Design of an experimental setup for delivering intracortical microstimulation in vivo via Spiking Neural Network.

Electroceutical approaches for the treatment of neurological disorders, such as stroke, can take advantage of neuromorphic engineering, to develop devices able to achieve a seamless interaction with the neural system. This paper illustrates the development and test of a hardware-based Spiking Neural Network (SNN) to deliver neural-like stimulation patterns in an open-loop fashion. Neurons in the SNN have been designed by following the Hodgkin-Huxley formalism, with parameters taken from neuroscientific literature. We then built the set-up to deliver the SNN-driven stimulation in vivo. We used deeply anesthetized healthy rats to test the potential effect of the SNN-driven stimulation. We analyzed the neuronal firing activity pre- and post-stimulation in both the primary somatosensory and the rostral forelimb area. Our results showed that the SNN-based neurostimulation was able increase the spontaneous level of neuronal firing at both monitored locations, as found in the literature only for closed-loop stimulation. This study represents the first step towards translating the use of neuromorphic-based devices into clinical applications.Clinical Relevance- Stroke represents one of the leading causes of long-term disability and death worldwide. Intracortical microstimulation is an effective approach for restoring lost sensory motor integration by promoting plasticity among the affected brain areas. Stimulation delivered via neuromorphic-based open-loop systems (i.e. neuromorphic prostheses) can pave the way to novel electroceutical strategies for brain repair.

Application of Hereditary Renal Cell Carcinoma Risk Criteria to a Large Prospective Database.

AIMS: To evaluate the clinical impact of the Canadian criteria for identifying patients and families at risk for hereditary renal cell carcinoma (RCC). MATERIALS AND METHODS: The Canadian hereditary RCC risk criteria were applied to patients from 16 centres in the Canadian Kidney Cancer information system (CKCis) prospective database. The primary end point was the proportion of patients who met at least one criterion. RESULTS: Between January 2011 and May 2017, 8388 patients were entered in the database; 291 had inadequate risk data; 2827 (35%) met at least one criterion for genetic testing (at-risk population). Most (83%) met just one criterion. The criterion of non-clear cell histology contributed the largest proportion of at-risk patients (59%), followed by age ≤ 45 years (28%). Sixty-one patients had documentation of genetic testing, with 56 being classified at-risk (2% of at-risk). Twenty patients (35%) of the patients at risk and tested for hereditary RCC were found to harbour a germline mutation. CONCLUSIONS: Application of the Canadian hereditary RCC risk criteria to a large prospective database resulted in 35% of patients being identified at risk for hereditary RCC who could qualify for genetic testing. However, the true incidence of hereditary RCC in this population is unknown as most patients did not have documented genetic testing carried out and, thus, the sensitivity and specificity of the criteria cannot be determined. The low proportion of at-risk patients who underwent genetic testing is disappointing and highlights that there may be gaps in reporting, knowledge and/or barriers in access to genetic testing.

Correction: S1PR1 drives a feedforward signalling loop to regulate BATF3 and the transcriptional programme of Hodgkin lymphoma cells.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

S1PR1 drives a feedforward signalling loop to regulate BATF3 and the transcriptional programme of Hodgkin lymphoma cells.

The Hodgkin/Reed-Sternberg cells of classical Hodgkin lymphoma (HL) are characterised by the aberrant activation of multiple signalling pathways. Here we show that a subset of HL displays altered expression of sphingosine-1-phosphate (S1P) receptors (S1PR)s. S1P activates phosphatidylinositide 3-kinase (PI3-K) in these cells that is mediated by the increased expression of S1PR1 and the decreased expression of S1PR2. We also showed that genes regulated by the PI3-K signalling pathway in HL cell lines significantly overlap with the transcriptional programme of primary HRS cells. Genes upregulated by the PI3-K pathway included the basic leucine zipper transcription factor, ATF-like 3 (BATF3), which is normally associated with the development of dendritic cells. Immunohistochemistry confirmed that BATF3 was expressed in HRS cells of most HL cases. In contrast, in normal lymphoid tissues, BATF3 expression was confined to a small fraction of CD30-positive immunoblasts. Knockdown of BATF3 in HL cell lines revealed that BATF3 contributed to the transcriptional programme of primary HRS cells, including the upregulation of S1PR1. Our data suggest that disruption of this potentially oncogenic feedforward S1P signalling loop could provide novel therapeutic opportunities for patients with HL.

