Disease phenotype and outcome of late-onset Crohn's disease are still poorly defined. METHODS In this Italian nationwide multicentre retrospective study, patients diagnosed ≥65 years (late-onset) were compared with young adult-onset with 16-39 years and adult-onset Crohn's disease 40-64 years. Data were collected for 3 years following diagnosis. RESULTS A total of 631 patients (late-onset 153, adult-onset 161, young adult-onset 317) were included. Colonic disease was more frequent in late-onset (P < 0005), stenosing behaviour was more frequent than in adult-onset (P < 0003), but fistulising disease was uncommon. Surgery rates were not different between the three age groups. Systemic steroids were prescribed more frequently in young adult-onset in the first year, but low bioavailability steroids were used more frequently in late-onset in the first 2 years after diagnosis (P < 0.036, P < 0.041, respectively). The use of immunomodulators and anti-TNF's even in patients with more complicated disease, that is, B2 or B3 behaviour (Montreal classification), remained significantly inferior (P < 0.0001) in late-onset compared to young adult-onset. Age at diagnosis, Charlson comorbidity index, and steroid used in the first year were negatively associated with the use of immunomodulators and biologics. Comorbidities, related medications and hospitalizations were more frequent in late-onset. Polypharmacy was present in 56% of elderly Crohn's disease patients. CONCLUSION Thirty-two percent of late-onset Crohn's disease presented with complicated disease behaviour. Despite a comparable use of steroids and surgery, immunomodulators and biologics were used in a small number of patients.

During osmotic demyelination syndrome (ODS), myelin and oligodendrocyte are lost according to specific patterns in centro- or extra-pontine regions. In both experimental model of ODS and human cases, brain lesions are locally correlated with the disruption of the blood brain-barrier (BBB). The initiation, the degree and the duration of blood-brain barrier (BBB) opening as well as its contribution to brain damages are still a matter of debate. Using a panel of intravascular tracers from low- to high- molecular weight (from 0.45 kDa 150 kDa), we have assessed the BBB permeability at different timings of ODS induced experimentally in mice. ODS was mimicked according to a protocol of rapid correction of a chronic hyponatremia. We demonstrated that BBB leakage towards smallest tracers Lucifer Yellow (0.45 kDa) and Texas Red-dextran (3 kDa) was delayed by 36 h compared to the first clues of oligodendrocyte loss (occurring 12 h post-correction of hyponatremia). At 48 h post-correction and concomitantly to myelin loss, BBB was massively disrupted as attested by accumulation of Evans Blue (69 kDa) and IgG (150 kDa) in brain parenchyma. Analysis of BBB ultrastructure verified that brain endothelial cells had minimal alterations during chronic hyponatremia and at 12 h post-correction of hyponatremia. However, brain endothelium yielded worsened alterations at 48 h, such as enlarged vesicular to tubular-like cytoplasmic profiles of pinocytosis and/or transcytosis, local basal laminae abnormalities and sub-endothelial cavities. The protein expressions of occludin and claudin-1, involved in inter-endothelial tight junctions, were also downregulated at 48 h post-correction of hyponatremia. Our results revealed that functional BBB opening occured late in pre-established ODS lesions, and therefore was not a primary event initiating oligodendrocyte damages in the mouse model of ODS.

In this case report, we studied Theory of Mind (ToM) and figurative language comprehension in a 7.2-year-old child, conventionally named RJ, with isolated and complete agenesis of the corpus callosum (ACC), a rare malformation due to the absence of the corpus callosum, the major tract connecting the two brain hemispheres. To study ToM, which is the capability to infer the other’s mental states, we used the classical false belief tasks, and to study figurative language, i.e., those linguistic usages involving non-literal meanings, we used tasks assessing metaphor and idiom comprehension. RJ’s intellectual level and his phonological, lexical, and grammatical abilities were all adequate. In both the ToM false belief tasks and novel sensory metaphor comprehension, RJ showed a delay of 3 years and a significant gap compared to a typically developing control group, while in idioms, his performance was at the border of average. These outcomes suggest that RJ has a specific pragmatic difficulty in all tasks where he must interpret the other’s communicative intention, as in ToM tasks and novel sensory metaphor comprehension. The outcomes also open up interesting insights into the relationships between ToM and figurative language in children with isolated and complete ACC.

