DECODER - DEveloper COmpanion for Documented and annotatEd code Reference

This work has been developed with the financial support of the European Union's Horizon 2020 research and innovation programme under grant agreement No. 824231Gil Pascual, M.; Pastor-Ricós, F.; Torres Bosch, MV.; Vos, TE. (2020). DECODER - DEveloper COmpanion for Documented and annotatEd code Reference. Springer. 643-644. http://hdl.handle.net/10251/178910S64364

L. plantarum WCFS1 enhances Treg frequencies by activating DCs even in absence of sampling of bacteria in the Peyer Patches

Probiotics such as L. plantarum WCFS1 can modulate immune responses in healthy subjects but how this occurs is still largely unknown. Immune-sampling in the Peyer Patches has been suggested to be one of the mechanisms. Here we studied the systemic and intestinal immune effects in combination with a trafficking study through the intestine of a well-established immunomodulating probiotic, i.e. L. plantarum WCFS1. We demonstrate that not more than 2-3 bacteria were sampled and in many animals not any bacterium could be found in the PP. Despite this, L. plantarum was associated with a strong increase in infiltration of regulatory CD103+ DCs and generation of regulatory T cells in the spleen. Also, a reduced splenic T helper cell cytokine response was observed after ex vivo restimulation. L. plantarum enhanced Treg cells and attenuated the T helper 2 response in healthy mice. We demonstrate that, in healthy mice, immune sampling is a rare phenomenon and not required for immunomodulation. Also in absence of any sampling immune activation was found illustrating that host-microbe interaction on the Peyer Patches was enough to induce immunomodulation of DCs and T-cells

Clinically Actionable Hypercholesterolemia and Hypertriglyceridemia in Children with Nonalcoholic Fatty Liver Disease

OBJECTIVE: To determine the percentage of children with nonalcoholic fatty liver disease (NAFLD) in whom intervention for low-density lipoprotein cholesterol or triglycerides was indicated based on National Heart, Lung, and Blood Institute guidelines. STUDY DESIGN: This multicenter, longitudinal cohort study included children with NAFLD enrolled in the National Institute of Diabetes and Digestive and Kidney Diseases Nonalcoholic Steatohepatitis Clinical Research Network. Fasting lipid profiles were obtained at diagnosis. Standardized dietary recommendations were provided. After 1 year, lipid profiles were repeated and interpreted according to National Heart, Lung, and Blood Institute Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction. Main outcomes were meeting criteria for clinically actionable dyslipidemia at baseline, and either achieving lipid goal at follow-up or meeting criteria for ongoing intervention. RESULTS: There were 585 participants, with a mean age of 12.8 years. The prevalence of children warranting intervention for low-density lipoprotein cholesterol at baseline was 14%. After 1 year of recommended dietary changes, 51% achieved goal low-density lipoprotein cholesterol, 27% qualified for enhanced dietary and lifestyle modifications, and 22% met criteria for pharmacologic intervention. Elevated triglycerides were more prevalent, with 51% meeting criteria for intervention. At 1 year, 25% achieved goal triglycerides with diet and lifestyle changes, 38% met criteria for advanced dietary modifications, and 37% qualified for antihyperlipidemic medications. CONCLUSIONS: More than one-half of children with NAFLD met intervention thresholds for dyslipidemia. Based on the burden of clinically relevant dyslipidemia, lipid screening in children with NAFLD is warranted. Clinicians caring for children with NAFLD should be familiar with lipid management

Hepatic Oxidative Stress in Fructose-Induced Fatty Liver Is Not Caused by Sulfur Amino Acid Insufficiency

Fructose-sweetened liquid consumption is associated with fatty liver and oxidative stress. In rodent models of fructose-mediated fatty liver, protein consumption is decreased. Additionally, decreased sulfur amino acid intake is known to cause oxidative stress. Studies were designed to test whether oxidative stress in fructose-sweetened liquid-induced fatty liver is caused by decreased ad libitum solid food intake with associated inadequate sulfur amino acid intake. C57BL6 mice were grouped as: control (ad libitum water), fructose (ad libitum 30% fructose-sweetened liquid), glucose (ad libitum 30% glucose-sweetened water) and pair-fed (ad libitum water and sulfur amino acid intake same as the fructose group). Hepatic and plasma thiol-disulfide antioxidant status were analyzed after five weeks. Fructose- and glucose-fed mice developed fatty liver. The mitochondrial antioxidant protein, thioredoxin-2, displayed decreased abundance in the liver of fructose and glucose-fed mice compared to controls. Glutathione/glutathione disulfide redox potential (EhGSSG) and abundance of the cytoplasmic antioxidant protein, peroxiredoxin-2, were similar among groups. We conclude that both fructose and glucose-sweetened liquid consumption results in fatty liver and upregulated thioredoxin-2 expression, consistent with mitochondrial oxidative stress; however, inadequate sulfur amino acid intake was not the cause of this oxidative stress

