R Alejandro

University of Miami, كورال غيبلز، فلوريدا, Florida, United States

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Publications (287)1020.67 Total impact

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    03/2015; 5(2):103-118. DOI:10.2217/dmt.14.51
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    ABSTRACT: Background: In long-standing type 1 diabetes (T1D), loss of endogenous insulin secretion and glucose dysregulation can lead to severe hypoglycemia and associated complications. Here, we report the serial consistency and the correlation between different scores that characterize glucose dysregulation using self-monitoring of blood glucose (SMBG), in a cohort of T1D individuals being evaluated for transplant eligibility in Clinical Islet Transplantation Consortium trials. Subjects and Methods: In total, 152 C-peptide-negative T1D subjects with at least one severe hypoglycemia episode in the prior year documented SMBG at enrollment and every 6 months until deemed ineligible or transplanted. SMBG was used to calculate the HYPO score, Lability Index (LI), and mean amplitude of glycemic excursion (MAGE). Additionally, a blinded continuous glucose monitoring system (CGMS) was worn for 72 h at enrollment and every 12 months. Results: In this cohort, LI was the most consistent (intraclass correlation coefficient=0.70) over time, followed by the HYPO score (0.51), with MAGE being the least consistent (0.36). Although MAGE and LI were highly correlated with each other, neither correlated with CGMS SD or glucose coefficient of variation (CV). Subjects spent a median of 97 min/day at <54 mg/dL using CGMS. The HYPO score correlated with CGMS time below 54 mg/dL and glucose CV. Conclusions: The HYPO score and LI are more consistent than MAGE in patients with established T1D experiencing severe hypoglycemic events and may be especially useful both for identifying subjects experiencing the greatest difficulty in maintaining glycemic control and for longitudinal assessment of novel interventions.
    Diabetes Technology &amp Therapeutics 01/2015; 17(4). DOI:10.1089/dia.2014.0289 · 2.29 Impact Factor
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    01/2015; 5(1):37-50. DOI:10.2217/dmt.14.50
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    ABSTRACT: The Collaborative Islet Transplant Registry (CITR) collects data on clinical islet isolations and transplants. This retrospective report analyzed 1017 islet isolation procedures performed for 537 recipients of allogeneic clinical islet transplantation in 1999–2010. This study describes changes in donor and islet isolation variables by era and factors associated with quantity and quality of final islet products. Donor body weight and BMI increased significantly over the period (p < 0.001). Islet yield measures have improved with time including islet equivalent (IEQ)/particle ratio and IEQs infused. The average dose of islets infused significantly increased in the era of 2007–2010 when compared to 1999–2002 (445.4 ± 156.8 vs. 421.3 ± 155.4 ×103 IEQ; p < 0.05). Islet purity and total number of β cells significantly improved over the study period (p < 0.01 and <0.05, respectively). Otherwise, the quality of clinical islets has remained consistently very high through this period, and differs substantially from nonclinical islets. In multivariate analysis of all recipient, donor and islet factors, and medical management factors, the only islet product characteristic that correlated with clinical outcomes was total IEQs infused. This analysis shows improvements in both quantity and some quality criteria of clinical islets produced over 1999–2010, and these parallel improvements in clinical outcomes over the same period.
    American Journal of Transplantation 10/2014; 14(11). DOI:10.1111/ajt.12872 · 6.19 Impact Factor
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    ABSTRACT: The effects of glucocorticoid during culture on human islet cells have been controversial. Exendin-4 (EX) enhances the insulin secretion and significantly improves clinical outcomes in islet cell transplantation. In this study, we examined the effects of glucocorticoids and EX on human islet cells during pretransplant culture.
