Filamin-A as a Balance between Erk/Smad Activities During Cardiac Valve Development

Mitral valve prolapse (MVP) affects 2.4% of the population and has poorly understood etiology. Recent genetic studies have begun to unravel the complexities of MVP and through these efforts, mutations in the FLNA (Filamin-A) gene were identified as disease causing. Our in vivo and in vitro studies have validated these genetic findings and have revealed FLNA as a central regulator of valve morphogenesis. The mechanisms by which FLNA mutations result in myxomatous mitral valve disease are currently unknown, but may involve proteins previously associated with mutated regions of the FLNA protein, such as the small GTPase signaling protein, R-Ras. Herein, we report that Filamin-A is required for R-Ras expression and activation of the Ras–Mek–Erk pathway. Loss of the Ras/Erk pathway correlated with hyperactivation of pSmad2/3, increased extracellular matrix (ECM) production and enlarged mitral valves. Analyses of integrin receptors in the mitral valve revealed that Filamin-A was required for β1-integrin expression and provided a potential mechanism for impaired ECM compaction and valve enlargement. Our data support Filamin-A as a protein that regulates the balance between Erk and Smad activation and an inability of Filamin-A deficient valve interstitial cells to effectively remodel the increased ECM production through a β1-integrin mechanism. As a consequence, loss of Filamin-A function results in increased ECM production and generation of a myxomatous phenotype characterized by improperly compacted mitral valve tissue. Anat Rec, 302:117–124, 2019. © 2018 Wiley Periodicals, Inc.     

Concomitant down-regulation of BRM and BRG1 in human tumor cell lines: differential effects on RB-mediated growth arrest vs CD44 expression

Mammalian cells express two homologs of the SWI2 subunit of the SWI/SNF chromatin-remodeling complex called BRG1 and BRM. Whether the SWI/SNF complexes formed by these two subunits perform identical or different functions remains an important question. In this report, we show concomitant down-regulation of BRG1 and BRM in six human tumor cell lines. This down-regulation occurs at the level of mRNA abundance. We tested whether BRM could affect aberrant cellular functions attributed to BRG1 in tumor cell lines. By transient transfection, we found that BRM can restore RB-mediated cell cycle arrest, induce expression of CD44 protein and suppress Cyclin A expression. Therefore, BRM may be consistently down-regulated with BRG1 during neoplastic progression because they share some redundant functions. However, assorted tissues from BRM null/BRG1-positive mice lack CD44 expression, suggesting that BRM-containing SWI/SNF complexes regulate expression of this gene under physiological conditions. Our studies further define the mechanism by which chromatin-remodeling complexes participate in RB-mediated cell cycle arrest and provide additional novel evidence that the functions of SWI/SNF complexes containing BRG1 or BRM are not completely interchangeable.     

Long-term renal function preservation after renal artery stenting in patients with progressive ischemic nephropathy.

We assessed the long-term effect of successful renal artery stent revascularization on renal function, blood pressure control, and survival in patients with progressive renal dysfunction due to ischemic nephropathy. Ischemic nephropathy presents a potentially serious risk of complete loss of renal function. Surgical renal revascularization is associated with significant risk of mortality/morbidity in this patient population. The potential role and long-term effect of renal artery stent revascularization in this patient population is not well defined. A cohort of 51 patients (mean age, 72 years; 52.9% men) with progressive azotemia, defined as a preprocedure serum creatinine (Scr) value of >or= 1.5 mg/dl and a negative slope of the reciprocal 1/Scr curve during the 12 months preceding revascularization, underwent successful primary stent deployment in 93 atherosclerotic renal artery lesions (42 bilateral, 9 solitary kidneys). Estimated glomerular filtration rate (EGFR) and serum creatinine values, blood pressure, antihypertensive medication requirements, and survival rates were monitored over a mean of 30-month follow-up. Renal artery duplex Doppler or renal angiography were performed at a mean of 13 months (range, 7-15 months) to assess stent patency. Stent implantation was successful in 92/93 (98.9%) stenotic renal arteries (mean preprocedure serum creatinine 2.3 +/- 0.9 mg/dl; range, 1.5-8.2 mg/dl). Forty-seven patients were eligible for 30-month follow-up of the procedural effect on renal function, blood pressure control, number of antihypertensive medications, and survival. At 1-year follow-up, the slope of the 1/Scr curve increased and the EGFR values significantly improved compared to preprocedure values (19.9 +/- 6.2 to 26.8 +/- 10.1 ml/min; P < 0.0001), serum creatinine decreased from the mean preprocedure value to 1.75 +/- 0.69 mg/dl (P < 0.001), with renal function improvement or stabilization observed in 94% of patients; three patients (7.3%) required permanent hemodialysis during the 30-month follow-up period. Systolic and diastolic blood pressure significantly decreased (from 177 +/- 28 to 148 +/- 25 mm Hg and from 92 +/- 15 to 78 +/- 14 mm Hg, respectively; P < 0.001) with fewer antihypertensive medications required to control blood pressure (3.5 +/- 0.9 vs. 1.9 +/- 1.3; P < 0.001). The patient survival rate after 30-month follow-up was 87%, with three deaths related to end-stage renal failure. Renal artery stent revascularization reversed progressive renal dysfunction within the first 12 months and maintained the improved level of renal function at 30-month follow-up while improving blood pressure control and reducing the number of antihypertensive medication requirements. Renal stent revascularization should be considered a valid therapeutic option for the long-term treatment of ischemic nephropathy.     

