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Banks W.A.,GRECC | Banks W.A.,University of Washington | Morley J.E.,GRECC | Morley J.E.,Saint Louis University | And 4 more authors.
Peptides | Year: 2010

Insulin detemir has a different profile of action on the central nervous system (CNS) than human insulin. It has been hypothesized that this is caused by an altered ability of insulin detemir to cross the blood-brain barrier (BBB). Here, we measured the permeability of the BBB to insulin detemir. We labeled insulin detemir with radioactive iodine (I-Det) and examined its ability to cross the BBB of the mouse. Permeation was assessed after intravenous injection and by brain perfusion in the presence or absence of excess insulin detemir. The ability of insulin detemir to inhibit human insulin transport across the BBB was also assessed. I-Det did not cross the BBB either after intravenous injection or when studied by brain perfusion, a method which removes or reduces the influence of circulating proteins. Unlabeled detemir was about 10 times less potent than human insulin at inhibiting the transport of radioactive human insulin across the BBB. The altered CNS profile of insulin detemir may be caused by its poor access to CNS receptors and by a block of human insulin from crossing the BBB.


Carlson N.G.,GRECC | Carlson N.G.,Neurovirology Laboratory 151B | Carlson N.G.,Research Service | Carlson N.G.,University of Utah | And 3 more authors.
Expert Opinion on Medical Diagnostics | Year: 2013

Introduction: Vitamin D has attracted a lot of attention in relation to multiple sclerosis (MS) and many other disorders; however, the evidence for a major role(s) for vitamin D in MS is compelling and multifactorial involving results from epidemiology, immunology, genetics, biochemistry and translational medicine. Areas covered: Multiple studies that illustrate that insufficient levels of vitamin D not only contribute to the risk of getting MS but may also worsen disease progression for MS patients are discussed. Genetic evidence also implicates vitamin D as being important in MS since individuals are at greater risk of getting MS if they harbor a mutation in a gene responsible for vitamin D synthesis (25-hydroxylase). Other modifiers of MS disease appear to interact with the vitamin D receptor. The Epstein-Barr virus (EBV) is a risk factor for MS and may in part worsen disease through the interactions between one of its gene products (EBNA-3) and the vitamin D receptor to attenuate vitamin D-regulated genes. Retrospective studies have shown that higher vitamin D levels are associated with a significant improvement of clinical and magnetic resonance imaging outcomes. Increasing clinical observations are also indicating adverse effects of low vitamin D in MS. Expert opinion: Mounting evidence from epidemiology, genetic, retrospective clinical studies and emerging basic science studies support a strong rationale for how vitamin D could be an important modifier of MS disease. Well-designed clinical trials are now ongoing and will provide further insight on how vitamin D supplementation may impact MS. © 2013 Informa UK, Ltd.


Murff H.J.,Vanderbilt University | Tindle H.A.,Vanderbilt University | Shrubsole M.J.,GRECC | Shrubsole M.J.,Vanderbilt University | And 7 more authors.
Prostaglandins Leukotrienes and Essential Fatty Acids | Year: 2016

Smoking is associated with lower n-3 long chain polyunsaturated fatty acids (LCPUFA) concentrations; however, limited studies have accounted for dietary PUFA intake or whether tobacco dose or smoking duration influences this association. We measured red blood cell phospholipid (RBC) membrane concentrations of fatty acids in 126 current smokers, 311 former smokers, and 461 never smokers using gas liquid chromatography and tandem mass spectrometry. Smokers had lower RBC membrane percentages of total n-3 LCPUFAs compared to former smokers or never smokers (median percent: 5.46, [interquartile range (IQR) 4.52, 6.28] versus 6.39; [IQR: 5.18, 7.85] versus 6.59; [IQR 5.34, 8.01]) (p<0.001) and this association remained after adjusting for dietary PUFA intake. Duration of smoking and cigarettes per day were not associated with RBC membrane n-3 LCPUFA differences. Smoking is associated with lower n-3 LCPUFA RBC membrane percentages and this association was not influenced by diet or smoking dose or duration. © 2016


Murff H.J.,Vanderbilt University | Murff H.J.,Vanderbilt Ingram Cancer Center | Shrubsole M.J.,Vanderbilt University | Shrubsole M.J.,Vanderbilt Ingram Cancer Center | And 9 more authors.
Cancer Prevention Research | Year: 2011

