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The interaction between T-cells/fatty acids involved in non-alcoholic fatty liver disease (NAFLD) and liver fibrosis progression is poorly understood. In this study, we conducted a comprehensive analysis of T-cell profiles of NAFLD patients to better understand their relationship with fatty acids and relevance to liver fibrosis. We analyzed the differences in T-cell profiles of peripheral blood mononuclear cells (PBMCs) between 40 NAFLD patients and 5 healthy volunteers (HVs), and their relationship with liver fibrosis stage or progression. Moreover, we analyzed the relationship between T-cell profiles and fatty acid compositions in vivo, and changes in T-cell profiles after treatment with fatty acids in vitro. T-cell profiles of NAFLD patients were different from those of HVs. The CD25+CD45+CD4+ T-cell frequency was increased in NAFLD patients with high liver fibrosis stage and progression, and this indicated immune activation. Despite such a state of immune activation, the PD1+CD4+ T-cell frequency was decreased in the same patients group. The PD1+CD4+ T-cell frequency had a significantly negative correlation with the serum fatty acid composition ratio C16:1n7/C16:0. Moreover, the PD1+CD4+ T-cell frequency was significantly decreased by in vitro treatment with fatty acids. In addition, its rate of frequency change was significantly different between C16:0 and C16:1n7 and decreased by artificially increasing the C16:1n7/C16:0 ratio. The analysis of PBMCs in NAFLD patients showed that T-cell profiles were different from those of HVs. And, it suggested that fatty acids modified T-cell profiles and were involved in liver fibrosis in NAFLD patients.

Aims: We aimed to evaluate the efficacy of vonoprazan (VPZ) as maintenance therapy for healed reflux esophagitis (RE). Methods: We enrolled 74 patients diagnosed with RE with frequency scale for the symptoms of gastroesophageal reflux disease (FSSG) total score ≥8 after at least 8 weeks of treatment with standard proton pump inhibitors (PPIs). These patients were switched to VPZ 20 mg for 4 weeks. We also enrolled 71 patients with no endoscopic evidence of erosive esophagitis who received maintenance therapy with VPZ 10 mg for 48 weeks. The primary end point was the proportion of patients who maintained healed RE refractory to PPIs after 48 weeks of maintenance therapy with on demand 10 mg VPZ. Secondary assessment included the proportion of patients with symptomatic nonrelapse at 48 weeks. Results: Fifty patients successfully completed 48-week maintenance therapy. Maintenance therapy with VPZ 10 mg prevented the relapse of esophageal mucosal breaks in 43 (86.0%) of 50 patients at 48 weeks. During the 48-week maintenance therapy, symptomatic nonrelapse rate for acid reflux-related symptom score of FSSG and acid reflux score of Gastrointestinal Symptom Rating Scale at 48 weeks were 70.0 and 72.0%, respectively. No serious adverse events were reported during the study. Conclusion: VPZ 10 mg is clinically effective for maintenance of healed RE for 48 weeks.

BACKGROUND AND AIMS Accurate diagnosis of non-alcoholic steatohepatitis (NASH) from non-alcoholic fatty liver disease (NAFLD) is clinically important. Therefore, there is a need for easier ways of diagnosing NASH. In this study, we investigated the serum fatty acid composition and evaluated the possibility of using the serum fatty acid composition as a diagnostic marker of NASH. METHODS The subjects were 78 NAFLD patients (non-alcoholic fatty liver [NAFL]: 30, NASH: 48) and 24 healthy individuals. Fatty acids extracted from the liver tissue and serum were identified and quantified by gas chromatography. In addition, we evaluated the relationship between serum and liver tissue fatty acid composition, patient background, and liver histology. The diagnostic performance of NASH was evaluated by calculating the area under the receiver operating characteristic (AUROC). RESULTS The results of the fatty acid analysis showed the C16:1n7/C16:0 ratio to have the strongest correlation between serum and liver tissue (r = 0.865, P

