tbuckley/cabot-search huggingface dataset:
End to state regulation of health costs in New York
Authors: D. Josefson
Journal: BMJ (1997)

<h3>ABSTRACT</h3> Ribosomes serve as the universally conserved translators of the genetic code into proteins and must support life across temperatures ranging from below freezing to above the boiling point of water. Ribosomes are capable of functioning across this wide range of temperatures even though the catalytic site for peptide bond formation, the peptidyl transferase center, is nearly universally conserved. Peptide bond formation by the ribosome requires correct positioning of the 3’ s-end of the aminoacylated tRNA (aa-tRNA) substrate, which is aided by an RNA hairpin in the ribosomal RNA (rRNA) of the large subunit, termed the A loop. Here we find that Thermoproteota, a phylum of thermophilic Archaea, substitute cytidine for uridine at large subunit rRNA positions 2554 and 2555 (<i>Escherichia coli</i> numbering) in the A loop, immediately adjacent to the binding site for the 3′-end of A-site tRNA. We show by cryo-EM that <i>E. coli</i> ribosomes with uridine to cytidine mutations at these positions retain the proper fold and post-transcriptional modification of the A loop. Additionally, these mutations do not exert a dominant negative effect on cellular growth, protect the large ribosomal subunit from thermal denaturation, and increase the mutational robustness of nucleotides in the peptidyl transferase center. This work identifies sequence variation in the peptidyl transferase center of the archaeal ribosome that likely confers stabilization of the ribosome at high temperatures and develops a stable mutant bacterial ribosome that can act as a scaffold for future ribosome engineering efforts.
Strain echocardiography tracks dobutamine-induced decrease in regional myocardial perfusion in nonocclusive coronary stenosis
Authors: Gabriel Yip, Bijoy Khandheria, Marek Belohlavek, Cristina Pislaru, James Seward, Kent Bailey, A.Jamil Tajik, Patricia Pellikka, Theodore Abraham
Journal: Journal of the American College of Cardiology (2004)
Phenytoin Therapy and Toxicities
Authors: DONALD F. LIPONI
Journal: Annals of Internal Medicine (1984)

Letters and Corrections1 October 1984Phenytoin Therapy and ToxicitiesDONALD F. LIPONI, PHARM.D.DONALD F. LIPONI, PHARM.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-101-4-568_1 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the editor: Many clinicians and patients will benefit from Dr. Troupin's lucid guidelines on when to measure anticonvulsant drug plasma concentrations (1). Although pharmacokineticists have detailed many characteristics of the anticonvulsant drugs, the mere availability of such measurements without appropriate interpretation has not led to an improvement in either seizure control or avoidance of side effects (2). As Dr. Troupin and others have stated, the treatment of epilepsy is a clinical issue and not only a laboratory matter.In discussing the therapeutic range, Dr. Troupin does not mention the specific alterations that occur in the desired therapeutic range of...References1. TROUPIN A. The measurement of anticonvulsant agent levels. Ann Intern Med. 1984;100:854-8. LinkGoogle Scholar2. BEARDSLEYFREEMANAPPEL RJF. Anticonvulsant serum levels are useful only if the physician appropriately uses them: an assessment of the impact of providing serum level data to physicians. Epilepsia. 1983;24:330-5. CrossrefMedlineGoogle Scholar3. TOZERWINTER TM. Phenytoin. In: EVANS WE, SCHENTAG JJ, JUSKO WJ, eds. Applied Pharmacokinetics. San Francisco: Applied Therapeutics; 1980:275-314. Google Scholar4. LIPONIWINTERTOZER DMT. Renal function and therapeutic concentrations of phenytoin. Neurology (NY). 1984;34:395-7. CrossrefMedlineGoogle Scholar5. SCHMIDTSELDON DL. Adverse Effects of Antiepileptic Drugs. New York: Raven Press; 1982. Google Scholar1. SCHMIDTSELDON OL. Adverse Effects of Antiepileptic Drugs. New York: Raven Press; 1982. Google Scholar2. RIKERDOWNESOLSONSMITH WHGB. Conjugate lateral gaze nystagmus and free phenytoin levels in plasma: lack of correlation. Epilepsia. 1978; 19:93-5. CrossrefMedlineGoogle Scholar3. TROUPIN A. The measurement of anticonvulsant agent levels. Ann Intern Med. 1984;100:854-8. LinkGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Brotman Medical Center Culver City, CA 90230 PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byAn update on CYP2C9 polymorphisms and phenytoin metabolism: implications for adverse effectsPhenytoin intoxication in critically ill patientsCharcoal hemoperfusion in the treatment of phenytoin overdose 1 October 1984Volume 101, Issue 4Page: 568-568KeywordsAnticonvulsantsAttentionBlood plasmaEpilepsyEpileptic seizuresResearch laboratoriesToxicity ePublished: 1 December 2008 Issue Published: 1 October 1984 PDF downloadLoading ...
Corporate Physicians: Between Medicine and Management
Authors: Jerzy Gajewski
Journal: JAMA (1988)

