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1.  Clinical impacts of additive use of olmesartan in hypertensive patients with chronic heart failure: the supplemental benefit of an angiotensin receptor blocker in hypertensive patients with stable heart failure using olmesartan (SUPPORT) trial 
Sakata, Yasuhiko | Shiba, Nobuyuki | Takahashi, Jun | Miyata, Satoshi | Nochioka, Kotaro | Miura, Masanobu | Takada, Tsuyoshi | Saga, Chiharu | Shinozaki, Tsuyoshi | Sugi, Masafumi | Nakagawa, Makoto | Sekiguchi, Nobuyo | Komaru, Tatsuya | Kato, Atsushi | Fukuchi, Mitsumasa | Nozaki, Eiji | Hiramoto, Tetsuya | Inoue, Kanichi | Goto, Toshikazu | Ohe, Masatoshi | Tamaki, Kenji | Ibayashi, Setsuro | Ishide, Nobumasa | Maruyama, Yukio | Tsuji, Ichiro | Shimokawa, Hiroaki | Shimokawa, H. | Fukuchi, M. | Goto, T. | Hiramoto, T. | Inoue, K. | Kato, A. | Komaru, T. | Ohe, M. | Sekiguchi, N. | Shiba, N. | Shinozaki, T. | Sugi, M. | Tamaki, K. | Hiramoto, T. | Inoue, K. | Kato, A. | Ogata, M. | Sato, S. | Sugi, M. | Ishide, N. | Ibayashi, S. | Maruyama, Y. | Ohno, I. | Tamaki, K. | Ogawa, H. | Kitakaze, M. | Tsuji, I. | Watanabe, T. | Sugiyama, K. | Oyama, S. | Nozaki, E. | Nakamura, A. | Takahashi, T. | Endo, H. | Fukui, S. | Nakajima, S. | Nakagawa, M. | Nozaki, T. | Yagi, T. | Horiguchi, S. | Fushimi, E. | Sugai, Y. | Takeda, S. | Fukahori, K. | Aizawa, K. | Ohe, M. | Tashima, T. | Sakurai, K. | Kobayashi, T. | Goto, T. | Matsui, M. | Tamada, Y. | Yahagi, T. | Fukui, A. | Takahashi, K. | Takahashi, K. | Kikuchi, Y. | Akai, K. | Kanno, H. | Kaneko, J. | Suzuki, S. | Takahashi, K. | Akai, K. | Katayose, D. | Onodera, S. | Hiramoto, T. | Komatsu, S. | Chida, M. | Iwabuchi, K. | Takeuchi, M. | Yahagi, H. | Takahashi, N. | Otsuka, K. | Koseki, Y. | Morita, M. | Shinozaki, T. | Ishizuka, T. | Onoue, N. | Yamaguchi, N. | Fujita, H. | Katoh, A. | Namiuchi, S. | Sugie, T. | Saji, K. | Takii, T. | Sugimura, A. | Ohashi, J. | Fukuchi, M. | Ogata, M. | Tanikawa, T. | Kitamukai, O. | Matsumoto, Y. | Inoue, K. | Koyama, J. | Tomioka, T. | Shioiri, H. | Ito, Y. | Kato, H. | Takahashi, C. | Kawana, A. | Sakata, Y. | Ito, K. | Nakayama, M. | Fukuda, K. | Takahashi, J. | Miyata, S. | Sugimura, K. | Sato, K. | Matsumoto, Y. | Nakano, M. | Shiroto, T. | Tsuburaya, R. | Nochioka, K. | Yamamoto, H. | Aoki, T. | Hao, K. | Miura, M. | Kondo, M. | Tatebe, S. | Yamamoto, S. | Suzuki, H. | Nishimiya, K. | Yaoita, N. | Sugi, M. | Yamamoto, Y. | Toda, S. | Minatoya, Y. | Takagi, Y. | Hasebe, Y. | Nihei, T. | Hanawa, K. | Fukuda, K. | Sakata, Y. | Takahashi, J. | Miyata, S. | Nochioka, K. | Miura, M. | Tadaki, S. | Ushigome, R. | Yamauchi, T. | Sato, K. | Tsuji, K. | Onose, T. | Abe, R. | Saga, C. | Suenaga, J. | Yamada, Y. | Kimura, J. | Ogino, H. | Oikawa, I. | Watanabe, S. | Saga, M. | Washio, M. | Nagasawa, K. | Nagasawa, S. | Kotaka, S. | Komatsu, W. | Hashimoto, R. | Ikeno, Y. | Suzuki, T. | Hamada, H.
European Heart Journal  2015;36(15):915-923.
