Depletion of Foxp3+ Regulatory T Cells Promotes Profibrogenic Milieu of Cholestasis-Induced Liver Injury

Background

Accumulating evidence suggests that Foxp3+ regulatory T (Treg) cells act as inhibitory mediators of inflammation; however, the in vivo mechanism underlying this protection remains elusive in liver diseases.

Aims

To clarify the in vivo role of Foxp3+ Treg cells in liver fibrosis, we used the DEREG mouse, which expresses the diphtheria toxin receptor under control of the Foxp3 promoter, allowing for specific deletion of Foxp3+ Treg cells.

Methods

Bile duct ligation-induced liver injury and fibrosis were assessed by histopathology, fibrogenic gene expression, and measurement of cytokine and chemokine levels.

Results

Depletion of Foxp3+ Treg cells enhanced Th17 cell response as demonstrated by the increase of IL-17+ cells and related gene expressions including Il17f, Il17ra, and Rorgt in the fibrotic livers of DEREG mice. Of note, infiltration of CD8+ T cells and Cd8 gene expression was significantly increased in the livers of DEREG mice. Consistent with increased IL-17+ and CD8+ T cell responses, DEREG mice generated higher levels of inflammatory cytokines (TNF-α, IL-6, and IL-12p70) and chemokines (MCP-1, MIP-1α, and RANTES). These results were concordant with severity of liver fibrosis and hepatic enzyme levels (ALT and ALP).

Conclusions

The present findings demonstrate that Foxp3+ Treg cells inhibit the profibrogenic inflammatory milieu through suppression of pro-fibrogenic CD8+ and IL-17+ T cells.

     

Altered Gut Microbiota Composition and Immune Response in Experimental Steatohepatitis Mouse Models

Background

Although several types of diet have been used in experimental steatohepatitis models, comparison of gut microbiota and immunological alterations in the gut among diets has not yet been performed.

Aim

We attempted to clarify the difference in the gut environment between mice administrated several experimental diets.

Methods

Male wild-type mice were fed a high-fat (HF) diet, a choline-deficient amino acid-defined (CDAA) diet, and a methionine-choline-deficient (MCD) diet for 8 weeks. We compared the severity of steatohepatitis, the composition of gut microbiota, and the intestinal expression of interleukin (IL)-17, an immune modulator.

Results

Steatohepatitis was most severe in the mice fed the CDAA diet, followed by the MCD diet, and the HF diet. Analysis of gut microbiota showed that the composition of the Firmicutes phylum differed markedly at order level between the mice fed the CDAA and HF diet. The CDAA diet increased the abundance of Clostridiales, while the HF diet increased that of lactate-producing bacteria. In addition, the CDAA diet decreased the abundance of lactate-producing bacteria and antiinflammatory bacterium Parabacteroides goldsteinii in the phylum Bacteroidetes. In CDAA-fed mice, IL-17 levels were increased in ileum as well as portal vein. In addition, the CDAA diet also elevated hepatic expression of chemokines, downstream targets of IL-17.

Conclusions

The composition of gut microbiota and IL-17 expression varied considerably between mice administrated different experimental diets to induce steatohepatitis.

     

Cutaneous Manifestations of Reactions to Biologics

Purpose of Review

The goal of this paper is to review the major adverse cutaneous reactions that have been reported to the most commonly used biologics.

Recent Findings

Anti-TNF agents and immune checkpoint inhibitors have significant, immune-mediated cutaneous manifestations that can necessitate discontinuation. Anti-TNF agents, IL-6 inhibitors, and IL-12/23 inhibitors can paradoxically cause psoriasis flares or unmask previously undiagnosed psoriasis. IL-17 inhibitors are unique in increasing risk for Candida infections. Benign injection site reactions, non-specific rash, cellulitis, and hypersensitivity reactions are relatively common adverse events.

Summary

A wide variety of cutaneous reactions caused by biologics have been reported, ranging from benign injection site reactions to life-threatening cutaneous reactions necessitating discontinuation of the implicated biologic agent.

