tbuckley/cabot-search huggingface dataset:
Ca2+ channel kinetics in acutely isolated fetal, neonatal, and adult rabbit cardiac myocytes.
Authors: G T Wetzel, F Chen, T S Klitzner
Journal: Circulation Research (1993)

Measurement of transsarcolemmal voltage-gated Ca2+ current (ICa) in myocytes isolated from immature rabbit heart has demonstrated an unexpectedly low level of Ca2+ channel activity. We have characterized the kinetic properties of ICa in acutely isolated 21-day fetal, 1-5-day-old neonatal, and adult cardiac myocytes by the whole-cell voltage-clamp technique. The membrane potential for half-maximal steady-state inactivation became less negative with maturation (-24 +/- 3 [mean +/- SEM] mV, n = 5; -19 +/- 2 mV, n = 5; and -11 +/- 2 mV, n = 6 for fetal, neonatal, and adult myocytes, respectively; p &lt; 0.005). In contrast, the membrane potential for half-maximal steady-state activation was not statistically different among the age groups studied. These parameters accurately predicted the voltage dependence of the sustained ICa present at the end of a 400-msec depolarization. This "window" current was significantly smaller in immature cells than in adult cells and occurred at a more negative membrane potential in the younger age groups. The time course of inactivation of ICa was not significantly different between age groups. However, ICa was inhibited by increasing the frequency of stimulation. This effect was most prominent in immature cells, particularly at more positive holding potentials. This developmental alteration in the frequency dependence of ICa was due in part to a prolonged time constant of recovery from inactivation in the younger age groups. In summary, the kinetic properties of ICa in immature cardiac cells place them at a relative disadvantage in terms of the total Ca2+ influx during a depolarization. Thus, the role of ICa in the control of cell contraction may change with development.
TGF- receptor II in epithelia versus mesenchyme plays distinct roles in the developing lung
Authors: H. Chen, F. Zhuang, Y-H. Liu, B. Xu, P. del Moral, W. Deng, Y. Chai, M. Kolb, J. Gauldie, D. Warburton, H. L. Moses, W. Shi
Journal: European Respiratory Journal (2008)

Transforming growth factor (TGF)-beta signalling plays important roles in regulating lung development. However, the specific regulatory functions of TGF-beta signalling in developing lung epithelial versus mesenchymal cells are still unknown. By immunostaining, the expression pattern of the TGF-beta type II receptor (TbetaRII) was first determined in the developing mouse lung. The functions of TbetaRII in developing lung were then determined by conditionally knocking out TbetaRII in the lung epithelium of floxed-TbetaRII/surfactant protein C-reverse tetracycline transactivator/TetO-Cre mice versus mesenchyme of floxed-TbetaRII/Dermo1-Cre mice. TbetaRII was expressed only in distal airway epithelium at early gestation (embryonic day (E)11.5), but in both airway epithelium and mesenchyme from mid-gestation (E14.5) to post-natal day 14. Abrogation of TbetaRII in mouse lung epithelium resulted in retardation of post-natal lung alveolarisation, with markedly decreased type I alveolar epithelial cells, while no abnormality in prenatal lung development was observed. In contrast, blockade of TbetaRII in mesoderm-derived tissues, including lung mesenchyme, resulted in mildly abnormal lung branching and reduced cell proliferation after mid-gestation, accompanied by multiple defects in other organs, including diaphragmatic hernia. The primary lung branching defect was verified in embryonic lung explant culture. The novel findings of the present study suggest that transforming growth factor-beta type II receptor-mediated transforming growth factor-beta signalling plays distinct roles in lung epithelium versus mesenchyme to differentially control specific stages of lung development.
Assessment of IAP (inhibitor of apoptosis) proteins as predictors of response to chemotherapy in advanced non-small-cell lung cancer patients
Authors: C.G. Ferreira, P. van der Valk, S.W. Span, J.M. Jonker, P.E. Postmus, F.A.E. Kruyt, G. Giaccone
Journal: Annals of Oncology (2001)
THE OBSESSIONAL PERSONALITY AND OBSESSIONAL ILLNESS
Authors: I. M. INGRAM
Journal: American Journal of Psychiatry (1961)

