Akira Sonoda

Ribavirin inhibits Zika virus (ZIKV) replication in vitro and suppresses viremia in ZIKV-infected STAT1-deficient mice

ABSTRACT Zika fever, a mosquito‐borne infectious disease caused by Zika virus (ZIKV), is an epidemic disease for which no effective therapy has been established. The recent outbreaks of ZIKV in Brazil and French Polynesia have been linked to a considerable increase in the incidence of fetal microcephaly and other diseases such as Guillain‐Barre syndrome. Because there is currently no specific therapy or vaccine, the early exploitation of a method to prevent expansion of ZIKV is a high priority. To validate commonly used antiviral drugs, we evaluated the effect of ribavirin, a drug used to treat hepatitis C with interferon‐&bgr; (IFN‐&bgr;), on ZIKV replication. In mammalian cells, we observed an inhibitory effect of ribavirin on ZIKV replication and ZIKV‐induced cell death without cytotoxic effect. Furthermore, we found that STAT1‐deficient mice, which lack type I IFN signaling, were highly sensitive to ZIKV infection and exhibited lethal outcome. Ribavirin abrogated viremia in ZIKV‐infected STAT‐1‐deficient mice. These data suggest that the inhibition of viral RNA‐dependent RNA polymerases may be effective for treatment of ZIKV infection. Our data provide a new insight into the mechanisms for inhibition of ZIKV replication and prevention of Zika fever. HighlightsRibavirin inhibits ZIKV replication in mammalian cells.Ribavirin prevents ZIKV‐induced apoptosis and cell death.Ribavirin administration abrogates viremia in ZIKV‐infected STAT1‐deficient mice.Leading to a prolonged survival.

A Revised Procedure for Analyzing Private Events.

One member of each pair of 52 undergraduates, referred to as a learner, was trained BC conditional discriminations, with B stimuli as the samples and C stimuli as the correct comparisons. Responses of the learner were either reinforced or punished by another member of each pair, an instructor, who had previously mastered AC conditional discriminations, with A stimuli as the samples. The B sample stimuli were presented simultaneously with the A stimuli so that only the instructor could see the latter. Each learner mastered the BC conditional discriminations from his or her instructor, regardless of whether the learner saw the instructor in advance or not. Performance was less accurate when the B stimuli corresponded 83.3% with the A stimuli than when they corresponded 100%. These results extend previous findings on private events obtained from only two of eight pairs when the stimuli always corresponded.

Stimulus control and generalization of remote behavioral history.

Two experiments were conducted to assess stimulus control and generalization of remote behavioral history effects with humans. Undergraduates first responded frequently under a fixed-ratio (FR) schedule in the presence of one line length (16 mm or 31 mm) and infrequently on a tandem FR 1 differential-reinforcement-of-low-rate (DRL) schedule when a second line length (31 mm or 16 mm) was present. Next, an FR 1 schedule in effect in the presence of either stimulus produced comparable response rates between the stimuli. Finally, a tandem FR 1 fixed-interval (FI) schedule was in effect under those same stimuli (Experiment 1) or under 12 line lengths ranging from 7 to 40 mm (Experiment 2). In both experiments, responses under the tandem FR 1 FI schedule were frequent in the presence of stimuli previously correlated with the FR schedule and infrequent in the presence of stimuli previously correlated with the tandem FR 1 DRL schedule. Short-lived but systematic generalization gradients were obtained in Experiment 2. These results show that previously established rates of behavior that disappear when the establishing contingencies are changed can subsequently not only reappear when the contingencies change, but are controlled by and generalize across antecedent stimuli.

Oral administration of antibiotics results in fecal occult bleeding due to metabolic disorders and defective proliferation of the gut epithelial cell in mice

Antibiotics sometimes exert adverse effects on the pathogenesis of colitis due to the dysbiosis resulting from the disruption of gut homeostasis. However, the precise mechanisms underlying colitogenic effects of antibiotic‐induced colitis are largely unknown. Here, we show a novel murine fecal occult bleeding model induced by the combinatorial treatment of ampicillin and vancomycin, which is accompanied by an enlarged cecum, upregulation of pro‐inflammatory cytokines IL‐6 and IL‐12, a reduction in Ki‐67‐positive epithelial cell number and an increase in the apoptotic cell number in the colon. Moreover, gas chromatography–tandem mass analysis showed that various kinds of metabolites, including glutamic acid and butyric acid, were significantly decreased in the cecal contents. In addition, abundance of butyric acid producer Clostridiales was dramatically reduced in the enlarged cecum. Interestingly, supplementation of monosodium glutamate or its precursor glutamine suppressed colonic IL‐6 and IL‐12, protected from cell apoptosis and prevented fecal occult blood indicating that the reduced level of glutamic acid is a possible mechanism of antibiotic‐induced fecal occult bleeding. Our data showed a novel mechanism of antibiotic‐induced fecal occult bleeding providing a new insight into the clinical application of glutamic acid for the treatment of antibiotic‐induced colitis.

Autoimmune sialadenitis is associated with the upregulation of chemokine/chemokine receptor pairs in T cell-specific TRAF6-deficient mice

Sialadenitis is an inflammatory condition affecting the salivary glands including the parotid, submandibular, and sublingual glands. There are several different types of sialadenitis, each with different sites of predilection. However, the pathogenic mechanism underlying the tissue specificity of sialadenitis is largely unknown. TRAF6 is a cytoplasmic adaptor protein that is necessary for the activation of dendritic cells in response to Toll-like receptor ligands, thereby regulating innate immune responses. We previously demonstrated that T cell-specific TRAF6-deficient mice (TRAF6ΔT mice) spontaneously develop systemic inflammatory disease. Here, we show that salivary secretion is reduced in TRAF6ΔT mice due to sialadenitis that occurs in the parotid and submandibular glands, but not the sublingual glands. Consistent with pathological findings, both CD4+ and CD8+ T cells predominantly infiltrated the submandibular glands; however, sublingual infiltration was rare in TRAF6ΔT mice. The TH1 cytokine IFN-γ, the TH1 cell attractant chemokine CCL2, and its cognate receptor CCR2 were upregulated concomitantly in both the submandibular and sublingual glands. Interestingly, the TH17 cell attractant chemokine CCL20 and its cognate receptor CCR6 were selectively increased in the submandibular glands, but not in the sublingual glands of TRAF6ΔT mice. Thus, the expression of TRAF6 in T cells might be implicated in tissue-specific sialadenitis by regulating the chemokine-chemokine receptor system.

