14 research outputs found
Discovering Europe's seabed geology: the EMODnet concept of uniform collection and harmonization of marine data
Maritime spatial planning, management of marine resources, environmental assessments and forecasting all require good seabed maps. Similarly there is a need to support the objectives to achieve Good Environmental Status in Europe's seas by 2020, set up by the European Commission's Marine Strategy Framework Directive. Hence the European Commission established the European Marine Observation and Data Network (EMODnet) programme in 2009, which is now in its fourth phase (2019–21). The programme is designed to assemble existing, but fragmented and partly inaccessible, marine data and to create contiguous and publicly available information layers which are interoperable and free of restrictions on use, and which encompass whole marine basins.
The EMODnet Geology project is delivering integrated geological map products that include seabed substrates, sedimentation rates, seafloor geology, Quaternary geology, geomorphology, coastal behaviour, geological events such as submarine landslides and earthquakes, and marine mineral occurrences. Additionally, as a new product during the ongoing and preceding phase of the project, map products on submerged landscapes of the European continental shelf have been compiled at various time frames. All new map products have a resolution of 1:100 000, although finer resolution is presented where the underlying data permit. A multi-scale approach is adopted whenever possible.
Numerous national seabed mapping programmes worldwide have demonstrated the necessity for proper knowledge of the seafloor. Acting on this, the European Commission established the European Marine Observation and Data Network (EMODnet) programme in 2009. The national geological survey organizations of Europe have a strong network of marine geological teams through the Marine Geology Expert Group of the association of European geological surveys (Eurogeosurveys). This network was the foundation of the EMODnet Geology consortium which today consists of the national geological surveys of Finland, the UK, Sweden, Norway, Denmark, Estonia, Latvia, Lithuania, Poland, The Netherlands, Belgium, France, Ireland, Spain, Italy, Slovenia, Croatia, Albania, Greece, Cyprus, Malta, Russia, Germany, Montenegro and Iceland, as well as marine teams of research organizations in Portugal (IPMA), Bulgaria (IO-BAS), Romania (GeoEcoMar), the UK (CEFAS), Greece (HCMR) and Ukraine (PSRGE, replaced in the fourth phase by Institute of Geological Sciences, NAS of Ukraine). The consortium is further strengthened with experts from six universities: Edge Hill University (UK), Sapienza University of Rome (Italy), University of Tartu (Estonia), University of Crete through FORTH-ICS, Institute of Marine Science and Technology of Dokuz Eylul University (Turkey), and EMCOL Research Centre of Istanbul Technical University – altogether, 30 partners and nine subcontractors. The EMODnet Geology programme is now in its fourth phase, which started in September 2019. In addition to geological information, the wider EMODnet programme aims to also bring together information from European seas on seabed habitats, physical properties, chemistry, biology, human activities and hydrography. This paper describes the EMODnet Geology project and the different end products which were delivered in the end of the third phase and will be further developed during the recent fourth phase of the project
Exenatide regulates pancreatic islet integrity and insulin sensitivity in the nonhuman primate baboon Papio hamadryas.
