According to General Chapter 1145 of Division IV in the Chinese Pharmacopoeia (2020 Edition), the test for depressor substances is a common method for drug testing. It determines whether the level of depressor substances in a test sample complies with the specified standards by comparing the extent of blood pressure reduction in anesthetized cats induced by the histamine reference substance and the test sample. If an out-of-specification (OOS) result occurs in the test for depressor substances, it may be caused by inherent quality issues of the drug or errors in the testing process. Therefore, analyzing the causes of OOS is particularly important for confirming the test results and evaluating drug quality. Cats are used as experimental animals in the test for depressor substances. Compared with conventional laboratory animals, they are less stable, surgery procedures are more challenging, and the testing process is more complex. These factors make it more difficult to investigate the causes of OOS in this test. Based on a review of the literature and practical work experience, this article analyzes the causes of OOS in the test for depressor substances from the following five aspects: (1) an analysis of the impact of drug standards on OOS from three aspects: standard determination, standard content, and standard drafting; (2) personnel qualifications, including pre-employment training, compliance with standard operating procedures during experimental operations, and the ability to operate instruments; (3) factors related to cats, used as experimental animals in the test for depressor substances, including physiological characteristics, genetic background, and abnormal conditions during the experiment; (4) reference substances, reagents, test samples, and key instruments such as the multi-channel physiological signal instrument; (5) experimental operations including animal anesthesia, arterial and venous catheterization, drug administration, and data processing. This article aims to provide reference approaches for professionals engaged in the testing of pharmaceuticals and biological products when analyzing the causes of OOS in the test for depressor substances.

According to General Chapter 1145 of Division IV in the Chinese Pharmacopoeia (2020 Edition), the test for depressor substances is a common method for drug testing. It determines whether the level of depressor substances in a test sample complies with the specified standards by comparing the extent of blood pressure reduction in anesthetized cats induced by the histamine reference substance and the test sample. If an out-of-specification (OOS) result occurs in the test for depressor substances, it may be caused by inherent quality issues of the drug or errors in the testing process. Therefore, analyzing the causes of OOS is particularly important for confirming the test results and evaluating drug quality. Cats are used as experimental animals in the test for depressor substances. Compared with conventional laboratory animals, they are less stable, surgery procedures are more challenging, and the testing process is more complex. These factors make it more difficult to investigate the causes of OOS in this test. Based on a review of the literature and practical work experience, this article analyzes the causes of OOS in the test for depressor substances from the following five aspects: (1) an analysis of the impact of drug standards on OOS from three aspects: standard determination, standard content, and standard drafting; (2) personnel qualifications, including pre-employment training, compliance with standard operating procedures during experimental operations, and the ability to operate instruments; (3) factors related to cats, used as experimental animals in the test for depressor substances, including physiological characteristics, genetic background, and abnormal conditions during the experiment; (4) reference substances, reagents, test samples, and key instruments such as the multi-channel physiological signal instrument; (5) experimental operations including animal anesthesia, arterial and venous catheterization, drug administration, and data processing. This article aims to provide reference approaches for professionals engaged in the testing of pharmaceuticals and biological products when analyzing the causes of OOS in the test for depressor substances.

