Search

Multiple changes in expression of genes that are important in beta cell function were identified by using oligonucleotide microarrays and real-time polymerase chain reaction (PCR) of pancreatic islets isolated from humans with type 2 diabetes versus normal glucose-tolerant controls. The expression of the transcription factor aryl hydrocarbon receptor nuclear translocator (ARNT) declined by 90 percent.

Xenotransplantation has seen recent global interest peak as a result of several clinical xenotransplants being performed in decedents and a live cardiac recipient. However, underpinning these latest transplants have been decades of invested scientific research programs that have been developing the ideal donor source animals to avoid the overwhelming hyperacute xenograft rejection seen using nongenetically modified animal organs, tissues, and cells. However, this also needs to be undertaken along with the development of safe and efficacious xenotransplantation technologies, immunosuppression, monitoring, disease screening, patient selection, societal education, and acceptance. Paralleling the advent of such extraordinary transplants have been several decades of establishment of world xenotransplantation authorities such as the International Xenotransplantation Association, and the development of guidance documents and regulations for the assessment of these cutting-edge technologies. Similar to all new technologies there remain outdated concerns and fears of the theoretical potential for transmission of xenozoonosis, ethical concerns, and outdated or appropriately educated societal concerns and religious views of the benefits or risks and issues for xenotransplantation use of organs, tissues, or cells from animals to human beings. Here, we discuss the development of xenotransplantation and the intricate balance in managing the various challenges with which we are faced: in the absolute benefits of xenotransplantation and the dichotomy in balancing the pros and cons of xenotransplantation with social, religious, ethical, scientific, and medical opinions. Ultimately, the benefits are to those patients suffering from the many and various diseases that drive the need for xenotransplantation. The hope is that it will be implemented as soon as possible to help the many millions of patients who can truly benefit. [ABSTRACT FROM AUTHOR]

The development of autoimmune disease type 1 diabetes (T1D) is determined by both genetic background and environmental factors. Environmental triggers include RNA viruses, particularly coxsackievirus (CV), but how they induce T1D is not understood. Here, we demonstrate that deletion of the transcription factor hypoxia-inducible factor-1α (HIF-1α) from β cells increases the susceptibility of non-obese diabetic (NOD) mice to environmentally triggered T1D from coxsackieviruses and the β cell toxin streptozotocin. Similarly, knockdown of HIF-1α in human islets leads to a poorer response to coxsackievirus infection. Studies in coxsackievirus-infected islets demonstrate that lack of HIF-1α leads to impaired viral clearance, increased viral load, inflammation, pancreatitis, and loss of β cell mass. These findings show an important role for β cells and, specifically, lack of β cell HIF-1α in the development of T1D. These data suggest new strategies for the prevention of T1D. • Type 1 diabetes is increasing worldwide, which must be due to environmental changes • Lack of β cell HIF1a increases risk of T1D after viral infection • β Cell HIF1a also decreases T1D after low doses of the β cell toxin streptozotocin • β Cell HIF1a is a major factor in determining whether insult leads to T1D or resolution Lalwani et al. describe a role for β cell hypoxia-inducible factor-1α (HIF1a) in determining whether β cell injury is followed by resolution and normal function or ongoing injury, autoimmunity, and type 1 diabetes. [ABSTRACT FROM AUTHOR]

Kidney transplantation is the optimum treatment for kidney failure in carefully selected patients. Technical surgical complications and second warm ischemic time (SWIT) increase the risk of delayed graft function (DGF) and subsequent short- and long-term graft outcomes including the need for post-transplant dialysis and graft failure. Intraoperative organ thermal regulation could reduce SWIT, minimizing surgical complications due to time pressure, and limiting graft ischemia-reperfusion injury. A novel ischemic-injury thermal protection jacket (iiPJ) was designed and fabricated in silicone composite and polyurethane (PU) elastomer prototypes. Both were compared with no thermal insulation as controls. Time to reach ischemic threshold (15°C) and thermal energy transfer were compared. A water bath model was used to examine the thermal protective properties of porcine kidneys, as a feasibility study prior to in vivo translation. In both iterations of the iiPJ, the time taken to reach the warm ischemia threshold was 35.2 ± 1.4 minutes (silicone) and 38.4 ± 3.1 minutes (PU), compared with 17.2 ± 1.5 minutes for controls (n = 5, P <.001 for both comparisons). Thermal energy transfer was also found to be significantly less for both iiPJ variants compared with controls. There was no significant difference between the thermal performance of the 2 iiPJ variants. Protection from SWIT by using a protective insulation jacket is feasible. With clinical translation, this novel strategy could facilitate more optimal surgical performance and reduce transplanted organ ischemia-reperfusion injury, in particular the SWIT, potentially affecting delayed graft function and long-term outcomes. • Protection from SWIT by using a thermal insulation jacket is feasible. • Intraoperative thermal insulation can double time taken to reach 15°C. • Both silicone and polyurethane are viable materials for thermal insulation. [ABSTRACT FROM AUTHOR]

