Citations

Liver fibrosis is the most important predictor of mortality in nonalcoholic fatty liver disease (NAFLD). Quantitative risk of mortality by fibrosis stage has not been systematically evaluated. We aimed to quantify the fibrosis stage–specific risk of all‐cause and liver‐related mortality in NAFLD. Through a systematic review and meta‐analysis, we identified five adult NAFLD cohort studies reporting fibrosis stage–specific mortality (0‐4). Using fibrosis stage 0 as a reference population, fibrosis stage–specific mortality rate ratios (MRRs) with 95% confidence intervals (CIs) for all‐cause and liver‐related mortality were estimated. The study is reported according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses statement. Included were 1,495 NAFLD patients with 17,452 patient years of follow‐up. Compared to NAFLD patients with no fibrosis (stage 0), NAFLD patients with fibrosis were at an increased risk for all‐cause mortality, and this risk increased with increases in the stage of fibrosis: stage 1, MRR = 1.58 (95% CI 1.19‐2.11); stage 2, MRR = 2.52 (95% CI 1.85‐3.42); stage 3, MRR = 3.48 (95% CI 2.51‐4.83); and stage 4, MRR = 6.40 (95% CI 4.11‐9.95). The results were more pronounced as the risk of liver‐related mortality increased exponentially with each increase in the stage of fibrosis: stage 1, MRR = 1.41 (95% CI 0.17‐11.95); stage 2, MRR = 9.57 (95% CI 1.67‐54.93); stage 3, MRR = 16.69 (95% CI 2.92‐95.36); and stage 4, MRR = 42.30 (95% CI 3.51‐510.34). Limitations of the study include an inability to adjust for comorbid conditions or demographics known to impact fibrosis progression in NAFLD and the inclusion of patients with simple steatosis and nonalcoholic steatohepatitis without fibrosis in the reference comparison group. Conclusion: The risk of liver‐related mortality increases exponentially with increase in fibrosis stage; these data have important implications in assessing the utility of each stage and benefits of regression of fibrosis from one stage to another. (H epatology 2017;65:1557‐1565).

AbstractBackgroundAn individualized, tissue‐engineered liver suitable for transplanting into a patient with liver disease would be of great benefit to the patient and the healthcare system. The tissue‐engineered liver would possess the functions of the original healthy organ. Two fields of study, (i) using decellularized tissue as cell scaffolding, and (ii) stem cell differentiation into functional cells, are coming together to make this concept feasible. The decellularized liver scaffolds (DLS) can interact with cells to promote cell differentiation and signal transduction and three‐dimensional (3D) stem cell aggregations can maintain the phenotypes and improve functions of stem cells after differentiation by undergoing cell‐cell contact. Although the effects of DLS and stem cell aggregation culture have been intensively studied, few observations about the interaction between the two have been achieved.MethodsWe established a method that combines the use of decellularized liver scaffolds and aggregation culture of MSCs (3D‐DLS) and explored the effects of the two on hepatic differentiation of human umbilical cord mesenchymal stem cells (hUC‐MSCs) in bioengineered hepatic tissue.ResultsA higher percentage of albumin‐producing cells, higher levels of liver‐specific transcripts, higher urea cycle‐related transcripts, and lower levels of stem cell‐specific transcripts were observed in the 3D‐DLS group when compared to that of hUC‐MSCs in monolayer culture (2D), aggregation culture (3D), monolayer on DLS culture (2D‐DLS). The gene arrays also indicated that 3D‐DLS induced the differentiation from the hUC‐MSC phenotype to the PHH phenotype. Liver‐specific proteins albumin, CK‐18, and glycogen storage were highly positive in the 3D‐DLS group. Albumin secretion and ammonia conversion to urea were more effective with a higher cell survival rate in the 3D‐DLS group for 14 days.ConclusionThis DLS and aggregation combination culture system provides a novel method to improve hepatic differentiation, maintain phenotype of hepatocyte‐like cells and sustain survival for 14 days in vitro. This is a promising strategy to use to construct bioengineered hepatic tissue.

AbstractCell‐based approaches, including hepatocyte transplantation and tissue‐engineered livers, offer promising alternatives and are expected to help support patients with liver diseases until liver transplantation or recovery via regeneration of the damaged liver. However, the success of cell therapies remains dependent on how well the cells are accepted after transplantation and is directly related to their degree of immunogenicity. In this study, hepatic differentiation of human umbilical cord mesenchymal stem cells (hUC‐MSCs) was induced in the traditional monolayer (2D) culture and newly established three‐dimensional (3D) aggregation culture with the porcine decellularized liver scaffold (DLS) system (3D‐DLS). We investigated the immunogenicity of these hepatocyte‐like cells in vitro. We found that monolayer hepatic differentiated hUC‐MSCs expressed higher levels of human leukocyte antigen‐DR (HLA‐DR) (P<.05) and lost the ability to inhibit lymphocyte proliferation (P<.05), in association with a lower level of prostaglandin E2 (PGE2) (P<.05) and a higher level of interferon‐γ (IFN‐γ) (P<.05) secretion, compared to undifferentiated hUC‐MSCs. The hepatocyte‐like cells differentiated in the 3D‐DLS system did not show an elevation of MHC‐II (P>.05), or cause obvious lymphocytes proliferation, and demonstrated more PGE2 (P<.05) and less IFN‐γ (P<.05) secretion. Hepatocyte‐like cells in the 3D‐DLS system presented a lower immunogenic phenotype than the 2D culture in vitro. Hepatocyte‐like cells in 3D‐DLS system also performed a higher immunosuppressive capacity than 2D culture.

