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1.  Exenatide improves hepatic steatosis by enhancing lipid use in adipose tissue in nondiabetic rats 
AIM: To investigate the metabolic changes in skeletal muscle and/or adipose tissue in glucagon-like peptide-1-induced improvement of nonalcoholic fatty liver disease (NAFLD).
METHODS: Male Wistar rats were fed either a control diet (control group) or a high-fat diet (HFD). After 4 wk, the HFD-fed rats were subdivided into two groups; one group was injected with exenatide [HFD-Ex(+) group] and the other with saline [HFD-Ex(-) group] every day for 12 wk. The control group received saline and were fed a control diet. Changes in weight gain, energy intake, and oxygen consumption were analyzed. Glucose tolerance tests were performed after 8 wk of treatment. Histological assessments were performed in liver and adipose tissue. RNA expression levels of lipid metabolism related genes were evaluated in liver, skeletal muscle, and adipose tissue.
RESULTS: Exenatide attenuated weight gain [HFD-Ex(-) vs HFD-Ex(+)] and reduced energy intake, which was accompanied by an increase in oxygen consumption and a decrease in the respiratory exchange ratio [HFD-Ex(-) vs HFD-Ex(+)]. However, exenatide did not affect glucose tolerance. Exenatide reduced lipid content in the liver and adipose tissue. Exenatide did not affect the expression of lipid metabolism-related genes in the liver or skeletal muscle. In adipose tissue, exenatide significantly upregulated lipolytic genes, including hormone-sensitive lipase, carnitine palmitoyltransferase-1, long-chain acyl-CoA dehydrogenase, and acyl-CoA oxidase 1 [HFD-Ex(-) vs HFD-Ex(+)]. Exenatide also upregulated catalase and superoxide dismutase 2 [HFD-Ex(-) vs HFD-Ex(+)].
CONCLUSION: In addition to reducing appetite, enhanced lipid use by exenatide in adipose tissue may reduce hepatic lipid content in NAFLD, most likely by decreasing lipid influx into the liver.
doi:10.3748/wjg.v20.i10.2653
PMCID: PMC3949274  PMID: 24627601
Adipose tissue; Energy expenditure; Exenatide; Glucagon-like peptide-1; Hepatic steatosis; Lipolysis; Nonalcoholic fatty liver disease
2.  A gait abnormality measure based on root mean square of trunk acceleration 
Background
Root mean square (RMS) of trunk acceleration is seen frequently in gait analysis research. However, many studies have reported that the RMS value was related to walking speed. Therefore, the relationship between the RMS value and walking speed should be considered when the RMS value is used to assess gait abnormality. We hypothesized that the RMS values in three sensing axes exhibit common proportions for healthy people if they walk at their own preferred speed and that the RMS proportions in abnormal gait deviate from the common proportions. In this study, we proposed the RMS ratio (RMSR) as a gait abnormality measure and verified its ability to discriminate abnormal gait.
Methods
Forty-seven healthy male subjects (24–49 years) were recruited to examine the relationship between walking speed and the RMSR. To verify its ability to discriminate abnormal gait, twenty age-matched male hemiplegic patients (30–48 years) participated as typical subjects with gait abnormality. A tri-axial accelerometer was attached to their lower back, and they walked along a corridor at their own preferred speed. We defined the RMSR as the ratio between RMS in each direction and the RMS vector magnitude.
Results
In the healthy subjects, the RMS in all directions related to preferred walking speed. In contrast, RMSR in the mediolateral (ML) direction did not correlate with preferred walking speed (rs = -0.10, p = 0.54) and represented the similar value among the healthy subjects. Moreover, the RMSR in the ML direction for the hemiplegic patients was significantly higher than that for the healthy subjects (p < 0.01).
Conclusions
These results suggest that the RMSR in the ML direction exhibits a common value when healthy subjects walk at their own preferred speed, even if their preferred walking speed were different. For subjects with gait abnormality, the RMSR in the ML direction deviates from the common value of healthy subjects. The RMSR in the ML direction may potentially be a quantitative measure of gait abnormality.
doi:10.1186/1743-0003-10-118
PMCID: PMC3882286  PMID: 24370075
Gait abnormality measure; Trunk acceleration; Root mean square (RMS) ratio
3.  Intrahepatic microcirculatory disorder, parenchymal hypoxia and NOX4 upregulation result in zonal differences in hepatocyte apoptosis following lipopolysaccharide- and D-galactosamine-induced acute liver failure in rats 
Although the mechanisms responsible for acute liver failure (ALF) have not yet been fully elucidated, studies have indicated that intrahepatic macrophage activation plays an important role in the pathogenesis of ALF through intrahepatic microcirculatory disorder and consequent parenchymal cell death. Intrahepatic microcirculatory disorder has been demonstrated in animal models using intravital microscopy; however, the limitations of this method include simultaneously evaluating blood flow and the surrounding pathological changes. Therefore, in this study, we devised a novel method involving tetramethylrhodamine isothiocyanate (TRITC)-dextran administration for the pathological assessment of hepatic microcirculation. In addition, we aimed to elucidate the mechanisms through which intrahepatic microcirculatory disorder progresses with relation to activated macrophages. ALF was induced in Wistar rats by exposure to lipopolysaccharide and D-galactosamine. Intrahepatic microcirculation and microcirculatory disorder in zone 3 (pericentral zone) of the livers of rats with ALF was observed. Immunohistochemical examinations in conjunction with TRITC-dextran images revealed that the macrophages were mainly distributed in zone 2 (intermediate zone), while cleaved caspase-3-positive hepatocytes, pimonidazole and hypoxia-inducible factor 1-α were abundant in zone 3. We also found that 4-hydroxy-2-nonenal and nicotinamide adenine dinucleotide phosphate oxidase (NOX)4-positive cells were predominantly located in the zone 3 parenchyma. The majority of apoptotic hepatocytes in zone 3 were co-localized with NOX4. Our results revealed that the apoptotic cells in zone 3 were a result of hypoxic conditions induced by intrahepatic microcirculatory disorder, and were not induced by activated macrophages. The increased levels of oxidative stress in zone 3 may contribute to the progression of hepatocyte apoptosis.
