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1.
JMIR Res Protoc ; 8(3): e11148, 2019 Mar 12.
Article in English | MEDLINE | ID: mdl-30860485

ABSTRACT

BACKGROUND: Electronic health records (EHRs) are ubiquitous. Yet little is known about the use of EHRs for prospective research purposes, and even less is known about patient perspectives regarding the use of their EHR for research. OBJECTIVE: This paper reports results from the initial obesity project from the Greater Plains Collaborative that is part of the Patient-Centered Outcomes Research Institute's National Patient-Centered Clinical Research Network (PCORNet). The purpose of the project was to (1) assess the ability to recruit samples of adults of child-rearing age using the EHR; (2) prospectively assess the willingness of adults of child-rearing age to participate in research, and their willingness (if parents) to have their children participate in medical research; and (3) to assess their views regarding the use of their EHRs for research. METHODS: The EHRs of 10 Midwestern academic medical centers were used to select patients. Patients completed a survey that was designed to assess patient willingness to participate in research and their thoughts about the use of their EHR data for research. The survey included questions regarding interest in medical research, as well as basic demographic and health information. A variety of contact methods were used. RESULTS: A cohort of 54,269 patients was created, and 3139 (5.78%) patients responded. Completers were more likely to be female (53.84%) and white (85.84%). These and other factors differed significantly by site. Respondents were overwhelmingly positive (83.9%) about using EHRs for research. CONCLUSIONS: EHRs are an important resource for engaging patients in research, and our respondents concurred. The primary limitation of this work was a very low response rate, which varied by the method of contact, geographic location, and respondent characteristics. The primary strength of this work was the ability to ascertain the clinically observed characteristics of nonrespondents and respondents to determine factors that may contribute to participation, and to allow for the derivation of reliable study estimates for weighting responses and oversampling of difficult-to-reach subpopulations. These data suggest that EHRs are a promising new and effective tool for patient-engaged health research.

2.
Ann Transl Med ; 6(7): 120, 2018 Apr.
Article in English | MEDLINE | ID: mdl-29955580

ABSTRACT

The hazard ratio (HR) is a measure of instantaneous relative risk of an increase in one unit of the covariate of interest, which is widely reported in clinical researches involving time-to-event data. However, the measure fails to capture absolute risk reduction. Other measures such as number needed to treat (NNT) and risk difference (RD) provide another perspective on the effectiveness of an intervention, and can facilitate clinical decision making. The article aims to provide a step-by-step tutorial on how to compute RD and NNT in survival analysis with R. For simplicity, only one measure (RD or NNT) needs to be illustrated, because the other measure is a reverse of the illustrated one (NNT=1/RD). An artificial dataset is composed by using the survsim package. RD and NNT are estimated with Austin method after fitting a Cox-proportional hazard regression model. The confidence intervals can be estimated using bootstrap method. Alternatively, if the standard errors (SEs) of the survival probabilities of the treated and control group are given, confidence intervals can be estimated using algebraic calculations. The pseudo-value model provides another method to estimate RD and NNT. Details of R code and its output are shown and explained in the main text.

3.
PLoS Genet ; 12(7): e1006133, 2016 07.
Article in English | MEDLINE | ID: mdl-27420916

ABSTRACT

Mitochondrial dysfunction underlies numerous age-related pathologies. In an effort to uncover how the detrimental effects of mitochondrial dysfunction might be alleviated, we examined how the nematode C. elegans not only adapts to disruption of the mitochondrial electron transport chain, but in many instances responds with extended lifespan. Studies have shown various retrograde responses are activated in these animals, including the well-studied ATFS-1-dependent mitochondrial unfolded protein response (UPRmt). Such processes fall under the greater rubric of cellular surveillance mechanisms. Here we identify a novel p38 signaling cascade that is required to extend life when the mitochondrial electron transport chain is disrupted in worms, and which is blocked by disruption of the Mitochondrial-associated Degradation (MAD) pathway. This novel cascade is defined by DLK-1 (MAP3K), SEK-3 (MAP2K), PMK-3 (MAPK) and the reporter gene Ptbb-6::GFP. Inhibition of known mitochondrial retrograde responses does not alter induction of Ptbb-6::GFP, instead induction of this reporter often occurs in counterpoint to activation of SKN-1, which we show is under the control of ATFS-1. In those mitochondrial bioenergetic mutants which activate Ptbb-6::GFP, we find that dlk-1, sek-3 and pmk-3 are all required for their life extension.


