POTENTIAL ADVANTAGE OF REPAGLINIDE MONOTHERAPY IN GLYCEMIC CONTROL IN PATIENTS WITH TYPE 2 DIABETES AND SEVERE RENAL IMPAIRMENT.

CONTEXT: Oral anti-diabetic drugs (OADs) are leading option for treatment of type 2 diabetes (T2D). However, availability of OADs are limited in the presence of renal impairment (RI). OBJECTIVE: In this study, we examined the efficacy of repaglinide, which is mainly metabolized and excreted via non-renal route, in patients with T2D and severe RI that consists mainly of chronic kidney disease (CKD) stage 4. DESIGN SUBJECTS AND METHODS: This was an open label, single arm, interventional study by repaglinide monotherapy. The primary efficacy end point was HbA1c change from baseline to week 12. RESULTS: Repaglinide treatment significantly reduced HbA1c levels from 7.7 ± 0.7% to 6.1 ± 0.3% (p<0.001) in 9 patients with severe RI (mean estimated glomerular filtration rate was 26.4 ± 7.5 mL/min/1.73m2). Focusing on 4 patients who received DPP-4 inhibitor monotherapy at enrolment, switching to repaglinide also significantly improved HbA1c levels. No hypoglycemic symptoms or severe hypoglycemia was reported in patients who completed the period of 12 weeks. CONCLUSIONS: We demonstrated the efficacy of repaglinide in patients with T2D and severe RI. In case that DPP-4 inhibitors are not enough to achieve targeted range of glycemic control, repaglinide is another good candidate.

Evaluation of efficacy and indications of surgical fixation for multiple rib fractures: a propensity-score matched analysis.

PURPOSE: The purpose of this study was to assess the effects of recent surgical rib fixation and establish its indications not only for flail chest but also for multiple rib fractures. METHODS: Between 2007 and 2015, 187 patients were diagnosed as having multiple rib fractures in our institution. After the propensity score matching was performed, ten patients who had performed surgical rib fixation and ten patients who had treated with non-operative management were included. Categorical variables were analyzed with Fischer's exact test and non-parametric numerical data were compared using the Mann-Whitney U test. Wilcoxon signed-rank test was performed for comparison of pre- and postoperative variables. All statistical data are presented as median (25-75 % interquartile range [IQR]) or number. RESULTS: The surgically treated patients extubated significantly earlier than non-operative management patients (5.5 [1-8] vs 9 [7-12] days: p = 0.019). The duration of continuous intravenous narcotic agents infusion days (4.5 [3-6] vs 12 [9-14] days: p = 0.002) and the duration of intensive care unit stay (6.5 [3-9] vs 12 [8-14] days: p = 0.008) were also significantly shorter in surgically treated patients. Under the same ventilating conditions, the postoperative values of tidal volume and respiratory rate improved significantly compared to those values measured just before the surgery. The incidence of pneumonia as a complication was significantly higher in non-operative management group (p = 0.05). CONCLUSIONS: From the viewpoints of early respiratory stabilization and intensive care unit disposition without any complications, surgical rib fixation is a sufficiently acceptable procedure not only for flail chest but also for repair of severe multiple rib fractures.

Robust singlet dimers with fragile ordering in two-dimensional honeycomb lattice of Li2RuO3.

When an electronic system has strong correlations and a large spin-orbit interaction, it often exhibits a plethora of mutually competing quantum phases. How a particular quantum ground state is selected out of several possibilities is a very interesting question. However, equally fascinating is how such a quantum entangled state breaks up due to perturbation. This important question has relevance in very diverse fields of science from strongly correlated electron physics to quantum information. Here we report that a quantum entangled dimerized state or valence bond crystal (VBC) phase of Li2RuO3 shows nontrivial doping dependence as we perturb the Ru honeycomb lattice by replacing Ru with Li. Through extensive experimental studies, we demonstrate that the VBC phase melts into a valence bond liquid phase of the RVB (resonating valence bond) type. This system offers an interesting playground where one can test and refine our current understanding of the quantum competing phases in a single compound.

