Involvement of the genus Corynebacterium in the pathogenesis of pigmented intratarsal keratinous cyst.

Intratarsal keratinous cyst (IKC) is a benign cystic lesion of the eyelid that retains keratin flakes. IKCs are usually yellow to white cystic lesions but rarely become brown or gray-blue, making clinical diagnosis difficult. The mechanisms by which dark brown pigments are generated in pigmented IKC are unclear. The authors report a case of pigmented IKC that had melanin pigments within the lining of the cyst wall and within the cyst. Focal infiltrates of lymphocytes were observed in the dermis, particularly beneath the cyst wall in areas with more melanocytes and intense melanin deposition. These pigmented parts faced bacterial colonies inside the cyst, which were identified to be Corynebacterium species in a bacterial flora analysis. The pathogenesis of pigmented IKC in relation to inflammation and bacterial flora is discussed.

Tacrolimus Up-regulates Expression of TGFß Receptor Type II via ERK, Providing Protection Against Intestinal Epithelial Injury.

BACKGROUND/AIM: Transforming growth factor ß (TGFß) signaling plays a key role in modulating intestinal epithelial cell (IEC) homeostasis. The present study aimed to investigate the direct effect of tacrolimus on TGFß signaling in IECs. MATERIALS AND METHODS: The protective effects of tacrolimus, with or without anti-TGFß antibody, in dextran sulfate sodium (DSS)-induced colitis were evaluated. RESULTS: Tacrolimus ameliorated IEC apoptosis-mediated mucosal destruction despite anti-TGFß treatment. TGFß receptor type II (TGFß-RII), phosphor-SMAD family members 2/3, and phosphor-extracellular signal-regulated kinase (ERK) expression in IECs was enhanced in tacrolimus-treated mice, and these positive effects were maintained despite anti-TGFß treatment. Moreover, tacrolimus induced TGFß-RII up-regulation through ERK activation. CONCLUSION: Our data indicate that tacrolimus directly activated TGFß-SMAD signaling via the ERK pathway in IECs, thereby providing protection against apoptosis-mediated intestinal epithelial injury.

Polygonum tinctorium leaves suppress sodium dextran sulfate-induced colitis through interleukin-10-related pathway.

Indigo naturalis, a herbal medicine purified from indigo-containing plants, such as Strobilanthes cusia, Isatis tinctoria, and Polygonum tinctorium, has been reported to be useful in the treatment of ulcerative colitis by activating the aryl hydrocarbon receptor. However, the aryl hydrocarbon receptor pathway causes crucial side effects, such as pulmonary arterial hypertension. Although P. tinctorium is one of the plant derivatives of indigo naturalis, it is not identical to it. To date, the pure leaves of P. tinctorium have not been reported to ameliorate ulcerative colitis. Therefore, we investigated the effect of pure P. tinctorium leaves, which are consumed in some regions, on experimental colitis induced in mice using sodium dextran sulfate. We found that P. tinctorium leaves ameliorated weight loss (P < 0.01) and pathological inflammatory changes in the colon (P < 0.05), enhanced mRNA expression of interleukin-10 (P < 0.05), and decreased expression of tumor necrosis factor-in colonic tissues (P < 0.05), as determined using quantitative real-time reverse transcription polymerase chain reaction. The intraperitoneal administration of an aryl hydrocarbon receptor antagonist did not antagonize the inhibition of mucosal destruction, whereas an anti-interleukin-10 receptor antibody did. These results suggest that P. tinctorium ameliorate sodium dextran sulfate-induced intestinal inflammation via interleukin-10-related pathway, independent of the aryl hydrocarbon receptor pathway. P. tinctorium leaves have the potential to be a new, safe treatment for ulcerative colitis.

Endoscopic and histopathologic features of Anti-PD-1-related collagenous colitis.

