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The craking of squalene was studied with and without heterogeneous catalysts. The thermal decomposition of squalene occurred suddenly as a chain reaction above 723 K, yielding linear C5 (isoprene) and C10 hydrocarbons selectively with a conversion of >90%. The decomposition mechanism may involve allyl bi-radicals, ˙CH2–C(CH3)CH–CH2˙, intermediates that convert to isoprene, CH2C(CH3)–CHCH2.

In temperate zones, seed-dispersal networks by migratory birds are formed on long time scale. In mid-October from 2005 to 2016, to explore the dynamics of the network structures, we examined interannual variability of fruit abundance, bird migration, and seed-dispersal networks in central Japan. For 12 years, the fruit abundance exhibited a remarkable fluctuation across years, with the number of fruiting plants and matured fruits fluctuating repeatedly every other year, leading to the periodic fluctuations. The abundance of migratory birds was also fluctuated. According to the abundance of fruits and migratory birds, the 12 years was classified into three types: frugivores and fruits were abundant, frugivores were abundant but fruits were scarce, and frugivores were scarce. The seed-dispersal networks were investigated by collecting faeces and vomits of migrants. Of the 6652 samples collected from 15 bird species, 1671 (25.1%) included seeds from 60 plant species. Main dispersers were composed of Turdus pallidus, T. obscurus, and Zosterops japonicus. The network structures were almost nested for 12 years. Specifically, the nested structure was developed in years when fruit abundance was low. GLM analyses showed the abundance of migrants, particularly T. pallidus and T. obscurus, had strong positive effects on nested structure. It may be caused by the fact the two Turdus species were more frequently functioning as generalist dispersers when fruit abundance was lower. Our study suggested fruit abundance and foraging behaviour of frugivores determine the network structures of seed dispersal on long time scale.

In temperate zones, the complex network of seed dispersal by migrant birds is formed and the structure is dynamic on long time scale. Over 12 years, we examined interannual variability of structures of bird dispersal networks and factors affecting them by observing the characteristics of fruit abundance, bird migration and bird dispersal interactions in central Japan. The fruit abundance exhibited a remarkable fluctuation across years, with the number of fruiting trees and matured fruits fluctuating repeatedly every other year, leading to the periodic fluctuations. The abundance of migrants was also fluctuated. According to the abundance of fruits and migrants, the 12 years as study period was classified into three types. The seed transporting frequency and the dispersal networks were investigated by collecting faeces of migrants. Of the 6652 samples collected from 15 bird species, 1671 (25.1%) included seeds from 60 plant species. Main dispersers were composed of Turdus pallidus, T. obscurus and Zosterops japonicus. The structures of bird dispersal networks were highly nested over 12 years, suggesting the networks are stable. Specifically, the nested structure developed in years when fruit abundance was low. GLM analyses showed the abundance of migrants, particularly T. pallidus and T. obscurus, had strong positive effects on construction of nested structure. The development of nested structure may be caused by the fact the two Turdus species were more frequently functioning as generalist dispersers when fruit abundance was lower. Our study revealed one of the mechanisms determining the structure of bird dispersal network on long time scale.

Diamond-Blackfan anemia is an autosomal dominant syndrome, characterized by anemia and a predisposition for malignancies. Ribosomal proteins are responsible for this syndrome, and the incidence of colorectal cancer in patients with this syndrome is higher than the general population. This patient's Diamond-Blackfan anemia was caused by a novel ribosomal protein S19 gene mutation, and he received chemotherapy for colorectal cancer caused by it. In his cancer, ribosomal proteins S19 and TP53 were overexpressed. He received 5FU and cetuximab; however, his anemia made chemotherapy difficult, and he did not survive long. Patients with Diamond-Blackfan anemia should be screened earlier and more often for colorectal cancer than usual.

Significance Peter D. Mitchell, a Nobel awardee in 1978, proposed that F o F 1 -ATP synthase converts energy between electrochemical potential of H + across biological membrane ( Δ μ ∼ H + ), which is established by respiratory chain complexes, and chemical potential of adenine nucleotide [ΔG (ATP) ]. However, the efficiency of the energy conversion has been a matter of debate for over 50 years. In this study, with a highly reproducible analytical system using F o F 1 -ATP synthase from thermophilic Bacillus , apparently perfect energy conversion was observed. Mitchell’s prediction thus has quantitative evidence.

This paper presents a highly effective desiccant rotor that can be regenerated at a temperature between 20 and 30°C, corresponding to return air exhausted from conditioned spaces. The desiccant rotor consists of a honeycomb structure, which is coated with organic polymer desiccant materials. For a specific operating condition, the desiccant rotor functions as a rotary total heat exchanger. Desiccant rotors with thickness of 0.2 m and more lead to both higher dehumidification and temperature efficiencies compared to conventional total rotary heat exchangers in different states of the inlet process and regeneration airflows. Both the dehumidification and temperature efficiencies achieve 100% at a thickness of 0.4 m, and at rotational speeds between 100 and 300 rph. Dehumidification, together with cooling, is very effective. For the desiccant rotor with a thickness of 0.4 m, the humidity change of the process air corresponds closely to isothermal dehumidification. In terms of the dehumidification and cooling...

