The nonlinear mixed-effects model with stochastic differential equations （SDEs） is used to model the population pharmacokinetic （PPK） data that are extended from ordinary differential equations （ODEs） by adding ...The nonlinear mixed-effects model with stochastic differential equations （SDEs） is used to model the population pharmacokinetic （PPK） data that are extended from ordinary differential equations （ODEs） by adding a stochastic term to the state equation. Compared with the ODEs, the SDEs can model correlated residuals which are ubiquitous in actual pharmacokinetic problems. The Bayesian estimation is provided for nonlinear mixed-effects models based on stochastic differential equations. Combining the Gibbs and the Metropolis-Hastings algorithms, the population and individual parameter values are given through the parameter posterior predictive distributions. The analysis and simulation results show that the performance of the Bayesian estimation for mixed-effects SDEs model and analysis of population pharmacokinetic data is reliable. The results suggest that the proposed method is feasible for population pharmacokinetic data.展开更多
The encounter of elongating RNA polymerase Ⅱ （RNAPⅡo） with DNA lesions has severe consequences for the cell as this event provides a strong signal for P53-dependent apoptosis and cell cycle arrest. To counteract p...The encounter of elongating RNA polymerase Ⅱ （RNAPⅡo） with DNA lesions has severe consequences for the cell as this event provides a strong signal for P53-dependent apoptosis and cell cycle arrest. To counteract prolonged blockage of transcription, the cell removes the RNAPⅡo-blocking DNA lesions by transcription-coupled repair （TC-NER）, a specialized subpathway of nucleotide excision repair （NER）. Exposure of mice to UVB light or chemicals has elucidated that TC-NER is a critical survival pathway protecting against acute toxic and long-term effects （cancer） of genotoxic exposure. Deficiency in TC-NER is associated with mutations in the CSA and CSB genes giving rise to the rare human disorder Cockayne syndrome （CS）. Recent data suggest that CSA and CSB play differential roles in mammalian TC-NER： CSB as a repair coupling factor to attract NER proteins, chromatin remodellers and the CSA- E3-ubiquitin ligase complex to the stalled RNAPⅡo. CSA is dispensable for attraction of NER proteins, yet in cooperation with CSB is required to recruit XAB2, the nucleosomal binding protein HMGN1 and TFⅡS. The emerging picture of TC-NER is complex： repair of transcription-blocking lesions occurs without displacement of the DNA damage-stalled RNAPⅡo, and requires at least two essential assembly factors （CSA and CSB）, the core NER factors （except for XPC-RAD23B）, and TC-NER specific factors. These and yet unidentified proteins will accomplish not only efficient repair of transcription-blocking lesions, but are also likely to contribute to DNA damage signalling events.展开更多
OBJECTIVE To compare the pharmacokinetics and pharmacodynamics of PEG30-rhG-CSF administered to beagle dogs at three different dosages with PEG20-rhG-CSF administered at one dosage, and to provide an experimental basi...OBJECTIVE To compare the pharmacokinetics and pharmacodynamics of PEG30-rhG-CSF administered to beagle dogs at three different dosages with PEG20-rhG-CSF administered at one dosage, and to provide an experimental basis for clinical trials.METHODS Beagle dogs received single, subcutaneous doses of PEG30-rhG-CSF at 100, 200 and 400 μg/kg or PEG20-rhG-CSF at 200 μg/kg. PEG30-rhG-CSF and PEG20-rhG-CSF concentrations in serum were analyzed using an enzymeqinked immunosorbent assay （ELISA）. WBC, ANC and PLT counts of whole blood samples were measured using fully automated analytic instrumentation. Pharmacokinetic and pharmacodynamic parameters were calculated using DAS 2.0 statistical analysis software.METHODS Beagle dogs received single, subcutaneous doses of PEG30-rhG-CSF at 100, 200 and 400 μg/kg or PEG20-rhG-CSF at 200μg/kg. PEG30-rhG-CSF and PEG20-rhG-CSF concentrations in serum were analyzed using an enzyme-linked immunosorbent assay （ELISA）. WBC, ANC and PLT counts of whole blood samples were measured using fully automated analytic instrumentation. Pharmacokinetic and pharmacodynamic parameters were calculated using DAS 2.0 statistical analysis software. RESULTS The pharmacokinetic