tbuckley/cabot-search huggingface dataset:
Tirapazamine Cytotoxicity for Neuroblastoma Is p53 Dependent
Authors: Bo Yang, C. Patrick Reynolds
Journal: Clinical Cancer Research (2005)

Abstract Relapse of neuroblastoma commonly occurs in hypoxic tissues, and is associated with an acquired and sustained high-level drug resistance, often due to p53 loss of function. Abrogating p53 function with HPV 16 E6 transduction in drug-sensitive neuroblastoma cell lines caused high-level drug resistance. Tirapazamine (TPZ) is a bioreductive agent that forms a toxic free radical in hypoxia. We determined in six neuroblastoma cell lines the cytotoxicity of TPZ using DIMSCAN, a digital imaging fluorescence assay, apoptosis and mitochondrial membrane potential (ΔΨm) by flow cytometry, and protein expression by immunoblotting. TPZ exhibited high cytotoxicity, especially in hypoxia (2% O2), for all four p53-functional neuroblastoma cell lines, achieving &amp;gt;3 logs of cell kill (LC99 ≤ 0.7 μg/mL). In p53-nonfunctional neuroblastoma cell lines, all TPZ LC99 values were &amp;gt;3.0 μg/mL (average clinically achievable level). TPZ (24 hours) induced apoptosis in &amp;gt;46% of cells in p53-functional cell lines but failed to cause apoptosis in p53 nonfunctional cell lines. Induction of p53 and p21 expression by TPZ was observed in a p53-functional cell line (SMS-SAN) but not in a p53-nonfunctional cell line (CHLA-90). Significant ΔΨm loss and glutathione (GSH) depletion in response to TPZ was observed in p53-functional cell lines (SMS-SAN, SMS-SAN EV, and CHLA-15) but not in p53-nonfunctional cell lines (SMS-SAN E6 and CHLA-90). N-Acetylcysteine inhibited TPZ-mediated ΔΨm loss and GSH depletion, but neither N-acetylcysteine nor Boc-d-fmk inhibited apoptosis caused by TPZ. In response to TPZ, ΔΨm loss preceded apoptosis. Thus, TPZ cytotoxicity for neuroblastoma cell lines in hypoxia occurred via a p53-dependent mitochondrial pathway that caused induction of p53 and p21, ΔΨm decrease, GSH depletion, and apoptosis. These data further define the mechanism of action of TPZ and suggest that as a single agent, TPZ would only have clinical activity against p53-functional neuroblastomas.
Evidence of pudendal neuropathy in patients with perineal descent and chronic straining at stool.
Authors: E S Kiff, P R Barnes, M Swash
Journal: Gut (1984)

In 17 women with chronic constipation, and abnormal perineal descent on straining at stool, there was more severe neurogenic damage to the external anal sphincter muscle and to its pudendal innervation in those patients with a long history than in those with a short history. These results suggest that recurrent trauma to the pudendal nerves can occur during perineal descent, and that this can lead to denervation and weakness of the external anal sphincter muscle.
Determination of antigen-specific memory/effector CD4+ T cell frequencies by flow cytometry: evidence for a novel, antigen-specific homeostatic mechanism in HIV-associated immunodeficiency.
Authors: S L Waldrop, C J Pitcher, D M Peterson, V C Maino, L J Picker
Journal: Journal of Clinical Investigation (1997)

The highly regulated secretion of effector cytokines by CD4+ T cells plays a critical role in immune protection against pathogens such as cytomegalovirus. Here, we directly compare the frequency and functional characteristics of cytomegalovirus-specific CD4+ memory/effector T cells in normal and HIV+ subjects using a novel, highly efficient multiparameter flow cytometric assay that detects the rapid intracellular accumulation of cytokine(s) after short-term (6 h) in vitro antigen stimulation. Responses in this assay correlate precisely with independent measures of sensitization history (e.g., seroreactivity), and allow the simultaneous assessment of multiple cytokines in single effector T cells. Healthy HIV- individuals manifested an average of 0.71, 0.72, 0.38, and 0.06% CD4+ T cells responding to cytomegalovirus with gamma-IFN, TNF-alpha, IL-2, and IL-4 production, respectively, with the simultaneous production of gamma-IFN, TNF-alpha, and IL-2 being the most common effector phenotype. Significantly, overall cytomegalovirus-specific CD4+ effector frequencies were markedly higher among 40% of HIV+ subjects (2.7-8.0%), and demonstrated a predominately polarized gamma-IFN+/TNF-alpha+/IL-2-/IL-4- phenotype. In contrast, CD4+ effector frequencies for heterologous, nonubiquitous viruses such as the mumps virus were low or absent in the HIV+ group. These data suggest the existence of homeostatic mechanisms in HIV disease that selectively preserve memory T cell populations reactive with ubiquitous pathogens such as cytomegalovirus-likely at the expense of T cell memory to more sporadically encountered infectious agents.
Beyond reasonable doubt: Who is the culprit in lipotoxicity in NAFLD/NASH?
Authors: D M van Rooyen, C Z Larter, W G Haigh, M W Yeh, G Ioannou, R Kuver
Journal: Hepatology (2012)

