Prognostic implications of resting distal coronary-to-aortic pressure ratio compared with fractional flow reserve: a 10-year follow-up study after deferral of revascularisation.

INTRODUCTION: The distal coronary-to-aortic pressure ratio (Pd/Pa) is a non-hyperaemic physiological index to assess the functional severity of coronary stenoses. Studies comparing Pd/Pa with fractional flow reserve (FFR) show superior diagnostic efficiency for myocardial ischaemia. Nevertheless, a direct comparison regarding long-term clinical outcomes is still not available. The present observational study compared the prognostic value of Pd/Pa and FFR for major adverse cardiac events (MACE) during a 10-year follow-up period after deferral of revascularisation. METHODS: Between April 1997 and September 2006, we evaluated 154 coronary stenoses (154 patients) in which revascularisation was deferred with intracoronary pressure and flow measurements during the resting and hyperaemic state. Long-term follow-up (median: 11.8 years) was performed to document the occurrence of MACE, defined as a composite of cardiac death, myocardial infarction and target vessel revascularisation. RESULTS: The study population comprised angiographically intermediate coronary stenoses, with a mean diameter stenosis of 53 ± 8%, and intermediate physiological severity with a median FFR of 0.82 (Q1, Q3: 0.76, 0.88). The association of Pd/Pa with long-term MACE was similar to that of FFR [FFR-standardised hazard ratio (sHR): 0.77, 95% confidence interval (CI): 0.61-0.98; Pd/Pa-sHR: 0.80, 95% CI: 0.67-0.96]. In the presence of disagreement between Pd/Pa and FFR, normal Pd/Pa was generally associated with high coronary flow reserve (CFR) and a favourable clinical outcome, whereas abnormal Pd/Pa was generally associated with CFR around the ischaemic cut-point and an impaired clinical outcome, regardless of the accompanying FFR value. CONCLUSION: The present study suggests that Pd/Pa provides at least equivalent prognostic value compared with FFR. When Pd/Pa disagreed with FFR, the baseline index conferred superior prognostic value in this study population.

Evaluation of Delivered Doses in Proton Beam Therapy for Prostate Cancer Using Positron Emission Tomography/Computed Tomography Imaging.

AIMS: Proton beams deposit energy along their paths and stop abruptly without penetrating the opposite side, making it difficult to detect their actual paths. However, confirming the path may lead to evaluating the actual doses to organs at risk in proton therapy for prostate cancer. As proton beams produce positron emitters through nuclear fragmentation reactions, theoretically, proton beam paths can be measured by positron emission tomography/computed tomography (PET/CT). Therefore, this study investigated whether conducting PET/CT examinations immediately after proton beam therapy helps to assess the doses delivered to the rectal and urinary bladder walls, which are the major sites of radiation-related toxicity. MATERIALS AND METHODS: Between June 2022 and June 2023, 51 consecutive patients with prostate cancer who underwent proton beam therapy were enrolled and imaged with PET/CT to measure these radioactive particles and validate the actual dose delivered to the rectal and urinary bladder walls. RESULTS: The delivered doses assessed using PET/CT after proton beam therapy strongly correlated with the planned volume for proton beam treatment. CONCLUSIONS: PET/CT exhibited potential as a valuable tool for validating the irradiated dose to organs at risk.

Exciton diffusion in air-suspended single-walled carbon nanotubes.

Direct measurements of the diffusion length of excitons in air-suspended single-walled carbon nanotubes are reported. Photoluminescence microscopy is used to identify individual nanotubes and to determine their lengths and chiral indices. Exciton diffusion length is obtained by comparing the dependence of photoluminescence intensity on the nanotube length to numerical solutions of diffusion equations. We find that the diffusion length in these clean, as-grown nanotubes is significantly longer than those reported for micelle-encapsulated nanotubes.

Pharmacokinetics and disposition of CS-8958, a long-acting prodrug of the novel neuraminidase inhibitor laninamivir in rats.

