tbuckley/cabot-search huggingface dataset:
“Arm's length” NHS bodies to be abolished in spending cull
Authors: Karen Hébert
Journal: BMJ (2004)

<h3>Abstract</h3> Fatty acid synthases (FASs) and polyketide synthases (PKSs) iteratively elongate and often reduce two-carbon ketide units in <i>de novo</i> fatty acid and polyketide biosynthesis. Cycles of chain extensions in FAS and PKS are initiated by an acyltransferase (AT), which loads monomer units onto acyl carrier proteins (ACPs), small, flexible proteins that shuttle covalently linked intermediates between catalytic partners. Formation of productive ACP-AT interactions is required for catalysis and specificity within primary and secondary FAS and PKS pathways. Here, we use the <i>Escherichia coli</i> FAS AT, FabD, and its cognate ACP, AcpP, to interrogate type II FAS ACP-AT interactions. We utilize a covalent crosslinking probe to trap transient interactions between AcpP and FabD to elucidate the first x-ray crystal structure of a type II ACP-AT complex. Our structural data are supported using a combination of mutational, crosslinking, and kinetic analyses, and long timescale molecular dynamics (MD) simulations. Together, these complementary approaches reveal key catalytic features of FAS ACP-AT interactions. These mechanistic inferences suggest that AcpP adopts multiple, productive conformations at the AT binding interface, allowing the complex to sustain high transacylation rates. Furthermore, MD simulations support rigid body subdomain motions within the FabD structure that may play a key role in AT activity and substrate selectivity. <h3>Significance Statement</h3> The essential role of acyltransferases (ATs) in fatty acid synthase (FAS) and polyketide synthase (PKS) pathways, namely the selection and loading of starter and extender units onto acyl carrier proteins (ACPs), relies on catalytically productive ACP-AT interactions. Here, we describe and interrogate the first structure of a type II FAS malonyl-CoA:ACP-transacylase (MAT) in covalent complex with its cognate ACP. We combine structural, mutational, crosslinking and kinetic data with molecular dynamics simulations to describe a highly flexible and robust protein-protein interface, substrate-induced active site reorganization, and key subdomain motions that likely govern FAS function. These findings strengthen a mechanistic understanding of molecular recognitions between ACPs and partner enzymes and provide new insights for engineering AT-dependent biosynthetic pathways.
Medical Impairment and Highway Crashes
Authors: Julian A. Waller
Journal: JAMA (1969)

Impairment to drivers or pedestrians from chronic medical problems, frequently acting at a subclinical level, is believed to be a contributing factor in 15% to 25% of crashes. In addition, alcoholism is a factor in a third of fatal crashes. Most drivers with medical problems should be reported to motor vehicle authorities. However, no more than a quarter of these drivers should have licenses revoked. For the rest, more effective control of the highway injury problem can result from efforts to simplify driving and walking tasks, to improve energy absorption capacity of vehicles and highways, and to improve emergency health services.
SAT0097 Changes In Bone Mineral Density in Patients with Recent-Onset Rheumatoid Arthritis
Authors: H. Heo, Y. J. Kim, B. S. Koo, M.-W. So, W. J. Seo, Y.-G. Kim, C.-K. Lee, B. Yoo
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Generalized bone loss and an increased risk of fractures are regarded as complications in rheumatoid arthritis. Variable clinical factors, inflammatory activity, and treatment regimens may contribute to the development of bone loss. <h3>Objectives</h3> We evaluated the association between the baseline disease activity and the changes in bone mineral density (BMD) after 1 year of treatment in a cohort of patients with recently diagnosed active rheumatoid arthritis (RA). <h3>Methods</h3> A total of 106 (92 women and 14 men) patients with recent onset RA from ASERA cohort were included in this study. Data on patient's demographic factors, disease activity score in 28 joints (DAS28), and anti-rheumatic drugs were obtained. Baseline and 1 year of follow up BMD in proximal femur sites (i.e., the total femur, femur neck, and trochanter) and lumbar spine were measured with dual energy X-ray absorptiometry. Univariate regression analyses were performed to determine association between clinical parameters and BMD loss after 1 year. <h3>Results</h3> The mean age of women and men was 50 ± 11 years and 59 ± 7 years, respectively and 54 patients in 92 women were postmenopausal status. The mean baseline DAS28 was 5.4 ± 1.2 (range; 2.6-8.6) and 30 (28.3%) patients were diagnosed as osteoporosis at baseline. After 1 year of treatment, the mean annualized rates of bone loss in the total femur, femur neck, trochanter, and L-spine were -1.41%/yr, -1.31%/yr, -2.07%/yr, and -0.78%/yr, respectively. Age, smoking, menopause, and high DAS28 were associated with prominent BMD loss in femur neck. Higher cumulative dose of corticosteroids was associated with significant bone loss in the spine and femur. The use of bisphosphonate had no significant protected effect against BMD loss in one year of treatment. <h3>Conclusions</h3> High baseline disease activity and increased dose of steroids are significantly associated with accelerated BMD loss in patients with active RA. Our findings suggest that suppression of inflammation at the initial treatment might reduce the bone loss and limited use of steroids can be essential for bone preservation. <h3>References</h3> Changes in bone mineral density in patients with recent onset, active rheumatoid arthritis. Annals of the rheumatic diseases (2008). 67(6). 823-8 <h3>Disclosure of Interest</h3> None Declared
Response to Letter Regarding Article, “Implementation of the Fifth Link of the Chain of Survival Concept for Out-of-Hospital Cardiac Arrest”
Authors: Takashi Tagami, Hiroyuki Yokota, Kazuhiko Hirata, Toshiyuki Takeshige, Masataka Satake, Junichiroh Matsui, Makoto Takinami, Shuichi Satake, Tokuo Yui, Kunihiro Itabashi, Toshio Sakata, Ryoichi Tosa, Shigeki Kushimoto, Hisao Hirama
Journal: Circulation (2013)
Transcatheter Subendocardial Infusion
Authors: Andreas Goette, Wolfgang Hartung, Michael Lesh, Clegg Honeycutt, Sidney Fleischman, David Swanson, Jonathan Langberg
Journal: Circulation (1996)

