Vitamin A is the parent compound of retinoids, which regulate gene transcription by binding to nuclear retinoid receptors. Recently, it has been suggested that retinoid signaling pathways are important for adult neural function in health and disease. In this mini review we will summarize the molecular pathway of retinoid and experimental data on this pathway relating to sleep regulation, which suggests that retinoid signaling mechanism may be involved in the homeostatic component of sleep electroencephalogram. J. Med. Invest. 55: 1-8, February, 2008

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A proper balance between cell adhesion and repulsion is essential for cellular morphogenesis during epithelial-mesenchymal transition and mesenchymal-epithelial transition. A number of ligand-receptor pairs including hepatocyte growth factor/scatter factor-Met and semaphorin-plexin are known to control this balance through the complex intracellular signaling pathways. Cell adhesion to other cells and extracellular matrix (ECM) is mediated by cell adhesion molecules (CAMs) and ECM receptors, respectively, which are associated with cytoskeleton through a variety of plaque proteins strengthening and/or weakening adhesion activities. Cell repulsion requires the downregulation of cell adhesion and the extensive changes in cytoskeletal dynamics. The endocytic recycling of CAMs and ECM receptors has recently emerged as an important mechanism to control the balance between cell adhesion and repulsion. Molecule interacting with CasL (MICAL) family proteins are originally identified as a plaque protein associated with ECM receptors integrins and implicated in semaphorin-plexin dependent repulsive axon guidance. We have recently shown that MICAL family protein JRAB/MICAL-L2 functions as an effector protein for Rab family small G protein Rab13 and regulates the endocytic recycling of tight junctional CAM occludin and controls the adhesion and repulsion of epithelial cells. J. Med. Invest. 55: 9-16, February, 2008

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Thymoma is the most common tumor of the anterior mediastinum. This tumor is associated with unique paraneoplastic syndromes (myasthenia gravis, pure red cell aplasia, hypogammaglobulinemia, and other autoimmune diseases). The rarity of this tumor has somewhat obscured the optimal treatment. Although the histologic classification of thymoma has remained a subject of controversy for many years, the WHO classification system, published in 1999, appeared to be an advance in our understanding of thymoma. The optimal treatment for thymoma depends on its clinical stage. Surgery remains the mainstay of treatment for thymic epithelial tumors. Thymomas also have a high response rate to chemotherapy or radiotherapy. Only surgical resection is performed for patients with stage I (non-invasive) thymoma. The value of postoperative radiotherapy in completely resected stage II or III tumors is questionable. Multimodality therapy involving surgery, chemotherapy and radiotherapy appears to increase the rate of complete resection and survival in advanced (stage III and IV) thymomas. J. Med. Invest. 55: 17-28, February, 2008

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Objectives: Circulating low molecular weight (<10 kDa) fluorophores (LMW-F) measured by non-specific fluorescence spectroscopy may detect small advanced glycation end-products (AGEs) not recognized by other assays. This longitudinal study assessed correlates of LMW-F and predictive power of LMW-F levels for vascular health in Type 1 diabetes (T1DM) patients. Methods: Fasting patients with T1DM (n=37) were studied twice at intervals of 12-60 months (mean±SD, 33±15 months). LMW-F levels were also measured once in 112 healthy control subjects. Results: Relative to controls, LMW-F levels were higher in diabetic subjects at initial and final time points (mean±SD), 5.4±1.9 AU/ml and 4.5±1.8 AU/ml respectively vs. 3.8±2.1 AU/ml; p=0.0001 and p=0.06). Baseline LMW-F levels predicted subsequent hs-CRP and oxLDL/LDL values. LMW-F levels decreased significantly over time in diabetes (5.4±1.9 vs. 4.5±1.8 AU/ml; p=0.02). Rises in LMW-F levels in individual diabetic subjects correlated significantly with worsening renal function (BUN), glycemia (HbA1c) and with vascular dysfunction (systemic vascular resistance). Conclusions: LMW-F levels predict levels of inflammation and oxidation in T1DM. Changes in LMW-F levels in T1DM reflect variations in glycemia and renal function. Biochemical characterization of LMW-F would facilitate understanding of the potential utility of LMW-F as a therapeutic target. J. Med. Invest. 55: 29-36, February, 2008