doi:10.3892/ijmm.2013.1573
PMCID: PMC3896462  PMID: 24317376
acute liver failure; macrophage; hypoxia; oxidative stress; microcirculation; apoptosis; nicotinamide adenine dinucleotide phosphate oxidase; pimonidazole; cleaved caspase-3; 4-hydroxy-2-nonenal; reactive oxygen species; hypoxia-inducible factor 1-α
4.  Efficient Subtractive Cloning of Genes Activated by Lipopolysaccharide and Interferon γ in Primary-Cultured Cortical Cells of Newborn Mice 
PLoS ONE  2013;8(11):e79236.
Innate immune responses play a central role in neuroprotection and neurotoxicity during inflammatory processes that are triggered by pathogen-associated molecular pattern-exhibiting agents such as bacterial lipopolysaccharide (LPS) and that are modulated by inflammatory cytokines such as interferon γ (IFNγ). Recent findings describing the unexpected complexity of mammalian genomes and transcriptomes have stimulated further identification of novel transcripts involved in specific physiological and pathological processes, such as the neural innate immune response that alters the expression of many genes. We developed a system for efficient subtractive cloning that employs both sense and antisense cRNA drivers, and coupled it with in-house cDNA microarray analysis. This system enabled effective direct cloning of differentially expressed transcripts, from a small amount (0.5 µg) of total RNA. We applied this system to isolation of genes activated by LPS and IFNγ in primary-cultured cortical cells that were derived from newborn mice, to investigate the mechanisms involved in neuroprotection and neurotoxicity in maternal/perinatal infections that cause various brain injuries including periventricular leukomalacia. A number of genes involved in the immune and inflammatory response were identified, showing that neonatal neuronal/glial cells are highly responsive to LPS and IFNγ. Subsequent RNA blot analysis revealed that the identified genes were activated by LPS and IFNγ in a cooperative or distinctive manner, thereby supporting the notion that these bacterial and cellular inflammatory mediators can affect the brain through direct but complicated pathways. We also identified several novel clones of apparently non-coding RNAs that potentially harbor various regulatory functions. Characterization of the presently identified genes will give insights into mechanisms and interventions not only for perinatal infection-induced brain damage, but also for many other innate immunity-related brain disorders.
doi:10.1371/journal.pone.0079236
PMCID: PMC3823591  PMID: 24244457
5.  Curcumin Prevents Replication of Respiratory Syncytial Virus and the Epithelial Responses to It in Human Nasal Epithelial Cells 
PLoS ONE  2013;8(9):e70225.
The human nasal epithelium is the first line of defense during respiratory virus infection. Respiratory syncytial virus (RSV) is the major cause of bronchitis, asthma and severe lower respiratory tract disease in infants and young children. We previously reported in human nasal epithelial cells (HNECs), the replication and budding of RSV and the epithelial responses, including release of proinflammatory cytokines and enhancement of the tight junctions, are in part regulated via an NF-κB pathway. In this study, we investigated the effects of the NF-κB in HNECs infected with RSV. Curcumin prevented the replication and budding of RSV and the epithelial responses to it without cytotoxicity. Furthermore, the upregulation of the epithelial barrier function caused by infection with RSV was enhanced by curcumin. Curcumin also has wide pharmacokinetic effects as an inhibitor of NF-κB, eIF-2α dephosphorylation, proteasome and COX2. RSV-infected HNECs were treated with the eIF-2α dephosphorylation blocker salubrinal and the proteasome inhibitor MG132, and inhibitors of COX1 and COX2. Treatment with salubrinal, MG132 and COX2 inhibitor, like curcumin, prevented the replication of RSV and the epithelial responses, and treatment with salubrinal and MG132 enhanced the upregulation of tight junction molecules induced by infection with RSV. These results suggest that curcumin can prevent the replication of RSV and the epithelial responses to it without cytotoxicity and may act as therapy for severe lower respiratory tract disease in infants and young children caused by RSV infection.
doi:10.1371/journal.pone.0070225
PMCID: PMC3776807  PMID: 24058438
6.  Investigation of the factors associated with circulating soluble CD36 levels in patients with HCV-related chronic liver disease 
Background
CD36, a class B scavenger receptor, participates in the pathogenesis of metabolic dysregulation such as insulin resistance, hepatic steatosis, and atherosclerosis. Persistent hepatitis C virus (HCV) infection often evokes these metabolic abnormalities. The primary purpose of this study was to investigate the role of CD36 in the pathogenesis of insulin resistance and hepatic steatosis caused by chronic HCV infection.
Methods
Forty-five patients with HCV-related chronic liver disease (CLD-C) were enrolled in this study. CD36 expression in the liver specimen was examined by an immunohistochemical procedure. The concentrations of circulating soluble form of CD36 (sCD36) and oxLDL were determined by the enzyme-linked innunosorbent assay. Insulin resistance was estimated by the values of HOMA-IR.
