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Maintenance of gastrointestinal health is challenging as it requires balancing multifaceted processes within the highly complex and dynamic ecosystem of the gastrointestinal tract. Disturbances within this vibrant environment can have detrimental consequences, including the onset of gastrointestinal cancers. Globally, gastrointestinal cancers account for ~19% of all cancer cases and ~22.5% of all cancer-related deaths. Developing new ways to more readily detect and more efficiently target these malignancies are urgently needed. Whereas members of the tumour microenvironment, such as immune cells and fibroblasts, have already been in the spotlight as key players of cancer initiation and progression, the importance of the nervous system in gastrointestinal cancers has only been highlighted in the past few years. Although extrinsic innervations modulate gastrointestinal cancers, cells and signals from the gut's intrinsic innervation also have the ability to do so. Here, we shed light on this thriving field and discuss neural influences during gastrointestinal carcinogenesis. We focus on the interactions between neurons and components of the gastrointestinal tract and tumour microenvironment, on the neural signalling pathways involved, and how these factors affect the cancer hallmarks, and discuss the neural signatures in gastrointestinal cancers. Finally, we highlight neural-related therapies that have potential for the management of gastrointestinal cancers.

Objective People exhibiting post-stroke lateropulsion actively push their body across the midline to the more affected side and/or resist weight shift toward the less affected side. Despite its prevalence and associated negative rehabilitation outcomes, no clinical practice guidelines exist for the rehabilitation of post-stroke lateropulsion. We aimed to develop consensus-based clinical practice recommendations for managing post-stroke lateropulsion using an international expert panel. Design This Delphi panel process conformed with Guidance on Conducting and Reporting Delphi Studies recommendations. Participants Panel members had demonstrated clinical and/or scientific background in the rehabilitation of people with post-stroke lateropulsion. Main Measures The process consisted of four electronic survey rounds. Round One consisted of 13 open questions. Subsequent rounds ascertained levels of agreement with statements derived from Round One. Consensus was defined a priori as ≥75% agreement (agree or strongly agree), or ≥70% agreement after excluding ‘unsure’ responses. Results Twenty participants completed all four rounds. Consensus was achieved regarding a total of 119 recommendations for rehabilitation approaches and considerations for rehabilitation delivery, positioning, managing fear of falling and fatigue, optimal therapy dose, and discharge planning. Statements for which ‘some agreement’ (50%–74% agreement) was achieved and those for which recommendations remain to be clarified were recorded. Conclusions These recommendations build on existing evidence to guide the selection of interventions for post-stroke lateropulsion. Future research is required to elaborate specific rehabilitation strategies, consider the impact of additional cognitive and perceptual impairments, describe positioning options, and detail optimal therapy dose for people with lateropulsion.

OBJECTIVES: To improve colorectal cancer (CRC) survival and lower incidence rates, colonoscopy and/or fecal immunochemical test screening are widely implemented. Although candidate DNA methylation biomarkers have been published to improve or complement the fecal immunochemical test, clinical translation is limited. We describe technical and methodological problems encountered after a systematic literature search and provide recommendations to increase (clinical) value and decrease research waste in biomarker research. In addition, we present current evidence for diagnostic CRC DNA methylation biomarkers. METHODS: A systematic literature search identified 331 diagnostic DNA methylation marker studies published before November 2020 in PubMed, EMBASE, Cochrane Library, and Google Scholar. For 136 bodily fluid studies, extended data extraction was performed. STARD criteria and level of evidence were registered to assess reporting quality and strength for clinical translation. RESULTS: Our systematic literature search revealed multiple issues that hamper the development of DNA methylation biomarkers for CRC diagnosis, including methodological and technical heterogeneity and lack of validation or clinical translation. For example, clinical translation and independent validation were limited, with 100 of 434 markers (23%) studied in bodily fluids, 3 of 434 markers (0.7%) translated into clinical tests, and independent validation for 92 of 411 tissue markers (22%) and 59 of 100 bodily fluids markers (59%). DISCUSSION: This systematic literature search revealed that major requirements to develop clinically relevant diagnostic CRC DNA methylation markers are often lacking. To avoid the resulting research waste, clinical needs, intended biomarker use, and independent validation should be better considered before study design. In addition, improved reporting quality would facilitate meta-analysis, thereby increasing the level of evidence and enabling clinical translation.

