tbuckley/cabot-search huggingface dataset:
Randomised, controlled trial of avocado–soybean unsaponifiable (Piascledine) effect on structure modification in hip osteoarthritis: the ERADIAS study
Authors: Emmanuel Maheu, Christian Cadet, Marc Marty, Dominique Moyse, Isabelle Kerloch, Philippe Coste, Maxime Dougados, Bernard Mazières, Tim D Spector, Hafid Halhol, Jean-Marie Grouin, Michel Lequesne
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objective</h3> To assess the ability of avocado–soybean unsaponifiable—Expanscience (ASU-E) to slow radiographic progression in symptomatic hip osteoarthritis (OA). <h3>Methods</h3> Prospective, randomised, double blind, parallel group, placebo controlled 3 year trial. Patients with symptomatic (painful ≥1 year, Lequesne Index between 3 and 10) hip OA (American College of Rheumatology criteria) and a minimum joint space width (JSW) of the target hip between 1 and 4 mm on a pelvic radiograph were randomly assigned to 300 mg/day ASU-E or placebo. Standing pelvis, target hip anteroposterior (AP) and oblique views were taken annually. The primary outcome was JSW change at year 3, measured at the narrowest point on pelvic or target hip AP view (manual measure using a 0.1 mm graduated magnifying glass). The full analysis dataset (FAS) included all patients having at least two successive radiographs. An analysis of covariance Mixed Model for Repeated Measurements with Missing at Random (for missing data) was performed to compare adjusted 3 year JSW changes (primary outcome) and the percentages of 'progressors' (JSW loss≥0.5 mm) between groups. <h3>Results</h3> 399 patients were randomised (345 kept in the FAS), aged 62 (35–84) years, 54% women, mean body mass index 27 (SD 4) kg/m<sup>2</sup>, mean symptom duration 4 (SD 5) years, 0–100 normalised Lequesne Index 30 (SD 9) and global pain visual analogue scale 37 (SD 23) mm. Mean baseline JSW was 2.8 (0.9) mm. There was no significant difference on mean JSW loss (−0.638 mm vs −0.672 mm, p=0.72, in the ASU-E and placebo groups, respectively) but there were 20% less progressors in the ASU-E than in the placebo group (40% vs 50%, respectively, p=0.040). No difference was observed on clinical outcomes. Safety was excellent. <h3>Conclusions</h3> 3 year treatment with ASU-E reduces the percentage of JSW progressors, indicating a potential structure modifying effect in hip OA to be confirmed, and the clinical relevance requires further assessment. <h3>Trial registration number on ClinicalTrial.gov</h3> NCT01062737
A genomic and evolutionary approach reveals non-genetic drug resistance in malaria
Authors: Jonathan D Herman, Daniel P Rice, Ulf Ribacke, Jacob Silterra, Amy A Deik, Eli L Moss, Kate M Broadbent, Daniel E Neafsey, Michael M Desai, Clary B Clish, Ralph Mazitschek, Dyann F Wirth
Journal: Genome biology (2014)

Abstract Background Drug resistance remains a major public health challenge for malaria treatment and eradication. Individual loci associated with drug resistance to many antimalarials have been identified, but their epistasis with other resistance mechanisms has not yet been elucidated. Results We previously described two mutations in the cytoplasmic prolyl-tRNA synthetase (cPRS) gene that confer resistance to halofuginone. We describe here the evolutionary trajectory of halofuginone resistance of two independent drug resistance selections in Plasmodium falciparum . Using this novel methodology, we discover an unexpected non-genetic drug resistance mechanism that P. falciparum utilizes before genetic modification of the cPRS . P. falciparum first upregulates its proline amino acid homeostasis in response to halofuginone pressure. We show that this non-genetic adaptation to halofuginone is not likely mediated by differential RNA expression and precedes mutation or amplification of the cPRS gene. By tracking the evolution of the two drug resistance selections with whole genome sequencing, we further demonstrate that the cPRS locus accounts for the majority of genetic adaptation to halofuginone in P. falciparum . We further validate that copy-number variations at the cPRS locus also contribute to halofuginone resistance. Conclusions We provide a three-step model for multi-locus evolution of halofuginone drug resistance in P. falciparum . Informed by genomic approaches, our results provide the first comprehensive view of the evolutionary trajectory malaria parasites take to achieve drug resistance. Our understanding of the multiple genetic and non-genetic mechanisms of drug resistance informs how we will design and pair future anti-malarials for clinical use.
Tuberculin reactivity as a predictor of survival time in inoperable bronchial carcinoma.
Authors: N J Snell
Journal: Thorax (1979)

