tbuckley/cabot-search huggingface dataset:
Abstract 25: The Role of cAMP-Phosphodiesterase 1C Signaling in Pathological Cardiac Remodeling and Dysfunction
Authors: Walter E Knight, Masayoshi Oikawa, Clint Miller, Chen Yan
Journal: Circulation Research (2014)

The cyclic nucleotides cAMP and cGMP play important roles in mediating both protective and detrimental signaling in heart failure. By acting as regulators of cAMP and cGMP, the phosphodiesterases play important roles in modulating this signaling. A comparison of PDE expression between control mice and mice given transverse aortic constriction revealed that expression of phosphodiesterase 1C (PDE1C) was increased significantly by TAC, both on the mRNA and protein levels. To determine whether this was protective or maladaptive, we performed TAC on mice with a genetic deletion of PDE1C. While TAC-operated WT mice experienced significant overall cardiac hypertrophy and cardiomyocyte hypertrophy, these were reduced in PDE1C KO mice. Cardiac function, as assessed by echocardiography, was also reduced significantly in WT TAC mice, but was preserved in PDE1C KO TAC mice. Histological analysis indicated that TAC-operated PDE1C KO mice also experienced reduced cardiomyocyte apoptosis compared to WT mice, indicating a potential cardioprotective mechanism for PDE1C deletion. Cardiomyocytes isolated from PDE1C KO mice experienced reduced Ang II or Iso-induced cell death compared to WT myocytes, indicating that this was a cardiomyocytes-specific effect of PDE1C deletion. Ang II-induced cardiomyocyte cell death and apoptosis were also blocked via pharmacological PDE1 inhibition. PDE1C is able to hydrolyze either cAMP or cGMP; therefore, it seemed possible that this protective mechanism was dependent on either PKA- or PKG-mediated signaling. While PKG inhibition did not alter the protective effect of PDE1 inhibition in isolated cardiomyocytes, PKA inhibition blocked it. Overexpression studies also indicated that PDE1C is localized to the cell membrane in cardiomyocytes. Therefore, we propose that by modulating a novel, membrane-localized, anti-apoptotic, cAMP/PKA-dependent pathway in cardiomyocytes, PDE1C potentially represents a novel therapeutic target in heart failure.
Nitric oxide
Authors: A J King, J L Troy, S Anderson, J R Neuringer, M Gunning, B M Brenner
Journal: Journal of the American Society of Nephrology (1991)

The role of nitric oxide in the modulation of systemic and renal hemodynamics was examined by using N omega-monomethyl-L-arginine (L-NMMA, 110 micrograms/kg/min), a competitive inhibitor of the conversion of L-arginine to nitric oxide. L-NMMA or saline vehicle (9.6 microL/min) was infused intravenously into anesthetized euvolemic Munich-Wistar rats. After 30 min, L-NMMA resulted in a uniform increase in mean arterial blood pressure (111 +/- 1 to 128 +/- 2 mmHg; P less than 0.05) and a modest reduction in renal plasma flow rate (4.4 +/- 0.2 to 4.2 +/- 0.1 mL/min; P less than 0.05), without change in glomerular filtration rate (1.16 +/- 0.03 to 1.15 +/- 0.03 mL/min); vehicle had no effect on these renal parameters. These rats were then subdivided to receive an intravenous infusion (37 microL/min) of either 10% glycine, 11.4% mixed amino acids, or equiosmolar dextrose. L-NMMA pretreatment markedly attenuated glycine-induced hyperfiltration (10 +/- 6 versus 33 +/- 5%, L-NMMA versus vehicle; P less than 0.05) and obliterated the renal hyperemic response (-7 +/- 6 versus 16 +/- 4%, L-NMMA versus vehicle; P less than 0.05). L-NMMA also caused modest blunting of the mixed amino acid-induced hyperfiltration (18 +/- 4 versus 30 +/- 4%, L-NMMA versus vehicle; P = 0.056) but failed to curtail the renal hyperemia (16 +/- 6 versus 20 +/- 4%). Dextrose had no effect on glomerular filtration rate or renal plasma flow.(ABSTRACT TRUNCATED AT 250 WORDS)
Immunological similarities between specific chloroplast ribosomal proteins from Chlamydomonas reinhardtii and ribosomal proteins from Escherichia coli.
Authors: R J Schmidt, A M Myers, N W Gillham, J E Boynton
Journal: Molecular Biology and Evolution (1984)