Adenomatous polyps are known precursor lesions for colorectal cancer and some hyperplastic polyps also have malignant potential. The use of aspirin and nonsteroidal anti-inflammatory drugs (NSAID) is associated with a reduced risk of adenomatous polyps; however, less evidence exists with regard to NSAID use and hyperplastic polyp risk. We conducted a colonoscopy-based case-control study including 2,028 polyp cases (1,529 adenomatous and 499 hyperplastic) and 3,431 polyp-free controls. Multivariate logistic regression models were constructed to derived adjusted ORs and 95% CIs as the measure of the association between NSAID use and polyp risk. Use of baby aspirin, regular aspirin, and nonaspirin NSAIDs, were associated with a reduced risk of adenomatous polyps (OR = 0.79, 95% CI: 0.66-0.93, OR = 0.73, 95% CI: 0.58-0.90, and OR = 0.67, 95% CI: 0.53-0.86, respectively). Baby aspirin was also associated with a reduced risk of hyperplastic polyps (OR = 0.74, 0.56-0.97). Although a dose response was seen with adenoma risk and regular use of any NSAIDs (less than 7 doses per week, 7 doses per week, and greater than 7 doses per week), a dose response was not seen with hyperplastic polyps. We found no evidence of interaction between NSAID dose and duration and polyp risk. The use of any NSAID regardless of type was associated with a reduced risk of adenomatous polyps; however, regular aspirin and COX-2 inhibitors use was not associated with hyperplastic polyp risk. ©2011 AACR.


Coppola J.-A.,Florida State University | Shrubsole M.J.,GRECC | Shrubsole M.J.,Vanderbilt University | Shrubsole M.J.,Vanderbilt Ingram Cancer Center | And 12 more authors.
Cancer Causes and Control | Year: 2015

Purpose: Abnormalities in lipid levels have been associated with colorectal neoplasm risk; however, few studies have adjusted for use of cholesterol-lowering medications. The objective of this study was to determine the association of plasma lipid levels with adenoma risk while accounting for statin medication use.Methods: We included 254 subjects with advanced adenoma, 246 with single small adenoma, 179 with multiple small adenoma cases, and 403 control participants in the Tennessee Colorectal Polyp Study who also had plasma lipid measurements performed. Data on the use of statin medications were available for 83.4 % of these participants. The association between plasma lipids and adenoma risk was evaluated using logistic regression models.Results: Participants in the highest quartile of HDL cholesterol (range 52–106 mg/dl) had an adjusted odds ratio of 0.49 (95 % CI 0.23, 1.07), 0.35 (95 % CI 0.13, 0.91), and 0.22 (95 % CI 0.09, 0.54) for single small, multiple small, and advanced adenomas compared to the lowest quartile (range 12–34 mg/dl), respectively. Participants with the highest quartile of triglyceride levels (range 178–721 mg/dl) had an adjusted odds ratio of 2.40 (95 % CI 1.26, 4.55), 1.67 (95 % CI 0.66, 4.23), and 2.79 (95 % CI 1.25, 6.23) for single small, multiple small, and advanced adenoma, respectively, compared to the lowest quartile (range 40–84 mg/dl). When restricted to individuals with known statin medication use, adjusting for statin use did not appreciably affect these results.Conclusion: We found a direct association between triglyceride plasma levels and an inverse association between plasma HDL cholesterol levels and adenoma risk. Both effects were not appreciably changed when accounting for the regular use of statin medication. © 2015, Springer International Publishing Switzerland.


PubMed | GRECC
Type: Journal Article | Journal: Peptides | Year: 2010

Insulin detemir has a different profile of action on the central nervous system (CNS) than human insulin. It has been hypothesized that this is caused by an altered ability of insulin detemir to cross the blood-brain barrier (BBB). Here, we measured the permeability of the BBB to insulin detemir. We labeled insulin detemir with radioactive iodine (I-Det) and examined its ability to cross the BBB of the mouse. Permeation was assessed after intravenous injection and by brain perfusion in the presence or absence of excess insulin detemir. The ability of insulin detemir to inhibit human insulin transport across the BBB was also assessed. I-Det did not cross the BBB either after intravenous injection or when studied by brain perfusion, a method which removes or reduces the influence of circulating proteins. Unlabeled detemir was about 10 times less potent than human insulin at inhibiting the transport of radioactive human insulin across the BBB. The altered CNS profile of insulin detemir may be caused by its poor access to CNS receptors and by a block of human insulin from crossing the BBB.

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