X-ray pumping of the 229Th nuclear clock isomer.

The metastable first excited state of thorium-229, 229mTh, is just a few electronvolts above the nuclear ground state1-4 and is accessible by vacuum ultraviolet lasers. The ability to manipulate the 229Th nuclear states with the precision of atomic laser spectroscopy5 opens up several prospects6, from studies of fundamental interactions in physics7,8 to applications such as a compact and robust nuclear clock5,9,10. However, direct optical excitation of the isomer and its radiative decay to the ground state have not yet been observed, and several key nuclear structure parameters-such as the exact energies and half-lives of the low-lying nuclear levels of 229Th-remain unknown11. Here we present active optical pumping into 229mTh, achieved using narrow-band 29-kiloelectronvolt synchrotron radiation to resonantly excite the second excited state of 229Th, which then decays predominantly into the isomer. We determine the resonance energy with an accuracy of 0.07 electronvolts, measure a half-life of 82.2 picoseconds and an excitation linewidth of 1.70 nanoelectronvolts, and extract the branching ratio of the second excited state into the ground and isomeric state. These measurements allow us to constrain the 229mTh isomer energy by combining them with γ-spectroscopy data collected over the past 40 years.

Clinical impact of cryoballoon posterior wall isolation using the cross-over technique in persistent atrial fibrillation.

BACKGROUND AND AIMS: Successful left atrial posterior wall isolation (LAPWI) using only the cryoballoon (CB) is technically challenging for the treatment of atrial fibrillation (AF). This study aimed to evaluate the efficacy of the cross-over technique, wherein an overlapped ablation is performed by placing the CB from both directions in contact with the LAPW. METHODS: This was a single-center, retrospective, observational study of 194 consecutive patients with persistent atrial fibrillation (PerAF) who underwent a first-time procedure of pulmonary vein isolation (PVI) + PWI (108 patients) or PVI-only (86 patients) using the CB. The cross-over technique was applied in all LAPWI. RESULTS: For ablation of the LA roof and bottom, respectively, a mean of 8.6 ± 1.0 (right to left [R→L] 4.3 ± 1.1 and left to right [L→R] 4.3 ± 1.1) and 9.1 ± 1.2 (R→L 4.6 ± 1.6 and L→R 4.5 ± 1.2) CB applications were delivered. LAPW was successfully isolated solely using the CB in 99.1% of patients. Although the PVI + PWI group had significantly longer procedure time, no severe adverse events were observed in either group. During a median follow-up of 19 months, freedom from recurrence of all atrial tachyarrhythmias was achieved in 93.5% of the PVI + PWI group and 72.9% of the PVI-only group (p = .011). CONCLUSIONS: LAPWI performed solely with the CB using the cross-over technique is feasibly, safe, and was independently associated with a significantly higher freedom from recurrence of atrial tachyarrhythmias compared with PVI alone in patients with PerAF.

Objective Evaluation With Noncontrast Computed Tomography Can Reveal Calcified Plaque Solidity in Peripheral Artery Diseases.