One hundred and two patients with inoperable bronchial carcinoma who had tuberculin tests at the time of diagnosis were followed up to see if there was any correlation between their degree of tuberculin reactivity and their subsequent survival time. There was a significant difference in survival between positive and negative tuberculin reactors (Log Rank Test P less than 0.05), the former having a median survival time almost twice that of the latter. This did not appear to be related to clinical differences between the groups at the time of testing, and other possible explanations are discussed. Tuberculin testing may be useful in helping to assess prognosis in patients with inoperable bronchial tumours.
DOPAMINE (3-HYDROXYTYRAMINE) AND BRAIN FUNCTION
Authors: OLEH HORNYKIEWICZ
Journal: Pharmacological Reviews (1966)

The whole body of evidence discussed in this article shows that brain dopamine can be regarded as a strong candidate for a physiologically active substance, regulating the functioning of some extrapyramidal centers, especially substantia nigra, striatum and pallidum. The following findings provide strong support for this view: The dopamine is mainly confined to the extrapyramidal regions mentioned; in these regions, the amine is localized in specific neurons and nerve terminals; its rate of turnover is of a high order of magnitude; is there a correlation between itsconcentration in the brain and the functional state of the extrapyramidal centers following administration of certain drugs; there is a striking relationship between some extrapyramidal disorders (drug-induced and genuine parkinsonism) and the lack of the amine in the substantia nigra, the striatum and the pallidum; and, finally, that substantia nigra exerts a direct influence on the concentration of the amine in the striatum by virtue of the nigro-striatal dopamine-containing fibers.

In the extrapyramidal centers, dopamine may have either inhibitory or excitatory activity. Neurophysiological evidence obtained in different species points to a predominantly inhibitory activity of dopamine on single neurons of the brain.

Evidence showing that in the retina and in the median eminence (including the pituitary stalk) dopamine may be the predominant catecholamine argues in favor of a specific function of the amine in these brain structures, although there are at present no direct findings to prove this suggestion.

From the evidence discussed in this article a good case can be made for the concept that the physiological activity of the brain dopamine is quite different from that of brain norepinephrine. There are as yet., however, no experiments to positively show that dopamine is a true neuro-transmitter substance in the brain. All central dopamine effects could equally well be explained by assuming that the amine is a modifier of synaptic transmission.

Therefore, in order to establish dopamine unequivocally as a central neurotransmitter substance, there is still one crucial experiment to be done: to demonstrate that upon stimulation of the relevant parts of the brain, dopamine is in fact released at synapses to exert by itself an effect on the neurons standing in synaptic relationship with the stimulated dopamine-containing terminals. It is to be hoped that we shall not have to wait too long for this experiment to be performed.
Selective depression of conduction of premature action potentials in canine Purkinje fibres by class lb antiarrhythmic drugs: comparison with la and Ic drugs
Authors: R. T PALLANDI, T. J CAMPBELL
Journal: Cardiovascular Research (1988)

Microelectrodes were used to record action potentials and to estimate their conduction velocity in canine Purkinje fibres 8-15 mm long mounted in a tissue bath. The effects of varying stimulation rates and protocols were studied in the presence of nine different class I antiarrhythmic drugs at each of two concentrations (high and low therapeutic range). In all cases, as stimulation rate increased (range of cycle lengths 1000 ms to 200 ms), conduction velocity in the presence of a drug fell progressively below that in control solution at the same rate. No major differences in rate dependent behaviour at steady state were observed between the subclasses Ia, Ib, and Ic. Differences were apparent, however, in the rate at which conduction velocity fell after a sudden decrease in cycle length. This was studied using two protocols. In the first of these, the conduction velocity was recorded of each action potential of a 20 beat train induced after a long rest period. In the presence of class Ib drugs (lignocaine, tocainide, and mexiletine) there was a rapid decline within 2-3 beats to a new equilibrium level of conduction velocity. Class Ia drugs (quinidine, disopyramide, and procainamide) required 12-16 beats to achieve equilibrium, and class Ic agents (flecainide, encainide, and lorcainide) produced slow falls in conduction velocity that did not reach equilibrium within the 20 beat trains. The second protocol involved interpolation of increasingly premature extrastimuli. Class Ib drugs progressively slowed conduction of premature beats as the diastolic interval was reduced below 300-400 ms.(ABSTRACT TRUNCATED AT 250 WORDS)
Extraordinary Sequence Divergence at Tsga8, an X-linked Gene Involved in Mouse Spermiogenesis
Authors: J. M. Good, D. Vanderpool, K. L. Smith, M. W. Nachman
Journal: Molecular Biology and Evolution (2010)

