Fast immune responses are mediated by innate immune receptors that react against conserved structures in pathogens, named pathogen-associated molecular patterns（PAMPs）and endogenous danger-associated molecular patterns （DAMPS）. PAMPS include lipopolysaccharides, peptidoglycan, and endogenous DAMPS include uric acid and cholesterol deposits. Innate immune system consist of two groups, toll-like receptors （TLRs）and nucleotide binding oligomerization domain（NOD）-like receptors（NLR）. NLRs recognize pathogens in the cytosol. We have previously revealed that multiple genetic variants of NOD1 and NOD2, components of NLRs, are associated with susceptibility to several diseases. Notably, NOD2 loss-of-function and gain-of-function mutations showed susceptibility to Crohn’s disease and Blau syndrome（early-onset sarcoidosis：EOS）, respectively. Furthermore, we have revealed that impaired recognition of intracellular Propionibacterium acnes resulting from a polymorphism in the NOD1 gene is involved in the increased susceptibility of Sarcoidosis in a Japanese population. Inflammasome, newly identified innate immune system, activates IL-1β and causes several lifestyle diseases including diabetes mellitus and atherosclerosis. Manipulating the activities of innate immune factors may produce new therapy for lifestyle diseases.

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Two domains within the ryanodine receptor（RyR2）of sarcoplasmic reticulum（SR）｛N-terminal（0-600）and central（2000-2500）domains：N-C domains｝，harboring many mutations in CPVT, was found to interact with each other as a regulatory switch for channel gating. Here, we investigated the role of inter-domain interaction in the pathogenesis of heart failure（HF）and lethal arrhythmia. In the SR from pacing-induced failing hearts, domain unzipping in N-C domains has already taken place. In failing（but not normal）cardiomyocytes, the frequency of Ca2+ sparks（SpF）was markedly increased at baseline. To assess whether the defective inter-domain interaction also causes CPVT, we developed knock-in（KI：RyR2R2474S/+）mice model harboring a human Arg-to-Ser（R2474S）mutation. In all KI mice, ventricular tachycardia was observed by exercise with treadmill. In response to isoproterenol（ISO），the SpF was markedly increased in KI, in association with the domain unzipping. Co-addition of dantrolene markedly diminished the SpF in both failing and KI cardiomyocytes. In conclusion, the defective inter-domain interaction within the RyR2 may induce the de-stabilized channel gating, as a common key mechanism of heart failure and lethal arrhythmia.

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It is important to understand the cellular properties of endoneurial microvascular endothelial cells and pericytes which constitute blood-nerve barrier（BNB），since this barrier structure in the peripheral nervous system（PNS）may play pivotal pathophysiological roles in various PNS disorders including inflammatory neuropathy and diabetic neuropathy. However, in contrast to blood-brain barrier（BBB），very few studies have been directed to BNB and no adequate cell lines originating from BNB had been launched. We successfully established human immortalized cell lines originating from BNB using temperature-sensitive SV40 large T antigen and the cellular properties of human cell lines are demonstrated in this manuscript. The humoral factors including bFGF and GDNF secreted by pericytes strengthened the barrier properties of PnMECs, suggesting that in the PNS, peripheral nerve pericytes support the BNB function and play the same role of astrocytes in the BBB. Furthermore, AGEs increased the expression of basement membrane molecules including fibronectin and collagen type IV in pericytes via TGF-β and VEGF signaling. Further accumulation of the knowledge concerning the cellular properties of BNB-forming cells will open the door to novel therapeutic strategies for diabetic neuropathy.

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Meningeal dissemination from breast cancer is reportedly rare in Japan. We describe a case of meningeal dissemination with local metastases to the bilateral optic nerve after peritonitis carcinomatosa in a patient who underwent surgery for breast cancer 7 years previously. The patiet was a 60-year-old woman with left breast cancer who underwent a muscle-preserving radical mastectomy（Br+Ax）．The tumor was classified as T2N1M0Stage II B. She received 6 cycles of paclitaxel every week, after which an aromatase inhibitor（exemestane）was administered for 5 years. Right ureteral stenosis and right hydronephrosis developed 7 years and 4 months after surgery. These findigs were compatible with peritonitis carcinomatosa resulting from breast, therefore, 6 cycles of the epirubicin-cyclo-phosphamide regimen were administered, and hydronephrosis was successfully resolved. However, 6 months later, she was readmitted to our hospital presenting with a sudden headache and, vision loss in both eyes. The patient was diagnosed with meningeal carcinomatosis breast cancer by enhanced magnetic resonance imaging（MRI）and cerebrospinal fluid cytology, and she died on the seventh day after readmission. MRI also revealed local metastases to the bilateral optic nerve. Despite various interventions, most patients with meningeal dissemination from breast cancer have poor prognosis within 6 months after diagnosis.

