tbuckley/cabot-search huggingface dataset:
Malonyl Coenzyme A Decarboxylase Inhibition Protects the Ischemic Heart by Inhibiting Fatty Acid Oxidation and Stimulating Glucose Oxidation
Authors: Jason R.B. Dyck, Jie-Fei Cheng, William C. Stanley, Rick Barr, Margaret P. Chandler, Steven Brown, David Wallace, Thomas Arrhenius, Charles Harmon, Guang Yang, Alex M. Nadzan, Gary D. Lopaschuk
Journal: Circulation Research (2004)

Abnormally high rates of fatty acid oxidation and low rates of glucose oxidation are important contributors to the severity of ischemic heart disease. Malonyl coenzyme A (CoA) regulates fatty acid oxidation by inhibiting mitochondrial uptake of fatty acids. Malonyl CoA decarboxylase (MCD) is involved in the decarboxylation of malonyl CoA to acetyl CoA. Therefore, inhibition of MCD may decrease fatty acid oxidation and protect the ischemic heart, secondary to increasing malonyl CoA levels. Ex vivo working rat hearts aerobically perfused in the presence of newly developed MCD inhibitors showed an increase in malonyl CoA levels, which was accompanied by both a significant decrease in fatty acid oxidation rates and an increase in glucose oxidation rates compared with controls. Using a model of demand-induced ischemia in pigs, MCD inhibition significantly increased glucose oxidation rates and reduced lactate production compared with vehicle-treated hearts, which was accompanied by a significant increase in cardiac work compared with controls. In a more severe rat heart global ischemia/reperfusion model, glucose oxidation was significantly increased and cardiac function was significantly improved during reperfusion in hearts treated with the MCD inhibitor compared with controls. Together, our data show that MCD inhibitors, which increase myocardial malonyl CoA levels, decrease fatty acid oxidation and accelerate glucose oxidation in both ex vivo rat hearts and in vivo pig hearts. This switch in energy substrate preference improves cardiac function during and after ischemia, suggesting that pharmacological inhibition of MCD may be a novel approach to treating ischemic heart disease.
Analysis of interleukin 6 receptor and gp130 expressions and proliferative capability of human CD34+ cells.
Authors: S Tajima, K Tsuji, Y Ebihara, X Sui, R Tanaka, K Muraoka, M Yoshida, K Yamada, K Yasukawa, T Taga, T Kishimoto, T Nakahata
Journal: The Journal of Experimental Medicine (1996)

We recently demonstrated that stimulation of gp130 by a combination of soluble interleukin 6 receptor (sIL-6R) and IL-6 but not IL-6 alone significantly stimulates the ex vivo expansion of primitive hematopoietic progenitors and the generation of erythroid cells from human CD34+ cells in the presence of stem cell factor (SCF). Here, we show that gp130 is found low positively on most CD34+ cells, whereas IL-6R is expressed on only 30-50% of these cells. Although most of the colonies generated from FACS-sorted CD34+IL-6R+ cells were granulocyte/macrophage (GM) colonies, CD34+IL-6R- cells gave rise to various types of colonies, including erythroid bursts, GM, megakaryocytes, and mixed colonies in methylcellulose culture with a combination of IL-6, sIL-6R, and SCF. Similar results were obtained in culture supplemented with a combination of IL-3, IL-6, SCF, granulocyte colony-stimulating factor, erythropoietin, and thrombopoietin. A limiting dilution analysis of long-term culture-initiating cells (LTC-IC) showed that the CD34+IL-6R- cells contained a larger number of LTC-IC than did the CD34+IL-6R+ cells. In a serum-free suspension of CD34+IL-6R- cells, the addition of sIL-6R to the combination of IL-6 and SCF dramatically increased the total and multipotential progenitors, whereas CD34+IL-6R+ cells failed to do so under the same conditions. These results indicate that most of the erythroid, megakaryocytic, and primitive human hematopoietic progenitors are included in the IL-6R- populations, and the activation of gp130 on these progenitors can be achieved by a complex of IL-6-sIL-6R, but not by IL-6 alone. The present culture system using IL-6, sIL-6R, and SCF may provide a novel approach for ex vivo expansion of human primitive hematopoietic progenitors.
Distinct Roles of FOXA2 and FOXA3 in Allergic Airway Disease and Asthma
Authors: Sung-Woo Park, Catherine Verhaeghe, Louis T. Nguyenvu, Rebecca Barbeau, Christopher J. Eisley, Yasuhiro Nakagami, Xiaozhu Huang, Prescott G. Woodruff, John V. Fahy, David J. Erle
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Rationale: Increased production of mucus is a prominent feature of asthma. IL-13–driven mucous cell metaplasia is associated with decreased expression of the transcription factor FOXA2 and increased expression of the related transcription factor FOXA3 in animal and cell culture models.Objectives: Establish how changes in FOXA2 and FOXA3 expression contribute to mucous metaplasia and determine whether FOXA2 and FOXA3 expression is altered in asthma.Methods: Mice expressing a Foxa2 transgene in airway epithelial cells and mice deficient in Foxa3 were analyzed after allergen sensitization and challenge. Expression of FOXA2, FOXA3, MUC5AC, and the highly IL-13–inducible gene CLCA1 was analyzed in airway biopsies from subjects with asthma and control subjects.Measurements and Main Results: Expression of a Foxa2 transgene reduced allergen-induced mucous metaplasia by 45% compared with control transgenic mice (P < 0.05) whereas inactivation of Foxa3 had no detectable effects on mucous metaplasia. Expression of FOXA2 was reduced in subjects with asthma and was negatively correlated with MUC5AC and CLCA1 levels in subjects with asthma. In contrast, FOXA3 expression was not significantly correlated with MUC5AC and was positively correlated with CLCA1.Conclusions: Increasing Foxa2 expression reduced mucous metaplasia in an allergic mouse model. Subjects with asthma had decreased FOXA2 expression, suggesting that therapeutic approaches that increase FOXA2 expression or function could be beneficial for reducing mucus production in asthma. Unlike FOXA2, FOXA3 did not regulate mucous metaplasia.
Biomarkers for Monitoring Antiangiogenic Therapy
Authors: Rupal S. Bhatt, Pankaj Seth, Vikas P. Sukhatme
Journal: Clinical Cancer Research (2007)