    Pancreas 07/2014; DOI:10.1097/MPA.0000000000000184 · 3.01 Impact Factor
  • Cytotherapy 04/2014; 16(4):S14. DOI:10.1016/j.jcyt.2014.01.034 · 3.10 Impact Factor
  • Transplantation 06/2013; 95(12):e73-e76. DOI:10.1097/TP.0b013e31829468e2 · 3.78 Impact Factor
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    ABSTRACT: to evaluate if there is an association between liver fat accumulation after islet transplantation (ITx) and graft survival.RESEARCH DESIGN AND METHODS: a cohort study was conducted in 34 subjects with type 1 diabetes post-allogeneic ITx. Liver fat content was evaluated by MRI (change in liver signal intensity on in-phase and opposed-phase images). Kaplan-Meier curves and Cox-regression analysis were performed with islet dysfunction duration as the dependent variable and fat liver content as an independent one. P values of <0.05 were significant (SSPS ©18.0 and MedCalc ©12.5).RESULTS: Patients' mean age was 40±8 years (diabetes duration: 31±12 years; male: 41%). Islet survival did not differ in patients without (51 months, 95%CI 40-62 months) or with steatosis (48 months, 95%CI 38-58 months; P=0.55) during islet dysfunction period. Nevertheless, survival curves appear to separate late in the follow-up, and after 40 months steatosis was associated with shorter graft survival (P LogRank=0.049). This association remained (RR 23.5, CI95% 1.1-516.0; P=0.045) after adjustments for possible confounding factors.CONCLUSIONS: In this sample of subjects with type 1 diabetes submitted to ITx, steatosis was not associated with islet failure in the whole cohort. However in subjects with functional islets after 40 months, a shorter graft survival was observed in those with steatosis during islet dysfunction period, even after adjustments to variables known to be associated withislet failure.
    Cell Transplantation 06/2013; 23(10). DOI:10.3727/096368913X668663 · 3.57 Impact Factor
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    ABSTRACT: Objective: We evaluated whether 1,5-anhydroglucitol(1,5-AG) (Glycomark®), a test for measuring post-prandial glucose and glucose variability, could be a tool for assessing short term glycemic control in islet cell transplant (ICT) subjects.Research Design and Methods: Data of 21 subjects with type-1 DM and allogenic islet transplantation, who had concomitant fructosamine, HbA1c, 1,5-AG (n=85 samples) and capillary glucose self-monitoring measurements (n=2979) were analyzed retrospectively at different time points after ICT.Results: A significant negative association was observed between 1,5-AG and HbA1c (p=0.02), but not with fructosamine. When HbA1c was divided in quartiles as <5.6, 5.6-5.9, 5.9-6.2 and >6.2, a decrease of an estimated 0.70±0.30 μg/mL in 1,5-AG was associated with each quartile of increase in HbA1c(p<0.0001). There was a significant decline of 1.64+/-0.3mg/dL in post-prandial glucose values for each 1 unit increase in 1,5-AG(p<0.0001). For those with HbA1c≥6.0% when 1,5-AG was ≥8.15 μg/mL, the mean estimated glucose level was 103.71+/-3.66mg/dl; whereas it was 132.12+/-3.71mg/dl when 1,5-AG was <8.15 μg/mL. The glucose variability (Glumax-Glumin(in subjects with 1,5-AG <8.15 μg/mL, was 46.23mg/dl greaterthan the subjects with 1,5-AG ≥8.15 μg/mL (HbA1c ≥ 6.0%). There was no significant association between glycomark and glucose variability where HbA1c <6%./,Conclusions: 1,5-AG significantly associated with post-prandial glucose levels and glucose variability in ICT recipients with near normal HbA1c (6.0%-6.5%) levels. These findings suggest that 1,5-AG can be used to differentiate those ICT subjects with higher glucose variability despite having near normal HbA1c. However, prospective studies are needed to evaluate the association between glycomark levels and the parameters of graft dysfunction/failure.