CS-8958, a prodrug of laninamivir (R-125489), is currently under development as an inhaled anti-influenza drug. In this study, the pharmacokinetics and disposition of CS-8958 were characterized in rats. After intratracheal administration of 14C-CS-8958, radioactivity was retained over long periods in the target tissues (trachea and lung) as its active metabolite R-125489 - 19.12% of the dose was retained in the lung at 24 h. After intratracheal administration of CS-8958, plasma R-125489 concentration was slowly eliminated, and its half-life (14.1 h) was considerably longer than that after intravenous administration of R-125489. The radioactivity of intratracheally administered 14C-CS-8958 was mainly excreted into the urine (67.5% of dose), and this excretion lasted over long periods. R-125489 accounted for most of the urinary radioactivity recovered after 24 h. These results demonstrated that CS-8958 administered intratracheally to rats was converted/hydrolysed to R-125489 in the target tissues, and that the R-125489 was slowly excreted into the urine via an absorption rate-limiting process. Such distinctive pharmacokinetics attributed to the slow release of R-125489 suggests the potential for a long-acting anti-influenza drug.

Deficit of state-dependent risk attitude modulation in gambling disorder.

Gambling disorder (GD) is often considered as a problem of trait-like risk preference. However, the symptoms of GD cannot be fully understood by this trait view. In the present study, we hypothesized that GD patients also had problem with a flexible control of risk attitude (state-dependent strategy optimization), and aimed to investigate the mechanisms underlying abnormal risk-taking of GD. To address this issue, we tested GD patients without comorbidity (GD group: n=21) and age-matched healthy control participants (HC group: n=29) in a multi-step gambling task, in which participants needed to clear 'block quota' (required units to clear a block, 1000-7000 units) in 20 choices, and conducted a task-functional magnetic resonance imaging (fMRI) experiment. Behavioral analysis indeed revealed a less flexible risk-attitude change in the GD group; the GD group failed to avoid risky choice in a specific quota range (low-quota condition), in which risky strategy was not optimal to solve the quota. Accordingly, fMRI analysis highlighted diminished functioning of the dorsolateral prefrontal cortex (dlPFC), which has been heavily implicated in cognitive flexibility. To our knowledge, the present study provided the first empirical evidence of a deficit of state-dependent strategy optimization in GD. Focusing on flexible control of risk attitude under quota may contribute to a better understanding of the psychopathology of GDs.

Frankliniella cephalica, a New Vector for Tomato spotted wilt virus.

Frankliniella cephalica (Crawford) is an invasive species of thrips found in the islands of Yaeyama in the Okinawa Prefecture, Japan. During the late 1990s to early 2000s, a species of thrips was isolated from wild flowers of Bidens pilosa L. and Ipomoea batatas L. growing close to cultivated fields. They were subsequently identified as F. cephalica using fine morphological characteristics with the help of Steve Nakahara (U.S. Department of Agriculture, Beltsville, MD) and Laurence Mound (CSIRO, Australia). Voucher specimens were deposited in the Laboratory of Insect Resources, Faculty of Agriculture, Tokyo University of Agriculture by Shuji Okajima (2). We investigated the ability of F. cephalica to vector Tomato spotted wilt virus (TSWV) by experimentally determining virus transmission efficiency. Newly hatched larvae as much as 12 h old underwent a viral acquisition-access period (AAP) of 24 h, during which they fed on the leaves of Datura stramonium infected with TSWV-O, a Japanese type isolate. Transmission efficiency of adults 4 days after emergence from molt (14 days after the AAP) was determined by a petunia leaf disk assay (3) in which the adults were individually allowed to feed for successive 24-h inoculation access periods (IAP) on two different leaf disks of Petunia × hybrida cv. Polo Blue. Transmission of the virus by the adults was considered positive if at least one of the leaf disks showed viral necrotic spot. We tested 20 randomly selected leaf disks with clear necrotic spots using a simplified rapid immunofilter paper assay. All selected disks were positive for TWSV. The transmission efficiencies were 24.6% for female (n = 57) and 54.4% for male (n = 125) adults. The efficiency was significantly different between sexes (Fisher's exact probability test, P < 0.001). We also examined changes in the virus infection site at different developmental stages in thrips using immunofluorescence microscopy with a polyclonal antibody to N protein of the virus (4). After a 6-h AAP feeding by first instar larvae, the virus was found initially to infect the epithelial cells and then spread throughout the midgut tissue in the second instar larvae 5 days after acquisition of the virus. In viruliferous adults, the virus was present in the salivary glands and on the basement membrane of the midgut tissue. These data indicate that F. cephalica is a new insect vector for TSWV. F. cephalica is a major insect pest of tropical crops in tropical and subtropical coastal belts (1). The presence of a thrips vector in weed hosts surrounding cultivated fields might increase the chance of crops in this habitat becoming infected with viruses. References: (1) M. Lamberts and J. H. Crane. Page 337 in: Advances in New Crops. J. Janick and J. E. Simon, eds. Timber Press, Portland, OR, 1990. (2) M. Masumoto and S. Okajima. Jpn. J. Appl. Entomol. Zool. 48:225, 2004. (3) T. Sakurai et al. Appl. Entomol. Zool. 39:71, 2004. (4) S. Tsuda et al. Ann. Phytopathol. Soc. Jpn. 60:216, 1994.

