tbuckley/cabot-search huggingface dataset:
Engineering of Human Pluripotent Stem Cells by AAV-mediated Gene Targeting
Authors: Iram F Khan, Roli K Hirata, Pei-Rong Wang, Yi Li, Jordan Kho, Angel Nelson, Yunwen Huo, Maja Zavaljevski, Carol Ware, David W Russell
Journal: Molecular Therapy (2010)

Precise genetic manipulation of human pluripotent stem cells will be required to realize their scientific and therapeutic potential. Here, we show that adeno-associated virus (AAV) gene targeting vectors can be used to genetically engineer human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). Different types of sequence-specific changes, including the creation and correction of mutations, were introduced into the human HPRT1 and HMGA1 genes (HPRT1 mutations being responsible for Lesch–Nyhan syndrome). Gene targeting occurred at high frequencies in both ESCs and iPSCs, with over 1% of all colony-forming units (CFUs) undergoing targeting in some experiments. AAV vectors could also be used to target genes in human fibroblasts that were subsequently used to derive iPSCs. Accurate and efficient targeting took place with minimal or no cytotoxicity, and most of the gene-targeted stem cells produced were euploid and pluripotent. Precise genetic manipulation of human pluripotent stem cells will be required to realize their scientific and therapeutic potential. Here, we show that adeno-associated virus (AAV) gene targeting vectors can be used to genetically engineer human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). Different types of sequence-specific changes, including the creation and correction of mutations, were introduced into the human HPRT1 and HMGA1 genes (HPRT1 mutations being responsible for Lesch–Nyhan syndrome). Gene targeting occurred at high frequencies in both ESCs and iPSCs, with over 1% of all colony-forming units (CFUs) undergoing targeting in some experiments. AAV vectors could also be used to target genes in human fibroblasts that were subsequently used to derive iPSCs. Accurate and efficient targeting took place with minimal or no cytotoxicity, and most of the gene-targeted stem cells produced were euploid and pluripotent.
The death of DNR
Authors: D. K Sokol
Journal: BMJ (2009)

Can a change of terminology improve end of life care?

In a scene in the film Dumb and Dumber , Lloyd Christmas, played by Jim Carrey, sees a fellow diner collapse in a restaurant. The man clutches his abdomen and complains of an ulcer. “It’s OK,” Christmas reassures the victim, “I know CPR.” The man resists mouth to mouth resuscitation. “It’s a lot easier if you just lay back,” Christmas notes.

While perhaps not quite as ignorant as the well meaning Christmas, many non-clinicians hold rosy views about the nature and effectiveness of cardiopulmonary resuscitation (CPR). Several studies have underlined their misplaced optimism: in one, the 269 respondents reported a mean expected survival rate for CPR of 65%1; in another, 81% of respondents over 70 years old believed the likelihood of leaving the hospital after a cardiac arrest to be at least 50%.2 The real figure, for all in-hospital cardiac arrests, is roughly 14%, and many survivors will have new functional or neurological impairments.3

The illusion of CPR’s effectiveness can lead patients and relatives to make ill informed choices about care at the end of …
Screening, ethics and the law.
Authors: E. S. Williams, G. J. Waldron
Journal: BMJ (1992)

Vitamin C depletion and pressure sores EDITOR,-Helen F Goode and colleagues cite the main risk factors for pressure sores in elderly people-namely, acute illness, poor mobility, long periods on high pressure surfaces, incontinence, and confusion.'They did not control for these effects so are unwise to conclude that there is a significant association between vitamin C and the development of pressure sores in elderly subjects with femoral neck fractures, particularly since the patients were unselected.Rather than seek a "clear cut risk factor which determines why one patient should develop a sore given the same conditions as another patient," the authors could perhaps have used an instrument such as the Waterlow pressure sore assessment score.2This instrument acknowledges that the risk of developing pressure sores is multifactorial, but its application allows an appropriate care plan to be constructed, including the allocation of equipment such as mattresses to prevent the condition arising in the first place.'Such a system is used routinely in many units caring for elderly people.
A Study of the Manifestations of Rheumatic Fever Following Cessation of Therapy
Authors: EDWARD E. FISCHEL, CHARLES W. FRANK, MARJORIE T. BELLOWS
Journal: Circulation (1958)

