Entecavir and tenofovir reduce hepatitis B virus-related hepatocellular carcinoma recurrence more effectively than other antivirals.

Nucleos(t)ide analogues (NAs) have been shown to decrease the risk of hepatocellular carcinoma (HCC) recurrence. This study evaluated whether high-potency NAs (entecavir and tenofovir disoproxil fumarate [TDF]) reduce the risk of tumour recurrence more potently than low-potency NAs after curative treatment of hepatitis B virus (HBV)-related HCC. This study included 607 consecutive HBV-related HCC patients treated with surgical resection or radiofrequency ablation. The patients were categorized into three groups according to antiviral treatment: group A (no antiviral; n = 261), group B (low-potency NA; n = 90) and group C (high-potency NA; n = 256). The primary end-point was recurrence-free survival (RFS). During the duration of follow-up, the median RFS was 29.4, 25.1, and 88.2 months in groups A, B and C, respectively (P < .001, log-rank test). The multivariate Cox analysis indicated that group C had a significantly longer RFS than both group A (adjusted hazard ratio [HR] = 0.39, P < .001) and group B (adjusted HR = 0.47, P < .001). When baseline characteristics were balanced using inverse probability weighting, group C still had a significantly longer RFS than group A (adjusted HR = 0.46, P < .001) and group B (adjusted HR = 0.59, P = .007). Group C had significantly lower risk of viral breakthrough than group B (HR = 0.19, P < .001). Viral breakthrough was an independent risk factor for shorter RFS among groups B and C (adjusted HR = 2.03, P = .007, time-dependent Cox analysis). Antiviral agents with high genetic barrier to resistance (entecavir and TDF) reduced the risk of HCC recurrence compared with other antivirals and no antiviral treatment, especially in patients with high baseline viral load.

Tannerella forsythia GroEL induces inflammatory bone resorption and synergizes with interleukin-17.

Tannerella forsythia is a major periodontal pathogen, and T. forsythia GroEL is a molecular chaperone homologous to human heat-shock protein 60. Interleukin-17 (IL-17) has been implicated in the pathogenesis of periodontitis and several systemic diseases. This study investigated the potential of T. forsythia GroEL to induce inflammatory bone resorption and examined the cooperative effect of IL-17 and T. forsythia GroEL on inflammatory responses. Human gingival fibroblasts (HGFs) and periodontal ligament (PDL) fibroblasts were stimulated with T. forsythia GroEL and/or IL-17. Gene expression of IL-6, IL-8, and cyclooxygenase-2 (COX-2) and concentrations of IL-6, IL-8, and prostaglandin E2 (PGE2 ) were measured by real-time reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assays, respectively. After stimulation of MG63 cells with T. forsythia GroEL and/or IL-17, gene expression of osteoprotegerin (OPG) was examined. After subcutaneous injection of T. forsythia GroEL and/or IL-17 above the calvaria of BALB/c mice, calvarial bone resorption was assessed by micro-computed tomography and histological examination. Tannerella forsythia GroEL induced IL-6 and IL-8 production in HGFs and PDL cells, and IL-17 further promoted IL-6 and IL-8 production. Both T. forsythia GroEL and IL-17 synergistically increased PGE2 production and inhibited OPG gene expression. Calvarial bone resorption was induced by T. forsythia GroEL injection, and simultaneous injection of T. forsythia GroEL and IL-17 further increased bone resorption. These results suggest that T. forsythia GroEL is a novel virulence factor that can contribute to inflammatory bone resorption caused by T. forsythia and synergizes with IL-17 to exacerbate inflammation and bone resorption.

Gingipain-dependent augmentation by Porphyromonas gingivalis of phagocytosis of Tannerella forsythia.

