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1.
ANZ J Surg ; 91(12): 2663-2668, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33956377

RESUMEN

BACKGROUND: This study aimed to describe the clinical outcomes of total pancreatectomy with islet autotransplantation (TP-IAT) in Australia. METHODS: Individuals selected for TP-IAT surgery according to the Minnesota Criteria (Appendix) without evidence of diabetes were evaluated including time to transplantation from pancreatectomy, islet numbers infused and post-transplantation HbA1c, C-peptide, total daily insulin and analgesic requirement. RESULTS: Sixteen individuals underwent TP-IAT from Australia and New Zealand between 2010 and 2020. Two recipients are deceased. The median islet equivalents/kg infused was 4244 (interquartile range (IQR) 2290-7300). The median C-peptide 1 month post-TP-IAT was 384 (IQR 210-579) pmol/L and at median 29.5 (IQR 14.5-46.5) months from transplant was 395 (IQR 139-862) pmol/L. Insulin independence was achieved in eight of 15 (53.3%) surviving recipients. A higher islet equivalents transplanted was most strongly associated with the likelihood of insulin independence (P < 0.05). Of the 15 surviving recipients, 14 demonstrated substantial reduction in analgesic requirement. CONCLUSION: The TP-IAT programme in Australia has been a successful new therapy for the management of individuals with chronic pancreatitis including hereditary forms refractory to medical treatment to improve pain management with 50% insulin independence rates.


Asunto(s)
Pancreatectomía , Pancreatitis Crónica , Australia/epidemiología , Humanos , Manejo del Dolor , Pancreatitis Crónica/cirugía , Trasplante Autólogo
2.
Transplant Proc ; 50(10): 3144-3151, 2018 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-30577180

RESUMEN

Anastomosing the renal artery and vein in transplant recipients without a cooling mechanism exposes the kidney to temperatures exceeding the metabolic threshold (15°C to 18°C), at which the protective effects of renal hypothermia are lost. This anastomotic time, or second warm ischemic time, can be deleterious to graft outcomes, especially if it is prolonged. Techniques to ameliorate organ warming prior to reperfusion have been designed, and range from simpler surface cooling techniques, to organ immersion in bags of ice slush, and the application of 'jackets' that incorporate their own internal cooling mechanism. The efficacy of these methods with respect to the minimization of kidney temperature prior to reperfusion and subsequent effects on graft outcomes are discussed using clinical and experimental data, in the setting of open, laparoscopic, and robotic kidney transplantation.


Asunto(s)
Hipotermia Inducida/métodos , Trasplante de Riñón/métodos , Laparoscopía/métodos , Procedimientos Quirúrgicos Robotizados/métodos , Isquemia Tibia/métodos , Anastomosis Quirúrgica , Temperatura Corporal , Humanos , Riñón/irrigación sanguínea , Arteria Renal
3.
Horm Metab Res ; 47(1): 16-23, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25350521

RESUMEN

Islet cell transplantation has emerged as a treatment modality for type 1 diabetes in the last 15 years due to the Edmonton protocol leading to consistent and sustained exogenous insulin independence post-transplantation. In recent years, consortia that involve both local and remote islet cell centers have been established, with local centers responsible for processing and shipping of islet cells, and remote centers only transplanting them. There are, however, few data on patient outcomes at remote centers. A tendency for high fasting glucose despite insulin independence was noted by us and others with an unknown mechanism. This review provides a brief history of islet cell transplantation, and focuses on the South Australian remote center experience: the challenges, screening criteria, and the impact on incretin hormone secretion of insulin independent transplant patients.


Asunto(s)
Diabetes Mellitus Tipo 1/terapia , Accesibilidad a los Servicios de Salud , Incretinas/metabolismo , Insulina/uso terapéutico , Trasplante de Islotes Pancreáticos , Tamizaje Masivo , Australia , Humanos
4.
Am J Transplant ; 14(6): 1300-9, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24842781

RESUMEN

The instant blood-mediated inflammatory reaction (IBMIR) is a major obstacle to the engraftment of intraportal pig islet xenografts in primates. Higher expression of the galactose-α1,3-galactose (αGal) xenoantigen on neonatal islet cell clusters (NICC) than on adult pig islets may provoke a stronger reaction, but this has not been tested in the baboon model. Here, we report that WT pig NICC xenografts triggered profound IBMIR in baboons, with intravascular clotting and graft destruction occurring within hours, which was not prevented by anti-thrombin treatment. In contrast, IBMIR was minimal when recipients were immunosuppressed with a clinically relevant protocol and transplanted with NICC from αGal-deficient pigs transgenic for the human complement regulators CD55 and CD59. These genetically modified (GM) NICC were less susceptible to humoral injury in vitro than WT NICC, inducing significantly less complement activation and thrombin generation when incubated with baboon platelet-poor plasma. Recipients of GM NICC developed a variable anti-pig antibody response, and examination of the grafts 1 month after transplant revealed significant cell-mediated rejection, although scattered insulin-positive cells were still present. Our results indicate that IBMIR can be attenuated in this model, but long-term graft survival may require more effective immunosuppression or further donor genetic modification.


