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Total pancreatectomy with islet autotransplantation is performed to treat chronic pancreatitis in children. Successful islet isolation must address the challenges of severe pancreatic fibrosis and young donor age. We have progressively introduced modifications to optimize enzymatic and mechanical dissociation of the pancreas during islet isolation. We evaluated 2 islet isolation metrics in 138 children-digest islet equivalents per gram pancreas tissue (IEQ/g) and digest IEQ per kilogram body weight (IEQ/kg), using multiple regression to adjust for key disease and patient features. Islet yield at digest had an average 4569 (standard deviation 2949) islet equivalent (IEQ)/g and 4946 (4009) IEQ/kg, with 59.1% embedded in exocrine tissue. Cases with very low yield (

This paper proposes a systems level solution for addressing the problem of mapping large moving targets with slow but complicated dynamics. Our approach utilizes the complementary nature of multiple sensing modalities. While this work is applicable to other domains we focus our efforts on mapping rotating and translating icebergs. Our solution involves a rigidly coupled combination of a line scan sensor - a subsurface multibeam sonar, with an area scan sensor - an optical camera. This allows the system to exploit the optical camera information to perform iceberg relative navigation which can directly be used by the multibeam sonar to map the iceberg underwater. This paper details the algorithm required to compute the scale of the navigation solution and corrections to find iceberg centric navigation and thus an accurate iceberg reconstruction. This approach is successfully demonstrated on real world iceberg data collected during the 2018 Sermilik campaign in Eastern Greenland. Due to the availability of iceberg mounted GPS observations during this research expedition we could also groundtruth our navigation and thus our systems level mapping efforts.

Large scale single cell omics profiling is revolutionising our understanding of cell types, especially in complex organs like the brain. This presents both an opportunity and a challenge for cell ontologies. Annotation of cell types in single cell 9omics data typically uses unstructured free text, making comparison and mapping of annotation between datasets challenging. Annotation with cell ontologies is key to overcoming this challenge, but this will require meeting the challenge of extending cell ontologies representing classically defined cell types by defining and classifying cell types directly from data. Here we present the Brain Data Standards Ontology (BDSO), a data driven ontology that is built as an extension to the Cell Ontology (CL). It supports two major use cases: cell type annotation, and navigation, search, and organisation of a web application integrating single cell omics datasets for the mammalian primary motor cortex. The ontology is built using a semi-automated pipeline that interlinks cell type taxonomies and necessary and sufficient marker genes, and imports relevant ontology modules derived from external ontologies. Overall, the BDS ontology provides an underlying structure that supports these use cases, while remaining sustainable and extensible through automation as our knowledge of brain cell type expands.

Background A total pancreatectomy and intraportal islet cell autotransplant (TPIAT) is increasingly being offered to patients with chronic pancreatitis (CP). The benefits include removal of the root cause of pain and amelioration of diabetes. However, the long-term durability of this operation remains unclear. Study Design Of the 742 patients who have undergone a TPIAT at our center, 215 who did so between 1998 and 2008 now have at least 10 years of follow-up time and were eligible for this single-center observational study. Our outcomes measures included abdominal pain relief, narcotic use, islet graft function (subdivided into 3 groups: insulin independence; partial graft function, defined by C-peptide level > 0.6 mg/dL; and no function, defined by C-peptide level Results The 10-year actuarial survival rate was 72%. A BMI > 30 kg/m2 (p = 0.04) predicted 10-year mortality. The rates of pain relief were 82% at 10 years and 90% at 15 years. Narcotic use declined with time: the rates were 50% at 5 years and 37% at 10 years. At 10 years, the rate of insulin independence was 20%; the rate of partial graft function, 32%. Transplantation of islet equivalents/kg > 4,000 was the strongest predictor of islet graft function at 10 years. Pediatric patients were more likely to have islet function than adults (p = 0.01). Health-related quality of life continued to improve at 10 years, even in patients on narcotics. Conclusions This represents the first and largest series to examine long-term outcomes (10 years or more) in TPIAT patients. In our series, this dual procedure produced durable pain relief and sustained islet graft function, even past 10 years postoperatively.

An understanding of long-term outcomes for kidney transplant(KTx) recipients who survive with graft function beyond a specific time posttransplant is the first step in creating protocols to optimize care for current and improve outcomes for future recipients. We studied 831KTx recipients-580 living donor(LD); 251 deceased donor(DD)—with graft survival(GS) >20 years. For primary LD recipients, 25-year patient survival(PS) was 83%; 35-year, 59%. Their 25-year death-censored graft survival(DCGS) was 89%; 35-year, 72%. DD recipients had lower PS(P 3 antigens, pretransplant type 1 diabetes mellitus(DM1); in CNI era, a history of rejection, female gender. New comorbidities after 20 years were common: CVD(13%, non-DM1;18%, DM1), infections(27%, non-DM1;37%, DM1), 20-29 years posttransplant. Cancer after 20 years included: nonmelanotic skin cancer,22%; solid organ,7%; post-transplant lymphoproliferative disease(PTLD),2%. To improve long-term outcomes, clinical trials on prevention, recognition, and treatment of new comorbidities are needed.

9 pages, 4 figures, 1 table, supporting information https://doi.org/10.1029/2020GL089765.-- Data Availability Statement Processed: SfM drone pointclouds, raw GPS data, multibeam pointclouds (doi: 10.18739/A2QF8JK6B), and CTD casts (doi: 10.18739/A2NG4GS8C) are uploaded to the Arctic Data Center, Increasing freshwater input to the subpolar North Atlantic through iceberg melting can influence fjord‐scale to basin‐scale ocean circulation. However, the magnitude, timing, and distribution of this freshwater have been challenging to quantify due to minimal direct observations of subsurface iceberg geometry and melt rates. Here we present novel in situ methods capturing iceberg change at high‐temporal and ‐spatial resolution using four high‐precision GPS units deployed on two large icebergs (>500 m length). In combination with measurements of surface and subsurface geometry, we calculate iceberg melt rates between 0.10–0.27 m/d over the 9‐day survey. These melt rates are lower than those proposed in previous studies, likely due to using individual subsurface iceberg geometries in calculations. In combining these new measurements of iceberg geometry and melt rate with the broad spatial coverage of remote sensing, we can better predict the impact of increasing freshwater injection from the Greenland Ice Sheet, With the funding support of the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2019-000928-S), of the Spanish Research Agency (AEI), This work was supported by NSF OPP grant 1552232

ispartof: TRANSPLANTATION DIRECT vol:7 issue:1 ispartof: location:United States status: published

OBJECTIVES Chronic pancreatitis (CP) is an infrequent but debilitating complication associated with CFTR mutations. Total pancreatectomy with islet autotransplantation (TPIAT) is a treatment option for CP that provides pain relief and preserves β-cell mass, thereby minimizing the complication of diabetes mellitus. We compared outcomes after TPIAT for CP associated with CFTR mutations to CP without CTFR mutations. METHODS All TPIATs performed between 2002 and 2014 were retrospectively reviewed: identifying 20 CFTR homozygotes (cystic fibrosis [CF] patients), 19 CFTR heterozygotes, and 20 age-/sex-matched controls without CFTR mutations. Analysis of variance and χ tests were used to compare groups. RESULTS Baseline demographics were not different between groups. Postoperative glycosylated hemoglobin and C-peptide levels were similar between groups, as were islet yield and rate of postoperative complications. At 1 year, 40% of CF patients, 22% of CFTR heterozygotes, and 35% of control patients were insulin independent. CONCLUSION Total pancreatectomy with islet autotransplantation is a safe, effective treatment option for CF patients with CP, giving similar outcomes for those with other CP etiologies.

