BACKGROUND:Plasma coagulation factors have been shown to be strongly associated with chronic kidney disease in many observational studies.Nevertheless,the causal relationship between plasma coagulation factors and chronic kidney disease has not been fully revealed.OBJECTIVE:To assess and explore the association between plasma coagulation factors and chronic kidney disease risk using a two-sample Mendelian randomization approach.METHODS:Genome-wide association study data of 39 plasma coagulation factors with different ID numbers were obtained from the GWAS Catalog database and chronic kidney disease genome-wide association analysis data(ebi-a-GCST003374)were obtained from the Open Genome-Wide Association Study database(IEU Open GWAS),where the sample size of the chronic kidney disease dataset was 117 165 cases and the number of single nucleotide polymorphisms was 2 179 497.Inverse variance weighting,MR-Egger regression,weighted median,weighted mode,and simple mode were used to explore causality.Meanwhile,Cochran Q test was used to assess the variability of single nucleotide polymorphism loci.Horizontal pleiotropy of single nucleotide polymorphisms was verified by MR-Egger intercept test.Sensitivity analyses were performed using the"leave-one-out"method to determine whether the Mendelian randomization results would be confounded by a single single nucleotide polymorphism site.RESULTS AND CONCLUSION:(1)A total of four plasma coagulation factors were associated with chronic kidney disease by Mendelian randomization analysis of 39 plasma coagulation factors and chronic kidney disease.Plasma coagulation factor V(FV)level(odds ratio[OR]=0.922,95％confidence interval[CI]:0.875-0.971,P=0.002),plasma FVII level(OR=0.719,95％CI:0.521-0.991,P=0.044),plasma FXa level(OR=1.113,95％CI:1.009-1.227,P=0.032),plasma antithrombin-level(OR=0.849,95％CI:0.739-0.975,P=0.020)were significantly associated with chronic kidney disease(all P＜0.05).Horizontal pleiotropy and heterogeneity were not detected.(2)Based on the two-sample Mendelian randomization in the genetic epidemiologic method,plasma FVII level,plasma antithrombin-level,and plasma FV level of coagulation factors were protective factors for the risk of chronic kidney disease,and plasma FXa level was a risk factor of chronic kidney disease.(3)The above results confirm that there is a significant potential causal relationship between plasma coagulation factors and chronic kidney disease.Although we analyzed the data of European populations from international databases,these data analyses have a reference value for the study of chronic kidney disease and coagulation factors in China,and they also provide innovative insights into the study of the genetic epidemiology of chronic kidney disease,and they also provide a certain reference value for the in-depth study of the related databases in China,including the China Health and Retirement Longitudinal Study database.Future studies can focus on the assessment of hypocoagulability or hypercoagulability of related coagulation factors in patients with chronic kidney disease.

BACKGROUND:Plasma coagulation factors have been shown to be strongly associated with chronic kidney disease in many observational studies.Nevertheless,the causal relationship between plasma coagulation factors and chronic kidney disease has not been fully revealed.OBJECTIVE:To assess and explore the association between plasma coagulation factors and chronic kidney disease risk using a two-sample Mendelian randomization approach.METHODS:Genome-wide association study data of 39 plasma coagulation factors with different ID numbers were obtained from the GWAS Catalog database and chronic kidney disease genome-wide association analysis data(ebi-a-GCST003374)were obtained from the Open Genome-Wide Association Study database(IEU Open GWAS),where the sample size of the chronic kidney disease dataset was 117 165 cases and the number of single nucleotide polymorphisms was 2 179 497.Inverse variance weighting,MR-Egger regression,weighted median,weighted mode,and simple mode were used to explore causality.Meanwhile,Cochran Q test was used to assess the variability of single nucleotide polymorphism loci.Horizontal pleiotropy of single nucleotide polymorphisms was verified by MR-Egger intercept test.Sensitivity analyses were performed using the"leave-one-out"method to determine whether the Mendelian randomization results would be confounded by a single single nucleotide polymorphism site.RESULTS AND CONCLUSION:(1)A total of four plasma coagulation factors were associated with chronic kidney disease by Mendelian randomization analysis of 39 plasma coagulation factors and chronic kidney disease.Plasma coagulation factor V(FV)level(odds ratio[OR]=0.922,95％confidence interval[CI]:0.875-0.971,P=0.002),plasma FVII level(OR=0.719,95％CI:0.521-0.991,P=0.044),plasma FXa level(OR=1.113,95％CI:1.009-1.227,P=0.032),plasma antithrombin-level(OR=0.849,95％CI:0.739-0.975,P=0.020)were significantly associated with chronic kidney disease(all P＜0.05).Horizontal pleiotropy and heterogeneity were not detected.(2)Based on the two-sample Mendelian randomization in the genetic epidemiologic method,plasma FVII level,plasma antithrombin-level,and plasma FV level of coagulation factors were protective factors for the risk of chronic kidney disease,and plasma FXa level was a risk factor of chronic kidney disease.(3)The above results confirm that there is a significant potential causal relationship between plasma coagulation factors and chronic kidney disease.Although we analyzed the data of European populations from international databases,these data analyses have a reference value for the study of chronic kidney disease and coagulation factors in China,and they also provide innovative insights into the study of the genetic epidemiology of chronic kidney disease,and they also provide a certain reference value for the in-depth study of the related databases in China,including the China Health and Retirement Longitudinal Study database.Future studies can focus on the assessment of hypocoagulability or hypercoagulability of related coagulation factors in patients with chronic kidney disease.