Results
Moderate to extensive hepatic CD36 expression was observed in the sinusoids of all enrolled CLD-C patients. CD36-positive sinusoids appeared to be identical to Kupffer cells. The severity of CD36 expression in the hepatic sinusoids was significantly correlated with the sCD36 level in sera of patients with CLD-C. The serum sCD36 levels were significantly correlated with body mass index and serum oxLDL levels in those patients. However, the serum sCD36 concentrations were independent of the values of HOMA-IR and the severity of hepatic steatosis.
Conclusions
These data suggest that the serum sCD36 levels reflect the severity of CD36 expression on the Kupffer cells in patients with CLD-C, and that the serum sCD36 levels were associated with obesity, although the levels were independent of insulin resistance and hepatic steatosis in those patients.
doi:10.1186/1758-5996-5-51
PMCID: PMC3846866  PMID: 24016701
CD36; Hepatic steatosis; Hepatitis C virus; Insulin resistance; Oxidized low-density lipoprotein
7.  Correction: SORL1 Is Genetically Associated with Late-Onset Alzheimer’s Disease in Japanese, Koreans and Caucasians 
PLoS ONE  2013;8(7):10.1371/annotation/fcb56ea7-d32a-4e45-818d-39cef330c731.
doi:10.1371/annotation/fcb56ea7-d32a-4e45-818d-39cef330c731
PMCID: PMC3738644
8.  Empirical voriconazole therapy for febrile neutropenic patients with hematological disorders: a prospective multicenter trial in Japan 
An open-label, prospective, multicenter study was conducted between October 2006 and March 2010 to assess the efficacy and safety of intravenous voriconazole (VRCZ) as empirical therapy for antibiotic-refractory febrile neutropenia in Japanese patients with hematological disorders. In addition, to find the patient groups that may benefit from antifungal therapy, the definition of invasive fungal infection proposed by EORTC/MSG (2002) was assessed in this study. Plasma (1-3)-β-d-glucan and Aspergillus PCR in blood were also measured to improve the diagnostic accuracy. A total of 103 patients (median age, 59 years), including 25 undergoing induction chemotherapies and 19 allogeneic hematopoietic cell transplants, were evaluable. Sixty-nine percent of the patients achieved resolution of clinical symptoms and 31 % achieved treatment success, defined as fulfilling the previously described five-part composite endpoint. Although VRCZ was discontinued in 9.7 % of the patients because of adverse effects, all the patients recovered soon after discontinuation of VRCZ. The treatment success rate of VRCZ appeared to be higher in patients categorized as “not classified” compared with “possible invasive fungal disease” according to the EORTC/MSG criteria. Moreover, six “not classified” patients were positive for either plasma (1-3)-β-d-glucan (n = 5) or Aspergillus PCR in blood (n = 2). The present study demonstrates that empirical VRCZ therapy is safe and effective in Japanese patients. Additionally, (1-3)-β-d-glucan and Aspergillus PCR tests were expected to provide additional information on the diagnosis of invasive fungal infections.
doi:10.1007/s10156-013-0634-5
PMCID: PMC3857881  PMID: 23813092
Prospective multicenter study; Voriconazole; Empirical antifungal therapy
9.  DNA Methylation Restricts Lineage-specific Functions of Transcription Factor Gata4 during Embryonic Stem Cell Differentiation 
PLoS Genetics  2013;9(6):e1003574.
DNA methylation changes dynamically during development and is essential for embryogenesis in mammals. However, how DNA methylation affects developmental gene expression and cell differentiation remains elusive. During embryogenesis, many key transcription factors are used repeatedly, triggering different outcomes depending on the cell type and developmental stage. Here, we report that DNA methylation modulates transcription-factor output in the context of cell differentiation. Using a drug-inducible Gata4 system and a mouse embryonic stem (ES) cell model of mesoderm differentiation, we examined the cellular response to Gata4 in ES and mesoderm cells. The activation of Gata4 in ES cells is known to drive their differentiation to endoderm. We show that the differentiation of wild-type ES cells into mesoderm blocks their Gata4-induced endoderm differentiation, while mesoderm cells derived from ES cells that are deficient in the DNA methyltransferases Dnmt3a and Dnmt3b can retain their response to Gata4, allowing lineage conversion from mesoderm cells to endoderm. Transcriptome analysis of the cells' response to Gata4 over time revealed groups of endoderm and mesoderm developmental genes whose expression was induced by Gata4 only when DNA methylation was lost, suggesting that DNA methylation restricts the ability of these genes to respond to Gata4, rather than controlling their transcription per se. Gata4-binding-site profiles and DNA methylation analyses suggested that DNA methylation modulates the Gata4 response through diverse mechanisms. Our data indicate that epigenetic regulation by DNA methylation functions as a heritable safeguard to prevent transcription factors from activating inappropriate downstream genes, thereby contributing to the restriction of the differentiation potential of somatic cells.
