tbuckley/cabot-search huggingface dataset:
The cardiac β-adrenoceptors: Where and why?
Authors: J NEUMANN
Journal: Cardiovascular Research (2006)

See article by Boivin et al.  [1]  (pages 69–78) in this issue. 

The family of G-protein-coupled heptahelical receptors are widely distributed in the human body. Of special clinical importance are β-adrenoceptors, which mediate the effects of the sympathetic nervous system. In the heart, they induce, at least to a large extent, the inotropic effects of catecholamines. They confer signals from their ligands to the cell, and this signal transduction process classically runs via G-proteins to downstream effectors. The best investigated effector is the enzyme adenylyl cyclase (AC), which catalyses the conversion of ATP to cAMP. Increases in cAMP levels are thought to lead mainly to activation of cAMP-dependent protein kinases (PKA). In turn, PKA increases the phosphorylation state of target proteins in the cardiac cell like the L-type Ca2+ channels, phospholamban, and other proteins (see Fig. 1). Some of these phosphorylation events increase the Ca2+ content of the cardiomyocytes, in this way not only elevating … 

* Tel.: +49 345 557 1686; fax: +49 345 557 18 35. Email address: joachim.neumann{at}medizin.uni-halle.de
Human Papillomavirus Infection and Reinfection in Adult Women: the Role of Sexual Activity and Natural Immunity
Authors: Helen Trottier, Silvaneide Ferreira, Patricia Thomann, Maria C. Costa, Joao S. Sobrinho, José Carlos M. Prado, Thomas E. Rohan, Luisa L. Villa, Eduardo L. Franco
Journal: Cancer Research (2010)

There is a paucity of data on whether or not women can be reinfected with human papillomavirus (HPV) types to which they were exposed to earlier in life and on the role of natural immunity. The observation of HPV infection at older ages may be explained by the reactivation of a latent infection or new exposure from sexual activity. Our objective was to analyze the association between reinfection and sexual activity. We analyzed data from 2,462 women enrolled in the Ludwig-McGill cohort and followed every 4 to 6 months for up to 10 years. We performed HPV typing and viral load measurements via PCR and determined HPV-16 seroreactivity at enrollment. Incidence of infection and reinfection were estimated for individual types. Adjusted relative risks (RR) for the association between infection/reinfection and new sexual partners were calculated using Cox regression. Rates of initial infection and reinfection postclearance were statistically comparable. RRs of initial infection or reinfection were consistently associated with new sexual partners [2.4 (95% confidence intervals; 95% CI, 2.0-3.1) for first infection, 3.7 (1.1-13.8) for reinfection with the same type, and 2.3 (1.5-3.7) for reinfection with a different type]. Reinfection in older women was also associated with new sexual partners (RR, 2.8; 95% CI, 1.4-5.3) as were new infections with HPV-16 among women with serologic evidence of prior HPV-16 exposure (RR, 3.0; 95% CI, 1.6-5.3). Viral loads at initial infection and at reinfection were comparable. HPV infection and reinfection were strongly associated with sexual activity. This study suggests that natural immunity does not play a role in controlling the extent of reinfections.
Acetylcholine Elicits a Rebound Stimulation of Ca <sup>2+</sup> Current Mediated by Pertussis Toxin–Sensitive G Protein and cAMP-Dependent Protein Kinase A in Atrial Myocytes
Authors: Yong Gao Wang, Stephen L. Lipsius
Journal: Circulation Research (1995)