Asunto(s)
Sangre , Rechazo de Injerto , Trasplante de Islotes Pancreáticos , Trasplante Heterólogo , Animales , Anticuerpos/sangre , Bovinos , Papio
5.
Diabetes Metab ; 40(3): 229-34, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24630734

RESUMEN

The aim of this study was to investigate the effectiveness of immunomodulatory peptides in preventing the spontaneous onset of Type 1 diabetes in NOD mice. Two such peptides, CP and C1, were injected intraperitoneally in NOD mice three times a week starting at two different time points, nine weeks and 11 weeks of age, and blood sugar levels monitored for the development of diabetes. CP was shown to be effective in delaying the onset of diabetes compared to control (P = 0.006). The timing of peptide administration was crucial since delay in treatment did not prevent the onset of diabetes (nine weeks versus 11 weeks of age). C1 was effective in delaying the onset of Type 1 diabetes with borderline significance when given at week 11 (P = 0.05). These findings confirm the efficacy of these peptides in the prevention and possible treatment for Type 1 diabetes and thereby create new opportunities for genetic manipulation.


Asunto(s)
Diabetes Mellitus Tipo 1/prevención & control , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Péptidos/farmacología , Linfocitos T/metabolismo , Animales , Diferenciación Celular , Células Cultivadas , Diabetes Mellitus Experimental/prevención & control , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/metabolismo , Femenino , Ratones , Ratones Endogámicos NOD , Factores de Tiempo
6.
Am J Transplant ; 13(11): 2819-30, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-24102948

RESUMEN

Foxp3(+) regulatory T cells (Tregs) have an essential role in immune and allograft tolerance. However, in both kidney and liver transplantation in humans, FOXP3(+) Tregs have been associated with clinical rejection. Therefore, the role and function of graft infiltrating Tregs have been of great interest. In the studies outlined, we demonstrated that Foxp3(+) Tregs were expanded in tolerant kidney allografts and in draining lymph nodes in the DBA/2 (H-2(d) ) to C57BL/6 (H-2(b) ) mouse spontaneous kidney allograft tolerance model. Kidney allograft tolerance was abrogated after deletion of Foxp3(+) Tregs in DEpletion of REGulatory T cells (DEREG) mice. Kidney allograft infiltrating Foxp3(+) Tregs (K-Tregs) expressed elevated levels of TGF-ß, IL-10, interferon gamma (IFN-γ), the transcriptional repressor B lymphocyte-induced maturation protein-1 (Blimp-1) and chemokine receptor 3 (Cxcr3). These K-Tregs had the capacity to transfer dominant tolerance and demonstrate donor alloantigen-specific tolerance to skin allografts. This study demonstrated the crucial role, potency and specificity of graft infiltrating Foxp3(+) Tregs in the maintenance of spontaneously induced kidney allograft tolerance.


Asunto(s)
Factores de Transcripción Forkhead/fisiología , Rechazo de Injerto/inmunología , Supervivencia de Injerto/inmunología , Tolerancia Inmunológica/inmunología , Trasplante de Riñón , Linfocitos T Reguladores/inmunología , Donantes de Tejidos , Tolerancia al Trasplante/inmunología , Aloinjertos , Animales , Citocinas/metabolismo , Genes Reporteros , Mediadores de Inflamación , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Trasplante de Piel , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/patología
7.
Transplant Proc ; 45(5): 1869-74, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23769060

