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A 72-year-old woman was reffered to our hospital for further examination of a tumor shadow in the left upper lung field which was detected in a mass screening chest X-ray. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed a chest wall tumor located in the left 4th intercostal space. The lesion was suspected to be neurogenic tumor and CT-guided needle biopsy was performed. The tumor was consisted of spindle-shaped cells, but immunohistochemistry demonstrated no evidence of neurogenic tumor. As a possibility of malignant tumor could not denied, we performed tumor resection under video-assisted surgery. The lesion was not originated from nerves, but adhered to the intercostal muscle. Histologically, the tumor was consisted of spidle-shaped cells without atypia which sparsely proliferate in the myxoid stroma adjacent to intercostal muscle. In immunohistochemistry, tumor cells were positive for vimentin, and negative for desmin, S-100 protein, smooth muscle actin, CD34 and factor VIII. It was diagnosed as intramuscular myxoma. This histology in the intercostal muscle is extremely rare.

The field of drug testing currently needs a new integrated assay system, as accurate as systems using native tissues, that will allow us to predict arrhythmia risks of candidate drugs and the relationship between genetic mutations and acquired electrophysiological phenotypes. This could be accomplished by combining the microelectrode array (MEA) system with cardiomyocytes (CMs) derived from human embryonic stem cells (hESC) and induced pluripotential stem cells. CMs have been successfully induced from both types, but their maturation process is not systematically controlled; this results in loss of beating potency and insufficient ion channel function. We generated a transgenic hESC line that facilitates maintenance of hESC-CM clusters every 2 weeks by expressing GFP driven by a cardiac-specific alphaMHC promoter, thereby producing a compact pacemaker lineage within a ventricular population over a year. Further analyses, including quantitative RT-PCR, patch-clamp, and MEA-mediated QT tests, demonstrated that replating culturing continuously enhanced gene expression, ionic current amplitudes, and resistance to K(+) channel blockades in hESC-CMs. Moreover, temporal three-dimensional (3D) culturing accelerated maturation by restoring the global gene repressive status established in the adhesive status. Replating/3D culturing thus produces hESC-CMs that act as functional syncytia suitable for use in regenerative medicine and accurate drug tests., (Copyright 2010 Elsevier B.V. All rights reserved.)

We have previously reported that the 2-amino-6-vinylpurine (AVP) nucleoside exhibits a highly efficient and selective crosslinking reaction toward cytosine and displayed an improved antisense inhibition in cultured cells. In this study, we further investigated the alkyl-connected AVP nucleoside analogs for more efficient crosslinking to the cytosine base (rC) of the target RNA. We synthesized three AVP analogs which connect the 2-amino-6-vinylpurine unit to the 2'-deoxyribose through a methylene, an ethylene, or a butylene linker. The ODN incorporating the AVP analog with the methylene or the butylene linker showed a slightly higher crosslinking to the target rC of RNA than the original AVP with no linker. In contrast, the AVP with the ethylene linker formed a selective and efficient crosslink to the rC of the target RNA., (Copyright 2010 Elsevier Ltd. All rights reserved.)

A 42-year-old woman was admitted to our hospital because of an abnormal shadow on chest X-ray. Chest computed tomography scan revealed a tumor 4.0 cm in diameter in the right segment S8. We resected the right lower lobe because of the possibility of lung cancer. Historical finding of the resected specimen revealed epithelial-myoepithelial carcinoma of the lung. The patient has remained disease-free for a year and 3 months postoperatively.

This study was conducted to investigate effects of glucagon intracerebroventricularly administered on feed intake and endocrine changes in sheep. Four male sheep (48-55 kg BW) were used. The animals were acclimatized to be fed alfalfa hay cubes at 12.00 hour. Human glucagon (40 and 80 microg/0.5 mL) was injected into the lateral ventricle at 12.00 hour. Blood samples were taken every 10 min from 30 min before to 180 min after the glucagon injection. Soon after the injection, the animals were given alfalfa hay cubes, and the amounts of the feed eaten within 2 h were measured. Feed intakes were significantly (P < 0.05) suppressed by 80 microg of glucagon. Plasma glucose levels in control animals were gradually decreased after the feeding, whilst those in glucagon-treated animals were temporarily elevated just after the feeding and then kept higher than control levels. Plasma insulin was abruptly elevated after the feeding and was maintained at higher levels than before the feeding in all treatments. Plasma NEFA concentrations were decreased after the feeding in all treatments. A tendency of increase in plasma cortisol levels occurred in glucagon-injected animals. The present study provides the first evidence that glucagon directly acts on the brain, then inhibiting feeding behavior and inducing endocrine responses in ruminants.