PURPOSE: The presence of severely calcified plaque remains problematic in endovascular therapy, and no specific endovascular treatment strategy has been established. Estimating plaque solidity before the procedure may help operators penetrate calcified plaque with a guide wire. The aim of this study was to establish a method of measuring plaque solidity with noncontrast computed tomography (CT). METHODS: This retrospective, single-center study included consecutive patients who, between October 2020 and July 2022, underwent noncontrast 5 mm and 1 mm CTs before endovascular therapy to penetrate calcified plaque with a wire in the common femoral, superficial femoral, and popliteal arteries. Three cross-sectional CT slices were selected. To target a calcified plaque lesion, the operator identified a region of interest, which corresponded to 24×24 pixels, and Hounsfield unit (HU) values of each pixel were displayed on the CT image. The average HU values and the ratio of number of pixels of lower values (130-599 HU) represented plaque solidity. We used the Mann-Whitney-Wilcoxon rank-sum test and the chi-square test to compare the solidity of plaques penetrated and not penetrated by the wire. RESULTS: We evaluated 108 images of 36 calcified plaque lesions (in 19 patients). The wire penetrated 28 lesions (77.8%) successfully. The average HU value was significantly lower in the lesions that the wire penetrated than in the others, in both the 5 mm CT slices (434.7±86.8 HU vs 554.3±112.7 HU, p=0.0174) and 1 mm slices (497.8±103.1 HU vs 593.5±114.5 HU, p=0.0381). The receiver operating curve revealed that 529.9 and 533.9 HU in the 5 and 1 mm slices, respectively, were the highest values at which wires could penetrate. Moreover, at the lesions that were penetrates successfully, the ratio of number of lower HU value pixels was significantly higher both in 5 mm slice CTs (74.7±13.4 vs 61.7±13.1%, p=0.0347) and 1 mm (68.7±11.8 vs 57.1±11.4%, p=0.0174). CONCLUSION: The use of noncontrast CT to evaluate plaque solidity was associated with successful wire penetration of calcified lesions in peripheral arteries. CLINICAL IMPACT: This study revealed an association between the wire penetration inside calcified plaque and plaque solidity estimated using non-contrasted computed tomography. The mean Hounsfield unit values of three cross-sections in calcified plaques were associated with the successful wire penetration. This wire penetration difficulty is associated with extended procedure time, excessive radiation exposure, usage of extra contrast agents, and increased medical costs. Therefore, estimating calcified plaque solidity before procedure enables us to choose effective and lean procedures. In addition, to predict the success of dilating calcified plaque from the inside is also beneficial when the operator wants to avoid extra scaffold implantation for target lesions.

Anti-Monomeric C-Reactive Protein Antibody Ameliorates Arthritis and Nephritis in Mice.

Conformation-specific Ags are ideal targets for mAb-based immunotherapy. Here, we demonstrate that the monomeric form of C-reactive protein (mCRP) is a specific therapeutic target for arthritis and nephritis in a murine model. Screening of >1800 anti-mCRP mAb clones identified 3C as a clone recognizing the monomeric, but not polymeric, form of CRP. The anti-mCRP mAb suppressed leukocyte infiltration in thioglycollate-induced peritonitis, attenuated rheumatoid arthritis symptoms in collagen Ab-induced arthritis model mice, and attenuated lupus nephritis symptoms in MRL/Mp-lpr/lpr lupus-prone model mice. These data suggest that the anti-mCRP mAb 3C has therapeutic potential against rheumatoid arthritis and lupus nephritis.

Mechanism of Enhanced Nifedipine Dissolution by Polymer-Blended Solid Dispersion through Molecular-Level Characterization.

We investigated the effect of polymer composition on nifedipine (NIF) dissolution through molecular-level characterization of NIF/hypromellose (HPMC)/Eudragit S (EUD-S) ternary solid dispersions. The dissolution rates and molecular states of NIF and polymers were evaluated in NIF/HPMC/EUD-S spray-dried samples (SPDs) with different polymer compositions. Blending of HPMC and EUD-S improved the dissolution property of each polymer. Moreover, polymer blending enhanced NIF dissolution from the NIF/polymer SPD with EUD-S/polymer wt % of 50-75%. NIF dissolved simultaneously with polymers from the NIF/polymer SPDs with high EUD-S/polymer wt %. In contrast, NIF and polymers separately dissolved from the NIF/polymer SPDs with EUD-S/polymer wt % of 10-25%, exhibiting a significantly reduced NIF dissolution rate. Fourier transform-infrared and solid-state NMR measurements revealed that HPMC and EUD-S formed molecular interactions with NIF via different interaction modes. Comprehensive analysis by spectroscopic measurements and modulated differential scanning calorimetry showed that the molecular interaction between NIF and EUD-S was stronger than that between NIF and HPMC. Furthermore, the 13C-spin-lattice relaxation time measurements revealed that EUD-S effectively restricted the molecular mobility of NIF compared with HPMC. The molecular interaction between NIF and EUD-S led to the simultaneous and fast dissolution of NIF with EUD-S from the NIF/polymer SPD with high EUD-S loading. Thus, enhanced NIF dissolution was ascribed to the fast dissolution properties of the blended polymer and to polymer-controlled NIF dissolution through the strong molecular interaction between NIF and EUD-S. To achieve efficient optimization of the formulation of polymer-blended solid dispersion with desired drug dissolution, it is necessary to consider both polymer-polymer and drug-polymer intermolecular interactions.

