tbuckley/cabot-search huggingface dataset:
Minitracheotomy: a simple alternative to tracheostomy in obstructive sleep apnoea.
Authors: C D Hanning
Journal: Thorax (1989)

Methicillin-resistant <i>Staphylococcus aureus</i> has emerged as a significant contributor to morbidity and mortality associated with influenza infection. In this study, we show in a mouse model that preceding influenza infection promotes <i>S. aureus</i> resistance to killing by antibiotics. This resistance coincides with influenza-induced accumulation of inflammatory monocytes in the lung. CCR type 2 (CCR2) is responsible for pulmonary monocyte recruitment after influenza infection. We found that antibiotic-treated Ccr2-deficient (Ccr2<sup>−/−</sup>) mice exhibit significantly improved bacterial control and survival from influenza and methicillin-resistant <i>S. aureus</i> coinfection, despite a delay in viral clearance. Mechanistically, our results from in vivo studies indicate that influenza-induced monocytes serve as reservoirs for intracellular <i>S. aureus</i> survival, thereby promoting bacterial resistance to antibiotic treatment. Blocking CCR2 with a small molecular inhibitor (PF-04178903), in conjunction with antibiotic treatment, enhanced lung bacterial clearance and significantly improved animal survival. Collectively, our study demonstrates that inflammatory monocytes constitute an important and hitherto underappreciated mechanism of the conflicting immune requirements for viral and bacterial clearance by hosts, which subsequently leads to exacerbated outcomes of influenza and <i>S. aureus</i> coinfection.
Complex interventions or complex systems? Implications for health economic evaluation
Authors: Alan Shiell, Penelope Hawe, Lisa Gold
Journal: BMJ (2008)

Although guidelines exist for evaluating complex interventions, they may be of little help in dealing with the multiple effects of interventions in complex systems such as hospitals. <b>Alan Shiell</b>,<b> Penelope Hawe</b>, and<b> Lisa Gold</b> explain why it is important to distinguish the two types of complexity
British benevolence and betrayal
Authors: Padmanabhan Badrinath
Journal: BMJ (2007)

We select the letters for these pages from the rapid responses posted on bmj.com favouring those received within five days of publication of the article to which they refer.Letters are thus an early selection of rapid responses on a particular topic.Readers should consult the website for the full list of responses and any authors' replies, which usually arrive after our selection. cnri/spl Acute bronchiolitis risk of hyponatraemiaBush and Thomson stated that electrolytes should be determined only in infants with bronchiolitis who are dehydrated. 1 However hyponatraemia is seen in up to 33% of children in hospital with this disease. 2It is unrelated to dehydration and has been associated with administration of intravenous fluids together with increased antidiuretic hormone values. 3 4 It can cause generalised tonic-clonic seizures, 2 which may be refractory to anticonvulsants.The National Patient Safety Agency has issued an alert aimed at reducing the risk of hyponatraemia in children -electrolytes should be determined before starting intravenous fluids and at least daily afterwards. 5 Fluids should be restricted in children with hyponatraemia who are receiving intravenous 0.9% saline (with 5% dextrose) and who have high antidiuretic hormone concentrations.
Growth Velocity in a Child on Prolonged Hemodialysis
Authors: James C. M. Chan
Journal: JAMA (1977)

SECONDARY hyperparathyroidism, renal osteodystrophy, and growth failure nearly invariably develop in children on prolonged hemodialysis.<sup>1-3</sup>We report our experience with a child who showed acceleration of growth velocity in response to treatment with the analogue (1-α-hydroxyvitamin D<sub>3</sub>) of the kidney hormone, 1,25 dihydroxyvitamin D<sub>3</sub>(1,25-[OH]<sub>2</sub>-D<sub>3</sub>). <h3>Report of a Case</h3> An 11-year-old girl entered the hemodialysis program for irreversible end-stage kidney failure secondary to focal segmental glomerulosclerosis. Over the next four years, she received four to six hours of dialysis treatment three times per week on parallel flow and/or coil disposable dialyzers. Vascular access, dialysis procedures, delivery system, and dietary and antihypertensive therapy were identical to the standard methods previously reported from this unit.<sup>1,4,5</sup>The caloric and protein intakes at 12,13, and 14 years of age are shown in the Table. Treatment with 1-α-hydroxyvitamin D<sub>3</sub>(1-α-OH-D<sub>3</sub>) was initiated four months prior to
Rheumatoid Lung Disease as Seen on PET/CT Scan
Authors: Sanjeev Bagga
Journal: Clinical Nuclear Medicine (2007)