Following cessation of therapy for acute rheumatic fever manifestations of rheumatic activity frequently reappear. The incidence of these manifestations and their severity were studied during the 3-week observational period in 257 patients treated as part of the Cooperative Clinical Trial on the treatment of rheumatic fever. From the analysis of these manifestations certain concepts may be derived concerning diagnostic and therapeutic criteria.
Liver adapts mitochondrial function to insulin resistant and diabetic states in mice
Authors: Andras Franko, Jürgen-Christoph von Kleist-Retzow, Susanne Neschen, Moya Wu, Philipp Schommers, Marlen Böse, Alexander Kunze, Ursula Hartmann, Carmen Sanchez-Lasheras, Oliver Stoehr, Michael Huntgeburth, Susanne Brodesser, Martin Irmler, Johannes Beckers, Martin Hrabé de Angelis, Mats Paulsson, Markus Schubert, Rudolf J. Wiesner
Journal: Journal of Hepatology (2013)
P190 QVA149 Once Daily Provides Significant Improvements in Lung Function Over 1 Year in Patients with COPD: The Enlighten Study: Abstract P190 Table 1
Authors: R Dahl, K Chapman, M Rudolf, R Mehta, P Kho, V Alagappan, I Berhane, H Chen, D Banerji
Journal: Thorax (2012)

<h3>Introduction</h3> QVA149 is a novel inhaled once-daily dual bronchodilator, containing a fixed-dose combination of the long-acting β<sub>2</sub>-agonist indacaterol and the long-acting muscarinic antagonist NVA237 (glycopyrronium) in development for the treatment of COPD. This study evaluated the long-term effect of QVA149 on lung function in patients with COPD. <h3>Methods</h3> This was a multicentre, double-blind, parallel group, placebo-controlled study in which patients with moderate-to-severe COPD were randomised (2:1) to receive QVA149 (110/50µg) or placebo once daily via the Breezhaler® device for 52 weeks. Treatment was taken in the morning at the same time of day. Lung function was measured as forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) at 30 and 60 minutes post-dose at clinic visits over 52 weeks. <h3>Results</h3> 339 patients (77% male, mean age 63 years; mean post-salbutamol FEV1 57% predicted, FEV1/FVC 54%) were randomised to receive QVA149 (n=226) or placebo (n=113); 86% and 79% of patients respectively completed treatment, respectively. QVA149 significantly increased FEV1 and FVC versus placebo at all assessment points (table). <h3>Conclusion</h3> QVA149 once daily provided rapid and clinically meaningful bronchodilation compared with placebo. No tachyphylaxis was observed and the bronchodilator effect was sustained over the 52 week treatment period. Ronal Dahl: he participated in advisory boards for Novartis, AstraZeneca, Boehringer-Ingelheim, Pﬁzer, ALK-Abello, UCB, Nycomed, Dainippon and ONO. Kenneth R Chapman: he holds the GSK-CIHR Research Chair in Respiratory Healthcare Delivery at the University Health Network, has served as a consultant to CSL Behring, GlaxoSmithKline, Novartis, Nycomed (Takeda), and Talecris (Grifols), and has received payment for lectures or service on speakers bureaus from Boehringer-Ingelheim, GlaxoSmithKline, Grifols, Nycomed (Takeda), Family Physicians Airways Group of Canada, Canadian Network for Respiratory Care, and Talecris. Michael Rudolf: he has been reimbursed by the following companies for speaking at educational meetings, for consultancy work, or for attending scientific conferences: Almirall, Astra-Zeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Merck Sharp and Dohme, Napp, Novartis, Pfizer, Schering-Plough, and Teva. Rajendra Mehta: he has no conflicts of interest.
Prevention of gastroduodenal damage induced by non-steroidal anti-inflammatory drugs: controlled trial of ranitidine.
Authors: R. S. Ehsanullah, M. C. Page, G. Tildesley, J. R. Wood
Journal: BMJ (1988)

