Transfusion-associated circulatory overload and high blood pressure: A multicentre retrospective study in Japan.

BACKGROUND: Transfusion-associated circulatory overload (TACO) is an adverse reaction associated with a high risk of mortality. The actual incidence of TACO and hypertension associated with transfusion in Japan is unknown. METHODS: A multicentre retrospective observational study was conducted across 23 institutions during the 1-year period of 2016. Patients were included if they developed TACO or their blood pressure (either systolic or diastolic) increased by at least 30 mmHg during the transfusion. TACO was confirmed by the primary physicians and transfusion medicine teams and recorded in the data on passive surveillance, and additional data were extracted from electronic medical records. RESULTS: In our patient cohort of 31 384 patients who underwent transfusion, the incidence of TACO and hypertension was 0·03% and 0·2%, respectively. However, 43% of the participating institutions didn't report any cases. When comparing risk factors between the TACO and hypertension groups, there were significant differences in comorbidities, such as abnormal findings on chest x-ray. Significant differences between the two groups were observed post-transfusion pulse rate, body temperature and oxygen saturation (P < 0·01). In the group of patients with hypertension, the level of BNP increased significantly after transfusion in 45% (5/11) of the patients. We identified 4 patients in the hypertension group who met the new ISBT's TACO criteria. CONCLUSION: Our study suggests that more attention should be given to TACO in Japan, particularly in terms of improving surveillance systems. For the early diagnosis of TACO, it is crucial to carefully monitor vital signs including blood pressure.

Discovery of clinical candidate Sivopixant (S-600918): Lead optimization of dioxotriazine derivatives as selective P2X3 receptor antagonists.

In previous work, we discovered a lead compound and conducted initial SAR studies on a novel series of dioxotriazines to identify the compound as one of the P2X3 receptor antagonists. This compound showed high P2X3 receptor selectivity and a strong analgesic effect. Although not selected for clinical development, the compound was evaluated from various aspects as a tool compound. In the course of the following study, the molecular structures of the dioxotriazines were modified based on pharmacokinetic/pharmacodynamic (PK/PD) analyses. As a result of these SAR studies, Sivopixant (S-600918) was identified as a clinical candidate with potent and selective antagonistic activity (P2X3 IC50, 4.2 nM; P2X2/3 IC50, 1100 nM) and a strong analgesic effect in the rat partial sciatic nerve ligation model (Seltzer model) of allodynia (ED50, 0.4 mg/kg).

Reduction in adverse transfusion reactions with increased use of washed platelet concentrates in Japan-A retrospective multicenter study.

Plasma removal by washing platelet concentrates (PCs) is effective in preventing adverse reactions to PC transfusions. The Japanese Red Cross Society (JRCS) started releasing washed PCs (WPCs) as a commercially approved blood product in September 2016. This retrospective multicenter study investigated the change in the number of transfused WPCs and the impact on the incidence of adverse reactions to PCs before and after the release. The numbers and types of transfused PCs and the adverse reactions to the PCs for a year before the start of the WPC release and for a year after the release were reported by 27 medical institutes in Japan. Transfusion information for approximately 8% of the amount of PCs supplied in Japan was analyzed during the study period. After the start of WPC release by the JRCS, the number of transfused WPCs doubled. The rate of adverse reactions to PCs decreased significantly (p = 0.0223), from 4.30% before the release to 4.05% after the release. The rates of adverse reactions to unwashed and WPCs were 4.13% and 0.84%, respectively. Allergic adverse reactions were significantly decreased after the release (3.60% before versus 3.37% after). No severe allergic reactions to WPCs were reported. The release of WPCs by the JRCS significantly reduced transfusion-related adverse reactions to PCs in Japan.

Hypoxic preconditioning reinforces cellular functions of autologous peripheral blood-derived cells in rabbit hindlimb ischemia model.