Peter D. Mitchell, a Nobel awardee in 1978, proposed that FoF1-ATP synthase converts energy between electrochemical potential of H+ across biological membrane (Δμ∼H+), which is established by respiratory chain complexes, and chemical potential of adenine nucleotide [ΔG(ATP)]. However, the efficiency of the energy conversion has been a matter of debate for over 50 years. In this study, with a highly reproducible analytical system using FoF1-ATP synthase from thermophilic Bacillus, apparently perfect energy conversion was observed. Mitchell’s prediction thus has quantitative evidence.

Hepatocellular carcinoma (HCC) is one of the most deadly cancers worldwide. We performed a proteomic study to understand the molecular mechanisms underlying metastasis in HCC. Among the 3491 protein spots observed by two-dimensional difference gel electrophoresis (2D-DIGE), we found that 197 and 88 protein spots had statistically significant differences in intensity between tumor and non-tumor tissues and between the tumors with and without vascular invasion, respectively. Mass spectrometry was used to identify the proteins corresponding to those protein spots. We found that compared to tumor tissues without vascular invasion, those with vascular invasion showed markedly upregulated expression of the macrophage-capping protein (CapG). The association of increased CapG expression with vascular invasion in the tumor tissues was confirmed by western blotting. CapG expression levels were equal for non-tumor tissues and tumor tissues without venous invasion, as assessed by 2D-DIGE and western blotting. Silencing of CapG reduced tumor invasion without affecting the proliferation of the HCC cells. These observations suggested that CapG is involved in the process of metastasis by promoting the invasiveness of tumor cells. It may therefore be worth investigating the clinical usefulness of CapG as a biomarker in risk-stratification therapy and as a therapeutic target in HCC.

Tree communities of secondary deciduous oak forests were surveyed in 13 forests (two in residential and 11 in rural areas) in the warm temperate Hokuriku District of Japan to understand the effects of fragmentation, location (residential or rural), and logging history. The rural forest logged most recently, where diameter at breast height was smallest, had a distinct canopy tree (>12 m) community due to an increase of trees from wind-dispersed seeds. The rural forest with gaps and the two residential forests also had different canopy tree communities from the other rural forests. In contrast, the tree community in the shrub layer (≤6 m) was not influenced by logging history and the existence of gaps but by location only. This was caused by an increase in evergreen trees (consequently causing poor light conditions on the forest floor) and a decrease in trees from wind-dispersed seeds in the residential forests. Among the rural forest patches, no negative effects of forest size and isolation on density of tree individuals were detected for any seed dispersal mode. This may be because many forest patches were arranged at distances of 10–50 m from neighboring patches in rural areas, which enables tree species with low dispersal ability to disperse their seeds to neighboring forests. However, as found in the residential forests, long-term abandonment and extensive fragmentation may gradually reduce tree diversity through loss of tree species with shade intolerance and low seed dispersal ability.

Microdomain structure of polyurethane elastomers (PUEs) during mechanical deformation was investigated using simultaneous small-angle X-ray scattering (SAXS)/wide-angle X-ray diffraction measurements. In the SAXS profile for the PUEs, a four-point pattern or a meridional scattering was observed during the deformation process depending on curing temperatures. The relationship between the initial microdmain structure and deformation behavior was discussed in detail.

A series of 5,5-dimethylthiohydantoin derivatives were synthesized and evaluated for androgen receptor pure antagonistic activities for the treatment of castration-resistant prostate cancer. Since CH4933468, which we reported previously, had a problem with agonist metabolites, novel thiohydantoin derivatives were identified by applying two strategies. One was the replacement of the alkylsulfonamide moiety by a phenylsulfonamide to avoid the production of agonist metabolites. The other was the replacement of the phenyl ring with a pyridine ring to improve in vivo potency and reduce hERG affinity. Pharmacological assays indicated that CH5137291 (17b) was a potent AR pure antagonist which did not produce the agonist metabolite. Moreover, CH5137291 completely inhibited in vivo tumor growth of LNCaP-BC2, a castration-resistant prostate cancer model.

Morphological control of poly(2,5-benzimidazole) (PBI) was examined by reaction-induced phase separation of oligomers during polymerization to prepare nanofibers. Three monomers, 3,4-diaminobenzoic acid (DABA), 3,4-diacetoamidebenzoic acid (DAcBA) and phenyl 3,4-diaminobenzoate (PDAB), were used to synthesize PBI. Polymerizations were carried out at 350 °C in a mixture of dibenzyltoluene isomers. Polymerization of DABA yielded spheres with plate-like crystals on their surface. Polymerization of DAcBA yielded almost no precipitates because of the high solubility of DAcBA oligomers. By contrast, polymerization of PDAB yielded aggregates of PBI nanofibers (of which the average diameter was ∼60 nm), which resembled nonwoven fabrics. These fibers were formed by precipitation of (2,5-benzimidazole) oligomers and their subsequent polymerization into a developing crystal structure. The structure of the monomer significantly influenced the morphology of the PBI product, and PDAB was preferable for the preparation of PBI nanofibers. The temperature of 10% N2 weight loss in these nanofibers was in the range of 634–644 °C and they were thermally stable. The network aggregates of poly(2,5-benzimidazole) nanofibers were prepared by the polymerization of phenyl 3,4-diaminobenzoate at 350 °C in a mixture of dibenzyltoluene isomers. The average diameter of the fibers was ∼60 nm. These fibers were formed by the crystallization of oligoimidazoles and the subsequent polymerization in them.

