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Phenotype distortion of lung resident mesenchymal stem cells (MSC) in preterm infants is a hallmark event in the pathogenesis of bronchopulmonary dysplasia (BPD). Here, we evaluated the impact of cyclic mechanical stretch (CMS) and hyperoxia (HOX). The negative action of HOX on proliferation and cell death was more pronounced at 80% than at 40%. Although the impact of CMS alone was modest, CMS plus HOX displayed the strongest effect sizes. Exposure to CMS and/or HOX induced the downregulation of PDGFRα, and cellular senescence preceded by p21 accumulation. p21 interference interfered with cellular senescence and resulted in aggravated cell death, arguing for a prosurvival mechanism. HOX 40% and limited exposure to HOX 80% prevailed in a reversible phenotype with reuptake of proliferation, while prolonged exposure to HOX 80% resulted in definite MSC growth arrest. Our mechanistic data explain how HOX and CMS induce the effects on MSC phenotype disruption. The results are congruent with the clinical observation that preterm infants requiring supplemental oxygen plus mechanical ventilation are at particular risk for BPD. Although inhibiting p21 is not a feasible approach, limiting the duration and magnitude of the exposures is promising. NEW & NOTEWORTHY Rarefication of lung mesenchymal stem cells (MSC) due to exposure to cyclic mechanical stretch (CMS) during mechanical ventilation with oxygen-rich gas is a hallmark of bronchopulmonary dysplasia in preterm infants, but the pathomechanistic understanding is incomplete. Our studies identify a common signaling mechanism mediated by p21 accumulation, leading to cellular senescence and cell death, most pronounced during the combined exposure with in principle reversible phenotype change depending on strength and duration of exposures.

Background: Fibrosis is often associated with aberrant repair mechanisms that ultimately lead to organ failure. In the lung, idiopathic pulmonary fibrosis (IPF) is a fatal form of interstitial lung disease (ILD) to which there is currently no curative therapy. From the cell biology point of view, the cell of origin and eventual fate of activated myofibroblasts (aMYFs) have taken center stage as these cells are believed to drive structural remodeling and lung function impairment. While aMYFs are now widely believed to originate from resident fibroblasts, the heterogeneity of aMYFs and ultimate fate during fibrosis resolution remain elusive. We have previously shown that aMYFs dedifferentiation and acquisition of a lipofibroblast (LIF)-like phenotype represent a route of fibrosis resolution., Methods: In this study, we combined genetic lineage tracing and single-cell transcriptomics in mice, and data mining of human IPF datasets to decipher the heterogeneity of aMYFs and investigate differentiation trajectories during fibrosis resolution. Furthermore, organoid cultures were utilized as a functional readout for the alveolar mesenchymal niche activity during various phases of injury and repair in mice., Results: Our data demonstrate that aMYFs consist of four subclusters displaying unique pro-alveologenic versus profibrotic profiles. Alveolar fibroblasts displaying a high LIF-like signature largely constitute both the origin and fate of aMYFs during fibrogenesis and resolution respectively. The heterogeneity of aMYFs is conserved in humans and a significant proportion of human aMYFs displays a high LIF signature., Conclusion: Our work identifies a subcluster of aMYFs that is potentially relevant for future management of IPF., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: Myofibroblasts (MYFs) are generally considered the principal culprits in excessive extracellular matrix deposition and scar formation in the pathogenesis of lung fibrosis. Lipofibroblasts (LIFs), on the other hand, are defined by their lipid-storing capacity and are predominantly found in the alveolar regions of the lung. They have been proposed to play a protective role in lung fibrosis. We previously reported that a LIF to MYF reversible differentiation switch occurred during fibrosis formation and resolution. In this study, we tested whether WI-38 cells, a human embryonic lung fibroblast cell line, could be used to study fibroblast differentiation towards the LIF or MYF phenotype and whether this could be relevant for idiopathic pulmonary fibrosis (IPF). Methods: Using WI-38 cells, Fibroblast (FIB) to MYF differentiation was triggered using TGF-β1 treatment and FIB to LIF differentiation using Metformin treatment. We also analyzed the MYF to LIF and LIF to MYF differentiation by pre-treating the WI-38 cells with TGF-β1 or Metformin respectively. We used IF, qPCR and bulk RNA-Seq to analyze the phenotypic and transcriptomic changes in the cells. We correlated our in vitro transcriptome data from WI-38 cells (obtained via bulk RNA sequencing) with the transcriptomic signature of LIFs and MYFs derived from the IPF cell atlas as well as with our own single-cell transcriptomic data from IPF patients-derived lung fibroblasts (LF-IPF) cultured in vitro . We also carried out alveolosphere assays to evaluate the ability of the proposed LIF and MYF cells to support the growth of alveolar epithelial type 2 cells. Results : WI-38 cells and LF-IPF display similar phenotypical and gene expression responses to TGF-β1 and Metformin treatment. Bulk RNA-Seq analysis of WI-38 cells and LF-IPF treated with TGF-β1, or Metformin indicate similar transcriptomic changes. We also show the partial conservation of the LIF and MYF signature extracted from the Habermann et al. scRNA-seq dataset in WI-38 cells treated with Metformin or TGF-β1, respectively. Alveolosphere assays indicate that LIFs enhance organoid growth, while MYFs inhibit organoid growth. Finally, we provide evidence supporting the MYF to LIF and LIF to MYF reversible switch using WI-38 cells. Conclusions: WI-38 cells represent a versatile and reliable model to study the intricate dynamics of fibroblast differentiation towards the MYF or LIF phenotype associated with lung fibrosis formation and resolution, providing valuable insights to drive future research., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: The precise origin of newly formed ACTA2+ (alpha smooth muscle actin-positive) cells appearing in nonmuscularized vessels in the context of pulmonary hypertension is still debatable although it is believed that they predominantly derive from preexisting vascular smooth muscle cells (VSMCs)., Methods: Gli1 Cre-ERT2 ; tdTomato flox mice were used to lineage trace GLI1+ (glioma-associated oncogene homolog 1-positive) cells in the context of pulmonary hypertension using 2 independent models of vascular remodeling and reverse remodeling: hypoxia and cigarette smoke exposure. Hemodynamic measurements, right ventricular hypertrophy assessment, flow cytometry, and histological analysis of thick lung sections followed by state-of-the-art 3-dimensional reconstruction and quantification using Imaris software were used to investigate the contribution of GLI1+ cells to neomuscularization of the pulmonary vasculature., Results: The data show that GLI1+ cells are abundant around distal, nonmuscularized vessels during steady state, and this lineage contributes to around 50% of newly formed ACTA2+ cells around these normally nonmuscularized vessels. During reverse remodeling, cells derived from the GLI1+ lineage are largely cleared in parallel to the reversal of muscularization. Partial ablation of GLI1+ cells greatly prevented vascular remodeling in response to hypoxia and attenuated the increase in right ventricular systolic pressure and right heart hypertrophy. Single-cell RNA sequencing on sorted lineage-labeled GLI1+ cells revealed an Acta2 high fraction of cells with pathways in cancer and MAPK (mitogen-activated protein kinase) signaling as potential players in reprogramming these cells during vascular remodeling. Analysis of human lung-derived material suggests that GLI1 signaling is overactivated in both group 1 and group 3 pulmonary hypertension and can promote proliferation and myogenic differentiation., Conclusions: Our data highlight GLI1+ cells as an alternative cellular source of VSMCs in pulmonary hypertension and suggest that these cells and the associated signaling pathways represent an important therapeutic target for further studies., Competing Interests: Disclosures None.

