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Search Results: 1 - 10 of 464364 matches for " Laurence A Bradley "
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A six-month double-blind, placebo-controlled, randomized clinical trial of duloxetine for the treatment of fibromyalgia
Amy S Chappell,Laurence A Bradley,Curtis Wiltse,Michael J Detke
International Journal of General Medicine , 2008,
Abstract: Amy S Chappell1, Laurence A Bradley2, Curtis Wiltse1, Michael J Detke1,3,4, Deborah N D’Souza1, Michael Spaeth51Lilly Research Laboratories, Indianapolis, IN, USA; 2University of Alabama at Birmingham, Birmingham, Alabama, USA; 3Indiana University School of Medicine, Indianapolis, IN, USA; 4Harvard Medical School, Boston, MA, USA; 5Practice for Internal Medicine/Rheumatology, Graefelfing, GermanyObjective: Assess the efficacy of duloxetine 60/120 mg (N = 162) once daily compared with placebo (N = 168) in the treatment of patients with fibromyalgia, during six months of treatment.Methods: This was a phase-III, randomized, double-blind, placebo-controlled, parallel-group study assessing the efficacy and safety of duloxetine.Results: There were no significant differences between treatment groups on the co-primary efficacy outcome measures, change in the Brief Pain Inventory (BPI) average pain severity from baseline to endpoint (P = 0.053) and the Patient’s Global Impressions of Improvement (PGI-I) at endpoint (P = 0.073). Duloxetine-treated patients improved significantly more than placebo-treated patients on the Fibromyalgia Impact Questionnaire pain score, BPI least pain score and average interference score, Clinical Global Impressions of Severity scale, area under the curve of pain relief, Multidimensional Fatigue Inventory mental fatigue dimension, Beck Depression Inventory-II total score, and 36-item Short Form Health Survey mental component summary and mental health score. Nausea was the most common treatment-emergent adverse event in the duloxetine group. Overall discontinuation rates were similar between groups.Conclusions: Although duloxetine 60/120 mg/day failed to demonstrate significant improvement over placebo on the co-primary outcome measures, in this supportive study, duloxetine demonstrated significant improvement compared with placebo on numerous secondary measures.Keywords: fibromyalgia, duloxetine, placebo, double-blind, trial, pain
A six-month double-blind, placebo-controlled, randomized clinical trial of duloxetine for the treatment of fibromyalgia
Amy S Chappell, Laurence A Bradley, Curtis Wiltse, Michael J Detke, Deborah N D’Souza, Michael Spaeth
International Journal of General Medicine , 2008, DOI: http://dx.doi.org/10.2147/IJGM.S3979
Abstract: six-month double-blind, placebo-controlled, randomized clinical trial of duloxetine for the treatment of fibromyalgia Original Research (5974) Total Article Views Authors: Amy S Chappell, Laurence A Bradley, Curtis Wiltse, Michael J Detke, Deborah N D’Souza, Michael Spaeth Published Date December 2008 Volume 2008:1 Pages 91 - 102 DOI: http://dx.doi.org/10.2147/IJGM.S3979 Amy S Chappell1, Laurence A Bradley2, Curtis Wiltse1, Michael J Detke1,3,4, Deborah N D’Souza1, Michael Spaeth5 1Lilly Research Laboratories, Indianapolis, IN, USA; 2University of Alabama at Birmingham, Birmingham, Alabama, USA; 3Indiana University School of Medicine, Indianapolis, IN, USA; 4Harvard Medical School, Boston, MA, USA; 5Practice for Internal Medicine/Rheumatology, Graefelfing, Germany Objective: Assess the efficacy of duloxetine 60/120 mg (N = 162) once daily compared with placebo (N = 168) in the treatment of patients with fibromyalgia, during six months of treatment. Methods: This was a phase-III, randomized, double-blind, placebo-controlled, parallel-group study assessing the efficacy and safety of duloxetine. Results: There were no significant differences between treatment groups on the co-primary efficacy outcome measures, change in the Brief Pain Inventory (BPI) average pain severity from baseline to endpoint (P = 0.053) and the Patient’s Global Impressions of Improvement (PGI-I) at endpoint (P = 0.073). Duloxetine-treated patients improved significantly more than placebo-treated patients on the Fibromyalgia Impact Questionnaire pain score, BPI least pain score and average interference score, Clinical Global Impressions of Severity scale, area under the curve of pain relief, Multidimensional Fatigue Inventory mental fatigue dimension, Beck Depression Inventory-II total score, and 36-item Short Form Health Survey mental component summary and mental health score. Nausea was the most common treatment-emergent adverse event in the duloxetine group. Overall discontinuation rates were similar between groups. Conclusions: Although duloxetine 60/120 mg/day failed to demonstrate significant improvement over placebo on the co-primary outcome measures, in this supportive study, duloxetine demonstrated significant improvement compared with placebo on numerous secondary measures.