     

Alterations in Docosahexaenoic Acid-Related Lipid Cascades in Inflammatory Bowel Disease Model Mice

Background

Inflammatory bowel disease (IBD) is an intestinal disorder, involving chronic and relapsing inflammation of the digestive tract. Dysregulation of the immune system based on genetic, environmental, and other factors seems to be involved in the onset of IBD, but its exact pathogenesis remains unclear. Therefore, radical treatments for ulcerative colitis and Crohn’s disease remain to be found, and IBD is considered to be a refractory disease.

Aims

The aim of this study is to obtain novel insights into IBD via metabolite profiling of interleukin (IL)-10 knockout mice (an IBD animal model that exhibits a dysregulated immune system).

Methods

In this study, the metabolites in the large intestine and plasma of IL-10 knockout mice were analyzed. In our analytical system, two kinds of analysis (gas chromatography/mass spectrometry and liquid chromatography/mass spectrometry) were used to detect a broader range of metabolites, including both hydrophilic and hydrophobic metabolites. In addition, an analysis of lipid mediators in the large intestine and ascites of IL-10 knockout mice was carried out.

Results

The levels of a variety of metabolites, including lipid mediators, were altered in IL-10 knockout mice. For example, high large intestinal and plasma levels of docosahexaenoic acid (DHA) were observed. In addition, arachidonic acid- and DHA-related lipid cascades were upregulated in the ascites of the IL-10 knockout mice.

Conclusions

Our findings based on metabolite profiles including lipid mediators must contribute to development of researches about IBD.

     

A Randomized Crossover Study Evaluating the Use and Acceptability of the SILCS Diaphragm Compared to Vaginal Applicators for Vaginal Gel Delivery

Introduction

This study aimed to assess acceptability and preferences for the SILCS diaphragm for vaginal gel delivery compared to a prefilled applicator.

Methods

A randomized crossover study among 115 women in South Africa, using both methods during five sex acts.

Results

We found no significant differences in acceptability between the two products. Experience of gel leakage after sex was greater when inserted via applicator. More women were interested in SILCS/gel for multipurpose protection (68%) than in either SILCS alone (17%) or microbicide gel alone (14%).

Conclusions

A SILCS gel delivery system for multipurpose prevention seems feasible and acceptable.

     

Ultra-Deep Genomic Sequencing of HCV NS5A Resistance-Associated Substitutions in HCV/HIV Coinfected Patients

Background and Aims

The prevalence of naturally occurring HCV-NS5A resistance-associated substitutions (RAS) to DAA drugs might affect the response to treatment in HCV/HIV coinfected subjects. There are limited data on the frequency of HCV-NS5A naturally occurring drug-RAS at baseline in HCV/HIV coinfected patients when ultra-deep sequencing methodologies are applied.

Methods

HCV-NS5A-RAS were evaluated among 25 subjects in each group. Patients were matched by age, gender, and hepatic fibrosis stage category to control for selection bias.

Results

Within subtype 1a, RAS were observed in 28% of HCV monoinfected and 48% of HCV/HIV coinfected subjects. More patients in the HCV/HIV coinfected group had clinically relevant mutations to DAA directed at NS5A.

Conclusion

While the clinical significance of this observation may be limited in highly drug adherent populations, some HCV/HIV coinfected persons may be at greater risk of viral resistance if suboptimal dosing occurs.

     

Long-Term Outcomes and Predictors of Sustained Response in Patients with Intestinal Behcet’s Disease Treated with Infliximab

Background

Intestinal Behcet’s disease (BD) is a specific subtype of BD. Effective drug therapy for intestinal BD remains elusive.

Aims

To investigate long-term outcomes and identify predictors of sustained response in intestinal BD patients receiving infliximab (IFX) treatment.

Methods

The medical records were reviewed of patients received IFX from September 2012 to March 2016. The cumulative probabilities of sustained response were calculated using the Kaplan–Meier. Predictor factors for sustained response were accessed by receiver operating characteristic curve.