To evaluate the prophylactic effect of ranitidine 150 mg twice daily in patients requiring one of the following non-steroidal anti-inflammatory drugs: naproxen, piroxicam, diclofenac, and indomethacin. In addition, risk factors were studied in order to help in targeting of such treatment to specific groups of patients.Double blind, placebo controlled, randomised, parallel group with endoscopic assessments at 0, 4, and 8 weeks.Multicentre outpatient study at secondary referral centres in five European countries. PATIENTS--297 patients with rheumatoid arthritis or osteoarthritis over the age of 18 without lesions in the stomach and duodenum at baseline endoscopy (after one week without taking non-steroidal anti-inflammatory drugs). Those taking other antirheumatic agents, concomitant ulcerogenic drugs, or treatment for peptic ulcers within the previous 30 days were excluded. Age, sex, arthritic disease, and type of non-steroidal anti-inflammatory drug used were comparable in the two treatment groups. In all, 263 patients completed the trial.Ranitidine 150 mg twice daily or placebo (plus the selected non-steroidal anti-inflammatory drug) was prescribed within five days after the baseline endoscopy for two consecutive periods of four weeks. Paracetamol was permitted during the study, but not antacids. Patients were withdrawn if the most severe grade of damage (including ulceration) was found at the four week endoscopy or when indicated, or with lesser damage at the investigator's discretion.Frequency of gastric and duodenal ulceration or lesions, or both.The cumulative incidence of peptic ulceration by eight weeks was 10.3% (27/263); 2 out of 135 (1.5%) developed duodenal ulceration in the ranitidine group, compared with 10 out of 126 (8%) taking placebo. The frequency of gastric ulceration was the same (6%) for the two groups at eight weeks. Though significantly fewer gastric lesions developed in the ranitidine group by eight weeks. The frequency of non-ulcerative lesions in the duodenum did not differ greatly for the two groups at either time point. Twelve out of 75 (16%) patients taking piroxicam developed peptic ulceration, of whom two thirds had duodenal ulceration. Patients with a history of peptic ulcer were particularly susceptible to recurrent ulceration, against which ranitidine offered some protection.Ranitidine 150 mg twice daily significantly reduced the incidence of duodenal ulceration but not gastric ulceration when prescribed concomitantly with one of four commonly used non-steroidal anti-inflammatory drugs.
beta-catenin expression in benign and malignant pilomatrix neoplasms
Authors: A.M. Hassanein, S.M. Glanz
Journal: British Journal of Dermatology (2004)

Beta-catenin is a 92-kDa protein, initially identified as a coprecipitating species with the E-cadherin cell-cell adhesive complex. It plays a role in signal transduction in the Wnt signalling pathway and has been identified as an oncogene in colon cancer and melanoma. Exon 3 beta-catenin-activating mutations were found in 75% of cases of pilomatricoma (PM). Previous studies have shown that nuclear and/or cytoplasmic staining may correlate with beta-catenin gene mutation.Because the immunohistochemical expression of beta-catenin in the nucleus or the cytoplasm correlates with beta-catenin mutation, we studied the immunohistochemical profile of beta-catenin expression in normal scalp hair follicles and in PM and pilomatrix carcinoma (PC).We reviewed 21 cases of PM and five cases of PC using immunohistochemical staining with commercially available antibody in a standard fashion on formalin-fixed paraffin-embedded tissue samples.All 26 tumours displayed both nuclear and cytoplasmic staining in the basaloid cells with focal membranous staining. Shadow cells were negative in all tumours. Normal control sections from the scalp displayed nuclear reactivity of the matrical cells, mostly concentrated in the supramatrical zone of hair follicles. Membranous staining was present along the intercellular junctions of the epidermis and along the outer and inner root sheaths of hair follicles. We have found similar patterns of beta-catenin nuclear and cytoplasmic expression in both PM and PC.Despite the shared beta-catenin expression, the biological behaviour of PM and PC is markedly different. These two tumours probably share the activation of a common cellular pathway that could be related to their shared method of keratinization or a shared dysfunction of the cellular adhesion complex and consequently tumorigenesis. To the best of our knowledge, this is the first report on the beta-catenin immunohistochemical expression profile in PC.
TUBERCULOSIS IN INFANCY AND CHILDHOOD: FROM THE STANDPOINT OF PREVENTIVE MEDICINE
Authors: C. McNeil
Journal: BMJ (1912)

