tbuckley/cabot-search huggingface dataset:
Rearrangement and selection of VH11 in the Ly-1 B cell lineage.
Authors: C E Carmack, S A Shinton, K Hayakawa, R R Hardy
Journal: The Journal of Experimental Medicine (1990)

One of the predominant VH genes utilized to encode the anti-BrMRBC specificity is a member of the small VH11 family rearranged to JH1. Using the polymerase chain reaction (PCR) we have determined that the frequency of B cells with a VH11 rearrangement is 10-20 times higher in Ly-1 B than in Ly-1- "conventional" B cells regardless of location (spleen or peritoneal cavity). Conventional B cells rearrange this gene at comparable levels in pre-B cells and in mature B cells utilizing all JH gene segments. In contrast, the increased levels of VH11 rearrangement in Ly-1 B are restricted to JH1 (and some JH2) and therefore appear to be the result of selection. Furthermore, most peritoneal Ly-1 B cells with VH11 rearrangements fall in a fraction stained by anti-BrMRBC antibody, likely bearing multivalent natural (likely self) antigen constitutively bound to their surface Ig receptors. Thus, we suggest that autoantigens are largely responsible for the accumulation of autoantibody specificities in the Ly-1 B cell lineage with time, whereas they do not exert this effect in the conventional B cells.
Training can help GPs provide a better death for patients
Authors: I. Torjesen
Journal: BMJ (2012)

GPs need better training to boost their confidence in talking about death to patients and to improve care at the end of life, says new research published by the coalition Dying Matters.

The coalition, set up by the National Council for Palliative Care to reduce people’s fear of dying by breaking down the taboo of talking about and preparing for death, has piloted a training package for GPs to build their confidence in talking about the issue.

Before undertaking the training 45% of 113 GPs said that they did not feel confident in talking to patients about death and dying, but after the …
Vasopressin Effect on Portal and Systemic Hemodynamics
Authors: Yvan J. Silva
Journal: JAMA (1969)

Parumbilical (portal) vein, arterial, and central venous pressures were monitored continuously during sham and vasopressin injection (Pitressin) infusion in ten adult patients in the intact, unanesthetized state. Five of these patients at rest (group A) had portal pressures greater than, and five (group B) lower than, 30 cm H<sub>2</sub>O. Twenty clinical units of vasopressin injection infused intravenously over 20 minutes caused an average fall in portal pressures of 19.8% (group A) and 25% (group B), abrupt arterial pressure elevations with bradycardia, and no changes in central venous pressure (CVP). Side portal flow diminished an average of 21%, and variable elevations of lactate levels in portal blood were observed. Valsalva maneuvers caused 46 to 64 cm H<sub>2</sub>O increases in portal pressure, unaffected by administration of the drug. In none of the patients in group A did vasopressin succeed in lowering portal pressure below 30 cm H<sub>2</sub>O.
Timeline: 200 Years of the<i>New England Journal of Medicine</i>
Authors: Daniel C. Müller, Ellen M.C. Duff, Kathy L. Stern
Journal: New England Journal of Medicine (2012)

This interactive timeline represents all the research and review articles and case reports published in the New England Journal of Medicine from 1812 to 2012. The expanding navigation panel at the top of the timeline is an overview of the 200 years, with articles color-coded by medical specialty. The user can select categories to display and can view the data as a percentage of articles or as the actual number of articles per year. The gray bands below the navigation panel provide historical context, showing events in medicine, . . .
Autoantibodies to the extracellular domain of the calcium sensing receptor in patients with acquired hypoparathyroidism.
Authors: Y Li, Y H Song, N Rais, E Connor, D Schatz, A Muir, N Maclaren
Journal: Journal of Clinical Investigation (1996)