RESUMEN

Type I diabetes mellitus (TID) results from the autoimmune destruction of the insulin-producing pancreatic ß-cells. Gene therapy is one strategy being actively explored to cure TID by affording non-ß-cells the ability to secrete insulin in response to physiologic stimuli. In previous studies, we used a novel surgical technique to express furin-cleavable human insulin (INS-FUR) in the livers of streptozotocin (STZ)-diabetic Wistar rats and nonobese diabetic (NOD) mice with the use of the HMD lentiviral vector. Normoglycemia was observed for 500 and 150 days, respectively (experimental end points). Additionally, some endocrine transdifferentiation of the liver, with storage of insulin in granules, and expression of some ß-cell transcription factors (eg, Pdx1, Neurod1, Neurog3, Nkx2-2, Pax4) and pancreatic hormones in both studies. The aim of this study was to determine if this novel approach could induce liver to pancreatic transdifferentiation to reverse diabetes in pancreatectomized Westran pigs. Nine pigs were used in the study, however only one pig maintained normal fasting blood glucose levels for the period from 10 to 44 days (experimental end point). This animal was given 2.8 × 10(9) transducing units/kg of the lentiviral vector expressing INS-FUR. A normal intravenous glucose tolerance test was achieved at 30 days. Reverse-transcription polymerase chain reaction analysis of the liver tissue revealed expression of several ß-cell transcription factors, including the key factors, Pdx-1 and Neurod1, pancreatic hormones, glucagon, and somatostatin; however, endogenous pig insulin was not expressed. Triple immunofluorescence showed extensive insulin expression, as was previously observed in our studies with rodents. Additionally, a small amount of glucagon and somatostatin protein expression was seen. Collectively, these data indicate that pancreatic transdifferentiation of the liver tissue had occurred. Our data suggest that this regimen may ultimately be used clinically to cure TID, however more work is required to replicate the successful reversal of diabetes in increased numbers of pigs.


Asunto(s)
Diferenciación Celular , Furina/química , Insulina/administración & dosificación , Lentivirus/genética , Hígado/citología , Páncreas/citología , Animales , Proteína Homeobox Nkx-2.2 , Proteínas de Homeodominio , Humanos , Insulina/química , Insulina/genética , Proteínas Nucleares , Reacción en Cadena de la Polimerasa , Porcinos , Factores de Transcripción
8.
Am J Transplant ; 13(7): 1850-8, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23668890

RESUMEN

Whilst initial rates of insulin independence following islet transplantation are encouraging, long-term function using the Edmonton Protocol remains a concern. The aim of this single-arm, multicenter study was to evaluate an immunosuppressive protocol of initial antithymocyte globulin (ATG), tacrolimus and mycophenolate mofetil (MMF) followed by switching to sirolimus and MMF. Islets were cultured for 24 h prior to transplantation. The primary end-point was an HbA1c of <7% and cessation of severe hypoglycemia. Seventeen recipients were followed for ≥ 12 months. Nine islet preparations were transported interstate for transplantation. Similar outcomes were achieved at all three centers. Fourteen of the 17 (82%) recipients achieved the primary end-point. Nine (53%) recipients achieved insulin independence for a median of 26 months (range 7-39 months) and 6 (35%) remain insulin independent. All recipients were C-peptide positive for at least 3 months. All subjects with unstimulated C-peptide >0.2 nmol/L had cessation of severe hypoglycemia. Nine of the 17 recipients tolerated switching from tacrolimus to sirolimus with similar graft outcomes. There was a small but significant reduction in renal function in the first 12 months. The combination of islet culture, ATG, tacrolimus and MMF is a viable alternative for islet transplantation.


Asunto(s)
Diabetes Mellitus Tipo 1/cirugía , Rechazo de Injerto/prevención & control , Inmunosupresores/uso terapéutico , Trasplante de Islotes Pancreáticos/métodos , Adolescente , Adulto , Anciano , Australia/epidemiología , Glucemia/metabolismo , Células Cultivadas , Diabetes Mellitus Tipo 1/sangre , Femenino , Estudios de Seguimiento , Rechazo de Injerto/epidemiología , Supervivencia de Injerto , Humanos , Incidencia , Insulina/sangre , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Sirolimus/uso terapéutico , Tacrolimus/uso terapéutico , Resultado del Tratamiento , Adulto Joven
9.
Cell Transplant ; 22(10): 1929-41, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23107388