An increasing number of patients with lung cancer are undergoing outpatient chemotherapy, and thus, it is very important to maintain the quality of life(QOL)of these patients. Ninjin-Youei-To(TJ-108), a Japanese traditional medicine, has been reported to improve the QOL of patients with advanced cancer. However, the effect of TJ-108 in patients with lung cancer undergoing outpatient chemotherapy is unknown. Therefore, we conducted this study. To investigate factors influencing the QOL of these patients, we administered a QOL questionnaire,"The QOL Questionnaire for Cancer Patients Treated with Anticancer Drugs"(QOL-ACD)to 15 patients with non-small cell lung cancer. Factors related to the overall QOL scores and other categories indicating"activity","physical condition","psychological condition","social relationship", and"face scale" were analyzed. No significant decrease in each of the evaluated factors was observed in this study.

The aim of the present study was to evaluate the efficacy of a potassium-competitive acid blocker (P-CAB), vonoprazan, for the maintenance therapy of healed reflux esophagitis (RE). A total of 60 patients were enrolled in this open-label, single-center, prospective study. All patients were diagnosed with RE with a frequency scale for the symptoms of gastroesophageal reflux disease (FSSG) total score ≥8 following treatment with standard proton pump inhibitors (PPIs) for a minimum of 8 weeks. Standard PPI treatment was switched to vonoprazan 20 mg once daily for 4 weeks. A total of 52 patients, who had no endoscopic evidence of erosive esophagitis following vonoprazan treatment, received maintenance therapy with vonoprazan 10 mg once daily for 24 weeks. Symptoms were evaluated using the FSSG and Gastrointestinal Symptom Rating Scale (GSRS). Upper gastrointestinal endoscopies were performed following 24 weeks of maintenance therapy. The primary endpoint was to determine the proportion of patients who exhibited maintenance of healed RE refractory to PPIs following 24 weeks of maintenance therapy with vonoprazan 10 mg once daily. Secondary endpoints included evaluation of the proportion of patients with symptomatic non-relapse at 24 weeks. Maintenance therapy with vonoprazan 10 mg once daily prevented relapse of esophageal mucosal breaks in 37/43 (86.0%) patients at 24 weeks. However, the number of patients with symptomatic relapse was 1 (1.9%) and 4 (7.7%) at 4 and 8 weeks, respectively. A total of 4 patients were withdrawn due to loss to follow-up. At the end of the 24-week maintenance period, the symptomatic non-relapse rate for acid reflux-associated and dysmotility symptom FSSG scores were 86.5 and 80.8%, respectively. Furthermore, the symptomatic non-relapse rate for reflux, abdominal pain, indigestion, diarrhea, and constipation GSRS scores at 24 weeks were 86.5, 80.8, 75.0, 71.2 and 76.9%, respectively. No serious adverse events were reported during the study. The mean gastrin level was 1,059 pg/ml. In conclusion, the results of the present study indicate that vonoprazan 10 mg once daily is effective for 24-week maintenance therapy of healed RE refractory to PPIs.

Molybdenum and graphite powders were mechanically alloyed. Carbon K X-ray emission spectra of the mechanically alloyed powders were measured using electron probe microanalyzer (EPMA) in order to investigate the solid state reaction process. In the early stage of the mechanical alloying (∼36ks), graphite did not react with molybdenum, but particle size of graphite became smaller. In the next stage of mechanical alloying (36 ∼ 144 ks), graphite react with molybdenum gradually as the time increases. Molybdenum carbides were formed on mechanical alloying for 288 ks. The mechanically alloyed powders for 288 ks were heat-treated in a vacuum. Mo-33 at%C system heat-treated at 1273 K was a mixture of Mo2C and molybdenum, while Mo-50at%C system heat-treated was a mixture of Mo 2 C, mechanically ground graphite and graphite.

