Accuracy and Feasibility of Three-Dimensional Ultrasound Testing in Eye Clinic and Emergency Department Patients with Vision Complaints.

BACKGROUND: Ocular emergencies comprise 2-3% of emergency department (ED) visits, with retinal detachment requiring emergency surgery. Two-dimensional ultrasound is a rapid bedside tool but is highly operator dependent. OBJECTIVE: We determined three-dimensional ultrasound (3DUS) feasibility, acceptability, and usability in eye pathology detection using the ophthalmologist examination as reference standard. METHODS: We performed a prospective, blinded cohort study of a 3DUS-enabling device in 30 eye clinic and ED patients with visual symptoms and calculated 3DUS performance characteristics. Two expert readers interpreted the 3DUS images for pathology. All participants completed surveys. RESULTS: 3DUS sensitivity was 0.81, specificity 0.73, positive predictive value 0.54, negative predictive value 0.91, and likelihood ratio (LR)+/LR- 3.03 and 0.26, respectively. Novice and expert sonographers had "substantial" agreement in correct diagnosis of abnormal vs. normal (κ = 0.68, 95% confidence interval 0.48-0.88). Most patients indicated that 3DUS is fast, comfortable, helps them understand their problem, and improves provider interaction/care, and all sonographers agreed; 4/5 sonographers felt confident performing ultrasound. Expert readers correctly identified an abnormal eye in 83/120 scans (76%) and correct diagnosis in 72/120 scans (65%), with no statistical difference between novice (79%; 69%) and expert (72%; 61%) sonographers (p = 0.39, p = 0.55), suggesting reduced operator dependence. Reader diagnosis confidence and image quality varied widely. Image acquisition times were fast for novice (mean 225 ± 83 s) and expert (201 ± 51) sonographers, with fast expert reader interpretation times (225 ± 136). CONCLUSIONS: A 3DUS-enabling device demonstrates a sensitivity of 0.81 and specificity of 0.73 for disease detection, fast image acquisition, and may reduce operator dependence for detecting emergent retinal pathologies. Further technological development is needed to improve diagnostic accuracy in identifying and characterizing retinal pathology.

Velocity changes in femoral vessel ultrasound with Doppler in Porcine hemorrhagic shock.

Objective: Physician-directed point-of-care ultrasound (PoCUS) is routinely used to identify the etiology of shock and guide therapy in the ICU. We performed a preclinical study to determine what changes are manifested in the femoral vessels during hemorrhagic shock on Duplex imaging and to generate a femoral vessel sonographic profile over the time course of shock. Design & setting: A preclinical study in swine was performed using a convenience sample of animals that were being used in a Trauma Surgery training lab. The animals developed progressive unregulated hemorrhage during the lab. Subjects: Six anesthetized swine underwent Duplex studies of the femoral vessels prior to any hemorrhage and at two time points after the start of hemorrhage. Interventions: N/A. Measurements: Femoral vessel imaging was performed using a portable ultrasound (Sonosite and Clarius). Main results: Femoral arterial peak systolic velocity decreased in all animals with hemorrhage, from a mean (SD) of 77 (27) cm/s pre-hemorrhage to 42 (17) and 32 (16) cm/s at the two post-hemorrhage time points. There were also changes to the arterial waveform morphology. Mean venous velocities also decreased with hemorrhage (20, 11, 7 cm/s). Animals with severe hemorrhage had a cessation of venous flow during positive pressure ventilation. Conclusion: In this preclinical study, both femoral peak systolic velocity and venous velocity decreased with hemorrhage. Femoral vessels represent an easily accessible target for non-invasive hemodynamic monitoring. Changes in femoral vessel Duplex waveforms and velocities should be studied both in a larger sample of animals with controlled hemorrhage and in human trauma patients to determine whether changes appear in early hemorrhage, before the onset of clinically evident hemorrhagic shock.

Systematic review and meta-analysis of the accuracy of MRI to diagnose appendicitis in the general population.

PURPOSE: To perform a systematic review and meta-analysis of all published studies since 2005 that evaluate the accuracy of magnetic resonance imaging (MRI) for the diagnosis of acute appendicitis in the general population presenting to emergency departments. MATERIALS AND METHODS: All retrospective and prospective studies evaluating the accuracy of MRI to diagnose appendicitis published in English and listed in PubMed, Web of Science, Cinahl Plus, and the Cochrane Library since 2005 were included. Excluded studies were those without an explicitly stated reference standard, with insufficient data to calculate the study outcomes, or if the population enrolled was limited to pregnant women or children. Data were abstracted by one investigator and confirmed by another. Data included the number of true positives, true negatives, false positives, false negatives, number of equivocal cases, type of MRI scanner, type of MRI sequence, and demographic data including study setting and gender distribution. Summary test characteristics were calculated. Forest plots and a summary receiver operator characteristic plot were generated. RESULTS: Ten studies met eligibility criteria, representing patients from seven countries. Nine were prospective and two were multicenter studies. A total of 838 subjects were enrolled; 406 (48%) were women. All studies routinely used unenhanced MR images, although two used intravenous contrast-enhancement and three used diffusion-weighted imaging. Using a bivariate random-effects model the summary sensitivity was 96.6% (95% confidence interval [CI]: 92.3%-98.5%) and summary specificity was 95.9% (95% CI: 89.4%-98.4%). CONCLUSION: MRI has a high sensitivity and specificity for the diagnosis of appendicitis, similar to that reported previously for computed tomography. J. Magn. Reson. Imaging 2016;43:1346-1354.

Convergence of presenilin- and tau-mediated pathways on axonal trafficking and neuronal function.