Polyclonal antibodies were elicited against seven of the 33 different proteins of the large subunit of the chloroplast ribosome from Chlamydomonas reinhardtii. Three of these proteins are synthesized in the chloroplast and four are made in the cytoplasm and imported. In western blots, six of the seven antisera are monospecific for their respective large subunit ribosomal proteins, and none of these antisera cross-reacted with any chloroplast small subunit proteins from C. reinhardtii. Antisera to the three chloroplast-synthesized ribosomal proteins cross-reacted with specific Escherichia coli large subunit proteins of comparable charge and molecular weight. Only one of the four antisera to the chloroplast ribosomal proteins synthesized in the cytoplasm cross-reacted with an E. coli large subunit protein. None of the antisera cross-reacted with any E. coli small subunit proteins. On the assumption of a procaryotic, endosymbiotic origin for the chloroplast, those chloroplast ribosomal proteins still synthesized within the organelle appear to have retained more antigenic sites in common with E. coli ribosomal proteins than have those which are now the products of cytoplasmic protein synthesis. Antisera to this cytoplasmically synthesized group of chloroplast ribosomal proteins did not recognize any antigenic sites among C. reinhardtii cytoplasmic ribosomal proteins, suggesting that the genes for the cytoplasmically synthesized chloroplast ribosomal proteins either are not derived from the cytoplasmic ribosomal protein genes or have evolved to a point where no antigenic similarities remain.
Abstract 1941: The Anti Von Willebrand Factor Aptamer ARC1779 Effectively Inhibits Platelet Activation and Adhesion
Authors: Daniel Duerschmied, Patricia Wagner, Madaline Gilbert, James Gilbert, Denisa Wagner, Robert Schaub
Journal: Circulation (2008)

Objectives Immediately after vessel wall damage, plasma von Willebrand factor (VWF) binds to exposed collagen and laminin, enabling the subsequent adhesion of platelets to immobilized VWF via glycoprotein (GP) Ibα. The GPIbα-VWF interaction is able to withstand high (arterial and intrastenotic) shear conditions, rendering this mechanism crucial for the initiation of hemostatic and thrombotic processes in the arterial circulation. In addition, released VWF promotes platelet activation. We have generated a nuclease-resistant anti-VWF A1 domain aptamer, ARC1779. Aptamers are nucleic acid molecules with high affinity and specificity due to the ability to fold into unique three dimensional structures. We examined the ability of ARC1779 to inhibit these platelet activation processes. Methods and Results Botrocetin-induced aggregation of platelet-rich plasma (IC90 ~100–300 nM) and shear force-induced platelet aggregation in whole blood (IC95 ~100 nM) were inhibited by ARC1779. Platelet adhesion was assessed under high shear conditions (1500/s) in a parallel plate flow chamber using calcein orange labeled platelets. ARC1779 at a concentration range of 7.5 nM − 375 nM produced a concentration dependent inhibition of platelet adhesion with an IC50 of 7.5 nM and IC90 of 75 nM. Almost complete abolition of platelet adhesion was achieved with 400 nM of the aptamer. Firm adhesion of platelets was assessed by monitoring time of adhesion of randomly selected adherent platelets treated with 200 nM of ARC1779. The time that ARC1779 treated platelets remained attached was significantly reduced compared to untreated platelets (p&lt;0.001). The occlusion time after electrical injury of carotid arteries in cynomolgus macaques was assessed and found to be significantly prolonged during ARC1779 treatment. At a concentration of 700 nM, ARC1779 inhibited occlusion of the injured carotid arteries as effectively as the GPIIb/IIIa antagonist abciximab at 1300 nM. The bleeding time was significantly shorter with ARC1779 than with abciximab. Conclusions ARC1779 constitutes a promising novel anti-platelet agent for various thrombotic indications.
Detection of Epstein-Barr Virus DNA in the Peripheral-Blood Cells of Patients With Nasopharyngeal Carcinoma: Relationship to Distant Metastasis and Survival
Authors: Jin-Ching Lin, Kuang Y. Chen, Wen-Yi Wang, Jian-Sheng Jan, Wen-Miin Liang, Chia-Shing Tsai, Yau-Huei Wei
Journal: Journal of Clinical Oncology (2001)

