High-Definition Videobronchoscopy for the Diagnosis of Airway Involvement in Sarcoidosis

BACKGROUND: The ability of high-definition (HD) videobronchoscopy to detect airway involvement in sarcoidosis has not been evaluated previously.RESEARCH QUESTION: What is the role of HD videobronchoscopy in the identification of sarcoidosis-associated airway abnormalities (AAs)? What are the patterns of AAs more commonly observed and more frequently associated with the detection of granulomas in endobronchial biopsy (EBB)?STUDY DESIGN AND METHODS: In this prospective international multicenter cohort study, consecutive patients with suspected sarcoidosis underwent airway inspection with an HD videobronchoscope and EBB using a standardized workflow. AAs were classified according to six patterns defined a priori: nodularity, cobblestoning, thickening, plaque, increased vascularity, and miscellaneous. We assessed diagnostic yield of EBB, prevalence of AAs, and interobserver agreement for different patterns of AAs. RESULTS: AAs were identified in 64 of 134 patients with sarcoidosis (47.8%), with nodularity (n = 23 [17.2%]), plaque (n = 19 [14.2%]), and increased vascularity (n = 19 [14.2%]) being the most prevalent. The diagnostic yield of EBB was 36.6%. AAs were significantly more prevalent in patients with than in those without nonnecrotizing granulomas on EBB (67.4% vs 36.5%; P = .001). Likewise, parenchymal disease on CT scan imaging was signifi- cantly more common in patients with than in those without nonnecrotizing granulomas on EBB (79.6% vs 54.1%; P = .003). On a per-lesion analysis, nonnecrotizing granulomas were seen especially in EBB samples obtained from areas of cobblestoning (9/10 [90%]) and nod-ularity (17/29 [58.6%]). The overall diagnostic yield of random EBB was low (31/134 [23.1%]). The interobserver agreement for the different patterns of AA was fair (Fleiss k = 0.34).INTERPRETATION: In a population with a large prevalence of White Europeans, HD video-bronchoscopy detected AAs in approximately one-half of patients with sarcoidosis. The diagnostic yield of EBB was higher in patients with parenchymal involvement on CT scan imaging and in those with AAs, especially if manifesting as cobblestoning and nodularity.TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT4743596; URL: www.clinicaltrials.go

Parents with binge eating disorders: Which are the influences on adult-child feeding interactions and on the child’s behavioral/emotional functioning?

Feeding during the first years of life represents one of the main domains of adult-child interactions and plays a crucial role in children’s later development. It has been suggested that some kinds of adult psychopathology are more likely to compromise early feeding exchanges. This is the case of parental Binge Eating Disorder (BED) which has resulted to be associated with poor parent–infant interactions during feeding and with children’s emotional and behavioral problems during infancy. The present study aimed to investigate, through a longitudinal research design, the influence of maternal and paternal BED diagnosis on parent–infant feeding interactions and on later children’s behavioral/emotional functioning. The study involved 408 families divided into four groups, according to the presence or absence of BED diagnosis in the parents: Group 1 included families with both parents diagnosed with BED, Group 2 and 3 included families with one parent diagnosed with BED, Group 0 was a healthy control. The assessment took place at two different points, when the children were respectively 18 (T1) and 36 months (T2). Feeding interactions were assessed through the Scale for the Assessment of Feeding Interactions (SVIA) while the children’s behavioral/emotional functioning was evaluated through the Child Behavior Check-List (CBCL). When compared to healthy controls, the groups with one or both parents diagnosed with BED showed higher scores on the SVIA and on the CBCL internalizing and externalizing scales, suggesting more difficulties in adult–child feeding interactions and in the children’s behavioral/emotional functioning. Maternal and paternal BED diagnosis resulted to have a direct effect on feeding interactions and an indirect effect on behavioral/emotional difficulties at 36 months, mediated by the quality of feeding exchanges, both at 18 and 36 months. Moreover the influence of maternal and paternal BED diagnosis resulted to assume a different weight over time. The presence of BED diagnosis in one or both parents appears to affect negatively the quality of adult–infant feeding exchanges and children’s behavioral/emotional functioning over time, thus affecting later child development. These results appear particularly important since they can help to understand more in depth the influence of parental BED diagnosis on child development and on family functioning

