Melatonin and organ transplantation: what is the relationship?

SUMMARY Melatonin has anti-inflammatory and antioxidant properties that can influence tissue growth and apoptosis. This aspect may influence the success of organ transplantation. OBJECTIVE To evaluate the relationship between melatonin and organ transplantation. METHODS A systematic review was performed in PubMed databases using the search terms: "melatonin physiology" or "melatonin therapy" and "transplant pharmacology" or "transplant physiology" or "transplant therapy" or "Transplant therapy". Experiments on the organs of the reproductive system were not included. After analysis, five articles were selected after reading the title and abstract of 50 manuscripts. The works were divided into two aspects: a) analysis of the influence of the organ transplantation procedure on melatonin production; b) action of melatonin on organ transplantation. RESULTS The cardiac transplantation surgical procedure, immunosuppression, and graft did not influence melatonin secretion in rodents, but there was a significant reduction of melatonin in the renal transplantation procedure in patients with renal insufficiency. Melatonin administration in experimental models decreased rejection and improved transplant success. CONCLUSION Studies show that melatonin can reduce organ and species dependence, and the use of melatonin decreases graft rejection.

RESUMO A melatonina tem propriedades anti-inflamatórias e antioxidantes que podem influenciar o crescimento e a apoptose dos tecidos. Esse aspecto pode influenciar o sucesso do transplante de órgãos. OBJETIVO Avaliar a relação entre a melatonina e o transplante de órgãos. MÉTODO A revisão sistemática foi realizada nas bases de dados do PubMed, usando os termos de pesquisa: "fisiologia da melatonina" ou "terapêutica da melatonina" e "farmacologia do transplante" ou "fisiologia do transplante" ou "terapêutica do transplante" ou "terapia do transplante". Não foram incluídos os experimentos sobre os órgãos do sistema reprodutivo. Após análise, cinco artigos foram selecionados após a leitura do título e do resumo de 50 manuscritos. Os trabalhos foram divididos em duas vertentes: a) análise da influência do procedimento de transplante de órgão na produção de melatonina; b) ação da melatonina sobre o transplante de órgãos. RESULTADOS O procedimento cirúrgico do transplante cardíaco, a imunossupressão e o enxerto não influenciaram a secreção de melatonina em roedores, mas houve redução significante da melatonina nos casos do procedimento de transplante renal em pacientes com insuficiência renal. A ministração de melatonina em modelos experimentais diminuiu a rejeição e melhorou o sucesso de transplante. CONCLUSÃO Os estudos mostram que a melatonina pode reduzir a dependência da espécie e do órgão e que o emprego da melatonina diminui a rejeição do órgão.

Preoperative subcutaneous sildenafil injection increases random flap survival in rats

Abstract Purpose: To investigate the effect of subcutaneous sildenafil on random flap survival. Methods: Fourteen Wistar rats, which were divided in to two groups, were used for this experimental study. Rats in the sildenafil group received subcutaneous sildenafil injections daily for seven days before flap elevation. At the end of the treatment period, 9x3 cm dorsal skin flaps were elevated and reinserted back into their place in all of the animals. Necrotic and whole flaps areas were recorded on graph papers. Seven days after the flap elevation samples for histological examination were taken and angiographies were performed to visualize the flap vascularization. Results: The calculated average percentage of necrotic flap areas were 18.29% and 42.26% in the sildenafil and control group respectively.(p=0.0233). In selected angiography images, vessels were found to be more prominent in the sildenafil group. The average number of capillary formations under light microscopy was higher in the sildenafil group (p= 0.0286). Conclusion: The subdermal high dose sildenafil has a positive effect on flap survival.

Conversion to Mycophenolate Mofetil Monotherapy in Liver Recipients: Calcineurin Inhibitor Levels are Key

Abstract: The use of calcineurin inhibitors (CNI) after liver transplantation is associated with post-transplant nephrotoxicity. Conversion to mycophenolate mofetil (MMF) monotherapy improves renal function, but is related to graft rejection in some recipients. Our aim was to identify variables associated with rejection after conversion to MMF monotherapy. Conversion was attempted in 40 liver transplant recipients. Clinical variables were determined and peripheral mononuclear blood cells were immunophenotyped during a 12-month follow- up. Conversion was classified as successful (SC) if rejection did not occur during the follow-up. MMF conversion was successful with 28 patients (70%) and was associated with higher glomerular filtration rates at the end of study. It also correlated with increased time elapsed since transplantation, low baseline CNI levels (Tacrolimus ≤ 6.5 ng/mL or Cyclosporine ≤ 635 ng/mL) and lower frequency of tacrolimus use. The only clinical variable independently related to SC in multivariate analysis was low baseline CNI levels (p = 0.02, OR: 6.93, 95%, CI: 1.3-29.7). Mean baseline fluorescent intensity of FOXP3+ T cells was significantly higher among recipients with SC. In conclusion, this study suggests that baseline CNI levels can be used to identify recipients with higher probability of SC to MMF monotherapy. Clinicaltrials.gov identification: NCT01321112.