Cancer induction by an organic arsenic compound, dimethylarsinic acid (cacodylic acid), in F344/DuCrj rats after pretreatment with five carcinogens.

Arsenic (As) is environmentally ubiquitous and an epidemiologically significant chemical related to certain human cancers. Dimethylarsinic acid (cacodylic acid; DMA) is one of the major methylated metabolites of ingested arsenicals in most mammals. To evaluate the effects of DMA on chemical carcinogenesis, we conducted a multiorgan bioassay in rats given various doses of DMA. One-hundred twenty-four male F344/DuCrj rats were divided randomly into 7 groups (20 rats each for groups 1-5; 12 rats each for groups 6 and 7). To initiate multiple organs and tissues, animals in groups 1-5 were treated sequentially with diethylnitrosamine (100 mg/kg body weight, i.p., single dose at the commencement) and N-methyl-N-nitrosourea (20 mg/kg body weight, i.p., 4 times, on days 5, 8, 11, and 14). Thereafter, rats received 1,2-dimethylhydrazine (40 mg/kg body weight, s.c., 4 times, on days 18, 22, 26, and 30). During the same period, the animals were sequentially administered N-butyl-N-(4-hydroxybutyl)nitrosamine (0.05% in the drinking water, during weeks 1 and 2) and N-bis(2-hydroxypropyl)nitrosamine (0.1% in the drinking water, during weeks 3 and 4; DMBDD treatment). After a 2-week interval, groups 2-5 were given 50, 100, 200, or 400 ppm DMA, respectively, in the drinking water. Groups 6 and 7, which were not given DMBDD treatment, received 100 and 400 ppm DMA during weeks 6-30. All rats were killed at the end of week 30. In the initiated groups (groups 1-5), DMA significantly enhanced the tumor induction in the urinary bladder, kidney, liver, and thyroid gland, with respective incidences in group 5 (400 ppm DMA) being 80, 65, 65, and 45%. Induction of preneoplastic lesions (glutathione S-transferase placental form-positive foci in the liver and atypical tubules in the kidney) was also significantly increased in DMA-treated groups. Ornithine decarboxylase activity in the kidneys of rats treated with 100 ppm DMA was significantly increased compared with control values (P < 0.001). In conclusion, DMA is acting as a promoter of urinary bladder, kidney, liver, and thyroid gland carcinogenesis in rats, and we speculate that this may be related to cancer induction by As in humans.

Induction of renal pelvic carcinoma by phenacetin in hydronephrosis-bearing rats of the SD/cShi strain.

