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Salt Lake City, UT, United States

Greenlee J.E.,Veterans Affairs Medical Center Salt Lake City | Greenlee J.E.,University of Utah
Current Treatment Options in Neurology | Year: 2013

Opinion statement: Paraneoplastic cerebellar degeneration is an uncommon autoimmune disorder characterized clinically by progressive, ultimately incapacitating ataxia and pathologically by destruction of cerebellar Purkinje cells, with variable loss of other cell populations. The disorder is most commonly associated with gynecological and breast carcinomas, small cell carcinoma of the lung, and Hodgkin's disease and in most cases comes on prior to identification of the underlying neoplasm. The hallmark of paraneoplastic cerebellar degeneration is the presence of an immune response reactive with intracellular proteins of Purkinje or other neurons or, less commonly, against neuronal surface antigens. Evidence-based treatment strategies for paraneoplastic cerebellar degeneration do not exist; and approaches to therapy are thus speculative. Diagnosis and treatment of the underlying neoplasm is critical, and characterization of the antibody response involved may assist in tumor diagnosis. Most investigators have initiated treatment with corticosteroids, plasma exchange, or intravenous immunoglobulin G. Cyclophosphamide, tacrolimus, rituximab, or possibly mycophenolate mofetil may warrant consideration in patients who fail to stabilize or improve on less aggressive therapies. Plasma exchange has been of questionable benefit when used alone but should be considered at initiation of treatment to achieve rapid lowering of circulating paraneoplastic autoantibodies. Because the course of illness is one of relentless neuronal destruction, time is of the essence in initiating treatment. Likelihood of clinical improvement in patients with longstanding symptoms and extensive neuronal loss is poor. © 2013 Springer Science+Business Media New York (outside the USA). Source

Donato A.J.,University of Colorado at Boulder | Donato A.J.,University of Utah | Donato A.J.,Veterans Affairs Medical Center Salt Lake City | Walker A.E.,University of Utah | And 9 more authors.
Aging Cell | Year: 2013

Aging impairs arterial function through oxidative stress and diminished nitric oxide (NO) bioavailability. Life-long caloric restriction (CR) reduces oxidative stress, but its impact on arterial aging is incompletely understood. We tested the hypothesis that life-long CR attenuates key features of arterial aging. Blood pressure, pulse wave velocity (PWV, arterial stiffness), carotid artery wall thickness and endothelium-dependent dilation (EDD; endothelial function) were assessed in young (Y: 5-7 month), old ad libitum (Old AL: 30-31 month) and life-long 40% CR old (30-31 month) B6D2F1 mice. Blood pressure was elevated with aging (P < 0.05) and was blunted by CR (P < 0.05 vs. Old AL). PWV was 27% greater in old vs. young AL-fed mice (P < 0.05), and CR prevented this increase (P < 0.05 vs. Old AL). Carotid wall thickness was greater with age (P < 0.05), and CR reduced this by 30%. CR effects were associated with amelioration of age-related changes in aortic collagen and elastin. Nitrotyrosine, a marker of cellular oxidative stress, and superoxide production were greater in old AL vs. young (P < 0.05) and CR attenuated these increase. Carotid artery EDD was impaired with age (P < 0.05); CR prevented this by enhancing NO and reducing superoxide-dependent suppression of EDD (Both P < 0.05 vs. Old AL). This was associated with a blunted age-related increase in NADPH oxidase activity and p67 expression, with increases in superoxide dismutase (SOD), total SOD, and catalase activities (All P < 0.05 Old CR vs. Old AL). Lastly, CR normalized age-related changes in the critical nutrient-sensing pathways SIRT-1 and mTOR (P < 0.05 vs. Old AL). Our findings demonstrate that CR is an effective strategy for attenuation of arterial aging. © 2013 The Anatomical Society and John Wiley & Sons Ltd. Source

Donato A.J.,University of Utah | Donato A.J.,Veterans Affairs Medical Center Salt Lake City | Morgan R.G.,University of Washington | Walker A.E.,University of Utah | And 2 more authors.
Journal of Molecular and Cellular Cardiology | Year: 2015

Cardiovascular disease (CVD) is the leading cause of death in the United States and aging is a major risk factor for CVD development. One of the major age-related arterial phenotypes thought to be responsible for the development of CVD in older adults is endothelial dysfunction. Endothelial function is modulated by traditional CVD risk factors in young adults, but advancing age is independently associated with the development of vascular endothelial dysfunction. This endothelial dysfunction results from a reduction in nitric oxide bioavailability downstream of endothelial oxidative stress and inflammation that can be further modulated by traditional CVD risk factors in older adults. Greater endothelial oxidative stress with aging is a result of augmented production from the intracellular enzymes NADPH oxidase and uncoupled eNOS, as well as from mitochondrial respiration in the absence of appropriate increases in antioxidant defenses as regulated by relevant transcription factors, such as FOXO. Interestingly, it appears that NFkB, a critical inflammatory transcription factor, is sensitive to this age-related endothelial redox change and its activation induces transcription of pro-inflammatory cytokines that can further suppress endothelial function, thus creating a vicious feed-forward cycle. This review will discuss the two macro-mechanistic processes, oxidative stress and inflammation, that contribute to endothelial dysfunction with advancing age as well as the cellular and molecular events that lead to the vicious cycle of inflammation and oxidative stress in the aged endothelium. Other potential mediators of this pro-inflammatory endothelial phenotype are increases in immune or senescent cells in the vasculature. Of note, genomic instability, telomere dysfunction or DNA damage has been shown to trigger cell senescence via the p53/p21 pathway and result in increased inflammatory signaling in arteries from older adults. This review will discuss the current state of knowledge regarding the emerging concepts of senescence and genomic instability as mechanisms underlying oxidative stress and inflammation in the aged endothelium. Lastly, energy sensitive/stress resistance pathways (SIRT-1, AMPK, mTOR) are altered in endothelial cells and/or arteries with aging and these pathways may modulate endothelial function via key oxidative stress and inflammation-related transcription factors. This review will also discuss what is known about the role of "energy sensing" longevity pathways in modulating endothelial function with advancing age. With the growing population of older adults, elucidating the cellular and molecular mechanisms of endothelial dysfunction with age is critical to establishing appropriate and measured strategies to utilize pharmacological and lifestyle interventions aimed at alleviating CVD risk. This article is part of a Special Issue entitled "SI: CV Aging". © 2015. Source

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