Mesenchymal hamartomas of the liver(MHLs) in adults are rare and potentially premalignant lesions, which present as solid/cystic neoplasms. We report a rare case of orthotopic liver transplantation in a patient with a...Mesenchymal hamartomas of the liver(MHLs) in adults are rare and potentially premalignant lesions, which present as solid/cystic neoplasms. We report a rare case of orthotopic liver transplantation in a patient with a giant MHL. In 2013, a 34-year-old female sought medical advice after a 2-year history of progressive abdominal distention and respiratory distress. Physical examination revealed an extensive mass in the abdomen. Computed tomography(CT) of her abdomen revealed multiple liver cysts, with the diameter of largest cyst being 16 cm × 14 cm. The liver hilar structures were not clearly displayed. The adjacent organs were compressed and displaced. Initial laboratory tests, including biochemical investigations and coagulation profile, were unremarkable. Tumor markers, including levels of AFP, CEA and CA19-9, were within the normal ranges. The patient underwent orthotopic liver transplantation in November 2013, the liver being procured from a 40-year-old man after cardiac death following traumatic brain injury. Warm ischemic time was 7.5 min and cold ischemic time was 3 h. The recipient underwent classical orthotopic liver transplantation. The recipient operative procedure took 8.5 h, the anhepatic phase lasting for 1 h without the use of venovenous bypass. The immunosuppressive regimen includedintraoperative induction with basiliximab and high-dose methylprednisolone, and postoperative maintenance with tacrolimus, mycophenolate mofetil, and prednisone. The recipient's diseased liver weighed 21 kg(dry weight) and measured 41 cm × 32 cm × 31 cm. Histopathological examination confirmed the diagnosis of an MHL. The patient did not experience any acute rejection episode or other complication. All the laboratory tests returned to normal within one month after surgery. Three months after transplantation, the immunosuppressive therapy was reduced to tacrolimus monotherapy, and the T-tube was removed after cholangiography showed no abnormalities. Twelve months after transplantation, the patient remains well and is fulfilling all normal activities. Adult giant MHL is extremely rare. Symptoms, physical signs, laboratory results, and radiographic imaging are nonspecific and inconclusive. Surgical excision of the lesion is imperative to make a definite diagnosis and as a cure. Liver transplantation should be considered as an option in the treatment of a non-resectable MHL.展开更多
There is a critical shortage of organs, cells, and corneas from deceased human donors worldwide. There are also shortages of human blood for transfusion. A potential solution to all of these problems is the transplant...There is a critical shortage of organs, cells, and corneas from deceased human donors worldwide. There are also shortages of human blood for transfusion. A potential solution to all of these problems is the transplantation of organs, cells, and corneas from a readily available animal species, such as the pig, and the transfusion of red blood cells from pigs into humans. However, to achieve these ends, major immunologic and other barriers have to be overcome. Considerable progress has been made in this respect by the genetic modification of pigs to protect their tissues from the primate immune response and to correct several molecular incompatibilities that exist between pig and primate. These have included knockout of genes responsible for the expression of major antigenic targets for primate natural anti-pig antibodies, insertion of human complement- and coagulation-regulatory transgenes, and knockdown of swine leukocyte antigens that stimulate the primate's adaptive immune response. As a result of these manipulations, the administration of novel immunosuppressive agents, and other innovations, pig hearts have now functioned in baboons for 6-8 months, pig islets have maintained normoglycemia in diabetic monkeys for 〉 1 year, and pig corneas have maintained transparency for several months. Clinical trials of pig islet trans- plantation are already in progress. Future developments will involve further genetic manipulations of the organ- source pig, with most of the genes that are likely to be beneficial already identified.展开更多
