tbuckley/cabot-search huggingface dataset:
Evaluating drug treatments for Parkinson's disease: how good are the trials?
Authors: K. Wheatley
Journal: BMJ (2002)

Keith Wheatley and colleagues make the case that most trials of drug treatment for Parkinson's disease have crucial methodological faults—and provide little reliable evidence on differences between classes of drugs

Parkinson's disease is one of the commonest causes of disability in older people, with over 100 000 patients in the United Kingdom and at least 8000 new cases diagnosed annually. Prevalence and incidence will both increase with the ageing population and the reduction in competing causes of mortality such as stroke and coronary heart disease.1 No cure currently exists, and medical treatment is directed towards alleviating symptoms.2 Levodopa relieves symptoms in most patients with Parkinson's disease, but long term use of levodopa is associated with motor complications such as involuntary movements (dyskinesias), along with a shortened response to each dose (wearing-off phenomenon) and unpredictable “on-off” fluctuations. A number of other drugs have been used,3 either alone or with reduced doses of levodopa, in an attempt to delay the onset of motor complications in early Parkinson's disease or to control complications once they have developed. These agents have primarily been from three classes of drug: dopamine agonists, monoamine oxidase type B inhibitors, and catechol- O -methyltransferase inhibitors.

Many randomised controlled trials have evaluated these drugs, but uncertainty about their relative effectiveness remains. This review assesses the methods used in these trials to reveal the quality of the existing evidence base.

#### Summary points

The prevalence of Parkinson's disease will increase as the population ages, making it important to identify reliably the most effective drug therapy

Although many randomised controlled trials have evaluated the efficacy of different classes of drugs in both early and later Parkinson's disease, uncertainty about best treatment remains because of small numbers, inadequate follow up, and inappropriate end points

Much larger trials are needed with long term follow …
A progression-free end-point for idiopathic pulmonary fibrosis trials: lessons from cancer
Authors: Carlo Vancheri, Roland M. du Bois
Journal: European Respiratory Journal (2012)

Idiopathic pulmonary fibrosis (IPF) is a progressive fibroproliferative disease that results in increasing morbidity. To date there is only one licensed therapy for this condition and other agents are needed for this attritional disease. Efforts to study other agents have been obstructed by an increasing division of opinion about the most clinically meaningful end-point of phase III clinical trials to demonstrate efficacy. Many clinicians believe that an agent that impedes progression of the disease is more than acceptable and will encourage the pharmaceutical industry to further develop their IPF programmes. We have been impressed by the behavioural and biological similarities of cancer and IPF, and wondered if lessons could be learned about clinical trial design from lung cancer studies. Here, we set out our arguments that the similarities with cancer justify comparing the magnitude of therapeutic effects in clinical trials in nonsmall cell lung cancer with those in successful trials in IPF. We demonstrate that efficacy is of a similar magnitude in the two chronic lung diseases. We recommend that the demonstration of similar magnitudes of progression-free disease effect in IPF, using appropriate indices, should be considered as clinically meaningful benefit in future phase III clinical trials of novel therapies.
Studies of Acute Coronary Syndromes in Women — Lessons for Everyone
Authors: Laura F. Wexler
Journal: New England Journal of Medicine (1999)

The news that cardiovascular disease is the leading cause of death among women has been so prominently publicized recently that researchers are occasionally asked to explain this apparent epidemic. In fact, cardiovascular disease has been the leading cause of death among women for many decades but is only now being carefully described and studied. Sex bias may account for some of the emphasis that has been placed on heart disease in men, but it seems understandable that the initial surge of interest in coronary artery disease in the 1950s centered on its emergence as a major cause of death and . . .
Treatment of Peripheral Diabetic Neuropathy
Authors: Louis F. Romain
Journal: JAMA (1978)

