Faculty Bibliography

Antithrombotic therapy for stroke prevention in patients with atrial fibrillation (AF) has dramatically shifted from warfarin, a vitamin K antagonist, to the direct oral anticoagulants (DOACs) such as dabigatran, apixaban, and rivaroxaban. In patients with contraindications to oral anticoagulation, left atrial appendage occlusion (LAAO) devices, such as the Watchmanâ„¢ device, may be considered; however, temporary postimplantation antithrombotic therapy is still a recommended practice. We present a case of complex antithrombotic management, post LAAO device implantation, designed to avoid drug interactions with concomitant rifampin use and remained necessary secondary to subsequent device leak. This case highlights the challenges of antithrombotic therapy post LAAO device placement in a complex, but representative, patient.

Infections caused by foodborne enteric pathogens including typhoidal and non-typhoidal Salmonella species can mimic symptoms of acute appendicitis. The association between such bacterial pathogens and pathology-proven acute appendicitis has been described, but this link is poorly understood. Here we describe a case of a young man with typhoid fever presenting with histology-proven acute appendicitis requiring urgent appendectomy, and provide a brief review of relevant literature to prompt more widespread recognition of this rare cause of a common surgical emergency.

Islet amyloidosis by IAPP contributes to pancreatic beta-cell death in diabetes, but the nature of toxic IAPP species remains elusive. Using concurrent time-resolved biophysical and biological measurements, we define the toxic species produced during IAPP amyloid formation and link their properties to induction of rat INS-1 beta-cell and murine islet toxicity. These globally flexible, low order oligomers upregulate pro-inflammatory markers and induce reactive oxygen species. They do not bind 1-anilnonaphthalene-8-sulphonic acid and lack extensive beta-sheet structure. Aromatic interactions modulate, but are not required for toxicity. Not all IAPP oligomers are toxic; toxicity depends on their partially structured conformational states. Some anti-amyloid agents paradoxically prolong cytotoxicity by prolonging the lifetime of the toxic species. The data highlight the distinguishing properties of toxic IAPP oligomers and the common features that they share with toxic species reported for other amyloidogenic polypeptides, providing information for rational drug design to treat IAPP induced beta-cell death.

Pancreatic β-cell survival remains poorly understood despite decades of research. GATA transcription factors broadly regulate embryogenesis and influence survival of several cell types, but their role in adult β-cells remains undefined. To investigate the role of GATA factors in adult β-cells, we derived β-cell-inducible Gata4- and Gata6-knockout mice, along with whole-body inducible Gata4 knockouts. β-Cell Gata4 deletion modestly increased the proportion of dying β-cells in situ with ultrastructural abnormalities suggesting endoplasmic reticulum (ER) stress. Notably, glucose homeostasis was not grossly altered in Gata4- and Gata6-knockout mice, suggesting that GATA factors do not have essential roles in β-cells. Several ER stress signals were up-regulated in Gata4 and Gata6 knockouts, most notably CHOP, a known regulator of ER stress-induced apoptosis. However, ER stress signals were not elevated to levels observed after acute thapsigargin administration, suggesting that GATA deficiency only caused mild ER stress. Simultaneous deletion of Gata4 and CHOP partially restored β-cell survival. In contrast, whole-body inducible Gata4 knockouts displayed no evidence of ER stress in other GATA4-enriched tissues, such as heart. Indeed, distinct GATA transcriptional targets were differentially expressed in islets compared with heart. Such β-cell-specific findings prompted study of a large meta-analysis dataset to investigate single nucleotide polymorphisms harbored within the human GATA4 locus, revealing several variants significantly associated with type 1 diabetes mellitus. We conclude that GATA factors have important but nonessential roles to promote ER integrity and β-cell survival in a tissue-specific manner and that GATA factors likely contribute to type 1 diabetes mellitus pathogenesis.

Germ line PERK mutations are associated with diabetes mellitus and growth retardation in both rodents and humans. In contrast, late embryonic excision of PERK permits islet development and was found to prevent onset of diabetes, suggesting that PERK may be dispensable in the adult pancreas. To definitively establish the functional role of PERK in adult pancreata, we generated mice harboring a conditional PERK allele in which excision is regulated by tamoxifen administration. Deletion of PERK in either young adult or mature adult mice resulted in hyperglycemia associated with loss of islet and β cell architecture. PERK excision triggered intracellular accumulation of proinsulin and Glut2, massive endoplasmic reticulum (ER) expansion, and compensatory activation of the remaining unfolded-protein response (UPR) signaling pathways specifically in pancreatic tissue. Although PERK excision increased β cell death, this was not a result of decreased proliferation as previously reported. In contrast, a significant and specific increase in β cell proliferation was observed, a result reflecting increased cyclin D1 accumulation. This work demonstrates that contrary to expectations, PERK is required for secretory homeostasis and β cell survival in adult mice.