Key Points An international panel established the first ever diagnostic criteria for iMCD based on review of 244 clinical cases and 88 tissue samples. The criteria require multicentric lymphadenopathy with defined histopathology, ≥2 clinical/laboratory changes, and exclusion of iMCD mimics.

Background: Plantar fasciotomy, a common operative procedure to relieve chronic heel pain, has been suggested to decrease foot arch stability. A systematic evaluation of the biomechanical consequences of partial or total plantar fascia release is essential to the understanding of the biomechanical rationale behind these operative procedures. Methods: A geometrical detailed three-dimensional (3-D) finite element (FE) model of the human foot and ankle, incorporating geometrical and contact nonlinearities, was constructed by 3-D reconstruction of MR images. Partial and complete plantar fascia releases were simulated to evaluate the corresponding biomechanical effects on load distribution of the bony, ligamentous, and encapsulated soft-tissue structures. Results: Partial and total plantar fascia release may decrease arch height but did not necessarily cause total collapse of the foot arch even with additional dissection of the long plantar ligament. Operative release of the plantar fascia was compromised by increased strains of the plantar ligaments and intensified stress in the midfoot and metatarsal bones. Load redistribution among the centralized metatarsal bones and focal stress relief at the calcaneal insertion were predicted with different types of fasciotomy. Conclusions: The FE model suggested that plantar fascia release may provide relief of focal stress and therefore could relieve associated heel pain. However, these operative procedures may pose a risk to arch stability and clinically may produce dorsolateral midfoot pain. The initial strategy for treating plantar fasciitis should be nonoperative. If surgery is necessary, partial release of less than 40% of the fascia is recommended to minimize the effect on arch instability and maintain normal foot biomechanics.

Purpose Long-term occlusion of coiled aneurysms frequently fails, probably because of poor intrasaccular healing and inadequate endothelialization across the aneurysm neck. The purpose of this study was to determine if attachment of autologous mesenchymal stem cells (MSCs) to platinum coils would improve the healing response in an elastase-induced aneurysm model in rabbits. Materials and methods With approval from the institutional animal care and use committee, aneurysms were created in rabbits and embolized with control platinum coils (Axium; Medtronic) (n=6) or coils seeded ex vivo with autologous adipose-tissue MSCs (n=7). Aneurysmal occlusion after embolization was evaluated at 1 month with angiography. Histological samples were analyzed by gross imaging and graded on the basis of neck and dome healing on H&E staining. Fibrosis was evaluated using a ratio of the total area presenting collagen. Endothelialization of the neck was quantitatively analyzed using CD31 immunohistochemistry. χ2 and Student's t-test were used to compare groups. Results Healing score (11.5 vs 8.0, p=0.019), fibrosis ratio (10.3 vs 0.13, p=0.006) and endothelialization (902 262 μm2 vs 31 810 μm2, p=0.041) were significantly greater in the MSC group. The MSC group showed marked cellular proliferation and thrombus organization, with a continuous membrane bridging the neck of the aneurysm. Angiographic stable or progressive occlusion rate was significantly lower in the MSC group (0.00, 95% CI 0.00 to 0.41) compared with controls (0.67, 95% CI 0.22 to 0.96) (p=0.02). Conclusions Autologous MSCs attached to platinum coils significantly improve histological healing, as they result in improved neck endothelialization and collagen matrix formation within the aneurysm sac.

Background and aim Disease activity for Crohn's disease (CD) and UC is typically defined based on symptoms at a moment in time, and ignores the long-term burden of disease. The aims of this study were to select the attributes determining overall disease severity, to rank the importance of and to score these individual attributes for both CD and UC. Methods Using a modified Delphi panel, 14 members of the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) selected the most important attributes related to IBD. Eighteen IOIBD members then completed a statistical exercise (conjoint analysis) to create a relative ranking of these attributes. Adjusted utilities were developed by creating proportions for each level within an attribute. Results For CD, 15.8% of overall disease severity was attributed to the presence of mucosal lesions, 10.9% to history of a fistula, 9.7% to history of abscess and 7.4% to history of intestinal resection. For UC, 18.1% of overall disease severity was attributed to mucosal lesions, followed by 14.0% for impact on daily activities, 11.2% C reactive protein and 10.1% for prior experience with biologics. Overall disease severity indices were created on a 100-point scale by applying each attribute's average importance to the adjusted utilities. Conclusions Based on specialist opinion, overall CD severity was associated more with intestinal damage, in contrast to overall UC disease severity, which was more dependent on symptoms and impact on daily life. Once validated, disease severity indices may provide a useful tool for consistent assessment of overall disease severity in patients with IBD.