tbuckley/cabot-search huggingface dataset:
Molecular mechanism of the camptothecin resistance of Glu710Gly topoisomerase IB mutant analyzed in vitro and in silico
Authors: Cinzia Tesauro, Blasco Morozzo della Rocca, Alessio Ottaviani, Andrea Coletta, Laura Zuccaro, Barbara Arnò, Ilda D'Annessa, Paola Fiorani, Alessandro Desideri
Journal: Molecular Cancer (2013)

Abstract Background DNA topoisomerases are key enzymes that modulate the topological state of DNA through the breaking and rejoining of DNA strands. Human topoisomerase IB can be inhibited by several compounds that act through different mechanisms, including clinically used drugs, such as the derivatives of the natural compound camptothecin that reversibly bind the covalent topoisomerase-DNA complex, slowing down the religation of the cleaved DNA strand, thus inducing cell death. Three enzyme mutations, which confer resistance to irinotecan in an adenocarcinoma cell line, were recently identified but the molecular mechanism of resistance was unclear. Methods The three resistant mutants have been investigated in S. cerevisiae model system following their viability in presence of increasing amounts of camptothecin. A systematical analysis of the different catalytic steps has been made for one of these mutants (Glu710Gly) and has been correlated with its structural-dynamical properties studied by classical molecular dynamics simulation. Results The three mutants display a different degree of camptothecin resistance in a yeast cell viability assay. Characterization of the different steps of the catalytic cycle of the Glu710Gly mutant indicated that its resistance is related to a high religation rate that is hardly affected by the presence of the drug. Analysis of the dynamic properties through simulation indicate that the mutant displays a much lower degree of correlation in the motion between the different protein domains and that the linker almost completely loses its correlation with the C-terminal domain, containing the active site tyrosine. Conclusions These results indicate that a fully functional linker is required to confer camptothecin sensitivity to topoisomerase I since the destabilization of its structural-dynamical properties is correlated to an increase of religation rate and drug resistance.
Runx1 Determines Nociceptive Sensory Neuron Phenotype and Is Required for Thermal and Neuropathic Pain
Authors: Chih-Li Chen, Daniel C. Broom, Yang Liu, Joriene C. de Nooij, Zhe Li, Chuan Cen, Omar Abdel Samad, Thomas M. Jessell, Clifford J. Woolf, Qiufu Ma
Journal: Neuron (2006)
Umbilical Hernia in Xhosa Infants and Children
Authors: Theodore James
Journal: Journal of the Royal Society of Medicine (1982)

During the period 12 March 1980 to 10 March 1981 a consecutive series of 1200 Xhosa (Black) infants and young children, ranging in age from the newborn to the prepubertal, who attended the general outpatients department for a variety of medical complaints were examined for umbilical herniation. None had undergone any surgical operation, and patients with conditions possibly associated with umbilical herniation were excluded. Evidence of umbilical protrusion was found in 742 (61.8%), with a similar incidence in males and females. The overall incidence was reflected in each age group by a preponderance of children with umbilical hernia. This study confirms the validity of a generally-held impression that in Black children there is a strong tendency towards the persistence of umbilical hernia when it appears after separation of the cord.
Impact of financial incentives on clinical autonomy and internal motivation in primary care: ethnographic study
Authors: Ruth McDonald, Stephen Harrison, Kath Checkland, Stephen M Campbell, Martin Roland
Journal: BMJ (2007)

<b>Objective</b> To explore the impact of financial incentives for quality of care on practice organisation, clinical autonomy, and internal motivation of doctors and nurses working in primary care. <b>Design</b> Ethnographic case study. <b>Setting</b> Two English general practices. <b>Participants</b> 12 general practitioners, nine nurses, four healthcare assistants, and four administrative staff. <b>Main outcome measure</b> Observation of practices over a five month period after the introduction of financial incentives for quality of care introduced in the 2004 general practitioner contract. <b>Results</b> After the introduction of the quality and outcomes framework there was an increase in the use of templates to collect data on quality of care. New regimens of surveillance were adopted, with clinicians seen as "chasers" or the "chased," depending on their individual responsibility for delivering quality targets. Attitudes towards the contract were largely positive, although discontent was higher in the practice with a more intensive surveillance regimen. Nurses expressed more concern than doctors about changes to their clinical practice but also appreciated being given responsibility for delivering on targets in particular disease areas. Most doctors did not question the quality targets that existed at the time or the implications of the targets for their own clinical autonomy. <b>Conclusions</b> Implementation of financial incentives for quality of care did not seem to have damaged the internal motivation of the general practitioners studied, although more concern was expressed by nurses.
OTITIC INTRACRANIAL INFECTION
Authors: H. L. Whale
Journal: BMJ (1925)

