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The Catechol-O-Methyltransferase (COMT) val158met Polymorphism Affects Brain Responses to Repeated Painful Stimuli
Marco L. Loggia, Karin Jensen, Randy L. Gollub, Ajay D. Wasan, Robert R. Edwards, Jian Kong
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0027764
Abstract: Despite the explosion of interest in the genetic underpinnings of individual differences in pain sensitivity, conflicting findings have emerged for most of the identified “pain genes”. Perhaps the prime example of this inconsistency is represented by catechol-O-methyltransferase (COMT), as its substantial association to pain sensitivity has been reported in various studies, but rejected in several others. In line with findings from behavioral studies, we hypothesized that the effect of COMT on pain processing would become apparent only when the pain system was adequately challenged (i.e., after repeated pain stimulation). In the present study, we used functional Magnetic Resonance Imaging (fMRI) to investigate the brain response to heat pain stimuli in 54 subjects genotyped for the common COMT val158met polymorphism (val/val = n 22, val/met = n 20, met/met = n 12). Met/met subjects exhibited stronger pain-related fMRI signals than val/val in several brain structures, including the periaqueductal gray matter, lingual gyrus, cerebellum, hippocampal formation and precuneus. These effects were observed only for high intensity pain stimuli after repeated administration. In spite of our relatively small sample size, our results suggest that COMT appears to affect pain processing. Our data demonstrate that the effect of COMT on pain processing can be detected in presence of 1) a sufficiently robust challenge to the pain system to detect a genotype effect, and/or 2) the recruitment of pain-dampening compensatory mechanisms by the putatively more pain sensitive met homozygotes. These findings may help explain the inconsistencies in reported findings of the impact of COMT in pain regulation.
Imaging the functional connectivity of the Periaqueductal Gray during genuine and sham electroacupuncture treatment
Carolyn E Zyloney, Karin Jensen, Ginger Polich, Rita E Loiotile, Alexandra Cheetham, Peter S LaViolette, Peichi Tu, Ted J Kaptchuk, Randy L Gollub, Jian Kong
Molecular Pain , 2010, DOI: 10.1186/1744-8069-6-80
Abstract: Forty-eight subjects, who were randomly assigned to receive either genuine or sham EA paired with either a high or low expectancy manipulation, completed the study. Direct comparison of each treatment mode's functional connectivity revealed: significantly greater connectivity between the PAG, left posterior cingulate cortex (PCC), and precuneus for the contrast of genuine minus sham; significantly greater connectivity between the PAG and right anterior insula for the contrast of sham minus genuine; no significant differences in connectivity between different contrasts of the two expectancy levels.Our findings indicate the intrinsic functional connectivity changes among key brain regions in the pain matrix and default mode network during genuine EA compared with sham EA. We speculate that continuous genuine EA stimulation can modify the coupling of spontaneous activity in brain regions that play a role in modulating pain perception.Acupuncture has been used to alleviate pain for thousands of years. Multiple randomized controlled trials (RCTs) and many meta-analyses have concluded that acupuncture effectively relieves clinical pain for disorders such as knee osteoarthritis [1], migraine [2] and chronic low back pain [3-5]. For instance, three recent large trials found that acupuncture is statistically, clinically [3-5], and cost-effectively [6-10] superior to either optimal guidelines-based conventional therapy, or waitlist controls for chronic low back pain. However, the lack of a significant clinical difference between genuine or sham (placebo) acupuncture has raised skepticism and limited acupuncture's acceptance.In parallel, brain imaging tools such as positron emission tomography (PET) and functional Magnetic Resonance Imaging (fMRI) have been used to investigate the neural mechanisms underlying acupuncture needle stimulation [11-28]} and acupuncture treatment effects [17,29-32]. The goal of these studies is to elucidate the changes in neural activity in brain ne
Are All Placebo Effects Equal? Placebo Pills, Sham Acupuncture, Cue Conditioning and Their Association
Jian Kong, Rosa Spaeth, Amanda Cook, Irving Kirsch, Brian Claggett, Mark Vangel, Randy L. Gollub, Jordan W. Smoller, Ted J. Kaptchuk
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0067485
