tbuckley/cabot-search huggingface dataset:
International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences
Authors: L. M. Fredrik Leeb-Lundberg, Francois Marceau, Werner Müller-Esterl, Douglas J. Pettibone, Bruce L. Zuraw
Journal: Pharmacological Reviews (2005)

Kinins are proinflammatory peptides that mediate numerous vascular and pain responses to tissue injury. Two pharmacologically distinct kinin receptor subtypes have been identified and characterized for these peptides, which are named B<sub>1</sub> and B<sub>2</sub> and belong to the rhodopsin family of G protein-coupled receptors. The B<sub>2</sub> receptor mediates the action of bradykinin (BK) and lysyl-bradykinin (Lys-BK), the first set of bioactive kinins formed in response to injury from kininogen precursors through the actions of plasma and tissue kallikreins, whereas the B<sub>1</sub> receptor mediates the action of des-Arg<sup>9</sup>-BK and Lys-des-Arg<sup>9</sup>-BK, the second set of bioactive kinins formed through the actions of carboxypeptidases on BK and Lys-BK, respectively. The B<sub>2</sub> receptor is ubiquitous and constitutively expressed, whereas the B<sub>1</sub> receptor is expressed at a very low level in healthy tissues but induced following injury by various proinflammatory cytokines such as interleukin-1β. Both receptors act through Gα<sub>q</sub> to stimulate phospholipase Cβ followed by phosphoinositide hydrolysis and intracellular free Ca<sup>2+</sup> mobilization and through Gα<sub>i</sub> to inhibit adenylate cyclase and stimulate the mitogen-activated protein kinase pathways. The use of mice lacking each receptor gene and various specific peptidic and nonpeptidic antagonists have implicated both B<sub>1</sub> and B<sub>2</sub> receptors as potential therapeutic targets in several pathophysiological events related to inflammation such as pain, sepsis, allergic asthma, rhinitis, and edema, as well as diabetes and cancer. This review is a comprehensive presentation of our current understanding of these receptors in terms of molecular and cell biology, physiology, pharmacology, and involvement in human disease and drug development.
Geminin deletion from hematopoietic cells causes anemia and thrombocytosis in mice
Authors: Kathryn M. Shinnick, Elizabeth A. Eklund, Thomas J. McGarry
Journal: Journal of Clinical Investigation (2010)

HSCs maintain the circulating blood cell population. Defects in the orderly pattern of hematopoietic cell division and differentiation can lead to leukemia, myeloproliferative disorders, or marrow failure; however, the factors that control this pattern are incompletely understood. Geminin is an unstable regulatory protein that regulates the extent of DNA replication and is thought to coordinate cell division with cell differentiation. Here, we set out to determine the function of Geminin in hematopoiesis by deleting the Geminin gene (Gmnn) from mouse bone marrow cells. This severely perturbed the pattern of blood cell production in all 3 hematopoietic lineages (erythrocyte, megakaryocyte, and leukocyte). Red cell production was virtually abolished, while megakaryocyte production was greatly enhanced. Leukocyte production transiently decreased and then recovered. Stem and progenitor cell numbers were preserved, and Gmnn–/– HSCs successfully reconstituted hematopoiesis in irradiated mice. CD34+Gmnn–/– leukocyte precursors displayed DNA overreplication and formed extremely small granulocyte and monocyte colonies in methylcellulose. While cultured Gmnn–/– megakaryocyte-erythrocyte precursors did not form erythroid colonies, they did form greater than normal numbers of megakaryocyte colonies. Gmnn–/– megakaryocytes and erythroblasts had normal DNA content. These data led us to postulate that Geminin regulates the relative production of erythrocytes and megakaryocytes from megakaryocyte-erythrocyte precursors by a replication-independent mechanism.
Primary plasma cell leukemia: Report of 17 new cases treated with autologous or allogeneic stem‐cell transplantation and review of the literature
Authors: Steven Saccaro, Rafael Fonseca, Diana M. Veillon, James Cotelingam, Mary L. Nordberg, Christopher Bredeson, Jonathan Glass, Reinhold Munker
Journal: American Journal of Hematology (2005)

