Vibrio parahaemolyticus is a human pathogen that naturally inhabits marine and estuarine environments. Infection with V. parahaemolyticus is often associated with the consumption of raw or undercooked seafood, causing gastroenteritis with watery diarrhea. The presence of two type III secretion system (T3SS) proteins, thermostable direct hemolysin (TDH) and TDH-related hemolysin (TRH), has been closely associated with the severity of diarrheal illness. TDH and TRH have various biological activities including hemolytic activity, cardiotoxicity, and enterotoxicity. T3SS1 is involved in cytotoxicity to host cells and orchestrates a multifaceted host cell infection by induction of autophagy, cell rounding, and cell lysis. T3SS2 is thought to be related to the enterotoxicity of V. parahaemolyticus. The activities of inducing diarrhea of each of the virulence factors were summarized in this review. J. Med. Invest. 57: 179-182, August, 2010

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Previously, multi-lectin positive spherical shaped deposits were detected in the hippocampal formation of degenerative demented and schizophrenic brains and reported they possessed some possibility as a predominant tool of postmortem diagnosis, more detected in schizophrenia cases than age-matched control cases. Multi-fluorescent immunohistochemical and lectin histochemical method and immuno electron microscope method were performed on 51 forensic autopsied brains containing 16 cases of schizophrenia. In multi-fluorescent staining, partial disrupted nucleus with decreased staining properties by mean of SYBR green were detected, and lectin and single strand DNA were co-stained in the portion of partial disrupted nucleus. In immuno electron microscope method, lectin positive structures were also detected in the portion of partial disrupted nucleus. These neurons were suspected in the process of apoptosis by their distinguishable features. Some experimental studies were reported that a kind of therapeutic products of major tranquillizers induced neuron apoptosis in dentate gyrus. As the lectin positive spherical shaped deposits were detected in not only 5 schizophrenia cases without drug treatment but also in 11 schizophrenia cases with drug treatment in this study, they might be detected as the intrinsic pathological change of schizophrenia. The lectin positive spherical shaped deposits detected in the hippocampal formation were suspected as the histopathological marker of the postmortem diagnosis for schizophrenia. Further examination for specifying group of neurons detected them in and initiated apoptosis are necessitated. J. Med. Invest. 57: 183-190, August, 2010

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Recent evidence in the fields of surgery, emergency and critical care medicine indicates that strict glycemic control results in lower mortality. Hyperglycemia occurs frequently in patients with and without diabetes during cardiovascular surgery, especially during cardiopulmonary bypass. However, strict glucose control is difficult to achieve during cardiovascular procedures. To establish effective intensive insulin therapy during cardiovascular surgery, we conduct continuous blood glucose monitoring and employ automatic control by using an artificial endocrine pancreas (the STG^®-22, Nikkiso, Tokyo, Japan). In this review, we will outline the present status and problems of conventional glycemic control for perioperative cardiovascular surgery and introduce the new perioperative blood glucose management method that we are testing now. We will also discuss the importance of perioperative glycemic control for cardiovascular surgery as well as future prospects. J. Med. Invest. 57: 191-204, August, 2010

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The objective of this study is to develop a device for noninvasive local tissue electrical impedance tomography (EIT) using divided electrodes with guard electrodes and to validate its effectiveness using bioequivalent phantoms. For this purpose, we prepared a measurement device and bioequivalent phantoms, measured the electrical characteristics of the phantoms, and validated the method using the phantoms. Monolayer phantoms mimicking the brain and muscle and bilayer phantoms consisting of muscle and brain layers were prepared. The relative differences between the measured electrical conductivities of the monolayer brain and muscle phantoms and the true values determined by the 4-electrode method were both less than 10%. The relative differences between the measured and true values in the bilayer phantoms were less than 20% in both layers. The biological impedance measurement device that we developed was confirmed to be effective for impedance measurement in bilayer phantoms with different electrical impedances. To develop a device for the early diagnosis of breast diseases, the development of a multi-layer phantom and demonstration of the effectiveness of the device for its examination are necessary. If the device that we developed makes impedance measurement in breast tumors possible, it may be used as a new diagnostic modality for breast diseases. J. Med. Invest. 57: 205-218, August, 2010

