Browsing by Author "Spence, John P."

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    Development and feasibility testing of a new device for home-based leg heat therapy in patients with lower extremity peripheral artery disease
    (Elsevier, 2024-11-08) Ro, Bohyun; Spence, John P.; Spence, Paul A.; Buckley, Christian; Motaganahalli, Raghu L.; Roseguini, Bruno T.; Surgery, School of Medicine
    People with symptomatic lower extremity peripheral artery disease (PAD) suffer from severe leg pain, walking impairment, and reduced quality of life, but few effective treatments are available. Emerging evidence suggests that regular heat therapy (HT) may improve cardiovascular and physical function in patients with PAD. However, the lack of accessible, practical modalities for unsupervised HT, especially for elderly individuals, has hindered clinical implementation. The goals of this study were to design and assess the feasibility of a portable leg HT system for elderly patients with PAD. Building on a cryotherapy water-circulating device used in sports recovery, we developed a new prototype system consisting of a single-touch controller unit integrating a heater, water pump, and air pump, and leg sleeves with inner-layer water-circulating pads and an outer layer of inflatable bladders. The system was designed to ensure efficient heat transfer through gentle pneumatic inflation, adapting to varying limb dimensions. Safety features included temperature sensors with auto shut-off and a built-in timer. The prototype's feasibility and safety were evaluated in a single-arm pilot trial with six symptomatic patients with PAD, who were asked to apply the therapy daily for 90 minutes for 12 weeks. Primary outcomes included completion rates, safety, and device usability. Secondary outcomes were changes in blood pressure, 6-minute walk distance, calf strength, sit-to-stand performance, and quality of life. Participants underwent a 90-minute supervised treatment session with the prototype HT units to assess the acute physiological responses before starting the 12-week intervention. Leg HT gradually increased leg skin temperature from 33.8 ± 0.8°C to 38.7 ± 0.7°C at 90 minutes and reduced arterial blood pressure, with mean reductions of 13 mm Hg in systolic and 12 mm Hg in diastolic blood pressure after treatment. All participants completed the 12-week program without serious adverse events, indicating that leg HT is safe and well-tolerated. The 6-minute walk distance improved by an average of 32 m, coupled with increased calf muscle strength and reduced time for the sit-to-stand test. Improvements were also observed in self-reported walking speed and quality of life. This study represents the first step in developing a portable leg heating system for elderly patients with PAD, demonstrating that home-based leg HT is feasible and safe. However, further engineering refinements are needed to enhance portability, simplify application, and encourage long-term adherence. Developing methods to track compliance with the treatment regimen will be crucial for the success of this unsupervised, home-based therapy.
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    Evaluation of aldehyde dehydrogenase 1 promoter polymorphisms identified in human populations
    (Ovid Technologies (Wolters Kluwer) - Lippincott Williams & Wilkins, 2003-09) Spence, John P.; Liang, Tiebing; Eriksson, C. J. Peter; Taylor, Robert E.; Wall, Tamara L.; Ehlers, Cindy L.; Carr, Lucinda G.; Department of Medicine, IU School of Medicine
    BACKGROUND: Cytosolic aldehyde dehydrogenase, or ALDH1A1, functions in ethanol detoxification, metabolism of neurotransmitters, and synthesis of retinoic acid. Because the promoter region of a gene can influence gene expression, the ALDH1A1 promoter regions were studied to identify polymorphism, to assess their functional significance, and to determine whether they were associated with a risk for developing alcoholism. METHODS: Sequence analysis was performed in the promoter region by using Asian, Caucasian, and African American subjects. The resulting polymorphisms were assessed for frequency in Asian, Caucasian, Jewish, and African American populations and tested for associations with alcohol dependence in Asian and African American populations of alcoholics and controls. The functional significance of each polymorphism was determined through in vitro expression analysis by using HeLa and HepG2 cells. RESULTS: Two polymorphisms, a 17 base pair (bp) deletion (-416/-432) and a 3 bp insertion (-524), were discovered in the ALDH1A1 promoter region: ALDH1A1*2 and ALDH1A1*3, respectively. ALDH1A1*2 was observed at frequencies of 0.035, 0.023, 0.023, and 0.012 in the Asian, Caucasian, Jewish, and African American populations, respectively. ALDH1A1*3 was observed only in the African American population, at a frequency of 0.029. By using HeLa and HepG2 cells for in vitro expression, the activity of the luciferase reporter gene was significantly decreased after transient transfection of ALDH1A1*3-luciferase compared with the wild-type construct ALDH1A1*1-luciferase. In an African American population, a trend for higher frequencies of the ALDH1A1*2 and ALDH1A1*3 alleles was observed in a population of alcoholics (p = 0.03 and f = 0.12, respectively) compared with the control population. CONCLUSIONS: ALDH1A1*2 and ALDH1A1*3 may influence ALDH1A1 gene expression. Both ALDH1A1*2 and ALDH1A1*3 produce a trend in an African American population that may be indicative of an association with alcoholism; however, more samples are required to validate this observation. The underlying mechanisms contributing to these trends are still unknown.