Peripheral blood mononuclear cell (PBMNC) is one of powerful tools for therapeutic angiogenesis in hindlimb ischemia. However, traditional approaches with transplanted PBMNCs show poor therapeutic effects in severe ischemia patients. In this study, we used autograft models to determine whether hypoxic pretreatment effectively enhances the cellular functions of PBMNCs and improves hindlimb ischemia. Rabbit PBMNCs were cultured in the hypoxic condition. After pretreatment, cell adhesion, stress resistance, and expression of angiogenic factor were evaluated in vitro. To examine in vivo effects, we autografted preconditioned PBMNCs into a rabbit hindlimb ischemia model on postoperative day (POD) 7. Preconditioned PBMNCs displayed significantly enhanced functional capacities in resistance to oxidative stress, cell viability, and production of vascular endothelial growth factor. In addition, autologous transplantation of preconditioned PBMNCs significantly induced new vessels and improved limb blood flow. Importantly, preconditioned PBMNCs can accelerate vessel formation despite transplantation on POD 7, whereas untreated PBMNCs showed poor vascularization. Our study demonstrated that hypoxic preconditioning of PBMNCs is a feasible approach for increasing the retention of transplanted cells and enhancing therapeutic angiogenesis in ischemic tissue.

Online reporting system for transfusion-related adverse events to enhance recipient haemovigilance in Japan: a pilot study.

BACKGROUND: A surveillance system for transfusion-related adverse reactions and infectious diseases in Japan was started at a national level in 1993, but current reporting of events in recipients is performed on a voluntary basis. A reporting system which can collect information on all transfusion-related events in recipients is required in Japan. METHODS: We have developed an online reporting system for transfusion-related events and performed a pilot study in 12 hospitals from 2007 to 2010. RESULTS: The overall incidence of adverse events per transfusion bag was 1.47%. Platelet concentrates gave rise to statistically more adverse events (4.16%) than red blood cells (0.66%) and fresh-frozen plasma (0.93%). In addition, we found that the incidence of adverse events varied between hospitals according to their size and patient characteristics. CONCLUSION: This online reporting system is useful for collection and analysis of actual adverse events in recipients of blood transfusions and may contribute to enhancement of the existing surveillance system for recipients in Japan.

Discovery of S-444823, a potent CB1/CB2 dual agonist as an antipruritic agent.

The optimization of a series of 3-carbamoyl 2-pyridone derivatives as CB agonists is reported. These efforts resulted in the discovery of 3-(2-(1-(cyclohexylmethyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocycloocta[b]pyridine-3-carboxamido)thiazol-4-yl)propanoic acid (21), a potent dual CB1/CB2 agonist without CNS side effects induced by CB1 receptor activation. It exhibited strong inhibition of scratching as a 1.0% acetone solution in the pruritic model.

Discovery of S-777469: an orally available CB2 agonist as an antipruritic agent.

The discovery of novel CB2 ligands based on the 3-carbamoyl-2-pyridone derivatives by adjusting the size of side chain at 1-, 5- and 6-position is reported. The structure-activity relationship around this template lead to the identification of S-777469 as a selective CB2 receptor agonist, which exhibited the significant inhibition of scratching induced by Compound 48/80 at 1.0 mg/kg po and 10 mg/kg po (55% and 61%, respectively).

CB 1/2 dual agonists with 3-carbamoyl 2-pyridone derivatives as antipruritics: reduction of CNS side effects by introducing polar functional groups.

Our lead compound 1 showed high affinity for both CB1 and CB2 receptors, suggesting the possibility of inducing psychoactive side effects through the CB1 receptor in the brain. To solve this issue, polar functional groups were introduced at the 3-position of the pyridone core of compound 1 to find CB1/2 dual agonists such as 17 and 20 which did not show any CNS side effects.

Hematopoietic progenitor cell count, but not immature platelet fraction value, predicts successful harvest of autologous peripheral blood stem cells.