A 59-year-old man was admitted to our hospital for abdominal mass and found to have a gastric cancer with peritoneal dissemination. Three courses of neoadjuvant chemotherapy combined with S-1 and CDDP were performed. This chemotherapy showed a substantial reduction of the size of primary tumor and peritoneal dissemination by CT examination. Surgical resection consisted of distal gasterectomy and D2 lymph node dissection was performed, and an ip catheter was placed through the douglas pouch, and the catheter was attached to the subcutaneous portal delivery system for ip chemotherapy. Operative cytology of ascites proved positive and remnant neoplasm cells were identified in the peritoneum. The pathological stage was determined as T3 N2 H0 P1 CY1 M0, pStage IV. Following surgery, we selected the ip administration of paclitaxel at a dose of 100 mg per body. Finally, the peritoneal dissemination was re-grown. However, we continued the ip chemotherapy for twenty-five times on ambulant basis. Most gastric cancer patients with peritoneal dissemination die within a few months, and there is no standard treatment for peritoneal dissemination from gastric cancer. In conclusion, a condition of no progression has been achieved and maintained for more than three years by intraperitoneal administration of paclitaxel for patient with peritoneal dissemination due to advanced gastric cancer.

A 47-year-old man with a history of surgery for gastric cancer had enlarging right hilar tumor. Primary or metastatic malignant tumor was suggested and the right upper lobectomy with systematic nodal dissection was performed. Pathological diagnosis was lymph node metastasis of the squamous cell carcinoma. He received no additional treatment, and is well without recurrence 5 years after resection.

A 52-year-old woman was admitted to our hospital because of an abnormal shadow on chest X-ray. Chest computed tomography scan and magnetic resonance imaging demonstrated an anterior mediastinal tumor. The tumor was extirpated completely with combined partial resection of the left lung through a median sternotomy. Microscopically, the tumor was diagnosed thymic cancer, basaloid carcinoma. The patient was treated with combination chemotherapy and radiation, postoperatively. We reported a case of thymic carcinoma.

Chromosomal deletions are widely involved in serious genetic diseases and in the pathogenesis of cancers. These deletions often generate loss of heterozygosity (LOH) of one of the alleles of a tumor suppressor gene. Because of the technical difficulty inherent in genetic manipulation studies of a chromosome-wide deficiency, it has not been experimentally determined whether chromosome deletions could be a trigger for cancer development. Using the Cre/inverted loxP system, we have developed a chromosome elimination cassette (CEC) that Cre-dependently induces whole or partial deletions of the CEC-tagged chromosomes. Most deletions are usually fatal, but diploid cells carrying small deletions have been obtained from mouse embryonic stem cells carrying a CEC transgene (CEC-ESC). Here, we further isolated various CEC-ESC clones and analyzed CEC integration sites using the fluorescence in-situ hybridization method. In 17 CEC-ESC clones possessing normal chromosome sets, 13 types of chromosomes out of 20 pairs of mouse chromosomes were tagged by CEC. Each CEC-tagged chromosome could become a future target for the creation of a Cre-inducible LOH by a combination of in vitro and in vivo genetic mutation.

The apoptosis-associated speck-like protein containing a caspase recruit domain (ASC) is involved in apoptosis and innate immunity and is a major adaptor molecule responsible for procaspase-1 activation. ASC mRNA is encoded by three exons: exons 1 and 3 encode a pyrin domain (PYD) and caspase recruit domain (CARD), respectively, and exon 2 encodes a proline and glycine-rich (PGR) domain. Here, we identified a variant ASC protein (vASC) lacking the PGR domain that was smaller than full length ASC (fASC) derived from fully transcribed mRNA and searched for differences in biochemical and biological nature. Both fASC and vASC were found to activate procaspase-1 to a similar degree, but the efficiency of IL-1beta excretion was significantly higher for vASC. There was also a marked structural difference observed in the fibrous aggregates formed by fASC and vASC. These results suggest that although the PGR domain is dispensable for procaspase-1 activation, it plays an important role in the regulation of the molecular structure and activity of ASC.

A 52-year-old man was admitted to our hospital because of an abnormal shadow on chest X-ray. Chest computed tomography scan and broncho-fiberscopic examination revealed a tumor at the left main bronchus. The tumor was removed completely by partial resection of the left main bronchus with thoracotomy. Historical finding of the resected specimen revealed a benign pleomorphic adenoma of the bronchus. The postoperative course was un-eventful for 9 years. We reported a rare case of pleomorphic adenoma of the bronchus.

