tbuckley/cabot-search huggingface dataset:
Professor Neil Harrison Cox BSc, MB ChB, FRCP (1956-2009)
Authors: Rona Mackie
Journal: British Journal of Dermatology (2010)

Journal Article Professor Neil Harrison Cox BSc, MB ChB, FRCP (1956–2009) Get access Rona Mackie Rona Mackie Glasgow, May 2010 Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 162, Issue 6, 1 June 2010, Pages 1414–1415, https://doi.org/10.1111/j.1365-2133.2010.09815.x Published: 01 June 2010
Clinical Profile of Long-Term Survivors and Nonsurvivors With Type 2 Diabetes
Authors: Viswanathan Mohan, Coimbatore Subramanian Shanthi Rani, Anandakumar Amutha, Sravan Dhulipala, Ranjit Mohan Anjana, Balasubramanian Parathasarathy, Ranjit Unnikrishnan
Journal: Diabetes Care (2013)

To compare clinical profile of long-term survivors and nonsurvivors with type 2 diabetes (T2DM).After conducting a retrospective survey of >200,000 case records, we identified T2DM survivors (>40 years of duration) and age at diagnosis and sex-matched T2DM nonsurvivors. Prevalence of complications and causes of death were analyzed. Retinopathy was diagnosed by retinal photography. Microalbuminuria and macroalbuminuria, peripheral vascular disease based on ankle-brachial index <0.9, coronary artery disease based on history of myocardial infarction or coronary revascularization, and neuropathy based on vibration perception threshold >20 V were compared in both groups.The mean duration of diabetes of survivors (n = 238) was 43.7 ± 3.9 years, and that of the nonsurvivors (n = 307), at time of death, was 22.4 ± 11.0 years (P < 0.001). Nonsurvivors had significantly higher systolic and diastolic blood pressures, plasma glucose, HbA1c, serum cholesterol, LDL cholesterol, and triglycerides and lower HDL cholesterol compared with long-term survivors (P < 0.001 for all parameters except systolic blood pressure, which was P = 0.027). Myocardial infarction (46.4%) and renal failure (16.6%) were the most common causes of death. Prevalence of most complications was higher among survivors because of longer duration and older age, as follows, for survivors versus nonsurvivors: retinopathy, 76 vs. 62%; microalbuminuria, 39.1 vs. 27.3%; macroalbuminuria, 8.4 vs. 23.7%; neuropathy, 86.5 vs. 63.5%; peripheral vascular disease, 23.1 vs. 11.4%; and coronary artery disease, 44.5 vs. 40.7%.Long-term survivors with T2DM had better glycemic and blood pressure control and more favorable lipid profiles.
Contribution of PI 3-kinase isoforms to angiotensin II- and α-adrenoceptor-mediated signalling pathways in cardiomyocytes☆
Authors: S WENZEL, Y ABDALLAH, S HELMIG, C SCHAFER, H PIPER, K SCHLUTER
Journal: Cardiovascular Research (2006)

Angiotensin II stimulation increases the formation of reactive oxygen species (ROS), the phosphorylation of p38 mitogen-activated protein kinase (MAPK), and the expression of transforming growth factor beta (TGFbeta) in adult cardiomyocytes. The aim of this study was to determine the involvement of PI 3-kinase and to specify the participation of different isoforms in the angiotensin II-induced formation of ROS in comparison to the hypertrophic pathway triggered by alpha-adrenoceptor stimulation.Freshly isolated myocytes were used to examine formation of ROS via H(2)DCF fluorescence. p38 MAPK phosphorylation, p70(S6)-kinase phosphorylation, PI 3-kinase, and TGFbeta expression were measured by Western blotting. Sense and antisense oligonucleotides were used to down-regulate diverse PI 3-kinase isoforms. Hypertrophy was measured by (14)C-phenylalanine incorporation and cell volume.Inhibition of PI 3-kinase by Ly294002 or wortmannin, two inhibitors, decreased formation of ROS, phosphorylation of p38 MAPK, and TGFbeta expression. Down-regulation of the p110beta isoform by antisense oligonucleotides inhibited the angiotensin II-induced signalling pathway but not the alpha-adrenoceptor-mediated hypertrophic growth of cardiomyocytes. In contrast, down-regulation of the p110alpha isoform decreased the alpha-adrenoceptor-mediated hypertrophic growth of cardiomyocytes but did not affect the angiotensin II-mediated signalling pathway.Thus, our study identifies an involvement of PI 3-kinase in the angiotensin II-induced formation of ROS and provides a biochemical basis for ligand-specific responses for angiotensin II and alpha-adrenoceptor stimulation as relates to hypertrophy.
An eye for an eye: Reciprocity and the calibration of redress
Authors: Andrew Dellis, David Spurrett
Journal: Behavioral and Brain Sciences (2012)