parameters of PEG30-rhG-CSF calculated from the serum concentration data determined by ELISA were as follows： the mean elimination half-life （t1/2ke） was 40.6 h （33.5-45.4 h）; the mean time to reach peak concentration （Tmax） was 19.2 h （11.7-24.0 h）; the drug clearance from the serum （CL） was decreased with increasing doses; the peak concentration （Cmax） and the area under the serum concentration-time curve （AUC） were increased with increasing doses. For PEG20-rhG- CSF, the half-life was shorter （12 h） and Tmax was achieved much earlier （10 h） relative to PEG30-rhG-CSF. The AUC of PEG30- rhG-CSF was much greater than that of PEG20-rhG-CSF, and the relative bioavailability with a subcutaneous injection was 158.7%. Administration of single doses of PEG30-rhG-CSF resulted in substantial increases in the absolute The time to reach ANC （ANCTmax） neutrophil count （ANC）. was 72 h. The maximum observed absolute neutrophil counts （ANCmax） and the area over the baseline effect curve （AOBEC） was increased with increasing doses. The effect-elimination half-life （t1/2E） ranged from 60 h to 80 h after subcutaneous administration. The PLT count was slightly elevated 8-12 h after s.c. injection, and declined after 24 h. CONCLUSION The mean elimination half-life of PEG30-rhG- CSF was longer than that of PEG20-rhG-CSF at the same dose, and the other main pharmacokinetic and pharmacodynamic parameters of PEG30-rhG-CSF, including C ANCmax, AUC and AOBEC were much greater than those following PEG20-rhG-CSF injection.展开更多
Background: Edge effects cause changes in bird community richness, abundance, and/or distribution within a landscape, but the avian guilds most influenced can vary among regions. Although Southeast Asia has the highes...Background: Edge effects cause changes in bird community richness, abundance, and/or distribution within a landscape, but the avian guilds most influenced can vary among regions. Although Southeast Asia has the highest rates of deforestation and projected species loss, and is currently undergoing an explosive growth in road infrastructure, there have been few studies of the effects of forest edges on avian communities in this region.Methods: We examined avian community structure in a dry evergreen forest in northeastern Thailand adjacent to a five-lane highway. We evaluated the richness and abundance of birds in 11 guilds at 24 survey points on three parallel transects perpendicular to the edge. At each point, 10-min surveys were conducted during February-August 2014 and March-August 2015. Vegetation measurements were conducted at 16 of the bird survey points and ambient noise was measured at all 24 survey points.Results: We found a strongly negative response to the forest edge for bark-gleaning, sallying, terrestrial, and understory insectivores and a weakly negative response for arboreal frugivore-insectivores, foliage gleaning insectivores, and raptors. Densities of trees and the percentage canopy cover were higher in the interior, and the ambient noise was lower. In contrast, arboreal nectarivore-insectivores responded positively to the forest edge, where there was a higher vegetation cover in the ground layer, a lower tree density, and a higher level of ambient noise.Conclusion: Planners should avoid road development in forests of high conservation value to reduce impacts on biodiversity. Where avoidance is impossible, a number of potential mitigation methods are available, but more detailed assessments of these are needed before they are applied in this region.展开更多
The desolvation of erythromycin acetone solvate was investigated under non-isothermal conditions by a thermogravimetric analyzer. This paper emphasized the kinetic analysis of non-isothermal TG-DTA data by Achar metho...The desolvation of erythromycin acetone solvate was investigated under non-isothermal conditions by a thermogravimetric analyzer. This paper emphasized the kinetic analysis of non-isothermal TG-DTA data by Achar method and Coats-Redfern method to fit various solid-state reaction models, and to achieve kinetic parameters of desolvation. The mechanism of thermal desolvation was evaluated using the kinetic compensation effect. The results show that kinetics of desolvation of erythromycin acetone solvate was compatible with the mechanism of a two-dimensional diffusion controlled and was best expressed by Valensi equation. Corresponding to the integral method and the differential method, the activation energy of desolvation of erythromycin acetone solvate was estimated to be 51.26—57.11 kJ/mol, and the pre-exponential factor was 8.077×106 s-1—4.326×107 s-1, respectively.展开更多