Purpose: To assess the prevalence of alterations in anthropometric parameters predictive of metabolic syndrome and cardiovascular risk among childhood brain tumor survivors., Methods: Anthropometric parameters predictive of metabolic syndrome and cardiovascular risk were analyzed [height, weight, BMI, waist circumference, hip circumference, waist-height ratio (WHtR), waist-hip ratio (WHR, blood pressure] of 25 patients who survived childhood brain tumors., Results: 21 patients (84%) showed alteration of at least one predictive anthropometric parameter. 11 patients (44%) showed a BMI > 75th percentile and 19 patients (76%) showed a pathological WHR value. A pathological WHtR (> 0.5), was identified in 17 patients (68%); the average WHtR observed was 0.53. 9 patients (36%) showed an alteration of all three anthropometric parameters considered. Comparing this subpopulation with the subpopulation with less than three altered parameters, a greater prevalence of the combined alteration was observed in the female sex compared to the male sex (67% vs. 26%). No significant differences were observed regarding the age of diagnosis and end of treatment nor the treatments carried out (chemotherapy, radiotherapy, steroid therapy) between the two groups., Conclusion: These results suggest that this population is at high risk of presenting pathological values of BMI, WHR and WHtR with consequent high risk of developing metabolic syndrome and cardiovascular diseases., (© 2024. The Author(s).)

In recent decades, the improvement of treatments and the adoption of therapeutic protocols of international cooperation has led to an improvement in the survival of children affected by brain tumors. However, in parallel with the increase in survival, long-term side effects related to treatments have been observed over time, including the activation of chronic inflammatory processes and metabolic alterations, which can facilitate the onset of metabolic syndrome and increased cardiovascular risk. The aim of this study was to find possible statistically significant differences in the serum concentrations of early biomarkers of metabolic syndrome and in the results of cardiopulmonary exercise testing between survivors of childhood brain tumors and healthy controls. This is a prospective and observational study conducted on a group of 14 male patients who survived childhood brain tumors compared with the same number of healthy controls. The concentrations of early metabolic syndrome biomarkers [adiponectin, leptin, TNF-α, IL-1, IL-6, IL-10, endothelin-1, apolipoprotein B, and lipoprotein (a)] were measured and a cardiopulmonary exercise test (CPET) was performed. Results: Childhood brain tumor survivors performed worse on average than controls on the CPET. Furthermore, they showed higher endothelin-1 values than controls ( p = 0.025). The CPET results showed an inverse correlation with leptin. The differences found highlight the greater cardiovascular risk of brain tumor survivors, and radiotherapy could be implicated in the genesis of this greater cardiovascular risk.

Aminoglycosides are broad-spectrum antibiotics largely used in children, but they have potential toxic side effects, including ototoxicity. Ototoxicity from aminoglycosides is permanent and is a consequence of its action on the inner ear cells via multiple mechanisms. Both uncontrollable risk factors and controllable risk factors are involved in the pathogenesis of aminoglycoside-related ototoxicity and, because of the irreversibility of ototoxicity, an important undertaking for preventing ototoxicity includes antibiotic stewardship to limit the use of aminoglycosides. Aminoglycosides are fundamental in the treatment of numerous infectious conditions at neonatal and pediatric age. In childhood, normal auditory function ensures adequate neurocognitive and social development. Hearing damage from aminoglycosides can therefore strongly affect the normal growth of the child. This review describes the molecular mechanisms of aminoglycoside-related ototoxicity and analyzes the risk factors and the potential otoprotective strategies in pediatric patients.

Background: Platinum compounds are a group of fundamental chemotherapeutics used in the treatment of solid tumors, but they are burdened by side effects, such as ototoxicity. The objective of this study was to evaluate the incidence of ototoxicity caused by platinum compounds and the risk factors affecting its appearance/progression., Methods: Data from 53 patients who received platinum compounds and who had been off therapy for at least 5 years were analyzed. We collected data relating to audiometry conducted annually from the end of treatment and for at least 5 subsequent years, as well as information concerning the oncological history and comorbidities., Results: At the end of the treatment, 17 patients (32.08%) presented ototoxicity, according to the Boston SIOP Ototoxicity Scale; the risk factors included a higher serum creatinine value at diagnosis, having undergone cranial radiotherapy, and needing magnesium supplementation. After 5 years from the end of the treatment, the number of patients with exhibiting ototoxicity was 31 (58.5%); the factors that influenced the onset/progression of the damage were having undergone radiotherapy (HR 1.23; p < 0.01) and having received therapy with aminoglycosides (HR 1.27; p < 0.01)., Conclusions: Ototoxicity caused by platinum compounds can occur even after the conclusion of the treatments, and the factors affecting its progression are radiotherapy and the aminoglycosides therapy.

Intra-amniotic infection (IAI) is one major driver for preterm birth and has been demonstrated by clinical studies to exert both beneficial and injurious effects on the premature lung, possibly due to heterogeneity in the microbial type, timing, and severity of IAI. Due to the inaccessibility of the intra-amniotic cavity during pregnancies, preclinical animal models investigating pulmonary consequences of IAI are indispensable to elucidate the pathogenesis of bronchopulmonary dysplasia (BPD). It is postulated that on one hand imbalanced inflammation, orchestrated by lung immune cells such as macrophages, may impact on airway epithelium, vascular endothelium, and interstitial mesenchyme, resulting in abnormal lung development. On the other hand, excessive suppression of inflammation may as well cause pulmonary injury and a certain degree of inflammation is beneficial. So far, effective strategies to prevent and treat BPD are scarce. Therapeutic options targeting single mediators in signaling cascades and mesenchymal stromal cells (MSCs)-based therapies with global regulatory capacities have demonstrated efficacy in preclinical animal models and warrant further validation in patient populations. Ante-, peri- and postnatal exposome analysis and therapeutic investigations using multiple omics will fundamentally dissect the black box of IAI and its effect on the premature lung, contributing to precisely tailored and individualized therapies.

The incidence of PAC is relatively infrequent among pregnant women. However, it has gradually increased in recent years, becoming a challenging area for clinicians that should take into account in the same way maternal benefits and fetal potential risks correlated to the antineoplastic treatment. None of the antineoplastic drugs is completely risk-free during the pregnancy, the timing of exposure and transplacental transfer properties influence the toxicity of the fetus. Despite the lack of guidelines about the management of PAC, several studies have described the use and the potential fetal and neonatal adverse events of antineoplastic drugs during pregnancy. We provide a review of the available literature about the transplacental passage and fetal effects of chemotherapy and targeted agents, to guide the clinicians in the most appropriate choices for the management of PAC.

Bronchopulmonary dysplasia (BPD) is a neonatal lung disease developing in premature babies characterized by arrested alveologenesis and associated with decreased Fibroblast growth factor 10 (FGF10) expression. One-week hyperoxia (HYX) exposure of newborn mice leads to a permanent arrest in alveologenesis. To test the role of Fgf10 signaling to promote de novo alveologenesis following hyperoxia, we used transgenic mice allowing inducible expression of Fgf10 and recombinant FGF10 (rFGF10) protein delivered intraperitoneally. We carried out morphometry analysis, and IF on day 45. Alveolospheres assays were performed co-culturing AT2s from normoxia (NOX) with FACS-isolated Sca1Pos resident mesenchymal cells (rMC) from animals exposed to NOX, HYX-PBS, or HYX-FGF10. scRNAseq between rMC-Sca1Pos isolated from NOX and HYX-PBS was also carried out. Transgenic overexpression of Fgf10 and rFGF10 administration rescued the alveologenesis defects following HYX. Alveolosphere assays indicate that the activity of rMC-Sca1Pos is negatively impacted by HYX and partially rescued by rFGF10 treatment. Analysis by IF demonstrates a significant impact of rFGF10 on the activity of resident mesenchymal cells. scRNAseq results identified clusters expressing Fgf10, Fgf7, Pdgfra, and Axin2, which could represent the rMC niche cells for the AT2 stem cells. In conclusion, we demonstrate that rFGF10 administration is able to induce de novo alveologenesis in a BPD mouse model and identified subpopulations of rMC-Sca1Pos niche cells potentially representing its cellular target., (© The Author(s) 2022. Published by Oxford University Press.)