An examination of premorbid personality in 77 inpatients with severe obsessional states shows that obsessional personality and illness are intimately connected and that the conventional obsessional traits, present in 84% of the group, justify their general acceptance when re-examined in their original setting. The description by Lewis of "obstinate, morose, irritable" and "submissive, vacillating, uncertain" types was applicable in only 39%, but the results suggest that certain obsessional traits may predispose to obsessional illness more than others.
Inhibition of the metabolism of endogenous retinoic acid as treatment for severe psoriasis: an open study with oral liarozole
Authors: P. DOCKX, J. DECREE, H. DKGREEF
Journal: British Journal of Dermatology (1995)

Retinoids derived from retinol or beta‐carotene are inactivated, among other ways, by enzymes belonging to the P450 cytochrome group. Liarozole, an Lmidazole‐containing compound, is known to be a potenl inhibitor of the cytochrome P450‐mediated metabolism of all‐trans retinoic acid. As a result, increased levels of this retinoid are found in skin and plasma. Therefore, in the treatment of psoriasis, therapeutic effects may be expected with liarozole which are similar to those observed with synthetic retinoids. In an open study, oral liarozole was given at a daily dose of 75 mg b.i.d., for 12 weeks to 31 patients with severe psoriasis. After 1 month, this dosage could be increased to 150 mg b.i.d. if there was no Improvement or only moderate improvement. Initially, the effect of liarozole was mainly on scaling. A decrease in the Psoriasis Area and Severity Index (PASI) score of 45% at week 4. of 69% at week 8 and of 77% at week 12 was obtained, compared with baseline. A further decrease in the PASl score of up to 87% was observed in the 16 patients who were allowed to continue treatment for a maximum period of 12 months. An excellent or good improvement was noted in 77% of the patients within 12 weeks of starting treatment. This response rate had increased to 88% by the last follow‐up visit. Nearly all patients (29 of 31) experienced adverse reactions, such as dry oral mucosa. headache and itching. These were mostly mild and transient, but four patients dropped out of the study because of an adverse event. Haematological. biochemical and cardiovascular parameters were not significantly influenced by liarozole. Six patients showed an increase in triglycerides. which normalized in three of four patients during further treatment. The results of this pilot study suggest that, at doses of 75–150mg b.i.d., liarozole is an active antipsoriatic drug, and may be a useful addition to the existing therapeutic armamentarium. Controlled studies should be performed to compare liarozole with standard oral treatments.
Effects of Vagus Stimulation and of Acetylcholine on Myocardial Contractility, O <sub>2</sub> Consumption and Coronary Flow in Dogs
Authors: GÜNTHER L. SCHREINER, ERIK BERGLUND, HANS G. BORST, ROBERT G. MONROE
Journal: Circulation Research (1957)

During vagus nerve stimulation the heart rate was maintained at a constant level by an electric pacemaker. Under these conditions no changes were found in ventricular function curves, myocardial oxygen consumption and coronary blood flow. Acetylcholine infusion, with heart rate maintained constant, caused decreased myocardial contractility and coronary and peripheral vasodilation.
α <sub>v</sub> β <sub>3</sub> Integrin Induces Tyrosine Phosphorylation–Dependent Ca <sup>2+</sup> Influx in Pulmonary Endothelial Cells
Authors: Sunita Bhattacharya, Xiaoyou Ying, Chenzhong Fu, Rashmi Patel, Wolfgang Kuebler, Steven Greenberg, Jahar Bhattacharya
Journal: Circulation Research (2000)