ObjectiveTo explore the effects of modified Danggui Beimu Kushen pills on tumor growth and T-cell subsets in H22 hepatocellular carcinoma-bearing mice and to provide an experimental basis for the treatment of hepatocellular carcinoma with modified Danggui Beimu Kushen pills combined with immune checkpoint antibodies. MethodA H22 hepatocellular carcinoma-bearing mouse model was established. The modeled mice were randomized into model， cisplatin， low- （4 g·kg^-1·d^-1）， medium- （8 g·kg^-1·d^-1）， and high-dose （16 g·kg^-1·d^-1） modified Danggui Beimu Kushen pills groups. After continuous administration for 14 days， the mice were sacrificed on day 15. The tumor volume was measured on days 0， 4， 8， 12， 15 of drug administration. Tumors were weighed and thymus index and spleen index were calculated. Spleen lymphocytes were co-cultured with H22 hepatoma cells， and the tumor cell-killing rate was detected by the cell counting kit-8 （CCK-8）. Real-time polymerase chain reaction was carried to determine the mRNA levels of programmed cell death protein-1 （PD-1） and lymphocyte activation gene-3 （LAG-3） in spleen and tumor tissues. The number of CD4⁺ and CD8⁺ T cells and the expression of PD-1 and LAG-3 were detected by immunohistochemistry （IHC）. ResultOn day 8 of drug administration， tumor volumes in all treatment groups decreased compared with that in the model group. On day 15， both tumor volume and tumor weight were significantly lower in the treatment groups than in the model group （P<0.01）， with the cisplatin group showing the most pronounced reduction. Compared with the model and cisplatin groups， medium- and high-dose modified Danggui Beimu Kushen pills increased the thymus index （P<0.01）. Compared with the model group， all treatment groups showed increased spleen index （P<0.05， P<0.01）， with the cisplatin group showing the most significant increase. Compared with the model and cisplatin groups， all the groups of modified Danggui Beimu Kushen pills demonstrated increased number of CD4⁺ and CD8⁺ T cells and tumor cell-killing rate in the spleen and tumor tissues （P<0.01） and down-regulated mRNA and protein levels of LAG-3 （P<0.05， P<0.01）. The high-dose group of modified Danggui Beimu Kushen pills had lower mRNA level of PD-1 in the tumor tissue than the model and cisplatin groups （P<0.01）. ConclusionModified Danggui Beimu Kushen pills may promote the proliferation and tumor microenvironment infiltration of CD4⁺ and CD8⁺ T cells in H22 tumor-bearing mice by down-regulating LAG-3 expression， thereby improving T-cell immune activity and inhibiting tumor growth. This study provides an experimental basis for the combination of modified Danggui Beimu Kushen pills and immune checkpoint antibodies in the treatment of hepatocellular carcinoma.

In recent years, the endovascular procedures has considerably evolved in concepts, technologies, materials and devices on cardiovascular surgery, and influenced the development and the future direction of cardiovascular surgery technology. Endovascular aorta repair is well recognized as the optimal therapy for patients presenting with acute or chronic pathology of distal aortic arch, descending aorta and thoraco-abdominal aorta. The use of catheter-based endovascular repair in the ascending aorta pathology including aneurysms, pseudoaneurysms, penetrating aortic ulcers and acute or chronic Stanford type A aortic dissection has been concerned and reported. Comparing to the open surgical procedures for ascending aorta and aortic root disease with high perioperative mortality and morbidity, the catheter-based endovascular repair has minimally invasive, expanding the alternative treatment of ascending aorta disease, especially for patients with high-risk profiles. However, due to the complex anatomy and functional properties, materials and devices, the use of this technique in ascending aorta and aortic root is still questionable. In addition, the long-term and reliable clinical research results is still inadequate, and the safety and effectiveness need further research.

In recent years, the endovascular procedures has considerably evolved in concepts, technologies, materials and devices on cardiovascular surgery, and influenced the development and the future direction of cardiovascular surgery technology. Endovascular aorta repair is well recognized as the optimal therapy for patients presenting with acute or chronic pathology of distal aortic arch, descending aorta and thoraco-abdominal aorta. The use of catheter-based endovascular repair in the ascending aorta pathology including aneurysms, pseudoaneurysms, penetrating aortic ulcers and acute or chronic Stanford type A aortic dissection has been concerned and reported. Comparing to the open surgical procedures for ascending aorta and aortic root disease with high perioperative mortality and morbidity, the catheter-based endovascular repair has minimally invasive, expanding the alternative treatment of ascending aorta disease, especially for patients with high-risk profiles. However, due to the complex anatomy and functional properties, materials and devices, the use of this technique in ascending aorta and aortic root is still questionable. In addition, the long-term and reliable clinical research results is still inadequate, and the safety and effectiveness need further research.