Clinical Significance of the Champagne Bottle Neck Sign in the Extracranial Carotid Arteries of Patients with Moyamoya Disease.

BACKGROUND AND PURPOSE: The champagne bottle neck sign represents a rapid reduction in the extracranial ICA diameters and is a characteristic feature of Moyamoya disease. However, the clinical significance of the champagne bottle neck sign is unclear. We investigated the relationship between the champagne bottle neck sign and the clinical and hemodynamic stages of Moyamoya disease. MATERIALS AND METHODS: We analyzed 14 patients with Moyamoya disease before revascularization (5 men, 9 women; age, 43.2 ± 19.3 years). The ratio of the extracranial ICA and common carotid artery diameters was determined using carotid ultrasonography or cerebral angiography; a ratio of < 0.5 was considered champagne bottle neck sign-positive. The clinical disease stage was determined using the Suzuki angiographic grading system. CBF and cerebral vasoreactivity also were measured. RESULTS: The ICA/common carotid artery ratio (expressed as median [interquartile range]) decreased as the clinical stage advanced (stages I-II, 0.71 [0.60-0.77]; stages III-IV, 0.49 [0.45-0.57]; stages V-VI, 0.38 [0.34-0.47]; P < .001). Lower ICA/common carotid artery ratio tended to occur in symptomatic versus asymptomatic arteries (0.47 [0.40-0.53] versus 0.57 [0.40-0.66], respectively; P = .06). Although the ICA/common carotid artery ratio was not related to cerebral perfusion, it decreased as cerebral vasoreactivity decreased (P < .01). All champagne bottle neck sign-positive arteries were classified as Suzuki stage ≥III, 73% were symptomatic, and 89% exhibited reduced cerebral vasoreactivity. In contrast, all champagne bottle neck sign-negative arteries were Suzuki stage ≤III, 67% were asymptomatic, and all showed preserved cerebral vasoreactivity. CONCLUSIONS: The champagne bottle neck sign was related to advanced clinical stage, clinical symptoms, and impaired cerebral vasoreactivity. Thus, detection of the champagne bottle neck sign might be useful in determining the clinical and hemodynamic stages of Moyamoya disease.

IL-4/IL-13 antagonist DNA vaccination successfully suppresses Th2 type chronic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a chronic disease with a Th2-type-cytokine dominant profile. Several cytokines and related peptides have been used for the treatment of AD but they were ineffective because of their limited biological half-life. We have recently developed a highly efficient mouse dominant negative interleukin (IL)-4/IL-13 antagonist (IL-4DM), which blocks both IL-4 and IL-13 signal transductions. OBJECTIVE: To examine the effects of IL-4DM in vivo in an AD model induced by the repeated exhibition of oxazolone (OX). METHODS: Plasmid DNA was injected intraperitoneally to cause an experimental AD-like dermatitis. The effect was evaluated by ear thickness, histological findings, and mast cells counts in the inflamed skin. The plasma IgE and histamine levels were measured. Cytokine production in skin and splenocytes were also analysed. RESULTS: Mice treated with control plasmid developed marked dermatitis with mast cells and eosinophil infiltration, and had increased plasma IgE and histamine levels with a Th2 type splenocyte cytokine profile. Treatment with mouse IL-4 DNA augmented the ear swelling and thickness with an increased dermal eosinophil count, plasma histamine level, and production of splenocyte IL-4. However, IL-4DM treatment successfully controlled the dermatitis, decreased the mast cell and eosinophil count, and suppressed plasma IgE and histamine levels. Splenocytes produced an increased level of IFN-gamma. CONCLUSION: These data showed that the simultaneous suppression of IL-4/IL-13 signals successfully controlled Th2-type chronic dermatitis. IL-4DM DNA treatment is a potent therapy for AD and related diseases.

Classification of the degradability of 30 pharmaceuticals in water with ozone, UV and H2O2.

