tbuckley/cabot-search huggingface dataset:
Conservatives say they will drop internal NHS targets and focus on outcomes
Authors: Adrian O’Dowd
Journal: BMJ (2008)

The Conservative party claims that, if it forms the next British government, performance of NHS organisations and not targets will be the focus of the NHS.

The Conservative party has published a green paper promising to drop internal NHS targets in favour of focusing on health outcomes in areas such as cancer, heart disease, stroke, after care, and patient satisfaction.

Party leader David Cameron and his health spokesperson Andrew Lansely were outlining their green paper called Delivering some of the best health in Europe .

This new policy approach could save tens of thousands of lives, …
Current state of tumour necrosis factor blockade in Wegener's granulomatosis
Authors: C Mukhtyar
Journal: Annals of the Rheumatic Diseases (2005)

Tumour necrosis factor α (TNFα) is likely to be involved in the pathogenesis of Wegener’s granulomatosis. This paper reviews published clinical trials of the anti-TNFα agents etanercept and infliximab with regard to their efficacy and safety in the treatment of Wegener’s granulomatosis. On the basis of the high rate of adverse events, particularly an increased incidence of cancers, the use of etanercept in the management of Wegener’s granulomatosis is not justified. However, the potential role for infliximab or the as yet untested adalimumab cannot be discounted. The development of novel approaches focusing on blockade of specific molecules including TNFα in the treatment of Wegener’s granulomatosis is awaited.
Mechanisms of an autoimmunity syndrome in mice caused by a dominant mutation in Aire
Authors: Maureen A. Su, Karen Giang, Kristina }umer, Huimin Jiang, Irena Oven, John L. Rinn, Jason J. DeVoss, Kellsey P.A. Johannes, Wen Lu, James Gardner, Angela Chang, Paula Bubulya, Howard Y. Chang, B. Matija Peterlin, Mark S. Anderson
Journal: Journal of Clinical Investigation (2008)

Homozygous loss-of-function mutations in AIRE cause autoimmune polyglandular syndrome type 1 (APS 1), which manifests in a classic triad of hypoparathyroidism, adrenal insufficiency, and candidiasis. Interestingly, a kindred with a specific G228W AIRE variant presented with an autosomal dominant autoimmune phenotype distinct from APS 1. We utilized a novel G228W-knockin mouse model to show that this variant acted in a dominant-negative manner to cause a unique autoimmunity syndrome. In addition, the expression of a large number of Aire-regulated thymic antigens was partially inhibited in these animals, demonstrating the importance of quantitative changes in thymic antigen expression in determining organ-specific autoimmunity. Furthermore, the dominant-negative effect of the G228W variant was exerted through recruitment of WT Aire away from active sites of transcription in the nucleus of medullary thymic epithelial cells in vivo. Together, these results may demonstrate a mechanism by which autoimmune predisposition to phenotypes distinct from APS 1 can be mediated in a dominant-negative fashion by Aire.
Is Pancreatic Diabetes (Type 3c Diabetes) Underdiagnosed and Misdiagnosed?
Authors: Philip D. Hardt, Mathias D. Brendel, Hans U. Kloer, Reinhard G. Bretzel
Journal: Diabetes Care (2008)

