tbuckley/cabot-search huggingface dataset:
Cyclosporine A Amplifies Ca2+ Signaling Pathway in LLC-PK1 Cells through the Inhibition of Plasma Membrane Ca2+ Pump
Authors: Vincenzo Calderaro, Mariarosaria Boccellino, Giovanni Cirillo, Lucio Quagliuolo, Domenico Cirillo, Alfonso Giovane
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Cyclosporine A (CsA), a neutral, highly hydrophobic cyclic peptide with 11 amino acids, is currently the most widely used immunosuppressive drug for preventing graft rejection and autoimmune diseases. Despite its efficacy, the use of CsA is limited by severe side effects, mainly nephrotoxicity and arterial hypertension. Single cell microfluorimetry was used to evaluate the role of CsA on Ca2+ signaling pathway in intact cells of the porcine proximal tubule-like cell line LLC-PK1; the assay of the in vitro activity of the plasma membrane Ca2+ pump (PMCA) was carried out through the preparation and isolation of membranes. The addition of CsA to incubation medium at doses ranging from 0.1 to 2 μM did not change the basal level of intracellular calcium ([Ca2+]i), whereas it affected the [Ca2+]i response to thapsigargin (TG), a powerful inhibitor of microsomal Ca2+ pump. In control studies, 5 μM TG produced a biphasic response: [Ca2+]i peaked with a 60-s lag, and it then declined to a plateau of elevated [Ca2+]i, which remains above basal. However, it became evident that CsA strengthened the Ca2+ response to TG because the addition of 5 μM TG to cells exposed to 400 nM CsA did not affect the peak response to TG, but it markedly affected the subsequent sustained phase ([Ca2+]i = 156 ± 4.84 versus 130 ± 3.28 nmol, mean ± SEM, n = 6, P < 0.001). In membrane preparations, 200 nM CsA brought about, in the presence of 10 μM calmodulin (CaM), a significant decrease of plasma membrane Ca2+ pump (PMCA) activity (46.96 ± 0.26 versus 53.48 ± 1.96 nmol · mg of protein−1 · min−1, n = 6, P < 0.02), a value similar to that obtained in the presence of equimolar amounts of cyclosporine H (CsH), a non-immunosuppressive analogue of CsA. These findings suggest that in this cell line CsA affects the Ca2+ export pathway through the reduction of the PMCA activity with consequent amplification and strengthening of [Ca2+]i response after exposure to agents that trigger intracellular Ca2+ release. The increased cell sensitivity during Ca2+ signaling events ensuing from the impairment of this "defense system" may be regarded as one of the basic mechanisms involved in the development of the side effects induced by CsA. E-mail: [email protected]
Progressive cauda equina syndrome and extensive calification/ossification of the lumbosacral meninges.
Authors: J Rotes-Querol, E Tolosa, R Rosello, J Granados
Journal: Annals of the Rheumatic Diseases (1985)

A patient with longstanding ankylosing spondylitis (AS) developed a cauda equina syndrome. The myelogram showed a block at the L2 level. Vertebral computerised tomography showed calcification in the centre of the spinal canal. The patient also had features suggestive of a diffuse idiopathic skeletal hyperostosis (DISH). Meningeal calcification has never been reported in AS, so we suggest that this is related to an associated DISH. Cauda equina syndrome has not been described in DISH, and calcification of meninges has not been reported in AS, so we suggest that the meningeal calcifications and associated cauda equina syndrome are related to DISH.
Overdiagnosis Due to Prostate-Specific Antigen Screening: Lessons From U.S. Prostate Cancer Incidence Trends
Authors: Ruth Etzioni, David F. Penson, Julie M. Legler, Dante di Tommaso, Rob Boer, Peter H. Gann, Eric J. Feuer
Journal: JNCI Journal of the National Cancer Institute (2002)

