Negative motor networks: Electric cortical stimulation and diffusion tensor imaging.

INTRODUCTION: This study investigated the networks of Negative motor areas (NMAs) using electric cortical stimulation and diffusion tensor imaging (DTI). METHODS: Twelve patients with intractable focal epilepsy, in which NMAs were identified by electrical cortical stimulation, were enrolled in this study. Electric stimulation at 50Hz was applied to the electrodes during motor tasks to identify the NMAs. DTI was used to identify the subcortical fibers originating from the NMAs found by electrical stimulation. RESULTS: NMAs were found in lateral frontal areas (premotor area (PM) and precentral gyrus) in all 12 patients, in pre-supplementary motor areas (pre-SMAs) in four patients, and in posterior parietal cortices (PPCs) in four. DTI detected fibers connecting to the ipsilateral PMs, PPCs and temporal regions via U-fibers, superior longitudinal fasciculus (SLF), and arcuate fasciculus (AF) from the lateral frontal NMAs. Pre-SMA-NMAs had connections with ipsilateral PMs and contralateral pre-SMAs via the frontal aslant tract and transcallosal commissural fibers, and PPC-NMAs with ipsilateral PMs via SLF and AF. CONCLUSION: This study found the characteristic cortical network of each NMA, and especially revealed new insight of pre-SMA-NMA and PPC NMA. These NMAs might be associated with different mechanism of negative motor response.

Effects of Antifreeze Protein Supplementation on the Development of Porcine Morulae Stored at Hypothermic Temperatures.

BACKGROUND: Short-term storage is valuable method to reuse manipulated embryos. OBJECTIVE: The present study evaluated the effects of antifreeze protein (AFP) supplementation on the quality and development of in vitro-produced porcine morulae after short-term storage (24 h). MATERIALS AND METHODS: The morulae were stored with various concentrations of AFP type III for 24 h at 5, 15 and 25C. RESULTS: Supplementation of AFP type III (1.0 microgram per mL) improved the developmental competence of embryos stored at 25C. The proportions of DNA-fragmented nuclei in the blastocysts did not differ between the embryos stored at 25C and the control embryos without storage treatment. However, the developmental competence of embryos stored at hypothermic temperatures decreased relative to that of the control embryos. CONCLUSION: Supplementation of AFP type III (1.0 microgram per mL) maintained the quality of embryos stored at 25C, but did not have beneficial effects on the development of embryos stored at hypothermic temperatures.

Rituximab for the treatment of type B insulin resistance syndrome: a case report and review of the literature.

BACKGROUND: Type B insulin resistance syndrome is a rare disease characterized by refractory transient hyperglycaemia and severe insulin resistance associated with circulating anti-insulin receptor antibodies. A standardized treatment regimen for type B insulin resistance syndrome has yet to be established. CASE REPORT: We report the case of a 64-year-old man undergoing haemodialysis for antineutrophil cytoplasmic antibody-associated vasculitis and diabetic nephropathy, who developed rapid onset of hyperglycaemia (glycated albumin 52.1%). Type B insulin resistance syndrome was diagnosed, on the basis of positivity for anti-insulin receptor antibodies and the man's autoimmune history of antineutrophil cytoplasmic antibody-associated vasculitis and idiopathic thrombocytopenic purpura. Although severe hyperglycaemia persisted in spite of corticosteroids and high-dose insulin therapy, rituximab treatment resulted in remarkable improvement of the man's severe insulin resistance and disappearance of anti-insulin receptor antibodies without any adverse effects. CONCLUSIONS: According to a literature review of 11 cases in addition to the present case, rituximab appears to be a safe and effective strategy for the treatment of corticosteroid-resistant type B insulin resistance syndrome.

The Japanese LupusPRO: A cross-cultural validation of an outcome measure for lupus.

