tbuckley/cabot-search huggingface dataset:
Blood on our hands: seeing the evil in inappropriate comparators
Authors: Kamran Abbasi
Journal: Journal of the Royal Society of Medicine (2013)

What is the value of fairness in medicine? Do unto others as you would have done unto you? Is it possible to say fairer than that? Fair tests of treatments presume a genuine uncertainty about which treatment is more beneficial or harmful. Yet too many clinical trials use inappropriate comparators to exaggerate the benefits of a new therapy. Fairness goes beyond transparency and disclosure of trial data. The results of many unfair trials are published, the data shared. Unfairness, in this instance, lies in selecting a comparator drug or dose of a drug that, for example, is known to be less effective or has a worse side-effect profile. In 56 out of 63 trials involving patients with highly active rheumatoid arthritis, potentially helpful treatments were withheld from 9224 out of 13,095 patients randomized to the control arms. Why? Because placebos or treatments known to be ineffective were used as controls.1
A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 ( SMAD4)
Authors: Carol J Gallione, Gabriela M Repetto, Eric Legius, Anil K Rustgi, Susan L Schelley, Sabine Tejpar, Grant Mitchell, Éric Drouin, Cornelius JJ Westermann, Douglas A Marchuk
Journal: The Lancet (2004)
Sleep-disordered breathing in unilateral diaphragm paralysis or severe weakness
Authors: J. Steier, C. J. Jolley, J. Seymour, S. Kaul, Y. M. Luo, G. F. Rafferty, N. Hart, M. I. Polkey, J. Moxham
Journal: European Respiratory Journal (2008)

Few data exist concerning sleep in patients with hemidiaphragm paralysis or weakness. Traditionally, such patients are considered to sustain normal ventilation in sleep. In the present study, diaphragm strength was measured in order to identify patients with unilateral paralysis or severe weakness. Patients underwent polysomnography with additional recordings of the transoesophageal electromyogram (EMG) of the diaphragm and surface EMG of extra-diaphragmatic respiratory muscles. These data were compared with 11 normal, healthy subjects matched for sex, age and body mass index (BMI). In total, 11 patients (six males, mean+/-sd age 56.5+/-10.0 yrs, BMI 28.7+/-2.8 kg x m(-2)) with hemidiaphragm paralysis or severe weakness (unilateral twitch transdiaphragmatic pressure 3.3+/-1.7 cmH(2)O (0.33+/-0.17 kPa) were studied. They had a mean+/-sd respiratory disturbance index of 8.1+/-10.1 events x h(-1) during non-rapid eye movement (NREM) sleep and 26.0+/-17.8 events x h(-1) during rapid eye movement (REM) sleep (control groups 0.4+/-0.4 and 0.7+/-0.9 events x h(-1), respectively). The diaphragm EMG, as a percentage of maximum, was double that of the control group in NREM sleep (15.3+/-5.3 versus 8.9+/-4.9% max, respectively) and increased in REM sleep (20.0+/-6.9% max), while normal subjects sustained the same level of activation (6.2+/-3.1% max). Patients with unilateral diaphragm dysfunction are at risk of developing sleep-disordered breathing during rapid eye movement sleep. The diaphragm electromyogram, reflecting neural respiratory drive, is doubled in patients compared with normal subjects, and increases further in rapid eye movement sleep.
Prevalence, Predictors, and Consequences of Late Nephrology Referral at a Tertiary Care Center
Authors: PRADEEP ARORA, GREGORIO T. OBRADOR, ROBIN RUTHAZER, ANNAMARIA T. KAUSZ, KLEMENS B. MEYER, CONSTANCE S. JENULESON, BRIAN J. G. PEREIRA
Journal: Journal of the American Society of Nephrology (1999)

