Comparative efficacy of 2 topical anesthetics for the placement of orthodontic temporary anchorage devices.

This study compared the effectiveness of topical benzocaine 20% versus a combination of lidocaine, tetracaine, and phenylephrine in providing sufficient analgesia for the placement of orthodontic temporary anchorage devices (TADs). The 2 topical anesthetics were tested against each other bilaterally using a randomized, double-blind, crossover design. The agents were left in place for the amount of time prescribed by the manufacturer. The TAD was then placed, and each subject rated the degree of pain on a Heft-Parker visual analogue scale. A pulse oximeter was used to record the preoperative and postoperative pulse rates. Statistically significant differences in perceived pain (P < .05) and success rate (P < .01) between drugs were seen, but no significant difference in pulse rate change between the topical anesthetics was observed (P > .05). It was concluded that when the efficacy of topical benzocaine and of a combination product was compared as the sole anesthetic to facilitate acceptable pain control for placement of orthodontic temporary anchorage devices, the combination product was considerably more efficacious.

AMPA RECEPTOR ALLOSTERISM: MEASUREMENT OF THE CONFORMATIONAL CHANGES IN THE LIGAND BINDING DOMAIN OF A FUNCTIONAL RECEPTOR

Ionotropic glutamate receptors are important excitatory neurotransmitter receptors in the mammalian central nervous system that have been implicated in a number of neuropathologies such as epilepsy, ischemia, and amyotrophic lateral sclerosis. Glutamate binding to an extracellular ligand binding domain initiates a series of structural changes that leads to the formation of a cation selective transmembrane channel, which consequently closes due to desensitization of the receptor. The crystal structures of the AMPA subtype of the glutamate receptor have been particularly useful in providing initial insight into the conformational changes in the ligand binding domain; however, these structures are limited by crystallographic constraint. To gain a clear picture of how agonist binding is coupled to channel activation and desensitization, it is essential to study changes in the ligand binding domain in a dynamic, physiological state. In this dissertation, a technique called Luminescence Resonance Energy Transfer was used to determine the conformational changes associated with activation and desensitization in a functional AMPA receptor (ÄN*-AMPA) that contains the ligand binding domain and transmembrane segments; ÄN*-AMPA has been modified such that fluorophores can be introduced at specific sites to serve as a readout of cleft closure or to establish intersubunit distances. Previous structural studies of cleft closure of the isolated ligand binding domain in conjunction with functional studies of the full receptor suggest that extent of cleft closure correlates with extent of activation. Here, LRET has been used to show that a similar relationship between cleft closure and activation is observed in the “full length” receptor showing that the isolated ligand binding domain is a good model of the domain in the full length receptor for changes within a subunit. Similar LRET investigations were used to study intersubunit distances specifically to probe conformational changes between subunits within a dimer in the tetrameric receptor. These studies show that the dimer interface is coupled in the open state, and decoupled in the desensitized state, similar to the isolated ligand binding domain crystal structure studies. However, we show that the apo state dimer interface is not pre-formed as in the crystal structure, hence suggesting a mechanism for functional transitions within the receptor based on LRET distances obtained.

Effect of progressive mandibular advancement on pharyngeal airway size in anesthetized adults.

BACKGROUND: General anesthesia in adult humans is associated with narrowing or complete closure of the pharyngeal airway. The purpose of this study was to determine the effect of progressive mandibular advancement on pharyngeal airway size in normal adults during intravenous infusion of propofol for anesthesia. METHODS: Magnetic resonance imaging was performed in nine normal adults during wakefulness and during propofol anesthesia. A commercially available intraoral appliance was used to manually advance the mandible. Images were obtained during wakefulness without the appliance and during anesthesia with the participants wearing the appliance under three conditions: without mandibular advancement, advancement to 50% maximum voluntary advancement, and maximum advancement. Using computer software, airway area and maximum anteroposterior and lateral airway diameters were measured on the axial images at the level of the soft palate, uvula, tip of the epiglottis, and base of the epiglottis. RESULTS: Airway area across all four airway levels decreased during anesthesia without mandibular advancement compared with airway area during wakefulness (P < 0.007). Across all levels, airway area at 50% advancement during anesthesia was less than that at centric occlusion during wakefulness (P = 0.06), but airway area with maximum advancement during anesthesia was similar to that during wakefulness (P = 0.64). In general, anteroposterior and lateral airway diameters during anesthesia without mandibular advancement were decreased compared with wakefulness and were restored to their wakefulness values with 50% and/or maximal advancement. CONCLUSIONS: Maximum mandibular advancement during propofol anesthesia is required to restore the pharyngeal airway to its size during wakefulness in normal adults.

