Supersaturated state of diazepam injection following dilution with infusion fluid

BackgroundSignificant precipitation produced by the dilution of diazepam (DZP) injection with an infusion fluid is a great concern for the clinical practice. In this study, the precipitation behavior under different conditions was investigated.MethodFor the sample preparation, DZP injections (Horizon injection and Cercine injection) were diluted with various infusion fluids (Saline, 5% glucose infusion fluid and Soldem 3A) at designated dilution ratios ranging from 1× to 40× (5 mg/mL to 0.125 mg/mL). In addition, to measure the solubility of DZP in the samples, the saturated solutions of DZP were prepared. The DZP concentrations in the samples were measured by high-performance liquid chromatography (HPLC). This study also investigated the precipitate using various analytical methods: infrared microscopy, 1H-NMR, differential scanning calorimetry, and powder X-ray deflection.ResultsFirst, the compatibility of injection with infusion fluids was investigated. Significant precipitation occurred at dilution ratios ranging from 2× to 20×. No significant effects of formulations and infusion fluids on the compatibility were observed. The solubility of DZP was then further investigated. The concentration of DZP dissolved in the admixtures was higher than the solubility. This indicated that DZP existed in a supersaturated state in the infusion fluid admixtures. In the next phase of this study, the precipitate was investigated using various analytical methods. Results showed that the precipitate in infusion fluid admixtures was mostly composed of DZP, but also contained small amounts of the ingredients of DZP injection, such as benzoic acid and benzyl alcohol.ConclusionsThis study clarified details of the precipitation occurring after dilution of DZP injection with infusion fluids. It is worth noting that DZP in an infusion admixture existed in a supersaturated state. These findings offer important insight into the clinical practice of DZP injection

The Effect of Moving to a Territorial Tax System on Profit Repatriation: Evidence from Japan

In an increasingly globalized world, the design of international tax systems in terms of taxation on foreign corporate incomes has received much attention from policymakers and economists alike. In the past, Japan\u27s worldwide tax system taxed foreign source income upon repatriation. However, to stimulate dividend repatriations from Japanese-owned foreign affiliates, Japan introduced a foreign dividend exemption in 2009 that exempts dividends remitted by Japanese-owned foreign affiliates to their parent firms from home taxation. This paper examines the effect of this dividend exemption on profit repatriations by Japanese multinationals. We find that the response of Japanese-owned affiliates to the dividend exemption was heterogeneous. More particularly, foreign affiliates with a large stock of retained earnings were generally more responsive to the reform and significantly increased dividend payments to their parent firms in response to the enactment of the dividend exemption system. Dividend payments by these affiliates also became more sensitive to withholding tax rates on dividends levied by host countries under the new exemption system.JEL Classification Codes: H25, F23http://www.grips.ac.jp/list/jp/facultyinfo/hasegawa_makoto

気管支喘息におけるHRCTによるLow attenuation area(LAA)と平均CT numberとの関連

The maximal percent low attenuation area < -950 HU (% LAA) among three anatomic lung levels on high resolution computed tomography (HRCT) was examined in patients with asthma, classified by the degree of % LAA, in relation to the mean CT number, % FVC of the predicted value, and FEV 1/FVC (FEV1%). 1 . The mean CT number was closely related to the degree of % LAA of the lungs. The mean CT number was significantly lower in patients with high % LAA (mean CT number-915.3HU, % LAA 37.6%) than in those with low % LAA (-852.9HU, 4.7%). 2. The FEV1% value was significantly lower in patients with high % LAA (47.8%) than in those with low % LAA (62.2%)(p<0.05). The % FVC value was also significantly lower in patients with high % LAA (77.1%) compared to the value in those with low % LAA (101.2%). The results suggest that a large volume of LAA<-950HU of the lungs can be observed in patients with asthma, and the % LAA is closely correlated with mean CT number and the values of FEV1% and % FVC.HRCT (high resolution computed tomography)により,-950HU以下のlow attenuation area(LAA)を3つの高さの肺野レベルで観察し,そのなかの最も高い値をmaximal% LAAとして表し,この値と平均CT number, % FVCおよびFEV1.0%の値と比較検討した｡1.平均CT numberは,maximal% LAAと密接な関連を示した｡そして,平均CT numberは,% LAAが低い症例(% LAA :4.7%, mean CT number:-852.9HU)に比べ,% LAAが高い症例(% LAA :37.6%, mean CT number:-915.3HU)において低い傾向が見られた｡2.FEV1.0%値は,% LAA値が低い症例(62.2%)に比べ% LAA値が高い症例(47.8%)において有意に低い値を示した(P<0.05)。% FVC値も同様% LAA値が低い症例(101.2%)に比べ高い症例(77.1%)で低い値を示したが両群間に有意の差は見られなかった｡これらの結果より,気管支喘息においも,HRCT上肺野で-950HU以下のLow attenuation area(LAA)を示す症例が見られること,そして,% LAAは,mean CT number,FEV1.0%や% FVC値とある程度関連していることが示唆された

