Prediction of Diabetic Macular Edema Using Knowledge Graph.

Diabetic macular edema (DME) is a significant complication of diabetes that impacts the eye and is a primary contributor to vision loss in individuals with diabetes. Early control of the related risk factors is crucial to reduce the incidence of DME. Artificial intelligence (AI) clinical decision-making tools can construct disease prediction models to aid in the clinical screening of the high-risk population for early disease intervention. However, conventional machine learning and data mining techniques have limitations in predicting diseases when dealing with missing feature values. To solve this problem, a knowledge graph displays the connection relationships of multi-source and multi-domain data in the form of a semantic network to enable cross-domain modeling and queries. This approach can facilitate the personalized prediction of diseases using any number of known feature data. In this study, we proposed an improved correlation enhancement algorithm based on knowledge graph reasoning to comprehensively evaluate the factors that influence DME to achieve disease prediction. We constructed a knowledge graph based on Neo4j by preprocessing the collected clinical data and analyzing the statistical rules. Based on reasoning using the statistical rules of the knowledge graph, we used the correlation enhancement coefficient and generalized closeness degree method to enhance the model. Meanwhile, we analyzed and verified these models' results using link prediction evaluation indicators. The disease prediction model proposed in this study achieved a precision rate of 86.21%, which is more accurate and efficient in predicting DME. Furthermore, the clinical decision support system developed using this model can facilitate personalized disease risk prediction, making it convenient for the clinical screening of a high-risk population and early disease intervention.

Real-time use of a computer-aided system for polyp detection during colonoscopy, an ambispective study.

OBJECTIVE: This study aimed to evaluate ambispectively the effectiveness of a real-time computer-aided detection (CADe) system on the number of polyp (PPC) or adenoma per colonoscopy (APC), and polyp (PDR) or adenoma detection rate (ADR). METHODS: Eight-five videos marked using the CADe system, together with the unmarked videos, were reviewed by two senior endoscopists. Polyps detected in the marked and unmarked videos were recounted in parallel. Additionally, 128 consecutive patients were enrolled for a prospective evaluation using a standard colonoscopy or the CADe monitor alternately every 2 weeks. The PC, APC, PDR and ADR were compared between the two groups. RESULTS: The total number of polyps reported in the unmarked and marked videos were 73 and 88, respectively (mean PPC 0.86 vs 1.04, P = 0.001). The proportion of polyps detected per colonoscopy increased by 20.5%. Of the 128 prospectively enrolled patients, 186 polyps were detected. The mean PPC was higher in the CADe colonoscopy than in the standard colonoscopy (1.66 vs 1.13, P = 0.039). The PDR using the CADe colonoscopy was significantly higher than that of the standard colonoscopy (78.1% vs 56.3%, P = 0.008). CONCLUSION: Real-time CADe system significantly increases the PDR and PPC under the situation of a high rate of polyp detection.

Overexpression of EIF5A2 is associated with poor survival and aggressive tumor biology in gallbladder cancer.

Gallbladder cancer (GBC) is a malignant tumor of the biliary tract. The main problem affecting the treatment of gallbladder cancer is late diagnosis and poor prognosis. EIF5A2 is one of two isoforms of the EIF5A family and is reported to be a new oncogenic protein in many human cancers. In this study, our results showed for the first time that EIF5A2 was overexpressed in GBC samples compared with non-tumor tissue. Overexpression of EIF5A2 was associated with lymph node metastasis, tumor differentiation, UICC (Union for International Cancer Control) staging, histological type, metastasis, and tumor size. Overexpression of EIF5A2 in gallbladder carcinoma tissues is also associated with poor prognosis in patients. The interference of EIF5A2 significantly inhibited the proliferation, cell cycle, migration and colony formation of GBC-SD cells in vitro. Our results suggest that EIF5A2 is a target oncogene and may be an important prognostic biomarker in the pathogenesis of gallbladder cancer.

Predicting the risk for colorectal cancer with personal characteristics and fecal immunochemical test.