Contributions of caspase-8 and -9 to liver injury from CYP2E1-produced metabolites of halogenated hydrocarbons.

1. Drug-induced liver injury is difficult to predict at the pre-clinical stage. This study aimed to clarify the roles of caspase-8 and -9 in CYP2E1 metabolite-induced liver injury in both rats and cell cultures in vitro treated with carbon tetrachloride (CCl4), halothane or sevoflurane. The human hepatocarcinoma functional liver cell line was maintained in 3-dimensional culture alone or in co-culture with human acute monocytic leukemia cells. 2. In vivo, laboratory indices of liver dysfunction and histology were normal after administration of sevoflurane. CCl4 treatment increased blood AST/ALT levels, liver caspase-3 and -9 activities and liver malondialdehyde, accompanied by centrilobular hepatocyte necrosis. Halothane increased AST/ALT levels, caspase-3 and -8 activities (but not malondialdehyde) concomitant with widespread hepatotoxicity. In vitro, CCl4 treatment increased caspase-9 activity and decreased both mitochondrial membrane potential (MMP) and cell viability. In co-culture, halothane increased caspase-8 activity and decreased MMP and cellular viability. There were no toxic responses in CYP2E1 knockdown in monoculture and co-culture. 3. CYP2E1-inducing compounds play a pivotal role in halogenated hydrocarbon toxicity. 4. Changes in hepatocyte caspase-8 and -9 activities could be novel biomarkers of metabolites causing DILI, and in pre-clinical development of new pharmaceuticals can predict nascent DILI in the clinical stage.

A cis-acting five-amino-acid motif controls targeting of ABCC2 to the apical plasma membrane domain.

ATP-binding cassette transporter isoform C2 (ABCC2) is exclusively targeted to the apical plasma membrane of polarized cells. Although apical localization of ABCC2 in hepatocytes is crucial for the biliary excretion of a variety of metabolites, the mechanism regulating its apical targeting is poorly understood. In the present study, an apical targeting signal was identified in the first cytoplasmic loop domain (CLD1) of ABCC2 in HepG2 cells. Overexpression of CLD1 significantly disturbed the apical targeting of FLAG-ABCC2 in a competitive manner, suggesting the presence of a saturable sorting machinery in HepG2 cells. Next, deletion analysis identified a potential targeting sequence within a 20-amino-acid long peptide (aa 272-291) of CLD1. Alanine scanning mutagenesis of this region in full-length ABCC2 further narrowed down the apical targeting determinant to five amino acids, S(283)QDAL(287). Of these, S(283) and L(287) were found to be conserved among vertebrate ABCC2 orthologs. Site-directed mutagenesis showed that both S(283) and L(287) were crucial for the targeting specificity of ABCC2. Introducing this apical targeting sequence into the corresponding region of ABCC1, an exclusively basolateral protein, caused the hybrid ABCC1 to partially localize in the apical membrane. Thus, the CLD1 of ABCC2 contains a novel apical sorting determinant, and a saturable sorting machinery is present in polarized HepG2 cells.

Hydrogen gas attenuates embryonic gene expression and prevents left ventricular remodeling induced by intermittent hypoxia in cardiomyopathic hamsters.

