Background
Fibromyalgia (FM) has been understudied in the elderly population, a group with particular vulnerabilities to pain, reduced mobility, and sleep disruption.
Aims
To characterize FM symptoms ...and treatments in a cohort of older subjects examined over time to determine the extent to which current, community-based treatment for older FM patients is in accord with published guidelines, and effective in reducing symptoms.
Methods
A longitudinal, observational study of 51 subjects with FM (range 55–95 years) and 81 control subjects (58–95 years) performed at Banner Sun Health Research Institute in Sun City, AZ, USA. Serial history and examination data were obtained over a 6-year period. FM data included medical history, medications, physical examination, tender point examination, neuropsychological testing, sleep and pain ratings, the Physical Function Subscale of the Fibromyalgia Impact Questionnaire, and other standardized scales to evaluate depression and other psychiatric symptoms, and cognitive and functional impairment.
Results
Pain and stiffness that interfered with physical activity, sleep, and mood were reported by 80 % or more of subjects. Over time, pain involved an increasing number of body areas. Over half of subjects were treated with NSAIDs, one-quarter with opioids, and one-quarter with estrogen. Few were treated with dual-acting antidepressants or pregabalin.
Discussion
In this cohort of elders with suboptimally treated FM, substantial persistence of symptoms was seen over time. In general, recommended treatments were either not used or not tolerated.
Conclusions
Age-appropriate treatments as well as education of primary care providers are needed to improve treatment of FM in the older population.
Increasing evidence indicates that maintenance of neuronal homeostasis involves theactivation of the cell cycle machinery in postmitotic neurons. Our recent findings suggestthat cell cycle activation ...is essential for DNA damage-induced neuronal apoptosis.However, whether the cell division cycle also participates in DNA repair and survival ofpostmitotic, terminally differentiated neurons, is unknown. Here, we tested thehypothesis that G1 phase components contribute to the repair of DNA and are involved inthe DNA damage response of postmitotic neurons. In cortical terminally differentiatedneurons, treatment with subtoxic concentrations of hydrogen peroxide (H2O2) causedrepairable DNA double-strand breaks (DSBs) and the activation of G1 components of thecell cycle machinery. Importantly, DNA repair was attenuated if cyclin-dependentkinases CDK4 and CDK6, essential elements of G0→G1 transition, were suppressed.Our data suggest that G1 cell cycle components are involved in DNA repair and survivalof postmitotic neurons.
Inflammation plays a crucial role in early stages of both insulin resistance and atherosclerosis development. Preclinical evidence suggests an important role for DPP-4 in the regulation of adipose ...tissue (AT) inflammation. The present study tests the hypothesis that DPP-4 inhibition by saxagliptin reduces adipose tissue inflammation independent of changes in glucose metabolism. Forty-four overweight or obese individuals without diabetes were randomized to receive once daily saxagliptin (5 mg) or matching placebo (2:1 randomization) for 6 weeks. Adipose tissue biopsies, 4 hour fat-enriched meal challenge tests, and endothelial function measurement were performed at baseline and at the end of each treatment. Forty-two participants completed the study (27 saxagliptin/15 placebo). There were no group differences in the AT expression of inflammation-related genes (MCP-1, CD36, CD68, IL-6, IL-8, TxNIP and adiponectin) and protein pathway activation (ERK, JNK and NFκB). Secretion of IL-8 from adipose tissue explants was reduced after saxagliptin compared to placebo (median fold-baseline 0.8 saxagliptin vs. 2.3 placebo, p=0.01) and there was also a trend for reduced IL-6 release (0.7 vs. 1.5, p=0.06). After the high-fat meal, plasma glucose was slightly lower after saxagliptin (4 hour AUC, 0.96 vs. 1.0, p=0.04) while insulin and triglycerides were similar between the two groups. There were no treatment differences in endothelial function.
In conclusion, reduced AT secretion of IL-8 and IL-6 (trend) in obese nondiabetic subjects suggests saxagliptin may directly reduce AT inflammation. However, this effect was relatively modest, with many other indicators of tissue inflammation remaining unchanged. The reduction in AT inflammation did not appear sufficiently potent to influence postprandial metabolism or endothelial function.
Disclosure
J. Koska: None. T. Osredkar: None. K. D'Souza: None. S. Sinha: None. C. Meyer: Employee; Self; Merck & Co., Inc. P. Reaven: Research Support; Self; AstraZeneca, Amgen Inc., Bristol-Myers Squibb Company.
Aims
To test whether liraglutide suppresses postprandial elevations in lipids and thus protects against high saturated fatty acid (SFA) diet‐induced insulin resistance.
