Randomized phase III and extension studies: efficacy and impacts on quality of life of naldemedine in subjects with opioid-induced constipation and cancer.

BACKGROUND: The efficacy and safety of naldemedine (a peripherally acting µ-opioid receptor antagonist) for opioid-induced constipation (OIC) in subjects with cancer was demonstrated in the primary report of a phase III, double-blind study (COMPOSE-4) and its open-label extension (COMPOSE-5). The primary end point, the proportion of spontaneous bowel movement (SBM) responders, was met. Here, we report results from secondary end points, including quality of life (QOL) assessments from these studies. PATIENTS AND METHODS: In COMPOSE-4, eligible adults with OIC and cancer were randomly assigned 1:1 to receive once-daily oral naldemedine 0.2 mg (n = 97) or placebo (n = 96) for 2 weeks, and those who continued on to COMPOSE-5 received naldemedine for 12 weeks (n = 131). Secondary assessments in COMPOSE-4 included the proportion of complete SBM (CSBM) responders, SBM or CSBM responders by week, and subjects with ≥1 SBM or CSBM within 24 h postinitial dose. Changes from baseline in the frequency of SBMs or CSBMs per week were assessed at weeks 1 and 2. Time to the first SBM or CSBM postinitial dose was also evaluated. In both studies, QOL impact was evaluated by Patient Assessment of Constipation-Symptoms (PAC-SYM) and PAC-QOL questionnaires. RESULTS: Naldemedine improved bowel function for all secondary efficacy assessments versus placebo (all P ≤ 0.0002). The timely onset of naldemedine activity versus placebo was evidenced by median time to the first SBM (4.7 h versus 26.6 h) and CSBM (24.0 h versus 218.5 h) postinitial dose (all P < 0.0001). In COMPOSE-4, significant differences between groups were observed with the PAC-SYM stool domain (P = 0.045) and PAC-QOL dissatisfaction domain (P = 0.015). In COMPOSE-5, significant improvements from baseline were observed for overall and individual domain scores of PAC-SYM and PAC-QOL. CONCLUSIONS: Naldemedine provided effective and timely symptomatic relief from OIC and improved the QOL of subjects with OIC and cancer. TRIAL REGISTRATION ID: www.ClinicalTrials.jp: JAPIC-CTI-132340 (COMPOSE-4) and JAPIC-CTI-132342 (COMPOSE-5).

Association between transforming growth factor-ß1 -509 C>T variants and hepatocellular carcinoma susceptibility: a meta-analysis.

The transcriptional activity of transforming growth factor-ß (TGF-ß) is increased in subjects with hepatocellular carcinoma (HCC). Recent studies have indicated that the -509C genotype in hepatitis B virus (HBV)-infected subjects and the -509T genotype in hepatitis C virus (HCV)-infected subjects can increase the transcriptional activity of the TGF-ß1 gene. We conducted a meta-analysis to clarify whether these two hepatitis viruses affect the association between TGF-ß1 C-509T variants and HCC susceptibility. Using data derived from 8 case-control studies available in the PubMed database (5 with Asian and 3 with Caucasian populations), including 1,427 cases and 3,735 controls [1,610 patients with chronic liver disease and 2,125 healthy controls], we calculated pooled odds ratios with corresponding 95% confidence intervals. We used dominant (TT + CT vs. CC), recessive (TT vs. CC + CT), and co-dominant (TT vs. CC and CT vs. CC) genetic models. An overall analysis showed no association between the TGF-ß1 C-509T variants and HCC susceptibility for all models. In contrast, a subgroup analysis, based on the infecting hepatitis viruses, provided the following results. Among the cases and controls with chronic liver disease, the TGF-ß1 C-509T variants were significantly associated with decreased HCC susceptibility for two models with HBV-infected subjects, whereas the variants were significantly associated with increased HCC susceptibility for one model with HCV-infected subjects. Among the cases and healthy controls, there was a significant association between the TGF-ß1 C-509T variants and increased HCC susceptibility for two models involving HCV-infected subjects. Among the cases and the entire control group, the same results were obtained for all genetic models with HCV-infected subjects. Although further data accumulation is required, our results suggest that these two hepatitis viruses affect the association between TGF-ß1 C-509T variants and HCC susceptibility in opposite manners.

