tbuckley/cabot-search huggingface dataset:
Leukocyte transmigration requires kinesin-mediated microtubule-dependent membrane trafficking from the lateral border recycling compartment
Authors: Zahra Mamdouh, Geri E. Kreitzer, William A. Muller
Journal: The Journal of Experimental Medicine (2008)

Diapedesis of leukocytes across endothelial cells is a crucial step in both the innate and adaptive immune responses. Surface molecules on leukocytes and endothelial cells critical for diapedesis have been identified, but the mechanisms underlying this process are not understood. Homophilic interaction between platelet/endothelial cell adhesion molecule (PECAM) on leukocytes and PECAM at the endothelial border triggers targeted recycling of membrane from a reticulum localized close to the endothelial cell lateral border. This membrane surrounds the transmigrating leukocyte (Mamdouh, Z., X. Chen, L.M. Pierini, F.R. Maxfield, and W.A. Muller. 2003. Nature. 421:748–753). How this process occurs and whether it is required for diapedesis independent of PECAM are not known. We now report that targeted recycling from this lateral border recycling compartment (LBRC) is required for diapedesis, is mediated by kinesin family molecular motors, and requires normally functioning endothelial microtubules. Selective disruption of microtubules or inhibition of kinesin motor domain blocked targeted recycling and diapedesis of monocytes. Furthermore, targeted recycling of membrane from the LBRC was required for transmigration of lymphocytes, which migrate independently of PECAM. Thus, trafficking of membrane from the LBRC to surround leukocytes may be a general requirement for migration of leukocytes across the endothelial cell border. Furthermore, these data provide the first demonstration of a role for endothelial microtubules and kinesins in promoting diapedesis, and a mechanism to explain targeted recycling.
Intracellular calcium transients and arrhythmia in isolated heart cells.
Authors: F T Thandroyen, A C Morris, H K Hagler, B Ziman, L Pai, J T Willerson, L M Buja
Journal: Circulation Research (1991)

Intracellular calcium ([Ca2+]i) elevation may mediate cardiac arrhythmias. However, direct measurement of the rapid alterations of [Ca2+]i on a beat-to-beat basis using fast temporal resolution and without signal averaging in the spontaneously beating in vivo heart is lacking. Furthermore, data from an isolated spontaneously beating myocyte preparation that develops arrhythmia similar to that in the in vivo heart are unavailable. We measured rapid changes of [Ca2+]i with fast temporal resolution in isolated spontaneously beating neonatal rat ventricular myocytes with cell-to-cell communication and characterized the interrelation between [Ca2+]i and arrhythmia. An elevated extracellular calcium ([Ca2+]o) concentration of 10.8 mM induced premature beats, a rapid beating rate (tachyarrhythmia), and chaotic or fibrillatory beating activity in a small group of myocytes. [Ca2+]i levels during systole increased from the nanomolar to micromolar concentration range before arrhythmia development. Spontaneous oscillations of [Ca2+]i during diastole could evoke a spontaneous tachyarrhythmia. In the presence of [Ca2+]i elevation, a spontaneous tachyarrhythmia could induce severe [Ca2+]i overload. Reduction of [Ca2+]i with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid AM (5 microM) in the presence of 10.8 mM [Ca2+]o reversed the arrhythmia. In single ventricular myocytes superfused with 10.8 mM [Ca2+]o, oscillations of membrane potential characteristic of transient inward current occurred that were prevented by ryanodine (0.1 microM), an inhibitor of Ca2+ flux across the sarcoplasmic reticulum. This study characterizes 1) an isolated multicellular myocyte model of arrhythmia similar to that evident in in vivo hearts, 2) elevation of [Ca2+]i with systolic [Ca2+]i levels of 1-3 microM and diastolic [Ca2+]i oscillations before the initiation of arrhythmia, 3) tachyarrhythmia as a cause of severe [Ca2+]i overload, which may be important in the perpetuation and degeneration of arrhythmias, and 4) reversal of arrhythmia with reduction of [Ca2+]i. The results in the isolated myocyte model may have relevance to the generation and perpetuation of certain cardiac arrhythmias associated with calcium overload.
Multiple factors affect vaccination status among Indian children, finds study
Authors: Cheryl Travasso
Journal: BMJ (2015)

Vaccination status of children in India is influenced by where they are born, their caste and religion, antenatal care, and whether their mother has been vaccinated against tetanus, a study has found. 