Carcinogenicity of phenacetin (PH) to the urinary tract was tested with the use of spontaneously hydronephrosis-bearing rats. In Experiment 1, 55 SD/cShi male rats were fed with 2% PH-containing diet for 85 weeks, and 32 SD/cShi male rats fed basal diet for 85 weeks served as controls. Forty-three of 53 rats fed with PH had renal pelvic carcinoma with lung metastases in three. The mean induction time was 78 weeks. Ureteral carcinoma and urinary bladder carcinoma were observed in 2 and 6 of 53 rats given PH, respectively. No urinary tract carcinoma was found in control animals. In Experiment 2, early lesions of the kidney affected by PH were also evaluated with the use of SD/cShi and Sprague-Dawley (SD) rats. Two groups of animals containing 6 SD/cShi or 6 SD male rats per group were fed 2% PH-containing diet for 8 weeks. Control animals containing 6 SD/cShi rats or 6 SD rats were fed basal diet for 8 weeks. Simple hyperplasia was found in 5 of 6 SD/cShi rats given PH and 2 of 6 SD/cShi control rats. Papillary necrosis was seen in 4 of 6 SD/cShi and 2 of 6 SD rats given PH. SD/cShi rats, especially those treated with PH, showed higher but not significant 5-bromo-2'-deoxyuridine labeling indices in the covering epithelium of the renal pelvis and papillae. In this short term experiment PH and its metabolites, N-hydroxyphenacetin and N-acetyl-p-aminophenol, were measured in urine and plasma by using high performance liquid chromatography. Significantly higher PH and slightly higher metabolites were detected in urine and plasma of SD/cShi rats compared to SD rats. These results indicated that the renal pelvis of SD/cShi rats had more sensitivity to PH carcinogenicity. This paper provides experimental proof of PH carcinogenicity toward the renal pelvis in an animal model.

Emotional cognition without awareness after unilateral temporal lobectomy in humans.

To investigate the function of the amygdala in human emotional cognition, we investigated the electrodermal activity (EDA) in response to masked (unseen) visual stimuli. Six epileptic subjects were investigated after unilateral temporal lobectomy. Emotionally valenced photographic slides (10 negative, 10 neutral) from the International Affective Picture System were presented to their unilateral visual fields under either subliminal or supraliminal conditions. An interaction between hemispheres and emotional valences was found only under the subliminal conditions; greater EDA responses to negative stimuli compared with neutral ones were observed when stimuli were presented to the intact hemispheres. The findings suggest that nonconscious emotional processing is reflected in EDA in a different manner from conscious emotional processing. Medial temporal structures, including the amygdala, thus appear to play a critical role in the neural substrates for this automatic processing.

Rhizoxin binding to tubulin at the maytansine-binding site.

The binding of rhizoxin, a potent inhibitor of mitosis and in vitro microtubule assembly, to porcine brain tubulin was studied. Tubulin possesses one binding site for rhizoxin per molecule with a dissociation constant (Kd) of 1.7.10(-7) M. Ansamitocin P-3, a homologue of maytansine, was a competitive inhibitor of rhizoxin binding, with an inhibition constant of 1.3.10(-7) M. Vinblastine also inhibited rhizoxin binding, but was not fully competitive, and the inhibition constant was 2.9.10(-6) M. In contrast, both rhizoxin and ansamitocin P-3 were potent inhibitors of vinblastine binding. Rhizoxin inhibited tau-promoted tubulin assembly, but it, differing from vinblastine, did not induce tubulin aggregation into spirals, even at a concentration as high as 2.10(-5) M. In addition, rhizoxin strongly inhibited vinblastine-induced tau-dependent tubulin aggregation. Rhizoxin binding to tubulin was completely independent from colchicine binding. These effects resemble those of maytansine. The results suggested that rhizoxin binds to the maytansine-binding site and that the binding sites of rhizoxin and vinblastine are not the same.

Usefulness of thyrotropin (TSH)-releasing hormone test and nocturnal surge of TSH for diagnosis of isolated deficit of TSH secretion.

