Budesonide Induces Favourable Histologic and Symptomatic Recovery in Patients with Non-responsive and Refractory Coeliac Disease When Given in an Open Capsule Format.

INTRODUCTION: Non-responsive disease (NRCD), where symptoms and enteropathy persist despite a prolonged gluten-free diet (GFD), is common. Refractory coeliac disease (RCD), characterised by malabsorption and extensive enteropathy, is rare but serious. In both, treatment options are limited. Topical budesonide may help and an open capsule format promoting proximal small intestinal delivery may be advantageous. AIM: To describe the effect of budesonide and its presentation on mucosal healing, symptoms, and tolerability in NRCD and RCD. METHODS: A retrospective cohort study of NRCD and RCD patients who received budesonide for enteropathy despite a strict GFD for over 12 months. Primary outcome was improvement in histology. Symptoms and adverse treatment effects were recorded. RESULTS: 50 patients with NRCD (n = 14; 86% F), RCD type 1 (n = 30; 60% F), and RCD type 2 (n = 6 based on aberrant duodenal T cells; 33% F) were identified. Common RCD symptoms were diarrhoea (68%), fatigue (40%), and weight loss (34%). 16 received closed capsule budesonide (CCB) 9 mg OD and 35 open capsule budesonide (OCB) 3 mg 3 times a day. Complete and partial mucosal healing was significantly higher after OCB compared to CCB (p < 0.001, Mann-Whitney U test). Symptom improvement was also significantly higher after OCB compared to CCB (p = 0.002, Mann-Whitney U test). Side effects were mild and self-limiting and were reported in 25% of both cohorts. CONCLUSION: OCB was well tolerated and associated with improvements in enteropathy (83%) and symptoms (90%) in NRCD and RCD. Our findings support OCB as the preferred 1st-line therapy for NRCD and RCD type 1.

KLF2 inhibits colorectal cancer progression and metastasis by inducing ferroptosis via the PI3K/AKT signaling pathway.

Krüppel-like factor 2 (KLF2) belongs to the zinc finger family and is thought to be a tumor suppressor gene due to its low expression in various cancer types. However, its functional role and molecular pathway involvement in colorectal cancer (CRC) are not well defined. Herein, we investigated the potential mechanism of KLF2 in CRC cell invasion, migration, and epithelial-mesenchymal transition (EMT). We utilized the TCGA and GEPIA databases to analyze the expression of KLF2 in CRC patients and its correlation with different CRC stages and CRC prognosis. RT-PCR, western blot, and immunohistochemistry assays were used to measure KLF2 expression. Gain-of-function assays were performed to evaluate the role of KLF2 in CRC progression. Moreover, mechanistic experiments were conducted to investigate the molecular mechanism and involved signaling pathways regulated by KLF2. Additionally, we also conducted a xenograft tumor assay to evaluate the role of KLF2 in tumorigenesis. KLF2 expression was low in CRC patient tissues and cell lines, and low expression of KLF2 was associated with poor CRC prognosis. Remarkably, overexpressing KLF2 significantly inhibited the invasion, migration, and EMT capabilities of CRC cells, and tumor growth in xenografts. Mechanistically, KLF2 overexpression induced ferroptosis in CRC cells by regulating glutathione peroxidase 4 expression. Moreover, this KLF2-dependent ferroptosis in CRC cells was mediated by inhibiting the PI3K/AKT signaling pathway that resulted in the suppression of invasion, migration, and EMT of CRC cells. We report for the first time that KLF2 acts as a tumor suppressor in CRC by inducing ferroptosis via inhibiting the PI3K/AKT signaling pathway, thus providing a new direction for CRC prognosis assessment and targeted therapy.

Downregulation of MCF2L Promoted the Ferroptosis of Hepatocellular Carcinoma Cells through PI3K/mTOR Pathway in a RhoA/Rac1 Dependent Manner.