The glucagon-like peptide-1 receptor agonist exenatide improves glycemic control by several and not completely understood mechanisms. Herein, we examined the effects of chronic intravenous exenatide infusion on insulin sensitivity, β cell and α cell function and relative volumes, and islet cell apoptosis and replication in nondiabetic nonhuman primates (baboons). At baseline, baboons received a 2-step hyperglycemic clamp followed by an l-arginine bolus (HC/A). After HC/A, baboons underwent a partial pancreatectomy (tail removal) and received a continuous exenatide (n = 12) or saline (n = 12) infusion for 13 weeks. At the end of treatment, HC/A was repeated, and the remnant pancreas (head-body) was harvested. Insulin sensitivity increased dramatically after exenatide treatment and was accompanied by a decrease in insulin and C-peptide secretion, while the insulin secretion/insulin resistance (disposition) index increased by about 2-fold. β, α, and δ cell relative volumes in exenatide-treated baboons were significantly increased compared with saline-treated controls, primarily as the result of increased islet cell replication. Features of cellular stress and secretory dysfunction were present in islets of saline-treated baboons and absent in islets of exenatide-treated baboons. In conclusion, chronic administration of exenatide exerts proliferative and cytoprotective effects on β, α, and δ cells and produces a robust increase in insulin sensitivity in nonhuman primates
Horizontal Branch Stars: The Interplay between Observations and Theory, and Insights into the Formation of the Galaxy
We review HB stars in a broad astrophysical context, including both variable
and non-variable stars. A reassessment of the Oosterhoff dichotomy is
presented, which provides unprecedented detail regarding its origin and
systematics. We show that the Oosterhoff dichotomy and the distribution of
globular clusters (GCs) in the HB morphology-metallicity plane both exclude,
with high statistical significance, the possibility that the Galactic halo may
have formed from the accretion of dwarf galaxies resembling present-day Milky
Way satellites such as Fornax, Sagittarius, and the LMC. A rediscussion of the
second-parameter problem is presented. A technique is proposed to estimate the
HB types of extragalactic GCs on the basis of integrated far-UV photometry. The
relationship between the absolute V magnitude of the HB at the RR Lyrae level
and metallicity, as obtained on the basis of trigonometric parallax
measurements for the star RR Lyrae, is also revisited, giving a distance
modulus to the LMC of (m-M)_0 = 18.44+/-0.11. RR Lyrae period change rates are
studied. Finally, the conductive opacities used in evolutionary calculations of
low-mass stars are investigated. [ABRIDGED]Comment: 56 pages, 22 figures. Invited review, to appear in Astrophysics and
Space Scienc
Hyperglycemia-induced oxidative stress and its role in diabetes mellitus related cardiovascular diseases
Diabetes mellitus is associated to an increased risk of cardiovascular diseases. Hyperglycemia is an important factor in cardiovascular damage, working through different mechanisms such as activation of protein kinase C, polyol and hexosamine pathways, advanced glycation end products production. All of these pathways, in association to hyperglycemia-induced mitochondrial dysfunction and endoplasmic reticulum stress, promote reactive oxygen species (ROS) accumulation that, in turn, promote cellular damage and contribute to the diabetic complications development and progression. ROS can directly damage lipids, proteins or DNA and modulate intracellular signaling pathways, such as mitogen activated protein kinases and redox sensitive transcription factors causing changes in protein expression and, therefore, irreversible