Methods
In a randomized ...placebo‐controlled crossover study, 32 participants with normal or mildly impaired glucose tolerance received liraglutide and placebo for 3 weeks each. Insulin suppression tests (IST) were conducted at baseline and after a 24‐hour SFA‐enriched diet after each treatment. Plasma glucose, insulin, triglycerides and non‐esterified fatty acids (NEFA) were measured over the initial 8 hours (breakfast and lunch) on the SFA diet. A subset of participants underwent ex vivo measurements of insulin‐mediated vasodilation of adipose tissue arterioles and glucose metabolism regulatory proteins in skeletal muscle.
Results
Liraglutide reduced plasma glucose, triglycerides and NEFA concentrations during the SFA diet (by 50%, 25% and 9%, respectively), and the SFA diet increased plasma glucose during the IST (by 36%; all P < .01 vs placebo). The SFA diet‐induced impairment of vasodilation on placebo (−9.4% vs baseline; P < .01) was ameliorated by liraglutide (−4.8%; P = .1 vs baseline). In skeletal muscle, liraglutide abolished the SFA‐induced increase in thioredoxin‐interacting protein (TxNIP) expression (75% decrease; P < .01 vs placebo) and increased 5′AMP‐activated protein kinase (AMPK) phosphorylation (50% vs −3%; P = .04 vs placebo).
Conclusions
Liraglutide blunted the SFA‐enriched diet‐induced peripheral insulin resistance. This effect may be related to improved microvascular function and modulation of TxNIP and AMPK pathways in skeletal muscle.
Amyloid containing deposits are a defining neuropathological feature of a wide range of dementias and movement disorders. The positron emission tomography tracer PIB (Pittsburgh Compound-B, ...2-4'-(methylamino)phenyl-6-hydroxybenzothiazole) was developed to target senile plaques, an amyloid containing pathological hallmark of Alzheimer's disease, formed from the amyloid-beta peptide. Despite the fact that PIB was developed from the pan-amyloid staining dye thioflavin T, no detailed characterisation of its interaction with other amyloid structures has been reported. In this study, we demonstrate the presence of a high affinity binding site (K(d) approximately 4 nM) for benzothiazole derivatives, including 3H-PIB, on alpha-synuclein (AS) filaments generated in vitro, and further characterise this binding site through the use of radioligand displacement assays employing 4-N-methylamino-4'-hydroxystilbene (SB13) (K(i) = 87 nM) and 2-(1-{6-(2-fluoroethyl(methyl)amino-2-naphthyl}ethylidene)malononitrile (FDDNP) (K(i) = 210 nM). Despite the presence of a high-affinity binding site on AS filaments, no discernible interaction of 3H-PIB was detected with amygdala sections from Parkinson's disease cases containing frequent AS-immunoreactive Lewy bodies and related neurities. These findings suggest that the density and/or accessibility of AS binding sites in vivo are significantly less than those associated with amyloid-beta peptide lesions. Lewy bodies pathology is therefore unlikely to contribute significantly to the retention of PIB in positron emission tomography imaging studies.
The novel naphtoxazine derivative and preferential D(3) vs D(2) receptor agonist, S32504, restores perturbed motor function in rodent and primate models of antiparkinsonian activity with a potency ...superior to those of two further, preferential D(3) receptor agonists, pramipexole and ropinirole. However, potential neuroprotective properties of S32054 have not, to date, been evaluated. Herein, employing several measures of cellular integrity, we demonstrate that S32504 robustly, concentration-dependently and completely protects terminally differentiated SH-SY5Y cells against 1-methyl-4-phenylpyridinium (MPP+)-induced cell death in vitro. Further, S32504 was substantially more potent than pramipexole and ropinirole, the latter of which was neurotoxic at high concentrations. In vivo, subchronic treatment with low (0.25 mg/kg) and high (2.5 mg/kg) doses of S32504 prior to and during treatment of mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, MPTP, provided complete protection against MPTP-induced tyrosine hydroxylase immunoreactive (TH-IR) neuronal death in the substantia nigra pars compacta and ventral tegmental area. A high dose of ropinirole (2.5 mg/kg) provided some protection but statistical significance was not attained, and a low dose (0.25 mg/kg) was ineffective. Neither drug afforded protection against the MPTP-induced loss of DA fibers in the striatum, as measured by TH-IR and dopamine transporter immunoreactive fiber counts. In conclusion, the novel naphotoxazine and dopaminergic agonist, S32504, robustly protects dopaminergic neurones against the neurotoxic effects of MPP(+) and MPTP in in vitro and in vivo models, respectively. The underlying mechanisms and therapeutic pertinence of these actions will be of interest to further evaluate in view of its potent actions in behavioral models of antiparkinson activity.