Abstract: Placebo treatments and healing rituals have been used to treat pain throughout history. The present within-subject crossover study examines the variability in individual responses to placebo treatment with verbal suggestion and visual cue conditioning by investigating whether responses to different types of placebo treatment, as well as conditioning responses, correlate with one another. Secondarily, this study also examines whether responses to sham acupuncture correlate with responses to genuine acupuncture. Healthy subjects were recruited to participate in two sequential experiments. Experiment one is a five-session crossover study. In each session, subjects received one of four treatments: placebo pills (described as Tylenol), sham acupuncture, genuine acupuncture, or no treatment rest control condition. Before and after each treatment, paired with a verbal suggestion of positive effect, each subject's pain threshold, pain tolerance, and pain ratings to calibrated heat pain were measured. At least 14 days after completing experiment one, all subjects were invited to participate in experiment two, during which their analgesic responses to conditioned visual cues were tested. Forty-eight healthy subjects completed experiment one, and 45 completed experiment two. The results showed significantly different effects of genuine acupuncture, placebo pill and rest control on pain threshold. There was no significant association between placebo pills, sham acupuncture and cue conditioning effects, indicating that individuals may respond to unique healing rituals in different ways. This outcome suggests that placebo response may be a complex behavioral phenomenon that has properties that comprise a state, rather than a trait characteristic. This could explain the difficulty of detecting a signature for “placebo responders.” However, a significant association was found between the genuine and sham acupuncture treatments, implying that the non-specific effects of acupuncture may contribute to the analgesic effect observed in genuine acupuncture analgesia.
Enhancing Affective Awareness of DisAbility through Shared Learning in a Social Work Classroom: A Collaborative Project  [PDF]
Randy Johner
Creative Education (CE) , 2016, DOI: 10.4236/ce.2016.715211
Abstract: This article describes a small collaborative social work classroom project that included mentoring partnerships between community members with disAbilities and a university class of undergraduate social work students that focused on increasing affective awareness with regard to their understanding of disAbility or diverse abilities and comfort levels in working with people with disAbilities. This project was grounded in critical disability studies theory that examines powerlessness, context, social values, and language. Through qualitative analysis of data that was comprised of student assigned reflective ruminations, personal interviews with community partners, participant observations and reflective journaling, project findings indicated that students’ experiences in the collaborative project had a positive impact on their understanding(s) of diverse abilities and comfort levels in working with people with disAbilities. Project recommendations include continued exploration of the pedagogical method in this project in order to support student learning outcomes in pre-service social work students, other health care pre-service students such as those in Education, Medicine, and Nursing and those students in interdisciplinary health-care service programs; and that further research is needed that examines diverse pedagogical methods that consider collaborative teaching methods that includes people with disAbilities. Continued classroom efforts are needed to assist pre-service social work students to support their understanding of the disability experience, and through that understanding, enhance their comfort levels in working with people with disAbilities; embracing the disability experience as an integral aspect of the human condition.
Patients with fibromyalgia display less functional connectivity in the brain’s pain inhibitory network
Karin B Jensen, Rita Loitoile, Eva Kosek, Frank Petzke, Serena Carville, peter Fransson, Hanke Marcus, Steven C.R Williams, Ernest Choy, Yves Mainguy, Olivier Vitton, Richard H Gracely, Randy Gollub, Martin Ingvar, Jian Kong
Molecular Pain , 2012, DOI: 10.1186/1744-8069-8-32
Abstract: We performed functional magnetic resonance imaging (fMRI) in 42 subjects; 14 healthy and 28 age-matched FM patients (2 patients per HC), during randomly presented, subjectively calibrated pressure pain stimuli. A seed-based functional connectivity analysis of brain activity was performed. The seed coordinates were based on the findings from our previous study, comparing the fMRI signal during calibrated pressure pain in FM and HC: the rostral anterior cingulate cortex (rACC) and thalamus.FM patients required significantly less pressure (kPa) to reach calibrated pain at 50?mm on a 0–100 visual analogue scale (p?<?.001, two-tailed). During fMRI scanning, the rACC displayed significantly higher connectivity to the amygdala, hippocampus, and brainstem in healthy controls, compared to FM patients. There were no regions where FM patients showed higher rACC connectivity. Thalamus showed significantly higher connectivity to the orbitofrontal cortex in healthy controls but no regions showed higher thalamic connectivity in FM patients.Patients with FM displayed less connectivity within the brain’s pain inhibitory network during calibrated pressure pain, compared to healthy controls. The present study provides brain-imaging evidence on how brain regions involved in homeostatic control of pain are less connected in FM patients. It is possible that the dysfunction of the descending pain modulatory network plays an important role in maintenance of FM pain and our results may translate into clinical implications by using the functional connectivity of the pain modulatory network as an objective measure of pain dysregulation.
