Proteomic Difference Analysis of Whole Blood and Bloodstains / 法医学杂志

OBJECTIVES@#To study the changes of protein levels in peripheral blood after it dried.@*METHODS@#The proteins from whole blood and bloodstains were detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and normalized by the label-free quantification (LFQ) method. The differential proteins were analyzed by using R 4.2.1 software, limma and edgeR package. The analysis of biological function, signaling pathway and subcellular localization for the differential proteins was then performed.@*RESULTS@#A total of 623 and 596 proteins were detected in whole blood and bloodstains, respectively, of which 31 were statistically significant in the quantitative results, including 10 up-regulated and 21 down-regulated proteins in bloodstains.@*CONCLUSIONS@#The protein abundances in whole blood and bloodstains are highly correlated, and the variation of protein abundances may be related to the changes of endogenous and structural proteins in cells. The application of proteomics technology can assist the screening and identification of protein biomarkers, thereby introducing new biomarkers for forensic research.

Cross-Platform Application of DNA Methylation Age Estimation Model in Eastern Chinese Han Population / 法医学杂志

OBJECTIVES@#To evaluate the forensic application value of an age estimation model based on DNA methylation in eastern Chinese Han population, and to provide a theoretical basis for exploring age estimation models suitable for different detection platforms.@*METHODS@#According to the 6 age-related methylation sites in the published blood DNA methylation age estimation models of Chinese Han population, the DNA methylation level of 48 samples was detected by pyrosequencing and next-generation sequencing (NGS). After submitting DNA methylation levels to the age estimation model, the DNA methylation ages were predicted and compared with their real ages.@*RESULTS@#The 6 DNA methylation sites in both detection techniques were age-related, with an R2 of 0.85 and a median absolute deviation (MAD) of 4.81 years when using pyrosequencing；with an R2 of 0.84 and MAD of 4.41 years when using NGS.@*CONCLUSIONS@#The blood DNA methylation age estimation model can be used under pyrosequencing and multi-purpose regional methylation enrichment sequencing technology based on NGS and it can accurately estimate the age.

Effects of acupuncture on pulmonary function and airway smooth muscle spasm in asthma rats / 中国针灸

OBJECTIVE@#To observe the effects of acupuncture at "Kongzui" (LU 6) and "Yuji" (LU 10) on the latent period of inducing asthma, pulmonary function and the expression of endothelin-1 (ET-1) and metallothionein-2 (MT-2) in asthma rats, and to explore the possible mechanism of acupuncture in alleviating airway smooth muscle spasm and improving the acute attack of asthma.@*METHODS@#A total of 40 male SD rats of SPF-grade were randomly divided into a normal group, a model group, a medication group and an acupuncture group, 10 rats in each group. Except for the normal group, ovalbumin sensitization method was used to establish the asthma model in the other 3 groups. Salbutamol nebulization was adopted in the medication group, while acupuncture was applied at bilateral "Kongzui" (LU 6) and "Yuji" (LU 10) in the acupuncture group. The intervention was given once a day for 14 days in the two groups. The latent period of inducing asthma and pulmonary function were observed, the levels of ET-1 and tumor necrosis factor (TNF)-α in serum and bronchoalveolar lavage fluid (BALF) were detected by ELISA method, the morphology of the airway was observed by Masson staining, the ultrastructure of the airway smooth muscle was observed by transmission electron microscopy, the mRNA and protein expression of ET-1 and MT-2 in lung tissue was detected by real-time PCR and Western blot methods.@*RESULTS@#Compared with the normal group, in the model group, the latent period of inducing asthma was shortened (P<0.01); the airway resistance (RL) was increased while the dynamic compliance (Cdyn) was decreased (P<0.01, P<0.05); the levels of ET-1 and TNF-α in serum and BALF were increased (P<0.01); collagen fibers and collagen depositions were found around the bronchi, airway smooth muscle was thickened, the cell damage was severe and mitochondria were swollen; the mRNA and protein expression of ET-1 was increased while the mRNA and protein expression of MT-2 was decreased (P<0.01). Compared with the model group, in the acupuncture group, the latent period of inducing asthma was prolonged (P<0.05), the RL was decreased while the Cdyn was increased (P<0.01, P<0.05). Compared with the model group, in the medication group and the acupuncture group, the levels of ET-1 and TNF-α in serum and BALF were decreased (P<0.01, P<0.05); collagen fibers and collagen depositions around the bronchi were reduced, the thickened airway smooth muscle was lightened, the cell damage was improved; the mRNA and protein expression of ET-1 was decreased while the mRNA and protein expression of MT-2 was increased (P<0.01). Compared with the medication group, the mRNA expression of MT-2 was increased in the acupuncture group (P<0.05).@*CONCLUSION@#Acupuncture at "Kongzui" (LU 6) and "Yuji" (LU 10) can improve the pulmonary function and alleviate the airway smooth muscle spasm in rats with asthma. Its mechanism may be related to the down-regulation of ET-1 expression and up-regulation of MT-2 expression.

