Resveratrol directly targets DDX5 resulting in suppression of the mTORC1 pathway in prostate cancer.

Resveratrol has various attractive bioactivities, such as prevention of cancer, neurodegenerative disorders, and obesity-related diseases. Therefore, identifying its direct binding proteins is expected to discover druggable targets. Sirtuin 1 and phosphodiesterases have so far been found as the direct molecular targets of resveratrol. We herein identified 11 novel resveratrol-binding proteins, including the DEAD (Asp-Glu-Ala-Asp) box helicase 5 (DDX5, also known as p68), using resveratrol-immobilized beads. Treatment with resveratrol induced degradation of DDX5 in prostate cancer cells. Depletion of DDX5 caused apoptosis by inhibiting mammalian target of rapamycin complex 1 (mTORC1) signaling. Moreover, knockdown of DDX5 attenuated the inhibitory activities of resveratrol against mTORC1 signaling and cancer cell growth. These data show that resveratrol directly targets DDX5 and induces cancer cell death by inhibiting the mTORC1 pathway.

Changes in the Small Intestine of a Cat Associated with Barium Sulphate Following Contrast Radiography.

A 7-year-old neutered male domestic short-haired cat that had undergone contrast radiography of the bowel with barium sulphate after acute episodes of vomiting 2 months previously, was presented with chronic vomiting, anorexia and weight loss. Abdominal radiography and ultrasonography revealed residual contrast enhancement and an obstruction of the small intestine. A contracted and stenosed ileum and distal jejunum were identified by exploratory laparotomy and surgically resected; subsequently, the clinical signs resolved. Histopathological examination of the ileum revealed mucosal ulceration with severe submucosal granulation tissue formation associated with scattered foreign crystalline material. Energy-dispersive X-ray spectroscopy revealed that the crystals contained barium sulphate. This is the first report in animals of the rare complication of barium sulphate incorporation into the gastrointestinal mucosa after contrast radiography.

Pioglitazone treatment and cardiovascular event and death in subjects with type 2 diabetes without established cardiovascular disease (JDDM 36).

AIMS: The protective association of pioglitazone with cardiovascular events and death was investigated over 6-years in large-scale type 2 diabetic subjects without established cardiovascular disease in a primary care setting. METHODS: A six-year observational cohort study including 2864 subjects with type 2 diabetes without established cardiovascular disease was performed. The primary endpoint was a composite of first occurrence of cardiovascular disease or death. The effect of pioglitazone use at a baseline year with a Cox proportional hazard model and the time-dependent use in each one-year examination interval with a pooled logistic regression model were analyzed. RESULTS: Baseline use of pioglitazone (n=493) did not show a statistically protective effect on the primary endpoint (n=175), although it tended to reduce the risk (adjusted hazard ratio 0.67 [95% CI: 0.43-1.05]). However, pooled logistic regression analysis indicated a significant protective association of pioglitazone with the primary endpoint (0.58 [0.38 to 0.87] and cardiovascular disease (0.54 [0.33-0.88]), independent of concurrent levels of blood glucose, blood pressure, lipids, albuminuria, and renal function. In particular, this protective association was observed in those with diabetic nephropathy regardless of the daily dose of pioglitazone. Among a total of 898 subjects who took pioglitazone during the period, 43% experienced a discontinuation at least once; however, serious adverse effects were rare. CONCLUSIONS: This observational study indicated a protective association of pioglitazone with cardiovascular disease and death in type 2 diabetic subjects without established vascular disease, particularly those with nephropathy.

Revisit to diffraction anomalous fine structure.

The diffraction anomalous fine structure (DAFS) method that is a spectroscopic analysis combined with resonant X-ray diffraction enables the determination of the valence state and local structure of a selected element at a specific crystalline site and/or phase. This method has been improved by using a polycrystalline sample, channel-cut monochromator optics with an undulator synchrotron radiation source, an area detector and direct determination of resonant terms with a logarithmic dispersion relation. This study makes the DAFS method more convenient and saves a large amount of measurement time in comparison with the conventional DAFS method with a single crystal. The improved DAFS method has been applied to some model samples, Ni foil and Fe3O4 powder, to demonstrate the validity of the measurement and the analysis of the present DAFS method.

