Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal lung disease characterized by the proliferation of fibroblasts and deposition of extracellular matrix. Since the prognosis of IPF is still poor, novel therapeutic modalities are strongly required. For this reason, to find molecular target for therapy of IPF is of much importance. The recent understanding of pathogenesis in IPF indicates the critical role of alveolar epithelial type II cells (AECII) and fibroblasts. Although the detailed mechanisms involved in IPF is still unclear, various profibrotic mediators which are produced by the injured AECII are thought to play a role in the progression of pulmonary fibrosis via stimulating fibroblasts. Among them, platelet-derived growth factor (PDGF) is one of critical growth factors by stimulating the proliferation and migration of fibroblasts. In this review, we discuss the role of PDGF in pulmonary fibrosis and the possibility as a therapeutic target for IPF. J. Med. Invest. 60: 175-183, August, 2013

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Objective: To evaluate the correlations between F-18 FDG uptake imaged with PET/CT and pathological findings in soft tissue lesions. Methods: Fifty-four soft tissue lesions in 47 patients were evaluated. The correlations between the degree of FDG uptake, pathological type and grade, and MRI signal intensity and/or enhancement pattern were evaluated. Tumor FDG uptake was quantified by the maximum standardized uptake value (SUVmax). Results: Thirty-one lesions were malignant and twenty-three lesions were benign. The difference between SUVmax in the malignant and benign groups was statistically significant (p<0.001). Malignant myxoid lesions and well differentiated liposarcoma showed low FDG uptake. Benign neurogenic lesions showed low FDG uptake while malignant neurogenic tumors showed high FDG uptake, and the difference between SUVmax in the benign and malignant lesions was statistically significant (p<0.001). In a neurofibromatosis type-1 patient who had multiple neurogenic tumors, FDG-PET/CT could distinguish malignant peripheral nerve sheath tumors from other benign lesions with similar MRI findings. Conclusions: FDG-PET/CT is useful for differentiating malignant from benign soft tissue lesions, but malignant soft tissue lesions may show various patterns on FDG-PET, and MRI may be helpful for a differential diagnosis. J. Med. Invest. 60: 184-190, August, 2013

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The type IIa sodium-dependent phosphate co-transporter (Npt2a) is important to maintain renal inorganic phosphate (Pi) homeostasis and the plasma Pi levels. It has reported that disorder of Pi metabolism in kidney can be risk factors for cardiovascular disease as well as hypercholesterolemia. However, the relationship between Pi and cholesterol metabolism has not been clarified. The current study investigated the effects of Npt2a gene ablation that is known as hypophosphatemia model on cholesterol metabolism in mice. Npt2a deficient (Npt2a^-/-) mice and wild type mice were fed diets with or without 2% cholesterol for 12 days. Plasma lipid and lipoprotein profile analysis revealed that plasma lipid levels (total, LDL and HDL cholesterol) were significantly higher in Npt2a^-/- mice than wild type (WT) mice. Interestingly, high cholesterol diet markedly increased plasma levels of total, LDL and HDL cholesterol in WT mice, but not Npt2a^-/- mice. On the other hand, there were no differences in body and liver weight, intake and hepatic lipid accumulation between WT and Npt2a^-/- mice. These results suggest that ablation of Npt2a gene induces hypercholesterolemia and affects the ability to respond normally to dietary cholesterol. J. Med. Invest. 60: 191-196, August, 2013

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Insulin stimulates glucose transporter 4 (GLUT4) vesicle recruitment from its intracellular storage site to the plasma membrane. Cysteine string protein 1 (CSP1) is a SNARE-binding protein involved in the vesicular trafficking of neurotransmitters and other exocytic processes. In this study, we investigated the involvement of CSP1 in insulin-dependent GLUT4 recruitment in 3T3-L1 adipocytes. Over-expression of wild-type CSP1 led to attenuated insulin-stimulated glucose uptake without any change in GLUT4 content in the plasma membrane, rather it inhibits docking by blocking the association of VAMP2 with syntaxin 4. In contrast, knockdown of CSP1 enhanced insulin-stimulated glucose uptake. The mRNA and protein expression of CSP1 was elevated in 3T3-L1 adipocytes in insulin resistant states caused by high levels of palmitate and chronic insulin exposure. Taken together, the results of this study suggest that CSP1 is involved in insulin resistance by interrupting GLUT4 vesicle docking with the plasma membrane. J. Med. Invest. 60: 197-204, August, 2013