Abstract Cholinergic inhibition of atrial contraction is typically followed by a rebound positive inotropic response. In the present study, we used a nystatin–perforated patch whole-cell recording method to determine whether acetylcholine (ACh) elicits a rebound stimulation of L-type Ca 2+ current (I Ca,L ) in cat atrial myocytes. ACh (1 μmol/L) decreased basal I Ca,L (−19±2%). Within ≈30 s of returning to ACh-free solution, basal I Ca,L exhibited a rebound increase above the control level (+61±7%) that returned to the control level within 4 to 5 minutes. ACh elicited concomitant changes in cell shortening, ie, a decrease followed by a rebound increase. The EC 50 and maximal response of ACh-induced inhibition and rebound stimulation of I Ca,L were 1.9×10 −9 mol/L and −30%, respectively, and 2.9×10 −8 mol/L and +64%, respectively. All effects of ACh on I Ca,L were blocked by prior exposure to 1 μmol/L atropine or 100 μmol/L AFDX116 and unaffected by 0.2 μmol/L pirenzepine or 1 μmol/L propranolol. In the presence of ACh, exposure to atropine elicited stimulation of I Ca,L . ACh-induced inhibition and rebound stimulation of current were independent of external Ca 2+ . Rebound stimulation of I Ca,L was associated with a negative shift in the voltage dependence of I Ca,L activation. Inhibition of protein kinase A by 50 μmol/L Rp-cAMPs decreased basal I Ca,L by 36±1% and abolished the rebound stimulation of I Ca,L . Forskolin (0.01 μmol/L) or isoproterenol (0.01 μmol/L) had no effect on basal I Ca,L , but each accentuated the rebound increase in I Ca,L . When adenylate cyclase was maximally stimulated with 1 μmol/L isoproterenol plus 2 μmol/L forskolin, ACh decreased I Ca,L but failed to elicit rebound stimulation of I Ca,L . Milrinone (10 μmol/L) increased basal I Ca,L by 70±7% and significantly attenuated the rebound stimulation of I Ca,L . Exposure to 1 mmol/L 8-bromo-cGMP elicited a small decrease in basal I Ca,L , attenuated ACh-induced inhibition, and enhanced the rebound stimulation of I Ca,L . Incubation in pertussis toxin prevented all ACh-induced changes in I Ca,L . Inhibition of nitric oxide synthase by 100 μmol/L N G -monomethyl- l -arginine (L-NMMA) decreased basal I Ca,L by −20±5%, prevented ACh-induced inhibition, and markedly attenuated the rebound stimulation of I Ca,L . We conclude that in cat atrial myocytes ACh acts via M 2 muscarinic receptors and pertussis toxin–sensitive G protein to inhibit basal I Ca,L and that on withdrawal ACh elicits a rebound stimulation of I Ca,L . Rebound stimulation of I Ca,L is mediated via cAMP-dependent protein kinase A enhanced by ACh-induced inhibition of phosphodiesterase. This mechanism contributes directly to the positive inotropic response that follows cholinergic inhibition of atrial contraction.
Malignant Lymphoreticular Tumors in Israel&lt;xref ref-type="fn" rid="FN1"&gt;1&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: M I Sacks, N Hulu, G Selzer, R Steinitz
Journal: JNCI Journal of the National Cancer Institute (1973)

