tbuckley/cabot-search huggingface dataset:
The Harvest suite for rapid core-genome alignment and visualization of thousands of intraspecific microbial genomes
Authors: Todd J Treangen, Brian D Ondov, Sergey Koren, Adam M Phillippy
Journal: Genome biology (2014)

Abstract Whole-genome sequences are now available for many microbial species and clades, however existing whole-genome alignment methods are limited in their ability to perform sequence comparisons of multiple sequences simultaneously. Here we present the Harvest suite of core-genome alignment and visualization tools for the rapid and simultaneous analysis of thousands of intraspecific microbial strains. Harvest includes Parsnp, a fast core-genome multi-aligner, and Gingr, a dynamic visual platform. Together they provide interactive core-genome alignments, variant calls, recombination detection, and phylogenetic trees. Using simulated and real data we demonstrate that our approach exhibits unrivaled speed while maintaining the accuracy of existing methods. The Harvest suite is open-source and freely available from: http://github.com/marbl/harvest .
Recurrent Meningococcal Infection With an Antigenically Identical Strain
Authors: J. McLeod Griffiss
Journal: JAMA (1974)

Meningococcal infection usually confers immunity in the form of bactericidal antibodies to both the infecting and unrelated strains of meningococci. Recurrent attacks are rare and documentation of the serogroup involved in both episodes of such attacks is rarer still. A case of recurrent group B meningococcal disease occurred in a child who developed bactericidal antibodies to both infecting strains. Both serogroup and serotype antigens of the two infecting strains were identical. (<i>JAMA</i>229:68-70, 1974)
What does tumour necrosis factor excess do to the immune system long term?
Authors: J Clark
Journal: Annals of the Rheumatic Diseases (2005)

Members of the tumour necrosis factor (TNF)/TNF-receptor (TNF-R) superfamily coordinate the immune response at multiple levels. For example, TNF, LTα, LTβ and RANKL provide signals required for lymphoid neogenesis, CD27, OX-40, 4-1BB and CD30 deliver costimulatory signals to augment immune responses, while pro-apoptotic members such as TNF, CD95L and TRAIL may contribute to the termination of the response. Biological identity of individual family members has been revealed through studies of gain of function or gene deficient mutants. Most notable are the development of spontaneous inflammatory polyarthritis in human TNF-globin transgenic mice, the auto-inflammatory syndromes resulting from mutations in the 55-kDa TNF-R, and, in particular, the obligatory role for the RANKL/RANK axis in osteoclastogenesis and bone remodelling. A growing appreciation of the molecular basis of signalling pathways transduced by TNF-R has provided a framework for better understanding the biology of this expanding family. For while the rapid and robust activation of NF-κB and MAPK pathways is typical of acute TNF-R engagement, the molecular basis of sustained receptor signalling remains a mystery, in spite of its relevance to chronic inflammatory and immune responses. Focusing on T cells, this report describes some of the molecular footprints of sustained TNF-R engagement and illustrates how these may influence immune function. A common theme arising is that prolonged TNF stimulation alters signalling thresholds over time. The authors propose that one major outcome of long term exposure to TNF is a state of localised IL-2 deficiency at sites of inflammation. The implications of this deficiency are discussed.
Interferon-α 2b Added to Melphalan-Prednisone for Initial and Maintenance Therapy in Multiple Myeloma
Authors: Martin Hjorth
Journal: Annals of Internal Medicine (1996)

Objective: To evaluate the addition of low-dose interferon-α2b to standard melphalan-prednisone therapy in patients with multiple myeloma. Design: Randomized, multicenter, phase III study. Setting: 15 university hospitals and 92 county hospitals in Sweden, Norway, Denmark, Finland, and Iceland. Patients: 583 patients with symptomatic multiple myeloma. Intervention: All patients received melphalan-prednisone every 6 weeks. Melphalan-prednisone therapy was interrupted after at least 8 courses in responding patients who achieved a plateau phase, and it was reinstituted at time of relapse. Patients randomly assigned to receive melphalan-prednisone and interferon also received interferon, 5 MU three times weekly, from the start of treatment through response, plateau phase, and relapse, until definitive failure of melphalan-prednisone occurred. Measurements: Survival was the main outcome measure. Secondary measures were response rate, response and plateau phase duration, and toxicity. All analyses were done according to the principle of intention-to-treat. Results: 45% of patients receiving melphalan-prednisone and 44% of patients receiving melphalan-prednisone and interferon achieved at least a partial response. Response duration and plateau phase duration were longer for patients receiving melphalan-prednisone and interferon than for patients receiving melphalan-prednisone alone (P < 0.05); the difference in median duration was 5 to 6 months. Toxicity was higher with melphalan-prednisone and interferon, and this led to premature discontinuation of interferon therapy in one third of patients and to a reduced overall dose intensity for melphalan. The median survival time was 29 months for patients receiving melphalan-prednisone and 32 months for patients receiving melphalan-prednisone and interferon. The risk ratio for death for patients receiving melphalan-prednisone compared with patients receiving melphalan-prednisone and interferon was 1.02 (95% CI, 0.89 to 1.40). Conclusions: Adding continuous low-dose interferon to standard melphalan-prednisone therapy does not improve response rate or survival. However, response duration and plateau phase duration are prolonged by maintenance therapy with interferon. *For a listing of members of the Nordic Myeloma Study Group, see the Appendix.
The role of cardiac myosin binding protein-C as a regulator of myofilament Ca2+ sensitivity
Authors: H KOGLER
Journal: Cardiovascular Research (2006)