Immersive virtual reality (IVR) may boost neglect recovery, as it can provide an engaging experience in a 3D environment. We designed an IVR rehabilitation game for neglect patients using the Oculus Rift. Multisensory cues were presented in the neglected visual field in a patient-tailored way. We acquired pilot data in 15 neurologically healthy controls and 7 stroke patients. First, we compared cybersickness before and after VR exposure. Second, we assessed the user experience through a questionnaire. Third, we tested whether neglect symptoms corresponded between the VR game and a computerized cancelation task. Fourth, we evaluated the effect of the multisensory cueing on target discrimination. Last, we tested two algorithms to tailor the game to the characteristics of the neglected visual field. Cybersickness significantly reduced after VR exposure in six stroke patients and was low in healthy controls. Patients rated the user experience neutral to positive. In addition, neglect symptoms were consistent between a computerized cancelation and VR rehabilitation task. The multisensory cue positively affected target discrimination in the game and we successfully presented sensory stimulation to the neglected visual field in a patient-tailored way. Our results show that it is promising to use gamified patient-tailored immersive VR for neglect rehabilitation. ispartof: Applied Neuropsychology-Adult vol:29 issue:5 pages:1-21 ispartof: location:United States status: Published online

Post-stroke lateropulsion is prevalent. The global inconsistency in terminology used to describe the condition presents obstacles in accurately comparing research results, reaching consensus on use of measurement tools, agreeing upon a consistent approach to rehabilitation, and translating research to clinical practice. Commencing in 2021, 20 international experts undertook a Delphi Process that aimed to compile clinical practice recommendations for the rehabilitation of lateropulsion. As a part of the process, the panel agreed to aim to reach consensus regarding terminology used to describe the condition. Improved understanding of the condition could lead to improved management, which will enhance patient outcomes after stroke and increase efficiency of healthcare resource utilisation. While consensus was not reached, the panel achieved some agreement that 'lateropulsion' is the preferred term to describe the phenomenon of 'active pushing of the body across the midline toward the more affected side, and / or actively resisting weight shift toward the less affected side'. This group recommends that 'lateropulsion' is used in future research and in clinical practice.

The N‐Myc Downstream‐Regulated Gene 4 (NDRG4), a prominent biomarker for colorectal cancer (CRC), is specifically expressed by enteric neurons. Considering that nerves are important members of the tumor microenvironment, we here establish different Ndrg4 knockout (Ndrg4 −/−) CRC models and an indirect co‐culture of primary enteric nervous system (ENS) cells and intestinal organoids to identify whether the ENS, via NDRG4, affects intestinal tumorigenesis. Linking immunostainings and gastrointestinal motility (GI) assays, we show that the absence of Ndrg4 does not trigger any functional or morphological GI abnormalities. However, combining in vivo, in vitro, and quantitative proteomics data, we uncover that Ndrg4 knockdown is associated with enlarged intestinal adenoma development and that organoid growth is boosted by the Ndrg4 −/− ENS cell secretome, which is enriched for Nidogen‐1 (Nid1) and Fibulin‐2 (Fbln2). Moreover, NID1 and FBLN2 are expressed in enteric neurons, enhance migration capacities of CRC cells, and are enriched in human CRC secretomes. Hence, we provide evidence that the ENS, via loss of Ndrg4, is involved in colorectal pathogenesis and that ENS‐derived Nidogen‐1 and Fibulin‐2 enhance colorectal carcinogenesis., Loss of enteric neuronal N‐Myc Downstream‐Regulated Gene 4 (Ndrg4) increases the release of the extracellular matrix proteins, Nidogen‐1 and Fibulin‐2, which accelerates intestinal growth in vitro and promotes colorectal cancer progression in vivo.

