Heterotopic Group Research Articles

Anatomic Position and Durability of Polytetrafluoroethylene Conduit ≥18 mm: Single-Center Experience

BackgroundConduit longevity after right ventricular outflow tract (RVOT) reconstruction is determined by the interaction of different factors. We evaluated the relationship between conduit anatomic position and long-term durability among ≥18 mm polytetrafluoroethylene (PTFE) conduits. MethodsA single-institution RVOT reconstructions using a PTFE conduit ≥18 mm were identified. Catheter-based interventions or the need for conduit replacement were comparatively assessed between orthotopic vs heterotopic conduit position. Time to the first reintervention, censored by death, was compared between the groups. ResultsA total of 102 conduits were implanted in 99 patients, with a median age of 13.2 years (interquartile range [IQR] 8.9-17.8 years), median weight of 47 kg (IQR, 29-67 kg), and body surface area of 1.4 m2 (IQR, 1-1.7 m2). Overall, 50.9% (n = 52) of conduits were placed in an orthotopic position after the Ross procedure in congenital aortic valve abnormalities (80% [n = 36]). Tetrology of Fallot in 39% (n = 18), followed by truncus arteriosus with 33% (n = 15), were the most common in the heterotopic position. Trileaflet configuration was similar (67% vs 69%; P = .32) between the groups. Survival free from reintervention was 91% (95% CI, 79-97) and 88% (95% CI, 71-95) in the orthotopic and the heterotopic group, respectively, at 5 years, without differences in the Kaplan Meier curves (log-rank >.05). ConclusionsRVOT reconstruction with PTFE conduits ≥ 8 mm showed >90% conduit survival free from replacement in our cohort at 5 years. The anatomic position of the PTFE conduit does not seem to impact intermediate durability.

Hemodynamic and perioperative management in two different preclinical pig-to-baboon cardiac xenotransplantation models.

The perioperative phase of preclinical cardiac xenotransplantations significantly affects the experimental outcome. Moderate or even severe hemodynamic and respiratory impairment occurs frequently in baboons after receiving a cardiac transplant. The perioperative management of such postoperative instability is very demanding, especially in the experimental setting. We compared perioperative changes of hemodynamic and laboratory findings during orthotopic and heterotopic thoracic cardiac xenotransplantations and describe our monitoring, treatment and intensive care. Twenty-eight pig-to-baboon cardiac xenotransplantations were performed using either the orthotopic (oHTx, n=5) or heterotopic thoracic (htHTx; n=23) technique. In both techniques, cardioplegia and an intraoperative cardiopulmonary bypass (CPB) were required. Preoperatively, intensive care (eg, transfusions, catecholamine therapy) was provided and fast extubation was targeted. A central venous catheter, afemoral arterial thermodilution catheter, a telemetric pressure transmitter and transthoracic echocardiography were used to monitor the animal. Baboon jackets with a tethering system were used to continuously apply medication postoperatively and permit blood sampling, also after extubation of the animal and transfer into the cage. Perioperative survival, hemodynamics, catecholamine doses, respiratory function and weaning from respirator were compared. Perioperative organ damage was evaluated based on laboratory findings 12hours after transplantation. Recipients could be weaned from CPB in the 20 htHTx and all five oHTx experiments, and three htHTx procedures were terminated during the operation. The time of cardiopulmonary bypass was significantly lower in the heterotopic group (oHTx median 171 [157-193] minutes; htHTx median 144 [100-190] minutes; P=.02). In 17 htHTx procedures, no inotropics were used, whereas epinephrine had to be administered in four of the five oHTx experiments; the mean time of catecholamine support was longer in the oHTx group (oHTx 972±348minutes vs htHTx 111±92minutes; P<.01). After htHTx, weaning off the respirator was possible in 19 of 20 cases (one died due to pneumothorax). After oHTx, three of the five baboons could be weaned off the respirator; in these cases, the arterial saturation was higher compared with the extubated baboons after htHTx (oHTx 99±1% vs htHTx 91±4%, P=.01). Intraoperative blood loss was similar between the two groups, and hemostasis was impaired after all procedures, but relevant postoperative bleeding never occurred. Intensive intra- and postoperative monitoring and care is required in both transplantation techniques as a requirement for successful weaning from CPB and respirator. After htHTx, the animals needed less catecholamines and were hemodynamically more stable. Even though pulmonary function was often impaired after htHTx, weaning from the respirator and extubation was more successful in this group.