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CD4⁺ and CD8⁺ T cells develop from CD4⁺CD8⁺ thymocytes. Although it has been reported that expression of the transcription factor Th-POK is important for CD4⁺ T cell development, the detailed mechanism regulating Th-POK expression is still obscure. By comparing the promoter regions of the Th-POK gene between human and mouse, I found that the region 3600 base pairs (bps) upstream from the transcription initiation site of the Th-POK gene was highly conserved. To identify the important element(s) regulating Th-POK expression in CD4⁺ T cells, I investigated the promoter activity of this region using a luciferase assay in the human T cell line Jurkat. I identified a positive regulatory element in this region 22 bps in length located 600 bp upstream from the transcription initiation site. This 22 bp element had a consensus binding sequence for SAP-1, which is encoded by the Elk4 gene and is activated by the Erk pathway. These data suggest that the 22 bp element might positively regulate Th-POK expression through Erk-SAP-1 signaling. J. Med. Invest. 57: 219-223, August, 2010

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Hyperbaric air (HBA) is used to improve healing of wounds including diabetic ulcer. The aim of this study was to clarify the effects of HBA exposure on lipid and glucose metabolism in db/db mice. HBA did not influence the weight of db/db mice. Serum levels of free fatty acid and triglyceride, but not glucose and insulin, were significantly decreased after 6 weeks of treatment with HBA. The mRNA expressions of CPT-1, PPARα and PGC-1α genes, which are related to lipid metabolism, were significantly up-regulated in the muscle and liver. Increases in TNFα and MCP1 mRNA, which impaired lipid metabolism, were also attenuated by HBA treatment. These results suggest that exposure of HBA could have beneficial effects on lipid metabolism in patients with type 2 diabetes mellitus. J. Med. Invest. 57: 224-231, August, 2010

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Human carcinosarcomas of esophagus are uncommon malignant neoplasms that are composed both carcinomatous and sarcomatous components. We established a novel cell line, HN-Eso-1, from the metastatic esophageal spindle cell carcinoma (so-called carcinosarcoma). In this study, we estimated the vascular endothelial growth factors (VEGFs) and VEGF receptors (VEGFRs). Reverse transcription polymerase chain reaction (RT-PCR) studies revealed that VEGF-A, -C, -D and VEGFR-1, -2 were upregulated. Cisplatin reduced the cell viability of HN-Eso-1 cells and VEGF attenuated its effect. These results suggest that expression of VEGF-A, VEGF-C, VEGF-D, VEGFR-1, and VEGFR-2 are involved in the cell’s autocrine system and that VEGF protected these cells from the anti-tumor agent. J. Med. Invest. 57: 232-236, August, 2010

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Purpose: Nicorandil opens adenosine triphosphate-sensitive potassium (K_ATP) channels in the cardiovascular system and is being increasingly used for the treatment of angina pectoris. In the present study, we tested whether intravenous anesthetic agent ketamine affected nicorandil-induced native vascular K_ATP channel activation. Methods: We used excised inside-out patch clamp configurations to investigate the direct effects of ketamine racemate and S-(+)-ketamine on the activities of K_ATP channels in cultured rat aortic smooth muscle cells. Furthermore, we also investigated whether intracellular MgADP could modulate ketamine inhibition. Results: Nicorandil significantly activated K_ATP channel activity, whereas this channel activity was completely blocked by glibenclamide, a specific K_ATP channel blocker. Ketamine racemate inhibited the nicorandil induced K_ATP channel activity (IC₅₀=34±1 µM, n=14), but S-(+)-ketamine was less potent than ketamine racemate in blocking nicorandil induced K_ATP channel activities (IC₅₀=226±7 µM, n=10). Application of MgADP to the intracellular side of the channel was able to decrease the inhibitory potency of ketamine racemate on nicorandil induced K_ATP channel activities. Conclusions: Our results indicate that ketamine inhibits nicorandil induced K_ATP channel activities in a dose dependent and stereoselective manner. Furthermore, increase of intracellular MgADP attenuates the inhibitory potency of ketamine racemate. J. Med. Invest. 57: 237-244, August, 2010