We aimed to predict colorectal cancer (CRC) based on the demographic features and clinical correlates of personal symptoms and signs from Tianjin community-based CRC screening data.A total of 891,199 residents who were aged 60 to 74 and were screened in 2012 were enrolled. The Lasso logistic regression model was used to identify the predictors for CRC. Predictive validity was assessed by the receiver operating characteristic (ROC) curve. Bootstrapping method was also performed to validate this prediction model.CRC was best predicted by a model that included age, sex, education level, occupations, diarrhea, constipation, colon mucosa and bleeding, gallbladder disease, a stressful life event, family history of CRC, and a positive fecal immunochemical test (FIT). The area under curve (AUC) for the questionnaire with a FIT was 84% (95% CI: 82%-86%), followed by 76% (95% CI: 74%-79%) for a FIT alone, and 73% (95% CI: 71%-76%) for the questionnaire alone. With 500 bootstrap replications, the estimated optimism (<0.005) shows good discrimination in validation of prediction model.A risk prediction model for CRC based on a series of symptoms and signs related to enteric diseases in combination with a FIT was developed from first round of screening. The results of the current study are useful for increasing the awareness of high-risk subjects and for individual-risk-guided invitations or strategies to achieve mass screening for CRC.

Xuebijing Injection () and Resolvin D1 Synergize Regulate Leukocyte Adhesion and Improve Survival Rate in Mice with Sepsis-Induced Lung Injury.

OBJECTIVE: To investigate the effect of combined application of Xuebijing Injection ( , XBJ) and resolvin D1 (RvD1) on survival rate and the underlying mechanisms in mice with sepsisinduced lung injury. METHODS: The cecal ligation and puncture (CLP) method was used to develop a mouse sepsis model. Specific pathogen free male C57BL/6 mice were randomly divided into 5 groups (n=20 each): sham, CLP, CLP+XBJ, CLP+RvD1 and CLP+XBJ+RvD1. After surgery, mice in the CLP+XBJ, CLP+RvD1 and CLP+XBJ+RvD1 groups were given XBJ (25 µL/g body weight), RvD1 (10 ng/g body weight), and their combination (the same dose of XBJ and RvD1), respectively. In each group, 12 mice were used to observe 1-week survival rate, while the rest were executed at 12 h. Whole blood was collected for flow cytometric analysis of leukocyte adhesion molecules CD18, lung tissues were harvested for observing pathological changes, and testing the activity of myeloperoxidase (MPO) and the expression of intercellular cell adhesion molecule 1 (ICAM-1). RESULTS: Compared with the CLP group, the histopathological damage of the lung tissues was mitigated, MPO activity was decreased in the CLP+XBJ and CLP+RvD1 groups (P<0.05). In addition, the 1-week survival rate was improved, proportion of CD18-expressing cells in whole blood and ICAM-1 protein expression in lung tissue were decreased in the CLP+XBJ+RvD1 group (P<0.05 or P<0.01). CONCLUSIONS: XBJ together with RvD1 could effectively inhibit leukocyte adhesion, reduce lung injury, and improve the survival rate of mice with sepsis.

Gastric submucosa is inferior to the liver as transplant site for autologous islet transplantation in pancreatectomized diabetic Beagles.

Intraportal transplantation of islets is no longer considered to be an ideal procedure and finding the extrahepatic alternative site is becoming a subject of high priority. Herein, in this study, we would introduce our initial outcomes of using gastric submucosa (GS) and liver as sites of islet autotransplantation in pancreatectomized diabetic Beagles. Total pancreatectomy was performed in Beagles and then their own islets extracted from the excised pancreas were transplanted into GS (GS group, n=8) or intrahepatic via portal vein (PV group, n=5). Forty-eight hours post transplantation, graft containing tissue harvested from the recipients revealed the presence of insulin-positive cells. All recipients in GS group achieved euglycemia within 1 day, but returned to a diabetic state at 6 to 8 days post-transplantation (mean survival time, 7.16±0.69 days). However, all of the animals kept normoglycemic until 85 to 155 days post-transplantation in PV group (mean survival time, 120±28.58 days; P<0.01 vs. GS group). The results of intravenous glucose tolerance test (IVGTT) confirmed that the marked improvement in glycometabolism was obtained in intrahepatic islet autotransplantation. Thus, our findings indicate that the liver is still superior to the GS as the site of islet transplantation, at least in our islet autotransplant model in pancreatectomized diabetic Beagles.

