A mathematical model for cell cycle-specific cancer virotherapy

Oncolytic viruses preferentially infect and replicate in cancerous cells, leading to elimination of tumour populations, while sparing most healthy cells. Here, we study the cell cycle-specific activity of viruses such as vesicular stomatitis virus (VSV). In spite of its capacity as a robust cytolytic agent,VSVcannot effectively attack certain tumour cell types during the quiescent, or resting, phase of the cell cycle. In an effort to understand the interplay between the time course of the cell cycle and the specificity of VSV, we develop a mathematical model for cycle-specific virus therapeutics. We incorporate the minimum biologically required time spent in the non-quiescent cell cycle phases using systems of differential equations with incorporated time delays. Through analysis and simulation of the model, we describe how varying the minimum cycling time and the parameters that govern viral dynamics affect the stability of the cancer-free equilibrium, which represents therapeutic success

Integrating eye health training into the primary child healthcare programme in Tanzania: a pre-training and post-training study.

OBJECTIVES: To evaluate a primary child eye care training module for use in the WHO/UNICEF Integrated Management of Newborn and Childhood Illness (IMNCI) programme by primary healthcare workers. DESIGN: Pre-training and post-training study. SETTING: Primary healthcare facilities in a semirural district, central Tanzania. PARTICIPANTS: 54 primary healthcare workers selected by the Ministry of Health were trained during routine IMNCI training. All these healthcare workers were assessed pre-intervention and post-intervention. A subgroup of 40 were also assessed 6 months after the completion of training. INTERVENTION: Training in an IMNCI eye module, developed for child primary healthcare workers with the Tanzania Ministry of Health and eye care experts. MAIN OUTCOME MEASURES: Knowledge, skills and attitudes were assessed using multiple choice questions, case studies and a self-assessment of skills using a Likert scale before and immediately after training, and 6 months later. A total score was derived. At 6 months, attitudes were assessed in semistructured interviews. RESULTS: 69% PHWs trained were nurses. The baseline (before training) score was 29.9 (95% CI 27.5 to 32.4) and increased by 11.2 points (95% CI 8.3 to 14) immediately after training, and by 12.4 points (95% CI 9.2 to 15.6) at 6 months post the training. Therefore, the post-training scores increased and there was no evident difference in scores from immediately after training to 6 months later. Self-assessed confidence in skills decreased from 9/18 (95% CI 9 to 10) to 6/18 (95% CI 6 to 7). At 6 months, the module was reported as easy to understand and use, with challenges including difficulties in examining children's eyes and poor referral systems. CONCLUSIONS: The module increased knowledge of child eye health in primary healthcare workers, which was maintained, and was acceptable. The module has since been included into the national IMNCI health policy in Tanzania

Infrared Properties of High Redshift and X-ray Selected AGN Samples

The NASA/ISO Key Project on active galactic nuclei (AGN) seeks to better understand the broad-band spectral energy distributions (SEDs) of these sources from radio to X-rays, with particular emphasis on infrared properties. The ISO sample includes a wide variety of AGN types and spans a large redshift range. Two subsamples are considered herein: 8 high-redshift (1 < z < 4.7) quasars; and 22 hard X-ray selected sources. The X-ray selected AGN show a wide range of IR continuum shapes, extending to cooler colors than the optical/radio sample of Elvis et al. (1994). Where a far-IR turnover is clearly observed, the slopes are < 2.5 in all but one case so that non-thermal emission remains a possibility. The highest redshift quasars show extremely strong, hot IR continua requiring ~ 100 solar masses of 500 - 1000 Kelvin dust with ~ 100 times weaker optical emission. Possible explanations for these unusual properties include: reflection of the optical light from material above/below a torus; strong obscuration of the optical continuum; or an intrinsic deficit of optical emission.Comment: 8 pages, 3 figures (2 color), to be published in the Springer Lecture Notes of Physics Series as part of the proceedings for "ISO Surveys of a Dusty Universe," a workshop held at Ringberg Castle, Germany, November 8 - 12, 1999. Requires latex style files for this series: cl2emult.cls, cropmark.sty, lnp.sty, sprmindx.sty, subeqnar.sty (included with submission

Patterning the Tips of Optical Fibers with Metallic Nanostructures Using Nanoskiving