Objective:To investigate the effects of rapid short-term altitude exposure on thyroid related hormone parameters in healthy male pilots.Methods:A total of 132 healthy male pilots who lived in the plain were selected by random number table method to enter the plateau, with an average altitude of 3 000 m, within 3 h by plane from the plain, with an average altitude of 100 m, from March 2023 to April 2023, and returned to the plain within 3 h by plane 15 d later. General physiological indices, thyroid related hormone parameters [thyroid stimulating hormone (TSH), total thyroid hormone (TT 4), free thyroxine (FT 4), free triiodothyronine (FT 3), total triiodothyronine (TT 3), thyroglobulin antibody (TgAb), anti-thyroid peroxidase antibody (TPOAb), and thyroglobulin (Tg)] were collected from the pilots 1 day before the rush into plateau exposure and after 15-day plateau exposure. The differences in thyroid related hormone parameters of the pilots before and after acute short-term plateau exposure were compared. Results:As compared with the parameters before entering the plateau, the heart rate, respiratory rate, systolic and diastolic blood pressure of pilots were increased and oxygen saturation was decreased after 15 d plateau exposure, and the differences were statistically significant ( t=8.65, 10.78, 13.39, 12.49, 17.72, all P<0.001). The levels of TSH, FT 4, TPOAb and Tg of pilots were all decreased after 15 d plateau exposure, and the differences were significant ( t=3.67, 2.17, Z=-4.63, -7.49, P=0.003, 0.049, <0.001, <0.001). The levels of TT 4 and TT 3 were elevated, with significant differences ( t=4.08, 2.55, P<0.001, =0.024). TgAb level was less discrete, but the difference was significant ( Z=-2.36, P=0.018). Conclusions:By rush into plateau and short-term exposure, the healthy male pilots showed decreased TSH, FT 4, TPOAb and Tg, and increased TT 4 and TT 3, and those may result in the thyroid gland due to acute stress and low-pressure hypoxia appeared related to the hormone metabolism and protein changes.

Objective To observe the changes of liver function,blood cell,and lung function of healthy young and middle-aged men before and after fast-advancing short-term high altitude exposure(FSHAE);and to explore the effects and possible mechanisms of FSHAE on the function of liver,blood cells,and lung tissues.Methods This study included 48 healthy young and middle-aged male volunteers,who collected physiological indicators,tested liver function indicators,blood cell indicators,and lung function-related indicators 1 day before entering the plateau(100m above sea level),and 15 days after FSHAE(3000m above sea level).Differences in the relevant parameters of each system were compared before and after FSHAE.Results Compared with those before entering the plateau,the physiological parameters of young and middle-aged men after 15 days of FSHAE heart rate increased significantly,respiratory rate increased,systolic blood pressure increased,mean arterial blood pressure increased,oxygen saturation decreased(P＜0.01),and diastolic blood pressure increased(P＜0.05),all of which were statistically significant;and the indicators of liver function:glutamic oxaloacetic aminotransferase,glutamic alanine aminotransferase increased(P＜0.01),glutamylamine aminotransferase,glutamate aminotransferase,glutaminase,and pulmonary function were increased(P＜0.01),glutamyl transpeptidase,alkaline phosphatase,and total bile acids were elevated,and total protein decreased(P＜0.05),and the differences were statistically significant.Hemocyte-related indexes:erythrocyte count,erythrocyte pressure volume,mean erythrocyte volume,mean hemoglobin volume,mean hemoglobin concentration,and hemoglobin were elevated,and platelet count decreased(P＜0.01),and the differences were statistically significant.although there was an elevation of leukocyte count(P＞0.05);Lung function-related indexes:decreased exertion lung volume(P＜0.05).There were decreased exertion expiratory volume in the first second,increased one-second rate(P＞0.05).Conclusion FSHAE can lead to oxidative stress in the organism,and acute hypoxic multisystemic injury will occur,with the simultaneous emergence of hypoxic adaptive regulation of various systems,self-compensatory repair of various organs of the organism,and there may be the possibility of interactions between various systems.

