Glycemic control is often difficult to achieve in patients with diabetes, especially in the presence of comorbid diseases or conditions such as steroid-use or liver cirrhosis, or in patients receiving enteral nutrition. Moreover, reactive hypoglycemia due to late dumping syndrome in people having undergone gastrectomy is also a matter of concern. Empirically and theoretically, the typical glycemic profiles associated with these conditions have been determined; however, what actually happens during a 24-h span is still somewhat obscure. In order to verify and provide information about the 24-h glycemic profiles associated with these conditions, 8 patients with the 4 above-mentioned conditions were monitored using a continuous glucose monitoring system (CGMS). For all 8 patients, CGMS provided detailed information regarding the 24-h glycemic profiles. The CGM results showed typical glycemic patterns for each condition, and we were moreover able to observe the effects of various practical treatments. Based on these cases, we conclude that the CGMS is highly useful for determining the glycemic patterns of patients with the aforementioned conditions in a practical setting; and this system may be used to monitor the treatment success of such cases. J. Med. Invest. 62: 1-10, February, 2015

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Spondylolysis is a stress fracture of the pars interarticularis, which in some cases progresses to spondylolisthesis (forward slippage of the vertebral body). This slip progression is prevalent in children and occurs very rarely after spinal maturation. The pathomechanism and predilection for children remains controversial despite considerable clinical and basic research into the disorder over the last three decades. Here we review the pathomechanism of spondylolytic spondylolisthesis in children and adolescents, and specifically the Tokushima theory of growth plate slippage developed from our extensive research findings. Clinically, we have observed the slippage site near the growth plate on MRI; then, using fresh cadaveric spines, we found the weakest link against forward shear loading was the growth plate. We subsequently developed an immature rat model showing forward slippage after growth plate injury. Moreover, finite element analysis of the pediatric spine clearly showed increased mechanical stress at the growth plate in the spondylolytic pediatric spine model compared with the intact pediatric spine. Thus, spondylolysis progresses to spondylolisthesis (forward slippage) in children and adolescents with the growth plate as the site of the slippage. Repetitive mechanical loading on to the growth plate may serve to separate the growth plate and subsequently progress to spondylolisthesis. J. Med. Invest. 62: 11-18, February, 2015

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Epigenetics is the study of changes in gene function that cannot be explained by changes in DNA sequence. A mammalian body contains more than two-hundred different types of cells, all derived from a single fertilized egg. Epigenetic gene regulation mechanisms essentially contribute to various processes of mammalian development. The essence of epigenetic regulation is the modulation of gene activity through changes in chromatin structure. DNA methylation and histone modifications are the major epigenetic mechanisms. Sex determination is the process of establishing a gender. Sry, the sex-determining gene in therian mammals, initiates testis differentiation. Recent studies have provided evidence that epigenetic mechanisms contribute to Sry regulation. J. Med. Invest. 62: 19-23, February, 2015

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Genetically encoded calcium indicators (GECIs) are powerful tools to monitor the dynamics of calcium ion (Ca²⁺) in living cells and organisms. With the help of GFP technology and DNA engineering, a dozen sets of GECIs have been developed so far. Their application has been widely extended into the analysis at the subcellular local, single and population of cell. In the past decades, GECIs have been dramatically improved in their performance and are becoming more and more useful for live imaging. In this review, the progress in the development of GECIs is discussed by introducing the history and emerging GECIs, which would help the selection of the appropriate GECI for a given application. J. Med. Invest. 62: 24-28, February, 2015

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Using proton magnetic resonance spectroscopy (¹H-MRS), we measured chemical metabolites in the left amygdala and the bilateral orbito-frontal cortex (OFC) in children with autism spectrum disorders (ASD). The concentrations of N-acetylaspartate (NAA) in these regions of ASD were significantly decreased compared to those in the control group. In the autistic patients, the NAA concentrations in these regions correlated with their social quotient. These findings suggest the presence of neuronal dysfunction in the amygdala and OFC in ASD. Dysfunction in the amygdala and OFC may contribute to the pathogenesis of ASD. We performed a near-infrared spectroscopy (NIRS) study to evaluate the mirror neuron system in children with ASD. The concentrations of oxygenated hemoglobin (oxy-Hb) were measured with frontal probes using a 34-channel NIRS machine while the subjects imitated emotional facial expressions. The increments in the concentration of oxy-Hb in the pars opercularis of the inferior frontal gyrus in autistic subjects were significantly lower than those in the controls. However, the concentrations of oxy-Hb in this area were significantly elevated in autistic subjects after they were trained to imitate emotional facial expressions. The results suggest that mirror neurons could be activated by repeated imitation in children with ASD. J. Med. Invest. 62: 29-36, February, 2015