Exocrine pancreatic insufficiency is frequently associated with diabetes, with high prevalence in both insulin-dependent or insulin-independent patients. Exocrine pancreatic failure has often been perceived as a complication of diabetes. In contrast, recent clinical observations lead to the notion that nonendocrine pancreatic disease is a critical factor for development rather than a sequel to diabetes. The incidence of diabetes caused by exocrine pancreatic disease appears to be underestimated and may comprise 8% or more of the general diabetic patient population. Nonendocrine pancreas disease can cause diabetes by multiple mechanisms. Genetic defects have been characterized, resulting in a syndrome of both exocrine and endocrine failure. Regulation of β-cell mass and physiological incretin secretion are directly dependent on normal exocrine function. Algorithms for diagnosis and therapy of diabetes should therefore address both endocrine and exocrine pancreatic function.
Intratumoral Metabolic Heterogeneity of Cervical Cancer
Authors: Elizabeth A. Kidd, Perry W. Grigsby
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Previous research has shown that the intertumoral maximum standardized uptake value (SUVMax) of F-18 fluorodeoxyglucose (FDG)–positron emission tomography (PET) for cervical cancer predicts disease outcome. The purpose of this study was to evaluate the pretreatment intratumoral metabolic heterogeneity of FDG. Experimental Design: This is a prospective cohort study of 72 patients with International Federation of Gynecology and Obstetrics stages Ib1 to IVa cervical cancer treated with chemoradiation. Three-dimensional FDG-PET threshold tumor volumes were calculated using image segmentation and an adaptive thresholding method for the primary cervix tumor from the pretreatment FDG-PET/computerized tomography. Intratumor heterogeneity was obtained for each patient's cervical tumor by taking the derivative (dV/dT) of the volume-threshold function from 40% to 80%. The association between intratumoral heterogeneity and tumor-specific factors and patient outcomes were determined. Results: The mean cervix tumor SUVMax was 12.4 (range, 3.0-38.4). The mean differential tumor heterogeneity was −1.074 (range, −0.107 to −5.623). There was no association between dV/dT and SUVMax (R2 = 0.069), but there was a relationship with dV/dT and tumor volume (R2 = 0.881). There was no correlation of dV/dT with tumor histology (P = 0.4905). Heterogeneity was significantly associated with the risk of lymph node metastasis at diagnosis (P = 0.0009), tumor response to radiation as evaluated by FDG-PET obtained 3 months after completing treatment (P = 0.0207), risk of pelvic recurrence (P = 0.0017), and progression-free survival (P = 0.03). Conclusions: Cervical intratumoral FDG metabolic heterogeneity on the pretreatment FDG-PET predicts risk of lymph node involvement at diagnosis, response to therapy, and risk of pelvic recurrence.
Rituximab (Anti-CD20 Monoclonal Antibody) for the Treatment of Patients With Relapsing or Refractory Aggressive Lymphoma: A Multicenter Phase II Study
Authors: B. Coiffier, C. Haioun, N. Ketterer, A. Engert, H. Tilly, D. Ma, P. Johnson, A. Lister, M. Feuring Buske, J.A. Radford, R. Capdeville, V. Diehl, F. Reyes
Journal: Blood (1998)
Incidence of New Primary Melanomas After Diagnosis of Stage III and IV Melanoma
Authors: Lisa Zimmer, Lauren E. Haydu, Alexander M. Menzies, Richard A. Scolyer, Richard F. Kefford, John F. Thompson, Dirk Schadendorf, Georgina V. Long
Journal: Journal of Clinical Oncology (2013)

