tbuckley/cabot-search huggingface dataset:
The Renal Clearance of Endogenous Estrogens in Late Pregnancy*
Authors: C. Harmon Brown, Benjamin D. Saffan, Carolyn M. Howard, John R. K. Preedy
Journal: Journal of Clinical Investigation (1964)

Although several studies have been published describing the renal excretion of certain steroid hormones (2, 3), or groups of hormones and hormone metabolites (4-8), an analysis of the re- nal clearance of endogenous estrogens has not so far been described.This has been due principally to the lack of adequate chemical methods for the determination of estrogens in plasma.Methods for the determination of plasma estrogens in late pregnancy, however, have recently become avail- able (9, 10), and it therefore appeared feasible to investigate the renal excretion of endogenous estrogens in this condition.An inspection of the general level of estrogen concentrations in ran- dom samples obtained from subjects in late preg- nancy had suggested that the concentration ratio of the three estrogens estrone (1,3,5-estratrien-3ol-17-one), estradiol-17,8 (1,3,5-estratriene-3, 17,3diol), and estriol (1,3,5-estratriene-3,f, 16a, 17,8triol) in plasma might differ from their concen- tration ratio in urine (11).A series of pregnant subjects was selected, and renal excretion studies of total' estrone, total estradiol-17,8, and total estriol were carried out.
CaMKII Inhibition in Heart Failure Makes Jump to Human
Authors: Donald M. Bers
Journal: Circulation Research (2010)

this issue of Circulation Research, Sossalla et al 1 show that acute inhibition of Ca 2ϩ /calmodulin-dependent protein kinase (CaMK)II in failing human myocardium causes functional improvement in contractility by restoring a positive force-frequency relationship (FFR) in cardiac trabeculae.The loss of this normal positive FFR (and often an induction of a negative FFR) is a functional hallmark of failing human myocardium 2 and has been seen as an intrinsic limitation of the failing heart to enhance contractility appropriately at higher heart rates.This failure of positive FFR also constitutes a reduction in functional cardiac reserve.So, why might CaMKII inhibition be beneficial in heart failure (HF)? CaMKII Activity in Heart Failure and Functional Molecular Targets4][5][6][7][8][9] It has also come to light that CaMKII has many different functional effects in cardiac myocytes, including alterations in ion channels, Ca 2ϩ handling proteins, myofilaments, and transcriptional regulation. 10 -12 Moreover, many of these CaMKII effects on myocyte properties have been implicated in hypertrophy, HF, and arrhythmias in animal models.4][15] Sossalla et al 1 provide important novel data that acute CaMKII inhibition in human HF myocardium causes functional improvement.This is an important validation step with respect to consideration of cardiac CaMKII inhibition as therapeutic strategy in human HF.So, what are some key acute functional effects of CaMKII that can alter cardiac Ca 2ϩ handling and excitability?CaMKII phosphorylates Thr17 on phospholamban (PLN), which can relieve the inhibitory effect of PLN on the sarcoplasmic reticulum (SR) Ca-ATPase and thereby enhance Ca 2ϩ uptake into the SR.This PLN effect of CaMKII would be positively inotropic and lusitropic (like PKA-dependent phosphorylation at Ser16 on PLN).These PLN effects could enhance arrhythmogenic events indirectly by enhancing SR Ca 2ϩ content (and enhancing diastolic SR Ca 2ϩ release), but
Atheroprotective Effects of High-Density Lipoproteins
Authors: Gerd Assmann, Jerzy-Roch Nofer
Journal: Annual Review of Medicine (2003)

Observational studies provide overwhelming evidence that a low high-density lipoprotein (HDL)-cholesterol level increases the risk of coronary events, both in healthy subjects and in patients with coronary heart disease. Based on in vitro experiments, several mechanistic explanations for the atheroprotective function of HDL have been suggested. However, few of these were verified in vivo in humans or in experiments with transgenic animals. The HDL functions currently most widely held to account for the antiatherogenic effect include participation in reverse cholesterol transport, protection against endothelial dysfunction, and inhibition of oxidative stress. This review summarizes current views on the molecular mechanism underlying these atheroprotective effects of HDL.
Depressive Effect of 7,12-Dimethylbenz[a]anthracene and Ionizing Irradiation on Bone Marrow Colony-Forming Cells2
Authors: J. K. Ball, S. Hoshino, J. A. McCarter
Journal: JNCI Journal of the National Cancer Institute (1973)

