tbuckley/cabot-search huggingface dataset:
Different ligands–different receptor conformations: Modeling of the hERα LBD in complex with agonists and antagonists
Authors: Ursula Egner, Nikolaus Heinrich, Marc Ruff, Monique Gangloff, Anke Mueller‐Fahrnow, Jean‐Marie Wurtz
Journal: Medicinal Research Reviews (2001)

Abstract The aim of this study is to compare crystal structures of nuclear receptor ligand binding domains in complex with different agonists and partial agonists to achieve a better understanding of the three‐dimensional structures and their ligand‐induced conformational changes. This led to the identification of structurally conserved “rigid” regions and more flexible parts of the proteins. The analysis was found to be of great value in fitting selected non‐steroidal compounds into the human estrogen receptor alpha (hERα) ligand binding pocket. The experimentally determined binding affinities for a number of 2‐aryl indoles and 2‐aryl indenones are in good agreement with the subsequently modeled binding interactions. To date, no crystal structure is published for a complex with a pure antagonist. We therefore used the available structural information on complexes with partial agonists and the crystal structure of a mutant protein in complex with estradiol displaying a similar conformation to predict binding interactions for antagonists. The results are discussed in detail. © 2001 John Wiley &amp; Sons, Inc. Med Res Rev, 21, No. 6, 523–539, 2001
Addiction and recovery
Authors: J. Bell
Journal: BMJ (2014)

I recently went to a hospice to say farewell to a long term patient of mine, now dying of disseminated cancer. When given the diagnosis and bleak prognosis 8 weeks earlier, he had declined palliative chemotherapy. He kept on working, but deteriorated rapidly, and developed gangrene and terrible pain. He was now in the hospice for a few days while equipment was installed at home to allow his wife to manage him for the remaining weeks.

I envisaged some difficulties managing his pain, as he had been maintained on prescribed heroin for several decades. He had been on quite a modest dose­—150 mg/day—but it was …
ATP-Sensitive K <sup>+</sup> Channels Mediate α <sub>2D</sub> -Adrenergic Receptor Contraction of Arteriolar Smooth Muscle and Reversal of Contraction by Hypoxia
Authors: Jun Tateishi, James E. Faber
Journal: Circulation Research (1995)

Abstract Evidence in rat skeletal muscle suggests that local metabolic control of blood flow is facilitated by the reliance on α 2D -adrenergic receptors (ARs) for constriction of arterioles, together with the strong sensitivity of this constriction to inhibition by hypoxia. The present study examined the role of ATP-sensitive K + (K ATP ) channels in the selective interaction between α 2D -ARs and hypoxia. Arterioles from rat cremaster muscle that possess both α 1D (α 1A/D )- and α 2D -AR subtypes were microcannulated, pressurized, and isolated in a tissue bath for measurement of changes in lumen diameter. Three studies first examined whether stimulation of α 2D - and α 1D -ARs involves inhibition of the K ATP channel. Concentration-dependent constriction by the K ATP antagonists glibenclamide (GLB, 0.01 to 10 μmol/L) and disopyramide (0.001 to 1 mmol/L) were abolished during α 2D stimulation but unaffected during α 1D stimulation. Activation of the K ATP channel by cromakalim inhibited α 2D constriction with greater potency than α 1D (EC 50 , 7.0±0.2 versus 6.3±0.1). Finally, GLB (0.5 μmol/L) abolished dose-dependent α 2D constriction, whereas α 1D was unaffected. These data suggest that α 2D but not α 1D stimulation is “coupled” with closure of the K ATP channel, leading to depolarization and contraction of vascular smooth muscle. In a second series, hypoxic (P o 2 , 6 mm Hg) inhibition of intrinsic smooth muscle tone was completely reversed by 0.1 μmol/L GLB, concentration-dependent GLB constriction was enhanced during hypoxia, and hypoxia reversed GLB constriction. These data confirm reports by others that hypoxia potentiates the activation of K ATP channels, leading to hyperpolarization and relaxation. Finally, GLB constriction, which was abolished by concomitant α 2D stimulation, was completely restored by simultaneous activation of K ATP channels with hypoxia. These findings suggest that the sensitivity of α 2D -AR constriction to inhibition by hypoxia arises through “antagonistic coupling” between these two stimuli, by which the α 2D -AR inhibits and hypoxia activates K ATP channels.
Laparoscopic sterilization through Cusco's speculum.
Authors: J O Greenhalf, H R Roberts
Journal: BMJ (1971)

incide with the peak blood levels of the drug, and also allows any resistant strains to pro- liferate.1 2The suggested regimen for covering sus- ceptible patients is to administer one mega- unit of crystaline penicillin 30 minutes pre- operatively and to follow this with 250 mg of phenoxymethyl penicillin orally, six hourly for five days.3For patients who are allergic to penicillin or having long-term penicillin prophylaxis erythromycin estolate orally is probably still the drug of choice.The cephalosporins are also suitable as an antibiotic cover.Recent work has suggested that the trimethropin/ sulphamethoxazole preparations may have a useful role in this field.-Iam, etc.,
Tetracycline in Pregnancy?
Authors: BENJAMIN G. NEWMAN
Journal: Annals of Internal Medicine (1971)