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Maraviroc is an orally available antagonist of the CCR5 chemokine receptor, which acts as a human immunodeficiency virus type 1 (HIV-1) coreceptor. Binding of maraviroc to this receptor blocks HIV-1 attachment to the coreceptor and prevents HIV-1 from entering host cells. Maraviroc does not require intracellular processing to exert this activity. Drug interaction studies have shown changes in maraviroc exposure when given with other anti-HIV medications, and thus quantification of maraviroc in human plasma is important to manage drug interactions and to evaluate the relationship between plasma concentrations and treatment response. We developed a conventional LC-MS method for determining plasma maraviroc concentrations, validated by estimating precision and accuracy for inter- and intraday analysis in the concentration range of 0.011-2.188 µg/ml. The calibration curve was linear within this range. The average accuracy ranged from 92.7% to 99.7%, while the relative standard deviations of both inter- and intraday assays were less than 7.1%. Recovery of maraviroc exceeded 86.7%. Our LC-MS method provides a conventional, accurate and precise way to determine the maraviroc concentration in human plasma. This method enables dose adjustment based on monitoring plasma maraviroc concentrations and permits management of drug interactions and toxicity. J. Med. Invest. 57: 245-250, August, 2010

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The aim of this research was to clarify the relation between the screening rates for five cancers (lung cancer, stomach cancer, colorectal cancer, uterus cancer, and breast cancer) and their mortality rate by using publicly accessible databases. The used information materials were those prepared by the Ministry of Health, Labour and Welfare, the Center for Cancer Control and Information Services, and the National Cancer Center. Our results were as follows: 1) regarding stomach and colorectal cancers, a positive correlation was found between the screening rate and the mortality rate (p<0.001); 2) in the relation between the screening rate and the mortality rate according to administrative divisions, the mortality rate decreased significantly when the lung cancer screening rate improved (p<0.005); 3) the mortality rate for breast cancer increased in those aged 50 or over; 4) the mortality rate for uterus cancer had been slightly increasing since 1990; and 5) regarding the screening rate, a positive correlation was found between breast cancer and uterus cancer (p<0.001). In future, improvement in lifestyle and in the knowledge of cancer should be promoted to enhance the screening rates. J. Med. Invest. 57: 251-259, August, 2010

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Salivary pH is associated with esophageal acid reflux and neutralization of esophageal acid. In this study, we assessed the association between nocturnal decline of salivary pH and airway hyperresponsiveness. Salivary pH was serially assessed in 9 patients with mild asthma (7 men and 2 women; mean age 33.3 years; mean %predicted FEV_1.0 89.4%) and 10 healthy volunteers (6 men and 4 women; mean age 31.2 years) using a pH indicator tape. The buffering capacity of saliva was defined as the median effective dose (ED₅₀) for acidification of saliva with 0.01 N HCl, and airway responsiveness was defined as the dose of methacholine producing a 35% fall in Grs (PD₃₅-Grs). There was a significant correlation between the values obtained from the pH indicator tape and those obtained from the electrometric pH meter. Using the indicator tape for sequential monitoring, we observed a nocturnal fall (ΔpH) in salivary pH in all subjects. A significant correlation was found between airway hyperresponsiveness (PD₃₅-Grs) and either ΔpH or ED₅₀ in mildly asthmatic patients. Vagal reflux dysfunction might contribute to nocturnal salivary pH as well as to airway hyperresponsiveness in mild asthmatics. J. Med. Invest. 57: 260-269, August, 2010