Stimulation of β1-adrenergic receptors in the heart by endogenous or exogenous agonists results in enhanced formation of the second messenger cyclic 3′,5′-adenosine monophosphate (cAMP), which in turn activates cAMP-dependent protein kinase (PKA). PKA-catalysed phosphorylation ultimately triggers a variety of target proteins to undergo orchestrated functional changes that together comprise the positive inotropic and lusitropic effects caused by β1-adrenoceptor activation. Both these effects serve to enhance cardiac output: the positive inotropic effect boosts myocyte contractility by optimizing Ca2+ homeostasis, mainly via phosphorylation of phospholamban, sarcoplasmic reticulum (SR) Ca2+-ATPase, and L-type Ca2+ channels. The positive lusitropic effect, on the other hand, accelerates myocyte relaxation, thereby facilitating an increase in cardiac output via elevation of heart rate. While the stimulation of Ca2+ reuptake into the sarcoplasmic reticulum to some extent speeds up relaxation, the efficiency of this mechanism is limited by the rate at which Ca2+ ions dissociate (Ca2+ off-rate) from the thin filament regulatory protein troponin-C (TnC), which is a prerequisite for relaxation to occur at the actomyosin cross-bridge level. Hence, mechanisms that decrease the Ca2+ affinity of TnC will favour rapid relaxation.

Treatment of detergent-permeabilised heart preparations with the catalytic subunit of PKA results in a decrease in Ca2+ sensitivity, an increased Ca2+ off-rate, and faster muscle relaxation [1] … 

*Heart Center Gottingen, Department of Cardiology, Robert-Koch-Str. 40, 37075 Gottingen, Germany. Tel.: +49 551 396380; fax: +49 551 392953. Email address: hkogler{at}med.uni-goettingen.de
Growth-promoting effects of substance P on endothelial cells in vitro. Synergism with calcitonin gene-related peptide, insulin, and plasma factors.
Authors: A C Villablanca, C J Murphy, T W Reid
Journal: Circulation Research (1994)

The purpose of this study was to determine the effects of the vasoactive perivascular neuropeptide substance P (SP) on the growth and function of vascular endothelial cells in serum-free culture conditions with cells quiescent in the G0-G1 phase of the cell cycle and to characterize the response. In addition, interactions between SP and other growth factors and neuropeptides including insulin, platelet factors, neurokinin A, neurokinin B, and calcitonin gene-related peptide (CGRP) were studied on endothelial cell growth and compared. Growth effects were determined by stimulation of tritiated thymidine incorporation into DNA and cell proliferation. SP exhibited differential effects on cell growth that were a function of concentration, incubation time, interaction with other growth factors, and cell culture conditions. DNA synthesis in response to SP showed a bell-shaped distribution with a maximal effect that was 10.5-fold over control at 500 micrograms/mL of SP after 48 hours of incubation. The effect showed marked synergism with insulin (10 micrograms/mL) and with CGRP (0.01 to 10 micrograms/mL), which is colocalized with SP in vivo. Insulin and CGRP alone had no significant effect on endothelial cell growth. Furthermore, no synergism was observed between SP and platelet-derived growth factor or platelet-derived endothelial cell growth factor. Endothelial cell proliferation increased in response to SP to 2.6-fold over control at 48 hours, was maximal at 10 micrograms/mL SP, and also demonstrated synergism with insulin (10 micrograms/mL). Our studies indicate that neuropeptides play a significant role in regulating endothelial cell growth and proliferation.(ABSTRACT TRUNCATED AT 250 WORDS)
Leukocyte extravasation into the pancreatic tissue in transgenic mice expressing interleukin 10 in the islets of Langerhans.
Authors: L Wogensen, X Huang, N Sarvetnick
Journal: The Journal of Experimental Medicine (1993)