We examined whether an additive treatment with an angiotensin receptor blocker, olmesartan, reduces the mortality and morbidity in hypertensive patients with chronic heart failure (CHF) treated with angiotensin-converting enzyme (ACE) inhibitors, β-blockers, or both. In this prospective, randomized, open-label, blinded endpoint study, a total of 1147 hypertensive patients with symptomatic CHF (mean age 66 years, 75% male) were randomized to the addition of olmesartan (n = 578) to baseline therapy vs. control (n = 569). The primary endpoint was a composite of all-cause death, non-fatal acute myocardial infarction, non-fatal stroke, and hospitalization for worsening heart failure. During a median follow-up of 4.4 years, the primary endpoint occurred in 192 patients (33.2%) in the olmesartan group and in 166 patients (29.2%) in the control group [hazard ratio (HR) 1.18; 95% confidence interval (CI), 0.96–1.46, P = 0.112], while renal dysfunction developed more frequently in the olmesartan group (16.8 vs. 10.7%, HR 1.64; 95% CI 1.19–2.26, P = 0.003). Subgroup analysis revealed that addition of olmesartan to combination of ACE inhibitors and β-blockers was associated with increased incidence of the primary endpoint (38.1 vs. 28.2%, HR 1.47; 95% CI 1.11–1.95, P = 0.006), all-cause death (19.4 vs. 13.5%, HR 1.50; 95% CI 1.01–2.23, P = 0.046), and renal dysfunction (21.1 vs. 12.5%, HR 1.85; 95% CI 1.24–2.76, P = 0.003). Additive use of olmesartan did not improve clinical outcomes but worsened renal function in hypertensive CHF patients treated with evidence-based medications. Particularly, the triple combination therapy with olmesartan, ACE inhibitors and β-blockers was associated with increased adverse cardiac events. This study is registered at
PMCID: PMC4466154  PMID: 25637937
Heart failure; Hypertension; Angiotensin II receptor blocker; Olmesartan
2.  Influence of cycloplegia with topical cyclopentolate on higher-order aberrations in myopic children 
Eye  2014;28(5):581-586.
To investigate the influence of cycloplegia with topical cyclopentolate on wavefront aberrations in myopic children.
This is a prospective, comparative study.
Twenty-eight myopic children with a mean age of 7.25±2.55 were enrolled in this study. We evaluated refraction and wavefront aberrations before and after cycloplegia with 1% cyclopentolate hydrochloride. Ocular and corneal aberrations were simultaneously measured and compared with each other. Individual Zernike components were also analyzed up to the sixth order. All these parameters were compared before and after cycloplegia.
Ocular higher-order aberrations (HOAs) significantly increased after cycloplegia (P=0.012 for spherical-like and P=0.015 for total HOAs). Corneal HOAs did not change after cycloplegia. When corneal and ocular HOAs were compared, the ocular HOAs were significantly smaller than the corneal HOAs in spherical-like aberrations (P<0.001) and total HOAs (P=0.006). As for individual Zernike components, ocular aberration generally showed smaller or equivalent values in comparison with corneal aberration. In addition, each Zernike component showed a large standard deviation.
Internal optics compensates for corneal HOAs in myopic children, and paralysis of tonic accommodation with cyclopentolate considerably affects ocular HOAs. However, inter-individual variation in each Zernike component is quite large in myopic children.
PMCID: PMC4017117  PMID: 24577253
3.  Management bundles for candidaemia: the impact of compliance on clinical outcomes 
The Mycoses Forum in Japan has developed management bundles for candidaemia to incorporate into bedside practice. The aim of this study was to investigate nationwide compliance with the bundles and their impact on clinical outcomes.
Non-neutropenic patients treated with antifungals for candidaemia were surveyed. Bundles consist of nine items to complete. Data were sent to the central office between July 2011 and April 2012.
Six hundred and eight patients were analysed. The compliance rate for achieving all elements was 6.9%, and it increased to 21.4% when compliance was analysed by the bundle except for oral switch. There was a significant difference in clinical success between patients with and without compliance [92.9% versus 75.8% (P = 0.011)]. Compliance with the bundles, however, failed to be an independent factor associated with favourable outcomes. When step-down oral therapy was excluded from the elements of compliance, compliance with the bundles was revealed to be an independent predictor of clinical success (OR 4.42, 95% CI 2.05–9.52) and mortality (OR 0.27, 95% CI 0.13–0.57). Independent individual elements contributing to clinical success were removal of central venous catheters within 24 h, assessment of clinical efficacy on the third to the fifth day and at least 2 weeks of therapy after clearance of candidaemia.
Compliance with the bundles for candidaemia had a beneficial effect on clinical outcomes. Promotion of the bundles approach may have the potential to narrow the gap between clinical evidence and bedside practice.
