Preventive effects of carvedilol on nitrate tolerance—a randomized, double-blind, placebo-controlled comparative study between carvedilol and arotinolol

AbstractObjectives. This study was designed to compare the preventive effect of nitrate tolerance between carvedilol with antioxidant properties and arotinolol without antioxidant properties.Background. The attenuation of cyclic guanosine monophosphate (cGMP) production due to inactivation of guanylate cyclase by increased superoxide has been reported as a mechanism of nitrate tolerance. Carvedilol has been known to combine alpha- and beta-blockade with antioxidant properties.Methods. To evaluate the preventive effect of nitrate tolerance, 24 patients with untreated hypertension were randomized to receive either carvedilol (10 mg twice a day [carvedilol group, n = 8]), arotinolol (10 mg twice a day [arotinolol group, n = 8]), or placebo (placebo group, n = 8). Vasodilatory response to nitroglycerin (NTG) was assessed with forearm plethysmography by measuring the change in forearm blood flow (FBF) before and 5 min after sublingual administration of 0.3 mg NTG, and at the same time blood samples were taken from veins on the opposite side to measure platelet cGMP. Plethysmography and blood sampling were obtained serially at baseline (day 0), 3 days after carvedilol, arotinolol or placebo administration (day 3) and 3 days after application of a 20 mg/24 h NTG tape concomitantly with carvedilol, arotinolol or placebo (day 6).Results. There was no significant difference in the response of FBF (%FBF) and cGMP (%cGMP) to sublingual administration of NTG on days 0 and 3 among the three groups. On day 6, %FBF and %cGMP were significantly lower in the arotinolol group and the placebo group than days 0 and 3, but these parameters in the carvedilol group were maintained.Conclusions. The results indicated that carvedilol with antioxidant properties may prevent the development of nitrate tolerance during continuous therapy with NTG compared with arotinolol without antioxidant properties

Primary non-Hodgkin's lymphoma of the rectum: a case report.

A rare gastrointestinal tract neoplasm, primary non-Hodgkin's B-cell lymphoma in a 39-year-old, asymptomatic woman is described. The tumor was originally localized in the rectum without evidence of any other lymphoma-involved organ and treated by curative surgical procedure associated with postoperative chemotherapy.</p

Rho and Anillin-dependent Control of mDia2 Localization and Function in Cytokinesis

Diaphanous-related formin, mDia, is an actin nucleation/polymerization factor functioning downstream of the small GTPase Rho. We found that, in addition to the Rho GTPase-mediated activation, the interaction between mDia2 and anillin is required for the localization and function of mDia2 in cytokinesis

Establishment of patient-derived organoids and a characterization-based drug discovery platform for treatment of pancreatic cancer

BACKGROUND: Pancreatic cancer is one of the most lethal tumors. The aim of this study is to provide an effective therapeutic discovery platform for pancreatic cancer by establishing and characterizing patient-derived organoids (PDOs). METHODS: PDOs were established from pancreatic tumor surgical specimens, and the mutations were examined using a panel sequence. Expression of markers was assessed by PCR, immunoblotting, and immunohistochemistry; tumorigenicity was examined using immunodeficient mice, and drug responses were examined in vitro and in vivo. RESULTS: PDOs were established from eight primary and metastatic tumors, and the characteristic mutations and expression of cancer stem cell markers and CA19-9 were confirmed. Tumorigenicity of the PDOs was confirmed in subcutaneous transplantation and in the peritoneal cavity in the case of PDOs derived from disseminated nodules. Gemcitabine-sensitive/resistant PDOs showed consistent responses in vivo. High throughput screening in PDOs identified a compound effective for inhibiting tumor growth of a gemcitabine-resistant PDO xenograft model. CONCLUSIONS: This PDO-based platform captures important aspects of treatment-resistant pancreatic cancer and its metastatic features, suggesting that this study may serve as a tool for the discovery of personalized therapies

Comparative antitumor activity of 5-fluorouracil and its prodrugs in combination with hyperthermia in vitro.

We investigated the antitumor activities of 5-fluorouracil (5-FU), 5'-deoxy-5-fluorouridine (5'-DFUR), 1-hexylcarbamoyl-5-fluorouracil (HCFU) and 1-(tetrahydro-2-furanyl)-5-fluorouracil (FT-207) in combination with hyperthermia in vitro. The antitumor effect of 5-FU (10(-4) M) was slightly enhanced by combination with hyperthermia (42 degrees C) for 2h, and the effect was determined to be additive. Synergistic enhancement of antitumor activity was obtained by the concurrent use of hyperthermia (42 degrees C, 2h) and 5'-DFUR (10(-4) M) or HCFU (10(-5) M). However, the antitumor effect of FT-207 (10(-4) M) in combination with hyperthermia was comparable that of hyperthermia alone. The synergistic enhancement of antitumor activity was not obtained for all drugs when the cells were preheated at 42 degrees C for 2h. On the other hand, when cells were pretreated with drugs before heat exposure, weak interactions were obtained after 5-FU and 5'-DFUR treatment, and a synergistic interaction was obtained after HCFU treatment. It is speculated that the metabolites of 5'-DFUR and HCFU enhance the cytotoxicity of 5-FU, or might change the threshold concentration for a cytotoxic effect of 5-FU in cancer cells.</p