TORSION of the gall bladder is a very rare condition, and in consequence I report the following case.A married woman, a-ged 54, with six children, whilst taking tea on February 17th, was seized with severe pain in the right upper abdomen.She vomited freq,uently bright green bile, and the pain and vomiting continued until the morning of February 19th, when she was admitted to the London Hospital.She had not previously had similar pain, nor flatulent dyspepsia, jaundice, or any abdominal condition, although, until seven years ago, she was alleged to have suffered from periodic " bilious attacks," con- sisting of headache, slight sickness, but no paini, lasting for about a day.She was always constipated.The temperature on admission was 990, pulse 94, and respirations 24.The abdomen was slightly distended, and did not move well on respiration.Tenderness and rigidity of the right upper abdomen were pronounced, and a rounded lump, suggestive of a distended gall bladder, could be felt.Acute cholecystitis with a gall stone in Hartmann's pouch obstructing the cystic duct was the clinical diagnosis.Operation.-Aright upper rectus incision was made and the rectus muscle retracted outwards.As soon as the peritoneal cavity was opened some serous fluid escaped and a black distended gall bladder presented.It was about 3J in.long, the shape of
Insulin, Glycemic Control, and C-Reactive Protein During Myocardial Infarction
Authors: Antonio Ceriello
Journal: Diabetes Care (2004)

In recent years, much attention has been paid to the evidence that hyperglycemia during myocardial infarction enhances the risk of mortality (1). A frequent event in medicine is the “new” discovery of an old finding, and the story of hyperglycemia and acute myocardial infarction is one of these cases. An unusually high prevalence of glycosuria in nondiabetic patients who have acute myocardial infarction was noted as early as 1931 (2). In 1975, it was reported that “[fasting blood glucose] level shortly after an acute myocardial infarction is a better guide to prognosis” (3). An association between hyperglycemia during a myocardial infarction and subsequent mortality was then reported in 1987 (4) and confirmed in 1989 (5), 1991 (6), and 1993 (7).

However, in 2000, the large meta-analysis of Capes et al. (1) raised the question to the scientific community, even though the evidence that lowering glucose decreases mortality in diabetic patients who have myocardial infarction was available (8). Recently, data are accumulating, reinforcing the evidence that the presence of …
The root of the phylogenetic tree of human populations
Authors: M. Nei, N. Takezaki
Journal: Molecular Biology and Evolution (1996)

Although African populations have been shown to be most divergent from any other human populations, it has been difficult to establish the root of the phylogenetic tree of human populations since the rate of evolutionary change may vary from population to population owing to the fluctuation of population size and other factors. However, the root can be determined by using the chimpanzee as an outgroup and by employing proper statistical methods. Using this strategy, we constructed phylogenetic trees of human populations for five different sets of gene frequency data. The data sets used were two sets of microsatellite loci data (25 and 8 loci, respectively), restriction fragment length polymorphism (RFLP) data (79 loci), protein polymorphism data (15 loci), and Alu insertion frequency data (4 loci). All these data sets showed that the root is located in the branch connecting African and non-African populations, and in the four data sets the root was established at a significant level. These results indicate that Africans are the first group of people that split from the rest of the human populations.
Systemic lupus erythematosus with C1q deficiency
Authors: N.M. Stone, A. Williams, J.D. Wilkinson, G. Bird
Journal: British Journal of Dermatology (2000)

Abstract We report a case of systemic lupus erythematosus associated with C1q deficiency. Our patient presented at the age of 6 years with cutaneous lupus. She later developed Raynaud’s phenomenon, non-scarring alopecia, oral ulceration and grand mal seizures due to cerebral vasculitis. Complement C3 and C4 levels were consistently normal during flares of her lupus and haemolytic activity of her complement was absent, suggesting a deficiency of an early component of the complement cascade. No C1q could be detected.
A dynamic model of the cardiac ventricular action potential. II. Afterdepolarizations, triggered activity, and potentiation.
Authors: C H Luo, Y Rudy
Journal: Circulation Research (1994)

