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Introduction: Patients with obstructive sleep apnea (OSA) suffer from several neurocognitive deficits. We investigated the cognitive and socio-cognitive profiles of patients with severe OSA, controlling for potentially relevant mediating variables (i.e. age, body-mass index, cognitive reserve and depression). Moreover, we studied the neuropsychological profile of a high-risk OSA phenotype characterized by severe OSA and severe nocturnal hypoxemia. Method: We assessed 29 previously untreated severe OSA patients with a mean age of 55.6 ( 9.9 years) and a mean apnea-hypopnea index (AHI) of 53.1 ( 17.4). A control group of 34 healthy participants was also enrolled. Participants completed an extensive neuropsychological battery that included social cognition, a relatively new investigation area among OSA patients. Data analysis: Data were analyzed with a Bayesian approach. Specifically, Bayesian ANCOVA was used to investigate whether the grouping variable could predict test performance. Age, body-mass index, cognitive reserve and state of depression were added as covariates to the null model to weight the effects of these potential confounding factors. Three groups were analyzed: healthy controls (H), OSA with severe apnea and severe nocturnal oxygen desaturation (D+), and OSA with severe apnea non-desaturators (D−). Performances on the various neuropsychological tests were treated as the dependent variables. Results: The results indicate that non-verbal reasoning, the theory of mind skills, and mental shifting ability were impaired in OSA patients. Patients with severe nocturnal hypoxemia underperformed compared to patients with the same severity of apnea but non-desaturators. Additionally, we observed a trend toward a worse performance among OSA desaturator patients in the following abilities: constructional ability, short term verbal memory, phonological fluency, and the ability to inhibit automatic and dominant responses. Conclusion: The data suggest a key role of hypoxemia in affecting cognitive functioning in OSA patients. Executive functions and the concomitant involvement of social cognition are particularly affected.

Objective: Aberrant activity of androgen receptor (AR) is the primary cause underlying development and progression of prostate cancer (PCa) and castration-resistant PCa (CRPC). Androgen signaling regulates gene transcription and lipid metabolism, facilitating tumor growth and therapy resistance in early and advanced PCa. Although direct AR signaling inhibitors exist, AR expression and function can also be epigenetically regulated. Specifically, lysine (K)-specific demethylases (KDMs), which are often overexpressed in PCa and CRPC phenotypes, regulate the AR transcriptional program. Methods: We investigated LSD1/UTX inhibition, two KDMs, in PCa and CRPC using a multi-omics approach. We first performed a mitochondrial stress test to evaluate respiratory capacity after treatment with MC3324, a dual KDM-inhibitor, and then carried out lipidomic, proteomic, and metabolic analyses. We also investigated mechanical cellular properties with acoustic force spectroscopy. Results: MC3324 induced a global increase in H3K4me2 and H3K27me3 accompanied by significant growth arrest and apoptosis in androgen -responsive and-unresponsive PCa systems. LSD1/UTX inhibition downregulated AR at both transcriptional and non-transcriptional level, showing cancer selectivity, indicating its potential use in resistance to androgen deprivation therapy. Since MC3324 impaired metabolic activity, by modifying the protein and lipid content in PCa and CRPC cell lines. Epigenetic inhibition of LSD1/UTX disrupted mitochondrial ATP production and mediated lipid plasticity, which affected the phosphocholine class, an important structural element for the cell membrane in PCa and CRPC associated with changes in physical and mechanical properties of cancer cells. Conclusions: Our data suggest a network in which epigenetics, hormone signaling, metabolite availability, lipid content, and mechano-metabolic process are closely related. This network may be able to identify additional hotspots for pharmacological intervention and un-derscores the key role of KDM-mediated epigenetic modulation in PCa and CRPC.(c) 2022 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

This paper focuses on the gut-lung axis in the context of Inflammatory Bowel Disease (IBD) and Chronic Obstructive Pulmonary Disease (COPD), highlighting the key role played by microbial dysbiosis and the impact of environmental and genetic factors on the innate and acquired immune system and on chronic inflammation in the intestinal and pulmonary tracts. Recent evidence indicates that Antigen-Presenting Cells (APCs) perform regulatory activity influencing the composition of the microbiota. APCs (macrophages, dendritic cells, B cells) possess membrane receptors known as Pattern Recognition Receptors (PRRs), a category of toll-like receptors (TLRs). PRRs recognise distinct microbial structures and microbial metabolites called Signals, which modulate the saprophytic microbial equilibrium of the healthy microbiota by recognising molecular profiles associated with commensal microbes (Microbe-Associated Molecular Patterns, MAMPs). During dysbiosis, pathogenic bacteria can prompt an inflammatory response, producing PAMPs (Pathogen-Associated Molecular Patterns) thereby activating the proliferation of inflammatory response cells, both local and systemic. This series of regulatory and immune-response events is responsible (together with chronic infection, incorrect diet, obesity, etc.) for the systemic chronic inflammation (SCI) known as "low-grade inflammation" typical of COPD and IBD. This review looks at immunological research and explores the role of the microbiota, looking at two recent clinical studies, SPIROMICS and AERIS. There is a need for further clinical studies to characterize the pulmonary microbiota and to obtain new information about the pathogenesis of lung disease to improve our knowledge and treatment strategies and identify new therapeutic targets.

IntroductionItaly became the second epicenter of the novel coronavirus disease 2019 (COVID-19) pandemic after China, surpassing by far China's death toll. The disease swept through Lombardy, which remained in lockdown for about two months, starting from the 8th of March. As of that day, the isolation measures taken in Lombardy were extended to the entire country. Here, assuming that effectively there was one case "zero" that introduced the virus to the region, we provide estimates for: (a) the day-zero of the outbreak in Lombardy, Italy; (b) the actual number of asymptomatic infected cases in the total population until March 8; (c) the basic (R0)and the effective reproduction number (Re) based on the estimation of the actual number of infected cases. To demonstrate the efficiency of the model and approach, we also provide a tentative forecast two months ahead of time, i.e. until May 4, the date on which relaxation of the measures commenced, on the basis of the COVID-19 Community Mobility Reports released by Google on March 29.MethodsTo deal with the uncertainty in the number of the actual asymptomatic infected cases in the total population Volpert et al. (2020), we address a modified compartmental Susceptible/ Exposed/ Infectious Asymptomatic/ Infected Symptomatic/ Recovered/ Dead (SEIIRD) model with two compartments of infectious persons: one modelling the cases in the population that are asymptomatic or experience very mild symptoms and another modelling the infected cases with mild to severe symptoms. The parameters of the model corresponding to the recovery period, the time from the onset of symptoms to death and the time from exposure to the time that an individual starts to be infectious, have been set as reported from clinical studies on COVID-19. For the estimation of the day-zero of the outbreak in Lombardy, as well as of the "effective" per-day transmission rate for which no clinical data are available, we have used the proposed SEIIRD simulator to fit the numbers of new daily cases from February 21 to the 8th of March. This was accomplished by solving a mixed-integer optimization problem. Based on the computed parameters, we also provide an estimation of the basic reproduction number R0 and the evolution of the effective reproduction number Re. To examine the efficiency of the model and approach, we ran the simulator to "forecast" the epidemic two months ahead of time, i.e. from March 8 to May 4. For this purpose, we considered the reduction in mobility in Lombardy as released on March 29 by Google COVID-19 Community Mobility Reports, and the effects of social distancing and of the very strict measures taken by the government on March 20 and March 21, 2020.ResultsBased on the proposed methodological procedure, we estimated that the expected day-zero was January 14 (min-max rage: January 5 to January 23, interquartile range: January 11 to January 18). The actual cumulative number of asymptomatic infected cases in the total population in Lombardy on March 8 was of the order of 15 times the confirmed cumulative number of infected cases, while the expected value of the basic reproduction number R0 was found to be 4.53 (min-max range: 4.40- 4.65). On May 4, the date on which relaxation of the measures commenced the effective reproduction number was found to be 0.987 (interquartiles: 0.857, 1.133). The model approximated adequately two months ahead of time the evolution of reported cases of infected until May 4, the day on which the phase I of the relaxation of measures was implemented over all of Italy. Furthermore the model predicted that until May 4, around 20% of the population in Lombardy has recovered (interquartile range: ∼10% to ∼30%).