Effect of RhoA gene silencing on proliferation and migration of gastric MGC-803 cells.

In this study, the expression of silencing RhoA gene in gastric MGC-803 Cells was investigated, in order to discuss the effect of RhoA gene on cell proliferation, cell cycles and tumor migration. SiRNA sequence of RhoA gene was designed and synthesized; MGC-803 cells were transfected by Lipofectamine(TM2000). The expression of RhoA gene in mRNA and protein after interference was detected by RT-PCR and Western blot; flow cytometry was used to detect the cell cycle; cell proliferation was detected by CCK-8 assay and cell migration was detected by scratch healing assay. RhoA expression in mRNA and protein of the experimental group was significantly lower than that of the control group and blank group, and the difference was statistically significant (P < 0.05). The growth rate significantly slowed down in experimental group; the cell cycle was arrested in the G0/G1 phase and the number of cells in S-phase reduced; there was a statistically significant difference (P < 0.05). Scratch healing assay showed that cell migration of the experimental group was significantly decreased, with a statistically significant difference (P < 0.05). Specific interference on RhoA gene expression could inhibit the proliferation and migration of MGC-803 cells; therefore, siRNA sequences of RhoA gene may be an effective target for the treatment of gastric cancer.

Berberine Prevents Intestinal Mucosal Barrier Damage During Early Phase of Sepsis in Rat through the Toll-Like Receptors Signaling Pathway.

Our previous study has shown berberine prevents damage to the intestinal mucosal barrier during early phase of sepsis in rat through mechanisms independent of the NOD-like receptors signaling pathway. In this study, we explored the regulatory effects of berberine on Toll-like receptors during the intestinal mucosal damaging process in rats. Male Sprague-Dawlay (SD) rats were treated with berberine for 5 d before undergoing cecal ligation and puncture (CLP) to induce polymicrobial sepsis. The expression of Toll-like receptor 2 (TLR 2), TLR 4, TLR 9, the activity of nuclear factor-kappa B (NF-κB), the levels of selected cytokines and chemokines, percentage of cell death in intestinal epithelial cells, and mucosal permeability were investigated at 0, 2, 6, 12 and 24 h after CLP. Results showed that the tumor necrosis factor-α (TNF-α ) and interleukin-6 (IL-6) level were significantly lower in berberine-treated rats compared to the control animals. Conversely, the expression level of tight junction proteins, percentage of cell death in intestinal epithelial cells and the mucosal permeability were significantly higher in berberine-treated rats. The mRNA expression of TLR 2, TLR 4, and TLR 9 were significantly affected by berberine treatment. Our results indicate that pretreatment with berberine attenuates tissue injury and protects the intestinal mucosal barrier in early phase of sepsis and this may possibly have been mediated through the TLRs pathway.

Risk factors for post-ERCP pancreatitis: a systematic review of clinical trials with a large sample size in the past 10 years.