Mobilized stem cells in the peripheral blood (PB) must be efficiently harvested at the appropriate time before autologous PB stem cell (PBSC) transplantation. Enumeration of CD34+ cells in the PB before apheresis predicts the number of PBSCs that can be collected, but the cytometric techniques used are complex and expensive. Therefore, it is necessary to identify an alternative to the CD34+ cell count in PBSC harvest-time monitoring. Fully automated flow cytometry using blood cell counters now allows reliable quantification of immature myeloid cells in the PB, referred to as hematopoietic progenitor cells (HPC), and reticulated platelets, expressed as the immature platelet fraction (IPF). Immature or reticulated platelets are thought to correlate with thrombopoietic activity of the marrow. Following a chemotherapy nadir, the recovery of white blood cell and platelet counts has been used to determine the right time for apheresis. Therefore, we examined whether the HPC count and IPF value could be used to predict PBSC mobilization in 20 patients with hematological malignancies. The HPC count was found to be correlated with the CD34+ cell count (r = 0.84, P < 0.01), whereas the IPF value was not (r = 0.37, P = 0.44). Therefore, the HPC count, but not the IPF value, is a possible predictor of the timing of autologous stem cell transplantation.

[Prevention of ABO-incompatible transfusion].

"Identification error between patient and blood product" is the main cause of ABO-incompatible blood transfusion, but "Phlebotomy error" also has serious consequences. In order to prevent ABO-incompatible transfusion, it is important to establish a management system of blood transfusion in the hospital, including a hospital transfusion committee and a responsible medical doctor. In addition, in large hospitals routinely carrying out a considerable number of blood transfusions, it is important to employ specialists in blood banking. More than 50 ml of ABO-incompatible blood transfusion (major ABO mismatch) causes a severe acute hemolytic reaction. Because there is little residual plasma in leukocyte-reduced red cell concentrate (RCC-LR), acute hemolysis is not detected on minor ABO mismatch blood transfusion. In the case of emergent blood transfusion, concerning the risk of acute hemolytic reaction, type-O RCC-LR blood transfusion is safer than ABO-identical RCC-LR when the blood of the patient is tested only once. When red cell antibody screening is not performed, there is a risk of hemolysis due to incompatible blood transfusion irrespective of the ABO blood group system, including a delayed hemolytic transfusion reaction.

Ligand effect on uranium isotope fractionations caused by nuclear volume effects: An ab initio relativistic molecular orbital study.

We have calculated the nuclear volume term (ln K(nv)) of the isotope fractionation coefficient (epsilon) between (235)U-(238)U isotope pairs by considering the effect of ligand coordination in a U(IV)-U(VI) reaction system. The reactants were modeled as [UO(2)Cl(3)](-) and [UO(2)Cl(4)](2-) for U(VI), and UCl(4) for U(IV). We adopted the Dirac-Coulomb Hartree-Fock method with the Gaussian-type finite nucleus model. The result obtained was ln K(nv)=0.001 90 at 308 K, while the experimentally estimated value of ln K(nv) is 0.002 24. We also discuss how the ligand affects the value of ln K(nv), especially for the various structures of different compounds, and different ligands within the halogen ion series (F, Cl, and Br).

Chromatographic Zinc Isotope Separation by Chelating Exchange Resin.

Zinc isotope separations were studied by displacement chromatography using the chelating properties of malate, citrate and lactate exchange resin and EDTA as ligands. After each chromatographic operation, the heavier zinc isotopes were found to preferentially fractionated into the carboxylate complex solution phase. The separation coefficients (epsilon) for zinc isotope separation had the largest value and were obtained for the isotopic pairs (68)Zn/(64)Zn (7.16 x 10(-4)) and (66)Zn/(64)Zn (3.08 x 10(-4)), respectively, at 298 +/- 1 K. The separation coefficient per unit mass differences (epsilon/DeltaM) for the isotopic pair of (68)Zn/(64)Zn was found to range around 1.55 x 10(-4).

High enrichment of 15N by chromatographic chemical process.