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Background: The purpose of this study was to evaluate the usefulness of the closed-loop system (STG-22; Nikkiso, Tokyo, Japan), a type of artificial endocrine pancreas for the continuous monitoring and control of intraoperative blood glucose in patients undergoing liver transplantation. Methods: Sixteen patients undergoing living-donor liver transplantation were enrolled in this study. Glucose levels were controlled with either a manual injection of insulin based on a commonly used sliding scale (manual insulin group, n=8) or a programmed infusion of insulin determined by the control algorithm of the artificial endocrine pancreas (programmed insulin group, n=8). The target glucose level range was set at 80-150 mg/dl. Results: The mean and SD of blood glucose concentration during surgery (Glu-Ave and Glu-SD, respectively) for the programmed insulin group were lower than for the manual insulin group. The coefficient of variability (Glu-CV=Glu-SD×100 /Glu-Ave) for the programmed insulin group was also lower than for the manual insulin group (20.1±4.9% vs. 26.9±6.1%; mean±SD). No hypoglycemia was detected in either group. Conclusion: The STG-22 closed-loop system is effective for maintaining strict blood glucose control during liver transplantation with minimal variability in blood glucose concentration. J. Med. Invest. 60: 205-212, August, 2013

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Background A congested flap is a good indication for leech therapy. However, determining the appropriate number of leeches as well as the appropriate application time in clinical cases is difficult. We analyzed hemodynamics in rabbit island flaps under leech therapy to find a suitable clinical procedure for determining the appropriate number of leeches to be used and the duration of therapy. Methods Island flaps were raised in 35 rabbit ears, and congestion was induced by venous clamping. Treatment involved use of 1 or 3 leeches and was begun 60 minutes after venous occlusion. Flaps were examined for area of surviving tissue, alterations in transcutaneous oxygen and carbon dioxide tension (TcPO₂ and TcPCO₂), and flow volume. Arteriole and venule diameters and flow velocities were examined microscopically. Results Flap survival area in the 3-leech therapy group was significantly larger than the 1-leech therapy group and the control group. With 3-leech therapy, TcPCO₂ decreased significantly, as did arteriole and venule diameters. After clamp release, TcPCO₂ and venule diameter continued to decrease in this group, and flow velocity increased significantly. Conclusions Leech therapy may salvage compromised flaps by replacing congested blood with new arterial blood and thus maintaining flap viability. TcPO₂ and TcPCO₂ monitoring may help evaluate the therapeutic effect and determine the appropriate number of leeches to apply and the duration of therapy. J. Med. Invest. 60: 213-220, August, 2013

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[Purpose] Diversity of gut microbiome has been recently reported to be lost in inflammatory bowel disease. We have previously reported that the Dai-kenchu-to (DKT) prevented the bacterial translocation through suppression of cytokine and apoptosis in rat’s fast stress model. The aim of this study was to evaluate the effect of DKT on maintenance of microbial diversity in rat’s intestine with inflammation. [Method] Wister rats were received the fast stress for 5 days. In DKT group, rats were administered with DKT (300 mg/kg/day) during the fast stress (DKT-group). The gut microbiomes were analyzed at before- and after- fast stress, and the effect of DKT for on microbial diversities of the gut were evaluated by the PCR-clone library method targeting the 16 S ribosomal RNA gene. [Result] In Control-group, Erysipelotrichaceae increased to 86% in after fast stress, OTU of before-fast stress was 111 and after fast stress was only 9 (changing rate: 58%). The diversity of microbiome was severely decreased. On the other hand, in DKT-group, diversity of microbiome was kept after fast stress (Lachnospiraceae: Ruminococcaceae: Coriobacteriales 54%, 22%, 5%), Operational taxonomic units of before fast stress was 52 and after fast stress was 55 (changing rate: 6%). Family Lachnospiraceae which includes butyrate-producing Clostridia (Clostridium IV and XIVa). [Conclusion] DKT prevented the reduction of diversity of microbiome in rat’s fast stress model. Our data suggested the new anti-inflammatory mechanism of DKT through gut microbiome. J. Med. Invest. 60: 221-227, August, 2013