Alzheimer's disease (AD) is a significant and growing health problem in the aging population. Although definitive mechanisms of pathogenesis remain elusive, genetic and histological clues have implicated the proteins presenilin (PS) and tau as key players in AD development. PS mutations lead to familial AD, and although tau is not mutated in AD, tau pathology is a hallmark of the disease. Axonal transport deficits are a common feature of several neurodegenerative disorders and may represent a point of intersection of PS and tau function. To investigate the contribution of wild-type, as opposed to mutant, tau to axonal transport defects in the context of presenilin loss, we used a mouse model postnatally deficient for PS (PS cDKO) and expressing wild-type human tau (WtTau). The resulting PS cDKO;WtTau mice exhibited early tau pathology and axonal transport deficits that preceded development of these phenotypes in WtTau or PS cDKO mice. These deficits were associated with reduced neurotrophin signaling, defective learning and memory and impaired synaptic plasticity. The combination of these effects accelerated neurodegeneration in PS cDKO;WtTau mice. Our results strongly support a convergent role for PS and tau in axonal transport and neuronal survival and function and implicate their misregulation as a contributor to AD pathogenesis.

Increased Human Wildtype Tau Attenuates Axonal Transport Deficits Caused by Loss of APP in Mouse Models.

Amyloid precursor protein (APP) is implicated in axonal elongation, synaptic plasticity, and axonal transport. However, the role of APP on axonal transport in conjunction with the microtubule associated protein tau continues to be debated. Here we measured in vivo axonal transport in APP knockout mice with Manganese Enhanced MRI (MEMRI) to determine whether APP is necessary for maintaining normal axonal transport. We also tested how overexpression and mutations of tau affect axonal transport in the presence or absence of APP. In vivo axonal transport reduced significantly in the absence of functional APP. Overexpression of human wildtype tau maintained normal axonal transport and resulted in a transient compensation of axonal transport deficits in the absence of APP. Mutant R406Wtau in combination with the absence of APP compounded axonal transport deficits and these deficits persisted with age. These results indicate that APP is necessary for axonal transport, and overexpression of human wildtype tau can compensate for the absence of APP at an early age.

Pen2 and presenilin-1 modulate the dynamic equilibrium of presenilin-1 and presenilin-2 gamma-secretase complexes.

gamma-Secretase is known to play a pivotal role in the pathogenesis of Alzheimer disease through production of amyloidogenic Abeta42 peptides. Early onset familial Alzheimer disease mutations in presenilin (PS), the catalytic core of gamma-secretase, invariably increase the Abeta42:Abeta40 ratio. However, the mechanism by which these mutations affect gamma-secretase complex formation and cleavage specificity is poorly understood. We show that our in vitro assay system recapitulates the effect of PS1 mutations on the Abeta42:Abeta40 ratio observed in cell and animal models. We have developed a series of small molecule affinity probes that allow us to characterize active gamma-secretase complexes. Furthermore we reveal that the equilibrium of PS1- and PS2-containing active complexes is dynamic and altered by overexpression of Pen2 or PS1 mutants and that formation of PS2 complexes is positively correlated with increased Abeta42:Abeta40 ratios. These data suggest that perturbations to gamma-secretase complex equilibrium can have a profound effect on enzyme activity and that increased PS2 complexes along with mutated PS1 complexes contribute to an increased Abeta42:Abeta40 ratio.

Lack of alpha-synuclein increases amyloid plaque accumulation in a transgenic mouse model of Alzheimer's disease.

Alpha-synuclein is a small soluble, cytosolic protein which associates with vesicular membranes. It is a component of intracellular Lewy bodies present in Parkinson's disease and a subset of Alzheimer's disease (AD). In addition, early studies identified a fragment of alpha-synuclein in the amyloid plaques of AD patients. Hypothesizing that alpha-synuclein might modify the AD pathogenic process, we crossed the Tg2576 strain of APP transgenic mice onto an alpha-synuclein knockout background to determine the effects of alpha-synuclein on Abeta production and plaque deposition. We found that alpha-synuclein deficiency does not affect the Abeta levels, nor does it alter the age of onset of plaque pathology. To our surprise, however, loss of alpha-synuclein leads to a significant increase in plaque load in all areas of the forebrain at 18 months of age. This is associated with an increase in another synaptic protein, synaptophysin. We thus conclude that alpha-synuclein is not involved in seeding of the plaques, but rather suppresses the progression of plaque pathology at advanced stages.

Deletion of presenilin 1 hydrophilic loop sequence leads to impaired gamma-secretase activity and exacerbated amyloid pathology.

gamma-Secretase processing of the amyloid precursor protein (APP) generates Abeta40 and Abeta42, peptides that constitute the principal components of the beta-amyloid plaque pathology of Alzheimer's disease (AD). The gamma-secretase activity is executed by a high-molecular-weight complex of which presenilin 1 (PS1) is an essential component. PS1 is a multi-pass membrane protein, and the large hydrophilic loop domain between transmembrane domains 6 and 7 has been shown to interact with various proteins. To determine the physiological function of the loop domain, we created a strain of PS1 knock-in mice in which the exon 10, which encodes most of the hydrophilic loop sequence, was deleted from the endogenous PS1 gene. We report here that the homozygous exon 10-deleted mice are viable but exhibit drastically reduced gamma-secretase cleavage at the Abeta40, but not the Abeta42, site. Surprisingly, this reduction of Abeta40 is associated with exacerbated plaque pathology when expressed on APP transgenic background. Thus, the PS1 loop plays a regulatory role in gamma-secretase processing, and decreased Abeta40, not increased Abeta42 is likely the cause for the accelerated plaque deposition in these animals. Our finding supports a protective role of Abeta40 against amyloid pathology and raises the possibility that impaired gamma-secretase activity could be the basis for AD pathogenesis in general.