PMCID: PMC4291239  PMID: 25326087
candidiasis; guidelines; intravenous catheters; invasive disease; fungal infections
4.  Evaluation of Nanodispersion of Iron Oxides Using Various Polymers 
In order to create Fe2O3 and Fe2O3·H2O nanoparticles, various polymers were used as dispersing agents, and the resulting effects on the dispersibility and nanoparticulation of the iron oxides were evaluated. It was revealed that not only the solution viscosity but also the molecular length of the polymers and the surface tension of the particles affected the dispersibility of Fe2O3 and Fe2O3·H2O particles. Using the dispersing agents 7.5% hydroxypropylcellulose-SSL, 6.0% Pharmacoat 603, 5.0% and 6.5% Pharmacoat 904 and 7.0% Metolose SM-4, Fe2O3 nanoparticles were successfully fabricated by wet milling using Ultra Apex Mill. Fe2O3·H2O nanoparticles could also be produced using 5.0% hydroxypropylcellulose-SSL and 4.0 and 7.0% Pharmacoat 904. The index for dispersibility developed in this study appears to be an effective indicator of success in fabricating nanoparticles of iron oxides by wet milling using Ultra Apex Mill.
PMCID: PMC4007256  PMID: 24799739
Dispersibility; iron oxide; nanoparticle; polymer; wet-milling
5.  Oral administration of an HSP90 inhibitor, 17-DMAG, intervenes tumor-cell infiltration into multiple organs and improves survival period for ATL model mice 
Blood Cancer Journal  2013;3(8):e132-.
In the peripheral blood leukocytes (PBLs) from the carriers of the human T-lymphotropic virus type-1 (HTLV-1) or the patients with adult T-cell leukemia (ATL), nuclear factor kappaB (NF-κB)-mediated antiapoptotic signals are constitutively activated primarily by the HTLV-1-encoded oncoprotein Tax. Tax interacts with the I κB kinase regulatory subunit NEMO (NF-κB essential modulator) to activate NF-κB, and this interaction is maintained in part by a molecular chaperone, heat-shock protein 90 (HSP90), and its co-chaperone cell division cycle 37 (CDC37). The antibiotic geldanamycin (GA) inhibits HSP90's ATP binding for its proper interaction with client proteins. Administration of a novel water-soluble and less toxic GA derivative, 17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride (17-DMAG), to Tax-expressing ATL-transformed cell lines, C8166 and MT4, induced significant degradation of Tax. 17-DMAG also facilitated growth arrest and cellular apoptosis to C8166 and MT4 and other ATL cell lines, although this treatment has no apparent effects on normal PBLs. 17-DMAG also downregulated Tax-mediated intracellular signals including the activation of NF-κB, activator protein 1 or HTLV-1 long terminal repeat in Tax-transfected HEK293 cells. Oral administration of 17-DMAG to ATL model mice xenografted with lymphomatous transgenic Lck-Tax (Lck proximal promoter-driven Tax transgene) cells or HTLV-1-producing tumor cells dramatically attenuated aggressive infiltration into multiple organs, inhibited de novo viral production and improved survival period. These observations identified 17-DMAG as a promising candidate for the prevention of ATL progression.
PMCID: PMC3763384  PMID: 23955587
17-DMAG; molecular chaperon; Tax; ATL; apoptosis; transgenic model
6.  A case of pneumonitis and encephalitis associated with human herpesvirus 6 (HHV-6) infection after bone marrow transplantation 
The British Journal of Radiology  2010;83(996):e255-e258.
Human herpesvirus 6 (HHV-6)-associated encephalitis or pneumonitis has been reported in immunocompetent and immunosuppressed individuals. Several MRI studies in patients with HHV-6-associated encephalitis have been presented. However, to the best of our knowledge, no studies describing thin-section CT imaging in patients with HHV-6-associated pneumonitis have been reported. Here we describe a case of HHV-6-associated encephalitis and pneumonitis that developed after bone marrow transplantation. Thin-section CT images of the chest revealed ground-glass attenuation, consolidation and centrilobular nodules in both lungs.
PMCID: PMC3473609  PMID: 21088083
7.  Intravascular lymphomatosis presenting as an ascending cauda equina: conus medullaris syndrome: remission after biweekly CHOP therapy 
A 63 year old man developed dysaesthesia in the legs followed by a subacute ascending flaccid paraparesis with sacral sensory and autonomic involvement. Intravascular lymphomatosis (IVL) was favoured by the presence of low grade fever and raised serum C reactive protein, CSF pleocytosis, raised lymphoma markers (serum LDH, soluble IL-2 receptor), and steroid responsiveness. Only muscle, among several organ biopsies, confirmed IVL. A cytogenetic study of the bone marrow showed chromosome 6 monosomy, as previously reported. The monosomy of chromosome 19, which bears the intercellular cell adhesion molecule-1, newly found in this case, may be related to the unique tumour embolisation of IVL. The CHOP regimen (six courses in 12 weeks) using granulocyte colony stimulating factor (G-CSF) led to gradual resolution of myeloradiculopathy and laboratory supported remission lasting for more than 13 months. The biweekly CHOP with G-CSF support may be a choice of chemotherapy in averting rapidly fatal IVL.

PMCID: PMC1736537  PMID: 10449569
8.  Chlorophyll derived from Chlorella inhibits dioxin absorption from the gastrointestinal tract and accelerates dioxin excretion in rats. 
Environmental Health Perspectives  2001;109(3):289-294.