Subject(s)
Caenorhabditis elegans Proteins/physiology , Caenorhabditis elegans/physiology , Gene Expression Regulation , MAP Kinase Kinase Kinases/physiology , Mitochondria/metabolism , Mitogen-Activated Protein Kinases/physiology , Animals , Electron Transport , Electron Transport Chain Complex Proteins/physiology , Genes, Reporter , Green Fluorescent Proteins/metabolism , Mutation , RNA Interference , Signal Transduction , Unfolded Protein Response , p38 Mitogen-Activated Protein Kinases/metabolism
4.
Article in English | MEDLINE | ID: mdl-26306821

ABSTRACT

BACKGROUND: Synucleinopathy is any of a group of age-related neurodegenerative disorders including Parkinson's disease, multiple system atrophy, and dementia with Lewy Bodies, which is characterized by α-synuclein inclusions and parkinsonian motor deficits affecting millions of patients worldwide. But there is no cure at present for synucleinopathy. Rapamycin has been shown to be neuroprotective in several in vitro and in vivo synucleinopathy models. However, there are no reports on the long-term effects of RAPA on motor function or measures of neurodegeneration in models of synucleinopathy. METHODS: We determined whether long-term feeding a rapamycin diet (14 ppm in diet; 2.25 mg/kg body weight/day) improves motor function in neuronal A53T α-synuclein transgenic mice (TG) and explored underlying mechanisms using a variety of behavioral and biochemical approaches. RESULTS: After 24 weeks of treatment, rapamycin improved performance on the forepaw stepping adjustment test, accelerating rotarod and pole test. Rapamycin did not alter A53T α-synuclein content. There was no effect of rapamycin treatment on midbrain or striatal monoamines or their metabolites. Proteins adducted to the lipid peroxidation product 4-hydroxynonenal were decreased in brain regions of both wild-type and TG mice treated with rapamycin. Reduced levels of the presynaptic marker synaptophysin were found in several brain regions of TG mice. Rapamycin attenuated the loss of synaptophysin protein in the affected brain regions. Rapamycin also attenuated the loss of synaptophysin protein and prevented the decrease of neurite length in SH-SY5Y cells treated with 4-hydroxynonenal. CONCLUSION: Taken together, these data suggest that rapamycin, an FDA approved drug, may prove useful in the treatment of synucleinopathy.

5.
J Cereb Blood Flow Metab ; 33(10): 1605-11, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23838831

ABSTRACT

Recent studies have challenged the prevailing view that reduced mitochondrial function and increased oxidative stress are correlated with reduced longevity. Mice carrying a homozygous knockout (KO) of the Surf1 gene showed a significant decrease in mitochondrial electron transport chain Complex IV activity, yet displayed increased lifespan and reduced brain damage after excitotoxic insults. In the present study, we examined brain metabolism, brain hemodynamics, and memory of Surf1 KO mice using in vitro measures of mitochondrial function, in vivo neuroimaging, and behavioral testing. We show that decreased respiration and increased generation of hydrogen peroxide in isolated Surf1 KO brain mitochondria are associated with increased brain glucose metabolism, cerebral blood flow, and lactate levels, and with enhanced memory in Surf1 KO mice. These metabolic and functional changes in Surf1 KO brains were accompanied by higher levels of hypoxia-inducible factor 1 alpha, and by increases in the activated form of cyclic AMP response element-binding factor, which is integral to memory formation. These findings suggest that Surf1 deficiency-induced metabolic alterations may have positive effects on brain function. Exploring the relationship between mitochondrial activity, oxidative stress, and brain function will enhance our understanding of cognitive aging and of age-related neurologic disorders.