Purpose New primary melanomas (NPMs) have developed in some patients with metastatic melanoma treated with BRAF inhibitors. We sought to determine the background incidence of spontaneous NPMs after a diagnosis of American Joint Committee on Cancer/International Union Against Cancer stage III or IV melanoma in patients not treated with a BRAF inhibitor. Patients and Methods Patients diagnosed with stage III or IV melanoma at Melanoma Institute Australia between 1983 and 2008 were analyzed, and those who received a BRAF inhibitor were excluded. Results Two hundred twenty-nine (5%) of 4,215 patients with stage III melanoma and 43 (1%) of 3,563 patients with stage IV melanoma had at least one NPM after diagnosis of stage III or IV disease. The 6-month, 1-year, and 10-year cumulative incidence rates of developing an NPM after stage III melanoma were 1.2% (95% CI, 0.86% to 1.51%), 1.8% (95% CI, 1.44% to 2.26%), and 5.9% (95% CI, 5.08% to 6.74%), respectively. The 3-month, 6-month, and 1-year cumulative incidence rates of NPM after diagnosis of stage IV melanoma were 0.2% (95% CI, 0.07% to 0.36%), 0.3% (95% CI, 0.15% to 0.51%), and 0.4% (95% CI, 0.25% to 0.7%), respectively. In both patients with stage III and stage IV melanoma, male patients and patients with a prior history of multiple primaries had a higher incidence of NPM. Conclusion Patients with stage III and stage IV melanoma remain at risk for development of further primary melanomas, particularly if they have a history of multiple primary melanomas before stage III or IV disease. The incidence rates are lower than those reported in patients receiving BRAF inhibitors. However, the results must be compared with caution because dermatologic assessment is more frequent in BRAF inhibitor trials.
Angiotensin II Dose-Dependently Stimulates Human Renal Proximal Tubule Transport by the Nitric Oxide/Guanosine 3′,5′-Cyclic Monophosphate Pathway
Authors: Ayumi Shirai, Osamu Yamazaki, Shoko Horita, Motonobu Nakamura, Nobuhiko Satoh, Hideomi Yamada, Masashi Suzuki, Akihiko Kudo, Hayato Kawakami, Franz Hofmann, Akira Nishiyama, Haruki Kume, Yutaka Enomoto, Yukio Homma, George Seki
Journal: Journal of the American Society of Nephrology (2014)

Stimulation of renal proximal tubule (PT) transport by angiotensin II (Ang II) is critical for regulation of BP. Notably, in rats, mice, and rabbits, the regulation of PT sodium transport by Ang II is biphasic: transport is stimulated by picomolar to nanomolar concentrations of Ang II but inhibited by nanomolar to micromolar concentrations of Ang II. However, little is known about the effects of Ang II on human PT transport. By functional analysis with isolated PTs obtained from nephrectomy surgery, we found that Ang II induces a dose-dependent profound stimulation of human PT transport by type 1 Ang II receptor (AT1)-dependent phosphorylation of extracellular signal-regulated kinase (ERK). In PTs of wild-type mice, the nitric oxide (NO) /cGMP/cGMP-dependent kinase II (cGKII) pathway mediated the inhibitory effect of Ang II. In PTs of cGKII-deficient mice, the inhibitory effect of Ang II was lost, but activation of the NO/cGMP pathway failed to phosphorylate ERK. Conversely, in human PTs, the NO/cGMP pathway mediated the stimulatory effect of Ang II by phosphorylating ERK independently of cGKII. These contrasting responses to the NO/cGMP pathway may largely explain the different modes of PT transport regulation by Ang II, and the unopposed marked stimulation of PT transport by high intrarenal concentrations of Ang II may be an important factor in the pathogenesis of human hypertension. Additionally, the previously unrecognized stimulatory effect of the NO/cGMP pathway on PT transport may represent a human-specific therapeutic target in hypertension.
Granzyme A is an interleukin 1 beta-converting enzyme.
Authors: M Irmler, S Hertig, H R MacDonald, R Sadoul, J D Becherer, A Proudfoot, R Solari, J Tschopp
Journal: The Journal of Experimental Medicine (1995)

Apoptosis is critically dependent on the presence of the ced-3 gene in Caenorhabditis elegans, which encodes a protein homologous to the mammalian interleukin (IL)-1 beta-converting enzyme (ICE). Overexpression of ICE or ced-3 promotes apoptosis. Cytotoxic T lymphocyte-mediated rapid apoptosis is induced by the proteases granzyme A and B. ICE and granzyme B share the rare substrate site of aspartic acid, after which amino acid cleavage of precursor IL-1 beta (pIL-1 beta) occurs. Here we show that granzyme A, but not granzyme B, converts pIL-1 beta to its 17-kD mature form. Major cleavage occurs at Arg120, four amino acids downstream of the authentic processing site, Asp116. IL-1 beta generated by granzyme A is biologically active. When pIL-1 beta processing is monitored in lipopolysaccharide-activated macrophage target cells attacked by cytotoxic T lymphocytes, intracellular conversion precedes lysis. Prior granzyme inactivation blocks this processing. We conclude that the apoptosis-inducing granzyme A and ICE share at least one downstream target substrate, i.e., pIL-1 beta. This suggests that lymphocytes, by means of their own converting enzyme, could initiate a local inflammatory response independent of the presence of ICE.
Molecular Mechanisms Mediating Proliferation/Differentiation Interrelationships During Progressive Development of the Osteoblast Phenotype
Authors: GARY S. STEIN, JANE B. LIAN
Journal: Endocrine Reviews (1993)