We investigated the effects of chlorophyll derived from Chlorella on gastrointestinal absorption of seven types of polychlorinated dibenzo-p-dioxin (PCDD) and 10 types of polychlorinated dibenzofuran (PCDF) in Wistar rats. Twenty-eight rats were randomly distributed into seven groups (n = 4). After overnight food deprivation, rats were given 4 g of the basal diet or 4 g of the chlorophyll diet containing 0.01-0.5% chlorophyll one time on day 1; each diet also contained 0.2 mL PCDD and PCDF standard solutions. The amounts of fecal excretion of PCDD and PCDF congeners from days 1 to 5 in the group fed 0.01% chlorophyll were 64.8% for 1,2,3,7,8-pentaCDD, 78.6% for 1,2,3,4,7,8-hexaCDD, 73.5% for 1,2,3,6,7,8-hexaCDD, 58.5% for 1,2,3,7,8,9-hexaCDD, 33.3% for 1,2,3,4,6,7,8-heptaCDD, 85.7% for 1,2,3,7,8-pentaCDF, 77.3% for 2,3,4,7,8-pentaCDF, 88.6% for 1,2,3,4,7,8-hexaCDF, 78.0% for 1,2,3,6,7,8-hexaCDF, 62.5% for 1,2,3,7,8,9-hexaCDF, 84.1% for 2,3,4,6,7,8-hexaCDF, 41.7% for 1,2,3,4,6,7,8-heptaCDF, and 40.0% for 1,2,3,4,6,7,8-heptaCDF greater (p < 0.01) than those of the control group, respectively. The fecal excretion of PCDD and PCDF congeners was remarkably increased along with the increasing dietary chlorophyll. The amounts of PCDD and PCDF congeners in rats on day 5 administered dioxin mixtures were lower in the 0.01% chlorophyll group than in the control group, ranging from 3.5 to 50.0% for PCDD congeners and from 3.7 to 41.7% lower for PCDF congeners, except for 2,3,7,8-tetrachlorodibenzofuran. The amount of PCDD and PCDF congeners in rats was remarkably decreased along with the increasing dietary chlorophyll. These findings suggest that chlorophyll is effective for preventing dioxin absorption via foods.
PMCID: PMC1240248  PMID: 11333191
9.  Effect of anticoagulants on binding and neutralization of lipopolysaccharide by the peptide immunoglobulin conjugate CAP18(106-138)-immunoglobulin G in whole blood. 
Infection and Immunity  1997;65(6):2160-2167.
The 18-kDa cationic protein CAP18 is an antimicrobial protein isolated from rabbit granulocytes that binds lipopolysaccharide (LPS) and inhibits many of its biological activities. We covalently coupled a synthetic peptide representing amino acids 106 to 138 of CAP18 to human immunoglobulin G (IgG) by using the heterobifunctional linker N-succinimidyl-3-(2-pyridyidithio)propionate. The ability of CAP18(106-138)-IgG to bind and neutralize LPS in whole blood in the presence and absence of anticoagulants was studied. Both CAP18(106-138) and CAP18(106-138)-IgG significantly suppressed LPS-induced tumor necrosis factor (TNF) production in whole blood in the absence of anticoagulants. EDTA potentiated the ability of CAP18(106-138) and CAP18(106-138)-IgG to decrease LPS-induced TNF production in a dose-dependent manner. In contrast, heparin inhibited the ability of CAP18(106-138) and CAP18(106-138)-IgG to suppress LPS-induced TNF production. EDTA also enhanced LPS capture in a fluid-phase binding assay that utilizes magnetic anti-IgG beads to capture CAP18(106-138)-IgG (and bound [3H]LPS) in whole blood. In contrast, heparin inhibited the binding dose dependently. We conclude that CAP18(106-138)-IgG binds to and neutralizes LPS in whole blood in the absence of anticoagulants. Further studies of its protective efficacy in animal models are warranted. Caution should be used in interpreting assays that measure the binding and neutralization of LPS in whole blood in the presence of calcium-binding anticoagulants or heparin.
PMCID: PMC175298  PMID: 9169746
10.  Effect of peripheral benzodiazepine receptor ligands on lipopolysaccharide-induced tumor necrosis factor activity in thioglycolate-treated mice. 
To investigate the effect of peripheral and central benzodiazepine receptor ligands on lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF) activity in mouse macrophages, three types of ligands, 4'-chlorodiazepam (pure peripheral), midazolam (mixed), and clonazepam (pure central), were compared. Midazolam and 4'-chlorodiazepam significantly suppressed LPS (1-microgram/ml)-induced TNF activity in thioglycolate-elicited mouse macrophages. In every concentration examined (0.001 to 100 microM), 4'-chlorodiazepam was the most effective agent, clonazepam was the least effective agent, and midazolam had an effect intermediate between those of the other two ligands. The peripheral benzodiazepine receptor ligands had a dose-dependent suppressive effect, and the 50% inhibitory concentrations were 0.01 microM for 4'-chlorodiazepam and 5 microM for midazolam. Concomitant use of PK 11195 (10 microM), an antagonist of the peripheral benzodiazepine receptor, reversed this suppressive effect with 4'-chlorodiazepam (10 microM) or midazolam (10 microM). PK 11195 showed this antagonistic effect in a dose-dependent manner. Intravenous 4'-chlorodiazepam (5 mg/kg of body weight) significantly suppressed LPS (100-micrograms)-induced TNF activity of sera (2 h postchallenge with LPS) from thioglycolate-treated mice. The present findings suggest that the peripheral benzodiazepine receptor plays an important role in modulating LPS-induced TNF activity in mouse macrophages.