Background Catheter ablation with radiofrequency energy is feasible in a limited subset of patients with ventricular tachycardia. The purpose of this study was to evaluate a technique for mapping and ablation of ventricular myocardium with the use of transcatheter subendocardial infusion. Methods and Results A needle-tipped deflectable electrode catheter was used to deliver reagents to endocardial target sites. This was equipped with two central lumens to allow sequential administration of mapping and ablation injectants with minimal admixture. The mapping injectant consisted of a mixture of lidocaine, iohexal, and glycerin; the ablation injectant contained ethanol, iohexal, and glycerin. Infusion of the mapping injectant (1 cm 3 over 3 or 5 seconds, n=14) produced a stain on fluoroscopy and increased local capture threshold by 61%. No lesions resulted from mapping infusions. Infusion of the ethanol-containing injectant (n=48) produced discrete lesions, with a mean volume ranging from 0.6 to 1.5 cm 3 . There was a direct relationship between infusion volume, infusion duration, and resultant lesion volume. Fibrosis in a region of healed myocardial infarction did not impair diffusion of the injectant or affect lesion dimensions. Microscopic analysis of chronic lesions showed a sharply demarcated border zone between fibrotic and normal myocardium. Conclusions Transcatheter subendocardial infusion can be used to reversibly impair local excitability and mark an injection site fluoroscopically. Subendocardial injection of ethanol can predictably ablate a large volume of ventricular myocardium. Additional study of this system in an arrhythmia model will help to define its potential for mapping and ablation of hypotensive ventricular tachycardia.
Information technology and telemedicine in sub-Saharan Africa
Authors: H. S F Fraser
Journal: BMJ (2000)

Many developing countries have an acute shortage of doctors, particularly specialists. Sub-Saharan Africa has, on average, fewer than 10 doctors per 100 000 people, and 14 countries do not have a single radiologist.1 The specialists and services that are available are concentrated in cities. Workers in rural health care, who serve most of the population, are isolated from specialist support and up to date information by poor roads, scarce and expensive telephones, and a lack of library facilities.2 Can information technology offer solutions? If so, what technologies are likely to be most effective and economical?

