tbuckley/cabot-search huggingface dataset:
Effect of age and environmental factors on insulin release from the perfused pancreas of the rat.
Authors: E Reaven, D Curry, J Moore, G Reaven
Journal: Journal of Clinical Investigation (1983)

In this study we examined the effect of age and various age-related environmental factors on maximal glucose-stimulated insulin release by the intact perfused pancreas. Male Sprague-Dawley rats were maintained from 40 d to 12 mo of age on standard chow, or on a sucrose-rich or calorie-restricted diet. At 12 mo, studies were carried out on the isolated pancreas of each animal to determine maximal (300 mg/ml) glucose-stimulated insulin secretion. After these studies were completed, each pancreas was perfused with formalin fixative and processed for morphometric estimation of the mass of the endocrine pancreas. Data from these older animals were compared with data from 2-mo-old control rats. The results indicate that maximal glucose-stimulated insulin secretion per unit endocrine pancreas was markedly reduced in all three groups of 12-mo-old rats, and was only 25-33% of that of 2-mo-old rats. Thus, aging led to a decline in insulin secretion per beta cell that was not modifiable by environmental manipulation. On the other hand, environmental factors can influence the development of endocrine tissue within the pancreas, and in so doing, modify total pancreatic insulin secretion. The mass of the endocrine pancreas of 12-mo-old rats fed either sucrose or chow was between three and four times that of 2-mo-old control rats, and these older rats were able to maximally secrete as much insulin per total pancreas as the young rats. In contrast, the endocrine cell mass of the calorie-restricted rats had not enlarged to this extent, and the maximally stimulated perfused pancreas from these rats secreted less insulin. These data suggest that the aging animal, challenged in vivo to secrete insulin, can overcome the loss of the beta cell response by expanding its pancreatic pool of beta cells. Although this compensation is successful in the 12-mo-old, obese, middle-aged rat, it is not yet clear what effect further aging would have on these events.
Dietary modulation of gluten sensitivity in a naturally occurring enteropathy of Irish setter dogs.
Authors: E J Hall, R M Batt
Journal: Gut (1992)

Gluten sensitivity in a naturally occurring enteropathy of Irish setter dogs, and the effects of excluding dietary cereal from birth on the subsequent response to gluten challenge were investigated. Peroral jejunal biopsy specimens were obtained at 1 year of age for morphometric and biochemical examinations, and intestinal permeability was assessed using 51Cr-ethylenediaminetetraacetic acid. Affected setters, reared on a normal wheat containing diet, exhibited partial villus atrophy, intraepithelial lymphocyte infiltration, reduced brush border alkaline phosphatase activity, and increased intestinal permeability. Gluten sensitivity was shown by introduction of a gluten free diet, which resulted in resolution of morphological and biochemical abnormalities and decreased intestinal permeability, and subsequent gluten challenge, which resulted in relapse. In contrast, littermates reared exclusively on a cereal free diet showed minimal changes when challenged with gluten, apart from intraepithelial lymphocyte infiltration. These findings document a gluten sensitive enteropathy in Irish setters and indicate that exclusion of dietary cereal from birth may modify subsequent expression of the disease.
Dispersal and Evolution of the Sinorhizobium meliloti Group II RmInt1 Intron in Bacteria that Interact with Plants
Authors: Manuel Fernández-López, Estefanía Muñoz-Adelantado, Moniek Gillis, Anne Willems, Nicolás Toro
Journal: Molecular Biology and Evolution (2005)

Group II introns are both self-splicing RNAs and mobile retroelements found in bacterial and archaeal genomes and in organelles of eukaryotes. They are thought to be the ancestors of eukaryote spliceosomal introns and non–long terminal repeat retrotransposons. We show here that RmInt1, a bacterial group II intron first described in the nitrogen-fixing symbiont of alfalfa (Medicago sativa) Sinorhizobium meliloti, is also present in other Sinorhizobium and Rhizobium species. The intron-homing sites in these species are IS elements of the ISRm2011-2 group as in S. meliloti, but ectopic insertion is also observed. We present evidence that these related bacteria have acquired RmInt1 by vertical inheritance from a common ancestor and by independent horizontal transfer events. We also show that RmInt1 is mobile in related taxa of bacteria that interact with plants and tends to evolve toward an inactive form by fragmentation, with loss of the 3′ terminus including the intron-encoded protein. Our results provide an overview of the evolution and dispersion of a bacterial group II intron.
Alternative view of CKD and QOF
Authors: A. Connor, D. O'Donoghue
Journal: BMJ (2010)