Abstract BACKGROUND &amp; AIMS: Type 2 diabetes and nonalcoholic steatohepatitis (NASH) are associated with insulin resistance and disordered cholesterol homeostasis. We investigated the basis for hepatic cholesterol accumulation with insulin resistance and its relevance to the pathogenesis of NASH. METHODS: Alms1 mutant (foz/foz) and wild-type NOD.B10 mice were fed high-fat diets that contained varying percentages of cholesterol; hepatic lipid pools and pathways of cholesterol turnover were determined. Hepatocytes were exposed to insulin concentrations that circulate in diabetic foz/foz mice. RESULTS: Hepatic cholesterol accumulation was attributed to up-regulation of low-density lipoprotein receptor via activation of sterol regulatory element binding protein 2 (SREBP-2), reduced biotransformation to bile acids, and suppression of canalicular pathways for cholesterol and bile acid excretion in bile. Exposing primary hepatocytes to concentrations of insulin that circulate in diabetic Alms1 mice replicated the increases in SREBP-2 and low-density lipoprotein receptor and suppression of bile salt export pump. Removing cholesterol from diet prevented hepatic accumulation of free cholesterol and NASH; increasing dietary cholesterol levels exacerbated hepatic accumulation of free cholesterol, hepatocyte injury or apoptosis, macrophage recruitment, and liver fibrosis. CONCLUSIONS: In obese, diabetic mice, hyperinsulinemia alters nuclear transcriptional regulators of cholesterol homeostasis, leading to hepatic accumulation of free cholesterol; the resulting cytotoxicity mediates transition of steatosis to NASH.
The Ile164 beta2-adrenergic receptor polymorphism adversely affects the outcome of congestive heart failure.
Authors: S B Liggett, L E Wagoner, L L Craft, R W Hornung, B D Hoit, T C McIntosh, R A Walsh
Journal: Journal of Clinical Investigation (1998)

The beta2-adrenergic receptor (beta2AR), an important modulator of cardiac inotropy and chronotropy, has significant genetic heterogeneity in the population. Because dysfunctional betaARs play a role in the pathogenesis of the failing ventricle, we tested the hypothesis that beta2AR polymorphisms alter the outcome of congestive heart failure. 259 patients with NYHA functional class II-IV heart failure due to ischemic or dilated cardiomyopathy were genotyped and prospectively followed, with the endpoint defined as death or cardiac transplantation. The allele frequencies between this group and those of 212 healthy controls also were compared and did not differ between the groups. However, those with the Ile164 polymorphism displayed a striking difference in survival with a relative risk of death or cardiac transplant of 4.81 (P < 0.001) compared with those with the wild-type Thr at this position. Age, race, gender, functional class, etiology, ejection fraction, and medication use did not differ between these individuals and those with the wild-type beta2AR, and thus the beta2AR genotype at position 164 was the only clear distinguishing feature between the two groups. The 1-yr survival for Ile164 patients was 42% compared with 76% for patients harboring wild-type beta2AR. In contrast, polymorphisms at amino acid positions 16 (Arg or Gly) or 27 (Gln or Glu), which also alter receptor phenotype, did not appear to have an influence on the course of heart failure. Taken together with cell-based and transgenic mouse results, this study establishes a paradigm whereby genetic variants of key signaling elements can have pathophysiologic consequences within the context of a disease. Furthermore, patients with the Ile164 polymorphism and heart failure may be candidates for earlier aggressive intervention or cardiac transplantation.
THE EFFECT OF ANOXIC ANOXIA ON THE HUMAN KIDNEY 1
Authors: Eugene Y. Berger, Morton Galdston, Seymour A. Horwitz, Roslyn Jackenthal, Marilyn Pruss
Journal: Journal of Clinical Investigation (1949)

Congestive heart failure is associated with re- duction of renal blood flow and retention of salt and water.The possibility has been raised that these changes may result from the concomitant renal anoxia (1, 2).The present studies are con- cerned with the effect of anoxia on the human kid- ney under situations of normal cardiovascular dynamics.
The Health Hazards of Asbestos Removal-Reply
Authors: Jerod M. Loeb
Journal: JAMA (1992)