Methods and Results: The levels of MCF2L were detected by PCR and western blotting assay. The effect of MCF2L on ferroptosis was confirmed by MTT, colony formation assay, Brdu, in vivo animal experiment, and the content of Iron, GSH, ROS, and MDA. The underlying mechanisms were explored by PCR, western blotting, and affinity precipitation assay. Our findings demonstrated that MCF2L is remarkedly upregulated in HCC tissues, and sorafenib can induce the levels of MCF2L, suggesting that MCF2L might function in sorafenib resistance of HCC. Further analysis showed that downregulation of MCF2L enhances HCC cell death induced by sorafenib, and ferroptosis inhibitor can reverse this process. Subsequent experiments showed that downregulation of MCF2L elevates the content of Iron, ROS, and MDA, which are all indicators of ferroptosis. Finally, mechanism analysis showed that MCF2L regulates the PI3K/AKT pathway in a RhoA/Rac1 dependent manner. Conclusions: Our study showed that targeting MCF2L may be a hopeful method to overcome sorafenib-resistance through inducing ferroptosis in HCC.

A Sensitive Whole Blood Assay Detects Antigen-Stimulated Cytokine Release From CD4+ T Cells and Facilitates Immunomonitoring in a Phase 2 Clinical Trial of Nexvax2 in Coeliac Disease.

Improved blood tests assessing the functional status of rare gluten-specific CD4+ T cells are needed to effectively monitor experimental therapies for coeliac disease (CD). Our aim was to develop a simple, but highly sensitive cytokine release assay (CRA) for gluten-specific CD4+ T cells that did not require patients to undergo a prior gluten challenge, and would be practical in large, multi-centre clinical trials. We developed an enhanced CRA and used it in a phase 2 clinical trial ("RESET CeD") of Nexvax2, a peptide-based immunotherapy for CD. Two participants with treated CD were assessed in a pilot study prior to and six days after a 3-day gluten challenge. Dye-dilution proliferation in peripheral blood mononuclear cells (PBMC) was assessed, and IL-2, IFN-γ and IL-10 were measured by multiplex electrochemiluminescence immunoassay (ECL) after 24-hour gluten-peptide stimulation of whole blood or matched PBMC. Subsequently, gluten-specific CD4+ T cells in blood were assessed in a subgroup of the RESET CeD Study participants who received Nexvax2 (maintenance dose 900 µg, n = 12) or placebo (n = 9). The pilot study showed that gluten peptides induced IL-2, IFN-γ and IL-10 release from PBMCs attributable to CD4+ T cells, but the PBMC CRA was substantially less sensitive than whole blood CRA. Only modest gluten peptide-stimulated IL-2 release could be detected without prior gluten challenge using PBMC. In contrast, whole blood CRA enabled detection of IL-2 and IFN-γ before and after gluten challenge. IL-2 and IFN-γ release in whole blood required more than 6 hours incubation. Delay in whole blood incubation of more than three hours from collection substantially reduced antigen-stimulated IL-2 and IFN-γ secretion. Nexvax2, but not placebo treatment in the RESET CeD Study was associated with significant reductions in gluten peptide-stimulated whole blood IL-2 and IFN-γ release, and CD4+ T cell proliferation. We conclude that using fresh whole blood instead of PBMC substantially enhances cytokine secretion stimulated by gluten peptides, and enables assessment of rare gluten-specific CD4+ T cells without requiring CD patients to undertake a gluten challenge. Whole blood assessment coupled with ultra-sensitive cytokine detection shows promise in the monitoring of rare antigen-specific T cells in clinical studies.

Development of a Novel Task-oriented Rehabilitation Program using a Bimanual Exoskeleton Robotic Hand.

A robot-assisted hand is used for the rehabilitation of patients with impaired upper limb function, particularly for stroke patients with a loss of motor control. However, it is unclear how conventional occupational training strategies can be applied to the use of rehabilitation robots. Novel robotic technologies and occupational therapy concepts are used to develop a protocol that allows patients with impaired upper limb function to grasp objects using their affected hand through a variety of pinching and grasping functions. To conduct this appropriately, we used five types of objects: a peg, a rectangular cube, a cube, a ball, and a cylindrical bar. We also equipped the patients with a robotic hand, the Mirror Hand, an exoskeleton hand that is fitted to the subject's affected hand and follows the movement of the sensor glove fitted to their unaffected hand (bimanual movement training (BMT)). This study had two stages. Three healthy subjects were first recruited to test the feasibility and acceptability of the training program. Three patients with hand dysfunction caused by stroke were then recruited to confirm the feasibility and acceptability of the training program, which was conducted on 3 consecutive days. On each day, the patient was monitored during 5 min of movement in a passive range of motion, 5 min of robot-assisted bimanual movement, and task-oriented training using the five objects. The results showed that both healthy subjects and subjects who had suffered a stroke in conjunction with the robotic hand could successfully grasp the objects. Both healthy subjects and those who had suffered a stroke performed well with the robot-assisted task-oriented training program in terms of feasibility and acceptability.