<h3>To the Editor.—</h3> Davis et al are thanked for their recent BRIEF REPORT on the treatment of peripheral diabetic neuropathy treated with amitriptyline hydrochloride and fluphenazine hydrochloride (238:2291, 1977). It is heartening for those who treat neuritis to see that there is still active thinking regarding an effective treatment. Their article has prompted me to review my experience with the treatment of diabetic neuropathy over the past two years. My files contain some 31 cases treated with combinations of tricyclic antidepressants and neuroleptic agents (antipsychotic agents). My results, using combinations of the tricyclic agents (amitriptyline, imipramine, and doxepin), along with one of the neuroleptic agents (fluphenazine, trifluoperazine, chlorpromazine, thioridazine, haloperidol, or chlorprothixene), has not been so successful. I have tried these agents in varying doses, mainly exceeding those of Davis et al, but without any notable success. I learned about this treatment at a number of meetings, where I found
ACCURACY AND REPRODUCIBILITY OF A NOVEL IN VIVO AUTOMATIC BORDER DETECTION SOFTWARE FOR THE ANALYSIS OF STENT NEOINTIMAL RESPONSE COMPARED TO HISTOLOGY IN A FAMILIAL HYPERCHOLESTEROLEMIC SWINE MODEL
Authors: Armando Tellez, Maxwell E. Afari, Rachel Lovec, Christopher L. Petersen, Yanping Cheng, Krzysztof Milewski, Genghua Yi, Jennifer C. McGregor, Greg L. Kaluza, Juan F. Granada
Journal: Journal of the American College of Cardiology (2011)
ABC of General Surgery in Children: SURGICALLY CORRECTABLE CAUSES OF VOMITING IN INFANCY
Authors: M. Davenport
Journal: BMJ (1996)

Clinical features suggesting a surgically correctable cause of vomiting * Bile stained vomit * Localised or asymmetric tenderness * Abdominal distension First week of life-in the postnatal ward Raaiograpn snowing nasogastric tube curled in upper pouch of oesophageal atresia (arrow) and large isolated stomach bubble caused by an associated duodenal atresia.
THE U.S. GOVERNMENT VERSUS CARCINOGENS
Authors: E. M. Whelan
Journal: CA A Cancer Journal for Clinicians (1978)

Medicine as an art demands constant evaluation, weighing new treatments against old practices, benefits against risks, successesagainst failures.On occasion, the evidence leads to different conclusions.Nowhere is this more evident than in the management of the cancer patient.OPINIONS will present the views of specialists on a wide spectrum of controversial subjects.It is hoped that the frank expression of ideas will provide aframework within which our readers may form their own opinions.
Lentiviral Vectors Displaying Modified Measles Virus gp Overcome Pre-existing Immunity in In Vivo-like Transduction of Human T and B Cells
Authors: Camille Lévy, Fouzia Amirache, Caroline Costa, Cecilia Frecha, Claude P Muller, Hasan Kweder, Robin Buckland, François-Loïc Cosset, Els Verhoeyen
Journal: Molecular Therapy (2012)

Gene transfer into quiescent T and B cells is important for gene therapy and immunotherapy approaches. Previously, we generated lentiviral vectors (LVs) pseudotyped with Edmonston (Ed) measles virus (MV) hemagglutinin (H) and fusion (F) glycoproteins (H/F-LVs), which allowed efficient transduction of quiescent human T and B cells. However, a major obstacle in the use of H/F-LVs in vivo is that most of the human population is vaccinated against measles. As the MV humoral immune response is exclusively directed against the H protein of MV, we mutated the two dominant epitopes in H, Noose, and NE. LVs pseudotyped with these mutant H-glycoproteins escaped inactivation by monoclonal antibodies (mAbs) but were still neutralized by human serum. Consequently, we took advantage of newly emerged MV-D genotypes that were less sensitive to MV vaccination due to a different glycosylation pattern. The mutation responsible was introduced into the H/F-LVs, already mutated for Noose and NE epitopes. We found that these mutant H/F-LVs could efficiently transduce quiescent lymphocytes in the presence of high concentrations of MV antibody-positive human serum. Finally, upon incubation with total blood, mimicking the in vivo situation, the mutant H/F-LVs escaped MV antibody neutralization, where the original H/F-LVs failed. Thus, these novel H/F-LVs offer perspectives for in vivo lymphocyte-based gene therapy and immunotherapy.
Initiation of once-daily pindolol treatment.
Authors: G Frithz
Journal: BMJ (1978)

<h3>Abstract</h3> The position of centrosome, the main microtubule-organizing center (MTOC), is instrumental in the definition of cell polarity. It is defined by the balance of tension and pressure forces in the network of microtubules (MTs). As MTs polymerize against the cell periphery, pressure increases and produces pushing forces on the MTOC. How the mechanical interplay between MTs and the actin network is involved in the regulation of these forces remains poorly understood, in particular because its investigation is technically limited by the structural and biochemical complexity of the cell cytoplasm. Here, in a cell-free assay, we used purified proteins to reconstitute the interaction of an aster of dynamic MTs with actin networks of various compositions and architectures in cell-sized microwells. In the absence of actin filaments, the positioning of the MTOC was highly sensitive to variations in MT length. The presence of a bulk actin filament network limited MTs deformation and displacement, and MTOCs were hold in place. In contrast, the assembly of a dense and branched actin network along the edges of the wells centered the MTOCs by preventing MT slippage and thus maintaining an isotropic balance of pushing forces. In agreement with this, an asymmetric peripheral actin network caused the MTOC to decenter by creating an asymmetry in the pushing forces. Numerical simulations demonstrated that steric hindrance by actin networks, at the tip or along the entire length of MTs, can modulate MTOC positioning, as observed in the experiments. Overall, our results show that actin networks can limit the sensitivity of MTOC positioning to MT length and enforce robust MTOC centering or decentering depending on its architecture.
Further Observations on the Etiology of the Right Bundle Branch Block Pattern Following Right Ventriculotomy
Authors: EHUD KRONGRAD, STEPHEN E. HEFLER, FREDERICK O. BOWMAN, JAMES R. MALM, BRIAN F. HOFFMAN
Journal: Circulation (1974)