The aryl-hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates numerous cellular responses. Originally investigated in toxicology because of its ability to bind environmental contaminants, AhR has attracted enormous attention in the field of immunology in the last 20 years. In addition, the discovery of endogenous and plant-derived ligands points to AhR also having a crucial role in normal cell physiology. Thus, AhR is emerging as a promiscuous receptor that can mediate either toxic or physiologic effects upon sensing multiple exogenous and endogenous molecules. Within this scenario, several factors appear to contribute to the outcome of gene transcriptional regulation by AhR, including the nature of the ligand as such and its further metabolism by AhR-induced enzymes, the local tissue microenvironment, and the presence of coregulators or specific transcription factors in the cell. Here, we review the current knowledge on the array of transcription factors and coregulators that, by interacting with AhR, tune its transcriptional activity in response to endogenous and exogenous ligands.

Objective:To evaluate the association of Composite Dietary Antioxidant Index (CDAI) and Dietary Inflammatory Index (DII) with the prevalence of high-grade cervical intraepithelial neoplasia (CIN).Design:A cross-sectional study was conducted on women with abnormal Papanicolaou test, who underwent high-risk human papillomavirus (HPV) screening and histological test through colposcopy. Dietary data were collected using a FFQ and used to assess both CDAI and DII.Setting:Women were recruited from 2012 to 2015 at the Cervical Cancer Screening Unit of the ‘Azienda Sanitaria Provinciale’ of Catania (Italy).Participants:The study included 539 women with a mean age of 40·2 years, who were classified as cases (n 127 with CIN2 or more severe lesions) and controls (n 412 with normal cervical epithelium or CIN1).Results:Although we observed a lower proportion of HPV-positive women among those with higher CDAI (P < 0·001), the index was not associated with the diagnosis of CIN2 or more severe lesions. By contrast, women with medium or high DII showed higher odds to be diagnosed with CIN2 or more severe lesions than those with low DII (OR = 2·15; 95 % CI 1·11, 4·17; P = 0·024 and OR = 3·14; 95 % CI 1·50, 6·56; P = 0·002, respectively), after adjusting for age, HPV status, educational level, BMI, smoking status, parity, use of oral contraceptives and supplements.Conclusions:Our findings suggested that a pro-inflammatory diet might be associated with an increased risk of CIN2 and more severe lesions. However, further prospective studies should be encouraged to support this evidence.

Background Aplasia cutis congenita (ACC) is a rare congenital condition characterized by the absence of skin layers and sometimes other underlying structures, in a localized or widespread area. The exact etiopathogenesis is not yet completely understood. Membranous ACC (MACC) also described as bullous or cystic ACC is a clinical subtype of ACC, covered with a membranous or glistening surface, and appears as a flat scar. There are less than 20 cases reported in the literature. It has been proposed an abortive form of a defective closure of the neural tube. On the other hand, the trisomy 18 is a chromosomal abnormality characterized by a broad clinical spectrum and the presence of defective closure of the neural tube. Case presentation We report on an 18-months-old Venezuelan boy, who presented on the parietal scalp a distinctive localized MACC appearing as an oval lesion covered with a membranous surface, characterized by the absence of hairs and the presence of a sharp hair collar. The karyotype in peripheral blood was 47,XY,+ 18. Conclusions This is the second case report of ACC in trisomy 18 and reinforces the interpretation of a non-fortuitous association as well as of a defective closure of the neural tube as pathogenetic mechanism. The case highlights the importance of examining for dermatological alterations such as ACC in cases of chromosomopathy.

Background Screening strategies to diagnose previously undetected atrial fibrillation (AF), especially silent AF (SAF), in at-risk populations may help reduce the number of strokes. We prospectively assessed the incidence rate of AF, including SAF, using an automated AF-detection capable sphygmomanometer in the General Practitioner (GP) setting. Methods This was a population-based prospective study of unselected general population of ≥65 years without prior AF. Participating GPs were requested, in the period February 2018–April 2019, to record all AF diagnoses including those derived from the AF-detection capable sphygmomanometer and confirmed by 12‑lead ECG or ECG Holter in asymptomatic patients. Results Overall, 14,987 patients assisted by 76 GPs accumulated 16,838 patient-years of follow up. The incidence rate of AF was 2.25% patient-years (95%CI 2.03–2.48). AF was more frequently detected in male, older, overweight, and patients with prior stroke, congestive heart failure, and chronic kidney disease. One in four patients had device-detected SAF (0.56% patient-years, 95%CI 0.46–0.69). Age, overweight, and the number of annual visits, were independent predictors of both SAF and AF. In addition, congestive heart failure, mitral valve disease were independent predictors of AF. Due to the interaction between blood pressure and age the risk of AF increased exponentially after 75 years of age in patients with higher systolic blood pressure values. Conclusion We found a higher than previously reported incidence rate of AF possibly by capturing SAF. Our simple protocol might be feasible in large-scale screening for AF and SAF in routine GP care.