An ultra-deep sequencing strategy to detect sub-clonal TP53 mutations in presentation chronic lymphocytic leukaemia cases using multiple polymerases.

Chronic lymphocytic leukaemia (CLL) is the most common clonal B-cell disorder characterized by clonal diversity, a relapsing and remitting course, and in its aggressive forms remains largely incurable. Current front-line regimes include agents such as fludarabine, which act primarily via the DNA damage response pathway. Key to this is the transcription factor p53. Mutations in the TP53 gene, altering p53 functionality, are associated with genetic instability, and are present in aggressive CLL. Furthermore, the emergence of clonal TP53 mutations in relapsed CLL, refractory to DNA-damaging therapy, suggests that accurate detection of sub-clonal TP53 mutations prior to and during treatment may be indicative of early relapse. In this study, we describe a novel deep sequencing workflow using multiple polymerases to generate sequencing libraries (MuPol-Seq), facilitating accurate detection of TP53 mutations at a frequency as low as 0.3%, in presentation CLL cases tested. As these mutations were mostly clustered within the regions of TP53 encoding DNA-binding domains, essential for DNA contact and structural architecture, they are likely to be of prognostic relevance in disease progression. The workflow described here has the potential to be implemented routinely to identify rare mutations across a range of diseases.

Prevalence of subdural collections in children with macrocrania.

BACKGROUND AND PURPOSE: The relationship between enlarged subarachnoid spaces and subdural collections is poorly understood and creates challenges for clinicians investigating the etiology of subdural collections. The purpose of this study was to determine the prevalence of subdural collections on cross sectional imaging in children with macrocephaly correlating with subarachnoid space enlargement. MATERIALS AND METHODS: The radiology information system of a large pediatric medical center was reviewed for "macrocrania" and "macrocephaly" on reports of cranial MRI/CT examinations in children <24 months of age, over a 24-month period. Head circumference was obtained from the clinical record. Studies were reviewed blindly for subdural collection presence and subarachnoid space size. Children with prior cranial surgery, parenchymal abnormalities, hydrocephalus, or conditions predisposing to parenchymal volume loss were excluded. Chart review was performed on those with subdural collections. RESULTS: Imaging from 177 children with enlarged head circumference was reviewed. Nine were excluded, for a final cohort of 168 subjects (108 with enlarged subarachnoid space). Subdural collections were identified in 6 (3.6%), all with enlarged subarachnoid space (6/108, 5.6%). In 4, subdural collections were small, homogeneous, and nonhemorrhagic. In 2, the collections were complex (septations or hemorrhage). Two children were reported as victims of child abuse (both with complex collections). No definitive etiology was established in the other cases. CONCLUSIONS: The prevalence of subdural collections in imaged children with macrocrania was 3.6%, all occurring in children with enlarged subarachnoid space. Our results suggest that enlarged subarachnoid space can be associated with some subdural collections in this cohort. Despite this, we believe that unexpected subdural collections in children should receive close clinical evaluation for underlying causes, including abusive head trauma.

Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding.

The t(8;21) translocation fuses the DNA-binding domain of the hematopoietic master regulator RUNX1 to the ETO protein. The resultant RUNX1/ETO fusion protein is a leukemia-initiating transcription factor that interferes with RUNX1 function. The result of this interference is a block in differentiation and, finally, the development of acute myeloid leukemia (AML). To obtain insights into RUNX1/ETO-dependant alterations of the epigenetic landscape, we measured genome-wide RUNX1- and RUNX1/ETO-bound regions in t(8;21) cells and assessed to what extent the effects of RUNX1/ETO on the epigenome depend on its continued expression in established leukemic cells. To this end, we determined dynamic alterations of histone acetylation, RNA Polymerase II binding and RUNX1 occupancy in the presence or absence of RUNX1/ETO using a knockdown approach. Combined global assessments of chromatin accessibility and kinetic gene expression data show that RUNX1/ETO controls the expression of important regulators of hematopoietic differentiation and self-renewal. We show that selective removal of RUNX1/ETO leads to a widespread reversal of epigenetic reprogramming and a genome-wide redistribution of RUNX1 binding, resulting in the inhibition of leukemic proliferation and self-renewal, and the induction of differentiation. This demonstrates that RUNX1/ETO represents a pivotal therapeutic target in AML.

Combining the interactome and deleterious SNP predictions to improve disease gene identification.