AIM To investigate the incidence, risk factors and clinical outcomes of acute antibody-mediated rejection(ABMR) after intestinal transplantation(ITx).METHODS A retrospective single-center analysis was performed to ide...AIM To investigate the incidence, risk factors and clinical outcomes of acute antibody-mediated rejection(ABMR) after intestinal transplantation(ITx).METHODS A retrospective single-center analysis was performed to identify cases of acute ABMR after ITx, based on the presence of donor-specific antibody(DSA), acute tissue damage, C4 d deposition, and allograft dysfunction.RESULTS Acute ABMR was identified in 18(10.3%) out of 175 intestinal allografts with an average occurrence of 10 d(range, 4-162) after ITx. All acute ABMR cases were presensitized to donor human leukocyte antigens class Ⅰand/or Ⅱ antigens with a detectable DSA. A positive cross-match was seen in 14(77.8%) cases and twelve of 18 patients(66.7%) produced newly-formed DSA following ITx. Histological characteristics of acute ABMR include endothelial C4 d deposits, interstitial hemorrhage, and severe congestion with focal fibrin thrombin in the lamina propria capillaries. Multivariate analysis identified a liver-free graft and high level of panel reactive antibodyas a significant independent risk factor. Despite initial improvement after therapy, eleven recipients(61.1%) lost transplant secondary to rejection. Of those, 9(50%) underwent graft removal and 4(22.2%) received second transplantation following acute ABMR. At an average follow-up of 32.3 mo(range, 13.3-76.4), 8(44.4%) recipients died.CONCLUSION Our results indicate that acute ABMR is an important cause of intestine graft dysfunction, particularly in a liver-exclusive graft and survivors are at an increased risk of developing refractory acute rejection and chronic rejection. More effective strategies to prevent and manage acute ABMR are needed to improve outcomes.展开更多
·AIM: To investigate whether decellularization using different techniques can reduce immunogenicity of the cornea, and to explore the decellularized cornea as a scaffold for cultured corneal endothelial cells(CEC...·AIM: To investigate whether decellularization using different techniques can reduce immunogenicity of the cornea, and to explore the decellularized cornea as a scaffold for cultured corneal endothelial cells(CECs).Transplantation of decellularized porcine corneas increases graft transparency and survival for longer periods compared with fresh grafts.·METHODS: Six-month-old wild-type pig corneas were cut into 100-200 μm thickness, and then decellularized by three different methods: 1) 0.1% sodium dodecyl sulfate(SDS); 2) hypoxic nitrogen(N2); and 3) hypertonic NaCl. Thickness and transparency were assessed visually. Fresh and decellularized corneas were stained with hematoxylin/eosin(H&E), and for the presence of galactose-α1,3-galactose(Gal) and N-glycolylneuraminic acid(NeuGc, a nonGal antigen). Also, a human IgM/IgG binding assay was performed. Cultured porcine CECs were seeded on the surface of the decellularized cornea and examined after H&E staining.· RESULTS: All three methods of decellularization reduced the number of keratocytes in the stromal tissue by 】80% while the collagen structure remained preserved. No remaining nuclei stained positive for Gal or NeuGc, and expression of these oligosaccharides on collagen was also greatly decreased compared to expression on fresh corneas. Human IgM/IgG binding to decellularized corneal tissue was considerably reduced compared to fresh corneal tissue. The cultured CECs formed a confluent monolayer on the surface of decellularized tissue.· CONCLUSION: Though incomplete, the significant reduction in the cellular component of the decellularized cornea should be associated with a significantly reduced in vivo immune response compared to fresh corneas.展开更多
Sepsis remains a major clinical problem with high morbidity and mortality. As new inflammatory mediators are characterized, it is important to understand their roles in sepsis. Interleukin 33(IL-33) is a recently desc...Sepsis remains a major clinical problem with high morbidity and mortality. As new inflammatory mediators are characterized, it is important to understand their roles in sepsis. Interleukin 33(IL-33) is a recently described member of the IL-1 family that is widely expressed in cells of barrier tissues. Upon tissue damage, IL-33 is released as an alarmin and activates various types of cells of both the innate and adaptive immune system through binding to the ST2/IL-1 receptor accessory protein complex. IL-33 has apparent pleiotropic functions in many disease models, with its actions strongly shaped by the local microenvironment. Recent studies have established a role for the IL-33-ST2 axis in the initiation and perpetuation of inflammation during endotoxemia, but its roles in sepsis appear to be organism and model dependent. In this review, we focus on the recent advances in understanding the role of the IL-33/ST2 axis in sepsis.展开更多
