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.

BACKGROUND:Previous studies have shown that N-methyl-D-aspartic acid receptor(NMDA)receptors are associated with fluorine,but the role in fluoride-induced endoplasmic reticulum stress remains unclear. OBJECTIVE:To observe the changes of excitatory neurotransmitter NMDA receptor and endoplasmic reticulum stress IRE1α-ASK1-JNK pathway protein expression in brain tissue of rats with experimental fluorosis,and to investigate the pathogenesis of neurological injury in fluorosis by giving NMDA receptor inhibitor to SH-SY5Y cells. METHODS:(1)Animal model:18 1-month-old SD rats were randomly divided into control group(drinking water fluoride content<0.5 mg/L),low fluoride group(drinking water fluoride content 10.0 mg/L)and high fluoride group(drinking water fluoride content 100.0 mg/L),with 6 rats in each group,half of each sex.After 6 months of fluoride intake,the rats were observed for the occurrence of dental fluorosis,and the 24-hour urinary fluoride content was measured.After anesthesia and euthanasia,the brain tissue of rats was taken to observe the pathological changes.Western blot assay was used to detect NMDA receptors and IRE1α,ASK1 and JNK protein expression in the brain tissue.(2)Cell model:SH-SY5Y cells were cultured in vitro and treated with sodium fluoride at final concentrations of 0.3 mmol/L and 3 mmol/L.The fluoride-stained cells were interfered with 10 μmol/L NMDA receptor antagonists Ifenprodil and MK-801 to observe the relevant protein changes. RESULTS AND CONCLUSION:(1)The incidence of dental fluorosis and urinary fluoride level in rats in the high fluoride group were significantly higher than that in the control and low fluoride groups(P<0.05).(2)Compared with the control group,the cytoplasm of neuronal cells in the CA3 area of the hippocampus in the low fluoride group was slightly more basophilic,while the neuronal cells in the CA3 area of the high fluoride group were disorganized,with increased basophilicity and some of the nuclei solidified.(3)In rat brain tissue,the expressions of NR2A in the high fluoride group and NR2B in the low fluoride group were significantly higher compared with the control group(P<0.05),and NR2B,IRE1,ASK1,and p-JNK protein expression levels were increased in the high fluoride group compared with the control and low fluoride groups(P<0.05).(4)In SH-SY5Y cells,NR1,NR2A and NR2B protein expressions were significantly increased in the high fluoride group compared to the control group(P<0.05).The protein levels of NR1 and NR2A were significantly reduced in the high fluorine + Ifenprodil group and high fluorine + MK-801 group compared with the high fluorine group(P<0.05).NR2B protein expression was significantly lower in the high fluorine + Ifenprodil group than that in the high fluorine group(P<0.05).(5)In SH-SY5Y cells,IRE1,ASK1,and p-JNK protein expression was significantly higher in the high fluoride group compared with the control group(P<0.05),while ASK1 and p-JNK protein expressions were significantly decreased in the high fluorine + Ifenprodil group and high fluorine + MK-801 group compared with the high fluorine group(P<0.05).IRE1 protein level was significantly lower in the high fluorine + Ifenprodil group than that in the high fluorine group(P<0.05).(6)It is concluded that excessive fluorine intake activates NMDA receptors in the central nervous system,causing increased expression of endoplasmic reticulum stress IRE1α,ASK1,and p-JNK proteins,and the use of NMDA receptor inhibitors has a mitigating effect on endoplasmic reticulum stress caused by fluorosis.

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.

Objective:To investigate the expression and significance of endoplasmic reticulum stress apoptosis pathway related proteins in renal cortex of rats with chronic fluorosis.Methods:Twenty four healthy SD rats were divided into 4 groups (6 rats/group, half male and half female) according to their body mass (100 - 120 g) by random number table method, rats in control group drank tap water (fluoride content < 0.5 mg/L), and in low, medium and high fluoride groups drank tap water with fluoride content (sodium fluoride) of 10, 50 and 100 mg/L, respectively. After 180 days of feeding, dental fluorosis was examined, 24-hour urine sample was collected and the content of fluoride in urine was detected by fluoride ion selective electrode method. Renal tissue was taken after anesthesia, and the pathological changes of renal cortex were observed by hematoxylin-eosin (HE) staining. The expressions of endoplasmic reticulum stress apoptosis pathway related proteins [inositol-requiring enzyme 1α (IRE1α), apoptosis signal-regulating kinase 1 (ASK1), C-Jun N-terminal kinase (JNK) and phosphorylated JNK (P-JNK)] were determined by immunohistochemical staining in rat renal cortex.Results:No dental fluorosis was found in control group. The incidence of dental fluorosis in low, medium and high fluoride groups were 2/6, 5/6 and 6/6, respectively. Compared with control group [(5.707 ± 1.190) mg/L], the urinary fluoride in low, medium and high fluoride groups [(17.028 ± 3.006), (34.378 ± 12.045), (94.759 ± 31.773) mg/L] was significantly higher ( P < 0.05), and the urinary fluoride in high fluoride group was higher than that in low and medium fluoride groups ( P < 0.05). HE staining showed that, compared with control group, the cell volume of renal tubules and glomeruli in medium and high fluoride groups increased, the cells arranged closely, and the eosinophilia of the cytoplasm increased. The immunohistochemical staining results showed that there was no significant difference in the expression of JNK protein in rat renal cortex between control group and low, medium and high fluoride groups ( F = 0.07, P > 0.05). The expressions of IRE1α, ASK1 and P-JNK proteins in rat renal cortex in high fluoride group were higher than those of control, low and medium fluoride groups ( P < 0.05), and the expressions of IRE1α and ASK1 proteins in medium fluoride group were significantly higher than those in control and low fluoride groups ( P < 0.05). Conclusion:Long-term excessive fluoride intake can lead to renal cortex injury in rats, and the mechanism of injury may be related to the activation of IRE1α-ASK1-JNK endoplasmic reticulum stress apoptosis pathway.