The study, published in the American Journal of Preventive Medicine , found that these associations remained after adjusting for state of residence, gender, age, household wealth, and mother’s education.1

The researchers attempted to identify cultural and sociodemographic factors that affected vaccination, using data from 108 057 children included in the nationally representative District Level Household and Facility Survey in 2008. Data …
Shark Cartilage, Cancer and the Growing Threat of Pseudoscience
Authors: Gary K. Ostrander, Keith C. Cheng, Jeffrey C. Wolf, Marilyn J. Wolfe
Journal: Cancer Research (2004)

Abstract The promotion of crude shark cartilage extracts as a cure for cancer has contributed to at least two significant negative outcomes: a dramatic decline in shark populations and a diversion of patients from effective cancer treatments. An alleged lack of cancer in sharks constitutes a key justification for its use. Herein, both malignant and benign neoplasms of sharks and their relatives are described, including previously unreported cases from the Registry of Tumors in Lower Animals, and two sharks with two cancers each. Additional justifications for using shark cartilage are illogical extensions of the finding of antiangiogenic and anti-invasive substances in cartilage. Scientific evidence to date supports neither the efficacy of crude cartilage extracts nor the ability of effective components to reach and eradicate cancer cells. The fact that people think shark cartilage consumption can cure cancer illustrates the serious potential impacts of pseudoscience. Although components of shark cartilage may work as a cancer retardant, crude extracts are ineffective. Efficiencies of technology (e.g., fish harvesting), the power of mass media to reach the lay public, and the susceptibility of the public to pseudoscience amplifies the negative impacts of shark cartilage use. To facilitate the use of reason as the basis of public and private decision-making, the evidence-based mechanisms of evaluation used daily by the scientific community should be added to the training of media and governmental professionals. Increased use of logical, collaborative discussion will be necessary to ensure a sustainable future for man and the biosphere.
Enhancement of human immunodeficiency virus type 1 infection by antisera to peptides from the envelope glycoproteins gp120/gp41.
Authors: S B Jiang, K Lin, A R Neurath
Journal: The Journal of Experimental Medicine (1991)

Human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins (gp120 and gp41) elicit virus-neutralizing antibodies (VNAB) and also antibodies enhancing HIV-1 infection (EAB). Several epitopes eliciting VNAB have been defined, the principal virus-neutralizing determinant being assigned to the V3 loop of gp120. To provide a background for a rational design of anti-HIV vaccines, it also appears important to define domains eliciting EAB. This was accomplished by screening antisera against synthetic peptides covering almost the entire sequence of gp120/gp41 for their enhancing effects on HIV-1 infection of MT-2 cells, a continuous T cell line. Many (16/30) of the antisera significantly enhanced HIV-1 in the presence of human complement. Antibodies to complement receptor type 2 (CR2) abrogated the antibody-mediated enhancement of HIV-1 infection. Antisera to V3 hypervariable loops of 21 distinct HIV-1 isolates were also tested for their enhancing effects on HIV-1IIIB infection. 11 of these sera contained VNAB and 10 enhanced HIV-1IIIB infection. All antisera with virus-enhancing activity contained antibodies crossreactive with the V3 loop of HIV-1IIIB, and the virus-enhancing activity increased with increasing serological crossreactivity. These results suggest that immunization with antigens encompassing V3 loops may elicit EAB rather than protective antibodies if epitopes on the immunogen and the predominant HIV-1 isolate infecting a population are insufficiently matched, i.e., crossreactive serologically but not at the level of virus neutralization.
The Bicentennial of the New York Hospital (1771-1971)
Authors: E. Hugh Luckey
Journal: JAMA (1971)

Institutions,, have character and personality. And like people these characteristics are the result of their origins, those who have influenced their lives, and their experiences. The New York Hospital, for one, was conceived as, and remains, a public institutional resource in health. From its inception it has had both public and private support. It is sometimes difficult to imagine the time of its origins, 200 years ago. New York City was a small metropolis with 30,000 people on May 16, 1769, when the young Dr. Samuel Bard gave his inaugural address at Trinity Church to the two medical graduates of King's College. He, at age 28, had been influential in the establishment of the King's College curriculum for medical studies, and, most fortunately, was given the privilege of greeting the first two bachelors of medicine on their graduation. His pleas and admonitions, which are set down in his paper, "A
Discoidin domain receptor 2 deficiency predisposes hepatic tissue to colon carcinoma metastasis
Authors: Iker Badiola, Elvira Olaso, Olatz Crende, Scott L Friedman, Fernando Vidal-Vanaclocha
Journal: Gut (2011)