In this study, our goal was to analyze nearly 4 decades of experience since the first living donor pancreas transplant in 1979, focusing on what constitutes optimal donor selection and ideal post donation follow-up. When combined with a living donor kidney transplant, a living donor pancreas transplant offers patients with concurrent renal failure and diabetes the option of a single procedure: a living donor simultaneous pancreas-kidney (SPK) transplant. Living donor SPK transplants not only can reduce the waiting time in areas where it is long but also, for highly sensitized patients, can electively identify a donor with a negative crossmatch. Although living donor pancreas (and simultaneous pancreas-kidney) transplants were initially performed open, they evolved to laparoscopic procedures in 1999. The technical failure rates have improved over the years. Guidelines for reducing donor morbidity have incorporated the use of biochemical markers and stricter donor selection criteria. Predonation assessment of donors’ beta-cell mass may help identify those at risk of developing diabetes. Living donor pancreas transplants can be performed safely and with good outcomes; they remain an important option for highly sensitized transplant candidates and can reduce waiting time in areas where it is long. For donors, stringent selection criteria, robust predonation counseling, and meticulous postdonation follow-up are essential.

Objectives:Fear of diabetes and major surgery may prohibit referral of young children severely affected by pancreatitis for total pancreatectomy with islet autotransplant (TPIAT). We evaluated outcomes in our youngest TPIAT recipients, 3 to 8 years of age at surgery.Methods:Medical records w

On December 20, 1893, 3 years after von Mering and Minkowski showed that total pancreatectomy in dogs resulted in diabetes mellitus,1 Dr. P. Watson Williams in Bristol, England, grafted three fragments of a pancreas obtained from a freshly slaughtered sheep into the subcutaneous tissue of a 15-year-old boy in extremis, 5 months after clinical onset of diabetes.2 The recipient died 3 days later, not of complications from the unsuccessful transplant but of unrelenting acidosis, a sequela of basically untreated diabetes. At autopsy, the recipient’s own pancreas was shriveled and sections showed little but fibrous stroma. According to Williams, the history and the postmortem examination left little doubt that the patient had “pancreatic diabetes” a case that “presented all the conditions that might lead one to hope for beneficial results from successful grafting of the pancreas, if anything can be hoped for in this direction at all.” He was not discouraged, and further stated that “failure was possibly due to obtaining the graft from a sheep that had been killed by bleeding....If ever I felt justified again in resorting to pancreatic grafts in a similar case, I should obtain them from a living animal anesthetized or dispense with the anesthetic altogether.”

© 2019 Elsevier Inc. Synapses are fundamental information-processing units of the brain, and synaptic dysregulation is central to many brain disorders (“synaptopathies”). However, systematic annotation of synaptic genes and ontology of synaptic processes are currently lacking. We established SynGO, an interactive knowledge base that accumulates available research about synapse biology using Gene Ontology (GO) annotations to novel ontology terms: 87 synaptic locations and 179 synaptic processes. SynGO annotations are exclusively based on published, expert-curated evidence. Using 2,922 annotations for 1,112 genes, we show that synaptic genes are exceptionally well conserved and less tolerant to mutations than other genes. Many SynGO terms are significantly overrepresented among gene variations associated with intelligence, educational attainment, ADHD, autism, and bipolar disorder and among de novo variants associated with neurodevelopmental disorders, including schizophrenia. SynGO is a public, universal reference for synapse research and an online analysis platform for interpretation of large-scale -omics data (https://syngoportal.org and http://geneontology.org). The SynGO consortium presents a framework to annotate synaptic protein locations and functions and annotations for 1,112 synaptic genes based on published experimental evidence. SynGO reports exceptional features and disease associations for synaptic genes and provides an online data analysis platform.

Background & Aims Therapeutic options are limited for patients with recurrent acute pancreatitis who have intractable symptoms despite maximal endoscopic and medical treatment, but equivocal or no morphologic or functional evidence of chronic pancreatitis. We performed a prospective observational cohort study to determine the efficacy of total pancreatectomy with islet autotransplantation (TPIAT) for these patients. Methods We collected data from all patients undergoing TPIAT at the University of Minnesota from 2007 through 2013; 49 patients (42 female; mean age, 32.8 ± 7.8 years) had a diagnosis of recurrent acute pancreatitis not provoked by intervention, with negative or equivocal findings from nondiagnostic imaging or pancreatic function tests for chronic pancreatitis, and intractable pain between episodes. Data on insulin use, narcotic requirements, pain scores, and health-related quality of life were collected before TPIAT; 3 months, 6 months, and 1 year afterward; and then yearly. Results All 49 patients studied required narcotics before TPIAT (45 daily users and 4 intermittent users); 2 had insulin-treated diabetes. At 1 year after TPIAT, 22 out of 48 patients (46%) reported no use of narcotic pain medications ( P P P = .019 for the mental component summary). At 1 year after TPIAT, 21 out of 48 patients (45%) were insulin independent; their mean percent glycosylated hemoglobin A 1c at 1 year after TPIAT was 6.0% ± 0.9% (5.2% ± 0.6% pre-TPIAT). Conclusions Patients with recurrent acute pancreatitis but lacking clear chronic pancreatitis benefit from TPIAT, with outcomes similar to those previously described for patients with chronic pancreatitis (improved quality of life and reduced narcotic use). For these patients who have otherwise limited surgical treatment options, TPIAT can be considered when medical and endoscopic therapies have failed.