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Objective: Systematic nodal dissection has been recommended for patients with resectable non-small cell lung cancer because of its staging accuracy. However, in patients with clinical stage I non-small cell lung cancer whether systematic nodal dissection provides more benefits than mediastinal lymph node sampling or not is controversial. In this retrospective study, we evaluated the effect of mediastinal lymph node sampling in patients with clinical stage I NSCLC. Methods: One hundred and nineteen consecutive patients with clinical stage I NSCLC, who underwent curative operation between January 1994 and December 2000, were retrospectively reviewed (dissection group = 58: sampling group= 61). Systematic nodal dissection was defined as complete removal of mediastinal lymph node, and mediastinal lymph node sampling was defined as removal of lymph node levels 3, 4, and 7 for right-sided tumors and levels 5, 6, and 7 for left-sided tumors. Results: The total number of removed mediastinal lymph nodes in patients who underwent systematic nodal dissection was 22.1 ± 9.7, which was significantly higher than that in patients who underwent mediastinal lymph node sampling of 11.4 ± 7.0 (p < 0.001). Postoperatively N2 disease was detected in 8 patients (13.8%) in the dissection group and 7 (11.5%) in the sampling group. After the median follow up of 79 months, the cancer specific survival rate at 5 year was 78.0% in the dissection group and 76.2% in the sampling group (p = 0.60). Conclusions: Mediastinal lymph node sampling showed the similar effect to systematic nodal dissection in patients with clinical stage I non-small cell lung cancer. J. Med. Invest. 55: 37-43, February, 2008

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Background: With the present method of intrapulmonary right-to-left shunt volume calculation, no differentiation can be made between the shunt volume shares of the right and left lungs. For a better understanding of pathophysiological processes during thorax surgery with side-separated ventilation, a side-separated shunt volume determination would be useful. Materials and Methods: In 14 young female pigs, catheters were implanted into the left atrium after left thoracotomy. After transient clamping of the ipsilateral pulmonary veins, pulmonary venous blood was selectively obtained from the right lung. Cardiac output (CO) and side-separated pulmonary perfusion were determined with flowprobes at the pulmonary trunk and the left pulmonary artery. The shunt volumes were determined before and after thoracotomy during two-lung ventilation (Two-LV), after one-lung (right) ventilation (One-LV) with a continuous positive airway pressure (CPAP) of +7.5, +5.0 cm H₂O, and under atelectasis of the non-dependent left lung (NDL). Results: After thoracotomy in lateral decubitus position and Two-LV, the shunt volumes of the two lungs differ. The right lung holds the major share (11.0 ± 1.7% CO) [mean ± SD]. The share of the left NDL is only 3.3 ± 1.4. Under One-LV (right) and CPAP in the NDL, the total pulmonary shunt volume rises. This is caused by the increase in the NDL shunt volume share to 8.8 ± 5.2 under CPAP +7.5 (p<0.05) and to 9.7 ± 2.5 under CPAP +5.0 (p < 0.05). Conclusions: The new intraoperative method of side-separated arterial blood gas analysis in conjunction with side-separated perfusion measurement makes side- separated right-to-left shunt volume determination possible and may lead to interesting new pathophysiological insights. J. Med. Invest. 55: 44-50, February, 2008

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Aim: To evaluate the usefulness of the newly designed 25-gauge (25-G) microcannula for transconjunctival sutureless vitrectomy (TSV).
Methods: 25-G TSV was performed on 20 consecutive eyes with the newly designed 25-G microcannulas. We studied usefulness, intraoperative and postoperative complications in these cases.
Results: No complications were recognized during surgery. Postoperative complications included blebs in five eyes, vitreous hemorrhage in one eye, high intraocular pressure (more than 22 mmHg) in one eye and a retinal tear in one eye. No eyes with low intraocular pressure (less than 10 mmHg) were noted.
Conclusions: This microcannula for 25-G vitrectomy is thought to be very useful and effective for performing 25-G vitrectomy safely. J. Med. Invest. 55: 51-53, February, 2008