Convenient and inexpensive methods to pattern the facets of optical fibers with metallic nanostructures would enable many applications. This communication reports a method to generate and transfer arrays of metallic nanostructures to the cleaved facets of optical fibers. The process relies on nanoskiving, in which an ultramicrotome, equipped with a diamond knife, sections epoxy nanostructures coated with thin metallic films and embedded in a block of epoxy. Sectioning produces arrays of nanostructures embedded in thin epoxy slabs, which can be transferred manually to the tips of optical fibers at a rate of approximately 2 min−1, with 88% yield. Etching the epoxy matrices leaves arrays of nanostructures supported directly by the facets of the optical fibers. Examples of structures transferred include gold crescents, rings, high-aspect-ratio concentric cylinders, and gratings of parallel nanowires.Chemistry and Chemical Biolog

Soil-sebum partition coefficients for high molecular weight polycyclic aromatic hydrocarbons (HMW-PAH)

In vitro high molecular weight polycyclic aromatic hydrocarbons (HMW-PAH) soil-sebum partition coefficients (KSS) were measured for twelve soils collected from former UK gasworks. Concentrations of ∑16 USEPA PAH in the soils ranged from 51 to 1440 mg/kg. Time series extractions (0.5, 1, 2, 4, 8 and 24 h) at skin temperature (32 °C) of HMW-PAH from sebum to soil for two samples were conducted to determine the maximum release time-step. The maximum HMW-PAH release time-step was determined as 4 h, which was subsequently used as the extraction time for the remaining samples. The 4 h extraction for all samples showed HMW-PAH KSS ranging from 0.06 to 1.4 (median = 0.59; mean = 0.59; standard deviation = 0.27; median absolute deviation = 0.29). Evaluation of KSS data for the 4 h extractions showed that soil type and selected HMW-PAH properties (literature based molecular weight and octanol-carbon partition coefficients) affect the amount of HMW-PAH released from soil into sebum

Blocking the apoE/Aβ interaction ameliorates Aβ-related pathology in APOE ε2 and ε4 targeted replacement Alzheimer model mice

Accumulation of β-amyloid (Aβ) in the brain is essential to Alzheimer’s disease (AD) pathogenesis. Carriers of the apolipoprotein E (APOE) ε4 allele demonstrate greatly increased AD risk and enhanced brain Aβ deposition. In contrast, APOE ε2 allele carries show reduced AD risk, later age of disease onset, and lesser Aβ accumulation. However, it remains elusive whether the apoE2 isoform exerts truly protective effect against Aβ pathology or apoE2 plays deleterious role albeit less pronounced than the apoE4 isoform. Here, we characterized APP(SW)/PS1(dE9)/APOE ε2-TR (APP/E2) and APP(SW)/PS1(dE9)/APOE ε4-TR (APP/E4) mice, with targeted replacement (TR) of the murine Apoe for human ε2 or ε4 alleles, and used these models to investigate effects of pharmacological inhibition of the apoE/Aβ interaction on Aβ deposition and neuritic degeneration. APP/E2 and APP/E4 mice replicate differential effect of human apoE isoforms on Aβ pathology with APP/E4 mice showing a several-fold greater load of Aβ plaques, insoluble brain Aβ levels, Aβ oligomers, and density of neuritic plaques than APP/E2 mice. Furthermore, APP/E4 mice, but not APP/E2 mice, exhibit memory impairment on object recognition and radial arm maze tests. Between the age of 6 and 10 months APP/E2 and APP/E4 mice received treatment with Aβ12-28P, a non-toxic, synthetic peptide homologous to the apoE binding motif within the Aβ sequence, which competitively blocks the apoE/Aβ interaction. In both lines, the treatment significantly reduced brain Aβ accumulation, co-accumulation of apoE within Aβ plaques, and neuritic degeneration, and prevented memory deficit in APP/E4 mice. These results indicate that both apoE2 and apoE4 isoforms contribute to Aβ deposition and future therapies targeting the apoE/Aβ interaction could produce favorable outcome in APOE ε2 and ε4 allele carriers. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40478-014-0075-0) contains supplementary material, which is available to authorized users

APOE genotype differentially modulates effects of anti-Aβ, passive immunization in APP transgenic mice

