tbuckley/cabot-search huggingface dataset:
Safeguarding children. Recognition and response in child protection: an educational programme for doctors in training
Authors: Faheem Shakur
Journal: BMJ (2009)

Details of possible non-accidental injuries frequently make the headlines for all the wrong reasons. A systematic approach to recognising and dealing with these injuries is the responsibility of everyone who comes into contact with children, and as more of these regrettable cases come to light, it makes sense to have a grounding in this vital issue.

Judging from the attendance at the course I went to list earlier this month, it looked like senior house officers from paediatrics, paediatric surgery, accident and emergency, and general practice programmes, as well as some registrars.

I did it this year while I was a specialist trainee year 1 in paediatrics, but there were a lot of foundation year 2 doctors on the course (many …
Visceral Adipose Tissue Drives Cardiac Aging Through Modulation of Fibroblast Senescence by Osteopontin Production
Authors: Daigo Sawaki, Gabor Czibik, Maria Pini, Julien Ternacle, Nadine Suffee, Raquel Mercedes, Geneviève Marcelin, Mathieu Surenaud, Elisabeth Marcos, Philippe Gual, Karine Clément, Sophie Hue, Serge Adnot, Stéphane N. Hatem, Izuru Tsuchimochi, Takehiko Yoshimitsu, Corneliu Hénégar, Geneviève Derumeaux
Journal: Circulation (2018)

Background: Aging induces cardiac structural and functional changes linked to the increased deposition of extracellular matrix proteins, including OPN (osteopontin), conducing to progressive interstitial fibrosis. Although OPN is involved in various pathological conditions, its role in myocardial aging remains unknown. Methods: OPN deficient mice (OPN-/-) with their wild-type (WT) littermates were evaluated at 2 and 14 months of age in terms of cardiac structure, function, histology and key molecular markers. OPN expression was determined by reverse-transcription polymerase chain reaction, immunoblot and immunofluorescence. Luminex assays were performed to screen plasma samples for various cytokines/adipokines in addition to OPN. Similar explorations were conducted in aged WT mice after surgical removal of visceral adipose tissue (VAT) or treatment with a small-molecule OPN inhibitor agelastatin A. Primary WT fibroblasts were incubated with plasma from aged WT and OPN-/- mice, and evaluated for senescence (senescence-associated β-galactosidase and p16), as well as fibroblast activation markers (Acta2 and Fn1). Results: Plasma OPN levels increased in WT mice during aging, with VAT showing the strongest OPN induction contrasting with myocardium that did not express OPN. VAT removal in aged WT mice restored cardiac function and decreased myocardial fibrosis in addition to a substantial reduction of circulating OPN and transforming growth factor β levels. OPN deficiency provided a comparable protection against age-related cardiac fibrosis and dysfunction. Intriguingly, a strong induction of senescence in cardiac fibroblasts was observed in both VAT removal and OPN-/- mice. The addition of plasma from aged OPN-/- mice to cultures of primary cardiac fibroblasts induced senescence and reduced their activation (compared to aged WT plasma). Finally, Agelastatin A treatment of aged WT mice fully reversed age-related myocardial fibrosis and dysfunction. Conclusions: During aging, VAT represents the main source of OPN and alters heart structure and function via its profibrotic secretome. As a proof-of-concept, interventions targeting OPN, such as VAT removal and OPN deficiency, rescued the heart and induced a selective modulation of fibroblast senescence. Our work uncovers OPN’s role in the context of myocardial aging and proposes OPN as a potential new therapeutic target for a healthy cardiac aging.
Guiding Doctors in Managing Their Careers
Authors: Ian Gurney
Journal: BMJ (2006)

Ruth Chambers, Kay Mohanna, Andrew Thornett, and Steve Field Radcliffe, 2006, £24.95, 144 pages

ISBN: 1 85775 611 8

Rating: ★★★/5



This book serves as a good example of the importance of thoroughly reading the title and back page before diving into the text. Anyone seeking guidance in managing their own career will find little to please them here. This is a guide to giving guidance, a “practical toolkit for tutors, trainers, mentors and appraisers,” and as such will hold little interest for a great number of BMJ Careers readers, who are more likely …
Loss of AZIN2 splice variant facilitates endogenous cardiac regeneration
Authors: Xinzhong Li, Xiang He, He Wang, Mengsha Li, Senlin Huang, Guojun Chen, Yuanwen Jing, Shifei Wang, Yanmei Chen, Wangjun Liao, Yulin Liao, Jianping Bin
Journal: Cardiovascular Research (2018)