As a result of the deteriorating climate of private practice, salaried positions—often dreaded in the past—are now attracting quite a number of physicians. At the same time many corporations, recognizing the need for medical services (more than their value), are offering alternative opportunities to practice some of the skills acquired through medical training. Diana Chapman Walsh, professor of behavioral sciences at the Boston University School of Public Health, undertook an ambitious project to analyze problems faced by physicians employed primarily by various industries. Her methodology included 127 separate interviews carried out between 1978 and 1982, as well as a special symposium in 1980 devoted to the subject of the corporate medical department. This was followed by an in-depth analysis of five selected corporations, resulting, as a final product, in an impressive 267-page scholarly dissertation. The author reviews in detail historical background leading to a contemporary form of "occupational medicine" and
Re: Emilio Bria, Enzo Maria Ruggeri, Edmondo Terzoli, Francesco Cognetti, Camillo Francesco Pollera and Diana Giannarelli. Adjuvant Chemotherapy for Bladder Cancer: The Chance for Meta-analyses Comparison. Eur Urol 2007;51:576-7
Authors: Claire Vale, Lesley Stewart, Jayne Tierney
Journal: European Urology (2006)
GSK1120212 (JTP-74057) Is an Inhibitor of MEK Activity and Activation with Favorable Pharmacokinetic Properties for Sustained <i>In Vivo</i> Pathway Inhibition
Authors: Aidan G. Gilmartin, Maureen R. Bleam, Arthur Groy, Katherine G. Moss, Elisabeth A. Minthorn, Swarupa G. Kulkarni, Cynthia M. Rominger, Symon Erskine, Kelly E. Fisher, Jingsong Yang, Francesca Zappacosta, Roland Annan, David Sutton, Sylvie G. Laquerre
Journal: Clinical Cancer Research (2011)

Despite their preclinical promise, previous MEK inhibitors have shown little benefit for patients. This likely reflects the narrow therapeutic window for MEK inhibitors due to the essential role of the P42/44 MAPK pathway in many nontumor tissues. GSK1120212 is a potent and selective allosteric inhibitor of the MEK1 and MEK2 (MEK1/2) enzymes with promising antitumor activity in a phase I clinical trial (ASCO 2010). Our studies characterize GSK1120212' enzymatic, cellular, and in vivo activities, describing its unusually long circulating half-life.Enzymatic studies were conducted to determine GSK1120212 inhibition of recombinant MEK, following or preceding RAF kinase activation. Cellular studies examined GSK1120212 inhibition of ERK1 and 2 phosphorylation (p-ERK1/2) as well as MEK1/2 phosphorylation and activation. Further studies explored the sensitivity of cancer cell lines, and drug pharmacokinetics and efficacy in multiple tumor xenograft models.In enzymatic and cellular studies, GSK1120212 inhibits MEK1/2 kinase activity and prevents Raf-dependent MEK phosphorylation (S217 for MEK1), producing prolonged p-ERK1/2 inhibition. Potent cell growth inhibition was evident in most tumor lines with mutant BRAF or Ras. In xenografted tumor models, GSK1120212 orally dosed once daily had a long circulating half-life and sustained suppression of p-ERK1/2 for more than 24 hours; GSK1120212 also reduced tumor Ki67, increased p27(Kip1/CDKN1B), and caused tumor growth inhibition in multiple tumor models. The largest antitumor effect was among tumors harboring mutant BRAF or Ras.GSK1120212 combines high potency, selectivity, and long circulating half-life, offering promise for successfully targeting the narrow therapeutic window anticipated for clinical MEK inhibitors.
Integrin-associated protein (CD47): an unusual activator of G protein signaling
Authors: Eric Brown
Journal: Journal of Clinical Investigation (2001)

