Probable effects of polypharmacy and equivalent doses of psychotropic drugs on prevalence of adverse drug events among psychiatric inpatients in a general hospital in Japan.

OBJECTIVE: In psychiatry, polypharmacy or high psychotropic drug doses increase adverse drug event (ADE) prevalence. However, the full relationship between polypharmacy and ADEs is unclear, and few studies have evaluated dose equivalents for psychotropic drugs for ADEs. Thus, we conducted a retrospective analysis to clarify the effects of polypharmacy and chlorpromazine (CP)-, diazepam (DAP)-, and imipramine- equivalent doses on all ADEs in inpatients. METHODS: Psychiatric inpatients in a Japanese hospital from April 1, 2016 to March 31, 2018, were enrolled. ADE severity and causality were assessed. Multiple logistic regression analyses were performed to evaluate ADE risk factors. RESULTS: Among 462 patients analyzed, out of 471 patients enrolled, 145 (31.4%) experienced ADEs. The causality assessment determined that "possible" was 96.5%. The most common ADEs were nervous system disorders (35%). Multiple logistic regression analyses indicated an increase in ADE prevalence with the number of drugs used (≥5; p = 0.026); CP-equivalent dose (p = 0.048); and endocrine, nutritional, and metabolic disorders (p = 0.045). DAP-equivalent dose; infectious and parasitic diseases; and injury, poisoning, and consequences of other external causes decreased ADE prevalence (p = 0.047, 0.022, and 0.021, respectively). CONCLUSIONS: Avoiding polypharmacy in psychiatric inpatients and adjusting drug regimens to safe equivalent doses could reduce ADEs during hospitalization.

Verification of the "Upward Variation in the Reporting Odds Ratio Scores" to Detect the Signals of Drug-Drug Interactions.

The reporting odds ratio (ROR) is easy to calculate, and there have been several examples of its use because of its potential to speed up the detection of drug-drug interaction signals by using the "upward variation of ROR score". However, since the validity of the detection method is unknown, this study followed previous studies to investigate the detection trend. The statistics models (the Ω shrinkage measure and the "upward variation of ROR score") were compared using the verification dataset created from the Japanese Adverse Drug Event Report database (JADER). The drugs registered as "suspect drugs" in the verification dataset were considered as the drugs to be investigated, and the target adverse event in this study was Stevens-Johnson syndrome (SJS), as in previous studies. Of 3924 pairs that reported SJS, the number of positive signals detected by the Ω shrinkage measure and the "upward variation of ROR score" (Model 1, the Susuta Model, and Model 2) was 712, 2112, 1758, and 637, respectively. Furthermore, 1239 positive signals were detected when the Haldane-Anscombe 1/2 correction was applied to Model 2, the statistical model that showed the most conservative detection trend. This result indicated the instability of the positive signal detected in Model 2. The ROR scores based on the frequency-based statistics are easily inflated; thus, the use of the "upward variation of ROR scores" to search for drug-drug interaction signals increases the likelihood of false-positive signal detection. Consequently, the active use of the "upward variation of ROR scores" is not recommended, despite the existence of the Ω shrinkage measure, which shows a conservative detection trend.

Improved Detection Criteria for Detecting Drug-Drug Interaction Signals Using the Proportional Reporting Ratio.

There is a current demand for "safety signal" screening, not only for single drugs but also for drug-drug interactions. The detection of drug-drug interaction signals using the proportional reporting ratio (PRR) has been reported, such as through using the combination risk ratio (CRR). However, the CRR does not consider the overlap between the lower limit of the 95% confidence interval of the PRR of concomitant-use drugs and the upper limit of the 95% confidence interval of the PRR of single drugs. In this study, we proposed the concomitant signal score (CSS), with the improved detection criteria, to overcome the issues associated with the CRR. "Hypothetical" true data were generated through a combination of signals detected using three detection algorithms. The signal detection accuracy of the analytical model under investigation was verified using machine learning indicators. The CSS presented improved signal detection when the number of reports was ≥3, with respect to the following metrics: accuracy (CRR: 0.752 → CSS: 0.817), Youden's index (CRR: 0.555 → CSS: 0.661), and F-measure (CRR: 0.780 → CSS: 0.820). The proposed model significantly improved the accuracy of signal detection for drug-drug interactions using the PRR.

Variation of strontium stable isotope ratios and origins of strontium in Japanese vegetables and comparison with Chinese vegetables.

