ABSTRACT
Remotely sensed interplanetary scintillation (IPS) data from the Institute for Space-Earth Environmental Research (ISEE), Japan, allows a determination of solar-wind parameters throughout the inner heliosphere. We show the 3D analysis technique developed for these data sets that forecast plasma velocity, density, and component magnetic fields at Earth, as well at the other inner heliospheric planets and spacecraft. One excellent coronal mass ejection (CME) example that occurred on the 10 March 2022 was viewed not only in the ISEE IPS analyses, but also by the spacecraft near Earth that measured the CME arrival at one AU. Solar Orbiter, that was nearly aligned along the Earth radial at 0.45 AU, also measured the CME in plasma density, velocity, and magnetic field. BepiColombo at 0.42 AU was also aligned with the STEREO A spacecraft, and viewed this CME. The instruments used here from BepiColombo include: 1) the European-Space-Agency Mercury-Planetary-Orbiter magnetic field measurements; 2) the Japan Aerospace Exploration Agency Mio spacecraft Solar Particle Monitor that viewed the CME Forbush decrease, and the Mercury Plasma Experiment/Mercury Electron Analyzer instruments that measured particles and solar-wind density from below the spacecraft protective sunshield covering. This article summarizes the analysis using ISEE, Japan real-time data for these forecasts: it provides a synopsis of the results and confirmation of the CME event morphology after its arrival, and discusses how future IPS analyses can augment these results.
ABSTRACT
A scaffold-hopping strategy towards a new pyrazolo[1,5-a]pyridine based core using molecular hybridization of two structurally distinct EP1 antagonists, followed by structure-activity relationship-guided optimization, resulted in the identification of potent EP1 antagonists exemplified by 4c, 4f, and 4j, which were shown to reduce pathological intravesical pressure in rats when administered at 1mg/kg iv.
Subject(s)
Drug Discovery , Pyrazoles/pharmacology , Pyridines/pharmacology , Receptors, Prostaglandin E, EP1 Subtype/antagonists & inhibitors , Animals , Dose-Response Relationship, Drug , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyridines/chemical synthesis , Pyridines/chemistry , Rats , Structure-Activity RelationshipABSTRACT
UNLABELLED: Bezafibrate is a widely used hypolipidemic agent and is known as a ligand of the peroxisome proliferator-activated receptors (PPARs). Recently this agent has come to be recognized as a potential anticholestatic medicine for the treatment of primary biliary cirrhosis (PBC) that does not respond sufficiently to ursodeoxycholic acid (UDCA) monotherapy. The aim of this study was to explore the anticholestatic mechanisms of bezafibrate by analyzing serum lipid biomarkers in PBC patients and by cell-based enzymatic and gene expression assays. Nineteen patients with early-stage PBC and an incomplete biochemical response to UDCA (600 mg/day) monotherapy were treated with the same dose of UDCA plus bezafibrate (400 mg/day) for 3 months. In addition to the significant improvement of serum biliary enzymes, immunoglobulin M (IgM), cholesterol, and triglyceride concentrations in patients treated with bezafibrate, reduction of 7α-hydroxy-4-cholesten-3-one (C4), a marker of bile acid synthesis, and increase of 4ß-hydroxycholesterol, a marker of CYP3A4/5 activity, were observed. In vitro experiments using human hepatoma cell lines demonstrated that bezafibrate controlled the target genes of PPARα, as well as those of the pregnane X receptor (PXR); down-regulating CYP7A1, CYP27A1, and sinusoidal Na(+) /taurocholate cotransporting polypeptide (NTCP), and up-regulating CYP3A4, canalicular multidrug resistance protein 3 (MDR3), MDR1, and multidrug resistance-associated protein 2 (MRP2). CONCLUSION: Bezafibrate is a dual PPARs/PXR agonist with potent anticholestatic efficacy in early-stage PBC patients with an incomplete biochemical response to UDCA monotherapy.