Integrin-associated protein (IAP), also known as CD47, was first discovered as a protein physically and functionally associated with the integrin αvβ3 but now is known to associate with additional integrins, such as α2β1 and αIIbβ3, and also to have ligands of its own. This very unusual member of the immunoglobulin (Ig) superfamily includes a single Ig domain, followed by a very hydrophobic region that spans the membrane five times, and a short cytoplasmic tail that demonstrates tissue-specific expression of four alternatively spliced isoforms. IAP binds both the large plasma and ECM glycoprotein thrombospondin (TSP) and a cell-based ligand, SIRPα, independent of its association with integrins. Ligation of the integrin/IAP complex on a variety of cells can induce adhesion, chemotaxis, spreading, secretion, and other sequelae of cell activation.

The work by Brittain et al., reported in this issue of the JCI (1), suggests that IAP-mediated activation may extend to circulating reticulocytes, cells not normally thought to respond to environmental cues by changing adhesive behavior. IAP may therefore play an important role in sickle-cell disease, in which large numbers of reticulocytes circulate and can adhere within small blood vessels. This work not only has implications for the pathophysiology and treatment of sickle cell anemia, but also raises important questions about the mechanisms of IAP signal transduction.

The IAP/integrin complex initiates signaling by an unusual mechanism. Ligand engagement of the integrin/IAP complex can activate heterotrimeric G protein signal transduction (2). To date, the only Gα subunit identified that is associated with this membrane complex is Gαi, and indeed, most of the identified functions of the complex are sensitive to pertussis toxin, which targets this subunit.
Anti-idiotypic antibodies against a human multiple organ-reactive autoantibody. Detection of idiotopes in normal individuals and patients with autoimmune diseases.
Authors: K Essani, J Satoh, B S Prabhakar, P R McClintock, A L Notkins
Journal: Journal of Clinical Investigation (1985)

We have recently isolated and characterized a human monoclonal autoantibody, MOR-h1 (multiple organ-reactive human 1), that reacts with antigens in multiple organs and have shown that this antibody binds to human growth hormone and a 35,000-mol wt protein. In the present study we generated three monoclonal anti-idiotypic antibodies (4E6, 3E5, and 3F6) against MOR-h1. These anti-idiotypic antibodies specifically reacted with MOR-h1 and not with 26 other multiple organ-reactive monoclonal IgM autoantibodies nor with pooled human IgM (myeloma proteins). The binding of the anti-idiotypic antibodies to MOR-h1 was inhibited by both human growth hormone and the 35,000-mol wt protein, which strongly suggests that these antibodies react with epitopes at or near the paratope on MOR-h1. The results of competitive binding experiments revealed that the epitope recognized by 4E6 is distinct from that recognized by 3E5 and 3F6. Using these anti-idiotypic antibodies, lymphocytes and sera from normal individuals were tested for the presence of the 4E6 and 3E5/3F6 idiotopes. By indirect immunofluorescence, the 4E6 idiotope was detected on an average of 1.1% of normal circulating B lymphocytes, and by enzyme-linked immunosorbent assays, the 4E6 and to a lesser extent the 3E5/3F6 idiotopes were found on IgG molecules in sera of normal individuals. In spite of the expression of idiotopes known to be present on MOR-h1, no MOR-h1-like antibody activity was detected in normal sera. Examination of sera from patients with several autoimmune diseases failed to show an increased expression of the 4E6 idiotope as compared with normal controls. These data suggest that anti-idiotypic antibody 4E6 recognizes a public idiotope, the expression of which is not restricted to autoimmune disease.
COMPARISON OF AMPLATZER® PFO VERSUS CARDIOSEAL/STARFLEX® VERSUS GORE HELEX DEVICES IN CLOSURE OF PATENT FORAMEN OVALE: A SINGLE-CENTER EXPERIENCE
Authors: Babak Haddadian, Alix J. Tercius, Naoyo Mori, Louie Kostopoulos, Satish Velagapudi, Kambiz Shetabi, Krishna Nagendran, Hani Hashim, Abdelazim Hashim, Andleeb Bangash, Anjan Gupta, Suhail Allaqaband, Tanvir Bajwa
Journal: Journal of the American College of Cardiology (2010)
Hepatic Metastases: Computed Tomography Versus Magnetic Resonance Imaging in 1997
Authors: M. R. Paley, P. R. Ros
Journal: Endoscopy (1997)