Acquired hypoparathyroidism (AH) has been considered to result from an autoimmune process but the self-antigens have not been identified. We studied 25 patients with AH, of which 17 had type I autoimmune polyglandular syndrome and 8 had AH associated with autoimmune hypothyroidism. Five of 25 (20%) AH sera reacted to a membrane-associated antigen of 120-140 kD in human parathyroid gland extracts using immunoblot analysis. This is the exact size of the calcium sensing receptor (Ca-SR). The AH sera were then tested by immunoblot using a membrane fraction of HEK-293 cells transfected with Ca-SR cDNA. Eight of 25 (32%) AH sera reacted to a 120-140-kD protein, which closely matched that recognized by the anti-Ca-SR IgG raised in rabbits. The Ca-SR cDNA was translated in vitro into two parts in order to identify the antigenic epitopes. By using this technique, 14 of 25 (56%) AH sera were positive to the extracellular domain of the Ca-SR, whereas none of the AH patients sera reacted to the intracellular domain. The reactivity of the positive sera was completely removed after pre-absorption with the Ca-SR containing membranes. Sera from 50 patients with various other autoimmune diseases as well as 22 normal controls were also tested, and none of them was positive. In conclusion, the Ca-SR has been identified as an autoantigen in AH.
Abstract 1036: ProNGF/p75NTR signaling promotes survival of merlin-deficient vestibular schwannoma cells by activating NF-kB
Authors: WeiYing Yue, Iram Ahmad, James Jason Clark, Geir Tryggvason, Erika A. Woodson, Marlan R. Hansen
Journal: Cancer Research (2011)

Abstract Vestibular schwannomas (VSs) represent benign Schwann cell (SC) neoplasms arising from the eighth cranial nerve and result from loss of function of the tumor suppressor gene, merlin. The mechanisms by which loss of merlin function promotes tumorigenesis in SCs is not well-defined. Denervation by axotomy leads to increased merlin inactivation by phosphorylation, increased p75NTR expression, JNK activation, and eventual death of normal SCs. In contrast to SCs, VS cells survive in the absence of axons. We found that p75NTR expression is elevated in sciatic nerves of mice harboring a SC specific dominant negative merlin mutation (P0SchΔ36-121) compared to nerves from wild-type mice suggesting that merlin status regulates p75NTR expression. Consistent with this we also find that p75NTR is over-expressed in primary human VS tissue compared with normal nerves. Treatment of normal rat SCs with proNGF, a high affinity p75NTR ligand, induces apoptosis by activating JNK. Primary cultured human VS cells, by contrast, display persistent JNK activity which promotes cell survival. Treatment of human primary VS cultures with the JNK inhibitors (I-JIP and SP600125) or JNK siRNA knock down results in decreased proliferation and increased apoptosis; treatment with proNGF protects cells from apoptosis due to JNK inhibition suggesting a p75NTR-mediated pro-survival signal in primary cultured VS cells. We explored the possibility that the pro-survival effect of p75NTR signaling results from activation of NF-κB. Indeed, proNGF treatment activated NF-κB in primary cultured VS cells while inhibition of JNK with SP600125 or siRNA-mediated JNK1/2 knockdown reduced NF-κB activity. Significantly, proNGF also activated NF-κB in primary cultured VS cells treated with JNK inhibitors. Thus, persistent JNK activity appears to be required for basal levels of NF-κB activity, but not for proNGF-induced NF-κB activity. To confirm that the increase in NF-κB activity by proNGF contributes to the prosurvival effect, we infected primary human VS cultures with Ad.IκB-SermutS32/36A virus which inhibits NF-κB activation. Compared to control virus, Ad.IκB-SermutS32/36A significantly increased VS cell apoptosis in VS cultures including those treated with proNGF. These results suggest that, in contrast to normal SCs which undergo apoptosis in response to p75NTR and JNK signaling, proNGF/p75NTR signaling provides a prosurvival response by activating NF-κB independent of JNK in merlin deficient VS cells. Such differences may account for the ability of human VS cells to proliferate and survive in the absence of axons. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1036. doi:10.1158/1538-7445.AM2011-1036
Chronic hepatitis B reactivation and systemic glucocorticosteroid therapy: reply from authors
Authors: C-H. Yang, C-T. Chiu
Journal: British Journal of Dermatology (2008)

Conflicts of interest: none declared. Sir, We thank Dr Wang and colleagues for their comments on our paper on reactivation of chronic hepatitis B virus (HBV) following systemic glucocorticosteroid therapy that was published in the September 2007 issue of this Journal.1 The authors raise two issues. Firstly, they question whether the hepatitis in four patients described in this article does not represent ‘reactivation’ because they do not have a baseline HBV DNA viral titre for reference, and thus cannot fit the definition of HBV reactivation. Secondly, Wang et al. question the feasibility of antiviral drug prophylaxis therapy as recommended by us. Regarding the first issue, the published article was limited by its scope as a retrospective study. As most dermatologists have traditionally neglected the risk of HBV infection and reactivation during corticosteroid therapy, only 21 of 98 patients (21%) were screened or recorded for serum hepatitis B markers status in this retrospective study. Thus, it was not possible to acquire a baseline HBV DNA viral titre. Even without a baseline HBV DNA viral titre for comparison, however, it is reasonable to conclude that there was a reactivation of HBV in these four patients based on the clinical history and course, as prednisolone is a known risk factor for HBV reactivation, as reported previously.2
Hirudin in acute myocardial infarction. Safety report from the Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9A Trial.
Authors: E M Antman
Journal: Circulation (1994)