Data on the frequency of the various types of malignant lymphoma in Israel were presented on the basis of a histologic re-evaluation of 396 lymphomas diagnosed during the period, January 1, 1967, to December 31, 1968. The reviewed cases represented 94.5% of the histologically diagnosed malignant lymphomas recorded in the Israel Cancer Registry during this period. The diagnosis of malignant lymphoma was confirmed in 371 (94%) of the cases reviewed. Reticulum cell sarcoma and lymphosarcoma each accounted for about one-third of all lymphomas and Hodgkin's disease for 27.5%. Hodgkin's disease predominated in young aduits, whereas lymphosarcoma and reticulum cell sarcoma predominated in the older age groups. The age-specific incidence rates for lymphosarcoma and reticulum cell sarcoma increased steeply in males >35 years old and in females >45 years old. The rates for Hodgkin's disease showed peaks in the 15- to 24-year and 55- to 64-year age groups in females and in the 35- to 44-year age group in males. The male/female ratio for cases of Hodgkin's disease was 1.17:1, but the sex ratio varied in the different age groups. Mixed cellularity (32% of cases) was the most common type of Hodgkin's disease encountered. Nodular sclerosis accounted for 27% of the cases, was found mainly in young adults, and occurred twice as often in females than in males. Preliminary data on possible differences between various population groups were presented. The special frequency of small intestinal lymphomas in non-Jews and in Jews born in Asia or Africa was confirmed. A comparison of age-specific and age-standardized incidence rates for malignant lymphoma in foreign-born Jews showed lower rates in males born in Europe or America in the younger age groups and in females born in Africa in the older age groups. In young adults (15–34 yr old), the rates for lymphosarcoma-reticulum sarcoma were higher in Jews born in Africa or Asia than in those born in Europe or America, whereas the rates for Hodgkin's disease seemed to be higher in Jews born in Europe or America. It was necessary to change the original cancer registry coding of 11.4% of the cases of malignant lymphoma reviewed. The information available in the cancer registry was fairly accurate with respect to Hodgkin's disease, but was of no value in separating lymphosarcoma from reticulum cell sarcoma. A high proportion of the latter cases were recorded as malignant lymphoma, type unspecified. The cancer registry data have very definite limitations with respect to the different types of leukemia. The registry figures may represent an underestimate for chronic lymphocytic leukemia.
Validation of Creatinine-Based Estimates of GFR When Evaluating Risk Factors in Longitudinal Studies of Kidney Disease
Authors: Xuelei Wang, Julia Lewis, Lawrence Appel, DeAnna Cheek, Gabriel Contreras, Marquetta Faulkner, Harold Feldman, Jennifer Gassman, Janice Lea, Joel Kopple, Mohammed Sika, Robert Toto, Tom Greene
Journal: Journal of the American Society of Nephrology (2006)

Whereas much research has investigated equations for obtaining estimated GFR (eGFR) from serum creatinine in cross-sectional settings, little attention has been given to validating these equations as outcomes in longitudinal studies of chronic kidney disease. A common objective of chronic kidney disease studies is to identify risk factors for progression, characterized by slope (rate of change over time) or time to event (time until a designated decline in kidney function or ESRD). The relationships of 35 baseline factors with eGFR-based outcomes were compared with the relationships of the same factors with iothalamate GFR (iGFR)-based outcomes in the African American Study of Kidney Disease and Hypertension (AASK; n = 1094). With the use of the AASK equation to calculate eGFR, results were compared between time to halving of eGFR or ESRD and time to halving of iGFR or ESRD (with effect sizes expressed per 1 SD) and between eGFR and iGFR slopes starting 3 mo after randomization. The effects of the baseline factors were similar between the eGFR- and iGFR-based time-to-event outcomes (Pearson R = 0.99, concordance R = 0.98). Small but statistically significant differences (P < 0.05, without adjustment for multiple analyses) were observed for seven of the 35 factors. Agreement between eGFR and iGFR was somewhat weaker, although still relatively high for slope-based outcomes (Pearson R = 0.93, concordance R = 0.92). Effects of covariate adjustment for age, gender, baseline GFR, and urine proteinuria also were similar between the eGFR and iGFR outcomes. Sensitivity analyses including death in the composite time-to-event outcomes or using the Modification of Diet in Renal Disease equation instead of the AASK equation provided similar results. In conclusion, the data from the AASK provide tentative support for use of outcomes that are based on an established eGFR formula using serum creatinine as a surrogate for measured iGFR-based outcomes in analyses of risk factors for the progression of kidney disease.
Enhanced Na <sup>+</sup> -Ca <sup>2+</sup> Exchange in the Infarcted Heart
Authors: Sheldon E. Litwin, John H. B. Bridge
Journal: Circulation Research (1997)