OBJECTIVE： To investigate the effects of Kangfuxin liquid on repairing cartilage defect model of knee osteoarthritis （KOA） in rabbits and its mechanism. METHODS： Totally 72 male New Zealand rabbits were selected and randomly divided into model control group and Kangfuxin low-dose， medium-dose， high-dose groups， with 18 rabbits in each group. A cartilage defect model of the medial femoral condyle of the right knee joint in rabbits was established by drilling after anesthesia surgery. Then the rabbits in each group were given medicine via articular cavity immediately. Kangfuxin low-dose， middle-dose and high-dose groups were given 20％， 40％， 80％ Kangfuxin liquid； model control group was given constant volume of normal saline consecutively， 0.2 mL/kg， once every 3 days. At 4th， 8th， 12th week after medication， the wound repair of cartilage defect in rabbits was observed. Immediately after medication and at 4th， 8th， 12th week after medication， repaired tissue of cartilage defect in rabbits was scored histologically with Wakitani scoring standard under light microscope. At 12th week after medication， pathological changes of repaired tissue of cartilage defect in rabbits were observed by Masson staining. The levels of NO， SOD and LPO in joint fluid and PYD in urine of rabbits were detected by ELISA. RESULTS： At 4th， 8th， 12th week after medication， compared with model control group， cartilage defects in rabbits were repaired well in Kangfuxin low-dose， medium-dose and high-dose groups. At 4th， 8th， 12th week after medication， compared with immediately after medication and model control group at same time point， histomorphological score of repairing cartilage defect of knee joint in rabbits decreased significantly in Kangfuxin low-dose， medium-dose and high-dose groups （P＜0.05）. At 12th week after medication， compared with model control group， the histopathology degree of cartilage defect of knee joint in rabbits was significantly alleviated in Kangfuxin low-dose， medium-dose and high-dose groups. At 4th， 8th， 12th week after medication， compared with model control group， the levels of NO and LPO in joint fluid and PYD level in urine were decreased to different extent in Kangfuxin low-dose， medium-dose and high-dose groups， while SOD level was increased to different extent； at 12th week after medication， the difference of each index has statistical significance （P＜0.05 or P＜0.01）. CONCLUSIONS： Kangangxin liquid can significantly repair cartilage defect of KOA cartilage defect model rabbits， the mechanism of which may be associated with increasing the expression of SOD and mediating NO-inhibited chondrocyte apoptosis.

Objective: To evaluate the feasibility and outcomes of the reconstruction of large anterior palatal fistulae by anteriorly based dorsal tongue flaps to provide a rational reference of anteriorly based dorsal tongue flaps for clinicians. Methods : Five patients with anterior hernia had a defect range of 1.0 cm × 1.0 cm to 1.5 cm × 2.0 cm, and the anterior tongue was 1.3 cm × 3.5 cm to 2.0 cm × 3.5 cm. The defects were all repaired with anteriorly based dorsal tongue flaps. The clinical efficacy was evaluated after operation, including whether the mucosal flap was infected, whether there was any shedding before the pedicle, and whether there was any perforation after operation. Thereafter, patients who were satisfied with their chewing, swallowing, speech function and appearance were followed up Results: All patients underwent successful reconstruction of palatal defects by anteriorly based tongue flaps, and no case of spontaneous detachment of the tongue flap occurred. Patients with palatal fistulae were followed up for 16-28 months, and no recurrence was encountered. The operation had no effect on the speech, agitation and swallowing function of the tongue, and patients were satisfied with the appearance. Conclusion The dorsal lingual mucosal flap pedicled with the anterior tongue is a safe and reliable method for repairing large anterior palatal fistula.