Control of three modes of intramolecular reactions, [2+2] and [4+2] cycloadditions, and Type-II cyclisation, is attempted in the photochemical reaction of N-(naphthylethyl)prop-2-enamides. The reactions are affected by the enamide substituents and the sensitisation conditions used. Acryloyl derivatives undergo [2+2] cycloaddition and Type-II cyclisation. The two reactions occur selectively depending on the sensitiser used, benzophenone sensitisation affording the [2+2] cycloadducts whereas the Type-II cyclisation products are obtained exclusively by benzene sensitisation. In contrast, photolysis of cinnamoyl derivatives results in the formation of [4+2] cycloadducts.

This article describes the feasibility evaluation of long atomic imaging over a 5-μm-long region for the comparative length measurement using a crystalline lattice as the reference scale and a dual-tunneling-unit scanning tunneling microscope (DTU-STM) as a detector. For suppression of the thermal deformation error, ultralow thermally drifted DTU-STM was developed. The body of the DTU-STM is fabricated from ultralow linear expansion glass and Super-Invar. A thermostabilized cell was utilized to reduce the temperature fluctuation to less than 0.05 K around the DTU-STM. In the thermostabilized cell, the minimum lateral element of thermal drift rate of less than 0.2 nm/h at room temperature was achieved with the DTU-STM. In order to decrease the measurement time and thus reduce the thermal drift error, the fast scanning axis was selected as the direction of the length measurement over the μm range. After attaining thermal equilibrium, a long atomic image of highly oriented pyrolytic graphite over a 5-μm-long region along the fast scanning axis was obtained using the DTU-STM in the thermostabilized cell.

Niobium or tungsten and graphite powders were mechanically alloyed. Carbon K X–ray spectra of the mechanically alloyed powders were measured using an electron probe microanalyzer (EPMA) in order to investigate the solid state reaction process. In the early stage of the mechanical alloying (10 hours), graphite did not react with metal, but particle size of graphite became smaller. In the next stage of the mechanical alloying (2–4 hours), micro–crystalline graphite powder reacted with metal. Polarization of the X–rays were measured for Nb 2 C and W 2 C, because a single crystal WC emitted polarized X–rays. The measurement of X–ray emission spectra was useful for the structural and chemical analysis of mechanical alloying reaction processes.

Camphene has been studied over ranges of pressure up to 9.5 GPa and temperature up to 1300 °C by in situ resist-volumetric, x-ray diffraction, and Raman scattering measurements as well as by postcompression analyses on retrieved samples. In the solid state, polymerized and amorphous phases appeared. The melting temperature was found to increase with increasing pressure and the melting line showed a small deflection at about 4 GPa, which was attributed to a triple point among the two solid phases and the liquid. Another amorphous phase was retrieved from a region right above the melting line. Heat treatment at temperatures beyond the melting line by about 200 °C and higher yielded turbostratic and graphitic carbons.

This paper presents a potential image processing method for calibrating the in-plane geometrical distortion of a scanning tunneling microscope (STM) image using a regular crystalline lattice, describes the assessment evaluation of comparative length measurement in the range of about 1 micrometer using a regular crystalline lattice as a reference scale and a dual tunneling unit-STM (DTU-STM) as a detector, and shows the results of direct length comparison between a scanning tunneling microscope (SEM) standard grating, whose pitch is 240 nm, and a regular crystalline lattice using a DTU-STM. The method is based on two-dimensional fast Fourier transform (FFT) analysis. The DTU- STM with one X-Y stage and two tunneling units independently controlled in the Z-axis direction has been utilized for comparative length measurement. To improve the measurement accuracy, the present method is used to process the raw images obtained from the DTU-STM. The results of assessment experiments, in which the cleaved surface of highly oriented pyrolytic graphite (HOPG) is used as a reference scale for measurement of lengths on the order of 1 micrometer, demonstrate the feasibility of the present image processing method and the comparative length measurement with sub-nanometer resolution using the DTU- STM. The value of the SEM standard grating pitch, which obtained from the direct length comparison with HOPG lattice spacing using the DTU-STM, was coincided with the value obtained from the conventional diffraction method within a error of 2 %.