Objective This study aimed to validate the Japanese version of the LupusPRO questionnaire for use with systemic lupus erythematosus patients. Methods Participants were 205 lupus patients recruited from three rheumatology centers in Japan. Demographic data were collected and quality of life was assessed using the LupusPRO and the Short Form Health Survey-12. Disease activity was evaluated by physicians using the Systemic Lupus Erythematosus Activity Index. Some participants completed questionnaires 10-14 days after the first survey. Internal consistency reliability, test-retest reliability, content validity and convergent validity were examined, and confirmatory factor analysis was performed. Results Participants' mean age was 47.8 ± 13.6 years. Older participants scored lower on physical quality of life and higher on coping than younger participants. The LupusPRO showed satisfactory test-retest reliability ( n = 111). Test-retest reliability was lower for the mental and social aspects of quality of life, indicating fluctuations in quality of life during the two-week interval. Internal consistency reliability was good and convergent validity with the corresponding domains of the Short Form Health Survey-12 was satisfactory. Confirmatory factor analysis showed a good model fit. Conclusion The Japanese LupusPRO is a reliable and valid measure to evaluate treatment interventions for systemic lupus erythematosus.

Preoperative prediction for regaining ambulatory ability in paretic non-ambulatory patients with metastatic spinal cord compression.

STUDY DESIGN: Retrospective multicenter study. OBJECTIVES: To analyze the predictive factors for postoperative ambulatory recovery in paretic non-ambulatory patients with metastatic spinal cord compression (MSCC). SETTING: Japan. METHODS: Eighty-two consecutive patients (74.4% men; mean age, 66.2 years) who could not walk before surgery due to cervical or thoracic MSCC and underwent posterior decompressive surgery between 2003 and 2014 were included. Patients were divided into two groups according to ambulatory status at 6 weeks after surgery: recovery (group R) and non-recovery (group NR). To evaluate the speed of progression of motor deficits, we assessed the period from onset of neurological symptoms to gait inability (T1). RESULTS: Fifty patients (61.0%) regained the ability to walk (group R). The period of T1 demonstrated a positive correlation with probability of ambulatory recovery (P=0.00; Kendall's tau-b=0.38), and a receiver operating characteristic curve analysis showed that the cutoff value of T1 was 5 days (area under the curve=0.72; P=0.001). In multivariate analysis, <6 days of T1 was one of the independent risk factors for failing to regain ambulatory ability (odds ratio, 8.74; P=0.00). CONCLUSIONS: The speed of progression of motor deficits can independently and powerfully predict the chance of postoperative ambulatory recovery as well as previously identified predictors. Since information about the speed of progression can be obtained easily by interviewing patients or family members, even if the patient is in an urgent state, our results will be helpful in clinical decision-making.

Glu311 and Arg337 Stabilize a Closed Active-site Conformation and Provide a Critical Catalytic Base and Countercation for Green Bioluminescence in Beetle Luciferases.

Beetle luciferases elicit the emission of different bioluminescence colors from green to red. Whereas firefly luciferases emit yellow-green light and are pH-sensitive, undergoing a typical red-shift at acidic pH and higher temperatures and in the presence of divalent heavy metals, click beetle and railroadworm luciferases emit a wider range of colors from green to red but are pH-independent. Despite many decades of study, the structural determinants and mechanisms of bioluminescence colors and pH sensitivity remain enigmatic. Here, through modeling studies, site-directed mutagenesis, and spectral and kinetic studies using recombinant luciferases from the three main families of bioluminescent beetles that emit different colors of light (Macrolampis sp2 firefly, Phrixotrix hirtus railroadworm, and Pyrearinus termitilluminans click beetle), we investigated the role of E311 and R337 in bioluminescence color determination. All mutations of these residues in firefly luciferase produced red mutants, indicating that the preservation of opposite charges and the lengths of the side chains of E311 and R337 are essential for keeping a salt bridge that stabilizes a closed hydrophobic conformation favorable for green light emission. Kinetic studies indicate that residue R337 is important for binding luciferin and creating a positively charged environment around excited oxyluciferin phenolate. In Pyrearinus green-emitting luciferase, the R334A mutation causes a 27 nm red-shift, whereas in Phrixotrix red-emitting luciferase, the L334R mutation causes a blue-shift that is no longer affected by guanidine. These results provide compelling evidence that the presence of arginine at position 334 is essential for blue-shifting the emission spectra of most beetle luciferases. Therefore, residues E311 and R337 play both structural and catalytic roles in bioluminescence color determination, by stabilizing a closed hydrophobic conformation favorable for green light emission, and also providing a base to accept excited oxyluciferin phenol proton, and a countercation to shield the negative charge of E311 and to stabilize excited oxyluciferin phenolate, blue-shifting emission spectra in most beetle luciferases.