Bioartificial liver assist devices (BALs) offer anopportunity for critical care physicians and transplantsurgeons to stabilize patients prior to orthotopic livertransplantation. Such devices may also act as a bridgeto...Bioartificial liver assist devices (BALs) offer anopportunity for critical care physicians and transplantsurgeons to stabilize patients prior to orthotopic livertransplantation. Such devices may also act as a bridgeto transplant, providing liver support to patientsawaiting transplant, or as support for patients post liv-ing-related donor transplant. Four BAL devices thatrely on hepatocytes cultured in hollow fiber membranecartridges (Circe Biomedical HepatAssist (r), VitagenELADTM, Gerlach BELS, and Excorp Medical BLSS)are currently in various stages of clinical evalua-tion. Comparison of the four devices shows that severalunique approaches based upon the same overall systemarchitecture are possible. Preliminary results of theExcorp Medical BLSS Phase I safety evaluation at theUniversity of Pittsburgh, after treating four patients(F, 41, acetominophen-induced, two support periods;M, 50, Wilson's disease, one support period; F, 53, a-cute alcoholic hepatitis, two support periods; F, 24,chemotherapy-induced, one support period) are pre-sented. All patients presented with hypoglycemia andtransient hypotension at the start of extracorporealperfusion. Hypoglycemia was treated by IV dextroseand the transient hypotension responded positively toIV fluid bolus. Heparin anticoagulation was used onlyin the second patient. No serious or adverse eventswere noted in the four patients. Moderate biochemicalresponse to support was noted in all patients. Morecomplete characterization of the safety of the BLSSrequires completion of the Phase I safety evaluation.展开更多
Background: Appropriate preclinical evaluation of a bioartificial liver assist device (BAL) demands a large animal model, as presented here, that demon- strates many of the clinical features of acute liver failure and...Background: Appropriate preclinical evaluation of a bioartificial liver assist device (BAL) demands a large animal model, as presented here, that demon- strates many of the clinical features of acute liver failure and that is suitable for clinical qualitative and quantitative evaluation of the BAL. A lethal canine liver failure model of acute hepatic failure that re- moves many of the artifacts evidenced in prior canine models is presented. Methods: Six male hounds, 24-30 kg, under isoflu- rane anesthesia, were administered 1.5 g/kg D- galactosamine intravenously. Canine supportive care followed a well-defined management protocol that was guided by electrolyte and invasive monitoring consisting of arterial pressure, central venous pres- sure, extradural intracranial pressure (ICP), pul- monary artery pressure, and end-tidal CO_2. The animals were treated until death-equivalent, defined as inability to sustain systolic blood pressure>80 mmHg for 20 minutes despite maximal fluids and 20 μg·kg^(-1)·min^(-1) dopamine infusion. Results: The mean survival time was 43.7±4.6 hours (mean±SE). All animals showed evidence of progressive liver failure characterized by increasing liver enzymes (aspartate transaminase from 26 to 5977 IU/L; alanine transaminase from 32 to 9740 IU/L), bilirubin (0.25 to 1.30 mg/dl), ammonia (19. 8 to 85. 3 μmol/L), and coagulopathy (pro- thrombin time from 8.7 to 46 s). Increased lability and elevations in intracranial pressures were ob- served. All animals were refractory to maintenance of cerebral perfusion pressure even with only mode- rately elevated intracranial pressure. Severe neuro- logic obtundation, seen in 2 of 6 animals, was associ- ated with elevations of ICP above 50 mmHg. Post- mortem liver histology showed evidence of massive hepatic necrosis. Postmortem blood and ascites mi- crobial growth was consistent with possible transloca- tion of intestinal microbes. Conclusions: The improved lethal canine liver failure model presented here reproduces many of the clinical features of acute liver failure. The model may prove useful for qualitative and quantitative evaluation of BALs.展开更多
Dear editor,Hepatopulmonary syndrome(HPS)is not uncommon in the setting of liver disease,especially in liver cirrhosis patients.The prevalence of HPS in liver cirrhosis patients varies from 4%to 47%.[1-3]About the def...Dear editor,Hepatopulmonary syndrome(HPS)is not uncommon in the setting of liver disease,especially in liver cirrhosis patients.The prevalence of HPS in liver cirrhosis patients varies from 4%to 47%.[1-3]About the definition of HPS,it is a pulmonary vascular disorder with evidence of intrapulmonary arterial venous shunt.[4]Pulmonary dyspnea and polycythemia are common presentations of HPS.Dyspnea,cyanosis and clubbed fingers were present in most of all cases.Spider nevi is another common clinical feature of patients with HPS.展开更多
