Current Challenges for the Early Detection of Alzheimer's Disease: Brain Imaging and CSF Studies

The development of prevention therapies for Alzheimer's disease (AD) would greatly benefit from biomarkers that are sensitive to the subtle brain changes that occur in the preclinical stage of the disease. Reductions in the cerebral metabolic rate of glucose (CMRglc), a measure of neuronal function, have proven to be a promising tool in the early diagnosis of AD. In vivo brain 2-[18F]fluoro-2-Deoxy-D-glucose-positron emission tomography (FDG-PET) imaging demonstrates consistent and progressive CMRglc reductions in AD patients, the extent and topography of which correlate with symptom severity. There is increasing evidence that hypometabolism appears during the preclinical stages of AD and can predict decline years before the onset of symptoms. This review will give an overview of FDG-PET results in individuals at risk for developing dementia, including: presymptomatic individuals carrying mutations responsible for early-onset familial AD; patients with Mild Cognitive Impairment (MCI), often a prodrome to late-onset sporadic AD; non-demented carriers of the Apolipoprotein E (ApoE) ε4 allele, a strong genetic risk factor for late-onset AD; cognitively normal subjects with a family history of AD; subjects with subjective memory complaints; and normal elderly followed longitudinally until they expressed the clinical symptoms and received post-mortem confirmation of AD. Finally, we will discuss the potential to combine different PET tracers and CSF markers of pathology to improve the early detection of AD

Risk Factors for SARS-CoV-2 Infection Among US Healthcare Personnel, May-December 2020

To determine risk factors for coronavirus disease (COVID-19) among US healthcare personnel (HCP), we conducted a case-control analysis. We collected data about activities outside the workplace and COVID-19 patient care activities from HCP with positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test results (cases) and from HCP with negative test results (controls) in healthcare facilities in 5 US states. We used conditional logistic regression to calculate adjusted matched odds ratios and 95% CIs for exposures. Among 345 cases and 622 controls, factors associated with risk were having close contact with persons with COVID-19 outside the workplace, having close contact with COVID-19 patients in the workplace, and assisting COVID-19 patients with activities of daily living. Protecting HCP from COVID-19 may require interventions that reduce their exposures outside the workplace and improve their ability to more safely assist COVID-19 patients with activities of daily living

Pro 2000 Elicits A Decline In Genital Tract Immune Mediators Without Compromising Intrinsic Antimicrobial Activity

OBJECTIVE: Vaginal microbicides should protect against infection without disrupting the mucosal environment or its mediators of host defense. The objective of this study was to examine the effect of 14 daily applications of 0.5% PRO 2000 or placebo gel on mediators of mucosal immunity and intrinsic antimicrobial activity. DESIGN AND METHODS: A randomized, prospective, double-blind, placebo-controlled study was conducted among 24 healthy, abstinent women. Levels of cytokines, chemokines, defensins, and other protective factors and intrinsic antimicrobial activity were determined in cervicovaginal lavage samples collected on study days 0, 7, 14, and 21. RESULTS: No increase in pro-inflammatory cytokines was observed. Rather cytokines and protective factors including interleukin (IL)-1 receptor antagonist, immunoglobulins and human beta-defensin 2 were lower in the drug compared with the placebo group. All of the mediators returned towards baseline on day 21. Women who were cycling had lower levels of most proteins on study days 7 and/or 14 compared with women on oral contraceptives; however, the magnitude of decline was greater in women who received PRO 2000 compared with placebo gel. The reduction in protective factors was not associated with a loss in the intrinsic anti-viral (HIV or herpes simplex virus) activity or anti-bacterial activity (Escherichia coli or Staphylococcus aureus). CONCLUSION: In contrast to experience with nonoxynol-9, PRO 2000 did not trigger an inflammatory response in cervicovaginal secretions. There was a modest reduction in mucosal immune mediators, but this loss was not associated with a reduction in intrinsic antimicrobial activity. © 2007 Lippincott Williams & Wilkins, Inc