Body mass index trajectories in young adulthood predict nonâ alcoholic fatty liver disease in middle age: The CARDIA cohort study

Background & AimsNonâ alcoholic fatty liver disease is an epidemic. Identifying modifiable risk factors for nonâ alcoholic fatty liver disease development is essential to design effective prevention programmes. We tested whether 25â year patterns of body mass index change are associated with midlife nonâ alcoholic fatty liver disease.MethodsIn all, 4423 participants from Coronary Artery Risk Development in Young Adults, a prospective populationâ based biracial cohort (age 18â 30), underwent body mass index measurement at baseline (1985â 1986) and 3 or more times over 25 years. At Year 25, 3115 had liver fat assessed by nonâ contrast computed tomography. Nonâ alcoholic fatty liver disease was defined as liver attenuation â ¤40 Hounsfield Units after exclusions. Latent mixture modelling identified 25â year trajectories in body mass index per cent change (%Î ) from baseline.ResultsWe identified four distinct trajectories of BMI%Î : stable (26.2% of cohort, 25â year BMI %Π = 3.1%), moderate increase (46.0%, BMI%Π = 21.7%), high increase (20.9%, BMI%Π = 41.9%) and extreme increase (6.9%, BMI%Π = 65.9%). Y25 nonâ alcoholic fatty liver disease prevalence was higher in groups with greater BMI %Î : 4.1%, 9.3%, 13.0%, and 17.6%, respectively (Pâ trend <.0001). In multivariable analyses, participants with increasing BMI%Î had increasingly greater odds of nonâ alcoholic fatty liver disease compared to the stable group: OR: 3.35 (95% CI: 2.07â 5.42), 7.80 (4.60â 13.23) and 12.68 (6.68â 24.09) for moderate, high and extreme body mass index increase, respectively. Associations were only moderately attenuated when adjusted for baseline or Y25 body mass index.ConclusionsTrajectories of weight gain during young adulthood are associated with greater nonâ alcoholic fatty liver disease prevalence in midlife independent of metabolic covariates and baseline or concurrent body mass index highlighting the importance of weight maintenance throughout adulthood as a target for primary nonâ alcoholic fatty liver disease prevention.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142937/1/liv13603.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142937/2/liv13603_am.pd

The natural history of primary sclerosing cholangitis in 781 children. A multicenter, international collaboration

There are limited data on the natural history of primary sclerosing cholangitis (PSC) in children. We aimed to describe the disease characteristics and long-term outcomes of pediatric PSC. We retrospectively collected all pediatric PSC cases from 36 participating institutions and conducted a survival analysis from the date of PSC diagnosis to dates of diagnosis of portal hypertensive or biliary complications, cholangiocarcinoma, liver transplantation, or death. We analyzed patients grouped by disease phenotype and laboratory studies at diagnosis to identify objective predictors of long-term outcome. We identified 781 patients, median age 12 years, with 4,277 person-years of follow-up; 33% with autoimmune hepatitis, 76% with inflammatory bowel disease, and 13% with small duct PSC. Portal hypertensive and biliary complications developed in 38% and 25%, respectively, after 10 years of disease. Once these complications developed, median survival with native liver was 2.8 and 3.5 years, respectively. Cholangiocarcinoma occurred in 1%. Overall event-free survival was 70% at 5 years and 53% at 10 years. Patient groups with the most elevated total bilirubin, gamma-glutamyltransferase, and aspartate aminotransferase-to-platelet ratio index at diagnosis had the worst outcomes. In multivariate analysis PSC-inflammatory bowel disease and small duct phenotypes were associated with favorable prognosis (hazard ratios 0.6, 95% confidence interval 0.5-0.9, and 0.7, 95% confidence interval 0.5-0.96, respectively). Age, gender, and autoimmune hepatitis overlap did not impact long-term outcome. CONCLUSION: PSC has a chronic, progressive course in children, and nearly half of patients develop an adverse liver outcome after 10 years of disease; elevations in bilirubin, gamma-glutamyltransferase, and aspartate aminotransferase-to-platelet ratio index at diagnosis can identify patients at highest risk; small duct PSC and PSC-inflammatory bowel disease are more favorable disease phenotypes

