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Objective: To verify whether growth hormone receptor (GHR) gene expression plays a role in growth of children with cystic fibrosis (CF), as a consequence of the chronic inflammatory condition and malnutrition., Design: We enrolled 49 prepubertal patients (24 males and 25 females) affected by CF in a stable clinical condition, 19 of whom had been diagnosed through newborn screening and 30 following presentation of symptoms. Patients had no significant comorbidity affecting growth or cystic fibrosis transmembrane conductance regulator (CFTR)-related diabetes requiring insulin therapy. Blood was collected during two follow-up visits to measure insulin-like growth factor (IGF-I), growth hormone-binding protein (GHBP), and GHR gene expression. Recruited as a control group were 52 healthy children, sex- and age-matched, were recruited as a control group., Methods: We compared body mass index (BMI), height, weight, IGF-I, GHBP, and GHR gene expression values (evaluated by Chemiluminescent Immunometric assay; ELISA and real-time PCR, respectively) in CF patients diagnosed through newborn screening (NBS) or by symptoms (late diagnosis [LD]) and in healthy controls., Results: BMI increased significantly in patients between the time of diagnosis and check-up ( P <0.001), particularly in the LD group; median value was lower at diagnosis and significantly higher ( P <0.001) at follow-up visits compared to controls. At initial evaluation, higher levels of IGF-I (not statistically significant) were found in both the NBS group and the LD group compared to the control group. At the second evaluation, significantly higher levels of IGF-I ( P =0.003) were found in both the NBS and LD groups compared to controls; GHR mRNA expression had significantly increased ( P =0.013) in LD patients compared with the first evaluation and was significantly higher in the NBS and LD groups than in controls. GHBP values had significantly increased ( P =0.047) in the NBS group after one year of therapy compared to first visit levels and were significantly higher ( P <0,0001) in the NBS and LD groups compared to controls., Conclusion: In our LD patients during childhood, we observed good auxological values and a GH/IGF-I axis function within normal range for the factor evaluated. However, earlier diagnosis through NBS might further minimize and prevent growth retardation, by reducing the duration of symptoms before treatment., (© 2019 Marshfield Clinic.)

Introduction: On the 27th of October 2017 the National Center for Rare Diseases of the Italian National Health Institute (NHI), clinicians of the Italian National Referral and Support Centres for Cystic Fibrosis, Paediatric Hospital "Bambino Gesù", Italian Cystic Fibrosis Society, and the Italian League for Cystic Fibrosis renewed the agreement about FC data flow for a 3 years period. The possibility to access data by third parties is among the most important new introduced within the agreement., Objectives: Aim of the present report is to improve the know-how on cystic fibrosis (CF) through a better characterization of Italian patients. Furthermore, the present Report aims at improving the care of CF patient. In particular, the Report should contribute to the following objectives: * to analize medium- and long-term clinical and epidemiological trends of the disesase; * to identify the main health care needs at regional and national level in order to contribute to the healthcare programmes and to the distribution of resources; * to compare Italian data with international ones., Design: Analyses and results described in the present Report are referred to patients in charge to the Italian National Referral and Support Centers for Cystic Fibrosis in the period 2015-2016. Data were sent by Centres by means of a specific software (Camilla, Ibis Informatica). Data underwent to a double quality control (QC): the first by NHI and the second at a European level (before the inclusion of the italian data within the European Cystic Fibrosis Registry). These QCs assure the completeness and the accuracy of data as well as their consistency with European core data. Finally, in 2017, an additional CQ was performed to further reduce the number of missing data and consequently improve the precision and the consistency in the nomenclature adopted for genetic mutations., Setting and Participants: A total of 29 different CF Centres (referral, support, and Paediatric Hospital "Bambino Gesù") sent their data referred to 2015-2016 years to ICFR . Data regarding Sardinia (Southern Italy) are missing and those from Treviso (Veneto Region, Northern Italy) and Rovereto (Trentino-Alto Adige Region, Northern Italy) are sent through Verona CF Centre., Results: The present Report has been organized into 10 sections. 1. Demography: estimated CF patients is 5,204 in 2015 and 5,362 in 2016; median age is 20.6 and 21.0, respectively. Prevalence is 8.6/100,000 residents in Italy in 2015 and 8.8 in 2016. Male percentage is 51.6% on average for 2015 and 2016; CF distribution showed higher frequency in patients aged from 7 to 35 years. The mean of patients aged more than 18 years is 56.5% on average in 2015 and 2016. 2. Diagnoses: most of the CF patients were diagnosed before 2 years of age (median value: 68%); a significant percentage of patients (median value: 13%) was diagnosed in adult age. 3. New diagnoses: new diagnoses were 169 in 2015 and 153 in 2016. Estimated incidence in 2015 was 1/4,176 living births in 2015 and 1/5,510 in 2016. 4. Genetics: 99.5% of patients underwent genetic analyses and in 96% of patients a mutation in Cystic Fibrosis Transmembrane Regulator (CFTR) gene was identified. [delta]508F was the most frequent mutation (44,7% in 2016). Furthermore, 16.0% and 3.4% of patients was characterized by the presence of at least one "residual function" mutation and gating, respectively. Finally, 21% of patients was a stop codons (class 1 mutation) carrier. 5. Lung function: FEV1 (forced expiratory volume in the first second) scores progressively decreased before adult age, in accordance with the natural history of the disease. FEV1% values in patients between 6 and 17 years of age is ≥70%; patients with a FEV1% value of 40% are less than 2% in the period 2015-2016. 6. Nutrition: most critical periods are during the first 6 months of life and during adolescence. Prevalence of malnourished male aged 12-17 years is constant in 2015-2016 and is always more than the prevalence observed in female. An increasing percentage of female patient with a suboptimal BMI value (35.5%) is observed among patients aged more than 18 years 7., Complications: it was estimated that, in 2016, hepatopathies without cirrhosis (17.7%) is the principal complications in patients aged less than 18 years; in patients aged more than 18 years the principal complication was due to hepatopathies without cirrhosis (29.5%) and diabetes (23.3%). 8. Transplantation: in 2015-2016, 74 patients were bipulmunary transplanted; age was comprised between 8 and 52 years, median age at transplantation was 29,6 years. Median waiting times for transplantation is estimated in 17 months (24 months in 2015 and 14 months in 2016). 9. Microbiology: analyses were referred to test performed in 2016. Percentage of adult patients with chronic Pseudomonas aeruginosa infection is 52.1% compared to 15.2% of paediatric patients; Staphylococcus aureus infection is present in 53.2% of adult patients and 52.8% of paediatric ones; Burkholderia Cepacia complex is present almost exclusively in adult patients (4.3%); Nontuberculous mycobacteria is present in 1.2% and 0.4% of adult and paediatric patients, respectively; Stenotrophomonas maltophilia infection is present in the 6.1% of adult patients and 4.9 of paediatric patients. 10. Mortality: 102 patients (49 males and 53 females; median age 36.9 years in 2015 and 36.5 in 2016) died in 2015-2016 (transplanted patients are not included)., Conclusions: The present Report shows that Italian CF population is growing (median age) and paediatric mortality is decreasing. A very low percentage of paediatric population is characterized by complication of pulmonary function; adult patients are characterized by an increase of age at death (more than 36 years of age in 2016).

Aspergillus is the causative agent of human diseases ranging from asthma to invasive infection. Genetic and environmental factors are crucial in regulating the interaction between the host and Aspergillus . The role played by the enzyme indoleamine 2,3-dioxygenase 1 (IDO1), which catalyzes the first and rate-limiting step of tryptophan catabolism along the kynurenine pathway, is increasingly being recognized, but whether and how genetic variation of IDO1 influences the risk of aspergillosis in susceptible patients is incompletely understood. In addition, whether the closely related protein IDO2 plays a similar role remains unexplored. In the present study, we performed genetic association studies in two different cohorts of susceptible patients [cystic fibrosis (CF) patients and recipients of hematopoietic stem cell transplantation (HSCT)], and identified IDO1 polymorphisms that associate with the risk of infection in both cohorts. By using human bronchial epithelial cells and PBMC from CF and HSCT patients, respectively, we could show that the IDO1 polymorphisms appeared to down-modulate IDO1 expression and function in response to IFNγ or Aspergillus conidia, and to associate with an increased inflammatory response. In contrast, IDO2 polymorphisms, including variants known to profoundly affect protein expression and function, were differently associated with the risk of aspergillosis in the two cohorts of patients as no association was found in CF patients as opposed to recipients of HSCT. By resorting to a murine model of bone marrow transplantation, we could show that the absence of IDO2 more severely affected fungal burden and lung pathology upon infection with Aspergillus as compared to IDO1, and this effect appeared to be linked to a deficit in the antifungal effector phagocytic activity. Thus, our study confirms and extends the role of IDO1 in the response to Aspergillus , and shed light on the possible involvement of IDO2 in specific clinical settings.