In almost one century, cardiovascular surgery has considerably evolved. Heart valve innovation has been one of the most important component during the evolution of cardiovascular surgery. The evolution of heart valve prostheses, including mechanical heart valves, biological heart valves, transcatheter heart valve, and tissue engineered heart valve, influence the development and the future direction of cardiovascular surgery technology. The early period of prosthetic valve development provided much information that is still of value today. We can learn more the good, the failure experiences from the pioneers of the valve innovation. In this ever evolving landscape, looking back into history will pave the way to the future.

Objective:To examine the clinical treatment methods and short- and mid-term results of traumatic aortic injury (TAI).Methods:The clinical data of 30 patients suffering from TAI who were admitted to Department of Cardiothoracic Surgery, General Hospital of Eastern Theater Command from January 2010 to December 2018 were summarized and analyzed retrospectively. All patients were diagnosed as TAI by aortic CT angiography. There were 20 males and 10 females, aging (46.4±15.2) years (range: 17 to 76 years). One patient was diagnosed as extensive intramural hematoma (IMH). The other 29 cases had aortic intimal injury, and the primary intimal tear of all these patients was located in the isthmus of descending aorta. There were 2 cases of ulcer-like changes combined with IMH, and 27 cases of traumatic aortic dissection (TAD) including 23 cases of localized TAD and 4 cases of extensive TAD. Endovascular repair, artificial vascular replacement or conservative treatment were performed according to the patient′s specific condition. The patients were followed up in outpatient or by telephone. The clinical data of all the patients of the in-hospital treatment and during follow-up period was analyzed retrospectively.Results:One patient with IMH was treated conservatively. Surgical intervention was performed in 29 cases with intimal injury, of which 14 cases underwent emergency surgery on the day of admission or the next day, and 15 cases underwent elective surgery. Twenty-seven cases underwent thoracic endovascular aortic repair (TEVAR), and 2 cases underwent artificial vascular replacement. Nine cases suffered combined operations in early or late stage. All patients were cured and discharged with in-hospital stay of (13.2±5.4) days (range: 7 to 30 days). There was no in-hospital death. Two patients underwent tracheotomy, and the rest had no serious complications. Up to the last follow-up in June 2019, 4 patients were lost to follow-up, and the remaining 26 patients were followed up for (50.6±34.1) months (range: 6 to 112 months) and survived healthily without new aortic events.Conclusions:Most of TAD cases are ascribed to Stanford type B aortic dissection, and a satisfactory short-term and mid-term result can be achieved by emergency TEVAR in most patients. Some patients can achieve good long-term results by open surgery with artificial vascular replacement.

Objective:To examine the clinical treatment methods and short- and mid-term results of traumatic aortic injury (TAI).Methods:The clinical data of 30 patients suffering from TAI who were admitted to Department of Cardiothoracic Surgery, General Hospital of Eastern Theater Command from January 2010 to December 2018 were summarized and analyzed retrospectively. All patients were diagnosed as TAI by aortic CT angiography. There were 20 males and 10 females, aging (46.4±15.2) years (range: 17 to 76 years). One patient was diagnosed as extensive intramural hematoma (IMH). The other 29 cases had aortic intimal injury, and the primary intimal tear of all these patients was located in the isthmus of descending aorta. There were 2 cases of ulcer-like changes combined with IMH, and 27 cases of traumatic aortic dissection (TAD) including 23 cases of localized TAD and 4 cases of extensive TAD. Endovascular repair, artificial vascular replacement or conservative treatment were performed according to the patient′s specific condition. The patients were followed up in outpatient or by telephone. The clinical data of all the patients of the in-hospital treatment and during follow-up period was analyzed retrospectively.Results:One patient with IMH was treated conservatively. Surgical intervention was performed in 29 cases with intimal injury, of which 14 cases underwent emergency surgery on the day of admission or the next day, and 15 cases underwent elective surgery. Twenty-seven cases underwent thoracic endovascular aortic repair (TEVAR), and 2 cases underwent artificial vascular replacement. Nine cases suffered combined operations in early or late stage. All patients were cured and discharged with in-hospital stay of (13.2±5.4) days (range: 7 to 30 days). There was no in-hospital death. Two patients underwent tracheotomy, and the rest had no serious complications. Up to the last follow-up in June 2019, 4 patients were lost to follow-up, and the remaining 26 patients were followed up for (50.6±34.1) months (range: 6 to 112 months) and survived healthily without new aortic events.Conclusions:Most of TAD cases are ascribed to Stanford type B aortic dissection, and a satisfactory short-term and mid-term result can be achieved by emergency TEVAR in most patients. Some patients can achieve good long-term results by open surgery with artificial vascular replacement.