Abstract A variety of antiangiogenic agents are currently available for the treatment of renal cell carcinoma. With these exciting new therapeutic agents comes the challenge of elucidating useful biomarkers to monitor patients receiving these therapies. Although many patients benefit from antiangiogenic therapies, it is often by achieving stability of their disease. Thus, development of noninvasive biomarkers of disease response and relapse is a crucial objective to aid in the management of patients. The current technologies being explored in this field include circulating plasma proteins, cells, and nucleic acids and novel imaging techniques. Surrogate markers of angiogenesis could help with selecting patients for therapy, determining optimal dosing of therapy, deciding whether to change therapy, and assessing appropriate salvage therapy.
ALKoma: A Cancer Subtype with a Shared Target
Authors: Hiroyuki Mano
Journal: Cancer Discovery (2012)

Anaplastic lymphoma kinase (ALK) is a receptor-type protein tyrosine kinase that is currently the focus of much attention in oncology. ALK is rendered oncogenic as a result of its fusion to NPM1 in anaplastic large cell lymphoma, to TPM3 or TPM4 in inflammatory myofibroblastic tumor, to EML4 in non-small cell lung carcinoma, and to VCL in renal medullary carcinoma. It is also activated as a result of missense mutations in neuroblastoma and anaplastic thyroid cancer. Whereas these various tumors arise in different organs, they share activated ALK, and a marked clinical efficacy with ALK inhibitors has already been shown for some of the tumors with ALK fusions. One of such compound, crizotinib, is now approved in the United States for the treatment of lung cancer positive for ALK rearrangement. I propose that tumors carrying abnormal ALK as an essential growth driver be collectively termed "ALKoma."
Spontaneous bacterial peritonitis in cirrhotic patients treated using paracentesis or diuretics: Results of a randomized study
Authors: Ricard Solà, Montserrat Andreu, Susana Coll, Maria Carme Vila, Maria Isabel Oliver, Vicente Arroyo
Journal: Hepatology (1995)

Diuretic treatment in cirrhotic patients with ascites increases ascitic fluid concentration of total protein and complement components, and opsonic activity. These changes are not observed in patients treated with paracentesis. Based on these data it has been suggested that therapeutic paracentesis may be associated with an increased risk of spontaneous bacterial peritonitis (SBP) development. To assess this possibility, 80 cirrhotic patients with tense ascites were randomly allocated in two therapeutic groups: group 1 (40 patients) was treated with total paracentesis associated with plasma volume expansion and group 2 was treated with diuretics. After mobilization of ascites, patients from both groups received diuretics to avoid reaccumulation of ascites; cases that developed tense ascites during follow-up (mean follow-up period, 60 ± 6 and 55 ± 4 weeks, respectively) were treated according to initial randomization. Patients from both groups had similar results regarding baseline clinical and standard laboratory data, ascitic fluid concentration of total protein, complement components, and opsonic activity. Sixteen patients (7 from group 1 and 9 from group 2) developed SBP during the study period. The 4-week and 1-year probability of SBP occurrence were 2.5% and 18.6%, respectively, in group 1 patients, and 11.9% and 24%, respectively, in group 2 patients. Therefore, our study indicates that therapeutic paracentesis does not increase the early- and long-term risk of SBP development in cirrhotic patients with tense ascites. (Hepatology 1995;21:340-344.)
Management of acute upper gastrointestinal bleeding: summary of NICE guidance
Authors: K. Dworzynski, V. Pollit, A. Kelsey, B. Higgins, K. Palmer
Journal: BMJ (2012)