PMCID: PMC284547  PMID: 8031051
11.  An antagonist of platelet-activating factor suppresses endotoxin-induced tumor necrosis factor and mortality in mice pretreated with carrageenan. 
Infection and Immunity  1993;61(2):699-704.
We found that carrageenan (CAR), that is, sulfated polygalactose, can enhance both lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF) production and the rate of lethality in mice (M. Ogata, S. Yoshida, M. Kamochi, A. Shigematsu, and Y. Mizuguchi, Infect. Immun. 59:679-683, 1991). It has been reported that platelet-activating factor (PAF) antagonists reduce the rate of mortality from endotoxin shock. However, there are few reports regarding the effect of PAF antagonists on TNF production. The aim of the present study is to examine the effect of TCV-309, a new PAF antagonist, on LPS-induced TNF production and mortality in mice pretreated with CAR. ddY mice (6 to 7 weeks old) were injected intraperitoneally with CAR (5 mg per mouse) and were then divided into two groups: mice treated with a PAF antagonist (TCV-309; Takeda Pharmaceutical Co.) and control mice. The mice treated with PAF antagonist received indicated doses of TCV-309 subcutaneously (s.c.) at 30 min before LPS injection, while the control mice received 1 ml of saline s.c. at the same time. All mice were stimulated by intravenous injection of LPS (50 micrograms per mouse) at 24 h after pretreatment with CAR. At intervals after injection of LPS, serum samples were obtained for a TNF assay in which cytotoxicity to L929 cells was measured. TCV-309 both significantly suppressed LPS-induced TNF production and reduced mortality in a dose-dependent manner. When TCV-309 was administered at 30 min before injection of LPS, the effect of TCV-309 on the suppression of TNF activity was at its peak. Treatment with TCV-309 (990 micrograms per mouse) s.c. significantly improved the survival rate after challenge with LPS compared with the survival rate of control mice. Although the 50% lethal dose of LPS was 15 micrograms per mouse for control mice, it increased to 102 micrograms per mouse for mice that were treated s.c. with TCV-309 (990 micrograms per mouse). Even in vitro, TCV-309 also inhibited LPS-induced TNF production in thioglycolate-elicited macrophages. It was concluded that PAF plays an important role in endotoxin-induced TNF production and mortality.
PMCID: PMC302782  PMID: 8423096
12.  Protective effects of a leukotriene inhibitor and a leukotriene antagonist on endotoxin-induced mortality in carrageenan-pretreated mice. 
Infection and Immunity  1992;60(6):2432-2437.
The leukotrienes and tumor necrosis factor (TNF) play an important role in the pathophysiology of septic shock, in which hypotension, leukopenia, thrombocytopenia, and hemoconcentration are observed. This study was performed to examine the effects of a 5-lipoxygenase inhibitor (AA-861), a selective leukotriene receptor antagonist (ONO-1078), and a cyclooxygenase inhibitor (indomethacin) on endotoxin-induced mortality and TNF production in mice. Mice were injected intraperitoneally with carrageenan (5 mg per mouse), which we previously reported as an effective priming agent for lipopolysaccharide (LPS)-induced TNF production and mortality (M. Ogata, S. Yoshida, M. Kamochi, A. Shigematsu, and Y. Mizuguchi, Infect. Immun. 59:679-683, 1991). The indicated doses of AA-861, ONO-1078, indomethacin, or controls were administrated subcutaneously 30 min before LPS (50 micrograms per mouse) provocation. The mortality of mice was significantly decreased by pretreatment with AA-861 (P less than 0.001) or ONO-1078 (P less than 0.01) but not by pretreatment with indomethacin. The 50% lethal dose of LPS in the mice treated with dimethyl sulfoxide or ethanol was 32 or 33 micrograms, respectively, and it increased to 83 micrograms with AA-861 or 59 micrograms with ONO-1078, respectively. Neither AA-861 nor ONO-1078 suppressed LPS-induced TNF production in sera. Treatment with AA-861 significantly decreased the leukopenia and thrombocytopenia, and ONO-1078 significantly decreased the hemoconcentration and thrombocytopenia. The role of endogenous TNF was also examined in the carrageenan-pretreated mice. Treatment with 2 x 10(5) U of rabbit anti TNF-alpha antibody intravenously 2 h before LPS challenge significantly suppressed the LPS-induced TNF activity and decreased the mortality. Therefore, both leukotrienes and TNF play important roles in endotoxin-induced shock and mortality.