Background: Novel molecular tests (MTs), such as ThyroSeq, may improve the management of thyroid nodules with indeterminate cytologic diagnoses; however, the impact of these tests on cost and outco...

Una review sulle scienze OMICHE nella gestione del paziente con sindrome dell’apnea ostruttiva del sonno.La sindrome da apnea ostruttiva nel sonno (OSA) è una condizione caratterizzata dalla presenza di completo o parziale collasso delle vie aeree superiori durante il sonno, con conseguente frammentazione del sonno associata a rapidi episodi di ipossia intermittente (IH) e attivazione del sistema nervoso simpatico e dello stress ossidativo. L’OSA è associata ad un ampio spettro di patologie cardiovascolari, metaboliche, neurocognitive e comorbidità che appaiono particolarmente evidenti nei pazienti obesi, interessando entrambi i sessi in modo diverso e variando la gravità a seconda del sesso e dell’età. Negli ultimi anni, gli studi sull’OSA sono aumentati considerevolmente, ma nella pratica clinica, si tratta ancora di una malattia altamente sottodiagnosticata. Ad oggi, il gold standard per la diagnosi di OSA è la polisonnografia notturna (PSG). Tuttavia, poiché non è adatto ad un gran numero di pazienti, anche l’Home Sleep Test (HST) è un metodo diagnostico accettato. Attualmente, l’obiettivo principale della ricerca è quello di identificare metodi non invasivi per ottenere un sistema di screening altamente predittivo e non invasivo per questa categoria di soggetti. I lavori più recenti indicano che la ricerca in questo campo ha compiuto progressi significativi nell’identificazione di possibili biomarcatori in OSA, utilizzando approcci OMICI, in particolare nel campo della proteomica e della metabolomica. In questa review, analizziamo una lista di questi biomarcatori presenti in letteratura.Obstructive sleep apnaea (OSA) syndrome is a condition characterised by the presence of complete or partial collapse of the upper airways during sleep, resulting in fragmentation of sleep associated with rapid episodes of intermittent hypoxia (IH), activation of the sympathetic nervous system and oxidative stress. OSA is associated with a broad spectrum of cardiovascular, metabolic and neurocognitive comorbidities that appear to be particularly evident in obese patients, while affecting both sexes in a different manner and varying in severity according to gender and age. In recent years, studies on OSA have increased considerably, but in clinical practice, it is still a highly underdiagnosed disease. To date, the gold standard for the diagnosis of OSA is nocturnal polysomnography (PSG). However, since it is not well suited for a large number of patients, the Home Sleep Test (HST) is also an accepted diagnostic method. Currently, the major aim of research is to identify non-invasive methods to achieve a highly predictive, non-invasive screening system for these subjects. The most recent reports indicate that research in this field has made significant progress in identifying possible biomarkers in OSA, using -OMIC approaches, particularly in the fields of proteomics and metabolomics. In this review, we analyse these OMIC biomarkers found in the literature.

Introduction: Harmonized neuropsychological assessment for neurocognitive disorders, an international priority for valid and reliable diagnostic procedures, has been achieved only in specific countries or research contexts.Methods: To harmonize the assessment of mild cognitive impairment in Europe, a workshop (Geneva, May 2018) convened stakeholders, methodologists, academic, and non-academic clinicians and experts from European, US, and Australian harmonization initiatives.Results: With formal presentations and thematic working-groups we defined a standard battery consistent with the U.S. Uniform DataSet, version 3, and homogeneous methodology to obtain consistent normative data across tests and languages. Adaptations consist of including two tests specific to typical Alzheimer's disease and behavioral variant frontotemporal dementia. The methodology for harmonized normative data includes consensus definition of cognitively normal controls, classification of confounding factors (age, sex, and education), and calculation of minimum sample sizes.Discussion: This expert consensus allows harmonizing the diagnosis of neurocognitive disorders across European countries and possibly beyond.

To illustrate a new technological advance in the standard drug-induced sleep endoscopy (DISE) model, a new machine was used, the Experimental 5 Video Stream System (5VsEs), which is capable of simultaneously visualizing all the decisional parameters on a single monitor, and recording and storing them in a single uneditable video. The DISE procedure was performed on 48 obstructive sleep apnea (OSA) or snoring patients. The parameters simultaneously recorded on a single monitor are (1) the pharmacokinetics and pharmacodynamics of propofol (through the target controlled infusion (TCI) pump monitor), (2) the endoscopic upper airway view, (3) the polygraphic pattern, and (4) the level of sedation (through the bispectral index (BIS) value). In parallel to the BIS recording, the middle latency auditory evoked potential (MLAEP) was also recorded and provided. Recorded videos from the 5VsEs machine were re-evaluated six months later by the same clinician and a second clinician to evaluate the concordance of the therapeutic indications between the two. After the six-month period, the same operator confirmed all their clinical decisions for 45 out of 48 videos. Three videos were no longer evaluable for technical reasons, so were excluded from further analysis. The comparison between the two operators showed a complete adherence in 98% of cases. The 5VsEs machine provides a multiparametric evaluation setting, defined as an &ldquo, all in one glance&rdquo, strategy, which allows a faster and more effective interpretation of all the simultaneous parameters during the DISE procedure, improving the diagnostic accuracy, and providing a more accurate post-analysis, as well as legal and research advantages.

Background Growing evidence suggests that hyperhomocysteinemia (HHcy) constitutes a risk factor for Alzheimer’s Disease (AD). The impact of HHcy on cognitive functions has mainly been investigated using screening neuropsychological tests that provide general, unspecific measures of cognitive level. Since an association between HHcy and temporo-mesial atrophy has been documented, we predicted that a fine-grained analysis of neuropsychological performance should show stronger Hcy effects on memory scores than on other cognitive scores. Objective To determine the influence of Hcy level on cognitive profile evaluated with specific, sensitive neuropsychological tests in a wide AD cohort. Methods 323 patients with AD were enrolled in a cross-sectional study and underwent a neuropsychological examination exploring several cognitive domains (memory, language, visuoperception, visuospatial abilities, executive function, constructional praxis, ideomotor praxis). The effects of Hcy levels and other risk factors (including cholesterol, smoking habits, triglycerides, apoEe4 allele) were analysed. Results Generalized Linear Model detected a significant drop in performance with increasing Hcy in 6/19 measures of cognitive functions, namely, in memory performance tasks as well as in Luria’s motor planning test, with effect sizes ranging 1.4%–2.8% (Eta-squared), partialling out effects of other predictors. Conclusions HHcy was associated with poor performance in short and long-term spatial and verbal memory more than with other cognitive dysfunctions. These results support the hypothesis that medial temporal networks might be vulnerable to HHcy, consistently with data from neuroimaging studies suggesting a link in AD between temporal atrophy and HHcy; the effect on Luria’s motor planning task suggests further involvement of frontal structures.