Background: Overdiagnosis of clinically insignificant prostate cancer is considered a major potential drawback of prostate-specific antigen (PSA) screening. Quantitative estimates of the magnitude of this problem are, however, lacking. We estimated rates of prostate cancer overdiagnosis due to PSA testing that are consistent with the observed incidence of prostate cancer in the United States from 1988 through 1998. Overdiagnosis was defined as the detection of prostate cancer through PSA testing that otherwise would not have been diagnosed within the patient's lifetime. Methods: We developed a computer simulation model of PSA testing and subsequent prostate cancer diagnosis and death from prostate cancer among a hypothetical cohort of two million men who were 60–84 years old in 1988. Given values for the expected lead time—that is, the time by which the test advanced diagnosis—and the expected incidence of prostate cancer in the absence of PSA testing, the model projected the increase in population incidence of prostate cancer associated with PSA testing. By comparing the model-projected incidence with the observed incidence derived from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) registry data, we determined the lead times and corresponding overdiagnosis rates that were consistent with the observed data. Results: SEER data on prostate cancer incidence from 1988 through 1998 were consistent with overdiagnosis rates of approximately 29% for whites and 44% for blacks among men with prostate cancers detected by PSA screening. Conclusions: Among men with prostate cancer that would be detected only at autopsy, these rates correspond to overdiagnosis rates of, at most, 15% in whites and 37% in blacks. The observed trends in prostate cancer incidence are consistent with considerable overdiagnosis among PSA-detected cases. However, the results suggest that the majority of screen-detected cancers diagnosed between 1988 and 1998 would have presented clinically and that only a minority of cases found at autopsy would have been detected by PSA testing.
Recent Advances in Varicella-Zoster Virus Infection
Authors: Jeffrey I. Cohen
Journal: Annals of Internal Medicine (1999)

Varicella-zoster virus has developed a complex strategy that allows it to remain latent in the body and avoid destruction by the immune system. Although varicella and zoster have been recognized since antiquity, several new clinical syndromes—including chronic chickenpox with persistent verrucous lesions and disseminated varicella without skin lesions—have been noted in patients with AIDS. Acyclovir has been the mainstay for treating severe varicella-zoster virus infections; however, newer antiviral agents, including valacyclovir and famciclovir, have expanded therapeutic options for treating adults with herpes zoster. The recently licensed live attenuated vaccine for varicella-zoster virus is effective in preventing chickenpox, and the vaccine's ability to stimulate immunity in seropositive adults suggests a promising strategy with which to modify the course of herpes zoster.
Atheromatous Changes in Cholesterol-Fed Rabbits Treated with Eggplant Extract
Authors: W. DONALD GRAHAM, JOYCE L. BEARE, HAROLD C. GRICE
Journal: Circulation Research (1959)

Cholesterol-induced changes in rabbits were studied with and without administration of an extract of eggplant. An anemia, accompanied by atrophic gastritis, developed in the cholesterol-fed animals. Their atheromatous plaques, and elevated serum cholesterol, lipoalbumin, α-lipoprotein, and neutral fat were not affected by the eggplant extract.
Enhanced detection of cholangiocarcinoma with serum trypsinogen-2 in patients with severe bile duct strictures
Authors: Marko Lempinen, Helena Isoniemi, Heikki Mäkisalo, Arno Nordin, Leena Halme, Johanna Arola, Krister Höckerstedt, Ulf-Håkan Stenman
Journal: Journal of Hepatology (2007)
Endothelial nitric oxide synthase activity is inhibited by the plasma membrane calcium ATPase in human endothelial cells
Authors: MaryLouisa Holton, Tamer M.A. Mohamed, Delvac Oceandy, Weiguang Wang, Santiago Lamas, Michael Emerson, Ludwig Neyses, Angel L. Armesilla
Journal: Cardiovascular Research (2010)

AimsNitric oxide (NO) plays a pivotal role in the regulation of cardiovascular physiology. Endothelial NO is mainly produced by the endothelial nitric oxide synthase (eNOS) enzyme. eNOS enzymatic activity is regulated at several levels, including Ca2+/calmodulin binding and the interaction of eNOS with associated proteins. There is emerging evidence indicating a role for the plasma membrane calcium ATPase (PMCA) as a negative regulator of Ca2+/calmodulin-dependent signal transduction pathways via its interaction with partner proteins. The aim of our study was to investigate the possibility that the activity of eNOS is regulated through its association with endothelial PMCA.
Troponin I Isoform Expression in Human and Experimental Atrial Fibrillation
Authors: Victor L.J.L. Thijssen, Jannie Ausma, Luisa Gorza, Huub M.W. van der Velden, Maurits A. Allessie, Isabelle C. Van Gelder, Marcel Borgers, Guillaume J.J.M. van Eys
Journal: Circulation (2004)