We present the case of a 63-year-old woman chronic smoker with a history of severe rheumatoid arthritis, who presented with dyspnea and cough. Her chest x-ray film and CT scan (as part of a PET/CT scan) showed multiple lung nodules and a left pleural effusion. A PET scan (as part of a PET/CT scan) revealed no uptake in the larger lung nodules and intense left pleural uptake. The findings favored rheumatoid lung disease with rheumatoid pleural involvement, but malignant involvement was not excluded. A CT-guided lung and pleural biopsy confirmed the diagnosis of rheumatoid lung disease. On the basis of these findings, the patient was put on immunomodulators and responded to treatment.
Maximal Androgen Blockade: Final Analysis of EORTC Phase III Trial 30853
Authors: L.J. Denis, F. Keuppens, P.H. Smith, P. Whelan, J.L. Carneiro de Moura, D. Newling, A. Bono, R. Sylvester, for the EORTC Genito-Urinary Tract Cancer Cooperative Group and the EORTC Data Center
Journal: European Urology (1998)
PATENT DUCTUS ARTERIOSUS
Authors: Morse J. Shapiro
Journal: JAMA (1952)

To the Editor:  —InThe Journalfor Sept 27, page 419, is an editorial on a paper by Rutstein, Nickerson, and Heald concerning the possible relationship between patent ductus arteriosus and maternal rubella. I should like to call attention to the fact that before any such statistical study can be of any significance it must be determined whether or not patent ductus arteriosus as an isolated lesion is in fact a developmental congenital lesion. I have pointed out in a number of articles that it has always been my impression that patent ductus arteriosus is not a developmental abnormality but is simply the result of failure of closure of the ductus when the newborn infant takes its first breath. The extensive studies of Barclay and his group at Oxford and the study of Clark and Kennedy and others support this view. Maternal rubella, and no doubt other infectious diseases, are
Doctors advise women not to drink any alcohol during pregnancy
Authors: Lisa Hitchen
Journal: BMJ (2007)

Officials in Nigeria have filed criminal and civil charges against Pfizer for its role in the deaths and disabilities of children who were treated with an experimental drug during a meningitis outbreak in Kano in 1996.The charges, filed by government prosecutors in Nigeria, follow three attempts by families of the children to sue in US courts.All three attempts were denied after Pfizer successfully argued that the US courts were not an appropriate forum.Four separate legal actions have been filed in Nigeria, including 31 criminal counts against 10 people, according to the Washington Post (www.washingtonpost.com, 2 Jun, "Pfizer faces new charges over Nigerian drug test").The plaintiffs also seek a total of $9bn (£4.5bn; €7bn) in civil suits.The charges stem from Pfizer's test of its unlicensed drug, trovafloxacin (Trovan) to treat 100 children with meningitis.A comparator group of 100 children were treated with a low dose of ceftriaxone.Suits on appeal in US courts charge Pfizer with causing harm to the children in both arms of the trial, alleging that a number of the children either died or were left deaf, mute, or brain damaged.The families allege that the company failed to tell them that their children were being enrolled in an experimental drug trial and that free, effective treatment was available from Médecins Sans Frontières at the same hospital.Five children in the trovafloxacin arm and six in the ceftriaxone arm died, according to Pfizer.Pfizer issued a statement in response to the charges, saying "Pfizer continues to emphasise-in the strongest terms-that the 1996 Trovan clinical study was conducted with the full knowledge of the Nigerian government and in a responsible and ethical way consistent with the company's abiding commitment to patient safety."Any allegations in these lawsuits to the contrary are simply untrue." Niger�ia files cr�iminal char�ges against Pfizer�
THE TREATMENT OF BRONCHIAL ASTHMA
Authors: ALBERT H. ROWE
Journal: JAMA (1925)

The treatment of bronchial asthma discussed in this article depends largely on the work of I. C. Walker and R. V. Cooke. To Walker, especially, belongs the credit of demonstrating, from 1917 to 1920, through thirty articles, that protein sensitization is the cause of most bronchial asthma and of outlining a workable method of diagnosis and treatment. To Cooke belongs the credit of demonstrating the importance of inhalants in the etiology of bronchial asthma. This paper is based on 234 cases of bronchial asthma in which the patients have cooperated satisfactorily in their treatment during the years 1923 and 1924. No cases are reported in which the patients have not cooperated and have not been under observation for a minimum of four months. In cases treated before 1923 the results were not as good as those reported here because of our lack of knowledge of many of the causes of
Medical students see that academic misconduct is common
Authors: G. Eysenbach
Journal: BMJ (2001)

EDITOR—Rennie and Crosby found that the threshold for cheating is low among medical students.1 In an accompanying editorial Glick commented that a “pervasive institutional culture of integrity is essential” to encourage professional conduct and minimise fraud.2 Academics should be a role model in terms of good scientific practice, but we are far from this ideal.