This article addresses the magnetohydrodynamics(MHD) flow of a third grade fluid over an exponentially stretching sheet. Analysis is carried out in the presence of first order chemical reaction. Both cases of construc...This article addresses the magnetohydrodynamics(MHD) flow of a third grade fluid over an exponentially stretching sheet. Analysis is carried out in the presence of first order chemical reaction. Both cases of constructive and destructive chemical reactions are reported. Convergent solutions of the resulting differential systems are presented in series forms. Characteristics of various sundry parameters on the velocity, concentration, skin friction and local Sherwood number are analyzed and discussed.展开更多
OBJECTIVE To reveal the biological effects and effective dosage in radiotherapy model which applies high single-dose irradiation by animal experiment. METHODS We inoculated subcutaneouly human pancreatic carcinoma cel...OBJECTIVE To reveal the biological effects and effective dosage in radiotherapy model which applies high single-dose irradiation by animal experiment. METHODS We inoculated subcutaneouly human pancreatic carcinoma cell line （MIA PaCa-2） in the lateral of the right lower extremity of the athymic mouse to grow transplantation tumor. While the median diameter of transplantation tumor reached 10 mm approximately, the animals were randomly divided into 7 groups （6 animals per group） and irradiation by different dose in one fixed with consciousness for fraction （0, 2, 5, 10, 17, 25, 35 Gy）. All were kept on to be bred for observation of the change in gross tumor volume, calculation of delayed growth time and delayed growth curve. RESULTS With increased dose per fraction, cutaneous reaction on the neoplasma surface of the animal, which was mainly moist yellow effusion was more and more severe. When dosage is less than 10 Gy, all animals showed similar effects, that＇s the delayed tumor growth was not obvious. Tumors receiving more than 10 Gy in one fraction showed very good biological effect and the delayed tumor growth was obviously related to dosage. The difference in delayed tumor growth between the 2 groups was statistically significant. The delayed tumor growth time in 10, 17, 25 Gy group was respectively 3 weeks, 6 weeks and more. CONCLUSION The biological effect of the model which applies high single-dose irradiation （more than 10 Gy in one fraction） was very good. The effect of delayed tumor growth was obviously related to the dosage after transplantation tumor was radiated. Because of its higher dose per fraction and biological effects, the model of high single-dose irradiation can get better clinical effects.展开更多
In order to find natural compounds of interest such as pesticides and therapeutic molecules, toxicological properties of seed methanolic extracts （SME） of nine Malagasy Albizia species were investigated. Toxicity wa...In order to find natural compounds of interest such as pesticides and therapeutic molecules, toxicological properties of seed methanolic extracts （SME） of nine Malagasy Albizia species were investigated. Toxicity was assessed on living animals by intraperitoneal and oral route, and pharmacological effects on isolated organs. All SME induced various disorders in mice but the signs of the nervous system disturbs were the earliest and the most often observed. The main organ lesions, examined on histological sections, induced vasodilatation, inflammatory infiltrate of neutrophil polymorphonuclears and hemorrhagic areas. At low concentrations （until 20 p.g/mL）, A. masikororum and A. viridis provoked on isolated auricular a positive inotrope effect followed by a progressive inhibition of the contraction and a complete atrial arrhythmia. Besides, A. viridis and A. bernieri induced some hepatic functional impairment after a chronic treatment during one month. Albizia greveana with a LD50 of 1.13-2 mg/kg was the most toxic and Albizia bernieri the least one with a LD50 of 52 mg/kg. Alkaloids and/or saponins, the major chemical groups found by phytochemical screening on these extracts, could be responsible of their toxicity.展开更多