Acute upper gastrointestinal bleeding is the commonest medical emergency managed by gastroenterologists in the United Kingdom. The most frequently identified source of bleeding is peptic ulcer disease, but other important causes exist, particularly oesophageal or gastric varices, which are classically associated with more severe bleeding. A large audit in the UK in 20071 indicated that the rate of mortality from acute upper gastrointestinal bleeding (about 7%) has not changed much over the past 50 years, and that service provision varies considerably across the UK. This article summarises the most recent recommendations from the National Institute for Health and Clinical Excellence (NICE) on the management of acute upper gastrointestinal bleeding.2

NICE recommendations are based on systematic reviews of the best available evidence and explicit consideration of cost effectiveness. When minimal evidence is available, recommendations are based on the Guideline Development Group’s experience and opinion of what constitutes good practice. Evidence levels for the recommendations are given in italic in square brackets.

### Risk assessment

At presentation with acute upper gastrointestinal bleeding, assess for risk of serious adverse events or need for intervention. To do this use the following formal risk assessment scoring systems for all patients with acute gastrointestinal bleeding: the Blatchford scoring system3 at first assessment and the full Rockall scoring system4 after endoscopy (tables 1⇓ and 2⇓). [ Based on low to very low quality evidence from prospective and retrospective case reviews ]

View this table:

Table 1 
 The Blatchford scoring system.3 For a patient with acute upper gastrointestinal bleeding, add up scores in the right hand column for each risk marker (if no value applies for a particular marker, score 0) to derive a total score* 



View this table:

Table 2 
 The full (post-endoscopy) Rockall scoring system.4 For a patient with acute upper gastrointestinal bleeding, add up scores at the top of the …
Restriction of primary responses to the IgG class and dependency of IgM responses on secondary immunization for the copolymers of L-glutamic acid, L-tyrosine, and L-alanine.
Authors: C Waltenbaugh, J Thèze, B Benacerraf
Journal: The Journal of Experimental Medicine (1977)

Primary responses to the linear polymers of L-glutamic acid, L-tyrosine, and L-alanine are restricted to the IgG class of antibodies. The appearance of specific IgM antibodies against these antigens is dependent upon secondary immunization, in contrast to many classical antigenic systems. The presence of an IgM response was verified by a direct plaque-forming cell assay, the inhibition of direct plaques by an antiserum specific for mouse micron-chain, and the physical separation of IgM and IgG GAT-specific antibodies by gel filtration. Preimmunization of the appropriate nonresponder strain with GAT or GT inhibits both the secondary IgM and IgG responses to GAT-MBSA and GT-MBSA, respectively. The tolerance observed is due to the induction of suppressor cells as demonstrated by cell transfer experiments.
Hyperinsulinemic Hypoglycemia with Nesidioblastosis after Gastric-Bypass Surgery
Authors: Geoffrey J. Service, Geoffrey B. Thompson, F. John Service, James C. Andrews, Maria L. Collazo-Clavell, Ricardo V. Lloyd
Journal: New England Journal of Medicine (2005)

We describe six patients (five women and one man; median age, 47 years; range, 39 to 54) with postprandial symptoms of neuroglycopenia owing to endogenous hyperinsulinemic hypoglycemia after Roux-en-Y gastric bypass surgery. Except for equivocal evidence in one patient, there was no radiologic evidence of insulinoma. Selective arterial calcium-stimulation tests, positive in each patient, were used to guide partial pancreatectomy. Nesidioblastosis was identified in resected specimens from each patient, and multiple insulinomas were identified in one. Hypoglycemic symptoms diminished postoperatively. We speculate that hyperfunction of pancreatic islets did not lead to obesity but that beta-cell trophic factors may have increased as a result of gastric bypass.
Identification of small molecule inhibitors of RANKL and TNF signalling as anti-inflammatory and antiresorptive agents in mice
Authors: Emmanuel Coste, Iain R Greig, Patrick Mollat, Lorraine Rose, Mohini Gray, Stuart H Ralston, Rob J van ‘t Hof
Journal: Annals of the Rheumatic Diseases (2013)