Abstract Cellular Ca 2+ regulation is abnormal in diseased hearts. We designed this study to assess the role of the Na + -Ca 2+ exchanger in excitation-contraction coupling in surviving myocardium of the infarcted heart. We measured cellular contractions and whole-cell currents in single left ventricular myocytes isolated from the hearts of rabbits with healed myocardial infarction (MI). Eight weeks after MI, rabbits had left ventricular dysfunction without overt heart failure. Myocytes isolated from regions adjacent to the infarcted zone were significantly longer than cells from control hearts. At low stimulation rates (0.5 Hz), the amplitude of field-stimulated contractions was increased (11.6±0.5% versus 10.2±0.6% resting cell length), whereas the time to peak shortening and action potential duration were prolonged in the MI cells. When stimulation frequency was increased to 2.0 Hz, cellular shortening did not change or decreased in myocytes from infarcted hearts, whereas control cells had a positive shortening-interval relationship. Cells from infarcted hearts had a significantly decreased (31%) L-type Ca 2+ current ( I Ca ) density but no change in the current-voltage relationship or the kinetics of I Ca inactivation. Maximal Na + -Ca 2+ exchange current density was significantly increased (32%) in the cells from infarcted hearts. Sarcoplasmic reticulum (SR) Ca 2+ content during a stable train of contractions, as estimated from caffeine-induced inward currents, was slightly increased ( P =NS) in the MI myocytes. To determine whether Na + -Ca 2+ exchange influenced SR Ca 2+ content, cells were clamped at potentials between −70 and +90 mV for 400 ms. The amplitude of the contraction during a subsequent clamp step to +10 mV was then measured as an index of SR loading that occurred during the preceding clamp step. Steps to positive potentials produced greater augmentation of the subsequent contraction in MI than in control myocytes. In myocytes from the infarcted heart, increased activity of the Na + -Ca 2+ exchanger may promote Ca 2+ entry or decrease Ca 2+ extrusion. This relative augmentation of inward Ca 2+ flux by the exchanger may enhance SR Ca 2+ loading and thus support contractility that would otherwise be impaired as a result of decreased Ca 2+ current. However, Ca 2+ influx by the exchanger may contribute to the prolongation of contractions in myocytes from infarcted hearts.
The impact of polycyclic aromatic hydrocarbons and fine particles on pregnancy outcome.
Authors: J Dejmek, I Solanský, I Benes, J Lenícek, R J Srám
Journal: Environmental Health Perspectives (2000)

The relationship between intrauterine growth retardation (IUGR) and exposure to particulate matter [less than/equal to] 10 microm (PM(10)) and particulate matter [less than and equal to] 2.5 microm (PM(2.5))( )in early pregnancy was recently studied in the highly polluted district of Teplice (Northern Bohemia). From this observation rose the question about the possible role of the carcinogenic fraction of polycyclic aromatic hydrocarbons (c-PAHs), which are usually bound to fine particles. The impact of c-PAHs and fine particles on IUGR was analyzed in Teplice and in Prachatice, a region with similarly high c-PAH but low particle levels. All European, single live births occurring in a 4-year period in Teplice (n = 3,378) and Prachatice (n = 1,505) were included. Detailed personal data were obtained via questionnaires and medical records. Mean PM(10), PM(2.5,) and c-PAHs levels during the 9 gestational months (GM) were estimated for each mother. Adjusted odds ratios (AORs) of IUGR for three levels of c-PAHs (low, medium, and high) and for continuous data were estimated after adjustment for a range of covariates using logistic regression models. In the present 4-year sample from Teplice, previously published results about increasing IUGR risk after exposure to particles in the first GM were fully confirmed, but no such effects were found in Prachatice. The AOR of IUGR for fetuses from Teplice exposed to medium levels of c-PAHs in the first GM was 1.60 [confidence interval (CI), 1.06-2. 15], and to high levels 2.15 (CI, 27-3.63). An exposure-response relationship was established by analyzing the continuous data. For each 10 ng increase of c-PAHs in the first GM, the AOR was 1.22 (CI, 1.07-1.39). About the same relationship was observed in Prachatice in spite of the low particle levels. The results prove that exposure to c-PAHs in early gestation may influence fetal growth. The particulate matter-IUGR association observed earlier may be at least partly explained by the presence of c-PAHs on particle surfaces.
Effects of cyclosporine A on skeletal muscle mitochondrial respiration and endurance time in rats.
Authors: J G Mercier, J F Hokanson, G A Brooks
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