BACKGROUND The Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9A trial compared the efficacy and safety of intravenous hirudin with heparin as adjunctive therapy to thrombolysis and aspirin in patients with acute myocardial infarction. The primary safety end point was the occurrence of major hemorrhage or anaphylaxis. METHODS AND RESULTS Based on experience in phase II trials, TIMI 9A used a hirudin bolus of 0.6 mg/kg followed by a fixed-dose 96-hour infusion of 0.2 mg/kg per hour. A modified weight-adjusted heparin regimen was used (5000-U bolus and infusion of 1000 U/h for patients &lt; 80 kg or 1300 U/h for patients &gt; or = 80 kg) with titration to a target activated partial thromboplastin time (aPTT) of 60 to 90 seconds. Because rates of hemorrhage in both treatment arms were higher than expected, randomization was suspended in TIMI 9A after 757 patients had been enrolled. Intracranial hemorrhage occurred in 1.7% of patients treated with hirudin and 1.9% of those treated with heparin (P = NS). Major spontaneous hemorrhage at a nonintracranial site occurred more frequently in hirudin--than in heparin-treated patients (7.0% versus 3.0%; P = .02), whereas major hemorrhage at instrumented sites was similar (5.2% in both hirudin and heparin groups). Patients who developed a major hemorrhage were older (P &lt; .001) and had higher aPTT values, especially in the first 12 hours after thrombolysis (P = .001). CONCLUSIONS The rate of major spontaneous hemorrhage for both heparin and hirudin in TIMI 9A was higher than that seen in TIMI 5, TIMI 6, and GUSTO 1. This was possibly a result of high levels of anticoagulation at the doses of heparin and hirudin used, low previous estimates of the hemorrhage risk at the doses of hirudin used in TIMI 9A due to the relatively small number of patients receiving that dose in earlier studies, and enrollment of patients at higher risk of hemorrhage. Because a prolonged aPTT was associated with an increased risk of major hemorrhage in both heparin- and hirudin-treated patients, it now appears important to monitor aPTT on a regular basis when using either antithrombin to identify those patients who require downward adjustment of the infusion. TIMI 9B has therefore been configured with a lower hirudin bolus (0.1 mg/kg) and infusion (0.1 mg/kg per hour) and lower heparin infusion (1000 U/h without weight adjustment). Infusions of both antithrombins will be titrated to a target aPTT of 55 to 85 seconds.
Effects of Rapamycin on Breast Cancer Cell Migration through the Cross-Talk of MAPK Pathway.
Authors: H. Zhao, K. Cui, F. Nie, G. Jin, F. Li, L. Wu, L. Wang, M. Brandl, N. Yilidirim, S. Zhang, A. Sun, S. Wong
Journal: Cancer Research (2009)

Abstract Phase I/II clinical studies with rapamycin analogs in breast and other cancers have demonstrated favorable responses. However, little is known on the effects of the mTOR inhibitor on breast cancer cell metastasis, which is a major cause of morbidity and death. We developed a highly sensitive 3-dimensional (3D) proliferation/invasion assay using quantitative bioluminescence (BL) imaging and applied this assay to evaluate the effects of rapamycin on the triple negative breast cancer cell line MDA-MB231. Without cytotoxicity of rapamycin on this cell line, rapamycin at 10nM inhibited the cell migration/invasion, but not at 1nM and 100nM, which was confirmed by the time-lapse single cell tracking analysis. The quantification of cytoskeleton changes showed most potent effects of 10nM rapamycin on the MDA-MB231 cells, with the formation and rearrangement of specialized cell membrane structures and actin fiber implicated in cell motility. Then, the Panorama Cell Signaling Antibody Microarray, enabling the global comparative analysis of cell signal proteins simultaneously, was exploited to analyze the effects of rapamycin on the cellular signaling network of the MDA-MB231 breast cancer cell line. 100nM rapamycin activated the MAPK pathway obviously, through the attenuated negative feedback of activated S6K1 to PI3K-Raf, which increased the expressions of activated Jun N-terminus kinase (JNK), Erk1/2, MEK-1, Raf-pS621, and MAPK-activated protein kinase 2 (MAPKAPK2) in the cells exposed to 100nM rapamycin. MEK inhibitor U0126 or PD98059 could restore the anti-migration effects of 100nM rapamycin on the MDA-MB231 cells. Furthermore, the combination of MEK inhibitors and rapamycin performed synergism on inhibiting the cell proliferation and migration/invasion. Accordingly, rapamycin at a certain dose suppresses MDA-MB231 cell migration/invasion, and the co-targeting of mTOR and MAPK pathways enhances the inhibition on cell proliferation and migration/invasion, underscoring the potential therapeutic utility of rapamycin, and rapamycin combining with MAPK inhibitors in triple negative breast cancer progression, and the results highlight the cross-talk homeostasis of mTOR and MAPK pathways in cancer treatment. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5080.
Book: Forensic Medicine: Clinical and Pathological Aspects
Authors: A. Vass
Journal: BMJ (2003)