Experiments were conducted to assess the degradability of 30 PPCPs, selected on the basis of consumption and environmental relevance, by O3 process, UV process and AOPs consisting of UV/ H2O2, O3/UV and O3/H2O2. A batch reactor with volume of 22L of water including the PPCPs was used. For UV process, combination of UV and H2O2 or O3 that can generate OH radicals was capable of degrading the PPCPs faster than UV radiation alone. On the other hand, O3 process and O3-based/UV-based AOPs could remove a variety of the PPCPs effectively, while some PPCPs such as 2-QCA, DEET and cyclophosphamide showed a relatively low degradability compared with the other PPCPs. However, further evaluation on formation of intermediate products resulting from the degradation of the parent PPCPs will be needed because DOC concentration was not decreased with lowered concentrations of the PPCPs.

Detection of cerebrospinal fluid leakage: initial experience with three-dimensional fast spin-echo magnetic resonance myelography.

BACKGROUND: The pathogenesis of cerebrospinal fluid (CSF) hypovolemia is supposed to be caused by CSF leakage through small dural defects. PURPOSE: To compare source three-dimensional (3D) fast spin-echo (FSE) images of magnetic resonance (MR) myelography with radionuclide cisternography findings, and to evaluate the feasibility of MR myelography in the detection of CSF leakage. MATERIAL AND METHODS: A total of 67 patients who were clinically suspected of CSF hypovolemia underwent indium-111 radionuclide cisternography, and 27 of those who had direct findings of CSF leakage were selected for evaluation. MR myelography with 3D FSE sequences (TR/TE 6000/203 ms) was performed at the lumbar spine for all patients. We evaluated source images and maximum intensity projection (MIP) images of MR myelography, and the findings were correlated with radionuclide cisternography findings. MR myelography of five healthy volunteers was used as a reference. The MR visibility of the CSF leakage was graded as definite (leakage clearly visible), possible (leakage poorly seen), or absent (not shown). RESULTS: CSF leakage was identified with source 3D FSE images in 22 (81.5%) of 27 patients. Of the 22 patients, 16 were graded as definite and six were graded as possible. For the definite cases, 3D FSE images clearly showed the extent of the leaked CSF in the paraspinal structures. In the remaining five patients with absent findings, radionuclide cisternography showed only slight radionuclide activity out of the arachnoid space. CONCLUSION: Source 3D FSE images of MR myelography seem useful in the detection of CSF leakage. Invasive radionuclide cisternography may be reserved for equivocal cases only.

Display of the epileptogenic zone on the frontal cortical surface using dynamic voltage topography of ictal electrocorticographic discharges.

To evaluate the usefulness of computerized brain-surface dynamic voltage topography (DVT) of ictal electrocorticographic (ECoG) discharges to localize and identify epileptogenic areas, 3 patients with intractable frontal lobe epilepsy who underwent epilepsy surgery after chronic subdural electrode recording were assessed. Cortical surfaces and subdural electrodes were photographed during initial surgery to create an electrode map that could be superimposed onto a picture of the brain surface. DVT was performed by calculating sequential amplitudes of ictal ECoG discharges, which were then superimposed onto the cortical and electrode maps. In all cases, DVT clearly identified the ictal onset zone and the early propagation area on the operative field. DVT allowed recognition of spatial relationships between the epileptogenic area and structural abnormalities, functional cortex, and cortical veins; and was useful to decide on the resection area.

Local delivery of angiotensin receptor blocker into the kidney ameliorates progression of experimental glomerulonephritis.

Intrarenally synthesized angiotensin II (Ang II) may be involved in the progression of glomerulonephritis, leading to irreversible glomerulosclerosis. There is increasing evidence that systemic angiotensin receptor blocker (ARB) treatment has beneficial effect on the prognosis of progressive glomerulonephritis and diabetic nephropathy. However, the cellular and molecular mechanisms behind this therapeutic effect of ARB remain unclear. In this study, we used a novel strategy of local ARB delivery via type-1 collagen sponge, to treat progressive glomerulonephritis that would result in irreversible glomerulosclerosis in our previously established rat model. At days 9 and 14 after disease induction, mild proteinuria, 20.7+/-4.7 and 10+/-1.3 mg/day, was found. Local ARB treatment reduced proteinuria significantly to 3.19+/-3.2 and 5.25+/-0.95 mg/day (P < 0.01), respectively. Scoring of glomerular matrix expansion and sclerotic index revealed that local ARB treatment significantly ameliorated glomerular pathology. Ang II type 1 receptor mRNA expression was remarkably enhanced in the Ang II group and ARB treatment reversed this effect at 14 days. Local delivery of ARB significantly improved glomerular blood flow levels, compared to the untreated disease control group, from 710+/-18.25 to 859.44+/-22.86 microm/s, respectively. Local delivery of ARB into the kidney affected local RAS and thus improved the renal injury and function in the potentially progressive glomerulosclerosis of rat model.

