Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo.

Multiple sclerosis involves an aberrant autoimmune response and progressive failure of remyelination in the central nervous system. Prevention of neural degeneration and subsequent disability requires remyelination through the generation of new oligodendrocytes, but current treatments exclusively target the immune system. Oligodendrocyte progenitor cells are stem cells in the central nervous system and the principal source of myelinating oligodendrocytes. These cells are abundant in demyelinated regions of patients with multiple sclerosis, yet fail to differentiate, thereby representing a cellular target for pharmacological intervention. To discover therapeutic compounds for enhancing myelination from endogenous oligodendrocyte progenitor cells, we screened a library of bioactive small molecules on mouse pluripotent epiblast stem-cell-derived oligodendrocyte progenitor cells. Here we show seven drugs function at nanomolar doses selectively to enhance the generation of mature oligodendrocytes from progenitor cells in vitro. Two drugs, miconazole and clobetasol, are effective in promoting precocious myelination in organotypic cerebellar slice cultures, and in vivo in early postnatal mouse pups. Systemic delivery of each of the two drugs significantly increases the number of new oligodendrocytes and enhances remyelination in a lysolecithin-induced mouse model of focal demyelination. Administering each of the two drugs at the peak of disease in an experimental autoimmune encephalomyelitis mouse model of chronic progressive multiple sclerosis results in striking reversal of disease severity. Immune response assays show that miconazole functions directly as a remyelinating drug with no effect on the immune system, whereas clobetasol is a potent immunosuppressant as well as a remyelinating agent. Mechanistic studies show that miconazole and clobetasol function in oligodendrocyte progenitor cells through mitogen-activated protein kinase and glucocorticoid receptor signalling, respectively. Furthermore, both drugs enhance the generation of human oligodendrocytes from human oligodendrocyte progenitor cells in vitro. Collectively, our results provide a rationale for testing miconazole and clobetasol, or structurally modified derivatives, to enhance remyelination in patients.

Is caries prevalence site-specific in cleft lip and palate patients? A systematic review and meta-analysis.

Background: Previous systematic reviews indicate that there is an increased prevalence of caries in cleft patients in comparison to their healthy control group. To date, the prevalence of caries between unilateral cleft lip and palate (UCLP) and bilateral cleft lip and palate (BCLP) has not been quantitatively evaluated. This review aims to include published studies that examined caries prevalence in patients with UCLP and BCLP to find out whether a quantitative difference exists in caries experience among them. Materials and Methods: Medline/PubMed, Scopus, and EBSCOhost databases were searched from inception to November 2021. The protocol was registered with PROSPERO registration no. CRD2021292425. Prevalence-based studies that evaluated caries experience using the decayed-missing-filled teeth (DMFT) index in the permanent dentition or dmft in case of primary dentition in patients with UCLP or BCLP were included in the analysis with the outcome given in mean and standard deviation. Meta-analysis was performed using a random effect model through a forest plot. An adapted version of the Newcastle-Ottawa Scale for cross-sectional studies was modified to assess the quality of included studies. Results: Three studies were included in the review. The difference in caries prevalence was statistically significant in the permanent and primary dentition which were evaluated using DMFT and dmft scores with P = 0.01 and P = 0.03, respectively. Forest plot values were obtained for permanent dentition (DMFT) and primary dentition (dmft), 0.57 (95% confidence interval [CI]: 1.03-0.11) and 0.36 (95% CI: 0.69-0.03), respectively. The result of the meta-analysis indicates that patients with BCLP have higher caries prevalence. Conclusion: The outcome of the study indicates a higher occurrence of caries in patients with BCLP than UCLP in both permanent and primary dentition.

Exploring global health programs in U.S. dental schools.

PURPOSE: The purpose of this study was to survey and describe key curricular and extracurricular components of U.S. dental schools' global health programs. METHODS: A 22-item web-based survey invitation was sent to administrators at all 66 US dental schools. Topics included both curricular and extracurricular global health activities offered, including Short-term Experiences in Global Health (STEGHs). Key components were identified and classified as domains and components for the purpose of discussion: Domain #1: Program support and administrative factors (components: a support, faculty support, and extracurricular activities), Domain #2: Academic teaching (components: global health track, didactic courses, and cultural awareness and communication teaching), and Domain #3: STEGHs, (components: School-based STEGHs, al organization-based STEGHs, and exchange programs). RESULTS: Most notably among respondents, 72% strongly agreed/agreed that global health should be a part of the dental curriculum, 81% strongly agreed/agreed that students benefit from participating in global health experiences, and 43% of schools had a faculty member dedicated to global health work. In this study of dental schools, 44% offered didactic courses in global health, and 62% of schools offered STEGHs. CONCLUSION: The results of this study offer a description of key components of global health education programs in U.S. dental schools. Schools surveyed offer a combination of both didactic courses and STEGH programs for their students. Global health education may improve dental students' skills related to managing a diverse patient population.

Failure rates and survival analysis of maxillary expansion appliances: a 24-year retrospective analysis.

PURPOSE: The purpose of this study was to describe the failure rates of maxillary expansion appliances (MEAs) and assess risk variables associated with failures and treatment time. METHODS: Retrospective chart reviews were performed on 436 primary or mixed dentition patients presenting with crossbite to a private practice between 1981-2005. Survival analysis was used to analyze and compare the types of MEAs with respect to the treatment time. The effect of demographic and clinical characteristics on appliance failure and treatment time was assessed using linear and logistic regression models. RESULTS: The average age at insertion of a MEA was 8 years, 4 months (+/-1.72 SD). Nineteen percent (n=84) of the MEAs failed, with a median treatment time for all appliances of 216 days (interquartile range=126 days). Cement loss (69%) was the most common type of failure. The likelihood of an appliance failing increased in children with a malocclusion other than Class I (adjusted odds ratio=1.91; 95% CI=1.16-3.14) and was nearly 4 times greater when a quad helix was used compare to the Haas appliance (adjusted odds ratio=3.60; 95% CI=1.92-6.75). The treatment time was significantly affected by the type of crossbite present and the occurrence of an appliance failure (P=.001). CONCLUSIONS: The use of a quad helix appliance and the presence of malocclusion other than Class I was significantly predictive of appliance failure. Treatment time was increased when MEAs failed and bilateral crossbite was present.