In Reply.  —The letter from Ms MacDonald raises several issues. The AMA Council on Scientific Affairs report on asbestos does not deny the importance of building inspections. However, decisions to remove asbestos should be evaluated on the basis of sound scientific criteria and not pressure from one or another special interest group. While asbestos is certainly a carcinogen, on the basis of most recent evidence, the threat it poses to building occupants is minimal. A new report released in September 1991 by the Health Effects Institute notes that arbitrarily removing asbestos from a well-maintained building is not justified and may actually in
Closed-Loop Obstruction of the Ascending Colon, with Incomplete Descent of the Cecum, Simulating Acute Cholecystitis
Authors: Eugene A. Gaston, Maurice E. Costin
Journal: New England Journal of Medicine (1948)

CLINICAL findings and laboratory tests frequently fail to indicate accurately the pathologic status of the gall bladder in acute cholecystitis. Gangrene with incipient or actual perforation may exist with minimal physical signs and with normal or only slightly elevated temperature and blood counts. For these reasons, and because of the ease and safety of cholecystectomy in the early stages of the disease, early operation is being advocated with increasing frequency.1 2 3 4 5 6 7 8 9 10 11 The purpose of this communication is to present 2 cases in which acute, closed-loop obstruction of the ascending colon in combination with incomplete descent of the cecum was mistaken for . . .
Greetings — With Regrets
Authors: Arnold S. Relman, Drummond Rennie, Marcia Angell
Journal: New England Journal of Medicine (1980)

A cheerful tradition dictates that at this season we send you our warmest greetings. We follow this amiable practice with pleasure and add our heartfelt thanks to all our readers, contributors, and reviewers for their lively, if sometimes contentious, support.Letters continue to flow into this office in increasing numbers, in turn provoking, delighting, and dismaying us. One notable genre consists of the letters from authors of rejected manuscripts, who question our editorial policy and practices, and sometimes our competence and motives. But the most common sentiment is the desire for a more detailed explanation of our editorial decision.We . . .
Self reported health and mortality: ecological analysis based on electoral wards across the United Kingdom
Authors: Dermot O'Reilly, Michael Rosato, Chris Patterson
Journal: BMJ (2005)

factors relating to the learning attitude and to relationships between prescribers).Strategies for improvement should include developing incentives for chronic considerations and for active learning in geriatrics by junior doctors 12 13 ; developing systems for reliable transfer of information; increasing involvement of patients; and encouraging communication between prescribers.We thank the participants who gave up their time to be interviewed.We also thank Michel Lambert and Felicity Smith
Shaving of Eyebrows
Authors: Jack E. Sebben
Journal: JAMA (1980)

To the Editor.—  Thomas J. Baker, MD (241:2207, 1979), discusses the question of shaving eyebrows before surgery in the eyebrow region. He concludes that the failure of the eyebrows to regrow is a  I would like to point out the basis for this myth. 1   The eyebrows will certainly regrow after they are cut or shaved. However, unlike the scalp or beard, many months are required for the return. This may be extremely distressing for the patient lacking a normal eyebrow, since there is no adjacent hair to conceal the defect.  A study of hair cycles shows the basis of this special problem with eyebrows. All human hairs have growing (anagen) and resting (telogen) phases. Each scalp hair grows for several years and then enters a resting phase for approximately three months before it is shed. At any one time 10% to 20% of the scalp hairs are in
Computerised Assessment of Maximum Urinary Flow: an Efficient, Consistent and Valid Approach
Authors: Wim P.J Witjes, Jean J.M.C.H de la Rosette, Annelise van den Berg-Segers, David Colongo, Gary Koch, Alexandre R Zlotta, Alexandre Colau, Michel J.A.M de Wildt, Hessel Wijkstra
Journal: European Urology (2002)
Mapping choice in the NHS: Analysis is only as good as data
Authors: Matthew Walmsley
Journal: BMJ (2005)