PURPOSE: Nasopharyngeal carcinoma (NPC) has been proved to be an Epstein-Barr virus (EBV)-associated cancer. By use of nested polymerase chain reactions (PCRs), we examined whether the presence of EBV DNA in the peripheral-blood cells (PBC) can serve as a prognostic indicator for NPC. PATIENTS AND METHODS: Peripheral blood from 124 patients with NPC who had no evidence of distant metastasis and 114 healthy volunteers with serologically positive findings for EBV infection was collected prospectively. Plasma and erythrocytes were separated. DNA was extracted from PBCs and analyzed by a nested PCR using primers specific to Epstein-Barr virus nuclear antigen 1 (EBNA-1). All patients were treated by radiotherapy with or without chemotherapy. Clinical parameters and status of EBNA-1 in PBCs were used for survival analysis using the Kaplan-Meier method and the Cox proportional hazards model. RESULTS: Positive rates of EBNA-1 DNA in PBCs of NPC patients and healthy volunteers are 71% and 14%, respectively (P = .001). No significant difference was observed with regard to the clinical characteristics of patients who were EBNA-1–positive (n = 88) and those who were EBNA-1–negative (n = 36). After a median follow-up period of 38 months (range, 24 to 56 months), 29 of 88 EBNA-1–positive patients and only one of 36 EBNA-1–negative patients developed distant metastases (P = .00015). Kaplan-Meier estimates of overall survival (P = .0010), metastasis-free survival (P = .0004), and progression-free survival (P = .0004) were significantly lower for the patients in the EBNA-1–positive group than for those in the EBNA-1–negative group. Multivariate Cox analysis confirmed the same results. CONCLUSION: The presence of EBNA-1 DNA in PBCs is a novel, important risk factor for patients with NPC that indicates a significantly higher risk of developing distant metastasis as well as a lower survival rate.
Immunologic Competence of Bone Marrow of Different Genotypes
Authors: Delta E. Uphoff
Journal: JNCI Journal of the National Cancer Institute (1969)

Marrow cells of different genotypes differ in their immunologic reactivity. This is indicated by the variability in survival patterns of lethally irradiated recipients of marrow from presensitized donors of different strains. A graft-versus-host reaction was induced when the presensitized donors and recipients were of the same H-2 genotype. The severity of a mild spontaneous reaction was increased by prior sensitization of the donor. The most severe spontaneous graft-versus-host reaction occurred when donor and recipient were of different H-2 genotypes. Pretreatment of these donors did not alter the survival pattern. The protective capacity of marrow of some genotypes was modified after contact with tissue antigens of the recipient. This modification resulted in an early mortality during the first week post irradiation that was not considered to be an accelerated graft-versus-host reaction primarily because it occurred in only a few combinations of strains and was not characteristic of strain combinations with the greatest antigenic disparity. The time of onset of the spontaneous and the induced graft-versus-host reaction indicated that the marrow cell suspension contained a primary stem cell that completely repopulated the entire hematopoietic system.
Interim [18F] Fluorodeoxyglucose Positron Emission Tomography (Pet) for Early Metabolic Assessment of Response to Peb Chemotherapy for Metastatic Seminoma: Preliminary Findings
Authors: P. Giannatempo, A. Alessi, D. Raggi, E. Farè, S. Tana, N. Nicolai, G. Serafini, M. Marongiu, B. Padovano, L. Piva, D. Biasoni, T. Torelli, M. Catanzaro, S. Stagni, M. Maffezzini, A.M. Gianni, L. Mariani, R. Salvioni, F. Crippa, A. Necchi
Journal: Annals of Oncology (2014)
Natural history of aspirin-induced asthma
Authors: A. Szczeklik, E. Niżankowska, M. Duplaga, on behalf of the Aiane Investigators
Journal: European Respiratory Journal (2000)