BACKGROUND: Post- endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is the most common and most severe complication associated with diagnostic and therapeutic ERCP. A multivariate analysis of risk factors for PEP is essential for identifying patients at high risk and subsequently choosing other suitable diagnoses. METHODS: Pertinent publications were identified through systematic searches of MEDLINE, Elsevier, and Springer; we performed a systematic review of 12 clinical studies published in the past ten years, selected out of 451 reviewed articles, in which risk factors for pancreatitis were identified. Seven probable risk factors were evaluated, and outcomes expressed in the case of dichotomous variables, as an odds ratio (OR) (with a 95% confidence interval, 95% CI). RESULTS: When the risk factors were analyzed, the OR for female gender was 1.40 (95% CI 1.24 to 1.58); the OR for previous PEP was 3.23 (95% CI 2.48 to 4.22); the OR for previous pancreatitis was 2.00 (95% CI 1.72 to 2.33); the OR for endoscopic sphincterotomy was 1.42 (95% CI 1.14 to 1.78); the OR for precut sphincterotomy was 2.11 (95% CI 1.72 to 2.59); the OR for Sphincter of Oddi dysfunction was 4.37 (95% CI 3.75 to 5.09); and the OR for non-prophylactic pancreatic duct stent was 2.10 (95% CI 1.63 to 2.69). CONCLUSIONS: It appears that female gender, previous PEP, previous pancreatitis, endoscopic sphincterotomy, precut sphincterotomy, Sphincter of Oddi dysfunction, and non-prophylactic pancreatic duct stent are the risk factors for post-ERCP pancreatitis.

Berberine prevents damage to the intestinal mucosal barrier during early phase of sepsis in rat through mechanisms independent of the NOD-like receptors signaling pathway.

NOD-like receptors play a crucial role in host defense against intestinal infection. We explored the regulatory effects of berberine on NLRs during the intestinal mucosal damaging process in rats. Male Sprague-Dawlay (SD) rats were treated with berberine for 5d before undergoing cecal ligation and puncture (CLP) to induce polymicrobiol sepsis. The expression of nucleotide-binding oligomerization domain 2 (NOD2), NLR family-pyrin domain containing 3 (NLRP3), the activity of nuclear factor-kappa B (NF-κB), the levels of selected cytokines and chemokines, percentage of cell death in intestinal epithelial cells, and mucosal permeability were investigated at 0h, 2h, 6h, 12h and 24h after CLP. Results showed that the Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) level in were significantly lower in berberine treated rats compared to the control animals. The tight junction proteins level, percentage of cell death in intestinal epithelial cells and the mucosal permeability were, on the other hand, significantly elevated in berberine treated rats. The expression of NOD and NLRP3, however, were not significantly affected by berberine treatment. Our results indicate that Pretreatment with berberine attenuates tissue injury and protects the intestinal mucosal barrier in early phase of sepsis but it is likely that the mechanisms of this preventive effect do not involve the NLR pathway.

[Effect mechanism of NOD like receptor signaling pathway on intestinal mucosal barrier of rat during early phase of acute intra-abdominal infection].