Atrial fibrillation (AF) is accompanied by re-expression of fetal genes and activation of proteolytic enzymes. In this study both aspects were addressed with respect to troponin I (TnI) isoform expression.Western blotting and real-time reverse transcription-polymerase chain reaction were used to study TnI isoform expression in patients with paroxysmal or chronic AF and in goats after 1, 2, 4, 8, and 16 weeks of AF. In addition to cardiac TnI (cTnI), low expression of slow-twitch skeletal TnI (ssTnI) protein was found in 60% of patients in sinus rhythm or paroxysmal AF and in 8% of patients with chronic AF. In adult goat atrium, ssTnI protein expression was undetectable. Calcium-dependent degradation of cTnI protein was found in 1 or 2 of 6 animals after 1 to 4 weeks of AF. Although always low, ssTnI mRNA levels were significantly higher in patients who expressed ssTnI protein than in those who did not. Relative ssTnI mRNA expression was significantly lower in patients with paroxysmal AF and chronic AF than in those in sinus rhythm. In goats there was a tendency toward higher relative levels of ssTnI at the onset of AF followed by a normalization when AF had become sustained.Atrial re-expression of ssTnI during paroxysmal AF in patients and during the first 2 weeks of pacing-induced AF in goats does not seem to be part of the process of AF-associated cardiomyocyte dedifferentiation but seems to result from transient cardiomyocyte stress at the onset of AF.
Bone loss after liver transplantation
Authors: Jennifer A. McDonald, Colin R. Dunstan, Pamela Dilworth, Kenneth Sherbon, Ross A.G. Sheil, Richard A. Evans, Geoffrey W. McCaughan
Journal: Hepatology (1991)

We studied 35 adult patients (mean age = 43 yr) referred for orthotopic liver transplantation. Spinal bone mineral density was measured by quantitative computed tomography scanning before transplantation (n = 35) and at 3 mo (n = 21) and 12 mo (n = 11) after orthotopic liver transplantation. The readings were corrected to age 50 yr, using the regression equations derived from normal control subjects. Quantitative bone histological studies were performed in 17 patients before orthotopic liver transplantation and 3 mo after orthotopic liver transplantation. Before orthotopic liver transplantation, the corrected spinal bone mineral density in men was 108 +/- 20 mg/cm3, less than in male control subjects (129 +/- 22 mg/cm3, p less than 0.005). In women patients the value was 117 +/- 27 mg/cm3, and in female control subjects 126 +/- 19 mg/cm3 (NS). However, women patients with primary biliary cirrhosis had lower spinal bone mineral density (106.5 +/- 14.8) than female control subjects (p less than 0.005). Histologically, the resorbing surface was near the normal mean, whereas the osteoblast surface, tetracycline surface and bone formation rate was lower in men (p less than 0.05) but not women. Spinal bone mineral density decreased by 24% in the first 3 mo after orthotopic liver transplantation with no further decrease at 12 mo. Five patients had vertebral fractures within 6 mo of orthotopic liver transplantation. One patient fractured a wrist and three had osteonecrosis of the hip or knee.(ABSTRACT TRUNCATED AT 250 WORDS)
IMMUNOGLOBULIN SPOTS ON THE SURFACE OF RABBIT LYMPHOCYTES
Authors: Benvenuto Pernis, Luciana Forni, Luisa Amante
Journal: The Journal of Experimental Medicine (1970)

Small and medium lymphocytes from the peripheral blood and lymphoid tissues of the rabbit react in suspension with antibodies directed against different immunoglobulin determinants. Through immunofluorescence, it was possible to show that numerous discrete spots on the surface of the positive lymphocytes carry immunoglobulin molecules. The positive lymphocytes are about one-half of all lymphocytes in the different preparations; thymus lymphocytes are all negative. With antisera specific for rabbit IgM as well as with antisera directed against allotypic determinants specific for IgM or IgG, it was possible to show that about nine-tenths of the immunoglobulin-positive lymphocytes carry IgM molecules on their surface. With antisera directed against a- and b-locus determinants, it was also possible to demonstrate that both heavy and light chains were present in the surface immunoglobulins. Furthermore, in animals which were heterozygous at the a or the b locus, it was found that each lymphocyte had immunoglobulins synthesized under the influence of only one of two alleles. A very small proportion of lymphocytes could be shown to have a specific surface reaction with one antigen (horse ferritin); the proportion of these cells increased very much after immunization.
Variability of hepatitis C virus
Authors: Peter Simmonds
Journal: Hepatology (1995)