Results

Totally, 27 active intestinal BD patients were enrolled. Sustained responses were observed in 17 patients, after a median follow-up duration 24 months (interquartile range 9–37). The proportion of clinical remission at week 14, 30, and 52 had occurred in 84.6, 70, and 70%, respectively, with the proportion of clinical remission of 69.2, 40, and 55%. The mucosal healing (MH) rate at week 14 was 72%. Kaplan–Meier estimated patients with achievement of clinical and biological responses at week 14 or MH was likely to remain sustained clinical response. ROC curve analysis revealed CRP level (of 6.85 mg/L) at week 14 is a potential predictor for discriminating patients with sustained response from relapse, with an area under the curve values of 0.837.

Conclusions

IFX is effective and safe for induction and maintenance therapy in Chinese patients with moderate-to-severe active intestinal BD. Early achievement of clinical response and mucosal healing might associate long-term response. A lower CRP level seems to be associated with a more benign clinical course.

     

Colonic tuberculosis mimicking Crohn's disease: case report

Background

Intestinal tuberculosis is a rare disease in western countries, affecting mainly immigrants and immunocompromised patients. Intestinal tuberculosis is a diagnostic challenge, especially when active pulmonary infection is absent. It may mimic many other abdominal diseases.

Case presentation

Here, we report a case of isolated colonic tuberculosis where the initial diagnostic workup was suggestive of Crohn's disease. Computed tomography findings however, raised the possibility of colonic tuberculosis and the detection of acid-fast bacilli in biopsy specimens confirmed the diagnosis.

Conclusions

In conclusion, this case highlights the need for awareness of intestinal tuberculosis in the differential diagnosis of chronic intestinal disease

     

Differences Between the Intestinal Lumen Microbiota of Aberrant Crypt Foci (ACF)-Bearing and Non-bearing Rats

Background

Multiple factors including host–microbiota interaction could contribute to the conversion of healthy mucosa to sporadic precancerous lesions. An imbalance of the gut microbiota may be a cause or consequence of this process.

Aim

The goal was to investigate and analyze the composition of gut microbiota during the genesis of precancerous lesions of colorectal cancer.

Methods

To analyze the composition of gut microbiota in the genesis of precancerous lesions, a rat model of 1, 2-dimethylhydrazine (DMH)-induced aberrant crypt foci (ACF) was established. The feces of these rats and healthy rats were collected for 16S rRNA sequencing.

Results

The diversity and density of the rat intestinal microbiota were significantly different between ACF-bearing and non-bearing group. ACF were induced in rats treated with DMH and showed increased expression of the inflammatory cytokines IL-6, IL-8, and TNF-α. Firmicutes was the most predominant phylum in both ACF-bearing and non-bearing group, followed by Bacteroidetes. Interestingly, although the density of Bacteroidetes decreased from the fifth week to the 17th week in both groups, it was significantly reduced in ACF-bearing group at the 13th week (P?<?0.01). At the genus level, no significant difference was observed in the most predominant genus, Lactobacillus. Instead, Bacteroides and Prevotella were significantly less abundant (P?<?0.01), while Akkermansia was significantly more abundant (P?<?0.05) in ACF-bearing group at the 13th week.

Conclusion

Imbalance of the intestinal microbiota existed between ACF-bearing and non-bearing rats, which could be used as biomarker to predict the genesis of precancerous lesions in the gut.

     

Transgenic Expression of Vitamin D Receptor in Gut Epithelial Cells Ameliorates Spontaneous Colitis Caused by Interleukin-10 Deficiency

Background

Vitamin D deficiency is common in patients with inflammatory bowel diseases. The vitamin D receptor (VDR) is a nuclear hormone receptor mediating the activity of vitamin D hormone. Our previous studies showed that intestinal epithelial VDR signaling inhibits colitis by protecting the mucosal epithelial barrier, and this activity is independent of non-epithelial immune VDR actions. Interleukin (IL)-10-deficient mouse is a chronic colitis model that develops colitis due to aberrant immune responses. Here we used IL-10 null (IL-10KO) model to assess the anti-colitic activity of epithelial VDR in the setting of an aberrant immune system.

Methods

We crossed IL-10KO mice with villin promoter-driven human (h) VDR transgenic (Tg) mice to generate IL-10KO mice that carry the hVDR transgene in intestinal epithelial cells (IL-10KO/Tg). IL-10KO and IL-10KO/Tg littermates were studied in parallel and followed for up to 25 weeks.

