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Feng X.,University of Alabama at Birmingham | McDonald J.M.,University of Alabama at Birmingham | McDonald J.M.,Veterans Administration Medical Center
Annual Review of Pathology: Mechanisms of Disease | Year: 2011

The skeleton provides mechanical support for stature and locomotion, protects vital organs, and controls mineral homeostasis. A healthy skeleton must be maintained by constant bone modeling to carry out these crucial functions throughout life. Bone remodeling involves the removal of old or damaged bone by osteoclasts (bone resorption) and the subsequent replacement of new bone formed by osteoblasts (bone formation). Normal bone remodeling requires a tight coupling of bone resorption to bone formation to guarantee no alteration in bone mass or quality after each remodeling cycle. However, this important physiological process can be derailed by a variety of factors, including menopause-associated hormonal changes, age-related factors, changes in physical activity, drugs, and secondary diseases, which lead to the development of various bone disorders in both women and men. We review the major diseases of bone remodeling, emphasizing our current understanding of the underlying pathophysiological mechanisms. Copyright © 2011 by Annual Reviews. All rights reserved.

Winges K.M.,Veterans Administration Medical Center
Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society | Year: 2013

Patients with multiple sclerosis (MS) demonstrate thinning of peripapillary retinal nerve fiber layer (RNFL) and decreased macular volume as measured by optical coherence tomography (OCT). To our knowledge, there are no previous reports from a large MS OCT database with strict quality control measures that quantitate RNFL and macula in patients with relapsing-remitting multiple sclerosis. The University of California Davis OCT Reading Center gathered OCT data at baseline as part of the North American phase 3 trial of fingolimod (Gilenya). Average RNFL thickness (RNFLT) and macular volume (TMV) were measured using time domain OCT (TD-OCT). RNFL quadrants, clock hours, and macular subfields were included. With strict quality control and accounting for signal strength differences, scans were categorized as "reduced" or "not reduced" for each field, based on being less than 5th percentile for age-matched controls derived from the normative database in the scanner software. Patients were deemed "abnormal" if at least 1 eye had reduced values for a given parameter. Patients with abnormalities in corresponding RNFL and macular subfields were compared by cross-tabulation. The TD-OCT data were prospectively collected from 939 of the 1,083 trial patients, 712 of whom met all final quality and data inclusion criteria. Of the final cohort, 242 (34.0%) demonstrated reduced (less than 5th percentile) average RNFLT in at least 1 eye. One hundred seventy-eight (25.0%) patients had reduced TMV. One hundred twenty-eight (18.0%) demonstrated both reduced TMV and RNFLT in the same eye, whereas 42 (5.8%) had reduced TMV and RNFLT in both eyes. Of the 242 patients with reduced average RNFL thickness, 128 (52.9%) also had reduced TMV. Fifty patients had reduced TMV in the absence of reduced RNFLT in at least 1 eye, a cohort prevalence of 7.0%. Quadrant and subfield analysis showed a predominance of temporal and inferior RNFL thinning, with inferior macular thinning corresponding best to RNFL thinning. RNFL and macular thinning/volume loss is common at baseline in relapsing-remitting multiple sclerosis, as measured by TD-OCT. When the RNFL is thin, the macular volume is reduced in more than half of the patients. There is a population of reduced TMV without any reduction in RNFLT. Documenting the prevalence and distribution of these structural abnormalities supports recent reports and suggests new retinal areas to probe for functional vision changes in MS.

Steinhardt J.J.,University of Maryland Baltimore County | Gartenhaus R.B.,University of Maryland Baltimore County | Gartenhaus R.B.,Veterans Administration Medical Center
Clinical Cancer Research | Year: 2012

Currently, two major classification systems segregate diffuse large B-cell lymphoma (DLBCL) into subtypes based on gene expression profiles and provide great insights about the oncogenic mechanisms that may be crucial for lymphomagenesis as well as prognostic information regarding response to current therapies. However, these current classification systems primarily look at expression and not dependency and are thus limited to inductive or probabilistic reasoning when evaluating alternative therapeutic options. The development of a deductive classification system that identifies subtypes in which all patients with a given phenotype require the same oncogenic drivers, and would therefore have a similar response to a rational therapy targeting the essential drivers, would significantly advance the treatment of DLBCL. This review highlights the putative drivers identified as well as the work done to identify potentially dependent populations. These studies integrated genomic analysis and functional screens to provide a rationale for targeted therapies within defined populations. Personalizing treatments by identifying patients with oncogenic dependencies via genotyping and specifically targeting the responsible drivers may constitute a novel approach for the treatment of DLBCL. ©2012 AACR.