Introduction Inflammatory joint diseases such as rheumatoid arthritis are associated with local bone erosions and systemic bone loss, mediated by increased osteoclastic activity. The receptor activator of nuclear factor (NF) κB ligand (RANKL) plays a key role in mediating inflammation-induced bone loss, whereas tumour necrosis factor (TNF) plays a central role in the inflammatory process. Here we tested whether a recently identified class of small molecule inhibitors of RANKL signalling (ABD compounds) also affect TNF signalling and whether these compounds inhibit inflammation in an animal model of rheumatoid arthritis. Methods The inhibitory effects of the ABD compounds on TNF-induced signalling were tested in mouse macrophage cultures by western blotting and in an NFκB luciferase-reporter cell line. The anti-inflammatory effects of the compounds were tested in the mouse collagen-induced arthritis model of rheumatoid arthritis. Results The ABD compounds ABD328 and ABD345 both inhibited TNF-induced activation of the NFκB pathway and the extracellular signal-regulated kinase (ERK) and Jun kinase (JNK) mitogen activated protein kinases (MAPKs). When tested in the mouse collagen-induced arthritis model of rheumatoid arthritis, the compounds suppressed inflammatory arthritis, inhibited joint destruction and prevented systemic bone loss. Furthermore, one of the compounds (ABD328) showed oral activity. Conclusions Here we describe a novel class of small molecule compounds that inhibit both RANKL- and TNF-induced NFκB and MAPK signalling in osteoclasts and macrophages, and inflammation and bone destruction in a mouse model of rheumatoid arthritis. These novel compounds therefore represent a promising new class of treatments for inflammatory diseases, such as rheumatoid arthritis.
Multivariate analysis based risk grouping of ewing tumours (ET) with extra-pulmonary metastatic disease (EPMD): Final results from the Euro Ewing 99 study
Authors: R. Ladenstein, J. Whelan, O. Oberlin, C. Weston, H. Jürgens
Journal: Journal of Clinical Oncology (2007)

9562 Background: To identify an effective treatment for patients with EPMD. Methods: 192 patients (pts) were registered. Median age is 15.8 years (yrs) (0.4–49.29). Primary site was extremity in 57 pts and axial/other in 135 pts (40.6% in the pelvis). Tumour volume was ≥ 200 ml in 114pts. Metastatic spread was bone marrow (BM) only in 19 pts, bone only in 93 pts and bone and BM in 79 pts. Six VIDE induction cycles were completed by 168 pts (85%). Local treatment included surgery when possible and/or radiotherapy (Rx) as indicated. Recommended HDT was busulphan (BU) 600 mg/m 2 and melphalan (MEL) 140 mg/m 2 with PSCR. Median follow up is 4.2 years (range: 1.9–6.6). Results: Partial remission or better was achieved after cycle 6 in 75/116 pts subjected to HDT/SCR (65%). The overall survival at 3 years for all 192 pts is 29% (95% CI=0.04). Significantly favourable univariate factors in the unselected cohort at diagnosis (Dx) were age &lt; 14 yrs (event free survival at 3 yrs (EFS) 37%, p=0.006), BM involvement only (EFS 47%, p=0.024), single bone lesions only (EFS 35%, p=0.009), extremities (EFS 34%, p=0.007) and tumour volume of &lt;200 ml (EFS 47%, p&lt;0.001). For pts receiving BuMel it is noteworthy that 37 pts of &lt;14a and EPMD achieved an EFS of 47% in comparison to older counterparts &gt;14a (EFS 22% (p=0.026). Multivariate analysis identified two major risk factors at Dx: primary tumour volume &gt;200 ml p&lt;0.001 (RR 2.25) and &gt; 5 bone metastases p=0.064 (RR 2.11). In these risk groups the 3 yr EFS was 56% for 35 pts with &lt;200 ml and &lt;5 bone lesions, for 17pts with &lt;200 ml &gt; 5 bone lesions 29%, for 67 pts &gt;200 ml or &lt; 5 bone lesions 19% and extremely dismal for 47 pts with &gt;200 ml and &gt; 5 bone lesions with 7% (p&lt;0.001). Conclusions: Groups with differing prognoses from EPMD have been identified from this prospectively followed cohort. Aggressive treatment with HDT appears effective only for sub groups of patients with EPMD and ET. No significant financial relationships to disclose.
The comparative effectiveness of abatacept versus anti-tumour necrosis factor switching for rheumatoid arthritis patients previously treated with an anti-tumour necrosis factor
Authors: Leslie R Harrold, George W Reed, Joel M Kremer, Jeffrey R Curtis, Daniel H Solomon, Marc C Hochberg, Jeffrey D Greenberg
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Both facilitatory and inhibitory effects of the sympathetic nervous system (SNS) on experimental arthritis have been reported. It is unknown whether such bidirectional effects are inherent to all experimental arthritis models and/or whether critical time windows exist for influences of the SNS on inflammation. <h3>Objectives</h3> To assess the effect of sympathectomy at different time points on the course and severity of murine antigen-induced arthritis (AIA). <h3>Methods</h3> AIA was induced in mice. Chemical sympathectomy with 6-hydroxydopamine was carried out either neonatally, in the immunisation phase, or immediately before AIA elicitation, or during the chronic phase. In sympathectomised and non-sympathectomised AIA mice the inflammatory process (joint swelling, histopathology of inflammation and joint destruction), pain-related behaviour and cellular and humoral immune responses were analysed. <h3>Results</h3> Sympathectomy during AIA induction or neonatal sympathectomy significantly reduced the severity of acute AIA. Neither sympathectomy in the immunisation phase nor in the chronic phase influenced AIA. Flare-up reactions were reduced by sympathectomy just before flare-up or during the initial acute AIA stage. Sympathectomised AIA mice showed less hyperalgesia. Sympathectomy significantly reduced interleukin (IL) 2, IL-17 and transforming growth factor β in supernatants from lymph nodes and/or spleen cells and antigen-specific Th1-associated IgG2a in serum; IgG1 titres were unaffected. The ß blocker, propranolol, and the norepinephrine reuptake inhibitor bupropion produced similar anti-inflammatory effects, whereas the ß-adrenergic agonist isoproterenol increased AIA severity in neonatally sympathectomised mice. <h3>Conclusions</h3> Sympathetic activity mainly increases the severity of acute episodes of immune-mediated arthritis. Therapeutic reduction of sympathetic activity at acute stages attenuates inflammation, hyperalgesia and proinflammatory immune parameters.
How to get better value healthcare
Authors: K. Abbasi
Journal: Journal of the Royal Society of Medicine (2007)