Objectives: Cancer patients treated with immune checkpoint inhibitors occasionally show persistent diarrhea accompanied by endoscopic features of ulcerative colitis. The endoscopic mucosal inflammation may appear mild in some patients compared to the clinical severity, which can make choosing a treatment challenging. In this study, we evaluated the factors that support the continuation of chemotherapy by assessing the endoscopic and histopathological characteristics of patients who experienced diarrhea after immune checkpoint inhibitor administration. Methods: This study included eight patients who were diagnosed with collagenous colitis based on pathological assessments. We retrospectively investigated these patients' backgrounds, laboratory data, and computed tomography images that were extracted from their medical records. We also summarized their endoscopic and pathologic findings. Results: All eight patients were being treated with anti-programmed cell death-1/programmed cell death-ligand 1 therapeutic agents and had a recent history of oral proton pump inhibitor therapy. The anti-programmed cell death-1-related collagenous colitis in these cases was characterized by endoscopically mild mucosal inflammation, high fecal calprotectin levels, and a lower frequency of intestinal wall thickening on computed tomography. Histological assessments showed CD8+ lymphocytes predominantly infiltrating the lamina propria and crypts of the colonic mucosa. Suspending the proton pump inhibitor therapy relieved the patients' symptoms and allowed the continuation of the anti-programmed cell death-1/programmed cell death-ligand 1 therapy. Conclusions: Anti-programmed cell death-1-related collagenous colitis is reversible; appropriate diagnosis of adverse events is crucial for the continuation of immune checkpoint inhibitor therapy.

Leptomeningeal and intraventricular myelomatosis manifesting an aggressive form of communicating hydrocephalus.

Leptomeningeal myelomatosis (LMM) is a fatal complication that occurs in < 1% of patients with multiple myeloma. Many patients with LMM present with neurologic symptoms referable to cranial neuropathies, while the manifestation of communicating hydrocephalus has been underrecognized. A Japanese man with Bence Jones protein-κ multiple myeloma developed fever and headache at age 54 years. He then became somnolent and went into a coma. Neuroimaging analyses identified rapidly progressive communicating hydrocephalus due to meningitis. He died 83 days after the onset of headache without any response to treatment at age 55 years. No symptoms or signs associated with cranial nerves were found during the course of illness. Postmortem examination revealed hydrocephalus and diffuse infiltration of myeloma cells into the subarachnoid space of the cerebrum, cerebellum, and brainstem. In addition, the interstitial tissue of the choroid plexuses was filled with myeloma cells. These myeloma cells were positive for CD156 and light chain κ. The Ki-67 labeling index in myeloma cells of the central nervous system (CNS) was 30-40%. Histopathological examination further revealed many myeloma cells on the surface of the lateral, third and fourth ventricles and at the area postrema of the medulla oblongata. Patients with LMM can develop an aggressive form of communicating hydrocephalus. Given that cerebrospinal fluid, produced by epithelial cells in the choroid plexuses of the ventricles, passes into the subarachnoid space through the third and fourth ventricles, myeloma cells may invade the CNS through the choroid plexuses.

Novel TNFAIP3 microdeletion in a girl with infantile-onset inflammatory bowel disease complicated by a severe perianal lesion.

A20 haploinsufficiency (HA20), a disease caused by loss-of-function TNFAIP3 mutations, manifests various autoinflammatory and/or autoimmune symptoms. Some cases of HA20 were initially diagnosed as very early onset inflammatory bowel disease (VEO-IBD). We performed whole-exome sequencing (WES) for a Japanese girl with infantile-onset IBD and a severe perianal lesion and detected a novel de novo 119 kb microdeletion containing only TNFAIP3 (arr[GRCh37] 6q23.3(138125829_138244816) × 1).

Cyclosporine protects from intestinal epithelial injury by modulating butyrate uptake via upregulation of membrane monocarboxylate transporter 1 levels.

