tbuckley/cabot-search huggingface dataset:
The FDA's assessment of follow-on protein products: a historical perspective
Authors: Janet Woodcock, Joseph Griffin, Rachel Behrman, Barry Cherney, Terrie Crescenzi, Blair Fraser, Dena Hixon, Christopher Joneckis, Steven Kozlowski, Amy Rosenberg, Lewis Schrager, Emily Shacter, Robert Temple, Keith Webber, Helen Winkle
Journal: Nature Reviews Drug Discovery (2007)
Inhibition of Rho-kinase protects the heart against ischemia/reperfusion injury
Authors: W Bao
Journal: Cardiovascular Research (2004)

To investigate the role of Rho A and Rho-kinase in acute myocardial ischemia/reperfusion injury and the protective effect of Rho-kinase inhibitor, Y-27632 [(R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)cyclohexanecarboxamide].Male CD1 mice were subjected to 30 min of coronary occlusion and 24 h reperfusion. Ischemia/reperfusion upregulated expression of Rho A in ischemic myocardium, and subsequently activated Rho-kinase. Y-27632 significantly inhibited the activation of Rho-kinase following ischemia/reperfusion. Treatment with Y-27632 at 10 and 30 mg/kg oral administration, reduced infarct size by 30.2% and 41.1%, respectively (P<0.01 vs. vehicle). Y-27632 also enhanced post-ischemia cardiac function. Left ventricular systolic pressure, +dP/dt and -dP/dt were significantly improved by 23.5%, 52.3%, and 59.4%, respectively (P<0.01 vs. vehicle). Moreover, Y-27632 reduced ischemia/reperfusion-induced myocardial apoptosis. The apoptotic myocytes in ischemic myocardium after 4 h reperfusion were reduced from 13.1% in vehicle group to 6.4% in Y-27632-treated group (P<0.01). Meanwhile, ischemia/reperfusion-induced downregulation of Bcl-2 in myocardium was remarkably attenuated in the treated animals. Ischemia/reperfusion resulted in remarkable elevation in serum levels of proinflammatory cytokines, interleukin-6 (IL-6), keratinocyte chemoattractant (KC) and granulocyte colony-stimulating factor (G-CSF), which was significantly suppressed by Y-27632. In addition, Y-27632 decreased ischemia/reperfusion-induced accumulation of neutrophils in the heart by 45% (P<0.01).These results suggest that Rho-kinase plays a pivotal role in myocardial ischemia/reperfusion injury. The cardiac protection provided by treatment with a selective Rho-kinase inhibitor is likely via anti-apoptotic effect and attenuation of ischemia/reperfusion-induced inflammatory responses. The finding of this study suggest a novel therapeutic approach to the treatment of acute myocardial ischemia/reperfusion injury.
The Kynurenine Pathway in Brain Tumor Pathogenesis
Authors: Seray Adams, Nady Braidy, Alban Bessesde, Bruce J. Brew, Ross Grant, Charlie Teo, Gilles J. Guillemin
Journal: Cancer Research (2012)

Abstract Brain tumors are among the most common and most chemoresistant tumors. Despite treatment with aggressive treatment strategies, the prognosis for patients harboring malignant gliomas remains dismal. The kynurenine pathway (KP) is the principal route of l-tryptophan catabolism leading to the formation of the essential pyridine nucleotide, nicotinamide adenine dinucleotide (NAD+), and important neuroactive metabolites, including the neurotoxin, quinolinic acid (QUIN), the neuroprotective agent, picolinic acid (PIC), the TH17/Treg balance modulator, 3-hydroxyanthranilic acid (3-HAA), and the immunosuppressive agent, l-Kynurenine (KYN). This review provides a new perspective on KP dysregulation in defeating antitumor immune responses, specifically bringing light to the lower segment of the KP, particularly QUIN-induced neurotoxicity and downregulation of the enzyme α-amino-β-carboxymuconate-ϵ-semialdehyde decarboxylase (ACMSD) as a potential mechanism of tumor progression. Given its immunosuppressive effects, 3-HAA produced from the KP may also play a role in suppressing antitumor immunity in human tumors. The enzyme indoleamine 2, 3-dioxygenase (IDO-1) initiates and regulates the first step of the KP in most cells. Mounting evidence directly implicates that the induction and overexpression of IDO-1 in various tumors is a crucial mechanism facilitating tumor immune evasion and persistence. Tryptophan 2, 3-dioxygenase (TDO-2), which initiates the same first step of the KP as IDO-1, has likewise recently been shown to be a mechanism of tumoral immune resistance. Further, it was also recently shown that TDO-2–dependent production of KYN by brain tumors might be a novel mechanism for suppressing antitumor immunity and supporting tumor growth through the activation of the Aryl hydrocarbon receptor (AhR). This newly identified TDO-2-KYN-AhR signaling pathway opens up exciting future research opportunities and may represent a novel therapeutic target in cancer therapy. Our discussion points to a number of KP components, namely TDO-2, IDO-1, and ACMSD, as important therapeutic targets for the treatment of brain cancer. Targeting the KP in brain tumors may represent a viable strategy likely to prevent QUIN-induced neurotoxicity and KYN and 3-HAA–mediated immune suppression. Cancer Res; 72(22); 5649–57. ©2012 AACR.
The Management of a Blood Bank at the Massachusetts Memorial Hospitals
Authors: Frank E. Barton
Journal: New England Journal of Medicine (1941)