It has been known for some time that low PLP blood levels are common in asthmatic patients,and supplementation with vitamin B6 may reduce the severity of asthma symptoms[12].In the current study,a comparison of PLP le...It has been known for some time that low PLP blood levels are common in asthmatic patients,and supplementation with vitamin B6 may reduce the severity of asthma symptoms[12].In the current study,a comparison of PLP levels in the plasma of asthmatic patients(n=52)and healthy controls(n=58)confirmed lower PLP concentrations in asthmatic patients,which correlated with reduced lung function and increased circulating eosinophils,suggestive of increased type 2 inflammation.Using several mouse models of acute lung inflammation,they confirmed that systemic or local administration of PLP reduced lung inflammation and eosinophil density,suggesting that PLP concentration may be directly controlling immune responses that lead to the development of allergic airway disease.ILC2s constitutively express ST2,and IL-33 profoundly promotes ILC2 expansion and secretion of IL-5 and IL-13 to mediate allergic reactions and support host defenses against parasitic worms.PLP reduces the number of type 2 innate lymphoid cells(ILC2s)and their expression of IL-5 and IL-13.Conversely,diet-induced vitamin B6 deficiency in mice increased papain-induced lung inflammation,including increasing the proportion of IL5+and IL-13+ILC2s.The authors revealed that PLP treatment decreased IL-33 levels in the bronchoalveolar lavage fluid(BALF)and lung and targeting IL-33 with an antibody during papain-induced lung inflammation did not reduce inflammation beyond that of PLP treatment alone.An important clue to the regulation of IL-33 was that PLP treatment did not modify IL-33 mRNA levels.Instead,pyridoxal(PL)treatment of a human alveolar basal epithelial cell line(A549)stably expressing full-length IL-33 with a hemagglutinin(HA)tag established that PL exposure potently decreased intracellular IL-33 protein levels.The researchers used this cell line to explore the underlying mechanisms and verified that PL conversion to PLP by pyridoxal kinase(PDXK)controlled the stability of IL-33.Consistent with these data,the IL-33 concentration and papain-induced lung inflammation were augmented significantly in PDXK-deficient mice.The author’s use of degradative pathway inhibitors and truncated IL-33 constructs pinpointed a mechanism involving protective ubiquitylation of the IL-33 N-terminal domain that is inhibited by vitamin B6.A comprehensive database search for proteome-wide known and predicted ubiquitin ligase/deubiquitinase-substrate interactions showed that mouse double minute 2 homolog(MDM2)was a likely E3 ubiquitin ligase interacting with IL-33.Recent studies have shown that MDM2,while best known for its regulation of p53,mediates the ubiquitination and stability of numerous nuclear proteins,including Foxp3,HDACs,and STATs[13,14,15].In the current work,MDM2 interacted with IL-33 via a RING domain to facilitate IL-33 stability via ubiquitination of lysines to control IL-33 homeostasis,and this ubiquitination could be inhibited by vitamin B6(Fig.2).It will be important for future studies to establish how precisely PLP suppresses the functional interactions between IL-33 and MDM2.展开更多
Modulation of alloimmune responses is critical to improving transplant outcome and promoting long-term graft survival.To determine mechanisms by which a nonhematopoietic erythropoietin(EPO)derivative,carbamylated EPO(...Modulation of alloimmune responses is critical to improving transplant outcome and promoting long-term graft survival.To determine mechanisms by which a nonhematopoietic erythropoietin(EPO)derivative,carbamylated EPO(CEPO),regulates innate and adaptive immune cells and affects renal allograft survival,we utilized a rat model of fully MHC-mismatched kidney transplantation.CEPO administration markedly extended the survival time of kidney allografts compared with the transplant alone control group.This therapeutic effect was inhibited when the recipients were given LY294002,a selective inhibitor of the phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)signaling pathway or anti-EPO receptor(EPOR)antibody,in addition to CEPO.In vitro,CEPO inhibited the differentiation and function of dendritic cells and modulated their production of proinflammatory and anti-inflammatory cytokines,along with activating the PI3K/AKT signaling pathway and increasing EPOR mRNA and protein expression by these innate immune cells.Moreover,after CD4^(+)T cells were exposed to CEPO the Th1/Th2 ratio decreased and the regulatory T cell(Treg)/Th17 ratio increased.These effects were abolished by LY294002 or anti-EPOR antibody,suggesting that CEPO regulates immune responses and promotes kidney allograft survival by activating the PI3K/AKT signaling pathway in an EPOR-dependent manner.The immunomodulatory and specific signaling pathway effects of CEPO identified in this study suggest a potential therapeutic approach to promoting kidney transplant survival.展开更多
