tbuckley/cabot-search huggingface dataset:
Pathogenesis of Macrophage Activation Syndrome and Potential for Cytokine- Directed Therapies
Authors: Grant S. Schulert, Alexei A. Grom
Journal: Annual Review of Medicine (2014)

Macrophage activation syndrome (MAS) is an acute episode of overwhelming inflammation characterized by activation and expansion of T lymphocytes and hemophagocytic macrophages. In rheumatology, it occurs most frequently in patients with systemic juvenile idiopathic arthritis (SJIA) and systemic lupus erythematosus. The main clinical manifestations include cytopenias, liver dysfunction, coagulopathy resembling disseminated intravascular coagulation, and extreme hyperferritinemia. Clinically and pathologically, MAS bears strong similarity to hemophagocytic lymphohistiocytosis (HLH), and some authors prefer the term secondary HLH to describe it. Central to its pathogenesis is a cytokine storm, with markedly increased levels of numerous proinflammatory cytokines including IL-1, IL-6, IL-18, TNFα, and IFNγ. Although there is evidence that IFNγ may play a central role in the pathogenesis of MAS, the role of other cytokines is still not clear. There are several reports of SJIA-associated MAS dramatically benefiting from anakinra, a recombinant IL-1 receptor antagonist, but the utility of other biologics in MAS is not clear. The mainstay of treatment remains corticosteroids; other medications, including cyclosporine, are used in patients who fail to respond.
My Magnanimous Mentor
Authors: A. Mark Clarfield
Journal: Annals of Internal Medicine (2012)

On Being a Doctor18 September 2012My Magnanimous MentorA. Mark Clarfield, MDA. Mark Clarfield, MDFrom Medical School for International Health, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel.Author, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-157-6-201209180-00012 Audio Reading - "My Magnanimous Mentor" Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads "My Magnanimous Mentor," by A.M. Clarfield. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail In my role as chief academic officer, one of the students popped by my office the other day asking for a letter of recommendation to support her residency application. I found myself bored by the whole process. How could that be?, I pondered, given that writing such letters is clearly a sacred duty for senior people like myself in helping their juniors. Perhaps I had been doing it for so long now that the process had become routine. Could it be that I was having a bad day? Burning out? Apparently, when practiced long enough, even rocket science can become ... Author, Article, and Disclosure InformationAuthors: A. Mark Clarfield, MDAffiliations: From Medical School for International Health, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel.Corresponding Author: A. Mark Clarfield, MD, Medical School for International Health, Bet Caroline, PO Box 653, Beer Sheva 84105, Israel; e-mail, [email protected]. PreviousarticleNextarticle Advertisement Audio Reading - "My Magnanimous Mentor" Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads "My Magnanimous Mentor," by A.M. Clarfield. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetails Metrics 18 September 2012Volume 157, Issue 6Page: 452-453KeywordsBeerEpidemiologyGlobal healthGratitudeMemoryResidencyTouch ePublished: 18 September 2012 Issue Published: 18 September 2012 Copyright & PermissionsCopyright © 2012 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
The effect of the carotid sinus baroreceptor reflex on blood flow and volume redistribution in the total systemic vascular bed of the dog.
Authors: M J Brunner, A A Shoukas, C L MacAnespie
Journal: Circulation Research (1981)

To quantify the relative contribution of blood flow redistribution and active changes in vascular capacity in the regulation of cardiac output, blood flow and volumes in two parallel vascular beds were measured in response to varying carotid sinus pressures. In nine dogs, carotid sinuses were isolated and intrasinus pressure was controlled. Two external reservoirs were placed between the caval veins and the right heart to measure changes in vascular capacity in splanchnic and extrasplanchnic vascular beds. At intrasinus pressures of 50 and 200 mm Hg, we have simultaneously measured arterial resistances, compliances, changes in flows, and "unstressed vascular volume," and time constants of venous drainage in the splanchnic and extrasplanchnic vascular beds. Compliances and time constants of venous drainage were found to be nearly equal in the two beds. A decrease in intrasinus pressure from 200 to 50 mm Hg resulted in a small redistribution of blood flow (about 5% of cardiac output) from the extrasplanchnic compartment to the splanchnic vascular bed. Changes in reservoir volumes were found to be around 7.0 ml/kg. The splanchnic vascular bed was responsible for a greater change in reservoir volume for a given change in intrasinus pressure. With any change in intrasinus pressure, the change in arterial resistance in the extrasplanchnic vascular bed was greater than that of the splanchnic vascular bed. Blood flow redistribution was not found to be a significant factor contributing to changes in reservoir volume. The changes in reservoir volume seen, must have been due to active changes in vascular capacity in the two channels chosen.
PATHOGENICITY FOR SUCKLING MICE OF COXSACKIE VIRUSES ADAPTED TO HUMAN AMNION CELLS
Authors: Fritz Lehmann-Grube, Jerome T. Syverton
Journal: The Journal of Experimental Medicine (1961)

