Cumulative mutagenesis of the basic residues in the 201-218 region of insulin-like growth factor (IGF)-binding protein-5 results in progressive loss of both IGF-I binding and inhibition of IGF-I biological action

We have reported previously that mutation of two conserved nonbasic amino acids (G203 and Q209) within the highly basic 201–218 region in the C-terminal domain of IGF-binding protein-5 (IGFBP-5) decreases binding to IGFs. This study reveals that cumulative mutagenesis of the 10 basic residues in this region, to create the C-Term series of mutants, ultimately results in a 15-fold decrease in the affinity for IGF-I and a major loss in heparin binding. We examined the ability of mutants to inhibit IGF-mediated survival of MCF-7 cells and were able to demonstrate that this depended not only upon the affinity for IGF-I, but also the kinetics of this interaction, because IGFBP-5 mutants with similar affinity constants (KD) values, but with different association (Ka) and dissociation (Kd) rate values, had markedly different inhibitory properties. In contrast, the affinity for IGF-I provided no predictive value in terms of the ability of these mutants to enhance IGF action when bound to the substratum. Instead, these C-Term mutants appeared to enhance the actions of IGF-I by a combination of increased dissociation of IGF-IGFBP complexes from the substratum, together with dissociation of IGF-I from IGFBP-5 bound to the substratum. These effects of the IGFBPs were dependent upon binding to IGF-I, because a non-IGF binding mutant (N-Term) was unable to inhibit or enhance the actions of IGF-I. These results emphasize the importance of the kinetics of association/dissociation in determining the enhancing or inhibiting effects of IGFBP-5 and demonstrate the ability to generate an IGFBP-5 mutant with exclusively IGF-enhancing activity

Sociodemographic, Disease, Health System, and Contextual Factors Affecting the Initiation of Biologic Agents in Rheumatoid Arthritis: A Longitudinal Study: Factors Influencing Initiation of Biologic Agents in RA

To analyze the effect of sociodemographic, disease, and health system characteristics and contextual features about the community of residence on the subsequent initiation of treatment with biologic agents for rheumatoid arthritis (RA)

English language proficiency, health literacy, and trust in physician are associated with shared decision making in rheumatoid arthritis.

ObjectiveTreat-to-target guidelines promote shared decision making (SDM) in rheumatoid arthritis (RA). Also, because of high cost and potential toxicity of therapies, SDM is central to patient safety. Our objective was to examine patterns of perceived communication around decision making in 2 cohorts of adults with RA.MethodsData were derived from patients enrolled in 1 of 2 longitudinal, observational cohorts [University of California, San Francisco (UCSF) RA Cohort and RA Panel Cohort]. Subjects completed a telephone interview in their preferred language that included a measure of patient-provider communication, including items about decision making. Measures of trust in physician, education, and language proficiency were also asked. Logistic regression was performed to identify correlates of suboptimal SDM communication. Analyses were performed on each sample separately.ResultsOf 509 patients across 2 cohorts, 30% and 32% reported suboptimal SDM communication. Low trust in physician was independently associated with suboptimal SDM communication in both cohorts. Older age and limited English proficiency were independently associated with suboptimal SDM in the UCSF RA Cohort, as was limited health literacy in the RA Panel Cohort.ConclusionThis study of over 500 adults with RA from 2 demographically distinct cohorts found that nearly one-third of subjects report suboptimal SDM communication with their clinicians, regardless of cohort. Lower trust in physician was independently associated with suboptimal SDM communication in both cohorts, as was limited English language proficiency and older age in the UCSF RA Cohort and limited health literacy in the RA Panel Cohort. These findings underscore the need to examine the influence of SDM on health outcomes in RA

Insulin-like growth factor binding protein-5 (IGFBP-5) induces premature cell death in the mammary glands of transgenic mice

We have previously demonstrated that IGFBP-5 production by mammary epithelial cells increases dramatically during involution of the mammary gland. To demonstrate a causal relationship between IGFBP-5 and cell death we created transgenic mice expressing IGFBP-5 in the mammary gland using a mammary-specific promoter, ß-lactoglobulin. DNA content in the mammary glands of transgenic mice was decreased as early as day 10 of pregnancy. Histological analysis indicated reduced numbers of alveolar end buds, with decreased ductal branching. Transgenic dams produced IGFBP-5 in their milk at concentrations similar to those achieved at the end of normal lactation. Mammary cell number and milk synthesis were both decreased by approximately 50% during the first 10 days of lactation. BrdU labelling was decreased, whereas DNA ladders were increased in transgenic animals on day 1 of lactation. On day 2 postpartum, the epithelial invasion of the mammary fat pad was clearly impaired in transgenic animals. The concentrations of the pro-apoptotic molecule caspase-3 and of plasmin were both increased in transgenic animals whilst the concentrations of 2 prosurvival molecules Bcl-2 and Bcl-xLwere both decreased. In order to examine whether IGFBP-5 acts by inhibiting the survival effect of IGF-I we examined IGF receptor phosphorylation and Akt phosphorylation and showed that both were inhibited. We attempted to "rescue" the transgenic phenotype by using growth hormone to increase endogenous IGF-I concentrations or by implanting minipumps delivering an IGF-1 analogue, R3-IGF-1, which binds weakly to IGFBP-5. Growth hormone treatment failed to affect mammary development suggesting that increased concentrations of endogenous IGF-1 are insufficient to overcome the high concentrations of IGFBP-5 produced by these transgenic animals. In contrast mammary development (gland weight and DNA content) was normalised by R3-IGF-I although milk production was only partially restored. This is the first demonstration that over-expression of IGFBP-5 can lead to; impaired mammary development, increased expression of the pro-apoptotic molecule caspase-3, increased plasmin generation and decreased expression of pro-survival molecules of the Bcl-2 family. It clearly demonstrates that IGF-I is an important developmental/survival factor for the mammary gland and, furthermore, this cell death programme may be utilised in a wide variety of tissues

Predictors of Stopping and Starting Disease‐Modifying Antirheumatic Drugs for Rheumatoid Arthritis

ObjectiveDisease-modifying antirheumatic drugs (DMARDs) are the standard of care for rheumatoid arthritis (RA); however, studies have found that many patients do not receive them. We examined predictors of starting and stopping DMARDs among a longitudinal cohort of patients with RA.MethodsStudy participants came from a cohort of RA patients recruited from a random sample of rheumatologists' practices in Northern California. We examined patterns and predictors of stopping and starting nonbiologic and biologic DMARDs during 1982-2009 based on annual questionnaires. Stopping was defined as stopping all DMARDs and starting was defined as transitioning from no DMARDs to any DMARDs across 2 consecutive years.ResultsThe analysis of starting DMARDs included 471 subjects with 1,974 pairs of years with no DMARD use in the first of 2 consecutive years. From this population, subjects started DMARD use by year 2 in 313 (15.9%) of the pairs. The analysis of stopping DMARDs included 1,026 subjects with 7,595 pairs of years with DMARD use in the first of 2 consecutive years; in 423 pairs (5.6%), subjects stopped DMARD use by year 2. In models that adjusted for RA-related factors, sociodemographics, and comorbidities, significant predictors of starting DMARDs included younger age, Hispanic ethnicity, shorter disease duration, and the use of oral glucocorticoids. In separate adjusted models, predictors of stopping DMARDs included Hispanic ethnicity and low income, while younger age was associated with a reduced risk of stopping.ConclusionEfforts to improve DMARD use should focus on patient age, ethnicity, and income and RA-related factors

California Health Benefits Review Program Analysis of California Assembly Bill AB 374 Step Therapy Coverage

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