The aims of this study were to determine a suitable method to correct the ventricular repolarization period against the RR interval in isolated perfused Langendorff guinea pig heart and to clarify the reliability of this model using several drugs. QT and RR intervals from an electrocardiogram and the epicardial monophasic action potential duration (MAP(90)) were measured. Two drugs clinically known to be QT-prolonging (E-4031, moxifloxacin) and two known to be non-QT-prolonging (verapamil, zatebradine) were used for the study. To determine a method of correcting the ventricular repolarization period against RR interval, heart rates were slowed with 0.3 µM zatebradine, a specific bradycardiac agent, and then accelerated with atrial pacing to obtain a wide range of MAP(90)/RR relationships. An exponential rate-correction model elicited the most appropriate algorithm for the relationship among the four models tested. Based on linear regression analysis, the exponential showed superior dissociation of corrected MAP(90)s against RR intervals than generic Bazett's and Fridericia's formulae. E-4031 and moxifloxacin prolonged the corrected QT (QTc) intervals and MAP(90) under atrial pacing at a cycle length of 0.25 sec (MAP(90(pacing))) dose-dependently; verapamil and zatebradine failed to prolong them, indicating that the reliability of this model was excellent. MAP(90(pacing)) prolongation by moxifloxacin, the positive compound in the clinical "Thorough QT/QTc Study", was seen at around QTc-prolonging concentrations in clinic, suggesting that the sensitivity would be appropriate for QT evaluation. We therefore concluded that the isolated guinea pig heart model is sufficiently sensitive and useful for assessing the potential QT prolongation of drugs.

We studied flowering and fruiting seasonality of understory shrubs of genus Medinilla (Melastomataceae) in the lower montane forest on Mount Kinabalu, Borneo, in relation to seasonal change in air temperature, rainfall, and solar radiation. Eight sympatric species showed either annual or biannual patterns. The number of species bearing f lower buds and flowers increased biannually, indicating that two seasons were favorable for flower budding and flowering of Medinilla species. Individuals of most species started flower budding during Januar y–March, showing strongly negative correlations with seasonal patterns of mean or minimum air temperature in previous a few weeks. The number of fruiting species peaked during May-August and increased when air temperature and solar radiation were high. These findings suggested that flowering activity of most Medinilla species may be regulated by seasonality of air temperature through floral initiation stimulated by low temperature. In addition, the high fruiting activity during period with high temperature and insolation indicated that such climatic conditions may facil i tate the development of fruits and seeds of understor y plants growing in cool and poor-light conditions, because photosynthesis and other physiological reactions are activated to produce compounds necessary for the development of fruits and seeds.

Poly[2,6-(1,4-phenylene)-benzobisimidazole] (PPBI) crystals were prepared by using reaction-induced crystallization of oligomers during solution polymerization of 1,2,4,5-tetraaminobenzene and diphenyl terephthalate. Polymerizations were carried out at a monomer concentration of 4.3 × 10−2 mol L−1 at 350 °C for 6 h. Brush-like PPBI crystals were obtained in a mixture of structural isomers of dibenzyltoluene, in which many needle-like crystals came out vertically from the surface of the ribbon-like crystals. Average width and thickness of the ribbon-like crystals were 0.75 μm and 0.11 μm, respectively. And average length and diameter of the needle-like crystals were 0.36 μm and 50 nm, respectively. The brush-like crystals possessed high crystallinity and exhibited good thermal resistance. The ribbon-like crystals were formed by the crystallization of imidazole oligomers at an initial stage of polymerization, and then the needle-like crystals grew from the surface of the ribbon-like crystals. Polymerization occurred on the crystals when the oligomers were crystallized, leading to the high molecular weight PPBI crystals.

Mitemcinal is an erythromycin derivative with motilin agonistic action, developed as a gastrointestinal motor-activating agent. The characteristics of mitemcinal-induced multinuclear hepatocytes (MNHs, hepatocytes with three or more nuclei per cell) from detailed morphological observations together with the results of a study on the mechanisms of MNH formation by combining cytocentrifuge preparations with 5-bromo-2’-deoxyuridine cumulative labeling are reported. MNHs were observed only in rats in the high-dose groups of the subchronic study, with a higher incidence in females and reversibility after twenty-eight days of drug withdrawal, but not observed in dogs. In the chronic study, the incidence increased relative to the dose. Histopathologically, MNHs were preferentially observed in the centrilobular zone, without nuclear atypia or mitotic figures. In the cell kinetic study, the labeling pattern of MNHs included all-positive, all-negative, and mixed labeling patterns of nuclei. The all-negative pattern indicated that the cells were formed by fusion of nondividing cells. The current results indicate that the cell kinetic approach effectively demonstrated the mechanism of mitemcinal-induced MNHs as fusion of hepatocytes and that drug-induced disturbance of mitosis is not involved in the multinucleation of MNHs by mitemcinal.