Introduction In the United States, there are about 17.6 million patients suffer from symptomatic coronary artery disease （CAD）, affecting 7.9% of adults ≥ 20 years of age.1 An estimated 10.2 million patients have ...Introduction In the United States, there are about 17.6 million patients suffer from symptomatic coronary artery disease （CAD）, affecting 7.9% of adults ≥ 20 years of age.1 An estimated 10.2 million patients have angina, and 500,000 patients will develop new angina pectoris each year. 1 A subset of angina patients are categorized as refractory when symptoms continue despite optimal medical therapy and revascularization.Routine daily activities become impossible without experiencing chest pain in this patient population.2展开更多
We used a potent and specific monoclonal antibody to somatostatin to test the physiologic inhibitory role of the tetradecapeptide somatostatin on pancreatic secretion.Somatostatin immunoneutralization increased both t...We used a potent and specific monoclonal antibody to somatostatin to test the physiologic inhibitory role of the tetradecapeptide somatostatin on pancreatic secretion.Somatostatin immunoneutralization increased both the total amylase and volume of pancreatic secretion.Cholecystokinin-A receptor antagonism abolished the stimulatory effect of somatostatin immunoneutralization.We conclude that somatostatin tonically inhibits pancreatic secretion in fasted rats via inhibition of the release or action of cholecystokinin.Furthermore,the source of these peptides is likely islet delta cells and intrapancreatic neurons,respectively.展开更多
基金The National Natural Science Foundation of China(No.11171065,81130068)the Natural Science Foundation of Jiangsu Province(No.BK2011058)the Fundamental Research Funds for the Central Universities(No.JKPZ2013015)
文摘The nonlinear mixed-effects model with stochastic differential equations （SDEs） is used to model the population pharmacokinetic （PPK） data that are extended from ordinary differential equations （ODEs） by adding a stochastic term to the state equation. Compared with the ODEs, the SDEs can model correlated residuals which are ubiquitous in actual pharmacokinetic problems. The Bayesian estimation is provided for nonlinear mixed-effects models based on stochastic differential equations. Combining the Gibbs and the Metropolis-Hastings algorithms, the population and individual parameter values are given through the parameter posterior predictive distributions. The analysis and simulation results show that the performance of the Bayesian estimation for mixed-effects SDEs model and analysis of population pharmacokinetic data is reliable. The results suggest that the proposed method is feasible for population pharmacokinetic data.
文摘The encounter of elongating RNA polymerase Ⅱ （RNAPⅡo） with DNA lesions has severe consequences for the cell as this event provides a strong signal for P53-dependent apoptosis and cell cycle arrest. To counteract prolonged blockage of transcription, the cell removes the RNAPⅡo-blocking DNA lesions by transcription-coupled repair （TC-NER）, a specialized subpathway of nucleotide excision repair （NER）. Exposure of mice to UVB light or chemicals has elucidated that TC-NER is a critical survival pathway protecting against acute toxic and long-term effects （cancer） of genotoxic exposure. Deficiency in TC-NER is associated with mutations in the CSA and CSB genes giving rise to the rare human disorder Cockayne syndrome （CS）. Recent data suggest that CSA and CSB play differential roles in mammalian TC-NER： CSB as a repair coupling factor to attract NER proteins, chromatin remodellers and the CSA- E3-ubiquitin ligase complex to the stalled RNAPⅡo. CSA is dispensable for attraction of NER proteins, yet in cooperation with CSB is required to recruit XAB2, the nucleosomal binding protein HMGN1 and TFⅡS. The emerging picture of TC-NER is complex： repair of transcription-blocking lesions occurs without displacement of the DNA damage-stalled RNAPⅡo, and requires at least two essential assembly factors （CSA and CSB）, the core NER factors （except for XPC-RAD23B）, and TC-NER specific factors. These and yet unidentified proteins will accomplish not only efficient repair of transcription-blocking lesions, but are also likely to contribute to DNA damage signalling events.