Makris U.E.,Southwestern Medical Center | Makris U.E.,Veterans Administration Medical Center | Abrams R.C.,New York Medical College | Gurland B.,Columbia University | Reid M.C.,New York Medical College
JAMA - Journal of the American Medical Association | Year: 2014

IMPORTANCE: Persistent pain is highly prevalent, costly, and frequently disabling in later life. OBJECTIVE: To describe barriers to the management of persistent pain among older adults, summarize current management approaches, including pharmacologic and nonpharmacologic modalities; present rehabilitative approaches; and highlight aspects of the patient-physician relationship that can help to improve treatment outcomes. This review is relevant for physicians who seek an age-appropriate approach to delivering pain care for the older adult. EVIDENCE ACQUISITION: Search of MEDLINE and the Cochrane database from January 1990 through May 2014, using the search terms older adults, senior, ages 65 and above, elderly, and aged along with non-cancer pain, chronic pain, persistent pain, pain management, intractable pain, and refractory pain to identify English-language peer-reviewed systematic reviews, meta-analyses, Cochrane reviews, consensus statements, and guidelines relevant to the management of persistent pain in older adults. FINDINGS: Of the 92 identified studies, 35 evaluated pharmacologic interventions, whereas 57 examined nonpharmacologic modalities; the majority (n = 50) focused on older adults with osteoarthritis. This evidence base supports a stepwise approach with acetaminophen as first-line therapy. If treatment goals are not met, a trial of a topical nonsteroidal anti-inflammatory drug, tramadol, or both is recommended. Oral nonsteroidal anti-inflammatory drugs are not recommended for long-term use. Careful surveillance to monitor for toxicity and efficacy is critical, given that advancing age increases risk for adverse effects. A multimodal approach is strongly recommended - emphasizing a combination of both pharmacologic and nonpharmacologic treatments to include physical and occupational rehabilitation, as well as cognitive-behavioral and movement-based interventions. An integrated pain management approach is ideally achieved by cultivating a strong therapeutic alliance between the older patient and the physician. CONCLUSIONS AND RELEVANCE: Treatment planning for persistent pain in later life requires a clear understanding of the patient's treatment goals and expectations, comorbidities, and cognitive and functional status, as well as coordinating community resources and family support when available. A combination of pharmacologic, nonpharmacologic, and rehabilitative approaches in addition to a strong therapeutic alliance between the patient and physician is essential in setting, adjusting, and achieving realistic goals of therapy. Copyright 2014 American Medical Association. All rights reserved.

Sharma M.,Veterans Administration Medical Center
Advances in experimental medicine and biology | Year: 2013

The global rise in terrorism has increased the risk of radiological events aimed at creating chaos and destabilization, although they may cause relatively limited number of immediate casualties. We have proposed that a self-administered test would be valuable for initial triage following terrorist use of nuclear/radiological devices. The urine proteome may be a useful source of the biomarkers required for developing such a test. We have developed and extensively used a rat model to study the acute and late effect of total body (TBI) and partial body irradiation on critical organ systems. This model has proven valuable for correlating the structural and functional effects of radiation with molecular changes. Results show that nephron segments differ with regard to their sensitivity and response to ionizing radiation. The urine proteome was analyzed using LC-MS/MS at 24 h after TBI or local kidney irradiation using a 10 Gy single dose of X rays. LC-MS/MS data were analyzed and grouped under Gene Ontology categories Cellular Localization, Molecular Function and Biological Process. We observed a decrease in urine protein/creatinine ratio that corroborated with decreased spectral counts for urinary albumin and other major serum proteins. Interestingly, TBI caused greater decline in urinary albumin than local kidney irradiation. Analysis of acute-phase response proteins and markers of acute kidney injury showed increased urinary levels of cystatin superfamily proteins and alpha-1-acid glycoprotein. Among proteases and protease inhibitors, levels of Kallikrein 1-related peptidase b24, precursor and products of chymotrypsin-like activity, were noticeably increased. Among the amino acids that are susceptible to oxidation by free radicals, oxidized histidine levels were increased following irradiation. Our results suggest that proteomic analysis of early changes in urinary proteins will identify biomarkers for developing a self-administered test for radiation biodosimetry.

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