Morphology control of polybenzimidazoles was examined by reaction-induced phase separation during polymerization. Polymerizations of 3,3′-diaminobenzidine with terephthalic acid or diphenyl terephthalate were carried out in poor solvents. The morphology of the precipitated poly[2,2′-(1,4-phenylene)-5,5′-bibenzimidazole] (PpBBI) was significantly influenced by the polymerization conditions, and the aggregates of nano-scale PpBBI fibers were obtained by the polymerization at a concentration of 3–5% and 320–350 °C in dibenzyltoluene. The average diameter of the fibers was ca. 50 nm and inherent viscosities of the precipitates were 0.35–0.58 dL g −1 . They possessed high crystallinity and thermal stability. The oligomers were precipitated first by the reaction-induced crystallization to form the highly crystalline lath-like crystals at an initial stage of polymerization. Then the lath-like crystals were split into disentangled aggregates of fine fibers with maintaining the high crystallinity. The polymerization mainly proceeded when the oligomers were registered into the crystals. The obtained aggregates of nano-scale fibers could be recognized as nonwoven fabrics. Morphology control of poly[2,2′-(1,3-phenylene)-5,5′-bibenzimidazole] was also examined and particles were mainly formed.

Mitemcinal is an erythromycin derivative, which acts as an agonist of the motilin receptor. For assessment of the carcinogenicity of mitemcinal, we conducted a short-term carcinogenicity study in p53 (+/-) C57BL/6 mice and a 104-week carcinogenicity study in CD(SD)IGS rats. There was no evidence of a carcinogenic potential in mouse when administered for 26 consecutive weeks at levels up to 250 mg/kg/day. In the rat study, an increased incidence of lymphoma was noted in 5/60 males and 8/60 females of the high dose group (60 mg/kg/day) compared to 1/60 and 0/60 in control males and females, respectively, with statistical significance in females. Rat lymphomas include different immunomorphologic types (T- or B-cell lineage). Immunohistochemical analysis revealed that lymphomas from mitemcinal-treated rats and spontaneous cases were of T-cell lineage. The overall weight of evidence suggests that the incidence of spontaneous lymphoma was enhanced in the rat study. They also indicate that the increased incidence of lymphomas was based on a non-genotoxic effect with a threshold dose-response and that the tumorigenesis was based on the strain or species specificity of background factors. The high dose in the rat study is approximately 1600-fold higher (AUC) than that of the clinical dose, a sufficient margin of safety for the clinical dose. We conclude that the risk of carcinogenesis due to mitemcinal in humans can be considered to be minimal and is to represent an acceptable risk for the continued administration of mitemcinal to humans.

The aim of this study was to assess the cardiovascular effect of MA-2029, a selective motilin receptor antagonist highly expected for the treatment of irritable bowel syndrome (IBS). MA-2029 inhibited the human ether-a-go-go-related gene (hERG) current at 100 microg/ml, but shortened action potential duration (APD) in isolated guinea pig papillary muscles at 10 and 100 microg/ml and the corrected QT (QTc) interval after oral administration of 30 and 300 mg/kg in conscious telemetered dogs. The discrepancy was probably caused by blockade of the Ca(2+) channel because MA-2029 inhibited the Ca(2+) current in isolated guinea pig myocytes. MA-2029 at 100 microg/ml also decreased the maximum rising velocity and action potential amplitude in the action potential study, indicating that MA-2029 has Na(+) channel blocking potential. In the cardiovascular study, MA-2029 at 30 mg/kg induced slight cardiovascular changes such as hypotension, QTc shortening, and PR prolongation possibly caused by Ca(2+) channel blockade. The plasma concentration at 4 hr after 30 mg/kg administration was 2.10 microg/ml, 200-fold higher than the effective concentration of MA-2029 as a motilin receptor antagonist. These results suggest that MA-2029 has sufficient cardiovascular safety although it inhibits multiple ion channels at supra-effective concentrations. On the other hand, cisapride, an effective IBS drug, showed clear hERG inhibition and APD prolongation at 100 ng/ml. Cisapride exhibited a narrow safety margin because it caused QT prolongation potential even at the therapeutic concentration. In conclusion, MA-2029 is a novel drug highly expected for the treatment of IBS with lower cardiovascular risk than cisapride.

Mitemcinal (GM-611) is a novel erythromycin-derived prokinetic agent that acts as an agonist at the motilin receptor. Erythromycin has shown QT prolongation and torsades de pointes (TdP) in humans and cisapride, a second class of prokinetic agents typified by the 5-HT(4) receptor agonist, has been terminated due to TdP. In this study an extended series of safety pharmacology protocols and evaluations have been undertaken to assess the potential risk of mitemcinal on QT prolongation or proarrhythmic effects. Mitemcinal and its metabolites, GM-577 and GM-625, inhibited the human ether-a-go-go-related gene (HERG) tail current in a concentration-dependent manner with IC(50) values of 20.2, 41.7, and 55.0 microM, respectively. Administration of 10 mg/kg mitemcinal in anesthetized guinea pigs resulted in a slight prolongation of the monophasic action potential (MAP) duration during atrial pacing at the plasma concentration of mitemcinal 1.1 microM, with low maximum increases in MAPD(70) (6.6%) and MAPD(90) (4.6%) relative to vehicle. A 10-min infusion of 20 mg/kg of mitemcinal in a proarrhythmic rabbit model did not evoke TdP even when QT and corrected QT (QTc) intervals were significantly prolonged. In this study, the Cmax plasma-free concentration of mitemcinal indicates that the prolongation was more than 400-fold that of the therapeutic dose. Our findings of a wide safety margin and the absence of TdP within this margin suggest that mitemcinal may provide sufficient safety in clinical use.