The prevalence of sleep apnea is very high in patients with heart failure (HF). The aims of this study were to investigate the influence of intermittent hypoxia (IH) on the failing heart and to evaluate the antioxidant effect of hydrogen gas. Normal male Syrian hamsters (n = 22) and cardiomyopathic (CM) hamsters (n = 33) were exposed to IH (repeated cycles of 1.5 min of 5% oxygen and 5 min of 21% oxygen for 8 h during the daytime) or normoxia for 14 days. Hydrogen gas (3.05 vol/100 vol) was inhaled by some CM hamsters during hypoxia. IH increased the ratio of early diastolic mitral inflow velocity to mitral annulus velocity (E/e', 21.8 vs. 16.9) but did not affect the LV ejection fraction (EF) in normal Syrian hamsters. However, IH increased E/e' (29.4 vs. 21.5) and significantly decreased the EF (37.2 vs. 47.2%) in CM hamsters. IH also increased the cardiomyocyte cross-sectional area (672 vs. 443 µm(2)) and interstitial fibrosis (29.9 vs. 9.6%), along with elevation of oxidative stress and superoxide production in the left ventricular (LV) myocardium. Furthermore, IH significantly increased the expression of brain natriuretic peptide, ß-myosin heavy chain, c-fos, and c-jun mRNA in CM hamsters. Hydrogen gas inhalation significantly decreased both oxidative stress and embryonic gene expression, thus preserving cardiac function in CM hamsters. In conclusion, IH accelerated LV remodeling in CM hamsters, at least partly by increasing oxidative stress in the failing heart. These findings might explain the poor prognosis of patients with HF and sleep apnea.

DEND syndrome due to V59A mutation in KCNJ11 gene: unresponsive to sulfonylureas.

Heterozygous activating mutations of KCNJ11 (Kir6.2) are the most common cause of permanent neonatal diabetes mellitus (NDM), and successful glycemic control has been obtained in several cases with oral sulfonylureas (SU). We have verified a lack of clinical response for both glycemic control and neurological features in an infant with permanent neonatal diabetes mellitus and DEND syndrome due to a V59A mutation in the KCNJ11 gene. Thus, our case reinforces that most cases with DEND syndrome are insensitive to SU.

Kre6 (yeast 1,6-ß-transglycosylase) homolog, PhTGS, is essential for ß-glucan synthesis in the haptophyte Pleurochrysis haptonemofera.

Haptophytes synthesize unique ß-glucans containing more ß-1,6-linkages than ß-1,3 linkages, as a storage polysaccharide. To understand the mechanism of the synthesis, we investigated the roles of Kre6 (yeast 1,6-ß-transglycosylase) homologs, PhTGS, in the haptophyte Pleurochrysis haptonemofera. RNAi of PhTGS repressed ß-glucan accumulation and simultaneously induced lipid production, suggesting that PhTGS is involved in ß-glucan synthesis and that the knockdown leads to the alteration of the carbon metabolic flow. PhTGS was expressed more in light, where ß-glucan was actively produced by photosynthesis, than in the dark. The crude extract of E. coli expressing PhKre6 demonstrated its activity to incorporate 14C-UDP-glucose into ß-glucan of P. haptonemofera. These findings suggest that PhTGS functions in storage ß-glucan synthesis specifically in light, probably by producing the ß-1,6-branch.

Impact of bystander cardiopulmonary resuscitation on neurological outcomes in patients undergoing veno-arterial extracorporeal membrane oxygenation.

BACKGROUND: Veno-arterial extracorporeal membrane oxygenation (V-A ECMO) requires a large amount of economic and human resources. The presence of bystander cardiopulmonary resuscitation (CPR) was focused on selecting appropriate V-A ECMO candidates. RESULT: This study retrospectively enrolled 39 patients with V-A ECMO due to out-of-hospital cardiac arrest (CA) between January 2010 and March 2019. The introduction criteria of V-A ECMO included the following: (1) < 75 years old, (2) CA on arrival, (3) < 40 min from CA to hospital arrival, (4) shockable rhythm, and (5) good activity of daily living (ADL). The prescribed introduction criteria were not met by 14 patients, but they were introduced to V-A ECMO at the discretion of their attending physicians and were also included in the analysis. Neurological prognosis at discharge was defined using The Glasgow-Pittsburgh Cerebral Performance and Overall Performance Categories of Brain Function (CPC). Patients were divided into good or poor neurological prognosis (CPC ≤ 2 or ≥ 3) groups (8 vs. 31 patients). The good prognosis group had a significantly larger number of patients who received bystander CPR (p = 0.04). The mean CPC at discharge was compared based on the combination with the presence of bystander CPR and all five original criteria. Patients who received bystander CPR and met all original five criteria showed significantly better CPC than patients who did not receive bystander CPR and did not meet some of the original five criteria (p = 0.046). CONCLUSION: Considering the presence of bystander CPR help in selecting the appropriate candidate of V-A ECMO among out-of-hospital CA cases.