Long noncoding RNAs (lncRNAs) are critical regulators of cardiovascular lineage commitment and heart wall development, but their roles in regulating endogenous cardiac regeneration are unclear. The present study investigated the role of human-derived lncRNA in regulating endogenous cardiac regeneration as well as the underlying mechanisms.We compared RNA sequencing data from human foetal and adult hearts and identified a novel lncRNA that was upregulated in adult hearts (Genesymbol NONHSAG000971/NONHSAT002258 or ENST00000497710.5), which was a splice variant of the AZIN2 gene (AZIN2-sv). We used quantitative PCR to confirm the increased expression of AZIN2-sv in adult rat hearts. Coexpression network analysis indicated that AZIN2-sv could regulate proliferation. Loss- and gain-of-function approaches demonstrated that AZIN2-sv negatively regulated endogenous cardiomyocyte proliferation in vitro and in vivo. Knockdown of AZIN2-sv attenuated ventricular remodelling and improved cardiac function after myocardial infarction. Phosphatase and tensin homolog (PTEN) was identified as a target of AZIN2-sv, their direct binding increased PTEN stability. Furthermore, AZIN2-sv acted as a microRNA-214 sponge to release PTEN, which blocked activation of the PI3 kinase/Akt pathway to inhibit cardiomyocyte proliferation.The newly discovered AZIN2-sv suppressed endogenous cardiac regeneration by targeting the PTEN/Akt pathway. Thus, AZIN2-sv may be a novel therapeutic target for preventing and treating heart failure.
Transcription-Associated Mutation Promotes RNA Complexity in Highly Expressed Genes—A Major New Source of Selectable Variation
Authors: Shengkai Pan, Michael W Bruford, Yusong Wang, Zhenzhen Lin, Zhongru Gu, Xian Hou, Xuemei Deng, Andrew Dixon, Jennifer A Marshall Graves, Xiangjiang Zhan
Journal: Molecular Biology and Evolution (2018)

Alternatively spliced transcript isoforms are thought to play a critical role for functional diversity. However, the mechanism generating the enormous diversity of spliced transcript isoforms remains unknown, and its biological significance remains unclear. We analyzed transcriptomes in saker falcons, chickens, and mice to show that alternative splicing occurs more frequently, yielding more isoforms, in highly expressed genes. We focused on hemoglobin in the falcon, the most abundantly expressed genes in blood, finding that alternative splicing produces 10-fold more isoforms than expected from the number of splice junctions in the genome. These isoforms were produced mainly by alternative use of de novo splice sites generated by transcription-associated mutation (TAM), not by the RNA editing mechanism normally invoked. We found that high expression of globin genes increases mutation frequencies during transcription, especially on nontranscribed DNA strands. After DNA replication, transcribed strands inherit these somatic mutations, creating de novo splice sites, and generating multiple distinct isoforms in the cell clone. Bisulfate sequencing revealed that DNA methylation may counteract this process by suppressing TAM, suggesting DNA methylation can spatially regulate RNA complexity. RNA profiling showed that falcons living on the high Qinghai–Tibetan Plateau possess greater global gene expression levels and higher diversity of mean to high abundance isoforms (reads per kilobases per million mapped reads ≥18) than their low-altitude counterparts, and we speculate that this may enhance their oxygen transport capacity under low-oxygen environments. Thus, TAM-induced RNA diversity may be physiologically significant, providing an alternative strategy in lifestyle evolution.
The end of the heparin pump?
Authors: M. Lloyd, C. C Callander, K. Stein, T. Nicholson, N. Grubb
Journal: BMJ (1999)