The discovery and characterization of the main causative agent of non-A, non-B hepatitis (NANBH) represent a major success in the application of cloning techniques in the identification of new infectious agents.'The technique that led to the characterization and the development of antibody tests for hepatitis C virus (HCV12 has since been applied successfully to determine the etiological agent of other diseases, such as hepatitis E virus, responsible for enterically transmitted NANBH.3HCV contains a positive sense RNA genome approximately 10,000 bases in length.In overall genome organization and presumed method of replication, it is most similar to members of the flauiviridae family particularly in the coding for a single polyprotein that is then cleaved into a series of structural proteins (nucleocapsid protein, two membrane glycoproteins) and nonstructural proteins, with presumed enzymatic roles in virus replication.Without a cell culture system to investigate differences in neutralization and cytopathic properties of HCV, nucleotide sequence comparisons and typing assays developed from sequence data have become the principal techniques for characterizing different variants of HCV.This type of analysis is relatively easy to perform, especially because viral sequences can be amplified by the polymerase chain reaction (PCR) directly from clinical specimens.Sequence comparisons of HCV have provided information about the virus a t several levels.It is possible to identify and classify HCV into a series of distinct "genotypes," which differ substantially in nucleotide sequence from one another and show varied geographical and epidemiological distributions.In particular, the inferred amino acid sequences of the envelope glycoproteins differ considerably, and it is likely that antibody elicited by infection with one genotype would fail to neutralize others.The extent of variation observed within HCV is comparable with that between serotypes of other RNA viruses, and may pose problems in the development of vaccines for HCV.
Heparin Blockade of Thrombin-Induced Smooth Muscle Cell Migration Involves Inhibition of Epidermal Growth Factor (EGF) Receptor Transactivation by Heparin-Binding EGF-Like Growth Factor
Authors: Andreas Kalmes, Beatrice R. Vesti, Günter Daum, Judith A. Abraham, Alexander W. Clowes
Journal: Circulation Research (2000)

Abstract —Agonists of G protein–coupled receptors, such as thrombin, act in part by transactivating the epidermal growth factor (EGF) receptor (EGFR). Although at first a ligand-independent mechanism for EGFR transactivation was postulated, it has recently been shown that this transactivation by various G protein–coupled receptor agonists can involve heparin-binding EGF-like growth factor (HB-EGF). Because thrombin stimulation of vascular smooth muscle cell migration is blocked by heparin and because heparin can displace HB-EGF, we investigated the possibility that thrombin stimulation of smooth muscle cells (SMCs) depends on EGFR activation by HB-EGF. In rat SMCs, EGFR phosphorylation and extracellular signal-regulated kinase (ERK) activation in response to thrombin are inhibited not only by the EGFR inhibitor AG1478 and by EGFR blocking antibody but also by heparin and by neutralizing HB-EGF antibody. HB-EGF–dependent signaling induced by thrombin is inhibited by batimastat, which suggests a requirement for pro-HB-EGF shedding by a metalloproteinase. We further demonstrate that this novel pathway is required for the migration of rat and baboon SMCs in response to thrombin. We conclude from these data that the inhibitory effect of heparin on SMC migration induced by thrombin relies, at least in part, on a blockade of HB-EGF–mediated EGFR transactivation. (Circ Res. 2000;87:92-98.)
BMI–Mortality Paradox and Fitness in African American and Caucasian Men With Type 2 Diabetes
Authors: Peter Kokkinos, Jonathan Myers, Charles Faselis, Michael Doumas, Raya Kheirbek, Eric Nylen
Journal: Diabetes Care (2012)

To assess the association between BMI, fitness, and mortality in African American and Caucasian men with type 2 diabetes and to explore racial differences in this association.We used prospective observational data from Veterans Affairs Medical Centers in Washington, DC, and Palo Alto, California. Our cohort (N = 4,156; mean age 60 ± 10.3 years) consisted of 2,013 African Americans (mean age, 59.5 ± 9.9 years), 2,000 Caucasians (mean age, 60.8 ± 10.5 years), and 143 of unknown race/ethnicity. BMI, cardiac risk factors, medications, and peak exercise capacity in metabolic equivalents (METs) were assessed during 1986 and 2010. All-cause mortality was assessed across BMI and fitness categories.There were 1,074 deaths during a median follow-up period of 7.5 years. A paradoxic BMI-mortality association was observed, with significantly higher risk among those with a BMI between 18.5 and 24.9 kg/m(2) (hazard ratio [HR] 1.70 [95% CI 1.36-2.1]) compared with the obese category (BMI ≥ 35 kg/m(2)). This association was accentuated in African Americans (HR 1.95 [95% CI 1.44-2.63]) versus Caucasians (HR 1.53 [1.0-2.1]). The fitness-mortality risk association for the entire cohort and within BMI categories was inverse, independent, and graded. Mortality risks were 12% lower for each 1-MET increase in exercise capacity, and ~35-55% lower for those with an exercise capacity >5 METs compared with the least fit (≤ 5 METs). CONCLUSIONS A paradoxic BMI-mortality risk association was observed in African American and Caucasian patients with diabetes. The exercise capacity-mortality risk association was inverse, independent, and graded in all BMI categories but was more potent in those with a BMI ≥ 25 kg/m(2).
Reproductive History and Oral Contraceptive Use in Relation to Risk of Triple-Negative Breast Cancer
Authors: A. I. Phipps, R. T. Chlebowski, R. Prentice, A. McTiernan, J. Wactawski-Wende, L. H. Kuller, L. L. Adams-Campbell, D. Lane, M. L. Stefanick, M. Vitolins, G. C. Kabat, T. E. Rohan, C. I. Li
Journal: JNCI Journal of the National Cancer Institute (2011)