Mitemcinal (GM-611) is a novel erythromycin-derived prokinetic agent that acts as an agonist at the motilin receptor. We investigated the QT-prolonging effects of mitemcinal using a halothane-anesthetized canine model. Intravenous administration of mitemcinal at doses of more than 8.3 mg/kg per 10 min significantly prolonged the QT interval corrected by Fridericia's corrections. Mitemcinal exhibited a bradycardiac effect and produced significantly greater prolongation in monophasic action potential duration (MAP(90)) at sinus rhythm compared with MAP(90) at pacing and showed reverse use-dependent prolongation of repolarization, suggesting that the negative chronotropic effect of mitemcinal potentiates the prolongation of the repolarization period. A technique using MAP/pacing electrodes allowed measurements of both MAP(90) and effective refractory period (ERP) simultaneously at the same ventricular site. Although mitemcinal slightly prolonged the MAP(90(CL400)) and ERP in comparison with the control group at the dose of 25 mg/kg per 10 min, the terminal repolarization period, the difference between MAP(90(CL400)) and ERP, did not increase suggesting the absence of a proarrhythmic effect even with a 7000-fold for the therapeutic blood concentration as free level. The electrophysiological results from mitemcinal in this study indicate that the risk of serious arrhythmia such as torsades de pointes, a major clinical concern related to QT interval prolongation, might be low.

Infrared Fabry–Perot filters were fabricated by stacking two silicon plates etched in KOH solution. When we applied a voltage between the plates, the spacing between them was decreased by an electrostatic force, which caused a shift in interference wavelength. The silicon plates were etched to 34 µm thickness to reduce the driving voltage. When the voltage was increased from 0 to 20 V, the wavelength of the interference peak shifted from 7.9 to 5.5 µm, corresponding to the decrease in the spacing from 7.9 to 5.5 µm. The peak transmittance increased to ~90% by coating an antireflection film on the outer surface of the filter. This coating was effective in suppressing the interference inside the silicon plates, which created a complicated spectrum.

Several QT correction (QTc) formulas have been used for assessing the QT liability of drugs. However, they are known to under- and over-correct the QT interval and tend to be specific to species and experimental conditions. The purpose of this study was to determine a suitable formula for halothane-anesthetized dogs highly sensitive to drug-induced QT interval prolongation. Twenty dogs were anesthetized with 1.5% halothane and the relationship between the QT and RR intervals were obtained by changing the heart rate under atrial pacing conditions. The QT interval was corrected for the RR interval by applying 4 published formulas (Bazett, Fridericia, Van de Water, and Matsunaga); Fridericia's formula (QTcF = QT/RR(0.33)) showed the least slope and lowest R(2) value for the linear regression of QTc intervals against RR intervals, indicating that it dissociated changes in heart rate most effectively. An optimized formula (QTcX = QT/RR(0.3879)) is defined by analysis of covariance and represents a correction algorithm superior to Fridericia's formula. For both Fridericia's and the optimized formula, QT-prolonging drugs (d,l-sotalol, astemizole) showed QTc interval prolongation. A non-QT-prolonging drug (d,l-propranolol) failed to prolong the QTc interval. In addition, drug-induced changes in QTcF and QTcX intervals were highly correlated with those of the QT interval paced at a cycle length of 500 msec. These findings suggest that Fridericia's and the optimized formula, although the optimized is a little bit better, are suitable for correcting the QT interval in halothane-anesthetized dogs and help to evaluate the potential QT prolongation of drugs with high accuracy.

Dynamics of phase separation induced by polymerization of 2-chlorostyrene in the presence of polystyrene was studied by an scanning electron microscope and a time-resolved light scattering instrument with varying initial monomer composition θ in the range from 0.4 to 0.6. Phase-separation rate increased with increasing θ or temperature. Phase being rich in poly(2-chlorostyrene) formed droplets initially and these droplets coagulated to form continuous domains at low temperatures. A maximum was found in the initial-composition dependence of the time when morphological change from droplets to continuous domains occurred. Qualitative discussion was made for the effects of initial composition change on morphological change of poly(2-chlorostyrene)-rich phase.

The authors have previously reported that the combination of fixation with periodate-lysine-paraformaldehyde (PLP) fixative and embedding in paraffin by the AMeX method (the PLP-AMeX method) resulted in better preservation of immunoreactivities and endogenous enzyme activities. In the present study, we investigated whether PLP-AMeX-processed tissue would be useful for in situ hybridization (ISH). The pancreases were removed from rats treated with or without streptozotocin (STZ), and was fixed in PLP fixative. After fixation, the specimens were processed and embedded in paraffin by the AMeX method. Paraffin sections were made on which ISH and immunohistochemical staining were performed. ISH was performed according to the non-radioactive method using digoxigenin-labeled oligodeoxynucleotides probes and anti-digoxigenin antibody. For ISH, a 28S rRNA antisense probe was used for evaluation of the level of hybridizable RNA in the sections. 28S rRNA was clearly detected in the various cells of the pancreas. Using an insulin antisense probe, the presence of insulin mRNA was clearly identified in the pancreatic islet-cells. Furthermore, optimal results for ISH of insulin mRNA and immunohistochemical staining of insulin could be obtained in consecutive sections from a PLP-AMeX-processed block. In the rats treated with STZ, the histological changes of pancreatic islet-cells and the changes in staining intensity of immunohistochemical staining for insulin protein and ISH for mRNA could be observed in the PLP-AMeX-processed sections. These findings suggest that hybridizable RNAs are well preserved by the PLP-AMeX method, and that the method is useful for ISH as well as immunohistochemical and enzyme histochemical analysis.