Prevalence of methicillin-resistant staphylococci isolated from different biological samples at Policlinico Umberto I of Rome: correlation with vancomycin susceptibility

The methicillin-resistance is increasing all over the world in the last decade. It is more frequent among coagulase-negative staphylococci (MRCoNS); infact the 52% of S. epidermidis strains results to be resistant to methicillin.The methicillin-resistant strains also show a reduced sensitivity towards the first-line agents such as glycopeptides and other antibiotics commonly used in therapy such as trimethoprim-sulphamethoxazole, imipenem, gentamycin, fosfomycin and chlarytromicin. Unlike MRSA (Methicillin-resistant S. aureus), MRCoNS resistance to glycopeptides generally concerns teicoplanin. Although vancomycin resistance is rare in Staphylococcus isolates, the detected shift towards higher values of MICs might affect patient's clinical outcome

Age and diabetes related changes of the retinal capillaries: an ultrastructural and immunohistochemical study

Normal human aging and diabetes are associated with a gradual decrease of cerebral flow in the brain with changes in vascular architecture. Thickening of the capillary basement membrane and microvascular fibrosis are evident in the central nervous system of elderly and diabetic patients. Current findings assign a primary role to endothelial dysfunction as a cause of basement membrane (BM) thickening, while retinal alterations are considered to be a secondary cause of either ischemia or exudation. The aim of this study was to reveal any initial retinal alterations and variations in the BM of retinal capillaries during diabetes and aging as compared to healthy controls. Moreover, we investigated the potential role of vascular endothelial growth factor (VEGF) and pro-inflammatory cytokines in diabetic retina.Transmission electron microscopy (TEM) was performed on 46 enucleated human eyes with particular attention to alterations of the retinal capillary wall and Müller glial cells. Inflammatory cytokines expression in the retina was investigated by immunohistochemistry.Our electron microscopy findings demonstrated that thickening of the BM begins primarily at the level of the glial side of the retina during aging and diabetes. The Müller cells showed numerous cytoplasmic endosomes and highly electron-dense lysosomes which surrounded the retinal capillaries. Our study is the first to present morphological evidence that Müller cells start to deposit excessive BM material in retinal capillaries during aging and diabetes. Our results confirm the induction of pro-inflammatory cytokines TNF-α and IL-1β within the retina as a result of diabetes.These observations strongly suggest that inflammatory cytokines and changes in the metabolism of Müller glial cells rather than changes in of endothelial cells may play a primary role in the alteration of retinal capillaries BM during aging and diabetes

A Novel null homozygous mutation confirms <i>CACNA2D2</i> as a gene mutated in epileptic encephalopathy

Contribution to epileptic encephalopathy (EE) of mutations in CACNA2D2, encoding α2δ-2 subunit of Voltage Dependent Calcium Channels, is unclear. To date only one CACNA2D2 mutation altering channel functionality has been identified in a single family. In the same family, a rare CELSR3 polymorphism also segregated with disease. Involvement of CACNA2D2 in EE is therefore not confirmed, while that of CELSR3 is questionable. In a patient with epilepsy, dyskinesia, cerebellar atrophy, psychomotor delay and dysmorphic features, offspring to consanguineous parents, we performed whole exome sequencing (WES) for homozygosity mapping and mutation detection. WES identified extended autozygosity on chromosome 3, containing two novel homozygous candidate mutations: c.1295delA (p.Asn432fs) in CACNA2D2 and c.G6407A (p.Gly2136Asp) in CELSR3. Gene prioritization pointed to CACNA2D2 as the most prominent candidate gene. The WES finding in CACNA2D2 resulted to be statistically significant (p = 0.032), unlike that in CELSR3. CACNA2D2 homozygous c.1295delA essentially abolished α2δ-2 expression. In summary, we identified a novel null CACNA2D2 mutation associated to a clinical phenotype strikingly similar to the Cacna2d2 null mouse model. Molecular and statistical analyses together argued in favor of a causal contribution of CACNA2D2 mutations to EE, while suggested that finding in CELSR3, although potentially damaging, is likely incidental

Exploiting the Properties of Ti-Doped CVD-Grown Diamonds for the Assembling of Electrodes