Eds Jason Payne-James, Anthony Busuttil, William Smock Greenwich Medical Media, £135, pp 840 ISBN 1 841100 269 Rating: ![Graphic][1]</img>![Graphic][2]</img>![Graphic][3]</img> Forensic medicine has humble and ancient origins. What are thought to be some of the first descriptions of how to examine injuries were found carved on pieces of bamboo dating back to the Qin dynasty in China, from about 220 BC. The first publication on forensic medicine in the United Kingdom was by William Hunter in the 18th century. His essays were on the injuries found on murdered bastard children. From these dark beginnings forensic medicine has developed into a large specialty with several subspecialties. Forensic medicine must be one of the most unusual, and certainly one of the most macabre, branches of medicine. This … [1]: /embed/inline-graphic-1.gif [2]: /embed/inline-graphic-2.gif [3]: /embed/inline-graphic-3.gif
Abstract LB-151: Spred1 and neurofibromin interact to negatively regulate Ras/Raf/MEK/ERK signaling
Authors: Irma B. Stowe, Timothy Stowe, Frank McCormick, Ellen Mercado
Journal: Cancer Research (2012)

Abstract The Ras/Mitogen Activated Protein Kinase (MAPK) plays a critical role in cell signaling downstream of receptor tyrosine kinases. The conserved Sprouty family proteins function as feedback regulators of Ras/MAPK signaling. Loss of function mutations in one family member, SPRED1, cause Legius syndrome, an autosomal dominant human disorder that resembles neurofibromatosis type 1 (NF1). Spred1 functions as a negative regulator of the Ras/MAPK pathway, however, the underlying molecular mechanism is poorly understood. We found Spred1 functioned by reducing Ras-GTP levels; SPRED1 loss-of function mutations identified in Legius syndrome patients were unable to regulate Ras activity levels. The N-terminal EVH1 domain of Spred1 was found to be crucial for its inhibitory function. Thus, we utilized tandem affinity purification of wild-type Spred1 and EVH1 domain mutants found in Legius syndrome to identify novel binding partners of the N-terminus. Analysis of protein complexes by mass spectrometry revealed neurofibromin, the NF1 gene product, as a novel Spred1 interacting protein. We show that neurofibromin is a Spred1 binding partner that is necessary for Spred1's inhibitory function. Spred1 requires neurofibromin to down-regulate Ras-GTP levels, and the interaction with Spred1 is required for neurofibromin localization to the plasma membrane. This novel mechanism leads to a better understanding of the regulation of the neurofibromin tumor suppressor protein. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-151. doi:1538-7445.AM2012-LB-151
THE FLOW AND COMPOSITION OF LYMPH IN RELATION TO THE FORMATION OF EDEMA
Authors: A. A. Weech, E. Goettsch, E. B. Reeves
Journal: The Journal of Experimental Medicine (1934)