Relação entre a renda mensal e o desejo de ter filhos procurados no parceiro afetivo por homens e mulheres homossexuais e heterossexuais / Relations between sexual partner's income and their desire to have children wanted by homosexual and heterosexual men and women

A eficácia do desempenho sexual, de um modo geral, depende de uma seleção rigorosa de parceirosfeita pelos membros de cada espécie. Entre os humanos, o critério financeiro é um dos aspectos quecaracterizam a diferença sexual na seleção de parceiros. Contudo, o comportamento sexual não podeser definido apenas pelos aspectos característicos de pessoas heterossexuais, pois também existemrelacionamentos homossexuais. A partir desta perspectiva, investigou-se, através de um website, aspreferências de homossexuais e heterossexuais por renda mensal e desejo de ter filhos no parceiro.Constatou-se que os heterossexuais desejam mais ter filhos do que os homossexuais. Além disso, paraambas as orientações, a “renda mensal” não demonstrou ser um critério seletivo na hora de escolherum parceiro(AU)

Serum levels of toxic AGEs (TAGE) may be a promising novel biomarker in development and progression of NASH.

Nonalcoholic fatty liver disease (NAFLD) ranges from simple steatosis to nonalcoholic steatohepatitis (NASH), leads to fibrosis and potentially cirrhosis, liver failure, and hepatocellular carcinoma, and is one of the most common causes of liver disease worldwide. NAFLD has also been implicated in other medical conditions such as insulin resistance, obesity, metabolic syndrome, hyperlipemia, hypertension, cardiovascular disease, and diabetes. Continuous hyperglycemia has been implicated in the pathogenesis of diabetic micro- and macro-vascular complications via various metabolic pathways, and numerous hyperglycemia-induced metabolic and hemodynamic conditions exist, including the increased generation of various types of advanced glycation end-products (AGEs). We recently demonstrated that glyceraldehyde-derived AGEs (Glycer-AGEs), the predominant components of toxic AGEs (TAGE), played an important role in the pathogenesis of angiopathy in diabetic patients. Moreover, a growing body of evidence suggests that the interaction between TAGE and the receptor for AGEs may alter intracellular signaling, gene expression, and the release of pro-inflammatory molecules and also elicits the generation of oxidative stress in numerous types of cells including hepatocytes and hepatic stellate cells. Serum levels of TAGE were significantly higher in NASH patients than in those with simple steatosis and healthy controls. Moreover, serum levels of TAGE inversely correlated with adiponectin (adiponectin is produced by adipose tissue and is an anti-inflammatory adipokine that can increase insulin sensitivity). Furthermore, immunohistochemical staining of TAGE showed intense staining in the livers of patients with NASH. Serum levels of TAGE may be a useful biomarker for discriminating NASH from simple steatosis. The administration of atorvastatin (10 mg daily) for 12 months significantly improved NASH-related metabolic parameters and significantly decreased serum levels of TAGE. The steatosis grade and NAFLD activity score were also significantly improved. These results demonstrated that atorvastatin decreased the serum levels of TAGE in NASH patients with dyslipidemia and suggest the usefulness of TAGE as a biomarker for the attenuation of NASH. Serum levels of TAGE were significantly higher in non-B or non-C hepatocellular carcinoma (NBNC-HCC) patients than in NASH subjects without HCC or control subjects. TAGE may be involved in the pathogenesis of NBNC-HCC, and could, therefore, be a biomarker that could discriminate NBNC-HCC from NASH. We propose that serum levels of TAGE are promising novel targets for the diagnosis of and therapeutic interventions against NASH.

Characteristics and verification of a car-borne survey system for dose rates in air: KURAMA-II.

