Colorectal cancer is a leading cause of cancer-related mortality worldwide. Therefore, an appropriate prevention strategy should be urgently established. Chemoprevention involves the use of oral agents to suppress the development of cancer. Recent progress in the molecular analysis of colorectal cancer has revealed many candidate molecules for chemoprevention. Many new agents targeting these molecules have also been developed. These agents are largely classified into three categories: 1) Signal transduction modulators including epidermal growth factor (EGF) receptor inhibitors, anti-vascular endothelial growth factor (VEGF) antibodies, and inhibitors of oncogene products. 2) Epigenetic modulators including peroxisome proliferative activated receptor (PPAR)-γ agonists, estrogen receptor (ER)-β, and histone deacetylase inhibitors. 3) Anti-inflammatory modulators including cyclooxygenase (COX)-2, EP 1-4, and NF-kB. Of these agents, some actually proceeded to human clinical trials, and have been shown to be active chemopreventive agents. J. Med. Invest. 56: 1-5, February, 2009

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Hyperglycemia and insulin resistance are common in many critically ill patients. Hyperglycemia increases the production of reactive oxygen species in cells, stimulates the production of the potent proinflammatory cytokines IL-8 and TNF-alpha, and enhances the expression of haem oxygenase-1, an inducible stress protein. It has been shown that administration of insulin and the semi-essential amino acid glutamine have been beneficial to the septic patient. The aim of our study is to test whether these two molecules, glutamine and insulin used in combination attenuate the proinflammatory responses in endothelial cells which have been triggered by hyperglycaemia. Our results demonstrate that a combination of insulin and glutamine are significantly more effective in reducing the expression of IL-8, TNF-alpha and HO-1 than insulin or glutamine alone.
J. Med. Invest. 56: 6-10, February, 2009

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Purpose: To access the necessity of topical steroids after uneventful cataract surgery, phaco-emulsification/aspiration plus intraocular lens (PEA+IOL) implantation. Design: Single-blind, randomized, prospective study. Participants: Twenty-one patients were prospectively randomized, 11 patients were assigned to the steroid group, and 10 to the non-steroid group. Methods: Between March and September 2007, in Mino Tanaka Hospital in Tokushima Prefecture, Japan, we performed PEA+IOL in 28 eyes of 21 patients and examined the visual acuity, corneal endothelium cell density, and anterior aqueous flare value after dividing all the patients into 2 groups, the topical steroid use and the non-steroid group.
Results: At 1 month postoperatively, no difference was observed between the 2 groups in terms of the outcomes described, and no cystoid macular edema was detected.
Conclusion: Topical steroid medication may not be absolutely essential after uneventful PEA+IOL. J. Med. Invest. 56: 11-15, February, 2009

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Objective: Imaging techniques such as CT, MRI and PET/CT have essential pre- and post-treatment roles in detecting tumors and evaluating the extension of malignant pleural mesothelioma (MPM). We sough to evaluate the advantages and limitations on FDG-PET/CT findings. Patients and Methods: We performed 13 FDG-PET/CT studies in 9 patients with MPM (8 males, 1 female, aged 51 to 84 years, 9 at the initial diagnosis, 4 follow up studies). We reviewed FDG-PET/CT findings of primary tumors, recurrent tumors, lymph nodes, metastasis. Results: All primary and recurrent tumors were FDG positive. The uptake patterns at initial diagnosis were; diffuse+multi-nodular uptake pattern in 5, diffuse irregular thickened uptake pattern in 2, some focal thickened pattern in one, and a slight diffuse uptake pattern in one. Two of the 3 patients diagnosed as N0 by PET and operated on had negative lymph nodes confirmed pathologically. The other patient diagnosed as N0 by PET, who had one month of time lag between PET/CT examination and surgery, was confirmed as N2 by extrapleural pneumonectomy. In 3 patients, hilar or mediastinal lymph nodes were difficult to distinguish from irregular pleural thickening. One patient had a FDG positive lymph node in the ipsilateral supraclavicular region confirmed as metastasis (N3). One patient had a FDG positive lymph node in the para-aortic region. Lung metastasis was seen in one patient (M1). In another patient, two focal nodular uptakes in the colon were detected and confirmed as colon polyps (pathologically Group 3-4). At restaging, 3 of 4 patients showed diffuse+multi-nodular uptake and one patient showed multi-nodular uptake. Conclusions: The utility of FDG-PET/CT is limited for evaluation of primary tumor extension and nodal status. FDG-PET/CT is useful for detecting distant metastasis and for evaluating activity in supraclavicular or abdominal lymph nodes. It is also useful for identifying unsuspected diseases. J. Med. Invest. 56: 16-20, February, 2009