Abstract Primary plasma cell leukemia (PPCL) is a rare hematologic malignancy characterized by the proliferation of plasma cells in blood, bone marrow, and other organs in the absence of established multiple myeloma. PPCL has a poor prognosis when treated with conventional therapy for multiple myeloma. We describe here 17 new cases of PPCL who underwent stem‐cell transplantation (SCT) (2 cases observed by the authors and 15 cases from the International Bone Marrow Transplant Registry [IBMTR]). The first case was diagnosed in a 21‐year‐old male who presented with leukocytosis and acute renal failure. He was treated with hyper‐CVAD, entered complete remission, and then proceeded to high‐dose chemotherapy with peripheral stem‐cell support. He is currently in complete remission 23 months after initial diagnosis and 19 months after autologous SCT. The second case was observed in a 31‐year‐old male who presented with leukocytosis and hepatic infiltration with plasma cells. He was treated with VAD chemotherapy and underwent allogeneic bone marrow transplantation from his HLA‐identical sister. He remained in complete remission for 3 years and then developed progressive refractory disease, dying 7 years after the initial diagnosis. In addition to these 2 cases, 15 further unpublished cases of PPCL from the IBMTR are reported here (treated between 1993 and 2001, 6 by autologous and 9 by allogeneic transplantation). Finally, the features of PPCL, the outcome, published data of SCT for PPCL, and indications for treatment are discussed. Am. J. Hematol. 78:288–294, 2005. © 2005 Wiley‐Liss, Inc.
Vasoconstrictor Effect of the Angiotensin-Converting Enzyme–Resistant, Chymase-Specific Substrate [Pro <sup>11</sup> <sub>D</sub> -Ala <sup>12</sup> ] Angiotensin I in Human Dorsal Hand Veins
Authors: John E. McDonald, Neal Padmanabhan, Mark C. Petrie, Chris Hillier, John M.C. Connell, John J.V. McMurray
Journal: Circulation (2001)

Background [Pro 11 D -Ala 12 ] angiotensin I is an ACE-resistant substrate specific for chymase. We used this peptide to determine whether a functionally significant non-ACE angiotensin (Ang) II–generating pathway exists in human dorsal hand veins. Methods and Results Using a modified Aellig technique, we studied the response to Ang I and [Pro 11 D -Ala 12 ] Ang I in dorsal hand veins in vivo in patients with coronary heart disease. We measured the venoconstrictor effect of each peptide given before and after a 6.25-mg oral dose of the ACE inhibitor captopril or matching placebo. Placebo or captopril was given in a double-blind, randomized fashion. Ang I induced a mean±SEM venoconstrictor response of 45±11%, 40±10%, 55±8%, and 4±4% before placebo, after placebo, before captopril, and after captopril, respectively. Hence, the response to Ang I was reproducible and was reduced significantly only after treatment with captopril ( P =0.002). [Pro 11 D -Ala 12 ] Ang I induced a mean venoconstrictor response of 42±9%, 49±9%, 48±10%, and 54±11% before placebo, after placebo, before captopril, and after captopril, respectively. Hence, captopril had no significant effect on the response to [Pro 11 D -Ala 12 ] Ang I. Conclusions We have demonstrated that [Pro 11 D -Ala 12 ] Ang I is able to induce venoconstriction in humans in vivo. With this specific pharmacological probe, we have shown that a non-ACE pathway capable of generating Ang II exists in human veins in vivo and is potentially functionally important. This pathway is likely to involve the enzyme chymase.
Inhibition of adrenergic vasoconstriction by endothelial cell shear stress.
Authors: B Tesfamariam, R A Cohen
Journal: Circulation Research (1988)

Isolated perfused rabbit carotid arteries were used to determine the effects of endothelial cell shear stress on the response to adrenergic nerve stimulation. Arterial segments with and without endothelium were cannulated and perfused with physiological salt solution. Adrenergic nerves were activated by transmural electrical field stimulation. Neurogenic vasoconstriction was significantly greater in segments without endothelium when compared with that of segments with endothelium. In segments with endothelium only, vasoconstriction was depressed when shear stress was increased by increasing the viscosity of the perfusate with dextran. Perfusion with methylene blue (2 X 10(-6) M), a guanylate cyclase inhibitor, increased vasoconstriction in segments with endothelium only. In the presence of methylene blue, vasoconstriction was no longer different between segments with and without endothelium, and perfusion with dextran had no effect. In a perfusion-cascade system, perfusion with dextran of donor segments with but not without endothelium caused further relaxation of a contracted bioassay ring. These results suggest that shear stress on endothelial cells modulates adrenergic vasoconstriction by augmenting release of endothelial cell-derived vasodilators.
Cord blood angiogenic progenitor cells are decreased in bronchopulmonary dysplasia
Authors: Christopher D. Baker, Vivek Balasubramaniam, Peter M. Mourani, Marci K. Sontag, Claudine P. Black, Sharon L. Ryan, Steven H. Abman
Journal: European Respiratory Journal (2012)

Bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, is associated with impaired vascular and alveolar growth. Antenatal factors contribute to the risk for developing BPD by unclear mechanisms. Endothelial progenitor cells, such as angiogenic circulating progenitor cells (CPCs) and late-outgrowth endothelial colony-forming cells (ECFCs), may contribute to angiogenesis in the developing lung. We hypothesise that cord blood angiogenic CPCs and ECFCs are decreased in preterm infants with moderate and severe BPD. We quantified ECFCs and the CPC/nonangiogenic-CPC ratio (CPC/non-CPC) in cord blood samples from 62 preterm infants and assessed their relationships to maternal and perinatal risk factors as well as BPD severity. The CPC/non-CPC ratio and ECFC number were compared between preterm infants with mild or no BPD and those with moderate or severe BPD. ECFC number (p&lt;0.001) and CPC/non-CPC ratio (p&lt;0.05) were significantly decreased in cord blood samples of preterm infants who subsequently developed moderate or severe BPD. Gestational age and birth weight were not associated with either angiogenic marker. Circulating vascular progenitor cells are decreased in the cord blood of preterm infants who develop moderate and severe BPD. These findings suggest that prenatal factors contribute to late respiratory outcomes in preterm infants.
CXCR2 Promotes Ovarian Cancer Growth through Dysregulated Cell Cycle, Diminished Apoptosis, and Enhanced Angiogenesis
Authors: Gong Yang, Daniel G. Rosen, Guangzhi Liu, Fan Yang, Xiaoqing Guo, Xue Xiao, Fengxia Xue, Imelda Mercado-Uribe, Jiaoti Huang, Sue-Hwa Lin, Gordon B. Mills, Jinsong Liu
Journal: Clinical Cancer Research (2010)

Chemokine receptor CXCR2 is associated with malignancy in several cancer models; however, the mechanisms involved in CXCR2-mediated tumor growth remain elusive. Here, we investigated the role of CXCR2 in human ovarian cancer.CXCR2 expression was silenced by stable small hairpin RNA in ovarian cancer cell lines T29Gro-1, T29H, and SKOV3. Western blotting, immunofluorescence, enzyme-linked immunosorbent assay, flow cytometry, electrophoretic mobility shift assay, and mouse assay were used to detect CXCR2, interleukin-8, Gro-1, cell cycle, apoptosis, DNA binding of NF-kappaB, and tumor growth. Immunohistochemical staining of CXCR2 was done in 240 high-grade serous ovarian carcinoma samples.Knockdown of CXCR2 expression by small hairpin RNA reduced tumorigenesis of ovarian cancer cells in nude mice. CXCR2 promoted cell cycle progression by modulating cell cycle regulatory proteins, including p21 (waf1/cip1), cyclin D1, CDK6, CDK4, cyclin A, and cyclin B1. CXCR2 inhibited cellular apoptosis by suppressing phosphorylated p53, Puma, and Bcl-xS; suppressing poly(ADP-ribose) polymerase cleavage; and activating Bcl-xL and Bcl-2. CXCR2 stimulated angiogenesis by increasing levels of vascular endothelial growth factor and decreasing levels of thrombospondin-1, a process likely involving mitogen-activated protein kinase, and NF-kappaB. Overexpression of CXCR2 in high-grade serous ovarian carcinomas was an independent prognostic factor of poor overall survival (P < 0.001) and of early relapse (P = 0.003) in the univariate analysis.Our data provide strong evidence that CXCR2 regulates the cell cycle, apoptosis, and angiogenesis through multiple signaling pathways, including mitogen-activated protein kinase and NF-kappaB, in ovarian cancer. CXCR2 thus has potential as a therapeutic target and for use in ovarian cancer diagnosis and prognosis.
When the next influenza pandemic comes
Authors: R T M. White
Journal: BMJ (1997)

An influenza virus may emerge against which most people in the world have no immunity. This will be the next influenza pandemic, with high attack rates in all ages, a risk of high death rates, and a heavy burden on health services. It is prudent to prepare for such a pandemic, particularly if there are actions that could prevent or reduce severe morbidity. At an international meeting in Washington in 1995, countries from around the world met to discuss their plans of attack.

Britain's health departments have now published their plans,1 revealing as much about the convoluted organisation of health services as about the epidemiology of influenza. The plans concentrate on the actions of central agencies, as a framework on which health authorities and trusts should make local plans. When most people working at the local level in the NHS are struggling with the existing workload and budgetary constraints, it is tempting to shy away from preparing for an influenza pandemic.