The car-borne survey system KURAMA-II, developed by the Kyoto University Research Reactor Institute, has been used for air dose rate mapping after the Fukushima Dai-ichi Nuclear Power Plant accident. KURAMA-II consists of a CsI(Tl) scintillation detector, a GPS device, and a control device for data processing. The dose rates monitored by KURAMA-II are based on the G(E) function (spectrum-dose conversion operator), which can precisely calculate dose rates from measured pulse-height distribution even if the energy spectrum changes significantly. The characteristics of KURAMA-II have been investigated with particular consideration to the reliability of the calculated G(E) function, dose rate dependence, statistical fluctuation, angular dependence, and energy dependence. The results indicate that 100 units of KURAMA-II systems have acceptable quality for mass monitoring of dose rates in the environment.

Photon dose mixed in monoenergetic neutron calibration fields using 7Li(p,n)7Be reaction.

The ambient dose equivalents H*(10) of photons mixed in the 144, 250 and 565 keV monoenergetic neutron fields were evaluated using measurements from an NaI(Tl) detector and calculations done using the MCNP-ANT code. It was found that H*(10) of the photons produced in the target assembly dominates the dose, particularly near the target. The H*(10) of the photons produced in other materials in the field increases with the increase in distance from the target and could not be neglected at a large distance from the target. The ratios of the H*(10) of the mixed photons to that of the monoenergetic neutrons for 144, 250 and 565 keV neutron fields, were evaluated to be below 5.5, 6.9 and 1.5 %, respectively. The ratios were calculated at calibration points between 100 and 500 cm from the target.

Development of portable long counter with two different moderator materials.

A portable, light-weight long counter (LC) with small dimensions was developed. This LC consists of a (3)He thermal neutron counter, a cylindrical moderator and outer shields. It was designed to have an almost flat response in a neutron energy range of 0.4 eV to 5 MeV. The portable LC has a radius of 11 cm and a length of 39 cm. Its weight was successfully reduced to 15 kg. Polystyrene was employed instead of polyethylene for the front part of the moderator in order to increase the sensitivity to low-energy neutrons. The response function calculated using the MCNP code was consistent with the results of experiments using monoenergetic neutron calibration fields.

A simplified pull-through angioplasty technique without a snare device. A technical note.

The pull-through angioplasty technique allows stable wire tension and stabilization of the device during the procedure. In this technique, a guide wire is passed from one sheath to another, usually with the aid of a snare device. We describe the treatment of occlusive subclavian artery disease and lesion at the origin of the vertebral artery employing a brachiofemoral pull-through technique without using a snare device. In this technique, the guide wire is advanced from the femoral artery to the brachial artery. The guide wire is directly inserted into the sheath placed at the brachial artery. The brachial artery is compressed proximal to the point of sheath insertion to prevent bleeding. The sheath is extracted temporally and the guide wire is caught outside of the body. The sheath is then introduced again through the guide wire. We used the pull-through technique without a snare device in seven cases, and we were able to build the pull-through system in six of these cases without a snare device. This pull-through technique without a snare device is not difficult to use, and may reduce the time and cost of angioplasty procedures.

The constitutional t(11;22): implications for a novel mechanism responsible for gross chromosomal rearrangements.

The constitutional t(11;22)(q23;q11) is the most common recurrent non-Robertsonian translocation in humans. The breakpoint sequences of both chromosomes are characterized by several hundred base pairs of palindromic AT-rich repeats (PATRRs). Similar PATRRs have also been identified at the breakpoints of other nonrecurrent translocations, suggesting that PATRR-mediated chromosomal translocation represents one of the universal pathways for gross chromosomal rearrangement in the human genome. We propose that PATRRs have the potential to form cruciform structures through intrastrand-base pairing in single-stranded DNA, creating a source of genomic instability and leading to translocations. Indeed, de novo examples of the t(11;22) are detected at a high frequency in sperm from normal healthy males. This review synthesizes recent data illustrating a novel paradigm for an apparent spermatogenesis-specific translocation mechanism. This observation has important implications pertaining to the predominantly paternal origin of de novo gross chromosomal rearrangements in humans.