BACKGROUND AND AIMS: A relationship between treatment outcomes and intestinal microbiota in patients with inflammatory bowel diseases has been demonstrated. Cyclosporine treatment leads to rapid improvement in severe ulcerative colitis. We hypothesized that the potent effects of cyclosporine would be exerted through relationships between intestinal epithelial cells (IECs) and the host microbiota. The present study was designed to elucidate the effects of cyclosporine on monocarboxylate transporter 1 (MCT1) regulation and butyrate uptake by IECs. METHODS: Colitis was induced in C57BL6 mice via the administration of 4% dextran sulfate sodium in drinking water, following which body weights, colon lengths, and histological scores were evaluated. To examine the role of butyrate in the protective effects of cyclosporine, MCT1 inhibitor and an antibiotic cocktail was administered and tributyrin (TB; a prodrug of butyrate) was supplemented; MCT1 protein expression and acetylated histone 3 (AcH3) signals in IECs, as well as the MCT1-membrane fraction of Caco-2 cells, were evaluated. To explore butyrate uptake, as s butyrate derivatives, 3-bromopyruvic acid (3-BrPA) and 1-pyrenebutyric acid were used. RESULTS: Treatment with cyclosporine inhibited body weight loss and colon length shortening. However, treatment with MCT1 inhibitor and the antibiotic cocktail negated the efficacy of cyclosporine, whereas TB supplementation restored its protective effect. Furthermore, cyclosporine upregulated MCT1 expression in the membrane and the AcH3 signal in IECs, while also inducing higher anti-inflammatory cytokine production compared to that in the vehicle-treated mice. The transcription level of MCT1 mRNA in IECs and Caco-2 cells did not increase with cyclosporine treatment; however, cyclosporine treatment increased membrane MCT1 expression in these cells and uptake of butyrate derivative. CONCLUSION: Cyclosporine treatment modulates butyrate uptake via the post-transcriptional upregulation of membrane MCT1 levels in IECs.

Diagnostic approach for patients with unidentified fever according to the classical criteria of fever of unknown origin in the field of autoimmune disorders.

Fever of unknown origin (FUO) is caused by various diseases, making differential diagnosis difficult. This study aimed to determine the clinical features of patients with FUO for use in daily medical practice. Medical records of patients who first visited our department for FUO between January 2008 and December 2017 were reviewed. We classified the diagnostic categories as infection, non-infectious inflammation, neoplasm, others, and unidentified through definitive diagnosis and compared the clinical characteristics of patients who fulfilled the criteria of classical FUO and those who did not. The most prevalent diseases in patients who fulfilled the criteria were adult-onset Still's disease, Behçet's disease (BD), and polymyalgia rheumatica, which do not have any specific image inspection or specific serological markers. BD and familial Mediterranean fever were most prevalent in patients who did not fulfill the criteria. All neoplasms fulfilled the criteria of classical FUO. The most useful diagnostic procedure was determined according to the criteria of each disease. The key factor that did not fulfill the criteria was periodic fever continuing for less than 3 weeks. When examining patients with FUO, we should strictly diagnose in accordance with the criteria of each disease and consider diseases that cause periodic fever.

Long-term maintenance of the mucosal healing induced by azacitidine therapy in a patient with intestinal Behçet's-like disease accompanied with myelodysplastic syndrome involving trisomy 8.

Myelodysplastic syndromes (MDSs) are a group of myeloid neoplasms characterized by blood cell deformation and dysfunction, and MDS with trisomy 8 is closely linked with intestinal Behçet's-like diseases. Intestinal Behçet's-like disease is refractory to conventional therapies, including prednisolone, immunomodulators, and anti-tumor necrosis factor α agents. Here, we describe a 56-year-old woman with intestinal Behçet's-like disease ascribed to MDS with trisomy 8 who had multiple intractable intestinal ulcers. She presented with periodic fever and abdominal pain. The genetic analysis showed a heterozygous E148Q mutation in the Mediterranean fever gene. The patient did not tolerate treatment with colchicine because of diarrhea; therefore, azacitidine therapy was initiated. One cycle of azacitidine therapy improved the multiple intestinal ulcers, and the periodic fever and abdominal pain gradually disappeared. After eight cycles of azacitidine therapy, ileocolonoscopy, histological assessment and capsule endoscopy revealed mucosal healing. Azacitidine therapy was continued, and mucosal healing was maintained for more than 2 years. This case suggests that azacitidine therapy which has immunoregulatory effects and epigenetic modulations, might control intestinal Behçet's-like disease associated with MDS involving trisomy 8.

A case of celiac disease with type I enteropathy-associated T-cell lymphoma in a Japanese male patient.

