Non-invasive in vivo determination of viable islet graft volume by 111In-exendin-3.
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ABSTRACT:
SUBMITTER: Eter WA
PROVIDER: S-EPMC5543140 | biostudies-other | 2017 Aug
REPOSITORIES: biostudies-other
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Project description:Islet transplantation is a novel promising strategy to cure type 1 diabetes. However, the long-term outcome is still poor, because both function and survival of the transplant decline over-time. Non-invasive imaging methods have the potential to enable monitoring of islet survival after transplantation and the effects of immunosuppressive drugs on transplantation outcome. (111)In-labeled exendin-3 is a promising tracer to visualize native and transplanted islets by SPECT (Single Photon Emission Computed Tomography). In the present study, we hypothesized that islet microvasculature plays an important role determining the uptake of exendin-3 in islets when monitoring transplant survival. We observed (111)In-exendin-3 accumulation in the transplant as early as three days after transplantation and an increase in the uptake up to three weeks post-transplantation. Islet-revascularization correlated with the increase in (111)In-exendin-3 uptake, whereas fully re-established islet vasculature coincided with a stabilized uptake of the radiotracer in the transplant. Here, we demonstrate the importance of islet vasculature for in vivo delivery of radiotracers to transplanted islets and we demonstrate that optimal and stable uptake of exendin four weeks after transplantation opens the possibility for long-term monitoring of islet survival by SPECT imaging.
| S-EPMC4614800 | biostudies-other
Project description:Islet transplantation has become a viable clinical treatment, but is still compromised by long-term graft failure. Exendin-4, a glucagon-like peptide 1 receptor agonist, has in clinical studies been shown to improve insulin secretion in islet transplanted patients. However, little is known about the effect of exendin-4 on other metabolic parameters. We therefore aimed to determine what influence exendin-4 would have on revascularized minimal human islet grafts in a state of graft failure in terms of glucose metabolism, body weight, lipid levels and graft survival. Introducing the bilateral, subcapsular islet transplantation model, we first transplanted diabetic mice with a murine graft under the left kidney capsule sufficient to restore normoglycemia. After a convalescent period, we performed a second transplantation under the right kidney capsule with a minimal human islet graft and allowed for a second recovery. We then performed a left-sided nephrectomy, and immediately started treatment with exendin-4 with a low (20?g/kg/day) or high (200?g/kg/day) dose, or saline subcutaneously twice daily for 15 days. Blood was sampled, blood glucose and body weight monitored. The transplanted human islet grafts were collected at study end point and analyzed. We found that exendin-4 exerts its effect on failing human islet grafts in a bell-shaped dose-response curve. Both doses of exendin-4 equally and significantly reduced blood glucose. Glucagon-like peptide 1 (GLP-1), C-peptide and pro-insulin were conversely increased. In the course of the treatment, body weight and cholesterol levels were not affected. However, immunohistochemistry revealed an increase in beta cell nuclei count and reduced TUNEL staining only in the group treated with a low dose of exendin-4 compared to the high dose and control. Collectively, these results suggest that exendin-4 has a potential rescue effect on failing, revascularized human islets in terms of lowering blood glucose, maintaining beta cell numbers, and improving metabolic parameters during hyperglycemic stress.
| S-EPMC4368803 | biostudies-literature
Project description:PurposeNoninvasive beta cell mass (BCM) quantification is a crucial tool to understand diabetes development and progression. [(111)In]exendin is a promising agent for in vivo beta cell imaging, but tracer testing has been hampered by the lack of well-defined rodent models.ProceduresBiodistribution and pancreatic uptake of [(111)In]exendin were compared in rats and mice. In selected models, the amount of [(111)In]exendin accumulation in the pancreas and other organs was determined using a model of alloxan-induced beta cell loss. GLP-1R expression levels were analyzed by RT-PCR and immunohistochemistry.ResultsNamely Brown Norway rats showed beta-cell-specific tracer accumulation and favorable pancreas-to-background ratios for noninvasive BCM determination. Mice displayed receptor-mediated [(111)In]exendin uptake in endocrine and exocrine pancreas, in spite of very low GLP-1R expression in exocrine tissue.ConclusionsRats display better characteristics for in vivo BCM determination than mice and are suggested as a more adequate model for humans.