Objective:To investigate the effects of rapid short-term altitude exposure on thyroid related hormone parameters in healthy male pilots.Methods:A total of 132 healthy male pilots who lived in the plain were selected by random number table method to enter the plateau, with an average altitude of 3 000 m, within 3 h by plane from the plain, with an average altitude of 100 m, from March 2023 to April 2023, and returned to the plain within 3 h by plane 15 d later. General physiological indices, thyroid related hormone parameters [thyroid stimulating hormone (TSH), total thyroid hormone (TT 4), free thyroxine (FT 4), free triiodothyronine (FT 3), total triiodothyronine (TT 3), thyroglobulin antibody (TgAb), anti-thyroid peroxidase antibody (TPOAb), and thyroglobulin (Tg)] were collected from the pilots 1 day before the rush into plateau exposure and after 15-day plateau exposure. The differences in thyroid related hormone parameters of the pilots before and after acute short-term plateau exposure were compared. Results:As compared with the parameters before entering the plateau, the heart rate, respiratory rate, systolic and diastolic blood pressure of pilots were increased and oxygen saturation was decreased after 15 d plateau exposure, and the differences were statistically significant ( t=8.65, 10.78, 13.39, 12.49, 17.72, all P<0.001). The levels of TSH, FT 4, TPOAb and Tg of pilots were all decreased after 15 d plateau exposure, and the differences were significant ( t=3.67, 2.17, Z=-4.63, -7.49, P=0.003, 0.049, <0.001, <0.001). The levels of TT 4 and TT 3 were elevated, with significant differences ( t=4.08, 2.55, P<0.001, =0.024). TgAb level was less discrete, but the difference was significant ( Z=-2.36, P=0.018). Conclusions:By rush into plateau and short-term exposure, the healthy male pilots showed decreased TSH, FT 4, TPOAb and Tg, and increased TT 4 and TT 3, and those may result in the thyroid gland due to acute stress and low-pressure hypoxia appeared related to the hormone metabolism and protein changes.

The integrity of lysosomes is of vital importance to survival of tumor cells. We demonstrated that LW-218, a synthetic flavonoid, induced rapid lysosomal enlargement accompanied with lysosomal membrane permeabilization in hematological malignancy. LW-218-induced lysosomal damage and lysosome-dependent cell death were mediated by cathepsin D, as the lysosomal damage and cell apoptosis could be suppressed by depletion of cathepsin D or lysosome alkalization agents, which can alter the activity of cathepsins. Lysophagy, was initiated for cell self-rescue after LW-218 treatment and correlated with calcium release and nuclei translocation of transcription factor EB. LW-218 treatment enhanced the expression of autophagy-related genes which could be inhibited by intracellular calcium chelator. Sustained exposure to LW-218 exhausted the lysosomal capacity so as to repress the normal autophagy. LW-218-induced enlargement and damage of lysosomes were triggered by abnormal cholesterol deposition on lysosome membrane which caused by interaction between LW-218 and NPC intracellular cholesterol transporter 1. Moreover, LW-218 inhibited the leukemia cell growth