AT a recent clinical meeting of the Boston Surgical Society, considerable interest was shown in the technical management of the blood bank at the Massachusetts Memorial Hospitals. The questions and discussions arising in that demonstration prompted the writing of this paper. No attempt is made to review the history of this subject. A recent survey of the literature on blood banks, with an excellent bibliography, is presented by Douglass.1 There are very few active blood banks in New England. The reason for this may be the fallacy that the management of a bank requires the services of several full-time technicians, as well as the expenditure of large sums of money. I shall endeavor to prove that this idea is wrong. A blood bank must have concrete reasons for its existence and demonstrable evidence of its value. The experience of the Massachusetts Memorial Hospitals is that a blood bank provides immediate availability of blood of various types, a safe blood from the standpoint of the transmission of syphilis, an economical blood (the cost of our transfusions has been materially reduced), a
VEGFR2 (KDR/Flk1) Signaling Mediates Axon Growth in Response to Semaphorin 3E in the Developing Brain
Authors: Anaïs Bellon, Jonathan Luchino, Katharina Haigh, Geneviève Rougon, Jody Haigh, Sophie Chauvet, Fanny Mann
Journal: Neuron (2010)
Kidney Donation and the Law
Authors: P. H. Addison
Journal: BMJ (1973)

<h3>Objectives</h3> Nigrostriatal dopaminergic denervation (NSDD) remains poorly characterized in cerebellar multiple system atrophy (MSA-C). We aimed to study NSDD progression in MSA-C and evaluate the capacity for [123I]-FP-CIT-SPECT and parkinsonism to differentiate MSA-C from idiopathic late-onset cerebellar ataxia (ILOCA). <h3>Methods</h3> We included 85 patients successively referred for sporadic late-onset cerebellar ataxia (SLOCA). Every 6 months, SARA, UPDRS-III, and SDFS scores were measured, and MSA-C diagnostic criteria were searched for. Striatal/occipital dopaminergic binding ratio was evaluated every year with [123I]-FP-CIT-scintigraphy. <h3>Results</h3> After a mean follow-up of 33.8 months, 33 patients had probable MSA-C, 8 possible MSA-C, and 44 ILOCA. SARA and UPDRS-III scores worsened faster in the probable MSA-C group (<i>p</i> &lt; 0.01) compared with the ILOCA group. The baseline striatal/occipital ratio was lower (2.3 vs 2.97; <i>p</i> &lt; 0.01) and more decreasing among patients with probable MSA-C (<i>p</i> &lt; 0.01). Weighting dysautonomia and parkinsonism and/or NSDD as additional and principal criterion, respectively, in the possible MSA-C diagnostic criteria slightly improved their specificity (81.6% vs 76.9%) and sensitivity (77.8% vs 72.2%) to predict a final diagnosis of probable MSA-C. <h3>Discussion</h3> Rapid symptom worsening and NSDD existence and progression predict MSA-C among patients with SLOCA. Parkinsonism, NSDD, and dysautonomia should be considered equivalent for possible MSA-C diagnosis.
Failing to Detect Occult Blood
Authors: DAVID M. HOVSEPIAN
Journal: Annals of Internal Medicine (1986)