Pharmacogenetic polymorphisms in Brazilian-born, first-generation Japanese descendants

Brazil hosts the largest Japanese community outside Japan, estimated at 1.5 million individuals, one third of whom are first-generation, Brazilian-born with native Japanese parents. This large community provides a unique opportunity for comparative studies of the distribution of pharmacogenetic polymorphisms in native Japanese versus their Brazilian-born descendants. Functional polymorphisms in genes that modulate drug disposition (CYP2C9, CYP2C19 and GSTM3) or response (VKORC1) and that differ significantly in frequency in native Japanese versus Brazilians with no Japanese ancestry were selected for the present study. Healthy subjects (200 native Japanese and 126 first-generation Japanese descendants) living in agricultural colonies were enrolled. Individual DNA was genotyped using RFLP (GSTM3*A/B) or TaqMan Detection System assays (CYP2C9*2 and *3; CYP2C19*2 and *3; VKORC1 3673G>A, 5808T>G, 6853G>C, and 9041G>A). No difference was detected in the frequency of these pharmacogenetic polymorphisms between native Japanese and first-generation Japanese descendants. In contrast, significant differences in the frequency of each polymorphism were observed between native or first-generation Japanese and Brazilians with no Japanese ancestry. The VKORC1 3673G>A, 6853G>C and 9041G>A single nucleotide polymorphisms were in linkage disequilibrium in both native and first-generation Japanese living in Brazil. The striking similarity in the frequency of clinically relevant pharmacogenetic polymorphisms between Brazilian-born Japanese descendants and native Japanese suggests that the former may be recruited for clinical trials designed to generate bridging data for the Japanese population in the context of the International Conference on Harmonization.

Pharmacogenetic polymorphisms in Brazilian-born, first-generation Japanese descendants.

Brazil hosts the largest Japanese community outside Japan, estimated at 1.5 million individuals, one third of whom are first-generation, Brazilian-born with native Japanese parents. This large community provides a unique opportunity for comparative studies of the distribution of pharmacogenetic polymorphisms in native Japanese versus their Brazilian-born descendants. Functional polymorphisms in genes that modulate drug disposition (CYP2C9, CYP2C19 and GSTM3) or response (VKORC1) and that differ significantly in frequency in native Japanese versus Brazilians with no Japanese ancestry were selected for the present study. Healthy subjects (200 native Japanese and 126 first-generation Japanese descendants) living in agricultural colonies were enrolled. Individual DNA was genotyped using RFLP (GSTM3 A/B) or TaqMan Detection System assays (CYP2C9 2 and 3; CYP2C19 2 and 3; VKORC1 3673G>A, 5808T>G, 6853G>C, and 9041G>A). No difference was detected in the frequency of these pharmacogenetic polymorphisms between native Japanese and first-generation Japanese descendants. In contrast, significant differences in the frequency of each polymorphism were observed between native or first-generation Japanese and Brazilians with no Japanese ancestry. The VKORC1 3673G>A, 6853G>C and 9041G>A single nucleotide polymorphisms were in linkage disequilibrium in both native and first-generation Japanese living in Brazil. The striking similarity in the frequency of clinically relevant pharmacogenetic polymorphisms between Brazilian-born Japanese descendants and native Japanese suggests that the former may be recruited for clinical trials designed to generate bridging data for the Japanese population in the context of the International Conference on Harmonization.

Carotid artery stenting for calcified lesions.