Marked improvement in gastric involvement in Behçet’s disease with adalimumab treatment

Gastric involvement is the least frequent manifestation of Behçets disease, and effective treatment for it unknown. Here the case of a patient with gastric involvement in Behçets disease that was markedly improved with adalimumab therapy is presented. A 68-year-old man developed an oral ulcer, erythema, folliculitis, and arthralgia. Behçets disease was suspected; then, prednisolone and colchicine were administered. Esophagogastroduodenoscopy showed a punched-out ulcer in the posterior wall of the gastric antrum. Ileocolonoscopy showed multiple punched-out ulcers in the terminal ileum. Capsule endoscopy showed multiple circular ulcers throughout the entire small intestine. A diagnosis of non-steroidal, anti-inflammatory, drug-induced enteritis was made. Withdrawal from diclofenac and initiation of lansoprazole healed the circular ulcers in the small intestine, but were ineffective for the gastric ulcer and punched-out ulcers in the terminal ileum. Eradication of Helicobacter pylori was also ineffective. A diagnosis of gastric involvement of Behçets disease was then made, and the gastric ulcer became steroid-dependent. Mesalazine powder was ineffective, and the patient was intolerant to azathioprine. Adalimumab healed the gastric ulcer, and prednisolone was withdrawn. The outcome of the present patient suggests that adalimumab is effective in the treatment of gastric involvement in Behçets disease.

Deep Ulcers in the Ileum Associated with Mycophenolate Mofetil

A 54-year-old man was treated with mycophenolate mofetil (MMF) after undergoing living donor renal transplantation. Two years later, he experienced repeated episodes of diarrhea, and his C-reactive protein (CRP) level was found to be 12.63 mg/dL. Ileocolonoscopy showed multiple deep, punched-out ulcers that were similar to Behçets disease (BD) and cytomegalovirus (CMV) in the ileum. CMV infection was suspected. However, anti-cytomegalovirus agents were ineffective. The patient was subsequently diagnosed with gastrointestinal toxicity of MMF and MMF was switched to mizoribine. His symptoms improved immediately, and his CRP level normalized. Six months later, the patients mucosa was healed.

Objective Endoscopic Analysis with Linked Color Imaging regarding Gastric Mucosal Atrophy: A Pilot Study

Objectives We aimed to determine whether linked color imaging (LCI), a new image-enhanced endoscopy that enhances subtle differences in mucosal colors, can distinguish the border of endoscopic mucosal atrophy. Methods This study included 30 patients with atrophic gastritis. In endoscopy, we continuously took images in the same composition with both LCI and white light imaging (WLI). In each image, the color values of atrophic and nonatrophic mucosae were quantified using the International Commission on Illumination 1976 (L∗, a∗, b∗) color space. Color differences at the atrophic border, defined as Euclidean distances of color values between the atrophic and nonatrophic mucosae, were compared between WLI and LCI for the overall cohort and separately for patients with Helicobacter pylori infection status. Results We found that the color difference became significantly higher with LCI than with WLI in the overall samples of 90 points in 30 patients. LCI was 14.79 ± 6.68, and WLI was 11.06 ± 5.44 (P < 0.00001). LCI was also more effective in both of the Helicobacter pylori-infected group (P = 0.00003) and the Helicobacter pylori-eradicated group (P = 0.00002). Conclusions LCI allows clear endoscopic visualization of the atrophic border under various conditions of gastritis, regardless of Helicobacter pylori infection status.

Chest High-resolution Computed Tomography Findings in 601 Patients with Inflammatory Bowel Diseases

RATIONALE AND OBJECTIVES Pulmonary involvement in inflammatory bowel disease may reflect the common embryonic origin of the gastrointestinal tract and the bronchial tree. No studies have compared pulmonary high-resolution computed tomography (HRCT) findings between ulcerative colitis (UC) and Crohn disease (CD). This study aimed to assess the relationship between pulmonary HRCT findings and inflammatory bowel disease activity and to compare HRCT findings between UC and CD. MATERIALS AND METHODS We retrospectively identified 601 consecutive patients (350 with UC and 251 with CD) who had undergone chest HRCT examinations at our institutions between April 2004 and April 2016. Parenchymal abnormalities, enlarged lymph nodes, and pleural effusion were evaluated on HRCT. RESULTS One hundred sixty-seven patients (94 men, 73 women; aged 12-86 years, mean: 47.2 years) with UC and 93 patients (61 men, 32 women; aged 12-71 years, mean: 37.9 years) with CD had abnormal findings on chest HRCT. The HRCT findings of UC and CD mainly consisted of centrilobular nodules (in 49.1% and 45.2% of cases, respectively) and bronchial wall thickening (in 31.7% and 54.8%, respectively). There was no relationship between HRCT findings and disease activity. Bronchial wall thickening was significantly more frequent in patients with CD than in those with UC (P < .001). CONCLUSION The main chest HRCT findings in UC and CD are centrilobular nodules and bronchial wall thickening. There are differences in HRCT findings between UC and CD.