Twentyâ fiveâ year trajectories of insulin resistance and pancreatic βâ cell response and diabetes risk in nonalcoholic fatty liver disease

Background & AimsInsulin resistance is a risk marker for nonâ alcoholic fatty liver disease, and a risk factor for liver disease progression. We assessed temporal trajectories of insulin resistance and βâ cell response to serum glucose concentration throughout adulthood and their association with diabetes risk in nonâ alcoholic fatty liver disease.MethodsThree thousand and sixty participants from Coronary Artery Risk Development in Young Adults, a prospective biâ racial cohort of adults age 18â 30 years at baseline (1985â 1986; Y0) who completed up to 5 exams over 25 years and had fasting insulin and glucose measurement were included. At Y25 (2010â 2011), nonâ alcoholic fatty liver disease was assessed by noncontrast computed tomography after exclusion of other liver fat causes. Latent mixture modelling identified 25â year trajectories in homeostatic model assessment insulin resistance and βâ cell response homeostatic model assessmentâ β.ResultsThree distinct trajectories were identified, separately, for homeostatic model assessment insulin resistance (lowâ stable [47%]; moderateâ increasing [42%]; and highâ increasing [12%]) and homeostatic model assessmentâ β (lowâ decreasing [16%]; moderateâ decreasing [63%]; and highâ decreasing [21%]). Y25 nonâ alcoholic fatty liver disease prevalence was 24.5%. Among nonâ alcoholic fatty liver disease, highâ increasing homeostatic model assessment insulin resistance (referent: lowâ stable) was associated with greater prevalent (OR 95% CI = 8.0, 2.0â 31.9) and incident (OR = 10.5, 2.6â 32.8) diabetes after multivariable adjustment including Y0 or Y25 homeostatic model assessment insulin resistance. In contrast, nonâ alcoholic fatty liver disease participants with lowâ decreasing homeostatic model assessmentâ β (referent: highâ decreasing) had the highest odds of prevalent (OR = 14.1, 3.9â 50.9) and incident (OR = 10.3, 2.7â 39.3) diabetes.ConclusionTrajectories of insulin resistance and βâ cell response during young and middle adulthood are robustly associated with diabetes risk in nonâ alcoholic fatty liver disease. Thus, how persons with nonâ alcoholic fatty liver disease develop resistance to insulin provides important information about risk of diabetes in midlife above and beyond degree of insulin resistance at the time of nonâ alcoholic fatty liver disease assessment.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146427/1/liv13747_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146427/2/liv13747.pd

Evaluation of a microbiological screening and acceptance procedure for cryopreserved skin allografts based on 14 day cultures

Viable donor skin is still considered the gold standard for the temporary covering of burns. Since 1985, the Brussels military skin bank supplies cryopreserved viable cadaveric skin for therapeutic use. Unfortunately, viable skin can not be sterilised, which increases the risk of disease transmission. On the other hand, every effort should be made to ensure that the largest possible part of the donated skin is processed into high-performance grafts. Cryopreserved skin allografts that fail bacterial or fungal screening are reworked into ‘sterile’ non-viable glycerolised skin allografts. The transposition of the European Human Cell and Tissue Directives into Belgian Law has prompted us to install a pragmatic microbiological screening and acceptance procedure, which is based on 14 day enrichment broth cultures of finished product samples and treats the complex issues of ‘acceptable bioburden’ and ‘absence of objectionable organisms’. In this paper we evaluate this procedure applied on 148 skin donations. An incubation time of 14 days allowed for the detection of an additional 16.9% (25/148) of contaminated skin compared to our classic 3 day incubation protocol and consequently increased the share of non-viable glycerolised skin with 8.4%. Importantly, 24% of these slow-growing microorganisms were considered to be potentially pathogenic. In addition, we raise the issue of ‘representative sampling’ of heterogeneously contaminated skin. In summary, we feel that our present microbiological testing and acceptance procedure assures adequate patient safety and skin availability. The question remains, however, whether the supposed increased safety of our skin grafts outweighs the reduced overall clinical performance and the increase in work load and costs