Administration of inhaled corticosteroids (ICS) is one of the most controversial issues in the treatment of stable chronic obstructive pulmonary disease (COPD). Associations between these drugs and increased incidence of severe pneumonia and other respiratory infections have already been reported in literature, as well as effects on the immune system and on the lung microbiota. ICS vary in their pharmacodynamic and pharmacokinetic properties, despite being widely considered therapeutically similar. The use of ICS requires, therefore, a deep knowledge of their pharmacokinetics and pharmacodynamics to obtain the maximum benefit and the least side effects. Defining new phenotypes-endotypes of COPD may lead to novel pharmacological and therapeutic scenarios while define the correct indications for prescription of ICS. Titration is certainly an important means by which these objectives can be achieved.

Besides platinum-based chemotherapy, no established treatment option exists for advanced non-small-cell lung cancer (NSCLC) patients with EGFR exon 20 (Ex20ins) insertion mutations. We sought to determine the clinical outcome of patients with this EGFR mutation subtype in the immunotherapy era. Thirty NSCLCs with EGFR Ex20ins mutations were identified, of whom 15 had received immune checkpoint blockade (ICB) treatment as monotherapy (N = 12), in combination with chemotherapy (N = 2) or with another immunotherapeutic agent (N = 1). The response rate was observed in 1 out of 15 patients (6.7%), median progression-free survival (PFS) was 2.0 months and median overall survival (OS) was 5.3 months. A trend towards an inferior outcome in terms of PFS and OS was observed for patients receiving ICB treatment in the first versus second line setting (PFS: 1.6 months versus 2.7 months, respectively, p = 0.16—OS: 2.0 months versus 8.1 months, respectively, p = 0.09). Median OS from the time of diagnosis of advanced disease was shorter for patients treated with ICB versus those who did not receive immunotherapy (12.9 months versus 25.2 months, respectively, p = 0.08), which difference remained associated with a worse survival outcome at multivariate analysis (p = 0.04). Treatment with ICB is poorly effective in NSCLCs with EGFR Ex20ins mutations, especially when given in the first-line setting. This information is crucial in order to select the optimal treatment strategy for patients with this subtype of EGFR mutation.

To quantify the annual healthcare resource utilization, costs and mortality rate for a large cohort of Italian patients with compensated (CC) and decompensated cirrhosis (DC).A population-based cohort study was conducted through the data-linkage of mortality for all-cause, hospitalizations and outpatient drugs and service databases of the Campania Region. All adults hospitalized with cirrhosis diagnosis (2007-2015) were grouped in CC and DC (prevalent patients) on January 1, 2016 and followed for 1-year. Incident patients with DC (2015) were also retrieved and followed from discharge date up to 1-year. Negative binomial regression was used to estimate Incidence Rate Ratios (IRRs) for predictors of all-cause hospitalizations. Costs were evaluated from the Italian National Health Service perspective and expressed in euro patient/year.A total of 21,433 prevalent cirrhotic patients (57.1% CC and 42.9% DC) and 1,371 incident patients with DC were identified. During a 1-year, 21.5% of prevalent patients with CC were admitted for acute events, 26.8% of those with DC and 55.4% of incident patients with DC. Ascites (IRR=1.71;95% CI: 1.37-2.14) and hepatic encephalopathy (IRR=1.35; 95% CI: 1.04-1.77) at index admission were strong predictors of hospitalizations in incident DC patients. The 1-year mortality rate was respectively 5.8% and 10.1% for prevalent patients with CC and DC and 35.6% for incident patients with DC. Direct costs amounted to 3,194€ patient/year for the prevalent CC group and 4,001€ patient/year for the DC group and 13,806 € patient/year for incident individuals with DC.The burden of cirrhosis dramatically differs between CC and DC patients, especially after the first decompensation episode. Ascites and hepatic encephalopathy at index admission were strong predictors of hospitalizations in incident DC patients.

The Tower of London (ToL) test is traditionally used to assess strategical reasoning, problem-solving, and mental planning in clinical populations. Here, we provide the Italian standardization norms for the original, 12-problem version of the ToL test. The performance of 216 Italian individuals ranging 18 to 89 in age was scored in terms of both Time ( Speed) and Accuracy—the time, and the number of attempts, necessary to find a solution. We performed univariate analyses on separate Time and Accuracy scores, using Age in years, Education in years, and Sex (male vs. female) as predictors. z scores and equivalent scores were provided. Moreover, we performed a bivariate analysis for the assessment of individuals’ performance in terms of Time and Accuracy simultaneously. This standardization allows clinicians to use the original, most widespread version of ToL with the Italian population, thus optimizing comparability with other clinical and experimental research worldwide. Critically, this article offers a new statistical perspective on how Time and Accuracy scores, which are typically related to each other, can be combined to obtain a single, consistent clinical categorization that captures most of the information contained in the patient’s performance.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 1 is a 2019 novel coronavirus, which only in the European area has led to more than 300,000 cases with at least 21,000 deaths. This manuscript aims to speculate that the manipulation of the microbial patterns through the use of probiotics and dietary fibers consumption may contribute to reduce inflammation and strengthen the immune system response in COVID-19 infection.The reviews of this paper are available via the supplemental material section.

To analyze the middle latency auditory evoked potential index (MLAEPi), compared to the standard bispectral index (BIS), as a method for evaluating the sedation level in drug-induced sleep endoscopy (DISE). In this controlled clinical study on a sample of 99 obstructive sleep apnea (OSA) or snoring patients, we compared the MLAEPi with the BIS after propofol infusion during the standard DISE technique in order to define the MLAEPi values within the observational window of the procedure. The DISE procedure was divided into eight steps, and we collected both MLAEPi and BIS data values from the same patient in every step. The MLAEPi showed a faster response than the BIS after propofol infusion during DISE. Therefore, the clinical use of the MLAEPi in evaluating the sedation level seems to be a good alternative to the current technological standards.

The treatment of childhood obesity represents a greater challenge for pediatricians. To date, it is multidisciplinary, including behavioral, dietary, pharmacological, and surgical options. Given the limited efficacy of available treatments, scientific research on finding new solutions is very active. Several drugs comprising Metformin, Glucagon-like peptide- 1 receptor agonists, Naltrexone-bupropion, Phentermine-Topiramate, and Lorcaserin have been studied as pediatric antiobesity agents. Findings from clinical trials showed a modest but significant effect of these drugs on weight loss, but long-term studies are needed to better define their exact role. Bariatric surgery is also promising for extremely obese adolescents. Moreover, a novel approach to treat obesity might be represented by compounds inducing browning of white adipose tissue, a complex process involved in body energy homeostasis, but at present evidence in humans is lacking. We aimed to review the current knowledge regarding the available new options for pediatric obesity treatment.

Obstructive Sleep Apnea Syndrome (OSA) is characterized by snoring associated with repeated apnea and/or obstructive hypopnea. The nasal airways of OSA patients, measured via acoustic rhinometry, could be significantly narrower than healthy subjects and this reduced nasal structure can impair olfactory function. The relationship between nasal structure and olfactory function, assessed via behavioral test results, indicates that there is a high prevalence of nasal airflow problems. Based on these assumptions, the purpose of this study was to carry out an assessment of olfactory perception in OSA patients through the Chemosensory Event-Related Potentials (CSERP), investigating the N1 component and the Late Positive Component (LPC). Twelve OSA patients, non-smokers, were recruited in the Pulmonary Rehabilitation Unit, scored with the Epworth Sleepiness Scales, after Polygraphic Recording, Apnea Hypopnea Index and Body Mass Index evaluation. The control group consisted of twelve healthy controls, non-smokers, recruited as volunteers. Subjects, during an EEG recording, performed an oddball olfactory recognition task based on two scents: rose and eucalyptus. Main results highlighted differences in N1 and LPC between OSA and controls. OSA patients presented faster N1 latencies and greater amplitude. The same trend was found in LPC, where OSA showed decreased latency and increased amplitude during rose stimulation, in the right inferior frontal cortex. and faster latencies in left centroparietal cortex OERP results can suggest an impairment in endogenous components. This result could be the consequence of the exogenous perceptual difficulty highlighted in N1 component. The increased arousal could also be related to the respiratory activity involved during the olfactory task.