Abstract. Despite improvements in dialysis care, mortality of patients with end-stage renal disease (ESRD) remains high. One factor that has thus far received little attention, but might contribute to morbidity and mortality, is the timing of referral to the nephrologist. This study examines the hypothesis that late referral of patients to the nephrologist might lead to suboptimal pre-ESRD care. Clinical and laboratory data were obtained from the patient records and electronic databases of New England Medical Center, its affiliated dialysis unit (Dialysis Clinics, Inc., Boston), and the office records of the outpatient nephrology clinic. Early (ER) and late (LR) referral were defined by the time of first nephrology encounter greater than or less than 4 mo, respectively, before initiation of dialysis. Multivariate models were built to explore factors associated with LR, and whether LR is associated with hypoalbuminemia or late initiation of dialysis. Of the 135 patients, 30 (22%) were referred late. There were no differences in age, gender, race, and cause of ESRD between ER and LR patients. However, there were significant differences in insurance coverage between these two groups. In the multivariate analysis, patients covered by health maintenance organizations were more likely to be referred late (odds ratio = 4.5) than patients covered by Medicare. Compared to ER, LR patients were more likely to have hypoalbuminemia (56% versus 80%), hematocrit &lt;28% (33% versus 55%), and predicted GFR &lt;5 ml/min per 1.73 m 2 (17% versus 40%) at the start of dialysis, and less likely to have received erythropoietin (40% versus 17%) or have a functioning permanent vascular access for the first hemodialysis (40% versus 4%). It is concluded that late referral to the nephrologist is common in the United States and is associated with poor pre-ESRD care. Pre-ESRD care of patients treated by nephrologists was also less than ideal. The patient-, physician-, and system-related factors behind this observation are unclear. Meanwhile, pre-ESRD educational efforts need to target patients, generalists, and nephrologists.
Coexpression of Glucose Transporter 1 and Matrix Metalloproteinase-2 in Human Cancers
Authors: S. Ito
Journal: JNCI Journal of the National Cancer Institute (2002)

Cancer cells express higher levels of glucose transporter proteins (Gluts) than do normal cells. Glut-1 overexpression is associated with invasiveness. Because matrix metalloproteinase-2 (MMP-2) is also overexpressed in cancer cells and is associated with invasiveness, we tested the hypothesis that Glut-1 may regulate MMP-2 expression.We transiently transfected Glut-1 complementary DNA (cDNA) or Glut-1 antisense oligonucleotides in the human rhabdomyosarcoma cell line RD and analyzed MMP-2 mRNA expression and cell invasiveness. Empty vector and sense oligonucleotides were used for controls. We analyzed MMP-2 promoter activity in transfectants with a luciferase reporter assay and with p53 and Ets-1 gel mobility shift assays. Eight human cancer cell lines and 80 human cancer specimens were analyzed for coexpression of Glut-1 and MMP-2 by western blot and immunohistochemical analyses, respectively.Overexpression of Glut-1 in RD cells increased MMP-2 expression 4.3-fold (95% confidence interval [CI] = 3.7-fold to 4.9-fold) and invasiveness 3.2-fold (95% CI = 2.6-fold to 3.8-fold) relative to control transfected cells. Conversely, suppression of Glut-1 expression by antisense oligonucleotides decreased MMP-2 expression by 71.5% (95% CI = 71.1% to 71.9%) and invasiveness by 53.0% (95% CI = 47.5% to 58.5%). Glut-1-mediated MMP-2 expression involved the binding of the transcription factor p53 but not Ets-1. All eight human cancer cell lines coexpressed Glut-1 and MMP-2 by western blotting, and 45 of 80 human tumor tissues coexpressed Glut-1 and MMP-2 by immunohistochemistry.MMP-2 expression and cell invasiveness are tightly associated with Glut-1 expression in human cancer cell lines. Because suppression of Glut-1 decreased MMP-2 expression and cancer cell invasion, Glut-1 could be a target for therapy of various cancers that overexpress Glut-1.
CONTROL BY FACTORS DISTINCT FROM THE S TRANSFORMING PRINCIPLE OF THE AMOUNT OF CAPSULAR POLYSACCHARIDE PRODUCED BY TYPE III PNEUMOCOCCI
Authors: Colin M. MacLeod, Marjorie R. Krauss
Journal: The Journal of Experimental Medicine (1953)

Pneumococci can possess the normal S transforming principle and yet produce amounts of capsular polysaccharide much less than would be expected if the quantity formed depended only on the nature of the S transforming principle.
Chronic Lymphatic Leukaemia in Man of 84
Authors: T. H. Tidswell
Journal: BMJ (1947)

stained fluid.Two tablets were returned whole.There was no haematemesis.His colour became waxy, but had improved before admission to hospital the same day at 2.5 p.m.He was very thirsty.A stool passed later in the day was dark and gave the guaiac reaction for blood.On admission he was rather flushed, listless, and drowsy, his pulse was regular and of good volume.There was neither tenderness nor abnormal resistance over his abdomen.Treat- ment consisted of mist.magnesium hydroxide and bismuth, along with glucose and saline, later changed to milk and subsequently to milk diet.By March 6 the vomiting had ceased, and on the 9th the stool was 'normal, with no blood.On the 13th the child was 'very well, but the stool 'was 'dark and the guaiac test positive.He had had no meat since admission.On the 16th the stool was again dark, and on the 1Sth he was well and there was no melaena.
Power Output Is Increased After Phosphorylation of Myofibrillar Proteins in Rat Skinned Cardiac Myocytes
Authors: Todd J. Herron, F. Steven Korte, Kerry S. McDonald
Journal: Circulation Research (2001)