BACKGROUND AND PURPOSE: Our aim was to assess the feasibility of carotid artery stent placement (CAS) for calcified lesions. MATERIALS AND METHODS: Using embolic protection devices (EPDs), we performed 51 CAS procedures in 43 patients with severe carotid artery stenosis accompanied by plaque calcification. Before intervention, all lesions were subjected to multidetector-row CT. The arc of the circumferential plaque calcification was measured on axial source images at the site of maximal luminal stenosis, and the total volume of the plaque calcification was determined. The angiographic outcome immediately after CAS, and intra- and postoperative complications were recorded. RESULTS: The mean arc of calcification was 201.1 +/- 72.3 degrees (range, 76-352 degrees ), and the mean of the total calcification volume was 154.9 +/- 35.4 mm(3) (range, 92-2680 mm(3)). Balloon rupture occurred in 1 procedure (2.0%) at predilation angioplasty; all 51 CAS procedures were successful without clinical adverse effects. Although there was a correlation between the arc of plaque calcification and residual stenosis (r = 0.6, P < .001), excellent dilation with residual stenosis < or =30% was achieved in all lesions. There was no correlation between the total volume of calcification and residual stenosis. None of the patients developed stroke or death within 30 days of the CAS procedure. CONCLUSION: CAS by using EPDs to treat lesions with plaque calcification is feasible even in patients with near-total circumferential plaque calcification.

Potassium channel openers accelerate epidermal barrier recovery.

BACKGROUND: Maintenance of a competent permeability barrier in the face of external and internal stressors requires signals between the stratum corneum interface and the metabolic machinery in the underlying nucleated layers. For example, reductions in the ion gradients for Ca2+ after acute barrier disruption stimulate lamellar body (LB) secretion, a response required to restore barrier homeostasis. Although alterations in external K+ levels also regulate barrier recovery after acute insults, the mechanisms whereby K+ regulates barrier function remain unknown. OBJECTIVES: To evaluate effects of regulators of K+ channels on barrier homeostasis in hairless mice. METHODS: We tested a number of chemically different drugs that alter intracellular K+ levels. Results Single applications of either K+ channel openers (i.e. 1-EBIO, minoxidil, diazoxide) or the K+ ionophore, valinomycin, accelerated barrier recovery after acute insults to murine skin, paralleled by a reduction in intracellular K+ levels in cultured human keratinocytes. In contrast, applications of K+ channel blockers (i.e. gilbenclamide, dequalinium) delayed barrier recovery. Alterations in intracellular K+ regulated barrier homeostasis by either stimulating (reduced K+) or inhibiting (elevated K+) LB secretion. Finally, development of epidermal hyperplasia, a downstream consequence of barrier disruption, was also inhibited by agents that reduce intracellular K+ levels. CONCLUSIONS: These results demonstrate that changes in K+ levels that can be presumed to occur after barrier disruption signal metabolic responses, i.e. LB secretion, which accelerates normalization of barrier function.

Paradoxical effects of beta-estradiol on epidermal permeability barrier homeostasis.

BACKGROUND: Previous studies have demonstrated that sex hormones modulate epidermal permeability barrier homeostasis, and when the balance of these hormones is altered at menopause or during the menstrual cycle, skin sensitivity or barrier function is changed. OBJECTIVES: To observe the direct effects of sex hormones on epidermal homeostasis. METHODS: We examined the effects of topical application of sex hormones on permeability barrier recovery after tape stripping in the hairless mouse. To avoid the influence of systemic hormonal alteration, we employed male animals. RESULTS: Application of androgen (testosterone or androsterone) delayed the barrier recovery, and the delay was overcome by co-application of beta-estradiol. Progesterone also delayed the barrier recovery, but in this case the delay was enhanced by beta-estradiol. CONCLUSIONS: These results suggest that changes in sex hormone balance might be associated with the skin dysfunction that often occurs during menopause, and at certain points during the menstrual cycle.

Construction of monoenergetic neutron calibration fields using 45Sc(p, n)45Ti reaction at JAEA.

The 8 and 27 keV monoenergetic neutron calibration fields have been developed by using (45)Sc(p, n)(45)Ti reaction. Protons from a 4-MV Pelletron accelerator are used to bombard a thin scandium target evaporated onto a platinum disc. The proton energies are finely adjusted to the resonance to generate the 8 and 27 keV neutrons by applying a high voltage to the target assemblies. The neutron energies were measured using the time-of-flight method with a lithium glass scintillation detector. The neutron fluences at a calibration point located at 50 cm from the target were evaluated using Bonner spheres. A long counter was placed at 2.2 m from the target and at 60 degrees to the direction of the proton beam in order to monitor the fluence at the calibration point. Fluence and dose equivalent rates at the calibration point are sufficient to calibrate many types of the neutron survey metres.