Persistent elevated C-reactive protein after treatment is an independent marker of a poor prognosis in patients with hepatocellular carcinoma

PURPOSE: The pretreatment C-reactive protein (CRP) level is reported to be a prognostic indicator in patients with hepatocellular carcinoma (HCC). METHODS: We investigated the prognostic implications of the changes in the CRP level after initial treatment in patients with HCC. We prospectively evaluated a cohort of 150 patients with newly diagnosed HCC. The patients were categorized into three groups: group 1 (n = 120) with pre- and post-treatment CRP <1.0 mg/dl, group 2 (n = 5) with pre-treatment CRP ≥1.0 mg/dl and post-treatment CRP <1.0 mg/dl, and group 3 (n = 25) with pre- and post-treatment CRP ≥1.0 mg/dl. RESULTS: The 1- and 3-year overall survival rates were 92.3 and 82.9 % for group 1, 80.0 and 53.3 % for group 2, and 58.8 and 4.2 % for group 3. The overall survival rate for group 3 was significantly lower than that for group 1 (P < 0.0001), or group 2 (P = 0.003). No significant difference was found between groups 1 and 2 (P = 0.627). A multi-variate analysis showed that albumin level (P = 0.049), the CRP group (P < 0.0001), and the Cancer of the Liver Italian Program (CLIP) score (P < 0.0001) were independently associated with the overall survival. CONCLUSIONS: A persistently elevated CRP level after initial treatment is an independent marker of a poor prognosis, and normalization of the CRP level after initial treatment is associated with a better outcome in patients with HCC (AU)

Persistent elevated C-reactive protein after treatment is an independent marker of a poor prognosis in patients with hepatocellular carcinoma.

PURPOSE: The pretreatment C-reactive protein (CRP) level is reported to be a prognostic indicator in patients with hepatocellular carcinoma (HCC). METHODS: We investigated the prognostic implications of the changes in the CRP level after initial treatment in patients with HCC. We prospectively evaluated a cohort of 150 patients with newly diagnosed HCC. The patients were categorized into three groups: group 1 (n = 120) with pre- and post-treatment CRP <1.0 mg/dl, group 2 (n = 5) with pre-treatment CRP ≥1.0 mg/dl and post-treatment CRP <1.0 mg/dl, and group 3 (n = 25) with pre- and post-treatment CRP ≥1.0 mg/dl. RESULTS: The 1- and 3-year overall survival rates were 92.3 and 82.9 % for group 1, 80.0 and 53.3 % for group 2, and 58.8 and 4.2 % for group 3. The overall survival rate for group 3 was significantly lower than that for group 1 (P < 0.0001), or group 2 (P = 0.003). No significant difference was found between groups 1 and 2 (P = 0.627). A multi-variate analysis showed that albumin level (P = 0.049), the CRP group (P < 0.0001), and the Cancer of the Liver Italian Program (CLIP) score (P < 0.0001) were independently associated with the overall survival. CONCLUSIONS: A persistently elevated CRP level after initial treatment is an independent marker of a poor prognosis, and normalization of the CRP level after initial treatment is associated with a better outcome in patients with HCC.

Effect of high-sensitivity C-reactive protein on the development of diabetes as demonstrated by pooled logistic-regression analysis of annual health-screening information from male Japanese workers.

AIM: The aim of this study was to determine the relationship between the development of diabetes mellitus and high-sensitivity C-reactive protein (HsCRP) adjusted for various potential confounders. METHODS: This 5-year prospective cohort study was conducted at a Japanese steel factory and involved male workers who had received annual health screenings between 2005 and 2010. The 7392 male participants were aged 19-75 years. The study endpoint, the development of diabetes mellitus, was defined as HbA(1c) greater or equal to 6.5% or the use of antidiabetic medication. The association between variables was investigated using pooled logistic regression adjusted for various covariates such as age, baseline body mass index (BMI) and increase in BMI from baseline, blood biochemistry, job schedule and job-related stress. RESULTS: The incidence rate of diabetes development per 1000 person-years was 13.9. Multivariate analysis showed a significant relationship between the development of diabetes and elevated levels of baseline HsCRP and increases in levels from baseline. The Odds ratios for a 2.9-fold (±1 geometric standard deviation) increase in baseline HsCRP and increase in HsCRP level from baseline were 1.18 [95% confidence interval (CI): 1.03-1.34; P=0.018] and 1.21 (95% CI: 1.03-1.41; P=0.018), respectively. CONCLUSION: The present study has indicated that HsCRP is an independent predictor for the development of diabetes in men, together with various confounders such as BMI, type of job schedule and job-related stress.

Comparison of the prognostic value of inflammation-based prognostic scores in patients with hepatocellular carcinoma.