Results

By 25 weeks of age, accumulatively 79 % IL-10KO mice developed prolapse, whereas only 40 % IL-10KO/Tg mice did so (P < 0.001). Compared with IL-10KO mice, IL-10KO/Tg littermates showed markedly reduced mucosal inflammation in both small and large intestines, manifested by attenuation in immune cell infiltration and histological damage and a marked decrease in pro-inflammatory cytokine production. IL-10KO/Tg mice also showed reduced intestinal epithelial cell apoptosis as a result of diminished PUMA induction and caspase 3 activation.

Conclusion

These observations demonstrate that targeting hVDR expression to intestinal epithelial cells is sufficient to attenuate spontaneous colitis caused by an ill-regulated immune system, confirming a critical role of the epithelial VDR signaling in blocking colitis development.

     

Effects of the Wars on Smoking Among Veterans

BACKGROUND

Educating medical students about health disparities may be one step in diminishing the disparities in health among different populations. According to adult learning theory, learners’ opinions are vital to the development of future curricula.

DESIGN

Qualitative research using focus group methodology.

OBJECTIVES

Our objectives were to explore the content that learners value in a health disparities curriculum and how they would want such a curriculum to be taught.

PARTICIPANTS

Study participants were first year medical students with an interest in health disparities (n?=?17).

APPROACH

Semi-structured interviews consisting of 12 predetermined questions, with follow-up and clarifying questions arising from the discussion. Using grounded theory, codes were initially developed by the team of investigators, applied, and validated through an iterative process.

MAIN RESULTS

The students perceived negative attitudes towards health disparities education as a potential barrier towards the development of a health disparities curriculum and proposed possible solutions. These solutions centered around the learning environment and skill building to combat health disparities.

CONCLUSIONS

While many of the students’ opinions were corroborated in the literature, the most striking differences were their opinions on how to develop good attitudes among the student body. Given the impact of the provider on health disparities, how to develop such attitudes is an important area for further research.

     

NF-E2-Related Factor 2 Suppresses Intestinal Fibrosis by Inhibiting Reactive Oxygen Species-Dependent TGF-β1/SMADs Pathway

Background and Aims

This study aimed to evaluate the antifibrotic effects of NF-E2-Related Factor 2 (Nrf2) on intestinal fibrosis. Intestinal fibrosis is a common complication of Crohn’s disease; however, its mechanism of intestinal fibrosis is largely unclear.

Methods

BALB/c mice received 2,4,6-trinitrobenzene sulfonic acid weekly via intrarectal injections to induce chronic fibrotic colitis. They also diet containing received 1% (w/w) tert-butylhydroquinone (tBHQ), which is an agonist of Nrf2. Human intestinal fibroblasts (CCD-18Co cells) were pretreated with tBHQ or si-Nrf2 followed by stimulation with transforming growth factor-β1 (TGF-β1), which transformed the cells into myofibroblasts. The main fibrosis markers such as α-smooth muscle actin, collagen I, tissue inhibitor of metalloproteinase-1, and TGF-β1/SMADs signaling pathway were detected by quantitative real-time RT-PCR, immunohistochemical analysis, and Western blot analysis. Levels of cellular reactive oxygen species (ROS) were detected by dichlorodihydrofluorescein diacetate.

Results

tBHQ suppressed the intestinal fibrosis through the TGF-β1/SMADs signaling pathway in TNBS-induced colitis and CCD-18Co cells. Moreover, Nrf2 knockdown enhanced the TGF-β1-induced differentiation of CCD-18Co cells. ROS significantly increased in TGF-β1-stimulated CCD-18Co cells. Pretreatment with H₂O₂, the primary component of ROS, was demonstrated to block the effect of tBHQ on reducing the expression of TGF-β1. Moreover, scavenging ROS by N-acetyl cysteine could inhibit the increasing expression of TGF-β1 promoted by Nrf2 knockdown.

Conclusions

The results suggested that Nrf2 suppressed intestinal fibrosis by inhibiting ROS/TGF-β1/SMADs pathway in vivo and in vitro.