RESUMEN

Islet cell transplantation as a therapy for type 1 diabetes has been limited by progressive graft loss. Significant immunosuppression including T-cell ablation has been used in an attempt to limit islet rejection. Here, we show that CD3(+) lymphocytes depleted of alloreactive T cells selected from a mixed lymphocyte reaction (MLR), where responder BALB/c splenocytes stained with carboxyfluorescein succinimidyl ester (CFSE) were stimulated with irradiated C57BL/6 splenocytes for 5 days, infused into diabetic immunodeficient mice are capable of restoring a broad T-cell repertoire and specifically do not reject islet transplants from the strain (C57BL/6) used in the original depletion. These mice demonstrate reconstitution with CD4(+) and CD8(+) T cells, the capacity to reject third-party grafts (CBA), and restoration of interferon-γ (IFN-γ) responses to third-party alloantigens. Over time, both forkhead box P3-positive (Foxp3(+)) T regulatory cells (Tregs) and γδ T cells expand, suggesting a role for peripheral tolerance, in addition to the initial depletion of alloreactive T cells, in long-term islet graft survival. Our results suggest that immune restoration with CD3(+) lymphocytes where alloreactive T cells are removed can restore cognate immunity without islet allograft loss and recurrence of diabetes.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Diabetes Mellitus Experimental/cirugía , Trasplante de Islotes Pancreáticos , Complejo Mayor de Histocompatibilidad/inmunología , Linfocitos T Reguladores/inmunología , Animales , Complejo CD3/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Factores de Transcripción Forkhead/metabolismo , Rechazo de Injerto/inmunología , Supervivencia de Injerto/inmunología , Tolerancia Inmunológica , Interferón gamma/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones SCID , Fenotipo , Linfocitos T Reguladores/metabolismo , Trasplante Homólogo
10.
Acta Anaesthesiol Scand ; 55(7): 851-61, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21574964

RESUMEN

BACKGROUND: Levosimendan has been proposed as an attractive alternative to adrenergic agents for the treatment of sepsis-induced heart failure and haemodynamic derangements. Its use in this setting is, however, still not well investigated. The aim of this study was to test the hypothesis that levosimendan is able to attenuate endotoxin-induced pulmonary hypertension and improve myocardial function in a porcine model. The secondary aims were to investigate its effect on renal and liver function, and the plasma cytokine response. METHODS: Endotoxaemia was induced in 18 pigs, randomized to placebo and Levosimendan groups. All pigs were fluid resuscitated and Noradrenalin infusion was given according to a predefined protocol. Systemic haemodynamics and myocardial function were measured using pulmonary artery catheterization and transthoracic echocardiography. Renal and liver function tests and cytokine concentrations were measured in plasma. RESULTS: Levosimendan did not attenuate endotoxin-induced pulmonary hypertension and did not improve myocardial function. There were no differences in renal or liver function. Increases in arterial lactate and decreases in base excess were observed in the Levosimendan group, as well as significant increases in plasma interleukin (IL)-6 and IL-8. CONCLUSIONS: Contrary to our hypothesis, levosimendan given in conjunction with a protocolized vasopressor and fluid resuscitation did not improve cardiac, renal or liver function in this model of acute porcine endotoxaemia. Hyperlactataemia, acidosis and increases in plasma pro-inflammatory cytokines were observed, the mechanisms and implications of which remain unclear.


Asunto(s)
Cardiotónicos/uso terapéutico , Endotoxemia/tratamiento farmacológico , Hidrazonas/uso terapéutico , Piridazinas/uso terapéutico , Animales , Presión Sanguínea/efectos de los fármacos , Citocinas/sangre , Ecocardiografía , Endotoxemia/fisiopatología , Pruebas de Función Cardíaca , Hemodinámica/fisiología , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/fisiopatología , Pruebas de Función Renal , Ácido Láctico/sangre , Lipopolisacáridos/toxicidad , Pruebas de Función Hepática , Circulación Pulmonar/efectos de los fármacos , Flujo Sanguíneo Regional/fisiología , Tamaño de la Muestra , Simendán , Porcinos , Equilibrio Hidroelectrolítico/fisiología
11.
Transplant Proc ; 41(10): 4389-93, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-20005405

RESUMEN

Porcine endogenous retrovirus (PERV) varies between pig breeds. Screening and analysis of PERV in putative pig breeds may provide basic parameters to evaluate the biological safety of xenotransplantation from pigs to humans. In this study, PERV was investigated among the conservation population of the Ningxiang pig. The result revealed that the genotype of PERV distribution was subtype A, 100%; subtype B, 100%; and subtype C, 100%. The env sequences of PERV-A and -B showed 11 clones detected by KpnI and MboI digestion, indicating that there existed multiple variants of PERV-A and -B in the Ningxiang pig. Reverse transcriptase polymerase chain reaction results showed that PERV had transcriptional activity in these individuals. In addition, PERV A/C recombinant was detected in most individuals of Ningxiang pig. Because PERV A/C recombinants increase the potential infectious risk, the breed may not be a proper donor for xenotransplantation.