The Spirit of Gezi: The Recomposition of Political Subjectivities in Turkey

There is a peculiar affinity between the global uprisings of the last few years--from Tahrir Square, to Syntagma, Zuccotti Park and the Indignados. Not only do these uprisings seem to share similar forms of political protest, they also appear to represent a cycle in which elements are passed over or imitated. In this chain of struggles, every event is also singular, shaped by the respective specificities of its spatio-temporal context. However, those differences, should not be read in an essentialist manner, as if Cairo and New York were incomparable and thus incompatible cases. Instead, we take those differences as different expressions of a common case--an understanding of democracy that challenges the established boundaries between the spheres of the economic, the political and the social. Within this context, the Gezi Uprising, during the summer of 2013 in Turkey--in all its singularity--has something to say about the general patterns of revolts in contemporary capitalism. In this article we aim to provide a theoretically informed account of the Gezi Uprising, which started with a small initiative to prevent the demolition of Gezi Park in the heart of Istanbul, next to Taksim Square, during May 2013 and grew into a nationwide uprising on 31 May 2014. It was an unexpected event, emerging at a point when oppositional forces began to lose hope in the face of the rising authoritarianism of the AKP (Adalet ve Kalkinma Partisi --Justice and Development Party) government. (i) It was 'sudden and puzzling', 'abrupt and spontaneous' for all. (1) According to the Ministry of Internal Affairs, two and a half million people took part in the uprising in seventy-nine cities of Turkey. It was undoubtedly the most significant spontaneous uprising in modern Turkish history. Our account gives a glimpse of the immediacy of the uprising based on the participatory observation of the authors (which was limited to its centre, Gezi Park in Istanbul) and also provides a discussion on its background conditions, inner dynamics and transformative nature as well as on the novel and emergent forms of collective political action, affects, language and subjectivity. We do acknowledge the limits of Gezi Uprising's novelties and that the forms we aim to reveal and discuss have not induced social change on a broader scale. They were rather emergent forms, which appeared to sprout during the uprising and weaken afterwards. However, we still think that those emergent forms were important as they signify new potentialities of collective political action and new understandings of democracy that are not bound by the hegemonic forms of politics and representation. One of the common features of the global uprisings was the heterogeneity of the participants. The protests did not only represent the concerns of a particular social group, but typically resonated with the desires of the 'multitude'. (ii) Indeed, resonance and heterogeneity were two important features of the Gezi Uprising as observed by the authors of this article, among many others. (iii) The heterogeneous composition of these events though, is often seen as a sign of their lack of a common ground. Following this argument, a common narrative on the new cycle of uprisings claims that due to the very diversity of their composition, they cannot result in an enduring movement, let alone a political party. We aim to contribute to the broader discussion on the global chain of uprisings through developing an alternative line of argument in the context of the Gezi case. We conceive these elements of heterogeneity and resonance as the conceptual infrastructures of a new virtual political subjectivity, which we analyse with the concept of recomposition. By using the concept of recomposition, we shift the emphasis 'from identity to becoming'. (2) Our analysis does not see the heterogeneity of the protestors as a weakness; on the contrary, we see it as a window of opportunity in the sense that Lefebvre defined the revolutionary moment as 'the spontaneous coming together in a moment of 'irruption; when disparate heterotopic groups suddenly see, if only for a fleeting moment, the possibilities of collective action to create something radically different'. …