In 2000 I introduced into the curriculum a seminar for fifth year medical students. We discussed principles of scientific integrity, according to guidelines of the German research …
Small-molecule activator of glutamate transporter EAAT2 translation provides neuroprotection
Authors: Qiongman Kong, Ling-Chu Chang, Kou Takahashi, Qibing Liu, Delanie A. Schulte, Liching Lai, Brian Ibabao, Yuchen Lin, Nathan Stouffer, Chitra Das Mukhopadhyay, Xuechao Xing, Kathleen I. Seyb, Gregory D. Cuny, Marcie A. Glicksman, Chien-Liang Glenn Lin
Journal: Journal of Clinical Investigation (2014)

Glial glutamate transporter EAAT2 plays a major role in glutamate clearance in synaptic clefts. Several lines of evidence indicate that strategies designed to increase EAAT2 expression have potential for preventing excitotoxicity, which contributes to neuronal injury and death in neurodegenerative diseases. We previously discovered several classes of compounds that can increase EAAT2 expression through translational activation. Here, we present efficacy studies of the compound LDN/OSU-0212320, which is a pyridazine derivative from one of our lead series. In a murine model, LDN/OSU-0212320 had good potency, adequate pharmacokinetic properties, no observed toxicity at the doses examined, and low side effect/toxicity potential. Additionally, LDN/OSU-0212320 protected cultured neurons from glutamate-mediated excitotoxic injury and death via EAAT2 activation. Importantly, LDN/OSU-0212320 markedly delayed motor function decline and extended lifespan in an animal model of amyotrophic lateral sclerosis (ALS). We also found that LDN/OSU-0212320 substantially reduced mortality, neuronal death, and spontaneous recurrent seizures in a pilocarpine-induced temporal lobe epilepsy model. Moreover, our study demonstrated that LDN/OSU-0212320 treatment results in activation of PKC and subsequent Y-box–binding protein 1 (YB-1) activation, which regulates activation of EAAT2 translation. Our data indicate that the use of small molecules to enhance EAAT2 translation may be a therapeutic strategy for the treatment of neurodegenerative diseases.
SC-07 * CYCLIC INTRANASAL APPLICATION OF NEURAL STEM CELL-MEDIATED ENZYM/PRODRUG THERAPY USING A NOVEL HSV-THYMIDINE KINASE VARIANT INHIBITS INTRACEREBRAL GLIOMA GROWTH AND IMPROVES SURVIVAL
Authors: L. Duhrsen, M. Reitz, M. Henze, J. Sedlacik, K. Riecken, B. Fehse, M. Westphal, N. O. Schmidt
Journal: Neuro-Oncology (2014)

We have recently introduced the concept of intranasal application of NSCs as a noninvasive and direct alternative delivery method for glioma-targeting NSCs. Here, we demonstrate that the repeated non-invasive intranasal administration of tumor-targeting NSC is able to deliver a suicide gene (TK.007) to intracerebrally growing human glioblastoma xenografts. Murine NSC were genetically modified to stably express a novel, codon-optimized HSVtk(A168H) mutant (TK.007). The biological activity of the NSC-mediated TK.007/ganciclovir (GCV) system was assessed in cell survival and bystander assays using various human glioma cell lines. Therapeutic effects of intratumoral and intranasal NSC-TK007 applications alone and the sequential combinations of both was tested using an intracranial U87 human glioblastoma model in nude mice. Therapeutic efficiency was determined by assessment of tumor size by 7T MR-imaging and by establishment of Kaplan-Meier survival curves. Tumor targeted migration was demonstrated by intravital imaging of luciferase-expressing NSC. Cell survival and bystander assays confirmed the GCV catalytic activity of NSC-expressed TK007 in a GCV dose dependent manner and a significant bystander effect at 12.5% of cells. Tumor targeted migration was mediated by intracerebral gradients of SDF-1. In glioma-bearing mice a single intratumoral application of NSC-TK007 followed by systemic prodrug application of GCV lead to a significant tumor growth inhibition of 72% versus the control groups at day 22 and translated in a prolonged survival time. Mice recieving a cyclic intranasal application of NSC-TK.007 alone displayed a signifcant longer survival than the controls. This effect was significantly enhanced when cyclic intranasal NSC-TK.007 therapy was preceded by a single intratumoral application of NSC-TK007 and led to a significant tumor growth inhibition of >95% and significantly improved survival time. Our findings establish that the intranasal application of therapeutically-modified NSC is a safe and non-invasive application method which allows a chronic treatment during the disease course.
The Duel between Dual Antiplatelet Therapies
Authors: Richard A. Lange, L. David Hillis
Journal: New England Journal of Medicine (2013)