Treatment of post-transplantation lymphoproliferative disorders after kidney transplant with rituximab and conversion to m-TOR inhibitor / Tratamiento de la enfermedad linfoproliferativa post-trasplante renal con Rituximab y conversión a inhibidor m-TOR

Abstract Background: Post-transplantation lymphoproliferative disorders are serious complications of organ transplantation which treatment is not yet standardized. Objective: To describe the clinical response, overall and graft survival of patients in our center with this complication after kidney transplantation, which received rituximab as part of their treatment as well as conversion to m-TOR. Methods: Retrospective study, which included patients, diagnosed with post-transplant lymphoproliferative disorders after kidney transplantation from January 2011 to July 2014. Results: Eight cases were found with a wide spectrum of clinical presentations. Most had monomorphic histology, 85% were associated with Epstein-Barr virus, 25% of patients had tumor involvement of the renal graft, and 12.5% ​​had primary central nervous system lymphoma. All patients were managed with reduction of immunosuppression, conversion to m-TOR (except one who lost the graft at diagnosis) and rituximab-based therapy. The overall response rate was 87.5% (62.5% complete response, 25% partial response). Survival was 87.5% with a median follow-up of 34 months. An additional patient lost the graft, with chronic nephropathy already known. All the remaining patients had stable renal function. Conclusions: There are no standardized treatment regimens for lymphoproliferative disorders after kidney transplantation, but these patients can be managed successfully with reduction of immunosuppression, conversion to m-TOR and rituximab-based schemes.

Resumen Antecedente: La enfermedad linfoproliferativa post-trasplante es una complicación grave del trasplante de órganos cuyo tratamiento aún no se encuentra estandarizado. Objetivo: Describir la respuesta clínica, supervivencia global y del injerto en pacientes con esta complicación post trasplante renal en nuestro centro y que recibieron rituximab como parte de su tratamiento y la conversión a m-TOR. Métodos: Estudio retrospectivo que incluyó pacientes con diagnóstico de enfermedad linfoproliferativa postrasplante renal entre enero de 2011 y julio de 2014. Resultados: Se encontraron ocho casos, con presentaciones clínicas variables. La mayoría correspondieron a histología monomórfica, en 85% se asoció con virus de Epstein-Barr, 25% de los pacientes tenían compromiso tumoral del injerto renal y 12.5% linfoma primario de sistema nervioso central. Todos los pacientes se manejaron con reducción de inmunosupresión, conversión a m-TOR (excepto uno que perdió el injerto al diagnóstico) y tratamiento basado en rituximab. La tasa de respuesta global fue del 87.5% (62.5% respuesta completa, 25% respuesta parcial). La supervivencia fue del 87.5% con una mediana de seguimiento de 34 meses. Un paciente adicional perdió el injerto renal, con nefropatía crónica ya conocida. Los pacientes restantes con función renal estable. Conclusiones: No existen esquemas estandarizados de tratamiento para la enfermedad linfoproliferativa post-trasplante renal, pero estos pacientes pueden ser manejados de forma exitosa con reducción de la inmunosupresión, conversión a m-TOR y esquemas basados en rituximab.

The positive effect of Botulinum toxin type A on the viability of random flap in tobacco exposed in rats

ABSTRACT PURPOSE: To evaluate the effect of Botulinum Toxin A in different time of tobacco exposure. METHODS: 60 male, Wistar rats were divided into two tobacco exposure groups: a 2- month or a 4-month regimen. After this period, these two groups were subdivided as two: saline solution(SS) or botulinum toxin A(Bonta), at the time of the surgery. Seven days before the SS or Bonta injection, the animals were submitted to a random flap (3x10cm). On the seventh postoperative day, all animals were assessed for total flap area, viable area, and the viable/ total area ratio. RESULTS: This study showed a difference between groups 2-month saline vs. BontA injection (p=0.04); groups 4-month saline vs. BontA injection (p=0.001); groups 2-month saline vs. 4-month BontA (p=0.003), and, between groups 2- month BontA vs. 4-month saline(p=0.03). CONCLUSIONS: Botulinum Toxin A increased random flap viability in tobacco-exposed rats. Two months of tobacco exposure had the same effect as exposure for four months.

Effects of insulin-like growth factor-1 on random pattern skin flap survival in rats

ABSTRACT PURPOSE: To investigate the effects of pharmacological delay with insulin-like growth factor-1 (IGF-1) on skin flap survival. METHODS: Thirty Sprague-Dawley rats were submitted to dorsal skin flap (3x9 cm). Seven days before the surgery, the animals were subdivided into three groups of 10 rats. In group 1 (controls), no injection was done. Seven days before the elevation, saline had been injected to the marked skin flap area in group 2 (sham group), and group 3 (experimental group) underwent a pharmacological delay with subcutaneous IGF-1 injections. On the seventh postoperative day, flap area was analyzed for survival. Tissue samples were obtained for histological and biochemical evaluations. RESULTS: Survival rates were 43.55 ± 16%, 21.40 ± 8%, and 43.12 ± 14% in groups 1, 2, and 3, respectively. Differences between group 2 and other groups were statistically significant. No significant difference was detected between all three groups for tissue or plasma vascular endothelial growth factor (VEGF) levels. There was no significant histological difference between groups. CONCLUSION: Although a single injection of insulin-like growth factor-1 (IGF-1) did not significantly increase flap survival, its wound healing features are still encouraging and further meticulously planned studies, especially with repeated applications or controlled-release methods, and combinations with binding protein are required.

