An update on the pathology and clinical management of gouty arthritis

Gouty arthritis is an inflammatory condition associated with debilitating clinical symptoms, functional impairments, and a substantial impact on quality of life. This condition is initially triggered by the deposition of monosodium urate crystals into the joint space. This causes an inflammatory cascade resulting in the secretion of several proinflammatory cytokines and neutrophil recruitment into the joint. While generally effective, currently available agents are associated with a number of adverse events and contraindications that complicate their use. Based on our increased understanding of the inflammatory pathogenesis of gouty arthritis, several new agents are under development that may provide increased efficacy and reduced toxicity

Predictors of fatigue severity in early systemic sclerosis: a prospective longitudinal study of the GENISOS cohort.

ObjectivesLongitudinal studies examining the baseline predictors of fatigue in SSc have not been reported. Our objectives were to examine the course of fatigue severity over time and to identify baseline clinical, demographic, and psychosocial predictors of sequentially obtained fatigue scores in early SSc. We also examined baseline predictors of change in fatigue severity over time.MethodsWe analyzed 1090 longitudinal Fatigue Severity Scale (FSS) scores belonging to 256 patients who were enrolled in the Genetics versus Environment in Scleroderma Outcomes Study (GENISOS). Predictive significance of baseline variables for sequentially obtained FSS scores was examined with generalized linear mixed models. Predictors of change in FSS over time were examined by adding an interaction term between the baseline variable and time-in-study to the model.ResultsThe patients' mean age was 48.6 years, 47% were Caucasians, and 59% had diffuse cutaneous involvement. The mean disease duration at enrollment was 2.5 years. The FSS was obtained at enrollment and follow-up visits (mean follow-up time = 3.8 years). Average baseline FSS score was 4.7(±0.96). The FSS was relatively stable and did not show a consistent trend for change over time (p = 0.221). In a multivariable model of objective clinical variables, higher Medsger Gastrointestinal (p = 0.006) and Joint (p = 0.024) Severity Indices, and anti-U1-RNP antibodies (p = 0.024) were independent predictors of higher FSS. In the final model, ineffective coping skills captured by higher Illness Behavior Questionnaire scores (p<0.001), higher self-reported pain (p = 0.006), and higher Medsger Gastrointestinal Severity Index (p = 0.009) at enrollment were independent predictors of higher longitudinal FSS scores. Baseline DLco % predicted was the only independent variable that significantly predicted a change in FSS scores over time (p = 0.013), with lower DLco levels predicting an increase in FSS over time.ConclusionsThis study identified potentially modifiable clinical and psychological factors that predict longitudinal fatigue severity in early SSc

PEGylated Domain I of Beta-2-Glycoprotein I Inhibits Thrombosis in a Chronic Mouse Model of the Antiphospholipid Syndrome

Antiphospholipid syndrome (APS) is an autoimmune disorder in which autoantibodies cause clinical effects of vascular thrombosis and pregnancy morbidity. The only evidence-based treatments are anticoagulant medications such as warfarin and heparin. These medications have a number of disadvantages, notably risk of haemorrhage. Therefore, there is a pressing need to develop new, more focused treatments that target the actual pathogenic disease process in APS. The pathogenic antibodies exert their effects by interacting with phospholipid-binding proteins, of which the most important is beta-2-glycoprotein I. This protein has five domains, of which the N-terminal Domain I (DI) is the main site for binding of pathogenic autoantibodies. We previously demonstrated bacterial expression of human DI and showed that this product could inhibit the ability of IgG from patients with APS (APS-IgG) to promote thrombosis in a mouse model. Since DI is a small 7kDa protein, its serum half-life would be too short to be therapeutically useful. We therefore used site-specific chemical addition of polyethylene glycol (PEG) to produce a larger variant of DI (PEG-DI) and showed that PEG-DI was equally effective as the non-PEGylated DI in inhibiting thrombosis caused by passive transfer of APS-IgG in mice. In this paper, we have used a mouse model that reflects human APS much more closely than the passive transfer of APS-IgG. In this model, the mice are immunized with human beta-2-glycoprotein I and develop endogenous anti-beta-2-glycoprotein I antibodies. When submitted to a pinch stimulus at the femoral vein, these mice develop clots. Our results show that PEG-DI inhibits production of thromboses in this model and also reduces expression of tissue factor in the aortas of the mice. No toxicity was seen in mice that received PEG-DI. Therefore, these results provide further evidence supporting possible efficacy of PEG-DI as a potential treatment for APS