Association of retinoic acid receptor genes with meningomyelocele.

BACKGROUND: Neural tube defects (NTDs) occur in as many as 0.5-2 per 1000 live births in the United States. One of the most common and severe neural tube defects is meningomyelocele (MM) resulting from failed closure of the caudal end of the neural tube. MM has been induced by retinoic acid teratogenicity in rodent models. We hypothesized that genetic variants influencing retinoic acid (RA) induction via retinoic acid receptors (RARs) may be associated with risk for MM. METHODS: We analyzed 47 single nucleotide polymorphisms (SNPs) that span across the three retinoic acid receptor genes using the SNPlex genotyping platform. Our cohort consisted of 610 MM families. RESULTS: One variant in the RARA gene (rs12051734), three variants in the RARB gene (rs6799734, rs12630816, rs17016462), and a single variant in the RARG gene (rs3741434) were found to be statistically significant at p < 0.05. CONCLUSION: RAR genes were associated with risk for MM. For all associated SNPs, the rare allele conferred a protective effect for MM susceptibility.

Association of folate receptor (FOLR1, FOLR2, FOLR3) and reduced folate carrier (SLC19A1) genes with meningomyelocele.

BACKGROUND: Meningomyelocele (MM) results from lack of closure of the neural tube during embryologic development. Periconceptional folic acid supplementation is a modifier of MM risk in humans, leading toan interest in the folate transport genes as potential candidates for association to MM. METHODS: This study used the SNPlex Genotyping (ABI, Foster City, CA) platform to genotype 20 single polymorphic variants across the folate receptor genes (FOLR1, FOLR2, FOLR3) and the folate carrier gene (SLC19A1) to assess their association to MM. The study population included 329 trio and 281 duo families. Only cases with MM were included. Genetic association was assessed using the transmission disequilibrium test in PLINK. RESULTS: A variant in the FOLR2 gene (rs13908), three linked variants in the FOLR3 gene (rs7925545, rs7926875, rs7926987), and two variants in the SLC19A1 gene (rs1888530 and rs3788200) were statistically significant for association to MM in our population. CONCLUSION: This study involved the analyses of selected single nucleotide polymorphisms across the folate receptor genes and the folate carrier gene in a large population sample. It provided evidence that the rare alleles of specific single nucleotide polymorphisms within these genes appear to be statistically significant for association to MM in the patient population that was tested.

Addressing Obesity: Fear of Crime, Perceptions of Disorder and Disaparities in Child and Adolescent Use of Public Parks

Abstract The objectives of this study were: 1) To determine factors which inhibit and facilitate child and adolescent use of outdoor spaces for healthy physical activity by race and ethnicity in four Houston communities and 2) To propose guidelines for encouraging and maintaining child and adolescent outdoor physical activity. Using local health data and Houston Police Department crime statistics, four communities were identified for the study that had the highest concentration of crime and the racial/ ethnic groups of interest. The researchers then identified public parks in the communities. At least two parks were observed in each of the four communities from 2010 to 2011 during spring, summer, fall and winter. The parks were observed for use by children and adolescents and to describe the condition of the park spaces. The communities were Alief (Asian), Sunnyside (Black), Eldridge- West Oaks (White) and Northside- Northline (Hispanic). Observations were made at varying hours of both day and night, weekdays and weekends. Photographs were taken and the condition of the spaces noted in detail. One hundred and twenty persons, 18 years and over, using the spaces or otherwise in these communities were conveniently sampled and interviewed about their health and the extent to which they, or any children or adolescents under their care, used the outdoor spaces of interest. Data were analyzed qualitatively and with basic descriptive statistics. The photographs, journal notes and observation notes of all investigators and key personnel were analyzed. Interview data were also coded to identify patterns and themes in the responses. The findings indicate disparities in the quality and quantity of park equipment and the maintenance of the areas. Where perceptions of disorder were described, there was often visible evidence to support the perceptions. In many cases, residents' perceptions of crime were corroborated by police data. While interview reports did not seem to support the expectation that the condition of the parks was a significant deterrent to their use by children and adolescents, the condition of the parks might be said to limit the extent of that use. Specific reports of disorder that inhibited use included hearing gunfire, seeing drug dependent homeless persons and/or suspected prostitutes in an area.