To enhance selection of appropriate deceased donors for pancreas transplants, we sought to determine whether HLA matching improved posttransplantation outcomes. In this single-center study of 1219 pancreas transplants, we correlated posttransplantation outcomes with HLA-A, -B, -C, -DR, and -DQ matches and mismatches. Rejection was linearly correlated with the number of mismatches. The individual number of HLA mismatches reached significance at four or more with a 2.3- to 2.9-fold increase in rejection. The effect was most predominant with HLA-B (1.8-fold with one mismatch and 2.0-fold with two mismatches) and -DR (1.9-fold with two mismatches) loci, whereas HLA-A, -C, and -DQ matches or mismatches did not independently predict acute rejection. The affect was strongest in solitary pancreas transplants, with little impact for simultaneous pancreas and kidney (SPK). In contrast, HLA matching did not affect graft or patient survival rates but was associated with a reduced risk of opportunistic infection. Avoidance of acute rejection saved an estimated $32 000 for solitary pancreas recipients and $52 000 for SPK recipients in hospital costs. Our data do not support the use of HLA matching for predicting pancreas graft survival but do support its significance for the reduction of acute rejection, particularly for solitary pancreas recipients.

Background/Objectives Total pancreatectomy and islet autotransplant (TP-IAT) is a potential treatment for children with severe refractory chronic pancreatitis. Cultures from the resected pancreas and final islet preparation are frequently positive for microbes. It is unknown whether positive cultures are associated with adverse outcomes in pediatric patients. Methods We reviewed the medical records of children (n = 86) who underwent TP-IAT from May 2006–March 2015 with emphasis on demographics, previous pancreatic interventions, culture results, islet yield, hospital days, posttransplant islet function, and posttransplant infections. We compared outcomes in patients with positive (n = 57) and negative (n = 29) cultures. Results Patients with positive cultures had higher rates of previous pancreas surgery ( P = 0.007) and endoscopic retrograde cholangiopancreatography ( P P = 1.00) or prolonged hospital length of stay ( P = 0.29). Patients with positive final islet preparation culture showed increased rates of graft failure at 2 years posttransplant ( P = 0.041), but not when adjusted for islet mass transplanted ( P = 0.39). Conclusions Positive cultures during pediatric TP-IATs do not increase the risk of posttransplant infections or prolong hospital length of stay. Endocrine function depends on islet mass transplanted.

The development of minimally invasive surgical approaches to donor nephrectomy (DN) has been driven by the potential advantages for the donor, with questions remaining about long-term outcomes.All living DN performed from June 1963 through December 2014 at the University of Minnesota were reviewed. Outcomes were compared among 4 DN techniques.We performed 4286 DNs: 2759 open DN (ODNs), 1190 hand-assisted (HA) laparoscopic DNs (LDNs), 203 pure LDN (P-LDNs), and 97 robot-assisted-LDN. Laparoscopic DN was associated with an older (P0.001) and heavier (P0.001) donor population. Laparoscopic DN was associated with a higher probability of left kidney procurement (P0.001). All 3 LDN modalities required a longer operative time (P0.001); robot-assisted-LDN took significantly longer than HA-LDN or P-LDN. Laparoscopic DN decreased the need for intraoperative blood transfusion (P0.001) and reduced the incidence of intraoperative complications (P0.001) and hospital length of stay (P0.001). However, LDN led to a significantly higher rate of readmissions, both short-term (30 day, P0.001) and long-term (30 day, P0.001). Undergoing HA-LDN was associated with a higher rate of an incisional hernia compared with all other modalities (P0.001). For recipients, LDN seemed to be associated with lower rates of graft failure at 1 year compared with ODN (P = 0.002). The odds of delayed graft function increased for kidneys with multiple arteries procured via P-LDN compared with HA-LDN (OR 3 [1,10]) and ODN (OR 5 [2, 15]).In our experience, LDN was associated with decreased donor intraoperative complications and hospital length of stay but higher rates of readmission and long-term complications.

Background Living donor segmental pancreas transplants (LDSPTx) have been performed selectively to offer a preemptive transplant option for simultaneous pancreas-kidney recipients and to perform a single operation decreasing the cost of pancreas after kidney transplant. For solitary pancreas transplants, this option historically provided a better immunologic match. Although short-term donor outcomes have been documented, there are no long-term studies. Methods We studied postdonation outcomes in 46 segmental pancreas living donors. Surgical complications, risk factors (RF) for development of diabetes mellitus (DM) and quality of life were studied. A risk stratification model (RSM) for DM was created using predonation and postdonation RFs. Recipient outcomes were analyzed. Results Between January 1, 1994 and May 1, 2013, 46 LDSPTx were performed. Intraoperatively, 5 (11%) donors received transfusion. Overall, 9 (20%) donors underwent splenectomy. Postoperative complications included: 6 (13%) peripancreatic fluid collections and 2 (4%) pancreatitis episodes. Postdonation, DM requiring oral hypoglycemics was diagnosed in 7 (15%) donors and insulin-dependent DM in 5 (11%) donors. RSM with three predonation RFs (oral glucose tolerance test, basal insulin, fasting plasma glucose) and 1 postdonation RF, greater than 15% increase in body mass index from preoperative (Δ body mass index >15), predicted 12 (100%) donors that developed postdonation DM. Quality of life was not significantly affected by donation. Mean graft survival was 9.5 (±4.4) years from donors without and 9.6 (±5.4) years from donors with postdonation DM. Conclusions LDSPTx can be performed with good recipient outcomes. The donation is associated with donor morbidity including impaired glucose control. Donor morbidity can be minimized by using RSM and predonation counseling on life style modifications postdonation.

National Institutes of Health (NIH), Monarch Initiative [OD #5R24OD011883]; Forums for Integrative Phenomics [U13 CA221044-01]; NCATS Data Translator [1OT3TR002019]; NCATS National Center for Digital Health Informatics Innovation [U24 TR002306];NIH Data Commons [1 OT3 OD02464-01 UNCCH]; Cost Action CA 16118 Neuro-MIG; British Heart Foundation Programme Grant [RG/13/5/30112]; Division of Intramural Research; NIAID; NIH; E-RARE project Hipbi-RD [01GM1608]; European Union's Horizon 2020 Research and Innovation Programme [779257]. Funding for open access charge: NIH; Donald A. Roux Family Fund (to P.N.R.). The Human Phenotype Ontology (HPO) - a standardized vocabulary of phenotypic abnormalities associated with 7000+ diseases - is used by thousands of researchers, clinicians, informaticians and electronic health record systems around the world. Its detailed descriptions of clinical abnormalities and computable disease definitions have made HPO the de facto standard for deep phenotyping in the field of rare disease. The HPO's interoperability with other ontologies has enabled it to be used to improve diagnostic accuracy by incorporating model organism data. It also plays a key role in the popular Exomiser tool, which identifies potential disease-causing variants from whole-exome or whole-genome sequencing data. Since the HPO was first introduced in 2008, its users have become both more numerous and more diverse. To meet these emerging needs, the project has added new content, language translations, mappings and computational tooling, as well as integrations with external community data. The HPO continues to collaborate with clinical adopters to improve specific areas of the ontology and extend standardized disease descriptions. The newly redesigned HPO website (www.human-phenotype-ontology.org) simplifies browsing terms and exploring clinical features, diseases, and human genes.