The Impact of Genome-Wide Supported Schizophrenia Risk Variants in the Neurogranin Gene on Brain Structure and Function
Esther Walton, Daniel Geisler, Johanna Hass, Jingyu Liu, Jessica Turner, Anastasia Yendiki, Michael N. Smolka, Beng-Choon Ho, Dara S. Manoach, Randy L. Gollub, Veit Roessner, Vince D. Calhoun, Stefan Ehrlich
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0076815
Abstract: The neural mechanisms underlying genetic risk for schizophrenia, a highly heritable psychiatric condition, are still under investigation. New schizophrenia risk genes discovered through genome-wide association studies (GWAS), such as neurogranin (NRGN), can be used to identify these mechanisms. In this study we examined the association of two common NRGN risk single nucleotide polymorphisms (SNPs) with functional and structural brain-based intermediate phenotypes for schizophrenia. We obtained structural, functional MRI and genotype data of 92 schizophrenia patients and 114 healthy volunteers from the multisite Mind Clinical Imaging Consortium study. Two schizophrenia-associated NRGN SNPs (rs12807809 and rs12541) were tested for association with working memory-elicited dorsolateral prefrontal cortex (DLPFC) activity and surface-wide cortical thickness. NRGN rs12541 risk allele homozygotes (TT) displayed increased working memory-related activity in several brain regions, including the left DLPFC, left insula, left somatosensory cortex and the cingulate cortex, when compared to non-risk allele carriers. NRGN rs12807809 non-risk allele (C) carriers showed reduced cortical gray matter thickness compared to risk allele homozygotes (TT) in an area comprising the right pericalcarine gyrus, the right cuneus, and the right lingual gyrus. Our study highlights the effects of schizophrenia risk variants in the NRGN gene on functional and structural brain-based intermediate phenotypes for schizophrenia. These results support recent GWAS findings and further implicate NRGN in the pathophysiology of schizophrenia by suggesting that genetic NRGN risk variants contribute to subtle changes in neural functioning and anatomy that can be quantified with neuroimaging methods.
Living with Uncertainty: Acting in the Best Interests of Women
Erica Gollub,Zena Stein
AIDS Research and Treatment , 2012, DOI: 10.1155/2012/524936
Abstract: A recent multi-country study on hormonal contraceptives (HC) and HIV acquisition and transmission among African HIV-serodiscordant couples reported a statistically significant doubling of risk for HIV acquisition among women as well as transmission from women to men for injectable contraceptives. Together with a prior cohort study on African women seeking health services, these data are the strongest yet to appear on the HC-HIV risk. This paper will briefly review the Heffron study strengths and relevant biological and epidemiologic evidence; address the futility of further trials; and propose instead an alternative framework for next steps. The weight of the evidence calls for a discontinuation of progestin-dominant methods. We propose here five types of productive activities: (1) scaling injectable hormones down and out of the contraceptive mix; (2) strengthening and introducing public health strategies with proven potential to reduce HIV spread; (3) providing maximal choice to reduce unplanned pregnancy, starting with quality sexuality education through to safe abortion access; (4) expanding provider training, end-user counseling and access to male and female barriers, with a special renewed focus on female condom; (5) initiating a serious research agenda to determine anti-STI/HIV potential of the contraceptive cervical cap. Trusting women to make informed choices is critical to achieve real progress in dual protection. 1. Introduction The recent Heffron et al. [1] multi-country study on hormonal contraceptives (HC) and HIV acquisition and transmission among African HIV-serodiscordant couples reported a statistically significant doubling of risk for HIV acquisition among women as well as transmission from women to men for injectable contraceptives. A more modest effect in the same direction was was also reported for combination oral contraceptives (COCs), although not attaining statistical significance. This study, together with Morrison et al.’s analyses [2, 3] on a cohort of African women seeking health services, represents the strongest data yet to appear on the association. It is unlikely that other study designs, including a randomized controlled trial (RCT), could provide stronger evidence for causal inference. Therefore goes our argument: these studies provide the weight of the evidence and the best we can get for the next decade. Of course, one study, however good, cannot make for certainty. But by now there have been over 50 published papers and several comprehensive reviews, emphasizing the different study populations and analytic