Asunto(s)
Retrovirus Endógenos/fisiología , Porcinos/genética , Animales , China , Cartilla de ADN , ADN Mitocondrial/genética , ADN Viral/sangre , ADN Viral/genética , ADN Viral/aislamiento & purificación , Retrovirus Endógenos/genética , Gammaretrovirus , Variación Genética , Humanos , Preservación de Órganos/métodos , Preservación de Órganos/normas , ARN Viral/sangre , ARN Viral/genética , ARN Viral/aislamiento & purificación , ADN Polimerasa Dirigida por ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Especificidad de la Especie , Porcinos/sangre , Porcinos/virología , Transcripción Genética , Trasplante Heterólogo/tendencias
12.
Am J Transplant ; 9(7): 1533-40, 2009 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-19459790

RESUMEN

Instant blood mediated inflammatory reaction (IBMIR) occurs when islets are exposed to blood and manifests clinically as portal vein thrombosis and graft failure. The aim of this study was to determine the impact of recombinant human activated protein C (rhAPC) and platelet inhibition on IBMIR in order to develop a better targeted treatment for this condition. Five thousand human islet cell equivalents (IEQ) were mixed in a PVC loop system with 7 mL of ABO compatible human blood and incubated with rhAPC, either alone or in combination with tirofiban. Admixing human islets and blood caused rapid clot formation, consumption of platelets, leukocytes, fibrinogen, coagulation factors and raised d-dimers. Islets were encased in a fibrin and platelet clot heavily infiltrated with neutrophils. Tirofiban monotherapy was ineffective, whereas rhAPC monotherapy prevented IBMIR in a dose-dependent manner, preserving islet integrity while maintaining platelet and leukocyte counts, fibrinogen and coagulation factor levels, and reducing d-dimer formation. The combination of tirofiban and low-dose rhAPC inhibited IBMIR synergistically with an efficacy equal to high dose rhAPC. Tirofiban and rhAPC worked synergistically to preserve islets, suggesting that co-inhibition of the platelet and coagulation pathways' contribution to thrombin generation is required for the optimal anti-IBMIR effect.


Asunto(s)
Inflamación/sangre , Inflamación/prevención & control , Trasplante de Islotes Pancreáticos/efectos adversos , Trasplante de Islotes Pancreáticos/inmunología , Inhibidores de Agregación Plaquetaria/administración & dosificación , Proteína C/administración & dosificación , Tirosina/análogos & derivados , Sistema del Grupo Sanguíneo ABO , Coagulación Sanguínea/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Humanos , Técnicas In Vitro , Linfocitos/efectos de los fármacos , Linfocitos/inmunología , Perfusión , Proteínas Recombinantes/administración & dosificación , Tirofibán , Trasplante Homólogo , Tirosina/administración & dosificación
13.
J Thromb Haemost ; 4(5): 1125-33, 2006 May.
Artículo en Inglés | MEDLINE | ID: mdl-16689767

RESUMEN

BACKGROUND: Experimental animal studies have shown that the intimal hyperplasia (IH) responsible for occlusion after successful revascularization procedures may be partially caused by a bone marrow-derived cell that migrates to the site of vascular injury. Concurrent studies have demonstrated an extensive role in wound healing for the circulating fibrocyte. OBJECTIVES: We aimed to trace the path of the circulating cell that contributes to IH and determine if it is the fibrocyte. METHODS AND RESULTS: We established an in vitro model whereby purified monocytes from six healthy human volunteers were cultured into fibrocytes. These cells were morphometrically similar to the vascular smooth muscle cell (VSMC) found in IH and expressed alpha-smooth muscle actin (alpha-SMA) as well as CD34, CD45 and Collagen I (Col I), markers indicative of the fibrocyte. In an in vivo ovine carotid artery synthetic patch graft model, carboxyfluorescein diacetate, succinimidyl ester (CFSE) labeled circulating leukocytes were observed throughout the graft as well as in the neointima in 18 sheep. These cells were shown to produce collagen and alpha-SMA at 1, 2 and 4 weeks. These cells then underwent immunohistochemical analysis and were found to express a set of markers unique to the fibrocyte (CD34, CD45, Vimentin and alpha-SMA) and also to double stain for CD34 and alpha-SMA. CONCLUSIONS: IH in an ovine carotid artery patch graft model is partially derived from a hematopoietic circulating progenitor cell that acquires mesenchymal features as it matures at the site of injury.