A method has been developed for the prediction of proteins involved in genetic disorders. This involved combining deleterious SNP prediction with a system based on protein interactions and phenotype distances; this is the first time that deleterious SNP prediction has been used to make predictions across linkage-intervals. At each step we tested and selected the best procedure, revealing that the computationally expensive method of assigning medical meta-terms to create a phenotype distance matrix was outperformed by a simple word counting technique. We carried out in-depth benchmarking with increasingly stringent data sets, reaching precision values of up to 75% (19% recall) for 10-Mb linkage-intervals (averaging 100 genes). For the most stringent (worst-case) data we attained an overall recall of 6%, yet still achieved precision values of up to 90% (4% recall). At all levels of stringency and precision the addition of predicted deleterious SNPs was shown to increase recall.

Development and characterization of immortalized fibroblastoid cell lines from an FA(C) mouse model.

Fanconi anemia (FA) is an autosomal recessive disorder, characterised by multiple congenital malformations, bone marrow failure and a predisposition to developing malignancies, especially leukemia. FA cells show increased levels of spontaneous chromosomal aberrations and a hypersensitivity to DNA cross-linking agents such as mitomycin C (MMC) and diepoxybutane (DEB). There are at least eight complementation groups involved in FA, and the genes for two of these groups, FA(A) and FA(C), have been isolated and cloned. Mouse models for FA(C) have been developed by replacing exon 8 or exon 9 of Fac with the neo gene. Mice homozygous for Fac mutations show reduced fertility and hypersensitivity to induction of chromosomal aberrations by MMC and DEB. To facilitate the study of cellular defects in vitro, transformed mouse fibroblast cell lines were established. Cell-killing experiments and cytogenetic analyses were performed on these cells following treatment with MMC and DEB. Fac-/- showed significant hypersensitivity to MMC and DEB as compared with Fac+/+ and +/- for both cellular phenotypes. This is consistent with results obtained from similar studies on human fibroblasts and lymphoblastoid cell lines. Therefore, these isogenic transformed mouse fibroblasts provide as in vitro model for further investigation of the hypersensitivity of Fanconi anemia cells to DNA cross-linking agents.

A randomized controlled study comparing elemental diet and steroid treatment in Crohn's disease.

BACKGROUND: Elemental diet is considered an effective primary treatment for active Crohn's disease, but it is usually given by a feeding tube. METHODS: Twenty-two patients (12 males, median age 30 years, range 18-60) with moderately active Crohn's disease were enrolled in a randomized study in which the efficacy of an elemental diet administered orally was compared to high-dose corticosteroids in achieving clinical and laboratory remission. Ten patients were treated by oral elemental diet (Peptamen, Clintec, USA) and 10 received corticosteroids. Both treatment regimens lasted 2 weeks. The two groups did not differ with respect to age, sex, body weight, location of disease, treatment or disease activity prior to the study. In all patients studied, simple Crohn's disease activity index, nutritional status (expressed as body mass index), percentage of ideal body weight, fat mass, fat free mass, erythrocyte sedimentation rate, interleukin-6, intestinal permeability (expressed as permeability index), prealbumin, retinol binding protein and multiskin test were evaluated before and after treatment. RESULTS: After 2 weeks of treatment, there were significant improvements in simple Crohn's disease activity index, erythrocyte sedimentation rate, permeability index, body mass index, prealbumin, retinol binding protein and multiskin test in the elemental diet group. There were significant improvements in simple Crohn's disease activity index and fat free mass in the corticosteroid group. CONCLUSIONS: These data suggest that, in the short term, an oral elemental diet is at least as effective as steroids in inducing remission of mild-moderately active Crohn's disease, but it may be more effective in improving the nutritional status of these patients, probably through a more rapid restoration of normal intestinal permeability.

Ocular naevus and hyperaemia with dilation of the conjunctival vessels: an early manifestation of Crohn's disease?

Two cases of male patients with Crohn's disease showing the same neonatal ocular abnormality, a sector hyperaemia with dilation of the vessels of the bulbar conjunctiva surrounding a naevus close to the limbus, are presented. In both cases, this manifestation worsened when Crohn's disease relapsed, and improved when the disease went into remission with steroid treatment. In Crohn's disease, eye involvement is reported in varying percentages, but the condition discussed here does not fit into any of the ocular patterns previously described in this disease, and could represent an early manifestation of Crohn's disease.