Subject(s)
Anticholesteremic Agents/therapeutic use , Bezafibrate/therapeutic use , Cholagogues and Choleretics/therapeutic use , Liver Cirrhosis, Biliary/drug therapy , Ursodeoxycholic Acid/therapeutic use , Adult , Aged , Aged, 80 and over , Anticholesteremic Agents/pharmacology , Bezafibrate/pharmacology , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Cytochrome P-450 CYP3A/drug effects , Drug Therapy, Combination , Female , Humans , Lipids/blood , Liver/enzymology , Liver Cirrhosis, Biliary/blood , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Male , Middle Aged , PPAR alpha/drug effects , Pregnane X Receptor , Receptors, Steroid/drug effects , Treatment Failure , Treatment OutcomeABSTRACT
AIM: Proton beam therapy is safe and more effective than conventional radiation therapy for the local control of nodular hepatocellular carcinoma (HCC). However, evaluating therapeutic response by imaging is not accurate during the early post-irradiation period. Therefore, we examined whether the histopathological study of biopsy specimens obtained at 3 weeks after irradiation can be used to more accurately assess therapeutic response. METHODS: Fifteen HCC lesions from 13 patients were treated with proton beam irradiation. Tissue biopsy samples were obtained using abdominal ultrasound-guided percutaneous fine-needle aspiration from the center of the tumor before, 3 weeks after and 1 year post-proton therapy. The specimens were examined after staining with hematoxylin-eosin (HE) and a MIB-1 antibody. RESULTS: MIB-1 labeling indices (LI) before treatment were 13.0 ± 8.5% (mean ± SD; range, 0.6-27.0), whereas those 3 weeks after proton therapy were significantly reduced to 3.2 ± 2.4% (range, 0.6-8.9) (P < 0.05). Although the tumor size was reduced, we did not observe a reduction in tumor blood flow by dynamic computed tomography or degenerative changes by HE. All lesions that displayed reduced MIB-1 LI at 3 weeks post-proton treatment were ultimately diagnosed as complete response at 1 year after treatment. In contrast, one case with increased MIB-1 LI at 3 weeks had significant tumor size progression at 1 year post-treatment. CONCLUSION: The percutaneous fine-needle aspiration biopsy of HCC is a safe and useful tool that can be used to evaluate the response to proton irradiation. In particular, MIB-1 LI may provide additional information to assess the therapeutic response of HCC during the early post-irradiated period.
ABSTRACT
Carnitine is a vitamin-like compound that plays important roles in fatty acid ß-oxidation and the control of the mitochondrial coenzyme A/acetyl-CoA ratio. However, carnitine is not added to ordinary enteral nutrition or total parenteral nutrition. In this study, we determined the serum carnitine concentrations in subjects receiving ordinary enteral nutrition (EN) or total parenteral nutrition (TPN) and in patients with inflammatory bowel diseases to compare its levels with those of other nutritional markers. Serum samples obtained from 11 EN and 11 TPN patients and 82 healthy controls were examined. In addition, 10 Crohn's disease and 10 ulcerative colitis patients with malnutrition who were barely able to ingest an ordinary diet were also evaluated. Carnitine and its derivatives were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The carnitine concentrations in EN and TPN subjects were significantly lower compared with those of the control subjects. Neither the serum albumin nor the total cholesterol level was correlated with the carnitine concentration, although a significant positive correlation was found between the serum albumin and total cholesterol levels. Indeed, patients with CD and UC showed significantly reduced serum albumin and/or total cholesterol levels, but their carnitine concentrations remained normal. In conclusion, only a complete blockade of an ordinary diet, such as EN or TPN, caused a reduction in the serum carnitine concentration. Serum carnitine may be an independent biomarker of malnutrition, and its supplementation is needed in EN and TPN subjects even if their serum albumin and total cholesterol levels are normal.
