A novel human glucocorticoid receptor SNP results in increased transactivation potential.

Glucocorticoids are one of the most widely used therapeutics in the treatment of a variety of inflammatory disorders. However, it is known that there are variable patient responses to glucocorticoid treatment; there are responders and non-responders, or those that need higher dosages. Polymorphisms in the glucocorticoid receptor (GR) have been implicated in this variability. In this study, ninety-seven volunteers were surveyed for polymorphisms in the human GR-alpha (hGRα), the accepted biologically active reference isoform. One isoform identified in our survey, named hGR DL-2, had four single nucleotide polymorphisms (SNPs), one synonymous and three non-synonymous, and a four base pair deletion resulting in a frame shift and early termination to produce a 743 amino acid putative protein. hGR DL-2 had a decrease in transactivation potential of more than 90%. Upon further analysis of the individual SNPs and deletion, one SNP, A829G, which results in a lysine to glutamic acid amino acid change at position 277, was found to increase the transactivation potential of hGR more than eight times the full-length reference. Furthermore, the hGRα-A829G isoform had a differential hyperactive response to various exogenous steroids. Increasing our knowledge as to how various SNPs affect hGR activity may help in understanding the unpredictable patient response to steroid treatment, and is a step towards personalizing patient care

Skeletal, Dentoalveolar, and Periodontal Changes of Skeletally Matured Patients with Maxillary Deficiency Treated with Microimplant‐assisted Rapid Palatal Expansion Appliances: A Pilot Study

Introduction: Microimplant‐assisted rapid palatal expansion (MARPE) has recently been offered to adult patients for correcting maxillary transverse deficiency. However, there is limited information in the literature on the success of this appliance and its skeletal and dental effects on skeletally matured patients. The purpose of this study was to investigate the immediate skeletal, dentoalveolar, and periodontal response to MARPE appliance using cone‐beam computed tomography in a skeletally matured patient as assessed by the cervical vertebral maturation method. Materials and Methods: Eight consecutively treated patients (2 females, 6 males; mean age of 21.9 ± 1.5 years) treated with a maxillary skeletal expander were included in the study. Measurements were taken before and after expansion to determine the amount of midpalatal suture opening, upper facial bony expansion, alveolar bone bending, dental tipping, and buccal bone thickness (BBT). Data were analyzed using a one‐way ANOVA and matched‐pair t‐test (α = 0.05). Results: Midpalatal suture separation was found in 100% of the patients with no dislodged microimplants. Total maxillary expansion was attributed to 41% skeletal, 12% alveolar bone bending, and 48% dental tipping. Pattern of midpalatal suture opening was found to be parallel in both the coronal and axial planes. On average, the absolute dental tipping ranged from 4.17° to 4.96° and the BBT was reduced by an average of 39% measured at the premolars and molars. Conclusions: The MARPE appliance can be a clinically acceptable, nonsurgical treatment option for correcting mild to moderate maxillary transverse discrepancies for skeletally matured adult patients with a healthy periodontium

Dazl Functions in Maintenance of Pluripotency and Genetic and Epigenetic Programs of Differentiation in Mouse Primordial Germ Cells In Vivo and In Vitro

Mammalian germ cells progress through a unique developmental program that encompasses proliferation and migration of the nascent primordial germ cell (PGC) population, reprogramming of nuclear DNA to reset imprinted gene expression, and differentiation of mature gametes. Little is known of the genes that regulate quantitative and qualitative aspects of early mammalian germ cell development both in vivo, and during differentiation of germ cells from mouse embryonic stem cells (mESCs) in vitro.We used a transgenic mouse system that enabled isolation of small numbers of Oct4DeltaPE:GFP-positive germ cells in vivo, and following differentiation from mESCs in vitro, to uncover quantitate and qualitative phenotypes associated with the disruption of a single translational regulator, Dazl. We demonstrate that disruption of Dazl results in a post-migratory, pre-meiotic reduction in PGC number accompanied by aberrant expression of pluripotency genes and failure to erase and re-establish genomic imprints in isolated male and female PGCs, as well as subsequent defect in progression through meiosis. Moreover, the phenotypes observed in vivo were mirrored by those in vitro, with inability of isolated mutant PGCs to establish pluripotent EG (embryonic germ) cell lines and few residual Oct-4-expressing cells remaining after somatic differentiation of mESCs carrying a Dazl null mutation. Finally, we observed that even within undifferentiated mESCs, a nascent germ cell subpopulation exists that was effectively eliminated with ablation of Dazl.This report establishes the translational regulator Dazl as a component of pluripotency, genetic, and epigenetic programs at multiple time points of germ cell development in vivo and in vitro, and validates use of the ESC system to model and explore germ cell biology

Effect of Prior Bilateral Oophorectomy on the Presentation of Breast Cancer in BRCA1 and BRCA2 Mutation Carriers

Purpose: To compare the presentation of invasive breast cancer in BRCA1 and BRCA2 mutation carriers with and without prior bilateral oophorectomy. Patients and methods: Women with a BRCA1 or BRCA2 mutation with the diagnosis of invasive breast cancer were identified from ten cancer genetics clinics. The medical history, medical treatment records and pathology reports for the breast cancers were reviewed. Information was abstracted from medical charts, including history (and date) of oophorectomy, date of breast cancer diagnosis, stage of disease, and pathologic characteristics of the breast cancer. Women with prior bilateral oophorectomy were matched by age, year of diagnosis, and mutation with one or more women who had two intact ovaries at the time of breast cancer diagnosis. Characteristics of the breast tumours were compared between the two groups

Objective, Subjective, and Self-Assessment of Preadolescent Orthodontic Treatment Need – A Function of Age, Gender, and Ethnic/Racial Background?