The X chromosome plays an important role in both adaptive evolution and speciation. We used a molecular evolutionary screen of X-linked genes potentially involved in reproductive isolation in mice to identify putative targets of recurrent positive selection. We then sequenced five very rapidly evolving genes within and between several closely related species of mice in the genus Mus. All five genes were involved in male reproduction and four of the genes showed evidence of recurrent positive selection. The most remarkable evolutionary patterns were found at Testis-specific gene a8 (Tsga8), a spermatogenesis-specific gene expressed during postmeiotic chromatin condensation and nuclear transformation. Tsga8 was characterized by extremely high levels of insertion-deletion variation of an alanine-rich repetitive motif in natural populations of Mus domesticus and M. musculus, differing in length from the reference mouse genome by up to 89 amino acids (27% of the total protein length). This population-level variation was coupled with striking divergence in protein sequence and length between closely related mouse species. Although no clear orthologs had previously been described for Tsga8 in other mammalian species, we have identified a highly divergent hypothetical gene on the rat X chromosome that shares clear orthology with the 5' and 3' ends of Tsga8. Further inspection of this ortholog verified that it is expressed in rat testis and shares remarkable similarity with mouse Tsga8 across several general features of the protein sequence despite no conservation of nucleotide sequence across over 60% of the rat-coding domain. Overall, Tsga8 appears to be one of the most rapidly evolving genes to have been described in rodents. We discuss the potential evolutionary causes and functional implications of this extraordinary divergence and the possible contribution of Tsga8 and the other four genes we examined to reproductive isolation in mice.
Effect of prednisolone on prostaglandin synthesis by rectal mucosa in ulcerative colitis: investigation by laminar flow bioassay and radioimmunoassay.
Authors: C J Hawkey, S C Truelove
Journal: Gut (1981)

The effect of two concentrations of prednisolone on synthesis of prostaglandin E2 (PGE2) by 40 rectal biopsies in organ culture was investigated using both laminar flow bioassay and radioimmunoassay (RIA). Prednisolone (concentration 8.33 x 10(-7)M) reduced mean synthesis of PGE2 to 36.4% of control values (measured by bioassay) or 26.2% of control values (measured by RIA). With prednisolone (concentration 5.66 X 10(-4) M) synthesis of PGE2 was 7.7% of control values (RIA). The two concentrations are similar respectively to those achieved in plasma after oral prednisolone and delivered topically by prednisolone enemata. Inhibition of PG synthesis may thus explain prednisolone9s anti-inflammatory action in the treatment of ulcerative colitis.
Lymphokine production by murine T cells in the mixed leukocyte reaction.
Authors: E Puré, K Inaba, J Metlay
Journal: The Journal of Experimental Medicine (1988)

Although the production of B cell stimulatory factors by cell lines and hybridomas is well established, production of specific lymphokines by normal T cells in response to antigen stimulation has not been analyzed. We have used bioassays and neutralizing mAbs to demonstrate that IL-2, IL-4, and B cell growth factors (BCGF) are produced during primary and secondary MLRs. IL-2 is detected in the first 12 h of both types of MLR. IL-4 and BCGF appear at 24-48 h in the conditioned medium of the primary MLR, and peak by 12 h in the secondary MLR. The amount of IL-4 in the primary response reaches a level that is 10% of that detected in the secondary. In contrast, BCGF production steadily increases over time in the primary MLR, and maximal production is equivalent to that made in the secondary response. Allogeneic dendritic cells and anti-Ig-activated B blasts both stimulated lymphokine production in the primary MLR, whereas small B cells were weak. In the secondary MLR, all three cell populations stimulated the production of IL-2, IL-4, and BCGF. Therefore, the release of several defined B cell stimulating factors can be detected in the conditioned media of responding primary T lymphocytes.
Standards for Statistical Models Used for Public Reporting of Health Outcomes
Authors: Harlan M. Krumholz, Ralph G. Brindis, John E. Brush, David J. Cohen, Andrew J. Epstein, Karen Furie, George Howard, Eric D. Peterson, Saif S. Rathore, Sidney C. Smith, John A. Spertus, Yun Wang, Sharon-Lise T. Normand
Journal: Circulation (2005)