BACKGROUND: APOE genotype is the foremost genetic factor modulating β-amyloid (Aβ) deposition and risk of sporadic Alzheimer’s disease (AD). Here we investigated how APOE genotype influences response to anti-Aβ immunotherapy. METHODS: APP(SW)/PS1(dE9) (APP) transgenic mice with targeted replacement of the murine Apoe gene for human APOE alleles received 10D5 anti-Aβ or TY11-15 isotype control antibodies between the ages of 12 and 15 months. RESULTS: Anti-Aβ immunization decreased both the load of fibrillar plaques and the load of Aβ immunopositive plaques in mice of all APOE backgrounds. Although the relative reduction in parenchymal Aβ plaque load was comparable across all APOE genotypes, APP/ε4 mice showed the greatest reduction in the absolute Aβ plaque load values, given their highest baseline. The immunization stimulated phagocytic activation of microglia, which magnitude adjusted for the post-treatment plaque load was the greatest in APP/ε4 mice implying association between the ε4 allele and impaired Aβ phagocytosis. Perivascular hemosiderin deposits reflecting ensued microhemorrhages were associated with vascular Aβ (VAβ) and ubiquitously present in control mice of all APOE genotypes, although in APP/ε3 mice their incidence was the lowest. Anti-Aβ immunization significantly reduced VAβ burden but increased the number of hemosiderin deposits across all APOE genotypes with the strongest and the weakest effect in APP/ε2 and APP/ε3 mice, respectively. CONCLUSIONS: Our studies indicate that APOE genotype differentially modulates microglia activation and Aβ plaque load reduction during anti-Aβ immunotherapy. The APOE ε3 allele shows strong protective effect against immunotherapy associated microhemorrhages; while, conversely, the APOE ε2 allele increases risk thereof. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13024-017-0156-1) contains supplementary material, which is available to authorized users

Adherence to the iDSI reference case among published cost-per-DALY averted studies

Background The iDSI reference case, originally published in 2014, aims to improve the quality and comparability of cost-effectiveness analyses (CEA). This study assesses whether the development of the guideline is associated with an improvement in methodological and reporting practices for CEAs using disability-adjusted life-years (DALYs). Methods We analyzed the Tufts Medical Center Global Health CEA Registry to identify cost-per-DALY averted studies published from 2011 to 2017. Among each of 11 principles in the iDSI reference case, we translated all methodological specifications and reporting standards into a series of binary questions (satisfied or not satisfied) and awarded articles one point for each item satisfied. We then calculated methodological and reporting adherence scores separately as a percentage of total possible points, measured as normalized adherence score (0% = no adherence; 100% = full adherence). Using the year 2014 as the dissemination period, we conducted a pre-post analysis. We also conducted sensitivity analyses using: 1) optional criteria in scoring, 2) alternate dissemination period (2014–2015), and 3) alternative comparator classification. Results Articles averaged 60% adherence to methodological specifications and 74% adherence to reporting standards. While methodological adherence scores did not significantly improve (59% pre-2014 vs. 60% post-2014, p = 0.53), reporting adherence scores increased slightly over time (72% pre-2014 vs. 75% post-2014, p<0.01). Overall, reporting adherence scores exceeded methodological adherence scores (74% vs. 60%, p<0.001). Articles seldom addressed budget impact (9% reporting, 10% methodological) or equity (7% reporting, 7% methodological). Conclusions The iDSI reference case has substantial potential to serve as a useful resource for researchers and policy-makers in global health settings, but greater effort to promote adherence and awareness is needed to achieve its potential

Caregiver Participation Engagement in Child Mental Health Prevention Programs: a Systematic Review

Prevention programs are a key method to reduce the prevalence and impact of mental health disorders in childhood and adolescence. Caregiver participation engagement (CPE), which includes caregiver participation in sessions as well as follow-through with homework plans, is theorized to be an important component in the effectiveness of these programs. This systematic review aims to (1) describe the terms used to operationalize CPE and the measurement of CPE in prevention programs, (2) identify factors associated with CPE, (3) examine associations between CPE and outcomes, and (4) explore the effects of strategies used to enhance CPE. Thirty-nine articles representing 27 unique projects were reviewed. Articles were included if they examined CPE in a program that focused to some extent on preventing child mental health disorders. There was heterogeneity in both the terms used to describe CPE and the measurement of CPE. The majority of projects focused on assessment of caregiver home practice. There were no clear findings regarding determinants of CPE. With regard to the impact of CPE on program outcomes, higher levels of CPE predicted greater improvements in child and caregiver outcomes, as well as caregiver-child relationship quality. Finally, a small number of studies found that motivational and behavioral strategies (e.g., reinforcement, appointment reminders) were successful in promoting CPE. This review highlights the importance of considering CPE when developing, testing, and implementing prevention programs for child mental health disorders. Increased uniformity is needed in the measurement of CPE to facilitate a better understanding of determinants of CPE. In addition, the field would benefit from further evaluating strategies to increase CPE as a method of increasing the potency of prevention programs