Continuous passages in primary human amnion cell cultures of Coxsackie prototype viruses A-9, A-10, A-11, A-13, A-14, A-15, A-18, B-1, B-2, B-4, and B-5 increased the titers, hastened and enhanced cytopathic effect, and in varying degrees caused loss of virulence for newborn mice. Only B-3 behaved differently in that neither adaptation to cells in vitro nor attenuation with respect to the original animal host could be observed. Types A-15, B-1, B-2, and B-5 slowly regained virulence when passed in mice after high concentration passages in amnion cells whereas all other viruses reverted to their original virulence after only 1 or 2 passages in the animal host. When these strains, however, were purified by cloning procedures, they too showed markedly increased stability. In all stages of attenuation, viruses multiplied extensively in vivo as could be shown by titration in amnion cell cultures. It is suggested that a genetic mechanism is operative leading to virus populations in which the majority of the particles is qualitatively changed.
Early endoscopic, laboratory and clinical predictors of poor disease course in paediatric ulcerative colitis
Authors: Amir Schechter, Christopher Griffiths, Juan Cristóbal Gana, Ron Shaoul, Raanan Shamir, Eyal Shteyer, Tali Bdolah-Abram, Oren Ledder, Dan Turner
Journal: Gut (2014)

<h3>Objective</h3> Data to support treatment algorithms in ambulatory paediatric UC are scarce. We aimed to explore the 1 year outcome in an inception cohort of paediatric UC patients and to identify early predictors of good outcome that might serve as short term treatment targets. <h3>Design</h3> A chart review of 115 children with new onset UC was performed (age 11±4.1 years; 58 (50%) males; 86 (75%) extensive colitis; 70 (61%) moderate–severe disease; 63 (55%) received steroids at baseline). We assessed the Paediatric Ulcerative Colitis Activity Index (PUCAI) and laboratory variables at the time of diagnosis and at 3 months, and endoscopy at diagnosis. <h3>Results</h3> The 3 month PUCAI was the strongest predictor of 1 year sustained steroid free remission (SSFR) (area under the receiver operating characteristic curve (AUROC)=0.7 (95% CI 0.6 to 0.8) and colectomy by 2 years (AUROC=0.75 (0.6 to 0.89)). SSFR was achieved in 9/54 (17%) children who had active disease (PUCAI ≥10) at 3 months (negative predictive value (NPV)=83%) and by 4/46 (8.6%) of those with a PUCAI score &gt;10; (NPV=91%, positive predictive value=52%; p&lt;0.001), implying that PUCAI &gt;10 at 3 months has a probability of 9% for achieving SSFR versus 48% with a PUCAI value of ≤10. None of the variables at baseline was predictive of SSFR or colectomy (endoscopic severity, disease extent, age, PUCAI or C reactive protein/erythrocyte sedimentation rate/albumin/haemoglobin; all AUROC&lt;0.6, p&gt;0.05) but baseline PUCAI predicted subsequent acute severe colitis and the need for salvage medical therapy. <h3>Conclusions</h3> Completeness of the early response appears more important than baseline UC severity for predicting outcome in children, and supports using PUCAI&lt;10 as a feasible treatment goal. Our data suggest that treatment escalation should be considered with a PUCAI value of ≥10 at 3 months.
AUSTRALIA ANTIGEN (A HEPATITIS-ASSOCIATED ANTIGEN)
Authors: Irving Millman, Lawrence A. Loeb, Manfred E. Bayer, Baruch S. Blumberg
Journal: The Journal of Experimental Medicine (1970)