Combined glycoprotein IIb/IIIa receptor inhibition and low-dose fibrinolysis for peripheral arterial thrombosis.

This feasibility study evaluated the therapeutic potential of combined GP IIb/IIIa receptor inhibition with abciximab and low-dose fibrinolysis with reteplase for treatment of acute femoropopliteal thrombosis. The simultaneous intra-arterial administration of abciximab in conjunction with low-dose reteplase (< or = 0.5 U/hr) was safe in 13 patients; 2 patients experienced major hemorrhagic complication at a reteplase dose of 1 U/hr. The primary success rate was 100%; all patients experienced an excellent clinical response with no clinical evidence of distal embolization. No patient required repeat endovascular or surgical revascularization during mean follow-up of 9.3 months. This promising new thrombolytic strategy for the treatment of peripheral arterial occlusive disease requires further study.     

Childhood traumatic brain injury: neuropsychological status at the time of hospital discharge

The present study examined the status at the time of hospital discharge of 22 children who had sustained moderate to severe closed head injuries. Despite an average length of stay of 46 days, on average the children performed significantly below normal on cognitive, memory, and motor tests. The children who did the worst were those who sustained their injuries riding in a vehicle, as opposed to being hit by a vehicle while walking or riding a bicycle. No reliable associations were found between neuroimaging data and cognitive measures; however, children whose scans showed more diffuse severe injury (e.g. white matter hemorrhages) performed more poorly than those who did not. Of further importance were detailed morphometric analyses of tissue quantity and ventricular volume that showed significantly increased ventricle to brain ratios (VBR) over a 3 to 4 week period following injury.     

The use of saturation in qualitative research

Understanding qualitative research is an important component of cardiovascular nurses' practice and allows them to understand the experiences, stories, and perceptions of patients with cardiovascular conditions. In understanding qualitative research methods, it is essential that the cardiovascular nurse understands the process of saturation within qualitative methods. Saturation is a tool used for ensuring that adequate and quality data are collected to support the study. Saturation is frequently reported in qualitative research and may be the gold standard. However, the use of saturation within methods has varied. Hence, the purpose of this column is to provide insight for the cardiovascular nurse regarding the use of saturation by reviewing the recommendations for which qualitative research methods it is appropriate to use and how to know when saturation is achieved. In understanding saturation, the cardiovascular nurse can be a better consumer of qualitative research.     

Achieving self-management goals among low income older adults with functional limitations

Although self-management interventions can improve symptoms and disease among older adults, there is a dearth of literature on how self-management behaviors may improve factors related to the older adults’ physical function. To fill this gap in the literature, we describe the patient-directed self-management goals in nursing visits that relate to physical function as part of a multi-component program. We analyze the self-management goals and outcomes of 367 low- income older adults with functional limitations who participated in the CAPABLE program: a program to reduce the health effects of impaired physical function in low-income older adults. We focus on the following self-management goals that participants chose with the nurses: pain management, depressive symptoms, incontinence, fall prevention, and communication with healthcare providers. The majority of participants chose pain (50%) or fall prevention (51%) as goals and partially or fully met their goals. Improvements across these areas may lead to improved physical function.     

The expression of the SWI/SNF ATPase subunits BRG1 and BRM in normal human tissues.

SWI/SNF is a chromatin-remodeling complex important in gene regulation, cytokine responses, tumorigenesis, differentiation, and development. As a multitude of signaling pathways require SWI/SNF, loss of SWI/SNF function is expected to have an impact on cellular phenotypes. The SWI/SNF ATPase subunits, BRG1 and BRM, have been shown to be lost in a subset of human cancer cell lines and human primary cancers and may represent tumor suppressor proteins. To better understand the biology of these proteins, the authors examined the expression pattern of BRG1 and BRM in a variety of normal tissues. BRG1 expression was predominantly seen in cell types that constantly undergo proliferation or self-renewal; in contrast, BRM was preferentially expressed in brain, liver, fibromuscular stroma, and endothelial cell types, cell types not constantly engaged in proliferation or self-renewal. This differential expression suggests that these proteins serve distinct functions in human tissues.