The endothelial alpha(v)beta(3) integrin occurs luminally, where its ligation by soluble agents may induce inflammatory signaling. We tested this hypothesis in bovine pulmonary artery endothelial cell monolayers with the use of vitronectin and cross-linking antibodies to ligate and aggregate the integrin. We quantified the endothelial cytosolic Ca(2+) concentration ([Ca(2+)](i)) according to the Fura 2 ratio imaging method in single cells of confluent monolayers. At baseline, endothelial [Ca(2+)](i) levels remained steady at 86 nmol/L for >20 minutes. Cross-linking of the alpha(v)beta(3) integrin through the sequential exposure of monolayers to anti-alpha(v)beta(3) monoclonal antibody LM609 and secondary IgG resulted in a [Ca(2+)](i) increase of 100% above baseline. This increase commenced in <0.5 minute, peaked in <2 minutes, and decayed to baseline in approximately 5 minutes. Similar responses occurred after the addition of vitronectin (400 microg/mL). In contrast, external Ca(2+) depletion blunted the cross-linking-induced [Ca(2+)](i) increase by 60%, a response that was completely inhibited when the monolayers were also pretreated with thapsigargin. Thus, the [Ca(2+)](i) increase was attributable in part to the release of Ca(2+) from endosomal stores but mostly to Ca(2+) influx across the plasma membrane. Induced aggregation of the alpha(v)beta(3) integrin enhanced tyrosine phosphorylation of phospholipase C-gamma1 and increased the accumulation of inositol-1, 4,5-trisphosphate. Genistein, a broad-spectrum tyrosine kinase inhibitor, abrogated both of these effects, as well as the alpha(v)beta(3)-induced [Ca(2+)](i) increases. We conclude that aggregation of the endothelial alpha(v)beta(3) integrin induces a rapid tyrosine phosphorylation-dependent increase in [Ca(2+)](i). This response may subserve the inflammatory role of alpha(v)beta(3) integrin in blood vessels.
Doctors call for head of World Medical Association to quit as “matter of priority”
Authors: Zosia Kmietowicz
Journal: BMJ (2009)

More than 700 doctors from around the world have called for the Israeli president of the World Medical Association to step down, calling him “unfit for office” and claiming that he has turned a blind eye to the “institutionalised involvement of doctors” in torture in Israel.

In a letter they say that the appointment of Yoram Blachar, president of the Israeli Medical Association since 1995, as president of the World Medical Association last November is “a matter of grave concern.” The signatories, who include professors and doctors from 43 countries, say that the appointment “makes a mockery of the principles on which the WMA was founded in 1947, which was a response to egregious abuses by Germany and Japan in World War Two.”