Prognostic factors for the evolution and reversibility of chronic rejection in pediatric liver transplantation

OBJECTIVE: Chronic rejection remains a major cause of graft failure with indication for re-transplantation. The incidence of chronic rejection remains high in the pediatric population. Although several risk factors have been implicated in adults, the prognostic factors for the evolution and reversibility of chronic rejection in pediatric liver transplantation are not known. Hence, the current study aimed to determine the factors involved in the progression or reversibility of pediatric chronic rejection by evaluating a series of chronic rejection cases following liver transplantation. METHODS: Chronic rejection cases were identified by performing liver biopsies on patients based on clinical suspicion. Treatment included maintaining high levels of tacrolimus and the introduction of mofetil mycophenolate. The children were divided into 2 groups: those with favorable outcomes and those with adverse outcomes. Multivariate analysis was performed to identify potential risk factors in these groups. RESULTS: Among 537 children subjected to liver transplantation, chronic rejection occurred in 29 patients (5.4%). In 10 patients (10/29, 34.5%), remission of chronic rejection was achieved with immunosuppression (favorable outcomes group). In the remaining 19 patients (19/29, 65.5%), rejection could not be controlled (adverse outcomes group) and resulted in re-transplantation (7 patients, 24.1%) or death (12 patients, 41.4%). Statistical analysis showed that the presence of ductopenia was associated with worse outcomes (risk ratio=2.08, p=0.01). CONCLUSION: The presence of ductopenia is associated with poor prognosis in pediatric patients with chronic graft rejection.

Botulinum toxin type A on cutaneous flap viability in diabetic and tobacco-exposed rats

PURPOSE:To investigate the effect of Botulinum toxin A (BoNTA) on skin flap viability in healthy, tobacco-exposed and diabetic rats.METHODS: Ninety male Wistar rats (250-300g) were randomly divided into six groups: control+saline (C1), control+BoNTA (C2), tobacco-exposed+saline (T1), tobacco-exposed+BoNTA (T2) diabetes+saline (D1) and diabetes+BoNTA (D2). A dorsal cutaneous flap (3×10cm) was performed. Survival area and total area of the flaps were measured. Lumen diameter, external arterial diameter and lumen/wall thickness ratio were recorded.RESULTS: Survival area increased in control group with BoNTA injection compared with control animals injected with saline (C2 x C1; 0.9±0.1 vs0.67±0.15, p= 0.001). A similar result was found in diabetes group injected with BontA (D2 x D1; 0.97±0.2 vs0.61±0.24, p=0.018). No difference was observed in skin flap viability in tobacco-exposed groups (T2 x T1; 0.74±0.24 vs 0.64±0.21, p=0.871). Lumen diameter (p= 0.004), external arterial diameter (p = 0.0046,) and lumen/wall thickness ratio (p= 0.003) were increased in diabetes+BoNTA-treated animals. This effect was not observed in control or in tobacco-exposed groups.CONCLUSIONS:Botulinum toxin A increased skin flap viability in control and diabetic rats on the seventh post-operative day. Increased lumen diameter, external arterial diameter, and lumen/wall thickness ratio were observed in the diabetes+BoNTA group. BoNTA had no effect in the tobacco-exposed group on the seventh postoperative day.

Foot reflexology in feet impairment of people with type 2 diabetes mellitus: randomized trial / Reflexologia podal no comprometimento dos pés de pessoas com diabetes mellitus tipo 2: ensaio randomizado / Reflexología podal en el comprometimiento de los pies de personas con diabetes mellitus tipo 2: ensayo aleatorio

AbstractObjective: to evaluate the effect of foot reflexology on feet impairment of people with type 2 diabetes mellitus.Method: this is a randomized, controlled and blind clinical trial. The sample was comprised by people with type 2 diabetes mellitus who, after being randomized into Treated group (n = 21) and Control group (n = 24), received guidelines on foot self-care. To the Treated Group it was also provided 12 sessions of foot reflexology. The scores of impairment indicators related to skin and hair, blood circulation, tissue sensitivity and temperature were measured by means of the instrument for assessing tissue integrity of the feet of people with diabetes mellitus. Chi-square test, Fisher exact test, Mann-Whitney test and regression analyzes were applied to the data, considering a significance level of 5% (P value <0.05).Results: participants who received the therapy showed better scores in some impairment indicators related to skin and hair (hair growth, elasticity/turgor, hydration, perspiration, texture and integrity of the skin/ skin peeling).Conclusion: the foot reflexology had a beneficial effect on feet impairment of people with type 2 diabetes mellitus, which makes it a viable therapy, deserving investment. This study was registered in the Brazilian Registry of Clinical Trials - RBR-8zk8sz.

