tbuckley/cabot-search huggingface dataset:
Blood and synovial fluid cytokine signatures in patients with juvenile idiopathic arthritis: a cross-sectional study
Authors: W. de Jager, E. P A H Hoppenreijs, N. M Wulffraat, L. R Wedderburn, W. Kuis, B. J Prakken
Journal: Annals of the Rheumatic Diseases (2006)

<b>Background:</b> Juvenile idiopathic arthritis (JIA) consists of a heterogeneous group of disorders with, for the most part, an unknown immunopathogenesis. Although onset and disease course differ, the subtypes of JIA share the occurrence of chronic inflammation of the joints, with infiltrations of immunocompetent cells that secrete inflammatory mediators. <b>Objective:</b> To identify a panel of cytokines specifically related to the inflammatory process in JIA. <b>Methods:</b> Using a new technology, the multiplex immunoassay, 30 cytokines were measured in plasma of 65 patients with JIA, of which 34 were paired with synovial fluid. These data were compared with plasma of 20 healthy controls and 9 patients with type I diabetes, a chronic inflammatory disease. <b>Results:</b> Patients with JIA had, irrespective of their subclassification, significantly higher levels of tumour necrosis factor α, macrophage inhibitory factor (MIF), CCL2, CCL3, CCL11, CCL22 and CXCL9 in plasma than controls. In paired plasma and synovial fluid samples of patients with JIA, significantly higher levels of interleukin (IL)6, IL15, CCL2, CCL3, CXCL8, CXCL9 and CXCL10 were present in synovial fluid. Cluster analysis in all patients with JIA revealed a predominant pro-inflammatory cytokine cluster during active disease and a regulatory/anti-inflammatory-related cytokine cluster during remission. Whether a discrimination profile of various cytokines could help in the determination of disease classification was tested. <b>Conclusion:</b> It is suggested that several cytokines (IL18, MIF, CCL2, CCL3, CCL11, CXCL9 and CXCL10) may correspond to the activation status during inflammation in JIA and could be instrumental in monitoring disease activity and outcomes of (new) immunotherapies.
Heavy Chain Ferritin siRNA Delivered by Cationic Liposomes Increases Sensitivity of Cancer Cells to Chemotherapeutic Agents
Authors: Xiaoli Liu, A.B. Madhankumar, Becky Slagle-Webb, Jonas M. Sheehan, Nodar Surguladze, James R. Connor
Journal: Cancer Research (2011)

Abstract Approximately half of all gliomas are resistant to chemotherapy, and new therapeutic strategies are urgently needed to treat this cancer. We hypothesized that disrupting iron homeostasis in glioma cells could block tumor growth, based on an acute requirement for high levels of iron to meet energy requirements associated with their rapid growth. Ferritin is best known as an intracellular iron storage protein, but it also localizes to tumor cell nuclei where it seems to protect DNA from oxidative damage and to promote transcription. In this study, we hypothesize that silencing the H-ferritin (heavy chain ferritin) gene could increase tumor sensitivity to chemotoxins. To test this hypothesis, H-ferritin siRNA was delivered to several human cancer cell lines by using cationic liposomes (C-liposome). H-ferritin siRNA decreased protein expression by 80% within 48 hours, and this decrease was associated with more than 50% decrease in the LD50 for DNA-alkylating agent carmustine (BCNU), which is commonly used to treat glioma in clinic. In a subcutaneous mouse model of human glioma, intratumoral injections of liposomes containing H-ferritin siRNA reduced the effective dose of BCNU needed for tumor suppression by more than 50%. A plasmid supercoil relaxation assay showed that H-ferritin specifically and directly protected DNA from BCNU treatment. H-ferritin siRNA additionally seemed to increase apoptosis in glioma cells in vitro upon H-ferritin knockdown. Overall, our results illustrate how silencing H-ferritin can effectively sensitize tumors to chemotherapy and also show the ability of C-liposomes to serve as a novel in vivo delivery tool for siRNAs. Cancer Res; 71(6); 2240–9. ©2011 AACR.
DNA-dependent protein kinase is one of a subset of autoantigens specifically cleaved early during apoptosis.
Authors: L A Casciola-Rosen, G J Anhalt, A Rosen
Journal: The Journal of Experimental Medicine (1995)