The letter, addressed to Edward Hill, chairman of the World Medical Association’s council, and to the council body, was sent by the lead signatory, Alan Meyers, assistant professor of paediatrics at Boston University, on 21 May. It lists numerous reports …
Risk of major cardiovascular events in patients with psoriatic arthritis, psoriasis and rheumatoid arthritis: a population-based cohort study
Authors: Alexis Ogdie, YiDing Yu, Kevin Haynes, Thorvardur Jon Love, Samantha Maliha, Yihui Jiang, Andrea B Troxel, Sean Hennessy, Steven E Kimmel, David J Margolis, Hyon Choi, Nehal N Mehta, Joel M Gelfand
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Objectives</h3> We aimed to quantify the risk of major adverse cardiovascular events (MACE) among patients with psoriatic arthritis (PsA), rheumatoid arthritis (RA) and psoriasis without known PsA compared with the general population after adjusting for traditional cardiovascular risk factors. <h3>Methods</h3> A population-based longitudinal cohort study from 1994 to 2010 was performed in The Health Improvement Network (THIN), a primary care medical record database in the UK. Patients aged 18–89 years of age with PsA, RA or psoriasis were included. Up to 10 unexposed controls matched on practice and index date were selected for each patient with PsA. Outcomes included cardiovascular death, myocardial infarction, cerebrovascular accidents and the composite outcome (MACE). Cox proportional hazards models were used to calculate the HRs for each outcome adjusted for traditional risk factors. A priori, we hypothesised an interaction between disease status and disease-modifying antirheumatic drug (DMARD) use. <h3>Results</h3> Patients with PsA (N=8706), RA (N=41 752), psoriasis (N=138 424) and unexposed controls (N=81 573) were identified. After adjustment for traditional risk factors, the risk of MACE was higher in patients with PsA not prescribed a DMARD (HR 1.24, 95% CI 1.03 to 1.49), patients with RA (No DMARD: HR 1.39, 95% CI 1.28 to 1.50, DMARD: HR 1.58, 95% CI 1.46 to 1.70), patients with psoriasis not prescribed a DMARD (HR 1.08, 95% CI 1.02 to 1.15) and patients with severe psoriasis (DMARD users: HR 1.42, 95% CI 1.17 to 1.73). <h3>Conclusions</h3> Cardiovascular risk should be addressed with all patients affected by psoriasis, PsA or RA.
Meta-Analysis: Convalescent Blood Products for Spanish Influenza Pneumonia: A Future H5N1 Treatment?
Authors: Thomas C. Luke, Edward M. Kilbane, Jeffrey L. Jackson, Stephen L. Hoffman
Journal: Annals of Internal Medicine (2006)

Background: Studies from the Spanish influenza era reported that transfusion of influenza-convalescent human blood products reduced mortality in patients with influenza complicated by pneumonia. Treatments for H5N1 influenza are unsatisfactory, and convalescent human plasma containing H5N1 antibodies could be an effective therapy during outbreaks and pandemics. Purpose: To determine whether transfusion with influenza-convalescent human blood products reduced the risk for death in patients with Spanish influenza pneumonia. Data Sources: Manual search of English-language journals from 1918 to 1925. Citations from retrieved studies were also searched. Study Selection: Published English-language studies that had at least 10 patients in the treatment group, used convalescent blood products to treat Spanish influenza pneumonia in a hospital setting, and reported on a control or comparison group. Data Extraction: Two investigators independently extracted data on study characteristics, outcomes, adverse events, and quality. Data Synthesis: Eight relevant studies involving 1703 patients were found. Treated patients, who were often selected because of more severe illness, were compared with untreated controls with influenza pneumonia in the same hospital or ward. The overall crude case-fatality rate was 16% (54 of 336) among treated patients and 37% (452 of 1219) among controls. The range of absolute risk differences in mortality between the treatment and control groups was 8% to 26% (pooled risk difference, 21% [95% CI, 15% to 27%]). The overall crude case-fatality rate was 19% (28 of 148) among patients who received early treatment (after <4 days of pneumonia complications) and 59% (49 of 83) among patients who received late treatment (after ≥4 days of pneumonia complications). The range of absolute risk differences in mortality between the early treatment group and the late treatment group was 26% to 50% (pooled risk difference, 41% [CI, 29% to 54%]). Adverse effects included chill reactions and possible exacerbations of symptoms in a few patients. Limitations: Studies were few and had many methodologic limitations. No study was a blinded, randomized, or placebo-controlled trial. Some pertinent studies may have been missed. Conclusions: Patients with Spanish influenza pneumonia who received influenza-convalescent human blood products may have experienced a clinically important reduction in the risk for death. Convalescent human H5N1 plasma could be an effective, timely, and widely available treatment that should be studied in clinical trials.
Deletion of autospecific T cells in T cell receptor (TCR) transgenic mice spares cells with normal TCR levels and low levels of CD8 molecules.
Authors: H S Teh, H Kishi, B Scott, H Von Boehmer
Journal: The Journal of Experimental Medicine (1989)