Regional differences in modelled net production and shallow remineralization in the North Atlantic subtropical gyre

© The Author(s), 2012. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Biogeosciences 9 (2012): 2831-2846, doi:10.5194/bg-9-2831-2012.We used 5-yr concomitant data of tracer distribution from the BATS (Bermuda Time-series Study) and ESTOC (European Station for Time-Series in the Ocean, Canary Islands) sites to build a 1-D tracer model conservation including horizontal advection, and then compute net production and shallow remineralization rates for both sites. Our main goal was to verify if differences in these rates are consistent with the lower export rates of particulate organic carbon observed at ESTOC. Net production rates computed below the mixed layer to 110 m from April to December for oxygen, dissolved inorganic carbon and nitrate at BATS (1.34±0.79 mol O2 m−2, −1.73±0.52 mol C m−2 and −125±36 mmol N m−2) were slightly higher for oxygen and carbon compared to ESTOC (1.03±0.62 mol O2 m−2, −1.42±0.30 mol C m−2 and −213±56 mmol N m−2), although the differences were not statistically significant. Shallow remineralization rates between 110 and 250 m computed at ESTOC (−3.9±1.0 mol O2 m−2, 1.53±0.43 mol C m−2 and 38±155 mmol N m−2) were statistically higher for oxygen compared to BATS (−1.81±0.37 mol O2 m−2, 1.52±0.30 mol C m−2 and 147±43 mmol N m−2). The lateral advective flux divergence of tracers, which was more significant at ESTOC, was responsible for the differences in estimated oxygen remineralization rates between both stations. According to these results, the differences in net production and shallow remineralization cannot fully explain the differences in the flux of sinking organic matter observed between both stations, suggesting an additional consumption of non-sinking organic matter at ESTOC.B. Mourino was supported by the Ramon y Cajal program from the Spanish Minister of Science and Technology. Funding for this study was provided by the Xunta de Galicia under the research project VARITROP (09MDS001312PR, PI B. Mourino) and by the Ministerio de Ciencia e Innovation MOMAC project (CTM2008-05914/MAR)

Incorporando un plan de Vida Saludable en la Terapia Familiar Conductual: Ejemplificando un Caso Clínico de una Mujer con historial de Violencia Doméstica, Negligencia Infantil, Abuso de Drogas y Obesidad

Women reported to child protective service agencies frequently report problems that significantly interfere with the health and well-being of their children and themselves. Behavioral treatment programs appear to be effective in managing these co-existing problems, such as domestic violence and substance abuse. However, evidence-supported interventions are rarely exemplified in complicated clinical cases, especially within child welfare settings. Therefore, in this case example, we describe the process of adapting an evidence-supported treatment to assist in managing significant co-existing health-related problems in a mother who was referred due to child neglect and drug abuse. At the conclusion of therapy, the participant reported improvements in perceived family relationships, illicit drug use, child maltreatment potential, whereas other health-related outcomes were mixed. Most improvements were maintained at 4-month follow-up. Issues relevant to implementing evidence-based treatments within community contexts are discussed, including methods of increasing the likelihood of valid outcome assessment, managing treatment integrity, and adjusting standardized treatments to accommodate co-occurring problems. This research was supported by a grant from the National Institute on Drug Abuse (1R01DA020548-01A1) awarded to Brad Donohue. The authors wish to thank Sally K. Miller, PhD, APN, FAANP and Associate Professor, UNLV School of Nursing for her work in completing the initial in-home health evaluation/physical for the current project.Las mujeres reportadas a las agencias de servicios de protección infantil, con frecuencia presentan problemas que interfieren con la salud y el bienestar de ellas y de sus hijos. Los programas de intervención conductual parecen ser eficaces en el manejo de problemas coexistentes como: la violencia doméstica y el abuso de drogas. Sin embargo, los tratamientos cuya eficacia ya ha sido demostrada en ocasiones anteriores, rara vez se han puesto en práctica en casos clínicos complicados, sobre todo en los centros de asistencia a menores. Por lo tanto, en este caso clínico, se describe el proceso de adaptación de un tratamiento eficaz para ayudar a controlar los problemas coexistentes de salud de una mujer acusada de negligencia infantil y abuso de drogas. Al finalizar el tratamiento, la participante informó sobre la mejoría en sus relaciones familiares, sobre su consumo de drogas y la negligencia infantil; aunque otros resultados relacionados con su salud no quedaron completamente claros. Gran parte de las mejorías se mantuvieron hasta 4 meses  después de haber concluido el tratamiento. Antes de implementar cada fase del tratamiento, discutimos los  contextos de la comunidad, aumentando así la probabilidad de obtener resultados positivos y respetando la integridad y el ajuste del tratamiento estándar para evitar que se presenten problemas en un futuro.Esta investigación se financió gracias a una subvención del Instituto Nacional de Drogodependencia (1R01DA020548-01A1) otorgada a Brad Donohue. Los autores desean agradecer a Sally K. Miller, PhD, APN, FAANP y Profesora Asociada de la Escuela de Enfermería de La Universidad de Nevada Las Vegas, por el examen físico inicial que se llevó a cabo en el domicilio de la participante de este proyecto