Six patients with idiopathic isolated deficit of TSH secretion were examined and reported on. Their clinical symptoms and routine biochemical data were unclear and were not specific for hypothyroidism. Serum triiodothyronine, free thyroxine and TSH levels were slightly low or low-normal. Basal metabolic rate and thyroidal (123)I-uptake were also slightly low or low-normal. The response of serum TSH to TRH stimulation was blunted in all patients. No nocturnal surge of serum TSH level could be seen in any of the patients. Empty sella was revealed in three patients, and pituitary microadenoma in one patient via magnetic resolution imaging. Antihuman pituitary cytosol antibody was seen in five patients. Autoimmunity may have played a role in the pathogenesis of idiopathic isolated TSH deficiency. Routine examination of thyroid function cannot easily detect this disease. TSH response to TRH stimulation and nocturnal surge of TSH should be examined when this disease is suspected.

Temporal lobe epilepsy in a genius of natural history: MRI volumetric study of postmortem brain.

Kumagusu Minakata (1867-1941), a Japanese genius devoted to natural history and folklore, is famous for his immense range of works, including his discovery of many new varieties of mycetozoa, or slime molds. His diary reveals that he was affected by epilepsy. In this study of his brain, we adopted a method of measuring the volume of the hippocampi by MRI of postmortem brain and found evidence of right hippocampal atrophy. This finding, together with the striking parallels between his behavior and the known behavioral syndrome in temporal lobe epilepsy (TLE), suggests that he was affected by TLE. The postmortem imaging analysis of brain, as performed in this study, offers a bridge between neuroscience and classic psychopathologic approaches to the creativity of geniuses.

Levcromakalim causes indirect endothelial hyperpolarization via a myo-endothelial pathway.

1. Effects of K+ channel opener, levcromakalim, on vascular endothelial cells were examined. Under voltage- and current-clamp conditions, application of acetylcholine to dispersed endothelial cells isolated from rabbit superior mesenteric artery (dispersed RMAECs) produced hyperpolarization and outward currents. On the other hand, dispersed RMAECs did not respond to levcromakalim. 2. When membrane potential was recorded from endothelium in a mesenteric arterial segment, exposure to levcromakalim in a concentration range of 0.1 to 3 microM caused concentration-dependent hyperpolarization. The hyperpolarization was observed in the absence of external Ca2+ and was inhibited by 10 microM glibenclamide. 3. The presence of 1 mM heptanol did not affect the levcromakalin-induced hyperpolarization, whereas treatment of the mesenteric arterial segment with 20 microM 18 beta-glycyrrhetinic acid significantly reduced the hyperpolarization. The response to acetylcholine of RMAECs in an arterial segment with 18 beta-glycyrrhetinic acid was, however, similar to that without 18 beta-glycyrrhetinic acid. 4. These suggest that although RMAECs themselves are functionally insensitive to levcromakalim, those in an arterial segment are hyperpolarized by levcromakalim via myo-endothelial electrical communication.

Assimilation of cellooligosaccharides by a cell surface-engineered yeast expressing beta-glucosidase and carboxymethylcellulase from aspergillus aculeatus

Since Saccharomyces cerevisiae lacks the cellulase complexes that hydrolyze cellulosic materials, which are abundant in the world, two types of hydrolytic enzymes involved in the degradation of cellulosic materials to glucose were genetically co-immobilized on its cell surface for direct utilization of cellulosic materials, one of the final goals of our studies. The genes encoding FI-carboxymethylcellulase (CMCase) and beta-glucosidase from the fungus Aspergillus aculeatus were individually fused with the gene encoding the C-terminal half (320 amino acid residues from the C terminus) of yeast alpha-agglutinin and introduced into S. cerevisiae. The delivery of CMCase and beta-glucosidase to the cell surface was carried out by the secretion signal sequence of the native signal sequence of CMCase and by the secretion signal sequence of glucoamylase from Rhizopus oryzae for beta-glucosidase, respectively. The genes were expressed by the glyceraldehyde-3-phosphate dehydrogenase promoter from S. cerevisiae. The CMCase and beta-glucosidase activities were detected in the cell pellet fraction, not in the culture supernatant. The display of CMCase and beta-glucosidase proteins on the cell surface was confirmed by immunofluorescence microscopy. The cells displaying these cellulases could grow on cellobiose or water-soluble cellooligosaccharides as the sole carbon source. The degradation and assimilation of cellooligosaccharides were confirmed by thin-layer chromatography. This result showed that the cell surface-engineered yeast with these enzymes can be endowed with the ability to assimilate cellooligosaccharides. This is the first step in the assimilation of cellulosic materials by S. cerevisiae expressing heterologous cellulase genes.