ABSTRACT
Metabolic dysfunction-associated steatohepatitis (MASH) - previously described as nonalcoholic steatohepatitis (NASH) - is a major driver of liver fibrosis in humans, while liver fibrosis is a key determinant of all-cause mortality in liver disease independent of MASH occurrence. CCAAT/enhancer binding protein α (CEBPA), as a versatile ligand-independent transcriptional factor, has an important function in myeloid cells, and is under clinical evaluation for cancer therapy. CEBPA is also expressed in hepatocytes and regulates glucolipid homeostasis; however, the role of hepatocyte-specific CEBPA in modulating liver fibrosis progression is largely unknown. Here, hepatic CEBPA expression was found to be decreased during MASH progression both in humans and mice, and hepatic CEBPA mRNA was negatively correlated with MASH fibrosis in the human liver. CebpaΔHep mice had markedly enhanced liver fibrosis induced by a high-fat, high-cholesterol, high-fructose diet or carbon tetrachloride. Temporal and spatial hepatocyte-specific CEBPA loss at the progressive stage of MASH in CebpaΔHep,ERT2 mice functionally promoted liver fibrosis. Mechanistically, hepatocyte CEBPA directly repressed Spp1 transactivation to reduce the secretion of osteopontin, a fibrogenesis inducer of hepatic stellate cells. Forced hepatocyte-specific CEBPA expression reduced MASH-associated liver fibrosis. These results demonstrate an important role for hepatocyte-specific CEBPA in liver fibrosis progression, and may help guide the therapeutic discoveries targeting hepatocyte CEBPA for the treatment of liver fibrosis.
Subject(s)
CCAAT-Enhancer-Binding Protein-alpha , Non-alcoholic Fatty Liver Disease , Humans , Mice , Animals , Hepatocytes/metabolism , Liver Cirrhosis/genetics , Liver Cirrhosis/metabolism , Liver/metabolism , Non-alcoholic Fatty Liver Disease/etiology , Disease Models, AnimalABSTRACT
HNF4α regulates various genes to maintain liver function. There have been reports linking HNF4α expression to the development of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis. In this study, liver-specific Hnf4a-deficient mice (Hnf4aΔHep mice) developed hepatosteatosis and liver fibrosis, and they were found to have difficulty utilizing glucose. In Hnf4aΔHep mice, the expression of fatty acid oxidation-related genes, which are PPARα target genes, was increased in contrast to the decreased expression of PPARα, suggesting that Hnf4aΔHep mice take up more lipids in the liver instead of glucose. Furthermore, Hnf4aΔHep/Ppara-/- mice, which are simultaneously deficient in HNF4α and PPARα, showed improved hepatosteatosis and fibrosis. Increased C18:1 and C18:1/C18:0 ratio was observed in the livers of Hnf4aΔHep mice, and the transactivation of PPARα target gene was induced by C18:1. When the C18:1/C18:0 ratio was close to that of Hnf4aΔHep mouse liver, a significant increase in transactivation was observed. In addition, the expression of Pgc1a, a coactivator of PPARs, was increased, suggesting that elevated C18:1 and Pgc1a expression could contribute to PPARα activation in Hnf4aΔHep mice. These insights may contribute to the development of new diagnostic and therapeutic approaches for NAFLD by focusing on the HNF4α and PPARα signaling cascade.
