Physical properties of root cementum: Part 26. Effects of micro-osteoperforations on orthodontic root resorption: A microcomputed tomography study.

INTRODUCTION: Studies have demonstrated the potential efficacy of micro-osteoperforations in accelerating tooth movement by amplifying the expression of inflammatory markers. The aim of this investigation was to examine the effects of micro-osteoperforations on orthodontic root resorption with microcomputed tomography. METHODS: This prospective controlled clinical trial involved 20 subjects requiring extraction of the maxillary first premolars as part of their orthodontic treatment. A buccal tipping force of 150 g was applied to both premolars. Using the Propel appliance (Propel Orthodontics, San Jose, Calif), micro-osteoperforations were applied at a depth of 5 mm on the mesial and distal aspects in the midroot region of the experimental side of the first premolar root; the contralateral side served as the control. After 28 days, both premolars were extracted. The teeth were scanned under microcomputed tomography, and the volumes of root resorption craters were calculated and compared. RESULTS: Premolars treated with micro-osteoperforation exhibited significantly greater average total amounts of root resorption than did the control teeth (0.576 vs 0.406 mm3). The total average volumetric root loss of premolars treated with micro-osteoperforation was 42% greater than that of the control teeth. CONCLUSIONS: This 28-day trial showed that micro-osteoperforations resulted in greater orthodontic root resorption. However, these results should be verified in patients who are undergoing full-length orthodontic treatment.

Examining the Spatial Varying Effects of Sociodemographic Factors on Adult Cochlear Implantation Using Geographically Weighted Poisson Regression.

OBJECTIVE: To (i) demonstrate the utility of geographically weighted Poisson regression (GWPR) in describing geographical patterns of adult cochlear implant (CI) incidence in relation to sociodemographic factors in a publicly funded healthcare system, and (ii) compare Poisson regression and GWPR to fit the aforementioned relationship. STUDY DESIGN: Retrospective study of provincial CI Program database. SETTING: Academic hospital. PATIENTS: Adults 18 years or older who received a CI from 2020 to 2021. INTERVENTIONS: Cochlear implant. MAIN OUTCOME MEASURES: CI incidence based on income level, education attainment, age at implantation, and distance from center, and spatial autocorrelation across census metropolitan areas. RESULTS: Adult CI incidence varied spatially across Ontario (Moran's I = 0.04, p < 0.05). Poisson regression demonstrated positive associations between implantation and lower income level (coefficient = 0.0284, p < 0.05) and younger age (coefficient = 0.1075, p < 0.01), and a negative association with distance to CI center (coefficient = -0.0060, p < 0.01). Spatial autocorrelation was significant in Poisson model (Moran's I = 0.13, p < 0.05). GWPR accounted for spatial differences (Moran's I = 0.24, p < 0.690), and similar associations to Poisson were observed. GWPR further identified clusters of implantation in South Central census metropolitan areas with higher education attainment. CONCLUSIONS: Adult CI incidence demonstrated a nonstationary relationship between implantation and the studied sociodemographic factors. GWPR performed better than Poisson regression in accounting for these local spatial variations. These results support the development of targeted interventions to improve access and utilization to CIs in a publicly funded healthcare system.

Poor early cortical differentiation of speech predicts perceptual difficulties of severely hearing-impaired listeners in multi-talker environments.

Hearing impairment disrupts processes of selective attention that help listeners attend to one sound source over competing sounds in the environment. Hearing prostheses (hearing aids and cochlear implants, CIs), do not fully remedy these issues. In normal hearing, mechanisms of selective attention arise through the facilitation and suppression of neural activity that represents sound sources. However, it is unclear how hearing impairment affects these neural processes, which is key to understanding why listening difficulty remains. Here, severely-impaired listeners treated with a CI, and age-matched normal-hearing controls, attended to one of two identical but spatially separated talkers while multichannel EEG was recorded. Whereas neural representations of attended and ignored speech were differentiated at early (~ 150 ms) cortical processing stages in controls, differentiation of talker representations only occurred later (~250 ms) in CI users. CI users, but not controls, also showed evidence for spatial suppression of the ignored talker through lateralized alpha (7-14 Hz) oscillations. However, CI users' perceptual performance was only predicted by early-stage talker differentiation. We conclude that multi-talker listening difficulty remains for impaired listeners due to deficits in early-stage separation of cortical speech representations, despite neural evidence that they use spatial information to guide selective attention.

Immune cell-based screening assay for response to anticancer agents: applications in pharmacogenomics.