1. The experimental observations have been summarized at the end of an earlier section. The more important facts only will be recapitulated here. The capacity of the lymphatics for removing fluid from the tissues greatly exceeds the rate at which freshly formed tissue fluid can be made available for removal. Edematous regions can be rendered non-edematous by the application of measures, such as massage, passive motion, or normal exercise, which activate the lymphatics. During continuous activity the rate of lymph flow is first variable and later relatively constant. Constant rates of flow must correspond to the production of fresh lymph. A study of the constant rates indicates that lymph formation in the edematous animal is certainly only slightly greater, and possibly not greater at all, than under conditions of normality. When the protein of plasma decreases, the protein of lymph is also lowered. The loss of protein from lymph takes place at a faster rate than from plasma, so that the ratio of serum protein to lymph protein is greater in the edematous than in the normal animal. In edematous animals the concentration of protein in lymph is of the same order of magnitude as the concentration in edema fluids. The two fluids are not, however, identical in composition. Minor fluctuations in the protein content of lymph always occur during a period of continuous collection. 2. The factors involved in the circulation and accumulation of tissue fluid are discussed. Reasons are given for offering the following suggestions. Significant differences in tissue pressure or tension exist between the states resulting from quiescence and activation of the lymphatics. The differences give rise to variations in the relative areas of capillary wall, functioning for filtration and reabsorption. When the lymphatics are activated it is possible that capillary reabsorption may be completely in abeyance. A decline in the proteins of plasma may be associated with a diminished permeability of the capillaries. Such a lowering of capillary permeability would account for two features, both of which have been demonstrated: (1) failure to observe an appreciably increased rate of lymph formation in the edematous animal, and (2) the extremely low concentration of protein in lymph from edematous animals. Although the difference between the protein concentrations of edema fluid and lymph from the same region is small, the conclusion is not yet justified that a similarly small difference exists between normal tissue fluid and normal lymph.
Infiltration of central nervous system in adult acute myeloid leukaemia.
Authors: M J Pippard, S T Callender, P W Sheldon
Journal: BMJ (1979)

Out of 64 consecutive unselected patients with acute myeloid leukaemia studied during 1973-6, five developed clinical evidence of spread to the central nervous system (CNS). Neuroradiological examination showed cerebral deposits in three, in whom rapid symptomatic relief was obtained with radiotherapy. In two of these patients who developed solid intracranial deposits haematological remission could be reinduced or maintained; they were still alive 86 and 134 weeks later. When patients presented with spread to the CNS complicating generalised uncontrolled leukaemia they had short survivals. CNS infiltration may respond dramatically to appropriate treatment provided that it is not associated with generalised uncontrolled leukaemia, which has a poor prognosis. In view of this, routine "prophylaxis" of the CNS in adult acute myeloid leukaemia does not seem justified at present.
Vasculogenesis Driven by Bone Marrow-Derived Cells Is Essential for Growth of Ewing's Sarcomas
Authors: Ling Yu, Bing Su, Mario Hollomon, Yong Deng, Valeria Facchinetti, Eugenie S. Kleinerman
Journal: Cancer Research (2010)

Abstract The role of vasculogenesis as opposed to angiogenesis in tumor formation has been little explored genetically. Endothelial cells that lack the MEK kinase MEKK3 cannot form vessels. In this study, we employed mice with hematopoietic deletions of the Mekk3 gene to evaluate the importance of vasculogenesis in the formation of Ewing's sarcoma tumors. Bone marrow cells (BM) from LacZ+ Mekk3-deficient conditional knockout mice (Mekk3Δflox/− mice) were transplanted into irradiated nude mice before injection of Ewing's sarcoma cells. Because the grafted Mekk3Δflox/− BM cells cannot contribute to vessel development in the same way as the host Mekk3+/+ endothelial cells, angiogenesis is normal in the model whereas vasculogenesis is impaired. Four weeks after BM transplant, Ewing's sarcoma TC71 or A4573 cells were injected, and tumor growth and vessel density were compared. Strikingly, chimeric mice transplanted with Mekk3Δflox/− BM exhibited a reduction in tumor growth and vessel density compared with mice transplanted with Mekk3Δflox/+ BM cells. Mekk3Δflox/− cells that were LacZ positive were visualized within the tumor; however, few of the LacZ+ cells colocalized with either CD31+ endothelial cells or desmin+ pericytes. Quantification of double-positive LacZ+ and CD31+ endothelial cells or LacZ+ and desmin+ pericytes confirmed that chimeric mice transplanted with Mekk3Δflox/− BM were impaired for tumor vessel formation. In contrast, siRNA-mediated knockdown of Mekk3 in TC71 Ewing's sarcoma cells had no effect on tumor growth or vessel density. Our findings indicate that vasculogenesis is critical in the expansion of the tumor vascular network. Cancer Res; 70(4); 1334–43