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Purposes: It is no doubt that regulatory T cells (Foxp3⁺CD4⁺CD25⁺T cells: Treg) play important roles in transplant immunity. We investigated the significance of Treg expression in acute stage of living donorrelated liver transplantation (LDLT) for the possibility of the sensitive marker for immunological state and homeostatic stress after liver transplantation. Methods: Peripheral blood was drawn from 5 recipients of LDLT preoperatively and on post operative 1, 4, 7, and 14 days. The peripheral blood mononuclear cells (PBMCs) were stained with CD4, CD25, Foxp3, and were analyzed with FACScan. This data was compared with clinical output of LDLT. Result: The populations of Treg were significantly decreased in all patients on day 1 after LDLT and significantly increased in patients who had early postoperative complications compared with patients who had no complications. Conclusions: The population of Treg in peripheral blood may reflect the surgical stress such as life-threatening complications after LDLT. J. Med. Invest. 62: 37-40, February, 2015

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Background: Recent studies have shown that strict perioperative blood glucose management may reduce mortality and morbidity in critically ill adult patients. The purpose of this study was to assess the accuracy and efficacy of the intraoperative application of a newly developed, next-generation artificial endocrine pancreas (STG-55, Nikkiso Co., Ltd., Tokyo, Japan). Methods: Twenty patients scheduled to undergo surgery were enrolled in this study. The STG-55 is designed to be more user-friendly than its conventional counterpart (STG-22) while maintaining the latter's fundamental functions, such as a closed-loop system using algorithms for insulin and glucose infusion. After anesthetic induction, a 20G intravenous catheter was inserted into a peripheral forearm vein and connected to a continuous blood glucose monitor. The resultant 105 scores for paired blood glucose values were compared by Bland-Altman analysis. Results: Stable blood glucose values were maintained automatically, and there were no complications related to use of the STG-55. A close correlation (r=0.96) was observed between continuous glucose measurements using the STG-55 and conventional intermittent glucose measurements. The difficulty of manipulation using this system was decreased by improved preparation procedures. Conclusion: The glycemic control system using the STG-55 could provide an alternative way to achieve effective and safe perioperative glycemic control. J. Med. Invest. 62: 41-44, February, 2015

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ZnO nanoparticles (NPs) have been widely used in various commercial products. Application of ZnO NPs is expected to apply to cancer diagnosis and therapy, used as drug delivery carriers. In the present study, the lethal dose 50 (LD₅₀) of intravenously administered ZnO NPs (0.3 mg/kg) was calculated in mice. Blood kinetics and tissue distribution of a toxic dose of ZnO NPs (0.2 mg/kg, 0.05 mg/kg) were investigated after intravenous exposure. In addition, 8-hydroxy-2'-deoxyguanosine (8-OHdG) was evaluated. Following the injection, ZnO NPs were rapidly removed from the blood and distributed to organs. Pulmonary emphysema was observed pathologically study in mice at 3 days after the 0.2 mg/kg dose and at 6 days after the 0.05 mg/kg dose. ZnO NPs were mainly accumulated in the lung and spleen within 60 min. From the long-term tissue distribution study, the liver showed peak concentration at 6 days, and spleen peaked at 1 day. The lungs kept high levels until 6 days. Tissue distribution and pathological study showed that the spleen, liver, and lungs are target organs for ZnO NPs. Accumulation in the liver and spleen may be due to the phagocytosis by macrophages. A dose-dependent increase in 8-OHdG was observed in mice treated with ZnO NPs. This study is the first to show information on kinetics and target organs following intravenous ZnO injection. J. Med. Invest. 62: 45-50, February, 2015