oxidative modifications. Hyperglycemia-induced oxidative stress induces endothelial dysfunction that plays a central role in the pathogenesis of micro- and macro-vascular diseases. It may also increase pro-inflammatory and pro-coagulant factors expression, induce apoptosis and impair nitric oxide release. Oxidative stress induces several phenotypic alterations also in vascular smooth-muscle cell (VSMC). ROS is one of the factors that can promote both VSMC proliferation/migration in atherosclerotic lesions and VSMC apoptosis, which is potentially involved in atherosclerotic plaque instability and rupture. Currently, there are contrasting clinical evidences on the benefits of antioxidant therapies in the prevention/treatment of diabetic cardiovascular complications. Appropriate glycemic control, in which both hypoglycemic and hyperglycemic episodes are reduced, in association to the treatment of dyslipidemia, hypertension, kidney dysfunction and obesity, conditions which are also associated to ROS overproduction, can counteract oxidative stress and, therefore, both microvascular and macrovascular complications of diabetes mellitus
Exenatide non causa pancreatite, iperplasia o displasia duttale e favorisce la neogenesi Beta cellulare nel pancreas esocrino di babbuino
In this study, we aimed to evaluate the effects of exenatide (EXE) treatment on exocrine pancreas of nonhuman primates. To this end, 52 baboons (Papio hamadryas) underwent partial pancreatectomy, followed by continuous infusion of EXE or saline (SAL) for 14 weeks. Histological analysis, immunohistochemistry, Computer Assisted Stereology Toolbox morphometry, and immunofluorescence staining were performed at baseline and after treatment. The EXE treatment did not induce pancreatitis, parenchymal or periductal inflammatory cell accumulation, ductal hyperplasia, or dysplastic lesions/pancreatic intraepithelial neoplasia. At study end, Ki-67-positive (proliferating) acinar cell number did not change, compared with baseline, in either group. Ki-67-positive ductal cells increased after EXE treatment (P = 0.04). However, the change in Ki-67-positive ductal cell number did not differ significantly between the EXE and SAL groups (P = 0.13). M-30-positive (apoptotic) acinar and ductal cell number did not change after SAL or EXE treatment. No changes in ductal density and volume were observed after EXE or SAL. Interestingly, by triple-immunofluorescence staining, we detected c-kit (a marker of cell transdifferentiation) positive ductal cells co-expressing insulin in ducts only in the EXE group at study end, suggesting that EXE may promote the differentiation of ductal cells toward a \u3b2-cell phenotype. In conclusion, 14 weeks of EXE treatment did not exert any negative effect on exocrine pancreas, by inducing either pancreatic inflammation or hyperplasia/dysplasia in nonhuman primate
Impact of obesity severity and duration on pancreatic β-and α-cell dynamics in normoglycemic non-human primates
Objective: Obesity is associated with high insulin and glucagon plasma levels. Enhanced \u3b2-cell function and \u3b2-cell expansion are responsible for insulin hypersecretion. It is unknown whether hyperglucagonemia is due to \u3b1-cell hypersecretion or to an increase in \u3b1-cell mass. In this study, we investigated the dynamics of the \u3b2-cell and \u3b1-cell function and mass in pancreas of obese normoglycemic baboons. Methods: Pancreatic \u3b2-and \u3b1-cell volumes were measured in 51 normoglycemic baboons divided into six groups according to overweight severity or duration. Islets morphometric parameters were correlated to overweight and to diverse metabolic and laboratory parameters. Results: Relative \u3b1-cell volume (R\u3b1V) and relative islet \u3b1-cell volume (RI\u3b1V) increased