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Purpose. To evaluate ¹⁸F-fluorodeoxyglucose (FDG) uptake and the pathological risk category of gastrointestinal stromal tumors (GISTs), and to investigate the possibility of determining the pathological risk category by positron emission tomography/computed tomography (PET/CT). Patients and Methods. We undertook 29 PET/CT studies in 20 patients with GISTs. Eleven of the 20 patients underwent PET/CT prior to therapy, with three of these also undergoing follow-up PET/CT after operation or imatinib therapy. Results. All eleven lesions imaged before treatment were FDG-positive on PET/CT. Seven of these eleven primary lesions were categorized as high risk and the other four primary lesions were categorized as low or intermediate risk. There was a significant difference between the maximum standardized uptake value (SUVmax) of the primary lesions categorized as high risk (11.8±3.15) and that of the primary lesions categorized as low and intermediate risk (2.88±0.47) (p<0.001). Recurrent tumors were also shown as FDG-positive. Conclusion. Primary GISTs and recurrent tumors can be detected by PET/CT. Our study suggests that the degree of FDG uptake is a useful indicator of risk category. In addition, PET/CT is probably useful for follow-up examinations of GIST after operation or imatinib therapy. J. Med. Invest. 57: 270-274, August, 2010

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Hyperphosphatemia adversely affects the prognosis of patients with chronic renal failure (CRF). We synthesized a titanium oxide-like compound (TAP) as a phosphate adsorbent for treatment of hyperphosphatemia in CFR patients. We evaluated the ability of TAP to adsorb inorganic phosphate in vitro and in vivo. TAP was shown to contain sulfate and hydroxyl groups by thermal analysis, which probably involved in phosphate adsorption through an ionic exchange mechanism. TAP constantly adsorbed phosphate (66.20-72.84 mg/g TAP) over a wide pH range (1.22-7.27) in vitro. To evaluate the phosphate binding potential of TAP in vivo, adenine-induced CRF rats were fed AIN-76 diet containing 3% TAP, 10% TAP, 3% sevelamer hydrochloride (clinical phosphate adsorbent), or 3% calcium carbonate, and serum levels of phosphate and calcium and urinary phosphate were compared with those in untreated CRF rats. Orally administered TAP showed the inhibitory effect on serum phosphate level in adenine-induced CRF rats, which was equivalent to that of sevelamer hydrochloride. These results indicate that TAP is a useful alternative phosphate-binder with fewer side effects than sevelamer hydrochloride and calcium carbonate. J. Med. Invest. 57: 275-283, August, 2010

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We have recently constructed a series of novel human immunodeficiency viruses (HIV-1s) that are tropic for a macaque cell line (mt; macaque cell-tropic) to generate and establish a primate experimental system for HIV-1/AIDS study. In order to determine biological properties of these viruses effectively, several other macaque cell lines with distinct characteristics that can be routinely and easily used, instead of primary cells, for infection experiments are required. In this study, we have examined four macaque cell lines for their surface expression of virus receptor molecules and for their genotype of a major anti-viral capsid gene. Furthermore, we monitored the susceptibility of the cell lines to a standard simian immunodeficiency virus (SIV) clone and three representative basic mt HIV-1 clones. Results obtained here have clearly indicated that these cell lines are exquisitely useful to characterize various SIVs and more importantly, mt HIV-1s. J. Med. Invest. 57: 284-292, August, 2010

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The purpose of this study was to explore the experience of patients with ischemic heart disease (IHD) during the transitional phase from hospitalization to discharge. Twenty-four patients who experienced IHD for the first time comprised the sample of the study. Semi-structured interviews were conducted during the transitional phase. The results of the qualitative inductive analysis showed two categories of illness experience: (i) the connection of heart attack experience with the self, and (ii) the instability of the self as a patient with heart disease. The participants were found to vacillate between the self as patient with a heart disease and the typical self before the disease onset. The transitional phase is the time when patients experience changes in their symptoms and physical conditions rather than a condition of stability signifying recovery. Patients are expected to manage the symptoms of their heart disease by themselves; however the participants showed signs and symptoms of confusion and anxiety about facilitating their own care. These findings suggest the importance of outpatient nursing practice focusing on the support and emphasis on nursing interventions for patient anxiety and alleviation of confusion through the management of symptoms of heart disease after discharge. J. Med. Invest. 57: 293-304, August, 2010