Subject(s)
Brain/metabolism , Cerebrovascular Circulation , Membrane Proteins/genetics , Memory/physiology , Mitochondria/metabolism , Mitochondrial Proteins/genetics , Adenosine Triphosphate/metabolism , Animals , Behavior, Animal/physiology , Blood Flow Velocity/genetics , Blood Flow Velocity/physiology , Brain/blood supply , Cerebrovascular Circulation/genetics , Glucose/metabolism , Hydrogen Peroxide/metabolism , Magnetic Resonance Imaging , Magnetic Resonance Spectroscopy , Male , Maze Learning/physiology , Membrane Proteins/deficiency , Mice , Mice, Knockout , Mitochondria/enzymology , Mitochondrial Proteins/deficiency , Oxygen Consumption/physiology
6.
PLoS One ; 7(9): e46140, 2012.
Article in English | MEDLINE | ID: mdl-23029411

ABSTRACT

The nematode Caenorhabditis elegans is a model organism that has seen extensive use over the last four decades in multiple areas of investigation. In this study we explore the response of the nematode Caenorhabditis elegans to acute anoxia using gas-chromatography mass-spectrometry (GC-MS). We focus on the readily-accessible worm exometabolome to show that C. elegans are mixed acid fermenters that utilize several metabolic pathways in unconventional ways to remove reducing equivalents - including partial reversal of branched-chain amino acid catabolism and a potentially novel use of the glyoxylate pathway. In doing so, we provide detailed methods for the collection and analysis of excreted metabolites that, with minimal adjustment, should be applicable to many other species. We also describe a procedure for collecting highly volatile compounds from C. elegans. We are distributing our mass spectral library in an effort to facilitate wider use of metabolomics.


Subject(s)
Caenorhabditis elegans/metabolism , Gas Chromatography-Mass Spectrometry , Amino Acids, Branched-Chain/metabolism , Anaerobiosis , Animals , Metabolic Networks and Pathways , Metabolomics , Oxygen/metabolism
7.
Article in English | MEDLINE | ID: mdl-22953036

ABSTRACT

The study was undertaken to explore the effect of rapamycin, an anti-inflammatory agent, on the metabolic profile of type 2 diabetic mice. Seven-month-old diabetic db/db mice and their lean littermate non-diabetic controls (db/m) were randomized to receive control chow or chow mixed with rapamycin (2.24 mg/kg/day) (each group n =20, males and females) for 4 months and sacrificed. Serum samples were analyzed for the measurement of glucose, creatinine, blood urea nitrogen (BUN), alkaline phosphatase (ALP), alanine aminotransferase (ALT), total cholesterol, total triglyceride, and total protein, using the automated dry chemistry analysis. Rapamycin elevated serum glucose in female diabetic mice. Serum creatinine tended to be higher in diabetic mice but was not affected by rapamycin; there was no difference in BUN levels among the groups. Serum ALP was elevated in diabetic mice and rapamycin lowered it only in female diabetic mice; serum ALT levels were increased in female diabetic mice, unaffected by rapamycin. Serum total protein was elevated in diabetic mice of both genders but was not affected by rapamycin. Diabetic mice from both genders had elevated serum cholesterol and triglycerides; rapamycin did not affect serum cholesterol but decreased serum total triglycerides in male diabetic mice. We conclude that rapamycin elicits complex metabolic responses in aging diabetic mice, worsening hyperglycemia in females but improving ALP in female diabetic and total triglycerides in male diabetic mice, respectively. The metabolic effects of rapamycin should be considered while performing studies with rapamycin in mice.

