Interpretation of a Unified Theory of Gravitation and Symmetry Breaking

The formalism of Moen and Moffat is interpreted as a Yang-Mills theory set in a space-time generally endowed with curvature and torsion

Summation Over Feynman Histories in Polar Coordinates

Use of polar coordinates is examined in performing summation over all Feynman histories. Several relationships for the Lagrangian path integral and the Hamiltonian path integral are derived in the central‐force problem. Applications are made for a harmonic oscillator, a charged particle in a uniform magnetic field, a particle in an inverse‐square potential, and a rigid rotator. Transformations from Cartesian to polar coordinates in path integrals are rather different from those in ordinary calculus and this complicates evaluation of path integrals in polars. However, it is observed that for systems of central symmetry use of polars is often advantageous over Cartesians

Pair-correlation Kinetics and the Reversible Diffusion-controlled Reaction

It has long been known that the time course of a bimolecular reaction occurring in a condensed host depends on the behavior of the nonequilibrium pair-correlation function for reactant pairs. The classical analysis of such reactions has led to a kind of standard rule: The association rate constant for a diffusion-controlled reaction is 4πDR and this rate constant produces the fastest possible kinetics. This result is only (approximately) true for the case of an irreversible reaction, however. Here, we reexamine this old problem, looking closely at the reversible case. We report a result that challenges the standard wisdom: When the reaction is highly reversible the relaxation of the related kinetics to equilibrium can be much faster than the model in which 4πDR is the association rate constant. We suggest that our work provides a natural resolution to a well-known, long-standing controversy in the study of electrically active impurities in silicon grown by the Czochralski method

Chronic widespread pain after motor vehicle collision typically occurs through immediate development and nonrecovery: results of an emergency department-based cohort study

Motor vehicle collision (MVC) can trigger chronic widespread pain (CWP) development in vulnerable individuals. Whether such CWP typically develops via the evolution of pain from regional to widespread or via the early development of widespread pain with non-recovery is currently unknown. We evaluated the trajectory of CWP development (American College of Rheumatology criteria) among 948 European-American individuals who presented to the emergency department (ED) for care in the early aftermath of MVC. Pain extent was assessed in the ED and 6 weeks, 6 months, and 1 year after MVC on 100%, 91%, 89%, and 91% of participants, respectively. Individuals who reported prior CWP at the time of ED evaluation (n = 53) were excluded. Trajectory modeling identified a two-group solution as optimal, with the Bayes Factor value (138) indicating strong model selection. Linear solution plots supported a non-recovery model. While the number of body regions with pain in the non-CWP group steadily declined, the number of body regions with pain in the CWP trajectory group (192/895, 22%) remained relatively constant over time. These data support the hypothesis that individuals who develop CWP after MVC develop widespread pain in the early aftermath of MVC which does not remit

Using emergency department-based inception cohorts to determine genetic characteristics associated with long term patient outcomes after motor vehicle collision: Methodology of the CRASH study

<p>Abstract</p> <p>Background</p> <p>Persistent musculoskeletal pain and psychological sequelae following minor motor vehicle collision (MVC) are common problems with a large economic cost. Prospective studies of pain following MVC have demonstrated that demographic characteristics, including female gender and low education level, and psychological characteristics, including high pre-collision anxiety, are independent predictors of persistent pain. These results have contributed to the psychological and social components of a biopsychosocial model of post-MVC pain pathogenesis, but the biological contributors to the model remain poorly defined. Recent experimental studies indicate that genetic variations in adrenergic system function influence the vulnerability to post-traumatic pain, but no studies have examined the contribution of genetic factors to existing predictive models of vulnerability to persistent pain.</p> <p>Methods/Design</p> <p>The Project CRASH study is a federally supported, multicenter, prospective study designed to determine whether variations in genes affecting synaptic catecholamine levels and alpha and beta adrenergic receptor function augment social and psychological factors in a predictive model of persistent musculoskeletal pain and posttraumatic stress disorder (PTSD) following minor MVC. The Project CRASH study will assess pain, pain interference and PTSD symptoms at 6 weeks, 6 months, and 1 year in approximately 1,000 patients enrolled from 8 Emergency Departments in four states with no-fault accident laws.</p> <p>Discussion</p> <p>The results from this study will provide insights into the pathophysiology of persistent pain and PTSD following MVC and may serve to improve the ability of clinicians and researchers to identify individuals at high risk for adverse outcomes following minor MVC.</p

Therapeutic target-site variability in α1-antitrypsin characterized at high resolution