基金Supported by National Natural Science Foundation of China,No.81400680the National High Technology Research and Development Program of China,No.2012 AA021001
文摘Mesenchymal hamartomas of the liver(MHLs) in adults are rare and potentially premalignant lesions, which present as solid/cystic neoplasms. We report a rare case of orthotopic liver transplantation in a patient with a giant MHL. In 2013, a 34-year-old female sought medical advice after a 2-year history of progressive abdominal distention and respiratory distress. Physical examination revealed an extensive mass in the abdomen. Computed tomography(CT) of her abdomen revealed multiple liver cysts, with the diameter of largest cyst being 16 cm × 14 cm. The liver hilar structures were not clearly displayed. The adjacent organs were compressed and displaced. Initial laboratory tests, including biochemical investigations and coagulation profile, were unremarkable. Tumor markers, including levels of AFP, CEA and CA19-9, were within the normal ranges. The patient underwent orthotopic liver transplantation in November 2013, the liver being procured from a 40-year-old man after cardiac death following traumatic brain injury. Warm ischemic time was 7.5 min and cold ischemic time was 3 h. The recipient underwent classical orthotopic liver transplantation. The recipient operative procedure took 8.5 h, the anhepatic phase lasting for 1 h without the use of venovenous bypass. The immunosuppressive regimen includedintraoperative induction with basiliximab and high-dose methylprednisolone, and postoperative maintenance with tacrolimus, mycophenolate mofetil, and prednisone. The recipient's diseased liver weighed 21 kg(dry weight) and measured 41 cm × 32 cm × 31 cm. Histopathological examination confirmed the diagnosis of an MHL. The patient did not experience any acute rejection episode or other complication. All the laboratory tests returned to normal within one month after surgery. Three months after transplantation, the immunosuppressive therapy was reduced to tacrolimus monotherapy, and the T-tube was removed after cholangiography showed no abnormalities. Twelve months after transplantation, the patient remains well and is fulfilling all normal activities. Adult giant MHL is extremely rare. Symptoms, physical signs, laboratory results, and radiographic imaging are nonspecific and inconclusive. Surgical excision of the lesion is imperative to make a definite diagnosis and as a cure. Liver transplantation should be considered as an option in the treatment of a non-resectable MHL.
文摘There is a critical shortage of organs, cells, and corneas from deceased human donors worldwide. There are also shortages of human blood for transfusion. A potential solution to all of these problems is the transplantation of organs, cells, and corneas from a readily available animal species, such as the pig, and the transfusion of red blood cells from pigs into humans. However, to achieve these ends, major immunologic and other barriers have to be overcome. Considerable progress has been made in this respect by the genetic modification of pigs to protect their tissues from the primate immune response and to correct several molecular incompatibilities that exist between pig and primate. These have included knockout of genes responsible for the expression of major antigenic targets for primate natural anti-pig antibodies, insertion of human complement- and coagulation-regulatory transgenes, and knockdown of swine leukocyte antigens that stimulate the primate's adaptive immune response. As a result of these manipulations, the administration of novel immunosuppressive agents, and other innovations, pig hearts have now functioned in baboons for 6-8 months, pig islets have maintained normoglycemia in diabetic monkeys for 〉 1 year, and pig corneas have maintained transparency for several months. Clinical trials of pig islet trans- plantation are already in progress. Future developments will involve further genetic manipulations of the organ- source pig, with most of the genes that are likely to be beneficial already identified.