Subject(s)
Hepatocyte Nuclear Factor 4 , Non-alcoholic Fatty Liver Disease , Animals , Mice , Hepatocyte Nuclear Factor 4/genetics , Hepatocyte Nuclear Factor 4/metabolism , Lipid Metabolism , Liver/metabolism , Liver Cirrhosis/metabolism , Mice, Inbred C57BL , Non-alcoholic Fatty Liver Disease/genetics , Non-alcoholic Fatty Liver Disease/pathology , PPAR alpha/genetics , PPAR alpha/metabolismABSTRACT
Mercury's magnetosphere is known to involve fundamental processes releasing particles and energy like at Earth due to the solar wind interaction. The resulting cycle is however much faster and involves acceleration, transport, loss, and recycling of plasma. Direct experimental evidence for the roles of electrons during this cycle is however missing. Here we show that in-situ plasma observations obtained during BepiColombo's first Mercury flyby reveal a compressed magnetosphere hosts of quasi-periodic fluctuations, including the original observation of dynamic phenomena in the post-midnight, southern magnetosphere. The energy-time dispersed electron enhancements support the occurrence of substorm-related, multiple, impulsive injections of electrons that ultimately precipitate onto its surface and induce X-ray fluorescence. These observations reveal that electron injections and subsequent energy-dependent drift now observed throughout Solar System is a universal mechanism that generates aurorae despite the differences in structure and dynamics of the planetary magnetospheres.
ABSTRACT
At Mercury, several processes can release ions and neutrals out of the planet's surface. Here we present enhancements of planetary ions (Na+-group ions) in Mercury's northern magnetospheric cusp during flux transfer event (FTE) "showers." FTE showers are intervals of intense dayside magnetopause reconnection, during which FTEs are observed in quick succession, that is, only separated by a few seconds. This study identifies 1953 FTE shower intervals and 1795 Non-FTE shower intervals. During the shower intervals, this study shows that the FTEs form a solar wind entry layer equatorward of the northern magnetospheric cusp. In this entry layer, solar wind ions are accelerated and move downward (i.e., planetward) toward the cusp, which sputter upward-moving planetary ions with a particle flux of 1 × 1011 m-2 s-1 within 1 min. The precipitation rate is estimated to increase by an order of magnitude during FTE showers, to 2 × 1025 s-1, and the neutral density of the exosphere could vary by >10% in response to this FTE-driven sputtering. Such rapid large-scale variations driven by dayside reconnection may explain the minute-to-minute changes in Mercury's exosphere, especially on the high latitudes, observed by ground-based telescopes on Earth. Our MESSENGER in situ observation of enhanced planetary ions in the entry layer likely corresponds to an escape channel for Mercury's planetary ions. Comprehensive, future multipoint measurements made by BepiColombo will greatly enhance our understanding of the processes contributing to Mercury's dynamic exosphere and magnetosphere.
ABSTRACT
To date, many studies have been conducted using 25-hydroxycholesterol, which is a potent regulator of lipid metabolism. However, the origins of this oxysterol have not been entirely elucidated. Cholesterol 25-hydroxylase is one of the enzymes responsible for the metabolism of 25-hydroxycholesterol, but the expression of this enzyme is very low in humans. This oxysterol is also synthesized by sterol 27-hydroxylase (CYP27A1) and cholesterol 24-hydroxylase(CYP46A1), but it is only a minor product of these enzymes. We now report that CYP3A synthesizes a significant amount of 25-hydroxycholesterol and may participate in the regulation of lipid metabolism. Induction of CYP3A by pregnenolone-16α-carbonitrile caused the accumulation of 25-hydroxycholesterol in a cell line derived from mouse liver. Furthermore, treatment of the cells with troleandomycin, a specific inhibitor of CYP3A, significantly reduced cellular 25-hydroxycholesterol concentrations. In cells that overexpressed human recombinant CYP3A4, the activity of cholesterol 25-hydroxylation was found to be higher than that of cholesterol 4ß-hydroxylation, a known marker activity of CYP3A4. In addition, 25-hydroxycholesterol concentrations in normal human sera correlated positively with the levels of 4ß-hydroxycholesterol (r = 0.650, P < 0.0001, n = 78), but did not significantly correlate with the levels of 27-hydroxycholesterol or 24S-hydroxycholesterol. These results demonstrate the significance of CYP3A on the production of 25-hydroxycholesterol.