A 45-year-old Japanese male patient who was diagnosed with celiac disease (CeD) developed type I enteropathy-associated T-cell lymphoma (EATL). In 2013, the patient was admitted to our hospital with worsening of diarrhea and weight loss. Pathological examination of biopsy specimens from the duodenum and ileum led to a diagnosis of suspected EATL. A previous total colonoscopy (TCS) indicated villous atrophy in the terminal ileum. The patient was changed to a gluten-free diet, and the nutritional status gradually improved. In September 2014, he experienced acute right lower abdominal pain. He underwent urgent surgery, and a perforation was identified in the ileum. A diagnosis of type I EATL was made following histopathological examination. After eight courses of CHOP therapy, the patient entered complete remission. TCS and esophagogastroduodenoscopy with magnifying narrow-band imaging performed in 2015 identified villous regrowth in the distal ileum and duodenum. Capsule endoscopy also found villous regrowth in the entire small intestine. To our knowledge, this is the first case of type I EATL following CeD with villous atrophy before EATL occurrence in a Japanese HLA-DQ2 carrier. The possibility of type I EATL occurring after CeD should be recognized, although CeD is quite rare in Japan.

A case of nivolumab-associated colitis, which relapsed after mucosal healing and was then successfully treated with mesalazine.

Currently, the number of patients treated with immune-checkpoint inhibitor involving nivolumab is increasing. Nevertheless, it causes various immune-related adverse events (irAEs). Here, we report the case of a patient who underwent long-term follow-up after suffering from nivolumab-associated colitis. The patient was a 57-year-old man who underwent resection of a bladder tumor. Following surgery, lymph node metastasis was detected, and he was treated by nivolumab. Two months after treatment with nivolumab, the patient complained of bloody diarrhea. Colonoscopy revealed pancolitis with erosions, loss of vascular pattern and erythema. Pathological findings indicated a disease state of pan-ulcerative colitis. As an irAE by nivolumab, the patient was started with 30 mg of prednisolone. Prednisolone treatment successfully induced clinical remission and mucosal healing. Nevertheless, eight months after stopping the steroid treatment, the colitis relapsed with diarrhea following elevation of fecal immunochemical test (FIT) and fecal calprotectin (CPT). The relapsed colitis was treated by mesalazine, and then diarrhea was improved. Nivolumab-associated colitis relapsed following mucosal healing suggesting that it is necessary to consider maintenance therapy as well as remission induction for long-term survivor. The present case also demonstrates that the FIT and CPT would be effective biomarker to assess the disease activity of nivolumab-associated colitis.

Successful adalimumab treatment and usefulness of capsule endoscopy for gut inflammation concomitant with ankylosing spondylitis.

Here we describe a 20-year-old man with ankylosing spondylitis and gut inflammation, who was successfully treated with adalimumab. Capsule endoscopy and ileocolonoscopy showed multiple erosions and aphthoid ulcers in the ileum and the ileocecal valve. Immunohistochemical analysis of the terminal ileum demonstrated that the number of IL-23p19 expressing macrophages was increased. Adalimumab was administered, and his back pain and abdominal symptoms improved. Adalimumab might be an effective treatment for gut inflammation related to ankylosing spondylitis.

Gastric Focal Neutrophil Infiltration and Wide Duodenal Gastric Foveolar Metaplasia Are Histologic Discriminative Markers for Crohn's Disease and Behçet's Disease.