Purpose Colonoscopy and the fecal immunochemical test (FIT) are currently the most widely used screening modalities for colorectal cancer (CRC), however, both with their own limitations. Here we aim to identify and validate stool-based DNA methylation markers for the early detection of CRC and investigate the biological pathways prone to DNA methylation. Methods DNA methylation marker discovery was performed using The Cancer Genome Atlas (TCGA) colon adenocarcinoma data set consisting of normal and primary colon adenocarcinoma tissue. The performance of the five best candidate markers and a previously identified marker, NDRG4, was evaluated on tissues and whole stool samples of healthy subjects and CRC patients using quantitative MSP assays. The results were compared and combined with FIT data. Finally, pathway and gene ontology enrichment analyses were performed using ToppFun, GOrilla and clusterProfiler. Results GDNF, HAND2, SLC35F3, SNAP91 and SORCS1 were ranked as the best performing markers. Gene combinations of all five markers, NDRG4 and FIT were evaluated to establish the biomarker panel with the highest diagnostic potential, resulting in the identification of GDNF/SNAP91/NDRG4/FIT as the best performing marker panel. Pathway and gene ontology enrichment analyses revealed that genes associated with the nervous system were enriched in the set of best performing CRC-specific biomarkers. Conclusion In silico discovery analysis using TCGA-derived data yielded a novel DNA-methylation-based assay for the early detection of CRC, potentially improving current screening modalities. Additionally, nervous system-related pathways were enriched in the identified genes, indicating an epigenetic regulation of neuronal genes in CRC.

Background The N-Myc Downstream-Regulated Gene (NDRG) family comprises four members that function in cellular processes like proliferation and differentiation. While NDRG1 and NDRG2 are extensively studied, knowledge regarding NDRG3 and NDRG4, despite its recognition as a well-established early-detection marker for colorectal cancer (Cologuard®), is sparse. Scope of review To summarize expression, biomarker potential and functional mechanisms of the NDRGs in the developing, mature and cancerous gut, we combine current literature and in silico analyses from the TCGA-database, GTEX Project, E14.5 mouse intestine and enteric neural crest cells, and an RNA-sequencing time-series of human embryonic colonic samples. Major conclusions This study reveals that all members display a differential expression pattern in the gut and that NDRG1, NDRG2 and NDRG4 (1) can serve as biomarker for colorectal cancer and (2) have tumor suppressive properties mainly affecting cell proliferation and epithelial-mesenchymal transition. General significance Similar effects of the NDRGs on the key-hallmarks of cancer, could implicate analogous functions in other tissue/cancer types.

Background Evidence is lacking concerning the effect of additional trunk rehabilitation on gait performance. Investigating gait performance by both clinical and biomechanical outcome measures might lead to new scientific insights into the importance of the trunk during gait rehabilitation in people suffering from stroke. This protocol was written according to the SPIRIT 2013 Statement. Methods and design An assessor-blinded randomized controlled trial will be conducted in patients with impaired trunk control after stroke. A total of 60 patients will be randomly allocated to the control or the experimental group by means of sealed opaque envelopes. They will receive either 16 h of additional trunk exercises (experimental group) or cognitive exercises (controls) for 1 h a day, 4 days a week for 4 weeks. Patients will also receive 2 h of standard care consisting of physiotherapy and occupational therapy. Gait performance will be assessed clinically by the Tinetti Test and biomechanically by means of a full body gait analysis. In addition, the effect of the exercise protocol on the trunk itself and trunk activities of daily living will be assessed by the Trunk Impairment Scale and the Barthel Index. Discussion Despite the evidence demonstrating the importance of trunk control after stroke, studies about the effects of trunk rehabilitation on gait performance are inconsistent. In the current study, a more sophisticated treatment protocol will be used to enlarge therapeutic improvements, the relationship between clinical and biomechanical measures of gait performance can be investigated, and the sustainability of the effects of trunk exercises over time will be examined. Since clinical improvements are of greater importance to patients and physiotherapists, clinical assessment scales will be used as primary outcome measures. Trial registration ClinicalTrials.gov, ID: NCT02708888. Registered on 2 March 2016. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-1989-1) contains supplementary material, which is available to authorized users.

The N-Myc downstream-regulated gene (NDRG) family consists of four members (NDRG1, NDRG2, NDRG3, NDRG4) that are differentially expressed in various organs and function in important processes, like cell proliferation and differentiation. In the last couple of decades, interest in this family has risen due to its connection with several disorders of the nervous system including Charcot-Marie-Tooth disease and dementia, as well as nervous system cancers. By combining a literature review with in silico data analysis of publicly available datasets, such as the Mouse Brain Atlas, BrainSpan, the Genotype-Tissue Expression (GTEx) project, and Gene Expression Omnibus (GEO) datasets, this review summarizes the expression and functions of the NDRG family in the healthy and diseased nervous system. We here show that the NDRGs have a differential, relatively cell type-specific, expression pattern in the nervous system. Even though NDRGs share functionalities, like a role in vesicle trafficking, stress response, and neurite outgrowth, other functionalities seem to be unique to a specific member, e.g., the role of NDRG1 in myelination. Furthermore, mutations, phosphorylation, or changes in expression of NDRGs are related to nervous system diseases, including peripheral neuropathy and different forms of dementia. Moreover, NDRG1, NDRG2, and NDRG4 are all involved in cancers of the nervous system, such as glioma, neuroblastoma, or meningioma. All in all, our review elucidates that although the NDRGs belong to the same gene family and share some functional features, they should be considered unique in their expression patterns and functional importance for nervous system development and neuronal diseases.