    Cell Transplantation 06/2013; 23(10). DOI:10.3727/096368913X669734 · 3.57 Impact Factor
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    ABSTRACT: Allogeneic islet transplantation (IT) provokes changes in metabolic responses and nutritional behaviors. The durability of these changes needs to be described as well as their impact on the recipients' lifestyle. The goal of this study was to investigate how islet transplantation influenced diet, exercise habits, and body composition during 10 years after IT. A retrospective study performed in 33 (14 males, 19 females) IT recipients used dietary, physical activity open- ended questionnaire and anthropometric measurements. Data were collected before transplantation, every 3 months up to the 18th and every 6 months thereafter. Data were grouped by gender and eras: pre-IT; 0-3 years; 4-6 years, and 7-10 years after IT. Reduction in body mass index (BMI) from pre-IT to 0-3 years was noted: 23.68 ± 2,18 kg/m(2) to 22.07 ± 2.94 kg/m(2) (P < .05). Increased values were observed from 0-3 years to 4-6 years in: waist circumference (WC) (76.68 ± 7.22 to 79.44 ± 7.58 cm), BMI (23,68 ± 2,18 to 22,75 ± 3,11 kg/m(2)) and weight (64.69 ± 11.98 to 67.43 ± 14 kg): (P < .03). WC increased continuously up to 7-10 years (86.33 ± 9.45 cm; P < .05). There was an average of 5.3 ± 5.6 h/wk of exercise during follow-up. From pre-IT to 0-3 years there was a 19% reduction in protein consumption (P < .05) and a 39% increase in calories from saturated fats (P < .05). A trend to reduce carbohydrates intake noted from pre-IT to 0-3 years was progressively inverted from then throughout 7-10 years (not significant). IT was associated with a significantly decreased BMI early on that it was not sustained. The subsequent weight gain and WC increase could be the result of chronic immunosuppressive therapy and/or voluntary change in eating habits. The increased consumption of carbohydrates could be related to an adaptation of a lifestyle or/and reintroduction of insulin after graft dysfunction. Active lifestyle might be result of the intensive clinical care after IT, concomitant awareness of the importance of routine physical exercise on blood glucose control, and diabetes management. Continuous follow-up of IT recipients is needed to better understand these changes and for comparison with subjects with type 1 diabetes mellitus.
    Transplantation Proceedings 06/2013; 45(5):2025-8. DOI:10.1016/j.transproceed.2013.01.031 · 0.95 Impact Factor
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    ABSTRACT: To evaluate the effect of lysofylline (LSF) induction therapy on immune responses in the early post-transplant period after islet infusion, we followed 13 islet transplant recipients for changes in levels of peri-transplant cytokines, whole blood lymphocyte phenotype and gene expression. All recipients received thymoglobulin, sirolimus, tacrolimus and enbrel, and 5/13 also received LSF treatments. Total lymphocytes, T and T cell subsets decreased to lower levels than B and NK cells after transplant. Recovery of lymphocytes and T cells was similar between control and LSF groups. B and NK cells recovered faster than T cells in both groups, but LSF group had higher B cell levels compared to controls. Levels of CD4+/CD25bright/Foxp3+ cells were higher in LSF group compared to controls. LSF group had lower levels of granzyme B (GB) and perforin in both T and NK cells. Serum cytokines in LSF group had a trend towards lower levels of TNF-α and IL1-β and higher levels of IFN-γ, IL-6 and IL-10. Expression of the cytotoxic lymphocyte (CL) genes GB, perforin, and fas ligand and TNF-α gene was lower in LSF group compare to controls. For the one patient in the control group with complete loss of graft function (undetectable c-peptide), expression of CL, IL-4, IL-6, IL-10, TNF-α, IFN-γ, TGF-β, and Foxp3 genes was increased. Overall, the data suggest trends towards reduced immunoreactivity in the LSF treated group.
    2013 Clinical Immunology Society Annual Meeting; 04/2013
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    ABSTRACT: To describe trends of primary efficacy and safety outcomes of islet transplantation in type 1 diabetes recipients with severe hypoglycemia from the Collaborative Islet Transplant Registry (CITR) from 1999 to 2010. A total of 677 islet transplant-alone or islet-after-kidney recipients with type 1 diabetes in the CITR were analyzed for five primary efficacy outcomes and overall safety to identify any differences by early (1999-2002), mid (2003-2006), or recent (2007-2010) transplant era based on annual follow-up to 5 years. Insulin independence at 3 years after transplant improved from 27% in the early era (1999-2002, n = 214) to 37% in the mid (2003-2006, n = 255) and to 44% in the most recent era (2007-2010, n = 208; P = 0.006 for years-by-era; P = 0.01 for era alone). C-peptide ≥0.3 ng/mL, indicative of islet graft function, was retained longer in the most recent era (P < 0.001). Reduction of HbA(1c) and resolution of severe hypoglycemia exhibited enduring long-term effects. Fasting blood glucose stabilization also showed improvements in the most recent era. There were also modest reductions in the occurrence of adverse events. The islet reinfusion rate was lower: 48% by 1 year in 2007-2010 vs. 60-65% in 1999-2006 (P < 0.01). Recipients that ever achieved insulin-independence experienced longer duration of islet graft function (P < 0.001). The CITR shows improvement in primary efficacy and safety outcomes of islet transplantation in recipients who received transplants in 2007-2010 compared with those in 1999-2006, with fewer islet infusions and adverse events per recipient.