Poor Nutritional Status during Recovery from Acute Myocardial Infarction in Patients without an Early Nutritional Intervention Predicts a Poor Prognosis: A Single-Center Retrospective Study.

Whether malnutrition during the early phase of recovery from acute myocardial infarction (AMI) could be a predictor of mortality or morbidity has not been ascertained. We examined 289 AMI patients. All-cause mortality and composite endpoints (all-cause mortality, nonfatal stroke, nonfatal acute coronary syndrome, and hospitalization for acute decompensated heart failure) during the follow-up duration (median 39 months) were evaluated. There were 108 (37.8%) malnourished patients with GNRIs of less than 98 on arrival; however, malnourished patients significantly decreased to 91 (31.4%) during the convalescence period (p < 0.01). The incidence rates of mortality and primary composite endpoints were significantly higher in the malnourished group than in the well-nourished group both on arrival and during the convalescence period (All p < 0.05). Nutrition guidance significantly improved GNRI in a group of patients who were undernourished (94.7 vs. 91.0, p < 0.01). Malnourished patients on admission who received nutritional guidance showed similar all-cause mortality with well-nourished patients, whereas malnourished patients without receiving nutritional guidance demonstrated significantly worse compared to the others (p = 0.03). The assessment of GNRI during the convalescence period is a useful risk predictor for patients with AMI. Nutritional guidance may improve the prognoses of patients with poor nutritional status.

mCRP as a Biomarker of Adult-Onset Still's Disease: Quantification of mCRP by ELISA.

Background: C-reactive protein (CRP) is a dynamic protein that undergoes conformational changes between circulating native pentameric CRP (pCRP), pentameric symmetrical forms (pCRP*) and monomeric (or modified) CRP (mCRP) forms. mCRP exhibits strong pro-inflammatory activity and activates platelets, leukocytes, and endothelial cells. Abundant deposition of mCRP in inflamed tissues plays a role in several disease conditions, such as ischemia/reperfusion injury, Alzheimer's disease, and cardiovascular disease. Although pCRP is typically quantified rather than mCRP for clinical purposes, mCRP may be a more appropriate disease marker of inflammatory diseases. Therefore, simple methods for quantifying mCRP are needed. Methods: We developed a specific enzyme-linked immunosorbent assay (ELISA) to measure plasma levels of mCRP. Plasma mCRP concentration was measured in patients with adult-onset Still's disease (AOSD) (n=20), polymyalgia rheumatica (PMR) (n=20), rheumatoid arthritis (RA) (n=30), infection (n=50), and in control subjects (n=30) using the developed ELISA. Results: We demonstrated that mCRP is elevated in some inflammatory autoimmune diseases, particularly AOSD. The mCRP concentration was also significantly higher among AOSD patients than RA, PMR patients and controls (477 ng/ml, 77 ng/ml, 186 ng/ml, and 1.2 ng/ml, respectively). Also, the mCRP (×1,000)/pCRP ratio was significantly higher among AOSD patients than RA, PMR, and infection patients (3.5, 0.6, 1,6, and 2.0, respectively). Conclusion: The plasma mCRP levels are elevated in some autoimmune diseases, particularly AOSD. The plasma mCRP levels may therefore be a potentially useful biomarker for AOSD.

Adiponectin, ALT and family history as critical markers for the development of type 2 diabetes in obese Japanese children.