There is an alternative perspective to Spence’s view that opportunistic screening for chronic kidney disease (CKD) is “bad medicine.”1 Referrals from primary care increased after the introduction of estimated glomerular filtration (eGFR) reporting, with a shift towards more advanced disease—suggesting that those with most to gain from specialist review are now more likely to …
Three year evaluation of a programme by general practitioners to help patients to stop smoking.
Authors: R L Richmond, A Austin, I W Webster
Journal: BMJ (1986)

A controlled study was undertaken to measure the effectiveness of general practitioners9 use of an intensive programme to help patients to stop smoking. Two hundred cigarette smokers who attended a general practice were allocated to either a treatment (n = 100) or a non-intervention control (n = 100) group. After the initial visit treatment consisted of an educational consultation and four follow up visits. Smoking state was assessed biochemically at six months and three years. Thirty five patients in the treatment group were abstinent at three years compared with eight in the control group (p less than 0.001). Sixty four patients attended the educational consultation and first follow up visit; of these, 45 were not smoking at the first follow up visit, 30 maintained abstinence up to six months, and 22 were still not smoking after three years. Among the 37 patients who completed the treatment programme and attended all the follow up visits 57% were abstinent at three years. The results of this study suggest that general practitioners can help patients to stop smoking.
Benzodiazepines on trial
Authors: S W Lewis
Journal: BMJ (1984)

29,39-Dideoxyuridine (ddU) is ineffective at controlling human immunodeficiency virus type 1 (HIV-1) infection in human T cells, because it is not biotransformed to the active 59-triphosphate. The metabolic block resides in the poor substrate affinity of ddU for cellular nucleoside kinases. This problem cannot be overcome by supplying the preformed nucleotides, because such compounds are unable to penetrate cells. To circumvent the requirement of ddU for enzymic phosphorylation, we have prepared bis(pivaloyloxymethyl) 29,39-dideoxyuridine 59-monophosphate (piv2 ddUMP), as a potential membrane-permeable prodrug of ddUMP, and investigated its metabolism and anti-HIV activity in two human T cell lines, one with wild-type thymidine kinase activity (MT-4) and the other deficient in thymidine kinase activity (CEM-tk-). The 59-mono-, di-, and triphosphates of ddU were formed in both cell lines after exposure to piv2-ddUMP. In contrast, phosphorylated metabolites were not observed in cells treated with ddU or ddUMP alone. piv2-ddUMP also reduced the cytopathic effects of HIV-1 in MT-4 cells (ED50, 4.75 microM) and inhibited virus production in culture fluid (ED50, 20 microM). In addition, piv2-ddUMP protected CEM-tk- cells from HIV-1 infection, as demonstrated by inhibition of intracellular p24 antigen levels (ED50, 3 microM) and reverse transcriptase activity in culture medium (Ed50, 2.5 microM). Based on these findings, we propose that the "masked nucleotide" strategy may make available for development nucleoside analogues hitherto considered inactive because of failure to undergo biotransformation to the corresponding 59-monophosphates. Moreover, by circumventing metabolic dependency on nucleoside kinases, the strategy may overcome acquired resistance to nucleoside analogues caused by the loss or depletion of nucleoside kinases.
Experts back research using primates
Authors: Michael Day
Journal: BMJ (2006)

Medical experiments on non-human primates will be vital in the fight against AIDS, tuberculosis, and malaria “for the foreseeable future,” a group of leading scientists has concluded. 

Their report, sponsored by the Academy of Medical Sciences, the Royal Society, the Medical Research Council, and the Wellcome Trust, adds that a ban on the use of monkeys would jeopardise important research into neurological diseases such as Parkinson's disease and dementia. 

The ban on research involving apes, should remain, however, the scientists say. 