BACKGROUND Soluble solids concentration (SSC), dry matter concentration (DMC) and flesh firmness (FF) are important fruit quality parameters in stone fruits. This study investigated the ability of a commercial visible/near-infrared (NIR) spectrometer to determine SSC, DMC and FF in nectarine, peach, apricot and Japanese plum cultivars at harvest. The work was conducted in summer 2019/2020 on 14 stone fruit cultivars at Tatura, Australia. Two sub-samples of 100 fruit each were collected before and after commercial maturity (± 5 days) in order to maximize sample variability. RESULTS Partial least square (PLS) regression models based on the second derivative of the absorbance in the 729-975 nm spectral region proved accurate for the prediction of SSC and DMC (R2CV > 0.750). Only the model generated for SSC in 'Golden May' apricot was less precise compared to other cultivars. No visible/NIR models were accurate enough to predict FF in the cultivars under study (R2CV

The outbreak of severe pneumonia due to the new SARS‐CoV‐2 has created a world emergency that is putting global public health institutions at high alert. Since the first official paper on January 20 up to now more than 10.000 publications have appeared on PubMed. Surprisingly, no single paper has been dealing with the potential impact of the COVID‐19 on Down Syndrome (DS). As COVID‐19 presents as an acute severe respiratory syndrome and DS is by far the most frequent chromosomal disease with the highest susceptibility to develop respiratory infections and complications (1), it seems timely to focus on this syndrome during the ongoing pandemic.

Context: Both frailty and multimorbidity are strong predictors of clinical endpoints for older people. In Italy, the interventions targeting chronicity are mainly based on the treatment of diseases: sufficient epidemiological literature is available about these strategies. Less is known about the territorial distribution of the frailty status. Aims: To estimate the prevalence of frailty in older people (65+) and to evaluate the relationship between frailty and multimorbidity. Methods and material: A group of general practitioners working in Veneto (Italy) was enrolled on a voluntary basis. Older individuals were both community dwelling and institutionalized patients, that is, the older people normally followed by Italian general practitioners. A centrally randomized sample was extracted from the pool of physician-assisted elderly. Each doctor evaluated the frailty status through the CSHA Clinical Frailty Scale and the multimorbidity status through the Charlson score (Frailty = CSHA Clinical Frailty Scale’s score >4; serious multimorbidity = Charlson score ≥4). Prevalence and its confidence interval (CI) 95% were evaluated through the Agresti’s method for proportions. The relation between frailty and multimorbidity was studied through a logistic regression model adjusted for age and sex. Results: Fifty-three physicians were enrolled, whose population of elderly individuals (N = 82919) was highly representative of the population of Veneto. The prevalence of frailty in the randomized sample of 2407 older people was 23.18% (CI 95%: 21.53%–24.91%). Sex was shown to be a strong predictor of frailty (female status OR = 1.58 p

The focus of this work was to investigate the toxicity of different metal nanoparticles (gold nanoparticles [AuNPs], silver nanoparticles [AgNPs], titanium dioxide nanoparticles [TiO2 NPs]) on brine shrimp Artemia salina. We investigated if nanoparticles could have an influence on hatching of cysts and on mortality of larvae. Larvae (also called nauplii) and cysts were exposed to NPs for 24 hr in artificial seawater on microplates. At the end of the test, we assessed the endpoint (immobility/death) for the larvae by a stereomicroscope. Nauplii that appeared completely motionless, were counted as dead, and the percentages of mortality were calculated for each treatment. Instead for the cysts, the percentages of not-hatched nauplii for each concentration considered were calculated by counting the number of whole cysts. Currently, nanoparticles toxicity has been investigated in several research; in our study we highlighted the nontoxicity of TiO2 NPs on A. salina nauplii as shown by low percentages of immobilization and on cysts because TiO2 NPs do not affect their hatching. Despite AuNPs exerted toxic effects on hatching, they did not affect larvae development as well as TiO2 NPs. Otherwise, AgNPs induced mortality of the larvae and inhibited cysts hatching.