The novel naphtoxazine derivative and preferential D
3 vs D
2 receptor agonist, S32504, restores perturbed motor function in rodent and primate models of antiparkinsonian activity with a potency ...superior to those of two further, preferential D
3 receptor agonists, pramipexole and ropinirole. However, potential neuroprotective properties of S32054 have not, to date, been evaluated. Herein, employing several measures of cellular integrity, we demonstrate that S32504 robustly, concentration-dependently and completely protects terminally differentiated SH-SY5Y cells against 1-methyl-4-phenylpyridinium (MPP+)-induced cell death in vitro. Further, S32504 was substantially more potent than pramipexole and ropinirole, the latter of which was neurotoxic at high concentrations. In vivo, subchronic treatment with low (0.25 mg/kg) and high (2.5 mg/kg) doses of S32504 prior to and during treatment of mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, MPTP, provided complete protection against MPTP-induced tyrosine hydroxylase immunoreactive (TH-IR) neuronal death in the substantia nigra pars compacta and ventral tegmental area. A high dose of ropinirole (2.5 mg/kg) provided some protection but statistical significance was not attained, and a low dose (0.25 mg/kg) was ineffective. Neither drug afforded protection against the MPTP-induced loss of DA fibers in the striatum, as measured by TH-IR and dopamine transporter immunoreactive fiber counts. In conclusion, the novel naphotoxazine and dopaminergic agonist, S32504, robustly protects dopaminergic neurones against the neurotoxic effects of MPP
+ and MPTP in in vitro and in vivo models, respectively. The underlying mechanisms and therapeutic pertinence of these actions will be of interest to further evaluate in view of its potent actions in behavioral models of antiparkinson activity.
Adjuvant-induced arthritic (AA) differentially affects norepinephrine concentrations in immune organs, and in vivo β-adrenergic receptor (β-AR) agonist treatment distinctly regulates ex vivo cytokine ...profiles in different immune organs. We examined the contribution of altered β-AR functioning in AA to understand these disparate findings. Twenty-one or 28 days after disease induction, we examined β 2-AR expression in spleen and draining lymph nodes (DLNs) for the arthritic limbs using radioligand binding and western blots and splenocyte β-AR-stimulated cAMP production using enzyme-linked immunoassay (EIA). During severe disease, β-AR agonists failed to induce splenocyte cAMP production, and β-AR affinity and density declined, indicating receptor desensitization and downregulation. Splenocyte β 2-AR phosphorylation (pβ 2-AR) by protein kinase A (pβ 2-ARPKA) decreased in severe disease, and pβ 2-AR by G protein-coupled receptor kinases (pβ 2-ARGRK) increased in chronic disease. Conversely, in DLN cells, pβ 2-ARPKA rose during severe disease, but fell during chronic disease, and pβ 2-ARGRK increased during both disease stages. A similar pβ 2-AR pattern in DLN cells with the mycobacterial cell wall component of complete Freund's adjuvant suggests that pattern recognition receptors (i.e., toll-like receptors) are important for DLN pβ 2-AR patterns. Collectively, our findings indicate lymphoid organ- and disease stage-specific sympathetic dysregulation, possibly explaining immune compartment-specific differences in β 2-AR-mediated regulation of cytokine production in AA and rheumatoid arthritis.
Abstract Chronic pain, sickness behaviors, and cognitive decline are symptoms in rheumatoid arthritis. In the adjuvant-induced arthritis Lewis rat model, we examined the dynamics of c-Fos expression ...in the hippocampus, a brain region important for these symptoms. Brain sections were stained for c-Fos using immunohistochemistry. c-Fos-positive nuclei were counted in CA1, CA2, CA3 and the dentate gyrus of the dorsal hippocampi from rats receiving no treatment or base-of-the-tail injections of (1 or 2) incomplete or complete Freund's adjuvant (low- or high-dose), (3), Mycobacterium butyricum cell wall suspended in saline, or (4) saline, and sacrificed 4, 14, 21, or 126 days post-immunization. Disease severity was evaluated by dorsoplantar foot pad widths and X-ray analysis. We report sustained dose- and subfield-dependent c-Fos expression with arthritis, but transient expression in nonarthritic groups, suggesting long-term genomic changes in rheumatoid arthritis that may be causal for behavioral changes, adaptation to chronic pain and/or cognitive decline associated with disease.
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