The improvement in childhood cancer treatments resulted in a marked improvement in the survival of pediatric cancer patients. However, as survival increased, it was also possible to observe the long-term side effects of cancer therapies. Among these, metabolic syndrome is one of the most frequent long-term side effects, and causes high mortality and morbidity. Consequently, it is necessary to identify strategies that allow for early diagnosis. In this review, the pathogenetic mechanisms of metabolic syndrome and the potential new biomarkers that can facilitate its diagnosis in survivors of pediatric tumors are analyzed.

Fibroblast growth factor receptor 2b (Fgfr2b) signaling is essential throughout lung development to form the alveolar epithelial lineage. However, its role in alveolar epithelial type 2 cells (AT2s) homeostasis was recently considered dispensable. Sftpc CreERT2 ; Fgfr2b flox/flox ; tdTomato flox/flox mice were used to delete Fgfr2b expression in cells belonging to the AT2 lineage, which contains mature AT2s and a novel Sftpc Low lineage-traced population called "injury activated alveolar progenitors" or IAAPs. Upon continuous tamoxifen exposure for either 1 or 2 weeks to delete Fgfr2b, a shrinking of the AT2 population is observed. Mature AT2s exit the cell cycle, undergo apoptosis and fail to form alveolospheres in vitro. However, the lung morphometry appears normal, suggesting the involvement of compensatory mechanisms. In mutant lungs, IAAPs which escaped Fgfr2b deletion expand, display enhanced alveolosphere formation in vitro and increase drastically their AT2 signature, suggesting differentiation towards mature AT2s. Interestingly, a significant increase in AT2s and decrease in IAPPs occurs after a 1-week tamoxifen exposure followed by an 8-week chase period. Although mature AT2s partially recover their alveolosphere formation capabilities, the IAAPs no longer display this property. Single-cell RNA seq analysis confirms that AT2s and IAAPs represent stable and distinct cell populations and recapitulate some of their characteristics observed in vivo. Our results underscore the essential role played by Fgfr2b signaling in the maintenance of the AT2 lineage in the adult lung during homeostasis and suggest that the IAAPs could represent a new population of AT2 progenitors., (© 2022. The Author(s).)

Even more than 50 years after its initial description, bronchopulmonary dysplasia (BPD) remains one of the most important and lifelong sequelae following premature birth. Tremendous efforts have been undertaken since then to reduce this ever-increasing disease burden but a therapeutic breakthrough preventing BPD is still not in sight. The inflammatory response provoked in the immature lung is a key driver of distorted lung development and impacts the formation of alveolar, mesenchymal, and vascular structures during a particularly vulnerable time-period. During the last 5 years, new scientific insights have led to an improved pathomechanistic understanding of BPD origins and disease drivers. Within the framework of current scientific progress, concepts involving disruption of the balance of key inflammatory and lung growth promoting pathways by various stimuli, take center stage. Still today, the number of efficient therapeutics available to prevent BPD is limited to a few, well-established pharmacological interventions including postnatal corticosteroids, early caffeine administration, and vitamin A. Recent advances in the clinical care of infants in the neonatal intensive care unit (NICU) have led to improvements in survival without a consistent reduction in the incidence of BPD. Our update provides latest insights from both preclinical models and clinical cohort studies and describes novel approaches to prevent BPD., (© 2022. The Author(s).)

Prognosis of metastatic neuroblastoma is very poor. Its treatment includes induction chemotherapy, surgery, high-dose chemotherapy, radiotherapy, and maintenance with retinoic acid, associated with the anti-GD2 monoclonal antibody (ch14.18) dinutuximab. Immunotherapy determined a significant improvement in survival rate and is also utilized in relapsed and resistant neuroblastoma patients. Five courses of dinutuximab 100 mg/m 2 are usually administered as a 10-day continuous infusion or over 5 consecutive days every 5 weeks. Dinutuximab targets the disialoganglioside GD2, which is highly expressed on neuroblastoma cells and minimally present on the surface of normal human neurons, peripheral pain fibers, and skin melanocytes. Anti GD2 antibodies bind to surface GD2 and determine the lysis of neuroblastoma cells induced by immune response via the antibody-dependent cellular cytotoxicity and the complement-dependent cytotoxicity. Dinutuximab has significant side effects, including neuropathic pain, peripheral neuropathy, hypersensitivity reactions, capillary leak syndrome, photophobia, and hypotension. The most important side effect is neuropathic pain, which is triggered by the same antibody-antigen immune response, but generates ectopic activity in axons, which results in hyperalgesia and spontaneous pain. Pain can be severe especially in the first courses of dinutuximab infusion, and requires the administration of gabapentin and continuous morphine infusion. This paper will focus on the incidence, mechanisms, characteristics, and treatment of neuropathic pain and peripheral neuropathy due to dinutuximab administration in neuroblastoma patients.

Alveolar type 2 (AT2) cells are heterogeneous cells, with specialised AT2 subpopulations within this lineage exhibiting stem cell properties. However, the existence of quiescent, immature cells within the AT2 lineage that are activated during lung regeneration is unknown. Sftpc CreERT2/+ ;tdTomato flox/flox mice were used for the labelling of AT2 cells and labelled subpopulations were analysed by flow cytometry, quantitative PCR, assay for transposase-accessible chromatin using sequencing (ATAC-seq), gene arrays, pneumonectomy and culture of precision-cut lung slices. Single-cell RNA-sequencing (scRNA-seq) data from human lungs were analysed.In mice, we detected two distinct AT2 subpopulations, with low tdTomato level (Tom Low ) and high tdTomato level (Tom High ). Tom Low cells express lower levels of the AT2 differentiation markers Fgfr2b and Etv5 , while Tom High , as bona fide mature AT2 cells, show higher levels of Sftpc , Sftpb , Sftpa1 , Fgfr2b and Etv5 expression. ATAC-seq analysis indicates that Tom Low and Tom High cells constitute two distinct cell populations, with specific silencing of Sftpc , Rosa26 and cell cycle gene loci in the Tom Low population. Upon pneumonectomy, the number of Tom Low but not Tom High cells increases and Tom Low cells show upregulated expression of Fgfr2b , Etv5 , Sftpc , Ccnd1 and Ccnd2 compared to Sham. Tom Low cells overexpress programmed cell death 1 ligand 1 (PD-L1), an immune inhibitory membrane receptor ligand, which is used by flow cytometry to differentially isolate these two subpopulations. In the human lung, data mining of a recent scRNA-seq AT2 data set demonstrates the existence of a PD-L1 Pos population. Therefore, we have identified a novel population of AT2 quiescent, immature progenitor cells in mouse that expand upon pneumonectomy and we have provided evidence for the existence of such cells in human., Competing Interests: Conflict of interest: N. Ahmadvand has nothing to disclose. Conflict of interest: F. Khosravi has nothing to disclose. Conflict of interest: A. Lingampally has nothing to disclose. Conflict of interest: R. Wasnick has nothing to disclose. Conflict of interest: I. Vasquez-Armendariz has nothing to disclose. Conflict of interest: G. Carraro has nothing to disclose. Conflict of interest: M. Heiner has nothing to disclose. Conflict of interest: S. Rivetti has nothing to disclose. Conflict of interest: Y. Lv has nothing to disclose. Conflict of interest: J. Wilhelm has nothing to disclose. Conflict of interest: A. Gunther has nothing to disclose. Conflict of interest: S. Herold has nothing to disclose. Conflict of interest: D. Al Alam has nothing to disclose. Conflict of interest: C. Chen has nothing to disclose. Conflict of interest: P. Minoo has nothing to disclose. Conflict of interest: J-S. Zhang has nothing to disclose. Conflict of interest: S. Bellusci has nothing to disclose., (Copyright ©The authors 2021.)