Effect of duloxetine in patients with fibromyalgia: tiredness subgroups
Laurence A Bradley, Robert Bennett, Irwin J Russell, Madelaine M Wohlreich, Amy S Chappell, Fujun Wang, Deborah N D'Souza, Harvey Moldofsky
Arthritis Research & Therapy , 2010, DOI: 10.1186/ar3081
Abstract: A post hoc analysis of pooled data from 4 double-blind, placebo-controlled studies of duloxetine in fibromyalgia was performed. The fibromyalgia impact questionnaire (FIQ) tiredness item score (0 to 10 scale) was used to define tiredness subgroups. Patients were stratified into 3 subgroups: mild (0 to 3), moderate (4 to 6), and severe (7 to 10) tiredness. Analysis of covariance models and logistic regressions were used to test treatment-by-tiredness subgroup interactions.Data from the first 3 months are included in this post hoc analysis (duloxetine N = 797, placebo N = 535). At baseline, the distribution of tiredness severity in the duloxetine and placebo groups respectively was 3.64% and 3.75% mild, 16.71% and 15.57% moderate, and 79.65% and 80.68% severe. Rates of clinically significant (≥30% and ≥50%) improvement in brief pain inventory (BPI) average pain were similar across the tiredness subgroups. Tiredness severity at baseline was not negatively associated with the effects of duloxetine on patients' reports of functional ability using the FIQ total score, FIQ measures of physical impairment, interference with work, pain, stiffness, and depression and the medical outcomes study short form-36 (SF-36).Studies of duloxetine in fibromyalgia have demonstrated clinically significant improvements in pain and functional ability (FIQ, SF-36). This post hoc analysis of data shows that the efficacy of duloxetine among patients with fibromyalgia does not vary as a function of baseline ratings of fatigue/tiredness.Fibromyalgia is a disorder that is found in approximately 2% of the general population and is characterized by chronic widespread pain and tenderness [1]. Additional symptoms that often accompany fibromyalgia are tiredness or fatigue, depressed mood, sleep disturbance, and headache [2,3]. We will use the term 'tiredness' throughout this report, due to our decision to use the fibromyalgia impact questionnaire (FIQ) outcome measure, unless we refer specifically to
Chronic pain, perceived stress, and cellular aging: an exploratory study
Kimberly T Sibille, Taimour Langaee, Ben Burkley, Yan Gong, Toni L Glover, Chris King, Joseph L Riley, Christiaan Leeuwenburgh, Roland Staud, Laurence A Bradley, Roger B Fillingim
Molecular Pain , 2012, DOI: 10.1186/1744-8069-8-12
Abstract: The relationship between chronic pain, stress, and TL was analyzed in 36 ethnically diverse, older adults, half of whom reported no chronic pain and the other half had chronic knee osteoarthritis (OA) pain. Subjects completed a physical exam, radiographs, health history, and psychosocial questionnaires. Blood samples were collected and TL was measured by quantitative polymerase chain reaction (qPCR). Four groups were identified characterized by pain status and the Perceived Stress Scale scores: 1) no pain/low stress, 2) no pain/high stress, chronic pain/low stress, and 4) chronic pain/high stress. TL differed between the pain/stress groups (p = 0.01), controlling for relevant covariates. Specifically, the chronic pain/high stress group had significantly shorter TL compared to the no pain/low stress group. Age was negatively correlated with TL, particularly in the