Subject(s)
Cytochrome P-450 CYP3A/metabolism , Cytochrome P-450 Enzyme System/metabolism , Enzyme Activation/drug effects , Hepatocytes/enzymology , Hydroxycholesterols/metabolism , Lipid Metabolism/physiology , Liver/enzymology , Animals , Blotting, Western , Cell Line , Cytochrome P-450 CYP3A/genetics , Cytochrome P-450 Enzyme Inhibitors , Electrophoresis, Polyacrylamide Gel , Gene Expression , Hepatocytes/cytology , Humans , Liver/cytology , Mice , Polymerase Chain Reaction , Pregnenolone Carbonitrile/pharmacology , RNA, Messenger/analysis , RNA, Messenger/biosynthesis , Steroid Hydroxylases , Troleandomycin/pharmacologyABSTRACT
The massive flare of 27 December 2004 from the soft gamma-ray repeater SGR 1806-20, a possible magnetar, saturated almost all gamma-ray detectors, meaning that the profile of the pulse was poorly characterized. An accurate profile is essential to determine physically what was happening at the source. Here we report the unsaturated gamma-ray profile for the first 600 ms of the flare, with a time resolution of 5.48 ms. The peak of the profile (of the order of 10(7) photons cm(-2) s(-1)) was reached approximately 50 ms after the onset of the flare, and was then followed by a gradual decrease with superposed oscillatory modulations possibly representing repeated energy injections with approximately 60-ms intervals. The implied total energy is comparable to the stored magnetic energy in a magnetar (approximately 10(47) erg) based on the dipole magnetic field intensity (approximately 10(15) G), suggesting either that the energy release mechanism was extremely efficient or that the interior magnetic field is much stronger than the external dipole field.
ABSTRACT
BACKGROUND/AIMS: Transnasal endoscopy is generally recognized as a less painful endoscopic procedure. The pretreatment procedure, particularly anesthesia of the nasal cavities, is reported to be vitally important for alleviating pain. METHODOLOGY: The study comprised 120 patients treated by the spray method, 203 treated by the stick method, and 100 treated by the stick + pharyngeal anesthesia method between April 2005 and March 2009. We investigated the pain levels using three pretreatment methods based on the results of a questionnaire. RESULTS: Pain at the time of insertion of an endoscope into the nasal cavity was common in all patients. It was experienced in 58.3%, 53.7% and 41.0% of patients treated by the spray, stick and stick + pharyngeal anesthesia methods, respectively. The pain was alleviated by the stick + pharyngeal anesthesia method significantly (p=0.022). Patients who did not experience any pain at the time of the endoscopic examination were 15.0%, 16.2% and 18.0%, respectively, with no significant differences. CONCLUSION: The least painful pretreatment procedure in the endoscopic examination was the stick + pharyngeal anesthesia method.
Subject(s)
Endoscopy, Digestive System/methods , Adult , Aged , Female , Humans , Male , Middle Aged , Nasal CavityABSTRACT
BACKGROUND/AIMS: Capsule endoscopy (CE) represents a significant advance in the investigation of small bowel diseases. Little is known about the clinical outcome of patients with obscure gastrointestinal bleeding (OGIB). METHODOLOGY: Seventy-eight patients underwent CE for OGIB and were followed up for at least 6 months after CE. The diagnostic yield of CE and the rate of re-bleeding during the follow-up period were established. RESULTS: Out of our 78 OGIB patients, 35 (44.9%) had significant lesions. There was a significant difference in the rate of identification of significant lesions between the on-going overt bleeding cases and previous overt bleeding cases (68.8% vs. 37.8%, respectively, p=0.043). Of the 46 patients with significant or insignificant lesions, 12 (26.1%) had one or more re-bleeding episodes during the follow-up period. On the other hand, only one (4%) of the 26 patients with negative findings had a re-bleeding episode (p=0.025). CONCLUSION: In conclusion, our study confirmed the role of CE in the diagnosis of OGIB, especially in the on-going overt bleeding cases. The OGIB patients with negative CE findings showed a low re-bleeding rate in the follow-up period. Further long-term follow-up studies are needed in future to examine the negative CE cases.