With the proliferation of efforts to report publicly the outcomes of healthcare providers and institutions, there is a growing need to define standards for the methods that are being employed. An interdisciplinary writing group identified 7 preferred attributes of statistical models used for publicly reported outcomes. These attributes include (1) clear and explicit definition of an appropriate patient sample, (2) clinical coherence of model variables, (3) sufficiently high-quality and timely data, (4) designation of an appropriate reference time before which covariates are derived and after which outcomes are measured, (5) use of an appropriate outcome and a standardized period of outcome assessment, (6) application of an analytical approach that takes into account the multilevel organization of data, and (7) disclosure of the methods used to compare outcomes, including disclosure of performance of risk-adjustment methodology in derivation and validation samples.
Is low-level lead pollution dangerous?
Authors: D Gloag
Journal: BMJ (1980)

Present-day Americans are said to have about 500 times more lead in their skeletons than Peruvians of 1800 years ago.1 Lead pollution has become widespread in developed countries, especially from the use of lead in industry and in petrol and from its contamination of canned foods and some water. Never theless, lead poisoning, which was first described by the Greek physician poet Nikander in the second century BC,2 is very rare, being associated with high blood concentrations over 3-9 pimol/1 (80 (xg/100 ml), or occasionally over 2-9 (xmol/1 (60 (xg/100 ml.). The current debate centres on whether concentrations usually considered safe?under 1-9 pimol/1 (40 (xg/100 ml)?may in fact cause subtle neurological and behavioural abnormalities.
Different strains of rats develop different clinical forms of adjuvant disease.
Authors: V Y Muir, D C Dumonde
Journal: Annals of the Rheumatic Diseases (1982)

Evidence is presented that a single injection of bacterial antigen in oil into a footpad of rats of 5 strains induced different clinical forms of adjuvant disease in the individual rat strains. Rats were injected with 300 micrograms heat-killed Mycobacterium tuberculosis in 50 microliters paraffin. Inflammatory lesions and clinical features were recorded on skeletal charts at frequent intervals after injection; methods of charting and quantifying the features are described. By individually marking the rats and using one or more charts per rat we obtained an objective record of the course of disease in each animal and thus a means of distinguishing clinical features from manifestations of disease severity. Evaluation of these records showed that there was a pattern of joint involvement and associated physical and clinical features specific to each strain and that such strain specificity was reproducible in groups of rats injected over periods up to 3 1/2 years. These results suggest that the clinical form of adjuvant disease developing in each rat in response to the injection of mycobacteria in oil is genetically determined, and that there are additional factors that interact with genetic ones to allow adjuvant disease to develop in a particular rat.
Changes in adipose tissue composition in malnourished patients before and after liver transplantation: A carbon-13 magnetic resonance spectroscopy and gas-liquid chromatography study
Authors: E. L. Thomas, S. D. Taylor-Robinson, M. L. Barnard, G. Frost, J. Sargentoni, B. R. Davidson, S. C. Cunnane, J. D. Bell
Journal: Hepatology (1997)