Establishment of orthotopic Lewis lung cancer model in mouse

背景与目的肺癌原位模型包括小鼠自发性肺肿瘤模型和气道内接种模型等，但自发性肺肿瘤模型耗时较长且成瘤率不能保证，而气道内接种模型成瘤部位及大小不稳定。本研究以3LL细胞系细胞接种于C57BL/6小鼠肺原位，与皮下接种模型比较，探讨其稳定性、转移特性，并建立小鼠肺原位癌模型的优化方法。方法将不同数量级的3LL细胞分别直接接种于C57BL/6小鼠左侧腋下制备皮下接种模型和以Matrigel悬浮后接种于其左肺制备原位接种模型，观察两种模型的生存期，并对小鼠进行解剖后行病理切片检查、免疫组化染色检测微血管密度、流式细胞仪检测CD44v。结果皮下组成瘤率分别为100%、66.7%、16.7%，未见明显转移。原位组成瘤率分别为100%、100%、83.3%，并可转移至对侧胸廓及肺脏。原位组中位生存期（38 d、35 d、23 d）明显少于皮下接种组（82 d、72 d、50 d）。原位接种组微血管密度（120.2±9.73）高于皮下组（92.6±7.12）。原位接种组肿瘤细胞悬液CD44v表达（26.46±1.56）%高于皮下接种组（23.13±1.02）%。结论以3LL细胞接种于小鼠肺部所建立的肺癌原位模型简单可靠，重复性高，具有较皮下接种模型更强的转移特性。

Determinants of outcome after heterotopic heart transplantation

Background Donor availability is currently the major factor limiting the use of heart transplantation as a treatment for severe heart failure. Heterotopic heart transplantation may address this issue by allowing the use of smaller donor organs, which otherwise may not be used. Methods We analyzed the outcome of 42 consecutive, adult heterotopic transplantations performed between 1993 and 1999 at our center and compared them with the 303 consecutive orthotopic transplants performed in adult patients during the same period. Results Univariate analysis showed a relative risk for death of 1.8 at 1 year after transplantation for the heterotopic group compared with the orthotopic transplantation group ( p = 0.04). Multiple regression analysis using a proportional hazards model showed that donor–recipient size-mismatch, i.e., donor body surface area ≤75% of recipient body surface area ( p = 0.0001), donor age ( p = 0.0001), and use of a female donor ( p = 0.04) were significant risk factors but heterotopic transplantation per se was not. A Kaplan-Meier survival analysis of heterotopic vs orthotopic transplantation showed that 30-day survival was 76% vs 87%. By 1 year, this was 59% vs 74%. At 3 years, the comparison was 56% vs 69%. Repeating this analysis after sub-dividing the heterotopic group into those size-matched vs size-mismatched, the 1-year survival was 81% vs 45%, respectively ( p = 0.02). Conclusions Heterotopic transplantation using a size-matched graft resulted in similar survival to that seen after orthotopic transplantation during the same period. Heterotopic transplantation with an undersized graft resulted in significantly decreased survival.

Histopathology of cardiac xenograft rejection in the pig-to-baboon model

Background: The use of pig organs transgenic for human decay accelerating factor (hDAF) has largely overcome the problems of hyperacute rejection. With improved immunosuppressive protocols, life supporting grafts are showing greater survival times bringing the possibility of clinical xenotransplantation closer. Examination of the histopathology of the rejection process provides insight into the underlying mechanism and may suggest ways in which new immunosuppressive strategies should be directed. Methods: 44 baboons (Papio anubis) underwent heart transplants of which 39 were from transgenic donors. The transplanted organs were examined histologically and stained for evidence of immunoglobulin and complement deposition as well as cellular infiltrates. Results: In the transgenic animals survival times were 2 to 99 days (mean 23.5) and the heterotopic group and 1 to 39 days (mean 11.7) in the orthotopic group. There were 3 cases of hyperacute rejection between the 2 groups. Rejected organs showed areas of old and recent myocardial infarction associated with vascular thrombosis. There was widespread deposition within vessels of immunoglobulins IgM and IgG together with complement fractions C3 and C5b to 9 in those organs that were rejected. The amount of complement positive in the longer surviving organs was less than those rejecting early. Cellular infiltate was predominantly macrophage with some later appearing T or natural killer cells. Conclusions: The histopathological changes support the importance of immunoglobulin and complement in delayed xenograft or acute vascular rejection. With time there is an increase in cellular infiltrate predominantly macrophages and these findings suggest an increasingly important role for the cells and the rejection process. The presence of areas of infarction and underlying vascular thrombosis is in keeping with endothelial activation and the establishment of procoagulant phenotype which may be due to immunoglobulin, complement, secreted cytokines and direct cellular effects.