Transgenic mice that carry on a large fraction of their T cells an alpha/beta T cell receptor that recognizes the male antigen in the context of H-2Db molecules were constructed. An mAb specific for the transgenic receptor was developed and used to analyze T cell subsets in male transgenic H-2b mice. The vast majority of immature CD4+8+ T cells that express the transgenic TCR were deleted in the male transgenic mouse. Nevertheless, the majority of T cells spared by this deletion process expressed a high level of the transgenic TCR. These T cells, however, had an abnormal CD4/CD8 phenotype in that they expressed either no CD8 molecules or only low levels.
Translational Induction of VEGF Internal Ribosome Entry Site Elements During the Early Response to Ischemic Stress
Authors: Stéphanie Bornes, Leonel Prado-Lourenco, Amandine Bastide, Catherine Zanibellato, Jason S. Iacovoni, Eric Lacazette, Anne-Catherine Prats, Christian Touriol, Hervé Prats
Journal: Circulation Research (2007)

Vascular endothelial growth factor-A (VEGF), a powerful factor involved in vasculogenesis and angiogenesis, is translationally regulated through 2 independent internal ribosome entry sites (IRESs A and B). IRESs enable an mRNA to be translated under conditions in which 5′-cap–dependent translation is inhibited, such as low oxygen stress. In the VEGF mRNA, IRES A influences translation at the canonical AUG codon, whereas the 5′ IRES B element regulates initiation at an upstream, in frame CUG. In this study, we have developed transgenic mice expressing reporter genes under the control of these 2 IRESs. We reveal that although these IRESs display low activity in embryos and adult tissues, they permit efficient translation at early time points in ischemic muscle, a stress under which cap-dependent translation is inhibited. These results demonstrate the in vivo efficacy of the VEGF IRESs in response to a local environmental stress such as hypoxia.
Phase I Trial of Preoperative Chemoradiation plus Sorafenib for High-Risk Extremity Soft Tissue Sarcomas with Dynamic Contrast-Enhanced MRI Correlates
Authors: Janelle M. Meyer, Kelly S. Perlewitz, James B. Hayden, Yee-Cheen Doung, Arthur Y. Hung, John T. Vetto, Rodney F. Pommier, Atiya Mansoor, Brooke R. Beckett, Alina Tudorica, Motomi Mori, Megan L. Holtorf, Aneela Afzal, William J. Woodward, Eve T. Rodler, Robin L. Jones, Wei Huang, Christopher W. Ryan
Journal: Clinical Cancer Research (2013)

Abstract Purpose: We conducted a phase I trial of the addition of sorafenib to a chemoradiotherapy regimen in patients with high-risk (intermediate/high grade, &amp;gt;5 cm) extremity soft tissue sarcoma undergoing limb salvage surgery. We conducted a correlative study of quantitative dynamic contrast-enhanced MRI (DCE-MRI) to assess response to treatment. Experimental Design: Patients were treated at increasing dose levels of sorafenib (200 mg daily, 400 mg daily, 400 mg twice daily) initiated 14 days before three preoperative and three postoperative cycles of epirubicin/ifosfamide. Radiation (28 Gy) was administered during cycle 2 with epirubicin omitted. The primary objective was to determine the maximum tolerated dose (MTD) of sorafenib. DCE-MRI was conducted at baseline, after 2 weeks of sorafenib, and before surgery. The imaging data were subjected to quantitative pharmacokinetic analyses. Results: Eighteen subjects were enrolled, of which 16 were evaluable. The MTD of sorafenib was 400 mg daily. Common grade 3–4 adverse events included neutropenia (94%), hypophosphatemia (75%), anemia (69%), thrombocytopenia (50%), and neutropenic fever/infection (50%). Of note, 38% developed wound complications requiring surgical intervention. The rate of ≥95% histopathologic tumor necrosis was 44%. Changes in DCE-MRI biomarker ΔKtrans after 2 weeks of sorafenib correlated with histologic response (R2 = 0.67, P = 0.012) at surgery. Conclusion: The addition of sorafenib to preoperative chemoradiotherapy is feasible and warrants further investigation in a larger trial. DCE-MRI detected changes in tumor perfusion after 2 weeks of sorafenib and may be a minimally invasive tool for rapid assessment of drug effect in soft tissue sarcoma. Clin Cancer Res; 19(24); 6902–11. ©2013 AACR.
Dynamic Changes of the Total Pore Area Available for Peritoneal Exchange in Children
Authors: MICHEL FISCHBACH, BO[Combining Diaeresis]RJE HARALDSSON
Journal: Journal of the American Society of Nephrology (2001)