Mucosa-associated lymphoid tissue (MALT) lymphoma of the lung is rare. We present a case of MALT lymphoma of the lung. A 64-year-old man was admitted to our hospital because of an abnormal shadow on chest X-ray. He was performed transbronchial lung biopsy (TBLB) in our hospital, but the results was not diagnostic. We performed surgical biopsy using thoracoscopy due to the possibility of malignancy. The pathological diagnosis was MALT lymphoma. He underwent an chemotherapy after the operation and has been followed up at an outpatient for 8 years.

Small bowel metastasis from lung cancer is rare. We present 2 cases of small bowel metastasis from lung cancer. A 69-year-old man with postoperative lung cancer was admitted to our hospital because of the development of anemia secondary to melena A 56-year-old man with postoperative lung cancer was admitted to our hospital because of weight loss and fever. Both patients were operated on with suspicion of small intestine tumor after some examinations. The metastatic tumors were found in the small intestines. Resection of metastasis to the small bowel of lung cancer is benefical for better prognosis.

Background: Laparoscopic surgery for colon cancer has been shown by several randomized, controlled trials to be an acceptable alternative to open surgery; however, laparoscopic rectal surgery has not been evaluated in a randomized trial. One of the most serious problems associated with laparoscopic rectal surgery are bowel clamping, irrigation, and transection of the rectum, and laparoscopic rectal surgery has not been as reliable as open rectal surgery., Materials and Methods: We present our new technique, the laparoscopic double-stapling technique, which eliminates these problems. This technique uses curved Doyen forceps introduced through the wound just above pubis symphysis for clamping the rectal wall at the anal side of the tumor. An endolinear stapler (length 60 mm) is inserted through the same wound, applied at the rectal wall parallel and caudal to the Doyen forceps, and transects the rectum under pneumoperitoneum. We used this technique for eight cases of rectal surgery., Results and Discussion: The laparoscopic double-stapling technique provided secure bowel clamping and rectal irrigation. The number of cartridges used in laparoscopic double-stapling technique cases was not more than 2, with an average of 1.6 per patient. None of the laparoscopic double-stapling technique cases experienced major complications., Conclusion: We consider that many cases of rectal cancer that are suitable for laparoscopic low anterior resection can undergo laparoscopic surgery by using this technique, which will improve the quality of rectal surgery.

The present study was conducted to investigate roles of ghrelin in glucose-induced insulin secretion in fasting- and meal-fed state in sheep. Castrated Suffolk rams were fed a maintenance diet of alfalfa hay cubes once a day. Hyperglycemic clamp (HGC) was carried out to examine glucose-induced insulin response from 48 to 53 h (fasting state) and from 3 to 8 h (meal-fed state) after feeding in Experiment 1 and 2 respectively. Total dose of 70 nmol/kg body weight of D-Lys3-GHRP6, a GH secretagogue receptor 1a (GHS-R1a) antagonist, was intravenously administered at 0, 60, and 120 min after the commencement of HGC. In the fasting state, the ghrelin antagonist significantly (P < 0.01) enhanced glucose-induced insulin secretion. In the meal-fed state, i.v. administration of synthetic ovine ghrelin (0.04 microg/kg body weight per min during HGC) significantly (P < 0.05) enhanced glucose-induced insulin secretion. d-Lys3-GHRP6 treatment suppressed ghrelin-induced enhancement of the insulin secretion. In conclusion, ghrelin has an inhibitory and stimulatory role in glucose-induced insulin secretion via GHS-R1a in fasting- and meal-fed state respectively.

Food intake in chickens is regulated in a manner similar to that in mammals. Corticotropin-releasing factor (CRF), which increases the plasma corticosterone concentration, plays an important role as a mediator of many appetite-suppressive peptides in the central nervous system in both species. Central administration of glucagon suppresses food intake in rats. However, the anorexigenic action of glucagon in chicks has not yet been identified. In the present study, we investigated the effects of central administration of glucagon on food intake in chicks. Intracerebroventricular administration of glucagon in chicks significantly suppressed food intake and significantly induced hyperglycemia. In contrast, peripheral administration of the same dose of glucagon did not influence food intake and plasma glucose concentration. These results suggest that glucagon functions in chicks as an appetite-suppressive peptide in the central nervous system. Intracerebroventricular administration of glucagon in chicks also significantly increased CRF mRNA expression and plasma corticosterone concentration, suggesting that CRF acts as a downstream molecule for a glucagon-induced appetite-suppressive pathway in chicks. It is likely that the induction of hyperglycemia by central administration of glucagon is involved in its anorexigenic action, because peripheral administration of glucose in chicks suppressed food intake. These results suggest that CRF- and/or hyperglycemia-mediated pathways are involved in the anorexigenic action of glucagon in chicks.