| S-EPMC5010585 | biostudies-literature
Project description:OBJECTIVE To investigate the influence of primary graft function (PGF) on graft survival and metabolic control after islet transplantation with the Edmonton protocol. RESEARCH DESIGN AND METHODS A total of 14 consecutive patients with brittle type 1 diabetes were enrolled in this phase 2 study and received median 12,479 islet equivalents per kilogram of body weight (interquartile range 11,072-15,755) in two or three sequential infusions within 67 days (44-95). PGF was estimated 1 month after the last infusion by the beta-score, a previously validated index (range 0-8) based on insulin or oral treatment requirements, plasma C-peptide, blood glucose, and A1C. Primary outcome was graft survival, defined as insulin independence with A1C < or =6.5%. RESULTS All patients gained insulin independence within 12 days (6-23) after the last infusion. PGF was optimal (beta-score > or =7) in nine patients and suboptimal (beta-score < or =6) in five. At last follow-up, 3.3 years (2.8-4.0) after islet transplantation, eight patients (57%) remained insulin independent with A1C < or =6.5%, including seven patients with optimal PGF (78%) and one with suboptimal PGF (20%) (P = 0.01, log-rank test). Graft survival was not significantly influenced by HLA mismatches or by preexisting islet autoantibodies. A1C, mean glucose, glucose variability (assessed with continuous glucose monitoring system), and glucose tolerance (using an oral glucose tolerance test) were markedly improved when compared with baseline values and were significantly lower in patients with optimal PGF than in those with suboptimal PGF. CONCLUSIONS Optimal PGF was associated with prolonged graft survival and better metabolic control after islet transplantation. This early outcome may represent a valuable end point in future clinical trials.
| S-EPMC2713623 | biostudies-literature
Project description:Transplant of hydrogel-encapsulated allogeneic islets has been explored to reduce or eliminate the need for chronic systemic immunosuppression by creating a physical barrier that prevents direct antigen presentation. Although successful in rodents, translation of alginate microencapsulation to large animals and humans has been hindered by large capsule sizes (≥500 μm diameter) that result in suboptimal nutrient diffusion in the intraperitoneal space. We developed a microfluidic encapsulation system that generates synthetic poly(ethylene glycol)-based microgels with smaller diameters (310 ± 14 μm) that improve encapsulated islet insulin responsiveness over alginate capsules and allow transplant within vascularized tissue spaces, thereby reducing islet mass requirements and graft volumes. By delivering poly(ethylene glycol)-encapsulated islets to an isolated, retrievable, and highly vascularized site via a vasculogenic delivery vehicle, we demonstrate that a single pancreatic donor syngeneic islet mass exhibits improved long-term function over conventional alginate capsules and close integration with transplant site vasculature. In vivo tracking of bioluminescent allogeneic encapsulated islets in an autoimmune type 1 diabetes murine model showed enhanced cell survival over unencapsulated islets in the absence of chronic systemic immunosuppression. This method demonstrates a translatable alternative to intraperitoneal encapsulated islet transplant.