We report a case of spontaneous pneumomediastinum, pneumothorax, emphysema subcutaneous and pneumorrhachis, occurring in an adolescent resulting positive to SARS-CoV-2 nasopharyngeal swab. At the admission in Emergency Department, the child presented with left cervical and sternal pain, without respiratory symptoms. Radiological studies showed sizeable pneumomediastinum, bilateral apical pneumothorax, massive emphysema subcutaneous and pneumorrhachis. Patients' clinical conditions stood stable during the monitoring and he only needed conservative management. To our knowledge, this is the first description of spontaneous pneumomediastinum, pneumothorax, emphysema subcutaneous and pneumorrhachis, in a COVID-19 adolescent without concomitant pneumonia.

Background: Observation Units (OU), as part of emergency department (ED), are areas reserved for short-term treatment or observation of patients with selected diagnoses to determine the need for hospitalization or home referral., Methods: In this retrospective cohort study, we analyzed similarities and differences of children admitted to the pediatric ED of the Fondazione Policlinico Universitario A. Gemelli IRCCS hospital in the first 2 years of OU activity, analyzing general patient characteristics, access modalities, diagnosis, triage, laboratory and instrumental examinations, specialist visits, outcome of OU admission and average time spent in OU. Furthermore, we compared total numbers and type of hospitalization of the first 2 years of OU activity with those of previous 2 years., Results: The most frequent diagnoses were abdominal pain, minor head injury without loss of consciousness, vomiting, epilepsy and acute bronchiolitis. The most performed laboratory examinations were blood count. The most commonly performed instrumental examination was abdominal ultrasound. Neurological counseling was the most commonly requested. Average time spent in OU was 13 h in 2016 and 14.1 h in 2017. Most OU admissions did not last longer than 24 h (90.5% in 2016 and 89.5% in 2017). In the years 2014-2015, 13.4% of pediatric patients accessing the ED were hospitalized, versus 9.9% the years 2016-2017 reducing pediatric hospital admissions by 3.6% (p <  0.001)., Conclusions: This study demonstrate that OU is a valid alternative to ordinary wards for specific pathologies. In accordance with the literature, our study showed that, in the first 2 years of the OU activity, admissions to hospital ward decreased compared with the previous 2 years with an increase of complex patients.

Tissue regeneration requires coordinated and dynamic remodeling of stem and progenitor cells and the surrounding niche. Although the plasticity of epithelial cells has been well explored in many tissues, the dynamic changes occurring in niche cells remain elusive. Here, we show that, during lung repair after naphthalene injury, a population of PDGFRα + cells emerges in the non-cartilaginous conducting airway niche, which is normally populated by airway smooth muscle cells (ASMCs). This cell population, which we term "repair-supportive mesenchymal cells" (RSMCs), is distinct from conventional ASMCs, which have previously been shown to contribute to epithelial repair. Gene expression analysis on sorted lineage-labeled cells shows that RSMCs express low levels of ASMC markers, but high levels of the pro-regenerative marker Fgf10. Organoid co-cultures demonstrate an enhanced ability for RSMCs in supporting club-cell growth. Our study highlights the dynamics of mesenchymal cells in the airway niche and has implications for chronic airway-injury-associated diseases., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Idiopathic Pulmonary Fibrosis (IPF) is an end-stage lung disease characterized by excessive extracellular matrix (ECM) deposition from activated myofibroblasts (MYFs) and tissue scarring. Eventually leading to stiffening of the lung, capable of assuming only limited gas exchange function. So far two drugs, pirfenidone [acting via TGF-β (transforming growth factor beta) inhibition] and nintedanib (a pan-tyrosine kinase receptor inhibitor) have been approved for IPF patients. They both act on the activated MYF by reducing the expression of fibrotic markers. Unfortunately, these drugs are only slowing down fibrosis formation and as such do not represent a cure for this lethal, devastating disease. We previously reported that activated MYF originate, at least in part, from lung fibroblast resident cells called lipofibroblasts (LIF). During resolution, these activated MYF can transdifferentiate into LIF. We propose that this reversible myogenic/lipogenic transdifferentiation switch paradigm can be used to screen for drugs capable of triggering the lipogenic differentiation of activated MYFs. Ideally, these drugs should also induce the reduction of pro-fibrotic markers alpha smooth muscle actin2 (ACTA2) and collagen 1A1 (COL1A1) in activated MYF and as such would represent important alternatives to the approved drugs. The goal of this review is to summarize the current knowledge and limitations of the current strategies aiming to carry out methodical pre-clinical drug screening in pertinent in vitro , ex vivo , and in vivo models of IPF. These models include (1) in vitro culture of primary fibroblasts from IPF patients, (2) ex vivo culture of precision cut lung slices from end-stage IPF lungs obtained from transplant patients, and (3) bleomycin-induced fibrosis mouse models in the context of lineage tracing of activated MYF during resolution. For all these assays, we propose the innovative use of lipogenic read outs for the LIFs., (Copyright © 2020 Lingampally, Jones, Bagari, Chen, Rivetti and Bellusci.)

Fibroblast growth factor 10 (Fgf10) is a secreted ligand acting via the Fibroblast growth factor receptor 2b (Fgfr2b). Fgf10/Fgfr2b signaling plays important roles both in the epithelium and in the mesenchyme during mammary gland development. Evidence in mice show that Fgf10 is critical for the induction of four out of five of the mammary placodes and for the formation of the white adipose tissue. Fgfr2b ligands also play important function in the maintenance of the terminal end buds, specialized structures at the tip of the ramified ducts during the postnatal phase of mammary gland development. Finally, in humans, FGF10 has been described to be expressed in 10% of the breast adenocarcinoma and activation of FGFR2b signaling correlates with a worse prognostic. Therefore, Fgf10 plays pleiotropic roles in both mammary gland development, homeostasis and cancer and elucidating its mechanism of action and cellular targets will be crucial to either enhance mammary gland development or to find innovative targets to treat aggressive breast cancer., (Copyright © 2020 Rivetti, Chen, Chen and Bellusci.)

Acute food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated allergy and is characterized by repetitive profuse vomiting episodes, often in association with pallor, lethargy, and diarrhea, presenting within 1-4 h from the ingestion of a triggering food. In 2017, the international consensus guidelines for the diagnosis and management of FPIES were published. They cover all aspects of this syndrome, which in recent decades has attracted the attention of pediatric allergists. In particular, the consensus proposed innovative diagnostic criteria. However, the diagnosis of acute FPIES is still currently discussed because the interest in this disease is relatively recent and, above all, there are no validated panels of diagnostic criteria. We propose some ideas for reflection on the diagnostic and suspicion criteria of acute FPIES with exemplary stories of children certainly or probably suffering from acute FPIES. For example, we believe that new definitions should be produced for mild forms of FPIES, multiple forms, and those with IgE-mediated symptoms. Moreover, we propose two clinical criteria to suspect acute FPIES and to refer the child to the diagnostic oral food challenge., Competing Interests: The authors declare that they have no conflict of interest.