Chromosome structure deficiencies in MCPH1 syndrome.

Mutations in the MCPH1 gene result in primary microcephaly in combination with a unique cellular phenotype of defective chromosome condensation. MCPH1 patient cells display premature chromosome condensation in G2 phase of the cell cycle and delayed decondensation in early G1 phase, observable as an increased proportion of cells with prophase-like appearance. MCPH1 deficiency thus appears to uncouple the chromosome cycle from the coordinated series of events that take place during mitosis such as some phases of the centrosome cycle and nuclear envelope breakdown. Here, we provide a further characterization of the effects of MCPH1 loss-of-function on chromosome morphology. In comparison to healthy controls, chromosomes of MCPH1 patients are shorter and display a pronounced coiling of their central chromatid axes. In addition, a substantial fraction of metaphase chromosomes shows apparently unresolved chromatids with twisted appearance. The patient chromosomes also showed signs of defective centromeric cohesion, which become more apparent and pronounced after harsh hypotonic conditions. Taking together, the observed alterations indicate additional so far unknown functions of MCPH1 during chromosome shaping and dynamics.

Interferon γ and plasminogen activator inhibitor 1 regulate adhesion formation after partial hepatectomy.

BACKGROUND: The pathophysiology of intra-abdominal adhesions has not been studied extensively. The aim of this study was to elucidate the molecular mechanisms underlying adhesion formation in a murine model and in patients undergoing hepatectomy. METHODS: Partial hepatectomy was performed using bipolar forceps in mice. Wild-type mice, antibodies to CD4 and interferon (IFN) γ, IFN-γ, natural killer T (NKT) cells and plasminogen activator inhibitor (PAI) 1 knockout (KO) mice were used. Recombinant hepatocyte growth factor (HGF) was tested for its ability to prevent adhesions. Liver specimens were obtained during surgery from patients undergoing hepatectomy. Adhesion formation was evaluated using a scoring system that ranged from 0 (no adhesions) to 5 (severe adhesions). Levels of IFN-γ and PAI-1 mRNA, and protein concentration of PAI-I were measured, and fluorescence immunostaining was performed. RESULTS: Adhesion formation depended on IFN-γ produced by NKT cells, and NKT KO mice developed few adhesions (mean(s.d.) 1·7(0·3) versus 4·6(0·4) in wild-type mice; P = 0·037). In wild-type mice, the level of PAI-1 mRNA increased after hepatectomy, followed by a decrease in the tissue plasminogen activator (tPA) mRNA level. Adhesion formation was inhibited completely in PAI-1 KO mice (0(0) versus 4·1(0·8) in wild-type mice; P = 0·002). HGF inhibited formation of abdominal adhesions after hepatectomy by reducing IFN-γ and PAI-1 levels, and increasing tPA levels compared with those in mice treated with phosphate-buffered saline (P < 0·001, P = 0·002 and P = 0·035 respectively). In human liver specimens, NKT cells accumulated in the liver after hepatectomy, and PAI-1 expression was increased 5·25-fold (P = 0·030). CONCLUSION: IFN-γ is a key molecule for abdominal adhesion formation after hepatectomy, acting via the reciprocal balance of PAI-1 and tPA. This molecular mechanism may also regulate adhesion formation in patients following hepatectomy. HGF inhibited formation of adhesions by regulating IFN-γ and PAI-1, suggesting that it may be an important target for prevention of adhesions after hepatectomy. SURGICAL RELEVANCE: Postoperative intra-abdominal adhesions can be asymptomatic or cause significant morbidity and mortality. Adhesion formation after hepatectomy has not been studied extensively. In the present study, the molecular mechanisms underlying intra-abdominal adhesions after hepatectomy were investigated in a murine model and in patients. Interferon (IFN) γ produced by natural killer T cells is a key molecule for adhesion formation after hepatectomy in mice, acting via the reciprocal balance between plasminogen activator inhibitor (PAI) 1 and tissue plasminogen activator, the pivotal factors in fibrinolytic activity. This mechanism was also involved in the regulation of adhesions in human tissue samples. Hepatocyte growth factor (HGF) strongly inhibited adhesion formation by regulating IFN-γ and PAI-1. These results indicate that IFN-γ and PAI-1 are possible therapeutic targets, and HGF could prevent postoperative adhesion formation after hepatectomy.