Ghrelin is an endogenous ligand for the GH secretagogue/ghrelin receptor (GHS-R) and stimulates feeding behavior and GH levels in rodents and humans. A preprandial increase in plasma ghrelin levels is seen in sheep on programmed feeding, followed by a postprandial rise in plasma GH levels, but effects on food intake and endocrine function are not defined in this ruminant species. We administered ghrelin to female sheep in various modes and measured effects on voluntary food intake (VFI) and plasma levels of GH, LH, prolactin, and cortisol. Whether administered intracerebroventricularly or iv, ghrelin consistently failed to stimulate VFI. On the other hand, ghrelin invariably increased plasma GH levels and alpha,beta-diaminopropanoic acid-octanoyl3 human ghrelin was more potent than ovine ghrelin. Bolus injection of ghrelin into the third cerebral ventricle reduced plasma LH levels but did not affect levels of prolactin or cortisol. These findings suggested that the preprandial rise in plasma ghrelin that is seen in sheep on programmed feeding does not influence VFI but is likely to be important in the postprandial rise in GH levels. Thus, ghrelin does not appear to be a significant regulator of ingestive behavior in this species of ruminant but acts centrally to indirectly regulate GH and LH secretion.

Approximately 20% of familial amyotrophic lateral sclerosis (FALS) arises from germ-line mutations in the superoxide dismutase-1 (SOD1) gene. However, the molecular mechanisms underlying the process have been elusive. Here, we show that a neuronal homologous to E6AP carboxyl terminus (HECT)-type ubiquitin-protein isopeptide ligase (NEDL1) physically binds translocon-associated protein-delta and also binds and ubiquitinates mutant (but not wild-type) SOD1 proportionately to the disease severity caused by that particular mutant. Immunohistochemically, NEDL1 is present in the central region of the Lewy body-like hyaline inclusions in the spinal cord ventral horn motor neurons of both FALS patients and mutant SOD1 transgenic mice. Two-hybrid screening for the physiological targets of NEDL1 has identified Dishevelled-1, one of the key transducers in the Wnt signaling pathway. Mutant SOD1 also interacted with Dishevelled-1 in the presence of NEDL1 and caused its dysfunction. Thus, our results suggest that an adverse interaction among misfolded SOD1, NEDL1, translocon-associated protein-delta, and Dishevelled-1 forms a ubiquitinated protein complex that is included in potentially cytotoxic protein aggregates and that mutually affects their functions, leading to motor neuron death in FALS.

We previously demonstrated that a transient surge in plasma levels of ghrelin occurs just prior to a scheduled meal and that this surge is modified by the feeding regimen. This suggests that the ghrelin secretion is regulated by the autonomic nervous system, especially the cholinergic projections to the stomach. To test this hypothesis, we investigated changes in plasma ghrelin levels at feeding time in rams by administering cholinergic blockers (atropine and hexamethonium) and a cholinergic accelerator (metoclopramide). The average food intake in each group infused with atropine, hexamethonium, metoclopramide, and saline was 150+/-28, 137+/-46, 153+/-50, and 1075+/-25g, respectively. Plasma ghrelin concentrations increased (P<0.05) after i.v. infusion of hexamethonium and gradually decreased (P<0.05) after i.v. infusion of metoclopramide. Plasma ghrelin levels in hexamethonium-treated animals were greater (P<0.05) than those of atropine-treated animals. Plasma ghrelin levels were significantly (P<0.05) higher in sheep given i.v. infusions of atropine or hexamethonium than the levels in normal- or pair-fed sheep infused with saline. Plasma ghrelin levels were similar in metoclopramide-treated, pair-fed, and control animals. These results support the possibility that ghrelin secretion is regulated by cholinergic neurons of the vagus and that cholinergic activity suppresses ghrelin secretion in sheep.

Ghrelin is a recently identified orexigenic hormone secreted by the stomach and has been implicated in meal-time hunger. Several experiments demonstrate a transient surge in ghrelin secretion shortly before a scheduled meal, suggesting from the involvement of cephalic mechanisms. If ghrelin secretion is stimulated by hunger in sheep, plasma levels of ghrelin should be modified by different feeding regimens that affect hunger drive. To test this hypothesis, we investigated changes in plasma ghrelin concentrations in fed Suffolk rams ad libitum and in rams either twice or four times daily. Plasma ghrelin levels increased (P<0.05) abruptly just before every feeding period in sheep fed twice and four times daily and then fell shortly after feeding. Peak levels of the pre-prandial ghrelin surge were higher (P<0.01) in animals fed twice daily than in animals fed four times daily, leading to greater (P<0.05) areas under response curves over 12h. In contrast, the plasma ghrelin levels remained relatively low and constant in sheep fed ad libitum, with no evidence of surges in plasma ghrelin levels. These results confirm that the transient surge in plasma ghrelin levels occurs just before feeding and demonstrate that this can be modified by the feeding regimen in sheep.