Australia antigen [Au(1)], a particle associated with viral hepatitis, was isolated from the plasma of a patient with chronic anicteric hepatitis and leukemia who had received radioactive phosphorus. We have found that the immunoreactivity and appearance of Au(1) in the electron microscope were not altered by treatment with enzymes including trypsin, pronase, lipase, phospholipase C, ribonuclease, deoxyribonuclease, amylase, and neuraminidase. In contrast, other serum constituents were degraded by these enzymes. Therefore, treatment of the patient's plasma with many enzymes was exploited as an initial step for the isolation of Au(1). Subsequently, Au(1) was purified from the enzyme-treated (32)P-labeled plasma by gel filtration through Sephadex G-200 and centrifugation through sucrose and in cesium chloride gradients. There were no detectable human serum components in the purest fractions, as tested by immunoelectrophoresis and immunodiffusion. The density of the purified Au(1) was 1.21 in CsCl. The particle measured about 200 A in diameter, was predominantly spherical in shape and appeared to be composed of subunits. Nucleic acids were not detected by spectrophotometric, radiochemical, and chemical analyses. Immunoreactivity of purified Au(1) was destroyed by heating for 1 hr at 85 degrees C but was stable at 56 degrees C. Treatment with Carnoy's solution (3 parts ethanol:1 part glacial acetic acid) followed by pronase disrupted the particles as seen with the electron microscope. These findings, combined with other published information on Australia antigen and viral hepatitis, suggest that the bulk of Australia antigen in the blood of this patient is an incomplete virus or virus capsid.
Asymmetric relationships between proteins shape genome evolution
Authors: Richard A Notebaart, Philip R Kensche, Martijn A Huynen, Bas E Dutilh
Journal: Genome biology (2009)

The relationships between proteins are often asymmetric: one protein (A) depends for its function on another protein (B), but the second protein does not depend on the first. In metabolic networks there are multiple pathways that converge into one central pathway. The enzymes in the converging pathways depend on the enzymes in the central pathway, but the enzymes in the latter do not depend on any specific enzyme in the converging pathways. Asymmetric relations are analogous to the "if->then" logical relation where A implies B, but B does not imply A (A->B).We show that the majority of relationships between enzymes in metabolic flux models of metabolism in Escherichia coli and Saccharomyces cerevisiae are asymmetric. We show furthermore that these asymmetric relationships are reflected in the expression of the genes encoding those enzymes, the effect of gene knockouts and the evolution of genomes. From the asymmetric relative dependency, one would expect that the gene that is relatively independent (B) can occur without the other dependent gene (A), but not the reverse. Indeed, when only one gene of an A->B pair is expressed, is essential, is present in a genome after an evolutionary gain or loss, it tends to be the independent gene (B). This bias is strongest for genes encoding proteins whose asymmetric relationship is evolutionarily conserved.The asymmetric relations between proteins that arise from the system properties of metabolic networks affect gene expression, the relative effect of gene knockouts and genome evolution in a predictable manner.
Nodal regulates energy metabolism in glioma cells by inducing expression of hypoxia-inducible factor 1 
Authors: J.-H. Lai, H.-J. Jan, L.-W. Liu, C.-C. Lee, S.-G. Wang, D.-Y. Hueng, Y.-Y. Cheng, H.-M. Lee, H.-I. Ma
Journal: Neuro-Oncology (2013)

A shift in glucose metabolism from oxidative phosphorylation to anaerobic glycolysis is the biochemical hallmark of malignant cancer cells. In the present study, we demonstrated that Nodal stimulated the expression of glycolytic enzymes and decreased reliance on mitochondrial oxidative phosphorylation in human glioma cancer cells. The shift in glucose metabolism was mediated by induction of the hypoxia-inducible factor (HIF). Nodal protein expression was shown to be correlated with expression levels of glucose transporter (Glut)–1, hexokinase (HK)-II, pyruvate dehydrogenase kinase (PDK)–1, the phosphorylation level of pyruvate dehydrogenase (PDH), glucose uptake, and lactate accumulation in human glioma cells. These effects were inversely correlated with mitochondrial oxygen consumption and ATP production. Knockdown of Nodal expression with specific small hairpin RNA reduced Glut-1, HK-II, and PDK-1 expressions and PDH phosphorylation. Nodal knockdown also reduced glucose uptake and lactate generation, which in turn increased mitochondrial membrane potential (Ψ), O2 utilization, and ATP synthesis. The ectopic expression of Nodal in low-expressing Nodal glioma cells resulted in the opposite results compared with those of Nodal knockdown glioma cells. Treatment of cells with recombinant Nodal increased HIF-1 expression, and this effect was regulated at the transcriptional level. Blockage of the Nodal receptor by a pharmacological inhibitor or Nodal knockdown in U87MG cells decreased HIF-1α expression. Furthermore, HIF-1α knockdown in U87MG cells decreased Glut-1, HK-II, and PDK-1 expressions and PDH phosphorylation, which were similar to results in Nodal knockdown cells. Taken together, these results suggest that Nodal affects energy metabolism through HIF-1α.
Activin and TGFβ use diverging mitogenic signaling in advanced colon cancer
Authors: Jessica Bauer, Ozkan Ozden, Naomi Akagi, Timothy Carroll, Daniel R. Principe, Jonas J. Staudacher, Martina E. Spehlmann, Lars Eckmann, Paul J. Grippo, Barbara Jung
Journal: Molecular Cancer (2015)