We investigated adipose tissue fatty acid composition in 22 moderately to severely malnourished patients with cirrhosis and in 22 healthy volunteers by in vivo carbon–13 magnetic resonance spectroscopy (MRS). Gas–liquid chromatography (GLC) of adipose tissue samples was also performed in 11 of the patients and in 4 volunteers. In vivo 13C magnetic resonance spectra were obtained from the subcutaneous adipose tissue before and after eight weeks following orthotopic liver transplantation (OLT). Adipose tissue biopsy samples were obtained for GLC analysis at the time of transplantation in the patients and at inguinal hernia repair in the 4 volunteers. No significant differences were found in the subcutaneous adipose tissue total–saturated, – polyunsaturated or –monounsaturated fatty acid composition between patients and healthy volunteers by in vivo 13C MRS. GLC analysis of adipose tissue samples confirmed that total levels of saturated, poly–, and monounsaturated fatty acids remained the same but revealed significant differences in levels of individual fatty acids, particularly n–3 fatty acids (total n–3, cirrhotics: .84% ± .07% vs. controls: 1.36% ± .13%, P &lt; .01). Eight weeks following transplantation, recipients showed a considerable increase in body mass (pretransplantation: 59.3 ± 3.2 vs. posttransplantation: 63.2 ± 3 kg, P &lt; .01). 13C MRS revealed a significant increase in saturated fatty acids (pretransplantation: 21.6 ± 2.8 vs. posttransplantation: 25.5% ± 1.2%, P &lt; .05) and a significant decrease in unsaturated fatty acids. The application of noninvasive MRS techniques may be important to identify the differential uptake of fats, examining both specific fatty acids and different body fat compartments. In the future, this may be useful in optimizing the dietary management of severely malnourished patients with chronic liver disease before liver transplantation.
Fractional Extraction and Transcapillary Exchange during Continuous and Instantaneous Tracer Administration
Authors: DAVID L. YUDILEVICH, EUGENE M. RENKIN, OSVALDO A. ALVAREZ, IVÁN BRAVO
Journal: Circulation Research (1968)

The relation between extraction fraction, E, measured by the multiple-tracer, instantaneous intra-arterial injection method and by single-tracer, continuous injection was studied by experiments on gastric wall, liver, and skeletal muscle of anesthetized dogs. E was calculated from ratios of diffusible to nondiffusible tracer concentrations in successive samples of venous blood. Initial extraction, E(0), was the same by instantaneous or continuous injection. E diminished with time due to back-diffusion. In liver, E(0) for water- 3 H, mannitol- 3 H, and glucose- 3 H remained close to unity, indicating that transcapillary transport was flow-limited. E(0) for 22 Na, 36 Cl, and mannitol- 3 H in gastric wall, and for 22 Na and 86 Rb in skeletal muscle were less than unity and decreased with increasing blood flow, indicating diffusion limitation. E for 86 Rb in skeletal muscle eventually reached a plateau level, due to the large "sink" for 86 Rb in cell K. Both E(0) and plateau E for 86 Rb in muscle increased during exercise. Permeability surface products PS were calculated from measured E's and blood flows, Q, by the relation PS = -Q ln (1 - E). Their values suggest that E(0) reflects relative capillary permeabilities to different tracers, but only for capillaries of fastest arteriovenous transit. Plateau E's, such as for 86 Rb in skeletal muscle, represent all the capillaries, but are influenced also by extracapillary barriers.
Resistance to reinfection with Schistosoma mansoni in occupationally exposed adults and effect of HIV-1 co-infection on susceptibility to schistosomiasis: a longitudinal study
Authors: Diana MS Karanja, Allen W Hightower, Daniel G Colley, Pauline NM Mwinzi, Karin Galil, Julius Andove, W Evan Secor
Journal: The Lancet (2002)
Dominance of the CD4+ T helper cell response during acute resolving hepatitis A virus infection
Authors: Yan Zhou, Benoît Callendret, Dan Xu, Kathleen M. Brasky, Zongdi Feng, Lucinda L. Hensley, Jeremie Guedj, Alan S. Perelson, Stanley M. Lemon, Robert E. Lanford, Christopher M. Walker
Journal: The Journal of Experimental Medicine (2012)

Hepatitis A virus (HAV) infection typically resolves within 4-7 wk but symptomatic relapse occurs in up to 20% of cases. Immune mechanisms that terminate acute HAV infection, and prevent a relapse of virus replication and liver disease, are unknown. Here, patterns of T cell immunity, virus replication, and hepatocellular injury were studied in two HAV-infected chimpanzees. HAV-specific CD8(+) T cells were either not detected in the blood or failed to display effector function until after viremia and hepatitis began to subside. The function of CD8(+) T cells improved slowly as the cells acquired a memory phenotype but was largely restricted to production of IFN-γ. In contrast, CD4(+) T cells produced multiple cytokines when viremia first declined. Moreover, only CD4(+) T cells responded during a transient resurgence of fecal HAV shedding. This helper response then contracted slowly over several months as HAV genomes were eliminated from liver. The findings indicate a dominant role for CD4(+) T cells in the termination of HAV infection and, possibly, surveillance of an intrahepatic reservoir of HAV genomes that decays slowly. Rapid contraction or failure to sustain such a CD4(+) T cell response after resolution of symptoms could increase the risk of relapsing hepatitis A.