Subject(s)
Capsule Endoscopy/methods , Gastrointestinal Hemorrhage/diagnosis , Adult , Aged , Aged, 80 and over , Female , Gastrointestinal Hemorrhage/therapy , Humans , Male , Middle AgedABSTRACT
The dipeptide N-acetyl-Arg{N(omega)-(N-methylcarbamoyl)}-N-methyl-Phe(2), which is a part of the natural-product cyclopentapeptide chitinase inhibitor argifin (1), inhibits chitinase B from Serratia marcescens (SmChiB) with a half-maximal inhibitory concentration (IC(50)) of 3.7 microM. Despite the relatively small size of 2, its inhibitory activity is comparable with that of 1 (IC(50)=6.4 microM). To elucidate the basis for this interesting phenomenon, we investigated the interaction between 2 and SmChiB using a combination of nuclear magnetic resonance spectroscopy and computational methods. The transferred nuclear Overhauser effect (TRNOE) experiment obtained structural information on the SmChiB-bound conformation of 2. The binding mode of 2 and SmChiB was modeled by the novel molecular-docking approach proposed in our laboratory, which can explicitly consider water-mediated hydrogen-bonding interactions in protein-ligand interfaces. The SmChiB-bound conformation of 2 in the resulting model satisfied all proton-proton distance constraints derived from the TRNOE experiment, indicating that our model structure of the 2-SmChiB complex is reasonable. A molecular dynamics (MD) simulation examined the stability of the resultant complex structure and suggested that 2 binds to SmChiB in a similar fashion to the binding mode observed for N(omega)-(N-methylcarbamoyl)-Arg(1) and N-methyl-Phe(2) of 1 in the crystal structure of the argifin-SmChiB complex. Finally, the binding free energies of 1 and 2 with SmChiB were estimated by the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method using the MD trajectory. The MM-PBSA calculation suggested that both 1 and 2 bind to SmChiB with similar affinities, which is consistent with their experimental IC(50) values. Energetic analysis revealed that the van der Waals interaction of 2 with SmChiB is much less than that of 1, but is completely compensated by the more favorable contribution of solute entropy and the total electrostatic component. The improved total electrostatic component was derived from more favorable electrostatic interactions. Therefore, we conclude that dipeptide 2 was also better optimized against SmChiB than 1 in an electrostatic point of view.
Subject(s)
Chitinases/antagonists & inhibitors , Chitinases/metabolism , Dipeptides/pharmacology , Peptides, Cyclic/pharmacology , Serratia marcescens/enzymology , Chitinases/chemistry , Dipeptides/chemistry , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy , Molecular Dynamics Simulation , Peptides, Cyclic/chemistry , Serratia marcescens/drug effects , ThermodynamicsABSTRACT
BACKGROUND AND AIM: The risks of peptic ulcer complications increase in association with low-dose aspirin (LDA) use. The endoscopic findings and clinical features of gastroduodenal ulcer have not been thoroughly investigated in patients taking LDA. METHOD: We classified 1,041 gastroduodenal ulcer patients into three groups [patients taking LDA (group A), patients taking nonaspirin nonsteroidal anti-inflammatory drug (NSAID) (group N), and patients taking neither aspirin nor nonaspirin NSAID (group C)] and 241 bleeding gastroduodenal ulcer patients into three corresponding groups (groups a, n, and c). We investigated the clinical features, endoscopic characteristics, and endoscopic treatment of the hemorrhagic lesion in the gastroduodenal ulcer patients taking LDA and compared them with those of the other groups. RESULTS: The frequency of bleeding events such as hematemesis, melena, and anemia was significantly higher in group A and N than in group C. The percentage of ulcers located in the antrum was higher in group A and N than in group C, and also higher in group a and n than in group c. The percentage of ulcers located in the body, fundus, and cardia was significantly higher in the bleeding patients than in all gastroduodenal ulcer patients. The percentage of cases that required additional endoscopic treatment in group a was higher than in group c. Duration of hospitalization of group a was significantly longer than that of group c. CONCLUSION: These results indicate that it is very important to prevent LDA-induced gastroduodenal ulcer complications, including bleeding.