There is a subset of patients with bronchial asthma who are susceptible to disease exacerbation upon receiving aspirin and other nonsteroidal anti-inflammatory drugs. This is a clinical syndrome, called aspirin-induced asthma (AIA), associated with alterations in arachidonate metabolism and cysteinyl-leukotriene overproduction. The natural history and clinical characteristics of this type of asthma were studied. Sixteen clinical centres in 10 European countries provided standardized information to the specially developed patient-oriented database regarding: medical history, physical examination, diagnosis, and treatment. Diagnosis of AIA was based on a typical history, confirmed by positive aspirin provocation tests, carried out in 91% of the patients. A total of 500 patients were enrolled in the study. AIA developed according to a pattern, characterized by a sequence of symptoms. First, persistent rhinitis, appearing at a mean age of 29.7+/-12.5 yrs, then asthma, aspirin intolerance and nasal polyposis appear. The clinical presentation in different European countries was remarkably similar. In females, who outnumbered males by 2.3:1, the onset of symptoms occurred significantly earlier and the disease was more progressive and severe than in males. Atopy, present in approximately a third of patients, led to earlier manifestation of rhinitis and asthma, but not of aspirin intolerance or nasal polyposis. A family history of aspirin intolerance, recorded in 6% of patients, had a less evident effect on the course of the disease than sex or atopy. Fifty one per cent of patients, in addition to inhaled steroids, required chronic systemic corticosteroid therapy at a mean dose of 8 mg prednisone x day(-1). Surprisingly, 15% of patients were unaware of intolerance to aspirin and learnt about it only after having provocation tests performed. All over Europe, aspirin-induced asthma develops in a similar characteristic way. Its course is influenced by sex and the presence of atopy. In half of the patients, asthma is severe, and steroid-dependent. The uniform natural history of aspirin-induced asthma might suggest a common underlying principle.
Pulmonary sequestration in asymptomatic adults; a plea for conservative observation
Authors: Artemios Dimitriou, Yehudit Rozenman, Issahar Ben Dov
Journal: European Respiratory Journal (2012)

Background: Pulmonary sequestration (PS) is a rare congenital anomaly.Due to recurrent infections, the treatment in children is surgical removal of the sequestrated lung and this recommendation expands to adulthood.   Objective: To test if asymptomatic or mildly symptomatic adults with PS could be offered conservative follow up instead of surgery.   Methods: We conducted a case series analysis of all patients above 20 yrs old, with sequestration seen in our institute from 2000-2012.Diagnosis, symptoms, patient characteristics, natural course and treatment were reviewed.   Results: During a median follow up of 7.8yrs, no major infection occurred and the lesion size remained unchanged in 4/5 patients while mild infection that resolved with oral antibiotics was noted in 1/5.   Conclusion: In asymptomatic or mildly symptomatic adult patient with lung sequestration, conservative follow up instead of surgery is a legitimate option.
Are DISH and OPLL genetically related?
Authors: S HAVELKA, M VESELÁ, A PAVELKOVÁ, Š RUZICKOVÁ, H KOGA, S MAEDA, I INOUE, L HALMAN
Journal: Annals of the Rheumatic Diseases (2001)

Fifty years ago, Forestier and Rotes-Querol published their fundamental paper on, what they called, senile ankylosing hyperostosis of the spine1—according to today's nomenclature, diffuse idiopathic skeletal hyperostosis (DISH).2 DISH is a systemic non-inflammatory disorder which might be classified as ossifying diathesis of entheses and ligaments. Ossification starts and extends from insertions of skeletal muscles, ligaments, and joint capsules. The most prominent features of DISH appear on the spine as flowing appositions of newly formed ectopic bone along the anterolateral aspect of the spine.