Despite improved early detection and treatment options, colorectal cancer (CRC) is one of the deadliest forms of cancer. I discovered that NDRG4, an established biomarker for the early detection of CRC (Cologuard®) is specifically expressed in the gut’s intrinsic nervous system: enteric nervous system (ENS). While defects in the ENS have been implicated in life-threatening conditions, its contribution to CRC is hardly studied. This is remarkable as cells in the “tumor microenvironment” can contribute to (colorectal) carcinogenesis. I uncovered that NDRG4 affects ENS development and GI-functioning. Moreover, loss of NDRG4 enhanced colorectal tumorigenesis by the increased release of soluble factors. These findings implicate that the ENS is an new member of the (tumor) microenvironment which opens new perspectives for the development of clinical applications (biomarkers and/or treatment) for GI-disorders.

Closely examining the effects, optimal regime and time window of prism adaptation (PA) promotes guidelines for effective rehabilitation practice. The effects of short-term repetitive PA on spatial neglect manifestations were evaluated in patients with heterogeneous post-stroke delays, using a digital Visuospatial Neglect Test Battery. Subsequently, potential differences in PA effects between acute, subacute or chronic neglect were explored. A multicentre randomised controlled trial was conducted in 43 right-hemisphere neglect patients. They were treated with a mild PA regime: seven sessions of experimental or placebo prism training over 7-12 days. The outcome measures were diverse neglect variables related to peripersonal navigation, visual extinction, visuospatial memory, bisection, cancellation, drawing and visual search. The treatment effects were assessed after a short and a long time interval. Two to 24 hours after PA, conventional effects were found for drawing and centred bisection, and novel effects for peripersonal visuospatial navigation, visual extinction, and non-motor memory (with caution). No effects were found for visual search times and cancellation. The assessments after three months were still indicative of PA benefits for navigational, drawing and memory functions. PA did not prove to be more effective in acute, subacute or chronic patients. The extension of effects is theoretically framed within the debate about the levels of cognitive processing that are impacted by PA. Clinical suggestions are formulated regarding PA implementation in neglect treatment.

Background: Very few ( Methods: For CRC, we identified 109 bodily fluid biomarker studies published before January 2019 in PubMed, Embase, Cochrane Library, or Google Scholar. For RCC, we identified 6 liquid biopsy studies up to January 2019 in these databases. Data extraction (study design, patient characteristics, disease stage, tumor location, technical assays, diagnostic measures) was performed on published reports. STARD criteria and Level of Evidence (LoE) were registered to assess reporting quality and strength for clinical translation, and forest plots were generated to summarize diagnostic performance of the biomarkers. Findings: Our systematic literature search revealed multiple issues that hamper the development of DNA methylation biomarkers for RCC and CRC diagnosis, including methodologic and technical heterogeneity and lack of validation or clinical translation. Among the most important issues were a lack of translation from tissue into liquid biopsy; for CRC 88/389 (23%) CRC markers were studied in liquid biopsies, and for RCC these numbers were 15/44 (34%). In addition, results showed a lack of independent validation, with 37/88 (42%) CRC markers and 9/15 (60%) RCC markers in liquid biopsies studied in more than one study or study population. Also, inappropriate marker identification and primer design, lack of true clinical need definition, and low reporting quality were issues that were recognized in our systematic literature searches. These issues all hamper the development of the field, keep the LoE low, and hinder the translation of DNA methylation biomarkers into clinical tests. Interpretation: Our systematic literature searches revealed that major requirements to develop clinically relevant diagnostic DNA methylation markers are often lacking. To avoid the resulting research waste, clinical needs, intended biomarker use, and independent validation should be better considered prior to study design. In addition, improved reporting quality would facilitate meta-analysis, thereby increasing LoE and enabling clinical translation. Reference: 1. Lommen et al. Eur Urol Oncol 2019; https://doi.org/10.1016/j.euo.2019.07.011. Citation Format: Kim Lommen, Zheng Feng, Cary J.G. Oberije, Alouisa J. P. van de Wetering, Selena Odeh, Alexander Koch, Maureen J. B. Aarts, Joep G. van Roermund, Leo J. Schouten, Egbert Oosterwijk, Nathalie Vaes, Ad A. M. Masclee, Beatriz Carvalho, Gerrit A. Meijer, Maurice P. Zeegers, James G. Herman, Vivianne C. Tjan-Heijnen, Veerle Melotte, Manon van Engeland, Kim Smits. Clinical translation of liquid biopsy DNA methylation biomarkers: Lessons from two systematic reviews [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A62.