β-Adrenergic stimulation increases stroke volume in mammalian hearts as a result of protein kinase A (PKA)-induced phosphorylation of several myocyte proteins. This study investigated whether PKA-induced phosphorylation of myofibrillar proteins directly affects myocyte contractility. To test this possibility, we compared isometric force, loaded shortening velocity, and power output in skinned rat cardiac myocytes before and after treatment with the catalytic subunit of PKA. Consistent with previous studies, PKA increased phosphorylation levels of myosin binding protein C and troponin I, and reduced Ca 2+ sensitivity of force. PKA also significantly increased both maximal force (25.4±8.3 versus 31.6±11.3 μN [ P &lt;0.001, n=12]) and peak absolute power output (2.48±1.33 versus 3.38±1.52 μW/mg [ P &lt;0.05, n=5]) during maximal Ca 2+ activations. Furthermore, PKA elevated power output at nearly all loads even after normalizing for the increase in force. After PKA treatment, peak normalized power output increased ≈20% during maximal Ca 2+ activations (n=5) and ≈33% during half-maximal Ca 2+ activations (n=9). These results indicate that PKA-induced phosphorylation of myofibrillar proteins increases the power output–generating capacity of skinned cardiac myocytes, in part, by speeding the step(s) in the crossbridge cycle that limit loaded shortening rates, and these changes likely contribute to greater contractility in hearts after β-adrenergic stimulation.
Cardiac Complications of Protein-Sparing Modified Fasting
Authors: Jerry M. Brown
Journal: JAMA (1978)

Cardiovascular abnormalities developed in a patient during a proteinsparing modified fasting diet. Syncope was the complaint at the time of examination. Hypotension, persistent QT<i>c</i>interval prolongation, and a low QRS voltage were observed before the development of refractory ventricular tachycardia. At autopsy, antemortem thrombi were attached to the left ventricular endocardium and a fenestrated aortic valvule. Strick proteinsparing modified fasting is not without risk of sudden death even with close medical supervision. (<i>JAMA</i>240:120-122, 1978)
An isokinetic eccentric programme for the management of chronic lateral epicondylar tendinopathy
Authors: Jean-Louis Croisier, Marguerite Foidart-Dessalle, France Tinant, Jean-Michel Crielaard, Bénédicte Forthomme
Journal: British Journal of Sports Medicine (2007)

Lateral epicondylitis represents a frequent overuse injury. In spite of many conservative treatment procedures, prolonged symptoms and relapse are frequently observed.To compare the outcome of patients performing an isokinetic eccentric training with that of age-, gender-, activity-matched patients receiving a non-strengthening classical rehabilitation.Ninety-two patients with unilateral chronic lateral epicondylar tendinopathy (mean duration of symptoms 8+/-3 months) were assigned either to a control group (n = 46) or to an eccentrically trained group (n = 46). The control group underwent a passive standardised rehabilitation programme that excluded strengthening exercises. In addition to this programme, the trained group also performed eccentric exercises based on the repetitive lengthening of the active musculo-tendinous unit. The latter exercises started with submaximal contraction intensity and slow speed movement. Modalities were progressively intensified (increase in intensity contraction and speed movement) over a long period of treatment. Programme effectiveness was assessed through pain score evaluation, a disability questionnaire, muscle strength measurement and ultrasonographic examination.Compared to the non-strengthening control group, the following observations were made in the eccentrically trained group: (1) a significantly more marked reduction of pain intensity, mainly after one month of treatment; (2) an absence of strength deficit on the involved side through bilateral comparison for the forearm supinator and wrist extensor muscles; (3) an improvement of the tendon image as demonstrated by decreasing thickness and a recovered homogenous tendon structure; and (4) a more marked improvement in disability status during occupational, spare time and sports activities.These results highlight the relevance of implementing isokinetic adapted eccentric training in the management of chronic lateral epicondylar tendinopathy.
Hip-Joint Disease: Its Symptomatology and Diagnosis
Authors: J. Z. Laurence
Journal: BMJ (1859)

