Quantification of the early pupillary dilation kinetic to assess rod and cone activity.

Rods, cones and melanopsin contribute in various proportions, depending on the stimulus light, to the pupil light response. This study used a first derivative analysis to focus on the quantification of the dynamics of pupillary dilation that immediately follows light-induced pupilloconstriction in order to identify novel parameters that reflect rod and cone activity. In 18 healthy adults, the pupil response to a 1 s blue light stimulus ranging from - 6.0 to 2.65 log cd/m <sup>2</sup> in dark-adapted conditions and to a 1 s blue light stimulus (2.65 log cd/m <sup>2</sup> ) in light-adapted conditions was recorded on a customized pupillometer. Three derivative parameters which describe the 2.75 s following the light onset were quantified: dAMP (maximal amplitude of the positive peak), dLAT (latency of the positive peak), dAUC (area under the curve of the positive peak). We found that dAMP and dAUC but not dLAT have graded responses over a range of light intensities. The maximal positive value of dAMP, representing maximal rate of change of early pupillary dilation phase, occurs at - 1.0 log cd/m <sup>2</sup> and this stimulus intensity appears useful for activating rods and cones. From - 0.5 log cd/m <sup>2</sup> to brighter intensities dAMP and dAUC progressively decrease, reaching negligible values at 2.65 log cd/m <sup>2</sup> indicative of a melanopsin-driven pupil response that masks the contribution from rods and cones to the early phase of pupillary dilation

Fokker-Planck type equations with Sobolev diffusion coefficients and BV drift coefficients

In this paper we give an affirmative answer to an open question mentioned in [Le Bris and Lions, Comm. Partial Differential Equations 33 (2008), 1272--1317], that is, we prove the well-posedness of the Fokker-Planck type equations with Sobolev diffusion coefficients and BV drift coefficients.Comment: 11 pages. The proof has been modifie

Prognostic impact of Ki-67 proliferative index in resectable pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by complex biological features and poor prognosis. A prognostic stratification of PDAC would help to improve patient management. The aim of this study was to analyse the expression of Ki-67 in relation to prognosis in a cohort of patients with PDAC who had surgical treatment

Cell therapy strategies and improvements for muscular dystrophy

Understanding stem cell commitment and differentiation is a critical step towards clinical translation of cell therapies. In past few years, several cell types have been characterized and transplanted in animal models for different diseased tissues, eligible for a cell-mediated regeneration. Skeletal muscle damage is a challenge for cell- and gene-based therapeutical approaches, given the unique architecture of the tissue and the clinical relevance of acute damages or dystrophies. In this review, we will consider the regenerative potential of embryonic and somatic stem cells and the outcomes achieved on their transplantation into animal models for muscular dystrophy or acute muscle impairment

Alteration of Cardiac Progenitor Cell Potency in GRMD Dogs

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SETD5 Gene Haploinsufficiency in Three Patients With Suspected KBG Syndrome

Mendelian disorders of the epigenetic machinery (MDEMs), also named chromatin modifying disorders, are a broad group of neurodevelopmental disorders, caused by mutations in functionally related chromatin genes. Mental retardation autosomal dominant 23 (MRD23) syndrome, due to SETD5 gene mutations, falls into this group of disorders. KBG syndrome, caused by ANKRD11 gene haploinsufficiency, is a chromatin related syndrome not formally belonging to this category. We performed high resolution array CGH and trio-based WES on three molecularly unsolved patients with an initial KBGS clinical diagnosis. A de novo deletion of 116 kb partially involving SETD5 and two de novo frameshift variants in SETD5 were identified in the patients. The clinical re-evaluation of the patients was consistent with the molecular findings, though still compatible with KBGS due to overlapping phenotypic features of KBGS and MRD23. Careful detailed expert phenotyping ascertained some facial and physical features that were consistent with MRD23 rather than KBGS. Our results provide further examples that loss-of-function pathogenic variants in genes encoding factors shaping the epigenetic landscape, lead to a wide phenotypic range with significant clinical overlap. We recommend that clinicians consider SETD5 gene haploinsufficiency in the differential diagnosis of KBGS. Due to overlap of clinical features, careful and detailed phenotyping is important and a large gene panel approach is recommended in the diagnostic workup of patients with a clinical suspicion of KBGS

Seasonality fluctuations recorded in fossil bivalves during the early Pleistocene: implications for climate change