Background The Gene Ontology (GO) consists of over 40,000 terms for biological processes, cell components and gene product activities linked into a graph structure by over 90,000 relationships. It has been used to annotate the functions and cellular locations of several million gene products. The graph structure is used by a variety of tools to group annotated genes into sets whose products share function or location. These gene sets are widely used to interpret the results of genomics experiments by assessing which sets are significantly over- or under-represented in results lists. F Hoffmann-La Roche Ltd. has developed a bespoke, manually maintained controlled vocabulary (RCV) for use in over-representation analysis. Many terms in this vocabulary group GO terms in novel ways that cannot easily be derived using the graph structure of the GO. For example, some RCV terms group GO terms by the cell, chemical or tissue type they refer to. Recent improvements in the content and formal structure of the GO make it possible to use logical queries in Web Ontology Language (OWL) to automatically map these cross-cutting classifications to sets of GO terms. We used this approach to automate mapping between RCV and GO, largely replacing the increasingly unsustainable manual mapping process. We then tested the utility of the resulting groupings for over-representation analysis. Results We successfully mapped 85% of RCV terms to logical OWL definitions and showed that these could be used to recapitulate and extend manual mappings between RCV terms and the sets of GO terms subsumed by them. We also show that gene sets derived from the resulting GO terms sets can be used to detect the signatures of cell and tissue types in whole genome expression data. Conclusions The rich formal structure of the GO makes it possible to use reasoning to dynamically generate novel, biologically relevant groupings of GO terms. GO term groupings generated with this approach can be used in. over-representation analysis to detect cell and tissue type signatures in whole genome expression data. Electronic supplementary material The online version of this article (10.1186/s13326-018-0175-z) contains supplementary material, which is available to authorized users.

In this article, we will review the changes that have occurred in islet transplantation at the birth of Pancreas 30 years ago. The first attempts at β-cell replacement in humans, pancreas and islet transplantation, were performed in the 1960s and 1970s. Although pancreas transplantation has been an accepted treatment for severe labile diabetes predating the emergence of the journal, allogeneic islet transplantation remains experimental. Current investigations within islet transplantation focus to improve islet function after transplantation. Improving islet viability during isolation, exploring ways to increase engraftment, and protection from the host immune system are some of the goals of these investigative efforts. The major barriers to clinical islet transplantation are shortage of human pancreas, the need for immunosuppression, and the inadequacy of the islet isolation process. It is generally accepted that islet encapsulation is an immunoisolation tool with good potential to address the first 2 of those barriers. We have therefore devoted a major part of this review to the critical factors needed to make it a clinical reality. With improved islet isolation techniques and determination of the best site of engraftment as well as improved encapsulation techniques, we hope that islet transplantation could someday achieve routine clinical use.

Total pancreatectomy with islet cell autotransplant (TPIAT) is a definitive therapeutic approach to pain management for patients with chronic pancreatitis that is non-responsive to maximum medical management. Total pancreatectomy (TP) results in brittle diabetes unless islet cell autotransplant (IAT) is concomitantly performed. Even with IAT, about 30 % of patients will require long-term basal-bolus insulin therapy due to significant endocrine insufficiency. The focus of this review is on the utility of whole organ pancreas transplantation toward improving quality of life, and decreasing the risk of mortality and overall cost of care for the subset of patients who experience endocrine and exocrine deficiency after pancreatic resection.

Pancreas retransplantation is associated with increased rates of technical failure and rejection compared to other organ transplants. As such, it is not routinely done, and outcomes are mostly known through registry data. Here we analyze the outcomes of primary versus retransplant for all pancreas transplants done in our program over nearly 35 years.Donor and recipient characteristics and outcomes data were prospectively gathered and recorded in our institutional database. Outcomes of primary and retransplants were reported overall, and then subgrouped by number (second, third, fourth). An in-depth analysis of transplants done after 2003 was included. Rates of technical failure, 1 year acute rejection, graft survival, and patient survival were compared.Two thousand one hundred forty-five pancreas transplants were performed at our institution between 1978 and 2012. Four hundred fifteen of these were retransplants. Improvements were seen in technical failure rates and graft survival for both primary and retransplants over time. There were no significant differences in technical failure or patient survival for primary versus retransplants overall, or by transplant number (second, third, fourth). Modern era retransplants had more acute rejection in the first year after transplantation. Retransplants (vs primary) had decreased mid-term death censored graft survival. Transplant type continues to be an important driver of outcome.Retransplant outcomes have improved over time, yet increased rejection and immunologic graft loss rates remain associated with pancreas retransplantation. In contrast, risk of technical failure and patient death for primary versus retransplants are similar. Therefore, pancreas retransplantation in highly selected candidates should be considered in experienced centers.

Cells are fundamental functional units of multicellular organisms, with different cell types playing distinct physiological roles in the body. The recent advent of single cell transcriptional profiling using RNA sequencing is producing “big data”, enabling the identification of novel human cell types at an unprecedented rate. In this review, we summarize recent work characterizing cell types in the human central nervous and immune systems using single cell and single nuclei RNA sequencing, and discuss the implications that these discoveries are having on the representation of cell types in the reference Cell Ontology (CL). We propose a method based on random forest machine learning for identifying sets of necessary and sufficient marker genes that can be used to assemble consistent and reproducible cell type definitions for incorporation into the CL. The representation of defined cell type classes and their relationships in the CL using this strategy will make the cell type classes findable, accessible, interoperable, and reusable (FAIR), allowing the CL to serve as a reference knowledgebase of information about the role that distinct cellular phenotypes play in human health and disease.

Arterial fistulas and pseudoaneurysms are rarely described significant arterial complications associated with pancreas transplantation that sometimes present with herald or catastrophic bleeding. We herein describe our institutional case series with a focus on management and outcomes. Of 2256 pancreas transplants, 24 arterial complications were identified in 23 recipients. Chart review was performed to describe the clinical characteristics, treatments and outcomes of the complications (pseudoaneurysm, arterial enteric/cystic/ureteric fistula, or arteriovenous fistula). Of these 23 patients, 57% had a failed allograft at the time of the complication. Nine patients underwent primary surgical repair of 10 complications, 13 were treated by endovascular methods, and one patient by medical management. In total, 3 embolized patients rebled, 2 of which had failed allografts prior to treatment. Of those with graft function that were treated by embolization alone, all retained graft function. Diagnosis of arterial complications requires a high degree of suspicion and should involve early systemic angiography to evaluate the pancreatic vasculature. Management can be endovascular or surgical and should be individualized. We report our center's evolution from a predominantly surgical to endovascular approach as a definitive vs stabilizing therapy, with selective coiling mostly reserved for well-defined peripheral lesions in patients with a functioning allograft. This article is protected by copyright. All rights reserved.