The aim of this report is to assess whether the research issues priorities are perceived differently according to the Stakeholders (SH)'s individual knowledge of research topics and degree of training in biomedical research. Four groups of SH were enrolled in this study: 1. Skilled SH, specifically trained in biomedicine; 2. Unskilled untrained SH who responded to a written questionnaire in 2015; 3. SH who were trained for one year in a course delivered by professionals; 4. Untrained SH who responded to an online questionnaire in 2017. The large ranking order variability observed among groups addresses the question that the choices are markedly influenced by the SH's backgrounds. Such results emphasize the need to consider the education level and the delivery of ad hoc training activities by professionals to broaden the base of SH who may be considered qualified to transfer the Patient Centered Outcome Research principles into practice., (Copyright © 2018 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

The corneal limbus is a privileged region on the border between two quite different microenvironments, where corneal epithelial stem cells, numerous melanocytes, and antigen-presenting cells are all concentrated within a richly vascularized and innervated stroma. This situation within the ocular surface confers on it the key functions of barrier, epithelial renewal and defense of the cornea. As an immunological crossroads and since the corneoscleral limbus is directly exposed to external insults such as caustic agents, ultraviolet radiation, microbial agents, and allergens, it is the potential site of many tumoral, degenerative or inflammatory pathologies and may progress under certain conditions to limbal stem cell deficiency., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Background: CFTR mutations permitting residual function (RF) of the CFTR protein are disease-causing. These mutations are associated with a pneumopathy that is delayed in onset and is slower in progression than are more common forms of cystic fibrosis (CF), although the disease may become severe in some patients. RF mutations are among the most frequent in Italy, thus encouraging investigation of their prevalence and associated phenotypes., Methods: Data from the Italian Registry were used to compare patients with at least one RF mutation with those homozygous for F508del., Results: A total of 806 patients bearing at least one RF mutation were identified among 5204 registered patients (15.5%). The RF patients were older than the F508del homozygotes (median age 26.0 years vs 19.8 years, respectively), with a higher median age at diagnosis (6.3 years vs 0.2 years, respectively) and a lower median sweat chloride value (76.0 mmol/L vs 100.0 mmol/L, respectively). In the RF group, lung infections and comorbidities were less prevalent than those in the F508del homozygotes, while better FEV 1 and nutritional status were observed at all ages. Within the RF group, RF/F508del subjects showed more severe pneumopathy than did patients with RF/other mutations. In particular, the 3849 + 10kbC → T/F508del subjects had worse FEV 1 and a higher prevalence of lung infections than did patients with other genotypes., Conclusions: Patients with RF mutations are numerous in Italy and have a milder disease phenotype than do F508del homozygotes. Inside the RF group, F508del heterozygotes and, in particular, 3849 + 10kbC → T/F508del patients showed more severe pneumopathy., (© 2018 Wiley Periodicals, Inc.)

Introduction: Mortality among children hospitalised for complicated severe acute malnutrition (SAM) remains high despite the implementation of WHO guidelines, particularly in settings of high HIV prevalence. Children continue to be at high risk of morbidity, mortality and relapse after discharge from hospital although long-term outcomes are not well documented. Better understanding the pathogenesis of SAM and the factors associated with poor outcomes may inform new therapeutic interventions., Methods and Analysis: The Health Outcomes, Pathogenesis and Epidemiology of Severe Acute Malnutrition (HOPE-SAM) study is a longitudinal observational cohort that aims to evaluate the short-term and long-term clinical outcomes of HIV-positive and HIV-negative children with complicated SAM, and to identify the risk factors at admission and discharge from hospital that independently predict poor outcomes. Children aged 0-59 months hospitalised for SAM are being enrolled at three tertiary hospitals in Harare, Zimbabwe and Lusaka, Zambia. Longitudinal mortality, morbidity and nutritional data are being collected at admission, discharge and for 48 weeks post discharge. Nested laboratory substudies are exploring the role of enteropathy, gut microbiota, metabolomics and cellular immune function in the pathogenesis of SAM using stool, urine and blood collected from participants and from well-nourished controls., Ethics and Dissemination: The study is approved by the local and international institutional review boards in the participating countries (the Joint Research Ethics Committee of the University of Zimbabwe, Medical Research Council of Zimbabwe and University of Zambia Biomedical Research Ethics Committee) and the study sponsor (Queen Mary University of London). Caregivers provide written informed consent for each participant. Findings will be disseminated through peer-reviewed journals, conference presentations and to caregivers at face-to-face meetings., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Background: Child stunting reduces survival and impairs neurodevelopment. We tested the independent and combined effects of improved water, sanitation, and hygiene (WASH), and improved infant and young child feeding (IYCF) on stunting and anaemia in in Zimbabwe., Methods: We did a cluster-randomised, community-based, 2 × 2 factorial trial in two rural districts in Zimbabwe. Clusters were defined as the catchment area of between one and four village health workers employed by the Zimbabwe Ministry of Health and Child Care. Women were eligible for inclusion if they permanently lived in clusters and were confirmed pregnant. Clusters were randomly assigned (1:1:1:1) to standard of care (52 clusters), IYCF (20 g of a small-quantity lipid-based nutrient supplement per day from age 6 to 18 months plus complementary feeding counselling; 53 clusters), WASH (construction of a ventilated improved pit latrine, provision of two handwashing stations, liquid soap, chlorine, and play space plus hygiene counselling; 53 clusters), or IYCF plus WASH (53 clusters). A constrained randomisation technique was used to achieve balance across the groups for 14 variables related to geography, demography, water access, and community-level sanitation coverage. Masking of participants and fieldworkers was not possible. The primary outcomes were infant length-for-age Z score and haemoglobin concentrations at 18 months of age among children born to mothers who were HIV negative during pregnancy. These outcomes were analysed in the intention-to-treat population. We estimated the effects of the interventions by comparing the two IYCF groups with the two non-IYCF groups and the two WASH groups with the two non-WASH groups, except for outcomes that had an important statistical interaction between the interventions. This trial is registered with ClinicalTrials.gov, number NCT01824940., Findings: Between Nov 22, 2012, and March 27, 2015, 5280 pregnant women were enrolled from 211 clusters. 3686 children born to HIV-negative mothers were assessed at age 18 months (884 in the standard of care group from 52 clusters, 893 in the IYCF group from 53 clusters, 918 in the WASH group from 53 clusters, and 991 in the IYCF plus WASH group from 51 clusters). In the IYCF intervention groups, the mean length-for-age Z score was 0·16 (95% CI 0·08-0·23) higher and the mean haemoglobin concentration was 2·03 g/L (1·28-2·79) higher than those in the non-IYCF intervention groups. The IYCF intervention reduced the number of stunted children from 620 (35%) of 1792 to 514 (27%) of 1879, and the number of children with anaemia from 245 (13·9%) of 1759 to 193 (10·5%) of 1845. The WASH intervention had no effect on either primary outcome. Neither intervention reduced the prevalence of diarrhoea at 12 or 18 months. No trial-related serious adverse events, and only three trial-related adverse events, were reported., Interpretation: Household-level elementary WASH interventions implemented in rural areas in low-income countries are unlikely to reduce stunting or anaemia and might not reduce diarrhoea. Implementation of these WASH interventions in combination with IYCF interventions is unlikely to reduce stunting or anaemia more than implementation of IYCF alone., Funding: Bill & Melinda Gates Foundation, UK Department for International Development, Wellcome Trust, Swiss Development Cooperation, UNICEF, and US National Institutes of Health., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Cystic fibrosis (CF) is a disorder affecting the respiratory, digestive, reproductive systems and sweat glands. This lethal hereditary disease has known or suspected links to the dysbiosis gut microbiota. High-throughput meta-omics-based approaches may assist in unveiling this complex network of symbiosis modifications., Objectives: The aim of this study was to provide a predictive and functional model of the gut microbiota enterophenotype of pediatric patients affected by CF under clinical stability., Methods: Thirty-one fecal samples were collected from CF patients and healthy children (HC) (age range, 1-6 years) and analysed using targeted-metagenomics and metabolomics to characterize the ecology and metabolism of CF-linked gut microbiota. The multidimensional data were low fused and processed by chemometric classification analysis., Results: The fused metagenomics and metabolomics based gut microbiota profile was characterized by a high abundance of Propionibacterium, Staphylococcus and Clostridiaceae, including Clostridium difficile, and a low abundance of Eggerthella, Eubacterium, Ruminococcus, Dorea, Faecalibacterium prausnitzii, and Lachnospiraceae, associated with overexpression of 4-aminobutyrate (GABA), choline, ethanol, propylbutyrate, and pyridine and low levels of sarcosine, 4-methylphenol, uracil, glucose, acetate, phenol, benzaldehyde, and methylacetate. The CF gut microbiota pattern revealed an enterophenotype intrinsically linked to disease, regardless of age, and with dysbiosis uninduced by reduced pancreatic function and only partially related to oral antibiotic administration or lung colonization/infection., Conclusions: All together, the results obtained suggest that the gut microbiota enterophenotypes of CF, together with endogenous and bacterial CF biomarkers, are direct expression of functional alterations at the intestinal level. Hence, it's possible to infer that CFTR impairment causes the gut ecosystem imbalance.This new understanding of CF host-gut microbiota interactions may be helpful to rationalize novel clinical interventions to improve the affected children's nutritional status and intestinal function., Competing Interests: The authors have declared that no competing interests exist.

