Original Article

ネコ32匹について,10% urethane-1% chloralose(5ml/kg)の腹腔内麻酔を行ない,横隔膜運動神経を機能的単一神経発射としてとり出し,その基本的特性と換気機構との相関および横隔膜神経支配について検討した。1)横隔膜運動神経線維について,機能的単一神経発射115本の発射パターンを自発呼吸下における気速曲線と対比し,I〜IV型に分類した。2)横隔膜神経におけるこれらの線維の構成は,I型40%,II型48%,III型10%そしてIV型は2%以下であった。3)I・II・III型の線維の基本的特性は,気道抵抗を加えた場合および呼気反射における発射パターンの変化からI型は相動性の要素を有し,II・III型は緊張性の要素を有している。4)これらの線維と換気機構の相関をみると,I型の線維は,主として効果的な吸気を瞬間的に行なうためにdynamicであり,II型の線維は,静的状態における吸気に主役を演じstaticである。さらに初期の呼出を円滑に行なわせるのにおもな役割を果たしている。III型は,主として腹圧に拮抗した緊張性の線維と考えられる。IV型については,ガンマ-運動線維である可能性について考察した。6)横隔膜筋支配については,腰部はI型,肋骨部は,I・II・III型の線維によって支配されていると考えられる。32 cats weighing 1.8 to 3.4 kg were intraperitoneally anesthetized with 10% urethane and 1% chloralose (5 ml/kg). 115 functionally unitary discharges of the phrenic nerve classified into four different types. Type I fibres initiate their firings after the beginning of the inspiratory phase and cease their activities prior to the onset of the expiratory flow change. Type II fibres fire with the very onset of the inspiratory phase and extend their activites untill the initial part of the expiration. The firings of Type III fibres dominate the whole inspiratory phase and initial two thirds of the expiration. Type IV showed continuously tonic firing throughout the whole respiratory cycle and increase their activities slightly during the inspiratory phase. Type I and II occupied more than 80% of all pattern. Modification of firing mode of each fibre type was observed under spontaneous respiration with air-way resistance and deflation reflex. The results may indicate characteristic features of each fibre type. Type I fibres may contribute to the kinetic contraction of the diaphragm and Type II the tonic one. Type III fibres were more tonic than Type II and may keep diaphragmatic tension against the intra-abdominal pressure. Type IV fibres probably belong to gamma motoneurons. Electromyographic observations suggested dominant innervation of Type I fibres to the pars cruralis. Pars costalis was mainly innervated by Type II fibres

In situ synthesis of natural rubber latex-supported gold nanoparticles for flexible SERS substrates

Natural rubber latex (NRL) from Hevea brasiliensis was used as a matrix to synthesize gold nanoparticles (AuNPs), leading to an organic-inorganic hybrid latex of NRL-supported AuNPs (AuNPs@NRL). The in situ and environmentally friendly preparation of AuNPs in an NRL matrix was developed by thermal treatment without using any other reducing agents or stabilizers because natural rubber particles and non-rubber components present in serum can serve as supporters for the synthesized AuNPs. As a result, the nanosized and well-dispersed AuNPs not only are decorated on the surface of natural rubber particles, but also can be found in the serum of NRL. The size of the AuNPs presented in NRL matrix can be controlled by adjusting the concentration of NRL. Furthermore, the flexible surface-enhanced Raman scattering (SERS) substrates made from the AuNPs@NRL through vacuum filtration presented good enhancement of the Raman probe molecule of 4-mercaptopyridine and outstanding SERS reproducibility. The capability of synthesizing the bio-supported nanohybrid latex provides a novel green and simple approach for the fabrication of flexible and effective SERS substrates

Global Metabolomic Profiling Reveals an Association of Metal Fume Exposure and Plasma Unsaturated Fatty Acids