Investigation of properties of the TIARA neutron beam facility of importance for calibration applications.

Evaluation of the properties for quasi-monoenergetic neutron calibration fields of high energies more than 20 MeV at TIARA is proceeding for development of the field. Among the properties needed for the development as the standard calibration field, we report on measurement of the neutron beam profile using an imaging plate with a polyethylene converter and on estimation of the contribution of scattered neutrons into the irradiation field based on pulse height distribution at various off-beam positions measured using an organic liquid scintillation detector.

siRNA-mediated knockdown of connective tissue growth factor prevents N-nitrosodimethylamine-induced hepatic fibrosis in rats.

Hepatic fibrosis is a dynamic process that involves the interplay of different cell types in the hepatic tissue. Connective tissue growth factor (CTGF) is a highly profibrogenic molecule and plays a crucial role in the pathogenesis of hepatic fibrosis. The aim of the present investigation was three-fold. First, we studied the expression of CTGF in the cultured hepatic stellate cells using immunohistochemical technique. Second, we induced hepatic fibrosis in rats through serial intraperitoneal injections of N-nitrosodimethylamine (NDMA; dimethylnitrosamine, DMN) and studied the upregulation of CTGF and TGF-beta1 during hepatic fibrogenesis. Third, we downregulated CTGF expression using CTGF siRNA and examined the role of CTGF siRNA to prevent the progression of NDMA-induced hepatic fibrosis. The results depicted strong staining of CTGF in the transformed hepatic stellate cells in culture. Serial administrations of NDMA resulted in activation of hepatic stellate cells, upregulation of CTGF and TGF-beta1 both at mRNA and protein levels and well-developed fibrosis in the liver. Immunostaining, Western blot analysis, semiquantitative and real-time RT-PCR studies showed downregulation of CTGF and TGF-beta1 after treatment with CTGF siRNA. The results of the present study demonstrated that CTGF gene silencing through siRNA reduces activation of hepatic stellate cells, prevents the upregulation of CTGF and TGF-beta1 gene expression and inhibits accumulation of connective tissue proteins in the liver. The data further suggest that knockdown of CTGF upregulation using siRNA has potential therapeutic application to prevent hepatic fibrogenesis.

Direct superficial temporal vein approach for dural carotid cavernous fistula.

SUMMARY: We present an alternative endovascular approach to treat dural carotid cavernous fistulae (dural CCF) that drain only into the superior ophthalmic vein. Four cases of cavernous dural AVFs that could not be treated via the inferior petrosal vein were accessed via the direct superficial temporal vein approach through the superior ophthalmic vein. Successful embolization was documented radiographically and clinically in all patients. The trans-superficial temporal vein approach is safe and useful for inaccessible dural CCFs through the inferior petrosal sinus.

Mechanisms of perianeurysmal edema following endovascular embolization of aneurysms.

SUMMARY: After coil embolization for an aneurysm, edema surrounding the aneurysm revealed by magnetic resonance imaging (MRI) is rarely seen and is usually associated with neurological symptoms. Perianeurysmal edema was found by postoperative MRI in three out of 182 patients with cerebral aneurysm, which was treated with Guglielmi Detachable Coil (GDC), and neurological symptoms developed simultaneously. In cases where neurological symptoms improved with conservative medical treatment, a temporary increase in the volume of an aneurysm, due to coil and thrombus formation, may result in edema. In cases where symptoms were not alleviated with conservative medical treatment, persistent water-hammer effect against the residual lumen of the aneurysm as well as an increase in the volume of aneurysm by hemorrhage in the aneurysmal wall may contribute to the development of perianeurysmal edema. Consideration of the mechanism of edema development by neurological symptoms, MRI findings, and angiographic findings is needed in order to select appropriate treatment.