Transgenic expression of interleukin 10 (IL-10) in the islets of Langerhans leads to a pronounced pancreatic inflammation, without inflammation of the islets of Langerhans and without diabetes. A scattered infiltration of macrophages (M pi) precedes localized accumulations of CD4+ and CD8+ T lymphocytes, B lymphocytes, and M pi. This recruitment of inflammatory cells to the pancreas is somewhat surprising, since the biological activities of IL-10 in vitro indicate that IL-10 is a powerful immunosuppressive cytokine. Since endothelial cells play a major role in leukocyte extravasation, we examined if vascular changes and extralymphoid induction of peripheral and mucosal type vascular addressins contributed to IL-10-induced homing of mononuclear cells to the pancreas. The endothelium lining small vessels was highly activated in areas of inflammation, as the endothelial cells became cuboidal, and exhibited increased expression of major histocompatibility complex class II (Ia), intercellular adhesion molecule 1, and von Willebrand Factor. Furthermore, induction of vascular addressins simultaneously with accumulation of mononuclear cells around islets and vessels indicated that the endothelial cells take on the phenotype of differentiated endothelium specialized for leukocyte extravasation. In conclusion, pancreatic inflammation and vascular changes are prominent in IL-10 transgenic mice. We hypothesize that IL-10, in addition to its immuno-inhibitory properties, is a potent recruitment signal for leukocyte migration in vivo. These effects are relevant for in vivo therapeutic applications of IL-10.
Central beta-adrenergic mechanisms may modulate ischemic ventricular fibrillation in pigs.
Authors: G W Parker, L H Michael, C J Hartley, J E Skinner, M L Entman
Journal: Circulation Research (1990)

A central noradrenergic process may permit expression of the stress-related increase in cardiac vulnerability to ventricular fibrillation (VF). Thus, the effect of central beta-adrenergic receptor blockade with L-propranolol (0.01 and 0.05 mg/kg) on ischemia-induced VF vulnerability was evaluated in the psychologically stressed pig model and compared with Ringer's solution and D-propranolol (0.05 mg/kg). The ischemia of a maximum 15-minute left anterior descending coronary artery occlusion was used since we previously determined that pigs surviving 15 minutes usually do not fibrillate. Time to the onset of VF was analyzed by time-to-event analysis and ranged from 0.75 to 13.8 minutes in vulnerable pigs. Intracerebroventricular administration of L-propranolol (0.05 mg/kg) prolonged the time to VF compared with Ringer's solution and D-propranolol (p less than 0.05). The high dose of L-propranolol also reduced the incidence of VF (7/15 fibrillated) compared with Ringer's solution (12/12 fibrillated) and D-propranolol (6/7 fibrillated). The lower dose of L-propranolol was without effect on VF vulnerability (7/9) fibrillated). The plasma concentration resulting from central administration of 0.05 mg/kg L-propranolol was found to be 9.05 +/- 3.25 ng/ml, which is significantly below therapeutic antiarrhythmic blood levels. We conclude that the reduced vulnerability to ischemia-induced VF after intracerebroventricular administration of propranolol is due to alteration of a central beta-adrenergic receptor-mediated phenomenon as opposed to an effect on the heart directly or to nonspecific membrane stabilization.
THE TREATMENT OF COLLES'S FRACTURE
Authors: A. S. B. Bankart
Journal: BMJ (1929)

Trick in the British Medical Journal of March 2nd (p.391), follow-in0 upon that of Edwards and Clayton in the Journal of January 12th, prompts me to offer a few remarks on tlhe treatmenit of Colles's fracture.Colles's fracture is at once the commonest (sharing this distinietion with fracture of the clavicle), one of the easiest to treat, and generally the worst treated, of all fractures of tlhe human body.The first-mentioned paper is "an endeavouir to ascer- tain the causes for the imiiperfect results that obtaini from the usual methods of treatment at present adopted."The
STUDIES ON THE FUNCTIONAL CAPACITY OF A DENERVATED HOMOTRANSPLANTED KIDNEY IN AN IDENTICAL TWIN WITH PARALLEL OBSERVATIONS IN THE DONOR 1
Authors: Neal S. Bricker, Warren R. Guild, John B. Reardan, John P. Merrill
Journal: Journal of Clinical Investigation (1956)

ml./mix.Donor Two-kidney control * Ci3 = inulin clearance; Cc, = endogenous creatinine clearance; CPH = p-aminohippurate clearance; F
Operative mortality in colorectal cancer: prospective national study
Authors: P. P Tekkis
Journal: BMJ (2003)