Pancreatic disorders in children represent a growing health problem in pediatric patients. In the past two decades, several advances have been made in the knowledge of pediatric pancreatic disorders, with better understanding of different etiologies and clinical manifestations of these disorders. Moreover, many efforts have been made in pancreatology, aiming to define guidelines in the management of pancreatitis in children, initially based on the available information in adults. A multidisciplinary and multicenter approach is necessary to better determine pancreatic disease pathways and treatment options in children., (Copyright © 2018 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

15-F 2t -Isoprostane, a reliable biomarker of oxidative stress, has been found elevated in exhaled breath condensate (EBC), a non-invasive technique for sampling of airway secretions, in patients with cystic fibrosis (CF). Azithromycin has antioxidant properties in experimental models of CF, but its effects on oxidative stress in CF patients are largely unknown. Primary objective of this pilot, proof-of-concept, prospective, parallel group, pharmacological study, was investigating the potential antioxidant effects of azithromycin in CF patients as reflected by EBC 15-F 2t -isoprostane. Secondary objectives included studying the effect of azithromycin on EBC and serum metabolic profiles, and on serum 15-F 2t -isoprostane. In CF patients who were on maintenance treatment with oral vitamin E (200 UI once daily), treatment with oral azithromycin (250 or 500 mg depending on body weight) plus vitamin E (400 UI once daily) (group A) ( n = 24) or oral vitamin E alone (400 UI once daily) (group B) ( n = 21) was not associated with changes in EBC 15-F 2t -isoprostane concentrations compared with baseline values after 8-weeks treatment or 2 weeks after treatment suspension. There was no between-group difference in post-treatment EBC 15-F 2t -isoprostane. Likewise, no within- or between-group differences in serum 15-F 2t -isoprostane concentrations were observed in either study group. NMR spectroscopy-based metabolomics of EBC shows that suspension of both azithromycin plus vitamin E and vitamin E alone has a striking effect on metabolic profiles in EBC. Between-group comparisons show that EBC metabolite distribution after treatment and 2 weeks after treatment suspension is different. Quantitative differences in ethanol, saturated fatty acids, acetate, acetoin/acetone, and methanol are responsible for these differences. Our study was unable to show antioxidant effect of azithromycin as add-on treatment with doubling the dose of oral vitamin E as reflected by 15-F 2t -isoprostane concentrations in EBC. Add-on therapy with azithromycin itself does not induce EBC metabolite changes, but its suspension is associated with EBC metabolic profiles that are different from those observed after vitamin E suspension. The pathophysiological and therapeutic implications of these findings in patients with stable CF are unknown and require further research. Preliminary data suggest that EBC NMR-based metabolomics might be used for assessing the effects of pharmacological treatment suspension in stable CF patients.

Background: Intestinal dysbiosis has been described in Cystic Fibrosis (CF) and probiotics have been proposed to restore microbial composition. Aim of the study was to investigate the effects of Lactobacillus rhamnosus GG (LGG) on clinical outcomes in children with cystic fibrosis (CF)., Methods: A multicentre, randomised double-blind, clinical trial was conducted in children with CF. After 6months of baseline assessment, enrolled children (2 to 16years of age) received Lactobacillus GG (6×10 9 CFU/day) or placebo for 12months. Primary outcomes were proportion of subjects with at least one pulmonary exacerbation and hospitalisation over 12months. Secondary endpoints were total number of exacerbations and hospitalisations, pulmonary function, and nutritional status., Results: Ninety-five patients were enrolled (51/95 female; median age of 103±50months). In a multivariate GEE logistic analysis, the odds of experiencing at least one exacerbation was not significantly different between the two groups, also after adjusting for the presence of different microbial organisms and for the number of pulmonary exacerbations within 6months before randomisation (OR 0.83; 95% CI 0.38 to 1.82, p=0.643). Similarly, LGG supplementation did not significantly affect the odds of hospitalisations (OR 1.67; 95% CI 0.75 to 3.72, p=0.211). No significant difference was found for body mass index and FEV1., Conclusions: LGG supplementation had no effect on respiratory and nutritional outcomes in this large study population of children with CF under stringent randomised clinical trial conditions. Whether earlier interventions, larger doses, or different strains of probiotics may be effective is unknown., (Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Purpose: To report the visual outcomes and complications of automated anterior lamellar therapeutic keratoplasty (ALTK) in adults and children, and to examine these outcomes as a function of age and etiology., Methods: A consecutive series of cases undergoing automated ALTK procedures performed at the Jules-Gonin Eye Hospital Lausanne, Switzerland, between June 2003 and January 2015. Only patients with at least 3 months of follow-up were included., Results: There were 53 eyes (24 right) of 51 patients (17 female, 16 juvenile), with a mean age of 34.8 years (range from 3 months to 88 years), analyzed. The mean follow-up was 35 (± 26) months. Diagnosis in the adult (n = 37) vs. juvenile (n = 16) eyes was different: opacity following surgical complication 8 vs. 0, congenital 1 vs. 1, dystrophy 5 vs. 2, infection 12 vs. 5, keratectasia 3 vs. 0, trauma 7 vs. 0, tumor 1 vs. 3, and allergy 0 vs. 5. Visual impairment as a consequence of corneal scarring was the principle indication for surgery in both adult (70%; 26) and juvenile eyes (63%; 10); other indications were choristoma, dermoid, other tumors, astigmatism, and congenital opacity. In adult vs. juvenile eyes, the mean visual acuity (spectacle and contact lenses) was, at last visit, 0.55 vs. 0.45 LogMAR (p = 0.78), with a range of 100% to hand movements. Failure occurred in 6 (16%) vs. 2 (13%) cases and complications were observed in 14 (38%) vs. 9 (56%) cases, however, more surgical revision was required in juvenile eyes, 4 (11%) vs. 7 (43%) (p = 0.01, Fisher test)., Conclusions: This study shows that anterior lamellar keratoplasty in children retains good visual function when combined with adequate amblyopic therapy. However, the rate of complications is higher in juveniles and requires more intensive interdisciplinary follow-up., Competing Interests: The authors declare no conflict of interest., (Georg Thieme Verlag KG Stuttgart · New York.)