The action potential model presented in our accompanying article in this journal is used to investigate phenomena that involve dynamic changes of [Ca2+]i, as described below. Delayed afterdepolarizations (DADs) are induced by spontaneous Ca2+ release from the sarcoplasmic reticulum (SR), which, in turn, activates both the Na(+)-Ca2+ exchanger (INaCa) and a nonspecific Ca(2+)-activated current (Ins(Ca)). The relative contributions of INaCa and of Ins(Ca) to the generation of DADs are different under different degrees of Ca2+ overload. Early afterdepolarizations (EADs) can be categorized into two types: (1) plateau EADs, resulting from a secondary activation of the L-type Ca2+ current during the plateau of an action potential, and (2) phase-3 EADs, resulting from activation of INaCa and Ins(Ca) by increased [Ca2+]i due to spontaneous Ca2+ release from the SR during the late repolarization phase. Spontaneous rhythmic activity and triggered activity are caused by spontaneous Ca2+ release from the SR under conditions of Ca2+ overload. Postextrasystolic potentiation reflects the time delay associated with translocation of Ca2+ from network SR to junctional SR. The cell is paced at high frequencies to investigate the long-term effects on the intracellular ionic concentrations.
Lipopolysaccharide Induces Disseminated Endothelial Apoptosis Requiring Ceramide Generation
Authors: Adriana Haimovitz-Friedman, Carlos Cordon-Cardo, Shariff Bayoumy, Mark Garzotto, Maureen McLoughlin, Ruth Gallily, Carl K. Edwards, Edward H. Schuchman, Zvi Fuks, Richard Kolesnick
Journal: The Journal of Experimental Medicine (1997)

The endotoxic shock syndrome is characterized by systemic inflammation, multiple organ damage, circulatory collapse and death. Systemic release of tumor necrosis factor (TNF)-α and other cytokines purportedly mediates this process. However, the primary tissue target remains unidentified. The present studies provide evidence that endotoxic shock results from disseminated endothelial apoptosis. Injection of lipopolysaccharide (LPS), and its putative effector TNF-α, into C57BL/6 mice induced apoptosis in endothelium of intestine, lung, fat and thymus after 6 h, preceding nonendothelial tissue damage. LPS or TNF-α injection was followed within 1 h by tissue generation of the pro-apoptotic lipid ceramide. TNF-binding protein, which protects against LPS-induced death, blocked LPS-induced ceramide generation and endothelial apoptosis, suggesting systemic TNF is required for both responses. Acid sphingomyelinase knockout mice displayed a normal increase in serum TNF-α in response to LPS, yet were protected against endothelial apoptosis and animal death, defining a role for ceramide in mediating the endotoxic response. Furthermore, intravenous injection of basic fibroblast growth factor, which acts as an intravascular survival factor for endothelial cells, blocked LPS-induced ceramide elevation, endothelial apoptosis and animal death, but did not affect LPS-induced elevation of serum TNF-α. These investigations demonstrate that LPS induces a disseminated form of endothelial apoptosis, mediated sequentially by TNF and ceramide generation, and suggest that this cascade is mandatory for evolution of the endotoxic syndrome.
Metabolic Effects of Alterations in Meal Frequency in Type 2 Diabetes
Authors: Leeanne Arnold, Jim I Mann, Madeleine J Ball
Journal: Diabetes Care (1997)

OBJECTIVE The effects of altering meal frequency on measures of glucose and lipid metabolism in type 2 diabetes were examined by comparing isocaloric dietary regimens in which daily food intake was provided by three or nine meals each day. RESEARCH DESIGN AND METHODS A total of 13 free-living men and women with type 2 diabetes or persistently impaired glucose tolerance participated in a randomized crossover study in which three- and nine-meal regimes were followed for 4-week periods. Fasting plasma lipid and lipoprotein, glucose and insulin concentrations were measured at weekly intervals and glucose, insulin, and triglyceride responses following a 75-g glucose load at weeks 2 and 4 of each diet period. Dietary intake was also recorded during these weeks. RESULTS Nutrient intakes and all measures of carbohydrate and lipid metabolism were similar on the three- and nine-meal regimes. CONCLUSIONS This longer-term study could not confirm the potential benefits of increased meal frequency suggested by comparable 4-week studies in type 2 diabetic individuals and acute experiments in individuals with diabetes. However, as there were no adverse effects of consuming nine meals per day, it would seem appropriate that meal frequency in those with type 2 diabetes should be left to personal choice, provided that energy balance is maintained.
OC-049 Duodenal bulb biopsies—are they a necessity in coeliac disease?: Abstract OC-049 Table 1
Authors: M Kurien, K E Evans, I Aziz, S S Cross, A D Hopper, M Hadjivassiliou, D S Sanders
Journal: Gut (2012)