Distribution of preneoplastic lesions and tumors, and beta-catenin gene mutations in colon carcinomas induced by 1,2-dimethylhydrazine plus dextran sulfate sodium.

Mucin-depleted foci (MDF) are considered as useful biomarkers in rat colon carcinogenesis. The purpose of the present study was to examine the mechanism(s) underlying rat colon carcinogenesis induced by 1,2-dimethylhydrazine (DMH) plus 1% Dextran Sulfate Sodium (DSS). Twelve male F344 rats were given subcutaneous injections (40mg/kg body) of DMH twice a week. They received DSS in the drinking water for 1 week after the first injection of DMH and then were maintained on tap water. The rats were sacrificed at 10 and 14 weeks after the first injection of DMH. Colon tissues were divided into 10 segments from anus to cecum (A/J) and stained with Alcian blue (AB) to identify MDF. We found that MDF and tumors were induced in the rat colon after treatment with DMH plus DSS and that the number of MDF in each segment of the colon was significantly correlated with that of tumors (p=0.006). In addition, we found that the beta-catenin protein was accumulated in cytoplasm and nuclei of MDF and the frequent beta-catenin gene mutations in the colon tumors. These results suggest that MDF is closely related to rat colon carcinogenesis induced by DMH plus DSS.

Turbulence of glomerular hemodynamics involved in progressive glomerulosclerosis.

There is increasing evidence that changes of glomerular hemodynamics or glomerular growth responses may promote the development of glomerulosclerosis. Major problems retarding research progress include lack of suitable experimental animal models, with the exception of the ablation model, and the need for in vivo real-time analysis of glomerular hemodynamics. This study examined the sequence of pathological changes from the viewpoints of microcirculation and histopathology, from the acute stage to the chronic course and the final stage of glomerulosclerosis, using the confocal laser scanning microscope system. There is a marked difference in prognosis between sham-operated (two-kidney) and nephrectomized (one-kidney) rats after injection with anti-Thy-1 antibody. The former reversibly returns to normal and the latter irreversibly go to progressive sclerosis, respectively. The turning point determining the progression of glomerulosclerosis in both groups seemed to be the period from 7 to 14 days after disease induction, when disturbance of local intraglomerular blood flow continued in the one-kidney groups. In conclusion, this study provides the first hemodynamic-based evidence showing that disturbance of intraglomerular microcirculation is a critical marker for progressive glomerulosclerosis.

Bone marrow cell infusion ameliorates progressive glomerulosclerosis in an experimental rat model.

Bone marrow (BM) cells contribute to the maintenance and repair of several compartments of the kidney, including the endothelium, interstitium, epithelium, and the mesangium. The aim of this study was to explore the therapeutic use of bone marrow-derived cells (BMDC) that can differentiate into endothelial and mesangial cells in a model of progressive glomerulosclerosis. To investigate the involvement of BMDC in glomerular repair, progressive glomerulosclerosis was induced in enhanced green fluorescent protein BM chimeric rats by a one-shot injection of anti-Thy-1.1 monoclonal antibody, followed by unilateral nephrectomy. Subsequently, these rats were treated with either a BM cell infusion or phosphate-buffered saline. Renal function, intravital glomerular hemodynamics, and histological alterations were examined 12 weeks after anti-Thy-1.1 monoclonal antibody injection. Inflammatory infiltration of macrophages in the kidneys was evaluated by immunofluorescence of ED-1. We also determined whether BMDC contributed to repair and regeneration of endothelial and mesangial cells by immunofluorescence monitoring. As a result, BM cell infusion improved renal function and glomerular hemodynamics, and histological alterations with reduced glomerular infiltration of macrophages, leading to dramatically reduced mortality in this model of progressive glomerulosclerosis. We also demonstrated that, in the BM cell infusion group, more BMDC contributed to repair and regeneration of endothelial and mesangial cells than in the untreated group. The present study provides us with a conceptual basis for the development of therapeutic stem cell strategies aimed at enhancing recovery from progressive glomerulosclerosis.