Quantitative contribution study and comparison between electrocoagulation, anode-electrocoagulation and chemical coagulation using polymer-flooding sewage.

This work aimed to quantify the contribution of electrocoagulation(EC) mechanisms on emulsified oil removal from polymer-flooding sewage (PFS), and also to quantitatively compare the performance of EC, anode-electrocoagulation(AEC) and chemical coagulation(CC) on PFS treatment. An apparatus which introduced the salt bridge was proposed to help separate the anode and cathode. To quantify the contribution of coagulation and oxidation individually, the EDTA, a chemical addictive which can inhibit the ability of Al3+ was added to shield the effect of coagulation. The experimental results show that in the PFS treatment by EC method, about 80% of emulsified oil in anode zone was removed by coagulation while only 11%-13% was oxidized; In cathode zone, about 13%-14% of the oil was removed by flotation. Besides, the results suggest that the separation of anode and cathode not only result in the low demulsification efficiency but also generated the fragile flocs. During the comparison and contrast of purification performance of EC, AEC and CC, the effects of treatment time and current densities(aluminum doses) on oil removal was investigated, the pH and absorption spectra evolution over time were also analyzed. The results showed that under all conditions studied, the EC performance outperforms AEC and far beyond CC.

Effect of a balanced nutrition meal replacement diet with altered macromolecular composition along with caloric restriction on body weight control.

The prevalence of obesity and its related metabolic syndrome (MetS) has shown an upsurge in recent years due to modified lifestyle patterns. The present study was designed to investigate the impact of a nutritionally balanced conventional meal replacement diet with modified macromolecular composition (rich in soy/pea protein and soluble fibers) and caloric restriction on Taiwanese obese subjects. Obese subjects (BMI > 27; n = 50, male 23, female 27) were recruited and requested to replace two meals per day (breakfast and lunch or dinner) with the balanced nutritional meal replacement diet (equal to 240 kcal) for 8 weeks with one regular meal and make sure that the daily target calorie limit (caloric restriction) was less than 1500 kcal day-1 for men and 1200 kcal day-1 for women. After eight weeks of intervention with a calorie-restricted balanced partial meal replacement diet, the levels of body weight, body fat, and waist circumference were significantly reduced by 4.1 kg, 2.38%, and 5.06 cm, respectively. The levels of serum total cholesterol (TC), triglycerides (TG) and low-density lipoprotein cholesterol (LDL-c) were significantly decreased (p < 0.05) with a significant increase (p < 0.05) in high-density lipoprotein cholesterol (HDL-c) levels after 8 weeks of intervention with the meal replacement diet. Moreover, the levels of insulin, homeostatic model assessment-insulin resistance (HOMA-IR), leptin, thiobarbituric acid reactive substances (TBARS) and cardiovascular risk factors were significantly attenuated (p < 0.05). To conclude, the present intervention with meal replacement and caloric restriction on obese subjects could concomitantly decrease the body weight and glycemic and cardiovascular risk factors and thereby lower the risk of various metabolic disorders.

Modified ride-on cars and mastery motivation in young children with disabilities: Effects of environmental modifications.

BACKGROUND: Independent mobility is important for children's psychological development. Modified ride-on cars are innovative, alternative options to enhance independent mobility, socialization, and motivation in young children with disabilities. AIM: We compared the effects of combining ride-on car use and a social interaction training program on mastery motivation and home affordances with a home education program in young children with disabilities. METHODS AND PROCEDURES: Twenty-nine children with disabilities aged 1-3 years were recruited. The treatment group (n = 15) received two 2-h sessions/week for 9 weeks of ride-on car training in a hospital environment in Taiwan. The control group (n = 14) underwent similar home education programs. No treatment except regular therapy was administered during the 9-week follow-up period. Assessments included the Revised Dimensions of Mastery Questionnaire-Chinese version and the Affordance in the Home Environment for Motor Development-Toddler version-Chinese version. OUTCOMES AND RESULTS: The treatment group (compared to controls) had significantly greater improvements in object persistence during the intervention. Both groups showed significant improvements in mastery pleasure and home affordances during the intervention. CONCLUSIONS AND IMPLICATIONS: This novel study showed the potential use of modified ride-on cars to enhance mastery motivation in a hospital environment.