Fifteen patients with various congenital heart defects were studied during open heart surgery in order to establish the precise mechanism by which a right ventriculotomy causes a right bundle branch block (RBBB) pattern on the scalar electrocardiogram (ECG). All required a right ventriculotomy for the correction of their defects. In each, the right ventriculotomy was carried out in steps, with incisions (3 to 7) of approximately 1 cm in length. Six simultaneous scalar ECG leads were recorded prior to the first incision and following each incision. The QRS duration was then measured and related to the length of the ventriculotomy. Following the right ventriculotomy, 12 of the 15 patients developed an RBBB pattern; the remaining three did not. In all cases, the total increase in QRS duration occurred during one specific incision of the right ventricular free wall and was not related to the total length of the ventriculotomy or to the sequence of the incisions. The site at which incision of the right ventricle caused the RBBB pattern was located at between 40 to 73% of the distance between the pulmonary artery annulus and the inferior border of the heart in nine patients; in three patients the site was higher on the right ventricular free wall. Our results explain why some patients who had a right ventriculotomy during open heart surgery do not develop an RBBB pattern on the scalar ECG. Also, since no relation was found between the length of the incision and the QRS duration, our results suggest that the ventriculotomy-induced RBBB pattern is unlikely to be due to disruption of a continuous Purkinje network but is probably due to disruption of a distal branch or branches of the right bundle.
PYRIMIDINE METABOLISM IN MAN. I. THE BIOSYNTHESIS OF OROTIC ACID*†
Authors: Lloyd H. Smith, Faith A. Baker
Journal: Journal of Clinical Investigation (1959)

Many studies of purine metabolism in man have been carried out.This is largely due to continued interest in the pathogenesis of gout and the ease of measuring serum and urinary uric acid.In contrast there have been few studies of pyrimidine metabolism in man.The major degradation products of pyrimidines are carbon dioxide and ammonia, which are lost in the general body pools.Only recently has a "pyrimidine disease," orotic aciduria, been described (1).The role of py- rimidine nucleotides in the formation of nucleic acids and in a number of coenzyme functions emphasizes the importance of quantitative data concerning pyrimidine metabolism in man.This report describes studies of the enzymatic steps in normal blood cells leading to the formation of the first pyrimidine product, orotic acid.EXPERIMENTAL PROCEDURE Preparation of reactants.Carbamylphosphate (CAP) was synthesized and analyzed as described by Jones, Spector and Lipmann (2).I-Carbamylaspartate-C14 (CAA-C") was prepared from I-aspartate and cyanate-C14 (3) and measured by the Koritz and Cohen procedure (4).Cyanate-C14 was synthesized by the fusion of potassium carbonate and urea-C14 (5).dl-Dihydroorotate-C14 (DHO-C14) was synthesized by the catalytic hydrogenation of orotate-C'4 (labeled in carbon 6) using a rhodium- alumina catalyst (6) and measured as described by Yates and Pardee (7).Nonlabeled l-dihydroorotate was syn- thesized by the method of Miller, Gordon and Englehardt (8).dl-5-Carboxymethylhydantoin-C14 (5-CMH-C") la- beled in the carboxyl group was prepared from the above dl-DHO-C1' (3) and measured as described by Lieberman and Kornberg (9).Nonlabeled 5-CMH was correspondingly prepared from carbamylaspartate.Bicarbonate-C14 was prepared from barium carbonate-C14 and analyzed as described by Zamecnik, Frantz, Loftfield and Stephenson (10).Uniformly labeled l-aspartate-C'4 was purchased
London vaccination summit is "milestone in global health"
Authors: P. Moszynski
Journal: BMJ (2011)

A conference held in London this week to commit pledges to the Global Alliance for Vaccines and Immunisation (GAVI) far exceeded expectations, organisers said. 