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Capecitabine monotherapy was administered for 25 patients with advanced or recurrent breast cancer, and the clinical therapeutic efficacy and its relationship to expression of 5-fluorouracil-related enzymes (i. e., thymidine phosphorylase (TP), thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD)) were investigated. The expressions of TP, TS and DPD were determined by immunohistochemical staining techniques and rated using a scoring system of 1∼4. The expression score for TP/DPD showed a statistically significant correlation with the clinical response, whereas the expression score for TP/TS also showed a correlation but it was not statistically significant. The number of patients was small, but the results revealed the potential of application of the TP/DPD expression score as a factor for predicting the efficacy of the drug in individual patients. J. Med. Invest. 55: 54-60, February, 2008

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Various intestinal symptoms or diseases are closely associated with intestinal motility, which may be altered by metabolic disturbances associated with diabetes and obesity. It is therefore important that drugs used in the treatment of metabolic disorders should not have any adverse effects on the intestine. In the present study, we examined whether [4-(4-bromo-2-cyano-phenylcarbamoyl)-benzyl]-phosphonic acid diethyl ester (NO-1886), a lipoprotein lipase activator with anti-diabetic and/or anti-obese activity, affects stimulant-induced intestinal contractility. Administration of NO-1886 to intestinal ring preparations of ileum, rectum and colon isolated from Wistar rats attenuated or relaxed contraction induced by a high K+ environment or acetylcholine (ACh). This effect of NO-1886 was dependent on extracellular Ca²⁺ and intracellular myosin light chain kinase activity. Our results also showed that ACh-induced colonic contraction was significantly higher in the obese Otsuka Long-Evans Tokushima Fatty (OLETF) than in the non-obese Long-Evans Tokushima Otsuka (LETO) rats. The hypercontractility observed in the colons of OLETF rats occurred concomitantly with an elevation in muscarinic M3 ACh receptor protein levels. Administration of NO-1886 attenuated the obesity-induced hypercontractility of the colonic rings of OLETF rats. Thus, intestinal contractile system would be a novel pharmacological target of the lipoprotein lipase activator NO-1886. J. Med. Invest. 55: 61-70, February, 2008

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Obesity in children has become a major global public health concern. The prevention of obesity must start from early childhood in order to establish sound lifestyle habits and promote healthy adulthood. In this study, we evaluated factors associated with the prevention of obesity and the development of healthy lifestyle habits in children. A cross-sectional, questionnaire-based survey was performed in elementary and junior high school students in Tokushima Prefecture, Japan, during the summer of 2004. The questionnaire consisted of 30 items such as physique, sleep, eating habits, diet, exercise, free time, and attending after-school lessons. Our study revealed that eating meals as a family every day is associated with a lower rate of obesity as well as getting good lifestyle habits such as eating balanced meals and getting enough sleep. Of the 3,291 students who responded to the questionnaire, 2,688 (81.7%) reported that they eat meals with their family every day. The percentage of students who eat meals with their family every day decreased with increasing school grade, with the lowest percent in the junior high school students. However, the results regarding female junior high school students revealed a marked association between eating meals with the family every day and good lifestyle habits. We recommend that parents and school teaching staff encourage the establishment of sound, healthy lifestyle habits in children from early childhood as an effective measure for the prevention of obesity. J. Med. Invest. 55: 71-77, February, 2008

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Hypoxia-inducible factor (HIF)-2α, a basic helix-loop-helix (bHLH)-PAS protein, is the principal regulator of the hypoxic transcriptional response. An immunohistochemical study reported strong HIF-2α expression in the cytoplasm of tumor infiltrative macrophages (TIMs). Thus we assessed the expression of HIF-2α in human cervical cancer tissue before radiation therapy and its relationship to the clinical outcome. Seventy three patients with histologically proven primary advanced squamous cell carcinoma of the uterine cervix underwent radiotherapy in Tokushima University Hospital after biopsy specimens were taken. Among 73 specimens stained for HIF-2α, 53 (72.6%) exhibited HIF-2α immunoreactivity in the TIMs. In only 5 of 73 cases, HIF-2α immunoreactivity was observed in the nuclei of tumor cells. The HIF-2α positive cell count ratio in TIMs was associated with disease-free survival (DFS) with the worst DFS (p=0.024) being in cases in the group with a high positive cell count ratio. A high HIF-2α positive cell count ratio in TIMs increased the risk of local recurrence (p=0.0142). These findings might suggest that the ratio of the HIF-2α positive cell in TIMs may be a new predictive indicator for prognosis before radiation therapy for uterine cervical cancer. J. Med. Invest. 55: 78-86, February, 2008

