The role of donor versus recipient tissue factor in coagulopathy during pig-to-primate xenotransplantation

The increasing demand for organs has stimulated the necessity in xenotransplantion, which promises an unlimited supply of organs for clinical use. However, coagulopathy of xenografts remains a major hurdle to successful pig-to-primate xenotransplantation. The ability to generate pigs expressing a human complement-regulatory protein (hCRP) and/or pigs in which the α1,3-Galactosyltransferase gene has been knocked-out (GT-KO) has largely overcome the barrier of hyperacute rejection (HAR) of a pig organ transplanted into a primate. However, acute humoral xenograft rejection (AHXR), presenting as microvascular thrombosis with/without consumptive coagulopathy (CC), ensures and results in graft failure. The causes of coagulopathy were believed to be humoral response-dependent. Xenoreactive antibodies (Abs) and activation of complement provoke porcine endothelial cells (ECs) from an anticoagulant to a procoagulant phenotype. In this study, I demonstrated that recipient platelets and monocytes were activated to express tissue factor (TF), an initiator of the coagulation cascade, after incubation with porcine ECs through humoral immune response-independent process. These observations were mirrored in the animal studies. Kidneys or livers from GT-KO pigs that express a hCRP transplanted into nonhuman primates were not susceptible to HAR. Nevertheless, most recipients developed CC, even when the grafts were still functioning. Activation of graft ECs and the measurable immune response were minimal. TF expression on recipient platelets plays a pivotal role in initiating CC. Therefore, understanding the interactions between porcine ECs and primate platelets may be crucial to prevent coagulopathy. On the other hand, the generation of GT-KO pigs has directed interest to the role of anti-nonGal Abs in intravascular thrombosis. My study revealed that anti-nonGal Abs activated porcine ECs to express TF, independent of complement activation. I also demonstrated that anti-P-selectin and vWF Abs and some anti-platelet agents, such as clopidogrel and eptifibatide, prevented TF expression on platelets after incubation with porcine ECs. Porcine ECs from pigs that expressed tissue factor pathway inhibitor (TFPI) were resistant to the activation induced by primate serum even with high titre anti-nonGal Abs. Atorvastatin not only inhibited this activation of platelets but also prevented the activation of porcine ECs induced by primate serum. Coagulopathy is increasingly recognized as barriers to successful xenotransplantation, many mechanisms of which are not associated with humoral immune response. Further manipulation of the immune response alone, with the risk of inducing infection and other complications, does not appear likely to resolve the challenge of xenograft coagulopathy. My results provide evidence for further genetic manipulation or systemic pharmaceutical treatment to prevent coagupolpathy seen after pig-primate xenotransplantation

Treatment and Prognosis of Hepatitis B Virus Concomitant with Alcoholism

Hepatitis B virus (HBV) infection is a global disease worldwide. The Asia-Pacific region has a high prevalence of viral hepatitis, and Taiwan is a region of high prevalence of chronic hepatitis B (CHB) with increasing alcoholic liver disease. We have investigated the prognosis and treatment of patients with concomitant hepatitis B virus (HBV) infection and alcoholism. The 10-year cumulative incidence of hepatocellular carcinoma (HCC) is much higher in patients with concomitant alcoholism and HBV infection than in those with alcoholism or HBV infection alone. Treatment with antiviral therapy and abstinence may be started in patients with decompensated cirrhosis and compensated cirrhosis with high HBV DNA. In pre-cirrhotic cases, treatment with antiviral therapy and abstinence may be started in patients with persistently elevated ALT levels and high HBV DNA, and significant fibrosis with minimal elevated or normal ALT levels and mild high HBV DNA. Treatment with antiviral therapy and abstinence reduces the incidence of HCC in patients with concomitant HBV infection and alcoholism. In conclusion, patients with concomitant HBV infection and alcoholism have high incidence of cirrhosis, HCC, and mortality. Treatment with antiviral therapy and abstinence may be started to reduce the incidence of cirrhosis, HCC, and mortality in these patients

Idiopathic Superior Mesenteric Vein Thrombosis Resulting in Small Bowel Ischemia in a Pregnant Woman

Background. Small bowel ischemia due to superior mesenteric vein thrombosis (MVT) is rare during pregnancy. However, additional precipitating factors should usually be identified. Case. A 31-year-old woman, pregnant at 34 weeks, was sent to the emergency department because of acute peritonitis. An emergency exploration revealed a segmental gangrene of the small intestine without any mechanical obstruction. Together with the termination of pregnancy, resection of the damaged small bowel was performed, and an end-to-end enterostomy was followed. Based on the operative and pathological findings, small bowel ischemia might be attributed to superior mesenteric vein thrombosis. Conclusion. Hypercoagulation state normally found in pregnant women is believed to lead to this catastrophic condition without other precipitating factors

Autophagy and Coagulation in Liver Cancer and Disorders

The physiological role of autophagy in metabolism of the body involves both protein synthesis and degradation. The autophagy-lysosome and the ubiquitin-proteasome systems are the two major intracellular proteolytic mechanisms. Autophagy in hepatocytes is known to be quite active and contribute to its normal functions and the pathogenesis of liver diseases. The role of autophagy in liver diseases has been widely studied, and growing evidence has now shown that autophagy is involved in the pathogenesis of cirrhosis and hepatocellular carcinoma (HCC). However, the role of autophagy in the progression of liver fibrosis and prognosis of human HCC is not well known. Recent studies have demonstrated that tissue factor (TF) combined with coagulation factor VII (FVII) has a pathological role by activating a protease-activated receptor 2 (PAR2) for tumor growth. Autophagy-related LC3A/B-II formation induced by the inhibition of TF/FVII/PAR2 coagulation axis, particularly by FVII knockdown, was selectively mediated by the Atg7 induction. These results are consistent with clinical observations that indicate the important role of FVII activation in regulating autophagy in HCC. In this chapter, we discuss our findings in which FVII promotes growth and progression in HCC through ERK-TSC/mTOR signaling to repress autophagy and may play a pivotal role in conferring cirrhosis and other liver diseases