Total Pancreatico-Duodenal Transplantation with Portal Venous Drainage: Metabolic Assessments in Diabetic Rats

A perfect metabolic correction of diabetes is essential to completely eradicate long-term chronic complications. Only a total pancreatic graft with portal venous drainage enables such an achievement. Isogenic Lewis rats were used for donors, recipients and controls. Pancreatico-duodenal transplantation was either heterotopic with systemic venous drainage (n = 12) or paratopic with portal drainage (n = 11). All animals were regularly monitored for non-fasting plasma glucose and insulin. Both techniques promptly restored the non-fasting plasma glucose to normal values (p < 0.003). Normo-insulinemia (47.4 ± 6.4 μU/ml) was obtained in the paratopic group, while the heterotopic group showed hyperinsulinism (132.0 ± 15.2 μU/ml). Perfect metabolic control justifies the additional technical difficulties of total paratopic pancreatic transplantation with portal venous drainage.

Transplantation of cryopreserved fetal ovarian tissue to adult recipients in mice.

Sixteen-day-old fetal mouse ovaries were slowly frozen in 1.5 mol dimethylsulfoxide ml-1 and subjected to one of two thawing procedures--fast thaw or slow thaw. Fresh and frozen-thawed fetal ovaries were transplanted orthotopically (to the bursal cavity) to either bilaterally or unilaterally ovariectomized adult female recipients. Fresh fetal ovaries were also transplanted heterotopically (under the kidney capsule) to intact, bilaterally or unilaterally ovariectomized adult females. Transplantation of fetal ovaries to bilaterally ovariectomized adult recipients resulted in restoration of cyclic activity within 20.5 +/- 4.7 (mean +/- SEM) days or 23.4 +/- 0.8 days in orthotopic and heterotopic groups, respectively. Developing follicles and corpora lutea were observed within 4 weeks after transplantation of fetal ovaries to heterotopic sites and within 6 weeks after transplantation to orthotopic sites. After orthotopic transplantation, 33% of the recipients became pregnant. Orthotopic or heterotopic transplantation to intact of unilaterally ovariectomized recipients resulted in quiescence of the fetal ovary. After cryopreservation, transplantation of fetal ovaries to bilaterally ovariectomized recipients resulted in restoration of cyclic activity within 19.3 +/- 2.1 days and 23.4 +/- 5.1 days after transplantation in slow thaw and fast thaw groups, respectively. Fertility was restored to 86% of fast thawed and 25% of slow thawed fetal ovary transplants to bilaterally ovariectomized adult recipients. No ovarian tissue was observed on the side of the fetal graft in unilaterally ovariectomized recipients that received frozen-thawed fetal ovaries. These results demonstrate that cryopreserved fetal ovarian tissue can be transplanted to adult recipients with subsequent restoration of fertility and that this process is dependent on the absence of the ovaries of the recipients.