Describe the surgical technique, complications, and long-term outcomes of total pancreatectomy and islet autotransplantation (TP-IAT) in a large series of pediatric patients.Surgical management of childhood pancreatitis is not clear; partial resection or drainage procedures often provide transient pain relief, but long-term recurrence is common due to the diffuse involvement of the pancreas. Total pancreatectomy (TP) removes the source of the pain, whereas islet autotransplantation (IAT) potentially can prevent or minimize TP-related diabetes.Retrospective review of 75 children undergoing TP-IAT for chronic pancreatitis who had failed medical, endoscopic, or surgical treatment between 1989 and 2012.Pancreatitis pain and the severity of pain statistically improved in 90% of patients after TP-IAT (P0.001). The relief from narcotics was sustained. Of the 75 patients undergoing TP-IAT, 31 (41.3%) achieved insulin independence. Younger age (P = 0.032), lack of prior Puestow procedure (P = 0.018), lower body surface area (P = 0.048), higher islet equivalents (IEQ) per kilogram body weight (P = 0.001), and total IEQ (100,000) (P = 0.004) were associated with insulin independence. By multivariate analysis, 3 factors were associated with insulin independence after TP-IAT: (1) male sex, (2) lower body surface area, and (3) higher total IEQ per kilogram body weight. Total IEQ (100,000) was the single factor most strongly associated with insulin independence (odds ratio = 2.62; P0.001).Total pancreatectomy and islet autotransplantation provides sustained pain relief and improved quality of life. The β-cell function is dependent on islet yield. Total pancreatectomy and islet autotransplantation is an effective therapy for children with painful pancreatitis that failed medical and/or endoscopic management.

Islet autotransplant (IAT) may ameliorate postsurgical diabetes following total pancreatectomy (TP), but outcomes are dependent upon islet mass, which is unknown prior to pancreatectomy. We evaluated whether preoperative metabolic testing could predict islet isolation outcomes and thus improve assessment of TPIAT candidates. We examined the relationship between measures from frequent sample IV glucose tolerance tests (FSIVGTT) and mixed meal tolerance tests (MMTT) and islet mass in 60 adult patients, with multivariate logistic regression modeling to identify predictors of islet mass ≥2500 IEQ/kg. The acute C-peptide response to glucose (ACRglu) and disposition index from FSIVGTT correlated modestly with the islet equivalents per kilogram body weight (IEQ/kg). Fasting and MMTT glucose levels and HbA1c correlated inversely with IEQ/kg (r values -0.33 to -0.40, p ≤ 0.05). In multivariate logistic regression modeling, normal fasting glucose (

Technical failure (TF) continues to have a significant impact on the success of pancreas transplantation. We assessed risk factors for TF in 1115 pancreas transplants performed at a single center between 1998 and 2011. The overall TF rate was 10.2%. In a multivariable model, donor BMI ≥ 30 (HR 1.87, p = 0.005), donor Cr ≥ 2.5 (HR 3.16, p = 0.007), donor age >50 (HR 1.73, p = 0.082) and preservation time >20 h (HR 2.17, p < 0.001) were associated with TF. Bladder drainage of exocrine secretions was protective (HR 0.54, p = 0.002). We incorporated these factors in a Composite Risk Model. In this model the presence of one risk factor did not significantly increase risk of TF (HR 1.35, p = 0.346). Two risk factors in combination increased risk greater than threefold (HR 3.65, p < 0.001) and three risk factors increased risk greater than sevenfold (HR 7.66, p =

Total pancreatectomy with islet autotransplantation (TPIAT) is increasingly performed with remote islet cell processing and preparation, i.e., with islet cell isolation performed remotely from the primary surgical site at an appropriately equipped islet isolation facility. We aimed to determine whether TPIAT using remote islet isolation results in comparable long-term glycemic outcomes compared with TPIAT performed with standard local isolation.We performed a retrospective cohort study of adult patients who underwent TPIAT at three tertiary care centers from 2010 to 2013. Two centers performed remote isolation and one performed local isolation. Explanted pancreata in the remote cohort were transported ∼130 miles to and from islet isolation facilities. The primary outcome was insulin independence 1 year following transplant.Baseline characteristics were similar between groups except the remote cohort had higher preoperative hemoglobin A1c (HbA1c; 5.43 vs. 5.25, P=0.02) and there were more females in the local cohort (58% vs. 76%, P=0.049). At 1 year, 27% of remote and 32% of local patients were insulin independent (P=0.48). Remote patients experienced a greater drop in fasting c-peptide (-1.66 vs. -0.64, P=0.006) and a greater rise in HbA1c (1.65 vs. 0.99, P=0.014) at 1-year follow-up. A preoperative c-peptide2.7 (odds ratio (OR) 4.4, 95% confidence interval (CI) 1.6-14.3) and3,000 islet equivalents/kg (OR 11.0, 95% CI 3.2-37.3) were associated with one-year insulin independence in the local group.At 1 year after TPIAT, patients undergoing remote surgery have equivalent rates of long-term insulin independence compared with patients undergoing TPIAT locally, but metabolic control is superior with local isolation.

High throughput imaging is now available to many groups and it is possible to generate a large quantity of high quality images quickly. Managing this data, consistently annotating it, or making it available to the community are all challenges that come with these methods. PhenoImageShare provides an ontology-enabled lightweight image data query, annotation service and a single point of access backed by a Solr server for programmatic access to an integrated image collection enabling improved community access. PhenoImageShare also provides an easy to use online image annotation tool with functionality to draw regions of interest on images and to annotate them with terms from an autosuggest-enabled ontology-lookup widget. The provenance of each image, and annotation, is kept and links to original resources are provided. The semantic and intuitive search interface is species and imaging technology neutral. PhenoImageShare now provides access to annotation for over 100,000 images for 2 species. The PhenoImageShare platform provides underlying infrastructure for both programmatic access and user-facing tools for biologists enabling the query and annotation of federated images. PhenoImageShare is accessible online at http://www.phenoimageshare.org .