Background: Welding-associated air pollutants negatively affect the health of exposed workers; however, their molecular mechanisms in causing disease remain largely unclear. Few studies have systematically investigated the systemic toxic effects of welding fumes on humans. Objectives: To explore the effects of welding fumes on the plasma metabolome, and to identify biomarkers for risk assessment of welding fume exposure. Methods: The two-stage, self-controlled exploratory study included 11 boilermakers from a 2011 discovery panel and 8 boilermakers from a 2012 validation panel. Plasma samples were collected pre- and post-welding fume exposure and analyzed by chromatography/mass spectrometry. Results: Eicosapentaenoic or docosapentaenoic acid metabolic changes post-welding were significantly associated with particulate (PM2.5) exposure (p<0.05). The combined analysis by linear mixed-effects model showed that exposure was associated with a statistically significant decline in metabolite change of eicosapentaenoic acid [(95% CI) = −0.013(−0.022∼−0.004); p = 0.005], docosapentaenoic acid n3 [(95% CI) = −0.010(−0.018∼−0.002); p = 0.017], and docosapentaenoic acid n6 [(95% CI) = −0.007(−0.013∼−0.001); p = 0.021]. Pathway analysis identified an association of the unsaturated fatty acid pathway with exposure (pStudy−2011 = 0.025; pStudy−2012 = 0.021; pCombined = 0.009). The functional network built by these fatty acids and their interactive genes contained significant enrichment of genes associated with various diseases, including neoplasms, cardiovascular diseases, and lipid metabolism disorders. Conclusions: High-dose exposure of metal welding fumes decreases unsaturated fatty acids with an exposure-response relationship. This alteration in fatty acids is a potential biological mediator and biomarker for exposure-related health disorders

Quantitative determination and pharmacokinetics of salvianolic acid l, a novel phenolic acid constituent from salvia miltiorrhiza, in rat plasma by high-performance liquid chromatography

A simple, rapid and selective HPLC method was developed for the determination of a novel phenolic acid constituent in rat plasma, salvianolic acid L (SAL), extracted from the dried root of Salvia miltiorrhiza (Danshen). Plasma samples were extracted by ethyl acetate after addition of the internal standard tinidazole. The appropriate separations were achieved using a C18 column with the mobile phase composed of a mixture of acetonitrile/water/formic acid (35:65:0.1, v/v/v) at the flow rate of 0.8 mL/min, and the wavelength of determination by diode-array detector (DAD) detection was 327 nm. Good linearity (r = 0.9996) was obtained within the concentration of 0.05-50 μg/mL. The intra- and inter-day assay precisions ranged from 0.60 to 5.91% and 3.52 to 7.00%, respectively. The accuracy was between 95.8 to 103.8%. In addition, the stability and extraction recovery involved in the method were also validated. This method was successfully applied to investigate the pharmacokinetic study of SAL in rats after a single intravenous administration dose of 2.0, 4.0, and 8.0 mg/kg, respectively.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Quantitative determination and pharmacokinetics of salvianolic acid l, a novel phenolic acid constituent from salvia miltiorrhiza, in rat plasma by high-performance liquid chromatography

A simple, rapid and selective HPLC method was developed for the determination of a novel phenolic acid constituent in rat plasma, salvianolic acid L (SAL), extracted from the dried root of Salvia miltiorrhiza (Danshen). Plasma samples were extracted by ethyl acetate after addition of the internal standard tinidazole. The appropriate separations were achieved using a C18 column with the mobile phase composed of a mixture of acetonitrile/water/formic acid (35:65:0.1, v/v/v) at the flow rate of 0.8 mL/min, and the wavelength of determination by diode-array detector (DAD) detection was 327 nm. Good linearity (r = 0.9996) was obtained within the concentration of 0.05-50 μg/mL. The intra- and inter-day assay precisions ranged from 0.60 to 5.91% and 3.52 to 7.00%, respectively. The accuracy was between 95.8 to 103.8%. In addition, the stability and extraction recovery involved in the method were also validated. This method was successfully applied to investigate the pharmacokinetic study of SAL in rats after a single intravenous administration dose of 2.0, 4.0, and 8.0 mg/kg, respectively.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Pharmacokinetics of single- and multiple-dose flumatinib in patients with chronic phase chronic myeloid leukemia