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Serine/arginine-rich splicing factor 3 (SRSF3), a member of the SRSF family, plays a wide-ranging role in gene expression. The human SRSF3 gene generates a major mRNA isoform encoding a functional, full-length protein and a PTC-containing isoform (SRSF3-PTC). The latter is expected to be degraded through the nonsense-mediated mRNA decay system. However, it was reported that SRSF3-PTC mRNA was produced under stressful conditions and translated into a truncated SRSF3 protein (SRSF3-TR). To disclose unknown functions of SRSF3-TR, we established Flp-In-293 cells stably expressing SRSF3-TR. The SRSF3-TR-expressing cells increased mRNA and protein levels of positive regulators for G1 to S phase transition (cyclin D1, cyclin D3, CDC25A, and E2F1) and accelerated their growth. c-Jun is required for progression through the G1 phase, the mechanism by which involves transcriptional control of the cyclin D1 gene. We also found that the JUN promoter activity was significantly increased in the Flp-In-293 cells stably expressing SRSF3-TR, compared with mock-transfected control cells. The SRSF3-TR-expressing cells increased c-Jun and Sp-1 levels, which are important for the positive autoregulation and basal transcription of JUN, respectively. Our results suggest that stress-inducible SRSF3-TR may participate in the acceleration of cell growth through facilitating c-Jun-mediated G1 progression under stressful conditions. J. Med. Invest. 60: 228-235, August, 2013

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In this study, we examined the effects of sensory inputs of visual-vestibulosomatosensory conflict induced by virtual reality (VR) on subjective dizziness, posture stability and visual dependency on postural control in humans. Eleven healthy young volunteers were immersed in two different VR conditions. In the control condition, subjects walked voluntarily with the background images of interactive computer graphics proportionally synchronized to their walking pace. In the visual-vestibulosomatosensory conflict condition, subjects kept still, but the background images that subjects experienced in the control condition were presented. The scores of both Graybiel’s and Hamilton’s criteria, postural instability and Romberg ratio were measured before and after the two conditions. After immersion in the conflict condition, both subjective dizziness and objective postural instability were significantly increased, and Romberg ratio, an index of the visual dependency on postural control, was slightly decreased. These findings suggest that sensory inputs of visual-vestibulosomatosensory conflict induced by VR induced motion sickness, resulting in subjective dizziness and postural instability. They also suggest that adaptation to the conflict condition decreases the contribution of visual inputs to postural control with re-weighing of vestibulosomatosensory inputs. VR may be used as a rehabilitation tool for dizzy patients by its ability to induce sensory re-weighing of postural control. J. Med. Invest. 60: 236-239, August, 2013

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The effects of repeated mild stress on DNA and lipid metabolic damages in multiple organs of dyslipidemic mice, and the preventive role of metallothionein (MT) were investigated. Female adult wild-type and MT-null mice fed high-fat diet (HFD) or standard diet (STD) were repeatedly subjected to fasting or restraint for three weeks. The liver, pancreas, spleen, bone marrow and serum samples were taken for evaluating DNA damage, MT, glutathione (GSH), corticosterone, carnitine and adiponectin. Body weights of restraint groups were reduced with the intensity of stress increased, even if the energy intakes were higher than those of STD group. Hepatic GSH levels were reduced in HFD control group and were further reduced in stress groups, especially in restraint groups, while the hepatic MT and serum corticosterone levels were increased in concert with the intensity of stress. Cellular DNA damages were generally increased by the restraint stress, especially in MT-null mice. Hepatic carnitine levels of MT-null mice were markedly lower than those of wild-type mice. The data suggest that MT plays a preventive role by acting as an antioxidant in corporation with GSH decreased by repeated stress and that MT may be an essential factor for inducing carnitine under the stress. J. Med. Invest. 60: 240-248, August, 2013

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Purposes: The purpose of this study was to verify the outcome of the emergency one stage resection and anastomosis procedure for patients with obstructed colorectal cancer. Methods: An emergency one stage resection and anastomosis procedure was performed for 40 patients with obstructive colorectal cancer. The outcome was verified and compared dividing into two groups. 17 patients under the age of 70 in (Group A), 23 patients 70 years and over in (Group B). Results: The operative mortality rate in both groups was 0%. As a result, postoperative complications were not significantly different between the two groups. The overall survival rate after a 5-year period in both groups was 41.8%, regarding all patients and the survival curves for the two groups, was not significantly different. The 5 year survival rate in stage II or III showed no differences between the two groups. Conclusion: The one-stage resection and anastomosis of the large bowel could be applied safely to emergency patients, which in turn allows for excellent short-term operative results in both groups mentioned. This particular procedure should be positively enforced, even in elderly patients in their 70’s. J. Med. Invest. 60: 249-255, August, 2013