Subject(s)
Aspirin/administration & dosage , Aspirin/adverse effects , Peptic Ulcer/chemically induced , Aged , Aged, 80 and over , Asian People , Aspirin/therapeutic use , Endoscopy, Gastrointestinal , Female , Gastrointestinal Hemorrhage/chemically induced , Gastrointestinal Hemorrhage/therapy , Humans , Male , Middle Aged , Peptic Ulcer/pathologyABSTRACT
BACKGROUND/AIMS: Although video capsule endoscopy (CE) is now an established modality for examining the small bowel, in almost 20 - 50 % cases, the capsule does not reach the colon by the end of the recording time. The aim of this study was to investigate whether metoclopramide increases the completion rate of CE examination. METHODOLOGY: One hundred patients who underwent CE were classified to receive either intravenous treatment with metoclopramide (metoclopramide group: 43 cases) or no treatment at all (control group: 57 cases). RESULTS: GTT was 18.9 +/- 21.6 min in the metoclopramide group and 37.4 +/- 45.3 min in the control group (p = 0.0053). The capsule reached the cecum in 31 cases (75.6%) of the metoclopramide group and in 38 cases (69.1%) of the control group (p = 0.482). The SBTT and the combined GTT and SBTT were 276.8 +/- 108.9 min, 293.0 +/- 109.4 min in the metoclopramide group and 305.5 +/- 86.9 min, 339.4 +/- 89.2 min in the control group (p = 0.122, p = 0.035). CONCLUSION: Although 10 mg of metoclopramide with intravenous drip had shortened the GTT and the combined GTT and SBTT, there was no improvement in the rate of complete small bowel examination and the results of diagnostic yield. Further investigations are necessary to evaluate the concomitant use of other prokinetics or preparations to improve the rate of complete small bowel examination.
Subject(s)
Capsule Endoscopy , Dopamine Antagonists/pharmacology , Gastrointestinal Transit/drug effects , Metoclopramide/pharmacology , Capsule Endoscopy/adverse effects , Chi-Square Distribution , Dopamine Antagonists/administration & dosage , Female , Humans , Intestine, Small , Male , Metoclopramide/administration & dosage , Middle Aged , Statistics, NonparametricABSTRACT
BACKGROUND/AIMS: Previous published data on the differentiated/undifferentiated mixed-type early gastric cancer treated with ESD are scarce. METHODOLOGY: The clinicopathological features of the pure differentiated type and differentiated/undifferentiated mixed type adenocarcinoma in final diagnosis of ESD specimens were investigated in 109 early gastric cancers patients treated with ESD. RESULTS: Of the pure differentiated type (102 patients) and differentiated / undifferentiated mixed type (7 patients) adenocarcinoma, submucosal invasive tumors were detected in 6 (5.9%) and 4 cases (57.1%) (p = 0.017), respectively. The mean tumor size was 10.95 +/- 5.12mm and 22.85 +/- 9.51mm (p = 0.0091), respectively. In the cases diagnosed as moderately differentiated adenocarcinoma by preoperative ESD biopsy, submucosal invasive tumors were detected in 2 (12.5%) and 4 cases (57.1%) (p = 0.038), respectively, and the mean tumor size was 12.50 +/- 5.88mm and 22.85 +/- 9.51mm (p = 0.016), respectively. During a median follow-up period of 30.3 months (range: 7-52 months), there were no recurrences or metastasis in any of the 7 mixed type cases. CONCLUSION: In conclusion, the results of our study suggest that large gastric tumors treated with ESD which are diagnosed as moderately differentiated adenocarcinoma in biopsy specimens potentially contain an undifferentiated component.