<h3>Background</h3> The transdifferentiation of hepatic stellate cells (HSCs) into myofibroblasts is a major mechanism for stroma development in hepatic metastasis, but their regulatory pathways remain unclear. Transdifferentiated HSCs from fibrotic liver express high levels of the fibrillar collagen receptor discoidin domain receptor 2 (DDR2), but it is unclear if DDR2 plays a direct profibrogenic role in the tumour microenvironment. <h3>Aim</h3> To assess the impact of DDR2 on the prometastatic role of HSC-derived myofibroblasts. <h3>Methods</h3> Hepatic metastases were induced in DDR2<sup>−/−</sup> and DDR2<sup>+/+</sup> mice by intrasplenic injection of MCA38 colon carcinoma cells, and their growth and features were characterised. Stromagenic, angiogenic and cancer cell proliferation responses were quantified in metastases by immunohistochemistry. The adhesion-, migration- and proliferation-stimulating activities of supernatants from primary cultured DDR2<sup>−/−</sup> and DDR2<sup>+/+</sup> HSCs, incubated in MCA38 cell-conditioned medium, were evaluated in primary cultured liver sinusoidal endothelium cells (LSECs) and MCA38 cells. Gene expression signatures from freshly isolated DDR2<sup>−/−</sup> and DDR2<sup>+/+</sup> HSCs were compared and DDR2-regulated genes were studied by RT-PCR under basal conditions and after stimulation with MCA38 tumour-conditioned media. <h3>Results</h3> Metastases were increased three fold in DDR2<sup>−/−</sup> livers, and contained a higher density of α−smooth muscle actin-expressing myofibroblasts, CD31-expressing microvessels and Ki67-expressing MCA38 cells than metastases in DDR2<sup>+/+</sup> livers. Media conditioned by MCA38-activated DDR2<sup>−/−</sup> HSCs significantly increased adhesion, migration and proliferation of LSECs and MCA38 cells, compared with DDR2<sup>+/+</sup> HSCs. DDR2 deficiency in HSCs led to decreased gene expression of interferon γ-inducing factor interleukin (IL)-18 and insulin-like growth factor-I; and increased gene expression of prometastatic factors IL-10, transforming growth factor (TGF)β and vascular endothelial growth factor (VEGF), bone morphogenetic protein-7 and syndecan-1. MC38 tumour-conditioned media further exacerbated expression changes in DDR2-dependent IL-10, TGFβ and VEGF genes. <h3>Conclusion</h3> DDR2 deficiency fosters the myofibroblast transdifferentiation of tumour-activated HSCs, generating a prometastatic microenvironment in the liver via HSC-derived factors. These findings underscore the role of stromal cells in conditioning the hepatic microenvironment for metastases through altered receptor–stroma interactions.
Fusokine Interleukin-2/Interleukin-18, a Novel Potent Innate and Adaptive Immune Stimulator with Decreased Toxicity
Authors: Bruce Acres, Murielle Gantzer, Christelle Remy, Nicolas Futin, Nathalie Accart, Olivier Chaloin, Johan Hoebeke, Jean-Marc Balloul, Stéphane Paul
Journal: Cancer Research (2005)

To redress the immune imbalances created by pathologies such as cancer, it would be beneficial to create novel cytokine molecules, which combine desired cytokine activities with reduced toxicities. Due to their divergent but complementary activities, it is of interest to combine interleukin-2 (IL-2) and IL-18 into one recombinant molecule for immunotherapy. Evaluation of a fusokine protein that combines murine IL-2/IL-18 shows that it is stable, maintains IL-2 and IL-18 bioactivities, has notably reduced IL-2 associated toxicities, and has a novel lymphocyte-stimulating activity. An adeno-viral expression system was used to explore the biology of this "fusokine". Inclusion of the IL-18 prosequence (proIL-18) increases the expression, secretion, and potency of this fusokine. In vivo gene transfer experiments show that Ad-IL-2/proIL-18 dramatically outdoes Ad-IL-2, Ad-proIL-18, or the combination of both, by inducing high rates of tumor rejection in several murine models. Both innate and adaptive effector mechanisms are required for this antitumor activity.
Congenital intrapericardial aneurysms of the left atrium.
Authors: U Thadani, W Whitaker, D A Watson
Journal: Thorax (1975)