ResumoObjetivo:avaliar o efeito da reflexologia podal no comprometimento dos pés de pessoas com diabetes mellitus tipo 2.Método:trata-se de um ensaio clínico, randomizado, controlado e mascarado. A amostra foi composta por pessoas com diabetes mellitus tipo 2 que, após serem randomizadas em grupo Tratado (n=21) e Controle (n=24), receberam orientações de autocuidado com os pés. Ao Grupo Tratado também foram fornecidas 12 sessões de reflexologia podal. Foram mensurados os escores de comprometimento de indicadores relacionados à pele e pelos, circulação sanguínea, sensibilidade e temperatura tissular por meio do Instrumento para avaliação da integridade tissular dos pés de pessoas com diabetes mellitus. Aos dados foram aplicados os testes Qui-Quadrado, Exato de Fisher, Mann-Whitney e Análises de regressão, considerando-se nível de significância de 5% (Valor P<0,05).Resultados:os participantes que receberam a terapia apresentaram melhores escores de comprometimento em alguns indicadores relacionados à pele e pelos (crescimento de pelos, elasticidade/tugor, hidratação, transpiração, textura e integridade da pele/descamação cutânea).Conclusão:a reflexologia podal apresentou efeito benéfico sobre o comprometimento dos pés de pessoas com diabetes mellitus tipo 2, o que a torna uma terapia viável e que merece investimento. Este estudo foi registrado no Registro Brasileiro de Ensaios Clínicos - RBR-8zk8sz.

ResumenObjetivo:evaluar el efecto de la reflexología podal en el comprometimiento de los pies de personas con diabetes mellitus tipo 2.Método:se trata de un ensayo clínico, aleatorio, controlado y enmascarado. La muestra estuvo compuesta por personas con diabetes mellitus tipo 2 que, después de ser tratadas aleatoriamente en los grupos Tratado (n=21) y Control (n=24), recibieron orientaciones de autocuidado de los pies. También, al Grupo Tratado se le suministraron 12 sesiones de reflexología podal. Fueron medidos los puntajes de comprometimiento de indicadores relacionados a la piel y pelos, circulación sanguínea, sensibilidad y temperatura tisular por medio de instrumento para evaluación de la integridad del tejido de los pies de personas con diabetes mellitus. Los datos fueron sometidos a las pruebas Chi-cuadrado, Exacta de Fisher, Mann-Whitney y Análisis de regresión, considerando un nivel de significación de 5% (Valor p<0,05).Resultados:los participantes que recibieron la terapia presentaron mejores puntajes de comprometimiento en algunos indicadores relacionados a la piel y pelos (crecimiento de pelos, elasticidad/turgencia, hidratación, transpiración, textura e integridad de la piel/descamación cutánea).Conclusión:la reflexología podal presentó efecto benéfico sobre el comprometimiento de los pies de personas con diabetes mellitus tipo 2, lo que la torna una terapia viable y que merece inversiones. Este estudio fue registrado en el Registro Brasileño de Ensayos Clínicos - RBR-8zk8sz.

Analysis of effect isoxsuprine hydrochloride and nicotine in the Transverse Rectus Abdominis Myocutaneous flap (TRAM) in rats

PURPOSE: To evaluate the effects of isoxsuprine and nicotine on TRAM. METHODS: Forty eight 48 Wistar rats distributed into four Groups (n=12). All rats received medication managed daily for 20 days: saline solution (SA), nicotine solution (NI), isoxsuprine solution (IS) and nicotine solution (NI) + isoxsuprine solution (IS). On day 21st the rats were submitted to the caudally based, right unipedicled TRAM flap and after 48 hours, made the macroscopic evaluation of the surface of the flap, photographic documentation and collection of material for histology. Data from macroscopic evaluation were analyzed by ANOVA and microscopic evaluation by Kruskal-Wallis test, with significance level of 5%. RESULTS: In the macroscopic evaluation of isoxsuprine Group retail presented absolute numbers: final area (p=0.001*) and viable area (p=0.006*) with the highest values; necrosis (p=0.001*) had the lowest value. Microscopic examination revealed no significant findings in the study of TRAM under the action of isoxsuprine and nicotine to the percentage of necrosis in the left and right cranial and caudal regions. CONCLUSIONS: There was significant improvement in viability of TRAM using the isoxsuprine solution alone. No influence using nicotine alone and in association with isoxsuprine. .