Introduction: The Italian Cystic Fibrosis Registry (ICFR) is based on a new agreement about the data flow towards the Registry signed on October, 4th 2016 by the Centre for Rare Diseases of the Italian National Institute of Health (NIH), the clinicians of the Italian National Referral and Support Centres for Cystic Fibrosis, the Paediatric Hospital "Bambino Gesù" (Rome), the Italian Cystic Fibrosis Society, and the Italian League for Cystic Fibrosis., Objectives: The aim of the present Report is to improve the knowledge on cystic fibrosis (CF) through the epidemiological description of Italian patients. The members of the Scientific and Technical Committee have to write a report on data collected by ICFR, in order to contribute to achieve the aims of ICFR itself, i.e., to improve the care of CF patients. In particular, the Report should contribute to the following objectives: - to analyze the medium and long-term clinical and epidemiological trends of the disease; - to identify the main healthcare needs at regional and national level in order to contribute to the healthcare programmes and to the distribution of resources; - to compare Italian data with the international ones., Design: Analyses and results described in the present Report are referred to patients in charge to the Italian National Referral and Support Centres for Cystic Fibrosis in the period 2011-2014. Data were sent by Centres by means of a specific software (Camilla, Ibis Informatica) and has undergone a double quality control (QC): the first by NIH and the second at a European level (before the inclusion of the Italian data within the European Cystic Fibrosis Registry). These QCs assure the completeness and accuracy of data as well as their consistency with European core data., Setting and Participants: A total of 29 different CF centres (referral, support, and Paediatric Hospital "Bambino Gesù") sent their data to ICFR; data referred to the period 2011-2014. Data regarding Sardinia Region (Southern Italy) are missing; data from Molise (Southern Italy) CF centre refer only to 2014., Results: The present Report has been organized into 10 sections. 1. Demography - number of Italian patients with cystic fibrosis (CF) in 2014 was 4,981 and their median age was 20.4 years; estimated 2014 CF prevalence was 8.2/100,000 residents in Italy; on average, 52.1% of the patients were male and CF distribution showed higher frequency in patients aged from 7 to 35 years. On average, 53.7% of CF patients are aged more than 18 years. 2. Diagnoses - most of the CF patients were diagnosed before two years of age (around 66%); a significant proportion of patients (on average, 12%) was diagnosed in adult age. 3. New diagnoses - new diagnoses were 187 in 2011, 200 in 2012, 160 in 2013, and 135 in 2014. Estimated incidence was 1/4,052 live births in 2011; 1/4,313 in 2012; 1/5,189 in 2013 and 1/8,243 in 2014. 4. Genetics - 99.5% of patients was studied at the molecular level, with identification of 90.1% of Cystic Fibrosis Transmembrane Regulator CFTR mutations; [delta]508F was the most frequent mutation (44.8% in 2014). 5. Lung function - FEV₁ (Forced Expiratory Volume in the first second) scores progressively decreased shortly before the start of adult age, in accordance with the natural history of the disease. Most of the patients between 6 and 17 years of age reported a FEV₁ % ≥ 70% of the predicted value, while the proportion of patients with severe lung disease (FEV₁ % <40% of the predicted value) is <2% over the period 2011-2014. 6. Nutrition - most critical periods come out during the first 6 months of life and during adolescence. Prevalence of malnourished male aged 12-17 years decreases over the period 2011-2014; an increasing percentage of patient (both male and female) with a suboptimal body mass index value is observed among patients aged more than 18 years 7. Complications - the presence of missing data represents an obstacle in the correct evaluation of prevalence value of complications related to Italian patients within ICFR. Nevertheless, it was estimated that, in 2014, the principal complication in patients aged <18 years was hepatopathies (15%), while in patients aged more than 18 years the principal complications were due to hepatopathies (25%) and diabetes (22%). 8. Transplantation - during the period 2011-2014, 135 patients ageed between 7 and 53 years received a double lung transplant; median age at transplantation was 32.5 years. Median duration of waiting list for transplantation is estimated in 11 months. 9. Microbiology - analyses were referred to test performed in 2014. Prevalence of adult patients with Pseudomonas aeruginosa chronic infection is 49.4% compared to 14.5% of paediatric patients; Staphylococcus aureus chronic infection is present in 48% of adult patients and 45.6% of paediatric patients; Burkholderia Cepacia complex is present almost exclusively in adult patients (4.9%); Nontuberculous mycobacteria is present in 0.9% and 0.3% of adult and paediatric patients, respectively; Stenotrophomonas maltophilia infection is present in 4.6% of patients (both adults and paediatric). 10. Mortality - RIFC data show that 176 patients (median age 32 years; 81 males and 95 females) died in the period 2011-2014., Conclusions: The present Report shows that CF population is growing (median age), so paediatric mortality is decreasing. A very low percentage of paediatric population is characterized by complication of pulmonary functions; adult patients are characterized by an increase of age at death (more than 30 years of age). ICFR Report may represent an important tool to analyze clinical and epidemiological trends of the disease as well as to identify the main healthcare needs at regional and national level to contribute to the healthcare programmes and to the distribution of the resources.

Background: Reaching a consensus on which parameters are most reliable at detecting progressive keratoconus patients with serial topography imaging is not evident. The aim of the study was to isolate the parameters best positioned to detect keratoconus progression using the Pentacam HR® measures based on the respective limits of repeatability and range of measurement., Method: Using the Pentacam HR®, a tolerance index was calculated on anterior segment parameters in healthy and keratoconic eyes. The tolerance index provides a scale from least to most affected parameters in terms of measurement noise relative to that observed in healthy eyes. Then, based on the "number of increments" from no disease to advanced disease, a relative utility (RU) score was also calculated. RU values close to 1 indicate parameters best positioned to detect a change in keratoconic eyes., Results: The tolerance index values indicated that 36% of ocular parameters for keratoconic eyes had repeatability limits which were wider than normative limits (worse), but 28% of the ocular parameters were narrower than normative limits (better). Considering only those parameters with a RU greater than 0.95, a small number of parameters were within this range, such as corneal curvature and asphericity indices., Conclusions: This study demonstrates that measurement error in keratoconic eyes is significantly greater than healthy eyes. Indices implemented here provide guidance on the levels of expected precision in keratoconic eyes relative to healthy eyes to aid clinicians in distinguishing real change from noise. Importantly maximal keratometry (Kmax), central corneal thickness (CCT) and thinnest corneal thickness (TCT) were highlighted as problematic indices for the follow-up of keratoconus in terms of repeatability.

Purpose: To assess safety, efficacy, and predictability of combined Implantable Collamer Lens phakic intraocular lens (pIOL) explantation and phacoemulsification and to report the rate of complications. A secondary aim was to examine whether intraocular lens (IOL) power calculation was affected by the pIOL in situ., Setting: Jules-Gonin Eye Hospital, Lausanne, Switzerland., Design: Retrospective case series., Methods: The records of patients having pIOL implantation with subsequent phacoemulsification were reviewed. Data analysis was performed between July 1, 2015, and December 31, 2015. The mean corrected distance visual acuity (CDVA), safety, stability of refraction, predictability of IOL power calculation, and postoperative complications were recorded., Results: The study comprised 38 eyes (29 patients). Of the eyes, 32 (82%) were within ±1.00 diopter (D) of the target refraction and 21 (57.9%) were within ±0.50 D. The mean CDVA after IOL implantation was significantly better than before pIOL implantation (P < .001) and similar to after pIOL implantation (P = .87). The safety of this multistepped procedure was good; on average, 1.6 Snellen lines of CDVA were gained over before pIOL implantation. Branch retinal vein occlusion occurred in 1 eye; no other sight-threatening complications were observed. Posterior capsule opacification developed in 15 eyes (39.5%) and was treated successfully with neodymium:YAG capsulotomy., Conclusions: The highest mean CDVA was recorded at the final visit. Good safety, stability, and predictability were also observed. Postoperative complications were few and in all but 1 case, not sight threatening. Overall, results indicate the combination of procedures does not negatively affect the final visual outcome., (Copyright © 2017 ASCRS and ESCRS. Published by Elsevier Inc. All rights reserved.)

Phagocytosis is a key mechanism of innate immunity, and promotion of phagosome maturation may represent a therapeutic target to enhance antibacterial host response. Phagosome maturation is favored by the timely and coordinated intervention of lipids and may be altered in infections. Here we used apoptotic body-like liposomes (ABL) to selectively deliver bioactive lipids to innate cells, and then tested their function in models of pathogen-inhibited and host-impaired phagosome maturation. Stimulation of macrophages with ABLs carrying phosphatidic acid (PA), phosphatidylinositol 3-phosphate (PI3P) or PI5P increased intracellular killing of BCG, by inducing phagosome acidification and ROS generation. Moreover, ABLs carrying PA or PI5P enhanced ROS-mediated intracellular killing of Pseudomonas aeruginosa, in macrophages expressing a pharmacologically-inhibited or a naturally-mutated cystic fibrosis transmembrane conductance regulator. Finally, we show that bronchoalveolar lavage cells from patients with drug-resistant pulmonary infections increased significantly their capacity to kill in vivo acquired bacterial pathogens when ex vivo stimulated with PA- or PI5P-loaded ABLs. Altogether, these results provide the proof of concept of the efficacy of bioactive lipids delivered by ABL to enhance phagosome maturation dependent antimicrobial response, as an additional host-directed strategy aimed at the control of chronic, recurrent or drug-resistant infections.