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Objectives: We evaluate whether integrated fluorodeoxyglucose-positron emission tomography and computed tomography (FDG-PET/CT) scan can diagnose the presence of lymph node metastasis more accurately than computed tomography (CT) scan alone. Methods: Forty-two patients with lung cancer preoperatively underwent integrated PET/CT scan using FDG and CT scan and underwent pulmonary resection and lymph node dissection. We judged cases as lymph node metastasis if the lymph node visually accumulated FDG at PET/CT scan and measured 1 cm or greater in the short axis at CT scan. We retrospectively analyzed whether our judgments in each modality were consistent with the pathological diagnosis. Results: Two-hundred and seventeen stations of lymph node were dissected and 21 stations (9.7%) were histologically diagnosed as positive metastasis. Thirty-two stations of lymph node visually accumulated FDG at PET/CT scan and 17 stations measured 1 cm or greater in the short axis at CT scan. Concerning the diagnosis of lymph node metastasis, PET/CT scan showed significantly higher sensitivity than CT scan (81% vs. 48%, p=0.024). The false-positive rate was significantly high in PET-positive lymph nodes measuring less than 1 cm in diameter. There were 4 false-negative lymph nodes with both scans. All of these were less than 7 mm in diameter and had a low percentage of metastatic foci in the lymph node. Concerning the diagnosis of N staging, there was no significant difference between PET/CT scan and CT scan (83% vs. 69%, p=0.124). However, the identification of N2 disease at PET/CT scan was significantly more accurate than that at CT scan (100% vs. 38%, p=0.031). Conclusions: PET/CT is superior to CT scan in lymph node staging. However, because the false-positive rate is high in PET-positive lymph nodes measuring less than 1 cm in diameter, we think that clinical background should be considered and other modalities or histological examinations should be undertaken if necessary. J. Med. Invest. 57: 305-313, August, 2010

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Glycoglycerolipids are mostly found in plants, however the beneficial effects of the glycoglycerolipids on mammalian body have not been understood. In this study, we investigated the effects of glycolipid extracts from spinach, which highly contained glycoglycerolipids, on mucosal injury induced by 5-fluorouracil (5-FU) in rats. Preadministration of glycolipid extracts from spinach (20 mg/kg body weight) prevented villous atrophy, misaligned crypts, and increased inflammatory cytokines in rat jejunum treated with 5-FU (300 mg/kg body weight) compared with the extracts from soybean. The glycolipid extracts from spinach highly contained monogalactosyl-diacylglycerol (MGDG) and diglactosyl-diacylglycerol (DGDG). In Caco-2 cells, MGDG and DGDG inhibited the production of reactive oxygen species induced by phorbol ester. We concluded that glycolipid extracts from spinach has anti-oxidative and anti-inflammatory effects, and the extract may be useful for prevention of drug-induced mucosal injury and other inflammatory diseases. J. Med. Invest. 57: 314-320, August, 2010

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Several conservative as well as surgical methods are used for the treatment of ingrown toenails until date. The conservative methods are either based on nail splinting or on orthonyxia, but no methods employing both principles have been reported thus far. Moreover, surgical methods usually involve postoperative pain, prolonged wound healing and restricted activities of daily living. Therefore, considering the need of a simplified, non-invasive method, in this study, we applied a novel splint to treat patients with ingrown toenails and estimated the clinical efficacy as well as rate of recurrence following treatment. The splint is a plate made of resin that is attached to the lateral edge of the nail using a bandage. We studied 61 patients (19 men and 42 women; mean age 36 years), with an average application duration of 9.3 months and an average follow-up period of 10 months in all patients. All patients experienced pain relief within a week of splint application and a decrease in the degree of nail deformity. Moreover, follow-up revealed a recurrence rate of 8.2%. Therefore, we believe that this new device is an excellent conservative treatment method for patients with ingrown toenails. J. Med. Invest. 57: 321-325, August, 2010