In the pathogenesis of periodontitis, Porphyromonas gingivalis plays a role as a keystone pathogen that manipulates host immune responses leading to dysbiotic oral microbial communities. Arg-gingipains (RgpA and RgpB) and Lys-gingipain (Kgp) are responsible for the majority of bacterial proteolytic activity and play essential roles in bacterial virulence. Therefore, gingipains are often considered as therapeutic targets. This study investigated the role of gingipains in the modulation by P. gingivalis of phagocytosis of Tannerella forsythia by macrophages. Phagocytosis of T. forsythia was significantly enhanced by coinfection with P. gingivalis in a multiplicity of infection-dependent and gingipain-dependent manner. Mutation of either Kgp or Rgp in the coinfecting P. gingivalis resulted in attenuated enhancement of T. forsythia phagocytosis. Inhibition of coaggregation between the two bacterial species reduced phagocytosis of T. forsythia in mixed infection, and this coaggregation was dependent on gingipains. Inhibition of gingipain protease activities in coinfecting P. gingivalis abated the coaggregation and the enhancement of T. forsythia phagocytosis. However, the direct effect of protease activities of gingipains on T. forsythia seemed to be minimal. Although most of the phagocytosed T. forsythia were cleared in infected macrophages, more T. forsythia remained in cells coinfected with gingipain-expressing P. gingivalis than in cells coinfected with the gingipain-null mutant or infected only with T. forsythia at 24 and 48 h post-infection. Collectively, these results suggest that P. gingivalis, mainly via its gingipains, alters the clearance of T. forsythia, and provide some insights into the role of P. gingivalis as a keystone pathogen.

Pathogenic potential of Tannerella forsythia enolase.

Although enolases are cytosolic enzymes involved in the glycolytic pathway, they can also be secreted or expressed on the surface of a variety of eukaryotic cells and bacteria. Surface-exposed enolases of eukaryotes and bacteria can function as plasminogen receptors. Furthermore, antibodies raised against bacterial enolases can react with host enolases, suggesting molecular mimicry between bacterial and host enzymes. In this study, we analyzed an enolase of the major periodontopathogen Tannerella forsythia, which is either secreted or present on the cell surface, via matrix-assisted laser desorption ionization time-of-flight mass spectrometry and immunofluorescence, respectively. The T. forsythia enolase retained the enzymatic activity converting 2-phosphoglycerate to phosphoenolpyruvate and showed plasminogen binding and activating ability, which resulted in the degradation of fibronectin secreted from human gingival fibroblasts. In addition, it induced proinflammatory cytokine production, including interleukin-1ß (IL-1ß), IL-6, IL-8, and tumour necrosis factor-α (TNF-a) in the human THP-1 monocytic cell line. Taken together, our results demonstrate that T. forsythia enolase plays a role in pathogenesis in the host by plasminogen activation and proinflammatory cytokine induction, which has the potential to exaggerate inflammation in periodontitis.

Evaluation of 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography in rat models with hepatocellular carcinoma with liver cirrhosis.

Liver cirrhosis is a predominant risk factor for hepatocellular carcinoma (HCC). However, the exact mechanism of the progression from cirrhosis to cancer remains unclear. The uptake of 2-[(18)F]-fluoro-2-deoxy-D-glucose ((18)F-FDG) is widely used as a marker of increased glucose metabolism to monitor the progression of cancer with positron emission tomography (PET)/computed tomography (CT). Here we investigated the feasibility of using (18)F-FDG PET/CT in the diethylnitrosamine (DEN) mediated experimental hepatocellular carcinoma model. Rats received weekly intraperitoneal injections of DEN for 16 weeks for induction of HCC. We recorded starting from 0 days or 0 weeks after the last DEN injection. The weight and survival rate of rats were then measured. Also, an (18)F-FDG PET scan and serum analysis were performed at minus 2, 0, plus 2, and plus 4 weeks after the last DEN injection. The body weight of rats was maintained between 350 g and 370 g during 14 and 20 weeks, and the rats were euthanized at 35 days after the last DEN injection. The serum levels of alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphate (ALP) were significantly higher at zero weeks after the last DEN injection. The (18)F-FDG uptake for the quantitative evaluation of HCC was done by measuring the region of interest (ROI). At minus two weeks after the last DEN injection, the ROI of rats had significantly increased compared to the normal group, in a time-dependent manner. These results suggest that FDG uptake serves as a good screening test to evaluate the feasibility of DEN-induced HCC.

Vertebral compression fractures may increase mortality in male patients with chronic obstructive pulmonary disease.