Author Summary
Animal bodies are constructed from many different specialized cell types that are generated during embryogenesis from a single fertilized egg, and acquire their specific characteristics through a series of differentiation steps. After being committed to a specific cell type, it is generally difficult for differentiated cells to convert to other cell types, at least partly because the cells maintain some memory or mark of their developmental history. Such cellular memory is mediated by “epigenetic” mechanisms, which function to stabilize the cell state. DNA methylation, a chemical modification of genomic cytosine residues, is one such mechanism. Genomic DNA methylation patterns in early embryonic cells are established in a cell-type-dependent manner, and these specific patterns are propagated through cell divisions in a clonal manner. However, our understanding of how DNA methylation controls cell differentiation and developmental gene regulation is limited. In this study, using an in vitro model of differentiation, we obtained evidence that DNA methylation modulates the cell's response to DNA-binding transcription factors in a cell-type-dependent manner. These findings extend our understanding of how cellular traits are stabilized within specific lineages during development, and may contribute to advances in cellular engineering.
doi:10.1371/journal.pgen.1003574
PMCID: PMC3694845  PMID: 23825962
10.  SORL1 Is Genetically Associated with Late-Onset Alzheimer’s Disease in Japanese, Koreans and Caucasians 
PLoS ONE  2013;8(4):e58618.
To discover susceptibility genes of late-onset Alzheimer’s disease (LOAD), we conducted a 3-stage genome-wide association study (GWAS) using three populations: Japanese from the Japanese Genetic Consortium for Alzheimer Disease (JGSCAD), Koreans, and Caucasians from the Alzheimer Disease Genetic Consortium (ADGC). In Stage 1, we evaluated data for 5,877,918 genotyped and imputed SNPs in Japanese cases (n = 1,008) and controls (n = 1,016). Genome-wide significance was observed with 12 SNPs in the APOE region. Seven SNPs from other distinct regions with p-values <2×10−5 were genotyped in a second Japanese sample (885 cases, 985 controls), and evidence of association was confirmed for one SORL1 SNP (rs3781834, P = 7.33×10−7 in the combined sample). Subsequent analysis combining results for several SORL1 SNPs in the Japanese, Korean (339 cases, 1,129 controls) and Caucasians (11,840 AD cases, 10,931 controls) revealed genome wide significance with rs11218343 (P = 1.77×10−9) and rs3781834 (P = 1.04×10−8). SNPs in previously established AD loci in Caucasians showed strong evidence of association in Japanese including rs3851179 near PICALM (P = 1.71×10−5) and rs744373 near BIN1 (P = 1.39×10−4). The associated allele for each of these SNPs was the same as in Caucasians. These data demonstrate for the first time genome-wide significance of LOAD with SORL1 and confirm the role of other known loci for LOAD in Japanese. Our study highlights the importance of examining associations in multiple ethnic populations.
doi:10.1371/journal.pone.0058618
PMCID: PMC3614978  PMID: 23565137
11.  Arm span–height difference is correlated with gastroesophageal reflux symptoms in aged Japanese subjects 
Previous studies have indicated an association between the symptoms of gastroesophageal reflux disease (GERD) and aging plus height. In this study we investigated whether the arm span–height difference was related to GERD symptoms with a focus on aged subjects in the general population, since the arm span reflects the height in young adulthood before decreasing due to vertebral deformities from aging. A total of 285 elderly individuals (105 females) who visited nursing homes for the elderly in Japan were enrolled in this study. The GERD symptoms were evaluated by the Frequency Scale for the Symptoms of GERD (FSSG). The body weight, height and arm span were measured, and information regarding medications and complications were reviewed in each nursing record. 50.5% of women had more than 3 cm of arm span–height difference. In contrast, only 37.3% of men had more than 3 cm of arm span–height difference. The FSSG scores indicated more than 70% of subjects complained of any GERD symptoms. There was a significant correlation between the FSSG score and the arm span–height difference in the subjects with more than 3 cm of arm span-height difference (r = 0.236; p = 0.012). The correlation between the arm span–height difference and the FSSG score was significant only in women in females in the present study. In conclusion, our findings indicate that vertebral deformity evaluated by the arm span–height difference might have some positive relationship to the pathogenesis of GERD symptoms in elderly Japanese individuals.
doi:10.3164/jcbn.12-89
PMCID: PMC3541425  PMID: 23341704
aging; kyphosis; orthopedics; sex difference; vertebral deformities
12.  Cell Surface Galectin-9 Expressing Th Cells Regulate Th17 and Foxp3+ Treg Development by Galectin-9 Secretion 
PLoS ONE  2012;7(11):e48574.
Galectin-9 (Gal-9), a β-galactoside binding mammalian lectin, regulates immune responses by reducing pro-inflammatory IL-17-producing Th cells (Th17) and increasing anti-inflammatory Foxp3+ regulatory T cells (Treg) in vitro and in vivo. These functions of Gal-9 are thought to be exerted by binding to receptor molecules on the cell surface. However, Gal-9 lacks a signal peptide for secretion and is predominantly located in the cytoplasm, which raises questions regarding how and which cells secrete Gal-9 in vivo. Since Gal-9 expression does not necessarily correlate with its secretion, Gal-9-secreting cells in vivo have been elusive. We report here that CD4 T cells expressing Gal-9 on the cell surface (Gal-9+ Th cells) secrete Gal-9 upon T cell receptor (TCR) stimulation, but other CD4 T cells do not, although they express an equivalent amount of intracellular Gal-9. Gal-9+ Th cells expressed interleukin (IL)-10 and transforming growth factor (TGF)-β but did not express Foxp3. In a co-culture experiment, Gal-9+ Th cells regulated Th17/Treg development in a manner similar to that by exogenous Gal-9, during which the regulation by Gal-9+ Th cells was shown to be sensitive to a Gal-9 antagonist but insensitive to IL-10 and TGF-β blockades. Further elucidation of Gal-9+ Th cells in humans indicates a conserved role of these cells through evolution and implies the possible utility of these cells for diagnosis or treatment of immunological diseases.
doi:10.1371/journal.pone.0048574
PMCID: PMC3492452  PMID: 23144904
13.  Migration to the pulmonary artery of nine metallic coils placed in the internal iliac vein for treatment of giant rectal varices 
Acta Radiologica Short Reports  2012;1(6):arsr.2012.120024.