Letters, Comments, and Corrections1 October 1971Tetracycline in Pregnancy?BENJAMIN G. NEWMAN, M.D.BENJAMIN G. NEWMAN, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-75-4-648_2 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the editor: The article, "Disseminated Gonococcal Infection," by Drs. Holmes, Counts, and Beaty in the June 1971 ANNALS raises an interesting question. In their Case 1, Patient J.J., they describe a 30-year-old pregnant woman who was hospitalized with gonococcal bacteremia.I was surprised to read that they treated this patient with 2 g of tetracycline daily. It is my understanding that tetracycline is contraindicated in pregnant women. Even if the patient were allergic to penicillin, the drug of choice, wouldn't an alternate drug such as erythromycin have been safer for both mother and fetus?...References1. SCHULTZ J, ADAMSON J, and WORKMAN W: Fatal liver disease after intravenous administration of tetracycline in high dosage. N Engl J Med 269:999-1004, 1963 CrossrefMedlineGoogle Scholar2. WHALLEY P, ADAMS R, and COMBES B: Tetracycline toxicity in pregnancy. JAMA 189:357-362, 1964 CrossrefMedlineGoogle Scholar3. HARCOURT J, JOHNSON N, and STOREY E: In vivo incorporation of tetracycline in teeth of man. Arch Oral Biol 7:431-436, 1962 CrossrefMedlineGoogle Scholar4. RENDLE-SHORT T: Tetracycline in teeth and bone. Lancet 2:1118, 1962 Google Scholar5. ANTHONY J: Effect on deciduous and permanent teeth of tetracycline deposition in utero. Postgrad Med 48:165-168, 1970 CrossrefMedlineGoogle Scholar6. GENOT M, GOLAN H, and PORTER P: Effect of administration of tetracycline in pregnancy on the primary dentition of the offspring. J Oral Med 25:75-79, 1970 MedlineGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAuthors: BENJAMIN G. NEWMAN, M.D.Affiliations: Academy Plaza Medical Center Philadelphia, Pa. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byAntimicrobial Agents in the Treatment of Obstetric and Gynecologic Infections 1 October 1971Volume 75, Issue 4 Page: 648-649 Keywords Bacteremia Drugs Erythromycin Fetuses Penicillin Pregnancy Tetracyclines ePublished: 1 December 2008 Issue Published: 1 October 1971 PDF downloadLoading ...
Quebec nurses enter third week of strike
Authors: D. Spurgeon
Journal: BMJ (1999)

A nurses' strike in the province of Quebec has found strong public support despite resulting in the cancellation of 16000 operations and thousands of medical appointments. Some doctors have joined the picket lines with the nurses, who have continued to provide emergency cover and essential services.

A huge majority of the province's 47000 nurses voted last weekend for a break of 48 hours in the strike, which has been going since 26 June, after the premier, Lucien Bouchard, agreed to resume bargaining. They went back to work temporarily on Tuesday but have vowed …
INTERPRETATION OF CHANGES IN “CENTRAL” BLOOD VOLUME AND SLOPE VOLUME DURING EXERCISE IN MAN*
Authors: Robert J. Marshall, John T. Shepherd
Journal: Journal of Clinical Investigation (1961)

The first series of observations was made on 4 sub- jects lying supine, standing, and then exercising with varying grades of severity on a treadmill inclined at an angle of 120 from the horizontal.The cardiac output was measured by the indicator dilution method.A no. 5 Lehman cardiac catheter was introduced into a brachial vein by percutaneous puncture and advanced until its tip lay at the lower end of the superior vena cava.The * Nine observations in four subjects.
Angiogenic Property of Hepatocyte Growth Factor Is Dependent on Upregulation of Essential Transcription Factor for Angiogenesis, ets-1
Authors: Naruya Tomita, Ryuichi Morishita, Yoshiaki Taniyama, Hiromi Koike, Motokuni Aoki, Hideo Shimizu, Kunio Matsumoto, Toshikazu Nakamura, Yasufumi Kaneda, Toshio Ogihara
Journal: Circulation (2003)