BACKGROUND: Vertebral compression fracture (VCF) is frequent in chronic obstructive pulmonary disease (COPD) patients. However, little is known about whether VCF affects mortality in COPD patients. OBJECTIVE: To investigate whether VCFs might increase death in COPD patients. METHODS: In this retrospective cohort study, we enrolled 254 COPD patients with a recent history of hospitalisation due to respiratory problems. Patients were assessed for VCF using quantitative morphometric analyses of lateral chest radiographs; 211 patients received follow-up examinations for 2 years. RESULTS: Of the 211 COPD patients analysed, 60 (28.4%) had VCF at enrolment. During the follow-up period, 33/60 (55.0%) patients with and 46/151 patients (30.5%) without VCF died (P = 0.003, log-rank test). Cox proportional hazard analysis revealed that VCF is an independent risk factor for death after adjusting for age, sex, body mass index, smoking, dyspnoea scale, forced expiratory volume in 1 sec (FEV1) and comorbidities (hazard ratio for VCF = 1.79, 95%CI 1.11-2.89, P = 0.02). CONCLUSION: VCF might be an independent risk factor for death in male COPD patients.

Rhodococcus aerolatus sp. nov., isolated from subarctic rainwater.

A Gram-stain-positive, rod-shaped and non-motile strain, designated PAMC 27367(T), was isolated from rainwater collected on the Bering Sea. Analysis of the 16S rRNA gene sequence of the strain showed an affiliation with the genus Rhodococcus. Phylogenetic analyses revealed that strain PAMC 27367(T) formed a robust clade with the type strains of Rhodococcus rhodnii, Rhodococcus aetherivorans and Rhodococcus ruber with 16S rRNA gene sequence similarities of 96.3 %, 95.8 % and 95.5 %, respectively. Cells of the strain grew optimally at 25 °C and at pH 6.5-7.0 in the presence of 0-2 % (w/v) sea salts. The major polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol, phosphatidylinositol mannoside and three unknown phospholipids. The major cellular fatty acids (>10 %) were iso-C16 : 0, C17 : 1ω8c and 10-methyl C17 : 0. Cell wall analysis showed that strain PAMC 27367(T) contained meso-diaminopimelic acid. The genomic DNA G+C content was 77.1 mol%. Based on the phylogenetic, chemotaxonomic and phenotypic data presented here, we propose a novel species with the name Rhodococcus aerolatus sp. nov., with PAMC 27367(T) ( = KCTC 29240(T) = JCM 19485(T)) as the type strain.

The 'either test positive' strategy for latent tuberculous infection before anti-tumour necrosis factor treatment.

SETTING: A ttertiary referral centre in South Korea. OBJECTIVES: The 'either test positive' strategy, incorporating both the tuberculin skin test (TST) and the T-SPOT(®).TB(T-SPOT) assay, was evaluated as a novel method for diagnosing latent tuberculous infection (LTBI) before treatment with anti-tumour necrosis factor (TNF) in patients with immune-mediated inflammatory diseases. DESIGN: From June 2008 to April 2012, 430 patients received anti-TNF treatment at our institution. TST and T-SPOT were performed simultaneously at baseline. LTBI was defined as a positive TST or a positive T-SPOT result. RESULTS: The positivity rates for the TST and T-SPOT assays were respectively 19.1% (82/430) and 44.2% (190/430), yielding an LTBI-positive rate of 48.6% (209/430). LTBI treatment was initiated in 46.0% (198/430) of patients and was completed by 89.4% (177/198). During follow-up (median 884 days), 0.9% (4/430) of the patients developed active tuberculosis (TB). All four TB patients were TST-negative at baseline, although two received LTBI treatment based on the baseline positive T-SPOT assay results. CONCLUSIONS: The either test positive strategy is a valid method for diagnosing LTBI before anti-TNF treatment, although it is not clear whether it is superior to other strategies.

Unique features of non-obstructive emphysema and pure airway obstruction.

SETTING: Emphysema without airway obstruction or airway obstruction without emphysema are often detected clinically, although they are commonly co-existent. We therefore tested the hypothesis that non-obstructive emphysema and pure airway obstruction have unique features. METHODS: A case-control observation study was undertaken retrospectively in a patient cohort at a single centre. Among 2662 subjects who underwent chest computed tomography and pulmonary function tests, we enrolled 90 patients with non-obstructive emphysema, 119 with pure airway obstruction, 81 with obstructive emphysema and 2031 subjects as normal controls. The features of the four groups were analysed and compared. RESULTS: Higher serum homocysteine (13.4 ± 7.4 vs. 11.6 ± 4.6 mol/l), higher rate of osteoporosis (15.8% vs. 4.5%), higher leukocyte count, higher male ratio, lower serum albumin and lower body mass index were observed in subjects with non-obstructive emphysema than in controls (P < 0.05). In multiple logistic regression analysis of groups without airway obstruction, osteoporosis, hyperhomocysteinaemia, hypoalbuminaemia and higher leukocyte count were independent factors associated with non-obstructive emphysema (P < 0.05). CONCLUSION: Hyperhomocysteinaemia, hypoalbuminaemia, osteoporosis and higher leukocyte count were independent predictors of non-obstructive emphysema.