BDIARNALparatively late, the various vomits followina a definite sequence of which faecal vomit is the last aid comparatively late stage, except in impacted gall stone, whether in the cystic dtuct or initestine, when it appears very early.4. The amount vomited is far greater than tlhe amount taken in.5. In cases of intestinal occltusion-say, of annular strictLure of the small intestine-the more the faecal vomiting, the more relieved the patient should feel.On the contrarv, the more toxic he appears.6.In cases that recover there is an intenise dliarrhoea at first of small quantity of dirty browil material, theni of large amount of light liquid, lemon-yellow faeces, showinlg that the liver cells have not regained their normal powers.7. If the faecal vomitinig occurs sometime suibsequienlt to the inisertion of a drainage tube in the peritoneal cases-that is, non-occlusioni cases-tlhen the patient will probably recover; wlhereas if operation is deferred unltil it has occulrredl the case is hopeless.Ani exception must be made in the case of impacted gall stonie, as faecal vomiting is so ofteni anl early symptom, and followed by temporary relief.8.A most fatal objection is that the higher up the obstruction
T Cell-Derived Protein S Engages TAM Receptor Signaling in Dendritic Cells to Control the Magnitude of the Immune Response
Authors: Eugenio A. Carrera Silva, Pamela Y. Chan, Leonel Joannas, Andrea E. Errasti, Nicola Gagliani, Lidia Bosurgi, Maurice Jabbour, Anthony Perry, Faye Smith-Chakmakova, Daniel Mucida, Hilde Cheroutre, Tal Burstyn-Cohen, Jonathan A. Leighton, Greg Lemke, Sourav Ghosh, Carla V. Rothlin
Journal: Immunity (2013)
Anti-peripheral nerve myelin antibodies in Guillain-Barre syndrome bind a neutral glycolipid of peripheral myelin and cross-react with Forssman antigen.
Authors: C L Koski, D K Chou, F B Jungalwala
Journal: Journal of Clinical Investigation (1989)

During acute-phase illness, serum of patients with Guillain-Barre syndrome (GBS) contain complement-fixing antibodies (Ab) to peripheral nerve myelin (PNM). We investigated PNM lipids as putative antigens for these Ab since GBS serum retained significant reactivity to PNM treated with protease. Ab binding to specific lipids was studied with a C1 fixation and transfer (C1FT) assay using fractions of PNM lipid reincorporated into liposomes as antigen targets or to lipids on HPTLC plates with peroxidase-labeled goat Ab to human IgM. Reactivity was detected to a neutral glycolipid (NGL) of human PNM with a similar number of carbohydrates residues to that of Forssman hapten (Forss). Anti-NGL Ab titers in GBS patients (50-220 U/ml) were significantly elevated over disease and normal controls (0-5 and 0-6 U/ml). We studied possible antigenic cross-reactivity of these Ab with Forss by first quantitating Ab activity with C1FT assay and liposomes containing Forss. All 12 GBS sera tested showed titers (54-272 U/ml) significantly elevated over 11 disease controls (0-22 U/ml) and 25 normal controls (0-11 U/ml). GBS serum Ab reacted with Forss isolated from dog nerve or sheep erythrocytes on HPTLC plates. Further, absorption of 80-100% of anti-NGL Ab activity and 17-97% of anti-PNM Ab activity from eight GBS patient serums was accomplished with liposomes containing Forss but not with control liposomes. In seven GBS patients anti-NGL Ab activity represented only a portion of anti-PNM Ab activity. These results suggest that a glycolipid with antigenic cross-reactivity to Forssman hapten may be responsible for some of the anti-PNM Ab activity in GBS.
Selective inhibition of endothelium-dependent vasodilator capacity by Escherichia coli endotoxemia.
Authors: J L Parker, H R Adams
Journal: Circulation Research (1993)