Keratitis-ichthyosis-deafness (KID syndrome) is a syndromes ichthyoses that is clinically and genetically heterogeneous requiring early and long-term multidisciplinary monitoring of affected individuals. A review of the clinical, etiopathogenic and therapeutic aspects is presented of this rare congenital ectodermal disorder.

Endotoxin tolerance aims at opposing hyperinflammatory responses to lipopolysaccharide (LPS) exposure. The aryl hydrocarbon receptor (AhR) participates in protection against LPS-mediated tissue damage, as it plays a necessary role in restraining the proinflammatory action of IL-1β and TNF-α while fostering the expression of protective TGF-β. TGF-β, in turn, promotes durable expression of the immune regulatory enzyme indoleamine 2,3-dioxygenase 1 (IDO1). IDO1 degrades L-tryptophan to L-kynurenine—an activating ligand for AhR—thus establishing a feed-forward loop. In this study, we further demonstrate that L-kynurenine also promotes the dissociation of the Src kinase–AhR cytosolic complex, leading to the activation of both genomic and non-genomic events in conventional dendritic cells (cDCs) primed with LPS. Specifically, the Src kinase, by phosphorylating the downstream target IDO1, triggers IDO1’s signaling ability, which results in enhanced production of TGF-β, an event key to establishing full endotoxin tolerance. We demonstrated that exogenous L-kynurenine can substitute for the effects of continued or repeated LPS exposure and that the AhR–Src–IDO1 axis represents a critical step for the transition from endotoxin susceptibility to tolerance. Moreover, much like fully endotoxin-tolerant dendritic cells (DCs) (i.e., treated twice with LPS in vitro), DCs—treated once with LPS in vitro and then with kynurenine—confer resistance on naïve recipients to an otherwise lethal LPS challenge. This may have clinical implications under conditions in which pharmacologically induced onset of endotoxin tolerance is a therapeutically desirable event.

This multiple case study explores the effects of a cognitive training program in children with mild to borderline intellectual disability. Experimental training effects were evaluated comparing pre-/post-test changes of (a) a baseline phase versus a training phase in the same participant, (b) an experimental training versus either a no intervention phase or a control training in two pairs of children matched for cognitive profile. Key elements of the training program included (1) exercises and card games targeting inhibition, switching, and verbal working memory, (2) guided practice emphasizing concrete strategies to engage in exercises, and (3) a variable amount of adult support. The results show that both verbal working memory analyzed with the listening span test and problem-solving tested with the Raven’s Matrices were significantly enhanced after the experimental training.

5-α-Reductase type 2 enzyme catalyzes the conversion of testosterone into dihydrotestosterone, a potent androgen responsible for male sexual development during the fetal period and later during puberty. Its deficiency causes an autosomal recessive disorder of sex development characterized by a wide range of under-virilization of external genitalia in patients with a 46,XY karyotype. Mutations in the SRD5A2 gene cause 5-α-Reductase deficiency; although it is an infrequent disorder, it has been reported worldwide, with mutational heterogeneity. Furthermore, it has been proposed that there is no genotype-phenotype correlation, even in patients carrying the same mutation. The aim of this review was to perform an extensive search in various databases and to select those articles with a comprehensive genotype and phenotype description of the patients, classifying their phenotypes using the external masculinization score (EMS). Thus, it was possible to objectively compare the eventual genotype-phenotype correlation between them. The analysis showed that for most of the studied mutations no correlation can be established, although the specific location of the mutation in the protein has an effect on the severity of the phenotype. Nevertheless, even in patients carrying the same homozygous mutation, a variable phenotype was observed, suggesting that additional genetic factors might be influencing it. Due to the clinical variability of the disorder, an accurate diagnosis and adequate medical management might be difficult to carry out, as is highlighted in the review.

