Transplantation, gene therapy and intestinal pathology in MNGIE patients and mice

Background: Gastrointestinal complications are the main cause of death in patients with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). Available treatments often restore biochemical homeostasis, but fail to cure gastrointestinal symptoms. Methods: We evaluated the small intestine neuromuscular pathology of an untreated MNGIE patient and two recipients of hematopoietic stem cells, focusing on enteric neurons and glia. Additionally, we evaluated the intestinal neuromuscular pathology in a mouse model of MNGIE treated with hematopoietic stem cell gene therapy. Quantification of muscle wall thickness and ganglion cell density was performed blind to the genotype with ImageJ. Significance of differences between groups was determined by two-tailed Mann-Whitney U test (P < 0.05). Results: Our data confirm that MNGIE presents with muscle atrophy and loss of Cajal cells and CD117/c-kit immunoreactivity in the small intestine. We also show that hematopoietic stem cell transplantation does not benefit human intestinal pathology at least on short-term. Conclusions: We suggest that hematopoietic stem cell transplantation may be insufficient to restore intestinal neuropathology, especially at later stages of MNGIE. As interstitial Cajal cells and their networks play a key role in development of gastrointestinal dysmotility, alternative therapeutic approaches taking absence of these cells into account could be required

Chitotriosidase is the primary active chitinase in the human lung and is modulated by genotype and smoking habit

Background: Chitinolytic enzymes play important roles in the pathophysiology of allergic airway responses in mouse models of asthma. Acidic mammalian chitinase (AMCase) and chitotriosidase (CHIT1) have chitinolytic activity, but relatively little is known about their expression in human asthma. Objective: We sought to determine the expression and activity of AMCase and CHIT1 in healthy subjects, subjects with asthma, and habitual smokers, taking account of the null 24-bp duplication in the CHIT1 gene. Methods: We measured chitinase activity in bronchoalveolar lavage (BAL) fluid at multiple pHs by using a synthetic chitin substrate. We also determined AMCase and CHIT1 gene expression in epithelial brushings and BAL fluid macrophages by means of real time RT-PCR. Paired DNA samples were genotyped for the CHIT1 duplication. Results: In all subgroups the pH profile of chitinase activity in BAL fluid matched that of CHIT1, but not AMCase, and chitinase activity was absent in subjects genetically deficient in active CHIT1. Although AMCase protein was detectable in lavage fluid, AMCase transcripts in macrophages were consistent with an isoform lacking enzymatic activity. Median chitinase activity in BAL fluid tended to be lower than normal in asthmatic subjects but was increased 7-fold in habitual smokers, where CHIT1 gene expression in macrophages was increased. Conclusions: Chitinase activity in the lung is the result of CHIT1 activity. Although AMCase protein is detectable in the lung, our data indicate that it is inactive. Chitinase activity is not increased in subjects with asthma and in fact tends to be decreased. The high levels of chitinase activity in habitual smokers result from upregulation of CHIT1 gene expression, especially in macrophages. Q Allergy Clin Immunol 2008;122:944-50.

A Systematic Review and Meta-analysis of Dietary Interventions Modulating Gut Microbiota and Cardiometabolic Diseases—Striving for New Standards in Microbiome Studies

Background & Aims: Cardiometabolic diseases (CMDs) have shared properties and causes. Insulin resistance is a risk factor and characteristic of CMDs and has been suggested to be modulated by plasma metabolites derived from gut microbiota (GM). Because diet is among the most important modulators of GM, we performed a systematic review of the literature to assess whether CMDs can be modulated via dietary interventions targeting the GM. Methods: A systematic review of the literature for clinical studies was performed on Ovid MEDLINE and Ovid Embase. Studies were assessed for risk of bias and patterns of intervention effects. A meta-analysis with random effects models was used to evaluate the effect of dietary interventions on clinical outcomes. Results: Our search yielded 4444 unique articles, from which 15 randomized controlled trials and 6 nonrandomized clinical trials were included. The overall risk of bias was high in all studies. In general, most dietary interventions changed the GM composition, but no consistent effect could be found. Results of the meta-analyses showed that only diastolic blood pressure is decreased across interventions compared with controls (mean difference: −3.63 mm Hg; 95% confidence interval, −7.09 to −0.17; I2 = 0%, P = .04) and that a high-fiber diet was associated with reduced triglyceride levels (mean difference: −0.69 mmol/L; 95% confidence interval, −1.36 to −0.02; I2 = 59%, P = .04). Other CMD parameters were not affected. Conclusions: Dietary interventions modulate GM composition, blood pressure, and circulating triglycerides. However, current studies have a high methodological heterogeneity and risk of bias. Well-designed and controlled studies are thus necessary to better understand the complex interaction between diet, microbiome, and CMDs. PROSPERO: CRD4202018840