Aims/Introduction: An association between the pathogenesis of type 2 diabetes mellitus (T2D) and that of metabolic syndrome (MS) in obese children has been suggested. We clarified the critical markers for the development of T2D in obese Japanese children. Methods: One hundred and seven obese children who visited our outpatient clinic were enrolled in this study. The obese subjects were divided into 3 groups: Group A, T2D (n = 19); Group B, MS but not T2D (n = 19); and Group C: non-T2D, non-MS (n = 69). In all the subjects, a biochemical examination was performed and the serum adiponectin and leptin levels were measured. Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were measured using computed tomography images. Results: Group A tended to have higher VAT values and VAT/SAT ratios and lower leptin and adiponectin levels, compared with Groups B and C. In Group A, the alanine aminotransferase (ALT) level was significantly higher and the aspartate aminotransferase (AST)/ALT ratio was significantly lower than in Group C. A receiver operating characteristic (ROC) analysis showed that the optimal cut-off point for adiponectin was 6.4 µg/mL (AUC = 0.859). The cut-off points for ALT, the AST/ALT ratio and VAT were 35 IU/L (AUC = 0.821), 0.85 (AUC = 0.794) and 78 cm2 (AUC = 0.713), respectively. Group A had a significantly higher frequency of a family history of T2D than Group B. Conclusions: Our study revealed that the adiponectin level, ALT level, AST/ALT ratio, VAT value and a family history of T2D may be critical characteristic markers for T2D among obese Japanese children.

Styrene Maleic Acid Copolymer-Based Micellar Formation of Temoporfin (SMA@ mTHPC) Behaves as A Nanoprobe for Tumor-Targeted Photodynamic Therapy with A Superior Safety.

Tumor-targeted photodynamic therapy (PDT) using polymeric photosensitizers is a promising anticancer therapeutic strategy. Previously, we developed several polymeric nanoprobes for PDT using different polymers and PDT agents. In the study, we synthesized a styrene maleic acid copolymer (SMA) micelle encapsulating temoporfin (mTHPC) that is a clinically used PDT drug, SMA@mTHPC, with a hydrodynamic size of 98 nm, which showed high water solubility. SMA@mTHPC maintained stable micelle formation in physiological aqueous solutions including serum; however, the micelles could be disrupted in the presence of detergent (e.g., Tween 20) as well as lecithin, the major component of cell membrane, suggesting micelles will be destroyed and free mTHPC will be released during intracellular uptake. SMA@mTHPC showed a pH-dependent release profile, for which a constant release of ≈20% per day was found at pH 7.4, and much more release occurred at acidic pH (e.g., 6.5, 5.5), suggesting extensive release of free mTHPC could occur in the weak acidic environment of a tumor and further during internalization into tumor cells. In vitro cytotoxicity assay showed a lower cytotoxicity of SMA@mTHPC than free mTHPC; however, similar in vivo antitumor effects were observed by both SMA@mTHPC and free THPC. More importantly, severe side effects (e.g., body weight loss, death of the mice) were found during free mTHPC treatment, whereas no apparent side effects were observed for SMA@mTHPC. The superior safety profile of SMA@mTHPC was mostly due to its micelle formation and the enhanced permeability and retention (EPR) effect-based tumor accumulation, as well as the tumor environment-responsive release properties. These findings suggested SMA@mTHPC may become a good candidate drug for targeted PDT with high safety.

Co-precipitation behaviour of single atoms of rutherfordium in basic solutions.

All superheavy elements (SHEs), with atomic numbers (Z) ≥104, have been artificially synthesized one atom at a time and their chemical properties are largely unknown. Because these heavy nuclei have short lifetimes as well as extremely low production rates, chemical experiments need to be carried out on single atoms and have mostly been limited to adsorption and extraction. We have now investigated the precipitation properties of the SHE Rf (Z = 104). A co-precipitation method with samarium hydroxide had previously established that the co-precipitation behaviour of a range of elements reflected these elements' tendency to form hydroxide precipitates and/or ammine complex ions. Here we investigated co-precipitation of Rf in basic solutions containing NH3 or NaOH. Comparisons between the behaviour of Rf with that of Zr and Hf (lighter homologues of Rf) and actinide Th (a pseudo-homologue of Rf) showed that Rf does not coordinate strongly with NH3, but forms a hydroxide (co)precipitate that is expected to be Rf(OH)4.

