Ghrelin and Functional Dyspepsia

The majority of patients with dyspepsia have no identifiable cause of their disease, leading to a diagnosis of functional dyspepsia (FD). While a number of different factors affect gut activity, components of the nervous and endocrine systems are essential for normal gut function. Communication between the brain and gut occurs via direct neural connections or endocrine signaling events. Ghrelin, a peptide produced by the stomach, affects gastric motility/emptying and secretion, suggesting it may play a pathophysiological role in FD. It is also possible that the functional abnormalities in FD may affect ghrelin production in the stomach. Plasma ghrelin levels are reported to be altered in FD, correlating with FD symptom score. Furthermore, some patients with FD suffer from anorexia with body-weight loss. As ghrelin increases gastric emptying and promotes feeding, ghrelin therapy may be a new approach to the treatment of FD

Establishment of leptin-Responsive cell lines from adult mouse hypothalamus

Leptin resistance is considered to be the primary cause of obesity. However, the cause of leptin resistance remains incompletely understood, and there is currently no cure for the leptin-resistant state. In order to identify novel drug-target molecules that could overcome leptin resistance, it would be useful to develop in vitro assay systems for evaluating leptin resistance. In this study, we established immortalized adult mouse hypothalamus-derived cell lines, termed adult mouse hypothalamus (AMH) cells, by developing transgenic mice in which SV40 Tag was overexpressed in chromogranin A-positive cells in a tamoxifendependent manner. In order to obtain leptin-responsive clones, we selected clones based on the phosphorylation levels of STAT3 induced by leptin. The selected clones were fairly responsive to leptin in terms of STAT3, ERK, and Akt phosphorylation and induction of c- Fos mRNA induction. Pretreatment with leptin, insulin, and palmitate attenuated the c-Fos mRNA response to leptin, suggesting that certain aspects of leptin resistance might be reconstituted in this cellular model. These cell lines are useful tools for understanding the molecular nature of the signal disturbance in the leptin-resistant state and for identifying potential target molecules for drugs that relieve leptin resistance, although they have drawbacks including de-differentiated nature and lack of long-time stability

IL-6–dependent spontaneous proliferation is required for the induction of colitogenic IL-17–producing CD8+ T cells

We propose a novel role for interleukin (IL) 6 in inducing rapid spontaneous proliferation (SP) of naive CD8+ T cells, which is a crucial step in the differentiation of colitogenic CD8+ T cells. Homeostasis of T cells is regulated by two distinct modes of cell proliferation: major histocompatibility complex/antigen–driven rapid SP and IL-7/IL-15–dependent slow homeostatic proliferation. Using our novel model of CD8+ T cell–dependent colitis, we found that SP of naive CD8+ T cells is essential for inducing pathogenic cytokine-producing effector T cells. The rapid SP was predominantly induced in mesenteric lymph nodes (LNs) but not in peripheral LNs under the influence of intestinal flora and IL-6. Indeed, this SP was markedly inhibited by treatment with anti–IL-6 receptor monoclonal antibody (IL-6R mAb) or antibiotic-induced flora depletion, but not by anti–IL-7R mAb and/or in IL-15–deficient conditions. Concomitantly with the inhibition of SP, anti–IL-6R mAb significantly inhibited the induction of CD8+ T cell–dependent autoimmune colitis. Notably, the transfer of naive CD8+ T cells derived from IL-17−/− mice did not induce autoimmune colitis. Thus, we conclude that IL-6 signaling is crucial for SP under lymphopenic conditions, which subsequently caused severe IL-17–producing CD8+ T cell–mediated autoimmune colitis. We suggest that anti–IL-6R mAb may become a promising strategy for the therapy of colitis

Verification of the Addiction Severity Index Japanese Version (ASI-J) as a Treatment-Customization, Prediction, and Comparison Tool for Alcohol-Dependent Individuals