The catalytic properties of CYP3A7 in the metabolism of endogenous and exogenous substrates were compared with those of CYP3A4 and CYP3A5 using COS-7 expressing enzymes. The highest activities of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone 3-sulfate (DHEA-S) 16alpha-hydroxylase were observed in COS-7 cells expressing CYP3A7. In contrast, the activity of testosterone 6beta-hydroxylase of CYP3A7 expressed in COS-7 cells was much less than that of CYP3A4 expressed in COS-7 cells. The rate of carbamazepine 10, 11-epoxidation was the greatest in COS-7 cells expressing CYP3A4, followed by CYP3A5 and CYP3A7. On the other hand, the formation of reductive metabolite of zonisamide was the highest in COS-7 cells expressing CYP3A4, followed by CYP3A7 and CYP3A5. Furthermore, the addition of triazolam resulted in a decrease in 6beta-hydroxylation catalyzed by CYP3A7, but not by CYP3A4, whereas the pretreatment of microsomes with triacetyloleandomycin (TAO) resulted in a decrease in the reaction catalyzed by CYP3A4, but not by CYP3A7. Together with these results, it was suggested that CYP3A7 exerts differential catalytic properties not only in metabolism of endogenous substrates but also in drug metabolism compared to CYP3A4 and CYP3A5., (Copyright 1998 Elsevier Science B.V.)

Objective: To determine whether the presence of telomerase activity in synovial tissues could provide insights into the pathogenesis of rheumatoid arthritis (RA)., Methods: Synovial tissue samples obtained from patients with RA or osteoarthritis (OA) were examined for telomerase activity using the telomeric repeat amplification protocol (TRAP)., Results: Telomerase activity was detected in over half the RA synovial tissues (14/25, 56%) but in no OA synovial tissue samples (0/15). Telomerase activity was detected in the mononuclear cells isolated from telomerase-positive RA synovial tissue, but not in cultured adherent cells. In RA synovial tissue with positive telomerase activity mononuclear cell infiltration levels were increased (p < 0.001). In addition, patients with RA with positive telomerase activity had undergone joint operations at an earlier age (p = 0.030) and more often (p = 0.023) compared to those without telomerase activity., Conclusion: Telomerase activity in RA synovial tissue is likely derived from infiltrating mononuclear cells and may be involved in the pathogenesis of RA. Clinically, the presence of telomerase activity in RA may be an indicator of a more aggressive phenotype.

Both the gamma-aminobutyric acid (GABA) receptor agonist, muscimol, and noradrenaline stimulated the feeding behavior of rats in the two environments. When noradrenaline or muscimol was administered, however, the food intake at 26 degrees C was greater than that at 33 degrees C. In addition, the stimulatory effect of noradrenaline on food intake was significantly depressed by propranolol pretreatment at both temperatures. The stimulatory effect of muscimol on food intake was significantly depressed by the propranolol pretreatment at 33 degrees C but not at 26 degrees C. Some eating-stimulatory subsystems associated with feeding behavior induced by noradrenaline or muscimol might have been depressed in the hot environment, thus the food intake increased by these drugs in rats acclimated to the hot environment was less than that in rats acclimated to the temperate environment.

The central mechanism controlling food intake in response to the change in environmental temperature has been little examined. The GABA agonist, muscimol, was injected into the lateral ventricle of rats which were acclimated to temperate (26 degrees C) and hot (33 degrees C) environments. Muscimol obviously stimulated the feeding behavior of rats in both environments. However, when muscimol was administered at doses of 100 and 250 ng, the food intake at 26 degrees C was greater than that at 33 degrees C. In addition, the stimulating effect of muscimol (250 ng) on food intake at 26 degrees C lasted longer than that at 33 degrees C. These findings suggested that there might be a difference in muscimol metabolism at the two temperatures.

During a 21-year period, 3040 patients with malignant tumors were treated at the Division of Surgery, Fukuyama National Hospital. Of these 86 (2.8%) were diagnosed as having double cancers. The simultaneous double cancer rate was 27.3%. Statistical study showed that the etiology had a relation to family history and previous therapy, but not to immunology. The prognosis was good and diagnosis by RI was non-specific.