BACKGROUND: Interpatient variability in immune and chemotherapeutic cytotoxic responses is likely due to complex genetic differences and is difficult to ascertain in humans. Through the use of a panel of genetically diverse mouse inbred strains, we developed a drug screening platform aimed at examining interstrain differences in viability on normal, noncancerous immune cells following chemotherapeutic cytotoxic insult. Drug effects were investigated by comparing selective chemotherapeutic agents, such as BEZ-235 and selumetinib, against conventional cytotoxic agents targeting multiple pathways, including doxorubicin and idarubicin. METHODS: Splenocytes were isolated from 36 isogenic strains of mice using standard procedures. Of note, the splenocytes were not stimulated to avoid attributing responses to pathways involved with cellular stimulation rather than toxicity. Cells were incubated with compounds on a nine-point logarithmic dosing scale ranging from 15 nM to 100 µM (37°C, 5% CO2). At 4 hours posttreatment, cells were labeled with antibodies and physiological indicator dyes and fixed with 4% paraformaldehyde. Cellular phenotypes (eg, viability) were collected and analyzed using flow cytometry. Dose-response curves with response normalized to the zero dose as a function of log concentration were generated using GraphPad Prism 6. RESULTS: Phenotypes were quantified using flow cytometry, yielding interstrain variation for measured endpoints in different immune cells. The flow cytometry assays produced over 16,000 data points that were used to generate dose-response curves. The more targeted agents, BEZ-235 and selumetinib, were less toxic to immune cells than the anthracycline agents. The calculated heritability for the viability of immune cells was higher with anthracyclines than the novel agents, making them better suited for downstream genetic analysis. CONCLUSION: Using this approach, we identify cell lines of variable sensitivity to chemotherapeutic agents and aim to identify robust, replicable endpoints of cellular response to drugs that provide the starting point for identifying candidate genes and cellular toxicity pathways for future validation in human studies.

A cellular genetics approach identifies gene-drug interactions and pinpoints drug toxicity pathway nodes.

New approaches to toxicity testing have incorporated high-throughput screening across a broad-range of in vitro assays to identify potential key events in response to chemical or drug treatment. To date, these approaches have primarily utilized repurposed drug discovery assays. In this study, we describe an approach that combines in vitro screening with genetic approaches for the experimental identification of genes and pathways involved in chemical or drug toxicity. Primary embryonic fibroblasts isolated from 32 genetically-characterized inbred mouse strains were treated in concentration-response format with 65 compounds, including pharmaceutical drugs, environmental chemicals, and compounds with known modes-of-action. Integrated cellular responses were measured at 24 and 72 h using high-content imaging and included cell loss, membrane permeability, mitochondrial function, and apoptosis. Genetic association analysis of cross-strain differences in the cellular responses resulted in a collection of candidate loci potentially underlying the variable strain response to each chemical. As a demonstration of the approach, one candidate gene involved in rotenone sensitivity, Cybb, was experimentally validated in vitro and in vivo. Pathway analysis on the combined list of candidate loci across all chemicals identified a number of over-connected nodes that may serve as core regulatory points in toxicity pathways.

In vitro and in vivo mouse models for pharmacogenetic studies.

The identification of causative genes underlying biomedically relevant phenotypes, particularly complex multigenic traits, is of vital interest to modern medicine. Using genome-wide association analysis, many studies have successfully identified thousands of loci (called quantitative trait loci or QTL), some of these associating with drug response phenotypes. However, the determination and validation of putative genes has been much more challenging. The actions of drugs, both efficacious and deleterious, are complex phenotypes that are controlled or influenced in part by genetic mechanisms.Investigation for genetic correlates of complex traits and pharmacogenetic traits is often difficult to perform in human studies due to cost, availability of relevant sample population, and limited ability to control for environmental effects. These challenges can be circumvented with the use of mouse models for pharmacogenetic studies. In addition, the mouse can be treated at sub- and supratherapeutic doses and subjected to invasive procedures, which can facilitate measures of drug response phenotypes, making identification of pharmacogenetically relevant genes more feasible. The availability of multiple mouse genetic and phenotypic resources is an additional benefit to using the mouse for pharmacogenetic studies.Here, we describe the contribution of animal models, specifically the mouse, towards the field of pharmacogenetics. In this chapter, we describe different mouse models, including the knockout mouse, recombinant mouse inbred strains, in vitro mouse cell-based assays, as well as novel experimental approaches like the Collaborative Cross recombinant mouse inbred panel, which can be applied to preclinical pharmacogenetics research. These approaches can be used to assess drug response phenotypes that are difficult to model in humans, thereby facilitating drug discovery, development, and application.