Age Estimation Based on DNA Methylation and Its Application Prospects in Forensic Medicine / 法医学杂志

With the improvement of DNA methylation detection techniques, studies on age-related methylation sites have found more age-specific ones across tissues, which improves the sensitivity and accuracy of age estimation. In addition, the establishment of various statistical models also provides a new direction for the age estimation of tissues from different sources. This review summarizes the related studies of age estimation based on DNA methylation from the aspects of detection technology, age-related cytosine phosphate guanine site and model selection in recent years.

Efficiency Analysis of Uncle-Nephew Relationship Identification by Increasing STR Markers and Adding Reference Samples / 法医学杂志

OBJECTIVES@#To estimate the system efficiency of uncle-nephew relationship identification by increasing STR markers and adding reference samples based on the test results of simulated data and real samples, so as to provide references for selecting the appropriate number of STRs and reference samples for uncle-nephew relationship identification.@*METHODS@#Five common models of uncle-nephew relationship identification were constructed by adding different reference samples. In each model, the likelihood ratio (LR) for 10 000 pairs of uncle-nephew relationships and 10 000 pairs of unrelated individuals were simulated by detecting 19, 39 or 55 STRs, and the system efficiency at different thresholds was simulated. The samples of the Han population in Zhejiang were collected, and 55 autosomal STRs were obtained by using SiFaSTRTM 23plex kit, Goldeneye® DNA ID 22NC kit and AGCU 21+1 PCR amplification kit. When 19, 39 and 55 STRs were detected, the LR of each model and system efficiency under different thresholds were calculated and compared with the simulation results.@*RESULTS@#Under the same detection system, the calculated results of simulated data and corresponding true samples were basically consistent. In the same model, there was a positive correlation between the system efficiency of uncle-nephew relationship identification and the number of STRs detected. Moreover, the system efficiency of introducing relatives was higher than identifying only two individuals. The order of preference for the introduction of relatives was the full sibling (or mother) of the uncle and the full sibling (or mother) of the nephew.@*CONCLUSIONS@#The system efficiency of uncle-nephew relationship identification could be improved by increasing the number of STRs and introducing known relatives, which would provide the basis for selecting the most appropriate detection system and reference individuals in actual cases.

Cultivation of interpersonal communication ability for residents via emotional quotient education in the standardized residency training / 中华医学教育探索杂志

Objective:To analyze the relationship between each dimension of emotional intelligence and interpersonal communication ability, and explore how to improve the interpersonal communication ability of residents through targeted emotional intelligence training.Methods:A total of 132 first-year residents of clinical medicine in the residency training base were jointly measured with emotional intelligence and interpersonal communication evaluation scale on the basis of self-assessment and grading. The differences between groups in self-assessment and grading were detected by one-way ANOVA, and the relationship between various dimensions of emotional intelligence and interpersonal communication ability was explored by correlation analysis and multiple linear stepwise regression analysis. SPSS 19.0 was used to conduct statistical analysis.Results:The self rating scale clearly divided the subjects into three levels. In the total score of emotional intelligence and its various dimensions, the differences between the three levels were statistically significant; the scores of the "good" group were higher than those of the "fair" group and the "slightly insufficient" group. There were statistical significance in the total score of emotional intelligence ( P<0.001) and its emotional perception ( P<0.001), self emotional management ( P<0.001), others' emotional management ( P<0.001) and emotional utilization ( P<0.001). In the total score of interpersonal communication ability and its various dimensions, the differences among the three levels were statistically significant. In the conflict management, the difference between the "good" group and the "fair" group was not statistically significant, and the differences in other items were statistically significant. The total score of emotional intelligence and its dimensions were positively correlated with interpersonal communication ability ( P<0.001), but the two dimensions that had the most significant impact on interpersonal communication ability were emotional perception and others' emotional management ( R2=0.531, P<0.001). Conclusion:By focusing on the cultivation of each dimensions of emotional perception and other emotional management for residents, it is expected to play a positive role in achieving the national goal of cultivating interpersonal communication skills.