A FUNCTIONAL relationship between cell growth and the initiation and progression of events associated with differentiation has been a fundamental question challenging developmental biologists for more than a century. In the case of bone, as observed with other cells and tissue, the relationship of growth and differentiation must be maintained and stringently regulated, both during development and throughout the life of the organism, to support tissue remodeling. For many years, bone was defined anatomically and examined largely in a descriptive manner by ultrastructural analysis and by biochemical and histochemical methods. These studies provided the basis for our understanding of bone tissue organization and orchestration of the progressive recruitment, proliferation, and differentiation of the various cellular components of bone tissue. Now, complemented by an increased knowledge of molecular mechanisms that are associated with and regulate expression of genes encoding phenotypic components of bone, and those that may control the progressive development and maturation of the bone cell phenotype, our understanding of bone cell and tissue differentiation is rapidly expanding.
Two MicroRNA Panels to Discriminate Three Subtypes of Lung Carcinoma in Bronchial Brushing Specimens
Authors: Wei Huang, Jie Hu, Da-wei Yang, Xin-ting Fan, Yi Jin, Ying-yong Hou, Ji-ping Wang, Yun-feng Yuan, Yun-shan Tan, Xiong-zeng Zhu, Chun-xue Bai, Ying Wu, Hong-guang Zhu, Shao-hua Lu
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

Rationale: Effective treatment for lung cancer requires accuracy in subclassification of carcinoma subtypes.Objectives: To identify microRNAs in bronchial brushing specimens for discriminating small cell lung cancer (SCLC) from non–small cell lung cancer (NSCLC) and for further differentiating squamous cell carcinoma (SQ) from adenocarcinoma (AC).Methods: Microarrays were used to screen 723 microRNAs in laser-captured, microdissected cancer cells from 82 snap-frozen surgical lung specimens. Quantitative reverse-transcriptase polymerase chain reaction was performed on 153 macrodissected formalin-fixed, paraffin-embedded (FFPE) surgical lung specimens to evaluate seven microRNA candidates discovered from microarrays. Two microRNA panels were constructed on the basis of a training cohort (n = 85) and validated using an independent cohort (n = 68). The microRNA panels were applied as differentiators of SCLC from NSCLC and of SQ from AC in 207 bronchial brushing specimens.Measurements and Main Results: Two microRNA panels yielded high diagnostic accuracy in discriminating SCLC from NSCLC (miR-29a and miR-375; area under the curve [AUC], 0.991 and 0.982 for training and validation data set, respectively) and in differentiating SQ from AC (miR-205 and miR-34a; AUC, 0.977 and 0.982 for training and validation data set, respectively) in FFPE surgical lung specimens. Moreover, the microRNA panels accurately differentiated SCLC from NSCLC (AUC, 0.947) and SQ from AC (AUC, 0.962) in bronchial brushing specimens.Conclusions: We found two microRNA panels that accurately discriminated between the three subtypes of lung carcinoma in bronchial brushing specimens. The identified microRNA panels may have considerable clinical value in differential diagnosis and optimizing treatment strategies based on lung cancer subtypes.
Understanding Variation in 30-Day Surgical Readmission in the Era of Accountable Care
Authors: Faiz Gani, Donald J. Lucas, Yuhree Kim, Eric B. Schneider, Timothy M. Pawlik
Journal: JAMA Surgery (2015)