T helper 9 (Th9) cells contribute to lung inflammation and allergy as sources of interleukin-9 (IL-9). However, the mechanisms by which IL-9/Th9 mediate immunopathology in the lung are unknown. Here we report an IL-9-driven positive feedback loop that reinforces allergic inflammation. We show that IL-9 increases IL-2 production by mast cells, which leads to expansion of CD25 + type 2 innate lymphoid cells (ILC2) and subsequent activation of Th9 cells. Blocking IL-9 or inhibiting CD117 (c-Kit) signalling counteracts the pathogenic effect of the described IL-9-mast cell-IL-2 signalling axis. Overproduction of IL-9 is observed in expectorates from cystic fibrosis (CF) patients, and a sex-specific variant of IL-9 is predictive of allergic reactions in female patients. Our results suggest that blocking IL-9 may be a therapeutic strategy to ameliorate inflammation associated with microbial colonization in the lung, and offers a plausible explanation for gender differences in clinical outcomes of patients with CF.

Purpose: To compare the stromal bed surface quality and the accuracy of dissection depth after deep lamellar cuts using the Leonardo Da Vinci (LDV) femtosecond laser (Z6) and the ONE Microkeratome., Methods: Deep lamellar cuts were performed on nine human donor corneoscleral buttons: five with the LDV femtosecond (FS) laser (Z6) (Ziemer) and four with the ONE Microkeratome (MK) (Moria). Corneal thickness was measured with ultrasound pachymetry before and after the dissection. The Stromal bed quality was evaluated using light microscopy (n = 4) and scanning electron microscopy (SEM) (n = 9). The surface roughness on SEM images was graded on the scale of 1 (smoothest) to 5 (roughest) by four observers, blinded to the method used. Particle analysis on the SEM images was performed in order to have an objective measure of smoothness., Results: The achieved dissection depth using the FS laser was 496.4 ± 46.4 µm when attempting 500 µm and 474 ± 60 µm with the microkeratome when attempting 350 µm. Histological evaluation of the corneoscleral buttons by both light and electron microscopy showed significantly smoother surface using the FS laser compared to the microkeratome. There were fewer and smaller particles observed in the SEM images of FS laser cut buttons (p < 0.001).The average observer based score of anterior surface roughness (50×) was 2.2 for the FS laser and 3.9 for the microkeratome dissections (p < 0.001)., Conclusions: The LDV femtosecond laser (Z6) platform is capable of creating deep corneal lamellar dissection with smoother surface quality and with more predictable cut depth as compared to the One Microkeratome.

Purpose: To compare the postoperative risk of inflammatory relapse in two groups of uveitic patients who underwent cataract surgery: one group had perioperative topical steroids alone and the other used topical and oral steroids., Methods: Prospective, randomized, unmasked, duocentric clinical trial conducted at the University of Parma (Italy), and the Jules Gonin Eye Hospital of Lausanne (Switzerland). Patients with a history of non-infectious uveitis requiring cataract surgery in 2009-2013 were assigned to two groups of perioperative prophylaxis: (A) intensive topical steroids alone; (B) the same topical regimen combined with oral steroids. Uveitis relapse over a period of 6 months was assessed., Results: In total, 52 eyes in 50 patients were randomized: 28 eyes were assigned to group A (topical) and 24 eyes to group B (topical + oral). Mean relapse-free survival time was 131 ± 11 days in group A and 150 ± 13 days in group B. This difference was not statistically significant (p = 0.42). At the end of follow-up, the groups were also comparable in terms of significant improvement in visual acuity (p < 0.01), mean central macular thickness (CMT) and IOP variation., Conclusions: Absolute and long-lasting control of ocular, and possibly systemic, inflammation predisposes uveitis patients to satisfactory results after cataract extraction and intraocular lens implantation. Despite a lower rate of recurrences following oral steroid supplementation, the efficacy of an intensive perioperative topical steroid regimen alone in preventing postoperative uveitis relapse was statistically comparable. Secondary outcomes were also comparable between the two groups. Transient IOP elevation should be expected until treatment discontinuation., (© 2016 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Importance: Intraocular collamer lenses (ICLs) are posterior chamber phakic lenses that provide a refractive surgery option for those with high myopia or astigmatism. The short-term and midterm results indicate good refraction stability, efficacy, and safety. Cataract has been suggested to be an important long-term complication of ICL implantation., Objective: To report the rates of cataract development and refractive outcomes 10 years after ICL implantation., Design, Setting, and Participants: The study included 133 eyes of 78 patients undergoing consecutive V4 model ICL implantations, which took place from January 1, 1998, through December 31, 2004, at Jules-Gonin Eye Hospital, Lausanne, Switzerland. Data analysis was performed from January 1, 2014, to May 31, 2014. The lenses implanted were as follows: 53 V4 model ICLs of -15.5 D or greater, 73 V4 model ICLs of less than -15.5 diopter (D), and 7 V4 model toric ICLs for myopia., Main Outcomes and Measures: Rate of cataract surgery, lens opacity, ocular hypertension, refractive safety, predictability, and stability., Results: A total of 133 eyes of 78 patients (34 men and 44 women, with a mean [SD] age of 38.8 [9.2] years at enrollment) met the inclusion criteria. The rate of lens opacity development was 40.9% (95% CI, 32.7%-48.8%) and 54.8% (95% CI, 44.7%-63.0%) at 5 and 10 years, respectively. Phacoemulsification was performed in 5 eyes (4.9%; 95% CI, 1.0%-8.7%) and 18 eyes (18.3%; 95% CI, 10.1%-25.8%) at 5 and 10 years after ICL implantation, respectively. The vault height (distance between the posterior ICL surface and anterior lens surface) measured a mean (SD) of 426 (344) μm immediately postoperatively, decreasing to 213 (169) μm at 10 years. A smaller vault height was associated with the development of lens opacity and phacoemulsification (P = .005 and .008, respectively). The intraocular pressure was 15 mm Hg postoperatively, and there was no significant increase in intraocular pressure observed until the 10-year follow-up (16 mm Hg, P = .02). At 10 years, 12 eyes (12.9%; 95% CI, 5.6%-19.6%) had developed ocular hypertension that required topical medication. At 10 years, the mean (SD) safety index was 1.25 (0.57), with a manifest spherical equivalent of -0.5 D at 1-year postoperatively vs -0.7 D at 10 years postoperatively in eyes aimed at emmetropia., Conclusions and Relevance: This retrospective single center study indicates that ICL implantation provides good long-term safety and stability of refraction in patients with high myopia compared with similar short-term studies. However, the rates of cataract formation and ocular hypertension at 10 years have important clinical implications, and as such this information should be part of the available patient information before ICL implantation.

Background: To report the use of intrastromal voriconazole injections combined with corneal debridement to treat deep recalcitrant fungal keratitis., History and Signs: Three patients (2 female and 1 male) with culture proven fungal keratitis (1 Fusarium, 1 Candida, 1 Pseudallescheria boydii) were included in this study. The patients were treated with repeated intrastromal voriconazole (100 mg/1 ml) in combination with corneal debridement., Therapy and Outcome: The mean age of the patients was 65 years. The mean number of injections was 5. The patients were injected every 2-3 days. This technique required repeated corneal debridement to achieve complete resolution in these three cases., Conclusions: Repeated intrastromal injection of voriconazole in combination with corneal debridement appears to be an effective and safe way to treat recalcitrant fungal keratitis, even in Fusarium keratitis., (Georg Thieme Verlag KG Stuttgart · New York.)

Dysregulated inflammasome activation contributes to respiratory infections and pathologic airway inflammation. Through basic and translational approaches involving murine models and human genetic epidemiology, we show here the importance of the different inflammasomes in regulating inflammatory responses in mice and humans with cystic fibrosis (CF), a life-threatening disorder of the lungs and digestive system. While both contributing to pathogen clearance, NLRP3 more than NLRC4 contributes to deleterious inflammatory responses in CF and correlates with defective NLRC4-dependent IL-1Ra production. Disease susceptibility in mice and microbial colonization in humans occurs in conditions of genetic deficiency of NLRC4 or IL-1Ra and can be rescued by administration of the recombinant IL-1Ra, anakinra. These results indicate that pathogenic NLRP3 activity in CF could be negatively regulated by IL-1Ra and provide a proof-of-concept evidence that inflammasomes are potential targets to limit the pathological consequences of microbial colonization in CF.