Association of folate metabolic pathway genes with human spina bifida meningomyelocele

Neural tube defects including spina bifida meningomyelocele (SBMM) are common malformations of the brain and spinal cord, and include all abnormalities resulting from lack of closure of the developing neural tube during embryological development.^ The specific aims of this study were to determine if single nucleotide polymorphic variants (SNPs) in the folate/homocysteine metabolic pathway genes confer a risk for NTD susceptibility within this SBMM population.^ In completion of the first specific aim, two novel SNPs were identified in the FOLR1 gene in Chromosome 11of patients including one in non-coding exon 1 with a C → T transition at nucleotide position 71578317 and another in non-coding exon 3 with a T → G transversion at nucleotide position 71579123. It will be important to determine if these variants are present in the respective parents of these individuals. If they are in fact de novo variants, then these SNPs may be more likely to contribute to the birth defect.^ The second project aim was to analyze genotypes associated with SBMM risk by transmission disequilibrium tests (TDT) and association was detected on several SNPs across the folate metabolic pathway genes in this population. SNPs with significant RC-TDT values were found within the DHFR gene (rs1650723), the MTRR gene (rs327592), the FOLR2 gene (rs13908), four tightly linked variants in the FOLR3 gene (rs7925545, rs7926875, rs7926987, rs7926360) and a variant in the SLC19A1 gene (rs1888530). The product of each of these genes performs a vital function in the folate metabolic pathway. It is conceivable, therefore, that if the individual SNP or SNPs can be proven to perturb the function in some way that they may be involved in the disruption of folate metabolism and in the resulting birth defect. Validating the results of this study in other independent populations will further strengthen the evidence that dysfunction of folate enzymes and receptors may confer SBMM risk in humans. ^

Functional studies of {\it twist\/} during mouse embryogenesis

A fundamental task in developmental biology is to understand the molecular mechanisms governing early embryogenesis. The aim of this study was to understand the developmental role of a putative basic helix-loop-helix (b-HLH) transcription factor, twist, during mouse embryogenesis.^ twist was originally identified in Drosophila as one of the zygotic genes, including snail, that were required for dorsal-ventral patterning. In Drosophila embryogenesis, twist is expressed in the cells of the ventral midline destined to form mesoderm. In embryos lacking twist expression, their ventral cells fail to form a ventral furrow and subsequently no mesoderm is formed.^ During mouse embryogenesis, twist is expressed after initial mesoderm formation in both mesoderm and cranial neural crest cell derivatives. To study the role of twist in vivo, twist-null embryos were generated by gene targeting. Embryos homozygous for the twist mutation die at midgestation. The most prominent phenotype in the present study was a failure of the cranial neural tube to close (exencephaly). twist-null embryos also showed defects in head mesenchyme, branchial arches, somites, and limb buds.^ To understand whether twist functions cell-autonomously and to investigate how twist-null cells interact with wild-type cells in vivo, twist chimeras composed of both twist-null and wild-type cells marked by the expression of the lacZgene were generated. Chimeric analysis revealed a correlation between the incidence of exencephaly and the contribution of the underlying twist-null head mesenchyme, thus strongly suggesting that twist-expressing head mesenchyme is required for the closure of the cranial neural tube. These studies have identified twist as a critical regulator for the mesenchymal fate determination within the cranial neural crest lineage. Most strikingly, twist-null head mesenchyme cells were always segregated from wild-type cells, indicating that the twist mutation altered the adhesive specificity of these cells. Furthermore, these results also indicated that twist functions cell-autonomously in the head, arch, and limb mesenchyme but non-cell-autonomously in the somites. Taken together, these studies have established the essential role of twist during mouse embryogenesis. ^