Unilateral neglect is usually investigated by adminstering stimuli (targets) in different positions, with targets being responded to by the patient (Hit) or omitted. In spite of this homogeneity of data type, neglect indices and diagnostic criteria vary considerably, causing inconsistencies in both clinical and experimental settings. We aimed at deriving a standard analysis which would apply to all tasks sharing this data form.A-priori theoretical reasoning demonstrated that the mean position of Hits in space (MPH) is an optimal index for correctly diagnosing and quantifying neglect. Crucially MPH eliminates the confounding effects of deficits that are different from neglect (non-lateral) but which decrease Hit rate. We ran a Monte Carlo study to assess MPH's (so far overlooked) statistical behavior as a function of numbers of targets and Hits.While average MPH was indeed insensitive to non-lateral deficits, MPH's variance (like that of all other neglect indices) increased dramatically with increasing non-lateral deficits. This instability would lead to alarmingly high false-positive rates (FPRs) when applying a classical diagnostic procedure that compares one patient with a control sample. We solved the problem by developing an equation that takes into account MPH instability and provides correct cut-offs and close-to-nominal FPRs, even without control subjects. We developed a computerized program which, given the raw data, yields the MPH, a z-score and a p-value.We provided a standard method that allows clinical and experimental neuropsychologists to diagnose and measure neglect in a consistent way across the vast majority of tasks.

Apnea notturna centrale da transitoria depressione ventilatoria polmonare e risposta chemo-recettoriale periferica causata da debolezza dei muscoli respiratori nei pazienti operati per l’apnea ostruttiva del sonno.

Obstructive sleep apnea (OSA) is the primary indication for tonsillectomy, one of the most common pediatric surgical procedures, commonly performed in association with adenoidectomy. The objective of this review article is to evaluate the role of the otorhinolaryngologist in pediatric OSA.A literature review has been performed on the following topics: peculiarities of sleep-disordered breathing in pediatric age; discrimination of sleep disorders; adenotonsillar hypertrophy; surgical techniques; adjuvant surgical procedures.The role of the otorhinolaryngologist in pediatric OSA is important for the evaluation of the upper airways and of essential biometric and polysomnographic data and for indication and execution of appropriate surgical treatment. In the majority of healthy children, adenotonsillectomy for OSA results in a dramatic improvement in respiratory parameters as measured by polysomnography. When post-surgical residual OSA occurs, it is essential to monitor patients by means of drug-induced sleep endoscopy (DISE).Otolaryngologic assessment is of paramount importance to correctly classify a child with OSA. Correct inspection of the upper airway and quantification of the quality of sleep through polysomnography lead to the right therapeutic choice. Knowledge of different surgical techniques helps to deal with residual OSA after studying the obstruction sites by drug-induced sedation endoscopy.

Hepatic encephalopathy (HE) describes a spectrum of potentially reversible neuropsychiatric changes observed in patients with hepatic dysfunction and/or portosystemic shunt. The aim of this study is to compare data from clinical trials and observational studies with Italian real-world (RW) data as for clinical outcomes; other aim is to evaluate economic burden of hepatic encephalopathy related to hospitalization for overt HE. The work is based on data from the Health Information Systems (SIS) of Marche Region, Italy (about 1.5 million patients) available for the period 2008-2014. 450 subjects were identified (62% men, mean age 68 years) with a first episode of overt HE (OHE) in the three-year period 2010-2012. The mortality in the index hospitalization was equal to 32.2%; the 2-year mortality rate for a specific cause was 24.3% while that for all cases was 33.1%. The proportion of patients discharged alive from the hospitalization index that in the following two years incurs in rehospitalization, correlated with OHE is on average 66.6%. These figures largely exceed those identified in clinical trials or observational studies. Assuming that the incidence of OHE cases observed in the Marche region is representative of the national one we could estimate a charge to the NHS equal to about € 200 million for hospital assistance in the first year from the OHE event.

This review paper aims to summarize the current state of knowledge on the role of the pneumologist in the diagnosis and respiratory treatment of children affected by obstructive Sleep Disordered Breathing (SDB).A literature review has been performed on the following topics: obstructive SDB and its clinical entities, indications for respiratory treatment of pediatric SDB, and Continuous Positive Airway Pressure (CPAP) and Noninvasive Positive Pressure Ventilation (NIPPV) treatment approach to obstructive SDB.OSDB is related to obesity, craniofacial pathologies, neuromuscular disorders and, most commonly, oadenotonsillar hypertrophy. Adenotonsillectomy is the first-choice treatment in children with obstructive apnea secondary to adenotonsillar hypertrophy. CPAP and NIPPV are recommended in cases where Obstructive Sleep Apnea (OSA) persists after surgery or when surgery is contraindicated. Treatment interventions are usually implemented gradually by separately addressing each abnormality that would predispose to obstructive SDB, then reevaluating after each intervention to detect any residual disease and to assess the need for additional treatment.Many pediatric patients continue to experience problems and symptoms such as hypersomnia and apnea after adenotonsillectomy and need CPAP/NIPPV treatment. Current knowledge is still incomplete, especially with regard to the mechanisms of pathogenesis of pediatric OSA, the factors affecting pediatric OSA, and the phenotypic variability of the disease. A better understanding of these aspects would contribute to the development of new therapies.

We propose STIMA, a short test for ideo-motor apraxia, allowing us to quantify the apraxic deficit according to action meaning and affected body segment. STIMA is based on a neurocognitive model holding that there are two processes involved in action imitation (i.e., a semantic route for recognizing and imitating known gestures, and a direct route for reproducing new gestures). The test allows to identify which imitative process has been selectively impaired by brain damage (direct vs. semantic route) and possible deficits depending on the body segment involved (hand/limb vs. hand/fingers). N = 111 healthy participants were administered with an imitation task in two separated blocks of known and new gestures. In each block, half of the gestures were performed mainly with the proximal part of the upper limb and the remaining half with the distal one. It resulted in 18 known gestures (nine proximal and nine distal) and 18 new gestures (nine proximal and nine distal) for a total of 36. Each gesture was presented up to a maximum of two times. Detailed criteria are used to assign the final imitation score. Cut offs, equivalent scores and main percentile scores were computed for each subscale. Participants imitated better known than new gestures, and proximal better than distal gestures. Age influenced performance on all subscales, while education only affected one subscale. STIMA is easy and quick to administer, and compared to previous tests, it offers important information for planning adequate rehabilitation programs based on the functional locus of the deficit.