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Lung cancer is the leading cause of malignancy-related death worldwide. In the present study, we reviewed the epidemiologic and clinical features of lung cancer in Tokushima Prefecture, Japan. Between January 1999 and December 2009, 2,183 patients with lung cancer were enrolled in this study. One thousand five hundred ninety-one (73%) patients were male and 592 (27%) patients were female. Median age was 70 years, with a range of 15-93 years. Seventy-six percent of patients had smoking history. One thousand nine hundred five (87%) patients were non-small cell lung cancer and the predominant histological type was adenocarcinoma (51%). Among all 2,183 patients, 702 (32%) belonged to elderly population. Four hundred seventy-one (22%), 213 (10%), 24 (1%), 116 (5%), 238 (11%), 370 (17%) and 678 (31%) patients had stage IA, IB, IIA, IIB, IIIA, IIIB and IV lung cancer, respectively. In Tokushima University Hospital, 516 (29%), 191 (11%), 58 (3%), 755 (43%) and 216 (12%) patients were initially treated with chemotherapy, chemo-radiotherapy, thoracic radiotherapy, operation and best supportive care, respectively. The median time to progression (TTP) and the median survival time (MST) of patients treated with chemotherapy and chemo-radiotherapy were 3.5 months, 13.0 months and 7.0 months, 18.0 months, respectively. The median TTP and the MST of 33 elderly patients treated with chemotherapy were 3.3 months and 18.0 months, respectively, which were comparable with those of total population. These results indicated the benefit of chemotherapy in elderly patients with advanced lung cancer by proper selection. J. Med. Invest. 57: 326-333, August, 2010

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We recently experienced a case of cerebral infarction incidentally found by whole body bone scintigraphy for the detection of bone metastasis from renal cell carcinoma. Additional bone SPECT and brain MR fusion images clearly demonstrated the wedge-shaped uptake of tracer corresponded to the abnormal intensity reflecting subacute cerebral infarction. Follow-up bone scan and fused images with MRI showed complete resolution of the abnormal uptake in chronic phase. A breakdown in the normal blood-brain barrier results in abnormal ionic calcium flux into the cells following altered cell membrane integrity leading to precipitation of calcium salts which eventually binds to bone imaging tracer such as ^99mTc-methylene diphosphonate. That is, increased accumulation of bone seeking agents represents lethal cell death. The recent development of software and hardware has enabled the fusion of functional and anatomic images. Image fusion between SPECT with various tracers and MRI is expected to provide clues as to the underlying cause of diseases and to decide our treatment planning in the near future. J. Med. Invest. 57: 334-337, August, 2010

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A 74-years old man was referred to our hospital for treatment of a rectal mass. Colonoscopy revealed villous tumor covering all the lower rectal lumen. Biopsy yielded a diagnosis of adenoma. CT examination showed tumor shadows of the rectum and the liver. Pelvic MRI examination showed a 10.5×8×7 cm tumor with high signal intensity on the T2 weighted images in the rectum. Rectosigmoidectomy with lymph node dissection was performed with the diagnosis of rectal cancer that metastasized to the liver. Histological and immuno- histochemical features showed coexistent poorly-differentiated small cell neuroendocrine cell (NEC) carcinoma and non-invasive well-differentiated adenocarcinoma in tubulovillous adenoma. However the chemotherapy with FOLFOX and Bevacizumab was performed postoperatively, the patient died in cancer 3 months after surgery. Rectal poorly-differentiated NEC carcinomas are thought to be a tumor with a high malignant potential. Recently, the UICC TNM classifications of malignant tumors, 7th edition and the Guidelines for colorectal NEC tumors of European Neuroendocrine Tumor Society have been published. They would be evaluated, and effective multimodal therapy for NEC carcinomas should be established. J. Med. Invest. 57: 338-344, August, 2010

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Excessive iron storage sometimes causes diabetes in patients with hemochromatosis, a disease caused by iron overloading. We performed an immunohistochemical analysis to study an autopsy case of aplastic anemia and diabetic hemochromatosis caused by frequent blood transfusions, and extensive hemosiderin deposition was observed in the liver and pancreas. The pancreatic islets of the patient and a control subject were stained to detect glucagon, insulin, and proinsulin. Significantly lower levels of immunoreactivity with both insulin antibodies and proinsulin antibodies, but not with glucagon antibodies, was observed in the islet cells in the patient’s tissue than in the islet cells of the control. Hemosiderin deposition in the islets is known to be exclusively distributed in the β-cells, thus, selective iron-induced damage to the β-cells may have affected insulin synthesis and secretion and led to glucose intolerance in the patient. J. Med. Invest. 57: 345-349, August, 2010

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