    Diabetes care 07/2012; 35(7):1436-45. DOI:10.2337/dc12-0063 · 8.57 Impact Factor
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    ABSTRACT: The seemingly inexorable decline in insulin independence after islet transplant alone (ITA) has raised concern about its clinical utility. We hypothesized that induction immunosuppression therapy determines durability of insulin independence. We analyzed the proportion of insulin-independent patients following final islet infusion in four groups of ITA recipients according to induction immunotherapy: University of Minnesota recipients given FcR nonbinding anti-CD3 antibody alone or T cell depleting antibodies (TCDAb) and TNF-α inhibition (TNF-α-i) (group 1; n = 29); recipients reported to the Collaborative Islet Transplant Registry (CITR) given TCDAb+TNF-α-i (group 2; n = 20); CITR recipients given TCDAb without TNF-α-i (group 3; n = 43); and CITR recipients given IL-2 receptor antibodies (IL-2RAb) alone (group 4; n = 177). Results were compared with outcomes in pancreas transplant alone (PTA) recipients reported to the Scientific Registry of Transplant Recipients (group 5; n = 677). The 5-year insulin independence rates in group 1 (50%) and group 2 (50%) were comparable to outcomes in PTA (group 5: 52%; p>0.05) but significantly higher than in group 3 (0%; p = 0.001) and group 4 (20%; p = 0.02). Induction immunosuppression was significantly associated with 5-year insulin independence (p = 0.03), regardless of maintenance immunosuppression or other factors. These findings support potential for long-term insulin independence after ITA using potent induction therapy, with anti-CD3 Ab or TCDAb+TNF-α-i.
    American Journal of Transplantation 04/2012; 12(6):1576-83. DOI:10.1111/j.1600-6143.2011.03977.x · 6.19 Impact Factor
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    ABSTRACT: The objective of this study was to identify predictors of insulin independence and to establish the best clinical tools to follow patients after pancreatic islet transplantation (PIT). Sequential metabolic responses to intravenous (I.V.) glucose (I.V. glucose tolerance test [IVGTT]), arginine and glucose-potentiated arginine (glucose-potentiated arginine-induced insulin secretion [GPAIS]) were obtained from 30 patients. We determined the correlation between transplanted islet mass and islet engraftment and tested the ability of each assay to predict return to exogenous insulin therapy. We found transplanted islet mass within an average of 16 709 islet equivalents per kg body weight (IEQ/kg BW; range between 6602 and 29 614 IEQ/kg BW) to be a poor predictor of insulin independence at 1 year, having a poor correlation between transplanted islet mass and islet engraftment. Acute insulin response to IVGTT (AIR(GLU) ) and GPAIS (AIR(max) ) were the most accurate methods to determine suboptimal islet mass engraftment. AIR(GLU) performed 3 months after transplant also proved to be a robust early metabolic marker to predict return to insulin therapy and its value was positively correlated with duration of insulin independence. In conclusion, AIR(GLU) is an early metabolic assay capable of anticipating loss of insulin independence at 1 year in T1D patients undergoing PIT and constitutes a valuable, simple and reliable method to follow patients after transplant.