Living Donor Liver Transplantation for Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a major worldwide health problem, which is expected to increase steadily due to different underlying liver diseases. Surgical treatment modalities including liver transplantation (LT) or liver resection (LR) are the mainstay options for early cases of HCC. Liver transplantation for well‐selected cases provides excellent survival outcomes comparable to nonmalignant indications of LT. Living donor liver transplantation (LDLT) is an alternative option or even the sole one in the current era of organ shortage problem and in some Asian countries where deceased organ donation is markedly reduced due to various reasons. The adoption of LDLT for HCC treatment elicited many dynamic changes and debates to the dilemma of LT as a whole. In this chapter, we focus on different perspectives of LDLT for HCC, including selection criteria evolution, controversial topics, ethical considerations, operative highlights, and other points

Optical music recognition of the singer using formant frequency estimation of vocal fold vibration and lip motion with interpolated GMM classifiers

The main work of this paper is to identify the musical genres of the singer by performing the optical detection of lip motion. Recently, optical music recognition has attracted much attention. Optical music recognition in this study is a type of automatic techniques in information engineering, which can be used to determine the musical style of the singer. This paper proposes a method for optical music recognition where acoustic formant analysis of both vocal fold vibration and lip motion are employed with interpolated Gaussian mixture model (GMM) estimation to perform musical genre classification of the singer. The developed approach for such classification application is called GMM-Formant. Since humming and voiced speech sounds cause periodic vibrations of the vocal folds and then the corresponding motion of the lip, the proposed GMM-Formant firstly operates to acquire the required formant information. Formant information is important acoustic feature data for recognition classification. The proposed GMM-Formant method then uses linear interpolation for combining GMM likelihood estimates and formant evaluation results appropriately. GMM-Formant will effectively adjust the estimated formant feature evaluation outcomes by referring to certain degree of the likelihood score derived from GMM calculations. The superiority and effectiveness of presented GMM-Formant are demonstrated by a series of experiments on musical genre classification of the singer

Room temperature gas sensing with a hybrid poly-Si/ZnO TFT cell

In this work, we study the capability of a novel poly-Si/Zno hybrid TFT cell in sensing NO2 gas. Fabrication and structural features of this cell are identical to that reported in one of our previous works [1] except that the IGZO TFT is replaced by a ZnO one. The equivalent circuit of the hybrid cell is shown in Fig. 1, in which the poly-Si TFT and ZnO TFT are employed as the amplifier and sensor, respectively. In the configuration, the top gate of the poly-Si TFT is electrically connected to the drain of the bottom-gated ZnO TFT, while the top surface of the ZnO channel is exposed to the environment for sensing purposes. For the electrical measurements conducted at room temperature, the current source (IIN) was set at 100 pA with a compliance VG of 2 V. Concentration of the NO2 gas in the ambient was varied from 0 ~100 ppm. Transfer characteristics of the cell are expressed by showing the drain current of the poly-Si TFT as a function of the back-gate bias (VBG) of the ZnO TFT. In the figure, we can see the I-V curves show a parallel and positive shift as the concentration of the NO2 gas is increased. Meanwhile, the transitions in the figure are steep with a slope of around -60 mV/dec whose absolute value is much smaller than the subthreshold slopes of the individual ZnO TFT (\u3e300 mV/dec). The finding provides good evidence showing the potential of this scheme in promoting measurement sensitivity compared with conventional oxide-semiconductor TFTs. The experimental results also show that UV irradiation can recover the characteristics. Please click Download on the upper right corner to see the full abstract

Palpation of preoperatively inserted indwelling angiocatheter facilitates intraoperative localization of obscure gastrointestinal bleeding of small intestinal origin

SummaryBackgroundPalpation of the indwelling angiographic catheter inserted before operation to localize obscure gastrointestinal bleeding of small intestinal origin during laparotomy has rarely been reported in the literature.PurposeThe purpose of the study is to investigate the role of palpable indwelling angiocatheter inserted before operation in localizing obscure gastrointestinal bleeding of small intestinal origin during laparotomy.MethodsBetween January 2003 and December 2010, seven patients who had a clinical impression of obscure gastrointestinal bleeding of small intestinal origin and angiographic extravasation from the mesenteric artery had an angiocatheter inserted into the distal mesenteric branch. During laparotomy the catheter was palpated to guide subsequent resection of the intestine. The clinical outcomes of these patients were retrospectively reviewed.ResultsDuring laparotomy the retained catheter failed to be palpated in one patient. Six patients underwent segmental resection of intestine under guidance of the palpated catheter. All six patients had positive identification of small bowel bleeding. The yield rate of intraoperative localization was 86% (6 out of 7). Two of the six patients ceased bleeding after operation, but died of underlying disease progression. Four of the six patients had an uneventful postoperative clinical course without recurrent bleeding after a median follow-up period of 25 months.ConclusionPalpation of the indwelling angiographic catheter selectively left before operation is effective for precisely locating obscure gastrointestinal bleeding of small intestinal origin during laparotomy