Donors committed a total of $4.3bn (£2.6bn; €3bn), exceeding the initial target of $3.7bn, enabling GAVI to “reach more children faster than planned and to accelerate the introduction of new vaccines.”

The latest pledges bring GAVI’s total available resources for the next five years to $7.6bn, which should see vaccination programmes such as those against rotavirus and pneumococcal infections being rolled out to more countries.

The alliance said that major public and private donors had “achieved a milestone in global health” by committing funding to vaccinate “more than 250 million of the world’s poorest children against life-threatening diseases by 2015 and …
Ethics experts agree that 250 cap for egg donation should be lifted
Authors: C. Dyer
Journal: BMJ (2010)

Clinicians and egg donors have signalled their support for a rise in the amount of compensation paid to women who donate eggs to infertile women in the United Kingdom, as the Human Fertilisation and Embryology Authority prepares to launch a public consultation on the subject.

Five of six speakers at a debate organised by the Progress Educational Trust and held at the Royal Society of Medicine on 20 October put forward arguments for removing the current cap of £250 (€280; $390) compensation for loss of earnings, although there was no agreement on where any new level should be set.

Lisa Jardine, the chairwoman of the authority, said in an interview last August …
P111 Azithromycin prescriptions in a teaching hospital–do we need to monitor for adverse effects?
Authors: P Rajagopalan, K De wit, J Barrett, R Breen
Journal: Thorax (2013)

<h3>Introduction</h3> Azithromycin appears to have an important role in management of a number of conditions including non-CF bronchiectasis and COPD but with possible adverse effects including hearing loss and liver dysfunction that necessitate appropriate patient monitoring. We have examined our use of azithromycin and how we screen for complications in our Chest clinics. <h3>Methods</h3> Data was collected on all azithromycin prescriptions provided at the Chest Clinic in a large UK teaching hospital over a 12 month period commencing 30-1–2012. In those patients receiving long-term azithromycin (≥12 Months), we collected data on parameters including sputum microbiology, previous NTM,liver function tests (LFTs), audiology testing and Qtc interval recording. <h3>Results</h3> 192 prescriptions corresponding to 112 patients were identified. 62 of 112 (56%) were prescribed long-term azithromycin. Bronchiectasis (60%), COPD(19%), asthma (8%), ILD(7%), Bronchiolitis and others (6%) were the variety of diseases for which Azithromycin was prescribed. 28% had pseudomonas colonisation. 51(46%) patients were prescribed long-term azithromycin. Of these, 21 (25%) had been on azithromycin for less than 12 months. Sixty eight (82%) patients on long-term azithromycin had had LFTs and 3(3.5%) had audiology testing in the preceding 12 months.21(25%)had documented ECGs with Qtc interval. No patients tested had hearing loss and no documented QTc prolongation. The other common side effect noticed was GI upset in 6 patients (5.6%). The dosing was mostly 250mg three times a week 103(92%) There was also 500mg three times a week in 20(18%) H.influenzae (42%)Staphylococcus aureus (21%)Moraxella catarrhalis (11%)coliform sp (10%). We identified no new NTM in our Cohort. <h3>Conclusion</h3> Although formal monitoring in this cohort was patchy, Significant documented adverse effects in this cohort were rare and optimal practice for long-term management of azithromycin use remains to be established.
Acquired alpha thalassemia associated with erythroleukemia
Authors: Parameswaran Anoop, Shabnam Roohi
Journal: American Journal of Hematology (2013)

