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Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disease with unknown etiology that can be characterized by the presence of demyelinated lesions. Prevailing treatment protocols in MS rely on the modulation of the inflammatory process but do not impact disease progression. Remyelination is an essential factor for both axonal survival and functional neurological recovery but is often insufficient. The extracellular matrix protein fibronectin contributes to the inhibitory environment created in MS lesions and likely plays a causative role in remyelination failure. The presence of the blood-brain barrier (BBB) hinders the delivery of remyelination therapeutics to lesions. Therefore, therapeutic interventions to normalize the pathogenic MS lesion environment need to be able to cross the BBB. In this review, we outline the multifaceted roles of fibronectin in MS pathogenesis and discuss promising therapeutic targets and agents to overcome fibronectin-mediated inhibition of remyelination. In addition, to pave the way for clinical use, we reflect on opportunities to deliver MS therapeutics to lesions through the utilization of nanomedicine and discuss strategies to deliver fibronectin-directed therapeutics across the BBB. The use of well-designed nanocarriers with appropriate surface functionalization to cross the BBB and target the lesion sites is recommended.

Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disease with unknown etiology that can be characterized by the presence of demyelinated lesions. Prevailing treatment protocols in MS rely on the modulation of the inflammatory process but do not impact disease progression. Remyelination is an essential factor for both axonal survival and functional neurological recovery but is often insufficient. The extracellular matrix protein fibronectin contributes to the inhibitory environment created in MS lesions and likely plays a causative role in remyelination failure. The presence of the blood–brain barrier (BBB) hinders the delivery of remyelination therapeutics to lesions. Therefore, therapeutic interventions to normalize the pathogenic MS lesion environment need to be able to cross the BBB. In this review, we outline the multifaceted roles of fibronectin in MS pathogenesis and discuss promising therapeutic targets and agents to overcome fibronectin-mediated inhibition of remyelination. In addition, to pave the way for clinical use, we reflect on opportunities to deliver MS therapeutics to lesions through the utilization of nanomedicine and discuss strategies to deliver fibronectin-directed therapeutics across the BBB. The use of well-designed nanocarriers with appropriate surface functionalization to cross the BBB and target the lesion sites is recommended.

International audience; Hepatocellular carcinomas (HCCs) exhibit a diversity of molecular phenotypes, raising major challenges in clinical management. HCCs detected by surveillance programs at an early stage are candidates for potentially curative therapies (local ablation, resection, or transplantation). In the long term, transplantation provides the lowest recurrence rates. Treatment allocation is based on tumor number, size, vascular invasion, performance status, functional liver reserve, and the prediction of early (< 2 years) recurrence, which reflects the intrinsic aggressiveness of the tumor. Well-differentiated, potentially low-aggressiveness tumors form the heterogeneous molecular class of nonproliferative HCCs, characterized by an approximate 50% b-catenin mutation rate. To define the clinical, pathological, and molecular features and the outcome of nonproliferative HCCs, we constructed a 1,133HCC transcriptomic metadata set and validated findings in a publically available 210-HCC RNA sequencing set. We show that nonproliferative HCCs preserve the zonation program that distributes metabolic functions along the portocentral axis in normal liver. More precisely, we identified two well-differentiated, nonproliferation subclasses, namely periportal-type (wild-type b-catenin) and perivenous-type (mutant b-catenin), which expressed negatively correlated gene networks. The new periportal-type subclass represented 29% of all HCCs; expressed a hepatocyte nuclear factor 4A-driven gene network, which was downregulated in mouse hepatocyte nuclear factor 4A knockout mice; were early-stage tumors by Barcelona Clinic Liver Cancer, Cancer of the Liver Italian Program, and tumor-node-metastasis staging systems; had no macrovascular invasion; and showed the lowest metastasis-specific gene expression levels and TP53 mutation rates. Also, we identified an eight-gene periportal-type HCC signature, which was independently associated with the highest 2-year recurrence-free survival by multivariate analyses in two independent cohorts of 247 and 210 patients. Conclusion: Well-differentiated HCCs display mutually exclusive periportal or perivenous zonation programs. Among all HCCs, periportal-type tumors have the lowest intrinsic potential for early recurrence after curative resection.

Liver transplantation (LT) in children now has a 20-year survival of >80%, but the longterm outcome of these grafts remains uncertain. Serial protocol liver biopsies after transplantation from several pediatric centres have demonstrated the gradual development of unexplained graft inflammation ("idiopathic" posttransplant hepatitis; IPTH) and graft fibrosis in biopsies obtained >12 months post-LT in children with good graft function and (near) normal liver biochemistry. Although the clinical significance of these findings is uncertain, there is evidence to suggest that IPTH may be a form of rejection or chronic antibody-mediated rejection as it is associated with the presence of auto/alloantibodies; de novo Class II donor-specific HLA antibodies (DSA); previous episodes of rejection, and may improve or be prevented with increased immunosuppression. Currently, the only method of diagnosing either hepatitis or fibrosis has been by serial protocol biopsies as neither serum markers of fibrosis nor noninvasive methods to detect fibrosis such as transient elastography (TE) are sufficiently validated in children. This review will focus on the diagnosis and management of idiopathic posttransplant hepatitis and graft fibrosis, discuss current methods for detecting graft injury, and potential mechanisms for their development.