Proteolytic cleavage of key substrates appears to be an important biochemical mechanism underlying the apoptotic process, and the centrality of interleukin 1 beta-converting enzyme (ICE)-like proteases as mediators of apoptosis has been suggested. The identification of the relevant substrates of the ICE protease family during apoptosis therefore constitutes a major challenge. Using human autoantibodies, we demonstrate here that a subset of autoantigens is specifically cleaved early during apoptosis. One of these cleaved molecules is identified as the catalytic subunit of the DNA-dependent protein kinase. The time courses of all proteolytic cleavages are identical and coincide with the onset of morphologic apoptosis. Furthermore, all cleavages share the same inhibition characteristics, which implicate an ICE-like activity(ies). We propose that cleavage of these autoantigens targets these molecules for an autoimmune response by revealing immunocryptic fragments in a proimmune apoptotic setting. Study of the immunogenicity of these fragments may yield insights into the autoimmune targeting of molecules. Moreover, the autoantibodies described will be valuable tools for the elucidation of mechanistically important proteolytic steps along the apoptotic pathway.
The rationing debate: Central government should have a greater role in rationing decisions The case for
Authors: J. Lenaghan
Journal: BMJ (1997)

Rationing decisions in the NHS have largely been controlled by the medical profession and have tended to be implicit, with little reference to agreed systems or criteria.1 Central government is responsible for deciding how resources for health care are distributed around Britain and sets the legal context, but should it do more and develop a national framework for rationing health care? A recent spate of reports and articles revealing variations in the provision of and access to healthcare services highlight the urgent need to address this question.

The House of Commons Select Committee on Health surveyed the priority setting practices of 49 health authorities, noting: “We have been struck by the seemingly enormous variation in access across the country.”2 Redmayne revealed that one in six health authorities are now excluding treatments from public provision,3 while a recent survey has shown that couples in Scotland are seven times more likely to get NHS in vitro fertilisation than those in the south west region.4

Variations in healthcare provision are nothing new, but the purchaser-provider split has made them more explicit, and, more importantly, revealed variations in the criteria used to justify these decisions. For example, in Humberside fertility treatment is provided to women until the age of 40, whereas Liverpool provides it until the age of 35.2 As New and Le Grand have observed, explicit rationing has not been accompanied by an explicit or shared understanding on how such decisions should be made.1

It has been argued that if the government increased the amount of resources available to the NHS, then this would remove the need to ration. However, this ignores the fact that decisions about whether to provide a treatment are not always determined by financial considerations alone. For instance, the new genetic technologies may …
Myocardial Force-Velocity Relationships in Clinical Heart Disease
Authors: PAUL G. HUGENHOLTZ, R. CURTIS ELLISON, CHARLES W. URSCHEL, ISRAEL MIRSKY, EDMUND H. SONNENBLICK
Journal: Circulation (1970)

Myocardial force-velocity relationships were studied in 33 children and young people with varying heart lesions. From analysis of left ventricular pressures and consideration of left ventricular geometry, measured from biplane angiocardiograms, maximal contractile element velocity (V max ) was determined by extrapolation of a stress-velocity plot to zero stress. The value of V max in each patient was compared with the assessment of cardiac function by usual hemodynamic criteria (left ventricular end-diastolic pressure [LVEDP], volume [LVEDV], and ejection fraction [EF]). In general, patients with normal LVEDP, LVEDV, and EF had values for V max above 3 circumferences/sec. Patients with elevated LVEDP or LVEDV or with EF below 0.5 had lower values for V max . Three patients whose usual catheterization data suggested normal ventricular function were found to have low V max . In all three, other evidence for myocardial abnormality was found. Several patients with excessive afterloads had impaired function by conventional criteria, yet had normal V max . Evaluation of myocardial mechanics in man with measurement of V max appears to aid significantly in evaluating patients with heart disease by giving an index to the state of the myocardium not available from routine catheterization data.
Rickettsial Antibodies in Multiple Sclerosis
Authors: E. J. Field, M. Chambers
Journal: BMJ (1970)

The serum of subjects with multiple sclerosis or other degenerative neurological diseases and that of normal controls does not differ significantly in its content of antibodies to several rickettsial antigens. There is no evidence for a rickettsial aetiology of multiple sclerosis, and no grounds for an extended clinical trial of Le Gac9s full method of treatment with antibiotics.
Effects of Oral Fat Load on Insulin Output and Glucose Tolerance in Healthy Control Subjects and Obese Patients Without Diabetes
Authors: Oliver Wuesten, Cristoph H. Balz, Reinhard G. Bretzel, Hans-Ulrich Kloer, Philip D. Hardt
Journal: Diabetes Care (2005)