Isolation and characterization of rainbow trout C-reactive protein.

An acute phase serum component, C-reactive protein (CRP), was isolated from the sera of rainbow trout (Salmo gairdneri). The isolation was based on its calcium-dependent binding affinity for pneumococcal C-polysaccharide (CPS) according to the isolation procedure of human C-reactive protein. In SDS-PAGE, the nonreduced CRP showed two subunits with molecular weights of 43,700 and 26,600, respectively, at a molar ratio of 1:1. The reduced CRP showed a single subunit of 26,600. The molecular weight of the native protein was estimated as 66,000 by native gradient PAGE and 81,400 by sedimentation equilibrium analysis using ultracentrifugation. The antigenic determinant on CPS-reactive site was destroyed by periodate oxidation, indicating that rainbow trout CRP is a glycoprotein. CRP levels in rainbow trout serum measured by the CPS-ELISA procedure showed that the rainbow trout CRP could behave as an acute phase reactant, following experimental infection with the fish pathogen Vibrio anguillarum.

Activation of trout macrophages and production of CRP after immunization with Vibrio anguillarum.

To examine the mechanism of the protection of rainbow trout (Salmo gairdneri) against Vibrio anguillarum in the early stage of immunization, the activation of macrophages and production of C-reactive protein (CRP) were investigated. Fish immunized with formalin-killed bacteria emulsified in Freund's complete adjuvant (FCA) resisted intraperitoneal challenge with living bacteria seven and ten days after immunization. The activation of macrophages was demonstrated by a significant increase of the chemiluminescent (CL) response and phagocytic activity. These fish also showed a significant increase of the CRP level in sera. Fish immunized with V. anguillarum alone or injected with FCA, however, did not resist the challenge. Though FCA itself increased CRP level and the sera enhanced phagocytic activity, increase of CL activity was weak. These results indicated that the increase of CL activity and opsonising effect of CRP on the phagocytosis of specifically activated macrophages concern to host defense in the early stage of infection.

Infrequent involvement of microsatellite instability in urinary bladder carcinomas of the NON/Shi mouse treated with N-butyl-N-(4-hydroxybutyl)nitrosamine.

Variation in the frequency of microsatellite instability (MSI) has been reported in different kinds of human malignant tumors, with less than one-third of invasive urinary bladder carcinoma cases estimated to be affected. Here we investigated the MSI for 27 microsatellite sequences in invasive urinary bladder carcinomas of the NON/Shi mouse induced by N-butyl-N-(4-hydroxybutyl)nitrosamine. A total of 28 urinary bladder carcinomas of both transitional cell and squamous cell types were studied. All were invasive (greater than pT3) and high-grade and 10 of them had metastasis. Only two (11%) of 18 primary bladder carcinomas without metastasis foci showed alterations in one or two loci. None of 10 pairs of urinary bladder carcinomas and metastasis foci demonstrated any alterations. In conclusion, MSI which represents a defect in the DNA mismatch repair system is infrequent and therefore unlikely to be a critical step in genesis of invasive mouse urinary bladder carcinomas.

Dose response of N-butyl-N-(4-hydroxybutyl)nitrosamine on urinary bladder carcinogenesis in mutant ODS rats lacking L-ascorbic acid synthesizing ability.

With a daily intake of 250 ppm total ascorbic acid, ODS and F344 male rats were given 0.0125%, 0.025% or 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in the drinking water for 12 weeks, and additional groups received 0.05% BBN for 2, 4 or 8 weeks. The experiment was terminated after a total of 36 weeks. A greater response to urinary bladder carcinogenesis was observed in both strains with increasing dose of BBN or longer treatment period. However, the magnitude of urinary bladder carcinogenesis in ODS rats given the higher BBN concentrations and/or long periods of BBN treatment was less than in comparably treated F344 rats, but not with lower concentrations of BBN and/or shorter periods of BBN treatment.