Markers of Cardiovascular Dysfunction in Adolescents With Anorexia Nervosa

Background . Cardiovascular complications contribute to the high morbidity and mortality rate among children with anorexia nervosa (AN). Advances in cardiac imaging permit a more comprehensive assessment of myocardial performance in children that could not be previously obtained with conventional imaging. Myocardial strain analysis is an emerging quantitative echocardiographic technique to characterize global and regional ventricular function in children. Objective . To assess global and regional left ventricular (LV0 function in children newly diagnosed with AN with conventional and quantitative 2-dimensional speckle tracking echocardiographic (2DSTE)–derived strain imaging. Materials . In a cross-sectional study of 30 patients with AN ( DSM-5 ) and 14 age-, sex-, and race-matched healthy children, markers of cardiovascular risk, conventional and 2DSTE measures of LV function, and structure were evaluated and compared. The AN cohort was further stratified by behavioral patterns (restrict, exercise, or purge). Results . Conventional measures and LV global strain were similar between controls and children with AN. A subgroup of AN children with purging behavior had LV remodeling characterized by significantly decreased LV mass index. Regional ventricular function at the apex, as measured by strain, was also decreased in all AN patients. Percent change from ideal body weight, body mass index Z -score, electrolyte profiles, heart rate, and blood pressure were similar. Conclusions . Subclinical regional ventricular dysfunction is present in children with AN. Ventricular remodeling exists in a subgroup of children with AN in association with purging behavior. Future studies may utilize strain imaging to identify those AN patients who are at an increased risk for developing significant cardiac dysfunction

Molecular Umbrellas: a Novel Class of Candidate Topical Microbicides To Prevent Human Immunodeficiency Virus and Herpes Simplex Virus Infections▿

Molecular umbrella compounds may function as novel topical microbicides to prevent human immunodeficiency virus (HIV) and herpes simplex virus (HSV) infections. In a preliminary structure-activity investigation, one umbrella compound, designated Spm8CHAS, was identified which inhibited both HIV and HSV infections with no cellular toxicity. The objectives of the current studies were to define its spectrum of antiviral activity, characterize its mechanism of action, and explore the possibility of combining Spm8CHAS with HIV-specific reverse transcriptase inhibitors. Spm8CHAS inhibited infections by laboratory and clinical R5 and X4 clade B and clade C HIV strains in cell culture. Ectocervical tissue explants exposed to HIV-1BaL in the presence of Spm8CHAS were completely protected (50% inhibitory concentration [IC50], 13.6 μg/ml), and transfer of virus to target T cells via migratory cells was abolished (IC50, 3.8 μg/ml). Spm8CHAS inhibited HSV-2 infection of epithelial cells 10,000-fold if present throughout the infection. Notably, adding Spm8CHAS to cultures following HSV entry significantly reduced viral infection, indicating that the drug also acts postentry. Subsequent studies indicated that Spm8CHAS blocks cell-to-cell spread of HSV. Confocal microscopy using a fluorescently labeled analog of Spm8CHAS demonstrated that this conjugate crosses the plasma cell membrane and is transported to the nucleus. Combinations of Spm8CHAS with UC-781 or 9-[R-2-(phosphonylmethoxy)propyl] adenine monohydrate in vitro exhibited additive anti-HIV activity with preserved anti-HSV activity. The abilities of Spm8CHAS to inhibit primary isolates of HIV, block HSV infection postentry, and cross cell membranes support the development of a combination microbicide containing Spm8CHAS with an HIV-specific reverse transcriptase inhibitor to prevent both HIV and HSV infections by multiple mechanisms

Mean-field models of structure and dispersion of polymer-nanoparticle mixtures

We review some recent research developments in coarse-grained modeling based on mean-field approaches of the equilibrium dispersion and structure of polymer nanoparticle composites. We focus on three issues: (i) dispersion and phase behavior of particles in homopolymer matrices; (ii) dispersion in mixtures of homopolymers with grafted nanoparticles; (iii) self-assembly and organization of nanoparticles in block copolymer matrices. In each of these topics, we highlight that the dispersability and the resulting structure of the nanoparticle suspension may exhibit far more complexities than one may deduce using simple miscibility criterion involving the energetic interactions between the polymer matrix and the particle. In each case, we review our own research contributions accompanied by a brief discussion of related theoretical studies and some possible future directions.Chemical Engineerin