Letters and Corrections1 September 1986Failing to Detect Occult BloodDAVID M. HOVSEPIAN, M.D., MARK E. LINSKEY, M.D., RICHARD FEDORAK, M.D.DAVID M. HOVSEPIAN, M.D.Search for more papers by this author, MARK E. LINSKEY, M.D.Search for more papers by this author, RICHARD FEDORAK, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-105-3-471_1 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the editor: In the June 1981Annals, Layne and associates (1) showed the insensitivity of guaiac slide tests for detecting blood in gastric juice. Subsequent investigators have confirmed the increased rate of false-negative results with Hemoccult II (Smith Kline Diagnostics, Sunnyvale, California) when the pH of the test specimen is below 4 (2-4). Buffering gastric juice with antacid (1), sodium hydroxide (2), or phosphate buffer (3) before its application on the Hemoccult II slide will improve sensitivity, but this is often impractical at the bedside. In 1983, Gastroccult (Smith Kline Diagnostics) was introduced as a guaiac-based slide test specifically...References1. LAYNEMELLOWLIPMAN EMT. Insensitivity of guaiac slide tests for detection of blood in gastric juice. Ann Intern Med. 1981;94:774-6. LinkGoogle Scholar2. ROSENTHALTHOMPSONSINGH PJM. Detection of occult blood in gastric juice. J Clin Gastroenterol. 1984;6:119-24. CrossrefMedlineGoogle Scholar3. STARLINGERSPORNSCHEMPERSCHIESSEL MPMR. The use of the Haemoccult test for detection of blood in gastric aspirates. Scand J Gastroenterol. 1983;18:723-7. CrossrefMedlineGoogle Scholar4. HAUSERQUIGLEYDRIEVER AMC. In vitro effect of cimetidine concentration and pH on guaiac-slide tests. Am J Hosp Pharm. 1983;40:626-9. MedlineGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: College of Physicians and Surgeons of Columbia University New York, NY 10032 PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 September 1986Volume 105, Issue 3Page: 471-471KeywordsDiagnostic techniquesGastroenterology and hepatologyHematologic testsPhosphatesSodium ePublished: 1 December 2008 Issue Published: 1 September 1986 PDF downloadLoading ...
Male Fertility in Hot Environment-Reply
Authors: Marcus B. Bond
Journal: JAMA (1984)

<h3>In Reply.—</h3> The comments of Dr Levine are appreciated and merit serious consideration in view of his careful research and many publications on the subject of environmental influences on human reproductive functions. There is no disagreement that hyperthermia causes a dose-related adverse effect on spermatogenesis in man. With modest, brief heat applications, ie, enough to cause a half-hour rise in testicular temperatures of 3 to 5 °C repeatedly, there is a decrease in sperm counts after two to three weeks that persists for several weeks. This is followed in about three months by a rebound to sperm count levels considerably above the pre—heat treatment levels.<sup>1,2</sup>The work of Rock and Robinson referred to by Dr Levine was research into possible therapy for oligospermic men. This group also used a specially constructed insulated and snug-fitting scrotal sac "worn almost constantly" for several weeks and achieved a decrease in the scrotal-rectal
Abdominal aortic aneurysm events in the women's health initiative: cohort study
Authors: F. A Lederle, J. C Larson, K. L Margolis, M. A Allison, M. S Freiberg, B. B Cochrane, W. F Graettinger, J D. Curb
Journal: BMJ (2008)

<b>Objective</b> To assess the association between potential risk factors and subsequent clinically important abdominal aortic aneurysm events (repairs and ruptures) in women. <b>Design</b> Large prospective observational cohort study with mean follow-up of 7.8 years. <b>Setting</b> 40 clinical centres across the United States. <b>Participants</b> 161 808 postmenopausal women aged 50-79 enrolled in the women's health initiative. <b>Main outcome measures</b> Association of self reported or measured baseline variables with confirmed abdominal aortic aneurysm events assessed with multiple logistic regression. <b>Results</b> Events occurred in 184 women and were strongly associated with age and smoking. Ever smoking, current smoking, and amount smoked all contributed independent risk. Diabetes showed a negative association (odds ratio 0.29, 95% confidence interval 0.13, 0.68), as did postmenopausal hormone therapy. Positive associations were also seen for height, hypertension, cholesterol lowering treatment, and coronary and peripheral artery disease. <b>Conclusions</b> Our findings confirm the strong positive associations of clinically important abdominal aortic aneurysm with age and smoking in women and the negative association with diabetes previously reported in men.
Graham Douglas McLean
Authors: Alan Fraser
Journal: BMJ (2005)

Former general practitioner Aberdeen (b Leicester 1938; q Aberdeen 1963), died from myelomatosis and amyloidosis on 25 November 2004.​2004.