8.
PLoS One ; 6(11): e26891, 2011.
Article in English | MEDLINE | ID: mdl-22132081

ABSTRACT

Mutations in insulin/IGF-1 signaling pathway have been shown to lead to increased longevity in various invertebrate models. Therefore, the effect of the haplo-insufficiency of the IGF-1 receptor (Igf1r(+/-)) on longevity/aging was evaluated in C57Bl/6 mice using rigorous criteria where lifespan and end-of-life pathology were measured under optimal husbandry conditions using large sample sizes. Igf1r(+/-) mice exhibited reductions in IGF-1 receptor levels and the activation of Akt by IGF-1, with no compensatory increases in serum IGF-1 or tissue IGF-1 mRNA levels, indicating that the Igf1r(+/-) mice show reduced IGF-1 signaling. Aged male, but not female Igf1r(+/-) mice were glucose intolerant, and both genders developed insulin resistance as they aged. Female, but not male Igf1r(+/-) mice survived longer than wild type mice after lethal paraquat and diquat exposure, and female Igf1r(+/-) mice also exhibited less diquat-induced liver damage. However, no significant difference between the lifespans of the male Igf1r(+/-) and wild type mice was observed; and the mean lifespan of the Igf1r(+/-) females was increased only slightly (less than 5%) compared to wild type mice. A comprehensive pathological analysis showed no significant difference in end-of-life pathological lesions between the Igf1r(+/-) and wild type mice. These data show that the Igf1r(+/-) mouse is not a model of increased longevity and delayed aging as predicted by invertebrate models with mutations in the insulin/IGF-1 signaling pathway.


Subject(s)
Aging/physiology , Receptor, IGF Type 1/metabolism , Signal Transduction , Aging/drug effects , Animals , Female , Gene Expression Regulation/drug effects , Glucose Tolerance Test , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta , Humans , Insulin/pharmacology , Insulin-Like Growth Factor Binding Protein 5/genetics , Insulin-Like Growth Factor Binding Protein 5/metabolism , Insulin-Like Growth Factor I/pharmacology , Longevity , Male , Mice , Mice, Inbred C57BL , Oxidative Stress/drug effects , Phosphorylation/drug effects , Proto-Oncogene Proteins c-akt/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Signal Transduction/drug effects
9.
Muscle Nerve ; 44(6): 947-56, 2011 Dec.
Article in English | MEDLINE | ID: mdl-22102466

ABSTRACT

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. We sought to determine whether peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) would have a beneficial effect on this disease. METHODS: PGC-1α transgenic mice were crossed with SOD1 mutant G93A DL mice. RESULTS: We observed a moderate but non-significant increase in average lifespan in PGC-1α/G93A DL mice, as compared with G93A DL mice (292 ± 3 days vs. 274 ± 7 days). Although the onset of ALS was not altered, progression of the disease was significantly slower (≈34% increase in duration) in the PGC-1α/G93A DL mice. These mice also exhibited markedly improved performance on the rotarod test, and the improved motor activity was associated with a decreased loss of motor neurons and less degeneration of neuromuscular junctions. CONCLUSION: A sustained level of excitatory amino acid transporter protein 2 (EAAT2) in astrocytes of the PGC-1α/G93A DL mice may contribute to neuronal protection.


Subject(s)
Amyotrophic Lateral Sclerosis/metabolism , Disease Models, Animal , Disease Progression , Neurons/metabolism , Trans-Activators/genetics , Alanine/genetics , Amino Acid Substitution/genetics , Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/pathology , Animals , Female , Glycine/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neurons/pathology , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha , Transcription Factors
10.
FASEB J ; 25(1): 398-408, 2011 Jan.
Article in English | MEDLINE | ID: mdl-20826540

