Clinical and pathological characterization of a novel transgenic animal model of diabetes mellitus expressing a dominant negative glucose-dependent insulinotropic polypeptide receptor (GIPR dn)

Clinical and pathological characterization of a novel transgenic animal model of diabetes mellitus expressing a dominant negative glucose-dependent insulinotropic polypeptide receptor (GIPR dn) Gastrointestinal hormones like glucose-dependent insulinotropic polypeptide have recently been shown to be involved in the pathogenesis of diabetes mellitus in humans and animals models of diabetes mellitus. The aim of this study was to characterize a novel transgenic mouse model expressing a dominant negative glucosedependent insulinotropic polypeptide receptor (GIPRdn) under the control of the rat insulin gene promoter and their non-transgenic counterparts. Detailed analysis of clinical parameters was performed, including urine glucose, blood or serum glucose and serum insulin values. In addition, oral and subcutaneous glucose tolerance tests were performed, and HbA1c levels and various serum parameters were determined. The detection of the daily food and water intake and the daily urine volume was performed in two age groups. Further, body and organ weights were determined. Qualitative and quantitative morphological changes of the pancreas and the kidneys were investigated in several age groups. Some of the parameters were studied in different diet groups, one of them received standard rodent chow, and the other received a carbohydrate-restricted diet until four months of age. All transgenic mice studied exhibited severe glucosuria from 21 days of age onwards. From 30 days of age onwards, GIPRdn transgenic males and females showed severe hyperglycemia and hypoinsulinemia (p<0.05). In male transgenic animals, the fasted body weight was found to be lower than in age-matched male control mice. The daily food and water intake and the 24-hour urine volume were significantly higher in all transgenic animals investigated. Histological and immunohistochemical survey of the pancreas revealed a striking change of the islet cell composition and distribution. Further, quantitative- stereological analysis of the pancreas revealed a significant reduction of the total volumes of pancreatic islets, B-cells in the islets and isolated B-cells in the exocrine pancreas indicating neogenesis of islets. Kidney changes included renal and glomerular hypertrophy, glomerulosclerosis and tubulo-interstitial changes. In conclusion, transgenic mice expressing a dominant negative GIP receptor under the control of the rat insulin gene promoter develop a severe diabetic phenotype and striking 138 histological changes of the endocrine pancreas. Further, advanced diabetesassociated organ lesions, particularly of the kidney were observed and therefore, GIPRdn transgenic mice are considered a valuable model for studying long-term complications of diabetes mellitus.Klinische und pathomorphologische Befunde bei einem neuartigen transgenen diabetischen Tiermodell, das einen dominant negativen glucose-dependent insulinotropic polypeptide Rezeptor (GIPR dn) exprimiert. In den letzten Jahren wurde beim Studium der Pathogenese des Diabetes mellitus die Aufmerksamkeit zunehmend auf die Beteiligung gastrointestinaler Hormone wie zum Beispiel glucose-dependent insulinotropic polypeptide gerichtet. Ziel dieser Studie war es, bei einem neuartigen transgenen Tiermodell, klinische und pathomorphologische Veränderungen eingehend zu charakterisieren. Bei den untersuchten Tieren handelte es sich um transgene Mäuse, die einen dominant negativen glucosedependent insulinotropic polypeptide Rezeptor (GIPRdn) unter der Kontrolle des Ratteninsulingenpromotors exprimieren und um nicht-transgene Geschwistertiere. Es erfolgte eine detaillierte Untersuchung Diabetes-relevanter klinischer Parameter, unter der Berücksichtigung von Harnglukoseausscheidung, Blut- bzw. Serumglukose- und Seruminsulinwerten. Zusätzlich wurden orale und subkutane Glukosetoleranztests durchgeführt und HbA1c -Werte sowie verschiedene Serumparameter bestimmt. Die tägliche Futter- und Wasseraufnahme und das tägliche Harnvolumen wurden bei zwei Altersgruppen gemessen. Körper- und Organgewichte wurden ebenfalls erfasst. Die Erfassung morphologischer und histopathologischer Veränderungen des Pankreas und der Nieren erfolgte sowohl qualitativ als auch quantitativ-stereologisch an mehreren Altersgruppen. Einige der untersuchten Parameter wurden an Tieren, die mit Haltungsfutter gefüttert wurden und an Vergleichstieren erhoben, die bis zum Alter von 4 Monaten mit einer kohlenhydratarmen Diät ernährt wurden. Alle untersuchten transgenen Tiere zeigten ab einem Alter von 21 Tagen eine schwere Glukosurie. Im Alter von 30 Tagen zeigten GIPRdn transgene männliche und weibliche Mäuse eine hochgradige Hyperglykämie und eine hochgradige Hypoinsulinämie. Bei männlich- transgenen Tieren war das Köpergewicht im Vergleich zu gleichgeschlechtlichen 139 Kontrolltieren reduziert (p<0.05). Die tägliche Futter- und Wasseraufnahme und das tägliche Harnvolumen war bei allen untersuchten transgenen Tieren signifikant höher als bei Kontrolltieren. Histologische und immunhistochemische Untersuchungen am Pankreas zeigten schwere Veränderungen der Zusammensetzung und Verteilung der Inselzellen auf. Diese qualitativen Befunde konnten durch quantitativstereologische Untersuchungen eingehend charakterisiert werden. Das Gesamtvolumen der Pankreasinseln und der B-Zellen in den Inseln war bei GIPRdn transgenen Mäusen signifikant niedriger als bei Kontrolltieren. Gleiches gilt für das Gesamtvolumen isolierter B-Zellen im exokrinen Pankreas, die als Indikator für Inselneogenese angesehen werden. Die festgestellten Nierenveränderungen umfassen renale und glomeruläre Hypertrophie, Glomerulosklerose und tubulointerstitielle Veränderungen. Die quantitativ-stereologische Auswertung konnte die subjektiven Befunde bestätigen, sowohl das Nierenvolumen als auch das mittlere Glomerulumvolumen waren bei transgenen Mäusen signifikant erhöht. Aus den erhobenen Befunden ergibt sich die Schlussfolgerung, dass transgene Mäuse, die einen dominant-negativen GIP Rezeptor unter der Kontrolle des Ratteninsulingenpromoters exprimieren eine hochgradigen diabetischen Phänotyp und prägnante histologische Veränderungen am endokrinen Pankreas entwickeln. Weiterhin konnten Diabetes-assoziierte Alterationen diverser Organe, insbesondere der Niere festgestellt werden, woraufhin GIPRdn transgene Mäuse als ein wertvolles Tiermodell für die Untersuchung diabetischer Spätkomplikationen angesehen werden