Radiotherapy with 8 MHz radiofrequency-capacitive regional hyperthermia for pain relief of unresectable and recurrent colorectal cancer.

PURPOSE: The purpose of this study was to assess the pain relief in patients with unresectable and recurrent colorectal cancer treated with radiation plus 8 MHz radiofrequency-capacitive regional hyperthermia and to identify predictors of the good outcome. METHODS: Between February 1986-May 2003, 41 patients with primarily unresectable and recurrent colorectal cancer that caused pain were treated with thermoradiotherapy at the hospital and retrospectively analysed. Radiotherapy was administered with a mean total radiation dose of 56 Gy. Hyperthermia was usually applied within 30 min after radiotherapy once or twice a week. For cooling of the skin surface, the overlay boluses were applied in addition to regular boluses. The external cooling unit has been used to reinforce the cooling ability of the overlay bolus and achieve strong surface cooling to reduce the preferential heating of the subcutaneous fat tissue and treat with more RF-output in 17 patients since January 1997. RESULTS: Pain relief was obtained in 83% of the patients. Multi-variate analysis by logistic regression to evaluate the effects of certain factors on pain relief (complete response + good response) was strongly correlated with the presence of radiating pain to leg(s) (p < 0.05). The median follow-up was 18 months. The median duration of pain relief was 7.0 months. For the 27 patients in whom the tumour temperature was estimated, the median duration of pain relief was 14.6 months for the patients with a mean average tumour temperature of > 42.5 degrees C and 5.7 months for those of < 42.5 degrees C (p < 0.05). In the 18 patients with radiating pain to leg(s), use of strong superficial cooling and the higher numbers of hyperthermia treatments were better prognostic factors for the duration of pain relief (p < 0.01 and p < 0.05, respectively). CONCLUSIONS: Radiotherapy with 8 MHz radiofrequency-capacitive regional hyperthermia provided an efficient, effective means on pain relief of treating unresectable and recurrent colorectal cancer. The duration of pain relief can be prolonged, if an adequate heating is achieved, especially in the patients with radiating pain to the leg(s).

Spatio-temporal analysis by voltage topography of ictal electroencephalogram on MR surface anatomy scan for the localization of epileptogenic areas.

A 15-year-old girl developed intractable epilepsy following a right transcallosal resection of the intraventricular teratoma. Magnetic resonance (MR) imaging showed a T (2)-prolonged subcortical lesion in the right frontal lobe as well as a residual intraventricular tumor. The integration of the voltage topography of ictal onset activities of the scalp-recorded electroencephalogram (EEG) and a surface anatomy scan of MR images clearly revealed the epileptogenic area on the cortex above the subcortical lesion, with the propagation pattern towards the frontopolar area. Excision of the epileptogenic cortex and underlying gliosis resulted in a successful cessation of the epilepsy. This non-invasive EEG technique provided useful information that accurately localized the epileptogenic area on a large structural abnormality without invasive intracranial electrocorticographic monitoring.

Modifying effects of Terminalia catappa on azoxymethane-induced colon carcinogenesis in male F344 rats.