ABSTRACT

Multiple stress resistance pathways were evaluated in the liver of Ames dwarf mice before and after exposure to the oxidative toxin diquat, seeking clues to the exceptional longevity conferred by this mutation. Before diquat treatment, Ames dwarf mice, compared with nonmutant littermate controls, had 2- to 6-fold higher levels of expression of mRNAs for immediate early genes and 2- to 5-fold higher levels of mRNAs for genes dependent on the transcription factor Nrf2. Diquat led to a 2-fold increase in phosphorylation of the stress kinase ERK in control (but not Ames dwarf) mice and to a 50% increase in phosphorylation of the kinase JNK2 in Ames dwarf (but not control) mice. Diquat induction of Nrf2 protein was higher in dwarf mice than in controls. Of 6 Nrf2-responsive genes evaluated, 4 (HMOX, NQO-1, MT-1, and MT-2) remained 2- to 10-fold lower in control than in dwarf liver after diquat, and the other 2 (GCLM and TXNRD) reached levels already seen in dwarf liver at baseline. Thus, livers of Ames dwarf mice differ systematically from controls in multiple stress resistance pathways before and after exposure to diquat, suggesting mechanisms for stress resistance and extended longevity in Ames dwarf mice.


Subject(s)
Diquat/toxicity , Dwarfism, Pituitary/metabolism , Liver/drug effects , Oxidative Stress , Animals , Blotting, Western , Dwarfism, Pituitary/genetics , Female , Gene Expression Regulation/drug effects , Genes, Immediate-Early/genetics , Glutamate-Cysteine Ligase/genetics , Heme Oxygenase-1/genetics , Herbicides/toxicity , Liver/metabolism , Longevity/genetics , Male , Membrane Proteins/genetics , Metallothionein/genetics , Mice , Mice, Mutant Strains , Mitogen-Activated Protein Kinases/metabolism , NAD(P)H Dehydrogenase (Quinone)/genetics , NF-E2-Related Factor 2/metabolism , Phosphorylation/drug effects , Protein Subunits/genetics , Reverse Transcriptase Polymerase Chain Reaction , Thioredoxin Reductase 1/genetics
11.
Proc Natl Acad Sci U S A ; 107(52): 22687-92, 2010 Dec 28.
Article in English | MEDLINE | ID: mdl-21149712

ABSTRACT

Cognitive dysfunction and memory loss are common features of Alzheimer's disease (AD). Abnormalities in the expression profile of immediate early genes that play a critical role in memory formation, such as the cAMP-response element binding protein (CREB), have been reported in the brains of AD patients. Here we show that amyloid-ß (Aß) accumulation, which plays a primary role in the cognitive deficits of AD, interferes with CREB activity. We further show that restoring CREB function via brain viral delivery of the CREB-binding protein (CBP) improves learning and memory deficits in an animal model of AD. Notably, such improvements occur without changes in Aß and tau pathology, and instead are linked to an increased level of brain-derived neurotrophic factor. The resulting data suggest that Aß-induced learning and memory deficits are mediated by alterations in CREB function, based on the finding that restoring CREB activity by directly modulating CBP levels in the brains of adult mice is sufficient to ameliorate learning and memory. Therefore, increasing CBP expression in adult brains may be a valid therapeutic approach not only for AD, but also for various brain disorders characterized by alterations in immediate early genes, further supporting the concept that viral vector delivery may be a viable therapeutic approach in neurodegenerative diseases.


Subject(s)
Alzheimer Disease/metabolism , Brain-Derived Neurotrophic Factor/metabolism , CREB-Binding Protein/metabolism , Learning Disabilities/metabolism , Memory Disorders/metabolism , Alzheimer Disease/physiopathology , Alzheimer Disease/therapy , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Animals , Blotting, Western , Brain/metabolism , Brain/pathology , CHO Cells , CREB-Binding Protein/genetics , Cricetinae , Cricetulus , Cyclic AMP Response Element-Binding Protein/metabolism , Disease Models, Animal , Gene Transfer Techniques , Genetic Therapy/methods , Humans , Learning Disabilities/physiopathology , Learning Disabilities/therapy , Lentivirus/genetics , Memory Disorders/physiopathology , Memory Disorders/therapy , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neurons/metabolism , Phosphorylation , tau Proteins/metabolism
12.
Endocrinology ; 151(7): 3277-85, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20463054