N,N-dimethylacrylamide (DMAA) was graft copolymerized on poly[(trimethylsilyl)propyne] (PTMSP) by single electron reduction of PTMSP with potassium naphthalenide (K-Naph), followed by anion polymerization of DMAA from the carbanion formed in the reduction. A hard and practically non-water-swelling PTMSP-gr-poly(DMAA) was obtained under the conditions using controlled amount of K-Naph and DMAA. The graft copolymer was characterized with regard to structure, number-averaged molecular weight, and the amount of grafting poly(DMAA) determined by the relative absorbance of the IR absorption band assigned to the CO and SiCH functionalities (ACO/ASiCH). The oxygen permeability and water contact angle (θ) of the graft copolymer were evaluated while varying the amount of grafting poly(DMAA). The graft copolymer proved to be highly oxygen permeable (165 Barrers) and hydrophilic (θ = 27°). Its transparency was also elucidated with UV–vis spectra. This graft copolymer was proposed as a promising candidate for use as a hard contact lens material. © 1998 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 36: 603–610, 1998

A clathrate host, N-[2-(3,5-dinitrobenzoylamino)-6-methylphenyl]phthalimide 1 is designed to achieve inclusion of N-substituted formamides. N,N-Dialkylformamides HCONR2 of various sizes 2a–e [2a: R = Me; 2b: R = Et; 2c: R = Pri; 2d: R2 = –(CH2)5–, 2e: R2 = –(CH2)2O(CH2)2–] and dimethyl sulfoxide have been included as the guests in a clathrate host 1, in the ratio 1∶1 in each case. The interaction between the host and guest has been investigated by X-ray analysis of complex 1·2c (1∶1). The phthalimide plane and the N-phenyl group are orthogonal, which makes a suitable space for recognition of the formamides.

Background & Aims Nonalcoholic fatty liver disease (NAFLD) is closely related to insulin resistance and lipid metabolism. Recent studies have suggested that the quality of fat accumulated in the liver is associated with the development of nonalcoholic steatohepatitis (NASH). In this study, we investigated the fatty acid composition in liver tissue and its association with the pathology in NAFLD patients. Methods One hundred and three patients diagnosed with NAFLD [simple steatosis (SS): 63, NASH: 40] were examined and their hepatic fatty acids were measured using gas chromatography. In addition, relationships between the composition and composition ratios of various fatty acids and patient backgrounds, laboratory test values, histology of the liver, and expression of fat metabolism-related enzymes were investigated. Results The C16:1n7 content, the C16:1n7/C16:0 and C18:1n9/C18:0 ratios were increased and the C18:0/C16:0 ratio was decreased in the NASH group. The C18:0/C16:0 and C18:1n9/C18:0 ratios were associated with the steatosis score in liver tissue, and the C16:1n7/C16:0 ratio was associated with the lobular inflammation score. The expressions levels of genes: SCD1, ELOVL6, SREBP1c, FAS and PPARγ were enhanced in the NASH group. In multivariate analysis, the C18:0/C16:0 ratio was the most important factor that was correlated with the steatosis score. In contrast, the C16:1n7/C16:0 ratio was correlated with lobular inflammation. Conclusion The fatty acid composition in liver tissue and expression of genes related to fatty acid metabolism were different between the SS and NASH groups, suggesting that the acceleration of fatty acid metabolism is deeply involved in pathogenesis of NASH.

N-Benzoyl-N-benzylcinnamamides 1, N-acetyl-N-(1-benzyl)cinnamamides 3 and N-[(1-benzyl)aminocarbonyl]-N-(1-benzyl)cinnamamides 5 have been irradiated by a high-pressure mercury lamp in the presence of benzil in benzene at room temperature to give 3-azatricyclo[5.2.2.01,5]undeca-8,10-dien-4-ones 2, 4 and 6 with high stereoselectivity. These are the first photo[4+2]cycloadducts of an enone and a benzene ring.