A Systematic Review and Meta-analysis of Dietary Interventions Modulating Gut Microbiota and Cardiometabolic Diseases—Striving for New Standards in Microbiome Studies

Background & Aims: Cardiometabolic diseases (CMDs) have shared properties and causes. Insulin resistance is a risk factor and characteristic of CMDs and has been suggested to be modulated by plasma metabolites derived from gut microbiota (GM). Because diet is among the most important modulators of GM, we performed a systematic review of the literature to assess whether CMDs can be modulated via dietary interventions targeting the GM. Methods: A systematic review of the literature for clinical studies was performed on Ovid MEDLINE and Ovid Embase. Studies were assessed for risk of bias and patterns of intervention effects. A meta-analysis with random effects models was used to evaluate the effect of dietary interventions on clinical outcomes. Results: Our search yielded 4444 unique articles, from which 15 randomized controlled trials and 6 nonrandomized clinical trials were included. The overall risk of bias was high in all studies. In general, most dietary interventions changed the GM composition, but no consistent effect could be found. Results of the meta-analyses showed that only diastolic blood pressure is decreased across interventions compared with controls (mean difference: −3.63 mm Hg; 95% confidence interval, −7.09 to −0.17; I2 = 0%, P = .04) and that a high-fiber diet was associated with reduced triglyceride levels (mean difference: −0.69 mmol/L; 95% confidence interval, −1.36 to −0.02; I2 = 59%, P = .04). Other CMD parameters were not affected. Conclusions: Dietary interventions modulate GM composition, blood pressure, and circulating triglycerides. However, current studies have a high methodological heterogeneity and risk of bias. Well-designed and controlled studies are thus necessary to better understand the complex interaction between diet, microbiome, and CMDs

Pathology review identifies frequent misdiagnoses in recurrent classic Hodgkin lymphoma in a nationwide cohort:implications for clinical and epidemiological studies

Patients treated for classic Hodgkin lymphoma (CHL) have a reported 13-fold increased risk of developing subsequent non-Hodgkin lymphoma (NHL). In light of the growing awareness of CHL mimickers, this study re-assesses this risk based on an in-depth pathology review of a nationwide cohort of patients diagnosed with CHL in the Netherlands (2006-2013) and explores the spectrum of CHL mimickers. Among 2,669 patients with biopsy-proven CHL, 54 were registered with secondary NHL. On review, CHL was confirmed in 25/54 patients. In six of these, the subsequent lymphoma was a primary mediastinal B-cell lymphoma/mediastinal gray zone lymphoma, biologically related to CHL and 19/25 were apparently unrelated B-cell NHL. In 29/54 patients, CHL was reclassified as NHL, including T-cell lymphomas with secondary Hodgkin-like B-blasts (n=15), Epstein Barr virus-positive diffuse large B-cell lymphoma (n=8), CD30+ T-cell lymphoma (n=3) and indolent B-cell proliferations (n=3). Higher age, disseminated disease at presentation, extensive B-cell marker expression and association with Epstein-Barr virus were identified as markers to alert for CHL mimickers. Based on these data, the risk of developing NHL after CHL treatment was re-calculated to 3.6-fold (standardized incidence ratio 3.61; confidence interval: 2.29-5.42). In addition, this study highlights the clinicopathological pitfalls leading to misinterpretation of CHL and consequences for the care of individual patients, interpretation of trials and epidemiological assessments.</p

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December 11, 200

Differential Enzymatic Activity of Common Haplotypic Versions of the Human Acidic Mammalian Chitinase Protein*

Mouse models have shown the importance of acidic mammalian chitinase activity in settings of chitin exposure and allergic inflammation. However, little is known regarding genetic regulation of AMCase enzymatic activity in human allergic diseases. Resequencing the AMCase gene exons we identified 8 non-synonymous single nucleotide polymorphisms including three novel variants (A290G, G296A, G339T) near the gene area coding for the enzyme active site, all in linkage disequilibrium. AMCase protein isoforms, encoded by two gene-wide haplotypes, and differentiated by these three single nucleotide polymorphisms, were recombinantly expressed and purified. Biochemical analysis revealed the isoform encoded by the variant haplotype displayed a distinct pH profile exhibiting greater retention of chitinase activity at acidic and basic pH values. Determination of absolute kinetic activity found the variant isoform encoded by the variant haplotype was 4-, 2.5-, and 10-fold more active than the wild type AMCase isoform at pH 2.2, 4.6, and 7.0, respectively. Modeling of the AMCase isoforms revealed positional changes in amino acids critical for both pH specificity and substrate binding. Genetic association analyses of AMCase haplotypes for asthma revealed significant protective associations between the variant haplotype in several asthma cohorts. The structural, kinetic, and genetic data regarding the AMCase isoforms are consistent with the Th2-priming effects of environmental chitin and a role for AMCase in negatively regulating this stimulus