Transcatheter venous embolization with metallic coils is a safe and reliable method for the treatment of pelvic congestion syndrome and pelvic varicocele. While rare, coil migration to the pulmonary arteries is potentially fatal. We report the migration to the pulmonary artery of a cluster of nine metallic microcoils placed in the internal iliac vein to obliterate giant rectal varices. Our patient suffered no severe sequelae. To avoid coil migration to the pulmonary arteries, the coils chosen for placement must take into consideration the characteristics of the target vessels, particularly of larger veins.
doi:10.1258/arsr.2012.120024
PMCID: PMC3738354  PMID: 23986845
Vascular; angiography; embolization; rectum; adults; varices
14.  Non-human primate model of amyotrophic lateral sclerosis with cytoplasmic mislocalization of TDP-43 
Brain  2012;135(3):833-846.
Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by progressive motoneuron loss. Redistribution of transactive response deoxyribonucleic acid-binding protein 43 from the nucleus to the cytoplasm and the presence of cystatin C-positive Bunina bodies are considered pathological hallmarks of amyotrophic lateral sclerosis, but their significance has not been fully elucidated. Since all reported rodent transgenic models using wild-type transactive response deoxyribonucleic acid-binding protein 43 failed to recapitulate these features, we expected a species difference and aimed to make a non-human primate model of amyotrophic lateral sclerosis. We overexpressed wild-type human transactive response deoxyribonucleic acid-binding protein 43 in spinal cords of cynomolgus monkeys and rats by injecting adeno-associated virus vector into the cervical cord, and examined the phenotype using behavioural, electrophysiological, neuropathological and biochemical analyses. These monkeys developed progressive motor weakness and muscle atrophy with fasciculation in distal hand muscles first. They also showed regional cytoplasmic transactive response deoxyribonucleic acid-binding protein 43 mislocalization with loss of nuclear transactive response deoxyribonucleic acid-binding protein 43 staining in the lateral nuclear group of spinal cord innervating distal hand muscles and cystatin C-positive cytoplasmic aggregates, reminiscent of the spinal cord pathology of patients with amyotrophic lateral sclerosis. Transactive response deoxyribonucleic acid-binding protein 43 mislocalization was an early or presymptomatic event and was later associated with neuron loss. These findings suggest that the transactive response deoxyribonucleic acid-binding protein 43 mislocalization leads to α-motoneuron degeneration. Furthermore, truncation of transactive response deoxyribonucleic acid-binding protein 43 was not a prerequisite for motoneuronal degeneration, and phosphorylation of transactive response deoxyribonucleic acid-binding protein 43 occurred after degeneration had begun. In contrast, similarly prepared rat models expressed transactive response deoxyribonucleic acid-binding protein 43 only in the nucleus of motoneurons. There is thus a species difference in transactive response deoxyribonucleic acid-binding protein 43 pathology, and our monkey model recapitulates amyotrophic lateral sclerosis pathology to a greater extent than rodent models, providing a valuable tool for studying the pathogenesis of sporadic amyotrophic lateral sclerosis.
doi:10.1093/brain/awr348
PMCID: PMC3286326  PMID: 22252998
TDP-43; Bunina bodies; cystatin C; cynomolgus monkeys; amyotrophic lateral sclerosis
15.  Polychlorinated dioxins, furans, and biphenyls in blood of children and adults living in a dioxin-contaminated area in Tokyo 
The soil of a residential area in Tokyo was found to contain dioxins, namely polychlorinated dioxins, furans, and dioxin-like biphenyls, the levels of which exceeded the environmental guideline [1,000 pg toxic equivalent (TEQ)/g] by up to 6.8 times. To assess the exposure levels of people living in this area and to study the possible relationship of blood dioxin concentrations of children with breast milk and/or formula feeding, a health survey was carried out in 2006, involving a total of 138 people, including 66 children aged 3–15 years, and blood dioxin concentrations and the characteristics and lifestyles of these people were analyzed. Mean ± standard error of the mean (SEM) of blood dioxin concentrations (pg/g-lipid) of group 1 (3–6 years old), group 2 (7–15 years old), and group 3 (≥16 years old) were 13 ± 1.9, 6.6 ± 0.65, and 10 ± 0.54, respectively. The congener/isomer profile of dioxins in blood samples differed markedly from that of the contaminated soil samples. According to the feeding mode of children, blood dioxin concentrations (pg/g-lipid) were 17 ± 2.9 for breast milk only, 7.4 ± 0.82 for both breast milk and formula, and 4.7 ± 1.1 for formula only, with a significant difference from one another. We conclude that people living in the dioxin-contaminated area are less likely to be exposed to excessive amounts of dioxins, and that blood dioxin concentrations of children aged 3–15 years seem to be strongly affected by breast feeding duration.
Electronic supplementary material
The online version of this article (doi:10.1007/s12199-010-0156-z) contains supplementary material, which is available to authorized users.
doi:10.1007/s12199-010-0156-z
PMCID: PMC2999684  PMID: 21432212
Blood; Breast feeding; Children; Dioxin; Soil
16.  Transplantation of Bone Marrow-Derived Mononuclear Cells Improves Mechanical Hyperalgesia, Cold Allodynia and Nerve Function in Diabetic Neuropathy 
PLoS ONE  2011;6(11):e27458.