Asunto(s)
Fibroblastos/citología , Túnica Íntima/patología , Animales , Hiperplasia , Inmunohistoquímica , Ovinos
14.
Aust Vet J ; 84(4): 129-33, 2006 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-16629192

RESUMEN

OBJECTIVE: To report on the first case of congenital heart defects in pigs in Australia. DESIGN: Retrospective analysis of case records from an inbred herd of "Westran" pigs at the University of Sydney, between January 2001 and December 2004. Detailed gross and histological examination of 15 hearts from pigs that had died or were euthanased in 2004. CASE DETAILS: The necropsy records from a population of 471 pigs that had died (106 pigs) or were euthanased for research purposes (365 pigs) were analysed and the incidence of heart defects recorded, together with basic demographic data. No attempts were made to diagnose the condition in live pigs. RESULTS: Congenital heart defects were diagnosed in 6.4% of pigs but this is likely to be an underestimate of the incidence of the deformity. Eighteen pigs died on the farm as a result of the defect, and 12 pigs were diagnosed with the defect as an incidental finding. The most common abnormality seen at necropsy was a sac-like dilatation on the right lateral surface of the right atrium. This was associated with secondary deformity and hypoplasia of the adjacent left ventricle, interventricular region and part of the right ventricle. All hearts showed atrial septal defects of varying size. CONCLUSION: This is the first reported case of congenital heart defects in pigs in Australia, and one of less than five reported cases of atrial septal defects in pigs in the world. The authors conclude that there may be an element of genetic predisposition to the malformation, since it has only been reported in this inbred line of pigs.


Asunto(s)
Cardiopatías Congénitas/veterinaria , Endogamia , Enfermedades de los Porcinos/epidemiología , Animales , Australia/epidemiología , Femenino , Cardiopatías Congénitas/diagnóstico , Cardiopatías Congénitas/epidemiología , Cardiopatías Congénitas/patología , Incidencia , Masculino , Miocardio/patología , Estudios Retrospectivos , Porcinos , Enfermedades de los Porcinos/diagnóstico , Enfermedades de los Porcinos/patología
15.
Int Angiol ; 21(3): 244-9, 2002 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-12384645

RESUMEN

BACKGROUND: Restenosis within vascular stents is primarily due to intimal thickening secondary to intimal hyperplasia (IH) which occurs maximally around stent struts. Dedifferentiation of vascular smooth muscle cells (VSMC) with subsequent migration and proliferation is believed to be a key event in IH formation. Matrigel (basement membrane protein) has been shown to inhibit dedifferentiation of VSMC in vitro. Our aim was to test the in vivo effect of Matrigel on IH formation using a novel sheep vascular stent model. METHODS: Twenty vascular stents were implanted in the renal arteries of ten sheep. The left renal artery of each sheep was used to deploy uncoated stent and the right renal artery was used to deploy Matrigel-coated stent. Five sheep were analysed at four weeks and five at eight weeks after stent implantation. The sheep were sacrificed at the end of the study periods and the stented renal artery segments were examined by histology. Luminal, intimal and medial areas were determined using computer-assisted morphometric analysis. RESULTS: All stent sites were widely patent without thrombosis. No luminal stenosis was seen angiographically. IH was quantified from histology cross-sections and expressed as an intima to media (I/M) ratio. The ratio was significantly reduced in the matrigel-coated sites at eight weeks (uncoated 0.49+/-0.23; Matrigel-coated 0.32+/-0.12; p value <0.05). CONCLUSIONS: The sheep renal artery vascular stent model is feasible for the study of stent biology. IH was reduced by Matrigel-coated stents.


Asunto(s)
Arteriosclerosis/etiología , Arteriosclerosis/prevención & control , Materiales Biocompatibles/uso terapéutico , Prótesis Vascular/efectos adversos , Colágeno/uso terapéutico , Oclusión de Injerto Vascular/etiología , Oclusión de Injerto Vascular/prevención & control , Laminina/uso terapéutico , Proteoglicanos/uso terapéutico , Stents/efectos adversos , Túnica Íntima/efectos de los fármacos , Túnica Íntima/patología , Animales , Arteriosclerosis/patología , Modelos Animales de Enfermedad , Combinación de Medicamentos , Femenino , Oclusión de Injerto Vascular/patología , Hiperplasia/etiología , Hiperplasia/patología , Hiperplasia/prevención & control , Arteria Renal/efectos de los fármacos , Arteria Renal/patología , Arteria Renal/cirugía , Ovinos , Factores de Tiempo , Túnica Media/efectos de los fármacos , Túnica Media/patología , Túnica Media/cirugía
17.
Transpl Immunol ; 9(1): 51-6, 2001 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-11680572