Nitrogen isotope enrichment experiments were conducted to obtain highly enriched (15)N by ion-exchange process. (15)NH(4)Cl ((15)N=80%) as feeding materials were used to perform the chromatographic operation with two different flow rates and column diameters. Both separation coefficient (epsilon) and height equivalent to a theoretical plate (HETP) have same values in two run experiments. The value of HETP was more enlarged when high enrichment of (15)N was obtained in comparison with that of low enrichment. 99.756% (15)N and 13.63 g (15)N whose percentage was over 99.0% were successfully achieved by 25 m chromatographic migration with the flow rate and column diameter at 50 cm(3)/mL, 3.0 cm, respectively. High flow rate and large column diameter have advantages to the enrichment of (15)N by ion exchange process.

An ab initio molecular orbital study of the nuclear volume effects in uranium isotope fractionations.

This paper discusses the nuclear volume dependence of uranium isotope fractionations in the U(3+)-U(4+) and U(4+)-UO(2) (2+) systems by reference to a series of ab initio molecular orbital calculations. Nuclear volume-dependent terms ( identical withln K(nv)) in isotope fractionation coefficients ( identical withepsilon) are calculated from the energetic balance of the isotopomers involved in the systems. We used the Dirac-Coulomb Hartree-Fock (DCHF) method with the Gaussian-type finite-nucleus model. We employed three types of generally contracted Gaussian basis sets to check the basis set dependences. In the U(3+)-U(4+) system, the present values of ln K(nv) for uranium, other than those with the smallest double-zeta basis set, are in good agreement with previous values of ln K(nv) obtained from a numerical atomic multiconfigurational DCHF method with the Fermi-type finite-nucleus model. The present calculations reasonably reproduce the experimental value of epsilon in the U(3+)-U(4+) system, and the value of ln K(nv) in the U(4+)-UO(2) (2+) system, obtained empirically by temperature-dependent fitting of the experimental epsilon values. For instance, in the U(4+)-UO(2) (2+) system, the present ab initio ln K(nv) value for a (235)U-(238)U isotope pair is 0.002 09 using the largest basis set, while the experimental value is 0.002 24. This paper also shows that nuclear volume effects are negligibly small on the U-O bond length and two force constants of UO(2) (2+). Hence, the molecular vibrational terms of the isotope fractionation coefficients mainly depend on the nuclear mass rather than the nuclear volume.

Chromatographic zinc isotope separation by phenol formaldehyde benzo crown resin.

New types of phenol formaldehyde resin having benzo crown as a functional group were synthesized and applied to zinc isotope chromatographic operation. Zinc adsorption and isotope separation capacities were dramatically improved by using phenol formaldehyde benzo-15-crown-5 resin. Zinc batch adsorption tests were performed by various dehydrated organic solvents. Separation coefficient, epsilon 8.1 x 10(-4) and height equivalent to a theoretical plate (HETP) 0.105 cm for the isotopic pair of 68Zn/64Zn in phenol formaldehyde benzo-15-crown-5 resin were obtained in the case of acetone as the solvent at 298+/-1K.

Cerium isotope effects in Ce(III) malate and lactate complex formation studied by long-distance displacement chromatography.

Isotope effects of cerium were observed in malate and lactate complex formations during the long-distance displacement chromatographic processes at 313 K. Heavier isotopes were found fractionated in the frontal edges of the Ce adsorption bands in both the systems, registering a preference of the heavier isotopes for the Ce(III) complexes in the solution phase over the simply hydrated Ce(III) ions in the resin phase. The fractionation coefficients epsilon for the 136Ce/140Ce, 138Ce/140Ce and 142Ce/140Ce isotopic pairs were 7.1 x 10(-6), 5.2 x 10(-6) and -2.1 x 10(-6) for the malate system, and 4.8 x 10(-6), 4.5 x 10(-6) and-2.6 x 10(-6) for the lactate system, respectively. They all show the mass-dependent law if the deviation of epsilon for the 138Ce/140Ce pair was considered merely due to the isobaric interference in Ce isotopic ratio measurements, suggesting the molecular vibration, rather than the nuclear field shift, mainly contributes to the Ce isotope effects in the complex formation systems. The absolute values of epsilon between the two systems are comparable, suggesting no instinct difference in structural properties between Ce malate and lactate complexes involved.