OBJECTIVE—Elevated plasma nonesterified fatty acid (NEFA) concentrations cause peripheral and hepatic insulin resistance and may play an important role in regulating glucose-induced insulin secretion. The aim of our study was to investigate the influence of physiologically elevated NEFA levels on glucose-stimulated insulin secretion in order to find evidence that NEFAs are a potential factor predisposing for type 2 diabetes and related metabolic disorders, which are known risk factors for cardiovascular disease. RESEARCH DESIGN AND METHODS—We combined an orally administered fat emulsion with an intravenous glucose tolerance test and measured the time course of NEFA, insulin, and glucose. In order to find pathological conditions we applied the experiment to healthy and obese subjects. RESULTS—The main findings are a significant increase in glucose-stimulated insulin secretion after oral fat load in both groups compared with the condition without preceding fat ingestion and a prolonged insulin secretion after fat load in obese patients compared with control subjects. CONCLUSIONS—The results provide evidence that fat ingestion modulates β-cell function and that NEFA is a plausible mediator that acts as a link between fat and glucose metabolism by modulating glucose-stimulated insulin secretion. Under the condition of elevated plasma levels of NEFA, this mechanism may be responsible for hyperinsulinemia in obese patients and a potential target of type 2 diabetes prevention strategies.
A Novel Signaling Pathway from Rod Photoreceptors to Ganglion Cells in Mammalian Retina
Authors: Ed Soucy, Yanshu Wang, Sheila Nirenberg, Jeremy Nathans, Markus Meister
Journal: Neuron (1998)

Current understanding suggests that mammalian rod photoreceptors connect only to an ON-type bipolar cell. This rod-specific bipolar cell excites the AII amacrine cell, which makes connections to cone-specific bipolar cells of both ON and OFF type; these, in turn, synapse with ganglion cells. Recent work on rabbit retina has shown that rod signals can also reach ganglion cells without passing through the rod bipolar cell. This route was thought to be provided by electrical gap junctions, through which rods signal directly to cones and thence to cone bipolar cells. Here, we show that the mouse retina also provides a rod pathway bypassing the rod bipolar cell, suggesting that this is a common feature in mammals. However, this alternative pathway does not require cone photoreceptors; it is perfectly intact in a transgenic mouse whose retina lacks cones. Instead, the results can be explained if rods connect directly to OFF bipolar cells.
Apolipoprotein B100 acts as a molecular link between lipid-induced endoplasmic reticulum stress and hepatic insulin resistance
Authors: Qiaozhu Su, Julie Tsai, Elaine Xu, Wei Qiu, Erika Bereczki, Miklos Santha, Khosrow Adeli
Journal: Hepatology (2009)

Abstract Accumulation of unfolded and misfolded proteins in the endoplasmic reticulum (ER) results in ER stress and lipid overload-induced ER stress has been implicated in the development of insulin resistance. Here, evidence is provided for a molecular link between hepatic apolipoprotein B100 (apoB100), induction of ER stress, and attenuated insulin signaling. First, in vivo upregulation of hepatic apoB100 by a lipogenic diet was found to be closely associated with ER stress and attenuated insulin signaling in the liver. Direct in vivo overexpression of human apoB100 in a mouse transgenic model further supported the link between excessive apoB100 expression and hepatic ER stress. Human apoB100 transgenic mice exhibited hypertriglyceridemia and hyperglycemia. In vitro, accumulation of cellular apoB100 by free fatty acid (oleate) stimulation or constant expression of wild-type or N-glycosylation mutant apoB50 in hepatic cells induced ER stress. This led to perturbed activation of glycogen synthase kinase 3 and glycogen synthase by way of the activation of c-Jun N-terminal kinase and suppression of insulin signaling cascade, suggesting that dysregulation of apoB was sufficient to disturb ER homeostasis and induce hepatic insulin resistance. Small interfering (si)RNA-mediated attenuation of elevated apoB level in the apoB50-expressing cells rescued cells from lipid-induced ER stress and reversed insulin insensitivity. Conclusion : These findings implicate apoB100 as a molecular link between lipid-induced ER stress and hepatic insulin resistance. (Hepatology 2009.)
Introduction of domiciliary mechanical insufflation-exsufflation can reduce the incidence of crisis admissions in patients with Duchenne muscular dystrophy (DMD)
Authors: Emily Ballard, Natalie Grey, Heinz Jungbluth, Elizabeth Wraige, Stam Kapetanakis, Craig Davidson, Nicholas Hart
Journal: European Respiratory Journal (2012)