Abstract. The most important of the parameters that describe exchange across the peritoneal membrane is the total pore area over diffusion distance (A 0 /Δx). It determines the rate of diffusion and mainly seems to reflect the number of capillaries available for exchange. In the present study, a simplified three-pore analysis was used to estimate A 0 /Δx from peritoneal equilibration tests. Two groups of children (mean age, 9.5 yr) who were on chronic peritoneal dialysis underwent studies with peritoneal equilibration tests. In the first group of children, three levels of fill volumes were used in each patient. In the second group of patients, the effects of posture and dwell time were analyzed from four consecutive peritoneal dialysis samples obtained after 15, 30, 60, and 90 min. As the fill volume was raised from 800 to 1400 ml/m 2 BSA, the steady-state A 0 /Δx increased significantly by 21%, i.e. , from 19,900 ± 1200 to 24,000 ± 1450 cm 2 /cm per 1.73 m 2 ( n = 8). A further increase to 2000 ml/m 2 did not result in any change of A 0 /Δx. Moreover, steady-state A 0 /Δx fell significantly when the patients were standing, 21,900 ± 1400 compared with 29,400 ± 1330 cm 2 /cm per 1.73m 2 ( n = 6) obtained in the supine position. There was a transient (&lt;30 min) increase in A 0 /Δx initially during the dwell, probably reflecting vasodilation and recruitment of capillaries. It is concluded that factors such as the intraperitoneal fill volume, posture, and dwell time all dynamically affect the total pore area available for exchange.
A Novel Senescence-Evasion Mechanism Involving Grap2 and Cyclin D Interacting Protein Inactivation by Ras Associated with Diabetes in Cancer Cells under Doxorubicin Treatment
Authors: Inkyoung Lee, Seon-Yong Yeom, Sook-Ja Lee, Won Ki Kang, Chaehwa Park
Journal: Cancer Research (2010)

Ras associated with diabetes (Rad) is a Ras-related GTPase that promotes cell growth by accelerating cell cycle transitions. Rad knockdown induced cell cycle arrest and premature senescence without additional cellular stress in multiple cancer cell lines, indicating that Rad expression might be critical for the cell cycle in these cells. To investigate the precise function of Rad in this process, we used human Rad as bait in a yeast two-hybrid screening system and sought Rad-interacting proteins. We identified the Grap2 and cyclin D interacting protein (GCIP)/DIP1/CCNDBP1/HHM, a cell cycle-inhibitory molecule, as a binding partner of Rad. Further analyses revealed that Rad binds directly to GCIP in vitro and coimmunoprecipitates with GCIP from cell lysates. Rad translocates GCIP from the nucleus to the cytoplasm, thereby inhibiting the tumor suppressor activity of GCIP, which occurs in the nucleus. Furthermore, in the presence of Rad, GCIP loses its ability to reduce retinoblastoma phosphorylation and inhibit cyclin D1 activity. The function of Rad in transformation is also evidenced by increased telomerase activity and colony formation according to Rad expression level. In vivo tumorigenesis analyses revealed that tumors derived from Rad knockdown cells were significantly smaller than those from control cells (P = 0.0131) and the preestablished tumors are reduced in size after the injection of siRad (P = 0.0064). Therefore, we propose for the first time that Rad may promote carcinogenesis at least in part by inhibiting GCIP-mediated tumor suppression.