Forkhead box protein 3 (FOXP3) transcription factor is expressed by immune cells and several human cancers and is associated with tumor aggressiveness and unfavorable clinical outcomes. NOTCH and transforming growth factor‑β (TGF‑β) protumorigenic effects are mediated by FOXP3 expression in several cancer models; however, their interaction and role in melanoma is unknown. We investigated TGF‑β‑induced FOXP3 gene expression during NOTCH1 signaling inactivation. Primary (WM35) and metastatic melanoma (A375 and A2058) cell lines and normal melanocytes (NHEM) were used. FOXP3 subcellular distribution was evaluated by immuno-cytochemical analysis. Gene expression levels were assessed by reverse transcription‑quantitative polymerase chain reaction. Protein levels were assessed by western blot analysis. The γ‑secretase inhibitor (GSI) was used for NOTCH1 inhibition and recombinant human (rh)TGF‑β was used for melanoma cell stimulation. Cell proliferation and viability were respectively assessed by MTT and Trypan blue dye assays. FOXP3 mRNA and protein levels were progressively higher in WM35, A375 and A2058 cell lines compared to NHEM and their levels were further increased after stimulation with rh‑TGF‑β. TGF‑β‑mediated FOXP3 expression was mediated by NOTCH1 signaling. Inhibition of NOTCH1 with concomitant rh‑TGF‑β stimulation determined the reduction in gene expression and protein level of FOXP3. Finally, melanoma cell line proliferation and viability were reduced by NOTCH1 inhibition. The results show that nn increase in FOXP3 expression in metastatic melanoma cell lines is a potential marker of tumor aggressiveness and metastasis. NOTCH1 is a central mediator of TGF‑β‑mediated FOXP3 expression and NOTCH1 inhibition produces a significant reduction of melanoma cell proliferation and viability.

Background & Aims: The effectiveness of direct-acting antivirals (DAAs) against hepatitis C virus (HCV), following successful treatment of early hepatocellular carcinoma (HCC), has been studied extensively. However, the benefit in terms of overall survival (OS) remains to be conclusively demonstrated. The aim of this study was to assess the impact of DAAs on OS, HCC recurrence, and hepatic decompensation. Methods: We prospectively enrolled 163 consecutive patients with HCV-related cirrhosis and a first diagnosis of early Barcelona Clinic Liver Cancer stage 0/A HCC, who had achieved a complete radiologic response after curative resection or ablation and were subsequently treated with DAAs. DAA-untreated patients from the ITA.LI.CA. cohort (n = 328) served as controls. After propensity score matching, outcomes of 102 DAA-treated (DAA group) and 102 DAA-untreated patients (No DAA group) were compared. Results: In the DAA group, 7/102 patients (6.9%) died, HCC recurred in 28/102 patients (27.5%) and hepatic decompensation occurred in 6/102 patients (5.9%), after a mean follow-up of 21.4 months. OS was significantly higher in the DAA group compared to the No DAA group (hazard ratio [HR] 0.39; 95% CI 0.17–0.91; p = 0.03). HCC recurrence was not significantly different between the DAA and No DAA groups (HR 0.70; 95% CI 0.44–1.13; p = 0.15). A significant reduction in the rate of hepatic decompensation was observed in the DAA group compared with the No DAA group (HR 0.32; 95% CI 0.13–0.84; p = 0.02). In the DAA group, sustained virologic response was a significant predictor of OS (HR 0.02; 95% CI 0.00–0.19; p

Discovered as a modulator of the toxic response to environmental pollutants, aryl hydrocarbon receptor (AhR) has recently gained attention for its involvement in various physiological and pathological pathways. AhR is a ligand-dependent transcription factor activated by a large array of chemical compounds, which include metabolites of l-tryptophan (l-Trp) catabolism as endogenous ligands of the receptor. Among these, 2-(1'H-indole-3'-carbonyl)thiazole-4-carboxylic acid methyl ester (ITE) has attracted interest in the scientific community, being endowed with nontoxic, immunomodulatory, and anticancer AhR-mediated functions. So far, no information about the binding mode and interactions of ITE with AhR is available. In this study, we used docking and molecular dynamics to propose a putative binding mode of ITE into the ligand binding pocket of AhR. Mutagenesis studies were then instrumental in validating the proposed binding mode, identifying His 285 and Tyr 316 as important key residues for ligand-dependent receptor activation. Finally, a set of ITE analogues was synthesized and tested to further probe molecular interactions of ITE to AhR and characterize the relevance of specific functional groups in the chemical structure for receptor activity.

Background and purpose While AD can be definitively confirmed by postmortem histopathologic examination, in vivo imaging may improve the clinician's ability to identify AD at the earliest stage. The aim of the study was to test the performance of amyloid PET using new processing imaging algorithm for more precise diagnosis of AD. Methods Amyloid PET results using a new processing imaging algorithm (MRI-Less and AAL Atlas) were correlated with clinical, cognitive status, CSF analysis, and other imaging. The regional SUVR using the white matter of cerebellum as reference region and scores from clinical and cognitive tests were used to create ROC curves. Leave-one-out cross-validation was carried out to validate the results. Results Forty-four consecutive patients with clinical evidence of dementia, were retrospectively evaluated. Amyloid PET scan was positive in 26/44 patients with dementia. After integration with 18F-FDG PET, clinical data and CSF protein levels, 22 of them were classified as AD, the remaining 4 as vascular or frontotemporal dementia. Amyloid and FDG PET, CDR 1, CSF Tau, and p-tau levels showed the best true positive and true negative rates (amyloid PET: AUC = .85, sensitivity .91, specificity .79). A SUVR value of 1.006 in the inferior frontal cortex and of 1.03 in the precuneus region was the best cutoff SUVR value and showed a good correlation with the diagnosis of AD. Thirteen of 44 amyloid PET positive patients have been enrolled in clinical trials using antiamyloid approaches. Conclusions Amyloid PET using SPM-normalized SUVR analysis showed high predictive power for the differential diagnosis of AD.