Going Global: Toward Competency-Based Best Practices for Global Health in Dental Education.

The Global Oral Health Interest Group of the Consortium of Universities for Global Health (GOHIG-CUGH) published recommended competencies to support development of competency-based global health education in dental schools. However, there has been no comprehensive, systematically derived, or broadly accepted framework for creating and delivering competency-based global health education to dental students. This article describes the results of a collaborative workshop held at the 2016 American Dental Education Association (ADEA) Annual Session & Exhibition designed to build on the GOHIG-CUGH competencies and start to develop systematic approaches for their practical application. Workshop organizers developed a preliminary theoretical framework for guiding the development of global health in dental education, grounded in published research. Collectively, workshop participants developed detailed outcomes for the theoretical framework with a focus on three educational practices: didactic, experiential, and research learning and how each can meet the competencies. Participants discussed learning objectives, keys to implementation, ethical considerations, challenges, and examples of success. Outcomes demonstrated that no educational practice on its own meets all 33 recommended competencies for dental students; however, the three educational practices combined may potentially cover all 33. Participants emphasized the significance of sustainable approaches to student learning for both students and communities, with identified partners in the communities to collaborate on the development, implementation, evaluation, and long-term maintenance of any student global health activity. These findings may represent early steps toward professional consensus and best practices for global health in dental education in the United States.

CC chemokine receptor 2 is protective against noise-induced hair cell death: studies in CX3CR1(+/GFP) mice.

Acoustic trauma was recently shown to induce an inflammatory response in the ear characterized by rapid entry of macrophages in the spiral ligament. The current study seeks to elucidate the mechanisms involved in summoning macrophages to the cochlear lateral wall and the role macrophages play in noise-induced injury or repair. CCL2 and its primary receptor, CCR2, are the most widely validated effectors of monocyte chemotaxis in vivo. CCL2-/- and CCR2-/- mice have been used extensively in studies of monocyte activation in neuronal injury. However, the function of CCL2 and CCR2 in the cochlea has not been studied. The present study examines the role of CCL2 and CCR2 in acoustic injury. CCL2-/- and CCR2-/- mice on a CX3CR1(+/GFP) background were exposed to octave band noise (8-16 kHz) for 2 h to determine the effect of CCL2 and CCR2 on monocyte migration into the cochlea, threshold shift, and cell survival. We found that threshold shift was unchanged in the two knockout mouse strains when compared to the background strain (CX3CR1(+/GFP)). Surprisingly, we found that monocyte migration was also unchanged, despite the absence of CCL2 or CCR2. However, there was a dramatic increase in noise-induced hair cell death in the CCR2-/- strain. This observation suggests that CCR2, independent of CCL2, plays a protective role in the cochlea after noise, and neither ligand nor receptor is necessary for monocyte migration. Possible mechanisms of neuroprotection by CCR2 are discussed.

Using iPSC-derived human DA neurons from opioid-dependent subjects to study dopamine dynamics.

INTRODUCTION: The dopaminergic (DA) system plays important roles in addiction. However, human DA neurons from drug-dependent subjects were not available for study until recent development in inducible pluripotent stem cells (iPSCs) technology. METHODS: In this study, we produced DA neurons differentiated using iPSCs derived from opioid-dependent and control subjects carrying different 3' VNTR (variable number tandem repeat) polymorphism in the human dopamine transporter (DAT or SLC6A3). In addition, the effects of valproic acid (VPA) exposures on iPSC-derived human DA neurons are also examined. RESULTS: We present the first evidence suggesting that the 3' VNTR polymorphism in the hDAT gene affects DAT expression level in iPSC-derived human DA neurons. In human DA neurons, which provide an appropriate cellular milieu, VPA treatment alters the expression of several genes important for dopaminergic neuron function including DAT, Nurr1, and TH; this might partly explain its action in regulating addictive behaviors. VPA treatment also significantly increased DA D2 receptor (Drd2) expression, especially in the opioid-dependent iPSC cell lines. CONCLUSIONS: Our data suggest that human iPSC-derived DA neurons may be useful in in vitro experimental model to examine the effects of genetic variation in gene regulation, to examine the underlying mechanisms in neurological disorders including drug addiction, and to serve as a platform for therapeutic development.

Determinants of dental referral practices among WIC nutritionists in North Carolina.

OBJECTIVES: To examine the effects of knowledge and confidence on dental referral practices among WIC nutritionists in North Carolina. METHODS: A questionnaire consisting of 118 Likert scale-type questions was administered to 92% of all WIC nutritionists in North Carolina (n = 324). The relationship of knowledge and confidence with frequent dental referrals was tested using logistic regression. RESULTS: Regression results found that confidence in performing oral health risk assessments (OR = 2.12; 95% CI = 1.13, 3.96), confidence in making dental referrals (OR = 3.02; 95% CI = 1.45-6.29), and confidence in expected outcomes that parents would seek dental care when advised to do so (OR = 3.11; 95% CI = 1.62, 5.97) were associated with more frequent dental referrals. CONCLUSIONS: The more confident WIC nutritionists feel about oral health, the more likely they are to make dental referrals. Screening and referral by WIC workers may benefit children by improving access to dental care, as the WIC clinic is frequently the first point of contact with a health professional.