Experimental tracheal and tracheoesophageal allotransplantation

We investigated the effects of allograft perfusion with a preservative technique and of combined thyrotracheoesophageal implantation on airway epithelium of long segments of thyrotracheal grafts allotransplanted on their own vascular pedicles into immunosuppressed pigs. Four groups of five animals each underwent heterotopic (into the neck) thyrotracheal (group 1) and thyrotracheoesophageal (group 2) and orthotopic thyrotracheal (group 3) and thyrotracheoesophageal (group 4) allotransplantation. Allograft revascularization included (1) interposition of donor right subclavian artery--incorporating the inferior thyroid artery--to recipient right carotid artery (end-to-end fashion) and (2) end-to-side anastomosis of donor anterior vena cava to recipient right external jugular vein. All thyrotracheoesophageal blocks were harvested after inferior thyroid artery perfusion with 4 degrees C Euro-Collins solution. The overall lengths of tracheal and esophageal grafts were 10.7 +/- 2.7 cm and 13.4 +/- 3.6 cm, respectively. In the heterotopic groups, all allografts were viable and histologically normal at postmortem examination and the incidence and severity of airway ischemia and rejections (at equal residual levels of cyclosporine) were not different between groups 1 and 2. In the orthotopic groups, the first two pigs died of airway collapse with histologically normal grafts. In the remaining pigs, temporary airway stenting was inserted and allografts remained viable and histologically intact for their entire length 30 days after transplantation. Transplanted tracheal smooth muscles had concentration-dependent contractions and relaxations similar to those of nontransplanted (native) tracheas. This study documents the feasibility of allotransplanting long tracheal and esophageal segments on their own vascular pedicles and demonstrates that allograft preservation and thyrotracheoesophageal transplantation are equally effective in minimizing airway ischemia. Thyrotracheoesophageal transplantation does not enhance recipient alloimmune response compared with thyrotracheal transplantation alone.

Prolongation of canine intestinal allograft survival with RS-61443, cyclosporine, and prednisone.

The efficacy of RS-61443 and cyclosporine utilized either alone or in combination was assessed in both a segmental heterotopic and total orthotopic canine intestinal transplant model. Twenty-eight dogs underwent segmental (150-cm) heterotopic intestinal transplants and five dogs total orthotopic transplants. Five heterotopic groups were compared: group 1, no immunosuppression; group 2, cyclosporine and prednisone; group 3, RS-61443, cyclosporine and prednisone; group 4, RS-61443 and prednisone; and group 5, RS-61443 and subtherapeutic cyclosporine. Group 3 animals achieved a median survival of 136 days, while the median survivals of groups 1, 2, 4, and 5 were < or = 10 days (P < .001). Twenty deaths in groups 1 through 5 were secondary to allograft rejection, two were due to infection, and two were unexplained. Four animals in group 3 were sacrificed, one at 83 days due to diarrhea and weight loss and three at the termination of the study. The median survival of five dogs undergoing total orthotopic transplantation (group 6) was 27.0 days and was significantly longer than groups 1, 4, and 5 (P < .01). No dog in this group had intestinal rejection--however, four were sacrificed due to weight loss and one died of malnutrition. The combination of RS-61443 and cyclosporine significantly prolonged intestinal allograft survival in both the heterotopic and orthotopic transplant models. Clinically, this combination may be promising for both combined liver-intestinal and isolated intestinal transplantation.

Resolution of severe pulmonary hypertension after heterotopic cardiac transplantation

In patients with severe congestive heart failure, a marked elevation in pulmonary vascular resistance limits the success of orthotopic cardiac transplantation, thus providing the rationale for heterotopic transplantation. To determine the changes in pulmonary hemodynamics after heterotopic cardiac transplantation, postoperative right heart pressures were serially measured in five patients who underwent this operation for end-stage congestive heart failure accompanied by severe secondary pulmonary hypertension and elevation in calculated pulmonary vascular resistance. Hemodynamics were compared with those of a matched group of 10 orthotopic cardiac transplant recipients.Preoperatively, pulmonary artery mean and wedge pressures, pulmonary vascular resistance and transpulmonary pressure gradient (pulmonary artery mean minus wedge pressure) were significantly higher in the heterotopic group. Postoperatively, significant improvement in pulmonary hemodynamics occurred in both groups and, by 12 months, the pulmonary artery mean pressure, wedge pressure, pulmonary vascular resistance and transpulmonary pressure gradient were similar in the two groups. These findings suggest that pulmonary hypertension secondary to congestive heart failure, even when severe and associated with a high pulmonary vascular resistance, is to a great extent reversible.