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The Stroop task is sometimes used in psychiatric research to elicit prefrontal activity, which presumably reflects cognitive functioning. Although there are two Stroop tasks (Kana script and Kanji script) in Japan, it is unclear whether these tasks elicit the same hemoglobin changes. Moreover, it is unclear whether psychological conditions or characteristics influence hemoglobin changes in the Japanese Stroop task. The aim of this study was to clarify whether hemoglobin changes elicited by the two Japanese Stroop tasks accurately reflected cognitive functioning. Hemoglobin changes were measured with multi-channel near-infrared spectroscopy (NIRS) in 100 healthy Japanese participants performing two Japanese Stroop tasks. The Beck-Depression Inventory (BDI), State-Trait-Anxiety Inventory (STAI), and Maudsley Obsessive Compulsive Inventory (MOCI) were administered to participants to identify psychological conditions or personality characteristics. Compared with the Kanji task, the Kana task produced a greater Stroop effect and a larger increase in oxyhemoglobin (oxy-Hb) concentration. Moreover there were no significant correlations between oxy-Hb concentration and BDI, STAI-trait, STAI-state, or MOCI scores. Therefore we found that a participant's psychological conditions or characteristics did not influence the hemodynamic changes during either task. These data suggest the Kana Stroop task is more useful than the Kanji Stroop task for NIRS studies in psychiatric research. J. Med. Invest. 62: 51-55, February, 2015

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The purpose of this research was to investigate the gender differences of the influential factors on the mental health condition among university teachers in the A university in Japan. A questionnaire survey was mailed to 924 university teachers in Japan, with a survey return rate of 43.8% (N=405). The General Health Questionnaire 28 (GHQ-28), Multidimensional Scale of Perceived Social Support (MSPSS), the Japanese version of the Brief Coping Orientation to Problems Experienced (COPE) and the Work Situation Questionnaire (WSQ) developed by the authors were administered to subjects. The GHQ-28 total score and all of sub-score of the woman was significantly higher than men. In the correlated factor of mental health, level of job satisfaction and job control, social support of significant others was observed in the both sexes. However, gender differences was observed in the coping style. Some copings including self-distraction and self-blame were related to the men, but the woman was related to the substance use. University teachers had some gender differences in the factors affecting their mental health condition. In order to improve university teacher's mental health condition, it is necessary to increase their level of job satisfaction and feeling of job control in the workplace. Especially, it was considered women's coping using substance use was important. J. Med. Invest. 62: 56-61, February, 2015

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The relationship between food avoidance during infancy and the growth of Japanese infants in a community health setting has not been well evaluated. In order to assess the growth of infants who avoided either of the three major allergen foods in Japan, eggs, milk or wheat, we employed the results of 4 physical checkups recorded in maternity passbooks and administrated a questionnaire on allergic diseases, height and weight at birth to the guardians of 1,132 infants at the age of 3.5 years. Data was obtained from 890 subjects (78.6%) and 662 subjects (58.5%) who met the inclusion criteria were analyzed. The height, weight and body mass index percentile scores of each subject were calculated. Subjects who avoided either of the three foods at 3.5 years had lower weight percentile scores at 1.5 years, lower height and weight percentile scores at 3.5 years, and lower weight growth rates, compared with the subjects who did not avoid any of the three foods at 3.5 years (P=0.02, 0.03, 0.03, 0.01). The results suggested that there was a negative relationship between physique and food avoidance in infants, and that physical and nutritional assessments are important for food avoiders. J. Med. Invest. 62: 62-67, February, 2015