肺気腫患者における吸入抗原に対するIgE抗体

To analyze the pathophysiological changes ot the airways in emphysema, bronchial responsiveness and the generation of leukotrienes B4 (LTB4) and C4 (LTC4) by peripheral leucocytes were examined in 22 patients with emphysema. The subjects were divided into two groups according to the presence or absence of IgE antibodies against inhalant allergens; RAST positive group and RAST negative group. 1. Smoking history, mean CT number and mean maximum % low attenuation area (% LAA) <-950HU of the lung on high resolution computed tomography (HRCT), and DLco value suggested that there were emphysematous changes of the lung in all subjects. However, these findings were not different between the two groups. 2. The level of serum IgE was significantly higher in RAST positive group than in RAST negative group. 3. The mean % increase in FEV1.0 after inhalation of β-agonists was higher in RAST positive group than in RAST negative group. The % increase more than 15% was found in 4 of the 9 subjects (44.4%) in RAST positive group and 2 of the 12 (16.7%) in RAST negative group. 4. The generation of LTC4 by leucocytes was significantly higher in RAST positive group than in RAST negative group (p<0.01). The generation of LTB4 was not significantly different between the two groups. The results suggest that IgE-mediated allergy participates in the bronchial responsiveness of patients with emphysema.肺気腫患者の気道病変を解析する目的で,22例の肺気腫患者を対象に,その気道反応および白血球のロイコトリエンB4,C4産生能について検討を加えた｡この際対象症例はIgE抗体の有無によってRAST陽性症例RAST陰性症例に分類された｡1.喫煙歴,平均CT値,high resolution computed tomography(HRCT)上の-950HU以下の% low attenuation area(% LAA),DLcoなどの値は,いずれも対象症例が高度な気腫化病変を有してい ることを示した｡2.血清IgE値は,RAST陽性例で陰性例に比べ有意の高値を示した｡3.β受容体刺激薬吸入後のFEV1.0の増加は,RAST陽性例で陰性例に比べ高度であった｡そして,吸入後のFEV1.0が15%以上の増加を示した症例は,RAST陽性例では9例中4例(44.4%),陰性例では12例中2例(16,7%)であった｡4.白血球のLTC4産生量は,RAST陽性例で陰性例に比べ有意に高い値であったが,LTB4産生は両者間に有意の差は見られなかった｡以上の結果より,IgEにmediateされるアレルギー反応が,肺気腫患者 の気道反応に関与している可能性が示唆された

The Japan Public Health Center-based Prospective Study for the Next Generation (JPHC-NEXT): Study Design and Participants

Background: Lifestyle and life-environment factors have undergone drastic changes in Japan over the last few decades. Further, many molecular epidemiologic studies have reported that genetic, epigenetic, and other biomarker information may be useful in predicting individual disease risk.Methods: The Japan Public Health Center-based Prospective Study for the Next Generation (JPHC-NEXT) was launched in 2011 to identify risk factors for lifestyle-related disease, elucidate factors that extend healthy life expectancy, and contribute toward personalized healthcare based on our more than 20 years’ experience with the JPHC Study. From 2011 through 2016, a baseline survey was conducted at 16 municipalities in seven prefectures across the country. A self-administered questionnaire was distributed to all registered residents aged 40–74, which mainly asked about lifestyle factors, such as socio-demographic situation, personal medical history, smoking, alcohol and dietary habits. We obtained informed consent from each participant to participate in this long follow-up study of at least 20 years, including consent to the potential use of their residence registry, medical records, medical fee receipts, care insurance etc., and to the provision of biospecimens (blood and urine), including genomic analysis.Results: As of December 31, 2016, we have established a population-based cohort of 115,385 persons (Response rate 44.1%), among whom 55,278 (47.9% of participants) have provided blood and urine samples. The participation rate was slightly higher among females and in the older age group.Conclusion: We have established a large-scale population-based cohort for next-generation epidemiological study in Japan

Platelet-to-Lymphocyte Ratio Multiplied by the Cytokeratin-19 Fragment Level as a Predictor of Pathological Response to Neoadjuvant Chemotherapy in Esophageal Squamous Cell Carcinoma