THE following essav is artly the result of a perusal of a variety of worlks on the subject of which it treats, partly of observations made at the bedside.In it I purpose giving a esum7}ev of the pathological phenomena presented to us during, life, in one of tile most inlportanit joints of the lhuman filame-important, not only for its magnituLde and funletions, but also for the variety of diseases to whicill it is subject.By far the most common disease of the hip is of a scrofulous nature.It has been known under a variety of denominations -in this country, inlost commonly as the morbus coxfe, a name wvrong in itself, implying tacitly, as it does, that that is the orllv (lisease to whichl the hip-joint is liable, which is far from being the case.Tlle disease in question was not unknown to the anicienits, amongst whlom may be ilyentioned more espe- cially Hippocrates, Galen, and the Arabitan writers.Tile fiirst scientific memoir on the subject, however, was that of Petit, in a paper, entitled Observations Anatontiques et Patho-loJiqueC sulr les Chuttes qui causent une Luxation dont les autellrs 11'ott point ecrit, read before the Academie Royale des Scicces, on February 2bth, 1772.Here we find what appears to miie to be a very meagre and ulnsatisfactory account of the disease.Overlooking the constitutional nature of the affection, Petit thought the ilead of the femur was displaced gradually froln its socket by a hypersecretion of fluid into the joint, con- sequent upon some severe contusion that this had suistained, and that after a certain lapse of time, tile bone was dislocated upwaids by tihe action of the muscles, so tllat the limb was shortened.
Frequency dependent effects on Cai transients and cell shortening in myocytes that survive in the infarcted heart
Authors: A Licata
Journal: Cardiovascular Research (1997)

Myocytes that survive in the epicardial border zone of the healing canine infarcted heart provide the substrate for inducible reentrant ventricular arrhythmias. These myocytes have been shown to have altered Ca2+ currents which could impact on Cai homeostasis in these cells.To directly measure and compare intracellular Ca2+ transients and cell shortening in myocytes dispersed from control noninfarcted hearts with those from epicardial border zone of 5 day infarcted canine hearts using the Ca2+ sensitive indicator fura-2/AM. Studies were designed to determine and compare the effects of rate and premature stimulation on intracellular Ca2+ in the two cell types.Epicardial cells from noninfarcted hearts (1) exhibited an increase in amplitude of the fura-2 ratio with decreasing pacing cycle length (CL), while cells from the infarcted heart showed the opposite effect; (2) showed more marked acceleration of relaxation of the Cai transient with decreasing CL than myocytes from the infarcted heart; (3) exhibited little or no post rest potentiation in contrast to cells from the infarcted heart; and (4) showed a more rapid recovery during restitution protocols than cells from the infarcted heart. Cell shortening differences were also observed between cell populations in that most cells from the infarcted zone did not show any degree of cell shortening despite the reasonable intracellular Ca2+ transient.The handling of intracellular Ca2+ in myocytes that have survived in the epicardial border zone is very different from that of normal epicardial myocytes suggesting that there may exist marked heterogeneity in intracellular Ca2+ handling in cells in the in situ healing infarcted heart. Electrophysiologic implications of these findings are discussed.
Placebo-Controlled Trial of 13-<i>cis</i>-Retinoic Acid Activity on Retinoic Acid Receptor-Beta Expression in a Population at High Risk: Implications for Chemoprevention of Lung Cancer
Authors: J. Ayoub, R. Jean-François, Y. Cormier, D. Meyer, Y. Ying, P. Major, C. Desjardins, W.E.C. Bradley
Journal: Journal of Clinical Oncology (1999)

To establish the incidence of abnormalities in the expression of retinoic acid receptor-beta (RARbeta) in bronchial cells and determine the capacity of 13-cis-retinoic acid (13-CRA) to correct such abnormalities.One hundred eighty-eight smokers had a medical indication for bronchoscopy and were studied with bronchial brushings. Bronchial brushing samples were obtained for cytology analysis and for molecular analysis. After RNA was extracted, RARbeta sequences were amplified by reverse transcriptase polymerase chain reaction and Southern blots were performed to assess RARbeta expression. Forty-four eligible individuals with diminished RARbeta expression consented to double-blind randomization to receive a placebo or 13-CRA 30 mg orally daily for 6 months. A second bronchoscopy was performed at the end of the treatment period. An analysis of variance was used to analyze changes in RARbeta expression before and after treatment.The 6-month treatment course was completed by 27 patients, and results were obtained for a total of 18 patients (eight patients treated with 13-CRA and ten treated with the placebo). In the placebo group, there was no difference between the results of RARbeta expression before and after treatment (P =.43). In the 13-CRA group, there was an upregulation of RARbeta expression at the end of 13-CRA treatment (P =.001). Cytologic changes were uncommon. Toxicities were primarily of grade 1. Palatal brushings were compared with bronchial brushings in 40 smokers. A perfect correlation of the results of RARbeta expression was obtained from 27 patients.RARbeta expression is frequently decreased in the bronchial epithelium of smokers and is upregulated at the end of 13-CRA treatment. These results support undertaking a phase III chemoprevention trial of 13-CRA treatment for lung cancer.
Location is Everything: Lipid Rafts and Immune Cell Signaling
Authors: Michelle Dykstra, Anu Cherukuri, Hae Won Sohn, Shiang-Jong Tzeng, Susan K. Pierce
Journal: Annual Review of Immunology (2003)