In Italy, the cohorts of women who were offered Human papillomavirus (HPV) vaccination in 2007/08 will reach the age (25years) for cervical cancer (CC) screening from 2017. The simultaneous shift from cytology-based screening to HPV test-based screening gives the opportunity for unprecedented reorganisation of CC prevention. The ONS (National Screening Monitoring Centre) Directive and the GISCi (Italian Group for Cervical Screening) identified the consensus conference as the most suitable method for addressing this topic. A summary of consensus recommendations is reported here. The main objective was to define the best screening methods in girls vaccinated against HPV and the knowledge required for defining evidence-based screening strategies. A Jury made recommendations about questions and proposals formulated by a panel of experts representative of Italian scientific societies involved in CC prevention and based on systematic reviews of literature and evidence. The Jury considered changing the screening protocols for girls vaccinated in their twelfth year as appropriate. Tailored screening protocols based on vaccination status could be replaced by "one size fits all" protocols only when a herd immunity effect has been reached. Vaccinated women should start screening at age 30, instead of 25, with HPV test. Furthermore, there is a strong rationale for applying longer intervals for re-screening HPV negative women than the currently recommended 5years, but research is needed to determine the optimal screening time points. For non-vaccinated women and for women vaccinated in their fifteenth year or later, the current protocol should be kept.

The frequency of dermatological manifestations in diseases due to mitochondrial DNA mutations is not well known, although multiple symmetric lipomatosis has been repeatedly associated to mitochondrial DNA mutations. Here, we present a patient suffering from multiple symmetric lipomatosis and other skin signs. We found a new mitochondrial DNA mutation, m.8357T>C, in the tRNALys -coding gene and, using a cybrid approach, confirmed its pathogenicity. A meta-analysis of the dermatological signs of the patient shows that they are not common in patients with confirmed mitochondrial DNA mutations and suggests that, in these cases, lipomatosis is not related to the oxidative phosphorylation dysfunction, but to an alteration of an additional function associated to particular mitochondrial tRNAs.

In many Vertebrate and invertebrate, the interaction mechanisms among gametes are based on a high affinity and specificity of recognition and link between specific saccharidic residues and receptors present on the surface of gametes. Literature data also suggest that Insects could use this strategy. In particular, Orthoptera Tettigoniidae spermatodesms and sperms undergo radical changes passing through the male to the female genital tracts that may be interpreted as well as a capacitation process. These changes could also concern the presence and distribution of surface glycoconjugates. Our study aims to highlight the presence and distribution of saccharide residues on the spermatozoa surface in five species of Orthoptera Tettigoniidae using a battery of lectins Fluorescein Isothiocyanate Conjugated and Gold Conjugated. The results of this investigation have shown that on the surface of the male gametes are present saccharide residues whose nature and distribution are species-specific, during their transfer to the female genital tract, they significantly undergo a change. These results let us hypothesize that also for this group of Insects, the glycoconjugates play a significant role in the process of interaction between gametes.

Acute myeloid leukemia (AML) is a heterogeneous group of diseases, whose classification is based on lineage-commitment and genetics. Although rare in childhood, it is the most common type of acute leukemia in adults, accounting for 80% of all cases in this age group. The prognosis of this disease remains poor (especially in childhood, as compared to acute lymphoblastic leukemia); however, overall survival has significantly improved over the past 30 years. The health of the oral cavity is a remarkable reflection of the systemic status of an individual. Identification of the signs and symptoms of oral lesions can act as a warning sign of hidden and serious systemic involvement. Moreover, they may be the presenting feature of acute leukemia and provide important diagnostic indicators. Primary oral alterations are identified in up to 90% of cases of acute myeloid leukemia and consist of petechiae, spontaneous bleeding, mucosal ulceration, gingival enlargement with or without necrosis, infections, hemorrhagic bullae on the tongue, and cracked lips. Poor oral hygiene is a well-known risk factor for local and systemic infectious complications. Oro-dental complications due to AML treatment can affect the teeth, oral mucosa, soft and bone tissue, and contribute to opportunistic infections, dental decay, and enamel discoloration. The treatment of acute myeloid leukemia is still associated with high mortality and morbidity. The management is multimodal, involving aggressive multidrug chemotherapy and, in most cases, allogenic bone marrow transplantation. Periodontal and dental treatment for patients with leukemia should always be planned and concerted with hematologists.