基金National High Technology Research and Development Program of China(No.2007BAI14IB04)Major State Basic Research Development Program(No.2004CB518902)
文摘OBJECTIVE To compare the pharmacokinetics and pharmacodynamics of PEG30-rhG-CSF administered to beagle dogs at three different dosages with PEG20-rhG-CSF administered at one dosage, and to provide an experimental basis for clinical trials.METHODS Beagle dogs received single, subcutaneous doses of PEG30-rhG-CSF at 100, 200 and 400 μg/kg or PEG20-rhG-CSF at 200 μg/kg. PEG30-rhG-CSF and PEG20-rhG-CSF concentrations in serum were analyzed using an enzymeqinked immunosorbent assay （ELISA）. WBC, ANC and PLT counts of whole blood samples were measured using fully automated analytic instrumentation. Pharmacokinetic and pharmacodynamic parameters were calculated using DAS 2.0 statistical analysis software.METHODS Beagle dogs received single, subcutaneous doses of PEG30-rhG-CSF at 100, 200 and 400 μg/kg or PEG20-rhG-CSF at 200μg/kg. PEG30-rhG-CSF and PEG20-rhG-CSF concentrations in serum were analyzed using an enzyme-linked immunosorbent assay （ELISA）. WBC, ANC and PLT counts of whole blood samples were measured using fully automated analytic instrumentation. Pharmacokinetic and pharmacodynamic parameters were calculated using DAS 2.0 statistical analysis software. RESULTS The pharmacokinetic parameters of PEG30-rhG-CSF calculated from the serum concentration data determined by ELISA were as follows： the mean elimination half-life （t1/2ke） was 40.6 h （33.5-45.4 h）; the mean time to reach peak concentration （Tmax） was 19.2 h （11.7-24.0 h）; the drug clearance from the serum （CL） was decreased with increasing doses; the peak concentration （Cmax） and the area under the serum concentration-time curve （AUC） were increased with increasing doses. For PEG20-rhG- CSF, the half-life was shorter （12 h） and Tmax was achieved much earlier （10 h） relative to PEG30-rhG-CSF. The AUC of PEG30- rhG-CSF was much greater than that of PEG20-rhG-CSF, and the relative bioavailability with a subcutaneous injection was 158.7%. Administration of single doses of PEG30-rhG-CSF resulted in substantial increases in the absolute The time to reach ANC （ANCTmax） neutrophil count （ANC）. was 72 h. The maximum observed absolute neutrophil counts （ANCmax） and the area over the baseline effect curve （AOBEC） was increased with increasing doses. The effect-elimination half-life （t1/2E） ranged from 60 h to 80 h after subcutaneous administration. The PLT count was slightly elevated 8-12 h after s.c. injection, and declined after 24 h. CONCLUSION The mean elimination half-life of PEG30-rhG- CSF was longer than that of PEG20-rhG-CSF at the same dose, and the other main pharmacokinetic and pharmacodynamic parameters of PEG30-rhG-CSF, including C ANCmax, AUC and AOBEC were much greater than those following PEG20-rhG-CSF injection.
基金supported by King Mongkut’s University of Technology Thonburi(Thailand)the National Science and Technology Development Agency(CPMO P-14-51347)supported by the Royal Golden Jubilee Ph.D.Program,Thailand(PHD/0036/2556)
文摘Background: Edge effects cause changes in bird community richness, abundance, and/or distribution within a landscape, but the avian guilds most influenced can vary among regions. Although Southeast Asia has the highest rates of deforestation and projected species loss, and is currently undergoing an explosive growth in road infrastructure, there have been few studies of the effects of forest edges on avian communities in this region.Methods: We examined avian community structure in a dry evergreen forest in northeastern Thailand adjacent to a five-lane highway. We evaluated the richness and abundance of birds in 11 guilds at 24 survey points on three parallel transects perpendicular to the edge. At each point, 10-min surveys were conducted during February-August 2014 and March-August 2015. Vegetation measurements were conducted at 16 of the bird survey points and ambient noise was measured at all 24 survey points.Results: We found a strongly negative response to the forest edge for bark-gleaning, sallying, terrestrial, and understory insectivores and a weakly negative response for arboreal frugivore-insectivores, foliage gleaning insectivores, and raptors. Densities of trees and the percentage canopy cover were higher in the interior, and the ambient noise was lower. In contrast, arboreal nectarivore-insectivores responded positively to the forest edge, where there was a higher vegetation cover in the ground layer, a lower tree density, and a higher level of ambient noise.Conclusion: Planners should avoid road development in forests of high conservation value to reduce impacts on biodiversity. Where avoidance is impossible, a number of potential mitigation methods are available, but more detailed assessments of these are needed before they are applied in this region.
文摘The desolvation of erythromycin acetone solvate was investigated under non-isothermal conditions by a thermogravimetric analyzer. This paper emphasized the kinetic analysis of non-isothermal TG-DTA data by Achar method and Coats-Redfern method to fit various solid-state reaction models, and to achieve kinetic parameters of desolvation. The mechanism of thermal desolvation was evaluated using the kinetic compensation effect. The results show that kinetics of desolvation of erythromycin acetone solvate was compatible with the mechanism of a two-dimensional diffusion controlled and was best expressed by Valensi equation. Corresponding to the integral method and the differential method, the activation energy of desolvation of erythromycin acetone solvate was estimated to be 51.26—57.11 kJ/mol, and the pre-exponential factor was 8.077×106 s-1—4.326×107 s-1, respectively.