<h3>Importance</h3> Readmission is a target area of quality improvement in surgery. While variation in readmission is common, to our knowledge, no study has specifically examined the underlying etiology of this variation among a variety of surgical procedures performed in a large academic medical center. <h3>Objective</h3> To quantify the variability in 30-day readmission attributable to patient, surgeon, and surgical subspecialty levels in patients undergoing a major surgical procedure. <h3>Design, Setting, and Participants</h3> Retrospective analysis of administrative claims data of patients discharged following a major surgical procedure at a tertiary care center between January 1, 2009, and, December 31, 2013. A total of 22 559 patients were included in this study and underwent a major surgical procedure performed by 56 surgeons practicing in 8 surgical subspecialties. <h3>Main Outcomes and Measures</h3> In-hospital morbidity, 30-day readmission, and proportional variation in 30-day readmission at patient, surgeon, and surgical subspecialty levels. <h3>Results</h3> Among the 22 559 patients in this study, patient age, race/ethnicity, and payer type differed across surgical subspecialties. Preoperative comorbidity was common and noted in 65.1% of patients. Postoperative complications were noted in 21.6% of patients varying from 2.1% following breast, melanoma or endocrine surgery to 37.0% following cardiac surgery. The overall 30-day readmission was 13.2% (n = 2975). Readmission varied considerably across the 8 different surgical subspecialties, ranging from 24.8% following transplant surgery (n = 557) to 2.1% following breast, melanoma, or endocrine surgery (n = 32). After adjusting for patient- and surgeon-level variables, factors associated with readmission included African American race/ethnicity (odds ratio, 1.23; 95% CI, 1.11-1.36;<i>P</i> &lt; .001), increasing comorbidity (Charlson Comorbidity Index score of 1: odds ratio, 1.16; 95% CI, 1.02-1.32;<i>P</i> = .02; and a Charlson Comorbidity Index score of ≥2 : odds ratio, 1.38; 95% CI, 1.24-1.53;<i>P</i> &lt; .001), postoperative complication (odds ratio, 1.19; 95% CI, 1.08-1.32;<i>P</i> = .001), and an extended length of stay (odds ratio, 1.78; 95% CI, 1.61-1.96;<i>P</i> &lt; .001). The majority of the variation in readmission was attributable to patient-related factors (82.8%) while surgical subspecialty accounted for 14.5% of the variability, and individual surgeon-level factors accounted for 2.8%. <h3>Conclusions and Relevance</h3> Readmission occurred in more than 1 in 10 patients, with considerable variation across surgical subspecialties. Variation in readmission was overwhelmingly owing to patient-level factors while only a minority of the variation was attributable to factors at the surgical subspecialty and individual surgeon levels.
Role of low-dose theophyllines in exacerbations of COPD
Authors: A B Palamarthy
Journal: Thorax (2010)

In the paper by Cosio and colleagues on the effect of low-dose theophylline on the anti-inflammatory effects of steroids during exacerbations of chronic obstructive pulmonary disease (COPD), the authors concluded that recovery of forced expiratory volume in 1 s 3 …
Effect of In Utero and Early-Life Conditions on Adult Health and Disease
Authors: Peter D. Gluckman, Mark A. Hanson, Cyrus Cooper, Kent L. Thornburg
Journal: New England Journal of Medicine (2008)

Many lines of evidence, including epidemiologic data and extensive clinical and experimental studies, indicate that early life events play a powerful role in influencing later susceptibility to certain chronic diseases. This review synthesizes evidence from several disciplines to support the contention that environmental factors acting during development should be accorded greater weight in models of disease causation.
INFECTIOUS CATARRH OF MICE
Authors: John B. Nelson
Journal: The Journal of Experimental Medicine (1937)