Understanding cell signaling pathways that contribute to metastatic colon cancer is critical to risk stratification in the era of personalized therapeutics. Here, we dissect the unique involvement of mitogenic pathways in a TGFβ or activin-induced metastatic phenotype of colon cancer. Mitogenic signaling/growth factor receptor status and p21 localization were correlated in primary colon cancers and intestinal tumors from either AOM/DSS treated ACVR2A (activin receptor 2) −/− or wild type mice. Colon cancer cell lines (+/− SMAD4) were interrogated for ligand-induced PI3K and MEK/ERK pathway activation and downstream protein/phospho-isoform expression/association after knockdown and pharmacologic inhibition of pathway members. EMT was assessed using epithelial/mesenchymal markers and migration assays. In primary colon cancers, loss of nuclear p21 correlated with upstream activation of activin/PI3K while nuclear p21 expression was associated with TGFβ/MEK/ERK pathway activation. Activin, but not TGFβ, led to PI3K activation via interaction of ACVR1B and p85 independent of SMAD4, resulting in p21 downregulation. In contrast, TGFβ increased p21 via MEK/ERK pathway through a SMAD4-dependent mechanism. While activin induced EMT via PI3K, TGFβ induced EMT via MEK/ERK activation. In vivo, loss of ACVR2A resulted in loss of pAkt, consistent with activin-dependent PI3K signaling. Although activin and TGFβ share growth suppressive SMAD signaling in colon cancer, they diverge in their SMAD4-independent pro-migratory signaling utilizing distinct mitogenic signaling pathways that affect EMT. p21 localization in colon cancer may determine a dominant activin versus TGFβ ligand signaling phenotype warranting further validation as a therapeutic biomarker prior to targeting TGFβ family receptors.
Markers of B-Cell Activation in Relation to Risk of Non-Hodgkin Lymphoma
Authors: Anneclaire J. De Roos, Dana K. Mirick, Kerstin L. Edlefsen, Andrea Z. LaCroix, Kenneth J. Kopecky, Margaret M. Madeleine, Larry Magpantay, Otoniel Martínez-Maza
Journal: Cancer Research (2012)

Abstract B-cell activation biomarkers have been associated with increased risk of non-Hodgkin lymphoma (NHL) in HIV-infected populations. However, whether a similar association may exist in general populations has not been established. We conducted a case-control study within the Women's Health Initiative Observational Study cohort to measure the B-cell activation biomarkers sCD23, sCD27, sCD30, sCD44, and CXCL13 in serum samples collected an average of 6 years before NHL diagnosis in 491 cases and 491 controls. Using logistic regression to estimate odds ratios, we observed strong associations between NHL and markers for all B-cell NHL and for major subtypes. Women with marker levels in the highest-versus-lowest quartile categories of CD23, CD27, CD30, or CXCL13 were at 2.8- to 5.5-fold increased risk of B-NHL. In addition, there were significant trends of risk with increasing levels of these markers present. Associations were strongest for cases with shortest lag times between blood draw and diagnosis (&amp;lt;3 years). However, there were also significant associations for cases with the longest prediagnostic lag (9 to 13 years). Taken together, our findings indicate a prominent role for B-cell activation among postmenopausal women in the etiology of B-cell NHL and/or in processes reflective of early disease development as early as 9 years before diagnosis. Cancer Res; 72(18); 4733–43. ©2012 AACR.
The Separation Anxiety Hypothesis of Panic Disorder Revisited: A Meta-Analysis
Authors: Joe Kossowsky, Monique C. Pfaltz, Silvia Schneider, Jan Taeymans, Cosima Locher, Jens Gaab
Journal: American Journal of Psychiatry (2013)