[Abstract ] Objective The aim of the study was to investigate the effects of recombinant human erythoropoietin (EPO) and bone marrow mesenchymal stem cell (BMSC) transplantation on renal inflammatory response following cardiopulmonary bypass (CPB). Methods Forty sprague-Dawley male rats were randomly divided into five groups (n=8):shame operation group, CPB group, EPO group, BMSC group and EPO +BMSC group.CPB model was built in shame operation group without CPB .The other four groups un-derwent CPB, following by jugular vein infusion of 1.5 ×106 BMSCs after an hour′s 100 L/kg/min bypass .Jugular vein infusion of 3000 IU/kg EPO was done in EPO group , while the combination of EPO with BMSCs was infused in EPO +BMSC group.The same volume of isotonic saline solution was infused via jugular vein in CPB group and shame operation group respectively .Rats were sacrificed at 24 hours after CPB termination .Blood samples were collected for the determi-nation of creatinine(Cr) and urea nitro(BUN) levels.HE staining was applied in the examination of renal tissues .ELISA was used in the determination of serum interleukin 6 (IL-6) and interleukin 10 (IL-10) levels and western blot was taken to test the expressions of tumor necrosis factor (TNF-α) and insulin-like growth factor 1 (IGF-1). Results In CPB group, the levels of Cr, BUN, IL-6 and the expression of TNF-αwere increased, while IL-10 level and of IGF-1 expression were decreased(P<0.05).TNF-αexpression was increased while IGF-1 expression was decreased in renal tissue (P<0.05).HE staining results showed the renal injury in EPO +BM-SC group was significantly lower than those in EPO group , BMSC group and CPB group , along with the decrease in the levels of Cr , BUN, IL-6, the increase in IL-10 level(P<0.05), as well as the decline of TNF-αexpression and the rise of IGF-1 expression(P<0.05). Conclusion The combination of EPO and BMSCs which reduces renal inflammatory response following CPB has protective effects on renal injury following CPB in rats , which is better than single application of EPO or BMSCs .

Objective To summarize the short-and mid-term results on endovascular repair of primary retrograde Stanford type A aortic dissection with an entry tear in distal aortic arch or descending aorta.Methods Between December 2009 and December 2014,21 male patients of primary retrograde Stanford type A aortic dissection with a mean age of (52 ± 9) years received endovascular repair in Department of Cardiothoracic Surgery,Jinling Hospital.Among the 21 cases,17 patients were presented as ascending aortic intramural hematoma,4 patients as active blood flow in false lumen and partial thrombosis,8 patients as ulcer on descending aorta combined intramural hematoma in descending aorta,and 13 patients as typical dissection changes.All patients received cndovascular stent-graft repair successfully,with 15 cases in acute phase and 6 cases in chronic phase.Results Cone stent was implanted in 13 cases,while straight stent in 8 cases,including 1 case of left common carotid-left subclavian artery bypass surgery and 1 case of restrictive bare-metal stent implantation.No perioperative stroke,paraplegia,stent fracture or displacement,limbs or abdominal organ ischemia or other severe complications occured,except for tracheotomy in 2 patients.Active blood flow in ascending aorta or aortic arch disappeared,and intramural hematoma started being absorbed on CT angiography images before discharge.All patients were alive during follow-up (6 to 72 months),and intramural hematoma in ascending aorta and aortic arch was absorbed thoroughly.Type Ⅰ endoleak and ulcer expansion were found in 1 patient,and type Ⅳ endoleak in distal stent was found in another one patient.Secondary ascending aortic dissection was found in 1 case two years later,which was cured by hybrid procedure with cardiopulmonary bypass.Conclusion Endovascular repair of primary retrograde Stanford type A aortic dissection was safe and effective,which correlated with favorable short-and mid-term results.