The report's chief author, David Weatherall, the leading malaria expert and professor of medicine at Oxford University, said the “huge discrepancy” between the numbers of monkeys used in medical experiments and the number of people …
p53 Pre- and Post-Binding Event Theories Revisited: Stresses Reveal Specific and Dynamic p53-Binding Patterns on the <i>p21</i> Gene Promoter
Authors: Jean-François Millau, Nathalie Bastien, Éric F. Bouchard, Régen Drouin
Journal: Cancer Research (2009)

Abstract p53 is a master transcription factor that prevents neoplasia and genomic instability. It is an important target for anticancer drug design. Understanding the molecular mechanisms behind its transcriptional activities in normal cells is a prerequisite to further understand the deregulation effected by mutant p53 in cancerous cells. Currently, how p53 coordinates transcription programs in response to stress remains unclear. One theory proposes that stresses induce pre-binding events that direct p53 to bind to specific response elements, whereas a second posits that, in response to stress, p53 binds most response elements and post-binding events then regulate transcription initiation. It is critical to establish the relevance of both theories and investigate whether stresses induce specific p53-binding patterns correlated with effector gene induction. Using unique in cellulo genomic footprinting experiments, we studied p53 binding to the five response elements of p21 in response to stresses and monitored p21 mRNA variant transcription. We show clear footprints of p53 bound to response elements in living cells and reveal that the binding of p53 to response elements is transient, subject to dynamic changes during stress responses, and influenced by response element pentamer orientations. We show further that stresses lead to specific p53-binding patterns correlated with particular p21 mRNA variant transcription profiles and that p53 binding is necessary but not sufficient to induce p21 transcription. Our results indicate that pre- and post-binding events act together to regulate adapted stress responses; this paves the way to the unification of pre- and post-binding event theories. [Cancer Res 2009;69(21):8463–71]
Intramuscular Mepacrine: Histological Effect
Authors: F. Hawking
Journal: BMJ (1943)

several separate examinations with the patient rotated in oblique positions in order to bring each diameter in turn parallel with the film.Linear objects can be measured provided that they are parallel with the film.The calculation of the size of the tumour or cavity in the lung and its depth from any part of the chest wall is a simple matter.A double exposure on one film will suffice, or two separate films may be taken if preferred.The method can be used as a check on tomography.The size and depth of opaque cerebral tumours could be determined in a similar manner.The dimensions of a vesical or biliary calculus, or other opaque object, could be determined and compared with its dimensions at a subsequent examination.The results would be comparable even though the position of the object had changed.No doubt other applications of this method will present themselves.
Abstract P1-02-07: Discordance for low and intermediate levels (1+ or 2+ by IHC) of HER2 protein expression in the phase III PRESENT trial
Authors: HS Rugo, M Melisko, NE Ben-Baruch, J Price Hiller, S Dahkil, L Sutton, R Mazanet, E Mittendorf
Journal: Cancer Research (2013)

Abstract Background Significant discordance has been described between different laboratories and between testing methodologies for HER2 overexpression and gene amplification. Concern has focused on missing patients who might benefit from treatment with HER2 targeted therapy. Concordance rates between local and central testing for tumors selected for HER2 0-2+ is not well described. We describe discordance rates between local and central testing performed to identify tumors with 1 and 2+ HER2 expression. Methods The PRESENT study is a multicenter, multinational, prospective, randomized, double-blind, controlled Phase 3 study assessing efficacy and safety of the peptide vaccine NeuVax, in HLA-A2 and/or A3 positive patients with early stage, node positive breast cancer expressing low and intermediate levels (1/2+ by IHC) of HER2 protein. PRESENT 2-step screening includes HLA testing followed by central lab confirmation of HER2 1 or 2+ expression using the DAKO HercepTest. Results 215 patients underwent central IHC testing for HER2. Discordance between local and central testing was seen in 54% (117/215); 34% (65/192) of those eligible by local results were ineligible on central testing, and 48% (11/23) of those not eligible by local results were eligible on central testing. Local testingCentral testing (IHC (%))IHC (n)01+2+3+0 (15)5 (33%)7 (47%3 (20%)—1+ (127)39 (31%)68 (53%)15 (12%)5 (4%)2+ (65)11 (17%)23 (35%)21 (32%)10 (16%)3+ (8)3 (38%)—1 (12%)4 (50%) Of those with 1 or 2+ local results, 8% (15/192) were found to be 3+ on central testing. Discordant rates varied by geographic location with higher rates seen in Eastern Europe and Russia. Conclusion Significant discordance exists between local and central laboratory test results for HER2 expression by IHC even at lower levels of expression, and current tests are defined by their ability to determine 3+ positivity. In order to improve accuracy of testing and to develop a companion diagnostic for NeuVax, the Leica Bond Oracle HER2 IHC System will be incorporated into future HER2 screening for the PRESENT trial. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-02-07.
Molecular basis of argininemia. Identification of two discrete frame-shift deletions in the liver-type arginase gene.
Authors: Y Haraguchi, J M Aparicio, M Takiguchi, I Akaboshi, M Yoshino, M Mori, I Matsuda
Journal: Journal of Clinical Investigation (1990)