The purpose of this study was to investigate the clinical results of total shoulder arthroplasty in patients with osteoarthritis of the shoulder. In 2001 and 2002, five shoulders in four patients with osteoarthritis of the shoulder without cuff tear underwent shoulder arthroplasty. Their average age was 79 years (range: 72 to 88 years). All the cases were female. We used modular Neer in all cases with bone cement both on glenoid components and humeral stems. The follow-up period averaged 20 months (range : 14 to 32 months). All the cases were investigated using the Japanese Orthopaedic Association shoulder score. The total and pain scores and post operative range of motion of the sholder improved in all cases. No radiological loosening of both components was found the final evaluation.

We developed a new method for the synthesis of an organic-soluble insulated molecular wire (IMW) with permethylated cyclodextrin (PMCD); this method involves click polymerization of linked [2]rotaxane containing azide and alkynyl groups at both ends of a π-conjugated guest.

Heat shock protein 90 (Hsp90) is a constitutively expressed molecular chaperone and plays an important role in the folding of client proteins with key regulatory roles in growth, survival, differentiation and metastasis. Because inhibition of Hsp90 degrades multiple oncogenic client proteins, it is considered to be an attractive anticancer therapy, and clinical trials of several Hsp90 inhibitors have been carried out. In the present study, two structurally distinct Hsp90 inhibitors, CH5164840 and CH5449302, were orally administered to beagle dogs to evaluate systemic toxicity. CH5164840 induced symptoms that suggest visual disorder, and ophthalmological observation and electroretinography (ERG) revealed loss of pupillary light reflex and abnormal waveforms, respectively. Histopathological examination showed changes in the photoreceptor cell layer and the outer nuclear layer of retina. On the other hand, while there were no clinical symptoms related to visual disorder, animals treated with CH5449302 showed similar abnormalities of ERG responses and histopathological changes in the photoreceptor cell layer and the outer nuclear layer of retina. The visual symptoms and abnormalities of ERG responses were noted at an earlier stage or lower dose than other toxicities in both compounds. Considering that two structurally distinct Hsp90 inhibitors induced a retinal toxicity in dogs after repeated administration, and that visual disorders were also reported in some clinical trials of Hsp90 inhibitors, it would seem highly likely that Hsp90 inhibition induces retinal toxicity. Also, our study indicated that a detailed ocular examination to evaluate the safety of Hsp90 inhibitors would be useful in both preclinical and clinical studies.

An altitudinal survey of correspondences between fruiting phenologies of fleshy-fruited tree species and seasonal dynamics of frugivorous birds on Mt. Kinabalu in Borneo was carried out for 50 weeks across four vegetation types: a hill forest (800 m asl), a lower montane forest (1700 m), an upper montane forest (2000-3000 m) and a subalpine forest (3000-3500 m). In the hill forest, a large fruiting peak following the general flowering phenomenon was observed during October-November in 1996 and a fruitless period was observed during February-April in 1997. During the fruitless period, the number of resident frugivorous birds decreased. A bimodal fruiting pattern was observed in the lower montane forest. A large number of frugivorous temperate migrants were observed when the fruiting peak occurred. The number of resident frugivorous birds increased and several lowland bird species were observed, when the number of resident birds decreased in the hill forest. In the upper montane forest and the subalpine forest, more continuous and irregular fruiting patterns without outstanding peaks were observed and the number of resident frugivorous birds was more stable throughout the year. These suggested (1) there was a strong relationship between fruiting seasonality and seasonal dynamics of temperate migrants in the lower montane forest; (2) seasonal altitudinal movements of lowland bird species to montane vegetation might occur during the fruitless period in the lowland forest; and (3) the continuous fruiting pattern in the higher vegetation zones might be related to the scarcity of available frugivorous birds. The hypothesis that the influx of temperate migrants into the montane vegetation of Mt. Kinabalu is affected by density and habits of resident frugivorous birds is supported. Montane vegetation in Borneo plays an important role as temporal refugia for temperate and altitudinal migrants by supplying fruit resources.

Behavior of solid particles in 2D fluidized bed was observed. The particles had a shape of circular cylindar and were arranged in a single layer in a narrow channel with liquid flow from below. Particles moved randomly, and formed clusters of various sizes. Their sizes and shapes were measured from video images. At the same time, pressure difference between upstream and downstream sides was measured. Spectra of the timewise variations of those quantities were obtained. Spectra concerned to particle cluster and the pressure difference were found to behave as f -1 and f -2 , respectively, where f is the frequency. A correlation between the pressure difference and the horizontal cluster width was recognized.

This paper reports a case of scapholunate dissociation, a popular group of traumatic carpal instability. The patient was a 29-year-old male who had fallen on his arm outstretched from his motorcycle. In spite of cast fixation for 2 weeks at another doctor, the wrist pain persisted for several weeks. We therefore performed ligamentous reconstruction of the scapholunate interosseous ligament with a tendon slip from extensor carpi radialis longus. 6 months after the operation, the patient has increased hand grip power with no wrist pain.Generally speaking, scapholunate dissociation is accompanied by both dorsiflexed lunate and voralflexed scaphoid. In this case, however, there was dorsiflexed intercalated segment instability deformity (DISI), but no rotary subluxation of the scaphoid (RSS), i. e., radiolunate angle and scapholunate angle were increased, but the radioscaphoid angle was within normal limit. In such cases, the dorsal capsulodesis (Blatt's method) may have little effects on the correction of DISI. The authors recommend that preoperative kinematic analysis be performed on the affected wrist.