Correlation between drug dissolution and resistance to water-induced phase separation in solid dispersion formulations revealed by solid-state NMR spectroscopy.

We aimed to elucidate the dissolution mechanism of solid dispersions (SDs) according to the carrier polymers used. Nifedipine (NIF) and polymers dissolved simultaneously from NIF/Eudragit® S (EUD-S), NIF/Eudragit® L (EUD-L), and NIF/hypromellose (HPMC)/EUD-S spray-dried samples (SPDs). In contrast, NIF dissolved separately from polymers from NIF/HPMC and NIF/HPMC/EUD-L SPDs due to the formation of an amorphous NIF-rich interface. Solid-state NMR spectroscopy indicated that NIF-EUD interactions were stronger than NIF-HPMC interactions. NIF/HPMC SPD exhibited weak interactions; thus, it failed to inhibit phase separation during the dissolution process and control NIF dissolution. The hygroscopicity of SPDs was higher with HPMC mixing and increased substitution ratio of methacrylic acid in EUD. Moreover, solid-state NMR spectroscopy revealed that the NIF-EUD interactions were hindered to a large extent by the absorbed water. During the dissolution process of NIF/HPMC/EUD-L SPD, the introduction of water to the NIF-EUD-L interaction site could induce the phase separation and poor controllability of NIF dissolution. Water-induced phase separation should be considered based on molecular-level characterization to obtain SDs with enhanced drug dissolution. An investigation of the molecular state change caused by the absorbed water using solid-state NMR spectroscopy will be helpful in understanding the dissolution mechanism of SDs.

Heart Failure with Hyperthyroidism Demonstrating Discrepancy between the Clinical Course and B-type Natriuretic Peptide Levels.

A 35-year-old Japanese man was emergently admitted to our hospital with chief complaints of palpitation and dyspnea. He has been treated for Basedow's disease. He was diagnosed with acute decompensated heart failure, atrial fibrillation and thyrotoxicosis. We started anti-thyroid agents and a treatment for heart failure with beta blockers and diuretics under anti-coagulation therapy. His B-type natriuretic peptide levels remained high, although the heart failure had been compensated and the heart rate was well controlled while hyperthyroidism still existed. We should bear in mind that a discrepancy can exist between the clinical course and the B-type natriuretic peptide level in heart failure patients complicated with hyperthyroidism.

Observation of the chemical reaction equilibria of element 104, rutherfordium: solid-liquid extraction of Rf, Zr, Hf and Th with Aliquat 336 resin from HCl.

We successfully observed the equilibrium state of the chemical reactions for superheavy elements on a one-atom-at-a-time scale; we investigated the time dependence of the extraction behaviour of element 104, Rf. The distribution coefficient of Rf in 9 M HCl was found to be higher than those of its homologous elements, probably due to differences in the chloride complexation of Rf.

Structural investigation of spherical hollow excipient Mannit Q by X-ray microtomography.

The structure of Mannit Q particles, an excipient made by spray-drying a d-mannitol solution, and Mannit Q tablets were investigated by synchrotron X-ray microtomography. The Mannit Q particles had a spherical shape with a hollow core. The shells of the particles consisted of fine needle-shaped crystals, and columnar crystals were present in the hollows. These structural features suggested the following formation mechanism for the hollow particles:during the spray-drying process, the solvent rapidly evaporated from the droplet surface, resulting in the formation of shells made of fine needle-shaped crystals.Solvent remaining inside the shells then evaporated slowly and larger columnar crystals grew as the hollows formed. Although most of the Mannit Q particles were crushed on tableting, some of the particles retained their hollow structures, probably because the columnar crystals inside the hollows functioned as props. This demonstrated that the tablets with porous void spaces may be readily manufactured using Mannit Q.