| S-EPMC6487074 | biostudies-literature
Project description:BackgroundCardiac output (CO) is a major diagnostic and prognostic factor in pre-capillary pulmonary hypertension (PH). Reference methods for CO determination, like thermodilution (TD), require invasive procedures and allow only steady-state measurements. The Modelflow (MF) method is an appealing technique for this purpose as it allows non-invasive and beat-by-beat determination of CO.MethodsWe aimed to compare CO values obtained simultaneously from non-invasive pulse wave analysis by MF (COMF) and by TD (COTD) to determine its precision and accuracy in pre-capillary PH. The study was performed on 50 patients with pulmonary arterial hypertension (PAH) or chronic thrombo-embolic PH (CTEPH). CO was determined at rest in all patients (n = 50) and during nitric oxide vasoreactivity test, fluid challenge or exercise (n = 48).ResultsBaseline COMF and COTD were 6.18 ± 1.95 and 5.46 ± 1.95 L·min-1, respectively. Accuracy and precision were 0.72 and 1.04 L·min-1, respectively. Limits of agreement (LoA) ranged from -1.32 to 2.76 L·min-1. Percentage error (PE) was ±35.7%. Overall sensitivity and specificity of COMF for directional change were 95.2% and 82.4%, (n = 48) and 93.3% and 100% for directional changes during exercise (n = 16), respectively. After application of a correction factor (1.17 ± 0.25), neither proportional nor fixed bias was found for subsequent CO determination (n = 48). Accuracy was -0.03 L·min-1 and precision 0.61 L·min-1. LoA ranged from -1.23 to 1.17 L·min-1 and PE was ±19.8%.ConclusionsAfter correction against a reference method, MF is precise and accurate enough to determine absolute values and beat-by-beat relative changes of CO in pre-capillary PH.
| S-EPMC4520479 | biostudies-literature
Project description:Advances in the field of stem cell technology have stimulated the development and increased use of allogenic bone grafts containing live mesenchymal stem cells (MSCs), also known as cellular bone matrices (CBMs). It is estimated that CBMs comprise greater than 17% of all bone grafts and bone graft substitutes used.To critically evaluate CBMs, specifically their technical specifications, existing published data supporting their use, US Food and Drug Administration (FDA) regulation, cost, potential pitfalls, and other aspects pertaining to their use.Areview of literature.A series of Ovid, Medline, and Pubmed-National Library of Medicine/National Institutes of Health (www.ncbi.nlm.nih.gov) searches were performed. Only articles in English journals or published with English language translations were included. Level of evidence of the selected articles was assessed. Specific technical information on each CBM was obtained by direct communication from the companies marketing the individual products.Five different CBMs are currently available for use in spinal fusion surgery. There is a wide variation between the products with regard to the average donor age at harvest, total cellular concentration, percentage of MSCs, shelf life, and cell viability after defrosting. Three retrospective studies evaluating CBMs and fusion have shown fusion rates ranging from 90.2% to 92.3%, and multiple industry-sponsored trials are underway. No independent studies evaluating spinal fusion rates with the use of CBMs exist. All the commercially available CBMs claim to meet the FDA criteria under Section 361, 21 CFR Part 1271, and are not undergoing FDA premarket review. The CBMs claim to provide viable MSCs and are offered at a premium cost. Numerous challenges exist in regard to MSCs' survival, function, osteoblastic potential, and cytokine production once implanted into the intended host.Cellular bone matrices may be a promising bone augmentation technology in spinal fusion surgery. Although CBMs appear to be safe for use as bone graft substitutes, their efficacy in spinal fusion surgery remains highly inconclusive. Large, nonindustry sponsored studies evaluating the efficacy of CBMs are required. Without results from such studies, surgeons must be made aware of the potential pitfalls of CBMs in spinal fusion surgery. With the currently available data, there is insufficient evidence to support the use of CBMs as bone graft substitutes in spinal fusion surgery.
| S-EPMC4402977 | biostudies-other
Project description:Non-invasive prenatal testing (NIPT) is accurate for fetal sex determination in singleton pregnancies, but its accuracy is not well established in twin pregnancies. Here, we present an accurate sex prediction model to discriminate fetal sex in both dichorionic diamniotic (DCDA) and monochorionic diamniotic/monochorionic monoamniotic (MCDA/MCMA) twin pregnancies. A retrospective analysis was performed using a total of 198 twin pregnancies with documented sex. The prediction was based on a multinomial logistic regression using the normalized frequency of X and Y chromosomes, and fetal fraction estimation. A second-step regression analysis was applied when one or both twins were predicted to be male. The model determines fetal sex with 100% sensitivity and specificity when both twins are female, and with 98% sensitivity and 95% specificity when a male is present. Since sex determination can be clinically important, implementing fetal sex determination in twins will improve overall twin pregnancies management.