Sustained virological response halts fibrosis progression: A long-term follow-up study of people with chronic hepatitis C infection.

BACKGROUND/AIMS: Long-term follow-up studies validating the clinical benefit of sustained virological response (SVR) in people with chronic hepatitis C (CHC) infection are lacking. Our aim was to identify rates and predictors of liver fibrosis progression in a large, well characterized cohort of CHC patients in whom paired liver fibrosis assessments were performed more than 10 years apart. METHODS: CHC patients who had undergone a baseline liver biopsy pre-2004 and a follow up liver fibrosis assessment more than 10 years later (biopsy or liver stiffness measurement (LSM) using transient elastography [FibroScan]) were identified. Subjects who had undergone a baseline liver biopsy but had no follow up fibrosis assessment were recalled for LSM. Fibrosis was categorised as mild-moderate (METAVIR F0-2 / LSM result of ≤ 9.5 kPa) or advanced (METAVIR F3-4/ LSM >9.5 kPa). The primary objective was to assess the association between SVR and the rate of liver fibrosis progression over at least 10 years, defined as an increase from mild-moderate fibrosis at baseline liver biopsy (METAVIR F0-2) to advanced fibrosis at follow-up liver fibrosis assessment. RESULTS: 131 subjects were included in this analysis: 69% male, 82% Caucasian, 60% G1 HCV, 25% G3 HCV. The median age at F/U fibrosis staging was 57 (IQR 54-62) years with median estimated duration of infection 33-years (IQR 29-38). At F/U, liver fibrosis assessment was performed by LSM in 86% and liver biopsy in 14%. The median period between fibrosis assessments was 14-years (IQR 12-17). 109 (83%) participants had received interferon-based antiviral therapy. 40% attained SVR. At F/U, there was a significant increase in the proportion of subjects with advanced liver fibrosis: 27% at baseline vs. 46% at F/U (p = 0.002). The prevalence of advanced fibrosis did not change among subjects who attained SVR, 30% at B/L vs 25% at F/U (p = 0.343). However, advanced fibrosis became more common at F/U among subjects with persistent viremia: 10% at B/L vs 31% at F/U (p = 0.0001). SVR was independently associated with protection from liver fibrosis progression after adjustment for other variables including baseline ALT (p = 0.011), duration of HCV infection and mode of acquisition. CONCLUSION: HCV eradication is associated with lower rates of liver fibrosis progression. The data support early treatment to prevent long-term liver complications of HCV infection.

Ride-On Car Training for Behavioral Changes in Mobility and Socialization Among Young Children With Disabilities.

PURPOSE: To characterize behavioral changes in mobility and socialization in children with disabilities aged 1 to 3 years while they are receiving ride-on car training in the hospital environment. METHODS: Ten young children with motor disabilities received ride-on car training for 9 weeks (2 hours per session, 2 sessions per week). The driving and socialization behaviors were videotaped for 20 minutes per session (1 session per week) within the same period. RESULTS: Independent mobility, visual attention to the switch, and positive facial expressions during the training period were significantly improved. CONCLUSIONS: Ride-on car training has positive effects on behavioral changes in mobility and socialization among young children with motor disabilities. This provides clinicians a novel option for implementing early mobility training in a hospital-based environment.

Modified Ride-On Cars and Young Children with Disabilities: Effects of Combining Mobility and Social Training.

BACKGROUND: Research has shown that the use of power mobility devices is safe and beneficial for motor and cognitive development in children with motor disabilities; nevertheless, strong evidence of the benefits for social skill development is limited. This study aimed to examine the effects of combining ride-on car training with an adult-directed, social interaction program in a hospital-based environment on mobility and social functions in young children with motor disabilities. METHODS: This study used a prospective, nonequivalent pretest-posttest control group design. Twenty-nine young children with motor disabilities, aged between 1 and 3 years, were recruited from local hospitals in Taiwan. The treatment group (n = 15) underwent 2-h ride-on car training sessions twice per week for a total of 9 weeks in the hospital environment. The control group (n = 14) underwent a 9-week home education program (mean: 200 min/week) focusing on mobility and social skills training. The Chinese version of the Pediatric Evaluation of Disability Inventory, Parenting Stress Index, and Goal Attainment Scaling were administered to all participants before and after the intervention, and at the end of the 9-week follow-up phase. RESULTS: Mobility and social functions significantly improved in both groups after the 9-week intervention, but this improvement was not maintained at the follow-up phase. The treatment group showed significantly better improvement in social function, parenting stress levels, and goal achievement than the control group at posttest. CONCLUSION: This two-group design study showed the benefits of combining a ride-on car use with a family-centered, structured, social interaction program for positive impacts on mobility, social function, and parenting stress levels. The combination of a modified ride-on car and a social training program has the potential to enhance socialization in young children with motor disabilities. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov, identifier NCT02527499.