chronic pain/high stress group (p = 0.03).Although preliminary in nature and based on a modest sample size, these findings indicate that cellular aging may be more pronounced in older adults experiencing high levels of perceived stress and chronic pain.A recent Institute of Medicine report documents the public health consequences of chronic pain in America with estimates of 116 million adults affected and costs of $635 billion annually [1]. One of the challenges illuminated in the report is the difficulty in identifying specific pathophysiological targets due to significant variability in the experience of chronic pain. Consequently, biological markers reflecting the physiological burden of chronic pain on an individual system would offer significant clinical and scientific utility.Leukocyte telomere length (TL) is a measure of cellular aging and is associated with age-related disease onset, chronic health conditions, psychosocial stress, and mortality [2-5]. Importantly, recent findings indicate a direct relationship between telomeres and mitochondria, connecting for the first time two major theories of ag
Pharmacological Inhibition of polysialyltransferase ST8SiaII Modulates Tumour Cell Migration
Yousef M. J. Al-Saraireh, Mark Sutherland, Bradley R. Springett, Friedrich Freiberger, Goreti Ribeiro Morais, Paul M. Loadman, Rachel J. Errington, Paul J. Smith, Minoru Fukuda, Rita Gerardy-Schahn, Laurence H. Patterson, Steven D. Shnyder, Robert A. Falconer
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0073366
Abstract: Polysialic acid (polySia), an α-2,8-glycosidically linked polymer of sialic acid, is a developmentally regulated post-translational modification predominantly found on NCAM (neuronal cell adhesion molecule). Whilst high levels are expressed during development, peripheral adult organs do not express polySia-NCAM. However, tumours of neural crest-origin re-express polySia-NCAM: its occurrence correlates with aggressive and invasive disease and poor clinical prognosis in different cancer types, notably including small cell lung cancer (SCLC), pancreatic cancer and neuroblastoma. In neuronal development, polySia-NCAM biosynthesis is catalysed by two polysialyltransferases, ST8SiaII and ST8SiaIV, but it is ST8SiaII that is the prominent enzyme in tumours. The aim of this study was to determine the effect of ST8SiaII inhibition by a small molecule on tumour cell migration, utilising cytidine monophosphate (CMP) as a tool compound. Using immunoblotting we showed that CMP reduced ST8iaII-mediated polysialylation of NCAM. Utilizing a novel HPLC-based assay to quantify polysialylation of a fluorescent acceptor (DMB-DP3), we demonstrated that CMP is a competitive inhibitor of ST8SiaII (Ki = 10 μM). Importantly, we have shown that CMP causes a concentration-dependent reduction in tumour cell-surface polySia expression, with an absence of toxicity. When ST8SiaII-expressing tumour cells (SH-SY5Y and C6-STX) were evaluated in 2D cell migration assays, ST8SiaII inhibition led to significant reductions in migration, while CMP had no effect on cells not expressing ST8SiaII (DLD-1 and C6-WT). The study demonstrates for the first time that a polysialyltransferase inhibitor can modulate migration in ST8SiaII-expressing tumour cells. We conclude that ST8SiaII can be considered a druggable target with the potential for interfering with a critical mechanism in tumour cell dissemination in metastatic cancers.