A patient with congenital intrapericardial aneurysm/diverticulum of the left atrium diagnosed preoperatively is described. A review of the 16 previously reported cases revealed that the majority of the patients present with palpitation and are found to have an abnormal cardiac shadow on chest radiography, as did this patient. The aneurysm appears to cause systemic emboli and paroxysmal or persistent atrial tachyarrhythmias which are often resistant to medical therapy. The presence of the aneurysm is suggested by an abnormal contour of the left cardiac border in the postero-anterior chest radiograph and this can be confirmed by angiocardiography. Surgical excision of the aneurysm is indicated in all patients to prevent the occurrence or recurrence of systemic emboli and atrial arrhythmias. Our patient has remained free of symptoms since her operation 14 months ago.
Use of budesonide Turbuhaler in young children suspected of asthma
Authors: H Bisgaard, S Pedersen, K Nikander
Journal: European Respiratory Journal (1994)

The question addressed in this study was the ability of young children to use a dry-powder inhaler, Turbuhaler. One hundred and sixty five children suspected of asthma, equally distributed in one year age-groups from 6 months to 8 yrs, inhaled from a Pulmicort Turbuhaler, 200 micrograms budesonide-dose-1, through a filter. The amount of drug trapped by the filter was used as a measure of drug released to the patient. None of the children had prior experience in the use of a Turbuhaler, but they were instructed carefully, together with their parents, in the clinic. The median dose released revealed an age-dependent increase, with a considerable scatter. Accordingly, the dose delivered could not be predicted in these young children. The limitation to effective use in young children appeared to be lack of sufficient co-operation, rather than physical limitations, as even some very young children appeared to obtain a sufficient activation of the device. It is likely that repeated training at home may improve these findings. In conclusion, our results indicate that dry-powder inhalers are not reliable in all circumstances for treatment of young children, and that careful and repeated tuition is required if such devices are to be used.
Mechanism of therapeutic effect of high-dose intravenous immunoglobulin. Attenuation of acute, complement-dependent immune damage in a guinea pig model.
Authors: M Basta, P Kirshbom, M M Frank, L F Fries
Journal: Journal of Clinical Investigation (1989)

Studies were performed in in vitro and in vivo models to assess the effect of intravenous immunoglobulin (IVIG) on the development of acute complement-mediated tissue damage. IVIG significantly increased the duration of survival and frequently prevented the death of guinea pigs injected with anti-Forssman antiserum to cause lethal Forssman shock; no control animal treated with albumin and/or maltose vehicle survived. The most pronounced effect was achieve by delivering IVIG as one slow injection at 1,800 mg/kg 3 h before Forssman shock was elicited. Infusion of guinea pig IgG at the same dosage was similarly protective. A strong positive correlation was found between IgG plasma levels and survival time in guinea pigs treated with graded doses of IVIG. Therapy itself did not affect C3 and C4 levels nor the capacity to activate these components. In vitro studies showed almost complete inhibition of C3 uptake onto IgG-sensitized erythrocytes using serum from an IVIG-treated animal. We suggest that supraphysiologic levels of IVIG act in part by preventing active C3 fragments from binding to target cells. Infusion of high dose IVIG may be a rational approach to modulating acute, complement-dependent tissue damage in a variety of diseases in man.
Thiol methyltransferase activity in inflammatory bowel disease
Authors: W E Roediger
Journal: Gut (2000)

<h3>BACKGROUND</h3> Luminal anionic sulphide may contribute to epithelial damage in ulcerative colitis. Thiol methyltransferase (TMT) governs sulphide detoxification by the colonic mucosa and circulating erythrocytes. <h3>AIMS</h3> To measure levels of TMT activity in erythrocytes of surgically treated cases of colitis or in rectal biopsies of defined groups of colitis. <h3>PATIENTS</h3> Venepuncture blood was obtained from 37 blood donors and 27 subjects who had previously undergone a proctocolectomy for colitis: 18 for ulcerative colitis and nine for Crohn9s colitis. Rectal biopsies from 122 cases were obtained: 47 without mucosal disease, 33 post-colon resection for cancer, 14 with moderate to severe ulcerative colitis, 15 with quiescent ulcerative colitis, seven with acute Crohn9s colitis, and six with radiation proctitis. <h3>METHODS</h3> TMT activity was measured by high performance liquid chromatography with radioactive detection to measure <sup>14</sup>C methylmercaptoethanol formation, the reaction product of cell extracts incubated with mercaptoethanol and <sup>14</sup>C S-adenosylmethionine. <h3>RESULTS</h3> Erythrocyte TMT activity of surgically treated cases of colitis was significantly elevated (p&lt;0.001) compared with control cases. TMT activity of rectal biopsies was significantly decreased (p&lt;0.02) in acute but not quiescent ulcerative colitis, Crohn9s colitis, or radiation colitis. <h3>CONCLUSIONS</h3> Erythrocyte TMT activity was persistently elevated after proctocolectomy for Crohn9s disease and ulcerative colitis. No primary defect of TMT activity was found in any case of unoperated colitis but mucosal activity was diminished with disease progression of ulcerative colitis. Studies of genetic control of TMT activity of erythrocytes in inflammatory bowel disease appear worthwhile.
Determining the best diagnostic biomarker for sepsis and prognosis assessment
Authors: Longxiang Su, Lixin Xie, Lin Feng, Qing Song, Hongjun Kang, Xingang Zhang, Zhixin Liang, Yanhong Jia, Dan Feng
Journal: European Respiratory Journal (2012)