Dysregulation of miR-106a and miR-591 confers paclitaxel resistance to ovarian cancer.

BACKGROUND: MicroRNAs are noncoding regulatory RNAs strongly implicated in carcinogenesis, cell survival, and chemosensitivity. Here, microRNAs associated with chemoresistance in ovarian carcinoma, the most lethal of gynaecological malignancies, were identified and their functional effects in chemoresistant ovarian cancer cells were assessed. METHODS: MicroRNA expression in paclitaxel (PTX)-resistant SKpac sublines was compared with that of the PTX-sensitive, parental SKOV3 ovarian cancer cell line using microarray and qRT-PCR. The function of differentially expressed microRNAs in chemoresistant ovarian cancer was further evaluated by apoptosis, cell proliferation, and migration assays. RESULTS: Upregulation of miR-106a and downregulation of miR-591 were associated with PTX resistance in ovarian cancer cells and human tumour samples. Transfection with anti-miR-106a or pre-miR-591 resensitized PTX-resistant SKpac cells to PTX by enhancing apoptosis (23 and 42% increase), and inhibited their cell migration (43 and 56% decrease) and proliferation (64 and 65% decrease). Furthermore, ZEB1 was identified as a novel target gene of miR-591, and BCL10 and caspase-7 were target genes of miR-106a, as identified by immunoblotting and luciferase assay. CONCLUSION: MiR-106a and miR-591 have important roles in conferring PTX resistance to ovarian cancer cells. Modulation of these microRNAs resensitizes PTX-resistant cancer cells by targeting BCL10, caspase-7, and ZEB1.

The effect of pretransplantation lamivudine resistance on the prognosis of liver transplant recipients.

BACKGROUND: Since the introduction of lamivudine to treat chronic hepatitis B (CHB), the prevalence of lamivudine resistance is increasing among orthotopic liver transplant (OLT) candidates in Korea. OBJECTIVE: The purpose of this study was to evaluate the effect of pre-OLT lamivudine-resistance on the post-OLT prognosis of recipients. MATERIAL AND METHODS: Consecutive OLT recipient at a single tertiary care center (n = 8) between September 1999 and August 2009 were tested preoperatively for genotypic lamivudine resistance. We compared overall survival as well as incidences of graft failure, recurrent hepatitis, and hepatocellular carcinoma (HCC) between patients with (n = 35) versus without (n = 46) lamivudine-resistance. RESULTS: Mortality occurred in 2 resistant and 3 nonresistant individuals. The occurrences of graft failure, recurrent hepatitis, and HCC were 1, 2, and 2 cases, respectively, in the resistance group versus 2, 2, and 2 cases, respectively, in the nonresistance cohort. Univariate analysis showed no significant difference in survival, graft failure, HCC occurrence, and recurrent hepatitis. CONCLUSIONS: Our results indicated that pre-OLT lamivudine-resistance did not significantly affect the post-OLT prognosis. Thus, lamivudine-resistance may not be a barrier when considering OLT in patients with underlying CHB as a therapeutic modality, if it is treated with appropriate antiviral agents.

BrRZFP1 a Brassica rapa C3HC4-type RING zinc finger protein involved in cold, salt and dehydration stress.