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We previously generated a prototype monkey-tropic human immunodeficiency virus type 1 (HIV-1) designated NL-DT5R. This viral clone has a small region of simian immunodeficiency virus (SIV) within Gag capsid (CA) protein and also SIV Vif protein, but displays a poor growth phenotype in simian cells. To improve the growth potential of NL-DT5R, we have constructed a series of its gag variant viruses. Out of fourteen viral clones generated, five were infectious for simian HSC-F cells, and two of the infectious variants grew similarly with NL-DT5R. Taking their genome structures into consideration, our data here clearly show that a narrow CA region within the Gag protein, i.e., the domain around cyclophilin A (CypA)-binding loop, is critical for the growth ability of HIV-1 in simian cells. J. Med. Invest. 56: 21-25, February, 2009

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Oxidative stress is a key factor in stimulating the expression of atrogenes, which are muscle atrophy-related ubiquitin ligases, in skeletal muscle, and it induces muscle atrophy during unloading. However, the effects of antioxidative nutrients on atrogene expression have not been demonstrated. We report on the inhibitory effects of polyphenols, such as epicatechin (EC), epicatechin gallate (ECg) and epigallocatechin gallate (EGCg) and quercetin, on atrogene expression up-regulated by three dimensional (3D)-clinorotation or glucocorticoid. These treatments markedly elevated the expression of atrogenes, including atrogin-1 and MuRF-1, in mouse C2C12 myoblasts and myotubes. Interestingly, EC, ECg, EGCg and quercetin significantly decreased the expression of atrogin-1 and MuRF-1 up-regulated by 3D-clinorotation, whereas they hardly affected atrogene expression induced by dexamethasone. ERK signaling is a well known MAPK pathway to mediate oxidative stress. Therefore, we also investigated the effect of these polyphenols on phosphorylation of ERK in C2C12 myotubes. As expected, EC, ECg, EGCg, and quercetin significantly suppressed phosphorylation of ERK, corresponding to the up-regulation of atrogenes induced by 3D-clinorotation. These results suggest that antioxidative nutrients, such as catechins and quercetin, suppress atrogene expression in skeletal muscle cells, possibly through the inhibition of ERK signaling. Thus, catechins and quercetin may prevent unloading-mediated muscle atrophy. J. Med. Invest. 56: 26-32, February, 2009

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Reactive oxygen species (ROS) derived from NADPH oxidase (Nox) homologues have been suggested to regulate osteoclast differentiation. However, no bone abnormalities have been documented in Nox1 deficient, Nox2 deficient, or Nox3 mutant mice. During receptor activator of nuclear factor-κB ligand (RANKL)-stimulated differentiation of a mouse macrophage cell line (RAW264.7) into osteoclasts, mRNA levels of Nox enzymes (Nox1-4) and their adaptor proteins were monitored by real-time reverse transcriptase PCR. RAW264.7 cells constitutively expressed abundant Nox2 mRNA and small amounts of Nox1 and Nox3 transcripts. RANKL markedly attenuated Nox2 mRNA expression in association with reciprocal up-regulation of Nox1 and Nox3 transcripts. Introduction of small interference RNA targeting p67^phox or p22^phox into RAW264.7 cells effectively down-regulated ROS generation and significantly suppressed the RANKL-stimulated differentiation, which was assessed by appearance of tartrate resistant acid phosphatase (TRAP)-positive, multinucleated cells having an ability to form resorption pits on calcium phosphate thin film-coated disks, and by expression of osteoclast marker genes (TRAP, cathepsin K, Atp6i, ClC-7, and NFATc1). Our results suggest that RANKL may stimulate switching between Nox homologues during osteoclast differentiation, and Nox-derived ROS may be crucial for RANKL-induced osteoclast differentiation. J. Med. Invest. 56: 33-41, February, 2009

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Drinking tea is recommended for promoting health due to its bioactive nutrients, such as catechins and caffeine. In Tokushima area, we have a unique traditional tea, named Awa tea, which are fermented with Lactobacillus pentosus and Lactobacillus plantarum. The present study was designed to investigate anti-obesity effects of the Awa tea and compare with those of non-fermented green tea. Obese male Wistar rats (19 weeks of age) were given by low energy diets containing 3% of Awa and green tea extracts, respectively, or without any tea extracts (control), for 4 weeks. Awa tea contained smaller amount of catechins than green tea, although they contained similar amounts of polyphenols. This finding indicates that there are distinct kinds of polyphenols from catechins. The diets containing Awa and green tea extracts further decreased whole body weight, fat tissue mass and plasma leptin level, compared with control diet. In addition, their diets increased the daily amount of lipid excreted to feces and total 24-h-energy consumption, compared with the control group. However, there is no significant difference in these anti-obesity effects between Awa tea and green tea. Our results indicate that Awa lactate-fermented tea as well as green tea similarly enhance the effect of diet restriction on obesity, at least in part, through the increase in fat energy consumption and the decrease in fat absorption in rats. J. Med. Invest. 56: 42-48, February, 2009