Purpose: To assess the agreement and repeatability of horizontal white-to-white (WTW) and horizontal sulcus-to-sulcus (STS) diameter measurements and use these data in combination with available literature to correct for interdevice bias in preoperative implantable collamer lens (ICL) size selection., Design: Interinstrument reliability and bias assessment study., Methods: A total of 107 eyes from 56 patients assessed for ICL implantation at our institution were included in the study. This was a consecutive series of all patients with suitable available data. The agreement and bias between WTW (measured with the Pentacam and BioGraph devices) and STS (measured with the HiScan device) were estimated., Results: The mean spherical equivalent was -8.93 ± 5.69 diopters. The BioGraph measures of WTW were wider than those taken with the Pentacam (bias = 0.26 mm, P < .01), and both horizontal WTW measures were wider than the horizontal STS measures (bias >0.91 mm, P < .01). The repeatability (Sr) of STS measured with the HiScan was 0.39 mm, which was significantly reduced (Sr = 0.15 mm) when the average of 2 measures was used. Agreement between the horizontal WTW measures and horizontal STS estimates when bias was accounted for was г = 0.54 with the Pentacam and г = 0.64 with the BioGraph., Conclusions: Large interdevice bias was observed for WTW and STS measures. STS measures demonstrated poor repeatability, but the average of repeated measures significantly improved repeatability. In order to conform to the US Food and Drug Administration's accepted guidelines for ICL sizing, clinicians should be aware of and account for the inconsistencies between devices., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to evaluate the metabolic effects of fatty pancreas (nonalcoholic fatty pancreas disease - NAFPD) in a group of obese paediatric patients with nonalcoholic fatty liver disease (NAFLD)., Methods: We included 121 consecutive children with echographic evidence of hepatic steatosis. All patients underwent to abdominal ultrasound to evaluate pancreatic echogenic pattern. We divided the patients into two groups on the basis of the presence of fatty pancreas. In all patients liver function tests, lipid and gluco-insulinemic profile were evaluated. A selected subset of patients (67) underwent to liver biopsy., Results: Of these 121 patients, 58 showed NAFPD and 63 patients exhibited a normal pancreatic echogenic pattern. No differences were found in age, transaminases serum levels, lipid profile and pancreatic enzymes between the two groups. The patients with NAFPD had a significantly higher z-BMI, fasting insulin, insulin resistance (HOMA-IR) and lower ISI respect to the group without fatty pancreas. The patients with fatty pancreas showed a more advanced form of liver disease, with higher values of fibrosis, ballooning and NAS score with respect to the group without NAFPD., Conclusions: Our study demonstrated that NAFPD is a frequent condition in obese paediatric patients affected by NAFLD. Our data suggest that pancreatic fat should not be considered an inert accumulation of fat, but as an additional factor able to affect glucose metabolism and severity of liver disease, increasing the risk of develop metabolic syndrome., (© 2015 John Wiley & Sons Ltd.)

Reaching a consensus in terms of interchangeability and utility (i.e., disease detection/monitoring) of a medical device is the eventual aim of repeatability and agreement studies. The aim of the tolerance and relative utility indices described in this report is to provide a methodology to compare change in clinical measurement noise between different populations (repeatability) or measurement methods (agreement), so as to highlight problematic areas. No longitudinal data are required to calculate these indices. Both indices establish a metric of least to most effected across all parameters to facilitate comparison. If validated, these indices may prove useful tools when combining reports and forming the consensus required in the validation process for software updates and new medical devices.

Several chronic transmissible (e.g. AIDS) and non transmissible diseases like cadiovascular disease, are associated with oxidative stress (EOX) and dyslipidemia. Has been reported that Spirulina can reduce them, this has been demonstrated in vitro and in animal models but scarcely in humans. Through a systematic review on last 5 years (keywords: Spirulina AND cholesterol, Spirulina AND oxidative stress) 8 intervention studies with humans were reported, finding that oral (1-10 g/d) subchronic (0.5-6 month) administration of Spirulina appears to have and hypolipidemic and antioxidant effect. However, no study was properly randomized and/or controlled and no biological mechanism was proposed to support these findings. The level of evidence and the absence of appropriate experimental designs do not allow validating Spirulina as a functional food for preventing dyslipidemic diseases and EOX, and hereby decrease the CVD. We do not found papers relating harmful effect., (Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.)

Angiogenesis plays a key role in tumor growth and cancer progression. TIE-2-expressing monocytes (TEM) have been reported to critically account for tumor vascularization and growth in mouse tumor experimental models, but the molecular basis of their pro-angiogenic activity are largely unknown. Moreover, differences in the pro-angiogenic activity between blood circulating and tumor infiltrated TEM in human patients has not been established to date, hindering the identification of specific targets for therapeutic intervention. In this work, we investigated these differences and the phenotypic reversal of breast tumor pro-angiogenic TEM to a weak pro-angiogenic phenotype by combining Boolean modelling and experimental approaches. Firstly, we show that in breast cancer patients the pro-angiogenic activity of TEM increased drastically from blood to tumor, suggesting that the tumor microenvironment shapes the highly pro-angiogenic phenotype of TEM. Secondly, we predicted in silico all minimal perturbations transitioning the highly pro-angiogenic phenotype of tumor TEM to the weak pro-angiogenic phenotype of blood TEM and vice versa. In silico predicted perturbations were validated experimentally using patient TEM. In addition, gene expression profiling of TEM transitioned to a weak pro-angiogenic phenotype confirmed that TEM are plastic cells and can be reverted to immunological potent monocytes. Finally, the relapse-free survival analysis showed a statistically significant difference between patients with tumors with high and low expression values for genes encoding transitioning proteins detected in silico and validated on patient TEM. In conclusion, the inferred TEM regulatory network accurately captured experimental TEM behavior and highlighted crosstalk between specific angiogenic and inflammatory signaling pathways of outstanding importance to control their pro-angiogenic activity. Results showed the successful in vitro reversion of such an activity by perturbation of in silico predicted target genes in tumor derived TEM, and indicated that targeting tumor TEM plasticity may constitute a novel valid therapeutic strategy in breast cancer.

Cystic fibrosis (CF), the most common autosomal recessive disease in whites, is caused by mutations in the CF transmembrane conductance regulator (CFTR). So far, >1900 mutations have been described, most of which are nonsense, missense, and frameshift, and can lead to severe phenotypes, reducing the level of function of the CFTR protein. Synonymous variations are usually considered silent without pathogenic effects. However, synonymous mutations exhibiting exon skipping as a consequence of aberrant splicing of pre-mRNA differ. Herein, we describe the effect of the aberrant splicing of the c.273G>C (G91G) synonymous variation found in a 9-year-old white (ΔF508) patient affected by CF and pancreatitis associated with a variant in chymotrypsin C (CTRC). Magnetic resonance imaging showed an atrophic pancreatic gland with substitution of the pancreatic parenchyma with three cysts. Genetic examination revealed compound heterozygosity for the c.1521&#95;1523delCTT (ΔF508) pathogenic variant and the c.273G>C (G91G) variant in CFTR. Sweat test results confirmed the diagnosis of CF. We have thus identified a synonymous variation (G91G) causing the skipping of exon 3 in a CF patient carrying the ΔF508 mutation. However, the clinical phenotype with pancreatic symptoms encouraged us to investigate a panel of pancreas-related genes, which resulted in finding a known sequence variation inside CTRC. We further discuss the role of these variants and their possible interactions in determining the current phenotype., (Copyright © 2015 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

There are few data about the impact of cystic fibrosis-related diabetes (CFRD) on growth. We analyzed 17 children with cystic fibrosis (CF) presenting with newly diagnosed CFRD during puberty, in comparison with a matched control group of 52 CF children with normal glucose tolerance (NGT). Anthropometric evaluation showed that body mass index at CFRD diagnosis was significantly reduced in children with CFRD, in comparison with children with NGT (CFRD: -0.48 ± 1.08 vs. NGT: 0.2 ± 0.99; P=0.01), and the same difference remained evident at the end of follow up (CFRD: -0.49 ± 0.95 vs. NGT: 0.13 ± 0.89; P=0.04). Height standard deviation score (SDS) at baseline was slightly but not significantly lower in CFRD children (CFRD: -0.71 ± 0.83 vs. NGT: -0.25 ± 1.08; P=0.08), while final height SDS was significantly reduced (CFRD: -1.61 ± 1.12 vs. NGT: -0.61 ± 1.15; P=0.003). Mean final height SDS of the whole group was lower than mean target height SDS (final height SDS: -0.86 ± 1.2 vs. target height SDS: -0.3 ± 0.85; P<0.001). Target adjusted final height was lower in CFRD children, although the difference between CFRD and NGT children did not reach statistical significance (CFRD: -0.8 ± 1.03 vs. NGT: -0.47 ± 0.9; P=0.09). Pubertal growth and final height are negatively affected by CFRD. Intensive insulin treatment does not appear to be effective in normalizing growth, even when treatment is started early in the course of the disease, before the onset of clinical deterioration., (© 2014 Wiley Periodicals, Inc.)