RESUMEN

Previously, we demonstrated that combination CTLA4-Fc and anti-CD40L mAb treatment results in tolerance to concordant, cellular islet xenografts. The aim of this study was to determine its effectiveness in a model of fetal pig pancreas (FPP) xenotransplantation. Survival of FPP fragment grafts were compared to the survival of rat islet or cardiac xenografts following short term CTLA4-Fc and anti-CD40L mAb treatment. Rat islet and FPP fragment grafts survived long-term. However, rat cardiac grafts were rejected by 52-91 days. Both rat islet and FPP grafts showed similar histology with intact islet structures and adjacent 'nests' of lymphocytes. Concordant vascularised rat hearts showed extensive polymorphonuclear infiltrate, concentric vasculitis and a perivascular infiltrate predominantly of CD8+ T cells. This suggests that this therapy is effective for prolonging islet xenografts and demonstrates that the cellular mechanism of rejection for vascularised and non-vascularised xenografts are different.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antígenos de Diferenciación/uso terapéutico , Antígenos CD28/inmunología , Antígenos CD40/inmunología , Ligando de CD40/inmunología , Trasplante de Corazón/inmunología , Inmunoconjugados , Trasplante de Islotes Pancreáticos/inmunología , Ratones/inmunología , Ratas/inmunología , Porcinos/inmunología , Trasplante Heterólogo/inmunología , Abatacept , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacología , Antígenos CD , Antígeno CTLA-4 , Vasos Coronarios/patología , Diabetes Mellitus Experimental/cirugía , Evaluación Preclínica de Medicamentos , Rechazo de Injerto/inmunología , Rechazo de Injerto/patología , Masculino , Ratones Endogámicos CBA , Miocardio/patología , Neutrófilos/inmunología , Especificidad de Órganos , Páncreas/irrigación sanguínea , Páncreas/embriología , Ratas Endogámicas , Especificidad de la Especie , Linfocitos T Citotóxicos/inmunología , Vasculitis/etiología , Vasculitis/inmunología , Vasculitis/patología
18.
Am J Surg ; 181(6): 492-8, 2001 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-11513772

RESUMEN

BACKGROUND: The potential of the calcium channel antagonist verapamil to cause apoptosis (programmed cell death) is of considerable importance in arterial injury where the loss of smooth muscle cells may contribute to a reduction in intimal hyperplasia development. The aim of this study was to determine whether verapamil induces vascular cell apoptosis after carotid artery synthetic grafting. METHODS: Thirty-two adult-female Merino sheep received gelatin sealed fusiform shape-Dacron grafts into the left common carotid artery at day 0. After operation animals were randomly allocated to either a control group or one of three treatment groups (groups 2, 3, and 4). Group 1 animals (n = 9) received no treatment. For the treatment groups, intravenous verapamil was given at a rate of 0.5 mg/kg per day in two divided doses. Group 2, 3, and 4 sheep were treated for 1, 2, and 4 weeks, respectively. Animals were sacrificed at 4 weeks. Apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP-fluorescent labelling. Proliferating cells and their phenotype were determined by doublestaining with antiproliferation cellular nuclei antigen and anti-alpha-actin or anti-HAM-56. RESULTS: There were significantly more apoptotic cells in the perigraft adventitia in the 4-week treatment group than in the control group (P <0.05). The average number of proliferating cells at 2 and 4 weeks in the intima were significantly less than in the control (P <0.05). The average numbers of macrophages inside graft matrix in the 2 and 4 weeks treatment groups were significantly less than for the control (P <0.05). The number of proliferating cells inside the graft was significantly lower at 4 weeks compared with control (P <0.05). There was negative correlation between intimal PCNA expression and perigraft apoptotic expression level (P <0.05). CONCLUSION: The antihypertensive agent verapamil inhibits intimal hyperplasia through enhancing adventitial cell apoptosis and inhibiting intimal cell proliferation after vascular grafting.


Asunto(s)
Apoptosis/efectos de los fármacos , Bloqueadores de los Canales de Calcio/farmacología , Oclusión de Injerto Vascular/prevención & control , Túnica Íntima/efectos de los fármacos , Verapamilo/farmacología , Análisis de Varianza , Animales , Arteria Carótida Común/patología , Arteria Carótida Común/cirugía , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Oclusión de Injerto Vascular/fisiopatología , Hiperplasia/patología , Inmunohistoquímica , Macrófagos/efectos de los fármacos , Fenotipo , Ovinos , Túnica Íntima/metabolismo , Túnica Íntima/patología
19.
Cardiovasc Surg ; 9(2): 166-76, 2001 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-11250186