When you begin a book with the words ‘Oh fuck!’, you'd better make it worth reading. When you begin a book about health care with those words and you happen to be a guru of evidence-based health care, you'd better make it essential reading or have lots of friends.​friends.



Figure 1





The release of last month's report by Derek Wanless, commissioned by the King's Fund, might mislead some observers into believing that the value of health care is a matter of recent concern. Wanless argues that increased funding of the NHS has produced better paid doctors, more obesity, and little in the way of better productivity when we consider clinical outcomes.

Debates about the value of health care are, of course, as old as health care itself. In recent times they have been heavily influenced by the random but incisive reflections of Archie Cochrane, the reluctant but pioneering analyses of Armenian Avedis Donabedian, and the succinct but piercing observations of John Muir Gray.

Money is at the heart of these considerations. No health service can afford to pay for all possible treatments. Increasing affluence brings greater demands for better health and health care. Better informed patients, an ageing population, new diseases, modern lifestyles and technological advances have placed unbearable costs on health systems.

But money alone is not the answer. The Law of Diminishing Benefit informs us that there comes a point when increased resource fails to deliver further health benefits, while the Law of Undiminished Harm describes how harm continues to increase despite greater resource. When these two effects are considered together it is possible to predict the health gain—the difference between benefit and harm at any level of resource. If plotted on a graph, the curve of health gain is a hump: the amount of resource that delivers the maximum health gain is the crown of the hump and is also the point at which value is at a maximum.

Value, though, means different things to different people. Payers, patients, clinicians, managers and industry all have their own perspective. There are dictionary definitions of value and numerical definitions of value. As well as attempting to understand and reconcile these differences, Muir Gray has created a series of single-page aides-memoire to help managers and payers achieve better value health care.

One failure of health care is the burden of information on health professionals. As befitting the man who coined the ‘Information Paradox,’ Muir Gray keeps his words few and well chosen. The complex thinking that helps determine value in health care is compressed into less than a hundred short, simple pages. For time-strapped professionals without the patience for even these few words, or those with a hunger for more, there is an associated radio station (http://www.soundshealthy.org), where Muir Gray draws you further into his world of better-value health care. It is also a world that resonates to the sound of Freddie Mercury singing Radio Ga Ga. The words ‘Oh fuck!’ spring to mind...