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A 74-year-old woman underwent a low anterior resection for rectal cancer with multiple lung metastases. After she had received chemotherapy with six courses of mFOLFOX6 regimen, multiple lung metastases disappeared and she was judged to have a complete response, and maintained as a complete response for 6 years after the surgery. In 6 years and 6 months, CEA marker was elevated and abdominal CT revealed solitary right adrenal metastasis. She underwent a resection of right adrenal gland. The adrenal tumor was confirmed a metastasis from the rectal cancer by pathological examination. Solitary adrenal metastasis of colorectal carcinoma is rare and has no characteristic clinical symptoms, and thus early diagnosis based on imaging findings is difficult. There is a high risk of recurrence in other organs in patients who have undergone for cases of adrenal gland metastasis from colorectal cancer. Thus, chemotherapy and radiotherapy should be considered as treatment options as well as surgery for cases of adrenal gland metastasis from colorectal cancer.

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The case is a male in his early seventies. We performed endoscopic submucosal dissection（ESD）for superficial esophageal cancer in the mid-esophagus. During procedure, the patient exhibited tachycardia and hypertension, and when treated with nicardipine for the same, he suddenly went into temporary cardiac arrest. His heart was quickly restarted by performing cardiac massage. Subsequently, under the observation of a cardiovascular internist ready for transcutaneous pacing, the procedure was continued and the lesion completely resected. On using a Holter electrocardiogram postoperatively, the patient was diagnosed with sick sinus syndrome. We hypothesize that the submucosal epinephrine injection administered during esophageal ESD was related to the tachycardia and hypertension, and we consider this is a rare case of esophageal ESD during which cardiac arrest due to sick sinus syndrome occurred after nicardipine administration.

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Adenoid cystic carcinoma（ACC）is a rare type of breast cancer that represents about 0.1% of all breast cancers, and considered as a good prognostic disease with rare instances of local recurrence or distant metastasis. We report a rare case of adenoid cystic carcinoma of the breast with the widely growth and the invasion to the skin.A 58-year-old woman visited our hospital because of a palpable tumor about 7cm in diameter with tenderness and skin redness in the C area of the left breast. A mammogram showed a lobulated mass with unclear border and resulted in category 4. An ultrasonogram showed a low-echoic tumor with partially unclear border and heterogeneous inner part. With core-needle biopsy, we suspected the histologic type of this tumor was ACC. Modified mastectomy with levelⅠaxillary lymph node dissection was performed. There was no lymph node metastasis or distant metastasis. Estrogen and progesterone receptors were negative, and no HER-2 expression in this tumor. She has been free from recurrence for 7 years after the operation. Thus we consider that once a complete excision of the local lesion is carried out, the prognosis is good, regardless of the progression or the invasion.

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Traumatic herniation of buccal fat pad is rare condition. We herein report a case of traumatic herniation of buccal fat pad caused by sticking toothbrush. Three-year-old boy was injured by falling down with a toothbrush in his mouth. He was admitted hemorrhage, and his mother took him to our department. The hemorrhage had been stopping, but the buccal fat pad extruded into the oral cavity. On the same day, we excised the buccal fat pad and stitched up the wound under the general anesthesia. His clinical course was uneventful and postoperative abscess formation was not observed. To prevent such injuries, we must inform the parents of the danger during brushing the teeth.

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A hepatic tumor was incidentally detected in an 80-year-old man who was undergoing examination for suspected squamous cell carcinoma of the left external auditory canal with positron emission tomography-computed tomography. Subsequently, the patient was referred to our department for further examination and treatment. The identified hepatic tumor was a 20-mm wide, hypervascular, solitary mass, and no associated chronic liver disorders were observed. Blood tests and imaging studies could not yield an appropriate diagnosis, and therefore, a percutaneous hepatic tumor biopsy was performed. On immunohistochemical staining, positive results were obtained for chromogranin A, synaptophysin, and cluster of differenti-ation 56（CD56），whereas the Ki-67 index was 70%, leading to a definite diagnosis of neuroendocrine carcinoma（small cell carcinoma）．Thus, the patient underwent transcatheter arterial chemoembolization（TACE）；however, after 4 months, endoscopic ultrasoundfine needle aspiration biopsy confirmed metastasis to the lymph nodes on the anterior surface of the pancreatic head. The patient underwent symptomatic treatment and was kept under observation；however, he died 14 months after TACE. The primary lesion could not be determined even during autopsy. From the clinical course, we believe that it was highly likely that the patient had a primary hepatic neuroendocrine carcinoma.

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A 70s-year-old man visited a nearby hospital with the complaint of a difficulty in swallowing lasted for approximately one month. Upper gastrointestinal endoscopic examination revealed tumorous lesion in the esophagus and stomach. We diagnosed endocrine cell carcinoma of the esophagus and gastric poorly differentiated adenocarcinoma with multiple metastasis in lymph nodes and the liver. Chemotherapy using CPT-11 and CDDP were successfully performed, then the regimen was changed to CPT-11 and CBDCA because of renal dysfunction. Now, from the diagnosis 9 months later, the chemotherapy still continues without exacerbation of the cancer. Endocrine cell carcinoma of the esophagus with gastric adenocarcinoma is a very rare disease and has no treatment guideline. In this case, we selected chemotherapy same as lung small cell carcinoma that performed successfully.

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