<h3>Objectives</h3> The aim of this study was to evaluate disease progression and overall survival in patients diagnosed with neuroendocrine carcinoma of the cervix treated with chemotherapy and radiation without surgical intervention; we hypothesize similar overall survival to the surgical intervened cases. <h3>Methods</h3> This study used a retrospective analysis of patients with neuroendocrine carcinoma of the cervix who were not surgically managed. Review was performed from 1990 to 2014. The data collected included demographics, stage of disease, and outcomes after each treatment. Specific chemotherapy regimen given and radiation dosage were reviewed. Overall survival and recurrence rates were calculated. <h3>Results</h3> A total of 16 patients met inclusion criteria. Six patients were diagnosed with stage I; these patients had 83.3% 2-year overall survival, 83.3% 5-year overall survival, and a recurrence rate of 16.6%. Three patients were diagnosed with stage II; these patients had 66.6% 2-year overall survival, 0% 5-year overall survival, and a recurrence rate of 100%. Seven patients were diagnosed with stage IV; these patients had 14.3% 2-year overall survival and 0% 5-year overall survival and never underwent remission. <h3>Conclusions</h3> Our findings noted a comparable overall survival with lower rates of recurrence in patients with early-stage disease using chemotherapy and radiation therapy alone as primary means of treatment. Nonsurgical management of neuroendocrine carcinoma of the cervix may be of benefit in early-stage disease.
Children with hepatitis C
Authors: Maureen M. Jonas
Journal: Hepatology (2002)

An estimated 240,000 children in the United States have antibody to hepatitis C virus (HCV) and 68,000 to 100,000 are chronically infected with HCV. Acute HCV infection is rarely recognized in children outside of special circumstances such as a known exposure from an HCV-infected mother or after blood transfusion. Most chronically infected children are asymptomatic and have normal or only mildly abnormal alanine aminotransferase levels. Although the natural history of HCV infection acquired in childhood seems benign in the majority of instances, the infection takes an aggressive course in a proportion of cases leading to cirrhosis and end-stage liver disease during childhood; the factors responsible for a more aggressive course are unidentified. An optimal approach to management of hepatitis C in children would be prevention, particularly of perinatal transmission, which is now the major cause of new cases of hepatitis C in children. Obstetrical factors may be important determinants of transmission, which, if confirmed, should lead to changes in the care of infected women. Therapy of HCV infection in children is also not well defined. There have been no large randomized, controlled trials of therapy in children with chronic hepatitis C. Small heterogeneous studies of interferon monotherapy have reported sustained virological response rates of 35% to 40%. There are few data regarding the use of combination therapy with interferon and ribavirin in children and no information on the use of peginterferon. Clearly, there are important needs for future epidemiologic and clinical research on hepatitis C in childhood.
Prevention of Congenital Malformations in Infants of Insulin-dependent Diabetic Mothers
Authors: Kurt Fuhrmann, Horst Reiher, Klaus Semmler, Friedericke Fischer, Michael Fischer, Eberhard Glöckner
Journal: Diabetes Care (1983)

From April 1977 to April 1981, 420 deliveries of infants of insulin-dependent diabetic women were performed in our department. Of the infants delivered, 23 had congenital malformations (5.5%). The malformation rate was 1.4% for infants of 420 nondiabetic women. Strict metabolic control was begun after 8 wk gestation in 292 of the diabetic women who delivered 22 infants with congenital malformations (7.5%). Intensive treatment was begun before conception in 128 diabetic women planning pregnancy. There was only one malformation in infants of this group (0.8%), a significant reduction from the anomaly rate in the late registrants (X2 = 7.84; P less than 0.01). These observations indicate that reasonable metabolic control started before conception and continued during the first weeks of pregnancy can prevent malformations in infants of diabetic mothers.
1,25 dihydroxyvitamin D3 stimulates phospholipase C-gamma in rat colonocytes: role of c-Src in PLC-gamma activation.
Authors: S Khare, M J Bolt, R K Wali, S F Skarosi, H K Roy, S Niedziela, B Scaglione-Sewell, B Aquino, C Abraham, M D Sitrin, T A Brasitus, M Bissonnette
Journal: Journal of Clinical Investigation (1997)