PMCID: PMC257177  PMID: 1587610
13.  Characterization of a cellular protease that cleaves Pseudomonas exotoxin. 
Infection and Immunity  1992;60(2):497-502.
Pseudomonas exotoxin (PE) is a 66-kDa bacterial toxin that is proteolytically cleaved by cells to produce an N-terminal fragment of 28 kDa and a C-terminal 37-kDa fragment which translocates to the cytosol and inhibits protein synthesis (M. Ogata, V.K. Chaudhary, I. Pastan, and D.J. FitzGerald, J. Biol. Chem. 265:20678-20685, 1990). When cells were broken by homogenization, the appropriate proteolytic activity was found associated with cellular membranes and not in a soluble fraction. Proteolysis of PE by crude membranes was stimulated by divalent cations, was ATP independent, and had a pH optimum of 5.5. When cells were disrupted by nitrogen cavitation and fractionated on Percoll gradients, proteolytic activity was present in fractions corresponding to the density of plasma membranes or endosomes but not in fractions containing lysosomes. Proteolytic activity was recovered in detergent extracts after crude membranes were treated with Nonidet P-40 or octylglucoside. Proteolysis of PE by either crude membranes or detergent extracts generated fragments of 28 and 37 kDa. The sizes of these fragments resembled those produced by intact cells. However, when the nontoxic mutant, PEgly276, which cannot be cleaved appropriately by intact cells, was incubated with membranes or extracts there was no production of the 28- and 37-kDa fragments.
PMCID: PMC257655  PMID: 1730481
14.  Enhancement of lipopolysaccharide-induced tumor necrosis factor production in mice by carrageenan pretreatment. 
Infection and Immunity  1991;59(2):679-683.
Tumor necrosis factor (TNF) is a cytokine which mediates endotoxin shock and causes multiple organ damage. It is thought that macrophage (MP) activation is necessary to increase lipopolysaccharide (LPS)-induced TNF production and lethality. Carrageenan (CAR) is sulfated polygalactose which destroys MP; it is used as a MP blocker. We found that CAR pretreatment can increase both endotoxin-induced TNF production and the mortality rate in mice. The ddY mice (7 to 8 weeks old) were injected intraperitoneally with CAR (5-mg dose) and challenged intravenously with LPS 24 h later. Without CAR pretreatment, LPS doses of less than 10 micrograms did not induce TNF in sera. After pretreatment, however, about 3 x 10(3) to 4 x 10(4) U of TNF per ml was produced after LPS injection at doses of 0.1 to 10 micrograms, respectively. TNF production was significantly increased by CAR pretreatment at LPS doses of more than 10 micrograms. CAR pretreatment rendered the mice more sensitive to the lethal effect of LPS; 50% lethal doses of LPS in CAR-pretreated mice and nonpretreated mice were 26.9 and 227 micrograms, respectively. The mortality of the two groups was significantly different at doses of 50, 100, and 200 micrograms of LPS. CAR increased LPS-induced TNF production and mortality within 2 h, much earlier than MP activators, which needed at least 4 days. Our results made clear that TNF production is enhanced not only by a MP activator but also by a MP blocker.
PMCID: PMC257810  PMID: 1987084
15.  Analysis of Pseudomonas exotoxin activation and conformational changes by using monoclonal antibodies as probes. 
Infection and Immunity  1991;59(1):407-414.
Pseudomonas exotoxin (PE) is a protein toxin composed of three structural domains. In its native form, the toxin is a 66,000-Mr proenzyme that must be activated to express full ADP-ribosylating activity. To study the process of activation and accompanying conformational changes, we have isolated 10 monoclonal antibodies to a 40,000-Mr fragment of the toxin (PE40) that exhibits full enzyme activity but lacks the toxin's cell-binding domain and contains amino acids 253 to 613 (comprising domains II, Ib, and III). By using mutant PE molecules in which all of domain I and portions of domains II, Ib, and III were deleted, the locations of the epitopes for each of the antibodies were determined. Eight of these monoclonal antibodies were further characterized. Of these eight, all reacted with soluble PE40 and an interleukin-2-PE40 conjugate, but only two reacted strongly with native soluble PE. However, all eight reacted with PE after it had been immobilized on nitrocellulose or after it had been activated to express full ADP-ribosylating activity. Antibodies were also assessed for their ability to neutralize the cytotoxic activity of either PE or interleukin-2-PE40. These antibodies should be useful as probes for monitoring the activation and processing of PE that occur during endocytosis and in determining the location of epitopes that are important for toxin activity.
PMCID: PMC257755  PMID: 1702764
16.  Cross-reactivity between haptenic muramyl di- or tripeptide derivatives and Mycobacterium bovis BCG: potential application for enhancing tumor immunity. 
Infection and Immunity  1986;54(3):768-773.