Triple-negative (ie, estrogen receptor [ER], progesterone receptor, and HER2 negative) breast cancer occurs disproportionately among African American women compared with white women and is associated with a worse prognosis than ER-positive (ER+) breast cancer. Hormonally mediated risk factors may be differentially related to risk of triple-negative and ER+ breast cancers. Using data from 155 723 women enrolled in the Women's Health Initiative, we assessed associations between reproductive and menstrual history, breastfeeding, oral contraceptive use, and subtype-specific breast cancer risk. We used Cox regression to evaluate associations with triple-negative (N = 307) and ER+ (N = 2610) breast cancers and used partial likelihood methods to test for differences in subtype-specific hazard ratios (HRs). Reproductive history was differentially associated with risk of triple-negative and ER+ breast cancers. Nulliparity was associated with decreased risk of triple-negative breast cancer (HR = 0.61, 95% confidence interval [CI] = 0.37 to 0.97) but increased risk of ER+ breast cancer (HR = 1.35, 95% CI = 1.20 to 1.52). Age-adjusted absolute rates of triple-negative breast cancer were 2.71 and 1.54 per 10 000 person-years in parous and nulliparous women, respectively; by comparison, rates of ER+ breast cancer were 21.10 and 28.16 per 10 000 person-years in the same two groups. Among parous women, the number of births was positively associated with risk of triple-negative disease (HR for three births or more vs one birth = 1.46, 95% CI = 0.82 to 2.63) and inversely associated with risk of ER+ disease (HR = 0.88, 95% CI = 0.74 to 1.04). Ages at menarche and menopause were modestly associated with risk of ER+ but not triple-negative breast cancer; breastfeeding and oral contraceptive use were not associated with either subtype. The association between parity and breast cancer risk differs appreciably for ER+ and triple-negative breast cancers. These findings require further confirmation because the biological mechanisms underlying these differences are uncertain.
A Technique for Transeptal Left Heart Catheterization via the Right External Jugular Vein
Authors: S. Bevegard, E. Carlens, B. Jonsson, I. Karlof
Journal: Thorax (1960)

Withtheaidofright heartcatheterization information aboutthepressure intheleft atrium canbeobtained indirectly using thecatheter inthe pulmonary arterial wedgeposition. Foranexact study ofdiseases within theleft chambers ofthe heart itisimportant tomeasurethepressure in theleftventricle andtoestimate thepressure gradients across themitral valveandtheleft ventricular outflow tract. Several methodsforleft heartcatheterization havebeenused.Whichmethod oneshould choose isdependent onthepurpose oftheexamination. Forphysiological studies thefollowing requirementsshould be fulfilled. (1)Catheterization should notcausea markedchangeoftheheart function anditshould bepossible todefine to whatextent function haschanged. (2)Whenthe catheter hasbeenintroduced asteady circulatory state should beobtained before estimating the pressures andthecardiac output.(3)Itshould be possible to studythe haemodynamics during exercise. (4)Theprocedure should not producemore morbidity thana rightheart catheterization. Transbronchial puncture oftheleft atrium, as described byFacquet, Lemoine, Alhomme,and Lefebvre (1952), Allison andLinden(1953), and Morrow, Braunwald, Haller, andSharp (1957), has beenwidely usedandveryfewcomplications have beenreported. We haveperformed catheterizationaccording tothis methodin42caseswithout serious complications, butbronchoscopy sometimeschanges thehaemodynamics considerably. Fourteen ofourpatients suffered frombronchial secretion andthearterial oxygensaturation was foundto decrease. Posterior percutaneous puncture oftheleft atrium introduced byBjork, Malmstrom, andUggla(1953) seemstoustobe risky (Bagger, Bjork, andMalmstr6m, 1957). The technique ofpuncture oftheleft atrium fromthe suprasternal notchusing a thinneedle, described