BACKGROUND: Inflammation-based prognostic scores including the Glasgow Prognostic Score (GPS), neutrophil to lymphocyte ratio (NLR), and Prognostic Nutritional Index (PNI) are associated with survival in patients with hepatocellular carcinoma (HCC). The aim of this study was to investigate the prognostic value of these inflammation-based prognostic scores in patients with HCC. METHODS: In total, 150 patients with newly diagnosed HCC were prospectively evaluated. Patients were divided according to the GPS, modified GPS, NLR, platelet to lymphocyte ratio (PLR), Prognostic Index (PI), and PNI. The area under the receiver operating characteristics curve (AUC) was calculated to compare the predictive ability of each of the scoring systems. A univariate and multivariate analysis were performed to identify the clinicopathological variables associated with overall survival. RESULTS: The GPS consistently had a higher AUC value at 6 months (0.768), 12 months (0.787), and 24 months (0.758) in comparison with other inflammation-based prognostic scores. A multivariate analysis showed that the GPS was independently associated with overall survival. CONCLUSION: This study demonstrates that the GPS, an inflammation-based prognostic score, is an independent marker of poor prognosis in patients with HCC and is superior to the other inflammation-based prognostic scores in terms of prognostic ability.

Observational 6-month open-label study of Japanese type 2 diabetes patients switching from NPH insulin to insulin detemir in basal-bolus regimen: 23rd article of the Japan Diabetes Clinical Data Management Study Group (JDDM23).

OBJECTIVE: Glycaemic control is critical to prevent diabetic complications and mortality. This 6-month, open-label, observational study assessed the efficacy and safety of switching Japanese patients with type 2 diabetes from neutral protamine Hagedorn (NPH) insulin to insulin detemir. METHODS: Patients with type 2 diabetes (n = 126) receiving basal-bolus insulin therapy with NPH insulin plus rapid-acting insulin analogues were recruited. NPH insulin was replaced with insulin detemir for 6 months. Glycosylated haemoglobin (HbA(1c)), fasting plasma glucose (FPG), daily glucose levels and hypoglycaemia were monitored. Nocturnal quality of life was assessed by insulin therapy related quality of life at night questionnaire. RESULTS: HbA(1c), FPG and body weight were all significantly reduced after treatment with insulin detemir for 6 months, without increasing severe hypoglycaemia. Insulin dose increased significantly over the same time. There were significant improvements in overall nocturnal quality of life, as well as well-being. CONCLUSIONS: Treatment with insulin detemir for 6 months resulted in substantial benefits, including reduced HbA(1c), FPG and body weight, and improvements in nocturnal quality of life, without increasing hypoglycaemia.

Chronic kidney disease categories and renal-cardiovascular outcomes in type 2 diabetes without prevalent cardiovascular disease: a prospective cohort study (JDDM25).

AIMS/HYPOTHESIS: In type 2 diabetic patients at low risk for cardiovascular disease (CVD), the relationship between the clinical course of nephropathy by stage of chronic kidney disease (CKD) and onset of CVD remains unclear. Clarification of this relationship is important for clinical decision-making for both low- and high-risk diabetic patients. METHODS: This 4 year prospective study enrolled 2,954 type 2 diabetic patients with no prevalent CVD, and serum creatinine <176.8 µmol/l. The risk for CVD onset (non-fatal and fatal CVD and stroke, and peripheral arterial disease) was assessed according to CKD stage categorised by urinary albumin-to-creatinine ratio (ACR; mg/mmol) and estimated GFR (eGFR; ml min(-1) 1.73 m(-2)). Association of progression from 'no CKD' stage (ACR <3.5 mg/mmol and eGFR ≥ 90 ml min(-1) 1.73 m(-2)) with risk for CVD onset was also evaluated. RESULTS: During follow-up (median 3.8 years), 89 CVD events occurred. Compared with patients with 'no CKD' as reference, those with ACR ≥ 35.0 mg/mmol with co-existing eGFR 60-89 ml min(-1) 1.73 m(-2) or <60 ml min(-1) 1.73 m(-2) showed increased risk for CVD onset, whereas those with eGFR ≥ 90 ml min(-1) 1.73 m(-2) did not. Those with ACR <3.5 mg/mmol and eGFR <60 ml min(-1) 1.73 m(-2) did not show any increased risk. Among patients with 'no CKD' stage at baseline, those who progressed to ACR ≥ 3.5 mg/mmol during follow-up showed an increased risk compared with those who did not, whereas those who progressed to eGFR <90 ml min(-1) 1.73 m(-2) did not have increased risk. CONCLUSIONS/INTERPRETATION: The risk for CVD was associated with progression of albuminuria stage rather than eGFR stage in type 2 diabetic patients at relatively low risk for CVD.