The intrinsic propensity of [alpha]1-antitrypsin to undergo conformational transitions from its metastable native state to hyperstable forms provides a motive force for its antiprotease function. However, aberrant conformational change can also occur via an intermolecular linkage that results in polymerization. This has both loss-of-function and gain-of-function effects that lead to deficiency of the protein in human circulation, emphysema and hepatic cirrhosis. One of the most promising therapeutic strategies being developed to treat this disease targets small molecules to an allosteric site in the [alpha]1-antitrypsin molecule. Partial filling of this site impedes polymerization without abolishing function. Drug development can be improved by optimizing data on the structure and dynamics of this site. A new 1.8 Å resolution structure of [alpha]1-antitrypsin demonstrates structural variability within this site, with associated fluctuations in its upper and lower entrance grooves and ligand-binding characteristics around the innermost stable enclosed hydrophobic recess. These data will allow a broader selection of chemotypes and derivatives to be tested in silico and in vitro when screening and developing compounds to modulate conformational change to block the pathological mechanism while preserving function

Genetic variant rs3750625 in the 3′UTR of ADRA2A affects stress-dependent acute pain severity after trauma and alters a microRNA-34a regulatory site

α2A adrenergic receptor (α2A-AR) activation has been shown in animal models to play an important role in regulating the balance of acute pain inhibition vs. facilitation after both physical and psychological stress. To our knowledge the influence of genetic variants in the gene encoding α2A-AR, ADRA2A, on acute pain outcomes in humans experiencing traumatic stress has not been assessed. In this study, we tested whether a genetic variant in the 3′UTR of ADRA2A, rs3750625, is associated with acute musculoskeletal pain (MSP) severity following motor vehicle collision (MVC, n = 948) and sexual assault (n = 84), and whether this influence was affected by stress severity. We evaluated rs3750625 because it is located in the seed binding region of miR-34a, a microRNA (miRNA) known to regulate pain and stress responses. In both cohorts, the minor allele at rs3750625 was associated with increased MSP in distressed individuals (stress*rs3750625 p = 0.043 for MVC cohort and p = 0.007 for sexual assault cohort). We further found that (1) miR-34a binds the 3′UTR of ADRA2A, (2) the amount of repression is greater when the minor (risk) allele is present, (3) miR-34a in the IMR-32 adrenergic neuroblastoma cell line affects ADRA2A expression, (4) miR-34a and ADRA2A are expressed in tissues known to play a role in pain and stress, (5) following forced swim stress exposure, rat peripheral nerve tissue expression changes are consistent with miR-34a regulation of ADRA2A. Together these results suggest that ADRA2A rs3750625 contributes to post-stress MSP severity by modulating miR-34a regulation

Variations in Institutional Review Board reviews of a multi-center, Emergency Department-based genetic research protocol

AbstractIntroductionIn the United States, institutional review boards (IRBs) oversee the scientific, ethical, and regulatory aspects of research conducted on human subjects. Institutional variations in the interpretation and application of federal and local regulations concerning genetic testing can have significant impact on the implementation of such studies.ObjectiveWe assessed variability in IRB review of a multi-center Emergency Department-based study examining genotypic and phenotypic predictors of pain and psychological outcomes after minor motor vehicle collision (Project CRASH). This is one of the first multi-center genetic research protocols based solely in the Emergency Department (ED).MethodsWe performed an observational study of sites participating in Project CRASH. We collected IRB information and correspondence from each site. We collected data that included information regarding institution demographics, original IRB application characteristics, subsequent IRB correspondence, and time interval between submission and approval. Descriptive statistics were used in analysis.ResultsAll sites that initially agreed to participate in Project CRASH also participated in this study (n = 7). The time interval in receiving IRB approval varied between 20-760 days (median 105, IQR 21-225). One site appeared to be an outlier (760 days). The most commonly requested changes were changes to the consent form.ConclusionInstitutional interpretation of regulations regarding our ED-based genetic study was highly variable. Although the majority of our results are consistent with other similar published studies, the mean time interval for approval for this genetic study is far greater than other reported studies

Association of Epidemiologic Factors and Genetic Variants Influencing Hypothalamic-Pituitary-Adrenocortical Axis Function With Postconcussive Symptoms After Minor Motor Vehicle Collision

To determine the influence of epidemiologic factors and the influence of genetic variants affecting FKBP5, a protein known to modulate hypothalamic-pituitary-adrenocortical (HPA) axis function, on the severity of somatic symptoms commonly termed “post-concussive” six and twelve months after motor-vehicle collision (MVC)