Ossification of the posterior longitudinal ligament of the spine (OPLL), on the other hand, involves the posterior aspect of vertebral bodies and discs, predominantly of the cervical spine.3Systematic studies of OPLL began in Japan 25 years ago. A varying proportion …
Adopting new NHS specification helps
Authors: P Duffy
Journal: BMJ (1995)

Avoiding drug errorsRead the label EDITOR,-The diversity of drug packaging that R E Ferner criticises has existed for many years.'What Ferner now identifies is a move towards standardisation through pharmaceutical manufacturers' adoption of the NHS ampoule labelling specification.The work leading to this has been described by Nunn.2The NHS specification seeks to establish a standard for labels, with the information presented in a consistent format and printed in the most legible way.The problem with diversity is that practitioners use features such as colour, shape, etc as a substitute for correct reading and inspection of the label.Use of such substitutes is both fallible and dangerous.The company whose products are illustrated in Femer's letter manufactures nearly 100 different ampoules.To differentiate between that number of products by use of colour, shape, etc is obviously impossible.Femer's hypothetical practitioner with modest presbyopia would obviously find it easier to read the labels illustrated than the text of the letter criticising the labels.The only way to be sure of the contents of an ampoule (or any other product) is to read the label.
Internalization of gap junctions in benign familial pemphigus (Hailey-Hailey disease) and keratosis follicularis (Darier's disease)
Authors: None Haftek, None Kowalewski, None Mesnil, None Blaszczyk, None Schmitt
Journal: British Journal of Dermatology (1999)

Hereditary skin disorders involving acantholysis, such as Hailey–Hailey disease and Darier's disease, have been genetically linked to distinct chromosomal parts which do not code for known structural proteins. Such evidence suggests that the genomic abnormalities underlying these dermatoses may concern functional/regulatory mechanisms of keratinocyte cohesion. Epidermal communication junctions (gap junctions) are responsible for direct coupling of cells and, thus, co‐ordinate the behaviour of keratinocytes within the tissue. Consequently, they remain one of the potential, and poorly studied, elements in the pathogenesis of hereditary acantholytic diseases. We have investigated the distribution and fate of gap junctions during non‐immune acantholysis, using fine immunolocalization methods at the light and electron microscopic levels. Our results demonstrate normal expression of epidermal gap junction proteins, connexins 26 and 43, in non‐lesional skin of Hailey–Hailey and Darier's diseases. The gap junctions were not primarily dismantled during acantholysis, typical of both of the studied dermatoses, but underwent internalization and subsequent cytoplasmic dispersion in the portions of cells which were no longer attached to the rest of the tissue. In Darier's disease, perifollicular acantholysis did not specifically concern epithelium of appendages coexpressing connexin 26 in addition to connexin 43, further indicating that the observed changes in gap junction localization were secondary to the loss of cell–cell contact. We demonstrated that the sequence of changes was identical in both diseases and that the previously described putative differences were apparently related to the degree of acantholysis present in the studied biopsies. The fate of the junctional structures and proteins, documented in the present study, is most probably a form of recycling process also used by normal keratinocytes during organogenesis and tissue differentiation.
Five-year administration of fenretinide: pharmacokinetics and effects on plasma retinol concentrations.
Authors: F Formelli, M Clerici, T Campa, M G Di Mauro, A Magni, G Mascotti, D Moglia, G De Palo, A Costa, U Veronesi
Journal: Journal of Clinical Oncology (1993)