Besides platinum-based chemotherapy, no established treatment option exists for advanced non-small-cell lung cancer (NSCLC) patients with EGFR exon 20 (Ex20ins) insertion mutations. We sought to determine the clinical outcome of patients with this EGFR mutation subtype in the immunotherapy era. Thirty NSCLCs with EGFR Ex20ins mutations were identified, of whom 15 had received immune checkpoint blockade (ICB) treatment as monotherapy (N = 12), in combination with chemotherapy (N = 2) or with another immunotherapeutic agent (N = 1). The response rate was observed in 1 out of 15 patients (6.7%), median progression-free survival (PFS) was 2.0 months and median overall survival (OS) was 5.3 months. A trend towards an inferior outcome in terms of PFS and OS was observed for patients receiving ICB treatment in the first versus second line setting (PFS: 1.6 months versus 2.7 months, respectively, p = 0.16—OS: 2.0 months versus 8.1 months, respectively, p = 0.09). Median OS from the time of diagnosis of advanced disease was shorter for patients treated with ICB versus those who did not receive immunotherapy (12.9 months versus 25.2 months, respectively, p = 0.08), which difference remained associated with a worse survival outcome at multivariate analysis (p = 0.04). Treatment with ICB is poorly effective in NSCLCs with EGFR Ex20ins mutations, especially when given in the first-line setting. This information is crucial in order to select the optimal treatment strategy for patients with this subtype of EGFR mutation.

Obstructive sleep apnoea (OSA) is characterized by repetitive interruptions of breathing, causing Chronic Intermittent Hypoxia (CIH) that can be involved in the development and progression of cardiovascular diseases. There is evidence showing a close relationship between OSA and atherosclerosis, even in patients who do not show co-morbidities such as hypertension, diabetes, high levels of lowdensity lipoprotein cholesterol (LDL-C), cigarette smoking and obesity, which can activate the endothelium. This endothelium activation due to CIH and specific to OSA seems to be dependent on a different pathway. The current first line therapy for OSA is the application of the continuous positive airway pressure (CPAP), but it alone is not enough to reduce cardiometabolic risk in patients with OSA. In contrast, statins, via their pleiotropic property, might be able to change inflammation and early atherosclerosis, lipid profile and cardiovascular outcomes in OSA. The role of statins in OSA patients with or without any co-morbidities could potentially prevent coronary vascular risk and stroke and in the future, represent an additional treatment option along with CPAP therapy. Strengthening the prevention strategies against atherosclerosis in OSA should be one of the focal aims for healthcare programs of the future.

A pediatric cognitive screening tool has been shaped in three versions according to school class to assess spatial and temporal orientation, language, reading, writing, drawing, number knowledge, memory, praxis and executive functions in children aged 6-13. It has been standardized on an Italian sample of 807 children. Raw scores were adjusted for critical variables (child's age and parents' education) and a cut-off for the resulting global cognitive score was made available for clinical practice. In line with previous research, adapting the Mini-Mental State Examination to pediatric neuropsychological assessment turned out to be useful in estimating global cognitive functioning in children.

BACKGROUND The non-classical HLA-class I molecule-g (HLA-G) gene shows a deletion/insertion (del/ins) polymorphism of a 14-base-pair sequence (14 bp) in the exon 8 at the 3' untranslated region. The presence of the 14 bp insertion allele has been associated to lower soluble HLA-G protein production, a protein with anti-inflammatory activities. So far, no studies have investigated the relationship between HLA-G 14 bp del/ins polymorphism and metabolic features of obese children and adolescents. We aimed to assess if the HLA-G ins/del polymorphism, and in particular the HLA-G ins/ins genotype determining lower sHLA-G production, is associated to insulin resistance (evaluated by homeostasis model assessment [HOMA]) in a population of obese children. METHODS We enrolled 574 obese children and adolescents. Anthropometric and laboratory data were collected. The white blood cell (WBC) count was evaluated as surrogate marker of inflammation. C-reactive protein (CRP) was available in 48 patients. HOMA was calculated. Patients were genotyped for the HLA-G del/ins polymorphism. RESULTS Subjects carrying the HLA-G ins/ins genotype, presented with higher HOMA, WBC and CRP values, compared to del/ins and del/del genotypes (P ≤ 0.0009, ≤0.02 and ≤0.0001, respectively). Comparison of the regression line slopes, performed for HOMA and WBC on the basis of HLA-G genotypes, showed that subjects carrying the HLA-G ins/ins genotype presented with a stronger correlation between HOMA and WBC, compared to the other genotypes (Model r2 3.13%, P ≤ 0.006). CONCLUSIONS We showed a strong association between HLA-G 14 bp ins/ins genotype and HOMA in obese children and adolescents. This association could be hypothetically modulated by subclinical inflammation.

Objectives We performed a cross-sectional study with the main aim of evaluating occupational exposure to polycyclic aromatic hydrocarbons (PAHs) in workers involved in the pavement construction of a new highway in Northern Italy, where modified bitumen was used as binder for Hot Mix Asphalt. Methods We applied a combined approach of air and biological monitoring. Both the aerosol and vapour phases of bitumen were collected applying the NIOSH 5506 method. The 16 PAHs listed as high priority by EPA were determined by HPLC-UV. End-of-shift urine samples were collected from 144 workers to determine 1-hydroxypyrene (1-OHP) and 2-naphthol (2-NAP) concentrations after enzyme digestion and HPLC-UV analysis. Socio-demographic and lifestyle information was collected by a questionnaire. Results Paving workers were actually exposed to PAHs, including carcinogenic compounds, that were measurable only in the aerosol phase. Higher exposure as well as dose levels were measured for the paver group. Biological monitoring confirmed that 1-OHP was less affected by smoking habits as compared to 2-NAP and showed a higher association with occupational exposure. Conclusion Carcinogenic PAH compounds were detectable only in the aerosol phase and this must be taken into account in the adoption of preventive measures. Biomonitoring supported the superiority of 1-OHP as compared to 2-NAP in assessing the internal dose in such workers.

Diverticular disease (DD) represent a wide variety of conditions associated with the presence of diverticula in the colon. The most serious form is an acute episode of diverticulitis which can lead to hospitalization and surgery with various types of consequences. The main aim of this study was to evaluate, from both cross-sectional and longitudinal perspective, the economic burden of diverticulitis in the real practice.A deterministic linkage was performed at individual user level between the different administrative sources of the Marche Region through anonymised ID number for a period of analysis between 1 January 2008 and 31 December 2014. We enrolled all patients with at least one hospitalization for "diverticulitis of the colon without mention of haemorrhage" (ICD-9-CM code 562.11) or "diverticulitis of the colon with haemorrhage" (ICD-9-CM code 562.13) as primary or secondary diagnosis. Cost and outcome were analysed considering transversally (for contemporaneous) and longitudinal (for cohort) perspective. Hospital mortality at one year after discharge was evaluated by mortality rates and Kaplan-Meier curve considering the surgery performed (or not performed) during the index hospitalization.Considering the cross-sectional perspective, 427 patients per year were estimated (about 35 patients per 100,000 adult residents) with an average number of hospitalization equal to 1.14. The direct healthcare costs incurred by the Marche region for episodes of diverticulitis in 2008-2014 amounted to approximately € 11.4 million (€ 1.6 million a year), of which € 10.9 million (95.5%) for the hospitalizations, € 246,000 (2.1%) for pharmaceutical treatment and € 270,000 (2.4%) for specialist outpatient services. The cohort analysis estimates an intra-hospital mortality rate equal to 5.9 per 100 patients' year (5.5 for non-surgery patients and 8.9 for surgery patients - P0.05). Kaplan-Meier curve demonstrate that there were no differences between intra-hospital mortality due to surgery during index hospitalization.Our study is the first analysis in Italy to use real-world data to measure the burden of DD with a cross-sectional and longitudinal perspective. This study could be useful for decision maker that could quantify the economic and epidemiological burden of DD in hospital.