Liver transplantation (LT) in children now has a 20-year survival of >80%, but the longterm outcome of these grafts remains uncertain. Serial protocol liver biopsies after transplantation from several pediatric centres have demonstrated the gradual development of unexplained graft inflammation ("idiopathic" posttransplant hepatitis; IPTH) and graft fibrosis in biopsies obtained >12 months post-LT in children with good graft function and (near) normal liver biochemistry. Although the clinical significance of these findings is uncertain, there is evidence to suggest that IPTH may be a form of rejection or chronic antibody-mediated rejection as it is associated with the presence of auto/alloantibodies; de novo Class II donor-specific HLA antibodies (DSA); previous episodes of rejection, and may improve or be prevented with increased immunosuppression. Currently, the only method of diagnosing either hepatitis or fibrosis has been by serial protocol biopsies as neither serum markers of fibrosis nor noninvasive methods to detect fibrosis such as transient elastography (TE) are sufficiently validated in children. This review will focus on the diagnosis and management of idiopathic posttransplant hepatitis and graft fibrosis, discuss current methods for detecting graft injury, and potential mechanisms for their development. Liver Transplantation 22 1593-1602 2016 AASLD.

The Fontan procedure has been used since 1971 as a palliative treatment for various (functionally) univentricular hearts. The systemic venous blood flows passively to the pulmonary arteries, without passing through a functional ventricle. This results in chronic systemic venous congestion, which may lead to liver fibrosis, cirrhosis and hepatocellular carcinoma. This review discusses possible screening modalities for liver fibrosis and cirrhosis in the Fontan population and proposes a screening protocol. We suggest starting screening for progression of fibrosis and cirrhosis in collaboration with the hepatologist circa 10 years after Fontan completion. The screening programme will consist of a yearly evaluation of liver laboratory tests in conjunction with imaging of the liver with ultrasound or MRI every two years. In case of liver fibrosis or cirrhosis, (reversible) causes should be ruled out (e.g. obstruction in the Fontan circuit). In case of severe fibrosis or cirrhosis, other complications of portal hypertension should be evaluated and screening for hepatocellular carcinoma is required on a regular (6-12 months) basis. As regards hepatocellular carcinoma, treatment should be discussed in a multidisciplinary team, before deciding a treatment modality. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

The Fontan procedure has been used since 1971 as a palliative treatment for various (functionally) univentricular hearts. The systemic venous blood flows passively to the pulmonary arteries, without passing through a functional ventricle. This results in chronic systemic venous congestion, which may lead to liver fibrosis, cirrhosis and hepatocellular carcinoma. This review discusses possible screening modalities for liver fibrosis and cirrhosis in the Fontan population and proposes a screening protocol.We suggest starting screening for progression of fibrosis and cirrhosis in collaboration with the hepatologist circa 10 years after Fontan completion. The screening programme will consist of a yearly evaluation of liver laboratory tests in conjunction with imaging of the liver with ultrasound or MRI every two years. In case of liver fibrosis or cirrhosis, (reversible) causes should be ruled out (e.g. obstruction in the Fontan circuit).In case of severe fibrosis or cirrhosis, other complications of portal hypertension should be evaluated and screening for hepatocellular carcinoma is required on a regular (6-12 months) basis. As regards hepatocellular carcinoma, treatment should be discussed in a multidisciplinary team, before deciding a treatment modality. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

The objective of this study was to review past studies that have used engineering analysis to examine cerebrospinal fluid hydrodynamics in cranial and spinal subarachnoid spaces in both healthy humans and those affected by type I Chiari malformation.A PubMed search of literature pertaining to cerebrospinal fluid hydrodynamics was performed with a particular focus on those that utilized methods such as computational fluid dynamics or experimental flow modeling.From the engineer's perspective, type I Chiari malformation is an abnormal geometry of the cerebellum that causes increased resistance to cerebrospinal fluid flow between the intracranial and spinal subarachnoid space. As such, understanding the hydrodynamics of cerebrospinal fluid in the craniospinal subarachnoid space has long been thought to be important in the diagnosis and management of type I Chiari malformation. Hydrodynamic quantification of cerebrospinal fluid motion in the subarachnoid space may better reflect the pathophysiology of the disorder and serve as a prognostic indicator in conjunction with geometric magnetic resonance measurements that are currently used clinically. This review discusses the results of studies that have sought to quantify the hydrodynamics of cerebrospinal fluid motion using computational and experimental modeling and critiques the methods by which the results were obtained.Researchers have found differences in cerebrospinal fluid velocities and pressures in type I Chiari malformation patients compared to healthy subjects. However, further research is necessary to determine the causal relationship between changes to hydrodynamic parameters such as cerebrospinal fluid velocity, pressure, resistance to flow, and craniospinal compliance and clinical aspects such as neurological symptoms, radiological evidence of severity, and surgical success.