Previous pandemics have been due to influenza A viruses and have occurred at irregular intervals: 1889, 1918, 1957, and …
Sensory Deficits and Distributed Hierarchical Dysfunction in Schizophrenia
Authors: David I. Leitman, Pejman Sehatpour, Beth A. Higgins, John J. Foxe, Gail Silipo, Daniel C. Javitt
Journal: American Journal of Psychiatry (2010)

Schizophrenia is characterized by widespread cognitive deficits that reflect distributed dysfunction across multiple cortical regions. Here the authors examined the relationship between lower- and higher-level dysfunction within the auditory domain using the event-related brain potentials mismatch negativity (MMN) and P300.Event-related brain potentials were obtained from 50 schizophrenia patients and 21 healthy subjects in two conditions: a standard condition employing fixed differences between standard tones and pitch deviants and a novel individualized condition employing tones matched to each individual's tone-discrimination threshold. The relationship among measures was assessed by multiple regression analysis and structural equation modeling.In the standard fixed-deviance condition, schizophrenia patients showed deficits of large effect size in generation of MMN (d>1.26) and P300 (d=1.08) relative to comparison subjects. Assessment of deviance-detection thresholds showed that patients required significantly elevated tone-matching thresholds relative to comparison subjects (d=0.97). When tone differences were individually adjusted to equate tone-matching performance across groups, the groups no longer differed significantly in MMN amplitude during deviant pitch tones, and the degree of deficit in P300 generation was significantly reduced. In both multiple regression analysis and structural equation modeling, MMN and diagnostic group were significant independent predictors of reduced P300 amplitude. MMN generation was well explained (>90% variance) by dipoles seeded within the bilateral auditory cortex.These findings confirm and extend previous reports of impaired basic sensory processing in schizophrenia and demonstrate significant contributions of early sensory processing dysfunction to higher-order cognitive impairments. Overall, the findings support distributed, hierarchical models of cognitive impairment in schizophrenia, consistent with glutamatergic and other widespread neurochemical models of the disorder.
Elevated Soluble Tumor Necrosis Factor Receptor 75 Concentrations Identify Patients With Liver Cirrhosis at Risk of Death
Authors: Frank Grünhage, Bettina Rezori, Markus Neef, Frank Lammert, Tilman Sauerbruch, Ulrich Spengler, Christoph Reichel
Journal: Clinical Gastroenterology and Hepatology (2008)
Immunopathogenesis of Libman-Sacks endocarditis. Assessment by light and immunofluorescent microscopy in two patients.
Authors: R F Shapiro, C N Gamble, K B Wiesner, J J Castles, A W Wolf, E J Hurley, A F Salel
Journal: Annals of the Rheumatic Diseases (1977)

The possible contribution of immunological mechanisms in the development of Libman-Sacks endocarditis was studied in 2 patients with systemic lupus erythematosus who underwent aortic valve replacement. Sections of verrucous lesions, stained with haematoxylin and eosin, showed three apparently distinct zones: an outer exudative zone of fibrin, nuclear debris, and haematoxylin-stained bodies; a middle organizing zone of proliferating capillaries and fibroblasts; and an inner zone of neovascularization which showed distinct, thin-walled junctional vessels. The striking finding was the apparently selective deposition of immunoglobulins and complement identified by direct immunofluorescence, within the walls of the small junctional vessels of the zone of neovascularization. We suggest that the observed immune deposits are immune complexes and that circulating immune complexes may play a critical role in the growth and proliferation of the verrucous lesion.
Divergence Population Genetics of Chimpanzees
Authors: Y.-J. Won
Journal: Molecular Biology and Evolution (2004)

The divergence of two subspecies of common chimpanzees (Pan troglodytes troglodytes and P. t. verus) and the bonobo (P. paniscus) was studied using a recently developed method for analyzing population divergence. Under the isolation with migration model, the posterior probability distributions of divergence time, migration rates, and effective population sizes were estimated for large multilocus DNA sequence data sets drawn from the literature. The bonobo and the common chimpanzee are estimated to have diverged approximately 0.86 to 0.89 MYA, and the divergence of the two common chimpanzee subspecies is estimated to have occurred 0.42 MYA. P. t. troglodytes appears to have had a larger effective population size (22,400 to 27,900) compared with P. paniscus, P. t. verus, and the ancestral populations of these species. No evidence of gene flow was found in the comparisons involving P. paniscus; however a clear signal of unidirectional gene flow was found from P. t. verus to P. t. troglodytes (2Nm = 0.51).
Fees for Life Insurance Examinations
Authors: P. Ransome-Wallis
Journal: BMJ (1970)