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Sp6 is a member of the Sp family of transcription factors that regulate a wide range of cellular functions, such as cell growth and differentiation. Sp6, also called epiprofin, is specifically expressed in tooth germ, limb bud, and hair follicle, but there is little information on its function.
To investigate the possible role of Sp6 in tooth development, first we established an Sp6-overproducing clone, CHA9, and analyzed the features of the cell, including cell proliferation and gene expression. The parental cells of CHA9 are the ameloblast-lineage G5 cells that we previously established from rat dental epithelia of lower incisor. Sp6 overproduction accelerated cell proliferation and induced the expression of ameloblastin mRNA, a marker of ameloblast differentiation. Second, we performed genome-wide screening of Sp6 target genes by microarray analysis. Out of a total 20,450 genes, 448 genes were up-regulated and 500 genes were down-regulated by Sp6. We found the expression of follistatin, a BMP antagonist, to be 22.4-fold lower in CHA9 than in control cells. Transfection of the Sp6-antisense construct into CHA9 cells restored follistatin expression back to equivalent levels seen in control cells, indicating that Sp6 regulates follistatin gene expression in ameloblasts.
Our findings demonstrate that the follistatin gene is one of the Sp6 target genes in ameloblasts and suggest that Sp6 promotes amelogenesis through inhibition of follistatin gene expression. J. Med. Invest. 55:87-98, February, 2008

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Our policy regarding the performance of radiotherapy to squamous cell carcinoma of the uterine cervix has not changed since 1969. We have already reported the treatment results which were as good as those from other institutions. Since 1978, Kampo therapy was first introduced in the treatment of cancer patients in dealing with problems such as the side effects of radiotherapy and chemotherapy and various types of general malaise. We analyzed our treatment results in order to re-evaluate the chemo-radiotherapy in combination with Kampo. Survival rates for 5, 10 and 15 years, respectively, were 90.9%, 71.6% and 71.6% for Stage IB, 78.9%, 61.8% and 41.8% for Stage II, 62.3%, 49.1% and 41.2% for Stage III and 53.1%, 36.5% and 16.7% for Stage IV.
The Kampo significantly extended the survival of patients with uterine cervical cancer. We intend to perform further research with more patients to explore how this therapy contributes to the prolonging of patients survival. J. Med. Invest. 55: 99-105, February, 2008

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No adequate serum predictive biomarker currently exists, which can identify the activity of renal cell carcinoma (RCC). We investigate the association of serum hepatocyte growth factor (HGF) and serum vascular endothelial growth factor (VEGF) levels with clinicopathologic parameters in untreated clear cell RCC patients. We measured serum levels of HGF and VEGF in 45 patients with untreated clear cell RCC and 45 healthy controls using an enzyme-linked immunosorbent assay (ELISA). Patients with clear cell RCC had significantly higher serum HGF and VEGF concentrations than healthy subjects: median, 1070.7 versus 728.3 pg/ml (p<0.0001) for HGF; and median, 397.5 versus 245.6 pg/ml (p=0.0003) for VEGF. We found a significant correlation between serum level of HGF and clinical stage and tumor grade. Survival of patients with high serum HGF (>1150 pg/ml) was significantly reduced compared to patients with low serum HGF concentrations (p=0.0044). In patients with nuclear grade 2 or high stage RCC, the higher serum HGF group exhibited significantly lower cause-specific survival (p=0.0087 and p< 0.05, respectively). No significant difference was observed between serum VEGF levels and cause-specific survival rate. Serum HGF might be a diagnostic and prognostic indicator in clear cell RCC, especially for patients with grade 2 or high stage RCC. J. Med. Invest. 55: 106-111, February, 2008

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Systemic lupus erythematosus (SLE) is a chronic disease that is characterized by an undulating course of exacerbations and remissions, and a major determinant of long-term prognosis is organ damage consequent to tissue injury that accompanies disease activity and toxicity of therapy. In this study, we evaluated which patients with SLE will develop an exacerbation and whether factors can be identified to predict the development of an exacerbation. Fifty-seven SLE patients (52 females) were included in this study. The exacerbation of SLE was found in 15 patients (26.3%). A relatively increased incidence of an exacerbation was found in younger SLE patients. An increased percentage of patients who had lupus nephritis at the time of diagnosis of SLE was found in patients with a subsequent exacerbation when compared with that in those without it. Increased incidence of an exacerbation was observed in patients who had decreased number of WBC and platelets, decreased level of C3 and CH50, and the presence positivity of anti-Sm antibodies at the time of the diagnosis. This study suggests that age, renal involvement, and the presence of decreased number of WBC and platelets, decreased level of complements anti-Sm antibodies are predictors of exacerbation. J. Med. Invest. 55: 112-119, February, 2008

