Investigation of the central molecular events that maintain persistent inflammatory pain states.

Noxious stimulation of the periphery leads to long-term changes in the excitability of dorsal horn neurons of the spinal cord. In the spinal cord the increased excitability of dorsal horn neurons requires the activation of a subset of superficial dorsal horn projection neurons that express the NK1 receptor. These lamina I neurons are crucial for the initiation and maintenance of persistent pain states and are the origin of a spino-bulbo-spinal loop that drives descending spinal facilitation, in part, via serotonergic axons. In many areas of the central nervous system some aspects of synaptic plasticity are thought to be controlled by the immediate early gene and transcription factor zif268 (also known as Egr-1, Krox-24 and NGF1-A). In the hippocampus, for example, zif268 is necessary for both late-LTP (long-term potentiation) and learning and memory. In the spinal cord, the expression of zif268 is activity dependant and associated with the induction of LTP in the dorsal horn. Here, I have shown that peripheral inflammation of the hindpaw with Complete Freund's Adjuvant (CFA) increased zif268 expression in dorsal horn neurons and was necessary for the development and maintenance of the inflammatory pain state. In addition, descending serotonergic pathways and lamina I projection neurons modulate spinal c-fos and zif268 expression following peripheral inflammation. Depletion of spinal serotonin increased c-fos expression without affecting zif268 expression in the dorsal horn following peripheral inflammation. However, in contrast, the ablation of lamina I NK1 expressing neurons in the dorsal horn that project to the brainstem significantly decreased spinal zif268 expression. The glucocorticoid receptor (GR) and serum- and glucocorticoid inducible kinase 1 (SGK1) are involved in synaptic plasticity and are potential downstream targets of zif268. I investigated the behavioural role of spinal GR following peripheral inflammation and the consequence of altering zif268 levels on GR and SGK1 expression in the dorsal horn. Using an antisense approach I show that both SGK1 and GR expression are regulated by zif268. I also demonstrated that GR expression in the dorsal horn was crucial for the maintenance of inflammatory pain states. While GR expression was positively regulated, SGK1 was negatively regulated by zif268 during the early stages of peripheral inflammation. In conclusion, these results indicate that zif268 dependent gene regulation in the dorsal horn is pivotal to the maintenance of inflammatory pain states and offer potential new targets for the development of future analgesic drugs

The medicinal plant Tabebuia impetiginosa potently reduces pro-inflammatory cytokine responses in primary human lymphocytes

Bark from the Handroanthus impetiginosus (Mart. ex DC.) Mattos (Bignoniaceae) tree has long been used in traditional South American healing practises to treat inflammation. However, its anti-inflammatory activity has not been closely examined. Here we use chemical extraction, qualitative phytochemical examination, toxicity testing and quantitative examination of anti-inflammatory activity on human cells ex vivo. All extracts were found to be nontoxic. We found different extracts exhibited unique cytokine profiles with some extracts outperforming a positive control used in the clinic. These results verify the immunomodulatory activity of Handroanthus impetiginosus (Mart. ex DC.) Mattos (Bignoniaceae) tree bark-derived compounds. Collectively, combining a lack of toxicity and potency in human immune cells supports further fractionation and research

Teleparallel Equivalent of Non-Abelian Kaluza-Klein Theory

Based on the equivalence between a gauge theory for the translation group and general relativity, a teleparallel version of the non-abelian Kaluza-Klein theory is constructed. In this theory, only the fiber-space turns out to be higher-dimensional, spacetime being kept always four-dimensional. The resulting model is a gauge theory that unifies, in the Kaluza-Klein sense, gravitational and gauge fields. In contrast to the ordinary Kaluza-Klein models, this theory defines a natural length-scale for the compact sub-manifold of the fiber space, which is shown to be of the order of the Planck length.Comment: Revtex4, 7 pages, no figures, to appear in Phys. Rev.