Multiple Glucagon-Producing Pancreatic Neuroendocrine Tumors in a Horse (Equus caballus)

Pancreatic neuroendocrine tumors of glucagon-producing cells are extremely rare in domestic animals. In this report, we describe for the first time, to our knowledge, the incidental finding of multiple glucagon-producing neuroendocrine tumors of the pancreas of a horse. The animal was euthanized due to severe local infection after tooth extraction. On postmortem examination, multiple white nodules of up to 4 cm in diameter were observed in the pancreas. Histologically, pancreatic nodules had the appearance of neuroendocrine neoplasms with positive immunoreactivity for glucagon, synaptophysin, chromogranin A, and neuron-specific enolase. Electron microscopy revealed numerous electron-dense granules, similar to those observed in normal pancreatic alpha cells, in the neoplastic cells. In addition, the left adrenal gland showed multiple hyperplastic foci and adenomas in the medulla that were identified as pheochromocytomas. Based on the morphologic appearance and immunohistochemical staining pattern of pancreatic nodules, a diagnosis of multiple glucagon-producing neuroendocrine tumors was made

Learning Outcomes and Technology in the ESL Classroom

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Antropocentrismo e os destinatários das normas ambientais

O presente trabalho discutirá a eficácia do Direito Ambiental brasileiro na proteção da fauna e flora nacionais à luz dos rompimentos de barragens ocorridos em Mariana (2015) e Brumadinho (2019). Inicialmente será realizada uma análise da evolução histórica do Direito Ambiental, passando por conceitos relevantes que moldaram o desenvolvimento deste ramo do Direito, como por exemplo, o antropocentrismo e o especismo. Posteriormente, serão apresentados os estudos de caso dos crimes ocorridos nas cidades mineiras, analisando princípios relevantes e o cabimento da responsabilidade ambiental em casos semelhantes. Por fim, serão examinadas as consequências legislativas, quais sejam, os projetos de lei propostos e as leis posteriormente sancionadas, além das consequências jurídicas enfrentadas pelas empresas criminosas

Trends in the Return and Prosecution of ISIS Foreign Terrorist Fighters in the United States

Approximately 300 Americans are estimated to have traveled or attempted to join the Islamic State (ISIS) as part of the group’s campaign in Syria and Iraq between 2013 and 2019. These individuals joined more than 53,000 men, women, and minors from roughly 80 countries. Often referred to as foreign (terrorist) fighters (FTF), these are individuals from third countries who travel to join a terrorist group to support its activities. In the United States (U.S.) context, the FTF designation does not denote the act of fighting itself, but rather the support of a designated foreign terrorist organization (FTO). While many of these radicalized individuals traveled alone to the conflict zone, others brought their families or formed new ones in-theater. As ISIS’ selfdeclared caliphate collapsed, many were killed, some fled to other locations, and many were captured and held by Kurdish forces. Men and some teenage boys were primarily placed in prisons, while women and minors were often moved into detention camps. Today, an estimated 10,000 male FTFs remain held in northeastern Syria including 2,000 men and boys from 60 countries outside Syria and Iraq (third country nationals, or TCNs). In addition, local camps hold close to 55,000 female FTF and FTF-affiliated family members, including roughly 10,000 TCN women and children. Some of these individuals have now been in detention for four years or more. The indefinite detention of FTF and FTF-affiliated families in northeastern Syria is not a tenable solution. In addition to clear humanitarian concerns, there is a significant security risk that the facilities’ inhabitants provide a groundswell of recruits to the still active ISIS campaign in the region. A 2022 U.S. military report puts it bluntly, “These children in the camp are prime targets for ISIS radicalization. The international community must work together to remove these children from this environment by repatriating them to their countries or communities of origin while improving conditions in the camp.” In lockstep, U.S. diplomatic leaders have made repatriation a policy priority empowered by a general domestic partisan consensus that the repatriation of FTF and FTF-affiliated families from northeastern Syria should be done expediently. Progress has been slow, while many Western nations were strongly resistant to bringing their detained citizens home, there is recent evidence for cautious optimism. Approximately 9,200 persons – including 2,700 TCNs and 6,500 Iraqis repatriated since 2019. This year, 13 countries have repatriated roughly 2,300 persons, including more than 350 TCNs. However, more work remains to be done. As of July 15, 2023, 39 U.S. persons have been officially repatriated, including both adults and minors. At least 11 additional U.S. persons have returned on their own accord, ten of whom remained in the U.S. following their return. Furthermore, the U.S. has made the decision to bring several non-U.S. persons to the U.S. to stand trial