The internet is making inroads into Africa: whereas three years ago only 12 countries in Africa had internet access, it is now available, at least in the capital city, in 53 out of 54 African countries.3 Free online resources include journals,4 research databases, and training courses.5

Email has many advantages …
CTLA-4 blockade in murine bone marrow chimeras induces a host-derived antileukemic effect without graft-versus-host disease
Authors: S Fevery, A D Billiau, B Sprangers, O Rutgeerts, C Lenaerts, J Goebels, W Landuyt, A Kasran, L Boon, X Sagaert, C De Wolf-Peeters, M Waer, P Vandenberghe
Journal: Leukemia (2007)
Abstract PD02-02: Characterization of Mammary Stem Cells during Embryogenesis
Authors: DD Engle, J Lin, B Spike, S Cheung, G. Wahl
Journal: Cancer Research (2010)

Abstract Mammary stem cells (MaSCs) play a key role in the development and maintenance of the breast. MaSCs self-renew and generate the different cell types of the breast such that a single MaSC can regenerate an entire functional mouse mammary gland. Similarly, tumors are heterogeneous, with some cells exhibiting potent tumor forming ability in transplantation studies. These cells exhibit the stem cell properties of self-renewal and multi-lineage differentiation in that they can serially regenerate the cellular complexity of the original tumor. These cells, referred to as cancer stem cells (CSCs), have in some cases been shown to be more resistant to cancer therapies. Therefore, if even a single CSC survives chemotherapy, it could result in cancer relapse. Consequently, an important goal is to be able to prospectively identify CSCs and elucidate critical growth control pathways to enable development of effective targeted therapies. Unfortunately, pure MaSCs or breast CSCs have not been isolated, precluding the generation of reagents to detect or eliminate them. My research takes a new direction to identify, isolate, and characterize MaSCs using properties central to mammary gland development and stem cell function. We isolated MaSCs during development and found that they are naturally enriched late in embryogenesis. We sorted the mammary cells at E18.5 using cell surface proteins we previously found to be expressed in the rudiment at E18.5 and were able to obtain MaSCs purified to a significantly higher degree than reported in the literature. These fetal MaSCs express several genes implicated in cancer, including erbB2, which is found in a subset of dangerous human cancers. In addition, like human cancers that over-express erbB2, fetal MaSC growth is inhibited by the erbB2 antagonist Lapatinib. The MaSC population isolated during fetal development is enriched for epithelial cells expressing both myoepithelial and luminal keratin markers as well as epithelial cells expressing neither of these markers. It is possible that either of these sub-populations contains the stem cell activity. We have focused on using high throughput single cell QPCR analysis to cluster the fetal MaSCs by their keratin marker expression pattern and identify cell surface markers that can be used to isolate viable cells for stem cell activity assays. Altogether, these experiments enabled isolation of highly enriched MaSC populations for elucidation of key growth pathways and set the stage for future in vivo analyses. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD02-02.
UK healthcare spend exceeded OECD average in 2009, new figures show
Authors: S. Arie
Journal: BMJ (2011)

Spending on healthcare in the United Kingdom exceeded the average of the Organisation of Economic Co-operation and Development member countries for the first time in 2009, a new report shows. Health spending accounted for 9.8% of gross domestic product (GDP) in the UK, whereas the OECD average was 9.6%. 

The share of the UK’s GDP allocated to health rose steadily throughout the whole of the past decade, particularly during the 2008-9 recession. It rose from 8.4% in 2007 to 9.8% in 2009.

The Health at a Glance report, the sixth in a series of annual reports, shows that spending on health is rising worldwide but that not enough is being done to prevent and manage chronic diseases.

It shows that across the 34 OECD countries health spending rose on average by 4% a year over the decade to 2009 and that the proportion of GDP spent on health rose to 9.6%, up 0.8% on the …
Lawsuits are set to obstruct Canada's blood inquiry
Authors: D. Spurgeon
Journal: BMJ (1996)

Canada's inquiry into contaminated blood products looks likely to be delayed by legal action. Organisations and individuals, alerted by the head of the inquiry that his report might contain findings of wrongdoing on their part, have taken legal action to prevent this from happening.

Mr Justice Horace Krever's report is due next September, but it seems certain to …
Vascular Endothelial Growth Factor Prevents Apoptosis and Preserves Contractile Function in Hypertrophied Infant Heart
Authors: Ingeborg Friehs, Rodrigo Barillas, Nikolay V. Vasilyev, Nathalie Roy, Francis X. McGowan, Pedro J. del Nido
Journal: Circulation (2006)