A Genome-Wide Association Study Suggests Novel Loci Associated with a Schizophrenia-Related Brain-Based Phenotype
Johanna Hass, Esther Walton, Holger Kirsten, Jingyu Liu, Lutz Priebe, Christiane Wolf, Nazanin Karbalai, Randy Gollub, Tonya White, Veit Roessner, Kathrin U. Müller, Tomas Paus, Michael N. Smolka, Gunter Schumann, IMAGEN Consortium , Markus Scholz, Sven Cichon, Vince Calhoun, Stefan Ehrlich
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0064872
Abstract: Patients with schizophrenia and their siblings typically show subtle changes of brain structures, such as a reduction of hippocampal volume. Hippocampal volume is heritable, may explain a variety of cognitive symptoms of schizophrenia and is thus considered an intermediate phenotype for this mental illness. The aim of our analyses was to identify single-nucleotide polymorphisms (SNP) related to hippocampal volume without making prior assumptions about possible candidate genes. In this study, we combined genetics, imaging and neuropsychological data obtained from the Mind Clinical Imaging Consortium study of schizophrenia (n = 328). A total of 743,591 SNPs were tested for association with hippocampal volume in a genome-wide association study. Gene expression profiles of human hippocampal tissue were investigated for gene regions of significantly associated SNPs. None of the genetic markers reached genome-wide significance. However, six highly correlated SNPs (rs4808611, rs35686037, rs12982178, rs1042178, rs10406920, rs8170) on chromosome 19p13.11, located within or in close proximity to the genes NR2F6, USHBP1, and BABAM1, as well as four SNPs in three other genomic regions (chromosome 1, 2 and 10) had p-values between 6.75×10?6 and 8.3×10?7. Using existing data of a very recently published GWAS of hippocampal volume and additional data of a multicentre study in a large cohort of adolescents of European ancestry, we found supporting evidence for our results. Furthermore, allelic differences in rs4808611 and rs8170 were highly associated with differential mRNA expression in the cis-acting region. Associations with memory functioning indicate a possible functional importance of the identified risk variants. Our findings provide new insights into the genetic architecture of a brain structure closely linked to schizophrenia. In silico replication, mRNA expression and cognitive data provide additional support for the relevance of our findings. Identification of causal variants and their functional effects may unveil yet unknown players in the neurodevelopment and the pathogenesis of neuropsychiatric disorders.
Randy Bax
International Journal of English Studies (IJES) , 2005, DOI: 10.6018/ijes.5.1.47941
Abstract: It has often been claimed that Frances Burney (1752-1840) was influenced linguistically by Samuel Johnson (1709-1784). Sorensen (1969: 390), and others with him, have even called her a "slavish imitator" of the language which Johnson used in his Rambler essays. Although far from simple guesswork, quantitative studies such as Sorensen's remain impressionistic, which makes it difficult to incorporate his (and similar) observations in quantitative socio-histoncal linguistic studies of the English language. In the present study, the question whether Burney was indeed a serious imitator of Johnson's usage is answered by looking at the problem from a quantitative rather than qualitative perspective, and addressed within the framework of histoncai social network analysis.
Buoy Dynamics in Subsurface Zones
Randy Guillen
Undergraduate Journal of Mathematical Modeling : One + Two , 2009, DOI: 10.5038/2326-3652.1.2.5
Abstract: The objective of this paper is to find the tension acting on a line that anchors a buoy submerged just beneath the surface of the ocean. Since the problem statement only gives the geometric shapes and dimensions of the buoy, we must use calculus to find its volume and surface area through integration of the volumes and surfaces of revolution formed by the specific parts of the buoy along an axis. The volume and surface area determine the buoyancy force and force of gravity, the two forces acting on the buoy that affect the tension in the line. After calculating this data, we were able to conclude that the tension affecting the line would be approximately 78 kN if the buoy was made of 1% carbon steel with a thickness of 6.35 mm. This problem is useful in several engineering disciplines.
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