Treatment of neonatal inbred CFW/D mice with 7, 12- dimethylbenzSTAa!anthracene (DMBA) or gamma -irradiation suppressed the number of colony-forming units (CFUs) or stem cells in the bone marrow. At 14 days after administration, DMBA (30 mu g) had induced an 85% depression; at 60 days post treatment, there was still a 60 to 70% suppression. The extent and duration of the depression after the neonatal exposure to 400 rads (whole body) were similar. The permanent reduction in CFUs after neonatal irradiation contrasted sharply with the short-term effect of such a dose administered to adult animals. For both DMBA and irradiation treatment, the extent of the depression was dose dependent at low doses only. The effect of DMBA on the number of bone marrow stem cells was not merely quantitative: The CFUs remaining after treatment had a diminished ability to form spleen colonies on secondary transplantation. (auth)
Prevalence of Fabry disease in patients with cryptogenic stroke: a prospective study
Authors: Arndt Rolfs, Tobias Böttcher, Marlies Zschiesche, Peter Morris, Bryan Winchester, Peter Bauer, Uwe Walter, Eilhard Mix, Mathias Löhr, Klaus Harzer, Ulf Strauss, Jens Pahnke, Annette Grossmann, Reiner Benecke
Journal: The Lancet (2005)
Limb salvage with isolated perfusion for soft tissue sarcoma: could less TNF-α be better?
Authors: S. Bonvalot, A. Laplanche, F. Lejeune, E. Stoeckle, C. Le Péchoux, D. Vanel, P. Terrier, J. Lumbroso, M. Ricard, G. Antoni, A. Cavalcanti, C. Robert, N. Lassau, J.Y. Blay, A. Le Cesne
Journal: Annals of Oncology (2005)
The sinusitis-infertility syndrome: Young's saint, old devil
Authors: P. C. Goeminne, L. J. Dupont
Journal: European Respiratory Journal (2010)

The sinusitis-infertility syndrome: Young's saint, old devilTo the Editors:Young's syndrome (YS) is a triad of bronchiectasis, chronic rhinosinusitis and infertility due to vas deferens obstruction, in which case cystic fibrosis (CF) and primary ciliary diskinesia are excluded.One assumed aetiology of YS is mercury exposure during childhood.During the 20th Century, mercury use was discouraged, thus reducing exposure.HENDRY et al. [1] postulated that this was the reason for the declining prevalence of YS.They observed a rate of 50% of YS in males with obstructive azoospermia who were born before 1955; however, this number plummeted to 17% in males born after 1955.So, if mercury poisoning is truly the aetiology, it is likely that YS is declining.Furthermore, there seems to be a lack of convincing evidence describing the sinusitis component of YS, raising doubt as to whether the syndrome is a real cause of chronic sinusitis [2].Nevertheless, YS is still regarded as a cause of bronchiectasis.In adult bronchiectatic populations, its presence is estimated to be ,3% [3,4].Conversely, YS was not found in our group of 342 patients with bronchiectasis.72 patients had non-CF bronchiectasis without YS.In the remaining 270 CF patients, 137 were male of which 10 had one missing genotype.Of these 10 patients, only three had a negative sweat test.They all had chronic rhinosinusitis.In these patients, genetic testing discovered heterozygosity for dF508.The first patient had no obstruction of the vas deferens but an atresia, being more suggestive for CF-like disease.The second patient showed exocrine pancreatic insufficiency, diabetes, distal intestinal obstruction syndrome and a sibling with CF.Finally, the third patient had exocrine pancreatic insufficiency and diabetes.Full sequencing of the CF gene did not show a second mutation in these patients.The clinical phenotype suggested a diagnosis of CF-like disease rather than YS in these patients.The inability to detect deep intronic mutations with complete CF transmembrane conductance regulator (CFTR) gene array and the possibility of changed expression in co-modulatory genes makes it difficult to exclude CF genotype completely.In conclusion, we believe that YS, when caused by mercury exposure, is declining.In all other cases, YS should probably be regarded as a CF-like disease and implies further investigation by more extensive screening of the CFTR gene, which may reveal CFTR gene disease, including the milder regions of the disease spectrum [5].Thus, once considered an old saint, YS has now become, thanks to scientific progress, truly an old devil.
Ontogeny of B-lymphocyte function. V. Thymus cell involvement in the functional maturation of B-lymphocytes from fetal mice transferred into adult irradiated hosts.
Authors: D H Sherr, M R Szewczuk, G W Siskind
Journal: The Journal of Experimental Medicine (1978)