Abstract General systems for reciprocity explain the same phenomena as the target article's proposed revenge system, and can explain other cooperative phenomena. We need more reason to hypothesise a specific revenge system. In addition, the proposed calculus of revenge is less sensitive to absolute magnitudes of revenge than it should be.
Activation of platelets by platelet-activating factor (PAF) derived from IgE-sensitized basophils. II. The role of serine proteases, cyclic nucleotides, and contractile elements in PAF-induced secretion.
Authors: P M Henson, Z G Oades
Journal: The Journal of Experimental Medicine (1976)

Secretion of serotonin from platelets induced by platelet-activating factor (PAF) derived from antigen-stimulated, IgE-sensitized rabbit basophils was studied to further characterize the biochemical requirements. Inhibition of secretion with diisopropylphosphofluoridate (DFP) was observed if the DFP was present during the reaction, but not if platelets or PAF were pretreated with the inhibitor. This suggested a role for an activatable serine protease in the secretion. Supporting evidence came from the observation that other protease inhibitors and a variety of low molecular weight amino acid esters were also inhibitory. TAMe was most effective, and AGLMe and LeuMe were inactive, indicating a specificity for different esters. Secretion was reduced by agents that increased intracellular cyclic AMP (cAMP), but enhanced by alpha-adrenergic stimulation, which reduced the levels of cAMP. Concurrent with PAF-induced secretion, a reduction in cAMP levels was observed. No effect of cyclic GMP or cholinergic stimulation was found. Secretion was inhibited by colchicine and enhanced by cytochalasin B, suggesting a role for microfilaments and microtubules. The effects of these three systems on PAF-induced secretion indicate the basic uniformity of the secretory process in platelets (and other cells) whatever the stimulus. The uniqueness of the reaction apparently lies in the stimulus-receptor interaction and the nature of the serine protease which is activated.
National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2·7 million participants
Authors: Goodarz Danaei, Mariel M Finucane, Yuan Lu, Gitanjali M Singh, Melanie J Cowan, Christopher J Paciorek, John K Lin, Farshad Farzadfar, Young-Ho Khang, Gretchen A Stevens, Mayuree Rao, Mohammed K Ali, Leanne M Riley, Carolyn A Robinson, Majid Ezzati
Journal: The Lancet (2011)
An F876L Mutation in Androgen Receptor Confers Genetic and Phenotypic Resistance to MDV3100 (Enzalutamide)
Authors: Manav Korpal, Joshua M. Korn, Xueliang Gao, Daniel P. Rakiec, David A. Ruddy, Shivang Doshi, Jing Yuan, Steve G. Kovats, Sunkyu Kim, Vesselina G. Cooke, John E. Monahan, Frank Stegmeier, Thomas M. Roberts, William R. Sellers, Wenlai Zhou, Ping Zhu
Journal: Cancer Discovery (2013)

Castration-resistant prostate cancer (CRPC) is the most aggressive, incurable form of prostate cancer. MDV3100 (enzalutamide), an antagonist of the androgen receptor (AR), was approved for clinical use in men with metastatic CRPC. Although this compound showed clinical efficacy, many initial responders later developed resistance. To uncover relevant resistant mechanisms, we developed a model of spontaneous resistance to MDV3100 in LNCaP prostate cancer cells. Detailed characterization revealed that emergence of an F876L mutation in AR correlated with blunted AR response to MDV3100 and sustained proliferation during treatment. Functional studies confirmed that AR(F876L) confers an antagonist-to-agonist switch that drives phenotypic resistance. Finally, treatment with distinct antiandrogens or cyclin-dependent kinase (CDK)4/6 inhibitors effectively antagonized AR(F876L) function. Together, these findings suggest that emergence of F876L may (i) serve as a novel biomarker for prediction of drug sensitivity, (ii) predict a "withdrawal" response to MDV3100, and (iii) be suitably targeted with other antiandrogens or CDK4/6 inhibitors.We uncovered an F876L agonist-switch mutation in AR that confers genetic and phenotypic resistance to the antiandrogen drug MDV3100. On the basis of this fi nding, we propose new therapeutic strategies to treat patients with prostate cancer presenting with this AR mutation.
Mutations in CLCN5 chloride channel in Japanese patients with low molecular weight proteinuria.
Authors: T Morimoto, S Uchida, H Sakamoto, Y Kondo, H Hanamizu, M Fukui, Y Tomino, N Nagano, S Sasaki, F Marumo
Journal: Journal of the American Society of Nephrology (1998)