The developments in computed tomography (CT) and magnetic resonance (MR) imaging that have taken place over the last two decades have dramatically increased our ability to detect and characterize focal liver lesions, and have led to the liver becoming the primary focus of interest in abdominal imaging. At the same time, advances in the medical and surgical treatment of secondary liver tumors have continued to be a challenge to these advances in radiology. It is clear that a successful outcome depends on knowledge of the size and location of the tumor burden, and accurate radiological assessment is crucial in identifying the subgroups of patients who may benefit from surgery and, at the same time, in preventing unnecessary radical surgery, with its high morbidity, in those likely to gain only a short-term benefit. The current period of limited resources, along with increased awareness of the effects of ionizing radiation, has led to competition between the two modalities, with considerable debate as to which offers the better noninvasive examination of the liver, particularly with regard to the detection and characterization of focal liver lesions. Arguments over each method's relative merits have tended to be overstated, but the parallel use of different diagnostic techniques is costly and inefficient. Each needs to be placed in an appropriate position on diagnostic pathways.
Locally Propagated Activation Immediately After Internal Defibrillation
Authors: Nipon Chattipakorn, Bruce H. KenKnight, Jack M. Rogers, Robert G. Walker, Gregory P. Walcott, Dennis L. Rollins, William M. Smith, Raymond E. Ideker
Journal: Circulation (1998)

Background —Electrical mapping studies indicate an interval of 40 to 100 ms between a defibrillation shock and the earliest activation that propagates globally over the ventricles (globally propagated activation, GPA). This study determined whether activation occurs during this interval but propagates only locally before being blocked (locally propagated activation, LPA). Methods and Results —In five anesthetized pigs, the heart was exposed and a 504-electrode sock with 4-mm interelectrode spacing was pulled over the ventricles. Ten biphasic shocks of a strength near the defibrillation threshold (DFT) were delivered via intracardiac catheter electrodes, and epicardial activation sequences were mapped before and after attempted defibrillation. Local activation was defined as dV/dt ≤−0.5 V/s. Postshock activation times and wave-front interaction patterns were determined with an animated display of dV/dt at each electrode in a computer representation of the ventricular epicardium. LPAs were observed after 40 of the 50 shocks. A total of 173 LPA regions were observed, each of which involved 2±2 (mean±SD) electrodes. LPAs were observed after both successful and failed shocks but occurred earlier ( P &lt;.0001) after failed (35±8 ms) than successful (41±16 ms) shocks, although the times at which the GPA appeared were not significantly different. On reaching the LPA region, the GPA front either propagated through it (n=135) or was blocked (n=38). The time from the onset of the LPA until the GPA front propagated to reach the LPA region was shorter ( P &lt;.01) when the GPA front was blocked (32±12 ms) than when it propagated through the LPA region (63±20 ms). Conclusions —LPAs exist after successful and failed shocks near the DFT. Thus, the time from the shock to the GPA is not totally electrically silent.
Characterization of Anti-Heart Mitochondria Autoantibodies Produced in Dogs following Myocardial Infarction
Authors: ROBERT E. KELLEY, MERLE S. OLSON, R. NEAL PINCKARD
Journal: Circulation Research (1974)

A complement-fixing, heart-reactive serum component that develops in dogs following experimental myocardial infarction was characterized with respect to its immunoglobulin nature and its subcellular membrane and organ specificities. The immunoglobulin nature of the heart-reactive serum factor was established by the following evidence: (1) the factor was not removed from the serum following absorption of up to 90% of the first component of dog complement with bovine serum albumin (BSA)-anti-BSA immune precipitates, (2) the serum factor sedimented in the 19S region of sucrose density gradients, and (3) affinity chromatography using a Sepharose column coupled with rabbit anti-dog µ-chain-specific antibody resulted in the removal of nearly all of the heart-reactive substance. The major subcellular autoantigenic locus of the dog heart was determined to be the outer mitochondrial membrane. Serum containing the autoantibody demonstrated a six-fold greater autoantibody titer when outer mitochondrial membrane was used as the test antigen than it did when inner mitochondrial membrane was used. Absorption experiments suggested that the autoantigenic determinants residing on inner and outer mitochondrial membranes were unique to the individual membranes. Significant cross-reaction of the anti-heart autoantibody between heart and skeletal muscle mitochondria was observed, but no cross-reaction was seen with dog liver mitochondrial membranes.
Dynamic Lymph Flow Imaging in Lymphedema Normal and Abnormal Patterns
Authors: K NAWAZ, M M HAMAD, S SADEK, M AWDEH, B EKLOF, H M ABDEL-DAYEM
Journal: Clinical Nuclear Medicine (1986)