Figure 1




After four years in dermatology Graham joined what is now the Garthdee Medical Practice in Aberdeen in 1968 and remained there until retirement in 1996. Graham was strongly principled and was mentor to many young GPs as a trainer. After retirement Graham and his wife, Margaret, led active lives. They travelled widely and grew proficient in French, Spanish, and Italian. Graham became a keen artist, especially of the human figure. He enjoyed yoga until he became ill. Graham's greatest love was ornithology and he pursued this enthusiastically abroad and near his country home in Fochabers. He leaves Margaret and a son.
Largest-Ever Outbreak of Ebola Virus Disease Thrusts Experimental Therapies, Vaccines Into Spotlight
Authors: Tracy Hampton
Journal: JAMA (2014)

Asefforts to successfully contain the largest outbreak of Ebola virus disease in history prove elusive, the mounting number of cases and deaths has brought research to developmuch-needed treatments andprotectivevaccines into the spotlight.Although theapprovalprocess for drugs and vaccines is typically slow and deliberate, the latestoutbreak,declaredby the World Health Organization (WHO) on August 8 as an international health emergency, has galvanized regulatoryofficials to consider proposals for providing as-yet unproven treatments under special emergency NewDrug Applications. “No one wants to see potentially unsafe drugs causing more harm than good. Buton theotherhand, givenavirus that can cause up to 90% case-fatality rates, we all want to see something done to help,” said Thomas Geisbert, PhD, of the University of TexasMedical BranchatGalveston. This latest outbreakappears tohavea55%to60% fatality rate.
BILATERAL TUBAL PREGNANCY.
Authors: HARRY GREENBERG
Journal: JAMA (1907)

<h3>History.</h3> —Mrs. M. B., aged 29, married 6 years, has one child 3 years old, no miscarriages, menses always regular and normal. The last menstruation occurred as usual after 28 days, but was accompanied by considerable pain, which necessitated her taking to bed. A piece of membrane was passed on the third day, after which the pain and flow ceased. The physician consulted diagnosed miscarriage and advised removal to a hospital for curettement. I saw her for the first time on the following day at the hospital. <h3>Examination.</h3> —Patient a medium-sized woman, poorly nourished, very anemic, mucous membranes almost white and skin of a dirty sallow color. She said she was always pale. She complained of feeling weak, loss of appetite, restlessness and sleeplessness. No pain. Temperature 101.8 F., pulse 100. Thoracic and abdominal organs negative. Uterus slightly enlarged and somewhat tender at the fundus. Uterine adnexa somewhat thickened. A
Novel N-(pyrimidin-4-yl)thiazol-2-amine derivatives as dual-action hypoglycemic agents that activate GK and PPARγ
Authors: Hui-peng Song, Kang Tian, Lei Lei, Zhu-fang Shen, Shou-xin Liu, Li-juan Zhang, Hong-rui Song, Xiao-feng Jin, Zhi-qiang Feng
Journal: Acta Pharmaceutica Sinica B (2011)

A series of novel N-(pyrimidin-4-yl)thiazol-2-amine derivatives have been synthesized and evaluated as glucokinase (GK) activators. Ethyl 2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl-amino)thiazole-5-carboxylate was found to be a potent dual-acting hypoglycemic agent activating both GK and PPARγ. When given orally to normal mice, the compound demonstrated significant efficacy in decreasing the glucose level after oral glucose loading.
β <sub>2</sub> -Adrenergic cAMP Signaling Is Uncoupled From Phosphorylation of Cytoplasmic Proteins in Canine Heart
Authors: Meike Kuschel, Ying-Ying Zhou, Harold A. Spurgeon, Sabine Bartel, Peter Karczewski, Sheng-Jun Zhang, Ernst-Georg Krause, Edward G. Lakatta, Rui-Ping Xiao
Journal: Circulation (1999)