Mutations in the CLCN5 gene have been demonstrated in three disorders of hypercalciuric nephrolithiasis, i.e., Dent's disease, X-linked recessive nephrolithiasis, and X-linked recessive hypophosphatemic rickets. Recently, a number of Japanese children with low molecular weight proteinuria (LMWP) showing symptoms similar to those shown by patients with Dent's disease in British families have also been reported to have mutations in the CLCN5 gene. The present study examines five unrelated Japanese families with LMWP, two of which lacked any signs other than LMWP, and three of which had several signs other than LMWP, i.e., hypercalciuria, aminoaciduria, hypophosphatemia, and rickets. One nonsense (E118X) and one missense (W22G) mutation were found in three patients in the two families having only LMWP. One genomic deletion including exons 5 to 8 in the CLCN5 gene was found in a patient with hypophosphatemic rickets, and a nonsense mutation (R347X) was found in one patient with LMWP and slight hypercalciuria. No mutations of the exons and exon-intron boundaries in the CLCN5 gene were found in one patient with LMWP, aminoaciduria, and hypokalemia. In addition to the predicted loss of chloride channel function in these nonsense and deletion mutations, the loss of function in the missense mutation W22G was confirmed in the Xenopus oocyte expression system. These results clarified four novel mutations in the CLCN5 genes, and additionally suggested that the loss-of-function mutation of the CLCN5 does not necessarily lead to hypercalciuria and nephrocalcinosis in the early stage of the disease, and that LMWP is an early and essential manifestation of disorders of the CLC-5 chloride channel.
The association between hip and groin injuries in the elite junior football years and injuries sustained during elite senior competition: Table 1
Authors: B J Gabbe, M Bailey, J L Cook, M Makdissi, E Scase, N Ames, T Wood, J J McNeil, J W Orchard
Journal: British Journal of Sports Medicine (2009)

Objective To establish the relationship between the history of hip and groin injuries in elite junior football players prior to elite club recruitment and the incidence of hip and groin injuries during their elite career. Design Retrospective cohort study. Setting Analysis of existing data. Participants 500 Australian Football League (AFL) players drafted from 1999 to 2006 with complete draft medical assessment data. Assessment of risk factors Previous history of hip/groin injury, anthropometric and demographic information. Main outcome measurement The number of hip/groin injuries resulting in ≥1 missed AFL game. Results Data for 500 players were available for analysis. 86 (17%) players reported a hip/groin injury in their junior football years. 159 (32%) players sustained a hip/groin injury in the AFL. Players who reported a previous hip or groin injury at the draft medical assessment demonstrated a rate of hip/groin injury in the AFL &gt;6 times higher (IRR 6.24, 95% CI 4.43 to 8.77) than players without a pre-AFL hip or groin injury history. Conclusions This study demonstrated that a hip or groin injury sustained during junior football years is a significant predictor of missed game time at the elite level due to hip/groin injury. The elite junior football period should be targeted for research to investigate and identify modifiable risk factors for the development of hip/groin injuries.
Intra-individual Change Over Time in DNA Methylation With Familial Clustering
Authors: Hans T. Bjornsson, Martin I. Sigurdsson, M. Daniele Fallin, Rafael A. Irizarry, Thor Aspelund, Hengmi Cui, Wenqiang Yu, Michael A. Rongione, Tomas J. Ekström, Tamara B. Harris, Lenore J. Launer, Gudny Eiriksdottir, Mark F. Leppert, Carmen Sapienza, Vilmundur Gudnason, Andrew P. Feinberg
Journal: JAMA (2008)

Context Changes over time in epigenetic marks, which are modifications of DNA such as by DNA methylation, may help explain the late onset of common human diseases.However, changes in methylation or other epigenetic marks over time in a given individual have not yet been investigated. ObjectivesTo determine whether there are longitudinal changes in global DNA methylation in individuals and to evaluate whether methylation maintenance demonstrates familial clustering. Design, Setting, and ParticipantsWe measured global DNA methylation by luminometric methylation assay, a quantitative measurement of genome-wide DNA methylation, on DNA sampled at 2 visits on average 11 years apart in 111 individuals from an Icelandic cohort (1991 and 2002-2005) and on average 16 years apart in 126 individuals from a Utah sample (1982-1985 and 1997-2005). Main Outcome Measure Global methylation changes over time.Results Twenty-nine percent of Icelandic individuals showed greater than 10% methylation change over time (PϽ.001).The family-based Utah sample also showed intraindividual changes over time, and further demonstrated familial clustering of methylation change (P=.003).The family showing the greatest global methylation loss also demonstrated the greatest loss of gene-specific methylation by a separate methylation assay. ConclusionThese data indicate that methylation changes over time and suggest that methylation maintenance may be under genetic control.
Frequent disruption of the RB pathway in indolent follicular lymphoma suggests a new combination therapy
Authors: Elisa Oricchio, Giovanni Ciriello, Man Jiang, Michael H. Boice, Jonathan H. Schatz, Adriana Heguy, Agnes Viale, Elisa de Stanchina, Julie Teruya-Feldstein, Alyssa Bouska, Tim McKeithan, Chris Sander, Wayne Tam, Venkatraman E. Seshan, Wing-Chung Chan, R.S.K. Chaganti, Hans-Guido Wendel
Journal: The Journal of Experimental Medicine (2014)