     

The Effect of Azathioprine on Anastomotic Healing: An Experimental Study in Rats

Purpose

The cytotoxic and immunosuppressive effects of azathioprine, which mitigate the disease activity in inflammatory bowel disease, may compromise the healing of intestinal anastomoses leading to an increased risk of anastomotic leakage. The effect of azathioprine treatment on intestinal healing was tested.

Methods

In an experimental study, rats were randomly given one oral dose of azathioprine (5 mg or 20 mg/kg body weight per day) or placebo. After 28 days of treatment, a left colonic anastomosis was performed. After three days of healing, the breaking strengths of the anastomoses were tested, along with measurements of azathioprine major metabolite concentrations: 6-thioguanine and 6-methyl-mercaptopurine.

Results

There were no significant differences in the anastomotic breaking strength between the three groups.

Conclusions

Daily treatment for four weeks with high or low azathioprine doses has no inhibitory effect on colonic healing in rats.

     

Possible Role of IL-25 in Eosinophilic Lung Inflammation in Patients with Chronic Eosinophilic Pneumonia

Purpose

Interleukin (IL)-25 and IL-33 induce IL-5 production by various types of cells, such as type 2 helper T (Th2) cells and type 2 innate lymphoid cells. The number of Th2 cells and concentration of IL-5 in the bronchoalveolar lavage fluid (BALF) are increased in patients with eosinophilic pneumonia (EP). To examine the contribution of IL-25 and IL-33 to eosinophilic inflammation of the lung in humans, we evaluated IL-5, IL-25 and IL-33 levels in the BALF of patients with EP.

Methods

IL-5, IL-25, and IL-33 concentrations in the BALF were measured by enzyme-linked immunosorbent assay in patients with acute eosinophilic pneumonia (AEP), chronic eosinophilic pneumonia (CEP), idiopathic pulmonary fibrosis (IPF), and sarcoidosis.

Results

The absolute number of eosinophils, and IL-5 levels, but not IL-33 levels, in the BALF were significantly higher in patients with EP than in patients with IPF and sarcoidosis. IL-25 levels in the BALF were significantly higher in patients with CEP, but not in patients with AEP, than in patients with IPF and sarcoidosis. The absolute number of eosinophils was significantly correlated with the IL-5 concentration in the BALF of patients with EP. IL-5 concentrations were significantly correlated with IL-25 concentrations in the BALF of patients with CEP, but not in patients with AEP. IL-5 levels were not correlated with IL-33 levels in the BALF of patients with EP.

Conclusions

Our findings suggest that IL-25 plays an important role via IL-5 in eosinophilic lung inflammation in patients with CEP.

     

S100A4 and P53 in myocardial collagen fibers of hypertrophic cardiomyopathy

Objective

The purpose of this work is to investigate the expression of S100A4 and P53 and their correlation with myocardial collagen fibers in hypertrophic cardiomyopathy (HCM).

Patients and methods

Myocardial tissue obtained from 10 patients undergoing HCM surgery (HCM group) was compared to myocardial tissue obtained from 10 traffic accident deaths (healthy control group). Collagen volume fractions were visualized and compared using sirius red F3B(SR) staining. Immunohistochemistry S-P and in situ hybridization techniques were used to test the different expressions of S100A4, P53 proteins, and their mRNA. Imaging and statistical methods were used for quantitative analysis.

Results

The collagen volume fraction in the HCM group was significantly higher than that in the control group. The integral optical density values of S100A4 and P53 in cardiomyocytes of the HCM group were also significantly higher than in the control group.

Conclusion

The increased content of collagen fibers and overexpression of S100A4 and P53 may play an important role in myocardial fibrosis of HCM, and they can be used in future HCM research. Blockade of S100A4 may have therapeutic potential in HCM by attenuating cardiac fibrosis.

     

Die Rolle der Selbsthilfegruppen in der Onkologie

Background

Little is known about self-help associations and their possibilities. Obstacles often prevent early contacts between affected people.

Objectives

The psychosocial support given by self-help associations in different phases is evaluated.

Materials and methods

Based on the experience of the Deutsche ILCO and from cooperation with other organizations and institutions, various dimensions of self-help groups are investigated.