Subject(s)
Adenocarcinoma/pathology , Adenocarcinoma/surgery , Endoscopy , Stomach Neoplasms/pathology , Stomach Neoplasms/surgery , Aged , Aged, 80 and over , Disease-Free Survival , Dissection , Female , Follow-Up Studies , Gastric Mucosa , Humans , Male , Middle Aged , Neoplasm Invasiveness , Treatment OutcomeABSTRACT
Carbon is a volatile element that has a considerable influence on the formation and evolution of planetary bodies, although it was previously believed to be depleted in the Moon. We present observations by the lunar orbiter KAGUYA of carbon ions emitted from the Moon. These emissions were distributed over almost the total lunar surface, but amounts were differed with respect to lunar geographical areas. The estimated emission fluxes to space were ~5.0 × 104 per square centimeter per second, which is greater than possible ongoing supplies from the solar wind and micrometeoroids. Our estimates demonstrate that indigenous carbon exists over the entire Moon, supporting the hypothesis of a carbon-containing Moon, where the carbon was embedded at its formation and/or was transported billions of years ago.
ABSTRACT
Formyl peptide receptor 2 (FPR2) agonists can stimulate resolution of inflammation and may have utility for treatment of diseases caused by chronic inflammation, including heart failure. We report the discovery of a potent and selective FPR2 agonist and its evaluation in a mouse heart failure model. A simple linear urea with moderate agonist activity served as the starting point for optimization. Introduction of a pyrrolidinone core accessed a rigid conformation that produced potent FPR2 and FPR1 agonists. Optimization of lactam substituents led to the discovery of the FPR2 selective agonist 13c, BMS-986235/LAR-1219. In cellular assays 13c inhibited neutrophil chemotaxis and stimulated macrophage phagocytosis, key end points to promote resolution of inflammation. Cardiac structure and functional improvements were observed in a mouse heart failure model following treatment with BMS-986235/LAR-1219.
Subject(s)
Pyrrolidinones/chemistry , Receptors, Formyl Peptide/agonists , Receptors, Lipoxin/agonists , Animals , Chemotaxis/drug effects , Disease Models, Animal , Drug Evaluation, Preclinical , HEK293 Cells , Heart Failure/pathology , Heart Failure/prevention & control , Humans , Macrophages/cytology , Macrophages/immunology , Macrophages/metabolism , Mice , Microsomes, Liver/metabolism , Neutrophils/cytology , Neutrophils/physiology , Phagocytosis/drug effects , Pyrrolidinones/metabolism , Pyrrolidinones/pharmacology , Pyrrolidinones/therapeutic use , Receptors, Formyl Peptide/genetics , Receptors, Formyl Peptide/metabolism , Receptors, Lipoxin/genetics , Receptors, Lipoxin/metabolism , Structure-Activity RelationshipABSTRACT
Argifin, a novel pentapeptide chitinase inhibitor isolated from Gliocladium fungal culture, is a promising candidate for the development of new fungicides, insecticides, and anti-asthma medications. In this study, we undertook rational molecular design of argifin-derivatives and tested them against chitinase B from Serratia marcescens (SmChiB). The work involved molecular dynamics simulation with explicit water molecules, the molecular docking calculation, and free-energy analysis using the molecular mechanics Poisson-Boltzmann surface area method. The custom-designed derivatives were synthesized via effective solid phase synthesis, developed recently in our laboratory, and their inhibitory activities were measured against SmChiB. Finally, we identified and obtained a derivative which exhibited 28-fold more inhibition than argifin itself, a compound in which the d-Ala(5) of argifin was replaced with d-Leu and the 4-benzylpiperdine was attached to l-Asp(4).