Carpal tunnel syndrome (CTS) is very common in orthopaedic practice. Many authors have reported that prevelence is 9 to 10 times more in female subjects in Japan. Over the last 4 years, we experienced 228 cases of CTS. The male-female ratio in these cases was about 1:3 in which incidence amongst males was higher compared to other studies. Therefore, in this study, we investigated male patients exclusively to reveal the causative factors, and compare the postoperative results with female patients.78 hands of 65 male patients with CTS were investigated postoperatively. The age of the patients ranged from 26 to 89 with an average age of 57 years. The average postoperative follow-up period was 13 months.The results of the operation were excellent in 38 hands, good in 23 hands, fair in 13 hands, and poor in the remaining 4. From our experience, the so-called idiopathic CTS cases are seen less in male patients than female. CTS in the male patients was mainly due to local causes such as wrist fracture and dislocation, Kienboeck's desease, tumors etc. in comparison with the female patients. The milder cases showed better results in female patients. On the other hand, the results of serere cases were less satisfactory for both sex. Moreover, patients with cervical spondylosis and also obesity showed less improvement. Factors such as snapping finger and diabetes mellitus were not found to affect the results.The results of this study therefore indicated no definite causes for the greater number of CTS in male subjects. Moreover, the reason for why results are less satisfactory in males than females was also not clear.

We have experienced five cases of subcutaneous flexor tendon rupture in patients without RA from 1990 to 1995. Subjects were three males and two females and their ages ranged from 53 to 64 years (average 60 years). In two cases the involved tendon was the FPL, the FDP tendon of the little finger was ruptured in two and the FDP and FDS of the index in one. Considering the mechanism of injury, all cases received flexion against force injury and the site of ruptures were in the carpal tunnel. Free tendon graft was performed in all patients using the palmaris longus tendon. The results were evaluated according to Buck-Gramcko's criteria. Three cases were graded as excellent, one good and one was satisfactory. From this study it can be suggested that free tendon graft for subcutaneous flexor tendon rupture is an effective treatment.

During past 7 years from 1988 to 1994, microsurgical replantations have been performed for 37 complete finger tip amputations in 34 patients. These fingers were classified according to Allen's criteria (type III-15, type IV-22). 5 of the 37 fingers resulted in failure, six fingers had partial necrosis, however the remaining 26 had no necrosis. Survival rate was 100% in clean cut amputation, 90% in blunt amputation, 60% in crush amputation and 50% in avulsion amputation.Postoperative results were evaluated in 25 fingers of 22 patients with a follow-up period more than 1 year. The paresthesia of the finger tip was present in 9 finger tips and cold intolerance was present in 8 finger tips. The average static 2 point discrimination test was 5.8mm, renging from 2-10mm. Nail deformity was seen in 3 finger tips and mallet deformity in 3 fingers. 8 finger tips had mild atrophy. Functional results by Tamai's criteria vudged 21 patients to be excellent and 1 patient good. Almost all patients wete satisfied with the results.From this study, we concluded that replantation with microvascular anastomosis is the first choice for finger tip amputation.

Adjunctive internal neurolysis of the median nerve followed by release of the transverse carpal ligament is widely performed for treating carpal tunnel syndrome. However, the efficacy of internal neurolysis is still controversial. In this series, eleven hands in eleven patients had internal neurolysis of the median nerve and carpal tunnel release, twelve hands in eleven patients had standard ligament release alone.Thenar muscle strength and bulk were recorded in all hands. Median nerve function was evaluated using the two-point discrimination test and electromyography. Preoperatively, all hands had severe thenar muscle atrophy with no motor response to stimulation.Analysing the postoperative data, the majority of hands in both groups achieved satisfactory results and there was no significant difference between the results of the two groups. Results of this study indicate that standard surgical release of the transverse carpal ligament is equally effective in patients with severe carpal tunnel syndrome. Therefore, it can be suggested that internal neurolysis is not necessary in the treatment of carpal tunnel syndrome.

From 1987 to 1992, eighty-four elbows of seventy-six patients with cubital tunnel syndrome who had surgical intervention were reviewed. Sixty-two elbows were from male patients and twenty-two were from female patients. In fifty-three elbows the right side was involved, the left side in thirty-one elbows and in eight cases both sides were affected. The average period from the onset of symptoms to the time of operation was two years and five months (range; one month to twenty years). Pre-operatively patients were graded into three groups according to symptoms and clinical examination as mild, moderate and severe into which there were 11, 63 and 10 cases respectively.In all cases, subcutaneous translocation of the ulnar nerve was performed along with a local fat flap. The follow-up period ranged from one year to six years and four months. During follow-up patients were evaluted according to Ikuta's criteria. There were 20 excellent, 56 good and 8 fair with no poor results, which was very satisfactory. These results led us to conclude that subcutaneous translocation of the ulnar nerve with a local fat flap is an effective method for treating cubital tunnel syndrome caused by vorious mechanisms due to its ability to produce a wide visual field allowing the ulnar nerve to be observed in detail.