# Dosage regimens for low molecular weight heparins differ {#article-title-2} EDITOR—Grubb et al's editorial reviewed the use of subcutaneous heparin; the advantages in efficacy and simplicity in the treatment of thromboembolic disease and angina now seem clear.1 A potential difficulty, which is clear in the everyday use of these agents, is the differing dosages required. Because the agents are commonly prescribed in a busy on-call setting, calculation errors are also more likely to occur. Five agents are mentioned, of which three are available in the United Kingdom. The table shows the dosage regimens for these agents. View this table: Dosage regimens for low molecular weight (LMW) heparins available in United Kingdom for treatment of thromboembolism and unstable angina Other agents with similar indications will probably be licensed. Perhaps it would be useful for regulatory bodies to introduce a uniform system of equivalent doses, similar to that used in insulin prescription. 1. 1.↵1. Grubb NR, 2. Bloomfield P, 3. Ludlam CA . The end of the heparin pump? BMJ 1998; 317: 1540–1542. [OpenUrl][1][FREE Full Text][2] # Epidural haematoma may occur after epidural and spinal regional anaesthesia {#article-title-4} EDITOR—In their editorial Grubb et al reviewed the advantages of low molecular weight heparins over unfractionated heparin in a variety of clinical situations and pointed out that they … [1]: {openurl}?query=rft.jtitle%253DBMJ%26rft.stitle%253DBMJ%26rft.issn%253D0007-1447%26rft.aulast%253DGrubb%26rft.auinit1%253DN.%2BR%26rft.volume%253D317%26rft.issue%253D7172%26rft.spage%253D1540%26rft.epage%253D1542%26rft.atitle%253DThe%2Bend%2Bof%2Bthe%2Bheparin%2Bpump%253F%26rft_id%253Dinfo%253Adoi%252F10.1136%252Fbmj.317.7172.1540%26rft_id%253Dinfo%253Apmid%252F9836650%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/ijlink?linkType=FULL&journalCode=bmj&resid=317/7172/1540&atom=%2Fbmj%2F319%2F7209%2F575.2.atom
Interleukin-12 armored chimeric antigen receptor (CAR) T cells for heterogeneous antigen-expressing ovarian cancer.
Authors: Oladapo O. Yeku, Terence Purdon, David R. Spriggs, Renier J. Brentjens
Journal: Journal of Clinical Oncology (2018)

12 Background: Immune escape via downregulation of tumor associated antigens (TAAs) is an important mechanism of resistance to Chimeric Antigen Receptor (CAR) T cell therapy. Particularly in solid tumor malignancies where antigen expression could be heterogeneous, the risk of antigen-low or antigen-negative relapse is significantly high. One strategy to overcome this limitation is to reengineer CAR T cells to engage other arms of the immune system such as endogenous cytotoxic T cells and dendritic cells (DC) to broaden the antitumor response beyond the TAA targeted by CAR T cells. This could be achieved by co-modifying CAR T cells with Interleukin-12 (IL-12). IL-12 is a proinflammatory cytokine produced by DCs, and macrophages, and has been shown to promote maturation of DCs and increase T-cell proliferation. We hypothesized that CAR T cells genetically engineered to constitutively secrete IL-12 will be efficacious against Muc16 ecto low (M Lo ) and Muc16 ecto high (M Hi ) heterogeneous tumors in a syngeneic mouse model of ovarian peritoneal carcinomatosis. Methods: ID8 mouse ovarian cancer cells with either low endogenous Muc16 ecto or transduced to express high levels of Muc16 ecto were generated. Mouse T cells were transduced with plasmids encoding second generation Muc16 or Muc16/IL-12-directed CARs. C57BL/6 mice were inoculated i.p with tumor cells and subsequently treated with CAR T cells. Results: Second generation and IL-12 armored CAR T cells (4H1128?-IL12) were cytotoxic against both M Lo and M Hi cells in vitro. However, 4H1128?-IL12 were significantly more efficacious at killing both M Lo and M Hi cancer cells. In vivo, treatment with 4H1128?-IL12 led to significantly improved survival in mice inoculated with a 50:50 mix of M Lo and M Hi cells. Peritoneal washes performed on mice that succumbed to disease showed equivalent eradication of M Lo and M Hi . Treatment with 4H1128?-IL12 resulted in increased mature peritoneal DC’s (CD11b + MHCII + ). Finally, surviving mice from 4H1128?-IL12 cohorts were found to have increased T-cell receptor (TCR-β) productive clonality. Conclusions: IL-12-secreting CAR T cells are efficacious against tumors with low and heterogeneous antigen expression.
MSc in oncology
Authors: Susannah Stanway, Susana Banerjee
Journal: BMJ (2011)

The MSc in oncology is a part time, postgraduate, two year taught course, followed by a one year supported research dissertation, run by the Institute of Cancer Research, London.

It is aimed at doctors who wish to pursue a career in clinical and medical oncology and leads to a postgraduate certificate, postgraduate diploma, or MSc in oncology. Most students have entered specialty oncology training in clinical or medical oncology, but doctors in other disciplines have attended in the past and are welcome. The course aims to deliver a theoretical understanding of cancer and research methodology, application of this knowledge in the clinical setting, critical awareness, and advanced communication skills.