Current guidelines for patients who are being considered for percutaneous coronary intervention (PCI) recommend dual antiplatelet therapy (aspirin and a platelet adenosine diphosphate [ADP]–receptor antagonist) to minimize periprocedural complications.1 Clopidogrel is usually administered in patients with stable angina,2 whereas patients with an acute coronary syndrome may benefit from a more potent ADP-receptor antagonist. In such patients, prasugrel3 or ticagrelor4 before PCI, as compared with clopidogrel, results in an absolute reduction in ischemic periprocedural complications of approximately 2 percentage points and a relative-risk reduction of 16 to 19%, albeit with an increased risk of bleeding. Unfortunately, because all these agents are . . .
491. Mosaic AAV Vectors Display Novel Properties for Neuronal Transduction
Authors: Stanley G. LeRoy, Laryssa A. Comer, Fabricio F. Costa, Marike L.D. Broekman, Miguel Sena-Esteves
Journal: Molecular Therapy (2006)

Adeno-Associated Virus (AAV) vectors are one of the most promising vehicles for in vivo gene delivery to the Central Nervous System because of high titers and the absence of neuro-toxicity. In addition to the classic serotype capsids, it is possible to construct chimeric, or mosaic serotypes using transcapsidation. We have produced AAV 1/2, AAV 1/8 and AAV 2/8 mosaic vectors by mixing AAV1, 2, and 8 complementing genomes at 1:1 ratios during packaging. The packaged vector genome was the same in all three mosaics carrying AAV2 inverted terminal repeats expressing GFP under the control of a CBA promoter. We produced mosaic vector stocks with titers of 1013 genome copies/ mL. We compared the gene transfer efficiency of these mosaic vectors, single serotypes vectors AAV1, 2, 5 and 8 and 1:1 mixtures of parental serotypes in primary mouse neuronal cortical cultures infected at MOIs of 104 and 3 x104. AAV1 was the most efficient of the single serotype vectors. The efficiency of the mixtures of single serotype AAVs was as good as the best of the single serotypes in the mixture. All three mosaics appeared to be more efficient than AAV1 regarding number of transduced cells and intensity of GFP expression. We also investigated the mosaic serotypes in two in vivo delivery modalities, cerebral intraventricular injections in neonatal mice and direct striatal injection in 6-8 week-old mice. We found that mosaic serotypes injected in neonates were able to efficiently transduce the cortex, hippocampus, striatum, olfactory bulb and the cerebellum. In adult mice, we compared the transduction efficiency of different AAV serotypes (1, 2, 5, 8 and mosaics 1/2, 1/8, 2/8) by Convection Enhanced Delivery (CED) to the mouse striatum. The mosaics showed lower gene transfer efficiency and distribution in the striatum than the best parental serotype (AAV8). However, the unique extra- striatal pattern of transduction for AAV1/8 and AAV2/8 vectors, with neuronal transduction in the ventral posteromedial and ventromedial thalamic nuclei, suggests that these mosaic capsids display new properties in vivo and can be used to generate AAV vectors with alternative in vivo tropism.
Accident and emergency services.
Authors: D V Skinner
Journal: BMJ (1991)

these first four patients, three had considerable arrhythmia; two developed heart failure, one of whom died.Death from ischaemic heart disease has been linked to environmental temperature,'13 and one Canadian study showed an excess of deaths from myocardial infarction on the day after heavy snowfall.4These authors postulated a snow shovelling effect, based on the time delay between snowfall and increased death rate and its relation to local snow clearance bylaws.Residents in Toronto are required to clear sidewalks of snow within a certain number of hours, and studies there showed in- creased deaths from cardiac causes on the day of snowfall.In Montreal the responsibility for clearing rests with the local authority and the increased death rate occurred on the following day, when private drives, steps, and paths were more likely to be cleared.In the United Kingdom snowfall is particularly ephemeral.We suggest that clearing snow from roads and pavements should be the local authority's responsibility and that people with cardiac risk factors should be advised to let nature clear the drive and to leave the shovel in the shed.
Desmond Joseph Atherton
Authors: D. Atherton
Journal: BMJ (2002)