Loss of cell cycle controls is a hallmark of cancer and has a well-established role in aggressive B cell malignancies. However, the role of such lesions in indolent follicular lymphoma (FL) is unclear and individual lesions have been observed with low frequency. By analyzing genomic data from two large cohorts of indolent FLs, we identify a pattern of mutually exclusive (P = 0.003) genomic lesions that impair the retinoblastoma (RB) pathway in nearly 50% of FLs. These alterations include homozygous and heterozygous deletions of the p16/CDKN2a/b (7%) and RB1 (12%) loci, and more frequent gains of chromosome 12 that include CDK4 (29%). These aberrations are associated with high-risk disease by the FL prognostic index (FLIPI), and studies in a murine FL model confirm their pathogenic role in indolent FL. Increased CDK4 kinase activity toward RB1 is readily measured in tumor samples and indicates an opportunity for CDK4 inhibition. We find that dual CDK4 and BCL2 inhibitor treatment is safe and effective against available models of FL. In summary, frequent RB pathway lesions in indolent, high-risk FLs indicate an untapped therapeutic opportunity.
Safety and efficacy of NA-1 in patients with iatrogenic stroke after endovascular aneurysm repair (ENACT): a phase 2, randomised, double-blind, placebo-controlled trial
Authors: Michael D Hill, Renee H Martin, David Mikulis, John H Wong, Frank L Silver, Karel G terBrugge, Geneviève Milot, Wayne M Clark, R Loch MacDonald, Michael E Kelly, Melford Boulton, Ian Fleetwood, Cameron McDougall, Thorsteinn Gunnarsson, Michael Chow, Cheemun Lum, Robert Dodd, Julien Poublanc, Timo Krings, Andrew M Demchuk, Mayank Goyal, Roberta Anderson, Julie Bishop, David Garman, Michael Tymianski
Journal: The Lancet Neurology (2012)
Human Podocytes Possess a Stretch-Sensitive, Ca2+-Activated K+ Channel
Authors: Michael J. Morton, Katie Hutchinson, Peter W. Mathieson, Ian R. Witherden, Moin A. Saleem, Malcolm Hunter
Journal: Journal of the American Society of Nephrology (2004)

Podocytes express many proteins characteristic of smooth muscle, such as actin and myosin. They also express receptors to several vasoactive agents, including acetylcholine and angiotensin II; these phenotypic properties suggest that podocytes are not static entities but may respond to physiologic stimuli. The electrophysiologic properties of a conditionally immortalized human podocyte cell line that expresses the specific podocyte proteins nephrin, podocin, and synaptopodin were examined by patch clamp. Channels that were highly K+-selective and had a conductance of 224 ± 11.5 pS in symmetrical 150 mM K+ solutions were identified. Channel activity was Ca2+- and voltage-dependent, being increased with an increase in Ca2+ or depolarization, and inhibited by penitrem A. The conductance and voltage- and Ca2+-dependence suggest that this is the large-conductance calcium-activated K+ channel, BK (KCNMA1)—this was supported by reverse transcription-PCR experiments that showed the presence of the BK encoding mRNA, along with expression of KCNMB subunit types 3 and 4. In sections of human glomeruli, immunocytochemistry revealed that BK co-localizes with the podocyte-specific protein nephrin, indicating that these channels are present in native human podocytes. In whole-cell experiments, penitrem A inhibited outward currents to the same extent as tetra-ethyl ammonium (TEA) but did not affect the membrane potential. Channel activity was also increased by applying suction to the patch pipette or by dilution of the bathing medium, indicating that these channels are stretch sensitive. Thus, these channels do not contribute to the resting membrane potential but are activated by a rise in intracellular Ca2+, membrane depolarization, cell swelling, or membrane stretch. By implication, these results suggest that podocytes may be able to respond to changes in the glomerular capillary pressure and modulate the GFR.
Effect of Steady Versus Oscillating Flow on Porcine Coronary Arterioles
Authors: Oana Sorop, Jos A.E. Spaan, Terrence E. Sweeney, Ed VanBavel
Journal: Circulation Research (2003)