The cholesterol absorption inhibitor ezetimibe has been shown to ameliorate non-alcoholic fatty liver disease (NAFLD) pathology in a single-armed clinical study and in experimental animal models. In this study, we investigated the efficacy of ezetimibe on NAFLD pathology in an open-label randomised controlled clinical trial. We had planned to enrol 80 patients in the trial, as we had estimated that, with this sample size, the study would have 90% power. The study intervention and enrolment were discontinued because of the higher proportion of adverse events (significant elevation in HbA1c) in the ezetimibe group than in the control group. Thirty-two patients with NAFLD were enrolled and randomised (allocation by computer program). Ezetimibe (10 mg/day) was given to 17 patients with NAFLD for 6 months. The primary endpoint was change in serum aminotransferase level. Secondary outcomes were change in liver histology (12 control and 16 ezetimibe patients), insulin sensitivity including a hyperinsulinaemic–euglycaemic clamp study (ten control and 13 ezetimibe patients) and hepatic fatty acid composition (six control and nine ezetimibe patients). Hepatic gene expression profiling was completed in 15 patients using an Affymetrix gene chip. Patients and the physician in charge knew to which group the patient had been allocated, but people carrying out measurements or examinations were blinded to group. Serum total cholesterol was significantly decreased in the ezetimibe group. The fibrosis stage and ballooning score were also significantly improved with ezetimibe treatment. However, ezetimibe treatment significantly increased HbA1c and was associated with a significant increase in hepatic long-chain fatty acids. Hepatic gene expression analysis showed coordinate downregulation of genes involved in skeletal muscle development and cell adhesion molecules in the ezetimibe treatment group, suggesting a suppression of stellate cell development into myofibroblasts. Genes involved in the l-carnitine pathway were coordinately downregulated by ezetimibe treatment and those in the steroid metabolism pathway upregulated, suggestive of impaired oxidation of long-chain fatty acids. Ezetimibe improved hepatic fibrosis but increased hepatic long-chain fatty acids and HbA1c in patients with NAFLD. These findings shed light on previously unrecognised actions of ezetimibe that should be examined further in future studies. Trial registration University Hospital Medical Information Network (UMIN) Clinical Trials Registry UMIN000005250. Funding The study was funded by grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and research grants from MSD.

Intramolecular pholocycloaddition of cyclopropene carboxylic acid allylic esters 1 results in an exclusive formation of 5-oxaspiro[2.4]hepta-4-ones 2, the hydrogen transferred rearrangement products, with induction of three stereogenic centers. Ring strain is crucial to alter the course of reaction from the [2+2] photocycloaddtion to the hydrogen transfer.

Norcaradiene derivatives 1, 5-(1-benzyloxycarbonyl-2-methyl-1-propenyl)-3-oxatricyclo[4.4.0.01,5]deca-7,9-dien-4-one, showed a restricted rotation in the 1H NMR spectra. VT 1H NMR measurements in CDCl3 revealed the existence of two rotamers at low temperature with ΔG≠ of 11.5 (250 K), 12.1 (263 K), and 13.9 kcal mol−1 (296 K) for norcaradienes with R = H, Me, and t-Bu, where R is the para substituent of the benzyloxy group, respectively. This restricted rotation was stopped in CDCl3 at ambient temperature by introducing intramolecular hydrogen bonding via reducing of the lactone moiety to the corresponding lactols. The observed conformational locking due to the intramolecular hydrogen bonding was unlocked by solvation, resulting in the formation of three conformers in methanol-d4 and dimethyl-d6 sulfoxide. VT 1H NMR measurements of the lactol derivative in dimethyl-d6 sulfoxide showed that two of the conformers interconverted with ΔG≠ of 17.4 kcal mol−1.

Thermal rearrangement of diastereomeric 7-vinylnorcaradienes 2 and 3 resulted in the formation of three products, two of which were derived from the vinylcyclopropane-cyclopentene rearrangement and the third from the Cope rearrangement. Almost identical product ratios from 2 and 3 suggested the existence of a common biradical as an intermediacy. The kinetic versus thermodynamic control of the rearrangement was achieved by the choice of the substituent (X) in norcaradienes 9.