Results

On the professional side, there is a lack of knowledge and of attitude. Suitable structures are rare.

Conclusions

The removal of barriers and development of effective structures are overdue.

     

Treatment of acute hepatitis C: recommendations from an expert panel of the Italian Society of Infectious and Tropical Diseases

Aim

This paper is aimed at providing practical recommendations for the management of acute hepatitis C (AHC).

Methods

This is an expert position paper based on the literature revision. Final recommendations were graded by level of evidence and strength of the recommendations.

Results

Treatment of AHC with direct-acting antivirals (DAA) is safe and effective; it overcomes the limitations of INF-based treatments.

Conclusions

Early treatment with DAA should be offered when available.

     

Effects of Vedolizumab Therapy on Extraintestinal Manifestations in Inflammatory Bowel Disease

Background

Approximately 15–20% of ulcerative colitis patients and 20–40% of those with Crohn’s disease experience extraintestinal manifestations (EIMs) of their inflammatory bowel disease (IBD). Clinicians who treat IBD must manage EIMs affecting multiple organs that variably correlate with intestinal disease activity. Vedolizumab is a monoclonal antibody for the treatment of IBD with a gut-selective mechanism of action.

Aims

This report evaluates whether vedolizumab is an effective treatment of EIMs, given its gut-specific mechanism of action.

Methods

We report 8 case studies of patients with various EIMs, including pyoderma gangrenosum, peripheral arthralgia/arthritis, axial arthropathies, erythema nodosum, and uveitis, who received vedolizumab therapy.

Results

Vedolizumab therapy was effective for pyoderma gangrenosum in ulcerative colitis, uveitis, erythema nodosum, polyarticular arthropathy, and ankylosing spondylitis/sacroiliitis but did not provide sustained benefit for the treatment of pyoderma gangrenosum in a patient with Crohn’s disease.

Conclusions

These cases demonstrate the potential of vedolizumab as a treatment of EIMs in patients with IBD.

     

Fettleberdiagnostik bei Diabetes mellitus Typ 2

Definition of terms

Under the term non-alcoholic fatty liver disease (NAFLD) both simple hepatic fat accumulation and non-alcoholic steatohepatitis (NASH) are combined. NASH is associated with liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC).

Epidemiological importance

In 2020, NAFLD will be the leading cause for liver transplantation in the USA, with rising financial costs for the healthcare system.

Comorbidities, diagnosis, and treatment

Type 2 diabetes (T2D) and metabolic syndrome (MetS) are important risk factors for the development of NAFLD, whereby these three diseases share similar pathophysiologic conditions, e.g., insulin resistance, obesity, and metabolic inflammation. Due to the rising number of patients with T2D and MetS, clinicians should aim to diagnose NAFLD early in this patient population and if necessary start treatment.

Goal

The aim of this work is to give an overview over the topic of NAFLD and diagnostic approaches in patients with T2D.

     

Strain elastography for assessment of liver fibrosis and prognosis in patients with chronic liver diseases

Background

Estimation of liver stiffness is essential in the treatment of liver diseases. Various procedures alternative to liver biopsy have been developed, and transient elastography using shear wave is an established method for evaluating liver stiffness and has been shown to be a prognostic indicator. In contrast, strain elastography (SE) has been applied to evaluate liver stiffness, however the significance remains uncertain.

Methods

We retrospectively analyzed 598 patients who underwent SE to evaluate the ability of estimating liver stiffness and the prognosis. Elasticity index (EI) was evaluated as an indicator of liver stiffness in this study.

Results

EI was increased as histological fibrosis advanced. EI was significantly different between mild fibrosis (F0–2) and advanced fibrosis (F3, 4). In contrast, EI was similar among those with different activity scores. EI showed better diagnostic performance in estimating advanced fibrosis than other serological markers and good reproducibility. Furthermore, EI was shown to be an independent prognostic factor in patients with chronic liver diseases and also with hepatocellular carcinoma (HCC) with advanced stage.

Conclusions

SE could estimate advanced liver fibrosis without influence of liver inflammation unlike other serological liver fibrosis markers. SE might be a prognostic factor in chronic liver diseases and HCC.