Relief from painful diabetic neuropathy is an important clinical issue. We have previously shown that the transplantation of cultured endothelial progenitor cells or mesenchymal stem cells ameliorated diabetic neuropathy in rats. In this study, we investigated whether transplantation of freshly isolated bone marrow-derived mononuclear cells (BM-MNCs) alleviates neuropathic pain in the early stage of streptozotocin-induced diabetic rats. Two weeks after STZ injection, BM-MNCs or vehicle saline were injected into the unilateral hind limb muscles. Mechanical hyperalgesia and cold allodynia in SD rats were measured as the number of foot withdrawals to von Frey hair stimulation and acetone application, respectively. Two weeks after the BM-MNC transplantation, sciatic motor nerve conduction velocity (MNCV), sensory nerve conduction velocity (SNCV), sciatic nerve blood flow (SNBF), mRNA expressions and histology were assessed. The BM-MNC transplantation significantly ameliorated mechanical hyperalgesia and cold allodynia in the BM-MNC-injected side. Furthermore, the slowed MNCV/SNCV and decreased SNBF in diabetic rats were improved in the BM-MNC-injected side. BM-MNC transplantation improved the decreased mRNA expression of NT-3 and number of microvessels in the hind limb muscles. There was no distinct effect of BM-MNC transplantation on the intraepidermal nerve fiber density. These results suggest that autologous transplantation of BM-MNCs could be a novel strategy for the treatment of painful diabetic neuropathy.
doi:10.1371/journal.pone.0027458
PMCID: PMC3220696  PMID: 22125614
17.  A nuclear factor-κB signaling pathway via protein kinase C δ regulates replication of respiratory syncytial virus in polarized normal human nasal epithelial cells 
Molecular Biology of the Cell  2011;22(13):2144-2156.
We established a respiratory syncytial virus (RSV)-infected model in polarized normal human nasal epithelial cells and found that the replication of RSV and the epithelial cell responses including induction of tight junctions were regulated via a protein kinase C δ/hypoxia-inducible factor-1α/nuclear factor-κβ pathway. The control of this pathway may be useful in therapy for RSV-induced respiratory pathogenesis.
Respiratory syncytial virus (RSV) is the major cause of bronchitis, asthma, and severe lower respiratory tract disease in infants and young children. The airway epithelium, which has a well-developed barrier regulated by tight junctions, is the first line of defense during respiratory virus infection. In upper airway human nasal epithelial cells (HNECs), however, the primary site of RSV infection, the mechanisms of replication and budding of RSV, and the epithelial cell responses, including the tight junctional barrier, remain unknown. To investigate the detailed mechanisms of replication and budding of RSV in HNECs and the epithelial cell responses, we established an RSV-infected model using human telomerase reverse transcriptase–-transfected HNECs. We first found that the expression and barrier function of tight junction molecules claudin-4 and occludin were markedly induced together with production of proinflammatory cytokines interleukin 8 and tumor necrosis factor-α in HNECs after RSV infection, and the induction of tight junction molecules possibly contributed to budding of RSV. Furthermore, the replication and budding of RSV and the epithelial cell responses in HNECs were regulated via a protein kinase C δ/hypoxia-inducible factor-1α/nuclear factor-κB pathway. The control of this pathway in HNECs may be useful not only for prevention of replication and budding of RSV, but also in therapy for RSV-induced respiratory pathogenesis.
doi:10.1091/mbc.E10-11-0875
PMCID: PMC3128518  PMID: 21562222
18.  Surgical management of severe scoliosis with high risk pulmonary dysfunction in Duchenne muscular dystrophy: patient function, quality of life and satisfaction 
International Orthopaedics  2010;34(5):695-702.
In a previous study, the authors reported the clinical and radiological results of Duchenne muscular dystrophy (DMD) scoliosis surgery in 14 patients with a low FVC of <30%. The purpose of this study was to determine if surgery improved function and QOL in these patients. Furthermore, the authors assessed the patients’ and parents’ satisfaction. %FVC increased in all patients after preoperative inspiratory muscle training. Scoliosis surgery in this group of patients presented no increased risk of major complications. All-screw constructions and fusion offered the ability to correct spinal deformity in the coronal and pelvic obliquity initially, intermediate and long-term. All patients were encouraged to continue inspiratory muscle training after surgery. The mean rate of %FVC decline after surgery was 3.6% per year. Most patients and parents believed scoliosis surgery improved their function, sitting balance and quality of life even though patients were at high risk for major complications. Their satisfaction was also high.
doi:10.1007/s00264-010-0957-0
PMCID: PMC2903179  PMID: 20155495
19.  Can the caudal extent of fusion in the surgical treatment of scoliosis in Duchenne muscular dystrophy be stopped at lumbar 5? 
European Spine Journal  2010;19(5):787-796.