ABSTRACT

Hypothalamic tuberoinfundibular dopaminergic (TIDA) neurons secrete dopamine, which inhibits pituitary prolactin (PRL) secretion. PRL has demonstrated neurotrophic effects on TIDA neuron development in PRL-, GH-, and TSH-deficient Ames (df/df) and Snell (dw/dw) dwarf mice. However, both PRL and PRL receptor knockout mice exhibit normal-sized TIDA neuron numbers, implying GH and/or TSH influence TIDA neuron development. The current study investigated the effect of porcine (p) GH on TIDA neuron development in Ames dwarf hypothalamus. Normal (DF/df) and dwarf mice were treated daily with pGH or saline beginning at 3 d of age for a period of 42 d. After treatment, brains were analyzed using catecholamine histofluorescence, tyrosine hydroxylase immunocytochemistry, and bromodeoxyuridine (BrdU) immunocytochemistry to detect BrdU incorporation. DF/df males and df/df treated with pGH experienced increased (P

Subject(s)
Dopamine/metabolism , Dwarfism/metabolism , Growth Hormone/pharmacology , Neurons/cytology , Neurons/drug effects , Animals , Body Weight/drug effects , Body Weight/genetics , Catecholamines/metabolism , Female , Genotype , Growth Hormone/administration & dosage , Hypothalamus/cytology , Hypothalamus/drug effects , Hypothalamus/metabolism , Immunohistochemistry , Male , Mice , Neurons/metabolism , Sex Factors , Swine , Time Factors , Tyrosine 3-Monooxygenase/metabolism
13.
Endocr Res ; 34(1-2): 43-58, 2009.
Article in English | MEDLINE | ID: mdl-19557590

ABSTRACT

The sexual dimorphism of life span and caloric restriction effects in numerous species suggest that estradiol (E2) is protective against oxidative damage. The only direct test of E2's protective effect in mice against in vivo oxidative stress to date may have been confounded by E2's direct chemical action as an antioxidant because it was administered at very high dosages. Therefore, we have identified a low yet physiologically effective dose of E2. We then administered this dose using subcutaneous time-release pellets to ovariectomized mice. Two weeks after E2 pellet implantation, sham-operated, ovariectomized, and ovariectomized E2-supplemented female mice were injected with a lethal dose of paraquat and their survival was followed. It was observed that ovariectomy exacerbates paraquat-induced mortality and is rescued by E2 supplementation. An equivalent experiment was performed on sham-operated, orchidectomized, and E2-supplemented orchidectomized male mice. The survival of male mice was improved by orchidectomy, and E2 gave no further benefit. We interpret the results to mean that E2 is protective against oxidative stress through its regulatory role and that testosterone diminishes protection against oxidative stress.


Subject(s)
Estradiol/pharmacology , Orchiectomy , Ovariectomy , Oxidative Stress/drug effects , Animals , Estradiol/administration & dosage , Female , Infusions, Subcutaneous , Male , Mice , Paraquat/poisoning , Testosterone/pharmacology
14.
J Gerontol A Biol Sci Med Sci ; 64(8): 819-27, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19414510

ABSTRACT

To probe the connection between longevity and stress resistance, we compared the sensitivity of Ames long-lived dwarf mice and control littermates with paraquat, diquat, and dobutamine. In young adult animals, 95% of male and 39% of female controls died after paraquat administration, but no dwarf animals died. When the experiment was repeated at an older age or a higher dosage of paraquat, dwarf mice still showed greater resistance. Dwarf mice also were more resistant to diquat; 80% of male and 60% of female controls died compared with 40% and 20% of dwarf mice, despite greater sensitivity of dwarf liver to diquat. Dwarf mice were also less sensitive to dobutamine-induced cardiac stress and had lower levels of liver and lung F(2)-isoprostanes. This is the first direct in vivo evidence that long-lived Ames dwarf mice have enhanced resistance to chemical insult, particularly oxidative stressors.


Subject(s)
Diquat/toxicity , Dwarfism/physiopathology , Longevity , Oxidative Stress , Paraquat/toxicity , Aging/metabolism , Alanine Transaminase/blood , Animals , Exercise Test , Female , Lipid Peroxidation , Liver/drug effects , Male , Mice , Mice, Inbred C57BL
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