Increased release of endothelium-derived relaxing factor/nitric oxide has been proposed as the final common pathway for vasodilator responses to gram-negative lipopolysaccharide (endotoxin). To test this hypothesis, we examined endothelium-dependent and endothelium-independent vasodilator agents in vascular smooth muscle isolated from guinea pigs 16 hours after injection of saline (control group) or induction of Escherichia coli endotoxemia; aortic rings (approximately 1 mm in diameter) were studied with standard isometric tension techniques. Endotoxemia resulted in a significant loss of vasodilator responses to the endothelium-dependent receptor agonists acetylcholine (10(-10)-10(-5) M) and ADP (10(-8)-10(-5) M). In contrast, endotoxemia did not affect vasodilator responses to either the endothelium-dependent receptor agonist substance P (10(-11)-10(-7) M), the endothelium-dependent and receptor-independent agonist A23187 (10(-9)-10(-6) M), or the endothelium-independent agonist nitroprusside (10(-10)-10(-4) M). The nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) inhibited the vasodilator response to acetylcholine more in vessels from lipopolysaccharide-injected than control guinea pigs. Unexpectedly, L-NAME converted the endothelium-dependent vasodilator action of ADP to an endothelium-dependent vasoconstrictor response that was blocked individually by the cyclooxygenase inhibitor indomethacin, the thromboxane synthase inhibitor dazoxiben, and the thromboxane A2 receptor antagonist SQ29548. We conclude that in vivo endotoxemia inhibits the constitutive isoform of nitric oxide synthase in endothelial cells by selectively disrupting receptor-coupled activation mechanisms shared by acetylcholine and ADP. Furthermore, since L-NAME unmasks a thromboxane A2-mediated vasoconstrictor action of the endogenous purinoceptor agonist ADP, drugs that inhibit nitric oxide synthase could exacerbate sepsis-induced vasoconstriction and ischemia by synergizing with lipopolysaccharide-induced inhibition of endothelial nitric oxide synthase.
Growth-Differentiation Factor 15 Predicts Worsening of Albuminuria in Patients With Type 2 Diabetes
Authors: Merel E. Hellemons, Magdalena Mazagova, Ron T. Gansevoort, Robert H. Henning, Dick de Zeeuw, Stephan J.L. Bakker, Hiddo J. Lambers-Heerspink, Leo E. Deelman
Journal: Diabetes Care (2012)

Development of micro- or macroalbuminuria is associated with increased risk of cardiorenal complications, particularly in diabetes. For prevention of transition to micro- or macroalbuminuria, more accurate prediction markers on top of classical risk markers are needed. We studied a promising new marker, growth-differentiation factor (GDF)-15, to predict transition to increasing stage of albuminuria in type 2 diabetes mellitus (T2DM). In addition, we looked at the GDF-15 potential in nondiabetic subjects with hypertension (HT).Case and control subjects were selected from the PREVEND cohort, a large (n = 8,592), prospective general population study on the natural course of albuminuria, with >10 years of follow-up and repeated albuminuria measurements. We found 24 T2DM and 50 HT case subjects transitioning from normo- to macroalbuminuria and 9 T2DM and 25 HT case subjects transitioning from micro- to macroalbuminuria (average follow-up 2.8 years). Control subjects with stable albuminuria were pair matched for age, sex, albuminuria status, and diabetes duration. GDF-15 was measured in samples prior to albuminuria transition.Prior to transition, GDF-15 was significantly higher in case subjects with T2DM than in control subjects (median [IQR] 1,288 pg/mL [885-1,546] vs. 948 pg/mL [660-1,016], P < 0.001). The odds ratio for transition in albuminuria increased significantly per SD of GDF-15 (2.9 [95% CI 1.1-7.5], P = 0.03). GDF-15 also improved prediction of albuminuria transition, with significant increases in C statistic (from 0.87 to 0.92, P = 0.03) and integrated discrimination improvement (0.148, P = 0.001). In HT, GDF-15 was also independently associated with transition in albuminuria stage (2.0 [1.1-3.5], P = 0.02) and improved prediction significantly.We identified GDF-15 as a clinically valuable marker for predicting transition in albuminuria stage in T2DM beyond conventional risk markers. These findings were confirmed in nondiabetic HT subjects.
Nanoparticle formulations of histone deacetylase inhibitors for effective chemoradiotherapy in solid tumors
Authors: Edina C. Wang, Yuanzeng Min, Robert C. Palm, James J. Fiordalisi, Kyle T. Wagner, Nabeel Hyder, Adrienne D. Cox, Joseph M. Caster, Xi Tian, Andrew Z. Wang
Journal: Biomaterials (2015)
Influenza kills up to 25 000 people a year in England and Wales, report says
Authors: Roger Dobson
Journal: BMJ (2006)

A new analysis of the burden of influenza in England and Wales has been published by a team from the Health Protection Agency's centre for infections. 

The authors say that flu causes between 10 500 and 25 000 deaths a year in England and Wales and is responsible for about 800 000 visits to GPs a year, a seventh of all visits for respiratory disease ( Journal of Infection 2006 Nov 9, doi: 10.1016/j.jinf.2006.09.017). 

“Although there are significant uncertainties, …
IDSA: Better, Faster Diagnostics for Infectious Diseases Needed to Curb Overtreatment, Antibiotic Resistance
Authors: Bridget M. Kuehn
Journal: JAMA (2013)

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