OBJECTIVE: To initially investigate the expressing regularity and effect of enterocyte NOD like receptors on gut mucosal barrier during early phase of acute intra-abdominal infection. METHODS: Sprague-Dawley (SD) rats were randomly allocated into control group (n=6) and experimental group (n=24). Acute intra-abdominal infection model was induced by cecal ligation and puncture (CLP). The level of NOD2 and NOD like receptor 3 (NLRP3) mRNA expression in gut mucosa was determined using fluorescent polymerase chain reaction (PCR); the expression of caspase-1 and tight junction protein was determined by Western blotting; the activity of nuclear factor-ΚB (NF-ΚB) was determined by electrophoretic mobility shift assay (EMSA); the level of serum interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) was determined by enzyme linked immunosorbent assay (ELISA). The dead cell percentage of enterocyte was observed by terminal deoxynucleotidyl transferase mediated nick end labeling, and the gut mucosal permeability using an in situ loop preparation of gut with fluorescence isothiocyanate-conjugated dextran was determined. RESULTS: NOD2 mRNA expression was quickly increased to a very high apex at 2 hours after operation, compared with the control group, the difference was statistically significant (75.50±13.03 vs. 1.00±0.00, P<0.01), and quickly descended at 6 hours, and then slowing descended. The expression of NLRP3 mRNA was decreased at 2 hours after the operation, then increased gradually, and peaked at 12 hours, which was significantly higher than that in control group (4.03±0.71 vs. 1.00±0.00,P<0.05). The level of caspase-1 was significantly higher than that in control group at 2 hours (3.56±0.14 vs. 2.10±0.11,P<0.01) and then gradually increased. The levels of Occludin, ZO-1 and Claudin-4 were obviously lowered than that in control group at 2-6 hours (2 hours Occludin: 7.24±1.13 vs. 12.72±1.34, 6 hours ZO-1: 0.47±0.09 vs. 1.57±0.17, 2 hours Claudin-4: 1.63±0.28 vs. 3.40±0.34, P<0.05 or P<0.01), and then all slowly decreased. The activity of NF-ΚB was quickly increased at 2 hours, obviously higher than that in control group (24.85±0.57 vs. 12.42±0.73, P<0.01), and then slowly decreased at a state of high expression. The expression of IL-6 in experimental group had a peak at 6 hours (compared with the control group, 3088.07±330.03 vs. 26.19±7.58,P<0.01), and then slowly decreased. The level of TNF-α was significantly higher than that in control group at 2 hours (110.75±19.18 vs. 7.86±3.58,P<0.01), and then gradually increased. The percentage of dead enterocyte was higher than that in control group with infection progress (0.12±0.02 vs. 0.03±0.01,P<0.05), and then gradually increased, so mucosal permeability was gradually increased too. Compared with the control group, the difference was statistically significant through 2 hours [glucosans: (35.75±4.66)% vs. (2.84±0.35)%, P<0.01]. The relevance analysis showed that NLRP3 have a little higher correlation with mucosal permeability and caspase-1 protein expression than other targets. Caspase-1 had a strong correlation with the percentage of dead cell, TNF-α and gut mucosal permeability. Gut mucosal permeability had highest correlation with the expression of caspase-1 protein. CONCLUSIONS: The data of our study suggested that NOD2 and NLRP3 take role in early phase of intra-abdominal infection, the huge wave of the expression level of NOD2 hinted that it was feed backed by some accurate mechanism in case of its express was too strong or too weak. The correlation of NLRP3, caspase-1, and percentage of dead cell imply they maybe have some extent of causation, and the percentage of dead cell in gut mucosa was as important as tight junction protein in maintaining the function of intestinal mucosal barrier.

[Impact of residual islet function on the glycemia changes of type 1 diabetic rats after gastric bypass].

OBJECTIVE: To investigate the relationship between the type 1 diabetic rats residual islet function and postoperative glycemia of gastric bypass procedure (GBP). METHODS: Intraperitoneal injection of STZ was used to produce type 1 diabetic rat model. According to the level of serum glucose, rats were divided into two groups: group 1 (fasting glucose 16.7-22.0 mmol/L, n=42) and group 2 (fasting glucose>22.0 mmol/L, n=54). Half rats of group 1 and group 2 received GBP, which were OP1 group (n=21) and OP2 group (n=27). The normal control group included 20 Wistar rats. The fasting glycemia and fasting C-peptide (C-P) were tested at postoperative weeks 1, 2, 3, and pancreas pathological slices were examined 3 weeks after surgery under microscope. RESULTS: After GBP, the C-P was elevated and the glycemia was well controlled in OP1 group compared with group 1 (P<0.05). But the C-P was not significantly increased and the glycemia control was poor compared with group 2 (P>0.05). Pathological examination revealed that there were partial islets residual in pancrease of group 1, the islets were shown obvious hyperplasia in OP1 group after GBP. There were almost no islets residual in pancrease of group 2, and the islets were shown no obvious hyperplasia in OP2 group after GBP. CONCLUSIONS: Residual islet function determines the glycemia changes of type 1 diabetic rats after gastric bypass.

[Early diagnosis and treatment of acute mesentric ischemia for 42 cases in single center].