Rapid discontinuation of prednisone after kidney transplantation potentially allows for minimization of steroid-related side effects. Although intermediate-term data with rapid discontinuation of prednisone have been promising, concern still exists regarding long-term outcomes. The 10-year experience is reported herein.Between October 1, 1999 and December 31, 2010, 1241 adult primary kidney transplants (791 living donor and 450 deceased donor) were performed using a protocol in which prednisone is discontinued after postoperative day 5. The 10-year actuarial recipient and graft survival rates and prednisone-related side effects were studied.Ten-year actuarial patient survival was 71% for living donor transplants and 62% for deceased donor transplants; 10-year graft survival was 61% for living donor transplants and 51% for deceased donor transplants, and was comparable to 10-year Scientific Registry of Transplant Recipients national data. Ten-year death-censored graft survival was 79% for living donor transplants and 80% for deceased donor transplants. Ten-year acute rejection rates were 25% for deceased donor transplants and 31% for living donor transplants; 10-year chronic rejection (interstitial fibrosis/tubular atrophy) rates were 39% for deceased donor transplants and 47% for living donor transplants. For nondiabetic recipients of living donor or deceased donor allografts, the incidence of new-onset diabetes was significantly lower than in historical controls on prednisone (P0.001). We also found significantly reduced rates of cataracts, avascular necrosis, and cytomegalovirus infection in some subgroups.Prednisone-related side effects can be minimized in a protocol incorporating rapid discontinuation of prednisone for maintenance immunosuppression. Ten-year patient and graft outcomes remain acceptable.

Purpose of review More than 160 living donor segmental pancreas/islet transplants have been done since the first in 1977, more than three-quarters at one institution. We review this three-decade experience to project future application. Initially, living donor pancreas transplants were done because the results with deceased donors were poor. As the results with deceased donors improved, the incentive to do living donor transplants declined but never disappeared. A living donor simultaneous pancreas-kidney transplant in a uremic diabetic can correct diabetes and pre-empt dialysis with one operation, obviating the high mortality rate of waiting for a deceased donor. Solitary pancreas transplant candidates with preformed human leukocyte antigen antibodies but a negative cross match to a living donor volunteer also benefit. Recent findings The technical failure rate of living donor pancreas transplants was high in the initial cases (>1/3), nearly double that for deceased donors, but has since declined to nearly zero. Living donor segmental pancreatectomy has little surgical morbidity (currently done laparoscopically) with only a small risk for diabetes by strict selection criteria. living donor and deceased donor graft survival rates are equivalent. Islet allografts have been done from three living donors, the last one successfully, showing the potential for further application. Summary The incentives for living donor transplants are to eliminate long-wait times for a deceased donor organ and to improve outcomes. With both the incentive is high, but either by itself is sufficient. As the number of pancreas transplant candidates increase, so will wait times for a deceased donor organ. For this reason, living donor pancreas/islet transplant volume will likely increase in the years to come.

Pancreas transplantation provides the only proven method to restore long-term normoglycemia in patients with insulin-dependent diabetes mellitus. Although many studies describe the very important risk factors for short-term survival of a pancreas transplant, there is not a lot of information available about factors that distinguish short-term from long-term graft function.The analysis of 18,159 pancreas transplants from the International Pancreas Transplant Registry, performed from 25 July 1978 to 31 December 2005, showed an improvement not only in short-term but also in long-term graft function. Most recent 5-year, 10-year and 20-year graft function for transplants with the appropriate follow-up time showed 80, 68 and 45%, respectively, for simultaneous pancreas/kidney transplants; 62, 46 and 16%, respectively, for pancreas after kidney; and 59, 39 and 12%, respectively, for pancreas transplants alone. Important factors influencing long-term function were factors that described the quality of the deceased donor. Pancreas transplants in younger or African-American recipients showed a higher risk of graft failure. Anti-T-cell induction therapy had a significant impact on long-term survival in solitary transplants.With a careful donor selection, not only short-term but also long-term pancreas graft function and, therefore, good metabolic control can be achieved for the diabetic patient.

People around the world are looking to marine ecosystems to provide additional benefits to society. As they consider expanding current uses and investing in new ones, new management approaches are needed that will sustain the delivery of the diverse benefits that people want and need. An ecosystem services framework provides metrics for assessing the quantity, quality, and value of benefits obtained from different portfolios of uses. Such a framework has been developed for assessments on land, and is now being developed for application to marine ecosystems. Here, we present marine Integrated Valuation of Ecosystem Services and Tradeoffs (InVEST), a new tool to assess (i.e., map, model, and value) multiple services provided by marine ecosystems. It allows one to estimate changes in a suite of services under different management scenarios and to investigate trade-offs among the scenarios, including implications of drivers like climate. We describe key inputs and outputs of each of the component ecosystem se...

FlyBase (http://flybase.org) is the leading database and web portal for genetic and genomic information on the fruit fly Drosophila melanogaster and related fly species. Whether you use the fruit fly as an experimental system or want to apply Drosophila biological knowledge to another field of study, FlyBase can help you successfully navigate the wealth of available Drosophila data. Here, we review the FlyBase web site with novice and less-experienced users of FlyBase in mind and point out recent developments stemming from the availability of genome-wide data from the modENCODE project. The first section of this paper explains the organization of the web site and describes the report pages available on FlyBase, focusing on the most popular, the Gene Report. The next section introduces some of the search tools available on FlyBase, in particular, our heavily used and recently redesigned search tool QuickSearch, found on the FlyBase homepage. The final section concerns genomic data, including recent modENCODE (http://www.modencode.org) data, available through our Genome Browser, GBrowse.

Total pancreatectomy (TP) and islet autotransplant (IAT) have been used to treat patients with painful chronic pancreatitis. Initial studies indicated that most patients experienced significant pain relief, but there were few validated measures of quality of life. We investigated whether health-related quality of life improved among pediatric patients undergoing TP/IAT.Nineteen consecutive children (aged 5-18 years) undergoing TP/IAT from December 2006 to December 2009 at the University of Minnesota completed the Medical Outcomes Study 36-item Short Form (SF-36) health questionnaire before and after surgery. Insulin requirements were recorded.Before TP/IAT, patients had below average health-related quality of life, based on data from the Medical Outcomes Study SF-36; they had a mean physical component summary (PCS) score of 30 and mental component summary (MCS) score of 34 (2 and 1.5 standard deviations, respectively, below the mean for the US population). By 1 year after surgery, PCS and MCS scores improved to 50 and 46, respectively (global effect, PCS P.001, MCS P = .06). Mean scores improved for all 8 component subscales. More than 60% of IAT recipients were insulin independent or required minimal insulin. Patients with prior surgical drainage procedures (Puestow) had lower yields of islets (P = .01) and greater incidence of insulin dependence (P = .04).Quality of life (physical and emotional components) significantly improve after TP/IAT in subsets of pediatric patients with severe chronic pancreatitis. Minimal or no insulin was required for most patients, although islet yield was reduced in patients with previous surgical drainage operations.