C3HC4-type RING zinc finger proteins are known to be essential in the regulation of plant processes, including responses to abiotic stress. Here, we identify, clone and examine the first C3HC4-type RING zinc finger protein (BrRZFP1) from Brassica rapa under stress conditions. Phylogenetic analysis of BrRZFP1 revealed strong sequence similarity to C3HC4-type zinc finger proteins from Arabidopsis that are induced by abiotic stresses. Diverse environmental stresses, including salt and cold, were found to induce BrRZFP1 transcripts greater than eightfold in B. rapa. Additional strong induction was shown of the stress hormone abscisic acid, together suggesting that BrRZFP1 could play a role as a general stress modulator. Similar profiles of induction for each of these stresses was found in both root and shoot tissues, although at much higher levels in roots. Constitutive expression of BrRZFP1 in Nicotiana tabacum was conducted to further analyse how changes in gene expression levels would affect plant stress responses. BrRZFP1 overexpression conferred increased tolerance to cold, salt and dehydration stresses. This was observed in several assays examining growth status throughout development, including increased germination, fresh weight and length of shoots and roots, as well as enhanced chlorophyll retention. These results suggest that the transcription factor BrRZFP1 is an important determinant of stress response in plants and that changes in its expression level in plants could increase stress tolerance.

Bryostatin-1 promotes long-term potentiation via activation of PKCα and PKCε in the hippocampus.

Activation of protein kinase C (PKC) by bryostatin-1 affects various functions of the central nervous system. We explored whether bryostatin-1 influenced synaptic plasticity via a process involving PKC. Our purpose was to examine whether bryostatin-1 affected the induction of hippocampal long-term potentiation (LTP) in Schaffer-collateral fibers (CA1 fibers) of the hippocampus, and/or influenced the intracellular Ca(2+) level of hippocampal neurons. We also determined the PKC isoforms involved in these processes. We found that bryostatin-1 strongly facilitated LTP induction, in a dose-dependent manner, upon single-theta burst stimulation (TBS). Further, intracellular Ca(2+) levels also increased with increasing concentration of bryostatin-1. The facilitative effects of bryostatin-1 in terms of LTP induction and enhancement of intracellular Ca(2+) levels were blocked by specific inhibitors of PKCα and PKCε, but not of PKCδ. Our results suggest that bryostatin-1 is involved in neuronal functioning and facilitates induction of LTP via activation of PKCα and/or PKCε.

Combined use of a TST and the T-SPOT®.TB assay for latent tuberculosis infection diagnosis before anti-TNF-α treatment.

BACKGROUND: Diagnosis of latent tuberculosis infection (LTBI) before anti-tumour-necrosis factor (anti-TNF) treatment is important. However, the tuberculin skin test (TST) has limitations, and the role of interferon-gamma release assays has not yet been determined. OBJECTIVE: To evaluate the combined use of TST and the T-SPOT(®).TB (T-SPOT) assay prior to anti-TNF treatment. METHODS: From July 2004 to March 2008, 281 patients were treated with anti-TNF agents. TST and T-SPOT were performed simultaneously at baseline. LTBI was defined as a positive TST of ≥10 mm induration or as a positive T-SPOT if TST was ≥5 mm but <10 mm. LTBI treatment was initiated, and patients were followed until August 2010. RESULTS: Positivity rates for TST and T-SPOT were respectively 33.6% (94/280) and 69.1% (186/269). LTBI treatment was initiated in 35.9% (101/281) of the patients, and active TB developed in 2.1% (6/281). Among the six TB patients, three were TST-negative at baseline and received no LTBI treatment, whereas all four who underwent T-SPOT showed positive results at baseline. CONCLUSION: In a TB-prevalent country, TST-defined LTBI diagnosis and treatment seem to be limited in preventing the development of TB before anti-TNF treatment. Further studies for T-SPOT alone or the combined use of TST and T-SPOT (either test positive strategy) for detecting LTBI are necessary.

The fate of injured corticospinal tracts in patients with intracerebral hemorrhage: diffusion tensor imaging study.

BACKGROUND AND PURPOSE: Little is known about the fate of the injured CST for a large number of patients with ICH. Using DTT, we investigated the longitudinal changes of injured CSTs in patients with an ICH. MATERIALS AND METHODS: We recruited 45 patients with CST injury by an ICH in the supratentorial subcortical area. Two longitudinal DTTs were acquired: 1 within 30 days and the other after 3 months from onset. DTTs for the CST were classified into 3 types: type A, the CST was preserved around the hematoma; type B, the CST was interrupted around the hematoma; and type C, the CST did not reach the hematoma. RESULTS: At the first DTT, the motor functions of type C were worse than those of types A and B (P < .01), and motor functions of type A were better than those of type C at the second DTT (P < .01). Of 14 type A, 2 changed to type B (14.3%) and 12 did not change (85.7%); of 12 type B, 11 changed to type A (91.7%) and 1 changed to type C (8.3%); of 19 type C, 3 changed to type A (15.8%) and 16 did not change (84.2%). CONCLUSIONS: We found that the injured CST could change from the early stage to the chronic stage during the motor recovery phase in patients with an ICH. These results would be helpful in prediction of longitudinal DTT changes from the early stage to the chronic stage following ICH.