Global engagement between schools and colleges of pharmacy in the United States and Africa is increasing. For a balanced and fruitful engagement, sensitivity towards the cultural and clinical needs of the people and professionals of the African region is critical. In this paper, we have divided the discussion into Southern, East, Central, and West Africa. General information about Africa, with unique aspects for individual subregions and countries, will be introduced. Stereotypes and misconceptions about the region and the people will also be discussed, along with recommendations for culturally sensitive engagement for pharmacy and other health care practitioners when hosting members from, or visiting this region. The paper is a resource for schools and colleges of pharmacy who are currently engaged or considering future outreach opportunities in Africa.
AUTISM: A Window Onto the Development of the Social and the Analytic Brain
Authors: Simon Baron-Cohen, Matthew K. Belmonte
Journal: Annual Review of Neuroscience (2005)

Although the neurobiological understanding of autism has been increasing exponentially, the diagnosis of autism spectrum conditions still rests entirely on behavioral criteria. Autism is therefore most productively approached using a combination of biological and psychological theory. The triad of behavioral abnormalities in social function, communication, and restricted and repetitive behaviors and interests can be explained psychologically by an impaired capacity for empathizing, or modeling the mental states governing the behavior of people, along with a superior capacity for systemizing, or inferring the rules governing the behavior of objects. This empathizing-systemizing theory explains other psychological models such as impairments of executive function or central coherence, and may have a neurobiological basis in abnormally low activity of brain regions subserving social cognition, along with abnormally high activity of regions subserving lower-level, perceptual processing--a pattern that may result from a skewed balance of local versus long-range functional connectivity.
GLUTATHIONE-DEPENDENT BIOACTIVATION OF HALOALKENES
Authors: M. W. Anders, W. Dekant
Journal: The Annual Review of Pharmacology and Toxicology (1998)

▪ Abstract Several halogenated alkenes are nephrotoxic in rodents. A mechanism for the organ-specific toxicity of these compounds to the kidney has been elucidated. The mechanism involves hepatic glutathione conjugation to dihaloalkenyl or 1,1-difluoroalkyl glutathione S-conjugates, which are cleaved by γ-glutamyltransferase and dipeptidases to cysteine S-conjugates. Haloalkene-derived cysteine S-conjugates may have four fates in the organism: (a) They may be substrates for renal cysteine conjugate β-lyases, which cleave them to form reactive intermediates identified as thioketenes (chloroalkene-derived S-conjugates), thionoacyl halides (fluoroalkene-derived S-conjugates not containing bromide), thiiranes, and thiolactones (fluoroalkene-derived S-conjugates containing bromine); (b) cysteine S-conjugates may be N-acetylated to excretable mercapturic acids; (c) they may undergo transamination or oxidation to the corresponding 3-mercaptopyruvic acid S-conjugate; (d) finally, oxidation of the sulfur atom in halovinyl cysteine S-conjugates and corresponding mercapturic acids forms Michael acceptors and may also represent a bioactivation reaction. The formation of reactive intermediates by cysteine conjugate β-lyase may play a role in the target-organ toxicity and in the possible renal tumorigenicity of several chlorinated olefins widely used in many chemical processes.
BALB/cfRIII: A New High Mammary-Tumor and High Leukemia Mouse Strain2
Authors: Francesco Squartini, Giovanni B. Bolis, Guido Rossi
Journal: JNCI Journal of the National Cancer Institute (1974)

Journal Article BALB/cfRIII: A New High Mammary-Tumor and High Leukemia Mouse Strain Get access Francesco Squartini, M.D., Francesco Squartini, M.D. 3Institute of Pathological Anatomy and Histology, Medical School, University of Pisa, Via Roma 57, 56100 Pisa, Italy Address reprint requests to Dr. Squilrtini Search for other works by this author on: Oxford Academic PubMed Google Scholar Giovanni B. Bolis, M.D., Giovanni B. Bolis, M.D. 4Division of Cancer Research, University of Perugia, 06100 Perugia, Italy Search for other works by this author on: Oxford Academic PubMed Google Scholar Guido Rossi Guido Rossi 4Division of Cancer Research, University of Perugia, 06100 Perugia, Italy Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 52, Issue 5, May 1974, Pages 1635–1641, https://doi.org/10.1093/jnci/52.5.1635 Published: 01 May 1974 Article history Received: 17 September 1973 Accepted: 16 January 1974 Published: 01 May 1974
Clinical Characteristics of Pheochromocytoma Patients With Germline Mutations in <i>SDHD</i>
Authors: Hilde Dannenberg, Francien H. van Nederveen, Mustaffa Abbou, Albert A. Verhofstad, Paul Komminoth, Ronald R. de Krijger, Winand N.M. Dinjens
Journal: Journal of Clinical Oncology (2005)