Gene polymorphism and frequencies of the NPC1L1 gene (rs2072183, rs217434 and rs217428) in Japanese patients with dyslipidemia.

WHAT IS KNOWN AND OBJECTIVE: Niemann-Pick C1-Like 1 (NPC1L1) plays a pivotal role in intestinal cholesterol absorption. Ezetimibe is known as an inhibitor for NPC1L1 and decreases concentration of low-density lipoprotein cholesterol (LDL-C) in blood. Responses of the decrease of serum LDL-C levels to ezetimibe have been reported to be different among NPC1L1 variants. However, there are still limited data concerning the genetic variation in the NPC1L1 gene, specifically, in Japanese patients with dyslipidemia. The purpose of this study is to elucidate genotype and allele frequencies of the NPC1L1 gene in Japanese patients with dyslipidemia. METHODS: Written informed consent was obtained from all participants. All patients were administered ezetimibe at the dose of 10 mg for once a day either alone or coadministered with statins. Patient's data were retrospectively obtained from their medical records. Genomic DNA was extracted from whole blood samples and analysed three NPC1L1 SNPs (rs2072183, rs217428 and rs217434) by the direct sequencing method. RESULTS AND DISCUSSION: We found that there is a significant difference of genotype frequencies between healthy Japanese and dyslipidemic subjects in rs2072183. No significant differences were observed in rs217428 and rs217434; however, comparison of our data with literature reports suggests that there are significant differences in the frequencies of rs217428 and rs217434 between Canadian and Japanese dyslipidemic patients. WHAT IS NEW AND CONCLUSION: Our study is the first report concerning the genotype and allele frequencies of the gene coding for NPC1L1 in Japanese patients with dyslipidemia. The most notable result was to demonstrate that there exists a significant difference in rs2072183 variant between healthy Japanese and dyslipidemic subjects and also found that there exists genetic variation of rs2072183 between Japanese and Canadian patients with dyslipidemia. Our results are expected to facilitate research in the proper use of ezetimibe-based mono- or combination therapies. Further studies will be required to evaluate the effects of rs2072183 on the efficacy of LDL cholesterol reduction by ezetimibe.

Spatiotemporal expression patterns of doublesex and mab-3 related transcription factor 1 in the chicken developing gonads and Mullerian ducts.