Objective: To demonstrate the usefulness of the Addiction Severity Index Japanese Version (ASI-J) in Japanese alcohol-dependent individuals. The ASI is a frequently used clinical and research instrument that measures severities in seven functional domains in people with substance abuse disorders. Methods: A total of 370 male inpatients with a history of alcohol dependence participated in the study. Forty-nine participants were excluded in the final analysis due to lack of reliability (i.e., patient misrepresentation or inability to understand). We used the ASI-J and a series of indexes that determined patient states during and post-treatment. Results: The correlations between ASI Composite Scores (CSs), which were calculated through a weighted formula and indicated the severity of each problem area, were significant but low in eight relations and not significant in 13 relations, indicating substantial independence of the problem areas. Significant differences were found in Family/Social CSs between abstinent and relapsed alcohol-dependent individuals. The questions of undesirable attitude were significantly related to the CSs of Employment, Drug use, Family/Social, and Psychiatric sections. Significant differences were observed in patient demographics, CS, and ASI Severity Rating (SR) and interviewer’s subjective scoring between alcohol-dependent individuals and drug abusers. CSs in Japanese alcohol-dependent individuals were generally similar to corresponding CSs in individuals from other countries, with the exception of The Netherlands. Conclusions: This study demonstrated that the ASI-J is useful for understanding individual profiles of problems for each patient and planning customized treatment. The ASI-J served as a predictive tool for relapse and compliance to treatment afterward and was shown to be useful as a comparison tool in clarifying similarities and differences between substance abuser groups

Effect of Heart Failure on Long‐Term Clinical Outcomes After Percutaneous Coronary Intervention Versus Coronary Artery Bypass Grafting in Patients With Severe Coronary Artery Disease

[Background] Heart failure might be an important determinant in choosing coronary revascularization modalities. There was no previous study evaluating the effect of heart failure on long‐term clinical outcomes after percutaneous coronary intervention (PCI) relative to coronary artery bypass grafting (CABG). [Methods and Results] Among 14 867 consecutive patients undergoing first coronary revascularization with PCI or isolated CABG between January 2011 and December 2013 in the CREDO‐Kyoto PCI/CABG registry Cohort‐3, we identified the current study population of 3380 patients with three‐vessel or left main coronary artery disease, and compared clinical outcomes between PCI and CABG stratified by the subgroup based on the status of heart failure. There were 827 patients with heart failure (PCI: N=511, and CABG: N=316), and 2553 patients without heart failure (PCI: N=1619, and CABG: N=934). In patients with heart failure, the PCI group compared with the CABG group more often had advanced age, severe frailty, acute and severe heart failure, and elevated inflammatory markers. During a median 5.9 years of follow‐up, there was a significant interaction between heart failure and the mortality risk of PCI relative to CABG (interaction P=0.009), with excess mortality risk of PCI relative to CABG in patients with heart failure (HR, 1.75; 95% CI, 1.28–2.42; P<0.001) and no excess mortality risk in patients without heart failure (HR, 1.04; 95% CI, 0.80–1.34; P=0.77). [Conclusions] There was a significant interaction between heart failure and the mortality risk of PCI relative to CABG with excess risk in patients with heart failure and neutral risk in patients without heart failure

Defect of Interferon γ Leads to Impaired Wound Healing through Prolonged Neutrophilic Inflammatory Response and Enhanced MMP-2 Activation.

Interferon (IFN)-&gamma; is mainly secreted by CD4+ T helper 1 (Th1), natural killer (NK) and NKT cells after skin injury. Although IFN-&gamma; is well known regarding its inhibitory effects on collagen synthesis by fibroblasts in vitro, information is limited regarding its role in wound healing in vivo. In the present study, we analyzed how the defect of IFN-&gamma; affects wound healing. Full-thickness wounds were created on the backs of wild type (WT) C57BL/6 and IFN-&gamma;-deficient (KO) mice. We analyzed the percent wound closure, wound breaking strength, accumulation of leukocytes, and expression levels of COL1A1, COL3A1, and matrix metalloproteinases (MMPs). IFN-&gamma;KO mice exhibited significant attenuation in wound closure on Day 10 and wound breaking strength on Day 14 after wound creation, characteristics that are associated with prolonged neutrophil accumulation. Expression levels of COL1A1 and COL3A1 mRNA were lower in IFN-&gamma;KO than in WT mice, whereas expression levels of MMP-2 (gelatinase) mRNA were significantly greater in IFN-&gamma;KO than in WT mice. Moreover, under neutropenic conditions created with anti-Gr-1 monoclonal antibodies, wound closure in IFN-&gamma;KO mice was recovered through low MMP-2 expression levels. These results suggest that IFN-&gamma; may be involved in the proliferation and maturation stages of wound healing through the regulation of neutrophilic inflammatory responses