An Unbiased Estimate of the Global Hubble Constant in the Region of Pisces-Perseus

We obtain an unbiased estimate of the global Hubble constant H0 in the volume of cz<12000km/s in the region of Pisces-Perseus. The Tully-Fisher (TF) relation is applied to a magnitude limited sample of 441 spirals selected from the Arecibo 21cm catalog. The photometry data were calibrated with CCD observations and we achieve 0.13mag for the photometric internal error. We use a maximum likelihood method for the TF analysis. Monte-Carlo simulations demonstrate that our method reproduces a given H0 at the 95% confidence level. By applying the method to our sample galaxies, we obtain the unbiased global Hubble constant H0=65+-2(+20,-14) km/s/Mpc; the first and the second terms represent the internal random error and the external errors, respectively. We also find a good agreement for our H0 with those recently obtained via Cepheid observation, the TF relation and supernovae. Hubble velocities of the spirals inferred from our H0 show no significant systematic difference from those given in the Mark III catalog. The same analysis for H0 is carried out using r-band photometry data of the Pisces-Perseus region given by Willick et al.(1997). We obtain a global H0 which is consistent with that obtained from our B-band analysis. A bulk motion in the Pisces-Perseus region is briefly discussed, based on our calibration of H0. Our r-band TF analysis supports the notion of a coherent streaming motion of the Pisces-Perseus ridge with -200km/s with respect to the CMB, in agreement with most modern studies.Comment: 40 pages, 27 postscript figures, to appear in Ap.J. Figures are included in the tex

高齢の非代償性心不全患者において、非心血管疾患、特に感染症は重要な死因である

BACKGROUND:Despite marked improvements in treatment strategies for heart failure (HF), the mortality rate of elderly patients with HF is still high. Detailed causes of death have not been fully understood.METHODS AND RESULTS:We studied 459 consecutive patients with acute decompensated HF (ADHF) emergently admitted to our hospital from 2007 to 2011. Patients were divided into 2 groups: <75 years old (younger group; n = 225) and ≥75 years old (elderly group; n = 234). All-cause death, cardiovascular death, and noncardiovascular death were assessed as adverse outcomes. Compared with the younger group, the elderly group was characterized by a higher proportion of women and hypertensive patients and higher left ventricular ejection fraction. During a mean follow-up of 20.7 months, a total of 174 patients (37.9%) died. All-cause death was significantly higher in the elderly group than in the younger group (46.6% vs 28.9%; P < .0001), and this difference was caused by an increase in noncardiovascular deaths (20.9% vs 9.3%; P < .001), especially deaths due to infection (10.7% vs 4.0%; P < .01). Cardiovascular deaths did not differ between the 2 groups.CONCLUSIONS:Noncardiovascular deaths, most of which were caused by infection, were frequent among elderly patients with ADHF.博士（医学）・甲第629号・平成27年3月16日Copyright © 2014 Elsevier Inc. All rights reserved

Galaxy Number Counts from the Sloan Digital Sky Survey Commissioning Data

We present bright galaxy number counts in five broad bands ($u', g', r', i', z'$) from imaging data taken during the commissioning phase of the Sloan Digital Sky Survey (SDSS). The counts are derived from two independent stripes of imaging scans along the Celestial Equator, one each toward the North and the South Galactic cap, covering about 230 and 210 square degrees, respectively. A careful study is made to verify the reliability of the photometric catalog. For galaxies brighter than $r^* = 16$, the catalog produced by automated software is examined against eye inspection of all objects. Statistically meaningful results on the galaxy counts are obtained in the magnitude range $12 \le r^* \le 21$, using a sample of 900,000 galaxies. The counts from the two stripes differ by about 30% at magnitudes brighter than $r^*= 15.5$, consistent with a local $2\sigma$ fluctuation due to large scale structure in the galaxy distribution. The shape of the number counts-magnitude relation brighter than $r^* = 16$ is well characterized by $N \propto 10^{0.6m}$, the relation expected for a homogeneous galaxy distribution in a ``Euclidean'' universe. In the magnitude range $16 < r^* < 21$, the galaxy counts from both stripes agree very well, and follow the prediction of the no-evolution model, although the data do not exclude a small amount of evolution. We use empirically determined color transformations to derive the galaxy number counts in the $B$ and $I_{814}$ bands. We compute the luminosity density of the universe at zero redshift in the five SDSS bands and in the $B$ band. We find ${\cal L}_{B} = 2.4 \pm 0.4 \times 10^8L_\odot h$Mpc$^{-3}$, for a reasonably wide range of parameters of the Schechter luminosity function in the $B$ band.Comment: 48 pages, 15 figure

The Sloan Digital Sky Survey: Technical Summary

The Sloan Digital Sky Survey (SDSS) will provide the data to support detailed investigations of the distribution of luminous and non- luminous matter in the Universe: a photometrically and astrometrically calibrated digital imaging survey of pi steradians above about Galactic latitude 30 degrees in five broad optical bands to a depth of g' about 23 magnitudes, and a spectroscopic survey of the approximately one million brightest galaxies and 10^5 brightest quasars found in the photometric object catalog produced by the imaging survey. This paper summarizes the observational parameters and data products of the SDSS, and serves as an introduction to extensive technical on-line documentation.Comment: 9 pages, 7 figures, AAS Latex. To appear in AJ, Sept 200