文摘This article addresses the magnetohydrodynamics(MHD) flow of a third grade fluid over an exponentially stretching sheet. Analysis is carried out in the presence of first order chemical reaction. Both cases of constructive and destructive chemical reactions are reported. Convergent solutions of the resulting differential systems are presented in series forms. Characteristics of various sundry parameters on the velocity, concentration, skin friction and local Sherwood number are analyzed and discussed.
文摘OBJECTIVE To reveal the biological effects and effective dosage in radiotherapy model which applies high single-dose irradiation by animal experiment. METHODS We inoculated subcutaneouly human pancreatic carcinoma cell line （MIA PaCa-2） in the lateral of the right lower extremity of the athymic mouse to grow transplantation tumor. While the median diameter of transplantation tumor reached 10 mm approximately, the animals were randomly divided into 7 groups （6 animals per group） and irradiation by different dose in one fixed with consciousness for fraction （0, 2, 5, 10, 17, 25, 35 Gy）. All were kept on to be bred for observation of the change in gross tumor volume, calculation of delayed growth time and delayed growth curve. RESULTS With increased dose per fraction, cutaneous reaction on the neoplasma surface of the animal, which was mainly moist yellow effusion was more and more severe. When dosage is less than 10 Gy, all animals showed similar effects, that＇s the delayed tumor growth was not obvious. Tumors receiving more than 10 Gy in one fraction showed very good biological effect and the delayed tumor growth was obviously related to dosage. The difference in delayed tumor growth between the 2 groups was statistically significant. The delayed tumor growth time in 10, 17, 25 Gy group was respectively 3 weeks, 6 weeks and more. CONCLUSION The biological effect of the model which applies high single-dose irradiation （more than 10 Gy in one fraction） was very good. The effect of delayed tumor growth was obviously related to the dosage after transplantation tumor was radiated. Because of its higher dose per fraction and biological effects, the model of high single-dose irradiation can get better clinical effects.
文摘In order to find natural compounds of interest such as pesticides and therapeutic molecules, toxicological properties of seed methanolic extracts （SME） of nine Malagasy Albizia species were investigated. Toxicity was assessed on living animals by intraperitoneal and oral route, and pharmacological effects on isolated organs. All SME induced various disorders in mice but the signs of the nervous system disturbs were the earliest and the most often observed. The main organ lesions, examined on histological sections, induced vasodilatation, inflammatory infiltrate of neutrophil polymorphonuclears and hemorrhagic areas. At low concentrations （until 20 p.g/mL）, A. masikororum and A. viridis provoked on isolated auricular a positive inotrope effect followed by a progressive inhibition of the contraction and a complete atrial arrhythmia. Besides, A. viridis and A. bernieri induced some hepatic functional impairment after a chronic treatment during one month. Albizia greveana with a LD50 of 1.13-2 mg/kg was the most toxic and Albizia bernieri the least one with a LD50 of 52 mg/kg. Alkaloids and/or saponins, the major chemical groups found by phytochemical screening on these extracts, could be responsible of their toxicity.
文摘Introduction In the United States, there are about 17.6 million patients suffer from symptomatic coronary artery disease （CAD）, affecting 7.9% of adults ≥ 20 years of age.1 An estimated 10.2 million patients have angina, and 500,000 patients will develop new angina pectoris each year. 1 A subset of angina patients are categorized as refractory when symptoms continue despite optimal medical therapy and revascularization.Routine daily activities become impossible without experiencing chest pain in this patient population.2
文摘We used a potent and specific monoclonal antibody to somatostatin to test the physiologic inhibitory role of the tetradecapeptide somatostatin on pancreatic secretion.Somatostatin immunoneutralization increased both the total amylase and volume of pancreatic secretion.Cholecystokinin-A receptor antagonism abolished the stimulatory effect of somatostatin immunoneutralization.We conclude that somatostatin tonically inhibits pancreatic secretion in fasted rats via inhibition of the release or action of cholecystokinin.Furthermore,the source of these peptides is likely islet delta cells and intrapancreatic neurons,respectively.