Obstructive sleep apnea syndrome (OSAS) is an independent and modifiable risk factor for cardiovascular diseases; however, the pathophysiological mechanisms underlying this association are not yet fully understood. Intermittent hypoxemia, one of the physiological markers of OSAS, is characterized by transient periods of oxygen desaturation followed by reoxygenation. The hypoxia-reoxygenation cycles are associated with oxidative stress that, in turn, triggers the activation of pathways that lead to cardiovascular damage. The results of several studies show that OSAS causes oxidative stress and that nasal continuous positive airway pressure therapy normalizes these biological abnormalities. In conclusion, treatment of OSAS with continuous positive airway pressure may lower cardiovascular risk by reducing sympathetic nerve activity, ambulatory blood pressure and arterial stiffness, and by increasing sensitivity of the arterial baroreflex. Newer modalities such as C-Flex and A-Flex also show promise as treatment options in the future. However, the evidence supporting the use of these alternative modalities remains scant, in particular with regards to long-term cardiovascular outcomes.

The increasing prevalence of type 2 diabetes has highlighted the importance of evidence-based guidelines for effective prevention, management and treatment. Diabetes self-management education (SME) produces positive effects on patient behaviours and health status. We analyzed the literature to identify (i) the level of integration between usual care and SME programs and (ii) any possible differences across them in terms of outcomes. Searches were made on three databases - PubMed, Scopus and Web of Science - to identify relevant publications on diabetes SME to 2015, which also describe the provider of usual care. In total, 49 studies met the inclusion criteria. We identified three levels of integration (high, medium and low) between usual care and SME programs based on the level of involvement of usual care professionals within the SME programs. In most cases, the primary care physician was responsible for the diabetes patients. Patient health behaviors and/or outcomes improve in most of the studies, independently from the level of integration. However, findings suggest that when patients/participants could perceive that usual care provider is highly involved in SME delivery, educational programs produced results that appear to be more positive.

INTRODUCTION:\ud Diverticular disease (DD), a herniation of the colonic mucosa through the muscle layer, covers a wide variety of conditions associated with the presence of diverticula in the colon. The most serious form is an acute episode of diverticulitis, which can lead to hospitalization and surgery with various types of consequences. The main aim of this study is to evaluate the economic burden of hospitalizations arising from acute episodes of diverticulitis using data from the administrative databases used in the Marche region in Italy and, as a secondary objective of this real-world data analysis, to study patient outcome variables following initial hospitalization for diverticulitis.\ud \ud METHOD:\ud A deterministic linkage was performed at individual user level between the different administrative sources of the Marche region through anonymous ID number for a period of analysis between 1 January, 2008 and 31 December, 2014. We enrolled all patients with at least one hospitalization for "diverticulitis of the colon without mention of haemorrhage" (ICD-9-CM code 562.11) or "diverticulitis of the colon with haemorrhage" (ICD-9-CM code 562.13) as primary or secondary diagnosis. For each patient we assessed the cost of hospitalization, of medicines and of specialist services considering a time-scale of one year or cohort analysis 365days after first admission.\ud \ud RESULTS:\ud The total number of residents in the Marche region who had at least one hospitalization for diverticulitis in the period 2008-2014 was 2987 (427 patients a year, corresponding to about 35 patients per 100,000 adult residents); the total number of admissions was 3453 (just over 490 a year). The direct healthcare costs incurred by the Marche region for episodes of diverticulitis in 2008-2014 amounted to approximately €11.4 million (€1.6 million a year), of which €10.9 million (95.5%) for the hospitalizations, € 246,000 (2.1%) for pharmaceutical treatment and €270,000 (2.4%) for specialist outpatient services. The average annual cost per patient was €3826, of which €3653 was for hospitalization, while pharmaceutical expenditure and specialist services accounted for €83 and €90, respectively. The cohort of patients undergoing a first admission for diverticulitis between 2010 and 2013 was made up of 1729 people (54.4% women, mean age 68.9 years), of whom 1500 (86.8%) did not undergo surgery while in hospital. Hospital mortality, recorded only for the over-65 age class, averaged 1.2%; for patients not receiving surgery during the initial hospitalization it was 0.5%, reaching 5.2% in patients undergoing surgery. The percentage of patients with one or more readmissions for diverticulitis within a year of the first was on average 7.8% and in 48% of cases this resulted in surgery.\ud \ud CONCLUSIONS:\ud Our study is the first analysis in Italy to use real-world data to measure the financial impact of diverticular disease. Assuming that the diagnostic and therapeutic behaviour identified in the Marche region could be representative of the situation nationwide, the estimated annual number of hospitalizations in Italy for acute episodes of diverticulitis is 19,000. The total amount of economic resources needed to treat patients suffering from acute episodes of diverticulitis is estimated at €63.5 million a year.

Objectives: To estimate the frequency of prolonged grief disorder (PGD) in 90 primary caregivers of patients with dementia who live in the community dwelling in Milan and to identify the relationship between grief intensity (GI) and other caregiver variables; another aim was to clarify the role of the objective cognitive and functional impairment of the patients and the level of deterioration perceived by caregivers. Design: Cross-sectional study. Results: In all, 16.7% of caregivers had PGD. Caregiver variables increasing GI and the risk of developing PGD were burden, anxiety, and some sociodemographic features. The objective level of patient’s deterioration was irrelevant for PGD probability/GI, while the deterioration level perceived by the caregiver increased PGD probability and GI. Conclusions: Caregivers of patients with dementia may experience grief symptoms that are associated with low educational level, high level of burden and anxiety, and high perceived deterioration of their demented relatives’ cognitive and functional abilities.

Amyotrophic Lateral Sclerosis (ALS) is a motor neuron disease characterized by the progressive atrophy of both the first and the second motor neurons. Although the cognitive profile of ALS patients has already been defined by the occurrence of language dysfunctions and frontal deficit symptoms, it is less clear whether the degeneration of upper and lower motor neurons affects motor imagery abilities. Here, we directly investigated motor imagery in ALS patients by means of an established task that allows to examine the presence of the effects of the biomechanical constraints. Twenty-three ALS patients and 23 neurologically unimpaired participants have been administered with the (1) hand laterality task (HLT) in which participants were asked to judge the laterality of a rotated hand and the (2) mirror letter discrimination task (MLD) in which participants were asked to judge whether a rotated alphanumeric character was in its canonical or mirror-reversed form (i.e. control task). Results show that patients present the same pattern of performance as unimpaired participants at the MLD, while at the HLT, they present only partially with the effects of biomechanical constraints. Taken together, our findings provide evidences that motor imagery abilities, related to the mental simulation of an action, are affected by this progressive disease.

Patients with type 2 diabetes (T2D) have disease-associated changes in B-cell function, but the role these changes play in disease pathogenesis is not well established. Data herein show B cells from obese mice produce a proinflammatory cytokine profile compared with B cells from lean mice. Complementary in vivo studies show that obese B cell–null mice have decreased systemic inflammation, inflammatory B- and T-cell cytokines, adipose tissue inflammation, and insulin resistance (IR) compared with obese WT mice. Reduced inflammation in obese/insulin resistant B cell–null mice associates with an increased percentage of anti-inflammatory regulatory T cells (Tregs). This increase contrasts with the sharply decreased percentage of Tregs in obese compared with lean WT mice and suggests that B cells may be critical regulators of T-cell functions previously shown to play important roles in IR. We demonstrate that B cells from T2D (but not non-T2D) subjects support proinflammatory T-cell function in obesity/T2D through contact-dependent mechanisms. In contrast, human monocytes increase proinflammatory T-cell cytokines in both T2D and non-T2D analyses. These data support the conclusion that B cells are critical regulators of inflammation in T2D due to their direct ability to promote proinflammatory T-cell function and secrete a proinflammatory cytokine profile. Thus, B cells are potential therapeutic targets for T2D.