The numbers and characteristics of the abstracts presented at the Annual Scientific Meetings (ASM) of the Transplantation Society of Australia and New Zealand (TSANZ) that are converted to peer-reviewed publications have not been analyzed previously. All abstracts presented at the TSANZ ASM from 2013 to 2017 were reviewed. A literature search was performed using a search algorithm to identify the full-text publications of the presented abstracts. Correlation between abstract characteristics and publication rate was then examined using Cox proportional hazards regression and Kaplan-Meier curves to distinguish the predictors for publication. Over the 5-year period, 576 abstracts were presented, with a total of 164 (28.6%) presentations converted to publications. The majority of publications occurred within the first 3 years, with the mean time to publication being 16.6 (standard deviation = 14.6) months. The median impact factor for published research was 4.74 (interquartile range = 3.06-5.58). Multivariate analysis identified clinical science papers, systematic reviews and surveys (likelihood ratio = 1.42, 5.02, and 2.01; P =.040,.000, and.010, respectively) as the most important predictors for publication. The rate of abstracts presented at the TSANZ ASM over 5 years that were converted to publication in a peer-reviewed journal was 28.6%. Clinical papers, systematic reviews, and surveys were more likely to be published. An ongoing strict abstract selection process will contribute to improving conversion of abstracts into full-text peer-reviewed articles. • The conversion of abstracts to journal publication at various specialty meetings ranges from 30% to 81%. • The conversion of abstract to publication for the TSANZ ASM was 28.6%. • Clinical papers, systematic reviews, and surveys were most likely to be published. • An ongoing strict abstract selection process will contribute to improving conversion of abstracts into publications. [ABSTRACT FROM AUTHOR]

Simultaneous pancreas-kidney (SPK) transplantation can be complicated by thrombosis in the early post-transplant period. We performed a single-center retrospective study examining risk factors, management, and outcomes of modern era SPK transplants. We reviewed 235 recipients over 10 years (January 1, 2008, to September 1, 2017). We used multivariate analysis to examine donor, recipient, and operative risk factors for thrombosis. Forty-one patients (17%) had a thrombosis diagnosed on postoperative imaging, but 61% of these patients (n = 25/41) did not lose their graft secondary to the thrombosis. Nine patients (22%) were managed with watchful waiting and serial imaging, 12 (29%) were managed with therapeutic anticoagulation, and 4 (10%) required laparotomy and graft thrombectomy. Sixteen of 235 pancreas grafts (6.8%) required pancreatectomy, and 10 of these cases occurred in the first half of the study, before 2012. The risk of thrombosis leading to graft loss increased 11.2-fold in recipients with a body mass index (calculated as weight in kilograms divided by height in meters squared) > 25 compared with others (odds ratio, 11.2; 95% CI, 1.1-116.7; P =.043). The majority of SPK transplants (61%) complicated by thrombosis of the pancreatic graft were salvaged by use of imaging, anticoagulation, and in select cases, laparotomy and graft thrombectomy. [ABSTRACT FROM AUTHOR]

Routine screening for microbial contamination in organ recovery perfusion transport solution (ORPTS) is by microbiological culture without broth enrichment. Our aim was to examine the clinical utility of broth enrichment of perfusion solution, through use of BACTEC (Becton Dickinson) blood culture media, in preventing wound complications for transplant recipients in comparison with culture without enrichment. We prospectively collected samples of ORPTS of 395 kidney (n = 250) or simultaneous pancreas-kidney (SPK, n = 145) donors over a 7-year period. Results of culture with and without broth enrichment (n = 285) using BACTEC blood culture media were examined to compare the sensitivity of BACTEC with non-BACTEC methods. We then conducted a paired analysis of 110 recipients with both BACTEC and non-BACTEC culture organ perfusion media. We examined the rates of wound infection and whether the use of targeted antimicrobials reduced infections in the BACTEC group and recipients with both types of cultures. Of 395 patients with cultures of ORPTS, first, the results of 79 cultures performed using BACTEC media only were compared with 206 non-BACTEC cultures (n = 285). Second, 110 cultures were performed using both methods. For the first part of the study, BACTEC media detected significantly greater microbial growth than non-BACTEC methods (n = 79, 64.6% vs n = 206, 14.6%; P <.001). In the 110 patients with both BACTEC (52.3%) and non-BACTEC cultures (9.9%), there was significantly higher sensitivity of the BACTEC method (P <.001); 68.2% of these patients had antimicrobial cover in the days immediately following transplant sufficient to cover the cultured organism. In the patients with appropriate antimicrobial cover, the rate of recipient wound infection was significantly reduced (P =.003). Routine screening of ORPTS with BACTEC broth enrichment should always be employed. When paired with antimicrobial prophylaxis, it has the potential to significantly reduce the risk of recipient wound infection. • BACTEC-enabled microbiological culture provides superior sensitivity to non-BACTEC culture methods for screening ORPTS for microbial growth. • Patients at increased risk for surgical site infections include SPK recipients, patients with organs from an older donor, and older recipients. • Microbial results from BACTEC culture, used in conjunction with targeted antimicrobial prophylaxis, can reduce the frequency of transplant surgical site infections. [ABSTRACT FROM AUTHOR]