Purpose :Genitopatellar syndrome and Say–Barber–Biesecker–Young–Simpson syndrome are caused by variants in the KAT6B gene and are part of a broad clinical spectrum called KAT6B disorders, whose variable expressivity is increasingly being recognized. Methods: We herein present the phenotypes of 32 previously unreported individuals with a molecularly confirmed diagnosis of a KAT6B disorder, report 24 new pathogenic KAT6B variants, and review phenotypic information available on all published individuals with this condition. We also suggest a classification of clinical subtypes within the KAT6B disorder spectrum. Results: We demonstrate that cerebral anomalies, optic nerve hypoplasia, neurobehavioral difficulties, and distal limb anomalies other than long thumbs and great toes, such as polydactyly, are more frequently observed than initially reported. Intestinal malrotation and its serious consequences can be present in affected individuals. Additionally, we identified four children with Pierre Robin sequence, four individuals who had increased nuchal translucency/cystic hygroma prenatally, and two fetuses with severe renal anomalies leading to renal failure. We also report an individual in which a pathogenic variant was inherited from a mildly affected parent. Conclusión: Our work provides a comprehensive review and expansion of the genotypic and phenotypic spectrum of KAT6B disorders that will assist clinicians in the assessment, counseling, and management of affected individuals. Sin financiación 8.822 JCR(2020) Q1, 15/176 Genetics & Heredity 3.509 SJR (2020) Q1, 7/96 Genetics (clinical) No data IDR 2020 UEM

Introduccion: La osteogenesis imperfecta (OI) es el trastorno oseo hereditario mas comun, con una incidencia de 1 en 10,000 a 25,000 nacimientos. Este trastorno esta causado principalmente por mutaciones de los genes que codifican las cadenas del colageno tipo I. En la mayoria de los casos, se presenta un patron de herencia autosomico dominante. La OI se caracteriza principalmente por un aumento en la fragilidad osea que da lugar a fracturas frecuentes que producen dolor, deformidad y discapacidad asociada con otras alteraciones. El objetivo del estudio fue exponer las caracteristicas clinicas y epidemiologicas de una serie de pacientes pediatricos con diagnostico de OI evaluados en la Universidad de Los Andes. Metodos: El presente trabajo consiste en el analisis de una serie de 37 casos pediatricos con diagnostico de OI, de acuerdo a la clasificacion clinica y radiologica de Sillence, evaluados en la consulta de la Unidad de Genetica Medica de la Universidad de Los Andes, entre enero de 2006 y diciembre de 2018. Resultados: La OI tipo I fue la de presentacion mas frecuente, con 31 pacientes (83.78%). El femur fue el hueso mas afectado de manera conjunta. Las escleras azules fueron el hallazgo adicional mas frecuente, en 32 pacientes (86.49%). Conclusiones: La OI representa el principal motivo de consulta por alteraciones en el sistema esqueletico en la Unidad de Genetica Medica de la Universidad de Los Andes. Ante la amplia forma clinica de presentacion, la evaluacion debe ser individual e interdisciplinaria. A traves de un estudio mas profundo se podra brindar el oportuno asesoramiento genetico familiar

Wolf-Hirschhorn syndrome is a polymalformative entity due to the microdeletion in the distal region of the short arm of chromosome 4 (4p16.3), which produces a series of clinical manifestations that can vary depending on the type and size of the genetic defect in this contiguous gene syndrome. Five patients are presented, three of them female, all with the primary clinical findings, characterized by "Greek warrior helmet appearance" facial feature, growth retardation and psychomotor development delay. In addition to the partial deletion in the distal region of the short arm of chromosome 4, two additional genetic alterations were found in two patients, through the use of single nucleotide polymorphism arrays. The clinical characteristics of Wolf-Hirschhorn syndrome are highlighted in order to guide the diagnosis, provide interdisciplinary medical care and, through its confirmation, provide adequate family genetic counseling.