Argininemia results from a deficiency of arginase (EC 3.5.3.1), the last enzyme of the urea cycle in the liver. We examined the molecular basis for argininemia by constructing a genomic library followed by cloning and DNA sequencing. Discrete mutations were found on two alleles from the patient, a product of a nonconsanguineous marriage. There was a four-base deletion at protein-coding region 262-265 or 263-266 in exon 3 that would lead to a reading-frame shift after amino acid residue 87 and make a new stop codon at residue 132. The other was a one-base deletion at 77 or 78 in exon 2 that would lead to a reading-frame shift after residue 26 and make a stop codon at residue 31. For confirmation, genomic DNAs from the patient and from her parents were amplified by the polymerase chain reaction method. The patient was shown to be a compound heterozygote, inheriting an allele with the four-base deletion from the father and the other allele with the one-base deletion from the mother. These data seem to be the first evidence of a case of argininemia caused by two different deletion mutations.
CLINICAL EXPERIENCE WITH A SIROLIMUS-ELUTING NITINOL STENT IN A BIODEGRADABLE POLYMER MATRIX USING THE CARDIOMIND® 0.014″ SPARROW® STENT SYSTEM
Authors: Roberto Botelho, Stefan Verheye, Robert J. Whitbourn, Rodolfo Staico, Jose R. Costa, Alexandre C. Abizaid
Journal: Journal of the American College of Cardiology (2010)
Effect of testosterone administration on upper airway collapsibility during sleep.
Authors: P A Cistulli, R R Grunstein, C E Sullivan
Journal: American Journal of Respiratory and Critical Care Medicine (1994)

Testosterone is thought to play a role in the pathogenesis of obstructive sleep apnea (OSA), but the mechanism is unclear. We present a case in which testosterone administration induced or exacerbated OSA in a 13-year-old male. We demonstrated that exacerbation of OSA by testosterone was associated with an increase in upper airway collapsibility during sleep, and that this improved after cessation of hormone administration. Our data strongly suggest that the mechanism by which testosterone administration may induce or exacerbate OSA is through an influence on neuromuscular control of upper airway patency during sleep.
Tumor necrosis factor-α overproduction in Fanconi's anemia
Authors: John C. Schultz, Nasrollah T. Shahidi
Journal: American Journal of Hematology (1993)

Abstract Various in vitro studies and clinical observations suggest that Fanconi's anemia (FA) patients are unable to detoxify adequately superoxide anions (O ) released by activated phagocytes. Recent studies have shown that certain lymphokines such as tumor necrosis factor‐α (TNF‐α) and interferon‐γ (IFN‐γ) can significantly enhance O production by phagocytic cells. To ascertain lymphokine production in FA patients, we measured TNF‐α and IFN‐γ production in vivo and in vitro. TNF‐α was detected in the plasma of 16 of 18 FA patients with concentrations ranging from 6 to 131 pg/ml (mean 31 pg/ml). TNF‐α was detected in only one of 25 control (healthy donor) plasma, and the level was very low (7 pg/ml). IFN‐γ levels in normal and patient plasma were negligible. Spontaneous and phytohemagglutinin (PHA)‐induced production of IFN‐γ and TNF‐α by cultured peripheral blood mononuclear cells did not differ significantly between FA patients and normal controls. The significance of overproduction of TNF‐α in vivo in the pathophysiology of FA is discussed. © 1993 Wiley‐Liss, Inc.
Markers of exposure to carcinogens.
Authors: G N Wogan
Journal: Environmental Health Perspectives (1989)