significantly with both overweight duration and severity. Conversely, in spite of the induction of insulin resistance, overweight produced only modest effects on relative \u3b2-cell volume (R\u3b2V) and relative islet \u3b2-cell volume (RI\u3b2V). Of note, RI\u3b2V did not increase neither with overweight duration nor with overweight severity, supposedly because of the concomitant, greater increase in RI\u3b1V. Baboons' body weights correlated with serum levels of interleukin-6 and tumor necrosis factor-\u3b1 soluble receptors, demonstrating that overweight induces abnormal activation of the signaling of two cytokines known to impact differently \u3b2-and \u3b1-cell viability and replication. Conclusion: In conclusion, overweight and insulin resistance induce in baboons a significant increase in \u3b1-cell volumes (R\u3b1V, RI\u3b1V), whereas have minimal effects on the \u3b2 cells. This study suggests that an increase in the \u3b1-cell mass may precede the loss of \u3b2 cells and the transition to overt hyperglycemia and diabetes
Chronic continuous exenatide infusion does not cause pancreatic inflammation and ductal hyperplasia in non-human primates
In this study, we aimed to evaluate the effects of exenatide (EXE) treatment on exocrine pancreas of nonhuman primates. To this end, 52 baboons (Papio hamadryas) underwent partial pancreatectomy, followed by continuous infusion of EXE or saline (SAL) for 14 weeks. Histological analysis, immunohistochemistry, Computer Assisted Stereology Toolbox morphometry, and immunofluorescence staining were performed at baseline and after treatment. The EXE treatment did not induce pancreatitis, parenchymal or periductal inflammatory cell accumulation, ductal hyperplasia, or dysplastic lesions/pancreatic intraepithelial neoplasia. At study end, Ki-67-positive (proliferating) acinar cell number did not change, compared with baseline, in either group. Ki-67-positive ductal cells increased after EXE treatment (P = 0.04). However, the change in Ki-67-positive ductal cell number did not differ significantly between the EXE and SAL groups (P = 0.13). M-30-positive (apoptotic) acinar and ductal cell number did not change after SAL or EXE treatment. No changes in ductal density and volume were observed after EXE or SAL. Interestingly, by triple-immunofluorescence staining, we detected c-kit (a marker of cell transdifferentiation) positive ductal cells co-expressing insulin in ducts only in the EXE group at study end, suggesting that EXE may promote the differentiation of ductal cells toward a \u3b2-cell phenotype. In conclusion, 14 weeks of EXE treatment did not exert any negative effect on exocrine pancreas, by inducing either pancreatic inflammation or hyperplasia/dysplasia in nonhuman primates
Plasma complement C3 levels are associated with insulin secretion independently of adiposity measures in non-diabetic individuals
Chronic Continuous Exenatide Infusion Does Not Cause Pancreatic Inflammation And Ductal Hyperplasia In Non-human Primates
In this study, we aimed to evaluate the effects of exenatide (EXE) treatment on exocrine pancreas of nonhuman primates. To this end, 52 baboons (Papio hamadryas) underwent partial pancreatectomy, followed by continuous infusion of EXE or saline (SAL) for 14 weeks. Histological analysis, immunohistochemistry, Computer Assisted Stereology Toolbox morphometry, and immunofluorescence staining were performed at baseline and after treatment. The EXE treatment did not induce pancreatitis, parenchymal or periductal inflammatory cell accumulation, ductal hyperplasia, or dysplastic lesions/pancreatic intraepithelial neoplasia. At study end, Ki-67-positive (proliferating) acinar cell number did not change, compared with baseline, in either group. Ki-67-positive ductal cells increased