We investigated the effects of 14 d of cyclosporine A (CsA) administration on skeletal muscle mitochondrial respiration and submaximal running endurance time in rats. Eight experimental (CsA) and eight control rats followed a 14-d feeding protocol of CsA (20 mg/kg/d) oral administration or placebo. Submaximal endurance exercise time (EET) was measured on a treadmill on Day 13 and mitochondria were isolated from the hind limb muscles homogenate on Day 15. The results showed (1) a significant decrease of EET in CsA versus control rats (29 +/- 8 min versus 60 +/- min, p < 0.001), (2) significantly lower state 3 and uncoupled mitochondrial respiration in CsA compared with control rats with pyruvate plus malate (p < 0.001, p < 0.01) as well as succinate plus rotenone (p < 0.01) as substrates, (3) no differences in coupling efficiency (ADP/O ratios), and (4) significant linear correlation between EET and state 3 respiration (r = 0.71, p < 0.05; r = 0.92, p < 0.001), and strong curvilinear relationship between EET and CsA state 3/mean control state 3 (r2 = 0.81, p < 0.001; r2 = 0.82, p < 0.001), respectively, with pyruvate plus malate and succinate plus rotenone. We conclude that 14 d of CsA oral administration decreases skeletal muscle mitochondrial electron chain capacity without changing coupling efficiency in rats. Results suggest that immunosuppressive therapy is responsible, in part, for poor exercise performance in transplant patients.
Obesity and Cancer Treatment: Weighing the Evidence
Authors: Jennifer J. Griggs, Michael S. Sabel
Journal: Journal of Clinical Oncology (2008)

Obesity rates in the United States have increased tremendously over the past few decades. 1 Obesity is associated with an increased risk of several cancers, including breast cancer, colorectal cancer, and endometrial cancer, and is associated with higher cancer mortality rates. 2,3 Multiple factors contribute to the unfavorable survival rates in obese patients with cancer, including a higher likelihood of comorbid conditions and a higher likelihood of unfavorable tumor characteristics. In addition, systematic underdosing of chemotherapy in overweight and obese patients with breast cancer, 4-7 which occurs in up to 40% of patients, may contribute to the poorer survival rates, particularly among those with estrogen receptor (ER)–negative cancers. 8 This issue of theJournalofClinicalOncology features three studies that broadly address the complicated relationship between weight, factors associated with obesity, and cancer, spanning the bench to the bedside. Creighton and colleagues 9 examined the effect of insulinlike growth factor-2 (IGF-1) exposure on gene expression profiles in MCF-7 breast cancer cells. After developing an IGF-1 gene signature, the investigators assessed the IGF activation score in tumor samples contained within publicly available expression profile databases. The IGF gene signature was associated in this study with other known poor prognostic factors, such as ER-negative status, higher tumor grade, and higher stage. The authors conclude “Transcriptional targets of IGF-1 represent pathways of increased aggressiveness and possibly hormone independence i n... breast cancer.” The findings of this study contribute to our understanding of cancer biology in obese patients, who have higher levels of IGF-1 activity 10 and, in some studies (including the paper by Litton and colleagues in this issue of the Journal 11 ), a higher likelihood of ER-negative breast cancer.
Platelet adhesion to human vascular endothelium is modulated by constitutive and cytokine induced nitric oxide
Authors: M. W Radomski, P. Vallance, G. Whitley, N. Foxwell, S. Moncada
Journal: Cardiovascular Research (1993)