Background— Although hepatocyte growth factor (HGF) is an angiogenic growth factor, it is still unclear how it exerts its angiogenic effects. Thus, we focused on the role of an essential transcription factor for angiogenesis, ets-1. In this study, we addressed the following specific questions: (1) what genes responsible for angiogenesis can be regulated by HGF and (2) whether upregulation of gene expression for angiogenesis is dependent on ets-1. Methods and Results— In human endothelial cells, HGF significantly stimulated the matrix-degrading pathway, such as the production of matrix metalloprotease-1 (MMP-1) through its specific receptor, c-met. In addition, HGF also significantly increased HGF itself and its specific receptor, c-met. Moreover, HGF significantly increased the transcription activity and mRNA expression of ets-1 in a time-dependent manner. Importantly, transfection of antisense ets-1 oligodeoxynucleotides (ODN) resulted in a significant reduction in MMP-1, HGF and c-met. Interestingly, HGF also stimulated ets-1 mRNA in vascular smooth muscle cells, similar to endothelial cells. Of importance, transfection of antisense ets-1 ODN resulted in a significant decrease in vascular endothelial growth factor (VEGF) and HGF expression, whereas HGF stimulated both HGF and VEGF expression. Moreover, in vivo transfection of ets-1 antisense ODN resulted in an inhibition of angiogenesis induced by the HGF gene in a rat ischemic hindlimb model. Conclusions— Here, we demonstrated that HGF stimulated the expression of MMP-1, VEGF, HGF itself, and c-met in human endothelial cells and vascular smooth muscle cells. Upregulation of angiogenesis-related genes was largely dependent on the induction of ets, especially ets-1. These data provide new information about the mechanisms of angiogenesis.
CpG Immunomer DNA Enhances Antisense Protein Kinase A RIα Inhibition of Multidrug-Resistant Colon Carcinoma Growth in Nude Mice: Molecular Basis for Combinatorial Therapy
Authors: Maria V. Nesterova, Natalie R. Johnson, Trina Stewart, Scott Abrams, Yoon S. Cho-Chung
Journal: Clinical Cancer Research (2005)

CpG DNAs induce cytokines, activate natural killer cells, and elicit vigorous T-cell response leading to antitumor effects. Antisense oligodeoxynucleotides targeted against the RIalpha subunit of protein kinase A (antisense PKA RIalpha) induce growth arrest, apoptosis, and differentiation in a variety of cancer cell lines in vitro and in vivo. This study investigated the use of a combinatorial therapy consisting of the RNA-DNA second-generation antisense PKA RIalpha and the CpG immunomer (CpG DNA linked through 3'-3' linkage containing two accessible 5' ends).HCT-15 multidrug-resistant colon carcinoma growth in nude mice was used as an experimental model. The inhibitory effect on tumor growth and apoptotic activity of antisense RIalpha and CpG immunomer, singly and in combination, were measured by tumor growth, levels of RIalpha subunit, and antiapoptotic and proapoptotic proteins. Effect on host-immune system was measured by mouse spleen size, interleukin-6 (IL-6) levels in mouse blood, and nuclear factor-kappaB (NF-kappaB) transcription activity in mouse spleen cells.In combination, CpG immunomer and antisense PKA RIalpha induced additive/supra-additive effect on the inhibition of tumor growth. Antisense RIalpha but not CpG immunomer increased Bax and Bak proapoptotic protein levels and decreased Bcl-2 and RIalpha protein levels in tumor cells. CpG immunomer but not antisense RIalpha induced an enlargement of mouse spleen, increased IL-6 levels in mouse blood, and increased NF-kappaB transcription activity in mouse spleen cells.These results show that type I PKA down-regulation and induction of apoptosis in tumor cells by antisense PKA RIalpha, and host-immune stimulation by CpG immunomer are responsible at the molecular level for the supra-additive effects of tumor growth inhibition. Thus, antisense PKA RIalpha and CpG immunomer in combination work cooperatively and as tumor-targeted therapeutics to treat human cancer.
What's happening to practice nursing?
Authors: D Jewell, P Turton
Journal: BMJ (1994)

Observers of general practice in the United Kingdom are quick to recognise the huge contribution practice nurses have made in recent years. In 1985, when Julian Tudor Hart described them as an underused resource, much of their work was concerned with relieving doctors of some of the simple tasks that doctors were keen to delegate.1 Since then many nurses have extended their activities into the management of chronic disease*RF 2-4* and disease prevention.5

