Dementia caregivers' coping strategies and their relationship to health and well-being: the Cache County Study.

OBJECTIVES: Prior research identifies that psychological outcomes among dementia caregivers are associated with their use of coping strategies. Few studies have tested the association of coping and health longitudinally. METHOD: This study examined factors associated with the use of coping strategies over time and their associations with physical and mental health outcomes in a population-based sample of 226 dementia caregivers in Cache County, Utah, USA. Caregivers annually completed the Ways of Coping Checklist-Revised, the Beck Anxiety Inventory, and a health interview. Care-recipient cognitive and functional abilities were obtained using the Mini-Mental State Exam and the Clinical Dementia Rating. Neuropsychiatric symptoms were assessed using the Neuropsychiatric Inventory. RESULTS: Caregivers most frequently identified providing care as a problem (37.6%). Linear mixed models of caregiver coping strategies found that the use of most strategies were stable except for increasing Avoidance among adult child caregivers (ß = 0.14, p = 0.048). On average, increased Wishful Thinking (ß = 2.48, p < 0.001) or Blames Self (ß = 1.06, p = 0.002) was associated with higher anxiety scores. Increased use of Blames Others among males (interaction, ß = 0.28, p = 0.02) and greater use of Wishful Thinking among younger caregivers (interaction, ß = -0.01, p = 0.01) were associated with more caregiver health conditions. Coping strategies were not associated with change in anxiety or health conditions over time. CONCLUSION: Our results emphasize the importance of caregiver coping strategies on caregiver health and well-being and may identify subgroups of persons at risk for worse outcomes.

MEF2A regulates the Gtl2-Dio3 microRNA mega-cluster to modulate WNT signaling in skeletal muscle regeneration.

Understanding the molecular mechanisms of skeletal muscle regeneration is crucial to exploiting this pathway for use in tissue repair. Our data demonstrate that the MEF2A transcription factor plays an essential role in skeletal muscle regeneration in adult mice. Injured Mef2a knockout mice display widespread necrosis and impaired myofiber formation. MEF2A controls this process through its direct regulation of the largest known mammalian microRNA (miRNA) cluster, the Gtl2-Dio3 locus. A subset of the Gtl2-Dio3 miRNAs represses secreted Frizzled-related proteins (sFRPs), inhibitors of WNT signaling. Consistent with these data, Gtl2-Dio3-encoded miRNAs are downregulated in regenerating Mef2a knockout muscle, resulting in upregulated sFRP expression and attenuated WNT activity. Furthermore, myogenic differentiation in Mef2a-deficient myoblasts is rescued by overexpression of miR-410 and miR-433, two miRNAs in the Gtl2-Dio3 locus that repress sFRP2, or by treatment with recombinant WNT3A and WNT5A. Thus, miRNA-mediated modulation of WNT signaling by MEF2A is a requisite step for proper muscle regeneration, and represents an attractive pathway for enhancing regeneration of diseased muscle.

The Mef2A transcription factor coordinately regulates a costamere gene program in cardiac muscle.

The Mef2 family of transcription factors regulates muscle differentiation, but the specific gene programs controlled by each member remain unknown. Characterization of Mef2A knock-out mice has revealed severe myofibrillar defects in cardiac muscle indicating a requirement for Mef2A in cytoarchitectural integrity. Through comprehensive expression analysis of Mef2A-deficient hearts, we identified a cohort of dysregulated genes whose products localize to the peripheral Z-disc/costamere region. Many of these genes are essential for costamere integrity and function. Here we demonstrate that these genes are directly regulated by Mef2A, establishing a mechanism by which Mef2A controls the costamere. In an independent model system, acute knockdown of Mef2A in primary neonatal cardiomyocytes resulted in profound malformations of myofibrils and focal adhesions accompanied by adhesion-dependent programmed cell death. These findings indicate a role for Mef2A in cardiomyocyte survival through regulation of costamere integrity. Finally, bioinformatics analysis identified over-represented transcription factor-binding sites in this network of costamere promoters that may provide insight into the mechanism by which costamere genes are regulated by Mef2A. The global control of costamere gene expression adds another dimension by which this essential macromolecular complex may be regulated in health and disease.

Myospryn is a calcineurin-interacting protein that negatively modulates slow-fiber-type transformation and skeletal muscle regeneration.

The calcium-calmodulin-regulated protein phosphatase calcineurin plays an important regulatory role in muscle differentiation, fiber-type determination, hypertrophy, and muscle regeneration. Because calcineurin functions in numerous processes in muscle, multiple mechanisms are likely necessary to ensure that the activity of this phosphatase is appropriately regulated. Here we demonstrate that the muscle-specific scaffolding protein myospryn modulates calcineurin signaling by inhibiting calcineurin-dependent transcriptional activity in C2C12 myoblasts through direct interaction with the enzyme via its noncanonical tripartite motif (TRIM-like). Consistent with these data, transgenic mice overexpressing both the TRIM-like domain of myospryn and constitutively active calcineurin displayed a severe attenuation in the ability of calcineurin to induce a slow-fiber phenotype. Furthermore, transgenic mice overexpressing the TRIM-like domain of myospryn displayed attenuated muscle regeneration after cardiotoxin-induced muscle injury. These results indicate that myospryn functions as a novel inhibitor of the calcineurin signaling pathway in skeletal muscle.

Modulation of angiotensin II-mediated cardiac remodeling by the MEF2A target gene Xirp2.

RATIONALE: The vasoactive peptide angiotensin II (Ang II) is a potent cardiotoxic hormone whose actions have been well studied, yet questions remain pertaining to the downstream factors that mediate its effects in cardiomyocytes. OBJECTIVE: The in vivo role of the myocyte enhancer factor (MEF)2A target gene Xirp2 in Ang II-mediated cardiac remodeling was investigated. METHODS AND RESULTS: Here we demonstrate that the MEF2A target gene Xirp2 (also known as cardiomyopathy associated gene 3 [CMYA3]) is an important effector of the Ang II signaling pathway in the heart. Xirp2 belongs to the evolutionarily conserved, muscle-specific, actin-binding Xin gene family and is significantly induced in the heart in response to systemic administration of Ang II. Initially, we characterized the Xirp2 promoter and demonstrate that Ang II activates Xirp2 expression by stimulating MEF2A transcriptional activity. To further characterize the role of Xirp2 downstream of Ang II signaling we generated mice harboring a hypomorphic allele of the Xirp2 gene that resulted in a marked reduction in its expression in the heart. In the absence of Ang II, adult Xirp2 hypomorphic mice displayed cardiac hypertrophy and increased beta myosin heavy chain expression. Strikingly, Xirp2 hypomorphic mice chronically infused with Ang II exhibited altered pathological cardiac remodeling including an attenuated hypertrophic response, as well as diminished fibrosis and apoptosis. CONCLUSIONS: These findings reveal a novel MEF2A-Xirp2 pathway that functions downstream of Ang II signaling to modulate its pathological effects in the heart.

An examination of mandated versus voluntary referral as a determinant of clinical outcome.

A literature review was undertaken to examine evidence for the effectiveness of psychotherapy with mandated clients. The primary question addressed was whether or not clients mandated to therapy, whether by court order or by order of their employers, show poorer outcomes than clients who enter therapy voluntarily. To this end, research on client resistance and motivational readiness to change was reviewed. This was followed by an examination of research on the effectiveness of mandated treatment. The question of the potential influence of relationship factors such as the therapeutic alliance was also addressed. The literature review was followed by suggestions for future research on the effectiveness of treatment for clients with mandated or voluntary referral status.