Introduction:  Current clinical practice lacks reliable diagnostic indicators for sepsis and its prognosis.  Objectives:  To describe the value of sTREM-1,sCD163,PCT,CRP,WBC and SOFA score during the course of sepsis, as well as their value in prognosis.  Methods: 130 subjects were picked out of 377 inpatients hospitalized at the RICU,SICU,and EICU. In light of Sepsis Guideline and 28-day survival, the 130 patients were divided into different subgroup. ELISA was applied, and test results were recorded on day 1,3,5,7,10,and 14.  Results:  On ICU admission day, the sepsis group display higher levels of sTREM-1,sCD163,PCT,and CRP than the SIRS group[180.92 (150.44) pg/ml vs. 29.41(20.77) pg/ml;2.22 (2.36) mg/dL vs. 0.88 (0.23) mg/dL;1.65 (10.1) ng/ml vs. 0.35 (1.58) ng/ml;11.76±8.09 mg/dl vs. 5.65±4.27mg/dl,  P ]. Although PCT,sTREM-1 and SOFA are good markers to identify the severity, sTREM-1 is more reliable. It proves to be a risk factor related to sepsis(OR=1.089,95%CI,1.045–1.136); its area under the ROC curve, meant for diagnosis, turns out 0.978(95%CI,0.958–0.997), and that for severity,0.9 (95%CI,0.823–0.977). For 14-day observation,sCD163,sTREM-1,PCT and SOFA continue to climb among non-survivors, while WBC and CRP go down. Both sCD163 and SOFA are risk factors impacting the survival time (HR=1.09,95%CI 1.035–1.154;HR=1.23, 95%CI 1.126–1.335). Their areas under the ROC curve, denoting prognosis, measures 0.696(95%CI,0.593-0.799)and 0.794(95%CI,0.705–0.833) respectively.  Conclusion:  With regard to sepsis diagnosis and severity, sTREM-1 is more ideal, and constitutes an risk factor. sCD163 and SOFA are of positive value in dynamic prognostic assessment, and may be taken as survival-impacting risk factors.
Antigen-presenting cells from nonresponder strain 2 guinea pigs are fully competent to present bovine insulin B chain to responder strain 13 T cells. Evidence against a determinant selection model and in favor of a clonal deletion model of immune response gene function.
Authors: G A Dos Reis, E M Shevach
Journal: The Journal of Experimental Medicine (1983)

To test directly the determinant selection hypothesis of immune response gene function, we primed strain 13 T lymphocytes in vitro with allogeneic bovine insulin pulsed strain 2 macrophages. Strain 2 macrophages were found to be fully competent to present bovine insulin B chain to strain 13 T cells despite the fact that strain 2 guinea pigs are normally totally unresponsive to this antigen. These results are incompatible with a strict interpretation of the determinant selection hypothesis, which would have predicted that strain 2 macrophages would have been restricted to the presentation of A chain loop determinants. In addition, a comparison of the reactivity profiles of self-Ia- and allo-Ia-restricted strain 13 T cells to a series of synthetic B chain peptide fragments revealed that the allo-Ia-restricted populations could be activated by autologous guinea pig insulin. Taken together, these observations strongly suggest that the clonal deletion of self-reactive cells is likely to be I region restricted and that nonresponsiveness to any protein antigen may result from a restriction in the T cell repertoire that is generated during ontogeny by a clonal deletion mechanism of tolerance to self.