Six patients with complications caused by malunion of the distal radius such as pain, ROM disturbance, entrapment neuropathy, etc were operated on by corrective osteotomy. Patients comprised five males and one female, ranging in age from 17 to 64 years (average age: 45.8 years). Their deformities were graded according to Frynkman's classification. Corrective osteotomy of the radius with bone grafting was performed in five and in one patient ulnar shortening was carried out. Excellent results were obtained in 5 cases and good in one. Four patients with neurological symptoms of the hand were cured by the operation. Average improvement of palmar tilt, radial inclination and ulnar variation were 23.6°, 6.2° and 1.8mm respectively. In conclusion, corrective osteotomy for malunion of the distal radius is thought to be very effective.

We experienced 3 cases with ulnar nerve palsy at Guyon's canal caused by a schwannoma.On preoperative examination, all cases had a tender mass at Guyon's camal. There was also loss of sensation in the volar side of the ring and little finger, and a positive Tinnel's sign. Atrophy of the first dorsal interosseus muscle was present in two cases.On electromyographical examination, termnal latency time of the abductor digiti minimi was delayed in all cases.Surgical exploration was performed in all cases and the tumour excised easily.When only using clinical examination, it was very difficult to distinguish between schwannoma with other causes of Guyon's canal syndrome.

Minority game-based interference management (MGIM) for spectrum sharing is implemented and its experimental results are reported. MGIM is a decentralized transmission scheduling for a lower-priority system to prevent severe interference at a higher-priority system only using one-bit feedback information from the higher-priority system. By using MGIM, it has been demonstrated that the transmitters of the lower-priority system learn appropriate transmission timing to achieve high transmission capability through computer simulations. To confirm its performance in actual environments, experiments are conducted with programmable wireless device called universal software radio peripheral.

Introduction Moxifloxacin is the most widely used positive reference agent in clinical cardiac repolarization studies, but it has not been characterized in common marmosets which are uniquely suited to studies in early-stage development due to their small size and minimal test article requirements. The purpose of this study was to evaluate the sensitivity of the common marmoset to detect moxifloxacin-associated QT interval prolongation. Methods Eight telemetered common marmosets were monitored for 24 h following oral administration of moxifloxacin by gavage at 0, 10, 30, and 100 mg/kg using a Latin square design. Concurrently, a pharmacokinetic evaluation in 8 non-telemetered animals was conducted. A rate-corrected QT (QTc) interval was derived using an individual probabilistic QT rate-correction. ∆∆QTc (placebo-adjusted QTc change from the individual baseline) was calculated and the relationship between pharmacokinetics (PK) and pharmacodynamics (PD) was analyzed. Results A slight, but not significant, increase in ∆∆QTc was detected with 10 mg/kg of moxifloxacin. Moxifloxacin at 30 and 100 mg/kg elicited dose-dependent increases in ∆∆QTc of 14.0 ± 3.6 and 35.0 ± 6.2 ms, respectively, with associated total moxifloxacin C max values of 6.5 ± 0.5 and 16.5 ± 1.6 µg/mL, respectively. From the PK/PD relationship, the plasma concentration which would attain ∆∆QTc of 5 to 10 ms was estimated to be 1.67–3.73 µg/mL. The results were consistent with typical clinical trial results (∆∆QTc of 6.6–14.8 ms at 2.5–3.5 µg/mL). Conclusions The present study demonstrates that the common marmoset is highly sensitive to moxifloxacin-associated changes in cardiac repolarization, assessed as ∆∆QTc. As such, this species is suitable for precise and reliable detection of small, but significant, drug-associated increases in QTc interval. Thus, the common marmoset should be regarded as a validated animal model for the detection of QT risk in early-stage drug development and represents an important addition to the current in vivo armamentarium.

Introduction: QT intervals are strongly influenced by preceeding heart rate history and are also characterized by rate-independent variability, leading to difficulty in precise rate-correction of the raw QT interval. The present study elucidates a novel analytical method that effectively addresses this problematic phenomenon in telemetered common marmosets. Methods: ECGs were collected from telemetered common marmosets (male and female) and analyzed by computerized algorithms. Descriptive statistics were calculated from the mean of QT intervals for 5-ms increments of RR. The QT interval was corrected for the RR interval by applying Bazett's, Fridericia's, and individual probabilistic QT rate-correction formulae. Results: The linear regression of log-transformed QT and RR intervals derived from a probabilistic approach yielded a well-correlated QT–RR fit. Assessed as the slope of the QTc–RR interval, application of individual probabilistic QT rate-corrections resulted in the most effective dissociation of the effects of rate from the raw QT interval, compared to generic rate-correction formulae. Using individual corrections, the QTc was stable while the interquartile range (IQR) of the QTc distribution was stable, spanning 5–10 ms for each subject over all physiological RR intervals. Heart rate variability distributions were centered about unity during both photoperiods and sinus arrhythmia was far less pronounced compared with measurements in dogs. Discussion: Probabilistic QT rate-correction eliminated the confounding effects of heart rate and provided a stable QTc baseline. These results indicate that application of this method of analysis in telemetered common marmosets results in a high degree of sensitivity for the consistent detection of small (5–10 ms) changes in the QTc interval.