Recently, the importance of lysosomes in the context of the metabolic syndrome has received increased attention. Increased lysosomal cholesterol storage and cholesterol crystallization inside macrophages have been linked to several metabolic diseases, such as atherosclerosis and non-alcoholic fatty liver disease (NAFLD). Two-hydroxypropyl-beta-cyclodextrin (HP-B-CD) is able to redirect lysosomal cholesterol to the cytoplasm in Niemann-Pick type C1 disease, a lysosomal storage disorder. We hypothesize that HP-B-CD ameliorates liver cholesterol and intracellular cholesterol levels inside Kupffer cells (KCs). Hyperlipidemic low-density lipoprotein receptor knockout (Ldlr(-/-)) mice were given weekly, subcutaneous injections with HP-B-CD or control PBS. In contrast to control injections, hyperlipidemic mice treated with HP-B-CD demonstrated a shift in intracellular cholesterol distribution towards cytoplasmic cholesteryl ester (CE) storage and a decrease in cholesterol crystallization inside KCs. Compared to untreated hyperlipidemic mice, the foamy KC appearance and liver cholesterol remained similar upon HP-B-CD administration, while hepatic campesterol and 7alpha-hydroxycholesterol levels were back increased. Thus, HP-B-CD could be a useful tool to improve intracellular cholesterol levels in the context of the metabolic syndrome, possibly through modulation of phyto- and oxysterols, and should be tested in the future. Additionally, these data underline the existence of a shared etiology between lysosomal storage diseases and NAFLD.

Background: Promoter methylation of N-myc Downstream-Regulated Gene 4 (NDRG4) in fecal DNA is an established early detection marker for colorectal cancer (CRC). Despite its connection to CRC, NDRG4 is predominantly studied in brain and heart, with little to no knowledge about its expression or role in other organs. In this study, we aimed to determine the whole-body expression of NDRG4, with a focus on the intestinal tract.Methods: We investigated NDRG4 expression throughout the body by immunohistochemistry, Western Blotting and in situ mRNA hybridization using tissues from NDRG4 wild-type, heterozygous and knockout mice and humans. In addition, we explored cell-specific expression of NDRG4 in murine whole-mount gut preparations using immunofluorescence and confocal microscopy.Key Results: NDRG4 is specifically expressed within nervous system structures throughout the body. In the intestinal tract of both mouse and man, NDRG4 immunoreactivity was restricted to the enteric nervous system (ENS), where it labeled cell bodies of the myenteric and submucosal plexuses and interconnecting nerve fibers. More precisely, NDRG4 expression was limited to neurons, as NDRG4 always co-localized with HuC/D (pan-neuronal marker) but never with GFAP (an enteric glial cell marker). Furthermore, NDRG4 was expressed in various neuropeptide Y positive neurons, but was only found in a minority (similar to 10%) of neurons expressing neuronal nitric oxide synthase.Conclusions and Inferences :NDRG4 is exclusively expressed by central, peripheral and enteric neurons/nerves, suggesting a neuronal-specific role of this protein. Our findings raise the question whether NDRG4, via the ENS, an understudied component of the tumor microenvironment, supports CRC development and/or progression.

The enteric nervous system (ENS) is the intrinsic neural network of the gastrointestinal tract, which is essential for regulating gut functions and intestinal homeostasis. The importance of the ENS is underscored by the existence of severe gastrointestinal diseases, such as Hirschsprung's disease and intestinal pseudo-obstruction, which arise when the ENS fails to develop normally or becomes dysregulated. Moreover, it is known that enteric neurons are involved in intestinal inflammation. However, the role of the ENS in colorectal cancer (CRC) carcinogenesis remains poorly understood, even though processes like perineural invasion and neoneurogenesis are important factors in CRC. Here we summarize how enteric neurons are affected during CRC and discuss the influence of enteric neurons, either direct or indirect, on the development and/or progression of CRC. Finally, we illustrate how the ENS could be targeted as a potential anti-cancer therapy, establishing the ENS as an integral part of the tumor microenvironment.