Although trials are ongoing, there is limited evidence to support the use of mechanical insufflations-exsufflation as a method of secretion clearance to prevent chest infections in patients with DMD. However our local unit practice is to provide a machine to DMD patients that are established on non invasive ventilation with a peak expiratory cough flow   2 episodes of chest sepsis per year requiring antibiotics and hospital admission (2) 1 episode of severe chest sepsis requiring invasive ventilation. The aim of the use of the cough assist machine is to reduce the frequency of hospital admissions and length of stay (LOS). We reviewed the prospective data from our DMD patient cohort over a 7 year period in which 32 patients had been issued with a machine. We reviewed the data for 12 months pre and post issue in order to establish the effect on admission frequency and LOS.  These data have showed a significant reduction in both hospital admission frequency and LOS for those patients using a domiciliary cough assist machine. These are the first data to add support to the use of domiciliary cough assist machines in DMD patients with an ineffective cough and previous episodes of chest sepsis already established on NIV.
Contact-dependent Stimulation and Inhibition of Dendritic Cells by Natural Killer Cells
Authors: Diego Piccioli, Silverio Sbrana, Emiliano Melandri, Nicholas M. Valiante
Journal: The Journal of Experimental Medicine (2002)

Natural killer (NK) cells and dendritic cells (DCs) are two distinct cell types of innate immunity. It is known that the in vitro interaction of human NK cells with autologous DCs results in DC lysis. Here we show that contact-dependent interactions between activated human NK cells and immature DCs (iDCs) provides a "control switch" for the immune system. At low NK/DC ratios, this interaction dramatically amplifies DC responses, whereas at high ratios it completely turns off their responses. Specifically, culture of activated human NK cells with iDCs, at low NK/DC ratios (1:5), led to exponential increases in DC cytokine production, which were completely dependent on cell-to-cell contact. DC maturation was also driven by cognate interactions with NK cells and maturation was dependent on endogenously produced TNF-alpha in the culture. At slightly higher NK/DC ratios (5:1), inhibition of DC functions was the dominant feature due to potent killing by the autologous NK cells. Resting NK cells also stimulated autologous DC maturation in a TNF-alpha/contact-dependent manner, however, increasing the NK/DC ratio only led to an enhancement of this effect.
Surface hydrophobicity of the rat colonic mucosa is a defensive barrier against macromolecules and toxins
Authors: A Lugea
Journal: Gut (2000)

<h3>BACKGROUND</h3> Mucosal surface hydrophobicity is a key factor of the gastric acid defence barrier. In the colon, surface hydrophobicity is high but its biological function remains unexplored. <h3>AIMS</h3> To investigate the functional changes of the barrier due to removal of the surface active phospholipid layer by a detergent, or to reinforcement of the surface active phospholipid by local application of a suspension of lipids. <h3>METHODS</h3> Surface hydrophobicity (contact angle measurement), colonic permeability (lumen to blood clearance of mannitol and dextran), and mucosal resistance against luminal aggression (distal colitis induced by dextran sodium sulphate, DSS) were investigated in three study groups: (<i>a</i>) rats pretreated with a detergent (Brij 35) known to remove surfactant lipids; (<i>b</i>) rats pretreated with a suspension of surface active lipids (tripalmitin and dipalmitoyl-phosphatidylcholine); and (<i>c</i>) control rats pretreated with the corresponding vehicles. <h3>RESULTS</h3> In controls, surface hydrophobicity was low on the caecal mucosa and high in colon and rectum. Detergent treatment reduced surface hydrophobicity, and increased colonic permeability to mannitol and dextran. Conversely, treatment with lipids increased surface hydrophobicity, and reduced colonic permeability. Administration of DSS induced a progressive loss of colonic surface hydrophobicity, and an increase in permeability to mannitol and dextran. Detergent treatment increased susceptibility to epithelial damage and mucosal inflammation by DSS. Treatment with lipids reduced susceptibility to DSS colitis. <h3>CONCLUSION</h3> Colonic surface hydrophobicity modulates permeability to hydrophilic molecules and protects against toxins.
Normative theory in decision making and moral reasoning
Authors: Natalie Gold, Andrew M. Colman, Briony D. Pulford
Journal: Behavioral and Brain Sciences (2011)