    American Journal of Transplantation 02/2012; 12(5):1275-89. DOI:10.1111/j.1600-6143.2011.03947.x · 6.19 Impact Factor
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    ABSTRACT: Open Journal of Biology and Biochemistry, 2012, 1-2 © Jayaraman et al.; licensee Ross Science Publishers ROSS Open Access articles will be distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided that the original work will always be cited properly. ABSTRACT Type 1 diabetes is an autoimmune disease in which insulin-producing beta cells are destroyed by auto-reactive T lymphocytes. Studies in mice indicate that incomplete deletion of self-reactive T-cells and compromised peripheral tolerance mechanisms can contribute to the manifestation of autoimmune diabetes. In patients with type 1 diabetes, defects in T regulatory cell numbers and function have been previously reported. In this study, we have ascertained the integrity of activation-induced cell death, a mechanism of peripheral T cell tolerance, in long-standing type 1 diabetes patients. Activation of peripheral blood derived T cells from non-diabetic individuals with a T cell mitogen and interleukin-2 rendered them susceptible to subsequent T-cell receptor/CD3-mediated apoptosis, as indicated by the dissipation of the mitochondrial membrane potential and activation of intracellular caspases. In contrast, similarly activated T lymphocytes from type 1 diabetes patients failed to undergo apoptosis when challenged with a bacterial superantigen or anti-CD3 antibody. Supplementation of T cell cultures with interleukin-4 or interleukin-18 failed to restore self-tolerance. However, both the expression of the Fas receptor and its ability to transduce apoptotic signal were comparable in T cells of type 1 diabetes patients and controls. Additionally, no marked difference in the T cell subsets was observed between controls and diabetes patients under all activation conditions analyzed. These data suggest that the abnormality in T-cell receptor-mediated apoptosis is cell autonomous in long-standing type 1 diabetes patients, which in addition to other defective peripheral tolerance mechanisms, likely to contribute to the manifestation of autoimmune diabetes.
  • Transplantation 01/2012; 94(10S):706. DOI:10.1097/00007890-201211271-01385 · 3.78 Impact Factor
  • Transplantation 01/2012; 94(10S):203. DOI:10.1097/00007890-201211271-00378 · 3.78 Impact Factor
  • Transplantation 01/2012; 94(10S):159. DOI:10.1097/00007890-201211271-00295 · 3.78 Impact Factor
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    ABSTRACT: Pancreatic islet transplantation is a promising treatment option for patients severely affected with type 1 diabetes. This report from CITR presents pre- and posttransplant human leukocyte antigen (HLA) class I sensitization rates in islet-alone transplantation. Data came from 303 recipients transplanted with islet-alone between January 1999 and December 2008. HLA class I sensitization was determined by the presence of anti-HLA class I antibodies. Panel-reactive antibodies (PRA) from prior to islet infusion and at 6 months, and yearly posttransplant was correlated to measures of islet graft failure. The cumulative number of mismatched HLA alleles increased with each additional islet infusion from a median of 3 for one infusion to 9 for three infusions. Pretransplant PRA was not predictive of islet graft failure. However, development of PRA >20% posttransplant was associated with 3.6-fold (p < 0.001) increased hazard ratio for graft failure. Patients with complete graft loss who had discontinued immunosuppression had significantly higher rate of PRA ≥ 20% compared to those with functioning grafts who remained on immunosuppression. Exposure to repeat HLA class I mismatch at second or third islet infusions resulted in less frequent development of de novo HLA class I antibodies when compared to increased class I mismatch. The development of HLA class I antibodies while on immunosuppression is associated with subsequent islet graft failure. The risk of sensitization may be reduced by minimizing the number of islet donors used per recipient, and in the absence of donor-specific anti-HLA antibodies, repeating HLA class I mismatches with subsequent islet infusions.
    Cell Transplantation 11/2011; 21(5):901-8. DOI:10.3727/096368911X612468 · 3.57 Impact Factor

Publication Stats

6k Citations
1,020.67 Total Impact Points

Institutions

  • 1984–2014
    • University of Miami
      • • Diabetes Research Institute
      • • Department of Medicine
      • • Department of Surgery
      • • Department of Cell Biology
      كورال غيبلز، فلوريدا, Florida, United States
  • 1991–2011
    • University of Milan
      • Faculty of Exercise and Sport Sciences
      Milano, Lombardy, Italy
  • 1992–2010
    • University of Miami Miller School of Medicine
      • • Department of Epidemiology and Public Health
      • • Division of Hospital Medicine
      • • Diabetes Research Institute (DRI)
      Miami, Florida, United States
  • 2006
    • University of California, San Diego
      • Department of Bioengineering
      San Diego, CA, United States
  • 2005
    • University of Utah
      Salt Lake City, Utah, United States
  • 2003–2004
    • Baylor College of Medicine
      Houston, Texas, United States
  • 1999
    • Aoki Diabetes Research Institute
      Sacramento, California, United States
  • 1994
    • Justus-Liebig-Universität Gießen
      Gieben, Hesse, Germany
  • 1991–1992
    • University of Pittsburgh
      • • Department of Medicine
      • • Department of Surgery
      Pittsburgh, Pennsylvania, United States