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Lifestyle modification is the foundation of treatment recommendations for non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). The design of clinical trials in NASH may be impeded by the lack of a systematic approach to identify and evaluate how lifestyle changes and/or modifications influence clinical trial outcomes and associated endpoints. Furthermore, there are additional uncertainties regarding the methods that can be utilised to better characterise and quantify lifestyle variables - which can influence disease activity and alter trial endpoints - to allow for comparisons of trial outcomes across different phases of research and/or within drug-classes. This summary by the Liver Forum's Standard of Care Working Group reviews currently available clinical data, identifies the barriers and challenges associated with the standard of care in NAFLD/NASH clinical trials, defines available assessments of lifestyle changes, and proposes approaches to better understand and define the influence of diet and exercise on NASH treatment in the context of different pharmacologic interventions. The ultimate objective is to propose tangible solutions which enable investigators, sponsors, and regulatory authorities to meaningfully interpret clinical trial outcomes and the impact of lifestyle modification on such outcomes as they pertain to phase I-IV clinical trials. (C) 2020 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.

Bone marrow (BM) and lymphocyte samples from aplastic anemia patients show up-regulated Fas and Fas-ligand (FasL) expression, respectively, supporting a relationship between immune-mediated BM destruction and the Fas apoptotic pathway. Mice with spontaneous lymphoproliferation (lpr) and generalized lymphoproliferative disease (gld) mutations exhibit abnormal expression of Fas and FasL, serving as potential models to elucidate underlying mechanisms of BM failure. We examined cellular and functional characteristics of lpr and gld mutants on the C57BL/6 (B6) background. Lymph node (LN) cells from lpr and gld mice produced less apoptosis when coincubated with C.B10-H2b/LilMcd (C.B10) BM cells in vitro. This functional difference was confirmed by infusing lpr, gld, and B6 LN cells into sublethally irradiated CB10 mice. All donor LN cells showed significant T cell expansion and activation, but only B6 LN cells caused severe BM destruction. Mice infused with gld LN cells developed mild to moderate BM failure despite receiving FasL-deficient effectors, thus suggesting the existence of alternative pathways or incomplete penetrance of the mutation. Paradoxically, mice that received Fas-deficient lpr LN cells also had reduced BM failure, likely due to down-regulation of proapoptotic genes, an effect that can be overcome by higher doses of lpr LN cells. Our model demonstrates that abnormal Fas or FasL expression interferes with the development of pancytopenia and marrow hypoplasia, validating a major role for the Fas/FasL cytotoxic pathway in immune-mediated BM failure, although disruption of this pathway does not completely abolish marrow destruction.

A 20-year-old man with acquired immunodeficiency syndrome (AIDS) and central nervous system (CNS) lymphoproliferative disease experienced improvement with highly active antiretroviral therapy (HAART) without radiation therapy. Our experience highlights the importance of biopsy in evaluating multifocal radiographic CNS lesions and the central role of HAART in treating AIDS-related CNS disease.

Key cellular events in the development of aplastic anemia are activation and expansion of T cells that are destructive of hematopoietic tissue. Human immune-mediated bone marrow failure has been modeled in mice by infusion of lymph node (LN) cells into major- or minor-histocompatibility antigen mismatched recipients; oligoclonal T cell expansion causes indiscriminant hematopoietic cell destruction, marked marrow hypoplasia, and fatal pancytopenia. We have utilized this simple model in order to dissect the molecular events responsible for T cell mediated, selective organ destruction. In mice with spontaneous mutations: lymphoproliferation (lpr) and generalized lymphoproliferative disease (gld), animals have an abnormal increase in lymphocytes and develop clinical manifestations similar to those seen in patients with systemic lupus erythematosus (SLE). In contrast to human SLE, the lpr and gld bone marrow appear unaffected by this typically self-destructive process. We examined C57BL/6 (B6) mice that carry the lpr and gld mutations along with normal B6 mice to define cellular and functional differences as they relate to BM damage. In our initial analyses of peripheral blood (PB), we found a reduced CD4 T cell proportion in lpr and gld mice (5.5±1.5%, 4.3±0.6%, 9.9±0.9%) and a reduced CD8 T cell proportion in gld mice when compared to B6 controls (13.4±1.9%, 7.9±0.9%, 12.7±1.8%). In the BM, both CD4 (1.5±0.3%, 2.3±0.3%, 1.0±0.1%) and CD8 (2.9±0.3%, 3.1±0.7%, 2.6±0.2%) T cell proportions were slightly increased in lpr and gld mice, while total number of BM cells was not significantly different among the three genotypes (438±48, 324±18, 350±27, millions). These findings indicated no PB lymphocyte accumulation and no BM destruction in lpr or gld mice. We then tested the hypothesis that lpr and gld BM cells were more resistant to immune attack by infusing 5 x 106 lymph node (LN) cells from minor-histocompatibility antigen-mismatched C.B10 mice into sublethally-irradiated (5 Gys) lpr, gld, and B6 recipients. At two weeks, all recipients infused with CB10 LN cells had reduced blood neutrophils, and gld and B6 recipients also had reduced RBCs, as compared to mice that did not receive LN cell infusions. This result suggests that lpr and gld hematopoietic cells, like those from B6 mice, are susceptible to immune-mediated destruction. We then examined lymphocyte function by co-incubating lpr, gld and B6 LN cells (effectors) with C.B10 BM cells (targets) in a cytotoxilux assay in vitro. B6 effectors produced 51–78% more apoptotic targets than did gld and lpr effectors. This difference was confirmed by the infusion of lpr, gld (15 x 106 cells/recipient) and B6 (5 x 106 cells/recipient) LN cells into sub-lethally irradiated CB10 mice in vivo. At three weeks, enumeration of blood neutrophils (0.69±0.60, 1.27±0.83, 0.08±0.03), RBCs (3.58±0.42, 4.80±1.20, 4.76±0.36), platelets (274± 94, 400±156, 298±91) and total BM cells (87± 23, 195±78, 82±6, millions) demonstrated that, despite massive lymphoproliferation, lymphocytes from lpr and gld mice were less effective in mediating BM cell destruction. Our results provide evidence supporting the role of Fas and Fas-ligand mediated programmed cell death in immune-mediated BM destruction. The ready availability of genetically modified mice with well characterized functional defects should allow a full description of the molecular pathways in immune-mediated marrow failure in this model.