Instrumentation and fusion to the sacrum/pelvis has been a mainstay in the surgical treatment of scoliosis in Duchenne muscular dystrophy (DMD) and is recommended to correct pelvic obliquity. The caudal extent of instrumentation and fusion in the surgical treatment of scoliosis in DMD has remained a matter of considerable debate, and there have been few studies on the use of segmental pedicle screw instrumentation for this pathology. From 2004 to 2007, a total of 28 patients with DMD underwent segmental pedicle screw instrumentation and fusion only to L5. Assessment was performed clinically and with radiologic measurements. All patients had a curve with the apex at L2 or higher preoperatively. Preoperative coronal curve averaged 74°, with a postoperative mean of 14°, and 17° at the last follow-up. The pelvic obliquity improved from 17° preoperatively to 6° postoperatively, and 6° at the last follow-up. Good sagittal plane alignment was recreated after surgery and maintained long term. In 23 patients with a preoperative L5 tilt of less than 15°, the pelvic obliquity was effectively corrected to less than 10° and maintained by adequately addressing spinal deformity, while five patients with a preoperative L5 tilt of more than 15° had a postoperative pelvic obliquity of more than 15°. Segmental pedicle screw instrumentation and fusion to L5 was effective and safe in patients with DMD scoliosis with a minimal L5 tilt (<15°) and a curve with the apex at L2 or higher, both initially and long term, obviating the need for fixation to the sacrum/pelvis. Segmental pedicle screw instrumentation and fusion to L5 was safe and effective in patients with DMD scoliosis with stable L5/S1 articulation as evidenced by a minimal L5 tilt of less than 15°, even though pelvic obliquity was significant. There was no major complication. With rigid segmental pedicle screw instrumentation, the caudal extent of fusion in the treatment of DMD scoliosis should be determined by the degree of L5 tilt. This method in appropriate patients can be a viable alternative to instrumentation and fusion to the sacrum/pelvis in the surgical treatment of DMD scoliosis.
doi:10.1007/s00586-010-1347-4
PMCID: PMC2899950  PMID: 20213296
Duchenne muscular dystrophy; Scoliosis; Pelvic obliquity; Lumbar 5 tilt; Pedicle screw instrumentation
20.  Blockade of AT1 Receptors Protects the Blood–Brain Barrier and Improves Cognition in Dahl Salt-Sensitive Hypertensive Rats 
American journal of hypertension  2010;24(3):362-368.
BACKGROUND
The present study tested the hypothesis that inappropriate activation of the brain renin–angiotensin system (RAS) contributes to the pathogenesis of blood–brain barrier (BBB) disruption and cognitive impairment during development of salt-dependent hypertension. Effects of an angiotensin II (AngII) type-1 receptor blocker (ARB), at a dose that did not reduce blood pressure, were also examined.
METHODS
Dahl salt-sensitive (DSS) rats at 6 weeks of age were assigned to three groups: low-salt diet (DSS/L; 0.3% NaCl), high-salt diet (DSS/H; 8% NaCl), and high-salt diet treated with ARB, olmesartan at 1 mg/kg.
RESULTS
DSS/H rats exhibited hypertension, leakage from brain microvessels in the hippocampus, and impaired cognitive functions, which were associated with increased brain AngII levels, as well as decreased mRNA levels of tight junctions (TJs) and collagen-IV in the hippocampus. In DSS/H rats, olmesartan treatment, at a dose that did not alter blood pressure, restored the cognitive decline, and ameliorated leakage from brain microvessels. Olmesartan also decreased brain AngII levels and restored mRNA expression of TJs and collagen-IV in DSS/H rats.
CONCLUSIONS
These results suggest that during development of salt-dependent hypertension, activation of the brain RAS contributes to BBB disruption and cognitive impairment. Treatment with an ARB could elicit neuroprotective effects in cognitive disorders by preventing BBB permeability, which is independent of blood pressure changes.
doi:10.1038/ajh.2010.241
PMCID: PMC3040273  PMID: 21164491
blood–brain barrier; blood pressure; cognitive impairment; hypertension; receptors; vascular cognitive impairment
21.  Pyrroloquinoline quinone inhibits the fibrillation of amyloid proteins 
Prion  2010;4(1):26-31.
Several neurodegenerative diseases involve the selective damage of neuron cells resulting from the accumulation of amyloid fibril formation. Considering that the formation of amyloid fibrils as well as their precursor oligomers is cytotoxic, the agents that prevent the formation of oligomers and/or fibrils might allow the development of a novel therapeutic approach to neurodegenerative diseases. Here, we show pyrroloquinoline quinone (PQQ) inhibits the amyloid fibril formation of the amyloid proteins, amyloid β (1–42) and mouse prion protein. The fibril formation of mouse prion protein in the presence of PQQ was dramatically prevented. Similarly, the fibril formation of amyloid β (1–42) also decreased. With further advanced pharmacological approaches, PQQ may become a leading anti-neurodegenerative compound in the treatment of neurodegenerative diseases.
PMCID: PMC2850417  PMID: 20083898
amyloid β; amyloid fibril; cytotoxicity; fibril formation; inhibitor; prion; pyrroloquinoline quinone
22.  Integrated care through disease-oriented clinical care pathways: experience from Japan’s regional health planning initiatives 
International Journal of Integrated Care  2011;11(Special 10th Anniversary Edition):e125.
Introduction
In April 2008, Japan launched a radical reform in regional health planning that emphasized the development of disease-oriented clinical care pathways. These ‘inter-provider critical paths’ have sought to ensure effective integration of various providers ranging among primary care practitioners, acute care hospitals, rehabilitation hospitals, long-term care facilities and home care.
Description of policy practice
All 47 prefectures in Japan developed their Regional Health Plans pursuant to the guideline requiring that these should include at least four diseases: diabetes, acute myocardial infarction, cerebrovascular accident and cancer. To illustrate the care pathways developed, this paper describes the guideline referring to strokes and provides examples of the new Regional Health Plans as well as examples of disease-oriented inter-provider clinical paths. In particular, the paper examines the development of information sharing through electronic health records (EHR) to enhance effective integration among providers is discussed.