Observation of cerium isotope fractionation in ion-exchange chromatography of Ce(III)-malate complex.

The cerium isotope fractionation between Ce(III)-malate complex in aqueous solution and cerium ions in a cation-exchange resin was conducted by displacement chromatography. The pH and the chemical composition of the eluent were optimized for maintaining the self-sharpening band boundaries and the 21 m chromatographic migration of the Ce band underwent. Graphite slurry was coated on the tantalum filament prior to sample loading for reducing the isobaric interferences in cerium isotopic ratio determination by mass spectrometry. From the experimental results, it was found that the heavier isotope was enriched in the front boundary part of the cerium adsorption band, which meant that the heavier isotope was preferentially fractionated into the Ce3+ malate complex rather than simply hydrated Ce3+ ions. The isotope separation coefficient for the 136Ce/140Ce and 142Ce/140Ce was 5.2 x 10(-5) and -1.9 x 10(-5), respectively, at 298 K.

Separation of calcium-48 isotope by crown ether chromatography using ethanol/hydrochloric acid mixed solvent.

Benzo-18-crown-6 ether resin embedded in porous silica beads was synthesized and used as the packing material for chromatographic separation of (48)Ca isotope. The aim of the present work is to develop efficient isotope enrichment process for double ß decay nuclide (48)Ca. To this end, ethanol/HCl mixed solvent was selected as the medium for the chromatographic separation. Adsorption of calcium on the resin was studied at different HCl concentrations and different ethanol mixing ratios in batch-wise experiments. A very interesting phenomenon was observed; Ca adsorption is controlled not by the overall HCl concentration of the mixed solvent, but by the initial concentration of added HCl solution. Calcium break-through chromatography experiments were conducted by using 75v/v% ethanol/25v/v% 8M HCl mixed solvent at different flow rates. The isotope separation coefficient between (48)Ca and (40)Ca was determined as 3.8×10(-3), which is larger than that of pure HCl solution system. Discussion is extended to the chromatographic HETP, height equivalent to a theoretical plate.

Separation of vanadium isotopes by ion-exchange chromatography.

Cation-exchange displacement chromatography of VO2+ was carried out for studying vanadium isotope effects in carboxylate ligand-exchange systems. The heavier isotope 51V was enriched in the carboxylate complex solution. The isotope separation coefficients epsilon(= alpha-1) for 50V/51V were 2.2 x 10(-4) and 2.4 x 10(-4) for citrate and lactate systems at 298 K, respectively. These values are much larger than those obtained in a previous study on the malate system. The existence of binuclear complexes of VO2+ may create the conditions for larger isotope fractionation. From the viewpoint of the process development of isotope separation, the heights equivalent to a theoretical plate of these processes were analyzed and found to be very small in each system due to the homogeneous, small and highly porous resin used. Citrate may be better than the other tested systems for the vanadium isotope separation.

Effect of alcohols on elution chromatography of trivalent actinides and lanthanides using tertiary pyridine resin with hydrochloric acid-alcohol mixed solvents.

Elution chromatography with a tertiary pyridine resin has been used to separate the trivalent actinides (An3+) from the lanthanides (Ln3+) using an alcoholic hydrochloric acid solvent. Trivalent Am and Cm were separated from the Ln by employing a 1 cm(phi) x 10 cm resin column with the mixed solvent system composed of concentrated hydrochloric acid (HCl) and alcohols. The distribution coefficients (Kd) and the separation factors between An and Ln (alpha(An)(Ln)) increased as the alcohol content of the solvent mixture increased. On the other hand, the Kd and alpha(An)(Ln) decreased drastically upon the addition of water to the solvent mixture. Among the four alcohols investigated (methanol, ethanol, n-propanol and n-butanol), the ethanol-HCl mixed solvent system showed the largest Kd and alpha(An)(Ln). The mechanism of adsorption for An and Ln cations on the pyridine resin is discussed in addition to the results presented herein.