文摘AIM To investigate the incidence, risk factors and clinical outcomes of acute antibody-mediated rejection(ABMR) after intestinal transplantation(ITx).METHODS A retrospective single-center analysis was performed to identify cases of acute ABMR after ITx, based on the presence of donor-specific antibody(DSA), acute tissue damage, C4 d deposition, and allograft dysfunction.RESULTS Acute ABMR was identified in 18(10.3%) out of 175 intestinal allografts with an average occurrence of 10 d(range, 4-162) after ITx. All acute ABMR cases were presensitized to donor human leukocyte antigens class Ⅰand/or Ⅱ antigens with a detectable DSA. A positive cross-match was seen in 14(77.8%) cases and twelve of 18 patients(66.7%) produced newly-formed DSA following ITx. Histological characteristics of acute ABMR include endothelial C4 d deposits, interstitial hemorrhage, and severe congestion with focal fibrin thrombin in the lamina propria capillaries. Multivariate analysis identified a liver-free graft and high level of panel reactive antibodyas a significant independent risk factor. Despite initial improvement after therapy, eleven recipients(61.1%) lost transplant secondary to rejection. Of those, 9(50%) underwent graft removal and 4(22.2%) received second transplantation following acute ABMR. At an average follow-up of 32.3 mo(range, 13.3-76.4), 8(44.4%) recipients died.CONCLUSION Our results indicate that acute ABMR is an important cause of intestine graft dysfunction, particularly in a liver-exclusive graft and survivors are at an increased risk of developing refractory acute rejection and chronic rejection. More effective strategies to prevent and manage acute ABMR are needed to improve outcomes.
基金Supported in part by NIH Grants#1RO3A 1096296-01 (HH), #IU19A1090959-01 (DKCC), #U01A 1066331 (DKCC), and #5P01 HL107152-02 (DKCC)Ocular Tissue Engineering and Regenerative Ophthalmology (OTERO) Postdoctoral Fellowship (WL)Sponsored Research Agreements Between the University of Pittsburgh and Revivicor, Blacksburg, VA
文摘·AIM: To investigate whether decellularization using different techniques can reduce immunogenicity of the cornea, and to explore the decellularized cornea as a scaffold for cultured corneal endothelial cells(CECs).Transplantation of decellularized porcine corneas increases graft transparency and survival for longer periods compared with fresh grafts.·METHODS: Six-month-old wild-type pig corneas were cut into 100-200 μm thickness, and then decellularized by three different methods: 1) 0.1% sodium dodecyl sulfate(SDS); 2) hypoxic nitrogen(N2); and 3) hypertonic NaCl. Thickness and transparency were assessed visually. Fresh and decellularized corneas were stained with hematoxylin/eosin(H&E), and for the presence of galactose-α1,3-galactose(Gal) and N-glycolylneuraminic acid(NeuGc, a nonGal antigen). Also, a human IgM/IgG binding assay was performed. Cultured porcine CECs were seeded on the surface of the decellularized cornea and examined after H&E staining.· RESULTS: All three methods of decellularization reduced the number of keratocytes in the stromal tissue by 】80% while the collagen structure remained preserved. No remaining nuclei stained positive for Gal or NeuGc, and expression of these oligosaccharides on collagen was also greatly decreased compared to expression on fresh corneas. Human IgM/IgG binding to decellularized corneal tissue was considerably reduced compared to fresh corneal tissue. The cultured CECs formed a confluent monolayer on the surface of decellularized tissue.· CONCLUSION: Though incomplete, the significant reduction in the cellular component of the decellularized cornea should be associated with a significantly reduced in vivo immune response compared to fresh corneas.
基金supported by the National Institutes of Health(RO1-GM 044100,RO1-GM 050441)
文摘Sepsis remains a major clinical problem with high morbidity and mortality. As new inflammatory mediators are characterized, it is important to understand their roles in sepsis. Interleukin 33(IL-33) is a recently described member of the IL-1 family that is widely expressed in cells of barrier tissues. Upon tissue damage, IL-33 is released as an alarmin and activates various types of cells of both the innate and adaptive immune system through binding to the ST2/IL-1 receptor accessory protein complex. IL-33 has apparent pleiotropic functions in many disease models, with its actions strongly shaped by the local microenvironment. Recent studies have established a role for the IL-33-ST2 axis in the initiation and perpetuation of inflammation during endotoxemia, but its roles in sepsis appear to be organism and model dependent. In this review, we focus on the recent advances in understanding the role of the IL-33/ST2 axis in sepsis.