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In chronic renal failure, inorganic phosphate (Pi) retention speeds up the progression to end-stage renal disease. The current therapy for hyperphosphatemia in patients with chronic renal failure consists of dietary Pi restriction combined with administration of Pi binders, but each therapy has practical problems. Thus, the discovery of foods or nutrients that inhibit Pi absorption may be useful for the treatment of hyperphosphatemia. In the present study, we investigated whether wakame (Undaria pinnatifida) is a useful food for the prevention of hyperphosphatemia in a rat model of renal failure. Feeding a diet containing 5% wakame significantly decreased plasma and urinary Pi levels and increased the amount of fecal Pi. In addition, wakame significantly reduced plasma blood urea nitrogen and plasma Pi levels in 5/6 nephrectomized rats fed a high-Pi diet. Biochemical analyses showed that the reduction of intestinal Pi absorption is the main reason for the decrease in plasma Pi levels in rats fed a diet containing wakame. In addition, feeding alginic acid and fucoidan, major components of wakame fiber, was effective in reducing plasma Pi levels in normal rats. Finally, we concluded that wakame may be a useful food for the prevention of hyperphosphatemia in rodents. J. Med. Invest. 62: 68-74, February, 2015

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VEGF-targeting anti-angiogenic drugs have enabled significant advances in cancer therapy. However, acquired resistance to VEGF-targeting drugs occurs, leading to disease progression. How tumors become the resistance remains fully uncertain. One of possible mechanisms for the resistance may be the direct effect of VEGF inhibitors on tumor cells expressing VEGF receptors (VEGF-R). We investigated here the direct effect of chronic VEGF inhibition on phenotype changes in cancer cells. To chronically inhibit cancer cell-derived VEGF, human colon cancer HCT116 cells were chronically exposed (3 months) to anti-VEGF neutralizing monoclonal antibody (HCT/mAb cells, blockade of VEGF alone) or VEGF-R tyrosine kinase inhibitor foretinib (HCT/fore cells, blockade of all VEGF family). HCT/mAb cells redundantly increased VEGF family member (VEGF, PlGF, VEGF-B, VEGF-R1 and VEGF-R2) and induced a resistance to hypoxia-induced apoptosis. By contrast, HCT/fore cells did not show the redundant increase in VEGF family member, but significantly increased a VEGF-independent pro-angiogenic factor FGF-2. HCT/fore cells showed increased migration and invasion activities in addition to a resistance to hypoxia-induced apoptosis. The resistance to apoptosis was significantly suppressed by inhibition of hypoxia-inducible factor-1α in HCT/mAb cells, but not in HCT/fore cells. These findings suggest that chronic inhibition of VEGF/VEGF-R accelerates malignant phenotypes of colon cancer cells. J. Med. Invest. 62: 75-79, February, 2015

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People who frequently consume whole grains show a lower incidence of arteriosclerotic disease than people who consume primarily refined grains. We examined whether or not rice bran extract containing the acylated steryl glucosides (ASG) fraction decreases blood LDL cholesterol levels in obese Japanese men with high blood levels of LDL cholesterol. The study utilized a randomized, double-blind design. A total of 51 subjects were randomly allocated to either a rice bran extract containing ASG fraction (RB-ASG) group or a placebo group. Subjects in the RB-ASG group received 30-50 mg/day of RB-ASG, and the placebo group took 9 capsules/day for 12 weeks. Before and after intake, height, weight, body fat percentage, systolic and diastolic blood pressure were measured, blood was collected, and visceral fat area, subcutaneous fat area, and abdominal circumference were determined based on umbilical computed tomography. Percentage decreases in blood LDL cholesterol, non-HDL cholesterol, LDL/HDL ratio, abdominal circumference and subcutaneous fat area were significantly better in the RB-ASG group than in the placebo group. These findings suggest that RB-ASG fraction may reduce blood LDL cholesterol levels and the risk of arteriosclerosis in obese Japanese men with high LDL cholesterol levels. J. Med. Invest. 62: 80-84, February, 2015

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We describe a case of untreated adult-onset Coats' disease with a proliferative epiretinal membrane (ERM) treated successfully with 25-gauge pars plana vitrectomy (25GPPV). A 26-year-old man presented with a 3-week history of decreased vision in his left eye. At the initial examination, the decimal best-corrected visual acuity (BCVA) was 0.7 in the left eye. Ophthalmoscopy revealed the typical appearance of Stage 2A Coats' disease but with a proliferative ERM in the posterior pole. The patient received 2 monthly intravitreal injections of 2.5 mg bevacizumab, 5 laser photocoagulations to the area of telangiectasia, and 1 session of cryoretinopexy. Nine months after the initial visit, a traction by the ERM on the parafoveal area developed causing macular edema which reduced the BCVA to 0.3. He underwent 25GPPV with the removal of the ERM. In addition, the peripheral telangiectasia was treated intraoperatively with both laser photocoagulation and cryoretinopexy. Postoperatively, the traction to the parafoveal area was released and the BCVA improved to 0.6 which remained stable during the follow-up period of 13 months. We conclude that 25GPPV combined with ERM peeling, laser photocoagulation, and cryoretinopexy can be effective for adult-onset Coats' disease associated with an ERM. J. Med. Invest. 62: 85-88, February, 2015