We examined the value of SDHD mutation screening in patients presenting with apparently sporadic and familial pheochromocytoma for the identification of SDHD-related pheochromocytomas.This retrospective study involved 126 patients with adrenal or extra-adrenal pheochromocytomas, including 24 patients with a family history of multiple endocrine neoplasia 2, von Hippel-Lindau disease, neurofibromatosis type 1, or paraganglioma (PGL). Conformation-dependent gel electrophoresis and sequence determination analysis of germline and tumor DNA were used to identify SDHD alterations. The clinical and molecular characteristics of sporadic and hereditary tumors were compared. We reviewed the literature and compared our results with those from previously published studies.Pathogenic germline SDHD mutations were identified in three patients: two (2.0%) of the 102 apparently sporadic pheochromocytoma patients and one patient with a family history of PGL. These patients presented with multifocal disease (two of three multifocal patients) or with a single adrenal tumor (one of 82 patients). In the literature, mutations are mostly found in patients </= 35 years of age or presenting with multifocal or extra-adrenal disease. All patients with an SDHD mutation developed extra-adrenal tumors (pheochromocytomas or PGLs) at presentation or during follow-up.SDHD gene mutations in patients presenting with apparently sporadic adrenal pheochromocytoma are rare. We recommend SDHD mutation screening for patients presenting with a family history of pheochromocytoma or PGL, multiple tumors, isolated adrenal or extra-adrenal pheochromocytomas, and age </= 35 years. Analysis of SDHD can also help to distinguish synchronous primary tumors from abdominal metastases.
THE SERUM DIPHENYLAMINE (DPA) REACTION IN EXPERIMENTAL ARTHRITIS
Authors: Alvin F. Coburn, Joan Haninger
Journal: The Journal of Experimental Medicine (1954)

The passive Arthus arthritis in the guinea pig provides an experimental model for studying reactions comparable to those which occur in rheumatic fever. The joint swelling in the Arthus reaction is followed by tissue injury which is reflected 24 hours later by a rise in the DPA level. The height of this rise is determined by the degree of injury, which in turn is determined both by the strength of the antibody injected and also by the number of antigen depots created. The swelling reaction and the DPA rise can be suppressed by sodium salicylate, cortisone, or splenin A. The amount of drug required to block a DPA rise (DPA unit) is approximately tenfold the amount required to inhibit the joint swelling by 50 per cent (Arthus unit). Even when the Arthus arthritis has completed the swelling phase, treatment with appropriate amounts of these drugs suppress a rise in DPA. It was pointed out that the DPA rise appears to be associated with the tissue injury that follows joint swelling; that the degree of a DPA rise is determined by the severity of the inflammatory process; and that the amount of an anti-inflammatory agent required to suppress a DPA rise depends on the intensity of the reaction.
MSc in general practice can be done over the Internet
Authors: J. Sanfey
Journal: BMJ (1996)

pc/dos/pgp262i.zip.Use of this software has been advocated by Ross Anderson, who has drawn up for the BMA interim guidelines on maintaining security in computerised information systems.)The Intemnet presents many challenges to the provision of health care,4 but our responses as doctors must be based on critical examination of the facts rather than knee jerk responses to media myths and gross generalisations.
Deregulation of apoptosis-related genes is associated with PRV1 overexpression and JAK2 V617F allele burden in Essential Thrombocythemia and Myelofibrosis
Authors: Raquel Tognon, Elainy PL Gasparotto, Renata P Neves, Natália S Nunes, Aline F Ferreira, Patrícia VB Palma, Simone Kashima, Dimas T Covas, Mary Santana, Elizabeth X Souto, Maria Aparecida Zanichelli, Belinda P Simões, Ana Maria de Souza, Fabíola A Castro
Journal: Journal of Hematology & Oncology (2012)