Coronary blood vessels are compressed by the contracting myocardium. This leads to oscillations in flow in especially the subendocardium. We examined the effects of steady and oscillating flow on isolated, cannulated subendocardial and subepicardial porcine arterioles. Steady flow-induced dilation in both vessel types, up to 12.9+/-0.8% of the passive diameter in subendocardials and 9.6+/-1.4% in subepicardials at 40 dyne/cm2. Dilation was completely abolished after treatment with 10 micromol/L L-NNA. Sinusoidal modulation of steady flow at 1.5 Hz and 50% to 200% amplitude did not affect dilation. Oscillating flow without a net forward component with peak-peak shear values up to 100 dyne/cm2 caused no dilation at all in these vessels. However, in the presence of 100 U/mL superoxide dismutase (SOD), oscillating flow induced dilation up to 19.5+/-2.3% in subendocardial vessels and 11.5+/-4.3% in subepicardials. LNNA (10 micromol/L) blocked this dilation by approximately 50%. SOD did not affect the magnitude of steady flow-induced dilation, but the response time after onset of steady flow shortened from 23.4+/-1.5 to 14.3+/-2.1 seconds. Diphenyleneiodinium, an inhibitor of NAD(P)H oxidase, uncovered dilation to oscillating flow in subendocardial vessels up to 9.5+/-1.6%. Flow causes production of both NO and O2-. During steady flow, the bioavailability of NO is sufficient to cause vasodilation. During oscillating flow, NO is quenched by the O2-, suppressing vasodilation. Considering the pulsatile nature of subendocardial flow and the vulnerability of this layer, pharmacological manipulation of the balance between NO and O2- may improve subendocardial perfusion.
NEW INSIGHTS INTO ERYTHROPOIESIS: The Roles of Folate, Vitamin B<sub>12</sub>, and Iron
Authors: Mark J. Koury, Prem Ponka
Journal: Annual Review of Nutrition (2004)

Erythropoiesis is the process in which new erythrocytes are produced. These new erythrocytes replace the oldest erythrocytes (normally about one percent) that are phagocytosed and destroyed each day. Folate, vitamin B12, and iron have crucial roles in erythropoiesis. Erythroblasts require folate and vitamin B12 for proliferation during their differentiation. Deficiency of folate or vitamin B12 inhibits purine and thymidylate syntheses, impairs DNA synthesis, and causes erythroblast apoptosis, resulting in anemia from ineffective erythropoiesis. Erythroblasts require large amounts of iron for hemoglobin synthesis. Large amounts of iron are recycled daily with hemoglobin breakdown from destroyed old erythrocytes. Many recently identified proteins are involved in absorption, storage, and cellular export of nonheme iron and in erythroblast uptake and utilization of iron. Erythroblast heme levels regulate uptake of iron and globin synthesis such that iron deficiency causes anemia by retarded production rates with smaller, less hemoglobinized erythrocytes.
An alternative pathway for fibrinolysis. I. The cleavage of fibrinogen by leukocyte proteases at physiologic pH.
Authors: E F Plow, T S Edgington
Journal: Journal of Clinical Investigation (1975)

An alternative fibrinolytic system, active at physiological pH, is present in peripheral blood leukocytes. The fibrinolytic proteases localized predominantly in the leukocyte granules are capable of degrading both fibrinogen and fibrin, and plasmin activity does not contribute significantly to this proteolytic event. The specificity of the alternative fibrinolytic proteases for fibrinogen and the characteristics of the derivative cleavage fragments are clearly distinguishable from the classical plasmin system. The high molecular weight derivatives of fibrinogen, generated by the alternative system, under physiological conditions, are larger than the plasmin-generated X fragment, exhibit immunoelectrophoretic mobility comparable to native fibrinogen, and are not coagulable by thrombin. Analysis of the constituent polypeptide chains of the fragments reveals cleavage of the Aalpha, Bbeta, and gamma chains of fibrinogen. The lower molecular weight derivatives of fibrinogen, generated by the alternative system, are structurally distinct from previously described fibrinogen degradation products and exhibit potent anticoagulant activity. This anticoagulant activity can be attributed to interference with normal fibrin polymerization. The proteases of the alternative fibrinolytic systems are actively secreted by leukocytes when stimulated to undergo a nonlytic release reaction. These results provide direct evidence for a fibrinolytic system resident in leukocyte granules that is associated with the leukocyte release reaction and is capable of generating unique fibrinogen cleavage fragments.