Bronchopulmonary dysplasia (BPD), characterized by alveoli simplification and dysmorphic pulmonary microvasculature, is a chronic lung disease affecting prematurely born infants. Pulmonary hypertension (PH) is an important BPD feature associated with morbidity and mortality. In human BPD, inflammation leads to decreased fibroblast growth factor 10 (FGF10) expression but the impact on the vasculature is so far unknown. We used lungs from Fgf10+/- versus Fgf10+/+ pups to investigate the effect of Fgf10 deficiency on vascular development in normoxia (NOX) and hyperoxia (HOX, BPD mouse model). To assess the role of fibroblast growth factor receptor 2b (Fgfr2b) ligands independently of early developmentaldefects, we used an inducible double transgenic system in mice allowing inhibition of Fgfr2b ligands activity. Using vascular morphometry, we quantified the pathological changes. Finally, we evaluated changes in FGF10, surfactant protein C (SFTPC), platelet endothelial cell adhesion molecule (PECAM) and alpha-smooth muscle actin 2 (α-SMA) expression in human lung samples from patients suffering from BPD. In NOX, no major difference in the lung vasculature between Fgf10+/- and control pups was detected. In HOX, a greater loss of blood vessels in Fgf10+/- lungs is associated with an increase of poorly muscularized vessels. Fgfr2b ligands inhibition postnatally in HOX is sufficient to decrease the number of blood vessels while increasing the level of muscularization, suggesting a PH phenotype. BPD lungs exhibited decreased FGF10, SFTPC and PECAM but increased α-SMA. Fgf10 deficiency-associated vascular defects are enhanced in HOX and could represent an additional cause of morbidity in human patients with BPD., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

We present a comparison between full field digital mammography and synthetic mammography, performed on several mammography systems from four different manufacturers. The analysis is carried out on both the digital and synthetic images of two commercially available mammography phantoms, and focuses on a set of objective metrics that encode the geometrical appearance of imaging features of diagnostic interest. In particular, we measured sizes and contrasts of several clusters of microcalcification specks, shapes and contrasts of circular masses, and the power spectrum of background regions mimicking the heterogeneous texture of the breast parenchyma. Despite the potential issues of tomosynthesis in terms of image blurring, the synthetic images do not highlight any globally significant differences in the rendering of the details of interest, when compared to the original digital mammograms: relative contrasts are generally preserved, as well as the geometry of broad structures. We conclude that, as far as the considered objective metrics are concerned, the image quality of synthetic mammography does not exhibit significant differences with respect to the one of full field digital mammography, for all the considered systems.

This article aims to present the protocol on Quality Controls in Digital Mammography published online in 2015 by the European Federation of Organisations for Medical Physics (EFOMP) which was developed by a Task Force under the Mammo Working Group. The main objective of this protocol was to define a minimum set of easily implemented quality control tests on digital mammography systems that can be used to assure the performance of a system within a set and acceptable range. Detailed step-by-step instructions have been provided, limiting as much as possible any misinterpretations or variations by the person performing. It is intended that these tests be implemented as part of the daily routine of medical physicists and system users throughout Europe in a harmonised way so allowing results to be compared. In this paper the main characteristics of the protocol are illustrated, including examples, together with a brief summary of the contents of each chapter. Finally, instructions for the download of the full protocol and of the related software tools are provided., (Copyright © 2018 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Objective: To identify the clinical characteristics and genetic etiology of a family affected with hereditary spastic paraplegia (HSP)., Methods: Clinical, genetic, and functional analyses involving genome-wide linkage coupled to whole-exome sequencing in a consanguineous family with complicated HSP., Results: A homozygous missense mutation was identified in the ACO2 gene (c.1240T>G p.Phe414Val) that segregated with HSP complicated by intellectual disability and microcephaly. Lymphoblastoid cell lines of homozygous carrier patients revealed significantly decreased activity of the mitochondrial aconitase enzyme and defective mitochondrial respiration. ACO2 encodes mitochondrial aconitase, an essential enzyme in the Krebs cycle. Recessive mutations in this gene have been previously associated with cerebellar ataxia., Conclusions: Our findings nominate ACO2 as a disease-causing gene for autosomal recessive complicated HSP and provide further support for the central role of mitochondrial defects in the pathogenesis of HSP.

Purpose: In this paper, the authors present a free software for assisting users in achieving the physical characterization of x-ray digital systems and image quality checks., Methods: The program was developed as a plugin of a well-known public-domain suite ImageJ. The software can assist users in calculating various physical parameters such as the response curve (also termed signal transfer property), modulation transfer function (MTF), noise power spectra (NPS), and detective quantum efficiency (DQE). It also includes the computation of some image quality checks: defective pixel analysis, uniformity, dark analysis, and lag., Results: The software was made available in 2009 and has been used during the last couple of years by many users who gave us valuable feedback for improving its usability. It was tested for achieving the physical characterization of several clinical systems for digital radiography and mammography. Various published papers made use of the outcomes of the plugin., Conclusions: This software is potentially beneficial to a variety of users: physicists working in hospitals, staff working in radiological departments, such as medical physicists, physicians, engineers. The plugin, together with a brief user manual, are freely available and can be found online (www.medphys.it/downloads.htm). With our plugin users can estimate all three most important parameters used for physical characterization (MTF, NPS, and also DQE). The plugin can run on any operating system equipped with ImageJ suite. The authors validated the software by comparing MTF and NPS curves on a common set of images with those obtained with other dedicated programs, achieving a very good agreement.

Purpose: A characterization of a clinical unit for digital radiography (FUJIFILM FDR D-EVO) is presented. This system is based on the irradiation side sampling (ISS) technology and can be equipped with two different scintillators: one traditional gadolinium-oxysulphide phosphor (GOS) and a needle structured cesium iodide (CsI) phosphor panel., Methods: The characterization was achieved in terms of response curve, modulation transfer function (MTF), noise power spectra (NPS), detective quantum efficiency (DQE), and psychophysical parameters (contrast-detail analysis with an automatic reading of CDRAD images). For both scintillation screens the authors accomplished the measurements with four standard beam conditions: RAQ3, RQA5, RQA7, and RQA9., Results: At the Nyquist frequency (3.33 lp/mm) the MTF is about 35% and 25% for CsI and GOS detectors, respectively. The CsI scintillator has better noise properties than the GOS screen in almost all the conditions. This is particularly true for low-energy beams, where the noise for the GOS system can go up to a factor 2 greater than that found for CsI. The DQE of the CsI detector reaches a peak of 60%, 60%, 58%, and 50% for the RQA3, RQA5, RQA7, and RQA9 beams, respectively, whereas for the GOS screen the maximum DQE is 40%, 44%, 44%, and 35%. The contrast-detail analysis confirms that in the majority of cases the CsI scintillator is able to provide improved outcomes to those obtained with the GOS screen., Conclusions: The limited diffusion of light produced by the ISS reading makes possible the achievement of very good spatial resolution. In fact, the MTF of the unit with the CsI panel is only slightly lower to that achieved with direct conversion detectors. The combination of very good spatial resolution, together with the good noise properties reached with the CsI screen, allows achieving DQE on average about 1.5 times greater than that obtained with GOS. In fact, the DQE of unit equipped with CsI is comparable to the best alternative methods available which are based on the same technology, and similar to others based on an a-Se direct conversion detectors.