Sex of birds is genetically determined by the inheritance of sex chromosomes (ZZ for male and ZW for female), and the Z-linked gene named doublesex and mab-3 related transcription factor 1 (DMRT1) is a candidate sex-determining gene in avian species. However, the mechanisms underlying sex determination in birds are not yet understood, and the expression patterns of the DMRT1 protein in urogenital tissues have not been identified. In the current study, we used immunohistochemistry to investigate the detailed expression patterns of the DMRT1 protein in the urogenital systems (including Müllerian ducts) in male and female chicken embryos throughout embryonic development. Gonadal somatic cells in the male indifferent gonads showed stronger expressions of DMRT1 compared with those in the female indifferent gonads well before the presumptive period of the sex determination, and Sertoli cells forming testicular cords expressed DMRT1 in the testes after sex determination. Germ cells expressed DMRT1 equally in males and females after sex determination. The expression was continuous in males, but in females it gradually disappeared from the germ cells in the central part of the cortex of the left ovary toward both edges. The DMRT1 was also detected in the tubal ridge, which is a precursor of the Müllerian duct, and at the mesenchyme and outermost coelomic epithelium of the Müllerian duct in both sexes. Strong expression was observed in the males, but it was restricted to coelomic epithelium after the regression of the duct started. Thus, we observed the detailed spatiotemporal expression patterns of DMRT1 in the developing chicken urogenital systems throughout embryonic development, suggesting its various roles in the development of urogenital tissues in the chicken embryo.

Optineurin is potentially associated with TDP-43 and involved in the pathogenesis of inclusion body myositis.

AIMS: Increasing evidences suggest a similarity in the pathophysiological mechanisms of neuronal cell death in amyotrophic lateral sclerosis (ALS) and myofibre degeneration in sporadic inclusion body myositis (sIBM). The aim of this study is to elucidate the involvement of ALS-causing proteins in the pathophysiological mechanisms in sIBM. METHODS: Skeletal muscle biopsy specimens of five patients with sIBM, two with oculopharyngeal muscular dystrophy (OPMD), three with polymyositis (PM), three with dermatomyositis (DM), three with neurogenic muscular atrophy, and three healthy control subjects were examined. We analysed the expression and localization of familial ALS-causing proteins, including transactive response DNA binding protein-43 (TDP-43), fused in sarcoma/translocated in liposarcoma (FUS/TLS), Cu/Zn superoxide dismutase (SOD1) and optineurin (OPTN) by immunohistochemistry. RESULTS: TDP-43, OPTN and, to a lesser extent, FUS/TLS were more frequently accumulated in the cytoplasm in patients with sIBM and OPMD than in patients with PM, DM, neurogenic muscular atrophy, or healthy control subjects. SOD1 was accumulated in a small percentage of myofibres in patients with sIBM and OPMD, and to a very small extent in patients with PM and DM. Confocal microscopy imaging showed that TDP-43 proteins more often colocalized with OPTN than with FUS/TLS, p62 and phosphorylated Tau. CONCLUSIONS: These findings suggest that OPTN in cooperation with TDP-43 might be involved in the pathophysiological mechanisms of skeletal muscular degeneration in myopathy with rimmed vacuoles. Further investigation into these mechanisms is therefore warranted.

Retention of tocilizumab and anti-tumour necrosis factor drugs in the treatment of rheumatoid arthritis.

OBJECTIVES: The retention of the anti-rheumatic agent tocilizumab (TCZ) has not been well documented in patients with rheumatoid arthritis (RA). We conducted an observational study to compare the retention of TCZ and anti-tumour necrosis factor (TNF) drugs in the treatment of patients with RA. METHOD: We reviewed continuation rates and causes of discontinuation of biological agents (biologics) by assessing medical records of patients with RA who were administered biologics at our institute from September 1999 to April 2012, using the Osaka University Biologics for Rheumatic Diseases (BiRD) registry. RESULTS: A total of 401 patients were included. TCZ, infliximab (IFX), etanercept (ETN), and adalimumab (ADA) were administered to 97, 103, 143, and 58 patients, respectively. There were some differences between the baseline characteristics of the groups. The median duration (range) of TCZ, IFX, ETN, and ADA administration was 2.5 (0.1-12.6), 1.9 (0.0-7.7), 2.9 (0.0-11.3), and 1.3 (0.0-3.4) years, respectively. Continuation rates for TCZ and ETN were significantly higher than those for IFX and ADA. Multivariate analyses showed that discontinuation due to lack or loss of efficacy was significantly less common in the TCZ group than in the other groups. Discontinuation due to overall adverse events was not significantly different between treatment groups. CONCLUSION: TCZ and ETN show better retention than IFX or ADA in the treatment of RA.