Children from socioeconomically disadvantaged and/or underrepresented minority backgrounds in the United States have limited or no access to orthodontic treatment. Objectives: To determine whether preadolescents' (a) objectively assessed orthodontic treatment need; (b) subjectively assessed orthodontic treatment need; and (c) self-perceptions of the psychologic aspects of their oral health-related quality of life and desire to have braces vary as a function of age, gender, ethnicity/race, and socioeconomic status (SES). Methods: Data were collected from 1,566 preadolescents (age range: 8 to 11 years; 47.3 percent male/52.7 percent female; 55.7 percent African-American/39.7 percent White/2.9 percent Hispanic) in oral exams and in face to face interviews. Malocclusion was determined with the Index of Orthodontic Treatment Need. Results: Children (17.2 percent) had definite treatment need, 33.7 percent were borderline, and 49.1 percent had little or no need. Objectively and subjectively assessed treatment need was not affected by the children's age or gender. However, girls were more critical of their smiles and wanted braces more than boys. The older the children were, the more critical they were and the more they wanted braces. African-American children and children in schools with higher percentages of children on free school lunches had less treatment need than White children and children in schools with lower percentages of students with free school lunches. While the provider-assessed treatment need was higher for White children than for Black children, Black children were less happy with their smiles than White children, and wanted braces more than White children. SES did not affect the children's self-perceptions. Conclusions: Findings showed that substantial percentages of the preadolescents have an orthodontic treatment need. Orthodontic need and child self-perceptions varied as a function of the children's age, gender, ethnicity/race, and SES.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65150/1/j.1752-7325.2008.00089.x.pd

The relationships between golf and health:A scoping review

OBJECTIVE: To assess the relationships between golf and health. DESIGN: Scoping review. DATA SOURCES: Published and unpublished reports of any age or language, identified by searching electronic databases, platforms, reference lists, websites and from consulting experts. REVIEW METHODS: A 3-step search strategy identified relevant published primary and secondary studies as well as grey literature. Identified studies were screened for final inclusion. Data were extracted using a standardised tool, to form (1) a descriptive analysis and (2) a thematic summary. RESULTS AND DISCUSSION: 4944 records were identified with an initial search. 301 studies met criteria for the scoping review. Golf can provide moderate intensity physical activity and is associated with physical health benefits that include improved cardiovascular, respiratory and metabolic profiles, and improved wellness. There is limited evidence related to golf and mental health. The incidence of golfing injury is moderate, with back injuries the most frequent. Accidental head injuries are rare, but can have serious consequences. CONCLUSIONS: Practitioners and policymakers can be encouraged to support more people to play golf, due to associated improved physical health and mental well-being, and a potential contribution to increased life expectancy. Injuries and illnesses associated with golf have been identified, and risk reduction strategies are warranted. Further research priorities include systematic reviews to further explore the cause and effect nature of the relationships described. Research characterising golf's contribution to muscular strengthening, balance and falls prevention as well as further assessing the associations and effects between golf and mental health are also indicated

Toxin-Specific Antibodies for the Treatment of Clostridium difficile: Current Status and Future Perspectives †

Therapeutic agents targeting bacterial virulence factors are gaining interest as non-antibiotic alternatives for the treatment of infectious diseases. Clostridium difficile is a Gram-positive pathogen that produces two primary virulence factors, enterotoxins A and B (TcdA and TcdB), which are responsible for Clostridium difficile-associated disease (CDAD) and are targets for CDAD therapy. Antibodies specific for TcdA and TcdB have been shown to effectively treat CDAD and prevent disease relapse in animal models and in humans. This review summarizes the various toxin-specific antibody formats and strategies under development, and discusses future directions for CDAD immunotherapy, including the use of engineered antibody fragments with robust biophysical properties for systemic and oral delivery

Testing gravitational-wave searches with numerical relativity waveforms: Results from the first Numerical INJection Analysis (NINJA) project

The Numerical INJection Analysis (NINJA) project is a collaborative effort between members of the numerical relativity and gravitational-wave data analysis communities. The purpose of NINJA is to study the sensitivity of existing gravitational-wave search algorithms using numerically generated waveforms and to foster closer collaboration between the numerical relativity and data analysis communities. We describe the results of the first NINJA analysis which focused on gravitational waveforms from binary black hole coalescence. Ten numerical relativity groups contributed numerical data which were used to generate a set of gravitational-wave signals. These signals were injected into a simulated data set, designed to mimic the response of the Initial LIGO and Virgo gravitational-wave detectors. Nine groups analysed this data using search and parameter-estimation pipelines. Matched filter algorithms, un-modelled-burst searches and Bayesian parameter-estimation and model-selection algorithms were applied to the data. We report the efficiency of these search methods in detecting the numerical waveforms and measuring their parameters. We describe preliminary comparisons between the different search methods and suggest improvements for future NINJA analyses.Comment: 56 pages, 25 figures; various clarifications; accepted to CQ