Defining Natural History: Assessment of the Ability of College Students to Aid in Characterizing Clinical Progression of Niemann-Pick Disease, Type C

Niemann-Pick Disease, type C (NPC) is a fatal, neurodegenerative, lysosomal storage disorder. It is a rare disease with broad phenotypic spectrum and variable age of onset. These issues make it difficult to develop a universally accepted clinical outcome measure to assess urgently needed therapies. To this end, clinical investigators have defined emerging, disease severity scales. The average time from initial symptom to diagnosis is approximately 4 years. Further, some patients may not travel to specialized clinical centers even after diagnosis. We were therefore interested in investigating whether appropriately trained, community-based assessment of patient records could assist in defining disease progression using clinical severity scores. In this study we evolved a secure, step wise process to show that pre-existing medical records may be correctly assessed by non-clinical practitioners trained to quantify disease progression. Sixty-four undergraduate students at the University of Notre Dame were expertly trained in clinical disease assessment and recognition of major and minor symptoms of NPC. Seven clinical records, randomly selected from a total of thirty seven used to establish a leading clinical severity scale, were correctly assessed to show expected characteristics of linear disease progression. Student assessment of two new records donated by NPC families to our study also revealed linear progression of disease, but both showed accelerated disease progression, relative to the current severity scale, especially at the later stages. Together, these data suggest that college students may be trained in assessment of patient records, and thus provide insight into the natural history of a disease

Prevention, diagnosis, and management of donor derived infections in pediatric kidney transplant recipients

Donor derived infections (DDIs) in pediatric kidney transplant recipients remain challenging to diagnose and can result in serious morbidity and mortality. This review summarizes the current guidelines and recommendations for prevention, diagnosis, and treatment of unexpected DDIs in pediatric kidney transplant recipients. We provide a contemporary overview of DDI terminology, surveillance, epidemiology, and recommended approaches for assessing these rare events with an emphasis on the pediatric recipient. To address prevention and risk mitigation, important aspects of donor and pediatric candidate evaluations are reviewed, including current Organ Procurement and Transplantation Network (OPTN) and American Society of Transplantation (AST) recommendations. Common unexpected DDI encountered by pediatric transplant teams including multi-drug resistant organisms, tuberculosis, syphilis, West Nile Virus, toxoplasmosis, Chagas disease, strongyloidiasis, candidiasis, histoplasmosis, coccidioidomycosis, and emerging infections such as COVID-19 are discussed in detail. Finally, we consider the general challenges with management of DDIs and share our experience with a novel application of next generation sequencing (NGS) of microbial cell-free DNA that will likely define a future direction in this field

Regulation of cardiac fibroblast collagen synthesis by adenosine: roles for Epac and PI3K

Rat cardiac fibroblasts (CF) express multiple adenosine (ADO) receptors. Pharmacological evidence suggests that activation of A2 receptors may inhibit collagen synthesis via adenylyl cyclase-induced elevation of cellular cAMP. We have characterized the signaling pathways involved in ADO-mediated inhibition of collagen synthesis in primary cultures of adult rat CF. ANG II stimulates collagen production in these cells. Coincubation with agents that elevate cellular cAMP [the ADO agonist, 5′-N-ethylcarboxamidoadensoine (NECA), and forskolin] inhibited the stimulatory effects of ANG II. However, direct stimulators and inhibitors of protein kinase A (PKA) did not alter ANG II-induced collagen synthesis, indicating that PKA does not mediate the inhibitory effects of NECA. Inhibitors of AMP-kinase (AMPK) and extracellular signal-regulated kinase 1/2 (ERK1/2) do not alter NECA-inhibited collagen synthesis. However, activation of exchange factor directly activated by cAMP (Epac) mimicked the effects of NECA on ANG II-stimulated collagen synthesis. Inhibition of phosphoinositol-3 kinase (PI3K) reduced the inhibitory effects of NECA on ANG II-induced collagen synthesis, suggesting that NECA acts via PI3K. Furthermore, inhibition of PI3K also relieved the inhibitory effect of Epac activation on ANG II-stimulated collagen synthesis. Thus it appears that ADO activates the A2R-Gs-adenylyl cyclase pathway and that the resultant cAMP reduces collagen synthesis via a PKA-independent, Epac-dependent pathway that feeds through PI3K