Former general practitioner Coventry, Whrwickshire (b Charley, Lancashire, 1920; q Manchester 1944; DObstRCOG), died on 9July 2002 after a series of strokes. After 10 years with a general practice in Cov entry, he left to establish a singlehanded prac tice in his home. No boundary existed between his work and his after-work activities. Today he would have been considered a workaholic, but he was simply at his most relaxed when with or on call for his patients. His favourite holiday was walking, particu larly in the Lake District His daily exercise was to gather and to saw logs for his fire. There was little he did not know about logs, their expert dissection, and the qualities they would demonstrate when they burned. He leaves a wife, Hildegard; four children; and seven grandchildren. [David Atherton] ^+
771. Complexes of Nucleic Acids with Multivalent Cationic Lipids for the Study of Delivery Pathways and Mechanisms: From Plasmid DNA to siRNA
Authors: Kai Ewert, Nathan F. Bouxsein, Christopher S. McAllister, Heather M. Evans, Charles E. Samuel, Cyrus R. Safinya
Journal: Molecular Therapy (2005)

Complexes of nucleic acids (NAs) with cationic lipids (CLs) are promising vectors with numerous potential applications, particularly in medicine. Striking differences are observed in their behavior, depending on the nature of the transported nucleic acid. As synthetic vectors, CL-NA complexes can carry NAs of arbitrary size and are safer and easier to produce than viruses. To design optimized lipid vectors, it is indispensable to better understand the mechanism of transfection and how it is affected by NA size, CL-NA complex structure, lipid structure and lipid composition. Tailored lipid molecules have proven extremely useful for this kind of investigations. We have designed several series of multivalent cationic lipids with systematically varied headgroup charge (+1 up to +16) and lipid tail. Experiments with lamellar DNA complexes of these lipids have identified the complex' membrane charge density |[oacute]|M, a lipid-independent measure of the bilayer composition, as a universal parameter for transfection: efficiency plots for diverse, mono- to pentavalent lipids merge onto a single curve when plotted against |[oacute]|M. We compare those results with recent investigations using the same new lipids complexed with short interfering RNA (siRNA) to effect RNA interference (RNAi). RNAi is a novel pathway for inducing post-transcriptional gene silencing: the introduction of synthetically prepared duplexes of 19-21 bp siRNA into mammalian cells leads to the sequence-specific reduction of target mRNAs by enzymatic cleavage and subsequent knockdown of their encoded proteins. The co-transfection of a target and a non-target reporter plasmid into cells, followed by CL-mediated delivery of a target-specific siRNA allows us to simultaneously probe the specific silencing efficiency (SE) of the target plasmid and the non-specific silencing of both plasmids. Varying the ratio of neutral to cationic lipid as well as the CL:siRNA charge ratio, we have created phase diagrams of specific, non-specific and effective silencing as a function of these parameters for several monovalent to pentavalent lipids. These phase diagrams facilitate the identification of regimes of optimum performance. In addition, x-ray diffraction was used to determine the structure of the CL-siRNA complexes. In the phase diagrams, regions with high levels of non-specific silencing are observed. We have used several cell toxicity and cell viability assays to investigate the causes of this non-specificity. In contrast to DNA complexes, evidence for both lipid and NA-based unspecific knockdown of proteins is found. Funding provided by NIH GM-59288, AI-20611 and AI-12520.
Treatment of patients with pancreatic endocrine tumours using a new long-acting somatostatin analogue symptomatic and peptide responses.
Authors: S M Wood, M E Kraenzlin, T E Adrian, S R Bloom
Journal: Gut (1985)

Seven patients with gut and pancreatic endocrine tumours have been treated with a long acting somatostatin analogue (SMS 201-995), given as a twice daily subcutaneous injection. This produced dramatic improvement in their endocrine related symptoms, in association with a fall in circulating tumour peptides. One of these patients has now been treated for seven months with this analogue which has controlled his previously life threatening diarrhoea caused by a malignant VIP secreting tumour. He gives his own injections twice daily, and has returned to a full and active life. This is a promising agent both for acute treatment of peptide hypersecretion, and for the long term management of some patients who are unresponsive to other available therapy.