A natural outbreak of an infectious catarrh in a colony of Swiss mice is reported. The disease was generally characterized by a peculiar chattering sound during life and by a rhinitis, an otitis media, and a pneumonia at autopsy. The pneumonia was slowly progressive and terminated fatally in a high percentage of cases. The mortality in a group of 75 naturally infected mice was 95 per cent over a period of 11 months. The disease was readily reproducible in susceptible mice by the nasal instillation of exudate from any locus of infection. It was also transmissible by direct contact. In both naturally and experimentally infected animals there was an incubation period of 10 days or more before symptoms were apparent. Recovery from the disease was not observed.
Differential Healing After Sirolimus, Paclitaxel, and Bare Metal Stent Placement in Combination With Peroxisome Proliferator-Activator Receptor γ Agonists
Authors: Aloke V. Finn, Michael John, Gaku Nakazawa, Rohini Polavarapu, Vinit Karmali, Xin Xu, Qi Cheng, Talina Davis, Chitra Raghunathan, Eduardo Acampado, Tucker Ezell, Scott Lajoie, Michael Eppihimer, Frank D. Kolodgie, Renu Virmani, Herman Kalman Gold
Journal: Circulation Research (2009)

Sirolimus-eluting coronary stents (SESs) and paclitaxel-eluting coronary stents (PESs) are used to reduce restenosis but have different sites of action. The molecular targets of sirolimus overlap with those of the peroxisome proliferator-activated receptor (PPAR)gamma agonist rosiglitazone (RSG) but the consequence of this interaction on endothelialization is unknown.Using the New Zealand white rabbit iliac model of stenting, we examined the effects of RSG on SESs, PESs, and bare metal stents endothelialization.Animals receiving SESs, PESs, or bare metal stents and either RSG (3 mg/kg per day) or placebo were euthanized at 28 days, and arteries were evaluated by scanning electron microscopy. Fourteen-day organ culture and Western blotting of iliac arteries and tissue culture experiments were conducted. Endothelialization was significantly reduced by RSG in SESs but not in PESs or bare metal stents. Organ culture revealed reduced vascular endothelial growth factor in SESs receiving RSG compared to RSG animals receiving bare metal stent or PESs. Quantitative polymerase chain reaction in human aortic endothelial cells (HAECs) revealed that sirolimus (but not paclitaxel) inhibited RSG-induced vascular endothelial growth factor transcription. Western blotting demonstrated that inhibition of molecular signaling in SES+RSG-treated arteries was similar to findings in HAECs treated with RSG and small interfering RNA to PPARgamma, suggesting that sirolimus inhibits PPARgamma. Transfection of HAECs with mTOR (mammalian target of rapamycin) short hairpin RNA and with Akt2 small interfering RNA significantly inhibited RSG-mediated transcriptional upregulation of heme oxygenase-1, a PPARgamma target gene. Chromatin immunoprecipitation assay demonstrated sirolimus interferes with binding of PPARgamma to its response elements in heme oxygenase-1 promoter.mTOR/Akt2 is required for optimal PPARgamma activation. Patients who receive SESs during concomitant RSG treatment may be at risk for delayed stent healing.
Cytisine and the failure to market and regulate for human health
Authors: Paul Aveyard, Robert West
Journal: Thorax (2013)

Cytisine is a partial nicotinic agonist found in high concentrations of laburnum, a plant that grows easily in many parts of the world. This makes it inexpensive to manufacture. The drug has been used for many years in eastern Europe as a smoking cessation aid. The drug came to prominence in the Western world following the development of varenicline, a manufactured nicotinic partial agonist, and the publication of a systematic review of cytisine by Etter in 2006.1 Etter's review and meta-analysis included several trials published in non-English language journals, most of which were not indexed in Pubmed. The review showed evidence of effectiveness, but the trials had methodological weaknesses that detracted from the evidence. In their article published online, Hajek and colleagues2 have updated this review. What has changed?

Since the Etter review, two more studies have been added to the meta-analysis. One of these is a large trial that, had it been done by a pharmaceutical company, might be said to be a typical phase III registration trial.3 The data are now stronger that cytisine is effective. Hajek …