The modifying effects of dietary administration of an herb, Terminalia catappa (TC), were investigated on rat colon carcinogenesis induced by a carcinogen azoxymethane (AOM). The number of aberrant crypt foci (ACF) and beta-catenin accumulated crypts (BCACs) in the colon, and proliferating cell nuclear antigen (PCNA) labelling index in the colonic epithelium were examined in a total of 36 male F344 rats. All animals were randomly divided into five experimental groups (4-10 rats in each group). At 6 weeks of age, rats in groups 1, 2 and 3 were given s.c. injections of AOM once a week for 2 weeks at a concentration of 20 mg/kg body weight. One week before the first injection of AOM, rats in groups 2 and 3 were fed a diet containing 0.02 and 0.1% TC, respectively, throughout the experiment. Rats in group 4 were fed a diet containing 0.1% TC. Rats in group 5 were served as untreated controls. All animals were sacrificed at the experimental week 5 after the start of the experiment. Oral administration of TC at both doses significantly decreased the numbers of both ACF/colon/rat (P<0.05 for 0.02% TC, P<0.005 for 0.1% TC) and BCAC/cm/rat (P<0.05 for both 0.02 and 0.1% TC), when compared with the control group (group 1). Colonic PCNA labelling index in groups 2 and 3 was also significantly lower than that in group 1 (P<0.001 for 0.02% TC, P<0.005 for 0.1% TC). These results suggest that TC has a potent short-term chemopreventive effect on biomarkers of colon carcinogenesis and this effect may be associated with the inhibition of the development of ACF and BCACs.

Surgical treatment for large and massive tears of the rotator cuff.

Patients with a large or massive tear of the rotator cuff were, when possible, treated with the McLaughlin procedure. A patch graft was used when it was impossible to perform this procedure. The patch group (group P) consisted of nine patients with nine shoulders (six men, three women) with a mean age of 62.8+/-6.9 years. The McLaughlin group (group M) consisted of 12 patients with 12 shoulders (ten men, two women) with a mean age of 52.3+/-8.6 years. Mean follow-up was 2 years 11 months in group P and 4 years 2 months in group M. Using the shoulder scoring system of the Japanese Orthopaedic Association (JOA score), the total score improved post-operatively in both groups. In group P, the post-operative score was 91.7 (pre-operative score 47.9) and in group M 92.0 (pre-operative score 54.2). Tears recurred in three shoulders within 2 months of the McLaughlin procedure, and these patients were excluded from the study. The rate of 're-tearing' was lower with a patch graft (0/13) than with the McLaughlin procedure (3/17).

Gemcitabine and vinorelbine followed by docetaxel in patients with advanced non-small-cell lung cancer: a multi-institutional phase II trial of nonplatinum sequential triplet combination chemotherapy (JMTO LC00-02).

To evaluate the efficacy and toxicity of the sequential nonplatinum combination chemotherapy consisting of gemcitabine (GEM) and vinorelbine (VNR) followed by docetaxel (DOC) in patients with advanced non-small-cell lung cancer (NSCLC), we conducted the multiinstitutional phase II study. A total of 44 chemotherapy-naive patients with advanced NSCLC were treated with GEM 1000 mg m(-2) and VNR 25 mg m(-2) intravenously on days 1 and 8 every 3 weeks for three cycles. DOC 60 mg m(-2) was then administrated intravenously at 3-week intervals for three cycles. Patients were evaluated for response and toxicity with each cycle of the treatment. The major objective response rate was 47.7% (95% confidence interval (CI), 33.8-62.1%). Median survival time (MST) was 15.7 months and 1-year survival rate was 59%. In the GEM/VNR cycle, grade 3/4 neutropenia occurred in 36.3%, grade 3/4 anaemia in two patients (4.5%) and grade 3 thrombocytopenia in one patient (2.3%). Grade 3 pneumonitis occurred in two patients (4.5%) in GEM/VNR cycles. In the DOC cycles, grade 3/4 neutropenia occurred in 39.4% but no patient experienced grade 3/4 anaemia or thrombocytopenia. Of the 44 eligible patients, 33 patients completed three cycles of GEM/VNR and 22 patients completed six cycles of planned chemotherapy (three cycles of GEM/VNR followed by three cycles of DOC). The sequential triplet nonplatinum chemotherapy consisted of GEM/VNR followed by DOC, and was very active and well tolerated. This study forms the basis for an ongoing phase III trial that compares this nonplatinum triplet and standard platinum doublet combination (carboplatin/paclitaxel).