Potential use of a dried saliva spot(DSS)in therapeutic drug monitoring and disease diagnosis / 药物分析学报

In recent years,scientific researchers have increasingly become interested in noninvasive sampling methods for therapeutic drug monitoring and disease diagnosis.As a result,dried saliva spot(DSS),which is a sampling technique for collecting dried saliva samples,has been widely used as an alternative matrix to serum for the detection of target molecules.Coupling the DSS method with a highly sensitive detection instrument improves the efficiency of the preparation and analysis of biological samples.Furthermore,dried blood spots,dried plasma spots,and dried matrix spots,which are similar to those of the DSS method,are discussed.Compared with alternative biological fluids used in dried spot methods,including serum,tears,urine,and plasma,saliva has the advantage of convenience in terms of sample collection from children or persons with disabilities.This review aims to provide integral strategies and guidelines for dried spot methods to analyze biological samples by illustrating several dried spot methods.Herein,we summarize recent advancements in DSS methods from June 2014 to March 2021 and discuss the advantages and disadvantages of the key aspects of this method,including sample preparation and method validation.Finally,we outline the challenges and prospects of such methods in practical applications.

Effects of Peripheral Blood Different Pretreatment Methods and Preservation Time on RNA Quality / 法医学杂志

OBJECTIVES@#To evaluate the effects of different pretreatment methods and preservation time on RNA quality of peripheral blood samples, and to optimize the preservation method of peripheral blood samples.@*METHODS@#Eight pretreatment methods were used to preprocess the peripheral blood from 3 healthy unrelated individuals and the treated samples were stored at -80 ℃. Total RNA of samples was extracted using Quick-RNATM Miniprep Plus kit. DNA/RNA ShieldTM was added to peripheral blood and total RNA was extracted after preservation at -80 ℃ for 0, 5, 10, 15, 30 and 60 days, respectively. The concentration, purity and integrity of RNA were determined. Statistical analyses were performed by SPSS 22.0 software to compare the differences in RNA yield, purity and integrity among the eight pretreatment methods.@*RESULTS@#In terms of purity, leukocyte pretreated with RNAlaterTM and directly cryopreservation peripheral blood showed the worst purity. The other six methods showed better purity. In terms of yield, blood cells with DNA/RNA ShieldTM came out with the highest yield, followed by peripheral blood with DNA/RNA ShieldTM. In terms of integrity, peripheral blood preserved in PAXgene Blood RNA tube method had the best integrity. Except for peripheral blood pretreated with DNA/RNA ShieldTM and blood cells pretreated with DNA/RNA shieldTM, the other five methods had statistical differences when compared to the method by keeping peripheral blood in PAXgene Blood RNA tube. The purity of RNA stored at six-time gradients ranged from 1.815 to 1.952. With the increase of storage time, RNA yield decreased from 4.516 ng to 1.039 ng, and RNA integrity decreased from 8.533 to 7.150.@*CONCLUSIONS@#According to the results of total RNA's yield, purity and integrity, peripheral blood pretreated with DNA/RNA ShieldTM was the best pretreatment method. After the pretreatment, samples can be preserved for up to 60 days in low temperature.

Design and application of / 中国针灸

On the base of the principle of penetrating moxibustion and in combination with free adjustment devices such as movable U-shaped moxa stick holder and movable clamp, a new type of moxibustion box exerted on the head is designed, with precise positioning and sufficient heat intensity.

Progress on Copy Number Variation and Its Application in Forensic Medicine / 法医学杂志

Recently, researches on copy number variation （CNV） have extended to every field, such as etiological exploration and precise treatment of complex diseases, as well as genetic breeding and evolution. The unique genetic characteristics of CNV have made people gradually believe that it could be used as a biological genetic marker to solve related problems. With the development of detection technology, application of CNV in forensic medicine will increase gradually. In this paper, the concept and development of CNV, as well as its application in forensic medicine are summarized, to provide new ideas for the practical application of CNV in the future.