Gender differences in maximum voluntary lip-closing force during lip pursing in healthy young adults.

The objectives of this study were to quantitatively evaluate the gender differences in the lip-closing force (LCF) generated during pursing-like lip-closing movement using a multidirectional LCF measurement system in healthy young adults. In 40 healthy subjects (20 women, 20 men; median age = 26·5 years, range = 22-41 years), LCF was recorded in eight directions during the performance of a voluntary pursing-like lip-closing task in four measurement sessions. The correlations between the total sum of the forces generated in all eight directions [total LCF (TLCF)] and each directional LCF (DLCF) and those between opposing DLCF were statistically analysed. The TLCF obtained from the highly reproducible measurements acquired in the four different sessions was normally distributed in both genders. The TLCF in men was significantly greater than that in women. Among the eight pairs of opposing DLCF, seven pairs of opposing DLCF showed significant correlations in men, while five pairs were significantly correlated in women. In men, no significant difference was observed between opposing DLCF; however, three pairs of opposing DLCF were significantly different in women. The present results quantitatively indicate that there are gender differences in the magnitude and directional specificity of the LCF produced during pursing-like lip-closing movement in healthy young adults.

Serum amyloid A low-density lipoprotein levels and smoking status in obese Japanese patients.

Serum amyloid A low-density lipoprotein (SAA-LDL) is formed by an oxidative interaction and is considered to be a new marker related to oxidative modification of LDL. As the effect of smoking on oxidized LDL is of concern, this study investigated the association between SAA-LDL and smoking status. A total of 578 Japanese obese outpatients (mean ± SD age 50.5 ± 14.3 years) were studied. Smoking status was examined via a self-reported questionnaire. Cardio metabolic variables, including high-sensitivity Creactive protein (hsCRP), were analysed in addition to SAA-LDL. There was an increasing trend in SAA-LDL levels from non- to ex- to current smokers, and significantly higher SAA-LDL levels were observed in current smokers versus non-smokers (median SAA-LDL level 36 µg/ml versus 28 µg/ml, respectively). This significant difference was reduced after adjusting for multiple confounders, including lipid levels. Smoking may be associated with increased levels of SAA-LDL in an obese Japanese population, but further studies are needed.

Active hexose correlated compound inhibits the expression of proinflammatory biomarker iNOS in hepatocytes.

BACKGROUND/AIMS: Excess production of nitric oxide (NO) by inducible nitric oxide synthase (iNOS) has been implicated as proinflammatory biomarker in liver injury. The application of active hexose correlated compound (AHCC) as a functional food in complementary and alternative medicine has increased. The possibility that AHCC might inhibit iNOS induction was investigated as a potential liver-protective effect. METHODS: Hepatocytes were isolated from rats by collagenase perfusion and cultured. Primary cultured hepatocytes were treated with interleukin-1ß in the presence or absence of AHCC-sugar fraction (AHCC-SF). RESULTS AND CONCLUSION: AHCC-SF inhibited the production of NO and reduced expressions of iNOS mRNA and its protein. AHCC-SF had no effects on either IκB degradation or nuclear factor-κB (NF-κB) activation. In contrast, AHCC-SF inhibited the upregulation of type I interleukin-1 receptor (IL-1RI) through the inhibition of Akt phosphorylation. Transfection experiments with iNOS promoter-luciferase constructs revealed that AHCC-SF reduced the levels of iNOS mRNA at both promoter transactivation and mRNA stabilization steps. AHCC-SF inhibited the expression of iNOS gene antisense transcript, which is involved in iNOS mRNA stabilization. These findings demonstrate that AHCC-SF suppresses iNOS gene expression through a IκB/NF-κB-independent but Akt/IL-1RI-dependent pathway, resulting in the reduction of NO production. AHCC-SF may have therapeutic potential for various liver injuries.

Low incidence of cardiovascular events in Japanese patients with Type 2 diabetes in primary care settings: a prospective cohort study (JDDM 20).