¿Influye el medio de preservación del injerto en los resultados y costos del trasplante hepático de donante fallecido?: Comparación de dos soluciones de preservación / Outcomes using two preservation solutions (UW/HTK) in liver transplantation from brain death donors

Background: Preservation solutions are critical for organ transplantation. In liver transplant (LT), the solution developed by the University Of Wisconsin (UW) is the gold-standard to perfuse deceased brain death donor (DBD) grafts. Histidine-Tryptophan-Ketoglutarate (HTK), formerly a cardioplegic infusion, has been also used in solid organ transplantation. Aim: To compare the outcomes of LT in our center using either HTK or UW solution. Patients and Methods: Retrospective study including 93 LT DBD liver grafts in 89 patients transplanted between March 1994 and July 2010. Forty-eight grafts were preserved with UW and 45 with HTK. Donor and recipient demographics, total infused volume, cold ischemia time, post-reperfusion biopsy, liver function tests, incidence of biliary complications, acute rejection and 12-month graft and patient survival were assessed. Preservation solution costs per liver graft were also recorded. Results: Donor and recipient demographics were similar. When comparing UW and HTK, no differences were observed in cold ischemia time (9.6 ± 3 and 8.7 ± 2 h respectively, p = 0.23), biliary complications, the incidence of acute rejection, primary or delayed graft dysfunction. Histology on post-reperfusion biopsies revealed no differences between groups. The infused volume was significantly higher with HTK than with UW (9 (5-16) and 6 (3-11) l, p < 0.001). The cost per procurement was remarkably lower using HTK. Conclusions: Perfusion of DBD liver grafts with HTK is clinically equivalent to UW, with a significant cost reduction.

Sirolimus Conversion Efficacy for Graft Function Improvement and Histopathology in Renal Recipients with Mild to Moderate Renal Insufficiency

This study was designed to evaluate whether sirolimus (SRL) conversion effectively improves renal function and histopathology in calcineurin inhibitor (CNI)-treated renal recipients with mild to moderate renal insufficiency. SRL conversion from CNI was performed in patients who underwent kidney transplantation from 6 months to 5 yr prior to screening. Forty-five patients were enrolled. The effect of SRL conversion on graft function was evaluated, and protocol biopsies were performed preconversion and 1 yr after conversion. Overall graft function after SRL conversion gradually improved, and the improvement in renal function was closely associated with the shorter duration of CNI exposure. When we divided the patients by the duration of CNI exposure, the patients with less than 1 yr of CNI exposure demonstrated significant improvement, but patients with a greater than 1 yr CNI exposure did not exhibit significant improvement. In contrast, protocol biopsies demonstrated no significant improvements in the modified "ah" score or other Banff scores after SRL conversion. Furthermore, the duration of CNI treatment prior to SRL conversion was not associated with histological findings 1 yr after SRL conversion. SRL conversion improved graft function in renal recipients with mild to moderate renal insufficiency, but this effect is not accompanied by histological improvement.

The effect of carbon dioxide therapy on composite graft survival

PURPOSE: To investigate the effect of carboxytherapy in auricular composite grafts in rabbits. METHODS: An experimental study was conducted using 20 rabbits randomly assigned to a treatment group of carboxytherapy or a control group of saline solution. In each ear, a circular graft with 1.5 cm or 2 cm of diameter was amputated and reattached. Animals underwent carbon dioxide or saline injection four times during the experiment. We analyzed clinical evolution of the animals, grafts survival, histopathology features and histomorphometry of collagen. RESULTS:The treated group had a significantly lower weight gain (p=0.038). Histopathology was not significantly different between groups. There was an increase in amount of collagen in 2 cm grafts submitted to carbon dioxide therapy (p=0.003). Carboxytherapy didn't influence graft survival rate for 1.5 cm grafts or 2 cm grafts (p=0.567 and p=0.777, respectively). CONCLUSIONS:Carbon dioxide therapy increased the amount of collagen in 2 cm grafts. CO2 was not significantly different from saline infusion on composite grafts survival, but this study suggests that there is a mechanical effect caused by distension which favored graft survival.

The effects of local nitroglycerin on the surgical delay procedure in prefabricated flaps by vascular implant in rats / Efeitos da nitroglicerina tópica na autonomização de retalhos pré-fabricados por implante vascular em ratos

PURPOSE: To evaluate the effect of local nitroglycerin on the viable area of a prefabricated flap for vascular implant in rats, and to investigate the surgical delay procedure. METHODS: A femoral pedicle was implanted under the skin of the abdominal wall in forty Wistar rats. The animals were divided into four groups of ten: group 1 - without surgical delay procedure and local nitroglycerin; group 2 - with surgical delay procedure, but without local nitroglycerin; group 3 - without surgical delay procedure, but with local nitroglycerin; and group 4 - with simultaneous surgical delay procedure and local nitroglycerin. The percentages of the viable areas, in relation to the total flap, were calculated using AutoCAD R 14. RESULTS: The mean percentage value of the viable area was 8.9% in the group 1. 49.4% in the group 2; 8.4% in the group 3 and 1.1% in the group 4. There was significant difference between groups 1 and 2 (p=0.005), 1 and 4 (p=0.024), 2 and 3 (p=0.003), 2 and 4 (p=0.001). These results support the hypothesis that the closure of the arterial venous channels is responsible for the phenomenon of surgical delay procedure. CONCLUSION: Local nitroglycerin did not cause an increase in the prefabricated viable flap area by vascular implantation and decreased the viable flap area that underwent delay procedures.