Evaluating the Efficiency of REPLI-g® Single Cell Kit for Trace DNA Amplification / 法医学杂志

Objective To evaluate the efficiency of REPLI-g® Single Cell Kit for sample DNA amplification, and explore its application value in forensic trace DNA amplification. Methods Three DNA extraction kits were selected to extract DNA from peripheral blood of 10 unrelated individuals. The DNA yield and purity of the three DNA extraction kits were compared. According to the results of comparison, one DNA sample was selected to concentrate and dilute, then used as the initial sample of whole genome amplification （WGA）. REPLI-g® Single Cell Kit was used to amplify the initial sample at the whole genome level. The amplification yield and amplification times were calculated, and the distribution of DNA fragments was detected by agarose gel electrophoresis. Goldeneye® DNA ID System 20A Kit was used to perform the STR typing of the initial sample and DNA samples amplified at the whole genome level to evaluate the performance of REPLI-g® Single Cell Kit in trace DNA amplication in terms of purity and yield as well as the success rate of STR typing. Results After comparison, one DNA sample was selected from QIAsymphony® DNA Investigator® Kit extracts to concentrate and dilute as the initial sample of WGA. After amplifying the whole genome of a series of initial samples by REPLI-g® Single Cell Kit, the lowest average of amplification yield reached 8.77×103 ng, while the average of the corresponding amplification times reached 1.40×106. DNA fragments were large and concentrated. The STR typing success rate of WGA samples became lower with the decrease of initial samples used, but when the amount of samples was lower than 0.5 ng, the STR typing success rate of samples after DNA WGA was higher than that of samples without DNA WGA. Conclusion REPLI-g® Single Cell Kit can increase the yield of template DNA. Especially for trace DNA, the STR typing success rate can be improved to a certain extent.

Application of Artificial Intelligence Technology in Pharmaceutical Field ：Visualization Analysis of Literature Based on Web of Science / 中国药房

OBJECTIVE： To investigate the research status，hotspots and frontiers of the artificial intelligence （AI） technology  applicated in pharmaceutical field， and to provide ideas for the development of related research in China. METHODS： Using bibliometric method， relevant journals and proceeding papers from 1998 to 2017 were searched from Web of Science database （“Article” and “Proceeding Paper” as retrieval words）. Using analysis and retrieval results of ISI Web of Knowledge and its function of creating citation report， CiteSpace 5.2.R1 software was employed to draw knowledge map； quantitative statistics and qualitative analysis was conducted to summarized the research volume， co-citation， main research countries/areas， main research  institutions， main researchers， research hotspots and research frontiers in this field. RESULTS： A total of 3 674 related literatures were retrieved， and the number of global published literatures in this field increased rapidly from 1998 to 2017； the dominant nations included America， China， Britain and Germany because of their large number of publications，but China showd an obvious lack of international cooperation and excellent core teams. From the researcher’s point of view， the research in this field was in a state of “partially concentrated and overall dispersed” and lacked team cooperation. The research hotspots contained important core of AI technology （machine learning algorithms） and its application in pharmaceutical field （drug discovery and design）， the classification of disease or adverse drug reaction， the establishment and optimization of pharmaceutical mode， drugs screening or pharmacodynamics prediction， the estbalishment of pharmaceutical database， etc. The recent research frontiers included “molecular docking” “machine learning” “Meta analysis” “precision medicine” “targeted therapy”， etc. CONCLUSIONS： AI applicated in pharmaceutical field is a hot research field with strong timeliness， and its application in the development of pharmaceutical industry is the general trend. However， there is still a gap between the current research level in this field in China and the international frontier research. In order to adapt to the international trend of the combination of AI technology and pharmacy， pharmacists in China should strengthen their cooperation with researchers in AI fields while doing well the basic work of experimental research and clinical trials，etc.

Research Progress on Discrimination of Monozygotic Twins / 法医学杂志

Individual identification plays an import role in the practice of forensic medicine, and often provides crucial evidence for the analysis and detection of criminal cases.However, for individual identification in complex situations, such as monozygotic (MZ) twins assumed to be genetically identical, it is impossible to distinguish one from the other by using traditional forensic DNA typing system.Therefore, how to discriminate the MZ twins has become and will continue to be one of the difficult problems in forensic field.This paper summarized the genetic and epigenetic changes recently identified in MZ pairs, which might provide a new insight to forensic discrimination of MZ twins.