after EXE treatment (P = 0.04). However, the change in Ki-67-positive ductal cell number did not differ significantly between the EXE and SAL groups (P = 0.13). M-30-positive (apoptotic) acinar and ductal cell number did not change after SAL or EXE treatment. No changes in ductal density and volume were observed after EXE or SAL. Interestingly, by triple-immunofluorescence staining, we detected c-kit (a marker of cell transdifferentiation) positive ductal cells co-expressing insulin in ducts only in the EXE group at study end, suggesting that EXE may promote the differentiation of ductal cells toward a β-cell phenotype. In conclusion, 14 weeks of EXE treatment did not exert any negative effect on exocrine pancreas, by inducing either pancreatic inflammation or hyperplasia/dysplasia in nonhuman primates.1851139150Xu, G., Stoffers, D.A., Habener, J.F., Bonner-Weir, S., Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats (1999) Diabetes, 48, pp. 2270-2276Farilla, L., Hui, H., Bertolotto, C., Kang, E., Bulotta, A., Di Mario, U., Perfetti, R., Glucagon-like peptide-1 promotes islet cell growth and inhibits apoptosis in Zucker diabetic rats (2002) Endocrinology, 143, pp. 4397-4408Hui, H., Wright, C., Perfetti, R., Glucagon-like peptide 1 induces differentiation of islet duodenal homeobox-1-positive pancreatic ductal cells into insulin-secreting cells (2001) Diabetes, 50, pp. 785-796Fineman, M.S., Bicsak, T.A., Shen, L.Z., Taylor, K., Gaines, E., Varns, A., Kim, D., Baron, A.D., Effect on glycemic control of exenatide (synthetic exendin-4) additive to existing metformin and/or sulfonylurea treatment in patients with type 2 diabetes (2003) Diabetes Care, 26, pp. 2370-2377Campbell, J.E., Drucker, D.J., Pharmacology, physiology, and mechanisms of incretin hormone action (2013) Cell Metab, 17, pp. 819-837Goldstein, B.J., Feinglos, M.N., Lunceford, J.K., Johnson, J., Williams-Herman, D.E., Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes (2007) Diabetes Care, 30, pp. 1979-1987. , Sitagliptin 036 Study GroupMeier, J.J., GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus (2012) Nat Rev Endocrinol, 8, pp. 728-742Meier, J.J., Nauck, M.A., Risk of pancreatitis in patients treated with incretin-based therapies (2014) Diabetologia, 57, pp. 1320-1324Forsmark, C.E., Billie, J., AGA institute technical review on acute pancreatitis (2007) Gastroenterology, 132, pp. 2022-2044Girman, C.J., Kou, T.D., Cai, B., Alexander, C.M., O'Neill, E.A., Williams-Herman, D.E., Katz, L., Patients with type 2 diabetes mellitus have higher risk for acute pancreatitis compared with those without diabetes (2010) Diabetes Obes Metab, 12, pp. 766-771Ben, Q., Xu, M., Ning, X., Liu, J., Hong, S., Huang, W., Zhang, H., Li, Z., Diabetes mellitus and risk of pancreatic cancer: A meta-analysis of cohort studies (2011) Eur J Cancer, 47, pp. 1928-1937Nauck, M.A., A critical analysis of the clinical use of incretin-based therapies: The benefits by far outweigh the potential risks (2013) Diabetes Care, 36, pp. 2126-2132Monami, M., Dicembrini, I., Nardini, C., Fiordelli, I., Mannucci, E., Glucagon-like peptide-1 receptor agonists and pancreatitis: A meta-analysis of randomized clinical trials (2014) Diabetes Res Clin Pract, 103, pp. 269-275Monami, M., Dicembrini, I., Mannucci, E., Dipeptidyl peptidase-4 inhibitors and pancreatitis risk: A meta-analysis of randomized clinical trials (2014) Diabetes Obes Metab, 16, pp. 48-56Wenten, M., Gaebler, J.A., Hussein, M., Pelletier, E.M., Smith, D.B., Girase, P., Noel, R.A., Bloomgren, G.L., Relative risk of acute pancreatitis in initiators of exenatide twice daily compared with other anti-diabetic medication: A follow-up study (2012) Diabet Med, 29, pp. 1412-1418Garg, R., Chen, W., Pendergrass, M., Acute pancreatitis in type 2 diabetes treated