The neurodegeneration that occurs in sporadic Alzheimer's disease (AD) is consistently associated with a number of characteristic histopathological, molecular, and biochemical abnormalities, including cell loss, abundant neurofibrillary tangles and dystrophic neurites, amyloid-β deposits, increased activation of pro-death genes and signaling pathways, impaired energy metabolism/mitochondrial function, and evidence of chronic oxidative stress. The general inability to convincingly link these phenomena has resulted in the emergence and propagation of various heavily debated theories that focus on the role of one particular element in the pathogenesis of all other abnormalities. However, the accumulating evidence that reduced glucose utilization and deficient energy metabolism occur early in the course of disease, suggests a role for impaired insulin signaling in the pathogenesis of AD. The present work demonstrates extensive abnormalities in insulin and insulin-like growth factorm typer I and II (IGF-I and IGF-II) signaling mechanisms in brains with AD, and shows that while each of the corresponding growth factors is normally made in central nervous system (CNS) neurons, the expression levels are markedly reduced in AD. These abnormalities were associated with reduced levels of insulin receptor substrate (IRS) mRNA, tau mRNA, IRS-associated phosphotidylinositol 3-kinase, and phospho-Akt (activated), and increased glycogen synthase kinase-3β activity and amyloid precursor protein mRNA expression. The strikingly reduced CNS expression of genes encoding insulin, IGF-I, and IGF-II, as well as the insulin and IGF-I receptors, suggests that AD may represent a neuro-endocrine disorder that resembles, yet is distinct from diabetes mellitus. Therefore, we propose the term, "Type 3 Diabetes" to reflect this newly identified pathogenic mechanism of neurodegeneration.

No abstract

We report a role for CA repeats in the 3 -untranslated region (3 -UTR) in regulating CD154 expression. Human CD154 is encoded by an unstable mRNA; this instability is conferred in cis by a portion of its 3 -UTR that includes a polypyrimidine-rich region and CA dinucleotide repeat. We demonstrate similar instability activity with the murine CD154 3 -UTR. This instability element mapped solely to a conserved 100-base CU-rich region alone, which we call a CU-rich response element. Surprisingly, the CA dinucleotide-rich region also regulated reporter expression but at the level of translation. This activity was associated with poly(A) tail shortening and regulated by heterogeneous nuclear ribonucleoprotein L levels. We conclude that the CD154 3 -UTR contains dual cis-acting elements, one of which defines a novel function for exonic CA dinucleotide repeats. These findings suggest a mechanism for the association of 3 -UTR CA-rich response element polymorphisms with CD154 overexpression and the subsequent risk of autoimmune disease.

IntroductionAccess to high-quality emergency care in low- and middle-income countries (LMIC) is lacking. Many countries utilise a strategy known as “task-shifting” where skills and responsibilities are distributed in novel ways among healthcare personnel. Point-of-care ultrasound (POCUS) has the potential to significantly improve emergency care in LMICs.MethodsPOCUS was incorporated into a training program for a ten-person cohort of non-physician Emergency Care Providers (ECPs) in rural Uganda. We performed a prospective observational evaluation on the impact of a remote, rapid review of POCUS studies on the primary objective of ECP ultrasound quality and secondary objective of ultrasound utilisation. The study was divided into four phases over 11 months: an initial in-person training month, two middle month blocks where ECPs performed ultrasounds independently without remote electronic feedback, and the final months when ECPs performed ultrasounds independently with remote electronic feedback. Quality was assessed on a previously published eight-point ordinal scale by a U.S.-based expert sonographer and rapid standardised feedback was given to ECPs by local staff. Sensitivity and specificity of ultrasound exam findings for the Focused Assessment with Sonography for Trauma (FAST) was calculated.ResultsOver the study duration, 1153 ultrasound studies were reviewed. Average imaging frequency per ECP dropped 61% after the initial in-person training month (p = 0.01) when ECPs performed ultrasound independently, but rebounded once electronic feedback was initiated (p = 0.001), with an improvement in quality from 3.82 (95% CI, 3.32–4.32) to 4.68 (95% CI, 4.35–5.01) on an eight-point scale. The sensitivity and specificity of FAST exam during the initial training period was 77.8 (95% CI, 59.2–83.0) and 98.5 (95% CI, 93.3–99.9), respectively. Sensitivity improved 88% compared to independent, non-feedback months whereas specificity was unchanged.ConclusionsRemotely delivered quality assurance feedback is an effective educational tool to enhance provider skill and foster continued and sustainable use of ultrasound in LMICs.