Evaluation of cell population data on the UniCel DxH 800 Coulter Cellular Analysis system as a screening for viral infection in children.

INTRODUCTION: The utility of WBC cell population data (CPD) for the differential diagnosis of viral infection from normal control, bacterial infection, and tuberculosis in children was investigated. METHODS: A data set of 602 total whole-blood samples were analyzed on the DxH 800 System for complete blood cell count (CBC) with leukocyte differential from children with the following sample breakdown: 77 confirmed diagnoses of viral infections (Epstein-Barr virus; 30, influenza A; 19, rota virus; 11, other viruses;17), 54 normal control, 71 bacterial infection, 17 TB patients, and 383 with various diseases. The mean (MN) and standard deviation (SD) of the volume (V), conductivity (C), five light-scatter measurements, and 14 calculated parameters were obtained for the leukocytes. RESULTS: Using a combination of the CBC and CPD parameter values, a decision rule, composed of 21 parameters, for the screening of viral infection in children was developed. Using this decision rule, 74 of 77 (96.1%) viral infections, two of 54 (3.7%) normal samples, one of 17 (5.9%) TB, and six of 71 (8.5%) bacterial infection samples were identified. The sensitivity was 96.1%, and specificity for normal control was 96.3% with an overall specificity of 93.7%. Fifty-nine samples of 383 samples (15.4%) collected from in-patient children with various diseases without confirmation of viral infection were included in this decision rule. CONCLUSION: In conclusion, the implementation of leukocytes CPD parameters can be useful in the detection of viral infection in children.

Clinical features of subjects with an isolated FEV1 reduction.

BACKGROUND: The clinical significance of an isolated reduction in forced expiratory volume in 1 second (FEV(1); i.e., low FEV(1), but normal forced vital capacity [FVC] and FEV(1)/FVC) has not been established. OBJECTIVE: To examine the clinical features of subjects with an isolated FEV(1) reduction. METHODS: Clinical, spirometry and radiological data were retrospectively collected from 15,192 subjects attending a medical check-up at the Health Promotion Center of the Asan Medical Center, Korea. Predicted spirometry values were calculated from the Korean reference equations, and the lower limit of normal was set at the 5th percentile. Subjects were divided into four groups: isolated FEV(1) reduction, normal (normal FVC, FEV(1) and FEV(1)/FVC), obstructive (low FEV(1)/FVC) and restrictive (low FVC and normal FEV(1)/FVC). The groups were compared in terms of clinical characteristics. RESULTS: Of the 15,192 subjects, 323 (2.1%) had an isolated FEV(1) reduction, 10,591 (69.7%) were normal, 951 obstructive (6.3%) and 3327 (22.0%) restrictive. The isolated FEV(1) reduction group had a higher proportion of subjects with smoking history (63.2% vs. 45.7%), radiology abnormalities (15.5% vs. 4.3%) and history of respiratory disease (8.4% vs. 3.0%) than the normal group (all P < 0.001). CONCLUSION: An isolated FEV(1) reduction suggests abnormal spirometry, and further study is needed to evaluate whether these cases belong to the obstructive or restrictive group.

Circadian regulation of mammalian target of rapamycin signaling in the mouse suprachiasmatic nucleus.