Clinical Features and Current Treatment Status for In-hospital Elderly Patients With Mitral Regurgitation / 中国循环杂志

Objective: To summarize the clinical features and treatment status for elderly in-hospital patients with mitral regurgitation (MR). Methods: A single center retrospective study was conducted in 1 741 patients admitted in our hospital from 2014-05-01 to 2015-04-30 with echocardiography confirmed moderate to severe MR. The patients were divided into 2 groups: Elderly group, n=680(39.06%)patients≥60 years of age and Non-elderly group,n=1 061(60.94%)patients<60 years.Clinical features and treatment status were studied and compared between 2 groups. Results: The mean age in Elderly group was (66.98±5.94) years and the most common type was degenerative MR (41.18%). Compared with Non-elderly group, Elderly group had more patients combining coronary artery disease (37.79% vs 17.43% ), more risk factors of atherosclerosis such as hypertension (45.44% vs 25.17%), diabetes (19.56% vs 8.48%) and hyperglycemia (35.29% vs 19.51%) all P<0.05; Elderly group had the higher EuroSCORE Ⅱ score (5.54±2.42) vs (3.15±1.66), greater left ventricular end diastolic diameter (57.72±12.37) mm vs (57.33±10.19) mm and less patients combining multiple valve disease (35.59% vs 40.81%), less patients received surgical treatment (54.71% vs 63.9%), all P<0.05. The surgery procedures (mitral valve replacement or mitral-plasty) were similar between 2 groups; compared with Non-elderly group, Elderly group had the higher application rate of bio-prosthetic valve (53.88% vs 18.67%), P<0.001. Conclusion: About 40% in-hospital moderate to severe MR patients were the elderly crowd, the most common pathogenesis was degenerative changes which leaded the higher incidences of cardiac complications, worse cardiac function and the higher risk scores for surgical treatment, there were less patients received surgery.

Nursing of 17 patients with pregnancy-associated fulminant type 1 diabetes and intrauterine fetal demise / 中华护理杂志

This paper retrospectively summarized and analyzed observation of the disease and nursing care of 17 patients with pregnancy-associated fulminant type 1 diabetes and intrauterine fetal demise.Through timely supplying blood capacity and improving renal perfusion,maintaining blood glucose homeostasis and acid-alkali,potassium balance,safety of the patients was guaranteed;by providing effective psychological nursing,puerperal dietary guidance and discharge guidance,patients' rehabilitation was improved.As a result,16 patients were in stable condition,and dead babies were delivered.Major bleeding event occurred in one patient after delivering the dead baby,and the patient developed shock as well as liver and kidney failure.The patient was transferred to ICU for further treatment and became stable and was discharged after two months.

Nursing care of 23 patients with acromegaly and diabetes mellitus treated by pituitary tumor resection / 中华护理杂志

This paper summarized the perioperative nursing of 23 patients with acromegaly and diabetes mellitus underwent pituitary adenoma resection via nasal transsphenoidal approach.The key points in nursing were:preoperative respiratory monitoring during sleep,psychological care,blood glucose monitoring,respiratory fitness training;postoperative individualized glycemic management,close observation of breathing and nasal congestion,differentiating diabetes insipidus and cerebral salt-wasting syndrome,close monitoring of traits of nasal exudate,to assist patients to get through the perioperative period.As a result of careful treatment and nursing,23 patients were recovered and discharged.

Effect of Electroacupuncture on Colonic IL-1β and nAchRα7mRNA in Ulcerative Colitis Rats / 上海针灸杂志