Objective Evidence suggests that childhood separation anxiety disorder may be associated with a heightened risk for the development of other disorders in adulthood. The authors conducted a meta-analysis to examine the relationship between childhood separation anxiety disorder and future psychopathology. Method PubMed, PsycINFO, and Embase were searched for studies published through December 2011. Case-control, prospective, and retrospective cohort studies comparing children with and without separation anxiety disorder with regard to future panic disorder, major depressive disorder, any anxiety disorder, and substance use disorders were included in the analysis. Effects were summarized as pooled odds ratios in a random-effects model. Results Twenty-five studies met all inclusion criteria (14,855 participants). A meta-analysis of 20 studies indicated that children with separation anxiety disorder were more likely to develop panic disorder later on (odds ratio=3.45; 95% CI=2.37–5.03). Five studies suggested that a childhood diagnosis of separation anxiety disorder increases the risk of future anxiety (odds ratio=2.19; 95% CI=1.40–3.42). After adjusting for publication bias, the results of 14 studies indicated that childhood separation anxiety disorder does not increase the risk of future depression (odds ratio=1.06; 95% CI=0.78–1.45). Five studies indicated that childhood separation anxiety disorder does not increase the risk of substance use disorders (odds ratio=1.27; 95% CI=0.80–2.03). Of the subgroup analyses performed, differences in comparison groups and sample type significantly affected odds ratio sizes. Conclusions A childhood diagnosis of separation anxiety disorder significantly increases the risk of panic disorder and any anxiety disorder. These results support a developmental psychopathology conceptualization of anxiety disorders.
A micropuncture study of renal salt and water retention in chronic bile duct obstruction.
Authors: N Bank, H S Aynedjian
Journal: Journal of Clinical Investigation (1975)

The mechanism of sodium retention by the kidney in rats with ligation of the common bile duct was studied with micropuncture techniques. 10-14 days after bile duct ligation, rats showed positive sodium balance and ascites formation. Measurements of renal blood flow and glomerular filtration rate yielded values that were not different from those in normal control animals. Likewise, single nephron filtration rte of surface nephrons was the same in the experimental rats as in the controls. Sodium reabsorption, however, was markedly increased in the proximal convoluted tubule, as well as in segments beyond the proximal convolutions. Single nephron filtration fraction, calculated from measurements of efferent arteriolar and arterial hematocrits, was significantly elevated in the cortical nephrons, even though whole kidney filtration fraction was the same as in normal rats. The calculated protein concentration of cortical peritubular blood was higher in the bile duct-ligated rats than in the normal controls. The observations are consistent with the view that sodium retention is the result of enhanced reabsorption primarily by cortical nephrons. The enhanced reabsorption can be accounted for by relative cortical ischemia due to efferent arteriolar vasoconstriction with the consequent elevation of peritubular colloid oncotic pressure.
Should the Use of Selective Serotonin Reuptake Inhibitors in Child and Adolescent Depression Be Banned?
Authors: David Cohen
Journal: Psychotherapy and Psychosomatics (2006)

European and US pharmaceutical agencies have recently warned against the use of selective serotonin reuptake inhibitors (SSRIs) in child and adolescent depression. This came as a surprise to many practitioners, who had made treatment decisions based on data from pharmaceutical trials using adult samples.The author reviews the recent literature relevant to the use of SSRIs in youth depression, including psychiatricclinical trials, pharmacology and drug safety data. Recommendations and rationales for the use of SSRIs in this context are offered.Ten publications, comprising a total of 2,046 patients, evaluated the efficacy of four SSRIs (fluoxetine, paroxetine, sertraline and citalopram) in child and adolescent depression. It is noted that an additional 6 trials (with a total of 1,234 patients) were not reported by the industry because of a lack of efficacy or problematic side effects, including suicidal behaviors. Meta-analyses revealed no data supporting the use of SSRIs, except for fluoxetine. To formulate recommendations for clinical practice, it is necessary to examine specific issues such as (1) the link between SSRIs, depression and suicidal risk; (2) SSRI age-related specific effects, and (3) the high placebo response in child and adolescent depression.An SSRI prescription is still a second-line option in severe and resistant forms of youth depression. However, in children and adolescents only specialists well trained in child and adolescent psychiatry should prescribe SSRIs.