hCG, the wonder of today's science
Laurence A Cole
Reproductive Biology and Endocrinology , 2012, DOI: 10.1186/1477-7827-10-24
Abstract: These 5 molecules, hCG, sulfated hCG, hyperglycosylated hCG, hCG free beta and hyperglycosylated free beta are produced by placental syncytiotrophoblast cells and pituitary gonadotrope cells (group 1), and by placental cytotrophoblast cells and human malignancies (group 2). Group 1 molecules are both hormones that act on the hCG/LH receptor. These molecules are central to human menstrual cycle and human pregnancy. Group 2 molecules are autocrines, that act by antagonizing a TGF beta receptor. These molecules are critical to all advanced malignancies.The hCG groups are molecules critical to both the molecules of pregnancy or human life, and to the advancement of cancer, or human death.Let's get to the point, why do we call human chorionic gonadotropin (hCG) the wonder of today's science. Firstly, hCG is an extreme molecule. It is the most acid protein in humans, some hCG variants have a peak isoelectric point (pI) stretching to pI 3.1. hCG variants are the most sialylated glycoproteins with up to 15 sialic acid residues per molecule. hCG variants are the most glycosylated of glycoproteins, hCG containing 30% sugar by molecular weight, hyperglycosylated hCG containing 39% sugar and hyperglycosylated hCG free ?-subunit containing 42% sugar by molecular weight. Finally, with its extreme molecular weights, hCG is the longest circulating molecule in human blood with a circulating half life of 36 hours. Secondly, as described in this review, there are amazingly 5 unique variants of hCG, each having identical amino acid sequence, produced by different cells and having independent functions. These are hCG, sulfated hCG, hyperglycosylated hCG, hCG free ?-subunit and hyperglycosylated hCG free ?-subunit. There is no other molecule like hCG.Finally, hCG and its variants have an incredibly wide spectrum of biological functions. These range from hyperglycosylated hCG and pregnancy implantation and placental development, to hyperglycosylated hCG and hCG and hemochorial placentatio
Biological functions of hCG and hCG-related molecules
Laurence A Cole
Reproductive Biology and Endocrinology , 2010, DOI: 10.1186/1477-7827-8-102
Abstract: hCG has numerous functions. hCG promotes progesterone production by corpus luteal cells; promotes angiogenesis in uterine vasculature; promoted the fusion of cytotrophoblast cell and differentiation to make syncytiotrophoblast cells; causes the blockage of any immune or macrophage action by mother on foreign invading placental cells; causes uterine growth parallel to fetal growth; suppresses any myometrial contractions during the course of pregnancy; causes growth and differentiation of the umbilical cord; signals the endometrium about forthcoming implantation; acts on receptor in mother's brain causing hyperemesis gravidarum, and seemingly promotes growth of fetal organs during pregnancy.Hyperglycosylated hCG functions to promote growth of cytotrophoblast cells and invasion by these cells, as occurs in implantation of pregnancy, and growth and invasion by choriocarcinoma cells. hCG free beta-subunit is produced by numerous non-trophoblastic malignancies of different primaries. The detection of free beta-subunit in these malignancies is generally considered a sign of poor prognosis. The free beta-subunit blocks apoptosis in cancer cells and promotes the growth and malignancy of the cancer. Pituitary hCG is a sulfated variant of hCG produced at low levels during the menstrual cycle. Pituitary hCG seems to mimic luteinizing hormone actions during the menstrual cycle.It is difficult to say who specifically was the discoverer of the hormone we call hCG. In 1912, Aschner stimulated the genital tract of guinea pigs with injections of a water-soluble extracts of human placenta [1]. In 1913, Fellner induced ovulation in immature rabbits with a saline extracts of human placenta [2]. In 1919, Hirose stimulated ovulation and normal luteal function in immature rabbits by repeated injection of human placental tissue [3]. All of these works show that there was a clear hormonal link between the placenta and the uterus [1-3]. In 1927, Ascheim and Zondek demonstrated that pregnant w
New discoveries on the biology and detection of human chorionic gonadotropin
Laurence A Cole
Reproductive Biology and Endocrinology , 2009, DOI: 10.1186/1477-7827-7-8