文摘Bioartificial liver assist devices (BALs) offer anopportunity for critical care physicians and transplantsurgeons to stabilize patients prior to orthotopic livertransplantation. Such devices may also act as a bridgeto transplant, providing liver support to patientsawaiting transplant, or as support for patients post liv-ing-related donor transplant. Four BAL devices thatrely on hepatocytes cultured in hollow fiber membranecartridges (Circe Biomedical HepatAssist (r), VitagenELADTM, Gerlach BELS, and Excorp Medical BLSS)are currently in various stages of clinical evalua-tion. Comparison of the four devices shows that severalunique approaches based upon the same overall systemarchitecture are possible. Preliminary results of theExcorp Medical BLSS Phase I safety evaluation at theUniversity of Pittsburgh, after treating four patients(F, 41, acetominophen-induced, two support periods;M, 50, Wilson's disease, one support period; F, 53, a-cute alcoholic hepatitis, two support periods; F, 24,chemotherapy-induced, one support period) are pre-sented. All patients presented with hypoglycemia andtransient hypotension at the start of extracorporealperfusion. Hypoglycemia was treated by IV dextroseand the transient hypotension responded positively toIV fluid bolus. Heparin anticoagulation was used onlyin the second patient. No serious or adverse eventswere noted in the four patients. Moderate biochemicalresponse to support was noted in all patients. Morecomplete characterization of the safety of the BLSSrequires completion of the Phase I safety evaluation.
基金This study was partially supported by a grant from Excorp Medical, Inc, Oakdale, MN., Steritek J7000 Intracranial Pressure Monitor provided by Ladd Research Industries, Williston, VT., and Datex Capnomac Ultima Anesthesia Monitor provided by Datex, Helsi
文摘Background: Appropriate preclinical evaluation of a bioartificial liver assist device (BAL) demands a large animal model, as presented here, that demon- strates many of the clinical features of acute liver failure and that is suitable for clinical qualitative and quantitative evaluation of the BAL. A lethal canine liver failure model of acute hepatic failure that re- moves many of the artifacts evidenced in prior canine models is presented. Methods: Six male hounds, 24-30 kg, under isoflu- rane anesthesia, were administered 1.5 g/kg D- galactosamine intravenously. Canine supportive care followed a well-defined management protocol that was guided by electrolyte and invasive monitoring consisting of arterial pressure, central venous pres- sure, extradural intracranial pressure (ICP), pul- monary artery pressure, and end-tidal CO_2. The animals were treated until death-equivalent, defined as inability to sustain systolic blood pressure>80 mmHg for 20 minutes despite maximal fluids and 20 μg·kg^(-1)·min^(-1) dopamine infusion. Results: The mean survival time was 43.7±4.6 hours (mean±SE). All animals showed evidence of progressive liver failure characterized by increasing liver enzymes (aspartate transaminase from 26 to 5977 IU/L; alanine transaminase from 32 to 9740 IU/L), bilirubin (0.25 to 1.30 mg/dl), ammonia (19. 8 to 85. 3 μmol/L), and coagulopathy (pro- thrombin time from 8.7 to 46 s). Increased lability and elevations in intracranial pressures were ob- served. All animals were refractory to maintenance of cerebral perfusion pressure even with only mode- rately elevated intracranial pressure. Severe neuro- logic obtundation, seen in 2 of 6 animals, was associ- ated with elevations of ICP above 50 mmHg. Post- mortem liver histology showed evidence of massive hepatic necrosis. Postmortem blood and ascites mi- crobial growth was consistent with possible transloca- tion of intestinal microbes. Conclusions: The improved lethal canine liver failure model presented here reproduces many of the clinical features of acute liver failure. The model may prove useful for qualitative and quantitative evaluation of BALs.
文摘Dear editor,Hepatopulmonary syndrome(HPS)is not uncommon in the setting of liver disease,especially in liver cirrhosis patients.The prevalence of HPS in liver cirrhosis patients varies from 4%to 47%.[1-3]About the definition of HPS,it is a pulmonary vascular disorder with evidence of intrapulmonary arterial venous shunt.[4]Pulmonary dyspnea and polycythemia are common presentations of HPS.Dyspnea,cyanosis and clubbed fingers were present in most of all cases.Spider nevi is another common clinical feature of patients with HPS.
基金supported by funding from the National Institutes of Health(R01HL22489 and R01AR073527)the Department of Defense(W81XWH-21–1–0896).