IntroductionFlumatinib is a novel, oral breakpoint cluster region-abelson (BCR-ABL) tyrosine kinase inhibitor that has demonstrated manageable safety and promising efficacy in patients with newly diagnosed chronic phase (CP) chronic myeloid leukemia (CML). MethodsThis study evaluated the pharmacokinetic (PK) profiles of flumatinib mesylate tablets at a dose of 400 mg and 600 mg in patients with CML-CP. The study was registered at chictr.org Identifier (ChiCTR2100044700). In this open-label, pharmacokinetic study, eligible patients were administered a single-dose of flumatinib 400 mg or 600 mg on day 1, followed by 2-day washout and 8 consecutive days of once-daily administration. Serial plasma samples were assayed for flumatinib and its metabolites (N-demethylate metabolite M1 and amide-bond hydrolytic metabolite M3).ResultsTwenty-nine patients were assigned to flumatinib 400 mg (n=14) or 600 mg (n=15). Serum concentrations of flumatinib reached maximum measured plasma concentration (Cmax) at a median time of 2 hours after each single dose, and then eliminated slowly with a mean apparent terminal disposition half-life (t1/2) from 16.0 to 16.9 hours. Following single- and multiple-dose administration, flumatinib exposure (Cmax, area under the concentration-time curve from 0 to t hours (AUC0-t), area under the concentration-time curve from 0 hours to infinity (AUC0-∞)) increased in an approximately dose-proportional manner. There was approximately 4.1- and 3.4- fold drug accumulation at steady-state after multiple-dose administration at 400 mg and 600 mg, respectively. The drug-related AEs associated with both treatments were primarily low-grade and tolerable events.ConclusionAnalysis of PK parameters indicated that flumatinib exposure increased in an approximately dose-proportional manner. Further research needs to be conducted in a large sample-size study

Thrombocytopenia Is Associated with Acute Respiratory Distress Syndrome Mortality: An International Study

Background: Early detection of the Acute Respiratory Distress Syndrome (ARDS) has the potential to improvethe prognosis of critically ill patients admitted to the intensive care unit (ICU). However, no reliable biomarkers are currently available for accurate early detection of ARDS in patients with predisposing conditions. Objectives: This study examined risk factors and biomarkers for ARDS development and mortality in two prospective cohort studies. Methods: We examined clinical risk factors for ARDS in a cohort of 178 patients in Beijing, China who were admitted to the ICU and were at high risk for ARDS. Identified biomarkers were then replicated in a second cohort of1,878 patients in Boston, USA. Results: Of 178 patients recruited from participating hospitals in Beijing, 75 developed ARDS. After multivariate adjustment, sepsis (odds ratio [OR]:5.58, 95% CI: 1.70–18.3), pulmonary injury (OR: 3.22; 95% CI: 1.60–6.47), and thrombocytopenia, defined as platelet count <80×103/µL, (OR: 2.67; 95% CI: 1.27–5.62)were significantly associated with increased risk of developing ARDS. Thrombocytopenia was also associated with increased mortality in patients who developed ARDS (adjusted hazard ratio [AHR]: 1.38, 95% CI: 1.07–1.57) but not in those who did not develop ARDS(AHR: 1.25, 95% CI: 0.96–1.62). The presence of both thrombocytopenia and ARDS substantially increased 60-daymortality. Sensitivity analyses showed that a platelet count of <100×103/µLin combination with ARDS provide the highest prognostic value for mortality. These associations were replicated in the cohort of US patients. Conclusions: This study of ICU patients in both China and US showed that thrombocytopenia is associated with an increased risk of ARDS and platelet count in combination with ARDS had a high predictive value for patient mortality