The Updated Zwicky Catalog (UZC)

The Zwicky Catalog of galaxies (ZC), with m_Zw<=15.5mag, has been the basis for the Center for Astrophysics (CfA) redshift surveys. To date, analyses of the ZC and redshift surveys based on it have relied on heterogeneous sets of galaxy coordinates and redshifts. Here we correct some of the inadequacies of previous catalogs by providing: (1) coordinates with <~2 arcsec errors for all of the Nuzc catalog galaxies, (2) homogeneously estimated redshifts for the majority (98%) of the data taken at the CfA (14,632 spectra), and (3) an estimate of the remaining "blunder" rate for both the CfA redshifts and for those compiled from the literature. For the reanalyzed CfA data we include a calibrated, uniformly determined error and an indication of the presence of emission lines in each spectrum. We provide redshifts for 7,257 galaxies in the CfA2 redshift survey not previously published; for another 5,625 CfA redshifts we list the remeasured or uniformly re-reduced value. Among our new measurements, Nmul are members of UZC "multiplets" associated with the original Zwicky catalog position in the coordinate range where the catalog is 98% complete. These multiplets provide new candidates for examination of tidal interactions among galaxies. All of the new redshifts correspond to UZC galaxies with properties recorded in the CfA redshift compilation known as ZCAT. About 1,000 of our new measurements were motivated either by inadequate signal-to-noise in the original spectrum or by an ambiguous identification of the galaxy associated with a ZCAT redshift. The redshift catalog we include here is ~96% complete to m_Zw<=15.5, and ~98% complete (12,925 galaxies out of a total of 13,150) for the RA(1950) ranges [20h--4h] and [8h--17h] and DEC(1950) range [-2.5d--50d]. (abridged)Comment: 34 pp, 7 figs, PASP 1999, 111, 43

LEAP2 Impairs the Capability of the Growth Hormone Secretagogue Receptor to Regulate the Dopamine 2 Receptor Signaling

The growth hormone secretagogue receptor (GHSR) signals in response to ghrelin, but also acts via ligand-independent mechanisms that include either constitutive activation or interaction with other G protein-coupled receptors, such as the dopamine 2 receptor (D2R). A key target of GHSR in neurons is voltage-gated calcium channels type 2.2 (CaV2.2). Recently, the liver-expressed antimicrobial peptide 2 (LEAP2) was recognized as a novel GHSR ligand, but the mechanism of action of LEAP2 on GHSR is not well understood. Here, we investigated the role of LEAP2 on the canonical and non-canonical modes of action of GHSR on CaV2.2 function. Using a heterologous expression system and patch-clamp recordings, we found that LEAP2 impairs the reduction of CaV2.2 currents induced by ghrelin-evoked and constitutive GHSR activities, acting as a GHSR antagonist and inverse agonist, respectively. We also found that LEAP2 prevents GHSR from modulating the effects of D2R signaling on CaV2.2 currents, and that the GHSRbinding N-terminal region LEAP2 underlies these effects. Using purified labeled receptors assembled into lipid nanodiscs and Forster Resonance Energy Transfer (FRET) assessments, we found that the N-terminal region of LEAP2 stabilizes an inactive conformation of GHSR that is dissociated from Gq protein and, consequently, reverses the effect of GHSR on D2R-dependent Gi activation. Thus, our results provide critical molecular insights into the mechanism mediating LEAP2 modulation of GHSR.Instituto Multidisciplinario de Biología Celula