The few comparisons between nurses' and doctors' technical excellence and acceptability to patients have mainly favoured nurses.2,4,5 The celebrated Burlington randomised trial of nurse practitioners, using appropriateness of clinical activity as a process measure and health status as an outcome measure, showed that they performed as well as general practitioners.6 In her account of nurses extending their role in the management of diabetic patients, Murphy reported a few patients at the end of the study specifically requesting nurses to take the leading role in their care and quoted one as saying, “The doctor does have the knowledge but when it comes to the practical the nurse has the practical.”4

A recent national census of practice nurses from the University of York confirms the trend for nurses to be taking on an increasing range of tasks.7 More than 80% of nurses are involved in clinics managing chronic diseases. A similar proportion reports giving advice on minor illnesses and more than 40% identify early signs of anxiety and depression.

Several factors are responsible for this change. Firstly, there is pressure from inside …
Assessment and management of non-visible haematuria in primary care
Authors: J. D Kelly, D. P Fawcett, L. C Goldberg
Journal: BMJ (2009)

#### Summary points

Many clinicians are not sure what constitutes clinically relevant haematuria; they are also unsure about when patients with haematuria should be referred for specialist assessment and whether they should be referred to a urologist, nephrologist, or both.

In 2006 the National Institute for Health Research, Health Technology Assessment (NIHR HTA) commissioned a systematic review of the evidence for the investigation of microscopic haematuria, with a view to developing an algorithm for assessing patients in primary care.1 They concluded that, “Given the paucity of evidence . . . it is not possible to derive an algorithm of the diagnostic pathway for haematuria that would be solely supported by existing evidence.” None the less, the investigation of microscopic haematuria is important because serious underlying conditions are present in a proportion of patients.

#### Sources and selection criteria

We drew on evidence published in the systematic reviews of the National Institute for Health and Clinical Excellence, Health Technology Assessment (microscopic haematuria),1 and guidelines for the early diagnosis and management of chronic kidney disease.1 2 We searched electronic databases, including Medline and the Cochrane database, to identify recent publications and studies that were deemed relevant but outside the inclusion criteria of the systematic review. We included the evidence presented in published guidelines for the investigation …
Adenosine receptors in regulation of dendritic cell differentiation and function
Authors: Sergey V. Novitskiy, Sergey Ryzhov, Rinat Zaynagetdinov, Anna E. Goldstein, Yuhui Huang, Oleg Y. Tikhomirov, Michael R. Blackburn, Italo Biaggioni, David P. Carbone, Igor Feoktistov, Mikhail M. Dikov
Journal: Blood (2008)
Spain considers charging for health care to help plug its financial deficit
Authors: M. Jara
Journal: BMJ (2010)

The Spanish government is considering introducing a fee per visit for publicly funded healthcare services in a bid to help plug the hole in its finances.

Health authorities in various autonomous regions like Catalonia, Valencia, Madrid, or Asturias, have backed this approach in the past few weeks, despite widespread opposition. 

The campaign group, the Madrid Network Against Privatisation of Public Health Care (CAS Madrid), states that the treasury is studying the feasibility of implementing a fee per visit system. 

The various options under consideration, it says, include charging …
Role of the endocrine pancreas in the kalemic response to acute metabolic acidosis in conscious dogs.
Authors: H J Adrogué, Z Chap, T Ishida, J B Field
Journal: Journal of Clinical Investigation (1985)