Purpose: The purpose of this study is to compare digital radiography systems using the metric effective detective quantum efficiency (eDQE), which better reflects digital radiography imaging system performance under clinical operating conditions, in comparison with conventional metrics such as modulation transfer function (MTF), normalized noise power spectra (NNPS), and detective quantum efficiency (DQE)., Methods: The eDQE was computed by the calculation of the MTF, the NNPS, the phantom attenuation and scatter, and estimation of x-ray flux. The physical characterization of the systems was obtained with the standard beam conditions RQA5 and RQA9, using the PA Chest phantom proposed by AAPM Report # 31 simulating the attenuation and scatter characteristics of the adult human thorax. The MTF (eMTF) was measured by using an edge test placed at the frontal surface of the phantom, the NNPS (eNNPS) was calculated from images of the phantom acquired at three different exposure levels covering the operating range of the system (E(0), which is the exposure at which a system is normally operated, 1/3 E(0), and 3 E0), and scatter measurements were assessed by using a beam-stop technique. The integral of DQE (IDQE) and eDQE (IeDQE) was calculated over the whole spatial frequency range., Results: The eMTF results demonstrate degradation due to magnification and the presence of scattered radiation. The eNNPS was influenced by the grid presence, and in some systems, it contained structured noise. At typical clinical exposure levels, the magnitude of eDQE(0) with respect to DQE(0) at RQA9 beam conditions was 13%, 17%, 16%, 36%, and 24%, respectively, for Carestream DRX-1, Carestream DRX-1C, Carestream Direct View CR975, Philips Digital Diagnost VM, and GE Revolution XR/d. These results were confirmed by the ratio of IeDQE and IDQE in the same conditions., Conclusions: The authors confirm the robustness and reproducibility of the eDQE method. As expected, the DR systems performed better than the CR systems due to their superior signal-to-noise transfer characteristics. The results of this study suggest the eDQE method may provide an opportunity to more accurately assess the clinical performance of digital radiographic imaging systems by accounting for factors such as the presence of scatter, use of an antiscatter grid, and magnification and focal spot blurring effects, which are not reflected in conventional DQE measures.

In idiopathic pulmonary fibrosis (IPF) patients the presence of missense polymorphisms (SNP) in members of the epidermal growth factor receptor (EGFR) family or their genetic association could influence the binding affinity of natural ligands, modifying the expression and the behavior of the correlated genes. EGFR family members are particularly involved in the epithelial injury and fibrotic process in IPF. Genetic variations in HER family of receptors may alter the possible therapeutic efficacy of EGFR inhibitors. This study aimed to analyze the relationships between IPF and specific EGF receptor family functional polymorphisms. We tested the presence of common EGFR, HER2 and HER3 non-synonymous SNPs in the peripheral blood of 20 Italian IPF patients and their association with the disease. Our data indicated that the HER2 variant allele frequency was significantly lower in patients than in controls, with an odds ratio of 0.31 (95% CI 0.080, 0.98). Our finding suggests that HER2 variant could be a protective factor against IPF onset.

Purpose: Here, we present a physical and psychophysical characterization of a new clinical unit (named AcSelerate) for digital radiography based on a thick a-Se layer. We also compared images acquired with and without a software filter (named CRF) developed for reducing sharpness and noise of the images and making them similar to images coming from traditional computed radiography systems., Methods: The characterization was achieved in terms of physical figures of merit [modulation transfer function (MTF), noise power spectra (NPS), detective quantum efficiency (DQE)], and psychophysical parameters (contrast-detail analysis with an automatic reading of CDRAD images). We accomplished measurements with four standard beam conditions: RAQ3, RQA5, RQA7, and RQA9., Results: The system shows an excellent MTF (about 50% at the Nyquist frequency). The DQE is about 55% at 0.5 lp/mm and above 20% at the Nyquist frequency and is almost independent from exposure. The contrast-detail curves are comparable to some of the best published data for other systems devoted to imaging in general radiography. The CRF filter influences both the MTF and NPS, but it does lead to very small changes on DQE. Also the visibility of CDRAD details is basically unaltered, when the filter is activated., Conclusions: As normally happens with detector based on direct conversion, the system presents an excellent MTF. The improved efficiency caused by the thick layer allows getting good noise characteristics and DQE results better (about 10% on average) than many of the computed radiography (CR) systems and comparable to those obtained by the best systems for digital radiography available on the market.

Cross-Reacting Material 197 (CRM197) is a diphtheria toxin non-toxic mutant that has shown antitumor activity in mice and humans. It is still unclear whether this anti-tumorigenic effect depends on its strong inflammatory-immunological property, its ability to inhibit heparin-binding epidermal growth factor (HB-EGF), or even its possible weak toxicity. CRM197 is utilized as a specific inhibitor of HB-EGF that competes for the epidermal growth factor receptor (EGFR), overexpressed in colorectal cancer and implicated in its progression. In this study we evaluate the effects of CRM197 on HT-29 human colon cancer cell line behaviour and, for CRM197 recognized ability to inhibit HB-EGF, its possible influence on EGFR activation. In particular, while HT-29 does not show any reduction of viability after CRM197 treatment (MTT modified assay), or changes in cell cycle distribution (flow cytometry), in EGFR localization, phospho-EGFR detected signals (immunohistochemistry) or in morphology (scanning electron microscopy, SEM) they show a change in the gene expression profile by microarray analysis (cDNA microarray SS-H19k8). The overexpression of genes like protein phosphatase 2, catalytic subunit, alpha isozyme (PPP2CA), guanine nucleotide-binding protein G subunit alpha-1(GNAI1) and butyrophilin, subfamily 2, member A1 (BTN2A1) has been confirmed with real-time-qPCR. This is the first study where the CRM197 treatment on HT-29 shows a possible scarce implication of endogenous HB-EGF on EGFR expression and cancer cell development. At the same time, our results show the alteration of a specific and selected number of genes.

Recent genomic research has identified interleukin-23 receptor (IL23R), nucleotide-binding oligomerization domain containing 2 caspase-activation recruitment domain 15 (NOD2/CARD15), autophagy related 16-like 1 (ATG16L1) and paired-like homeobox 2b (PHOX2B) as susceptibility loci for Crohn's Disease (CD). Our aim was to investigate these gene variants in a group of CD patients and to analyse the correlation to sub-phenotypes such as gender, smoking habits, disease behaviour at diagnosis, severity of disease and extra-intestinal manifestations. Nineteen patients with CD and 20 healthy controls were included in the study. The gene variants IL23R rs7517847 and rs11209026, NOD2/CARD15 rs2066845, PHOX2B rs16853571, ATG16L1 rs2241879 and rs2241880 were genotyped by PCR followed by sequencing. The frequency of the G risk allele of IL23R rs7517847 was found to be increased in patients with CD (42%) compared to that in control subjects (20%) [odds ratio (OR), 2.9; 95% confidence interval [CI], 1.06-7.9; P=0.03]. In addition, the homozygous condition GG was also associated with CD (OR, 8.70; 95% CI, 0.9-81.6; P=0.038). The analysis of correlation of genotype to sub-phenotypes showed an association of ATG16L1 rs2241879 with the lack of extra-intestinal manifestations (OR, 0.03; 95% CI, 0.002-0.45; P=0.006), and the patients defined as non-smokers displayed an increased frequency of the risk allele C (P=0.03). The present study confirms the association of the heterozygous and homozygous IL23R rs7517847 variant with CD and suggests an additive effect of smoking to the ATG16L1 rs2241879 C risk allele SNP, in the context of the multifactorial model established for the development of CD and a protective effect of the same allele against extra-intestinal manifestations.