with exenatide or sitagliptin: A retrospective observational pharmacy claims analysis (2010) Diabetes Care, 33, pp. 2349-2354Drucker, D.J., Sherman, S.I., Bergenstal, R.M., Buse, J.B., The safety of incretin-based therapies: Review of the scientific evidence (2011) J Clin Endocrinol Metab, 96, pp. 2027-2031Elashoff, M., Matveyenko, A.V., Gier, B., Elashoff, R., Butler, P.C., Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies (2011) Gastroenterology, 141, pp. 150-156Macconell, L., Brown, C., Gurney, K., Han, J., Safety and tolerability of exenatide twice daily in patients with type 2 diabetes: Integrated analysis of 5594 patients from 19 placebo-controlled and comparator-controlled clinical trials (2012) Diabetes Metab Syndr Obes, 5, pp. 29-41White, W.B., Cannon, C.P., Heller, S.R., Nissen, S.E., Bergenstal, R.M., Bakris, G.L., Perez, A.T., Zannad, F., Alogliptin after acute coronary syndrome in patients with type 2 diabetes (2013) N Engl J Med, 369, pp. 1327-1335. , EXAMINE InvestigatorsScirica, B.M., Bhatt, D.L., Braunwald, E., Steg, P.G., Davidson, J., Hirshberg, B., Ohman, P., Raz, I., Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus (2013) N Engl J Med, 369, pp. 1317-1326. , SAVOR-TIMI 53 Steering Committee and InvestigatorsDrucker, D.J., Sherman, S.I., Gorelick, F.S., Bergenstal, R.M., Sherwin, R.S., Buse, J.B., Incretin-based therapies for the treatment of type 2 diabetes: Evaluation of the risks and benefits (2010) Diabetes Care, 33, pp. 428-433Butler, A.E., Campbell-Thompson, M., Gurlo, T., Dawson, D.W., Atkinson, M., Butler, P.C., Marked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors (2013) Diabetes, 62, pp. 2595-2604Harja, E., Lord, J., Skyler, J.S., An analysis of characteristics of subjects examined for incretin effects on pancreatic pathology (2013) Diabetes Technol Ther, 15, pp. 609-618Bonner-Weir, S., In'T Veld, P.A., Weir, G.C., Reanalysis of study of pancreatic effects of incretin therapy: Methodological deficiencies (2014) Diabetes Obes Metab, 16, pp. 661-666Nachnani, J.S., Bulchandani, D.G., Nookala, A., Herndon, B., Molteni, A., Pandya, P., Taylor, R., Alba, L.M., Biochemical and histological effects of exendin-4 (exenatide) on the rat pancreas (2010) Diabetologia, 53, pp. 153-159Matveyenko, A.V., Dry, S., Cox, H.I., Moshtaghian, A., Gurlo, T., Galasso, R., Butler, A.E., Butler, P.C., Beneficial endocrine but adverse exocrine effects of sitagliptin in the human islet amyloid polypeptide transgenic rat model of type 2 diabetes: Interactions with metformin (2009) Diabetes, 58, pp. 1604-1615Gier, B., Matveyenko, A.V., Kirakossian, D., Dawson, D., Dry, S.M., Butler, P.C., Chronic GLP-1 receptor activation by exendin-4 induces expansion of pancreatic duct glands in rats and accelerates formation of dysplastic lesions and chronic pancreatitis in the Kras (G12D) mouse model (2012) Diabetes, 61, pp. 1250-1262Tatarkiewicz, K., Smith, P.A., Sablan, E.J., Polizzi, C.J., Aumann, D.E., Villescaz, C., Hargrove, D.M., Parkes, D.G., Exenatide does not evoke pancreatitis and attenuates chemically induced pancreatitis in normal and diabetic rodents (2010) Am J Physiol Endocrinol Metab, 299, pp. 1076-E1086Nyborg, N.C., Mølck, A.M., Madsen, L.W., Knudsen, L.B., The human GLP-1 analog liraglutide and the pancreas: Evidence for the absence of structural pancreatic changes in three species (2012) Diabetes, 61, pp. 1243-1249Vrang, N., Jelsing, J., Simonsen, L., Jensen, A.E., Thorup, I., Søeborg, H., Knudsen, L.B., The effects of 13 wk of liraglutide treatment on endocrine and exocrine pancreas in male and female ZDF rats: A quantitative and qualitative analysis revealing no evidence of drug-induced pancreatitis (2012) Am J Physiol Endocrinol Metab, 303, pp. 