OBJETIVO: Avaliar o efeito da nitroglicerina tópica sobre a área viável de um modelo de retalho pré-fabricado por implante vascular em ratos e analisar o mecanismo de autonomização cirúrgica aplicada a retalhos pré-fabricados. MÉTODOS: Foram utilizados 40 ratos Wistar. No primeiro tempo cirúrgico - 20 ratos foram submetidos a implante do pedículo femoral na região subdérmica da parede abdominal, e 20 submetidos à autonomização cirúrgica de retalho cutâneo de parede abdominal e, simultaneamente, implante do pedículo femoral na região subdérmica deste retalho. No segundo tempo - após três semanas e em todos os animais, era elevado um retalho cutâneo ilhado, pediculado unicamente nos vasos implantados e divididos em quatro grupos de dez animais: grupo 1, com retalhos submetidos unicamente a implante do pedículo femoral na região subdérmica da parede abdominal; grupo 2, com retalhos submetidos à autonomização cirúrgica e implante do pedículo femoral na região subdérmica deste retalho; grupo 3, com retalhos submetidos unicamente a implante do pedículo femoral na região subdérmica da parede abdominal tratados com nitroglicerina tópica; grupo 4, com retalhos submetidos à autonomização cirúrgica e implante do pedículo femoral na região subdérmica deste retalho tratados com nitroglicerina tópica. O percentual de área viável, em relação à área total do retalho, foi calculado sete dias após o segundo tempo cirúrgico. RESULTADOS: O valor médio de área viável alcançou 8,9% no grupo 1; 49,4% no grupo 2; 8,4% no grupo 3; e 1,1% no grupo 4. Houve diferença significante entre os grupos 1 e 2 (p=0,005); 1 e 4 (p=0,024); 2 e 3 (p=0,003) e 2 e 4 (p=0,001). Os resultados fortaleceram a hipótese de que o fechamento dos canais arteriovenosos é o principal mecanismo responsável pelo aumento da área viável observada em retalhos submetidos à autonomização cirúrgica.CONCLUSÃO: A nitroglicerina tópica não induziu ao aumento da área viável dos retalhos pré-fabricados por implante vascular e diminuiu a área viável dos retalhos submetidos à autonomização.

The imbalance between Treg and Th17 cells caused by FTY720 treatment in skin allograft rejection

OBJECTIVES: FTY720 modulates CD4+T cells by the augmentation of regulatory T cell activity, secretion of suppressive cytokines and suppression of IL-17 secretion by Th17 cells. To further understand the process of graft rejection/acceptance, we evaluated skin allograft survival and associated events after FTY720 treatment. METHODS: F1 mice (C57BL/6xBALB/c) and C57BL/6 mice were used as donors for and recipients of skin transplantation, respectively. The recipients were transplanted and either not treated or treated with FTY720 by gavage for 21 days to evaluate the allograft survival. In another set of experiments, the immunological evaluation was performed five days post-transplantation. The spleens, axillary lymph nodes and skin allografts of the recipient mice were harvested for phenotyping (flow cytometry), gene expression (real-time PCR) and cytokine (Bio-Plex) analysis. RESULTS: The FTY720 treatment significantly increased skin allograft survival, reduced the number of cells in the lymph nodes and decreased the percentage of Tregs at this site in the C57BL/6 recipients. Moreover, the treatment reduced the number of graft-infiltrating cells and the percentage of CD4+ graft-infiltrating cells. The cytokine analysis (splenocytes) showed decreased levels of IL-10, IL-6 and IL-17 in the FTY720-treated mice. We also observed a decrease in the IL-10, IL-6 and IL-23 mRNA levels, as well as an increase in the IL-27 mRNA levels, in the splenocytes of the treated group. The FTY720-treated mice exhibited increased mRNA levels of IL-10, IL-27 and IL-23 in the skin graft. CONCLUSIONS: Our results demonstrated prolonged but not indefinite skin allograft survival by FTY720 treatment. This finding indicates that the drug did not prevent the imbalance between Tr1 and Th17 cells in the graft that led to rejection.

Synergistic suppression of pre-perfusion of donor livers with recipient serum and cobra venom factor treatment on hyperacute rejection following liver xenotransplantation / Supressão sinérgica da rejeição hiperaguda no xenotransplante hepático com uso da pre-perfusão dos fígados doadores tratados com soro do receptor e com fator veneno de cobra