Progression of paralysis is the most useful factor for differentiating malignant from benign intramedullary tumors.

STUDY DESIGN: Retrospective study. OBJECTIVES: The purpose of this study was to identify the clinical factors for differentiating malignant from benign intramedullary spinal cord tumors. SETTING: Niigata, Japan. METHODS: We conducted a retrospective review of charts and images. Preoperative paralysis including walking ability, urinary function, magnetic resonance imaging (MRI) findings and pathological diagnosis were evaluated in 33 consecutive cases of intramedullary spinal cord tumor, and the clinical factors that were useful for differentiating malignant from benign tumors were identified. RESULTS: Early progression of paralysis was the most valuable feature for differentiating malignant from benign tumors. Malignant tumors were suspected in only three of ten cases on the basis of MRI findings. CONCLUSION: Simple assessment of walking ability is easy to perform and is useful for predicting the pathological malignancy of intramedullary tumors of the spinal cord.

Associated demographics of persistent exhaled nitric oxide elevation in treated asthmatics.

BACKGROUND: The fraction of exhaled nitric oxide (FENO) is reduced by anti-inflammatory treatment in asthma. However, the FENO level is also regulated by individual demographics and there is considerable variation among clinically stable patients. OBJECTIVE: We hypothesized that some demographics may be responsible for persistent FENO elevation despite inhaled corticosteroids (ICS) therapy in asthma. METHODS: This was a prospective observational study. We initially screened 250 stable asthmatics and determined the FENO cut-off point for identifying poorly controlled asthma defined by one of the following criteria: Asthma control test <20, or forced expiratory volume in one-second % of predicted <80%, or peak expiratory flow variability <80% (Study 1). After 12-weeks, 229 patients who maintained high or low FENO were selected and the independent factors which might contribute to a high FENO were examined (Study 2). RESULTS: A FENO level >39.5 p.p.b. yielded 67% sensitivity and 76% specificity for identifying the patients with poorly controlled asthma. The persistent high FENO group (≥ 40 p.p.b.) was more likely to be ex-smokers, to show evidence of atopy (positive specific IgE, higher serum IgE and blood eosinophils), and to have allergic comorbidities. Especially, past smoking history, blood eosinophils, and chronic rhinosinusitis were identified to be independent predictors of high FENO. Neither the dose of ICS nor other medication use showed any difference between the groups. CONCLUSIONS AND CLINICAL RELEVANCE: These results suggested that past smoking history, blood eosinophilia, and chronic rhinosinusitis are involved in the persistent airway inflammation detected by FENO. Although their relative contributions on FENO values should be further quantified, clarification of the features of the subjects with high FENO might provide clues for adjustment of the treatment approach in asthma.

Identification of an FBN1 mutation in bovine Marfan syndrome-like disease.