文摘It has been known for some time that low PLP blood levels are common in asthmatic patients,and supplementation with vitamin B6 may reduce the severity of asthma symptoms[12].In the current study,a comparison of PLP levels in the plasma of asthmatic patients(n=52)and healthy controls(n=58)confirmed lower PLP concentrations in asthmatic patients,which correlated with reduced lung function and increased circulating eosinophils,suggestive of increased type 2 inflammation.Using several mouse models of acute lung inflammation,they confirmed that systemic or local administration of PLP reduced lung inflammation and eosinophil density,suggesting that PLP concentration may be directly controlling immune responses that lead to the development of allergic airway disease.ILC2s constitutively express ST2,and IL-33 profoundly promotes ILC2 expansion and secretion of IL-5 and IL-13 to mediate allergic reactions and support host defenses against parasitic worms.PLP reduces the number of type 2 innate lymphoid cells(ILC2s)and their expression of IL-5 and IL-13.Conversely,diet-induced vitamin B6 deficiency in mice increased papain-induced lung inflammation,including increasing the proportion of IL5+and IL-13+ILC2s.The authors revealed that PLP treatment decreased IL-33 levels in the bronchoalveolar lavage fluid(BALF)and lung and targeting IL-33 with an antibody during papain-induced lung inflammation did not reduce inflammation beyond that of PLP treatment alone.An important clue to the regulation of IL-33 was that PLP treatment did not modify IL-33 mRNA levels.Instead,pyridoxal(PL)treatment of a human alveolar basal epithelial cell line(A549)stably expressing full-length IL-33 with a hemagglutinin(HA)tag established that PL exposure potently decreased intracellular IL-33 protein levels.The researchers used this cell line to explore the underlying mechanisms and verified that PL conversion to PLP by pyridoxal kinase(PDXK)controlled the stability of IL-33.Consistent with these data,the IL-33 concentration and papain-induced lung inflammation were augmented significantly in PDXK-deficient mice.The author’s use of degradative pathway inhibitors and truncated IL-33 constructs pinpointed a mechanism involving protective ubiquitylation of the IL-33 N-terminal domain that is inhibited by vitamin B6.A comprehensive database search for proteome-wide known and predicted ubiquitin ligase/deubiquitinase-substrate interactions showed that mouse double minute 2 homolog(MDM2)was a likely E3 ubiquitin ligase interacting with IL-33.Recent studies have shown that MDM2,while best known for its regulation of p53,mediates the ubiquitination and stability of numerous nuclear proteins,including Foxp3,HDACs,and STATs[13,14,15].In the current work,MDM2 interacted with IL-33 via a RING domain to facilitate IL-33 stability via ubiquitination of lysines to control IL-33 homeostasis,and this ubiquitination could be inhibited by vitamin B6(Fig.2).It will be important for future studies to establish how precisely PLP suppresses the functional interactions between IL-33 and MDM2.
基金supported by the National Natural Science Foundation of China(No.81470977,No.81970652)the Guangdong Basic and Applied Basic Research Foundation(No.2019A1515011219)the Science and Technology Planning Project of Guangzhou(No.201803010016).S.Z.is supported by the National Institutes of Health grants R01 AR059103,Star Award and R61 AR073409.
文摘Modulation of alloimmune responses is critical to improving transplant outcome and promoting long-term graft survival.To determine mechanisms by which a nonhematopoietic erythropoietin(EPO)derivative,carbamylated EPO(CEPO),regulates innate and adaptive immune cells and affects renal allograft survival,we utilized a rat model of fully MHC-mismatched kidney transplantation.CEPO administration markedly extended the survival time of kidney allografts compared with the transplant alone control group.This therapeutic effect was inhibited when the recipients were given LY294002,a selective inhibitor of the phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)signaling pathway or anti-EPO receptor(EPOR)antibody,in addition to CEPO.In vitro,CEPO inhibited the differentiation and function of dendritic cells and modulated their production of proinflammatory and anti-inflammatory cytokines,along with activating the PI3K/AKT signaling pathway and increasing EPOR mRNA and protein expression by these innate immune cells.Moreover,after CD4^(+)T cells were exposed to CEPO the Th1/Th2 ratio decreased and the regulatory T cell(Treg)/Th17 ratio increased.These effects were abolished by LY294002 or anti-EPOR antibody,suggesting that CEPO regulates immune responses and promotes kidney allograft survival by activating the PI3K/AKT signaling pathway in an EPOR-dependent manner.The immunomodulatory and specific signaling pathway effects of CEPO identified in this study suggest a potential therapeutic approach to promoting kidney transplant survival.