Background —Recent studies of β-adrenergic receptor (β-AR) subtype signaling in in vitro preparations have raised doubts as to whether the cAMP/protein kinase A (PKA) signaling is activated in the same manner in response to β 2 -AR versus β 1 -AR stimulation. Methods and Results —The present study compared, in the intact dog, the magnitude and characteristics of chronotropic, inotropic, and lusitropic effects of cAMP accumulation, PKA activation, and PKA-dependent phosphorylation of key effector proteins in response to β-AR subtype stimulation. In addition, many of these parameters and L-type Ca 2+ current ( I Ca ) were also measured in single canine ventricular myocytes. The results indicate that although the cAMP/PKA-dependent phosphorylation cascade activated by β 1 -AR stimulation could explain the resultant modulation of cardiac function, substantial β 2 -AR–mediated chronotropic, inotropic, and lusitropic responses occurred in the absence of PKA activation and phosphorylation of nonsarcolemmal proteins, including phospholamban, troponin I, C protein, and glycogen phosphorylase kinase. However, in single canine myocytes, we found that β 2 -AR–stimulated increases in both I Ca and contraction were abolished by PKA inhibition. Thus, the β 2 -AR–directed cAMP/PKA signaling modulates sarcolemmal L-type Ca 2+ channels but does not regulate PKA-dependent phosphorylation of cytoplasmic proteins. Conclusions —These results indicate that the dissociation of β 2 -AR signaling from cAMP regulatory systems is only apparent and that β 2 -AR–stimulated cAMP/PKA signaling is uncoupled from phosphorylation of nonsarcolemmal regulatory proteins involved in excitation-contraction coupling.
OBSERVATIONS CONCERNING THE PRODUCTION AND EXCRETION OF CHOLESTEROL IN MAMMALS
Authors: Meyer Friedman, Sanford O. Byers, Eichi Shibata
Journal: The Journal of Experimental Medicine (1953)

The absorption of oral cholesterol by rats was followed directly by analyses of the thoracic lymph and indirectly by calculating the deficit of fecal cholesterol under the amount fed. The two methods checked within about 20 per cent, with fecal analyses indicating the greater absorption. The absorbed cholesterol was found to be deposited in the liver, only very minor quantities being found in other organs or plasma. Bile is necessary for normal absorption of cholesterol, although very small amounts are absorbed even in its absence. Excess oral cholic acid increases the absorption of cholesterol by otherwise normal animals. The rat absorbs about 47 per cent of a single 50 mg. dose of cholesterol and about 34 per cent of a 100 mg. dose.
Gastrointestinal involvement in systemic mastocytosis.
Authors: R W Ammann, D Vetter, P Deyhle, H Tschen, H Sulser, M Schmid
Journal: Gut (1976)

Four consecutive patients with systemic mastocytosis were studied. One patient had a malabsorption syndrome with only minor histological changes of the intestinal mucosa. Another patient with ulcer diathesis had a gastric secretory pattern resembling Zollinger-Ellison syndrome. Serum gastrin and histamine levels were consistently normal in all patients. Endoscopy of stomach and colon disclosed urticaria-like papulae either spontaneously or after topical provocation in all patients. No increase of mast cells was found in multiple mucosal biopsies. A markedly increased gastric tissue content of histamine was found, however, in the three patients studied. The findings suggest that urticaria-like lesions associated with a high tissue content of histamine may be more important that hyperhistaminaemia in causing the various gastrointestinal symptoms.
TEMPORAL TRENDS IN THE MANAGEMENT OF SEVERE HYPERGLYCEMIA AMONG PATIENTS HOSPITALIZED WITH ACUTE MYOCARDIAL INFARCTION
Authors: Lakshmi VENKITACHALAM, Kensey Riley, Kasia Lipska, Silvio E. Inzucchi, Abhinav Goyal, John A. Spertus, Frederick A. Masoudi, Philip G. Jones, Mikhail Kosiborod
Journal: Journal of the American College of Cardiology (2010)
An Acute Infection of the Respiratory Tract With Atypical Pneumonia
Authors: Hobart A. Reimann
Journal: JAMA (1984)

Infections of the respiratory tract are among the most common afflictions of mankind, and pneumonia, which occasionally accompanies or follows them, is the third most common cause of death in the United States. Any progress made in the knowledge of such infections is therefore urgently needed. Only recently has the physician been armed with comparatively simple methods for the diagnosis of one of these diseases, epidemic influenza, which is now known to be caused by a filtrable virus. Methods for isolating and identifying the virus of the common cold are still too complicated for the average clinical laboratory in routine diagnosis. The discovery of the causative agent of influenza permits separation of the disease as an entity from the undifferentiated group of infections of the respiratory tract and provides a standard, so to speak, against which other entities may be compared. The discovery also confirmed a long established impression gained
Assessment of Coronary Plaque Progression in Coronary Computed Tomography Angiography Using a Semiquantitative Score
Authors: Sam J. Lehman, Christopher L. Schlett, Fabian Bamberg, Hang Lee, Patrick Donnelly, Leon Shturman, Matthias F. Kriegel, Thomas J. Brady, Udo Hoffmann
Journal: JACC. Cardiovascular imaging (2009)