Obstructive sleep apnoea (OSAS) is an underdiagnosed chronic disease with a high prevalence in adults. It is becoming a significant social problem, since it is associated with a worsening in quality of life and increase in mortality. The cost-effectiveness ratio of diagnostic and therapeutic management of OSAS is a strategic issue to counteract the expected increasing demand of objective testing. OSAS patients with any clinical evidence of comorbidities must be studied using simplified and less expensive systems such as Home Sleep Testing (HST). On the other hand, Sleep Laboratory Polysomnography (PSG) is the gold standard to manage OSAS patients with comorbidities. It should be pointed out that the use of HST can lead to incorrect diagnosis in poorly selected OSAS subjects. This short review discusses various topics for the proper diagnosis and treatment of OSAS in view of epidemiological factors and results in terms of costs and social benefit of the disease. Whatever the strategy chosen and/or the organisational model adopted for managing OSAS, it cannot and should not take into account only cost-effectiveness. Long-term prospective studies evaluating cost-effectiveness ratios and outcomes of OSAS treatment of hospital management models versus home care models are needed.L’apnea ostruttiva del sonno (OSAS) è una malattia cronica eccessivamente sotto-diagnosticata con un’alta prevalenza negli adulti. L’OSAS sta diventando un problema sociale significativo perché associata ad un peggioramento della qualità della vita ed un aumento della mortalità. Il rapporto costo-efficacia nella gestione diagnostica e terapeutica dell’OSAS è un problema strategico per contrastare la crescente domanda di test oggettivi. I pazienti OSAS che non presentano comorbilità clinicamente evidenti devono essere studiati utilizzando un sistema semplificato e poco costoso, come l’Home Sleep Testing (HST). Al contrario, la Sleep Laboratory Polisomnography (PSG) rimane il gold standard per la gestione dei pazienti con OSAS in presenza di comorbidità. Occorre sottolineare che l’uso di HST potrebbe portare ad una diagnosi errata in soggetti OSAS non ben selezionati. Questa breve rassegna si propone di offrire argomenti di riflessione sulla corretta diagnosi e trattamento dell’OSAS, in rapporto ai dati di prevalenza e alle ricadute sui costi/benefici sociali della malattia. Attualmente non può essere solo il rapporto costo/efficacia a definire il modello organizzativo adottato per la gestione dell’OSAS, in quanto si rendono necessari ulteriori studi prospettici a lungo termine, volti a validare in maniera definitiva tale rapporto nonché il confronto tra il trattamento con modelli di gestione ospedaliera versus l’assistenza domiciliare.

Neuropsychological assessment is critical in both diagnosis and prognosis of patients with epilepsy. Beyond electrophysiological and anatomical alterations, other factors including different ethnic-cultural and linguistic backgrounds might affect neuropsychological performance. Only a few studies considered migration and acculturation effects and they typically concerned nonclinical samples. The current study aimed at investigating the influence of ethnic background and time spent in Italy on a full neuropsychological battery administered to both Italian and foreign-born patients and at providing a brief interview for obtaining relevant information on each patient's transcultural and language-related history. Clinical reports from 43 foreign-born patients with drug-resistant epilepsy were collected from the archives of Milan Niguarda Hospital. Epileptogenic zone, age, education, profession, illness duration, seizure frequency, handedness, and gender were considered in selecting 43 Italian controls. Ethnicity (Italian/foreign-born) and years spent in Italy were analyzed as main predictors on 21 neuropsychological scales by means of General(ized) Linear Models. An additional analysis studied two composite scores of overall verbal and nonverbal abilities. Ethnicity significantly affected the following: the verbal overall score, Verbal Fluency, Naming, Token-test, Digit Span, Attentional Matrices, Trail-Making-Test, Line-Orientation-Test, and Raven matrices; no effects were found on the nonverbal overall score, Word Pairs Learning, Episodic Memory, reading accuracy, visual span, Bells test, Rey Figure, and face memory and recognition. No significant effects of years spent in Italy emerged. While years spent in Italy does not predict neuropsychological performance, linguistic background had a strong impact on it. With respect to Italian-speaking patients, those who were foreign-born showed large task-related variability, with an especially low performance on language-related tests. Hence, language tests should not be considered as valid measures of neuropsychological impairment in this population, not even in foreign-born patients with good Italian fluency. Clinicians should consider such asymmetries in order to improve the accuracy of neuropsychological assessment of foreign-born patients.

The Milner Landmark Task allows the disentanglement of perceptual and response-related components of unilateral neglect. If these two components reflect separate functional systems, then cases should be observed in which the two components evolve differently across time. To test this hypothesis we surveyed a continuous series of 21 right hemisphere stroke patients. Five patients from the sample were affected by unilateral neglect at the outset and could be submitted to repeated administrations of the Landmark task in the first weeks post stroke. Two versions of the task were used, Landmark-Manual and Landmark-Verbal, differing in the type of response required. Two patients showed independent changes in the perceptual and the response-related component of neglect, hence confirming the view of separate functional systems underlying them. Dissociations between the task versions were found, witnessing a role of the type of response. Unexpectedly, one patient showed an initial leftward deviation of the subjective midpoint of the stimulus line, which later reversed to a classical rightward deviation. We interpreted such a pattern in terms of co-existing "productive" and "negative" components of perceptual neglect.

OBJECTIVE: Recent studies in patients with Hirschsprung's disease (HD) suggest that morphological abnormalities of the intramural intestinal plexuses are not restricted to the colon. In this report, symptoms and objective tests of gastrointestinal (GI) motor dysfunction were determined long after operative treatment to see whether evidence of a more widespread and relevant motility disturbance could be detected. METHODS: Twenty-one children were available for study an average of 6.6 yr after surgery for HD. All of these patients underwent evaluation of bowel frequency per week, total GI transit time (TGTT), and a scintigraphic gastric emptying test using solid food; anorectal manometry and segmental colonic transit times were performed in a subset of patients. Results were compared with findings in appropriately matched controls. RESULTS: Frequency of defecation per week in patients with HD after surgery was not different from that in control children, but TGTT was significantly longer (p < 0.01). Percentage retention of gastric isotope at 60 min exceeded the normal range in 12 of 21 (57.1%) patients, and colonic transit was abnormal in all six children studied. Symptoms persisted in two-thirds of patients postoperatively, and transit abnormalities were more common in the symptomatic subset (p = 0.026). CONCLUSIONS: Our data show that, in a subset of patients with HD, GI motor dysfunction persists long after surgical correction. The heterogeny of basic defects responsible for HD could provide the substrate for these motor abnormalities that, in turn, seem at least partially responsible for continuation of the symptomatic state.