We felt that a structured programme promoting learning of clinical and scientific skills that focused specifically on cancer care would help equip us with the essential tools to become confident leaders in the future. Colleagues who had done this …
What’s hot that the other lot got
Authors: George William Nava
Journal: Thorax (2018)

Mepolizumab is a monoclonal antibody that interferes with interleukin-5 signalling to reduce blood eosinophil level and is licenced for use in severe refractory eosinophilic asthma. The clinical relevance of eosinophilic inflammation in chronic obstructive pulmonary disease (COPD) is being increasingly recognised. Pavord et al ( NEJM 2017;377:1613–1629) describe the METREX and METREO trials, which evaluated the effect of mepolizumab in frequent exacerbator phenotype patients with COPD. METREX and METREO were international, phase 3, double-blinded, randomised clinical trials. Patients with COPD on triple inhaled therapy who had had at least two moderate or one severe exacerbation in the preceding year were recruited and stratified by blood eosinophil level. Non-eosinophilic patients were excluded from METREO. Eight hundred and thirty-seven (METREX) and 675 (METREO) patients were randomised to receive 4 weekly mepolizumab (METREX: 100 mg, METREO: 100 mg or 300 mg assigned 1:1) or placebo as add on to their COPD therapy for 52 weeks. The primary end point of both studies was annual rate of moderate or severe exacerbations. Secondary end points included time to first exacerbation, frequency of hospital attendance and changes to patient-reported outcomes. The data were analysed in a modified intention-to-treat population. In METREX, exacerbation frequency and time to first exacerbation …
Everyone with asthma should have a metered dose inhaler and a spacer
Authors: Duncan Keeley
Journal: BMJ (2018)

Bush and Griffiths are right to draw attention to the growing evidence of suboptimal management of asthma exacerbations in children in the UK and the associated mortality.1 They also remind us that metered dose inhalers with spacers are equivalent or superior to nebulisers in all but the most severe exacerbations.

Metered dose inhalers with spacers …
PCSK9 INHIBITORS IN PATIENTS WITH FAMILIAL HYPERCHOLESTEROLEMIA AND/OR CVD: THE IMPACT OF A SYSTEMATIC, TEAM-BASED APPROACH TO PRESCRIPTION ON RATES OF INSURANCE APPROVAL AND LIPID LOWERING
Authors: Thomas Knickelbine, Ross Garberich, Susan White, Sandra Oberembt, Samantha Wills, Michael Miedema, Emmanouil Brilakis
Journal: Journal of the American College of Cardiology (2018)
The Lung Microbiota of Healthy Mice Are Highly Variable, Cluster by Environment, and Reflect Variation in Baseline Lung Innate Immunity
Authors: Robert P. Dickson, John R. Erb-Downward, Nicole R. Falkowski, Ellen M. Hunter, Shanna L. Ashley, Gary B. Huffnagle
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Rationale: The “gut–lung axis” is commonly invoked to explain the microbiome’s influence on lung inflammation. Yet the lungs harbor their own microbiome, which is altered in respiratory disease. The relative influence of gut and lung bacteria on lung inflammation is unknown.Objectives: To determine whether baseline lung immune tone reflects local (lung–lung) or remote (gut–lung) microbe–host interactions.Methods: We compared lung, tongue, and cecal bacteria in 40 healthy, genetically identical, 10-week-old mice, using 16S ribosomal RNA gene quantification and sequencing. We measured inflammatory cytokines, using a multiplex assay of homogenized lung tissue. We compared lung bacteria in healthy mice treated with varied durations of systemic antibiotics.Measurements and Main Results: Lung bacterial communities are highly variable among mice, cluster strongly by cage, shipment, and vendor, and are altered by antibiotics in a microbiologically predictable manner. Baseline lung concentrations of two key inflammatory cytokines (IL-1α and IL-4) are correlated with the diversity and community composition of lung bacterial communities. Lung concentrations of these inflammatory cytokines correlate more strongly with variation in lung bacterial communities than with that of the gut or mouth.Conclusions: In the lungs of healthy mice, baseline innate immune tone more strongly reflects local (lung–lung) microbe–host interactions than remote (gut–lung) microbe–host interactions. Our results independently confirm the existence and immunologic significance of the murine lung microbiome, even in health. Variation in lung microbiota is likely an important, underappreciated source of experimental and clinical variability. The lung microbiome is an unexplored therapeutic target for the prevention and treatment of inflammatory lung disease.
Survival after surgical or radiotherapeutic treatment for high-risk localized prostate cancer: A National Cancer Database analysis with comprehensive treatment group imbalances adjustments.
Authors: Ronald D. Ennis, Liangyuan Hu, Shannon Nicole Ryemon, Joyce Lin, Madhu Mazumdar
Journal: Journal of Clinical Oncology (2018)