[Background] The standard treatment for resectable advanced esophageal squamous cell carcinoma in Japan is surgery followed by neoadjuvant chemotherapy, and it is important to predict the effect of neoadjuvant chemotherapy before treatment. Therefore, this study aims to extract conventional blood examination data, such as tumor markers and/or inflammatory/nutritional index levels, that can predict the pathological response of patients with esophageal squamous cell carcinoma to neoadjuvant chemotherapy. [Methods] We retrospectively analyzed the medical records of 66 patients with thoracic esophageal squamous cell carcinoma who received neoadjuvant chemotherapy, followed by curative esophagectomy at Tottori University Hospital between June 2009 and December 2019. [Results] We demonstrated that the product of the platelet-to-lymphocyte ratio (PLR) multiplied by the cytokeratin-19 fragment (CYFRA) level, which was termed “PLR-CYFRA,” is the most accurate indicator that predicts the pathological response to neoadjuvant chemotherapy, with the highest area under the curve [0.795 (95% confidence interval: 0.665–0.925), P < 0.001] in receiver operating characteristic analyses. Therefore, we divided patients into the PLR-CYFRALow (< 237.6, n = 21) and PLR-CYFRAHigh (≥ 237.6, n = 45) groups and found that the percentage of PLR-CYFRALow was significantly higher in patients with a better pathological response (P < 0.001). Furthermore, patients with good pathological response had significantly better prognoses in terms of disease-specific survival (P = 0.014), recurrence-free survival (P = 0.014), and overall survival (P = 0.032). In the multivariate analysis, PLR-CYFRA was an independent predictor of the pathological response of patients with esophageal squamous cell carcinoma to neoadjuvant chemotherapy (P = 0.002). [Conclusion] Pretreatment PLR-CYFRA might be a useful and simple tool that predicts the pathological effect of neoadjuvant chemotherapy in esophageal squamous cell carcinoma

Ambient fine and coarse particles in Japan affect nasal and bronchial epithelial cells differently and elicit varying immune response

Ambient particulate matter (PM) epidemiologically exacerbates respiratory and immune health, including allergic rhinitis (AR) and bronchial asthma (BA). Although fine and coarse particles can affect respiratory tract, the differences in their effects on the upper and lower respiratory tract and immune system, their underlying mechanism, and the components responsible for the adverse health effects have not been yet completely elucidated. In this study, ambient fine and coarse particles were collected at three different locations in Japan by cyclone technique. Both particles collected at all locations decreased the viability of nasal epithelial cells and antigen presenting cells (APCs), increased the production of IL-6, IL-8, and IL-1β from bronchial epithelial cells and APCs, and induced expression of dendritic and epithelial cell (DEC) 205 on APCs. Differences in inflammatory responses, but not in cytotoxicity, were shown between both particles, and among three locations. Some components such as Ti, Co, Zn, Pb, As, OC (organic carbon) and EC (elemental carbon) showed significant correlations to inflammatory responses or cytotoxicity. These results suggest that ambient fine and coarse particles differently affect nasal and bronchial epithelial cells and immune response, which may depend on particles size diameter, chemical composition and source related particles types

肺気腫患者におけるロイコトリエンB4,C4産生能と高分解能CTによる平均CT値との関連

The generation of leukotrienes B4 (LTB4) and C4 (LTC4) by peripheral leukocytes stimulated with Ca ionophore A23187 was examined in 17 patients with pulmonary emphysema. They were divided into three groups according to the mean CT number; A (<-940 HU), B (-940 ≦, <-930 HU), and C (-930 HU ≦ ).1. The values of FVC (% predicted), FEV1.0% and DLco (% predicted) showed a tendency to decrease as the mean CT number was smaller. The value of % FVC was significantly lower in patients with group A than in those with group C (p<0.05). 2. The generation of both LTB4 and LTC4 was significantly higher in patients with emphysema compared to the generation in healthy subjects (LTB4;p<0.05, LTC4;P<0.05). 3. The generation of LTB4 and LTC4 in patients with emphysema was higher as the mean CT number was larger (severity of the disease become less). The LTC4 production was significantly higher in patients with group C(mild or moderate type of emphysema) than in those with group A(advanced type of emphysema). These results suggest that the generation of LTB4 and LTC4 is higher in patients with mild or moderate type of emphysema than in those with advanced type of the disease.肺気腫患者17名を対象として,カルシウムイオノフォアA23187による末梢血白血球からのロイコトリエンB4(LTB4), ロイコトリエンC4(LTC4)の産生能の検討を行った｡対象は高分解能CTによる平均CT値によってA(<940HU), B(-940≦,<-930HU),C(-930HU≦)の3群に分類した｡1.% FVC,FEV1.0%,% DLcoが低下するにつれて平均CT値が低下する傾向が見られた｡% FVC値はC群に比較して,A群において有意に低値を示した(p<0.05)｡2.LTB4とLTC4の産生能は健常人に比較して,肺気腫患者において有意に高値を示した(LTB4;p<0.05,LTC4;p<0.05)。3.肺気腫患者におけるLTB4とLTC4の産生能は平均CT値が上昇するにつれて(軽症症例ほど)高値を示した｡またLTC4産生能はC群(早期肺気腫症例)においてA群(進行肺気腫症例)に比して有意に高値を示した｡以上より肺気腫におけるLTB4,LTC4産生能は進行例に比較すると,軽･中等症例において高値であることが示唆された