The aim was to study whether basal or cytokine stimulated generation of nitric oxide (NO) modulates platelet adhesion to human umbilical vein endothelial cells (HUVEC).The adhesion of 111In labelled human platelets to transfected HUVEC (SGHEC-7) was measured either alone or after incubation of SGHEC-7 cells for 18 h with interleukin-1 beta (IL-1 beta) and/or tumour necrosis factor alpha (TNF alpha). The activity of NO synthase in these cells was measured by formation of citrulline. The effects of dexamethasone (0.3 microM) and NG-monomethyl-L-arginine (L-NMMA, 100 microM) on these two variables were determined.Stimulation of SGHEC-7 cells with IL-1 beta or TNF alpha (each at 1-30 ng.ml-1) caused them to express the inducible NO synthase, an effect that was prevented by dexamethasone. Platelet adhesion to unstimulated SGHEC-7 cells was < 0.1% (n = 3) and was increased to 0.7 (SEM 0.2)% by L-NMMA but was not affected by dexamethasone. Stimulation of the cells with IL-1 beta and TNF alpha increased platelet adhesion to a maximum of 2.2(0.4)%. This increase was enhanced by both dexamethasone and L-NMMA. The effect of L-NMMA was prevented by L-arginine.Inhibition of NO synthesis by L-NMMA potentiates platelet adhesion to unstimulated SGHEC-7 cells, showing that basally released NO regulates platelet adhesion. Stimulation of SGHEC-7 cells by cytokines increases their adhesive properties but at the same time causes them to express the inducible NO synthase. Nitric oxide generated by this enzyme contributes to the modulation of the adhesive properties of the endothelial cells. Thus both constitutive and inducible NO synthases modulate endothelial cell thrombogenicity.
NO mobilizes intracellular Zn2+ via cGMP/PKG signaling pathway and prevents mitochondrial oxidant damage in cardiomyocytes
Authors: Y JANG, H WANG, J XI, R MUELLER, E NORFLEET, Z XU
Journal: Cardiovascular Research (2007)

Our aim was to determine if NO prevents mitochondrial oxidant damage by mobilizing intracellular free zinc (Zn(2+)).Zn(2+) levels were determined by imaging enzymatically isolated adult rat cardiomyocytes loaded with Newport Green DCF. Mitochondrial membrane potential (DeltaPsi(m)) was assessed by imaging cardiomyocytes loaded with tetramethylrhodamine ethyl ester (TMRE).S-nitroso-N-acetylpenicillamine (SNAP) dramatically increased Zn(2+), which was blocked by both ODQ and NS2028, two specific inhibitors of guanylyl cyclase. The protein kinase G (PKG) inhibitor KT5823 blocked the effect of SNAP while the PKG activator 8-Br-cGMP mimicked the action of SNAP, indicating that the cGMP/PKG pathway is responsible for the effect of SNAP. The increased Zn(2+) was prevented by 5-hydroxydecanoate (5HD) but was mimicked by diazoxide, implying that mitochondrial K(ATP) channel opening may account for this effect. Since chelation of Zn(2+) blocked the preventive effect of SNAP on H(2)O(2)-induced loss of DeltaPsi(m) and exogenous zinc (1 microM ZnCl(2)) prevented dissipation of DeltaPsi(m), Zn(2+) may play a critical role in the protective effect of NO. The MEK (mitogen-activated protein kinase or extracellular signal-regulated kinase) inhibitor PD98059 blocked the preventive effects of SNAP and zinc on DeltaPsi(m), indicating that extracellular signal-regulated kinase (ERK) mediates the protective effect of both these compounds on mitochondrial oxidant damage. A Western blot analysis further showed that ZnCl(2) significantly enhances phosphorylation of ERK, confirming the involvement of ERK in the action of Zn(2+).In isolated cardiomyocytes, NO mobilizes endogenous zinc by opening mitochondrial K(ATP) channels through the cGMP/PKG pathway. In these cells, Zn(2+) may be an important mediator of the action of NO on the mitochondrial death pathway.