Within the pancreatic β-cells, insulin secretory granules (SGs) exist in functionally distinct pools, displaying variations in motility as well as docking and fusion capability. Current therapies that increase insulin secretion do not consider the existence of these distinct SG pools. Accordingly, these approaches are effective only for a short period, with a worsening of glycemia associated with continued decline in β-cell function. Insulin granule age is underappreciated as a determinant for why an insulin granule is selected for secretion and may explain why newly synthesized insulin is preferentially secreted fromβ-cells. Here, using a novel fluorescent timer protein, we aimed to investigate the preferential secretion model of insulin secretion and identify how granule aging is affected by variation in the β-cell environment, such as hyperglycemia. We demonstrate the use of a fluorescent timer construct, syncollin-dsRedE5TIMER, which changes its fluorescence from green to red over 18 h, in both microscopy and fluorescence-assisted organelle-sorting techniques. We confirm that the SG-targeting construct localizes to insulin granules in β-cells and does not interfere with normal insulin SG behavior. We visualize insulin SG aging behavior in MIN6 and INS1 β-cell lines and in primary C57BL/6J mouse and nondiabetic human islet cells. Finally, we separated young and old insulin SGs, revealing that preferential secretion of younger granules occurs in glucose-stimulated insulin secretion. We also show that SG population age is modulated by the β-cell environment in vivo in the db/db mouse islets and ex vivo in C57BL/6J islets exposed to different glucose environments. [ABSTRACT FROM AUTHOR]

Background This study aimed to identify the most effective solution for in situ perfusion/preservation of the pancreas in donation after brain death donors, in addition to optimal in situ flush volume(s) and route(s) during pancreas procurement. Methods Embase, Medline and Cochrane databases were utilized (1980–2017). Articles comparing graft outcomes between two or more different perfusion/preservation fluids (University of Wisconsin (UW), histidine–tryptophan–ketoglutarate (HTK) and/or Celsior) were compared using random effects models where appropriate. Results Thirteen articles were included (939 transplants). Confidence in available evidence was low. A higher serum peak lipase (standardized mean difference 0.47, 95% CI 0.23–0.71, I 2 = 0) was observed in pancreatic grafts perfused/preserved with HTK compared to UW, but there were no differences in one-month pancreas allograft survivals or early thrombotic graft loss rates. Similarly, there were no significant differences in the rates of graft pancreatitis, thrombosis and graft survival between UW and Celsior solutions, and between aortic-only and dual aorto-portal perfusion. Conclusion UW cold perfusion may reduce peak serum lipase, but no quality evidence suggested UW cold perfusion improves graft survival and reduces thrombosis rates. Further research is needed to establish longer-term graft outcomes, the comparative efficacy of Celsior, and ideal perfusion volumes. [ABSTRACT FROM AUTHOR]

Aim: DPP-4/CD26 degrades the incretins GLP-1 and GIP. The localization of DPP-4 within the human pancreas is not well documented but is likely to be relevant for understanding incretin function. We aimed to define the cellular localization of DPP-4 in the human pancreas from cadaveric organ donors with and without diabetes.Methods: Pancreas was snap-frozen and immunoreactive DPP-4 detected in cryosections using the APAAP technique. For co-localization studies, pancreas sections were double-stained for DPP-4 and proinsulin or glucagon and scanned by confocal microscopy. Pancreata were digested and cells in islets and in islet-depleted, duct-enriched digests analyzed for expression of DPP-4 and other markers by flow cytometry.Results: DPP-4 was expressed by pancreatic duct and islet cells. In pancreata from donors without diabetes or with type 2 diabetes, DPP-4-positive cells in islets had the same location and morphology as glucagon-positive cells, and the expression of DPP-4 and glucagon overlapped. In donors with type 1 diabetes, the majority of residual cells in islets were DPP-4-positive.Conclusion: In the human pancreas, DPP-4 expression is localized to duct and alpha cells. This finding is consistent with the view that DPP-4 regulates exposure to incretins of duct cells directly and of beta cells indirectly in a paracrine manner. [ABSTRACT FROM AUTHOR]