The cells of both the adaptive and innate immune systems express a dizzying array of receptors that transduce and integrate an enormous amount of information about the environment that allows the cells to mount effective immune responses. Over the past several years, significant advances have been made in elucidating the molecular details of signal cascades initiated by the engagement of immune cell receptors by their ligands. Recent evidence indicates that immune receptors and components of their signaling cascades are spatially organized and that this spatial organization plays a central role in the initiation and regulation of signaling. A key organizing element for signaling receptors appears to be cholesterol- and sphingolipid-rich plasma membrane microdomains termed lipid rafts. Research into the molecular basis of the spatial segregation and organization of signaling receptors provided by rafts is adding fundamentally to our understanding of the initiation and prolongation of signals in the immune system.
Signals from intra-abdominal fat modulate insulin and leptin sensitivity through different mechanisms: Neuronal involvement in food-intake regulation
Authors: Tetsuya Yamada, Hideki Katagiri, Yasushi Ishigaki, Takehide Ogihara, Junta Imai, Kenji Uno, Yutaka Hasegawa, Junhong Gao, Hisamitsu Ishihara, Akira Niijima, Hiroyuki Mano, Hiroyuki Aburatani, Tomoichiro Asano, Yoshitomo Oka
Journal: Cell Metabolism (2006)
Update on the safety profile of certolizumab pegol in rheumatoid arthritis: an integrated analysis from clinical trials
Authors: V P Bykerk, J Cush, K Winthrop, L Calabrese, O Lortholary, M de Longueville, R van Vollenhoven, X Mariette
Journal: Annals of the Rheumatic Diseases (2013)

Objective To report the long-term safety data of certolizumab pegol (CZP) in rheumatoid arthritis (RA) accumulated as of 30 November 2011. Design Data from 10 completed randomised controlled trials (RCT) of CZP in RA and several open-label extensions (OLE) were pooled across all doses. Reported adverse events (AE) occurred between the first dose and 84 days after the last dose. All deaths, serious infectious events (SIE) and malignancies were reviewed by external experts, classified according to predefined rules, and validated by an external steering committee. Incidence rates (IR) and event rates (ER) per 100 patient-years (PY) are presented. Results 4049 RA patients who received CZP were included in the safety pooling; total exposure 9277 PY, mean exposure 2.1 years (range 0.04–7.6). SIE, most frequently pneumonia (IR 0.73/100 PY), were the most common serious AE, occurring more frequently in CZP compared to placebo-treated patients in RCT (IR 5.61/100 PY vs 1.35/100 PY, odds ratio (OR) 4.35, 95% CI 0.65 to 29.30). SIE rates were lower in the CZP-treated population including OLE (ER 4.33/100 PY). 44 patients developed tuberculosis (IR 0.47/100 PY), 39 from high endemic regions. 58 deaths occurred in CZP-exposed patients (IR 0.63/100 PY) and 70 developed malignancies excluding non-melanoma skin cancer (IR 0.76/100 PY), including five lymphomas (IR 0.05/100 PY). Conclusions No new or unexpected safety signals associated with CZP emerged in this updated long-term safety analysis. While SIE rates were higher for CZP than for placebo in RCT, the rate decreased with continued exposure to CZP. These rates are consistent with data previously reported for CZP and other tumour necrosis factor inhibitors.
Need for Reclassification of Diabetes Secondary to Iron Overload in the ADA and WHO Classifications
Authors: Christina Ellervik, Henrik Birgens, Thomas Mandrup-Poulsen
Journal: Diabetes Care (2014)

In the current classifications of diabetes by the American Diabetes Association (ADA) (2006) (1) and the World Health Organization (WHO) (1999) (2), hereditary hemochromatosis is listed under the heading “diseases of the exocrine pancreas”; however, this classification does not comply with the current evidence of diabetes secondary to iron overload.

The common form of hereditary hemochromatosis is an autosomal recessive disease characterized by lifelong iron accumulation. Nonhereditary hemochromatosis may arise from chronic use of iron supplements, chronic liver disease, and chronic erythrocyte transfusion therapy for anemia in patients with ineffective erythropoiesis; e.g., patients with β-thalassemia major. Iron accumulates mainly in the endocrine pancreas, liver, and heart, leading to diabetes, liver …