RESUMEN

The present study examined the distribution of immunocompetent cells in synthetic vascular grafts in an experimental sheep model. Sixty-two adult Merino sheep underwent synthetic patch closure of a longitudinal arteriotomy in the left common carotid artery. The synthetic patch materials used were gelatin sealed Dacron (n=10), fluoropassivated Dacron (n=10), Fluoropassiv (n=12), polyurethane (n=10), expanded polytetrafluoroethylene (n=10) and carbon-lined expanded polytetrafluoroethylene (n=10). The sheep were sacrificed after four weeks when the prosthetic patches were harvested and fixed in 10% neutral buffered formalin. Transverse sections were taken along the graft and paraffin embedded. Serial sections were stained with cell type specific antibodies to identify T-lymphocytes (CD3(+)), dendritic cells (S-100(+)), endothelial cells (von Willebrand factor(+)) and smooth muscle cells (smooth muscle alpha-actin(+)). All six graft types contained CD3(+) and S-100(+) cells in the neointima, within the synthetic matrix and in the perigraft layer. Three different tissue responses to synthetic materials were observed and the grafts were classified accordingly into three groups: (1) gelatin sealed Dacron, fluoropassivated Dacron and Fluoropassiv; (2) expanded polytetrafluoroethylene and carbon-lined expanded polytetrafluoroethylene; (3) polyurethane. The three synthetic materials in Group 1 showed almost identical reactions with least accumulation of immunocompetent cells within the synthetic material but greater accumulation of immuno-inflammatory infiltrates in the perigraft vascular tissue. In this group, new vessels penetrated into the synthetic material and there was prominent formation of foreign body (giant) cells. Group 2 showed greater accumulation of immunocompetent cells within the synthetic material itself but only sparse immuno-inflammatory infiltrates in the perigraft tissue. Group 3 showed a high degree of inflammatory response within both the synthetic material and the perigraft vascular tissue. These observations demonstrate that immunocompetent cells colonise the synthetic matrix of grafts and accumulate in the perigraft tissue, but inflammatory responses vary in different graft types.


Asunto(s)
Prótesis Vascular , Células Dendríticas/inmunología , Linfocitos T/inmunología , Animales , Complejo CD3 , Arteria Carótida Común , Femenino , Inmunohistoquímica , Modelos Animales , Tereftalatos Polietilenos , Politetrafluoroetileno , Proteínas S100 , Ovinos , Túnica Íntima/patología
20.
Xenotransplantation ; 7(3): 197-205, 2000 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-11021665

RESUMEN

Cytokine-induced expression of inducible nitric oxide synthetase (iNOS) and production of nitric oxide (NO) by pancreatic islet cells has been suggested as one potential mechanism for beta cell destruction. In this study, we investigated the role of iNOS and NO in islet primary non-function. Islets were assessed for their function, viability and expression of iNOS. Adult rat and pig islets isolated by collagenase digestion and fetal pig pancreas (FPP) grafts isolated by collagenase digestion or high oxygen culture were transplanted into C57BL6 mice and nude mice. iNOS protein was detected by immunohistochemistry. iNOS protein was found in normal rat and pig pancreas and adult rat and pig islets that were isolated by collagenase digestion and transplanted into either C57BL6 mice or nude mice. iNOS was not detected in fetal pig islet grafts, regardless of whether collagenase was used in the isolation process. In adult pig islet grafts, the presence of iNOS protein correlated with high levels of islet cell apoptosis and primary non-function. Despite the persistent presence of iNOS in rat islets, there was no evidence that it had a deleterious effect on rat islet viability, or function. Therefore, in isolated adult pig islets, there was a correlation between iNOS expression and apoptosis, suggesting that iNOS activation may be deleterious to the adult pig islets. However, other factors such as the fragility of the islet capsule may be equally important. By contrast, fetal pig islets did not express iNOS and this may be an important reason for their enhanced viability when compared with adult islet tissue.


Asunto(s)
Diabetes Mellitus Experimental/cirugía , Trasplante de Tejido Fetal/fisiología , Supervivencia de Injerto , Trasplante de Islotes Pancreáticos/fisiología , Islotes Pancreáticos/enzimología , Óxido Nítrico Sintasa/metabolismo , Trasplante Heterólogo/fisiología , Animales , Células Cultivadas , Trasplante de Tejido Fetal/patología , Feto , Islotes Pancreáticos/citología , Islotes Pancreáticos/embriología , Trasplante de Islotes Pancreáticos/patología , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Óxido Nítrico Sintasa de Tipo II , Ratas , Ratas Wistar , Porcinos , Factores de Tiempo , Trasplante Heterólogo/patología
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