Objective To compare the effects of electroacupuncture at points Shangjuxu(ST37), Zusanli(ST36), Xiajuxu(ST39) and Yanglingquan(GB34) on colonic expressions of interleukin-1b (IL-1b) and nicotinic acetylcholine receptor a7 mRNA (nAchRa7mRNA) in ulcerative colitis rats and investigate if large intestine lower He-Sea point Shangjuxu has relative specificity to fu organ diseases. Method Seventy healthy SD rats were randomized into blank, model, Shangjuxu, Zusanli, Xiajuxu, Yanglingquan and Chengjin groups, 10 rats, half male and half female, each. A rat model of ulcerative colitis was made by induction of 2-4-6 three nitrobenzene sulfonic acid/ethanol solution enema in every group except the blank group. After successful model making and ten days of treatment, rat colonic mucosal ulcers and inflammation were observed macroscopically, colonic IL-1bcontent was measured by ELISA and the expression of nAchRa7mRNA was determined by RT-PCR. Result Compared with the model group, colonic lesions were reduced in varying degrees, colonic IL-1b content was significantly lower and the expression of nAchRa7mRNA was higher in every acupoint group (P<0.05, P<0.01);the colonic ulcer score was lower in the Shangjuxu and Zusanli groups (P<0.05, P<0.01). Compared with the Shangjuxu group, colonic expression of nAchRa7mRNA was lower in the other four acupoint groups (P<0.01); colonic mucosal ulcers and inflammatory lesions were more severe and the colonic ulcer score and the IL-1bcontent were higher in the Xiajuxu, Yanglingquan and Chengjin groups (P<0.05, P<0.01). Conclusion The mechanism of electroacupuncture treatment for ulcerative colitis may be that it regulates abnormal immunologic function by modulating IL-1b and nAchRa7mRNA and reduces mucosal lesions. The overall therapeutic effect of Shangjuxu is better than those of Zusanli, Xiajuxu, Yanglingquan and Chengjin, indicating that Shangjuxu has relative specificity to fu organ large intestine.

Comparison of electroacupuncture at lower-sea points on HMGB 1 and nAchR α7 in rats with acute gastric mucosal lesion / 中国针灸

<p><b>OBJECTIVE</b>To observe the influence of electroacupuncture (EA) at lower-sea points of stomach, large intestine, small intestine and gallbladder on interleukin-1β (IL-1β), high mobility group protein 1 (HMGB 1) and alpha 7 nicotinic acetylcholine receptor (nAchR α7) in rats with acute gastric mucosal lesion (AGML), so as to explore whether there is relative specificity in treating gastric viscera disease by stimulating Zusanli (ST 36).</p><p><b>METHODS</b>Sixty healthy SD rats were randomly assigned into a blank group, a model group, a Zusanli group, a Shangjuxu group, a Xiajuxu group and a Yanglingquan group, ten rats in each one (half male and half female). The WRS method was applied to induce the AGML model except the rats in the blank group. The rats in the blank group were treated with routine diet; the rats in the model group were treated with immobilization at rat platform, 30 min per time; the rats in the Zusanli group, Shangjuxu group, Xiajuxu group and Yanglingquan group were treated with acupuncture and connected with EA device (dilatational wave 10 Hz/50 Hz, positive electrode on the left side and negative electrode on the right side, intensity was appropriate when rat hind leg slightly shook), 30 min per time. The treatment was given once a day. After consecutive 10-day treatment, the gastric tissue was collected and the damage of gastric mucosa was evaluated; ELISA method was applied to measure the content of serum IL-1β and tissue HMGB 1; the Western blot method was applied to measure the expression of nAchR α7 receptor.</p><p><b>RESULTS</b>(1) Compared with the model group, the ulcer index (UI) of gastric mucosa, serum IL-1β and tissue HMGB 1 were lower, and the expression of nAchR α7 was increased in the remaining groups (<0.05,<0.01). (2) Compared with the Zusanli group, the UI of gastric tissue, serum IL-1β and tissue HMGB 1 were higher in the Shangjuxu group, Xiajuxu group and Yanglingquan group (<0.05,<0.01), and the expression of nAchRα7 was reduced in the Yanglingquan group (<0.01).</p><p><b>CONCLUSIONS</b>(1) EA at digestive system-related lower-sea points, through IL-1β, HMGB 1 and nAchR α7, could regulate immune response, lighten inflammatory reaction and reduce mucosal injury, which could realize the intervention effect on AGML rats. (2) From the comparison, it is concluded the intervention effect of Zusanli group is superior to the other groups, partly indicating the relative specificity between Zusanli and stomach.</p>

Development of a mechanism-based pharmacokinetic/pharmacodynamic model to characterize the thermoregulatory effects of serotonergic drugs in mice