Abstract Normative theories can be useful in developing descriptive theories, as when normative subjective expected utility theory is used to develop descriptive rational choice theory and behavioral game theory. “Ought” questions are also the essence of theories of moral reasoning, a domain of higher mental processing that could not survive without normative considerations.
Mutation site-specific differences in arrhythmic risk and sensitivity to sympathetic stimulation in the LQT1 form of congenital long QT syndrome
Authors: Wataru Shimizu, Minoru Horie, Seiko Ohno, Kotoe Takenaka, Masato Yamaguchi, Masami Shimizu, Takashi Washizuka, Yoshifusa Aizawa, Kazufumi Nakamura, Tohru Ohe, Takeshi Aiba, Yoshihiro Miyamoto, Yasunao Yoshimasa, Jeffrey A Towbin, Silvia G Priori, Shiro Kamakura
Journal: Journal of the American College of Cardiology (2004)
Effective Anti-Neu–Initiated Antitumor Responses Require the Complex Role of CD4+ T Cells
Authors: Eric D. Mortenson, SaeGwang Park, Zhujun Jiang, Shengdian Wang, Yang-Xin Fu
Journal: Clinical Cancer Research (2013)

Abstract Purpose: Targeting oncogenic receptors with antibodies has been thought to suppress tumor growth mainly by interrupting oncogenic signals. Recently, the essential role for adaptive immunity, and CD8+ T cells in particular, has been established as a major factor for anti-HER2/neu–mediated tumor regression. However, the role of CD4+ T cells is still being defined. The purpose of this study was to explore whether and to what extent CD4+ T cells are involved in mediating the effects of anti-HER2/neu therapy. Experimental Design: The role of CD4+ T cells was examined using a transplant model of the rat HER2/neu–overexpressing cell line TUBO. Tumor-bearing mice were treated with anti-neu therapy in conjunction with CD4 depletion or CD40L blockade. The effects of CD4 depletion on the antitumor response were examined by tumor growth analysis and enzyme-linked immunospot (ELISPOT). Results: In addition to CD8+ T cells, CD4+ T cells are also essential for anti-neu antibody-mediated tumor regression, but B cells are not required. The role for CD4+ cells is necessary throughout anti-neu therapy and not limited to helping CD8+ T cells. Expression of IFN-γ is necessary for anti-neu therapy and IFN-γ induces MHC-II expression in TUBO cells promoting direct recognition by CD4+ T cells. Furthermore, intratumoral depletion of CD4+ T cells or blockade of the activating cell-surface protein CD40L inhibits the antitumor response. Conclusions: This study reveals the essential role of CD4+ T cell for anti-neu–mediated tumor regression. Clin Cancer Res; 19(6); 1476–86. ©2013 AACR.
Long-Term Serotonin Administration Induces Heart Valve Disease in Rats
Authors: Björn I. Gustafsson, Karin Tømmerås, Ivar Nordrum, Jan P. Loennechen, Anders Brunsvik, Erik Solligård, Reidar Fossmark, Ingunn Bakke, Unni Syversen, Helge Waldum
Journal: Circulation (2005)

Background— The purpose of this study was to investigate whether rats dosed with serotonin develop changes similar to those seen in human carcinoid heart disease. Methods and Results— Ten Sprague-Dawley rats were given serotonin injections subcutaneously once daily for 3 months; controls were given saline. A long-lasting hyperserotoninemia with a &gt;10-fold increase in both platelet-poor plasma and dialysate from the femoral muscles appeared. The animals developed clinical signs such as flushing and loose stools. After 3 months, 6 of 10 rats given serotonin had pathological echocardiographs. Two animals had a combination of aortic and pulmonary valve insufficiency, 1 had isolated aortic valve insufficiency, and 3 had isolated pulmonary valve insufficiency. Histopathological examination revealed shortened and thickened aortic cusps and carcinoidlike plaques characterized by a collection of myofibroblasts within an extracellular matrix of collagen ground substance. Immunostaining for Ki-67 demonstrated an increased number of proliferating subendocardial cells. In the control group, no pathological changes were seen. With the use of reverse-transcription polymerase chain reaction, normal rat aortic cusps were shown to express mRNA for serotonin receptors 5-HT 1A , 5-HT 2A , and 5-HT 2B and the serotonin transporter 5-HTT. Conclusions— For the first time, long-term serotonin administration was performed in rats. Morphological and echocardiographic changes similar to those seen in human carcinoid heart disease developed. This study demonstrates that serotonin most likely is involved in the pathogenesis of carcinoid heart disease.