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The erythematous patches and vesicles that are observed in coma patients, usually from an overdose of medication, are known as coma blisters. However, it is unknown whether the degenerated sweat gland is a necrosis or apoptosis. We immunohistochemically examined such skin lesions to investigate the characteristics and pathogenesis of the coma blister. Skin lesions were obtained from a forensic autopsy case, a woman in her thirties, of caffeine intoxication. Those lesions were observed in the left femoral, the lower left thigh, and the right knee. Histologically, the skin lesions showed that the keratinocytes had necrosed and the epidermis was thin in some areas. Eccrine sweat gland degeneration was observed. Obvious inflammatory cell infiltrations were not detected. Immunohistochemically, we stained each skin lesion against CD3, CD8, CD45RO, cytokeratin, 70 kD heat shock protein, ubiquitin, 150 kD oxygen regulated protein, and caspase-cleaved keratin 18 neo-epitope M30. They were also stained with an in situ apoptosis detection kit. Degenerated sweat glands featured CD45RO and M30 immunoreactivity. Immunohistochemical staining for CD45RO, CK-L, and M30 might be useful to observe sweat gland degeneration in the coma blister. Therefore, the apoptosis might be related to coma blisters and sweat gland degenerations. J. Med. Invest. 60: 256-261, August, 2013

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A patient with hepatic epithelioid angiomyolipoma (Epi-AML) with arterioportal venous shunting, who was successfully treated by a laparoscopic left lateral sectionectomy, is presented herein. AML is an uncommon benign neoplasm of the liver. Tumors composed predominantly of epithelioid cells have been subcategorized into Epi-AML, and the treatment strategy for Epi-AML is currently undetermined. There are no reports describing Epi-AML with arterioportal venous shunting to date. An arterioportal venous shunting of the liver tumor was suggested to be one of the malignant signs of the liver tumor. It would be important to differentiate Epi-AML with arterioportal venous shunting from hepatocellular carcinoma and hypervascular metastatic tumors. Minimally invasive resection, such as laparoscopic hepatectomy, for patients having Epi-AML with arterioportal venous shunting may be recommended. J. Med. Invest. 60: 262-266, August, 2013

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A large well-differentiated hepatocellular carcinoma (HCC) with fatty change is rare, and to date only a few cases have been reported. Herein, we present a 68-year-old man who developed a well-differentiated HCC with extensive fatty metamorphosis. The patient was referred to our institute because of a rapidly growing tumor in the left lobe of the liver. Ultrasonography showed a hyperechoic lesion with a peripheral hypoechoic area. Dynamic contrast-enhanced computed tomography (CT) scan in all three phases revealed the tumor which showed diffuse low attenuation with internal irregular enhancement. He underwent left lateral segmentectomy at the liver. Histological diagnosis confirmed well-differentiated HCC and the surrounding non-cancerous area was diagnosed as non-alcoholic steatohepatitis. The patient is still alive without recurrence after 17 months of follow-up. J. Med. Invest. 60: 267-271, August, 2013

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A PediaSat^TM oximetry catheter (PediaSat: Edwards Lifesciences Co., Ltd., Irvine, CA, U. S. A.), which facilitates continuous measurement of central venous oxygen saturation (ScvO₂), may be useful for surgery for pediatric congenital heart disease. We used PediaSat during a bidirectional Glenn shunt. The patient was a 13-month-old boy. Under a diagnosis of left single ventricle (pulmonary atresia, right ventricular hypoplasia, atrial septal defect) and residual left aortic arch/left superior vena cava, a modified right Blalock-Taussig shunt was performed. Cyanosis deteriorated, so a bidirectional Glenn shunt was scheduled. After anesthesia induction, a 4.5 Fr double-lumen (8 cm) PediaSat was inserted through the right internal jugular vein for continuous ScvO₂ monitoring. Furthermore, the probe of a near-infrared, mixed blood oxygen saturation-measuring monitor was attached to the forehead for continuous monitoring of the regional brain tissue mixed blood oxygen saturation (rSO₂) (INVOS^TM 5100C, Covidien; Boulder, CO, U. S. A.). Blockage of the right pulmonary artery and right superior vena cava decreased the oxygen saturation, ScvO₂, and rSO₂, but increased the central venous pressure. Although changes in ScvO₂ were parallel to those in rSO₂, the former showed more marked changes. A combination of ScvO₂ and rSO₂ for monitoring during Glenn shunt may be safer. J. Med. Invest. 60: 272-275, August, 2013

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Splenic vascular lesions are relatively rare and are usually found incidentally. However, the vascular lesions associated with Kasabach-Merritt syndrome, such as hemangioma, can be life-threatening. We herein describe the case of a young adult female patient with a huge splenic vascular lesion, aneurysms of the splenic artery, and increased plasma levels of fibrin/fibrinogen degradation products and D-dimers. Hand-assisted laparoscopic splenectomy was performed, after which the coagulopathy was drastically improved. Minimally invasive surgical intervention such as hand-assisted laparoscopic splenectomy should be considered as the first treatment choice in such a case. J. Med. Invest. 60: 276-279, August, 2013

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