55 Background: There are no randomized trials to guide a high-risk localized prostate cancer patient’s treatment decision between radiotherapeutic and surgical options. Comparative studies have been limited by their ability to match patients based on pre-treatment prognostic variables and to adjust for the cancer–related, medical and socioeconomic differences between patients who choose radiotherapeutic or surgical approaches. Methods: We analyzed the outcome of all patients in the National Cancer Database with high-risk clinically localized prostate cancer with complete prognostic data who were treated with either radical prostatectomy (RP), external beam radiotherapy (EBRT) combined with androgen deprivation (AD) or EBRT+brachytherapy (brachy)±AD. Inverse probability of treatment weighting (IPTW) was used to adjust for covariate imbalance between treatment groups. Time-dependent Cox proportional hazards (TDCPH) model was then used to evaluate differences between treatment groups. Because of imbalances in the frequency of pathologic lymph node sampling between the treatment groups, a predictive model of pathologic nodal (pLN) status was built using PSA, Gleason score and clinical T stage and predicted pLN status was used to repeat the IPTW and TDCPH model. Results: 42,765 patients were analyzed. There was no statistically significant difference in survival between RP and EBRT+brachy±AD (HR 1.17 (0.88, 1.55)). However, EBRT+AD was associated with higher mortality than RP (HR 1.53 (1.22, 1.92)). Adjustment for predicted pLN status did not change the results. Subset analysis of EBRT+AD patients who received ≥7920 cGy narrowed the difference but remained significant (HR 1.32 (1.02, 1.66)). Conclusions: After comprehensively adjusting for imbalances in prostate cancer prognostic factors, other medical conditions and socioeconomic factors, this analysis showed no difference in survival between patients treated with RP vs. EBRT+brachy±AD. EBRT+AD was associated with lower survival. Randomized trials comparing these three methods of treatment are urgently needed.
Lipoxins Regulate the Early Growth Response–1 Network and Reverse Diabetic Kidney Disease
Authors: Eoin P. Brennan, Muthukumar Mohan, Aaron McClelland, Christos Tikellis, Mark Ziemann, Antony Kaspi, Stephen P. Gray, Raelene Pickering, Sih Min Tan, Syed Tasadaque Ali-Shah, Patrick J. Guiry, Assam El-Osta, Karin Jandeleit-Dahm, Mark E. Cooper, Catherine Godson, Phillip Kantharidis
Journal: Journal of the American Society of Nephrology (2018)

Background The failure of spontaneous resolution underlies chronic inflammatory conditions, including microvascular complications of diabetes such as diabetic kidney disease. The identification of endogenously generated molecules that promote the physiologic resolution of inflammation suggests that these bioactions may have therapeutic potential in the context of chronic inflammation. Lipoxins (LXs) are lipid mediators that promote the resolution of inflammation. Methods We investigated the potential of LXA 4 and a synthetic LX analog (Benzo-LXA 4 ) as therapeutics in a murine model of diabetic kidney disease, ApoE −/− mice treated with streptozotocin. Results Intraperitoneal injection of LXs attenuated the development of diabetes-induced albuminuria, mesangial expansion, and collagen deposition. Notably, LXs administered 10 weeks after disease onset also attenuated established kidney disease, with evidence of preserved kidney function. Kidney transcriptome profiling defined a diabetic signature (725 genes; false discovery rate P ≤0.05). Comparison of this murine gene signature with that of human diabetic kidney disease identified shared renal proinflammatory/profibrotic signals (TNF- α , IL-1 β , NF- κ B). In diabetic mice, we identified 20 and 51 transcripts regulated by LXA 4 and Benzo-LXA 4 , respectively, and pathway analysis identified established (TGF- β 1, PDGF, TNF- α , NF- κ B) and novel (early growth response–1 [EGR-1]) networks activated in diabetes and regulated by LXs. In cultured human renal epithelial cells, treatment with LXs attenuated TNF- α –driven Egr-1 activation, and Egr-1 depletion prevented cellular responses to TGF- β 1 and TNF- α . Conclusions These data demonstrate that LXs can reverse established diabetic complications and support a therapeutic paradigm to promote the resolution of inflammation.
Fish Consumption and Mortality from Coronary Heart Disease
Journal: New England Journal of Medicine (1985)

indicate damage to the muscle and myoneural junction.Such changes do not occur in primary muscle disorders, denervation atrophy, or drug toxicity.2Similar changes at the myoneural junction have, however, been reported in Becker's type of progressive muscular dystrophy.3In the absence of other factors known to precipitate muscle damageourdata indicate that isotretinoin may induce reversible damage to skeletal muscle.Since there were no symptoms or signs of damage to the myoneural junction we refrained from performing a study of "jitter" or repetitive nerve stimulation.We cannot offer an adequate explanation for our findings, although muscle pain and stiffness are features ofchronic vitamin A toxicity.4A recent experiment showed that retinoic acid given in large doses to pregnant mice modified the phenotype expression of developing muscles in the fetus and increased creatine kinase activity.5