To evaluate the utility of 87Sr/86Sr ratio for determining the geographical provenance of vegetables, we compared 87Sr/86Sr ratios and Sr concentrations in five vegetable species grown in Japan and China, and we also examined the relationships between 87Sr/86Sr ratios in vegetables, the soil-exchangeable pool, irrigation water, and fertilizer from 20 Japanese agricultural areas. The vegetable 87Sr/86Sr ratios in Japan were similar for all species within a given agricultural area, but tended to be low in northeast Japan and high in southwest Japan. The median 87Sr/86Sr ratio in Japanese vegetables was similar to that in fertilizer, suggesting that in addition to rock-derived Sr, vegetables contain Sr derived from fertilizers. In most cases, the 87Sr/86Sr ratios for the Japanese and Chinese vegetables differed by approximately 0.710. Linear discriminant analysis using both 87Sr/86Sr and the Sr concentration allowed more accurate discrimination between vegetables from the two countries.

Tracing the Geographical Origin of Onions by Strontium Isotope Ratio and Strontium Content.

The strontium (Sr) isotope ratio ((87)Sr/(86)Sr) and Sr content were used to trace the geographical origin of onions from Japan and other countries, including China, the United States of America, New Zealand, Australia, and Thailand. The mean (87)Sr/(86)Sr ratio and Sr content (dry weight basis) for onions from Japan were 0.70751 and 4.6 mg kg(-1), respectively, and the values for onions from the other countries were 0.71199 and 12.4 mg kg(-1), respectively. Linear discriminant analysis was performed to classify onions produced in Japan from those produced in the other countries based on the Sr data. The discriminant equation derived from linear discriminant analysis was evaluated by 10-fold cross validation. As a result, the origins of 92% of onions were correctly classified between Japan and the other countries.

[Determination of gossypol in feeds by HPLC].

An HPLC method for determination of goosypol in feed was developed. Gossypol in food was extracted with acetic acid-water-phosphoric acid (85 : 15 : 1) for 20 min in a water bath at 100 degrees C. The extract was diluted with acetone-water (1 : 1), and injected into the HPLC. HPLC was performed with a Shodex C18M4E (4.6 mm i.d.x250 mm) column at a flow-rate of 1.0 mL/min, using a mobile phase of methanol-water (9 : 1) adjusted to pH 2.6 with phosphoric acid, and gossypol was detected with a UV detector (254 nm). A recovery test was conducted with cottonseed spiked with gossypol at 1,000 and 5,000 mg/kg, and with 2 kinds of formula feed spiked with gossypol at 58 and 580 mg/kg. The mean recoveries of gossypol were 90.8-105.0% and the relative standard deviations (RSD) were within 3.0%. A collaborative study was conducted with cottonseed and formula feed spiked with gossypol at 305 mg/kg in 8 laboratories. The average content of gossypol in cottonseed was 6,090 mg/kg, and the repeatability and reproducibility as the relative standard deviation (RSD(r) and RSD(R)) were 3.3% and 4.4%, while the mean recovery, RSD(r) and RSD(R) of gossypol in formula feed were 87.0%, 2.7% and 5.5%, respectively.

The interaction of the Wnt and Notch pathways modulates natural killer versus T cell differentiation.

The Wnt and Notch signaling pathways have been independently shown to play a critical role in regulating hematopoietic cell fate decisions. We previously reported that induction of Notch signaling in human CD34(+)CD38(-) cord blood cells by culture with the Notch ligand Delta 1 resulted in more cells with T or natural killer (NK) lymphoid precursor phenotype. Here, we show that addition of Wnt3a to Delta 1 further increased the percentage of CD34(-)CD7(+) and CD34(-)CD7(+)cyCD3(+) cells with increased expression of CD3 epsilon and preT alpha. In contrast, culture with Wnt3a alone did not increase generation of CD34(-)CD7(+) precursors or expression of CD3 epsilon or preT alpha gene. Furthermore, Wnt3a increased the amount of activated Notch1, suggesting that Wnt modulates Notch signaling by affecting Notch protein levels. In contrast, addition of a Wnt signaling inhibitor to Delta 1 increased the percentage of CD56(+) NK cells. Overall, these results demonstrate that regulation of Notch signaling by the Wnt pathway plays a critical role in differentiation of precursors along the early T or NK differentiation pathways. Disclosure of potential conflicts of interest is found at the end of this article.

Dose-dependent effects of the Notch ligand Delta1 on ex vivo differentiation and in vivo marrow repopulating ability of cord blood cells.