Lithium is the main therapeutic agent for the treatment of bipolar disorders but nerve cells are not the sole target of this drug. Indeed, lithium has been reported to target numerous cell types and to affect cell proliferation, differentiation and death. Lithium targets a variety of enzymes among which there is GSK-3beta and a number of cell responses elicited by lithium are mediated by the Wnt pathway that is involved in medulloblastoma (MB) pathogenesis. We studied the in vitro effects of lithium on two different MB cell lines: D283MED and DAOY. High doses of lithium inhibited GSK3-beta, decreased cell proliferation and induced non-apoptotic cell death in both cell lines independently by intracellular levels of beta-catenin that is consistently high only in D283MED. At clinical doses, the anti-neoplastic effects were observed only in this cell line, highlighting the importance of a specific molecular background in determining the target therapy response. In conclusion, lithium could be a promising drug in MB, but an accurate molecular profile predictive of drug response still needs to be clarified.

Evidence from the literature widely supports the efficacy of screening for colorectal cancer (CRC) in reducing mortality. A blood-based assay, potentially, represents a more accessible early detection tool for the identification of circulating tumour cells originating from a primary tumour site in the body. The present work aimed at identifying a set of specific mRNAs expressed in colon tissue but not in blood cells. These mRNAs may represent useful markers for early detection of circulating colon cancer cells by a simple, qualitative RT-PCR assay, following RNA extraction from peripheral blood samples. Using a data-mining tool called cDNA digital gene expression displayer (DGED), based on serial analysis of gene expression (SAGE) from the Cancer Genome Anatomy Project (CGAP) database, 4-colon and 14-blood cDNA libraries were analyzed. We selected 7 genes expressed in colon tissue but not in blood and were able to test 6 of them by RT-PCR in peripheral blood of CRC patients and healthy controls. We present a relatively easy and highly reproducible technique for the detection of mRNA expression of genes as candidate markers of malignancy in blood samples of patients with colon cancer. SAGE DGED provided a list of the best candidate mRNAs predicted to detect colon cells in the blood, namely those encoding the following proteins: hypothetical protein LOC644844 (LOC644844, whose cDNA was not amplifiable), fatty acid binding protein 1 (FABP1), carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5), mucin 13 cell surface associated (MUC13), guanylate cyclase activator 2A (GUCA2A), amiloride binding protein 1 (ABP1), galactoside-binding, solute carrier family 26, member 3 (SLC26A3). The mRNA expression of these genes was evaluated in 8 samples from subjects diagnosed with CRC and 9 from healthy controls. We observed the expression of 2 of the 6 investigated genes in the blood samples of the vast majority of patients considered, but also in a subset of the controls. Our data confirm the extreme sensitivity of RT-PCR, making this technique able to detect minimal amounts of mRNA expressed in a non-tissue-specific manner. Moreover, DGED remains a powerful tool to identify candidate epithelial markers in blood, such as colon related mRNAs. However, to date, none of these qualified as tumour markers.

Purpose: In this study, five different units based on three different technologies-traditional computed radiography (CR) units with granular phosphor and single-side reading, granular phosphor and dual-side reading, and columnar phosphor and line-scanning reading-are compared in terms of physical characterization and contrast detail analysis., Methods: The physical characterization of the five systems was obtained with the standard beam condition RQA5. Three of the units have been developed by FUJIFILM (FCR ST-VI, FCR ST-BD, and FCR Velocity U), one by Kodak (Direct View CR 975), and one by Agfa (DX-S). The quantitative comparison is based on the calculation of the modulation transfer function (MTF), noise power spectrum (NPS), and detective quantum efficiency (DQE). Noise investigation was also achieved by using a relative standard deviation analysis. Psychophysical characterization is assessed by performing a contrast detail analysis with an automatic reading of CDRAD images., Results: The most advanced units based on columnar phosphors provide MTF values in line or better than those from conventional CR systems. The greater thickness of the columnar phosphor improves the efficiency, allowing for enhanced noise properties. In fact, NPS values for standard CR systems are remarkably higher for all the investigated exposures and especially for frequencies up to 3.5 lp/mm. As a consequence, DQE values for the three units based on columnar phosphors and line-scanning reading, or granular phosphor and dual-side reading, are neatly better than those from conventional CR systems. Actually, DQE values of about 40% are easily achievable for all the investigated exposures., Conclusions: This study suggests that systems based on the dual-side reading or line-scanning reading with columnar phosphors provide a remarkable improvement when compared to conventional CR units and yield results in line with those obtained from most digital detectors for radiography.

Epidermal growth factor receptor (EGFR) family members (EGFR, HER2, HER3 and HER4) have been extensively investigated for its possible involvement in cancer development and progression. In colorectal cancer (CRC) EGFR family has been found frequently over-expressed, thus therapy targeting EGFR has been developed. Interestingly, it has been observed that genetic variants in these receptors may alter the therapeutic efficacy of EGFR inhibitors. Polymorphic variants in members of the EGFR family could influence different biologic activities, such as ligands affinity, dimerization efficiency, kinase activity, expression levels, with a consequent impact in signalling pathways and cell behaviour. This study aimed to verify whether single nucleotide polymorphisms (SNPs) of EGFR family members could represent susceptibility factors able to influence the risk to develop CRC. Peripheral blood of 70 Italian colon cancer patients and 72 healthy controls was used as a source of genomic DNA to investigate EGFR, HER2 and HER3 common non-synonymous SNPs. Genetic association tests were performed to verify a possible relationship with CRC. Evidence of genotype association was found for the R521K EGFR polymorphism under a dominant mode of inheritance (Mid-P=0.031). Genotypes with the variant allele of EGFR R521K SNP confer a risk reduction to develop CRC.

Background: Digital mammography systems, thanks to a physical performance better than conventional screen-film units, have the potential of reducing the dose to patients, without decreasing the diagnostic accuracy., Purpose: To achieve a physical and clinical comparison between two systems: a screen-film plate and a dual-side computed radiography system (CRM; FUJIFILM FCR 5000 MA)., Material and Methods: A unique feature of the FCR 5000 MA system is that it has a clear support medium, allowing light emitted during the scanning process to be detected on the "back" of the storage phosphor plate, considerably improving the system's efficiency. The system's physical performance was tested by means of a quantitative analysis, with calculation of the modulation transfer function, detective quantum efficiency, and contrast-detail analysis; subsequently, the results were compared with those achieved using a screen-film system (SFM; Eastmann Kodak MinR-MinR 2000). A receiver operating characteristic (ROC) analysis was then performed on 120 paired clinical images obtained in a craniocaudal projection with the conventional SFM system under standard exposure conditions and also with the CRM system working with a dose reduced by 35% (average breast thickness: 4.3 cm; mean glandular dose: 1.45 mGy). CRM clinical images were interpreted both in hard copy and in soft copy., Results: The ROC analysis revealed that the performances of the two systems (SFM and CRM with reduced dose) were similar (P>0.05): the diagnostic accuracy of the two systems, when valued in terms of the area underneath the ROC curve, was found to be 0.74 for the SFM, 0.78 for the CRM (hard copy), and 0.79 for the CRM (soft copy)., Conclusion: The outcome obtained from our experiments shows that the use of the dual-side CRM system is a very good alternative to the screen-film system.

Ideally, medical x-ray imaging systems should be designed to deliver maximum image quality at an acceptable radiation risk to the patient. Quality assurance procedures are employed to ensure that these standards are maintained. A quality control protocol for direct digital radiography (DDR) systems is described and discussed. Software to automatically process and analyze the required images was developed. In this paper, the initial results obtained on equipment of different DDR manufacturers were reported. The protocol was developed to highlight even small discrepancies in standard operating performance.