Muramyl di- or tripeptide (MDP or MTP) hapten derivatives bearing various structures were synthesized, and the correlation of these structures with cross-reactivity with Mycobacterium bovis BCG and their applicability to enhance induction of syngeneic tumor immunity were investigated. The cross-reactivity of MDP or MTP haptens to BCG was examined by T-cell proliferation responses of lymph node cells from BCG-primed C3H/He mice in the stimulation with MDP- or MTP-coupled syngeneic cells. A haptenic MDP derivative (designated L4-MDP) stimulated proliferative responses appreciably. Derivatives in which alanine in the peptide portion of L4-MDP was replaced by methylalanine or valine failed to induce stimulation. However, the cross-reactivity with BCG was regained in the MTP derivative that was formed by adding lysine to dipeptide containing methylalanine or valine. Whether this cross-reactive pattern was correlated with enhanced induction of tumor immunity was further investigated. According to the established protocol for the augmented induction of tumor immunity, BCG-primed C3H/He mice were immunized with various haptenic MDP-coupled syngeneic X5563 tumor cells. Immunization with tumor cells conjugating BCG-cross-reactive haptens resulted in enhanced tumor immunity, whereas immunization with tumor cells coupling non-cross-reactive haptens failed to produce anti-X5563 tumor immunity. These results indicate that the peptide portion in these haptenic structures is critical in the generation of BCG cross-reactivity leading to enhanced tumor immunity.
PMCID: PMC260235  PMID: 3491048
17.  Importance of anticomplement immunofluorescence antibody titration for diagnosing varicella-zoster virus infection in Bell's palsy. 
Journal of Clinical Pathology  1986;39(11):1254-1258.
Anticomplement Immunofluorescence was used for antibody titration against varicella-zoster virus (VZV) in 43 patients with peripheral facial palsy. Nine of 31 patients (29%) with Bell's palsy and eight of 12 patients (75%) with Ramsey-Hunt syndrome had anticomplement immunofluorescence antibody titres of greater than or equal to 1/10. On the other hand, none of 14 patients with herpes simplex virus (HSV) infection and 51 healthy adults showed anticomplement immunofluorescence antibody titres of greater than or equal to 1/10. The anticomplement immunofluorescence antibody titre in two patients with Ramsey-Hunt syndrome increased later and decreased sooner than the indirect immunofluorescence antibody titre, becoming undetectable at 66 and 104 days, respectively, after onset of the disease. There was no cross reaction between anti-VZV and anti-HSV antibodies in the patients who showed a positive antibody rise for VZV. As the acute stage of VZV infection is obscure in the patients with peripheral facial palsy without herpes the screening of anticomplement immunofluorescence antibody to VZV at titres greater than or equal to 1/10 may be useful for the diagnosis of VZV infection in patients with peripheral facial palsy.
PMCID: PMC1140774  PMID: 3025268
18.  Mortality among Japanese Zen priests. 
A cohort study was done on 1396 deaths seen among 4352 Japanese male Zen priests during a follow up period from 1 January 1955 to 31 December 1978. Standardised mortality ratios were computed for major causes of death by comparing with the counterparts of the general Japanese male population. The SMR for all causes of death was 0.82 (p less than 0.001) and the SMR values for cerebrovascular diseases, pneumonia and bronchitis, peptic ulcer, liver cirrhosis, cancer of the respiratory organs, and cancer of the lung were all significantly smaller than unity. Taking regional mortality differences into account, a similar computation was made dividing the cohort into two subcohorts--that is, the priests living in eastern Japan and those in western Japan. Both subcohorts showed a highly significantly smaller SMR than unity for all causes of death. With the exception of only a few causes of death for which the observed number of deaths was small, they also showed such reduced SMRs for nearly all of the causes of death tested. A questionnaire survey on the current life style of active priests showed that they smoke less, eat less, meat and fish as they follow the more traditional Japanese dietary habits, and live in less polluted areas, but their drinking habits do not differ much from that of the average Japanese adult man. Possible reasons for their reduced mortality are discussed.
PMCID: PMC1052341  PMID: 6747517
20.  Salt and geographical mortality of gastric cancer and stroke in Japan. 
Age- and sex-adjusted mortality rates of gastric cancer and stroke in the years 1974-6 for 46 prefectures and 12 regions in Japan were related to regional differences of average per capita daily intake of salt during the period 1966-70 to test Joossen's hypothesis that salt is a common cause of both gastric cancer and stroke. While mortality rates of stroke were strongly correlated with salt intake in 12 regions (r = 0.85, p less than 0.001), mortality rates of gastric cancer showed hardly any correlation with salt intake (r = 0.02). There was no strong correlation between the two diseases in perfectural or regional mortality rates (r = 0.20). It was concluded that geographical mortality of gastric cancer and stroke in Japan did not support Joossens's hypothesis, and other evidence against the salt hypothesis has also been referred to.