Objective: Eye drops of aganirsen, an antisense oligonucleotide preventing insulin receptor substrate-1 expression, inhibited corneal neovascularization in a previous dose-finding phase II study. We aimed to confirm these results in a phase III study and investigated a potential clinical benefit on visual acuity (VA), quality of life (QoL), and need for transplantation., Design: Multicenter, double-masked, randomized, placebo-controlled phase III study., Participants: Analysis of 69 patients with keratitis-related progressive corneal neovascularization randomized to aganirsen (34 patients) or placebo (35 patients). Patients applied aganirsen eye drops (86 μg/day/eye) or placebo twice daily for 90 days and were followed up to day 180., Main Outcome Measures: The primary end point was VA. Secondary end points included area of pathologic corneal neovascularization, need for transplantation, risk of graft rejection, and QoL., Results: Although no significant differences in VA scores between groups were observed, aganirsen significantly reduced the relative corneal neovascularization area after 90 days by 26.20% (P = 0.014). This improvement persisted after 180 days (26.67%, P = 0.012). Aganirsen tended to lower the transplantation need in the intent-to-treat (ITT) population at day 180 (P = 0.087). In patients with viral keratitis and central neovascularization, a significant reduction in transplantation need was achieved (P = 0.048). No significant differences between groups were observed in the risk of graft rejection. However, aganirsen tended to decrease this risk in patients with traumatic/viral keratitis (P = 0.162) at day 90. The QoL analyses revealed a significant improvement with aganirsen in composite and near activity subscores (P = 0.039 and 0.026, respectively) at day 90 in the per protocol population. Ocular and treatment-related treatment-emergent adverse events (TEAEs) were reported in a lower percentage with aganirsen compared with placebo. Only 3 serious TEAEs (2 with aganirsen and 1 with placebo) were considered treatment-related., Conclusions: This first phase III study on a topical inhibitor of corneal angiogenesis showed that aganirsen eye drops significantly inhibited corneal neovascularization in patients with keratitis. The need for transplantation was significantly reduced in patients with viral keratitis and central neovascularization. Topical application of aganirsen was safe and well tolerated., (Copyright © 2014 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: When treating peripheral ectatic disease-like pellucid marginal degeneration (PMD), corneal cross-linking with UV-A and riboflavin (CXL) must be applied eccentrically to the periphery of the lower cornea, partly irradiating the corneal limbus. Here, we investigated the effect of standard and double-standard fluence corneal cross-linking with riboflavin and UV-A (CXL) on cornea and corneal limbus in the rabbit eye in vivo., Methods: Epithelium-off CXL was performed in male New Zealand White rabbits with two irradiation diameters (7 mm central cornea, 13 mm cornea and limbus), using standard fluence (5.4 J/cm(2)) and double-standard fluence (10.8 J/cm(2)) settings. Controls were subjected to epithelial removal and riboflavin instillation, but were not irradiated with UV-A. Following CXL, animals were examined daily until complete closure of the epithelium, and at 7, 14, 21, and 28 days. Animals were killed and a corneoscleral button was excised and processed for light microscopy and immunohistochemistry., Results: For both irradiation diameters and fluences tested, no signs of endothelial damage or limbal vessel thrombosis were observed, and time to re-epithelialization was similar to untreated controls. Histological and immunohistochemical analysis revealed no differences in the p63 putative stem cell marker expression pattern., Conclusions: Even when using fluence twice as high as the one used in current clinical CXL settings, circumferential UV-A irradiation of the corneal limbus does not alter the regenerative capacity of the limbal epithelial cells, and the expression pattern of the putative stem cell marker p63 remains unchanged. This suggests that eccentric CXL may be performed safely in PMD., (Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.)

We report a case of a 2,5 years old female, referred to our center for pancreatitis. Medical investigation revealed history of acute recurrent pancreatitis (ARP) since 1 year of age. Family history was negative for pancreatitis. Abdominal ultrasonography and magnetic resonance excluded both biliary tract stenosis and anatomic abnormalities. Calcium metabolic disorders, viral and bacterial infections were ruled out. Molecular sequencing of CFTR revealed heterozygosis for the mutation S1235R, a CFTR-related disorders associated mutation. Fecal elastase-1 (E1) was 529 μg/gr feces (normal value 200-500 μg/gr feces). No mutation of PRSS1 gene was detected but heterozygosity for p.Lys41Asn (c.123G>C), a new mutation of SPINK1 gene, was revealed. We speculate that the association of both SPINK1 and CFTR gene mutations may be responsible of ARP in our patient. Further studies need to better elucidate the role of genetic factors in ARP, as well as the influence of environmental factors.

Rationale: Hypoxia regulates the inflammatory-antiinflammatory balance by the receptor for advanced glycation end products (RAGE), a versatile sensor of damage-associated molecular patterns. The multiligand nature of RAGE places this receptor in the midst of chronic inflammatory diseases., Objectives: To characterize the impact of the hypoxia-RAGE pathway on pathogenic airway inflammation preventing effective pathogen clearance in cystic fibrosis (CF) and elucidate the potential role of this danger signal in pathogenesis and therapy of lung inflammation., Methods: We used in vivo and in vitro models to study the impact of hypoxia on RAGE expression and activity in human and murine CF, the nature of the RAGE ligand, and the impact of RAGE on lung inflammation and antimicrobial resistance in fungal and bacterial pneumonia., Measurements and Main Results: Sustained expression of RAGE and its ligand S100B was observed in murine lung and human epithelial cells and exerted a proximal role in promoting inflammation in murine and human CF, as revealed by functional studies and analysis of the genetic variability of AGER in patients with CF. Both hypoxia and infections contributed to the sustained activation of the S100B-RAGE pathway, being RAGE up-regulated by hypoxia and S100B by infection by Toll-like receptors. Inhibiting the RAGE pathway in vivo with soluble (s) RAGE reduced pathogen load and inflammation in experimental CF, whereas sRAGE production was defective in patients with CF., Conclusions: A causal link between hyperactivation of RAGE and inflammation in CF has been observed, such that targeting pathogenic inflammation alleviated inflammation in CF and measurement of sRAGE levels could be a useful biomarker for RAGE-dependent inflammation in patients with CF.

We conducted direct observation of 23 caregiver-infant pairs for 130 hours and recorded wash-related behaviors to identify pathways of fecal-oral transmission of bacteria among infants. In addition to testing fingers, food, and drinking water of infants, three infants actively ingested 11.3 ± 9.2 (mean ± SD) handfuls of soil and two ingested chicken feces 2 ± 1.4 times in 6 hours. Hand washing with soap was not common and drinking water was contaminated with Escherichia coli in half (12 of 22) of the households. A one-year-old infant ingesting 1 gram of chicken feces in a day and 20 grams of soil from a laundry area of the kitchen yard would consume 4,700,000-23,000,000 and 440-4,240 E. coli, respectively, from these sources. Besides standard wash and nutrition interventions, infants in low-income communities should be protected from exploratory ingestion of chicken feces, soil, and geophagia for optimal child health and growth.

Objective: Hepatic steatosis is strongly associated with insulin resistance, but causative mechanisms that link these conditions are still largely unknown. Nowadays, it is difficult to establish whether fatty liver is the cause of insulin resistance or instead the complex metabolic derangements of insulin resistance determine hepatic steatosis and its progression to fibrosis. In patients with familial hypobetalipoproteinemia (FHBL), hepatic steatosis is because of the genetically determined defective form of apolipoprotein B, independently of metabolic derangements. Therefore patients with FHBL represent a good in vivo model to evaluate the relationships between fatty liver and insulin sensitivity., Methods: We evaluated insulin resistance through HOMA-IR in 60 children with echografic and histological features of steatosis; 30 of whom had nonalcoholic fatty liver disease (NAFLD) and 30 had FHBL., Results: All patients had histological features of hepatic steatosis. Patients with FHBL were hypolipidemic, as expected. No significant differences between two groups were observed in liver function tests. IRI and HOMA-IR were statistically higher in NAFLD subjects compared to the FHBL group., Conclusion: In our study, we demonstrated that in children with FHBL, hepatic steatosis is dissociated from insulin resistance. This finding suggests that fat accumulation per se may be not a sufficient causal factor leading to insulin resistance, and that other mediators may be involved in the development of alteration in glucose metabolism and metabolic syndrome in patients with NAFLD., (© 2012 John Wiley & Sons Ltd.)