Neglect patients' performance during cancellation tasks is characterized by left sided omissions and, in many cases, by the production of inappropriate material of various kinds in the ipsilesional space, e.g. additional marks over already cancelled targets, marks drawn away from targets, scribbles, irrelevant drawings. It is unclear whether these behaviours, which have collectively been called perseverative, are functionally and anatomically connected and whether they correlate with the severity of neglect. Here we report a retrospective study on 33 right brain damaged patients with neglect after right hemisphere lesions in whom we measured the intensity of perseveration of the three following kinds: (1) 'additional marks' (AM) perseveration where patients cancelled a target with two or more well separated marks; (2) 'scribble' perseveration, where patients, instead of cancelling the target with a single pen stroke as required by the task, performed multiple pen strokes without breaking the pen-to-paper contact, with the final product being a scribble; (3) 'flying marks' (FM) perseveration where patients produced cancellation marks well away from the targets. We found that AM and FM perseveration correlated with neglect severity, while 'scribble' perseveration did not. The lesion-symptom mapping showed three separate anatomical areas in the right hemisphere: 'scribble' perseveration was associated with lesions of the orbitofrontal cortex and caudate nucleus; AM perseveration was associated with damage to the rolandic operculum, superior temporal gyrus and inferior frontal gyrus; FM perseveration was associated with damage to the dorsal premotor cortex and the temporal pole. Neglect severity followed damage to a region which grossly corresponds to the sum of the regions associated with AM and FM perseveration respectively. This complex behavioural and anatomical pattern is interpreted in terms of a three-factor model, in which AM perseveration is caused by a deficit of disengagement of attention from the right side (also causing omissions), FM perseveration is caused by directional hypokinesia (also causing left-side omissions), and 'scribble' perseveration is the consequence of a failure to inhibit an initiated motor act, which is completely separate (both anatomically and functionally) from the disorder inducing omissions. © 2013 Elsevier Ltd.

Obstructive sleep apnea syndrome (OSAS) is a highly prevalent sleep disorder associated with severe cardiovascular events, morbidity and mortality. Recent evidence has highlighted OSAS as an independent risk factor for an excessive platelet activation and arterial thrombosis, but the underlying mechanisms have not yet been determined. Studies in cell culture and animal models have significantly increased our understanding of the mechanisms of inflammation in OSAS. Hypoxia is a critical pathophysiological element that leads to an intense sympathetic activity, in association with systemic inflammation, oxidative stress and procoagulant activity. While platelet dysfunction and/or hypercoagulability play an important role in the pathogenesis of vascular disease, there are limited studies on the potential role of blood viscosity in the development of vascular disease in OSAS. Further studies are required to determine the precise role of hypercoagulability in the cardiovascular pathogenesis of OSAS, particularly its interaction with oxidative stress, thrombotic tendency and endothelial dysfunction. Nasal continuous positive airway pressure (nCPAP), the gold standard treatment for OSAS, not only significantly reduced apnea-hypopnoea indices but also markers of hypercoagulability, thus representing a potential mechanisms by which CPAP reduces the rate of cardiovascular morbidity and mortality in OSAS patients.

Rationale.The gold standard for the diagnosis of Obstructive Sleep Apnea (OSA) is polysomnography, whose access is however reduced by costs and limited availability, so that additional diagnostic tests are needed.Objectives.To analyze the diagnostic accuracy of the Obstructive Airway Adult Test (OAAT) compared to polysomnography for the diagnosis of OSA in adult patients.Methods.Ninety patients affected by OSA verified with polysomnography (AHI ≥ 5) and ten healthy patients, randomly selected, were included and all were interviewed by one blind examiner with OAAT questions.Measurements and Main Results.The Spearman rho, evaluated to measure the correlation between OAAT and polysomnography, was 0.72 (p<0.01). The area under the ROC curve (95% CI) was the parameter to evaluate the accuracy of the OAAT: it was 0.91 (0.81–1.00) for the diagnosis of OSA (AHI ≥ 5), 0.90 (0.82–0.98) for moderate OSA (AHI ≥ 15), and 0.84 (0.76–0.92) for severe OSA (AHI ≥ 30).Conclusions.The OAAT has shown a high correlation with polysomnography and also a high diagnostic accuracy for the diagnosis of OSA. It has also been shown to be able to discriminate among the different degrees of severity of OSA. Additional large studies aiming to validate this questionnaire as a screening or diagnostic test are needed.

In this study, a series of tests exploring long-term verbal memory (the Short Story Test), attention (a modified version of Attentional Matrices and the Trail Making Test) and frontal functions (a modified version of the Frontal Assessment Battery) have been standardised on an Italian population of 283 children aged 5-14. Raw scores for each test have been adjusted for a series of variables (child's age, years of parents' education, handedness, gender) and transformed in equivalent scores enabling direct comparison across measures. This study was promoted by LICE (the Italian League Against Epilepsy) in order to provide Italian instruments standardised on the developmental age population and to study some of the most frequently impaired cognitive functions in epilepsy.

We describe an infant with juvenile chronic myelogenous leukemia (JCML), the diagnosis of which was made by the characteristic clinical and hematologic findings. The absence of a related HLA-compatible donor for bone marrow transplantation coupled with the awareness that chemotherapy is usually ineffective prompted our decision to treat the patient with lymphoblastoid interferon-alpha [alpha(Ly)-IFN]. During the 26-month course of treatment with alpha(Ly)-IFN an incomplete regression of hematologic and clinical findings was achieved. The above results, along with the easy administration and absence of considerable side effects, suggest that alpha(Ly)-IFN may be a useful therapeutic tool in patients affected by JCML awaiting bone marrow transplantation.

Twelve children with developmental dyslexia underwent a four-month treatment with tachistoscopic presentation of words, according to Bakker's methodology. One group received standard lateral presentation of words on a PC screen, while the other group received the same stimuli in random lateral position. The spatial distribution of visual attention was measured by means of the Form-Resolving Field (FRF; ), which was administered along with reading tests, before and after treatment. The FRF of children who received random presentation widened at -12.5 degrees on the left side, while the FRF in the group that received standard lateral presentation narrowed at that position. Both groups significantly improved in reading accuracy for both words and nonwords. Some hypotheses are proposed concerning the mechanisms responsible for the changes in the FRF and their correlation with improvements in word and nonword reading. The results of the present study are also compared with data suggesting a left "minineglect" in dyslexia.

We performed limiting dilution culture of T cells from a patient affected by primary immunodeficiency as a result of complete lack of adenosine deaminase (ADA) activity and also affected by insulin-dependent diabetes mellitus (type I diabetes). Despite the occurrence of immunodeficiency, we were able to raise and grow T cell clones derived from this patient in long-term culture. These T cells displayed ADA enzymatic activity and produced interleukin-2 after engagement of their T cell receptor (TCR)/CD3 complex. We analyzed the TCR repertoire of such clones by nucleotide sequencing of TCR β chains. The results show that the T cell clones express different Vβ but similar J regions. However, the CDR3 regions which are implicated in antigen recognition were found to be heterogeneous.

Estrogen (E) deficiency leads to an expansion of the pool of tumor necrosis factor (TNF)-producing T cells through an IFN-γ-dependent pathway that results in increased levels of the osteoclastogenic cytokine TNF in the bone marrow. Disregulated IFN-γ production is instrumental for the bone loss induced by ovariectomy (ovx), but the responsible mechanism is unknown. We now show that mice with T cell-specific blockade of type β transforming growth factor (TGFβ) signaling are completely insensitive to the bone-sparing effect of E. This phenotype results from a failure of E to repress IFN-γ production, which, in turn, leads to increased T cell activation and T cell TNF production. Furthermore, ovx blunts TGFβ levels in the bone marrow, and overexpression of TGFβin vivoprevents ovx-induced bone loss. These findings demonstrate that E prevents bone loss through a TGFβ-dependent mechanism, and that TGFβ signaling in T cells preserves bone homeostasis by blunting T cell activation. Thus, stimulation of TGFβ production in the bone marrow is a critical “upstream” mechanism by which E prevents bone loss, and enhancement of TGFβ levelsin vivomay constitute a previously undescribed therapeutic approach for preventing bone loss.

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.