The flavonoid 7-mono-O-(beta-hydroxyethyl)-rutoside (monoHER) is an effective protector against doxorubicin induced toxicity which has been related to the antioxidant activity of monoHER. The present study examines the potential relevance of the direct scavenging activity of the flavonoid.The potency of the direct antioxidant effect was confirmed by its instantaneous protection against intracellular oxidative stress in human umbilical vein endothelial cells at therapeutically achievable concentrations (EC50= 60 nM) underpinning the involvement of a direct scavenging activity. This direct effect of monoHER is substantiated by (i) its site specific scavenging effect, i.e. on a molecular level monoHER is positioned at the location of radical formation, (ii) its position in the antioxidant network, i.e. on a biochemical level oxidized monoHER quickly reacts with ascorbate or glutathione, (iii) its location in the vascular system, i.e. on a cellular level monoHER is localized in the endothelial and smooth muscle cells in the vascular wall.It is concluded that the flavonoid monoHER can display a physiologically important direct antioxidant effect.

Objective Contraversive pushing (CP) is a neurologic disorder characterized by a lateral postural imbalance. Pusher patients actively push toward their contralesional side due to a misperception of the body's orientation in relation to gravity. Although not every patient with CP suffers from spatial neglect (SN), both phenomena are highly correlated in right-hemispheric patients. The present study investigates whether peripersonal visuospatial functioning differs in neglect patients with versus without CP (NP+ vs. NP- patients). Method Eighteen right-hemispheric stroke patients with SN were included, of which 17 in a double-blind case-control study and 1 single case with posterior pushing to supplement the discourse. A computer-based visuospatial navigation task, in which lateralized deviation can freely emerge, was used to quantify visuospatial behavior. In addition, visuospatial orienting was monitored using line bisection. Results Significant intergroup differences were found. The NP+ patients demonstrated a smaller ipsilesional navigational deviation and more cross-over (contralesional instead of ipsilesional deviation) in long line bisection. As such, they demonstrated a contraversive (contralesionally directed) shift in comparison with the NP- patients. Conclusions These findings highlight the similarity between 2 systems of space representation. They are consistent with a coherence between the neural processing system that mainly provides for postural control, and the one responsible for nonpredominantly postural, visuospatial behavior.

Computerized as well as paper-and-pencil tasks are applied in mapping visuospatial neglect in experimental research and clinical practice. This article presents a new kind of computer-based assessment method, using an electronic pen display and user-friendly software. The approach is tailored to specific spatial processes and highlights the usefulness of a pen display in neglect patients. The advantages of the introduced method are illustrated by a recently designed battery of classic, as well as new, types of tests. The development of the appropriate stimuli and the assorted scoring systems is addressed, as well as the resulting types of task implementation and data generation. The diagnostic value of the different visuospatial neglect tests is demonstrated by comparative analyses between a neglect group and a control group. Among the benefits of the proposed assessment method are (1) the opportunity to perform standardized repeated measurements to quantify recovery, (2) online performance monitoring, (3) flexible employment, (4) the collection of exact data over a short period, and (5) the easy availability of more refined quantitative as well as interesting qualitative information, especially as compared to classic or paper-and-pencil tasks. To indicate that this method also lends itself well to measures for treatment procedures, an illustration is given with respect to specific measurements during prism adaptation. The tasks of the Visuospatial Neglect Test Battery and the prism adaptation measures are illustrated by a case study. The outlined applications are discussed with respect to experimental as well as clinical purposes.