AIMS: To investigate whether a reduced incidence of cardiovascular disease in Type 2 diabetes can be achieved in a newly recruited cohort following the recently advanced concept of multifactorial treatment and followed in primary care settings as compared with earlier cohorts. METHODS: A prospective study was performed in primary care settings at multiple clinics nationwide in the Japan Diabetes Clinical Data Management (JDDM) study group. Subjects were 2984 patients with Type 2 diabetes without prevalent cardiovascular disease. The main outcome measure was the first event of non-fatal or fatal coronary heart disease, ischaemic stroke or peripheral artery disease, and the incidence was compared with other representative cohorts. RESULTS: There were 90 cardiovascular events over 10,827 person-years of follow-up with a dropout rate of 6%. The incidences (per 1000 person-years, 95% confidence interval) of composite, coronary heart disease, ischaemic stroke and peripheral artery disease in the JDDM study were 8.3 (6.6-10.0), 4.4 (3.2-5.6), 3.1 (2.1-4.2), and 0.7 (0.2-1.2), respectively. Each incidence was lowest in the JDDM study compared with other cohorts (P < 0.01 vs. each cohort). In the JDDM study, significant variables predictive of the occurrence of a cardiovascular event were age, duration of diabetes, HbA(1c), HDL cholesterol and urinary albumin. CONCLUSION: The novel finding of low cardiovascular disease occurrence in this study may be conferred by the feasibility at primary care settings for providing patients with Type 2 diabetes with favourable control of blood glucose, blood pressure and lipids, coupled with unique ethnicity/country factors.

Regulatory relationship between tactile sensation at the vermilion of the lips and lip-closing force.

The objectives of this study were to identify the regulatory relationship between tactile sensation at the vermilion of the lips and the output of pursing-like lip-closing force (LCF), as measured by a multidirectional LCF measurement system. Thirty-six healthy subjects were divided into Anaesthesia and Vaseline groups. The tactile detection threshold (TDT) at six sites on the vermilion and the maximum voluntary LCFs in eight directions were recorded before and during partial or whole application of the agent and 6 h after whole application (Recovery). Five per cent lidocaine gel and Vaseline was applied to the vermilion in the Anaesthesia and Vaseline groups, respectively. These agents were applied to either the right part of the vermilion of the lower lip (Partial) or the whole vermilion (Whole). Partial application of 5% lidocaine gel significantly decreased the magnitudes of six of eight directional LCFs, while it only increased the TDT at one site. The subsequent whole application of 5% lidocaine gel did not affect the magnitude of the LCFs in five of these six directions although its application increased the TDTs at all sites. These reductions in LCF were reversed after recovery from surface anaesthesia. Vaseline application did not affect either TDT or LCF in any conditions. We concluded that tactile sensation at the vermilion of the lips is related to the output of LCF, without any particular directional specificity. The present results suggest the presence of a common synaptic drive ordering the pursing of the relevant muscles.

Reliability of novel multidirectional lip-closing force measurement system.

This study aimed to quantify the directional specificity of multidirectional lip-closing force (LCF) and evaluate the reliability of multidirectional LCF measurements made using a novel system. In fourteen healthy subjects (seven females, seven males, median age = 28 years), LCFs in eight directions and electromyograms (EMGs) from four parts of the orbicularis oris muscles (OOM) were recorded during voluntary pursing-like lip closure tasks. The quantitative reliability was assessed from repeated measurements of the LCFs in the eight directions and from summed values for all eight directions [total lip-closing force (TLCF)]. The intra- and inter-investigator reliabilities for TLCF were assessed by the interclass correlation of the measurements by the same investigator and two investigators, respectively. Lip-closing forces showed directional specificity in vertical, horizontal and oblique directions but those in oblique and horizontal directions were symmetrical bilaterally. The quantitative reliability of measurements was between 0·735 and 0·948 in the eight directions and that of TLCF was 0·934. Interclass correlations of intra- and inter-investigator reliabilities were 0·96 [lower limit of 95% confidence interval (95% LL), 0·87] and 0·96 (95% LL, 0·91), respectively. The intra- and inter-investigator differences of measurements were randomly distributed in the whole range of measurements. The 95% confidence intervals of these differences were significantly narrower than those of the limits of agreement (mean ± 1·96 s.d.). In 13 subjects, Pearson's correlation coefficients between LCF and EMGs from OOM were above 0·95. We conclude that this system has a reasonable quality and reliability for quantitative measurements of multidirectional LCF for evaluating lip functions.

Morphology of brachial plexus and axillary artery in bonobo (Pan paniscus).

A left brachial plexus and axillary artery of bonobo (Pan paniscus) were examined, and the interrelation between the brachial plexus and the axillary artery was discussed. This is the first report of the brachial plexus and the axillary artery of bonobo. The bonobo brachial plexus formed very similar pattern to that of other ape species and human. On the other hand, the branches of the bonobo axillary artery had uncommon architecture in comparison with human case. The axillary artery did not penetrate the brachial plexus and passes through all way along anterior to the brachial plexus. Only 4.9% of human forelimbs have this pattern. Moreover, the brachial artery runs through superficially anterior to branches of the brachial plexus.