PURPOSE: To investigate synergistic suppression of donor liver pre-perfusion with recipient serum (RS) and cobra venom factor (CVF) treatment on hyperacute rejection (HAR) following liver xenotransplantation. METHODS: Guinea-pigs (GP, n=24) and Sprague-Dawley rats (SD, n=24) were recruited. Before transplantation, serum was collected from SD rats and used for preparation of inactivated complements. GP and SD rats were randomly assigned into four groups (n=6), respectively: RS group, CVF group, RS+CVF group and control group. Orthotopic liver xenotransplantation was performed with modified two-cuff technique. The survival time and liver function of recipients, morphological and pathological changes in rat livers were investigated. RESULTS: There was no piebald like change in the recipient livers in all experiment groups. The survival time of recipients in all experiment groups was longer than that in control group (p<0.05). Moreover, the survival time in the RS+CVF group was markedly longer than that in the RS group (p<0.01) and CVF group (p<0.05). The serum ALT level in all experiment groups were lower than that in the control group (p<0.05). Furthermore, the ALT level in the RS+CVF group was significantly lower than that in the CVF group (p<0.05) and RS group (p<0.01). The histological damages were significantly improved when compared with the control group, and the histological damages in the RS+CVF group were milder than those in the remaining groups (p<0.05) CONCLUSION: Pre-perfusion of donor liver with recipient serum and cobra venom factor treatment can exert synergistic suppressive effects on the hyperacute rejection following liver xenotransplantation.

OBJETIVO: Investigar a supressão sinérgica da pré-perfusão do doador de fígado com soro do receptor (SR) e tratamento com fator veneno de cobra (FVC) na rejeição hiperaguda (RHA) após o xenotransplante de fígado. MÉTODOS: Foram utilizados Cobaias (GP, n=24) e ratos Sprague-Dawley (SD, n=24). Antes do transplante foram coletadas amostras de soro dos ratos SD e usados para a preparação dos complementos inativados. Cobaias GP e ratos SD foram randomicamente distribuídos em quatro grupos (n=6), respectivamente: grupo RS, grupo FVC, grupo SR+FVC e grupo controle. Xenotransplante ortotópico do fígado foi realizado com a técnica de dois cuffs modificados. Foram investigados o de tempo de sobrevida, a função hepática dos receptores e alterações morfopatológicas em fígados de ratos. RESULTADOS: Não houve alteração na coloração do parênquima dos fígados nos receptores. O tempo de sobrevida dos receptores em todos os grupos experimentais foi mais longo do que o grupo controle (p<0,05). Além disso, o tempo de sobrevida do grupo SR+ FVC foi marcadamente maior do que o grupo SR (p<0,01) e o grupo FVC (p<0,05). O nível sérico ALT foi menor em todos os grupos experimentais do que o grupo controle (p<0,05). O nível de ALT no grupo SR+ FVC foi significantemente menor do que no grupo FVC (p<0,05) e o grupo SR (p<0,01). As alterações histológicas foram significantemente melhoradas quando comparado com o grupo controle, e os danos histológicos no grupo SR+ FVC foram mais moderados do que nos grupos restantes (p<0,05). CONCLUSÃO: Pré-perfusão do fígado doador com soro do receptor e fator veneno de cobra pode exercer efeito supressor sinérgico da rejeição hiperaguda após xenotransplante de fígado.

Survival of living-related kidney graft recipients in the era of modern immunosuppressive treatment

Currently, there is no consensus about immunosuppressive therapy following kidney transplantation. Acute rejection rates and allograft survival rates are the clinical outcomes traditionally used to compare the efficacy of various immunosuppressive regimens. Therefore, we conducted this study to evaluate whether patient survival rates improved in the era of modern immunosuppressive treatment during living-related kidney transplantation. Retrospective cohort study in a university-based tertiary internal medicine teaching hospital performed between 1999 and 2009 and patients followed up to 7 years. Survival rates were assessed in 38 patients receiving basiliximab and mycophenolate mofetil [regimen A] and 32 patients receiving antithymocyte globulin and azathioprine [regimen B]. The rest of the regimen [cyclosporine A and steroids] remained the same. A secondary end point was acute rejection episode. Seven-year survival rates were 100% and 72% [P=.001] and 7-year acute rejection-free survival rates were 82% and 53% [P=.03], in groups A and B, respectively. Long-term survival after living-related kidney transplantation has improved in the era of modern immunosuppressive treatment

Capsaicin on the viability of random-pattern skin flaps in rats / Capsaicina na viabilidade de retalhos isquêmicos randômicos em ratos

PURPOSE: To evaluate the effects of capsaicin on the viability of ischemic random-pattern skin flaps in rats. METHODS:Forty EPM1-Wistar rats were randomized into two groups of 20 animals each, the capsaicin group and the control group. A random-pattern skin flap measuring 10 x 4cm was raised and a plastic barrier was placed between the flap and the donor site. After the surgical procedure, the control group was treated with an inert vehicle in the form of a cream applied uniformly to a rayon bandage which, in turn, was applied to the surface of the skin flap. The capsaicin group was treated in the same way, but in this case capsaicin was added to the cream. This procedure was repeated for two consecutive days. RESULTS: There was a significantly smaller amount of flap necrosis in the capsaicin group (35.07 percent) than in the control group (44.75 percent) (p=0.035). CONCLUSION:Topical administration of capsaicin improved the viability of ischemic random-pattern skin flaps in rats.