Mutations in the gene encoding fibrillin-1 (FBN1), a component of the extracellular microfibril, cause Marfan syndrome (MFS). Frequent observation of cattle with a normal withers height, but lower body weight than age-matched normal cattle, was recently reported among cattle sired by phenotypically normal Bull A, in Japanese Black cattle. These cattle also showed other characteristic features similar to the clinical phenotype of human MFS, such as a long phalanx proximalis, oval face and crystalline lens cloudiness. We first screened a paternal half-sib family comprising 36 affected and 10 normal offspring of Bull A using the BovineSNP50 BeadChip (illumina). Twenty-two microsatellite markers mapped to a significant region on BTA10 were subsequently genotyped on the family. The bovine Marfan syndrome-like disease (MFSL) was mapped onto BTA10. As FBN1 is located in the significant region, FBN1 was sequenced in Bull A, and three affected and one normal cattle. A G>A mutation at the intron64 splicing accepter site (c.8227-1G>A) was detected in 31 of 36 affected animals (84.7%). The c.8227-1G>A polymorphism was not found in 20 normal offspring of Bull A or in 93 normal cattle unrelated to Bull A. The mutation caused a 1-base shift of the intron64 splicing accepter site to the 3' direction, and a 1-base deletion in processed mRNA. This 1-base deletion creates a premature termination codon, and a 125-amino acid shorter Fibrillin-1 protein is produced from the mutant mRNA. We therefore conclude that the c.8227-1G>A mutation is causative for MFSL. Furthermore, it was suggested that Bull A exhibited germline mosaicism for the mutation, and that the frequency of the mutant sperm was 14.9%.

Tropical Peatland Hydrology Simulated With a Global Land Surface Model.

Tropical peatlands are among the most carbon-dense ecosystems on Earth, and their water storage dynamics strongly control these carbon stocks. The hydrological functioning of tropical peatlands differs from that of northern peatlands, which has not yet been accounted for in global land surface models (LSMs). Here, we integrated tropical peat-specific hydrology modules into a global LSM for the first time, by utilizing the peatland-specific model structure adaptation (PEATCLSM) of the NASA Catchment Land Surface Model (CLSM). We developed literature-based parameter sets for natural (PEATCLSMTrop,Nat) and drained (PEATCLSMTrop,Drain) tropical peatlands. Simulations with PEATCLSMTrop,Nat were compared against those with the default CLSM version and the northern version of PEATCLSM (PEATCLSMNorth,Nat) with tropical vegetation input. All simulations were forced with global meteorological reanalysis input data for the major tropical peatland regions in Central and South America, the Congo Basin, and Southeast Asia. The evaluation against a unique and extensive data set of in situ water level and eddy covariance-derived evapotranspiration showed an overall improvement in bias and correlation compared to the default CLSM version. Over Southeast Asia, an additional simulation with PEATCLSMTrop,Drain was run to address the large fraction of drained tropical peatlands in this region. PEATCLSMTrop,Drain outperformed CLSM, PEATCLSMNorth,Nat, and PEATCLSMTrop,Nat over drained sites. Despite the overall improvements of PEATCLSMTrop,Nat over CLSM, there are strong differences in performance between the three study regions. We attribute these performance differences to regional differences in accuracy of meteorological forcing data, and differences in peatland hydrologic response that are not yet captured by our model.

Native incretins prevent the development of atherosclerotic lesions in apolipoprotein E knockout mice.

AIMS/HYPOTHESIS: Several lines of evidence suggest that incretin-based therapies suppress the development of cardiovascular disease in type 2 diabetes. We investigated the possibility that glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) can prevent the development of atherosclerosis in Apoe (-/-) mice. METHODS: Apoe (-/-) mice (17 weeks old) were administered GLP-1(7-36)amide, GLP-1(9-36)amide, GIP(1-42) or GIP(3-42) for 4 weeks. Aortic atherosclerosis, oxidised LDL-induced foam cell formation and related gene expression in exudate peritoneal macrophages were determined. RESULTS: Administration of GLP-1(7-36)amide or GIP(1-42) significantly suppressed atherosclerotic lesions and macrophage infiltration in the aortic wall, compared with vehicle controls. These effects were cancelled by co-infusion with specific antagonists for GLP-1 and GIP receptors, namely exendin(9-39) or Pro(3)(GIP). The anti-atherosclerotic effects of GLP-1(7-36)amide and GIP(1-42) were associated with significant decreases in foam cell formation and downregulation of CD36 and acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT-1) in macrophages. GLP-1 and GIP receptors were both detected in Apoe (-/-) mouse macrophages. Ex vivo incubation of macrophages with GLP-1(7-36)amide or GIP(1-42) for 48 h significantly suppressed foam cell formation. This effect was wholly abolished in macrophages pretreated with exendin(9-39) or (Pro(3))GIP, or with an adenylate cyclase inhibitor, MDL12,330A, and was mimicked by incubation with an adenylate cyclase activator, forskolin. The inactive forms, GLP-1(9-36)amide and GIP(3-42), had no effects on atherosclerosis and macrophage foam cell formation. CONCLUSIONS/INTERPRETATION: Our study is the first to demonstrate that active forms of GLP-1 and GIP exert anti-atherogenic effects by suppressing macrophage foam cell formation via their own receptors, followed by cAMP activation. Molecular mechanisms underlying these effects are associated with the downregulation of CD36 and ACAT-1 by incretins.