Metabolic acidosis due to organic acids infusion fails to elicit hyperkalemia. Although plasma potassium levels may rise, the increase is smaller than in mineral acid acidosis. The mechanisms responsible for the different effects of organic acid acidosis and mineral acid acidosis remain undefined, although dissimilar hormonal responses by the pancreas may explain dissimilar hormonal responses by the pancreas may explain the phenomena. To test this hypothesis, beta-hydroxybutyric acid (7 meq/kg) or hydrochloric acid (3 meq/kg) was infused over 30 min into conscious dogs (n = 12) with chronically implanted catheters in the portal, hepatic, and systemic circulation, and flow probes were placed around the portal vein and hepatic artery. Acid infusion studies in two groups of anesthetized dogs were also done to assess the urinary excretion of potassium (n = 14), and to evaluate the effects of acute suppression of renal electrolyte excretion on plasma potassium and on the release/uptake of potassium in peripheral tissues of the hindleg (n = 17). Ketoacid infusion caused hypokalemia and a significant increase in portal vein plasma insulin, from the basal level of 27 +/- 4 microU/ml to a maximum of 84 +/- 22 microU/ml at 10 min, without changes in glucagon levels. By contrast, mineral acid acidosis of similar severity resulted in hyperkalemia and did not increase portal insulin levels but enhanced portal glucagon concentration from control values of 132 +/- 25 pg/ml to 251 +/- 39 pg/ml at 40 min. A significant decrease in plasma glucose levels due to suppression of hepatic release was observed during ketoacid infusion, while no changes were observed with mineral acid infusion. Plasma flows in the portal vein and hepatic artery remained unchanged from control values in both acid infusion studies. Differences in renal potassium excretion were ruled out as determinants of the disparate kalemic responses to organic acid infusion compared with HCl acidosis. Evaluation of the arteriovenous potassium difference across the hindleg during ketoacid infusion demonstrates that peripheral uptake of potassium is unlikely to be responsible for the observed hypokalemia. Although the tissue responsible for the different kalemic responses could not be defined with certainty, the data are compatible with an hepatic role in response to alterations in the portal vein insulin and/or glucagon levels in both acid infusion studies. We propose that cellular uptake of potassium is enhanced by hyperinsulinemia in ketoacid infusion, and release of potassium results from increased glucagon levels in HCl acidosis. Whether the changes in plasma potassium that other types od organic acid acidosis produce are accounted for by a similar hormonal mechanism remains to be determined.
Degeneration and Domestication of a Selfish Gene in Yeast: Molecular Evolution Versus Site-Directed Mutagenesis
Authors: Vassiliki Koufopanou, Austin Burt
Journal: Molecular Biology and Evolution (2005)

VDE is a homing endonuclease gene in yeasts with an unusual evolutionary history including horizontal transmission, degeneration, and domestication into the mating-type switching locus HO. We investigate here the effects of these features on its molecular evolution. In addition, we correlate rates of evolution with results from site-directed mutagenesis studies. Functional elements have lower rates of evolution than degenerate ones and higher conservation at functionally important sites. However, functionally important and unimportant sites are equally likely to have been involved in the evolution of new function during the domestication of VDE into HO. The domestication event also indicates that VDE has been lost in some species and that VDE has been present in yeasts for more than 50 Myr.
Skiing injuries: a study from a Danish community.
Authors: B Møller-Madsen, B W Jakobsen, I Villadsen
Journal: British Journal of Sports Medicine (1990)

A Danish investigation of skiing injuries is presented from the casualty wards of two hospitals. The material consisted of 119 skiing injuries. Fifty-three per cent of the patients were women. Eighty-three injuries occurred abroad, mainly in Austria and Norway. Injury rate was not related to sex. The highest injury rate was found in the age group 20 to 29 years old. The most frequent injuries were sprains (knee 43, finger 14), fractures (39) and contusions (19). Injuries requiring hospitalization were common. None of these resulted in permanent major disability.
Bicarbonate-dependent and -independent intracellular pH regulatory mechanisms in rat hepatocytes. Evidence for Na+-HCO3- cotransport.
Authors: D Gleeson, N D Smith, J L Boyer
Journal: Journal of Clinical Investigation (1989)

Using the pH-sensitive dye 2,7-bis(carboxyethyl)-5(6)-carboxy-fluorescein and a continuously perfused subconfluent hepatocyte monolayer cell culture system, we studied rat hepatocyte intracellular pH (pHi) regulation in the presence (+HCO3-) and absence (-HCO3-) of bicarbonate. Baseline pHi was higher (7.28 +/- 09) in +HCO3- than in -HCO3- (7.16 +/- 0.14). Blocking Na+/H+ exchange with amiloride had no effect on pHi in +HCO3- but caused reversible 0.1-0.2-U acidification in -HCO3- or in +HCO3- after preincubation in the anion transport inhibitor 4,4'-diisothiocyano-2,2'-disulfonic acid stilbene (DIDS). Acute Na+ replacement in +HCO3- alos caused acidification which was amiloride independent but DIDS inhibitible. The recovery of pHi from an intracellular acid load (maximum H+ efflux rate) was 50% higher in +HCO3- than in -HCO3-. Amiloride inhibited H+ effluxmax by 75% in -HCO3- but by only 27% in +HCO3-. The amiloride-independent pHi recovery in +HCO3- was inhibited 50-63% by DIDS and 79% by Na+ replacement but was unaffected by depletion of intracellular Cl-, suggesting that Cl-/HCO3- exchange is not involved. Depolarization of hepatocytes (raising external K+ from 5 to 25 mM) caused reversible 0.05-0.1-U alkalinization, which, however, was neither Na+ nor HCO3- dependent, nor DIDS inhibitible, findings consistent with electroneutral HCO3- transport. We conclude that Na+-HCO3- cotransport, in addition to Na+/H+ exchange, is an important regulator of pHi in rat hepatocytes.