Methods have been developed for the detection of exposure to carcinogens and other DNA damaging agents in experimental animals and man through the detection of carcinogens or their metabolic derivatives in body fluids, or through adducts bound covalently to DNA or hemoglobin. The successful use of urinary markers of genotoxic exposures has been reported with respect to nitrosoproline as an indicator of exposure to N-nitroso compounds. The same approach has been used to detect AFB1 and AFB1-N7-Gua as markers of exposure to aflatoxin B1; of 3-methyladenine produced as a result of exposure to methylating agents; and thymine glycol as an indicator of exposure to agents causing oxidative damage to DNA. Detection of adducts formed between genotoxic agents and hemoglobin has been reported in studies of populations occupationally exposed to ethylene oxide, in which 3-hydroxyhistidine and 3-hydroxyvaline have been measured, and in smokers, whose hemoglobin has been found to contain levels of 4-aminobiphenyl and 3-hydroxyvaline that were correlated with the frequency of cigarette smoking. Detection of DNA adducts of genotoxic agents in the cells and tissues of exposed individuals has also been accomplished through the use of several types of analytical methods. Immunoassays and physicochemical methods have been applied to detect adducts formed through the major intermediate in the activation of benzo(a)pyrene, the 7,8-diol-9,10-epoxide (BPDE). This adduct has been found in the DNA of peripheral leukocytes of workers in foundries, aluminum manufacturing plants, roofers, and coke oven plants, and also in cigarette smokers.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of short term sacral nerve stimulation on anal and rectal function in patients with anal incontinence
Authors: C J Vaizey, M A Kamm, I C Turner, R J Nicholls, J Woloszko
Journal: Gut (1999)

Some patients with faecal incontinence are not amenable to simple surgical sphincter repair, due to sphincter weakness in the absence of a structural defect.To evaluate the efficacy and possible mode of action of short term stimulation of sacral nerves in patients with faecal incontinence and a structurally intact external anal sphincter.Twelve patients with faecal incontinence for solid or liquid stool at least once per week.A stimulating electrode was placed (percutaneously in 10 patients, operatively in two) into the S3 or S4 foramen. The electrode was left in situ for a minimum of one week with chronic stimulation.Evaluable results were obtained in nine patients, with early electrode displacement in the other three. Incontinence ceased in seven of nine patients and improved notably in one; one patient with previous imperforate anus and sacral agenesis had no symptomatic response. Stimulation seemed to enhance maximum squeeze pressure but did not alter resting pressure. The rectum became less sensitive to distension with no change in rectal compliance. Ambulatory studies showed a possible reduction in rectal contractile activity and diminished episodes of spontaneous anal relaxation.Short term sacral nerve stimulation notably decreases episodes of faecal incontinence. The effect may be mediated via facilitation of striated sphincter muscle function, and via neuromodulation of sacral reflexes which regulate rectal sensitivity and contractility, and anal motility.
The nuclear receptor LXRα controls the functional specialization of splenic macrophages
Authors: Noelia A-Gonzalez, Jose A Guillen, Germán Gallardo, Mercedes Diaz, Juan V de la Rosa, Irene H Hernandez, Maria Casanova-Acebes, Felix Lopez, Carlos Tabraue, Susana Beceiro, Cynthia Hong, Pedro C Lara, Miguel Andujar, Satoko Arai, Toru Miyazaki, Senlin Li, Angel L Corbi, Peter Tontonoz, Andres Hidalgo, Antonio Castrillo
Journal: Nature Immunology (2013)
Ads From the Partnership for a Drug-Free America-Reply
Authors: Richard D. Bonnette
Journal: JAMA (1992)

<h3>In Reply.</h3> —There are a number of generalizations, inaccuracies, and unsound logical conclusions drawn by Mr DuBay in his letter about a PDFA print message that appeared in JAMA.<sup>1</sup> The message, "First, rule out drug use," was developed by the Health Care Task Force of the PDFA—a group of communications specialists who represent some of the country's most prestigious health care companies and associations—and is one of many designed to communicate important antidrug messages to health care professionals. As with all PDFA messages, it was carefully researched and thoroughly checked for accuracy. We stand by the message, 100%. This message does not directly or indirectly claim that cannabis use causes mental illness, as DuBay infers. Its intent and purpose are clear: to encourage psychiatrists to include drug use—marijuana or any other mind-altering substance, in casual or heavy quantities— when evaluating a patient's overall psychiatric profile. Health care professionals can