Enantioseparation of N -(1-arylethyl)amides and α -[ N -(3,5-dinitrobenzoyl)]amino esters was achieved by column chromatography on silica gel modified with a chiral acylurea which has two ( S )-1-(1-naphthyl)ethyl moieties in a pseudo-C 2 symmetric position around an axis of the urea-carbonyl.

The photolysis and thermolysis of 7,8-diaza-3-oxatricyclo[4.2.1.02,5]non-7-enes were studied. Photolysis showed a novel [4π + 2π + 2π] cycloreversion in a formal way, the first example in azoalkane chemistry. This cycloreversion was found to be sensitized by the benzophenone produced. In contrast, thermolysis showed the typical decomposition pattern of azoalkanes, extrusion of nitrogen and subsequent σ-bond formation of the resulting biradical to afford the tricyclic oxetanes

Resolution of racemic amides was achieved by column chromatography on silica gel modified with a chiral acylurea which has two ( S )-1-phenylethyl moieties in a pseudo-C 2 symmetric position around an axis of the urea-carbonyl.

Preparation and stereochemical behavior of new examples of isolable rotamers are described. Reaction of hydroxylactone 2 with isocyanates 3 – 11 gave the corresponding 12 – 20 in good yields. Among them, ortho di-substituted ones gave isolable rotamers. The behavior of ortho mono-substituted derivatives is also discussed.

A highly diastereoselective one-pot tandem Michael-Michael addition reaction developed in a rotamerically locked conformation is described. Reaction of isocyanates 8 – 13 with hydroxylactone 14 gave tandem Michael-Michael adducts 22 – 26 in good to excellent yields. The intermediate tricyclic oxazolidinones consisted of rotamer pairs 16 – 19, and the rotation barriers of some of these compounds were determined. The tandem addition reaction was highly accelerated by introducing conformation anchoring group X. A new versatile synthesis of octahydroacridines 27 – 29 using the tandem adducts is also described.

Hard BN films with cubic BN (c-BN) phase and soft BN films without c-BN phase were deposited on Si wafer by a reactive ion plating process with a hot cathode plasma discharged within parallel magnetic field. These BN films were left in air with relative humidity of about 30%, 65-85% and 100% for about 3000 hours. The atmospheric degeneration of these BN films was investigated by SEM observation and EPMA measurements. Small particles such as boron oxide, boric acid or ammonium borate were formed at the surface of soft BN films left in air. All BN films were cracked after leaving in air. The cracking became faster with an increase in the relative humidity of air. The cracking of soft BN films occurred more rapidly than that of hard BN films. The cracking of hard BN films was retarded by post annealing.

Irradiation of aromatic carbonyl compounds in hexamethylphosphoric triamide (HMPA) resulted in the cross-coupling of ketyl radicals with the HMPA-derived radical generated via hydrogen abstraction from it. The results on acetolysis, methanolysis, and the reaction with thionyl chloride of the resulting coupling products are described.

A convenient synthesis of natural (±)-blastmycino-lactol from the aldol addition reaction of n-pentanoylurea and (±)-2-benzyloxypropionaldehyde is described.

The relation between the separability and the stereochemistry of the acylurea derivatives prepared from chiral mono-, bi- and tricyclic acids and N,N′-bis((S)-1-phenylethyl)carbodiimide were investigated. Conventionally separated diastereomers by silica gel column chromatography were converted to optically pure methyl esters of the corresponding acids upon methanolysis.

The aldol reaction of the boron enolate bearing the titled chiral auxiliary proceeded with high face selectivity.

The intramolecular radical cyclisation of cyclic homoallylic xanthates were explored. In five- or six-membered ring systems, the homoallylic xanthates were easily cyclised to give fused thionolactone derivatives. The thionolactones were converted into their corresponding lactones in high yield, which constitutes a transformation of homoallylic alcohols into lactones.

The first example of intramolecular radical cyclization of ketene radical synthon is presented. Intramolecular radical cyclization of 2-bromo-ketene-S,S-acetals proceeded highly regioselectively to give the corresponding 5-exo-trig cyclized γ-lactones.