Purpose: In recent years, many approaches have been investigated on the development of full-field digital mammography detectors and implemented in practical clinical systems. Some of the most promising techniques are based on flat panel detectors, which, depending on the mechanism involved in the x-ray detection, can be grouped into direct and indirect flat panels. Direct detectors display a better spatial resolution due to the direct conversion of x rays into electron-hole pairs, which do not need an intermediate production of visible light. In these detectors the readout is usually achieved through arrays of thin film transistors (TFTs). However, TFT readout tends to display noise characteristics worse than those from indirect detectors. To address this problem, a novel clinical system for digital mammography has been recently marketed based on direct-conversion detector and optical readout. This unit, named AMULET and manufactured by FUJIFILM, is based on a dual layer of amorphous selenium that acts both as a converter of x rays (first layer) and as an optical switch for the readout of signals (second layer) powered by a line light source. The optical readout is expected to improve the noise characteristics of the detector. The aim is to obtain images with high resolution and low noise, thanks to the combination of optical switching technology and direct conversion with amorphous selenium. In this article, the authors present a characterization of an AMULET system., Methods: The characterization was achieved in terms of physical figures as modulation transfer function (MTF), noise power spectra (NPS), detective quantum efficiency (DQE), and contrast-detail analysis. The clinical unit was tested by exposing it to two different beams: 28 kV Mo/Mo (namely, RQA-M2) and 28 kV W/Rh (namely, W/Rh)., Results: MTF values of the system are slightly worse than those recorded from other direct-conversion flat panels but still within the range of those from indirect flat panels: The MTF values of the AMULET system are about 45% and 15% at 5 and 8 lp/mm, respectively. On the other hand, however, AMULET NNPS results are consistently better than those from direct-conversion flat panels (up to two to three times lower) and flat panels based on scintillation phosphors. DQE results lie around 70% when RQA-M2 beams are used and approaches 80% in the case of W/Rh beams. Contrast-detail analysis, when performed by human observers on the AMULET system, results in values better than those published for other full-field digital mammography systems., Conclusions: The novel clinical unit based on direct-conversion detector and optical reading presents great results in terms of both physical and psychophysical characterizations. The good spatial resolution, combined with excellent noise properties, allows the achievement of very good DQE, better than those published for clinical FFDM systems. The psychophysical analysis confirms the excellent behavior of the AMULET unit.

Most noncemented total hip replacements combine a titanium alloy stem, a CoCrMo femoral head and an ultra-high molecular weight polyethylene (UHMWPE) acetabular cup. In spite of its nickel content of up to 1% and the resulting biocompatibility issues in some clinical situations, the higher cost and some difficulties in machining, CoCrMo alloy is preferred to titanium alloys thanks to its outstanding tribological properties, higher hardness and elastic modulus. Nowadays most of the heads of hip prostheses use CoCrMo as bearing material. The present study investigates the effect of various surface treatments and combinations of treatments, such as electrochemical oxidation (anodization), laser surface melting and barrel polishing, on the tribological properties of commercially pure grade 2 titanium. The aim of the study was to characterize surface treatments capable of improving the tribological properties of titanium surface to the same extent as CoCrMo. The tribological properties were characterized by multidirectional pin-on-flat screening wear tests, using UHMWPE pins as bearing surface. The experiments showed the possibility of improving the wear resistance of titanium to the degree of CoCrMo. Although further efforts will be required to optimize the treatments studied, the results are encouraging enough to warrant pursuing this direction of investigation.

The purpose of this study was to perform a complete evaluation of three pieces of clinical digital mammography equipment. Image quality was assessed by performing physical characterization and contrast-detail (CD) analysis. We considered three different FFDM systems: a computed radiography unit (Fuji "FCR 5000 MA") and two flat-panel units, the indirect conversion a-Si based GE "Senographe 2000D" and the direct conversion a-Si based IMS "Giotto Image MD." The physical characterization was estimated by measuring the MTF, NNPS, and DQE of the detectors with no antiscatter grid and over the clinical range of exposures. The CD analysis was performed using a CDMAM 3.4 phantom and custom software designed for automatic computation of the contrast-detail curves. The physical characterization of the three digital systems confirms the excellent MTF properties of the direct conversion flat-panel detector (FPD). We performed a relative standard deviation (RSD) analysis, for investigating the different components of the noise presented by the three systems. It turned out that the two FPDs show a significant additive component, whereas for the CR system the statistical noise is dominant. The multiplicative factor is a minor constituent for all the systems. The two FPDs demonstrate better DQE, with respect to the CR system, for exposures higher than 70 microGy. The CD analysis indicated that the three systems are not statistically different for detail objects with a diameter greater than 0.3 mm. However, the IMS system showed a statistically significant different response for details smaller than 0.3 mm. In this case, the poor response of the a-Se detector could be attributed to its high-frequency noise characteristics, since its MTF, NEQ, and DQE are not inferior to those of the other systems. The CD results were independent of exposure level, within the investigated clinical range. We observed slight variations in the CD results, due to the changes in the visualization parameters (window/level and magnification factor). This suggests that radiologists would benefit from viewing images using varied window/level and magnification.

Aim: New models of care are proposed to reduce the costs of traditional hospitalization and to improve the utilization of resources in surgery. Day surgery is widely employed in breast surgery. In this study we report the conversion rate and causes in ordinary hospitalization and we identify some contraindications related to breast surgery in day surgery., Methods: A cohort study was performed on 306 patients operated on between July 1999 and December 2001 for breast lesions with uncertain interpretation at the clinical and/or instrumental examination. Those patients who lived at a distance of less than 50 km from the hospital, had a telephone, a suitable house, direct family support and, if necessary, could benefit from home health care in addition to hospitalization, were considered as eligible to day surgery. The kind of anesthesia and hospital admission were established after clinical, psycho-emotional, and socio-familiar evaluation of the patients by the surgeon and the anesthetist., Results: A total of 250 excisional biopsies and 56 biopsies with a Mammotome were performed. Surgery was performed under local anesthesia in 278 patients and general anesthesia in 28 subjects. Observation exceeding 24 hours was only necessary in 10 patients reporting hypotension syndrome and anxiety. The conversion rate in ordinary hospitalization was 0.3%. Postoperative morbidity was 1%., Conclusion: Day surgery is an effective model of care in breast surgery for diagnostic and therapeutic purposes without axillary dissection. A good selection of patients, perfect interdisciplinary collaboration, and an efficient structural organization are necessary to control the complication and conversion rates of traditional hospitalization.

The authors have studied stillbirth, early neonatal death rate, perinatal death rate following weight classes, weight distribution in live born and death causes between 1977 and 1981. These data permit to evaluate the degree of efficiency in the obstetrical and neonatological department. Weight distribution pattern has been fairly constant and low-weight incidence similar to that found by other authors. Perinatal death rate has remained stable in time around 11,4%. Still births have increased particularly in weight classes between 1001 and 2000 g. Early newborn death rate has decreased in weight classes between 2001 and 2500 and over 4000 g. Asphyxia was the most frequent death cause in weight classes between 1501 and 2000 g and between 2501 and 4000 g. These data are similar to those found in british and swedish studies. The authors insist that every effort must be made to reduce not only perinatal death rate but also to prevent future handicaps.

The AA. report a typical case of methemoglobinemia from carrot soup ingestion in an infant. In the discussion they point out: first, clinical findings for diagnosis of methemoglobinemia; second, criteria for an etiological diagnosis; third, they analyse the pathogenesis of methemoglobinemia resulting from carrot soup in infants. At last the AA. briefly indicate how to prevent and treat this complication.

Three patients with transient hyperphosphatasemia of infancy are described and compared to other 79 cases reported in literature. Etiopathogenesis is discussed and the good prognosis of this condition is emphasized.