Understanding the transformations of the climate system may help to predict and reduce the effects of global climate change. The geological record provides a unique archive that documents the long-term fluctuations of environmental variables, such as seasonal change. Here, we investigate how seasonal variation in seawater temperatures varied in the Mediterranean Sea during the early Pleistocene, approaching the Early-Middle Pleistocene Transition (EMPT) and the beginning of precession-driven Quaternary-style glacial–interglacial cycles. We performed whole-shell and sclerochemical stable isotope analyses (δ18O, δ13C) on bivalves, collected from the lower Pleistocene Arda River marine succession (northern Italy), after checking shell preservation. Our results indicate that seawater temperature seasonality was the main variable of climate change in the Mediterranean area during the early Pleistocene, with the Northern Hemisphere Glaciation (NHG) exerting a control on the Mediterranean climate. We show that strong seasonality (14.4–16.0 °C range) and low winter paleotemperatures (0.8–1.6 °C) were likely the triggers leading to the establishment of widespread populations of so called “northern guests” (i.e., cold water taxa) in the Mediterranean Sea around 1.80 Ma. The shells postdating the arrival of the “northern guests” record a return to lower seasonal variations and higher seawater paleotemperatures, with seasonality increasing again approaching the EMPT; the latter, however, is not associated with a corresponding cooling of mean seawater paleotemperatures, showing that the observed seasonality variation represents a clear signal of progressive climate change in the Mediterranean Sea

Comparative transcriptome profiling of the injured zebrafish and mouse hearts identifies miRNA-dependent repair pathways.

The adult mammalian heart has poor regenerative capacity. In contrast, the zebrafish heart retains a robust capacity for regeneration into adulthood. These distinct responses are consequences of a differential utilization of evolutionary-conserved gene regulatory networks in the damaged heart. To systematically identify miRNA-dependent networks controlling cardiac repair following injury, we performed comparative gene and miRNA profiling of the cardiac transcriptome in adult mice and zebrafish. Using an integrated approach, we show that 45 miRNA-dependent networks, involved in critical biological pathways, are differentially modulated in the injured zebrafish vs. mouse hearts. We study, more particularly, the miR-26a-dependent response. Therefore, miR-26a is down-regulated in the fish heart after injury, whereas its expression remains constant in the mouse heart. Targets of miR-26a involve activators of the cell cycle and Ezh2, a component of the polycomb repressive complex 2 (PRC2). Importantly, PRC2 exerts repressive functions on negative regulators of the cell cycle. In cultured neonatal cardiomyocytes, inhibition of miR-26a stimulates, therefore, cardiomyocyte proliferation. Accordingly, miR-26a knockdown prolongs the proliferative window of cardiomyocytes in the post-natal mouse heart. This novel strategy identifies a series of miRNAs and associated pathways, in particular miR-26a, which represent attractive therapeutic targets for inducing repair in the injured heart

Clinical practice guidelines for diagnosis, treatment and follow-up of exocrine pancreatic ductal adenocarcinoma: Evidence evaluation and recommendations by the italian association of medical oncology (AIOM)

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death in women (7%) and the sixth in men (5%) in Italy, with a life expectancy of around 5% at 5 years. From 2010, the Italian Association of Medical Oncology (AIOM) developed national guidelines for several cancers. In this report, we report a summary of clinical recommendations of diagnosis, treatment and follow-up of PDAC, which may guide physicians in their current practice. A panel of AIOM experts in upper gastrointestinal cancer malignancies discussed the available scientific evidence supporting the clinical recommendations

9q34.3 microduplications lead to neurodevelopmental disorders through EHMT1 overexpression

Both copy number losses and gains occur within subtelomeric 9q34 region without common breakpoints. The microdeletions cause Kleefstra syndrome (KS), whose responsible gene is EHMT1. A 9q34 duplication syndrome (9q34 DS) had been reported in literature, but it has never been characterized by a detailed molecular analysis of the gene content and endpoints. To the best of our knowledge, we report on the first patient carrying the smallest 9q34.3 duplication containing EHMT1 as the only relevant gene. We compared him with 21 reported patients described here as carrying 9q34.3 duplications encompassing the entire gene and extending within ~\u20093 Mb. By surveying the available clinical and molecular cytogenetic data, we were able to discover that similar neurodevelopmental disorders (NDDs) were shared by patient carriers of even very differently sized duplications. Moreover, some facial features of the 9q34 DS were more represented than those of KS. However, an accurate in silico analysis of the genes mapped in all the duplications allowed us to support EHMT1 as being sufficient to cause a NDD phenotype. Wider patient cohorts are needed to ascertain whether the rearrangements have full causative role or simply confer the susceptibility to NDDs and possibly to identify the cognitive and behavioral profile associated with the increased dosage of EHMT1