Abstract: For 88 years regular hCG has been known as a promoter of corpus luteal progesterone production, even though this function only explains 3 weeks of a full gestations production of regular hCG. Research in recent years has explained the full gestational production by demonstration of critical functions in trophoblast differentiation and in fetal nutrition through myometrial spiral artery angiogenesis.While regular hCG is made by fused villous syncytiotrophoblast cells, extravillous invasive cytotrophoblast cells make the variant hyperglycosylated hCG. This variant is an autocrine factor, acting on extravillous invasive cytotrophoblast cells to initiate and control invasion as occurs at implantation of pregnancy and the establishment of hemochorial placentation, and malignancy as occurs in invasive hydatidiform mole and choriocarcinoma. Hyperglycosylated hCG inhibits apoptosis in extravillous invasive cytotrophoblast cells promoting cell invasion, growth and malignancy. Other non-trophoblastic malignancies retro-differentiate and produce a hyperglycosylated free beta-subunit of hCG (hCG free beta). This has been shown to be an autocrine factor antagonizing apoptosis furthering cancer cell growth and malignancy.New applications have been demonstrated for total hCG measurements and detection of the 3 hCG variants in pregnancy detection, monitoring pregnancy outcome, determining risk for Down syndrome fetus, predicting preeclampsia, detecting pituitary hCG, detecting and managing gestational trophoblastic diseases, diagnosing quiescent gestational trophoblastic disease, diagnosing placental site trophoblastic tumor, managing testicular germ cell malignancies, and monitoring other human malignancies. There are very few molecules with such wide and varying functions as regular hCG and its variants, and very few tests with such a wide spectrum of clinical applications as total hCG.In 1920 Hirose showed a hormonal link between a human placental hormone and progesterone produc
Insect taxonomy in species-rich countries: the way forward?
Mound, Laurence A.;
Anais da Sociedade Entomológica do Brasil , 1998, DOI: 10.1590/S0301-80591998000100001
Abstract: there are two extremes in taxonomic behavior - publishing quickly as new taxa become available, and waiting a lifetime in the hope of publishing results that cannot be faulted. neither of these extremes meets the needs of contemporary biologists in furthering our understanding of the evolution and maintenance of biological diversity. part of the reason for these extremes is our failure to define suitable objectives for taxonomy. instead of emphasising the units of biological diversity, we should concentrate on investigating patterns, structural, biological, ecological, temporal, and geographical, because it is these patterns that will generate novel ideas about the evolutionary history of organisms, and that will be most likely to be of interest to the future of our own species. to investigate these patterns, we need to give greater thought to ensuring that our methods of data acquisition are consistent with our methods of data analysis. even if we take seriously as our objective the description of all living species, then we should be devising methods of sampling natural diversity that are statistically acceptable, not haphazard. however, the following comments, credited to willis jepson (1867-1946) in the latest edition of the jepson manual of higher plants of california, seem appropriate to our problems as insect taxonomists: "the botanist's objective is a furtherance of knowledge of living plants. he wishes to discover new facts and establish new principles. if wise, he will never try to produce a work which is perfect, complete and final. any such work would be a paradox and at cross purposes with our knowledge of living things and our ideas of endless evolution associated with them. completion, perfection, finality, represent an anomaly, a contradiction in the field of biology. the far seeing botanist will strive to do work which is inspiring, productive of thought and promoting the soundest progress, so that botanical science will ever advance into new and mo
Thysanoptera biodiversity in the Neotropics
A. Mound,Laurence;
Revista de Biología Tropical , 2002,
Abstract: it is suggested that descriptive taxonomy of thrips must be integrated into biological studies if we are to understand patterns of evolutionary and ecological diversity. collecting and describing new taxa is easy, but understanding their position in ecosystems and how they have contributed to the origin and maintenance of biological diversity is more important yet more difficult. many authors fail to appreciate that individual thrips species are commonly highly polymorphic, both within and between sexes, with the result that 20% of species names and 30% of generic names are currently placed into synonymy. the biological significance of such polymorphism has been little studied, but the presence of large and small males in a species is presumed to indicate some form of male/male competition for resources; this is particularly common in fungus feeding species. amongst phytophagous species, the recognition of the host plants on which thrips actually breed is a prerequisite to understanding patterns of diversity, some thrips lineages being associated with particular groups of plants whereas others exploit a diverse range of plants. attempts to understand the diversity of thrips, including the application of cladistic methods, are severely limited by the lack of studies on the biology of individual species, although thrips exhibit a wide range of interesting biological phenomena, including various levels of sociality, gallinduction, specific pollination associations, virus transmission, and ectoparasitism
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