Islet autotransplantation (IAT) is performed at the time of total pancreatectomy (TP) to prevent or minimize post-surgical diabetes. Corticosteroids induce insulin resistance and present a risk to islet autografts, through glucotoxicity and increased metabolic demand on a marginal islet mass. We present four IAT recipients treated with oral or injected corticosteroids after transplant for medical conditions unrelated to chronic pancreatitis or TPIAT. Hyperglycemia or insulin resistance was evident in all four patients, including reversion to long-term insulin therapy in two patients. One patient receiving corticosteroid injections had a transient increase in hemoglobin A1c (+0.6% above baseline), and one patient given a one time dose of oral dexamethasone exhibited hyperglycemia despite high insulin (>200 mU/L) and C-peptide (15.3 ng/mL) production on an oral glucose tolerance test. IAT recipients have insufficient islet mass to compensate for the insulin resistance induced by corticosteroids. Caution should be given to using these agents in IAT recipients. When corticosteroids are medically necessary, insulin therapy should be administered temporarily to compensate for the increased metabolic demand and minimize long-term risks on the islet graft.

Previously, recurrence of insulin-dependent diabetes mellitus after pancreas transplants was only sporadically reported. Newer data, however, indicate recurrence rates as high as 5%. After identical-twin pancreas transplants, diabetes recurs in the absence of immunosuppressive therapy - strong evidence that it is an autoimmune disease. After deceased donor pancreas transplants, immunologic markers (autoantibodies, autoreactive T cells) herald recurrence. Selective destruction of β cells, still relatively uncommon, is not restricted to MHC compatibility. The development of diabetes in living pancreas donors is rare; it can be largely avoided by meticulous metabolic evaluation before donation and prevention of obesity after donation.

Chylous ascites as a result of laparoscopic donor nephrectomy (LDN) is a rare complication which carries significant morbidity, including severe protein-calorie malnutrition and an associated immunocompromised state. We report a patient who underwent hand-assisted left LDN and subsequently developed chylous ascites. He failed conservative therapy including low-fat diet with medium-chain triglycerides (LFD/MCT) and oral protein supplementation as well as strict NPO status with intravenous (IV) total parenteral nutrition (TPN) and subcutaneous (SQ) somatostatin analogue administration. Laparoscopic re-exploration and intracorporeal suture ligation and clipping of leaking lymph channels successfully sealed the chyle leak. We review the literature to date including diagnosis, incidence, management options, psychosocial aspects and clinical outcomes of chylous ascites after LDN.

OBJECTIVES: The probability of insulin independence after intraportal islet autotransplantation (IAT) for chronic pancreatitis (CP) treated by total pancreatectomy (TP) relates to the number of islets isolated from the excised pancreas. Our goal was to correlate the islet yield with the histopathologic findings and the clinical parameters in pediatric (age

Bellin MD, Blondet JJ, Beilman GJ, Dunn TyB, Balamurugan AN, Thomas W, Sutherland DER, Moran A. Predicting islet yield in pediatric patients undergoing pancreatectomy and autoislet transplantation for chronic pancreatitis. Background/Objective: Chronic pancreatitis (CP) in children is associated with significant morbidity and can lead to narcotic dependence. Total pancreatectomy (TP) may be indicated in refractory CP to relieve pain; simultaneous islet autotransplant (IAT) may prevent postsurgical diabetes. About half of pediatric patients are insulin independent 1 yr after IAT. Insulin independence correlates best with the number of islets available for transplantation (islet yield). Currently there is no known method to predict islet yield in a given patient. We assessed the ability of preoperative metabolic tests to predict islet yields in 10 children undergoing TP/IAT. Design/Methods: Hemoglobin A1c (HbA1c) and mixed meal tolerance tests (MMTT) were obtained prior to surgery in 10 patients age ≤ 18 yr. Fasting glucose, C-peptide, and creatinine were used to calculate the C-peptide to glucose* creatinine ratio (CPGCR). C-peptide peak and area under the curve (AUC) were determined from 2 h MMTT. Linear regressions were performed to predict islet yield from baseline test results. Results: Islet yield ranged from 7000 to 434 000 islet equivalents (IE) (mean 222 452 ± 148 697 IE). Islet yield was well predicted from body weight and fasting plasma glucose (R 2 = 57%, adjusted for overfitting by bootstrap). Islet yield was positively associated with CPGCR, peak C-peptide, and AUC C-peptide and negatively associated with HbA1c. Conclusions: Pilot data from 10 pediatric patients suggest that simple preoperative measurement of fasting plasma glucose may give a useful prediction of islet yield. Islet yield correlates with HbA1c and C-peptide levels. This information allows individual candidates to weigh the specific risk of becoming diabetic against the benefit of pain relief should they undergo TP-IAT.

The advantages of living donor pancreas transplants for the recipient include good HLA matching, lower immunologic risk, less immunosuppression, lower risk of infection and of posttransplant malignancies, and shorter pancreas graft preservation time. In 2008, a total of 155 segmental pancreas transplants using living donors were reported to the International Pancreas Transplant Registry from six countries. Pancreas living donors need to undergo a thorough pretransplant endocrinologic workup in order to minimize the risk of metabolic complications. The pretransplant workup has evolved over time, after initial reports showed that up to 25% of living donors had elevated hemoglobin A(1c) levels after donation. Avoiding obesity after donation diminishes the risk of long-term metabolic complications. The risk of surgical complications for the donor (such as pancreatitis, pancreatic leak or fistula, pancreatic abscess, and pancreatic pseudocyst) is less than 5%. If both the donor and recipient operations are technically successful, the long-term graft survival rate is significantly higher for living (versus deceased) donor pancreas transplant recipients. Future long-term studies of metabolic function in living donors are warranted to determine whether living donor pancreas transplants can safely be applied more widely and whether living donors can be used for islet transplants.

Background Immunotherapy with Complete Freund's adjuvant (CFA) is effective in ameliorating autoimmunity in diabetic nonobese diabetic (NOD) mice. We investigated whether CFA treatment up-regulates CD4+CD25+Foxp3+ regulatory T cells and increases transforming growth factor (TGF)-beta1 production in diabetic NOD mice. Methods New-onset diabetic NOD mice were treated with CFA and exendin-4, a potent analog of glucagon-like peptide-1. Reversal of diabetes was determined by monitoring blood glucose level. Ameliorating autoimmunity through immunoregulation was assessed by adoptive transfer. Regulatory T cells in the peripheral blood, spleen, thymus, and pancreatic nodes were measured. TGF-beta1 in plasma and the insulin content in the pancreas were also measured. Immunostainings for insulin and BrdU were performed. Results New-onset diabetes could be reversed in 38% of NOD mice treated with CFA alone and in 86% of NOD mice treated with both CFA and exendin-4. Diabetes adoptive transfer by splenocytes from CFA-treated NOD mice was delayed. The percentage of CD4+CD25+Foxp3+ regulatory T cells in the pancreatic lymph nodes of CFA-treated NOD mice was significantly increased at 1, 5, and 15 to 17 weeks after treatment. TGF-beta1 in the plasma of CFA-treated NOD mice was also significantly increased. Combining CFA with exendin-4 treatment significantly increased the insulin content and the numbers of insulin and BrdU double-labeled beta cells in the islets. Conclusions Our results demonstrated that CFA treatment ameliorates autoimmunity in diabetic NOD mice by up-regulating CD4=CD25+Foxp3+ regulatory T cells and increasing TGF-beta1 production. Exendin-4 enhanced the effect of CFA on reversing diabetes in NOD mice by stimulating beta-cell replication.