Our laboratory has previously demonstrated that 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) rapidly stimulated polyphosphoinositide (PI) hydrolysis, raised intracellular Ca2+, and activated two Ca2+-dependent protein kinase C (PKC) isoforms, PKC-alpha and -betaII in the rat large intestine. We also showed that the direct addition of 1,25(OH)2D3 to isolated colonic membranes failed to stimulate PI hydrolysis, but required secosteroid treatment of intact colonocytes, suggesting the involvement of a soluble factor. Furthermore, this PI hydrolysis was restricted to the basal lateral plasma membrane of these cells. In the present studies, therefore, we examined whether polyphosphoinositide-phospholipase C-gamma (PI-PLC-gamma), a predominantly cytosolic isoform of PI-PLC, was involved in the hydrolysis of colonic membrane PI by 1,25(OH)2D3. This isoform has been shown to be activated and membrane-associated by tyrosine phosphorylation. We found that 1,25(OH)2D3 caused a significant increase in the biochemical activity, particulate association, and the tyrosine phosphorylation of PLC-gamma, specifically in the basal lateral membranes. This secosteroid also induced a twofold increase in the activity of Src, a proximate activator of PLC-gamma in other cells, with peaks at 1 and 9 min in association with Src tyrosine dephosphorylation. 1,25(OH)2D3 also increased the physical association of activated c-Src with PLC-gamma. In addition, Src isolated from colonocytes treated with 1,25(OH)2D3, demonstrated an increased ability to phosphorylate exogenous PLC-gamma in vitro. Inhibition of 1,25(OH)2D3-induced Src activation by PP1, a specific Src family protein tyrosine kinase inhibitor, blocked the ability of this secosteroid to stimulate the translocation and tyrosine phosphorylation of PLC-gamma in the basolateral membrane (BLM). Src activation was lost in D deficiency, and was reversibly restored with the in vivo repletion of 1,25(OH)2D3. These studies demonstrate for the first time that 1,25(OH)2D3 stimulates PLC-gamma as well as c-Src in rat colonocytes, and indicate that PLC-gamma is a direct substrate of secosteroid-activated c-Src in these cells.
ELECTROMYOGRAMS IN DIAGNOSIS AND PROGNOSIS OF TETANUS
Authors: Arthur L. Watkins
Journal: JAMA (1942)

In the absence of trauma the diagnosis of tetanus is easily overlooked, and even in the presence of an infected wound and obvious lockjaw the bacteriologic studies may be negative. Tetanus toxin is known to act on the skeletal muscle, causing contracture as a characteristic manifestation.<sup>1</sup>In local tetanus produced experimentally the action potentials of affected muscles have been shown to present constant activity with diphasic spikes.<sup>2</sup>This abnormal electrical activity is a specific effect induced by tetanus toxin and when demonstrated should be of diagnostic value. Consequently, in a case of suspected tetanus of obscure origin, electromyograms were taken from the affected muscles and a test devised to quantitate the abnormality present for the purpose of prognosis and to aid in following the course of progress. <h3>REPORT OF CASE</h3><h3>History.—</h3> A man aged 21 entered the Massachusetts Eye and Ear Infirmary Jan. 28, 1941 because of
Ethics code for professional medical writers emphasises transparency and completeness of research reporting
Authors: S. Mayor
Journal: BMJ (2010)

People who write and submit articles on behalf of the pharmaceutical, biotechnology, and medical device industries should ensure accuracy and completeness and avoid any practices that promote commercial products when developing research communications, an updated international code of ethics recommends.

The International Society for Medical Publications Professionals, an independent, not for profit organisation, has revised its code of ethics in line with evolving developments in medical publishing. The aim is to ensure integrity and transparency in the publication of medical research.

Several recent reports have raised …
Secrecy in the NHS
Authors: N. Craft
Journal: BMJ (1994)

Seven years ago we collected 20 examples of secrecy surrounding health and the NHS in Britain.1 This month we repeated the exercise, and in three days we have discovered 30 examples. We will be pleased to hear of more.

(1) Paragraph 330 of the Terms and Conditions of Service for Hospital Medical and Dental Staff says that “A practitioner shall be free, without prior consent of the employing authority, to publish books, articles, etc, and to deliver any lecture or speak, whether on matters arising out of his or her hospital service or not.” A growing number of trust hospitals have contracts which have replaced this with a gagging clause.

The BMA's database records the following trusts as having at some time inserted a confidentiality or conflict of interest clause, or both, into contracts:

Frimley Park Hospital; Walsgrave Hospital; St Helens and Knowsley Community Health; Mid Staffordshire General Hospitals; North Staffordshire Hospital Centre; Leicester Royal Infirmary; Royal Devon and Exeter Hospital; Ashford Hospital, Middlesex; and Heatherwood and Wexham Park Hospitals. For example, a recent confidentiality clause from a contract given to a consultant working for West Kent Health Authority reads: “In the course of your work you may have access to confidential information which should not be disclosed to any other person unless in the pursuit of your duties or with the specific permission of the employing authority.”

Hansard reports that in March 1994, Dawn Primarolo (then opposition spokesperson for health) asked the secretary of state for health “what freedom NHS trusts have to vary the terms and conditions for service for hospital medical and dental staff in relation to the freedom of practitioners to publish articles or to speak on any issue without the prior consent of their employer.” The health minister, Brian Mawhinney, replied in a written …