Although significant advances have been made over the last decade with respect to our understanding of stem cell biology, progress has been limited in the development of successful techniques for clinically significant ex vivo expansion of hematopoietic stem and progenitor cells. We here describe the effect of Notch ligand density on induction of Notch signaling and subsequent cell fate of human CD34+CD38- cord blood progenitors. Lower densities of Delta1(ext-IgG) enhanced the generation of CD34+ cells as well as CD14+ and CD7+ cells, consistent with early myeloid and lymphoid differentiation, respectively. However, culture with increased amounts of Delta1(ext-IgG) induced apoptosis of CD34+ precursors resulting in decreased cell numbers, without affecting generation of CD7+ cells. RNA interference studies revealed that the promotion of lymphoid differentiation was primarily mediated by Delta1 activation of Notch1. Furthermore, enhanced generation of NOD/SCID repopulating cells was seen following culture with lower but not higher densities of ligand. These studies indicate critical, quantitative aspects of Notch signaling in affecting hematopoietic precursor cell-fate outcomes and suggest that density of Notch ligands in different organ systems may be an important determinant in regulating cell-fate outcomes. Moreover, these findings contribute to the development of methodology for manipulation of hematopoietic precursors for therapeutic purposes.

Characterization of the Prr1 response regulator with special reference to sexual development in Schizosaccharomyces pombe.

The histidine (His)-to-Aspartate (Asp) phosphorelay is a paradigm of intracellular signaling systems through protein phosphorylation in both prokaryotes and eukaryotes. The fission yeast Schizosaccharomyces pombe has three histidine kinases (Phk1/Mak2, Phk2/Mak3, and Phk3/Mak1), together with two response regulators (Mcs4 and Prr1). The results of recent extensive studies suggested that these His-to-Asp phosphorelay components are involved in oxidative stress responses through the transcriptional regulation of several scavenger genes for toxic free radicals. It was also suggested that they were somehow implicated in control of both the mitotic and meiotic cell proliferations. Among these S. pombe His-to-Asp phosphorelay components, however, the function of Prr1 is less clear. We here characterized a mutant, named prr1-D418N, specifying an altered Prr1 protein that presumably acts as a gain-of-function (or constitutive-active) mutant, with special reference to sexual development. The mutant cells showed a striking phenotype in that they underwent mating even in a nitrogen-sufficient medium, under which conditions the wild-type cells hardly did so. Furthermore, the mutant cells underwent mating very rapidly in a nitrogen-deficient medium. Under anaerobic (or micro-aerobic) growth conditions, the wild-type cells were not capable of undergoing sexual development even in a nitrogen-deficient medium. The prr1-D418N cells underwent mating efficiently under such anaerobic growth conditions. Taken these together, it was suggested that the function of Prr1 is closely linked to the well-characterized signaling pathways for induction of the sexual development, in a way that this response regulator regulates a critical step of the initiation of meiosis through activating the transcription of ste11+, mam2+, and mei2+, in S. pombe.

His-to-Asp phosphorelay circuitry for regulation of sexual development in Schizosaccharomyces pombe.

The fission yeast Schizosaccharomyces pombe has three histidine kinases (Phk1/Mak2, Phk2/Mak3, and Phk3/Mak1), and two response regulators (Mcs4 and Prr1). The results of recent extensive studies on the S. pombe His-to-Asp phosphorelay circuitry suggested that it is involved in oxidative stress responses through the transcriptional regulation of several scavenger genes for toxic free radicals. The functions of these histidine kinases have not yet been fully characterized. Here we characterize a homothallic (h90) mutant lacking the genes for all the histidine kinases, with special reference to sexual development. Homothallic phk1/2/3delta cells underwent mating precociously in a nitrogen-deficient medium. Surprisingly, the mutant cells underwent mating even in a nitrogen-sufficient medium, under which conditions wild-type cells did so rarely if at all. Under anaerobic (or microaerobic) growth conditions, wild-type cells did not undergo sexual development even in a nitrogen-deficient medium, but the homothallic phk1/2/3delta cells mated efficiently. Oxidative reagents such as H2O2 induced sexual development in wild-type cells grown anaerobically. On the basis of these results, we propose the novel view that the S. pombe His-to-Asp phosphorelay, initiated by the Phk histidine kinases, is crucial for regulation of sexual development. This Phk-mediated signaling pathway is linked to the well-documented canonical pathway for induction of the sexual development, in that both converge at the initiation of meiosis through activation of ste11+, mam2+, and mei2+ transcription.