Circadian (24-h) rhythms influence virtually every aspect of mammalian physiology. The main rhythm generation center is located in the suprachiasmatic nucleus (SCN) of the hypothalamus, and work over the past several years has revealed that rhythmic gene transcription and post-translational processes are central to clock timing. In addition, rhythmic translation control has also been implicated in clock timing; however the precise cell signaling pathways that drive this process are not well known. Here we report that a key translation activation cascade, the mammalian target of rapamycin (mTOR) pathway, is under control of the circadian clock in the SCN. Using phosphorylated S6 ribosomal protein (pS6) as a marker of mTOR activity, we show that the mTOR cascade exhibits maximal activity during the subjective day, and minimal activity during the late subjective night. Importantly, expression of S6 was not altered as a function of circadian time. Rhythmic S6 phosphorylation was detected throughout the dorsoventral axis of the SCN, thus suggesting that rhythmic mTOR activity was not restricted to a subset of SCN neurons. Rather, rhythmic pS6 expression appeared to parallel the expression pattern of the clock gene period1 (per1). Using a transgenic per1 reporter gene mouse strain, we found a statistically significant cellular level correlation between pS6 and per1 gene expression over the circadian cycle. Further, photic stimulation triggered a coordinate upregulation of per1 and mTOR activation in a subset of SCN cells. Interestingly, this cellular level correlation between mTOR activity and per1 expression appears to be specific, since a similar expression profile for pS6 and per2 or c-FOS was not detected. Finally, we show that mTOR activity is downstream of the ERK/MAPK signal transduction pathway. Together these data reveal that mTOR pathway activity is under the control of the SCN clock, and suggests that mTOR signaling may contribute to distinct aspects of the molecular clock timing process.

Association of restrictive ventilatory dysfunction with insulin resistance and type 2 diabetes in koreans.

AIMS: To investigate associations of obstructive and restrictive patterns of ventilatory dysfunction with insulin resistance and type 2 diabetes mellitus (DM) in Koreans. METHODS: We cross-sectionally examined clinical, laboratory, and pulmonary function data on 35,456 Korean adults (age 18-93 years, 40% women) recorded during regular health check-ups. Insulin resistance (IR) was determined from fasting serum insulin concentration and homeostasis model assessment (HOMA). RESULTS: Individuals with type 2 DM and those with pre-diabetes (impaired fasting glucose levels) showed a higher prevalence of both restrictive (18% and 11%, respectively, VS. 8%; P<0.01) and obstructive (4.3% and 3.2%, respectively, VS. 2.3%; P<0.01) ventilatory dysfunction than did individuals with normal fasting glucose levels. Compared to subjects with normal ventilatory function, those with restrictive or obstructive ventilatory dysfunction were older, had higher systolic and diastolic blood pressure, and had elevated glucose and HbA1c levels. However, serum triglyceride, fasting insulin, and HOMA-IR were higher only in subjects with restrictive ventilatory dysfunction, and not in those with obstructive ventilatory dysfunction. On logistic regression analysis, the age and gender-adjusted odds ratio (OR) of restrictive ventilatory dysfunction for type 2 DM was 1.59 (95% confidence interval, 1.43-1.78). The increased OR remained significant after controlling for exercise, drinking, and smoking habits, presence of hypertension, body mass index, and waist circumference (OR=1.38 [1.23-1.55]). However, further adjustment for HOMA-IR attenuated the OR (1.11 [0.97-1.26]), making the OR statistically insignificant. In contrast, obstructive ventilatory dysfunction was not independently related to type 2 DM status. CONCLUSION: Restrictive ventilatory dysfunction is independently associated with type 2 DM, probably VIA insulin resistance.

The effect of co-existing solutes on arsenate removal with hydrotalcite compound.

Hydrotalcite (HTAL-Cl), an inorganic anion exchanger, is of use as an adsorbent for the removal of arsenate (As(V)) in water systems. The adsorption properties of HTAL-Cl for As(V) and the effects of co-existing anions on the As(V) removal performance were investigated in this work. Under the conditions of pH>or=4, the adsorption capacity for As(V) gradually decreased with an increase of pH, but As(V) was removed effectively within the range of pH = 5-8. Co-existing anions interfered As(V) removal, and the effect decreased in the order of HPO(4)(2-) > HCO(3)(-) > SO(4)(2-) > Cl(-). In binary solute systems containing phosphate and As(V), the maximum adsorption capacity of HTAL-Cl was 0.95 mmol g(-1) for phosphate and 0.65 mmol g(-1) for As(V): the total of these values corresponded to the maximum adsorption capacity for As(V) in single solute systems. The adsorption isotherms in these binary solute systems were approximated by the following modified Langmuir equations:As(V): q(As) = 18.7 radicalC(As)/(1 + 21.5 radicalC(P) + 12.8 radicalC(As)), phosphate : q(P) = 33.1 radicalC(P)/(1 + 21.5 radicalC(P) + 12.8 radicalC(As)). The column adsorption experiments showed that the adsorbed As(V) was released by the phosphate adsorption, because phosphate was adsorbed more strongly on HTAL-CL than As(V).