OBJECTIVE: To investigate the early diagnosis and treatment of acute mesenteric ischemia. METHODS: Forty-two patients with acute mesenteric ischemia from June 2007 to November 2011 were reviewed retrospectively. All patients were diagnosed with DSA and (or) CT and (or) surgery. In this group, there were 32 cases of acute occlusion of meseteric ischemia (AOMI), 9 cases of superior mesenteric venous thrombosis (SMVT) and 1 case of non-occlusive mesenteric ischemia. The patients were treated using comprehensive treatment including early intervention treatment and application of the principle of damage control. The survival of all patients was followed up for 6 months or more in outpatient. RESULTS: (1) Of the 32 AOMI cases, 4 cases healing by systemic anticoagulation; The 19 cases received interventional treatment, including 10 cases received simply interventional treatment, surgery after the failure of intervention in 5 cases, 3 patients died without surgery and postoperative interventional treatment one cases were cured; Eight cases received surgery treatment; One case gave up. (2) Of the 9 SMVT cases, 2 cases healing by systemic anticoagulation; The 6 cases received interventional treatment, including 1 cases received simply interventional treatment, surgery after the failure of intervention in 1 cases, 4 cases to consider intestinal necrosis received interventional treatment again after surgery; One patient died without treatment. (3) Eight cases received delay abdomen close treatment with the principle of damage control surgery. The overall mortality rate of 23.8% (10/42). Interventional treatment of 26 cases, 4 deaths, a mortality rate of 15.3%; The abdomen delayed close of 8 cases, 1 death. CONCLUSIONS: The results show that early diagnosis and treatment is critical to reduce AMI mortality. Comprehensive treatment of early intervention treatment and application of the principle of damage control can significantly reduce the mortality of AMI.

Preservation of non-heart-beating donor livers in extracorporeal liver perfusion and histidine-trytophan-ketoglutarate solution.

AIM: To compare the preservation of non-heart-beating donor (NHBD) livers in cold histidine-trytophan-ketoglutarate (HTK) solution and extracorporeal liver perfusion (ECLP). METHODS: Livers harvested from healthy pigs were stored for 10 h in cold HTK solution (group A, n = 4) or perfused with oxygenated autologous blood at body temperature (group B, n = 4). Both groups were then tested on the circuit for 4 h. Bile production, hemodynamic parameters, hepatocyte markers and reperfusion injury of extracorporeal livers were tested in each group. Liver tissues from each group were examined at the end of reperfusion. RESULTS: At 1, 2, 3 and 4 h after reperfusion, bile production, hemodynamic parameters, hepatocyte markers and reperfusion injury of livers in group A were statistically different from those in group B (P < 0.05 or P < 0.01). CONCLUSION: ECLP is better than HTK solution to preserve NHBD livers. ECLP can assess the graft viability before liver transplantation.

Establishment and evaluation of the system of extracorporeal liver perfusion in pigs.

BACKGROUND: In recent years, extracorporeal liver perfusion (ECLP) has been regarded as a treatment of acute liver failure (ALF); but the system of ECLP has many problems. The purpose of this experiment was to detect the factors affecting the system of ECLP and to establish a stable and effective system of ECLP. METHODS: Livers were harvested from health pigs, according to the different styles of perfusion and oxygenation, which were randomly divided into 3 groups. The livers in group A (n=4) were subjected to single portal vein perfusion, oxygenating perfusion blood; the livers in group B (n=4) to dual (portal vein and hepatic artery) vessel perfusion, oxygenating blood, together; and the livers in group C (n=4) to dual (portal vein and hepatic artery) vessel perfusion, but oxygenating blood, separately. The perfusion time, the data of bile production, and hemodynamic parameters of extracorporeal livers in each group were tested. The histological examination of liver tissues from each group was performed at the end of perfusion. RESULTS: The perfusion time of the liver in group A is significantly shorter than in groups B and C (P<0.05). At 1, 3, 6 hours after perfusion, the data of bile production and hemodynamic parameters of livers in group A were statistically different from those of livers in groups B and C (P<0.05). At 1, 3, 6 hours after perfusion, the data of group B were not statistically different from those of livers in group C (P>0.05). But at 12 hours after perfusion, the data of group B were statistically different from those of livers in group C (P<0.01). CONCLUSION: The system of ECLP, which is performed by dual (portal vein and hepatic artery) vessel perfusion and oxygenating blood separately, is more stable and effective to keep the function of extracorporeal liver.