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    Expression profiling and QTL analysis: a powerful complementary strategy in drug abuse research
    (Wiley, 2005-03) Spence, John P.; Liang, Tiebing; Foroud, Tatiana; Lo, David; Carr, Lucinda G.; Department of Medicine, IU School of Medicine
    Alcoholism is a complex disease exhibiting a multifactorial mode of transmission. To simplify the genetic and phenotypic complexity of the alcoholic phenotype, alcohol-preferring (P) and -non-preferring (NP) rats were developed on the basis of alcohol preference and consumption as an animal model of alcoholism. Total gene expression analysis (TOGA) and quantitative trait loci (QTL) analysis were applied to selectively bred, inbred P and NP rats as complementary studies to identify genetic factors that contribute to alcohol preference and consumption. TOGA analysis was utilized to screen for differential expression in several brain regions involved in the mesocorticolimbic dopamine (DA) system. Genes exhibiting differences in expression were then screened for an association to the alcohol preference phenotype, the quantitative trait of a previously identified QTL. By evaluating differences in gene expression for linkage to a quantitative trait, this combined approach was implemented to identify alpha-synuclein, a candidate gene for alcohol preference.
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    From QTL to candidate gene: a genetic approach to alcoholism research
    (Bentham Science, 2009-05) Spence, John P.; Liang, Tiebing; Liu, Lixiang; Johnson, Philip L.; Foroud, Tatiana; Carr, Lucinda G.; Shekhar, Anantha; Department of Psychiatry, IU School of Medicine
    A major focus of research in alcohol-related disorders is to identify the genes and pathways that modulate alcohol-seeking behavior. In light of this, animal models have been established to study various aspects of alcohol dependence. The selectively bred alcohol-preferring (P) and -nonpreferring (NP) lines were developed from Wistar rats to model high and low voluntary alcohol consumption, respectively. Using inbred P and NP strains, a strong QTL (LOD-9.2) for alcohol consumption was identified on rat chromosome 4. To search for candidate genes that underlie this chromosomal region, complementary molecular-based strategies were implemented to identify genetic targets that likely contribute to the linkage signal. In an attempt to validate these genetic targets, corroborative studies have been utilized including pharmacological studies, knock-out/transgenic models as well as human association studies. Thus far, three candidate genes, neuropeptide Y (Npy), alpha-synuclein (Snca), and corticotrophin-releasing factor receptor 2 (Crhr2), have been identified that may account for the linkage signal. With the recent advancements in bioinformatics and molecular biology, QTL analysis combined with molecular-based strategies provides a systematic approach to identify candidate genes that contribute to various aspects of addictive behavior.
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    Glutathione S-transferase 8-8 expression is lower in alcohol-preferring than in alcohol-nonpreferring rats
    (Wiley Online Library, 2004-11) Liang, Tiebing; Spence, John P.; Foroud, Tatiana; Ellison, Julie A.; Lumeng, Lawrence; Li, Ting-Kai; Carr, Lucinda G.; Department of Medical and Molecular Genetics, IU School of Medicine
    OBJECTIVE: A primary focus of alcohol research is to provide novel targets for alcohol treatment by identifying genes that predispose individuals to drink alcohol. Animal models of alcoholism developed by selective breeding are invaluable tools to elucidate both the genetic nature and the underlying biological mechanisms that contribute to alcohol dependence. These selected lines (high alcohol preferring and low alcohol preferring) display phenotypic and genetic differences that can be studied to further our understanding of alcohol preference and related genetic traits. By combining molecular techniques, genetic and physiological factors that underlie the cause of alcoholism can be identified. METHODS: Total gene expression analysis was used to identify genes that are differentially expressed in specific brain regions between alcohol-naive, inbred alcohol-preferring (iP) and -nonpreferring (iNP) rats. Quantitative reverse transcriptase-polymerase chain reaction, in situ hybridization, Western blot, and sequence analysis were used to further characterize rat glutathione S-transferase 8-8 (rGST 8-8). RESULTS: Lower expression of rGST 8-8 mRNA was observed in discrete brain regions of iP compared with iNP animals, and these expression differences were confirmed. To determine additional expression patterns of rGST 8-8, we used in situ hybridization. Rat GST 8-8 was highly expressed in hippocampus, the choroid plexus of the dorsal third ventricle and the lateral ventricle, and ependymal cells along the dorsal third ventricle and the third ventricle. Western blot analysis showed that rGST 8-8 protein levels were lower in the hippocampus and the amygdala of iP compared with iNP. A silent single-nucleotide polymorphism in the coding region and three single-nucleotide polymorphisms in the 3'-UTR were identified in the rGST 8-8 cDNA. CONCLUSION: There is regional variation of rGST 8-8 expression in the brain, at both the mRNA and protein level, and the iP strain has lower innate rGST 8-8 levels than the iNP strain in discrete brain regions.
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    Social learning and amygdala disruptions in Nf1 mice are rescued by blocking p21-activated kinase
    (Nature Publishing Group, 2014-11) Molosh, Andrei I.; Johnson, Philip L.; Spence, John P.; Arendt, David; Federici, Lauren M.; Bernabe, Cristian; Janasik, Steven P.; Segu, Zaneer M.; Khanna, Rajesh; Goswami, Chirayu; Zhu, Weiguo; Park, Su-Jung; Li, Lang; Mechref, Yehia S.; Clapp, D. Wade; Shekhar, Anantha; Department of Psychiatry, IU School of Medicine
    Children with Neurofibromatosis type 1 (NF1) are increasingly recognized to have high prevalence of social difficulties and autism spectrum disorders (ASD). We demonstrated selective social learning deficit in mice with deletion of a single Nf1 gene (Nf1+/−), along with greater activation of mitogen activated protein kinase pathway in neurons from amygdala and frontal cortex, structures relevant to social behaviors. The Nf1+/− mice showed aberrant amygdala glutamate/GABA neurotransmission