Measurement of Trace I-129 Concentrations in CsI Powder and Organic Liquid Scintillator with Accelerator Mass Spectrometry

Levels of trace radiopurity in active detector materials is a subject of major concern in low-background experiments. Procedures were devised to measure trace concentrations of I-129 in the inorganic salt CsI as well as in organic liquid scintillator with Accelerator Mass Spectrometry (AMS) which leads to improvement in sensitivities by several orders of magnitude over other methods. No evidence of their existence in these materials were observed. Limits of < 6 X 10^{-13} g/g and < 2.6 X 10^{-17} g/g on the contaminations of I-129 in CsI and liquid scintillator, respectively, were derived.These are the first results in a research program whose goals are to develop techniques to measure trace radioactivity in detector materials by AMS.Comment: Proceedings of 10th International Conference on Accelerator Mass Spectrometr

Health and social care service utilisation and associated expenditure among community-dwelling older adults with depressive symptoms

AIMS: Late-life depression has substantial impacts on individuals, families and society. Knowledge gaps remain in estimating the economic impacts associated with late-life depression by symptom severity, which has implications for resource prioritisation and research design (such as in modelling). This study examined the incremental health and social care expenditure of depressive symptoms by severity. METHODS: We analysed data collected from 2707 older adults aged 60 years and over in Hong Kong. The Patient Health Questionnaire-9 (PHQ-9) and the Client Service Receipt Inventory were used, respectively, to measure depressive symptoms and service utilisation as a basis for calculating care expenditure. Two-part models were used to estimate the incremental expenditure associated with symptom severity over 1 year. RESULTS: The average PHQ-9 score was 6.3 (standard deviation, s.d. = 4.0). The percentages of respondents with mild, moderate and moderately severe symptoms and non-depressed were 51.8%, 13.5%, 3.7% and 31.0%, respectively. Overall, the moderately severe group generated the largest average incremental expenditure (US$5886; 95$3849; 95% CI 2520-5177 or a 176% increase) and the moderate group (US$1843; 95$691; 95% CI 444-939), then gradually fell to negative between scores of 12 (US$- 35; 95$ -171; 95% CI - 417 to 76) and soared to positive and rebounded at the score of 23 (US$601; 95% CI -1652 to 2854). CONCLUSIONS: The association between depressive symptoms and care expenditure is stronger among older adults with mild and moderately severe symptoms. Older adults with the same symptom severity have different care utilisation and expenditure patterns. Non-psychiatric healthcare is the major cost element. These findings inform ways to optimise policy efforts to improve the financial sustainability of health and long-term care systems, including the involvement of primary care physicians and other geriatric healthcare providers in preventing and treating depression among older adults and related budgeting and accounting issues across services

Serum magnesium and calcium levels in relation to ischemic stroke : Mendelian randomization study

ObjectiveTo determine whether serum magnesium and calcium concentrations are causally associated with ischemic stroke or any of its subtypes using the mendelian randomization approach.MethodsAnalyses were conducted using summary statistics data for 13 single-nucleotide polymorphisms robustly associated with serum magnesium (n = 6) or serum calcium (n = 7) concentrations. The corresponding data for ischemic stroke were obtained from the MEGASTROKE consortium (34,217 cases and 404,630 noncases).ResultsIn standard mendelian randomization analysis, the odds ratios for each 0.1 mmol/L (about 1 SD) increase in genetically predicted serum magnesium concentrations were 0.78 (95% confidence interval [CI] 0.69-0.89; p = 1.3 7 10-4) for all ischemic stroke, 0.63 (95% CI 0.50-0.80; p = 1.6 7 10-4) for cardioembolic stroke, and 0.60 (95% CI 0.44-0.82; p = 0.001) for large artery stroke; there was no association with small vessel stroke (odds ratio 0.90, 95% CI 0.67-1.20; p = 0.46). Only the association with cardioembolic stroke was robust in sensitivity analyses. There was no association of genetically predicted serum calcium concentrations with all ischemic stroke (per 0.5 mg/dL [about 1 SD] increase in serum calcium: odds ratio 1.03, 95% CI 0.88-1.21) or with any subtype.ConclusionsThis study found that genetically higher serum magnesium concentrations are associated with a reduced risk of cardioembolic stroke but found no significant association of genetically higher serum calcium concentrations with any ischemic stroke subtype

Track E Implementation Science, Health Systems and Economics

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138412/1/jia218443.pd

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362