Background— Cardiac hypertrophy is an adaptive response to increased workload that, if unrelieved, leads to heart failure. It has been reported that cardiomyocyte apoptosis contributes to failure, and that vascular endothelial growth factor (VEGF) treatment of hypertrophied myocardium increases capillary density and improves myocardial perfusion. In this study we hypothesized that VEGF treatment reduces cardiomyocyte apoptosis and thereby preserves myocardial contractile function. Methods and Results— Newborn rabbits underwent aortic banding. At 4 and 6 weeks of age, hypertrophied animals were treated with intrapericardial administration of recombinant VEGF protein. Three groups of animals were investigated: age-matched controls (C), untreated hypertrophied (H), and VEGF-treated hypertrophied hearts (T). Cardiomyocyte apoptosis was determined by TUNEL staining and PARP cleavage (immunoblotting of nuclear extracts) and cardiac function by transthoracic echocardiography. Death attributable to severe heart failure occurred in 14 of 43 untreated and 2 of 29 VEGF-treated animals ( P &lt;0.01). TUNEL-positive cardiomyocyte nuclei (n/1000 nuclei) were significantly increased in untreated hearts at 5 weeks (H: 10±1.8 versus T: 3±0.7) and at 7 weeks (H: 13±3.6 versus T: 5±1.5; P &lt;0.05). Increased apoptosis in untreated hypertrophy was also confirmed by the presence of PARP cleavage (H: 74±7 versus T: 41±4 arbitrary densitometry units; P &lt;0.05). VEGF treatment preserved left ventricular mass, prevented dilation (T: 1.01±0.06 versus H: 0.77±0.07; P &lt;0.05), and preserved contractility indices compared with untreated hearts. Conclusions— Lack of adaptive capillary growth impairs myocardial perfusion and substrate delivery in hypertrophying myocardium. VEGF treatment reduces myocardial apoptosis and prolongs survival in a model of severe progressive left ventricular hypertrophy. Promoting capillary growth with VEGF reduces apoptosis, preserves myocardial contractile function, and delays the onset of failure in pressure-loaded infant myocardium.
Pulling the plug on futility
Authors: C. Weijer, C. Elliott
Journal: BMJ (1995)

If the fashionableness of a new idea can be measured by the number of publications it generates these are piping times for the idea of “medical futility.” As it has been developed in the medical literature futility provides a basis for doctors to refuse demands for treatment from patients and families. According to the results of a Medline search, articles on futility have undergone a small scale population explosion: two articles in 1987, five in 1990, and 23 in 1993. As with any new intellectual tack, after the initial intoxication has begun to wear off we must ask soberly: “Are we any further ahead?”

The idea of futility is admittedly seductive. Over the past few years the familiar “right to die” issue has been turned on its head. Rather than refusing life sustaining treatment in the face of intransigent doctors, patients (and their surrogates) have begun to demand treatment that doctors are reluctant to provide, either because its efficacy is questionable or, more problematically, because it serves goals that the doctors are reluctant to endorse. The most contentious of these cases have been those in which families have asked for aggressive life sustaining treatment for anencephalic children1 or patients in …
Prophylactic Portacaval Anastomosis in Cirrhotic Patients with Esophageal Varices
Authors: Harold O. Conn, W. W. Lindenmuth
Journal: New England Journal of Medicine (1968)

This controlled prospective investigation of prophylactic portacaval anastomosis includes 68 cirrhotic patients. Although portacaval shunts were created in 25 with low operative mortality (8 per cent), and hemorrhage from varices was practically eliminated by portacaval shunts (4 per cent), the 31 control subjects not operated on enjoyed greater survival despite more frequent variceal hemorrhage (39 per cent). Fifty per cent of the control group and 68 per cent of the prophylactic-shunt group died during a follow-up period of 51 to 108 months. The major cause of death in the control group was variceal hemorrhage; in the prophylactic-shunt group it was hepatic failure. These observations show that prophylactic portacaval anastomosis in unselected cirrhotic patients does not reduce mortality. All 12 of the control patients who bled from esophageal varices had had ascites. They also had more frequent signs of decompensated cirrhosis, more abnormal liver-function tests and more severe portal hypertension than the control subjects who did not bleed from varices. Ascites may serve as an omen of impending hemorrhage and may help identify patients with increased risk of variceal bleeding.
Regional distribution of acid mucopolysaccharides in the kidney
Authors: C. W. Castor, J. A. Greene
Journal: Journal of Clinical Investigation (1968)