Hemoglobin H (HbH) inclusions are typically seen in alpha thalassemia, inherited as an autosomal recessive hemoglobinopathy. Occasionally, HbH inclusions can occur as acquired defects in bone marrow disorders associated with ineffective erythropoiesis. A 33-year-old male presented with history of anemia and leukopenia over a 6-month period, with no lymphadenopathy or hepatosplenomegaly. His hemogram showed Hb concentration of 8.5 g/dl, total white cell count 1,700/mm3, and platelet count of 242,000/mm3, with low mean corpuscular volume (74 fl) and mean corpuscular Hb (23 pg). Peripheral smear showed hypochromic microcytic erythrocytes, mild polychromasia, 5% nucleated red cells, trilineage dysplasia, and occasional myeloblasts. He was transfusion independent and had normal levels of serum ferritin, total iron binding capacity, and transferrin saturation. There was no family history of hemoglobinopathies. He had reticulocytosis (2.6%) and a normal level of HbA2 (1.54%) on electrophoresis. Serum levels of vitamin B12 (490 pg/ml) and folic acid (19.6 ng/ml) were within normal limits. An HbH supravital stain preparation revealed “golf ball” type inclusions in 15% of red cells (Image 1a). Bone marrow aspirate (Image 1b) showed trilineage dysplasia, 69% erythroblasts, and 11% myeloblasts (35% of non-erythroid nucleated cells), consistent with transformation of myelodysplastic syndrome (MDS) to M6 subtype of acute myeloid leukemia (AML). Erythroleukemia often results from transformation of MDS 1, 2. Patients with clonal hematological disorders may occasionally undergo changes in alpha globin synthesis, leading to acquired alpha thalassemia (AAT). This has been reported in association with MDS, AML, acute lymphoblastic leukemia, myelofibrosis, and essential thrombocythemia 3. It is now known that the underlying molecular defect in such acquired cases is with the trans-acting regulator of globin gene expression, in contrast to cis-acting mutations in inherited alpha thalassemia 4. Over 85% of patients with AAT reported to date have been elderly males, with a median age at diagnosis of 68 years. A review by Steensma et al. identified that AAT has been reported in only 10 patients younger than 50 years of age 3. Anecdotal evidence indicates that the development of AAT is associated with a worsening of the underlying clonal disorder 3. The technical and photographic support from BC Sangamesh and LB Manigantan is acknowledged with gratitude.
Procainamide-induced psychosis
Authors: I. D. McCrum
Journal: JAMA (1978)

ALTHOUGH a number of standard textbooks and reference sources indicate that psychosis can occur during procainamide hydrochloride administration, we found few cases of documentation. To our knowledge, the following case report is the first detailed description of such a psychosis. <h3>Report of a Case</h3> A 45-year-old man was admitted to the medical intensive care unit after a routine ECG showed unifocal premature ventricular contractions (PVCs) of 16 to 22/min, with occasional periods of bigeminy. He gave no history of cardiac symptoms or illness. Hospital records verified intermittent psychotic behavior during a ten-year period, which was thought to reflect a manic-depressive illness. On admission, his medications consisted of lithium carbonate, 300 mg four times a day (serum lithium level, 0.55 mEq/liter); haloperidol, 2 mg twice daily; and trihexphenidyl hydrochloride, 5 mg daily. Evaluation by a cardiologist failed to show any obvious cause for the arrhythmia. Lithium therapy was discontinued without any
706 MUTATION RTA181T/SW172* IS ASSOCIATED WITH LOWER HBSAG LEVELS THAN OTHER MUTATIONS IN HBV POLYMERASE CODON 181 AND OVERLAPPING SURFACE CODON 172 -IMPLICATIONS FOR VACCINATION?
Authors: M. Bruce, M. Horner, D. Shang, I. Fletcher, A. Suddle, P.M. Harrison, K. Agarwal, I. Carey
Journal: Journal of Hepatology (2011)
RELATION BETWEEN THE SYNTAX SCORE AND CULPRIT LESION MORPHOLOGY IN NON-ST-SEGMENT ELEVATION ACUTE CORONARY SYNDROME -AN OPTICAL COHERENCE TOMOGRAPHY STUDY
Authors: Kenichiro Saka, Kiyoshi Hibi, Nobuhiko Maejima, Mitsuaki Endo, Noriaki Iwahashi, Kengo Tsukahara, Masami Kosuge, Toshiaki Ebina, Satoshi Umemura, Kazuo Kimura
Journal: Journal of the American College of Cardiology (2012)
Hepatitis C virus E2 protein interaction with the human dendritic cell membrane: Role of beta-1 integrins, CD81 and other tetraspanins
Authors: P. Sanz-Cameno, S. Martin, J. Medina, I. Arce, M. Gomez, M.J. Borque, R. Moreno-Otero
Journal: Journal of Hepatology (2003)
Pathobiology: An Introduction
Authors: Nelson R. Niles
Journal: JAMA (1972)

Medical textbooks are changing. These changes, perhaps not enough for the accelerating evolution of medical practice and curriculum, are nevertheless profound by present standards. The new<i>Pathobiology</i>responds to the new demands. It is concise, well written, broad in scope, and innovative. It will please many in various fields, both neophytes and old hands. If a core of knowledge and ideas in pathology exists, a diversified group of academic pathologists must be able to agree on it, and it must include basic descriptions of both anatomic and functional lesions and concepts of pathogenesis. Terminology is important, although the glossary should be kept brief. In some ways<i>Pathobiology</i>is not a good text for medical students, for it is a little too superficial and inconsistent. At least I would find it difficult to incorporate into our program, although that may just indicate the depth of my rut. I require fuller discussions