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Kaur G Mohan P Pawlik M DeRosa S Fajiculay J Che S Grubb A Ginsberg SD Nixon RA Levy E 《The American journal of pathology》2010,177(5):2256-2267
In vitro studies have shown that cystatin C (CysC) is neuroprotective. Here we demonstrate that CysC is neuroprotective in vivo, in a mouse model of the inherited neurodegenerative disorder, progressive myoclonic epilepsy type 1 (EPM1). Loss-of-function mutations in the cystatin B (CysB) gene, an intracellular cysteine protease inhibitor, lead to this human disease. A CysB-knockout (CysBKO) mouse model develops symptoms that mimic EPM1. CysB deficiency in these mice results in enhanced cathepsin B and D activities, indicating lysosomal dysfunction. We show that expression of CysC is enhanced in the brains of CysBKO mice. Crossbreeding of CysBKO mice with either CysC-overexpressing transgenic mice or CysC-knockout mice demonstrates that clinical symptoms and neuropathologies, including motor coordination disorder, cerebellar atrophy, neuronal loss in the cerebellum and cerebral cortex, and gliosis caused by CysB deficiency, are rescued by CysC overexpression and exacerbated by CysC deficiency. Thus, CysC effectively rescues the CysB loss-of-function mutations, facilitating the reversal of pathophysiological changes and suggesting a novel therapeutic intervention for patients with EPM1 and other neurodegenerative disorders. 相似文献
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Pain management is a challenge when working with persons who have cognitive impairment that affects their ability to understand and communicate. This article focuses on pain assessment and treatment in persons who have dementia, but the challenges and principles are relevant to the spectrum of cognitive impairment. Fundamental principles guiding pain assessment and treatment in this population are (1) that behavioral disturbance is the result of an unmet need that causes discomfort, (2) that the behavioral disturbances that result from the unmet need of uncontrolled pain may be identical to those caused by other unmet needs (e.g., thirst, needing to toilet, understimulation, overstimulation, depression, psychosis, uncomfortable clothing), and therefore (3) that any pain treatment protocol for this population must target discomfort behaviors in general and then attempt to determine their causes. Pain assessment and treatment approaches based on these principles are outlined, and then two cases are presented to illustrate the application of these approaches. 相似文献
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Jonathan J. Shuster 《CTS Clinical and Translational Science》2015,8(2):132-136
Despite unequivocal evidence that smoking cessation is beneficial in terms of survival, there is at present no firm evidence that smoking cessation programs save lives. While they do increase quit rates, the collective evidence from randomized trials is inconclusive with respect to long‐term survival. Withdrawal symptoms and the potential for harm when a subjects relapses after a prolonged period of cessation (e.g., 5+ years) might mitigate some or all of the benefits of the sustained quitters. This paper will review the key survival epidemiology and argue for a large randomized field trial of about 30,000 subjects, followed personally for 5 years and collectively for 15 years through the National Death Index. The intervention should be personalized, but reproducible through a treatment assignment algorithm. Personal coaching should be a major part of the intervention. Important short‐term data on healthcare utilization should also be collected. Strong financial motivation for quitting (or prevention of smoking in the first place) is also presented. This paper is intended to motivate a large collective effort amongst the US Clinical and Translational Science Awardees to design the intervention and bring together the interested players to conduct the study. 相似文献
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Malnutrition is common in patients with cancer and is associated with a variety of negative outcomes. These can include reduced treatment tolerance and worsened cancer prognosis. Various aspects of aging, including sensory, physical, or psychosocial changes, place older patients at a particularly high risk for malnutrition, and these geriatric factors must be identified early and addressed. Despite the lack of available evidence on the optimal nutritional interventions for older adults with cancer, the oncologist must be prepared to address the common nutritional concerns that arise in both advanced cancer and survivorship settings. While BMI, weight loss, and serum albumin are commonly used as surrogates of malnutrition, the use of a comprehensive screening tool may promote early identification of disrupted eating patterns and allow for prompt intervention. New digital technologies have also demonstrated promise to improve nutritional assessment capabilities. Use of conventional nutritional support in conjunction with novel nutraceutical and anti-cachexia approaches may enhance the effectiveness of interventions and improve our ability to reverse malnutrition-associated alterations in body composition. Future geriatric-focused nutrition research will be crucial in helping guide our patients and effectively addressing their dietary and lifestyle concerns. 相似文献
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Hyperghrelinemia in Prader‐Willi syndrome begins in early infancy long before the onset of hyperphagia
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