We have shown recently that concurrent harmaline, a monoamine oxidase-A inhibitor (MAOI), potentiates serotonin (5-HT) receptor agonist 5-methoxy--dimethyltryptamine (5-MeO-DMT)-induced hyperthermia. The objective of this study was to develop an integrated pharmacokinetic/pharmacodynamic (PK/PD) model to characterize and predict the thermoregulatory effects of such serotonergic drugs in mice. Physiological thermoregulation was described by a mechanism-based indirect-response model with adaptive feedback control. Harmaline-induced hypothermia and 5-MeO-DMT-elicited hyperthermia were attributable to the loss of heat through the activation of 5-HTreceptor and thermogenesisthe stimulation of 5-HTreceptor, respectively. Thus serotonergic 5-MeO-DMT-induced hyperthermia was readily distinguished from handling/injection stress-provoked hyperthermic effects. This PK/PD model was able to simultaneously describe all experimental data including the impact of drug-metabolizing enzyme status on 5-MeO-DMT and harmaline PK properties, and drug- and stress-induced simple hypo/hyperthermic and complex biphasic effects. Furthermore, the modeling results revealed a 4-fold decrease of apparent SCvalue (1.88-0.496 µmol/L) for 5-MeO-DMT when harmaline was co-administered, providing a quantitative assessment for the impact of concurrent MAOI harmaline on 5-MeO-DMT-induced hyperthermia. In addition, the hyperpyrexia caused by toxic dose combinations of harmaline and 5-MeO-DMT were linked to the increased systemic exposure to harmaline rather than 5-MeO-DMT, although the body temperature profiles were mispredicted by the model. The results indicate that current PK/PD model may be used as a new conceptual framework to define the impact of serotonergic agents and stress factors on thermoregulation.

Relationship between expression of endothelial nitric oxide synthase and NADPH oxidase in lungs of mice exposed to chronic hypoxia / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To explore the relationship between the expression of endothelial nitric oxide synthase (eNOS) and NADPH oxidase (NOX) in the lungs of mice treated by chronic hypoxic exposure.</p><p><b>METHODS</b>Thirty male wild-type (WT) C57Bl/6 mice and thirty male eNOS-knockout (KO) C57BL/6 mice were randomly divided into normoxic groups (exposed to normoxia for 7 days or 21 days), hypoxic groups (exposed to 10% oxygen for 7 days or 21 days), and treatment groups (exposed to 10% oxygen and orally administrated 10 mmol/L 4-hydroxy TEMPO in drinking water for 7 days or 21 days) (n=6 in each group). The remodeling of the small pulmonary arteries was evaluated by the percentage of media wall thickness (MT%). The weight ratio of right ventricle to left ventricle plus septum (RV/[LV+S]) was calculated to evaluate the hypertrophy of right ventricle. Real-time PCR was used to measure the mRNA expression of NOX2, NOX4, and eNOS in mouse lungs. ELISA was used to determine the concentration of reactive oxygen species (ROS) in mouse lungs.</p><p><b>RESULTS</b>In WT mice and KO mice, the hypoxic groups had significantly increased pulmonary vascular remodeling and RV/[LV+S] compared with the normoxic and treatment groups (P<0.05), but there were no significant differences between the normoxic and treatment groups (P>0.05). In WT mice, the hypoxic and treatment groups had significantly lower ROS concentrations than the normoxic group (P<0.05), but there were no significant differences between the hypoxic and treatment groups (P>0.05). In WT mice, the mRNA expression of eNOS, NOX2, and NOX4 was significantly higher in the hypoxic group than in the normoxic group (P<0.05), and 4-hydroxy TEMPO reversed their over-expression. In the normoxic group, the KO mice had significantly higher NOX2 and NOX4 mRNA expression than the WT mice (P<0.05); in KO mice, the hypoxic group showed no significant changes in NOX4 mRNA expression (P>0.05), but had significantly reduced NOX2 mRNA expression (P<0.05), as compared with the normoxic group; the treatment group had reduced expression of NOX2 mRNA expression and increased NOX4 mRNA expression (P<0.05), as compared with the hypoxic group.</p><p><b>CONCLUSIONS</b>eNOS plays a key role in the regulation of expression of NOX2 and NOX4 in the lungs exposed to hypoxia. It suggests that NOX and eNOS may physically interact with one another in pulmonary vascular remodeling induced by chronic hypoxia.</p>