Inhibition of microRNA-33b in humanized mice ameliorates nonalcoholic steatohepatitis

マイクロRNA-33bの阻害は非アルコール性脂肪肝炎を改善する --核酸医薬による治療応用へ--. 京都大学プレスリリース. 2023-06-13.Nonalcoholic steatohepatitis (NASH) can lead to cirrhosis and hepatocellular carcinoma in their advanced stages; however, there are currently no approved therapies. Here, we show that microRNA (miR)-33b in hepatocytes is critical for the development of NASH. miR-33b is located in the intron of sterol regulatory element–binding transcription factor 1 and is abundantly expressed in humans, but absent in rodents. miR-33b knock-in (KI) mice, which have a miR-33b sequence in the same intron of sterol regulatory element–binding transcription factor 1 as humans and express miR-33b similar to humans, exhibit NASH under high-fat diet feeding. This condition is ameliorated by hepatocyte-specific miR-33b deficiency but unaffected by macrophage-specific miR-33b deficiency. Anti-miR-33b oligonucleotide improves the phenotype of NASH in miR-33b KI mice fed a Gubra Amylin NASH diet, which induces miR-33b and worsens NASH more than a high-fat diet. Anti-miR-33b treatment reduces hepatic free cholesterol and triglyceride accumulation through up-regulation of the lipid metabolism–related target genes. Furthermore, it decreases the expression of fibrosis marker genes in cultured hepatic stellate cells. Thus, inhibition of miR-33b using nucleic acid medicine is a promising treatment for NASH

Two male steroid-dependent asthmatics treated with etidronate

男性のステロイド依存性気管支喘息患者にエチドロネートを4年間の長期間にわたり投与した経験を得たので報告する｡症例は,男性のステロイド依存性気管支喘息で,エチドロネート200mg/日･14日間投与を4ケ月おきに4年間にわたり反復投与し,活性型ビタミンD製剤 (VD)投与と併用した2例と,活性型VD製剤を単独授与した2例｡椎体圧迫骨折数,境骨耗骨密度,海綿骨骨密度,皮質骨骨密度について,椎体X線像,PQCT(Stratec XCT960)を用いて4ケ月毎に測定し,48ケ月後の効果を検討した｡エチドロネートを投与した症例1では,総骨密度と海綿骨はやや増加を認め皮質骨密度は減少していた｡エチドロネートを授与した症例2では,総骨密度,海綿骨,皮質骨密度はいずれも減少を認めたが,VD単独投与した2例よりもやや減少が抑制されていたようであった｡VD単独投与した2例ではいずれの項目も減少を認めた｡これらの症例からは,エチドロネートは男性のステロイドによる骨傷害にも有効と考えられたが,現在投与継続途中であり,今後さらに検討を続ける必要がある｡We report an experience about administration of etidronate to male steroid-dependent asthmatics for a long time. For 4 years, two men with steroid-dependent asthma were treated with etidronate (200 mg / day, for 14 days) every 4 months and 25-hydroxyvitamin D3 (VD) together, and two patients were treated with VD alone. Vertebral fractures were evaluated by the lateral spinal X-ray films, and radial total bone mineral density (BMD) , trabecular BMD and the cortical BMD were measured by pQCT (Stratec XCT960) every four months. Trabecular and total BMD increased but cortical BMD decreased in the case 1 who was treated with both etidronate and VD. In the case 2 with etidronate and VD treatments, total and trabecular BMD decreased, but reduction of these indices seemed to be more suppressed than that in two patients with VD alone. According to these experiences, etidronate may be effective against the steroid-induced bone injury in men. Since periods treatment are not en-ough long to evaluate therapeutic effect of etid-ronate, we will have to continue the examination of these cases further more from now on