Dynamic imaging of lymphatic flow was performed in 23 patients complaining of lymphedema of the lower extremities. All were injected intradermally with 1 mCi of Tc-99m human serum albumin (HSA) in the medial web on the dorsum of both feet. Image acquisition for the lower pelvis and both thighs was started within 5 minutes. An extra-large field-of-view gamma camera (General Electric 500A) with a low-energy, all-purpose collimator interfaced to a General Electric Star computer was used. Images were acquired in dynamic-byte mode, 128 X 128 matrix size, every one minute up to 40 minutes. Delayed images for the same region and for both legs were taken at 90 minutes. Time-activity curves from equal regions of interest over the inguinal regions on both sides were generated. Three patterns were recognized. Normal flow (12 patients) with symmetric or slightly increased or decreased flow on one side than the other and characterized by early appearance of medial bands, inguinal and pelvic lymph nodes in the early and the delayed images. Time-activity curves showed a stepladder rise in pulses every 3 to 4 minutes. Enhanced pattern (six patients), characterized by fast flow of lymph through the dilated lymphatics, and occasionally by subcutaneous pooling and increase in the number and size of inguinal and pelvic lymph nodes on the affected side.(ABSTRACT TRUNCATED AT 250 WORDS)
Meeting Report: Structural Determination of Environmentally Responsive Proteins
Authors: Leslie Reinlib
Journal: Environmental Health Perspectives (2005)

The three-dimensional structure of gene products continues to be a missing lynchpin between linear genome sequences and our understanding of the normal and abnormal function of proteins and pathways. Enhanced activity in this area is likely to lead to better understanding of how discrete changes in molecular patterns and conformation underlie functional changes in protein complexes and, with it, sensitivity of an individual to an exposure. The National Institute of Environmental Health Sciences convened a workshop of experts in structural determination and environmental health to solicit advice for future research in structural resolution relative to environmentally responsive proteins and pathways. The highest priorities recommended by the workshop were to support studies of structure, analysis, control, and design of conformational and functional states at molecular resolution for environmentally responsive molecules and complexes; promote understanding of dynamics, kinetics, and ligand responses; investigate the mechanisms and steps in posttranslational modifications, protein partnering, impact of genetic polymorphisms on structure/function, and ligand interactions; and encourage integrated experimental and computational approaches. The workshop participants also saw value in improving the throughput and purity of protein samples and macromolecular assemblies; developing optimal processes for design, production, and assembly of macromolecular complexes; encouraging studies on protein-protein and macromolecular interactions; and examining assemblies of individual proteins and their functions in pathways of interest for environmental health.
Effect of Ba 679 BR, a novel long-acting anticholinergic agent, on cholinergic neurotransmission in guinea pig and human airways.
Authors: T Takahashi, M G Belvisi, H Patel, J K Ward, S Tadjkarimi, M H Yacoub, P J Barnes
Journal: American Journal of Respiratory and Critical Care Medicine (1994)

We investigated the effect of Ba 679 BR, a novel long-acting antimuscarinic agent, on cholinergic neural responses in guinea pig and human airways. Ba 679 BR, atropine, and ipratropium bromide inhibited electrical field stimulation (EFS)-induced contraction with IC50 values of 0.17, 0.74, and 0.58 nM, respectively, in guinea pig trachea. Ba 679 BR had a slower onset and longer duration of action than atropine or ipratropium bromide (the times required to attain 50% of the maximum response were 34.8, 3.8, and 7.6 min, respectively, and the times required for 50% recovery of the response were 540, 31.6, and 81.2 min, respectively). Ba 679 BR, as well as atropine and ipratropium bromide, facilitated evoked [3H]acetylcholine release (an inhibitory effect on prejunctional muscarinic M2 receptors). The facilitation of acetylcholine release by Ba 679 BR was lost 2 h after washout, however, when there was still complete blockade of cholinergic contractile responses evoked by EFS (an effect on airway smooth muscle M3 receptors), confirming binding studies that suggest that Ba 679 BR shows "kinetic receptor subtype selectivity" for M3 over M2 receptors. The high potency, slow onset, and long duration of action of Ba 679 BR were also observed in human bronchi, suggesting that Ba 679 BR may be a useful drug to provide convenient therapy for patients with obstructive airway disease.