The ultimate goal of clinical transplantation is for the recipients to achieve long-term survival, with continuing graft function, that is equivalent to that of the age-matched general population. We studied subsequent outcome in kidney transplant recipients with 10 years of graft function. In all, 2202 kidney transplant recipients survived with graft function10 years. For 10-year survivors, the actuarial 25-year patient survival rate for primary transplant living donor (LD) recipients was 57%; graft survival, 43%. For primary transplant deceased donor (DD) recipients, the actuarial 25-year patient survival rate was 39%; graft survival, 27%. The two major causes of late graft loss were death (with graft function) and chronic allograft nephropathy (tubular atrophy and interstitial fibrosis). The two major causes of death with function were cardiovascular disease (CVD) and malignancy. For nondiabetic recipients, the mean age at death with function from CVD was 54 +/- 13 years; for diabetic recipients, 53 +/- 7 years. By 20 years posttransplant, morbidity was common:40% recipients had skin cancer (mean age for nondiabetic recipients, 53 +/- 13 years; for diabetics, 49 +/- 8 years),10% had non-skin cancer (mean age for nondiabetic recipients, 53 +/- 16 years; for diabetics, 46 +/- 9 years), and30% had CVD (mean age for nondiabetic recipients, 53 +/- 15 years; for diabetics, 47 +/- 9 years). We conclude that long-term transplant recipients have a high rate of morbidity and early mortality. As short-term results have improved, more focus is needed on long-term outcome.

We examined a group of SPK recipients that had early (

Background A total pancreatectomy is the last resort in the treatment of chronic pancreatitis because it results in complete endocrine and exocrine pancreatic insufficiency. More than 50% of total pancreatectomy patients experience severe glucose control problems, which cause up to 50% of late deaths. Study Design Between June 1, 1986, and May 15, 2007, we performed 26 pancreas allotransplants (18 primary, 8 retransplants) in 18 patients who had previously undergone a total pancreatectomy for chronic pancreatitis. All patients had a history of labile diabetes mellitus with hypoglycemic unawareness; secondary diabetic complications developed in 12. The median time interval from the total pancreatectomy to the pancreas allotransplant was 5 years (range 9 months to 22 years). Of the 26 transplants, 6 were performed in the cyclosporine (CSA) era, 15 in the tacrolimus (TAC) era, and 5 in the calcineurin inhibitor (CNI)-free era. Results Patient survival rates at 1 and 3 years in both the CSA and TAC eras were 100% and 100%; in the CNI-free era, at 1 year, the survival rate was 40%. Pancreas graft survival rates in the CSA era were 67% and 50% at 1 and 3 years, respectively; in the TAC era, 73% and 51%, respectively; and in the CNI-free era, at 1 year, 40% (p=0.13). The mean number of rejection episodes in the CSA era was 2.1; in the TAC era, 1.4; and in the CNI-free era, 0.6. Conclusions Our series of pancreas allotransplants in patients with a previous total pancreatectomy for chronic pancreatitis showed that pancreas graft survival rates of more than 70% can be achieved with TAC-based immunosuppression; pancreas transplants can successfully treat both endocrine and exocrine insufficiency; and sequential pancreas allotransplants should be considered a treatment option in patients with pancreatectomy-induced brittle diabetes mellitus or with progression of secondary complications of diabetes mellitus.

Background. A pancreas transplant alone (PTA) in a nonuremic patient with brittle diabetes mellitus remains a rare procedure because the tradeoff for insulin independence is lifelong immunosuppression. Methods. Herein we report our results at the University of Minnesota of 513 PTAs from December 17, 1966, through December 31, 2006. Of these recipients, 87% had previously experienced hypoglycemic unawareness and 23% experienced coma and/or seizures. These transplants spanned four immunosuppressive eras: pre-cyclosporine A (pre-CsA) era (16%), CsA era (23%), tacrolimus (TAC) era (47%), and calcineurin-inhibitor (CNI)-free era (14%). Results. The overall patient survival rate at 1 year posttransplant was about 95%; at 5 years, it was 90%. The pancreas graft survival rate at 1 year increased significantly from the pre-CsA era (31%) to the TAC era (75%), thanks to a significant decline in immunologic and technical failures. The CNI-free protocol, because of its high infection and hematologic infection rate, did not further improve outcome. Risk factors for subsequent kidney failure (13% at 5 years posttransplant) were serum creatinine levels > 1.5 mg/dl at the time of the pancreas transplant and recipient age

Background and Objectives Acquired red cell aplasia (RCA) is a rare disorder and can be either idiopathic or associated with certain diseases, pregnancy, or drugs. In exceptionally rare cases, it has been reported to co-exist with other autoimmune cytopenias. We report a high incidence of RCA and autoimmune hemolytic anemia (AIHA) in pancreas transplant recipients on alemtuzumab-based maintenance therapy. Design and Methods Between February 2003 and July 2005, 357 pancreas transplant recipients were treated with immunosuppressive regimens containing the lymphocyte-depleting antibody alemtuzumab, the T-cell activation inhibitor daclizumab, and the anti-metabolite mycophenolate mofetil (MMF). We retrospectively reviewed medical records, blood bank data and bone marrow biopsy specimens of patients with a Transplant Information Services database diagnosis of RCA and AIHA from February 2003 to November 2005. Results Severe RCA, AIHA, and idiopathic thrombocytopenic purpura (ITP) occurred independently or in combination, in 20 out of 357 (5.6%) pancreas transplant recipients, 12 to 24 months following the initiation of the aforementioned immunosuppressive regimens. Severe opportunistic infections developed late in 14/20 (70%) of these patients. Atypical morphologic features, including variable dysgranulopoiesis, variable megakaryocytic hyperplasia with normal or low peripheral platelet counts, and atypical lymphoid aggregates were found in bone marrow trephine sections of 11 patients in whom the diagnosis of RCA was made. Interpretation and Conclusions We hypothesize that the combination of alemtuzumab, daclizumab and MMF can result in immune dysregulation thereby permitting autoantibody formation. Because the use of these three immune suppressants is becoming increasingly common, it is important to recognize the severe hematologic complications that can arise.