Improved suppression of circulating complement does not block acute vascular rejection of pig-to-rhesus monkey cardiac transplants.

At present, acute vascular rejection (AVR) remains a primary obstacle inhibiting long-term graft survival in the pig-to-non-human primate transplant model. The present study was undertaken to determine whether repetitive injection of low dose Yunnan-cobra venom factor (Y-CVF), a potent complement inhibitor derived from the venom of Naja kaouthia can completely abrogate hemolytic complement activity and subsequently improve the results in a pig-to-rhesus monkey heterotopic heart transplant model. Nine adult rhesus monkeys received a heterotopic heart transplant from wild-type pigs and the recipients were allocated into two groups: group 1 (n = 4) received repetitive injection of low dose Y-CVF until the end of the study and group 2 (n = 5) did not receive Y-CVF. All recipients were treated with cyclosporine A (CsA), cyclophosphamide (CyP) and steroids. Repetitive Y-CVF treatment led to very dramatic fall in CH50 and serum C3 levels (CH50 < 3 units/C3 remained undetectable throughout the experiment) and successfully prevented hyperacute rejection (HAR), while three of five animals in group 2 underwent HAR. However, the continuous suppression of circulating complement did not prevent AVR and the grafts in group 1 survived from 8 to 13 days. Despite undetectable C3 in circulating blood, C3 deposition was present in these grafts. The venular thrombosis was the predominant histopathologic feature of AVR. We conclude that repetitive injection of low dose Y-CVF can be used to continuously suppress circulating complement in a very potent manner and successfully prevent HAR. However, this therapy did not inhibit complement deposition in the graft and failed to prevent AVR. These data suggest that using alternative pig donors [i.e. human decay accelerating factor (hDAF)-transgenic] in combination with the systemic use of complement inhibitors may be necessary to further control complement activation and improve survival in pig-to-non-human primate xenotransplant model.

TMVA, a novel GPIb-binding protein, significantly prevents platelet microthrombi formation and prolongs discordant cardiac xenograft survival.

In xenotransplantation, donor endothelium is the first target of immunological attack. Activation of the endothelial cell by preformed natural antibodies leads to platelet binding via the interaction of the glycoprotein (GP) Ib and von Willebrand factor (vWF). TMVA is a novel GPIb-binding protein purified from the venom of Trimeresurus mucrosquamatus. In this study, the inhibitory effect of TMVA on platelet aggregation in rats and the effect on discordant guinea pig-to-rat cardiac xenograft survival were investigated. Three doses (8, 20 or 40 microg/kg) of TMVA were infused intravenously to 30 rats respectively. Platelet aggregation rate was assayed 0.5, 12, and 24 h after TMVA administration. Wister rats underwent guinea pig cardiac cervical heterotopic transplantation using single dosing of TMVA (20 microg/kg, i.v., 0.5 h before reperfusion). Additionally, levels of TXB(2) and 6-keto-PGF(1alpha) within rejected graft tissues were determined by radioimmunoassay. Treatment with TMVA at a dose of 20 or 40 microg/kg resulted in complete inhibition of platelet aggregation 0.5 h after TMVA administration. Rats receiving guinea pig cardiac xenografts after TMVA therapy had significantly prolonged xenograft survival. Histologic and immunopathologic analysis of cardiac xenografts in TMVA treatment group showed no intragraft platelet microthrombi formation and fibrin deposition. Additionally, the ratio of 6-keto-PGF(1alpha) to TXB(2) in TMVA treatment group was significantly higher than those in control group. We conclude that the use of this novel GPIb-binding protein was very effective in preventing platelet microthrombi formation and fibrin deposition in a guinea pig-to-rat model and resulted in prolongation of xenograft survival. The increased ratio of PGI(2)/TXA(2) in TMVA treatment group may protect xenografts from the endothelial cell activation and contribute to the prolongation of xenograft survival.