Background Craniosynostosis is described as the premature fusion of cranial sutures that belongs to a group of alterations which produce an abnormal phenotype. Case report Two unrelated female patients with clinical findings of Apert syndrome-characterized by acrocephaly, prominent frontal region, flat occiput, ocular proptosis, hypertelorism, down-slanted palpebral fissures, midfacial hypoplasia, high-arched or cleft palate, short neck, cardiac anomalies and symmetrical syndactyly of the hands and feet-are present. In both patients, a heterozygous missense mutation (c.755C>G, p.Ser252Trp) in the FGFR2 gene was identified. Conclusions Two cases of Apert syndrome are described. It is important to recognize this uncommon entity through clinical findings, highlight interdisciplinary medical evaluation, and provide timely genetic counseling for the family.

Background Cutis laxa (CL) is a group of rare connective tissue disorders mainly characterized by wrinkled, redundant, inelastic, and sagging skin. Besides skin anomalies, in most CL forms multiple organs are involved, leading to severe multisystem disorders involving skeletal, cardiovascular, pulmonary, and central nervous systems. CL might be challenging to diagnose because of its different inheritance patterns, extensive phenotypic variability, and genetic heterogeneity. Herein, we report the clinical and molecular characterization of an 18‐month‐old infant with signs suggestive of recessive cutis laxa type 1C (ARCL1C), although with a relatively mild presentation. Methods To confirm the clinical suspicion, mutational screening of all the exons and intron‐flanking regions of the latent transforming growth factor‐beta binding protein 4 gene (LTBP4) was performed by Sanger sequencing on an ABI3130XL Genetic Analyzer. Results Apart from the presence of the dermatological hallmark, the reported patient did not show pulmonary emphysema, which is the most common and discriminative finding of ARCL1C together with gastrointestinal and urinary involvement. Indeed, pulmonary involvement only included episodes of respiratory distress and diaphragmatic eventration; intestinal dilation and tortuosity and hydronephrosis were also present. Molecular analysis disclosed the novel homozygous c.1450del (p.Arg484Glyfs*290) pathogenic variant in exon 12 of LTBP4, thus leading to the diagnosis of ARCL1C. Conclusion Our findings expand both the knowledge of the clinical phenotype and the allelic repertoire of ARCL1C. The comparison of the patient's features with those of the other patients reported up to now offers future perspectives for clinical research in this field.

A novel battery (BAFE; Valeri et al. 2015) was used in order to assess three executive function (EF) abilities (working memory, inhibition and shifting) in a sample of 27 intellectually able preschoolers with autism spectrum disorder (ASD) compared with 27 typically developing children matched on age and nonverbal IQ. Differences in EF skills were analyzed in participants with distinct ASD symptom severity. Children with ASD performed worse than typical controls on both set-shifting and inhibition, but not on visuo-spatial working memory. Additionally, children with more severe ASD symptoms showed a worse performance on inhibition than children with milder symptoms. These results confirm the presence of EF deficits and highlight a link between ASD symptoms and EF impairments in preschool age.

Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the first step in the kynurenine pathway of tryptophan (Trp) degradation that produces several biologically active Trp metabolites. L-kynurenine (Kyn), the first byproduct by IDO1, promotes immunoregulatory effects via activation of the Aryl hydrocarbon Receptor (AhR) in dendritic cells (DCs) and T lymphocytes. We here identified the nuclear coactivator 7 (NCOA7) as a molecular target of 3-hydroxyanthranilic acid (3-HAA), a Trp metabolite produced downstream of Kyn along the kynurenine pathway. In cells overexpressing NCOA7 and AhR, the presence of 3-HAA increased the association of the two molecules and enhanced Kyn-driven, AhR-dependent gene transcription. Physiologically, conventional (cDCs) but not plasmacytoid DCs or other immune cells expressed high levels of NCOA7. In cocultures of CD4+ T cells with cDCs, the co-addition of Kyn and 3-HAA significantly increased the induction of Foxp3+ regulatory T cells and the production of immunosuppressive transforming growth factor β in an NCOA7-dependent fashion. Thus, the co-presence of NCOA7 and the Trp metabolite 3-HAA can selectively enhance the activation of ubiquitary AhR in cDCs and consequent immunoregulatory effects. Because NCOA7 is often overexpressed and/or mutated in tumor microenvironments, our current data may provide evidence for a new immune check-point mechanism based on Trp metabolism and AhR.