Toll-like Receptor Expression and Signaling in Peripheral Blood Mononuclear Cells Correlate With Clinical Outcomes in Acute Hepatitis C Virus Infection.

BACKGROUND: Mechanisms by which spontaneous clearance of acute hepatitis C occurs are unclear. A critical role for the innate immune system and IFNL4 polymorphisms has been proposed. This study investigates whether Toll-like receptor (TLR) expression and signaling during acute hepatitis C correlates with clinical outcomes. METHODS: Participants identified from the Australian Trial in Acute Hepatitis C and the Networks study were followed longitudinally from the time of diagnosis of acute hepatitis C. Peripheral blood mononuclear cells (PBMCs) and plasma were collected at and 2 time points after diagnosis. At each time point, TLR2, TLR4, and CD86 expression on peripheral blood monocytes, natural killer (NK) cells, and NK T cells was measured, as well as the response of PBMCs to stimulation with TLR ligands. Cytokine and chemokine levels were measured in stimulated PBMCs and plasma. RESULTS: We identified 20 participants with acute hepatitis C (10 with hepatitis C virus [HCV] monoinfection and 10 with HCV and human immunodeficiency virus coinfection). Eleven participants (55%) spontaneously cleared HCV. Acute hepatitis C and spontaneous clearance was associated with lower TLR4 expression on monocytes (P = .009) and NK cells (P = .029). Acute hepatitis C and spontaneous clearance was also associated with a reduced interferon γ response to TLR4 (P = .038) and TLR7/8 stimulation (P = .035), a reduced interleukin 6 response to TLR7/8 stimulation (P = .037), and reduced IFN-γ-inducible protein 10 (IP-10) response to TLR2 stimulation (P = .042). Lower plasma IP-10 levels were associated with spontaneous clearance (P = .001). CONCLUSIONS: These findings implicate TLR4 signaling as playing a critical role in the outcome of acute hepatitis C.

Study on technology of high-frequency pulsed magnetic field strength measurement.

High-frequency transient weak magnetic field is always involved in researches about biomedical engineering field while common magnetic-field sensors cannot work properly at frequencies as high as MHz. To measure the value of MHz-level weak pulsed magnetic-field strength accurately, this paper designs a measurement and calibration method for pulsed magnetic-field. In this paper, a device made of Nonferromagnetic material was independently designed and applied to pulsed magnetic field measurement. It held an accurately relative position between the magnetic field generating coil and the detecting coil. By applying a sinusoidal pulse to the generator, collecting the induced electromotive force of the detector, the final magnetic field strength was worked out through algorithms written in Matlab according to Faraday's Law. Experiments were carried out for measurement and calibration. Experiments showed that, under good stability and consistency, accurate measurement of magnetic-field strength of a sinepulse magnetic-field can be achieved, with frequency at 0.5, 1, 1.5 MHz and strength level at micro-Tesla. Calibration results carried out a measuring relative error about 2.5%.

Real-time histology with the endocytoscope.

Endoscopic Imaging has progressed tremendously over the last few decades. Novel imaging technologies such as high-resolution and high-magnification white light endoscopy, narrow band imaging, optimal band imaging, autoflourescence imaging and optical coherence tomography not only aid the endoscopist in detecting malignant or pre-malignant lesions but also assist in predicting histology. Recently, the introduction of Endocytoscopy (EC) and Confocal Endomicroscopy has taken us into a new realm of diagnostic endoscopy. With the ability to magnify up to 1000 ×, cellular structures can be visualized in real-time. This advance in technology could potentially lead to a paradigm shift negating the need to obtain biopsies. EC is, however, still in the early stages of development and further research needs to be carried out before it can be accepted as standard practice. This review will focus on the diagnostic utility of the Endocytoscope.