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We placed negative electrodes on the body and positive electrodes at the medial and lateral canthi, measured their potentials separately, evaluated their characteristics, and analyzed cross-talk.
We recorded EOG in 6 normal subjects and found the following. The potential at the medial was lower than that at the lateral canthus in the bilateral eyes. The polarity of waves at the lateral was reverse to that at the medial canthus in the bilateral eyes. We recorded EOG in 6 patients with unilateral anophthalmia and found the following. On the anophthalmia side, the potential at the lateral was considerably lower than that at the medial canthus. The polarity of the potential was the same between the medial and lateral canthi.
The mean cross-talk to the medial canthus on the anophthalmia side was 8.7%-54.0% of the potential at the medial canthus on the normal side. The mean cross-talk to the lateral canthus on the anophthalmia side was 4.4%-16.9%. The influence of cross-talk of the other eye was marked at the medial but slight at the lateral canthus. In EOG recording, results with minimum errors due to cross-talk can be obtained by paying attention to the potential at the lateral canthus. J. Med. Invest. 55: 120-126, February, 2008

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We examine serum level of galectin-3 in patients with bladder cancer. We used serum samples of 67 patients with urological diseases and classified these patients into bladder cancer group (n=43) and control group (n=24). Galectin-3 concentration was measured by ELISA (Human Galectin-3 Assay Kit, IBL). And we selected the patient with high serum galectin-3 concentration (Urothelial Carcinoma, G3, pT3a pN0M0), we performed immunohistochemical staining with the VECTASTAIN ABC (Avidin Biotinylated enzyme Complex) system. Median value of serum galectin-3 concentration was 1068 pg/ml (range 551-2028) in the cancer group vs 584 pg/ml (range 259-1262) in controls. Serum galectin-3 concentration of the bladder cancer patients was statistically higher than that of controls (p<0.0005). There was no apparent correlation in serum galectin-3 concentration with the clinico-pathological features such as stage and grade. Higher expression of galectin-3 was observed in bladder cancer tissue than in normal bladder tissue. We suggest the measurement of serum galectin-3 is useful for diagnosis of bladder cancer. J. Med. Invest. 55: 127-132, February, 2008

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In inflammatory and oxidative liver injury, virus proteins and reactive oxygen species are involved in the regulation of proinflammatory cytokine production by macrophages. This study investigated the effects of estradiol (E2) and progesterone on the unstimulated and oxidative stress-stimulated production of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, macrophage inflammatory protein (MIP)-2, and macrophage chemotactic protein (MCP)-1 by peritoneal macrophages isolated from male and female mice. E2 inhibited the cytokine production of TNF-α, IL-1β, MIP-2, and MCP-1 by the unstimulated macrophages from males and females, which was then further stimulated by progesterone. The exposure to hydrogen peroxide in the macrophages from both sexes induced the production of cytokine. The hydrogen peroxide-stimulated cytokine production was suppressed by E2 and enhanced by progesterone. The sex hormone effects on the unstimulated and stimulated macrophages were blocked by their receptor antagonists and showed no significant difference between male and female subjects. These findings suggest that E2 may play a favorable role in the course of persistent liver injury, by inhibiting proinflammatory cytokine production, which, in addition, progesterone may counteract the favorable E2 effects through their receptors. J. Med. Invest. 55: 133-141, February, 2008

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We report an autopsy case of rapid progressive atypical carcinoid of the lung discovered as multiple nodular shadows. The patient was an 82-year-old man with non-productive cough. Both chest radiography and computed tomography revealed multiple nodules in both the lung and pleural effusion. Multiple metastases to bone and liver were also noted. Samples from the wall-side pleural lesion were obtained by video-assisted thoracoscopic surgery under local anesthesia, and histological examination led to a diagnosis of atypical carcinoid. Treatment was ineffective and the patient died on day 39 after admission. The primary site was identified as the lung after autopsy. We believe that early detection is crucial in the treatment of atypical carcinoid due to poor prognosis. J. Med. Invest. 55: 142-146, February, 2008