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A 30-year-old female was referred to our hospital for further examination of liver dysfunction. A huge, soft mass was noted in her left upper quadrant on physical examination. Abdominal ultrasonography and computed tomography revealed a huge cystic tumor of 20 cm in the hilus of the spleen. Serum CA19-9 was 491 U/ml, and splenectomy was performed under suspicion of a malignant cystic tumor. The inner surface of the cyst was lined by squamous epithelial cells that were immunohistochemically positive for CA19-9. Serum CA19-9 level was normalized after the surgery. Our case of a very rare, huge epidermoid cyst of the spleen suggests that measurement of the serum CA19-9 level is useful for evaluating therapeutic efficacy of a splenic epidermoid cyst. J. Med. Invest. 62: 89-92, February, 2015

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Teriparatide, a recombinant form of parathyroid hormone, were well recognized as a useful option for the treatment of the osteoporosis. Although some side effects of teriparatide include headache, nausea, dizziness, and limb pain were reported. Here we present a 80-year-old woman of transient asymptomatic hypotension with once-weekly subcutaneous injection of teriparatide for the treatment of osteoporosis with hypertension disease as acute-phase reactions. Systolic blood pressure decreased in both 30 min and 60 min after injection compared with before injection. Heart rate increased with passage of time. Statistically significant were observed among before, 30 min, 60 min after injection of teriparatide. Slight nausea was seen as subjective symptoms with the first and second injection after 30 min. This case indicates careful attention, at least 1 hr, was recommended with weekly subcutaneous injections of teriparatide in the treatment for osoteoproteic patient with hypertension decreases. This is a first report, to the best of our knowledge, to demonstrate the transient asymptomatic hypotension after once-weekly injection of teriparatide with hypertension disease. Transient hypotension occurred after injection of teriparatide during the treatment period and was asymptomatic except for the first 2 injections. J. Med. Invest. 62: 93-96, February, 2015

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Salmonella osteomyelitis of the radius in a healthy individual is very rare. We present such a case involving the distal radius of a healthy 23-year-old man without underlying disease or possible episode. He had right wrist pain for approximately 3 years, and osteolytic lesion was seen in the right distal radius. He underwent surgical treatment, and salmonella was isolated from pus in the lesion. Postoperative antibiotics successfully treated his infection. He had no sign of recurrence, but the point of entry for infection remains unknown. J. Med. Invest. 62: 97-99, February, 2015

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Microsurgery for lumbar disc herniation that requires surgical intervention has been well described. The methods vary from traditional open discectomy to minimally invasive techniques. All need adequate preanesthetic preparation of patients as general anesthesia is required for the procedure, and nerve monitoring is necessary to prevent iatrogenic nerve injury. Conventional surgical techniques sometimes require the removal of the corresponding lamina to assess the nerve root and herniated disc, and this may increase the risk for posterior instability of the vertebral body. Should this occur, fusion surgery may be needed, further increasing morbidity and cost. We present here a case of lumbar herniated disc fragments causing acute cauda equina syndrome that were endoscopically resected through a transforaminal approach in an awake patient under local anesthesia. Percutaneous endoscopic discectomy under local anesthesia proved to be a better alternative to open back surgery as it made immediate intervention possible, was associated with fewer perioperative complications and morbidity, minimized soft tissue damage, and allowed early rehabilitation with a better outcome and greater patient satisfaction. In addition to these advantages, percutaneous endoscopic discectomy protects other approaches that may be needed in subsequent surgeries, whether open or minimally invasive. J. Med. Invest. 62: 100-102, February, 2015

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