Discussion and conclusion
Japan’s reform in 2008 is unique in that the concept of ‘disease-oriented regional inter-provider critical paths’ was adopted as a national policy and all 47 prefectures developed their Regional Health Plans simultaneously. How much the new regional health planning policy has improved the quality and outcome of care remains to be seen and will be evaluated in 2013 after the five-year planned period of implementation has concluded. Whilst electronic health records appear to be a useful tool in supporting care integration they do not guarantee success in the application of an inter-provider critical path.
PMCID: PMC3226016  PMID: 22128281
regional health planning; disease management; critical path; electronic health record; care pathways; Japan
23.  Feasibility study of two schedules of sunitinib in combination with pemetrexed in patients with advanced solid tumors 
Investigational New Drugs  2010;30(2):639-646.
Summary
Background Sunitinib is an oral multitargeted tyrosine kinase inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptors, as well as of other receptor types. We have performed a feasibility study to investigate the safety of sunitinib in combination with pemetrexed for treatment of advanced refractory solid tumors. Methods Sunitinib was administered once daily on a continuous daily dosing (CDD) schedule (37.5 mg/day) or a 2-weeks-on, 1-week-off treatment schedule (50 mg/day, Schedule 2/1) in combination with pemetrexed at 500 mg/m2 on day 1 of repeated 21-day cycles. Results Twelve patients were enrolled in the study: six on the CDD schedule and six on Schedule 2/1. None of the treated patients experienced a dose-limiting toxicity. Toxicities were manageable and similar in type to those observed in monotherapy studies of sunitinib and pemetrexed. Pharmacokinetic analysis did not reveal any substantial drug–drug interaction. One patient with squamous cell lung cancer showed a partial response and five patients had stable disease. Conclusions Combination therapy with sunitinib administered on Schedule 2/1 (50 mg/day) or a CDD schedule (37.5 mg/day) together with standard-dose pemetrexed (500 mg/m2) was well tolerated in previously treated patients with advanced solid tumors.
doi:10.1007/s10637-010-9565-5
PMCID: PMC3277823  PMID: 20960028
Sunitinib; Pemetrexed; Feasibility study; Solid tumors
24.  The 28-amino acid form of an APLP1-derived Aβ-like peptide is a surrogate marker for Aβ42 production in the central nervous system 
EMBO Molecular Medicine  2009;1(4):223-235.
Surrogate markers for the Alzheimer disease (AD)-associated 42-amino acid form of amyloid-β (Aβ42) have been sought because they may aid in the diagnosis of AD and for clarification of disease pathogenesis. Here, we demonstrate that human cerebrospinal fluid (CSF) contains three APLP1-derived Aβ-like peptides (APL1β) that are generated by β- and γ-cleavages at a concentration of ∼4.5 nM. These novel peptides, APL1β25, APL1β27 and APL1β28, were not deposited in AD brains. Interestingly, most γ-secretase modulators (GSMs) and familial AD-associated presenilin1 mutants that up-regulate the relative production of Aβ42 cause a parallel increase in the production of APL1β28 in cultured cells. Moreover, in CSF from patients with pathological mutations in presenilin1 gene, the relative APL1β28 levels are higher than in non-AD controls, while the relative Aβ42 levels are unchanged or lower. Most strikingly, the relative APL1β28 levels are higher in CSF from sporadic AD patients (regardless of whether they are at mild cognitive impairment or AD stage), than those of non-AD controls. Based on these results, we propose the relative level of APL1β28 in the CSF as a candidate surrogate marker for the relative level of Aβ42 production in the brain.
doi:10.1002/emmm.200900026
PMCID: PMC3378133  PMID: 20049724
Alzheimer disease; APLP1; Aβ-like peptides; cerebrospinal fluid; presenilin/γ-secretase
25.  An Integrated High-density Linkage Map of Soybean with RFLP, SSR, STS, and AFLP Markers Using A Single F2 Population 
Abstract
Soybean [Glycine max (L.) Merrill] is the most important leguminous crop in the world due to its high contents of high-quality protein and oil for human and animal consumption as well as for industrial uses. An accurate and saturated genetic linkage map of soybean is an essential tool for studies on modern soybean genomics. In order to update the linkage map of a F2 population derived from a cross between Misuzudaizu and Moshidou Gong 503 and to make it more informative and useful to the soybean genome research community, a total of 318 AFLP, 121 SSR, 108 RFLP, and 126 STS markers were newly developed and integrated into the framework of the previously described linkage map. The updated genetic map is composed of 509 RFLP, 318 SSR, 318 AFLP, 97 AFLP-derived STS, 29 BAC-end or EST-derived STS, 1 RAPD, and five morphological markers, covering a map distance of 3080 cM (Kosambi function) in 20 linkage groups (LGs). To our knowledge, this is presently the densest linkage map developed from a single F2 population in soybean. The average intermarker distance was reduced to 2.41 from 5.78 cM in the earlier version of the linkage map. Most SSR and RFLP markers were relatively evenly distributed among different LGs in contrast to the moderately clustered AFLP markers. The number of gaps of more than 25 cM was reduced to 6 from 19 in the earlier version of the linkage map. The coverage of the linkage map was extended since 17 markers were mapped beyond the distal ends of the previous linkage map. In particular, 17 markers were tagged in a 5.7 cM interval between CE47M5a and Satt100 on LG C2, where several important QTLs were clustered. This newly updated soybean linkage map will enable to streamline positional cloning of agronomically important trait locus genes, and promote the development of physical maps, genome sequencing, and other genomic research activities.
doi:10.1093/dnares/dsm027
PMCID: PMC2779910  PMID: 18192280
soybean; linkage map; SSR; RFLP; AFLP; STS

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