To develop a mathematical model that will predict the probability of death after surgery for colorectal cancer.Descriptive study using routinely collected clinical data.The database of the Association of Coloproctology of Great Britain and Ireland (ACPGBI), encompassing 8077 patients with a new diagnosis of colorectal cancer in 73 hospitals during a 12 month period.A three level hierarchical logistic regression model was used to identify independent predictors of operative mortality. The model was developed on 60% of the patient population and its validity tested on the remaining 40%.Overall postoperative mortality was 7.5% (95% confidence interval 6.9% to 8.1%). Independent predictors of death were age, American Society of Anesthesiology (ASA) grade, Dukes's stage, urgency of the operation, and cancer excision. When tested the predictive model showed good discrimination (area under the receiver operating characteristic curve = (0.775) and calibration (comparison of observed with expected mortality across different procedures; Hosmer-Lemeshow statistic = 6.34, 8 df, P = 0.610).Clinicians can predict postoperative death by using a simple numerical table derived from the statistical model of the ACPGBI. The model can be used in everyday practice for preoperative counselling of patients and their carers as a part of multidisciplinary care. It may also be used to compare the outcomes between multidisciplinary teams for colorectal cancer.
Uracil/Tegafur Plus Cisplatin with Concurrent Radiotherapy for Locally Advanced Non-Small-Cell Lung Cancer
Authors: Yukito Ichinose, Yushi Nakai, Shoji Kudoh, Hiroshi Semba, Susumu Yoshida, Toshihiro Nukiwa, Hidehiko Yamamoto, Yoshio Yamane, Hisanobu Niitani
Journal: Clinical Cancer Research (2004)

Abstract Purpose: To evaluate the efficacy and toxicity of a novel combination treatment using concurrent radiotherapy with cisplatin plus UFT, which is comprised of uracil and tegafur, in locally advanced non-small cell lung cancer (NSCLC) patients. Experimental Design: In this Phase II trial, patients with unresectable stage III NSCLC were treated with the oral administration of UFT (400 mg/m2/d tegafur) on days 1–14 and days 29–42 whereas 80 mg/m2 cisplatin was administered i.v. on days 8 and 36. Radiotherapy, with a total dose of 60 Gy, was delivered in 30 fractions from day 1. Results: Seventy patients were enrolled and eligible, as follows: 57 males/13 females; mean age 61 ranging from 36 to 74; performance status 0/1:45/25; stage IIIA/IIIB, 14/56. A complete response was observed in two patients and a partial response in 54 patients, and the overall response rate was 81% (95% confidence interval; 70–89%). The median survival, the 1- and 2-year survival rates were 16.5 months, 67% and 33%, respectively. Grade 3/4 leukopenia occurred in 14%/1% of the patients. Grades 3 non-hematological toxicities were only reported in three patients with nausea, two with esophagitis and one with pneumonitis whereas no grade 4 non-hematological toxicity was observed. Conclusions: UFT plus cisplatin with concurrent radiotherapy is considered to be a feasible and effective treatment for locally advanced NSCLC patients. Additional study of this concurrent chemoradiotherapy is warranted.
Increased glucose effectiveness in normoglycemic but insulin-resistant relatives of patients with non-insulin-dependent diabetes mellitus. A novel compensatory mechanism.
Authors: J E Henriksen, F Alford, A Handberg, A Vaag, G M Ward, A Kalfas, H Beck-Nielsen
Journal: Journal of Clinical Investigation (1994)