BACKGROUND/AIMS: Behçet's disease (BD) with intestinal lesions and Crohn's disease (CD) share clinical features. However, no report has compared the 2 diseases with regard to lesions of the upper gastrointestinal tract (UGT). We aimed to evaluate endoscopic and histologic findings of UGT in CD and BD. METHODS: We retrospectively assessed the endoscopic records and biopsy samples of 84 Helicobacter pylori-negative patients (50 CD, 34 BD). In duodenal samples, MUC5AC immunohistochemical analysis was performed to identify gastric foveolar metaplasia. RESULTS: In endoscopic findings, bamboo joint-like appearance (17/50 CD, 0/34 BD) and erosions (14/50 CD, 2/34 BD) were significantly more frequent in CD gastric lesions (p < 0.001, and p = 0.012). In histologic findings of stomach, focal neutrophil infiltration in lamina propria (15/48 CD, 1/34 BD) was significantly more frequent in CD (p < 0.001). In that of duodenum, wide gastric foveolar metaplasia (19/49 CD, 1/34 BD) was significantly more frequent in CD duodenal lesions (p = 0.013). The mean maximum width of the gastric foveolar metaplasia was 114.0 ± 10.6 and 29.5 ± 4.5 µm for CD and BD respectively (p = 0.003). CONCLUSIONS: In H. pylori-negative patients, gastric focal neutrophil infiltration and wide duodenal gastric foveolar metaplasia were important for distinguishing CD from BD.

Successful treatment with tacrolimus of refractory pyoderma gangrenosum with pouchitis after restorative proctocolectomy for ulcerative colitis.

We describe herein a case of severe relapsed pyoderma gangrenosum (PG) concomitantly with severe pouchitis treated by tacrolimus. A 25-year-old woman had undergone proctocolectomy with construction of ileo-anal pouch surgery for refractory ulcerative colitis (UC). She first developed PG with refractory pouchitis, and infliximab (IFX) was administered to induce remission due to resistance to glucocorticoid therapy. After achieving remission, IFX was stopped. Five years later, severe skin ulcers concomitantly with severe pouchitis recurred and treatment with 30 mg oral prednisolone (PSL) combined with topical tacrolimus showed partial improvement. When PSL was tapered to 15 mg, the skin ulcers and diarrhea aggravated. Endoscopy revealed multiple ulcers in the ileal pouch. Treatment with oral tacrolimus was initiated for severe pouchitis and refractory PG. Forty days later, all skin ulcers became scars and multiple ulcers in the ileal pouch were also improved. Our case suggests that oral tacrolimus treatment could be a valuable treatment option for UC patients with refractory PG and pouchitis.

Humoral hypercalcemia due to gastric carcinoma secreting parathyroid hormone-related protein during chemotherapy: a case report.

Humoral hypercalcemia due to a gastric carcinoma-secreting parathyroid hormone-related protein (PTHrP) is a rare disease associated with poor prognosis. A 61-year-old male with gastric cancer who had been receiving chemotherapy showed serum hypercalcemia and an elevated level of serum PTHrP with a suppressed intact parathyroid hormone level. Computed tomography revealed stable disease 4 weeks prior, and the laboratory examination revealed no adverse effects 2 weeks prior. The biopsy at the time of diagnosis was immunohistochemically positive for PTHrP later. Despite intensive care, the patient died of multiorgan failure on the 14th day after admission. In case of undifferentiated gastric cancer, the possibility of humoral hypercalcemia of malignancy caused by gastric cancer should be considered even when the patient is receiving chemotherapy.

Contribution of bone morphogenetic protein-2 to aortic valve calcification in aged rat.

Although aging is well established as an important risk factor for aortic stenosis, the mechanism of age-related aortic valve calcification is yet unknown. Here, we investigated this mechanism in tissue and cellular levels using middle-aged rats. Aortic valve specimens were obtained by dissecting from 9-week-old (young) and 30-week-old (aged) male Wistar rats. In the aged rats, the main risk factors for aortic stenosis in plasma were still in the normal range; however, their number of calcified specimens was significantly increased in comparison with the young rats. Aortic valve interstitial cells (AVICs) obtained from explants of aortic valve specimens were cultured for 14 days after reaching confluence. Spontaneous calcification, the expressions of calcigenic genes, that is, BMP-2, alkaline phosphatase (ALP), and osterix (osteogenic transcription factor) and ALP enzyme activity in AVICs from aged rats were enhanced in comparison with those from young rats. However, neither typical calcification inducing reagents (dexamethasone, ß-glycerophosphate, and high concentration of phosphate) nor tumor necrosis factor-α (an inflammatory cytokine) accelerated the spontaneous calcification of AVICs from aged rats. These results suggest that aortic valve calcification progresses with age partly through an activation of the BMP-2 pathway.