MEDIAJONAL 497 sider treating the depression, both by anti- depressives and removing the cause.Possibly family doctors, with their knowledge of the whole patient and her environment, have the advantage over both clinic doctors and gynaecologists.To sum up, I feel that in any future study of this problem, factors such as past medical and psychiatric history, parity and continuing social, family, and financial his- tory must be taken into account, which is why the whole business is so difficult.-Iam, etc., K. L. OLDERSHAW.London S.E.15"Signs of Rain" SIR,-In the summer of 1957 there was a discussion in your correspondence columns about the authorship of that delightful little poem "Signs of Rain."I wrote in favour of Jenner and offered to send a copy to any- one interested.'To my astonishment I had letters from nearly two hundred doctors, mainly from abroad, from California to Australia.
Parachute deformity of the tricuspid valve.
Authors: S Milo, J Stark, F J Macartney, R H Anderson
Journal: Thorax (1979)

A parachute deformity of the tricuspid valve occurred in a heart with atrioventricular concordance, double outlet right ventricle, and straddling mitral valve. Although to the best of our knowledge parachute deformity of the tricuspid valve has not previously been reported, in this case its presence was insignificant in relation to the other lesions.
Comparison of the in vitro performance of originator and generic drug-combination dry powder inhalers
Authors: Naomi Teekamp, Paul Hagedoorn, Bernard G. Huijbers, Doetie Gjaltema, Henderik W. Frijlink, Anne H. De Boer
Journal: European Respiratory Journal (2013)

Rationale: Efficacy of inhalation therapy is dependent on device performance and drug choice. To reach intended sites of action in the airways, inhaled drug particles must have optimal aerodynamic size distribution, adjusted to the delivery flow rate. For dry powder inhalers (DPIs), the critical factors are the inhaler resistance and the fine particle fraction (FPF) of the delivered dose. These can vary, depending on the device characteristics. However, because of different test conditions, the few studies available on the aerosol properties of different inhalers are often not comparable.

Methods: In order to investigate different device properties, the in vitro performance of three combination inhalers (two originator, Symbicort® Turbuhaler® [S-TBH] and Seretide® Diskus® [S-D], and one generic, Rolenium® Elpenhaler® [R-E]) were compared at 2, 4 and 6 kPa, under the same test conditions.

Results: Flow rates at 4 kPa varied between 59 L/min (S-TBH) and 69 L/min (R-E). Delivered doses and FPF (both as % of label claim) varied considerably more. At 4 kPa, the delivered doses of the inhaled corticosteroid (ICS) component were 95% (S-TBH), 87% (SD) and 85% (R-E). FPFs <5µm (and 1–3µm) for ICS were 51% (30%) for S-TBH, 23% (13%) for S-D and 16% (6%) for R-E. FPFs and delivered doses of the β-agonist components of S-TBH and S-D were slightly lower than the corresponding values for the ICS component, but not in the case of R-E.

Conclusions: This study shows that different DPIs deliver significantly different FPFs (by a factor 2-3; S-TBH > S-D > R-E) with different flow rates at the same inhalation effort, which may have clinical implications in terms of drug distribution in the airways.
A role for IgG immune complexes during infection with the intracellular pathogen <i>Leishmania </i>
Authors: Suzanne A. Miles, Sean M. Conrad, Renata G. Alves, Selma M.B. Jeronimo, David M. Mosser
Journal: The Journal of Experimental Medicine (2005)

We examined the role of immunoglobulin (Ig)G antibodies in mediating host defense to the intracellular parasite, Leishmania. We show that IgG not only fails to provide protection against this intracellular pathogen, but it actually contributes to disease progression. The JH strain of BALB/c mice, which lack IgG because they have a targeted deletion in the Ig heavy chain (J) locus, were more resistant to infection with Leishmania major than were normal BALB/c mice. However, the passive administration of anti-Leishmania IgG caused JH mice to develop large lesions containing high numbers of parasites. Antibody administration correlated with an increase in interleukin (IL) 10 production in lesions, and blocking the murine IL-10 receptor prevented antibody-mediated disease exacerbation. In human patients with active visceral leishmaniasis, high IgG levels are predictive of disease. Patients with ongoing disease had high IgG antibody titers and no delayed-type hypersensitivity (DTH) responses to Leishmania antigens. This pattern was reversed upon disease resolution after treatment, resulting in a decrease in total IgG, which was accompanied by a progressive increase in DTH responsiveness. We conclude that IgG can cause a novel form of immune enhancement due to its ability to induce IL-10 production from macrophages.