OBJETIVO: Avaliar os efeitos da capsaicina na viabilidade de retalhos isquêmicos randômicos em ratos. MÉTODOS: Quarenta ratos EPM1-Wistar foram distribuídos ao acaso em dois grupos de 20 animais cada, um grupo capsaicina e um grupo controle. Um retalho isquêmico randômico medindo 10 x 4cm foi elevado e uma barreira plástica foi colocada entre o retalho e a área doadora. Após o procedimento cirúrgico, o grupo controle foi tratado com um veículo inerte sob a forma creme aplicado uniformemente sobre uma atadura de rayon, que, por sua vez, foi aplicada à superfície do retalho. O grupo capsaicina foi tratado da mesma forma, porém a capsaicina foi adicionada ao creme. Este procedimento foi repetido por dois dias consecutivos. RESULTADOS: Houve uma quantidade significativamente menor da necrose do retalho no grupo capsaicina (35,07 por cento) comparado ao grupo controle (44,75 por cento) (p=0,035). CONCLUSÃO: A administração tópica da capsaicina melhorou a viabilidade de retalhos isquêmicos randômicos em ratos.

Cyclic AMP prolongs graft survival by suppressing apoptosis and inflammatory gene expression in acute cardiac allograft rejection

This study was designed to investigate the effects of cAMP on immune regulation and apoptosis during acute rat cardiac allograft rejection. We found that the production of immune markers such as inflammatory cytokines (IL-1beta, IL-6, and TNF-alpha), iNOS expression, and nitric oxide (NO) production, was significantly increased in the blood and transplanted hearts of allograft recipients, but not of isograft controls. These increases were effectively suppressed by the administration of the membrane permeable cAMP analog dibutyryl cAMP (db-cAMP). Administration of db-cAMP reduced allograft-induced elevation of several biochemical markers, such as adhesion molecule expression, iron-nitrosyl complex formation, caspase-3 activation, and apoptotic DNA fragmentation in an animal model. Furthermore, treatment of allograft recipients with db-cAMP prolonged median graft survival to 11 days compared with a median graft survival time of 8 days in saline-treated allograft recipients. These results suggest that db-cAMP exerts a beneficial effect on murine cardiac allograft survival by modulating allogeneic immune response and cytotoxicity.

Nicotine on rat TRAM flap / Nicotina em retalho TRAM em ratos

PURPOSE: The transverse rectus abdominis myocutaneous (TRAM) flap is one of the preferential techniques used in breast reconstruction following mastectomy. Nicotine has a detrimental effect on cutaneous flap survival; although there are no experimental studies proving this effect on musculocutaneous flaps. The aim of this study is to verify the effect of nicotine on the rat TRAM flap. METHODS: 30 Wistar EPM-1 rats were randomly distributed in two groups: control and experimental. The animals of the control group received saline solution injected subcutaneously, in a volume of 0.2 ml, twice a day, during 28 days in the preoperative period. The animals of the experimental group were treated with nicotine, injected subcutaneously, in a dose of 2 mg/kg twice a day, during 28 days in the preoperative period. All the animals were submitted to the caudally based, right unipedicled TRAM flap. 48 hours after the procedure, a study of the viable area of the flap was done through photographic documentation. Statistical analysis was performed with nonparametric Mann-Whitney's test. RESULTS: The experimental group had significantly greater area of necrosis when compared with the control group (p<0.001). CONCLUSION: Nicotine increased the area of necrosis of the TRAM flap, in rats.

OBJETIVOS: O retalho musculocutâneo transverso do músculo reto do abdome (TRAM) é uma das principais opções na reconstrução do relevo mamário pós-mastectomia. A nicotina tem efeito deletério na viabilidade de retalhos cutâneos; porém, não foram encontrados trabalhos experimentais comprovando este efeito em retalhos musculocutâneos. O objetivo deste trabalho é investigar o efeito da nicotina na viabilidade do retalho TRAM, em ratos. MÉTODOS: Foram utilizados 30 ratos da linhagem Wistar EPM-1. Os animais foram distribuídos aleatoriamente em dois grupos: controle e experimento. Os animais do grupo controle foram tratados com solução salina injetada no tecido celular subcutâneo num volume de 0,2 ml, duas vezes ao dia, durante 28 dias no período pré-operatório. Os animais do grupo experimento foram tratados com nicotina injetada no tecido celular subcutâneo em uma dose de 2mg/kg/2 vezes ao dia, durante 28 dias no período pré-operatório. Todos os animais foram submetidos ao procedimento do retalho TRAM de base caudal unilateral à direita (pedículo não dominante). 48 horas depois, foi feita a avaliação da área viável de superfície do retalho, por documentação fotográfica. Para análise dos resultados foram utilizados testes não paramétricos: Mann-Whitney. RESULTADOS: O grupo experimento apresentou uma área de necrose maior, quando comparado com o grupo controle (p<0,001). CONCLUSÃO: A nicotina aumentou a área de necrose do retalho TRAM, em ratos.