Kidneys from 20 dogs were dissected into cortical and medullary components and analysed for acid mucopolysaccharide content. Heparitin sulfate accounted for approximately 80% of cortical acid mucopolysaccharide, 10% was chondroitin sulfate B, and 10% was low molecular weight hyaluronic acid. Medullary tissue exhibited a 4- to 5-fold higher concentration of acid mucopolysaccharide than did cortical tissue, and the dominant compound was moderately highly polymerized hyaluronic acid. While chondroitin sulfates A and (or) C were not detected in this study, the presence of minor amounts of these substances could not be excluded. A model experiment indicated that hyaluronic acid retards sodium diffusion, apparently due to its viscous properties rather than its electronegativity.
Hodgkin's Disease in Siblings
Authors: Seymour Grufferman, Philip Cole, Peter G. Smith, Robert J. Lukes
Journal: New England Journal of Medicine (1977)

An incidence survey of Hodgkin's disease in Greater Boston during 1959–1973 detected five sibling pairs under the age of 45. The expected number is 0.7; thus, siblings of young adults with Hodgkin's disease have about a sevenfold excess risk of the disease (P = 0.0008). Eight sibling pairs, not in the incidence series, were also identified. Among all 13 pairs, 12 were sex concordant; the number expected is 6.8 (P = 0.01). The literature includes 46 sibling pairs under 45 of which 30 are sex concordant. The expected number is 23.9 (P = 0.05). Combining the present and the literature series suggests that siblings of the same sex as an affected person have a risk of Hodgkin's disease double that of siblings of the opposite sex. The sex concordance suggests that the excess Hodgkin's disease among siblings of affected persons is due either to inter-personal transmission of an etiologic agent by prolonged or intimate contact or to common-source exposures. (N Engl J Med 296:248–250, 1977)
PTH-046 Analysis of Metachronous Colorectal Adenoma Sites Suggests Proximal Occurrence is More Probable
Authors: R Rosser, B M Corfe, K S Chapple
Journal: Gut (2013)

<h3>Introduction</h3> A human sporadic colorectal adenoma may influence the formation of another adenoma even after its removal, with up to 60% of such patients developing metachronous adenomas following adenoma excision. However data regarding the occurrence site of a metachronous colorectal adenoma relative to the index adenoma is scarce. Therefore, we investigated whether a metachronous colorectal adenoma was more likely to occur in the same, proximal or distal segment as the index adenoma. <h3>Methods</h3> A prospectively–maintained database was interrogated to identify all colonoscopies performed over a ten-year period at a single university teaching hospital. All patients undergoing polypectomy were cross-referenced against a histological database to confirm adenoma status. Patients with synchronous adenomas were excluded. The site of adenoma removal at index and subsequent colonoscopy was recorded and categorised into three groups (proximal, distal or same segment). <h3>Results</h3> 15,121 colonoscopies and 4759 polyp events were recorded. 361 patients (235 male, 126 female, median age [range] 66 [32–91] years) developed a single metachronous adenoma at follow-up colonoscopy. Metachronous adenomas were more likely to develop in a different bowel segment (61%, 95% c.i. 56% &gt; 66%) to that of the index adenoma (39%, 95% c.i. 34% &gt; 44%; <i>P</i> &lt; 0.01 one way Chi-squared test). Metachronous adenomas were more likely to occur at a site proximal (41%, 95% c.i. 36% &gt; 46%) to the index adenoma than either the same segment (39%, 95% c.i. 34% &gt; 44%) or a more distal segment (20%, 95% c.i. 16% &gt; 24%; <i>P</i> &lt; 0.01 one way Chi-squared test). Proximally-sited metachronous adenomas were more likely to occur in a segment further away (mean [SD] segments travelled 3.5 [2.3]) from the index adenoma than distally-sited metachronous adenomas (2.6 [1.8] segments travelled; <i>P</i> &lt; 0.01 Kruskal-Wallis one way ANOVA). <h3>Conclusion</h3> A metachronous human sporadic colorectal adenoma is more likely to be found in a section of the colorectum proximal to that of the index adenoma. Travel in segments may be significant. Taken together, the data suggest research effort into underlying mechanisms of metachronous adenoma is needed. <h3>Disclosure of Interest</h3> None Declared.
Smoking in Pregnancy and Subsequent Child Development
Authors: N. R. Butler, H. Goldstein
Journal: BMJ (1973)

A national sample of several thousand children has been followed longitudinally from birth. At the ages of 7 and 11 years physical and mental retardation due to smoking in pregnancy has been found, and this deficit increases with the number of cigarettes smoked after the fourth month of pregnancy. Children of mothers who smoked 10 or more cigarettes a day are on average 1.0 cm shorter and between three and five months retarded on reading, mathematics, and general ability compared with the offspring of non-smokers, after allowing for associated social and biological factors.