Contains fulltext : 125609.pdf (Publisher’s version ) (Open Access) BACKGROUND & AIMS: While non-alcoholic steatohepatitis (NASH) is characterized by hepatic steatosis combined with inflammation, the mechanisms triggering hepatic inflammation are unknown. In Ldlr(-/-) mice, we have previously shown that lysosomal cholesterol accumulation in Kupffer cells (KCs) correlates with hepatic inflammation and cholesterol crystallization. Previously, cholesterol crystals have been shown to induce the activation of inflammasomes. Inflammasomes are protein complexes that induce the processing and release of pro-inflammatory cytokines IL-1b and IL-18 via caspase-1 activation. Whereas caspase-1 activation is independent of caspase-11 in the canonical pathway of inflammasome activation, caspase-11 was found to trigger caspase-1-dependent IL-1b and IL-18 in response to non-canonical inflammasome activators. So far, it has not been investigated whether inflammasome activation stimulates the formation of cholesterol crystals. We hypothesized that inflammasome activation in KCs stimulates cholesterol crystallization, thereby leading to hepatic inflammation. METHODS: Ldlr (-/-) mice were transplanted (tp) with wild-type (Wt) or caspase-1/11(-/-) (dKO) bone marrow and fed either regular chow or a high-fat, high-cholesterol (HFC) diet for 12 weeks. In vitro, bone marrow derived macrophages (BMDM) from wt or caspase-1/11(-/-) mice were incubated with oxLDL for 24h and autophagy was assessed. RESULTS: In line with our hypothesis, caspase-1/11(-/-)-tp mice had less severe hepatic inflammation than Wt-tp animals, as evident from liver histology and gene expression analysis in isolated KCs. Mechanistically, KCs from caspase-1/11(-/-)-tp mice showed less cholesterol crystals, enhanced cholesterol efflux and increased autophagy. In wt BMDM, oxLDL incubation led to disturbed autophagy activity whereas BMDM from caspase-1/11(-/-) mice had normal autophagy activity. CONCLUSION: Altogether, these data suggest a vicious cycle whereby disturbed autophagy and decreased cholesterol efflux leads to newly formed cholesterol crystals and thereby maintain hepatic inflammation during NASH by further activating the inflammasome.

Although differential right-hemisphere dysfunction has been implicated in attention deficit hyperactivity disorder (ADHD) for more than 15 years, this relation remains controversial. Neuroimaging studies suggest asymmetric dysfunction, but neuropsychological evidence in support of this is rather inconsistent. This study examined attentional asymmetry in ADHD adults with a psychophysical extinction task. The interference from right- or left-hemifield distractors with contralateral orientation sensitivity was determined. In a previous study using this paradigm, right brain-damaged patients with left neglect displayed asymmetric distractor interference, meaning a significant interference from a right distractor with left-hemifield orientation sensitivity but no interference from a left distractor with right-hemifield orientation sensitivity. A similar but less pronounced asymmetry was observed in a group of ADHD adults (n = 16). These results indicate dysfunction of right-hemisphere attentional circuits in ADHD.

Background: We recently described that the N- Myc Downstream- Regulated Gene 4 (NDRG4), an established early- detection DNA- methylation marker for colorectal cancer (CRC), is specifically expressed by enteric neurons. So far, our studies focused on how enteric neuronal NDRG4 is involved in the development and pro-gression of CRC. However, the role of NDRG4 in the development and function of the enteric nervous system (ENS) during gastrointes-tinal homeostasis also remains to be elucidated.Methods: To explore the role of ndrg4 in ENS morphogenesis and intestinal motility, we used a (i) morpholino (MO) and (ii) CRISPR- Cas9 knockdown approach in transgenic zebrafish (Danio rerio) ex-pressing the fluorescent- kaede- protein in enteric precursor cells and enteric neurons (Tg(- 8.3phox2b:kaede) zebrafish). We quantified the number of enteric neurons in the distal intestine and created spati-otemporal maps from video recordings to examine intestinal motility in wild- type and ndrg4- knockdown (ndrg4−/−) zebrafish larvae (5 and 7 days post- fertilization (dpf), respectively).Results: In agreement with mouse and human expression studies, we found that ndrg4 is also expressed within the GI- tract of zebrafish larvae. In 5dpf zebrafish, loss of ndrg4 is associated with a significant reduction in the number of enteric neurons: (i) average number 102.4 control- injected vs. 67.4 ndrg4- MO injected (P < 0.001) and (ii) aver-age number 110.9 ndrg4+/+ vs. 97.8 ndrg4−/− zebrafish (P = 0.028). Although the frequency, velocity and contraction interval of peri-staltic waves were not affected in 7dpf ndrg4−/− zebrafish, their travel distance was significantly shorter in ndrg4−/− as compared to ndrg4+/+ zebrafish (P = 0.040).Conclusion: This is the first study describing ndrg4 expression in the zebrafish intestinal tract. Our data suggest that loss of ndrg4 has consequences for ENS development and function.