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Purpose: A congenital extrahepatic portosystemic shunt (CEPS) is a rare abnormality. The shunts are classified into 2 types. Of these, a type 2-shunt is a side-to-side one, which may be treated by a simple shunt division. The aim of this retrospective study was to clarify the effects of a surgical shunt division on 4 children with type 2-CEPS. Patients: Between June 2002 and June 2008, 4 children with type 2-CEPS underwent a surgical shunt division. Various clinical factors of each patient, including shunt types, shut ratios evaluated by portal scintigraphy using ¹²³I-iodoamphetamine, serum levels of ammonia and total bile acids before and after surgery were evaluated. Findings: Two children had a conventional open surgery and the other two had a laparoscopic surgery. The serum levels of ammonia as well as total bile acids of these children decreased significantly to the normal levels within a month after the surgical shunt divisions. All the children had a better clinical course. Conclusions: A shunt division, especially by laparoscopic surgery, is an effective therapy for type 2-CEPS. To the best of our knowledge by reviewing literatures, our cases are the youngest ones treated by laparoscopic shunt division. J. Med. Invest. 56: 49-54, February, 2009

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Three constructs having mutated PKA-target motif at ¹⁵²SRRTS of AQP5, an exocrine type water channel, were prepared and fused to C-terminus of green fluorescence protein cDNA to examine the effects of blocking of phosphorylation at ¹⁵²SRRTS (a consensus PKA-target motif of AQP5) on translocation or trafficking of the chimeric proteins expressed in the Madin-Darby canine kidney-II (MDCK-II) cells. H-89 treatment increased translocation of wild-type GFP-AQP5 to the apical membrane. All 3 mutant molecules translocated 1.5 to 2 times more than the control wild-type GFP-AQP5. Colchicine but not cytochalasin B inhibited the translocation of wild-type GFP-AQP5. Present results suggest dephosphorylation of this consensus sequence increase GFP-AQP5 translocation, and that microtubules but not microfilaments are involved in this event. J. Med. Invest. 56: 55-63, February, 2009

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Neurofibromatosis type 1 (formerly known as von Recklinghausen’s disease) is an autosomal dominant disorder, which results from the proliferation of the neural crest cells, thus affecting any organ system. Several pulmonary manifestations have hitherto been reported, including chest wall deformities, diffuse lung disease, thoracic neoplasms, pulmonary arterial hypertension, central hypoventilation, diaphragmatic paralysis and meningocele. However, eosinophilic lung disorders have not been described. An unusual case of chronic eosinophilic pneumonia in a patient with neurofibromatosis type 1, is reported herein. He had a propitious outcome, following corticosteroid treatment. This is the first well-documented case of chronic eosinophilic pneumonia and neurofibromatosis type 1 in the same patient. These clinical entities might share common pathogenic mechanisms, as suggested by the present study, that could explain their co-existence. J. Med. Invest. 56: 64-69, February, 2009

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Clear-cell sarcoma (CCS) is a rare, malignant, soft-tissue tumor, which involves the extremities, particularly the foot and foot joint tendons and aponeuroses. It is morphologically similar to but histochemically distinct from malignant melanoma. CCS arising in the gastrointestinal tract has rarely been reported. The prognosis of CCS is reportedly poor because of the high incidence of metastases at the time of initial diagnosis and the high frequency of recurrence. We report a case of early-stage CCS of the small intestine detected by ¹⁸F-fluoro-2-deoxy D-glucose Positron Emission Tomography/Computed Tomography (FDG-PET/CT) during the comprehensive examination of an inflammatory reaction. In this case, FDG-PET/CT clearly visualized the lesion, which was difficult to detect by contrast CT. J. Med. Invest. 56: 70-75, February, 2009

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¹⁸F-fluorodeoxyglucose positron emission tomography (¹⁸F-FDG PET/CT) was performed to evaluate a left femoral subcutaneous mass in a patient with von Recklinghausen’s disease (vRd) that gradually enlarged, causing pain and numbness. The left femoral mass showed intense FDG uptake with the maximum standardized uptake value (SUVmax) of 9.0. Other subcutaneous masses considered benign and neurogenic in nature also showed FDG uptake (SUVmax around 3 or less), but the degree of FDG uptake differed considerably from the left femoral mass. This observation suggested that the degree of FDG uptake may be a useful indicator of malignant transformation. Incidentally, PET/CT also showed an asymptomatic large abdominal mass with intense FDG uptake (SUVmax 8.8). The abdominal mass was resected and confirmed as gastrointestinal stromal tumor (GIST) of the small intestine. Three months later, the left femoral mass was operated on and pathologically diagnosed as a malignant peripheral nerve sheath tumor (MPNST). Various malignant diseases are known to occur with high frequency in vRd. Therefore, vRd patients need to have periodical examinations including PET/CT. We present a rare case of a patient with vRd with a MPNST of the left femur and coincidental GIST of the small intestine. J. Med. Invest. 56: 76-79, February, 2009

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