SMC protein complexes and higher-order chromosome dynamics.

The structural maintenance of chromosome (SMC) family of proteins represents an expanding group of chromosomal ATPases that are highly conserved among Bacteria, Archaea and Eukarya. During the past year, significant progress has been made towards understanding the cellular functions and molecular activities of this new class of proteins. Emerging evidence suggests that eukaryotic SMC proteins form large protein complexes with non-SMC subunits and act as key components for a wide variety of higher-order chromosome dynamics.

The SMC family: from chromosome condensation to dosage compensation.

Recent genetic analyses in yeasts and biochemical studies in vertebrate cells have led to the discovery of a family of putative ATPases that play a fundamental role in chromosome condensation and segregation in mitosis. One of the members was also found to be involved in dosage compensation in Caenorhabditis elegans, providing a new link between global regulation of gene expression and chromosome structure. This unique family of proteins may control higher-order chromosome dynamics by regulated self-assembly or mechanochemical activity.

Correlation between the pharmacological efficacy of cyclosporine and tacrolimus as evaluated by the lymphocyte immunosuppressant sensitivity test (LIST) and the MTT assay procedure in patients before and after renal transplantation.

OBJECTIVES: Cyclosporine and tacrolimus are calcineurin inhibitors that are used to prevent acute rejection in renal transplant recipients. The lymphocyte immunosuppressant sensitivity test (LIST) can predict the pharmacological efficacy of these immunosuppressive agents for renal transplant recipients. There is a correlation between cyclosporine and tacrolimus pharmacological efficacy as evaluated by LIST by the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay procedure prior to renal transplantation. However, the LIST can also evaluate patients before and after the transplantation. MATERIALS AND METHODS: The present study examined the relationship between cyclosporine and tacrolimus pharmacological efficacy by LIST using the MTT assay in 16 renal transplant recipients at 1, 3 and 12 months after transplantation, as well as before the operation. RESULTS: The relationship of cyclosporine and tacrolimus pharmacological efficacy gave a significant Kendall and Spearman's coefficient correlation in these transplant recipients by the LIST using the MTT assay procedure immediately prior to renal transplantation (rk = 0.711, rs = 0.877, p < 0.01). Furthermore, correlations between the cyclosporine and tacrolimus IC50 values were also observed with a significant Kendall and Spearman's coefficient correlation at 1 and 12 months after transplantation (rk1month = 0.65, rs1month = 0.829, p < 0.01, and k12month = 0.433, rs12month = 0.603, p < 0.01, respectively). However, no statistically significant relationship was observed between the pharmacological efficacies of the calcineurin inhibitors at 3 months after transplantation (rk3month = 0.117, rs3month = 0.1, p > 0.05). CONCLUSIONS: Both cyclosporine and tacrolimus exhibit pharmacological efficacy by the inhibition of calcineurin. However, the correlation between cyclosporine and tacrolimus pharmacological efficacies may be altered, due to immunosuppressive therapy or clinical events at 3 months after renal transplantation.