The 24-hour heart rate behavior in long-term survivors of cardiac transplantation

A detailed computerized analysis of heart rate (HR) behavior during ambulatory monitoring was performed in 19 long-term survivors of cardiac transplantation (12 orthotopic, 7 heterotopic) and in 10 normal volunteers. Compared with normal hearts, the transplanted denervated and the recipient innervated hearts in the heterotopic group showed higher average HRs over the whole 24 hours, the waking and sleeping periods. The rates of the denervated and the recipient hearts did not differ significantly. The maximal HR was similar in all 3 groups, but the minimal HR was lower in the normal hearts than in denervated and recipient hearts. The 24-hour RR interval variability was greatly reduced in the denervated hearts (60 ± 22 ms) compared with the recipient (89 ± 26 ms) and normal (151 ± 38 ms) hearts. During arousal from sleep, the magnitude, time and rate of the HR change were significantly reduced in the denervated hearts compared with the innervated hearts and in the recipient compared with the normal hearts. These findings demonstrate that denervated hearts can show significant variations in HR during the 24-hour period, but to a lesser extent than normal hearts. The widest deviation from normal occurs during sleep, when the denervated heart shows minimal slowing probably due to lack of parasympathetic innervation. In heterotopic transplant recipients, the patients' own HR responses also are significantly blunted.

Cardiac xenotransplantation in primates

Successful cardiac xenotransplantation would alleviate the severe shortage of donor organs that presently limits the availability of cardiac transplantation. Early attempts at human xenotransplantation achieved minimal success. However, the effectiveness of cyclosporine in nonhuman xenotransplant models has received little experimental investigation. We have therefore studied the effect of cyclosporine-based immunosuppression in primate cardiac xenograft models using cynomolgus monkey donors and baboon recipients. Donor hearts were transplanted heterotopically into the necks of recipients or in the orthotopic position. Recipients were treated with no immunosuppression (controls), cyclosporine and steroids, or cyclosporine, steroids, azathioprine, and antithymocyte globulin. Statistically significant prolongation of graft survival compared to the control group was observed in the heterotopic groups. Mean survival time of the cyclosporine-treated and steroid-treated heterotopic grafts was 61 days compared to 6 days for grafts in the control group (p = 0.01); the addition of azathioprine and antithymocyte globulin yielded a mean survival of 84 days (p less than 0.01). No significant increase in graft survival was noted in the orthotopic groups treated with either immunosuppressive regimen. Although long-term use of human xenografts as an alternative for heart replacement is not supported by these data, further investigation of the orthotopic model is clearly justified.

Ovarian transplantation by selective microvascular anastomoses in the rabbit.

Autotransplantation of the ovary by microvascular anastomoses was performed in 42 rabbits by three different procedures: orthotopic replantation with selective end-to-end anastomoses of the ovarian vessels; heterotopic transplantation in the groin area, with anastomosis of the ovarian vessels on the inferior epigastric vessels; heterotopic transplantation in the groin with the ovary included in a peritoneal sac to prevent adhesions. Three weeks later, at day 3 of a pseudo-pregnancy, the grafts were examined and morphology, presence of adhesions and ovulation were compared with those of a control group. The long-term vascular patency rate was 78%. The ovulation rate was 71.5% in the orthotopic group, 50% in the heterotopic group and 83.5% in the heterotopic group with the ovary in a peritoneal sac. Subcutaneous transplantation of the ovary within a peritoneal sac provides a new and useful experimental model for the study of tubo-ovarian function and for recovery of postovulatory oocytes.