PURPOSE Monitoring of fenretinide (4HPR) levels, kinetics, and effects on retinal was performed in patients who participated in a phase I trial and who continued to be treated for 5 years as phase III trial patients. Accumulation of 4HPR in the breast was also assessed. PATIENTS AND METHODS Plasma concentrations of 4HPR, of its main metabolite N-(4-methoxyphenyl)retinamide (4MPR), and of retinol were assayed by high-performance liquid chromatography (HPLC) in breast cancer patients treated orally with 4HPR 200 mg/d for 5 years with a 3-day drug interruption at the end of each month. RESULTS 4HPR, at 200 mg/d, resulted in average 4HPR plasma levels of approximately 1 mumol/L, which remained steady and caused steady retinol level reduction; 4MPR levels, similar to those of 4HPR, slightly but significantly increased during the first 35 months, but at 5 years they were similar to those at 5 months. During daily treatment, baseline retinol concentrations were reduced by 71%; after a 3-day drug interruption, all patients recovered and the mean reduction was 38%. After discontinuation of 5-year treatment, 4HPR and 4MPR half-lives (t1/2 beta) were 27 and 54 hours, respectively, similar to those reported after 28 daily treatments. After 6 and 12 months, the concentrations of 4HPR were at the limit of detectability (0.01 mumol/L), whereas those of 4MPR were five times higher. Baseline retinol concentrations were already recovered after 1 month. Accumulation of this retinoid in the breast was evidenced by concentrations of 4HPR and 4MPR in nipple discharge and in breast biopsies that were 10 and 20 times higher, respectively, than those found in plasma. CONCLUSION 4HPR, at 200 mg/d for 5 years, resulted in constant drug plasma levels and constant retinol level reduction. After treatment interruption, 4HPR plasma concentrations decreased at the limit of detectability at 6 months and baseline retinol plasma concentrations were recovered after 1 month.
Pulmonary Neutrophil Infiltration in Murine Sepsis
Authors: Habib M. Razavi, Le Feng Wang, Sean Weicker, Marta Rohan, Cedrin Law, David G. McCormack, Sanjay Mehta
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

Nitric oxide (NO) derived from inducible NO synthase (iNOS) contributes to the pathophysiology of acute lung injury (ALI). The effect of iNOS on pulmonary neutrophil infiltration in ALI is not known. Thus, we assessed pulmonary microvascular neutrophil sequestration through intravital videomicroscopy and pulmonary neutrophil infiltration, reflected by myeloperoxidase activity and lavage neutrophil counts, after induction of sepsis by cecal ligation/perforation in wild-type (iNOS+/+) versus iNOS-/- mice. Pulmonary microvascular neutrophil sequestration was attenuated in septic iNOS-/- versus iNOS+/+ mice (15 +/- 1 vs. 20 +/- 1 leukocytes per field, p < 0.05), but lavage neutrophil counts were greater in iNOS-/- mice (5.7 +/- 1.5% vs. 0.7 +/- 0.1%, p < 0.05) between 6 and 18 hours after cecal ligation and perforation. When iNOS+/+ bone marrow was transplanted into bone marrow-depleted iNOS-/- mice (+ to - chimeras; iNOS limited to marrow-derived inflammatory cells), septic pulmonary microvascular neutrophil sequestration and lavage neutrophil counts were restored to levels seen in septic iNOS+/+ mice. In contrast, in - to + chimeras, pulmonary neutrophil trafficking was similar to iNOS-/- mice. In vitro cytokine-stimulated neutrophil transendothelial migration was significantly greater for iNOS-/- versus iNOS+/+ neutrophils (7.9 +/- 0.7% vs. 3.8 +/- 0.6%, p < 0.05) but was independent of endothelial iNOS. Thus, neutrophil iNOS-derived NO is an important autocrine modulator of pulmonary neutrophil infiltration in murine sepsis.