Quantitative determination and pharmacokinetics of salvianolic acid l, a novel phenolic acid constituent from salvia miltiorrhiza, in rat plasma by high-performance liquid chromatography

A simple, rapid and selective HPLC method was developed for the determination of a novel phenolic acid constituent in rat plasma, salvianolic acid L (SAL), extracted from the dried root of Salvia miltiorrhiza (Danshen). Plasma samples were extracted by ethyl acetate after addition of the internal standard tinidazole. The appropriate separations were achieved using a C18 column with the mobile phase composed of a mixture of acetonitrile/water/formic acid (35:65:0.1, v/v/v) at the flow rate of 0.8 mL/min, and the wavelength of determination by diode-array detector (DAD) detection was 327 nm. Good linearity (r = 0.9996) was obtained within the concentration of 0.05-50 μg/mL. The intra- and inter-day assay precisions ranged from 0.60 to 5.91% and 3.52 to 7.00%, respectively. The accuracy was between 95.8 to 103.8%. In addition, the stability and extraction recovery involved in the method were also validated. This method was successfully applied to investigate the pharmacokinetic study of SAL in rats after a single intravenous administration dose of 2.0, 4.0, and 8.0 mg/kg, respectively.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Compatibility-tuned distribution of nanoparticles in co-continuous rubber structures toward microwave absorption enhancement

Development of novel and versatile approaches to engineer composites with light density, broad effective bandwidth and high microwave absorption (MA) capacity is of great importance. Here, co-continuous natural rubber/epoxidized natural rubber (NR/ENR) blends with a selective distribution of conductive carbon black nanoparticles (CCBs), have been fabricated by tow-roll mixing. ENR with abundant epoxide groups shows inferior wettability to CCB than NR, which is responsible for the preferential location of CCB in the NR/ENR blend. Increasing the epoxidation level of ENR promotes the preferential location of CCB and creates stronger dielectric loss, thus enhancing the MA properties of CCB/NR/ENR composites. When the epoxidation level increases to 40 mol%, the MA capacity of the composite has been significantly enhanced by 40%. Meanwhile, the qualified frequency bandwidth (RL < −10 dB) of composites with ENR is 85% broader than that of CCB/NR composites. Such a novel approach of compatibility-tuned nanoparticles distribution in co-continuous rubber blends will significantly promote the multi-functional use of rubber and carbonaceous resources

Mutant-allele fraction heterogeneity is associated with non-small cell lung cancer patient survival

Genetic intratumor heterogeneity is associated with tumor occurrence, development and overall outcome. The present study aims to explore the association between mutant-allele fraction (MAF) heterogeneity and patient overall survival in lung cancer. Somatic mutation data of 939 non-small cell lung cancer (NSCLC) cases were obtained from The Cancer Genome Atlas. Entropy-based mutation allele fraction (EMAF) score was used to describe the uncertainty of individual somatic mutation patterns and to further analyze the association with patient overall survival. Results indicated that association between EMAF and overall survival was significant in the discovery set [hazard ratio (H)R=1.62; 95% confidence interval (CI): 1.08–2.41; P=0.018] and replication set (HR=1.63; 95% CI: 1.11–2.37; P=0.011). In addition, EMAF was also significantly different in lung adenocarcinoma and squamous cell carcinoma. Furthermore, a significant difference was indicated in early-stage patients. Results from c-index analysis indicated that EMAF improved the model predictive performance on the 3-year survival beyond that of traditional clinical staging, particularly in early-stage patients. In conclusion, EMAF successfully reflected MAF heterogeneity among patients with NSCLC. Additionally, EMAF improved the predictive performance in early-stage patient prognosis beyond that of traditional clinical staging. In clinical application, EMAF appears to identify a subset of early-stage patients with a poor prognosis and therefore may help inform clinical decisions regarding the application of chemotherapy after surgery