Maintenance of corneal transparency is crucial for vision and depends mainly on the endothelium, a non-proliferative monolayer of cells covering the inner part of the cornea. When endothelial cell density falls below a critical threshold, the barrier and "pump" functions of the endothelium are compromised which results in corneal oedema and loss of visual acuity. The conventional treatment for such severe disorder is corneal graft. Unfortunately, there is a worldwide shortage of donor corneas, necessitating amelioration of tissue survival and storage after harvesting. Recently it was reported that the ROCK inhibitor Y-27632 promotes adhesion, inhibits apoptosis, increases the number of proliferating monkey corneal endothelial cells in vitro and enhance corneal endothelial wound healing both in vitro and in vivo in animal models. Using organ culture human cornea (N = 34), the effect of ROCK inhibitor was evaluated in vitro and ex vivo. Toxicity, corneal endothelial cell density, cell proliferation, apoptosis, cell morphometry, adhesion and wound healing process were evaluated by live/dead assay standard cell counting method, EdU labelling, Ki67, Caspase3, Zo-1 and Actin immunostaining. We demonstrated for the first time in human corneal endothelial cells ex vivo and in vitro, that ROCK inhibitor did not induce any toxicity effect and did not alter cell viability. ROCK inhibitor treatment did not induce human corneal endothelial cells proliferation. However, ROCK inhibitor significantly enhanced adhesion and wound healing. The present study shows that the selective ROCK inhibitor Y-27632 has no effect on human corneal endothelial cells proliferative capacities, but alters cellular behaviours. It induces changes in cell shape, increases cell adhesion and enhances wound healing ex vivo and in vitro. Its absence of toxicity, as demonstrated herein, is relevant for its use in human therapy.

Background: To evaluate outcomes after optimized laser in situ keratomileusis (LASIK) for astigmatism correction with flap created by a mechanical microkeratome or a femtosecond laser., Patients and Methods: In this retrospective study, a total of 102 eyes of 71 consecutive patients were enrolled undergoing optimized LASIK treatments using the Allegretto laser system (WaveLight Laser Technologie AG, Erlangen, Germany). A mechanical microkeratome for flap creation was used (One Use, Moria®) in 46 eyes (31 patients, spherical equivalent [SE] -4.44 D ± 2.4) and a femtosecond laser was used (LDV, Ziemer®) in 56 eyes (40 patients, spherical equivalent [SE] -3.07 D ± 3.3). The two groups were matched for inclusion criteria and were operated under similar conditions by the same surgeon., Results: Overall, the preoperative spherical equivalent was -9.5 diopters (D) to +3.37 D; the preoperative manifest astigmatism was between -1.5 D and -3.5 D. At 6 months postoperatively, the mean postoperative uncorrected distance visual acuity (UDVA) was 0.93 ± 0.17 (range 0.4 to 1.2) in the Moria group and 1.0 ± 0.21 (range 0.6 to 1.6) in the Femto group, which was statistically significant (p = 0.003). Comparing the cylinder power there was a statistical difference between the two groups (p = 0.0015)., Conclusions: This study shows that the method of flap creation has a significant impact on postoperative astigmatism with a significantly better postoperative UDVA in the Femto group. These findings suggest that the femtosecond laser provides a better platform for LASIK treatment of astigmatism than the commonly used microkeratome., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: To evaluate the long-term efficacy of multilayer amniotic membrane transplantation for reconstruction of epithelium and stroma in non-traumatic corneal perforations (less than 2 mm) or deep ulcers with descemetocele., Design: Retrospective, non-comparative, interventional case series., Patients and Methods: Eleven consecutive patients with non-traumatic corneal perforations or deep corneal ulcers with descemetocele refractory to conventional treatments: herpetic or zoster keratitis (n = 4), Sjögren's syndrome (n = 2), rosacea (n = 1), hydrops (n = 1), mucous membrane pemphigoid (n = 1), bacterial keratitis (n = 1) and perforation after protontherapy for melanoma (n = 1). Intervention was: multilayer amniotic membrane transplantation with cryopreserved amniotic membrane. Complication rate and clinical outcome were evaluated in this long-term follow-up., Results: Mean follow-up was 32 months (12 to 60). Integration of the multilayer amniotic membrane was obtained in 10 cases after one year. Corneal epithelium healed above the membrane in 10 cases within 3 weeks and remained stable after 32 months in 9 cases. Thickness of the stroma was increased and remained stable during the follow-up in 9 cases. In one case herpetic keratitis recurred with a corneal perforation. The clearing of the amniotic membrane was gradually obtained over a period of 11 months. Complications occurred in 15% of the eyes during the long-term follow-up., Conclusion: Multilayer amniotic membrane transplantation is a safe and efficient technique for a long restoration of the corneal integrity after non-traumatic corneal perforations or deep corneal ulcers with descemetocele. Long-term prognosis of these eyes depends of the gravity of the initial disease., (Georg Thieme Verlag KG Stuttgart · New York.)

According to the World Health Organization, 5.1% of blindnesses or visual impairments are related to corneal opacification. Cornea is a transparent tissue placed in front of the color of the eye. Its transparency is mandatory for vision. The ocular surface is a functional unit including the cornea and all the elements involved in maintaining its transparency i.e., the eyelids, the conjunctiva, the lymphoid tissue of the conjunctiva, the limbus, the lacrymal glands and the tear film. The destruction of the ocular surface is a disease caused by : traumatisms, infections, chronic inflammations, cancers, toxics, unknown causes or congenital abnormalities. The treatment of the ocular surface destruction requires a global strategy including all the elements that are involved in its physiology. The microenvironnement of the ocular surface must first be restored, i.e., the lids, the conjunctiva, the limbus and the structures that secrete the different layers of the tear film. In a second step, the transparency of the cornea can be reconstructed. A corneal graft performed in a healthy ocular surface microenvironnement will have a better survival rate. To achieve these goals, a thorough understanding of the renewal of the epitheliums and the role of the epithelial stem cells are mandatory., (© Société de Biologie, 2013.)

Mucous membrane pemphigoid (MMP) is a progressive inflammatory disease of autoimmune etiology. We performed a retrospective analysis of clinical signs and treatment on 16 patients. Conjunctival biopsies were performed in all patients and showed typical immuno-deposits at the basement membrane zone. The mean age at presentation was 69 years, 60 % were female.12 patients demonstrated ocular involvement (11 bilaterally). At the time of referral to our hospital, 92 % had reached an advanced stage III or IV. All patients presented conjunctival fibrosis with resultant fornix foreshortening. Trichiasis and symblepharon were found in 11 patients. Keratitis was found in 11 patients resulting in ulceration in 5 cases. Complications required surgical interventions included: entropion surgery (n = 2), tarsorrhaphy (n = 1), amniotic membrane transplantation (n = 2), keratoplasty (n = 1). Systemic immunomodulatory therapy is the treatment of choice. Dapsone (n = 8), steroids (n = 8), azathioprine (n = 5), cyclophosphamide (n = 2), mycophenolate mofetil (n = 4) and methotrexate (n = 1) were used concomitantly or consecutively. Early diagnosis can prevent ocular complications. Immunomodulatory therapy has provided an avenue for preserving vision. The management of MMP requires a multidisciplinary approach., (© Georg Thieme Verlag KG Stuttgart · New York.)

Introduction: In this study we describe and discuss the way we daily act in remote telematic tracking of CF outpatients, a procedure which has been improved through our daily experience in telehomecare., Materials and Methods: Currently, there are almost 30 patients involved in our telehomecare project. We describe and discuss intervention parameters and the way we manage a register of performances in spreadsheet format. We also describe the training program for the patients and their and the procedures through which we maintain contacts with patients and Vivisol assistance and the periodical satisfaction surveys., Results: (from 15 of february 2010 to 24 of may 2011). Total transmissions 882, Spirometry 1317, SaO2 291, Compliance (transmissions/patient days) 8,91%, Hospital controls 19, Total contacts 722, Phone calls 494., Discussion: We analyze the 2010 - 2011 data. We discuss the compliance of patients toward Telehomecare, the efficacy of cell phone in establishing contact with patients and the relevancy of symptoms' rescue in diagnosing the pulmonary relapse episodes. We discuss medico-legal aspects of telemedicine activity, in the light of standards and legislation, including issues related to the processing of privacy and security data. We discuss the professional team needs and requirements, dedicated to the activities of telemedicine and procedures related to clinical risk management. We conclude by underlying how telemedicine represents a promising new tool for patients and health professionals, and that under certain conditions it can improve the assistance, working conditions and also to reduce costs. However, its usage has to be followed by precise studies about its efficacy, and also by paying particular attention to the partly new issues that derive from it.