253-E264Chavez, A.O., Lopez-Alvarenga, J.C., Tejero, M.E., Triplitt, C., Bastarrachea, R.A., Sriwijitkamol, A., Tantiwong, P., Folli, F., Physiological and molecular determinants of insulin action in the baboon (2008) Diabetes, 57, pp. 899-908Guardado-Mendoza, R., Davalli, A.M., Chavez, A.O., Hubbard, G.B., Dick, E.J., Majluf-Cruz, A., Tene-Perez, C.E., Folli, F., Pancreatic islet amyloidosis, beta-cell apoptosis, and alpha-cell proliferation are determinants of islet remodeling in type-2 diabetic baboons (2009) Proc Natl Acad Sci U S A, 106, pp. 13992-13997Guardado-Mendoza, R., Jimenez-Ceja, L., Majluf-Cruz, A., Kamath, S., Fiorentino, T.V., Casiraghi, F., Velazquez, A.O., Folli, F., Impact of obesity severity and duration on pancreatic α- And β-cells dynamics in normoglycemic non-human primates (2013) Int J Obes (Lond), 37, pp. 1071-1078Kamath, S., Chavez, A.O., Gastaldelli, A., Casiraghi, F., Halff, G.A., Abrahamian, G.A., Davalli, A.M., Folli, F., Coordinated defects in hepatic long chain fatty acid metabolism and triglyceride accumulation contribute to insulin resistance in non-human primates (2011) PLoS One, 6, p. 27617Casiraghi, F., Lertwattanarak, R., Luzi, L., Chavez, A.O., Davalli, A.M., Naegelin, T., Comuzzie, A.G., Folli, F., Energy expenditure evaluation in humans and non-human primates by SenseWear Armband: Validation of energy expenditure evaluation by SenseWear Armband by direct comparison with indirect calorimetry (2013) PLoS One, 8, p. 73651Bommineni, Y.R., Dick, E.J., Jr., Malapati, A.R., Owston, M.A., Hubbard, G.B., Natural pathology of the Baboon (Papio spp.) (2011) J Med Primatol, 40, pp. 142-155Guardado-Mendoza, R., Dick, E.J., Jr., Jimenez-Ceja, L.M., Davalli, A., Chavez, A.O., Folli, F., Hubbard, G.B., Spontaneous pathology of the baboon endocrine system (2009) J Med Primatol, 38, pp. 383-389Coelho, A.M., Jr., Carey, K.D., A social tethering system for nonhuman primates used in laboratory research (1990) Lab Anim Sci, 40, pp. 388-394McClure, H.M., Chandler, F.W., A survey of pancreatic lesions in nonhuman primates (1982) Vet Pathol Suppl, 7, pp. 193-209Mandarim-De-Lacerda, C.A., Stereological tools in biomedical research (2003) An Acad Bras Cienc, 75, pp. 469-486Quinn, A.R., Blanco, C.L., Perego, C., Finzi, G., La Rosa, S., Capella, C., Guardado-Mendoza, R., Folli, F., The ontogeny of the endocrine pancreas in the fetal/newborn baboon (2012) J Endocrinol, 214, pp. 289-299Hruban, R.H., Adsay, N.V., Albores-Saavedra, J., Compton, C., Garrett, E.S., Goodman, S.N., Kern, S.E., Offerhaus, G.J., Pancreatic intraepithelial neoplasia: A new nomenclature and classification system for pancreatic duct lesions (2001) Am J Surg Pathol, 25, pp. 579-586Hruban, R.H., Takaori, K., Klimstra, D.S., Adsay, N.V., Albores-Saavedra, J., Biankin, A.V., Biankin, S.A., Yonezawa, S., An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms (2004) Am J Surg Pathol, 28, pp. 977-987Bonner-Weir, S., Inada, A., Yatoh, S., Li, W.C., Aye, T., Toschi, E., Sharma, A., Transdifferentiation of pancreatic ductal cells to endocrine beta-cells (2008) Biochem Soc Trans, 36, pp. 353-356Egan, A.G., Blind, E., Dunder, K., De Graeff, P.A., Hummer, B.T., Bourcier, T., Rosebraugh, C., Pancreatic safety of incretin-based drugs: FDA and EMA assessment (2014) N Engl J Med, 370, pp. 794-797Butler, A.E., Janson, J., Bonner-Weir, S., Ritzel, R., Rizza, R.A., Butler, P.C., Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes (2003) Diabetes, 52, pp. 102-110Mezza, T., Muscogiuri, G., Sorice, G.P., Clemente, G., Hu, J., Pontecorvi, A., Holst, J.J., Kulkarni, R.N., Insulin resistance alters islet morphology in non-diabetic humans (2014) Diabetes, 63, pp. 994-1007Holland, T., Holland, C., Unbiased histological examinations in toxicological experiments (or, the informed leading the blinded examination) (2011) Toxicol Pathol, 39, pp. 711-71