20 normoglycemic first degree relatives of non-insulin-dependent diabetes mellitus (NIDDM) patients were compared with 20 matched subjects without any family history of diabetes using the intravenous glucose tolerance test with minimal model analysis of glucose disappearance and insulin kinetics. Intravenous glucose tolerance index (Kg) was similar in both groups (1.60 +/- 0.14 vs 1.59 +/- 0.18, x 10(-2) min-1, NS). However, insulin sensitivity (Si) was reduced (3.49 +/- 0.43 vs 4.80 +/- 0.61, x 10(-4) min-1 per mU/liter, P = 0.05), whereas glucose effectiveness (Sg) was increased (1.93 +/- 0.14 vs 1.52 +/- 0.16, x 10(-2) min-1, P < 0.05) in the relatives. Despite insulin resistance neither fasting plasma insulin concentration (7.63 +/- 0.48 vs 6.88 +/- 0.45, mU/liter, NS) nor first phase insulin responsiveness (Phi1) (3.56 +/- 0.53 vs 4.13 +/- 0.62, mU/liter min-1 per mg/dl, NS) were increased in the relatives. Phi1 was reduced for the degree of insulin resistance in the relatives so that the Phi1 x Si index was lower in the relatives (11.5 +/- 2.2 vs 16.7 +/- 2.0, x 10(-4) min-2 per mg/dl, P < 0.05). Importantly, glucose effectiveness correlated with Kg and with basal glucose oxidation but not with total glucose transporter 4 (GLUT4) content in a basal muscle biopsy. In conclusion we confirm the presence of insulin resistance in first degree relatives of NIDDM patients. However, insulin secretion was altered and reduced for the degree of insulin resistance in the relatives, whereas glucose effectiveness was increased. We hypothesize that increased glucose effectiveness maintains glucose tolerance within normal limits in these "normoinsulinemic" relatives of NIDDM patients.
Specific amino acid (L-arginine) requirement for the microbiostatic activity of murine macrophages.
Authors: D L Granger, J B Hibbs, J R Perfect, D T Durack
Journal: Journal of Clinical Investigation (1988)

The microbiostatic action of macrophages was studied in vitro employing peritoneal cytotoxic macrophages (CM) from mice acting against Cryptococcus neoformans cultured in Dulbecco's medium with 10% dialyzed fetal bovine serum. Fungistasis was measured using electronic particle counting after lysis of macrophages with detergent. Macrophage fungistasis failed in medium lacking only L-arginine. Complete fungistasis was restored by L-arginine; restoration was concentration dependent, maximal at 200 microM. Deletion of all other essential amino acids did not abrogate fungistasis provided that L-arginine was present. Of twenty guanido compounds, including D-arginine, only three (L-arginine, L-homoarginine, and L-arginine methylester) supported fungistasis. Known activators or mediators of macrophage cytotoxicity (endotoxin, interferon gamma, tumor necrosis factor) did not replace L-arginine for CM-mediated fungistasis. The guanido analogue NG-monomethyl-L-arginine was a potent competitive inhibitor of CM-mediated fungistasis giving 50% inhibition at an inhibitor/L-arginine ratio of 1:27. Although CM completely blocked fungal reproduction via an L-arginine-dependent mechanism, the majority of the dormant fungi remained viable. Thus, this mechanism is viewed as a microbiostatic process similar or identical to the tumoristatic effect of macrophages. This suggests the production of a broad spectrum biostatic metabolite(s) upon consumption of L-arginine by cytotoxic macrophages.
VH gene expression is restricted in anti-IgG antibodies from MRL autoimmune mice.
Authors: S E Arant, J A Griffin, W J Koopman
Journal: The Journal of Experimental Medicine (1986)

Antibodies directed against IgG and DNA are found in the sera of autoimmune MRL/Mp lpr/lpr mice. Little is known of the molecular mechanisms underlying expression of such autoantibodies. We have investigated the binding diversity and pattern of VH gene expression in a panel of murine anti-IgG antibodies. We constructed eight hybridoma clones secreting IgM antibodies that bound to mouse IgG by using spleen cells from MRL/Mp lpr/lpr mice varying in age from 4 to 15 wk; one clone was derived from a 32-wk-old MRL +/+ mouse. The monoclonal IgM products exhibited varying binding specificities for intact mouse IgG, fragments of mouse IgG [Fc, Fab, (Fab')2], and heterologous IgG. Two of these antibodies crossreacted with B and/or Z DNA. Probes from seven of eight identified mouse VH gene families (7183, S107, Q52, J558, J606, 36-60, and 3609) were hybridized under high-stringency conditions with cytoplasmic RNA blots from each clone. Six clones hybridized only with the probe from the five-member 36-60 family. The remaining three clones crosshybridized with the 36-60 probe and the probe from the 60 member J558 family, perhaps reflecting somatic mutation from the original germline VH gene resulting in recognition by a probe from another family, in addition to the probe from the original germline family. Our results indicate that spontaneous MRL lpr/lpr anti-IgG antibodies are encoded predominantly by the 36-60 VH gene family and imply a nonrandom selection of this VH gene family in the production of these antibodies.