PMCID: PMC1052254  PMID: 6875444
21.  In vitro susceptibility of varicella-zoster virus to E-5-(2-bromovinyl)-2'-deoxyuridine and related compounds. 
The in vitro susceptibility of eight strains of varicella-zoster virus (VZV) to E-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) was examined in human embryonic fibroblasts by the following techniques: inhibition of focus formation by either cell-free VZV (4-day assay) or cell-associated VZV (2-day assay), inhibition of viral antigen formation (2-day assay), and inhibition of viral cytopathogenicity (15-day assay). The 50% inhibitory dose (ID50) of BVDU ranged from 0.001 microgram/ml (2-day assay) to 0.01 microgram/ml (15-day assay). BVDU appeared highly selective in its anti-VZV activity since even at concentrations as high as 100 micrograms/ml, BVDU did not markedly affect the viability of the host cells. The ID50 of BVDU for VZV was comparable to that of IVDU (E-5-(2-iodovinyl)-2'-deoxyuridine). Both drugs inhibited the replication of VZV at a much lower concentration than did other antiviral compounds such as iododeoxyuridine, ethyldeoxyuridine, arabinosylcytosine, arabinosyladenine, phosphonoacetic acid, iododeoxycytidine, and acycloguanosine. BVDU and IVDU were virtually inactive against a thymidine kinase-deficient VZV mutant, suggesting that phosphorylation by the viral enzyme is responsible, at least in part, for the selective anti-VZV activity of the compounds.
PMCID: PMC181824  PMID: 6282207
22.  Appearance of immunoglobulin G Fc receptor in cultured human cells infected with varicella-zoster virus. 
Infection and Immunity  1979;26(2):770-774.
After infection with varicella-zoster virus, HeLa and human embryo lung cells developed a receptor for the Fc portion of human and rabbit immunoglobulin G. The receptor was detected by both hemadsorption and immunofluorescence, using antibody-coated erythrocytes and heat-aggregated immunoglobulin G. However, sheep erythrocytes sensitized with F(ab')2 of anti-sheep erythrocyte antibody did not adsorb to the receptor. When cell-free varicella-zoster virus was inoculated into the HeLa cell monolayer, the Fc receptor appeared at first 6 h after infection; varicella-zoster virus antigen in the cytoplasm and detectable cytopathic effects appeared later.
PMCID: PMC414681  PMID: 232695
23.  Type-specific indirect hemagglutinating antibody in patients with Pseudomonas aeruginosa Infection. 
Journal of Clinical Microbiology  1978;8(5):489-495.
Lipopolysaccharide antigens were extracted from heated cell extracts of several serotypes of Pseudonomas aeruginosa. Indirect hemagglutination with the extracts indicated specific reactivity with sera from rabbits immunized with homologous serotypes of P. aeruginosa. Sera from healthy adults and patients infected with P. aeruginosa were studied subsequently and shown to possess antibodies against P. aeurginosa. In patients infected with P. aeruginosa type E, indirect hemagglutination antibody against type E was resistant to 2-mercaptoethanol (2-ME) and classified as immunoglobulin G. In patients infected with any other type of P. aeruginosa and in healthy adults, it was sensitive to 2-ME and classified as immunoglobulin M. The antibody in the seven patients infected with P. aeruginosa was titrated during the course of infection with lipopolysaccharide antigen prepared from the infecting strain. As a result, all patients either possessed 2-ME-resistant antibody or showed antibody rise to homotypic antigen during the infection. However, no patient showed 2-ME-resistant antibody against hetero-typic lipopolysaccharide antigens. In hospitalized patients, the incidence of anti body against type E, G, and I Pseudomonas strains was greater than that against type A. In particular, 2-ME-resistant antibody to all four serotypes was detected at a higher rate in hospitalized patients than in healthy adults.
PMCID: PMC275284  PMID: 103887
24.  Abducens nerve palsy as initial symptom of trigeminal schwannoma. 
The insidious onset and slow progression of symptoms may cause delay in the recognition of trigeminal schwannomas. Two cases with abducens nerve palsy as an initial symptom are reported, in both of whom the tumour was growing mainly below and anterior to the intracavernous portion of the internal carotid artery. Early detection of clinical symptoms and thorough radiological investigations are important in the early diagnosis of these lesions.
PMCID: PMC492942  PMID: 591987
25.  Cloned origin of DNA replication in c-myc gene can function and be transmitted in transgenic mice in an episomal state. 
Nucleic Acids Research  1990;18(18):5425-5432.
The c-myc protein has recently been shown to interact with a region possessing putative origin of DNA replication and enhancer activities located 2 kb upstream of the c-myc gene itself. Transgenic mice were obtained by injecting constructs containing this region, termed pmyc(H-P), into fertilized mouse eggs. The transgenic elements were capable of efficient replication in all mouse tissues examined and were maintained in an episomal state even in highly differentiated cells. Moreover, pmyc(H-P) was transmittable to the progeny throughout several generations, which suggests that the fragment derived from the region upstream of the c-myc gene possesses sequences necessary for partition, stability and DNA replication of the plasmid in the cells. In addition, we have shown that the plasmid might be captured only by eggs, not by sperm.
PMCID: PMC332220  PMID: 2216716

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