Objective:To evaluate the effect of portal vein restriction combined with hepatic artery ligation on Sprague Dawley(SD) rats liver regeneration and injury.Methods:Twenty-four healthy and clean SD male rats, 250-280 g, 7-8 weeks old, were randomly divided into portal vein ligation (PVL) group, mild restriction group and moderate restriction group with 8 rats in each group. In PVL group, the right, caudal and left branches of portal vein were ligated, and only the right branches of portal vein were preserved. The operation of mild and moderate restriction group was the same as PVL, however, the left branch of the portal vein was slightly and moderately restricted, and the left branch of the hepatic artery was ligated at the same time. At 72 hours after the operation, the left middle lobe was stained with hematoxylin-eosin and the total necrosis score was calculated. The right middle lobe was immunostained for Ki-67 and the number of positive cells was counted. The liver regeneration rate of the right middle lobe was calculated and the serum liver function indexes were measured.Results:The hepatic regeneration rate of right middle lobe in PVL group was (109.1±10.9)%, while that in moderate restriction group was (105.0±12.3)%, which was significantly higher than that in the mild restriction group (67.1±6.4)%, the differences were statistically significant ( P<0.05). The Ki-67 result was also higher in the PVL group than the mild restriction group. The total necrosis score was 4.50(3.25, 6.00) in moderate restriction group, 2.00(1.25, 3.00) in PVL group and 0(0, 0.75) in mild restriction group. The three groups showed a decreasing trend and the differences were statistically significant ( P<0.05). Alanine aminotransferase in mild restriction group was (48.4±11.4) U/L, was significantly lower than that in PVL group (67.2±12.2) U/L and moderate restriction group (74.3±14.2) U/L, the difference was statistically significant ( P<0.05). There were no significant differences in serum levels of aspartate aminotransferase, albumin and total bilirubin among the three groups ( P>0.05). Conclusion:Appropriate portal vein restriction combined with hepatic artery ligation can effectively induce the regeneration of liver tissue on the reserved lobe and control the damage of liver tissue on the occluded lobe.

Value-based medicine is a new medical model which develops on the basis of evidence-based medicine and perfectly combines the skills and experiences of doctors with patients and hospitals’ value. According to the definition and connotation of the value-based medicine,this paper introduced its preliminary application at different stages(theoretical teaching,internship and practice) of digestive disease courses by teaching theory courses and letting students involved in the management of different individuals of the same disease. Meanwhile,this paper discussed on its effects.

OBJECTIVETo investigate the prophylactic and therapeutic effect of oxymatrine on experimental liver fibrosis and to reveal its mechanism.

METHODSBy establishing D-galactosamine-induced rat liver fibrosis model, we observed the effect of oxymatrine on serum and tissue biochemical indexes, content of liver hydroxyline, expression of TGF?1 mRNA and changes of tissue pathology.

RESULTSThere was a decline of liver hydroxyline and serum AST and ALT in oxymatrine group compared to those of the D-GalN group. The hydroxyline content in oxymatrine pretreatment group was (0.50 0.11)mug/mg compared with (0.99 0.14)mug/mg in D-GalN group (t=8.366, P<0.01). The content in oxymatrine treatment group was (0.44 0.04)mug/mg compared with 0.70 0.06 in D-GalN group (t=9.839, P<0.01). The SOD activity was (149.81 15.28) NU/mg in oxymatrine pretreatment group and (95.22 16.33) NU/mg in the model group (t=7.309, P<0.01); (157.68 19.54) NU/mg in the treatment group compared with (119.88 14.94) NU/mg in the model group (t=4.348, P<0.01). MDA in the pretreatment group was (2.06 0.17) nmol/mg, lower than (4.57 0.37) nmol/mg in the model group (t=17.529, P<0.01). In the treatment group, it was (1.76 0.24)nmol/mg, lower than (3.10 0.17) nmol/mg in the model group (t=12.697, P<0.01). TGF?1 mRNA reduced in the pretreatment and treatment groups as compared with that in the model group (0.21 0.01 vs 0.50 0.01, t=48.665, P<0.01; 0.18 0.02 vs 0.38 0.01, t=22.464, P<0.01). Electron microscopy showed that oxymatrine group had milder hepatocyte degeneration and less fibrosis accumulation than did the model group. Microscopy revealed wide septa expansion from the portal area to the central venous, piecemeal and confluent necrosis and pseudo-nodular formation in part of the lobular in the model group. While in oxymatrine group these lesions were much improved.

CONCLUSIONSOxymatrine shows prophylactic and therapeutic effect in D-galactosamine induced rat liver fibrosis. This is partly by protecting hepatocyte and suppressing fibrosis accumulation through anti-lipoperoxidation.

Alkaloids ; therapeutic use ; Animals ; Anti-Arrhythmia Agents ; therapeutic use ; Calcium Hydroxide ; metabolism ; Chemoprevention ; Disease Models, Animal ; Galactosamine ; Liver Cirrhosis ; chemically induced ; drug therapy ; metabolism ; pathology ; prevention & control ; Liver Function Tests ; Male ; Quinolizines ; RNA, Messenger ; metabolism ; Rats ; Rats, Wistar ; Superoxide Dismutase ; metabolism ; Transforming Growth Factor beta ; genetics ; metabolism