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From May, 1999 to August, 2006, we performed laparoscopic diagnosis and treatment for 103 cases of impalpable testes. Among those we found 5 cases of male pseudohermaphroditism of different etiologies. Three males presented by impalpable testes with ambiguous genitalia and 2 females presented by primary amenorrhea. All of them have 46-XY normal male chromosomal pattern. In the first 3 cases, the etiology was complete gonadal dysgenesis, and 2 cases with persistent Mullerian syndrome. Timed gonadectomy for the first case and laparoscopic orchiopexy for the other 2 cases were performed. For the other 2 female cases, the etiology was complete androgen insensitivity syndrome and laparoscopic bilateral orchiectomy was performed for both of them. All the procedures were done without complications with satisfactory results. J. Med. Invest. 55: 147-150, February, 2008

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Background: Choroidal hemorrhage is usually seen as expulsive hemorrhage related to surgical invasion and is rarely observed in the absence of surgery or trauma. In this report, we describe a case of choroidal hemorrhage caused by hypertension related to chronic renal failure. Case: A 32-year-old man presented with sudden visual loss, eye pain and swelling in his left eye. He had a history of renal failure and hypertension. Eye examination demonstrated choroidal hemorrhage associated with ocular hypertension in his left eye and marked hypertensive retinopathy in his right eye. Observations: He was treated with hemodialysis and antihypertensive drugs. Upon repeat eye examinations, a gradual reabsorption of the choroidal hemorrhage was observed, although vitreous hemorrhage appeared in the left eye. The vitreous hemorrhage was treated with vitrectomy with the patient regaining good visual acuity post-surgery. Conclusions: This rare case suggests that patients with severe background disease need to be carefully observed. J. Med. Invest. 55: 151-155, February, 2008

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Numbers of individuals infected with Human Immunodeficiency Virus (HIV) are increasing in Japan. The majority of them are Men who have sex with men and a part of them take drugs as ‘Sex drug’ at their sexual intercourse. Especially, Amyl nitrite, Methamphetamine, 5-methoxy-N, N-diisopropyltryptamine (5-MeO-DIPT; Foxy), and 3, 4-methylenedioxy- methamphetamine (MDMA; Ecstasy) are used, and they sometimes cause the physical and mental disorders. However, the actual drug inducing troubles among Japanese HIV-infected drug users had not yet been discussed enough.
In this report, we describe three cases with HIV infection; a case developed severe neuroleptic malignant syndrome (NMS) after taking 5-MeO-DIPT, a case with persistent convulsion due to multiple drug intake and a case with rhabdomyolysis due to the non-subjective methamphetamine intake. Through these cases, we raise and discuss several underlying problems associated with drug use among HIV-infected individuals. J. Med. Invest. 55: 156-160, February, 2008

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Cholangiolocellular carcinoma (CLC) is an extremely rare malignant liver tumor which was first defined by Steiner, et al. in 1957 (1). CLC is thought to be derived from Hering’s canal because tumor glands of CLC are morphologically similar to cholangioles. Recently, Theise, et al. reported that Hering’s canal might be composed of hepatic stem cells (3). In addition, CLC sometimes contains a hepatocellular carcinoma (HCC) or cholangiocellular carcinoma (CCC) component within the tumor. Those findings suggest that CLC might originate from hepatic stem cells. On the other hand, because of its low frequency, clinicopatholigical features of CLC have not been fully clarified yet. We herein report a case of a 71-year old man with CLC. Based on preoperative imagings, the hepatic tumor was diagnosed as HCC, and he underwent a partial hepatectomy. The tumor contained both a HCC and CCC-like area. In immunohistochemistry, cytokeratin (CK) 7, CK20, CAM5.2 was positive, and CK19 was negative, therefore the tumor was diagnosed as CLC. The diagnostic criteria have not been described clearly, so CLC is difficult to diagnose preoperatively. Further studies are needed to clarify the clinical and clinicopatholigical features of CLC. J. Med. Invest. 55: 161-165, February, 2008

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