A hybrid chemical vapor deposition (CVD)‐powder flowing technique specifically developed in lab has been employed to produce high‐quality polycrystalline diamond layers containing Ti inclusions. Morphology, structural features, and surface composition of nanocomposite diamond‐based samples produced by different growth times have been analyzed by scanning electron microscopy, Raman and Auger spectroscopy, respectively. The CVD methodology adopted for the Ti incorporation in the diamond lattice does not perturb the crystalline quality of the diamond matrix, therefore maintaining the outstanding properties of the C‐sp3 phase. The functional properties of the nanocomposite layers have been tested by nanoindentation and I–V measurements. The electrochemical performance of the diamond/Ti electrodes is evaluated by performing cyclic voltammetry in different media, namely, acidic, neutral, and basic aqueous solutions, and by estimating the rate constant of heterogeneous electron transfer to diamond surface for the ferro/ferricyanide redox couple. The rather good electrochemical performances, the mechanical strength, and the chemical inertness of the Ti‐doped diamond electrodes produced by the CVD approach, comply with the whole set of technological requirements, such as robustness, long durability, and biocompatibility, required for use in hostile environments or in biological systems

Maml1 acts cooperatively with Gli proteins to regulate Sonic hedgheog signaling pathway

Sonic hedgehog (Shh) signaling is essential for proliferation of cerebellar granule cell progenitors (GCPs) and its misregulation is linked to various disorders, including cerebellar cancer medulloblastoma. The effects of Shh pathway are mediated by the Gli family of transcription factors, which controls the expression of a number of target genes, including Gli1. Here, we identify Mastermind-like 1 (Maml1) as a novel regulator of the Shh signaling since it interacts with Gli proteins, working as a potent transcriptional coactivator. Notably, Maml1 silencing results in a significant reduction of Gli target genes expression, with a negative impact on cell growth of NIH3T3 and Patched1−/− mouse embryonic fibroblasts (MEFs), bearing a constitutively active Shh signaling. Remarkably, Shh pathway activity results severely compromised both in MEFs and GCPs deriving from Maml1−/− mice with an impairment of GCPs proliferation and cerebellum development. Therefore Maml1−/− phenotype mimics aspects of Shh pathway deficiency, suggesting an intrinsic requirement for Maml1 in cerebellum development. The present study shows a new role for Maml1 as a component of Shh signaling, which plays a crucial role in both development and tumorigenesis

NOTCH3 inactivation increases triple negative breast cancer sensitivity to gefitinib by promoting EGFR tyrosine dephosphorylation and its intracellular arrest.

Notch dysregulation has been implicated in numerous tumors, including triple-negative breast cancer (TNBC), which is the breast cancer subtype with the worst clinical outcome. However, the importance of individual receptors in TNBC and their specific mechanism of action remain to be elucidated, even if recent findings suggested a specific role of activated-Notch3 in a subset of TNBCs. Epidermal growth factor receptor (EGFR) is overexpressed in TNBCs but the use of anti-EGFR agents (including tyrosine kinase inhibitors, TKIs) has not been approved for the treatment of these patients, as clinical trials have shown disappointing results. Resistance to EGFR blockers is commonly reported. Here we show that Notch3-specific inhibition increases TNBC sensitivity to the TKI-gefitinib in TNBC-resistant cells. Mechanistically, we demonstrate that Notch3 is able to regulate the activated EGFR membrane localization into lipid rafts microdomains, as Notch3 inhibition, such as rafts depletion, induces the EGFR internalization and its intracellular arrest, without involving receptor degradation. Interestingly, these events are associated with the EGFR tyrosine dephosphorylation at Y1173 residue (but not at Y1068) by the protein tyrosine phosphatase H1 (PTPH1), thus suggesting its possible involvement in the observed Notch3-dependent TNBC sensitivity response to gefitinib. Consistent with this notion, a nuclear localization defect of phospho-EGFR is observed after combined blockade of EGFR and Notch3, which results in a decreased TNBC cell survival. Notably, we observed a significant correlation between EGFR and NOTCH3 expression levels by in silico gene expression and immunohistochemical analysis of human TNBC primary samples. Our findings strongly suggest that combined therapies of TKI-gefitinib with Notch3-specific suppression may be exploited as a drug combination advantage in TNBC treatment