| S-EPMC6609680 | biostudies-other
Project description:IntroductionExperimental work provides insight into potential lung protective strategies. The objective of this study was to evaluate markers of ventilator-induced lung injury after two different ventilation approaches: (1) a "conventional" lung-protective strategy (volume control (VC) with low tidal volume, positive end-expiratory pressure (PEEP) and paralysis), (2) a physiological approach with spontaneous breathing, permitting synchrony, variability and a liberated airway. For this, we used non-invasive Neurally Adjusted Ventilatory Assist (NIV-NAVA), with the hypothesis that liberation of upper airways and the ventilator's integration with lung protective reflexes would be equally lung protective.MethodsIn this controlled and randomized in vivo laboratory study, 25 adult White New Zealand rabbits were studied, including five non-ventilated control animals. The twenty animals with aspiration-induced lung injury were randomized to ventilation with either VC (6 mL/kg, PEEP 5 cm H2O, and paralysis) or NIV-NAVA for six hours (PEEP?=?zero because of leaks). Markers of lung function, lung injury, vital signs and ventilator parameters were assessed.ResultsAt the end of six hours of ventilation (n?=?20), there were no significant differences between VC and NIV-NAVA for vital signs, PaO2/FiO2 ratio, lung wet-to-dry ratio and broncho-alveolar Interleukin 8 (Il-8). Plasma IL-8 was higher in VC (P <0.05). Lung injury score was lower for NIV-NAVA (P?=?0.03). Dynamic lung compliance recovered after six hours in NIV-NAVA but not in VC (P <0.05). During VC, peak pressures increased from 9.2?±?2.4 cm H2O (hour 1) to 12.3?±?12.3 cm H2O (hour 6) (P <0.05). During NIV-NAVA, the tracheal end-expiratory pressure was similar to the end-expiratory pressure during VC. Two animals regurgitated during NIV-NAVA, without clinical consequences, and survived the protocol.ConclusionsIn experimental acute lung injury, NIV-NAVA is as lung-protective as VC 6 ml/kg with PEEP.
| S-EPMC4057206 | biostudies-literature
Project description:GLP-1 analogues, such as exendin-4, preserve functional β-cell mass in various model systems and are revolutionising management of type 2 diabetes. Yet, comparatively little is known about effectiveness in the face of severe β-cell depletion. Moreover, direct and sequential effects of exendin-4 on islet-specific gene expression over time in vivo are not well characterised. To address these issues and others, we have examined the time-dependent effects of exendin-4 treatment on β-cell mass regulation alongside accompanying changes in islet gene expression in vivo. Context-dependent actions were assessed by comparing effects on normal islets and also following massive toxigenetic β-cell ablation in pIns-MYCERTAM transgenic mice in vivo. Despite over 90% loss of β-cell mass, exendin-4 treatment normalised blood glucose and insulin levels in hyperglycaemic mice, though benefits rapidly waned on withdrawal of treatment. As exendin-4 did not arrest the decline in β-cell mass or turnover in this study, we could directly isolate effects on function of surviving β-cells. Improved glucose homeostasis was associated with dynamic changes in multiple islet genes and pathways in vivo favouring glucose-stimulated insulin secretion, such as Irs2, Pdx1, Sox4, glucokinase, and glycolysis pathway. Several key growth pathways and epigenetic regulators were also differentially expressed. Thus, even in the face of extensive β-cell loss exendin-4 can markedly improve hyperglycaemia by differential gene expression in surviving islet cells.
2014-04-11 | GSE37936 | GEO