Lethally irradiated mice reconstituted with adult thymus cells and neonatal or fetal liver cells produce an anti-2,4-dinitrophenyl or anti-bovine gamma globulin response of restricted heterogeneity of affinity in comparison with the response of mice reconstituted with B cells from adult donors. In addition, mice reconstituted with day 15 fetal B cells and adult thymus cells produce relatively few indirect plaque-forming cells (PFC). It was found that B cells acquire the capacity to produce a heterogeneous response, of predominantly indirect PFC within 7 days of transfer only when thymus cells are transferred along with the B cells. B cells from fetal or neonatal donors transferred without young adult thymus cells develop the capacity to generate indirect PFC within 13 days after transfer to adult recipients, but continue to produce a response of restricted heterogeneity of affinity for up to 28 days after transfer. Thus, it has been shown that cells present in the thymus facilitate, or are necessary for the functional maturation of B lymphocytes. Furthermore, the data suggest that maturation of the B-cell population to produce a heterogeneous response is controlled independently of its maturation to be capable of producing indirect PFC.
Genetic Variation at 8q24 as a Susceptibility Factor for Prostate Cancer: Definitive Results from Epidemiologic Studies?
Authors: Elizabeth A. Platz
Journal: Cancer Research (2007)

In this issue of Cancer Research , two epidemiologic studies investigating the association between genetic variants on chromosome 8q24 and prostate cancer are published. The purpose of this editorial is to comment on the importance and implications of these findings and to explain the rationale of
Genetic Variations and Patient-Reported Quality of Life Among Patients With Lung Cancer
Authors: Jeff A. Sloan, Mariza de Andrade, Paul Decker, Jason Wampfler, Curtis Oswold, Matthew Clark, Ping Yang
Journal: Journal of Clinical Oncology (2012)

Purpose Recent evidence has suggested a relationship between the baseline quality of life (QOL) self-reported by patients with cancer and genetic disposition. We report an analysis exploring relationships among baseline QOL assessments and candidate genetic variations in a large cohort of patients with lung cancer. Patients and Methods QOL data were provided by 1,299 patients with non–small-cell lung cancer observed at the Mayo Clinic between 1997 and 2007. Overall QOL and subdomains were assessed by either Lung Cancer Symptom Scale or Linear Analog Self Assessment measures; scores were transformed to a scale of 0 to 10, with higher scores representing better status. Baseline QOL scores assessed within 1 year of diagnosis were dichotomized as clinically deficient (CD) or not. A total of 470 single nucleotide polymorphisms (SNPs) in 56 genes of three biologic pathways were assessed for association with QOL measures. Logistic regression with training/validation samples was used to test the association of SNPs with CD QOL. Results Six SNPs on four genes were replicated using our split schemes. Three SNPs in the MGMT gene (adjusted analysis, rs3858300; unadjusted analysis, rs10741191 and rs3852507) from DNA repair pathway were associated with overall QOL. Two SNPs (rs2287396 [GSTZ1] and rs9524885 [ABCC4]) from glutathione metabolic pathway were associated with fatigue in unadjusted analysis. In adjusted analysis, two SNPs (rs2756109 [ABCC2] and rs9524885 [ABCC4]) from glutathione metabolic pathway were associated with pain. Conclusion We identified three SNPs in three glutathione metabolic pathway genes and three SNPs in two DNA repair pathway genes associated with QOL measures in patients with non–small-cell lung cancer.
Expression of Self-antigen in the Thymus
Authors: Ana C. Anderson, Vijay K. Kuchroo
Journal: The Journal of Experimental Medicine (2003)

For many years, it has been hypothesized that a major factor in organ-specific autoimmunity is a lack of central tolerance to self-antigens that are sequestered behind anatomical barriers in organs such as the eye, testis, and brain. However, numerous studies published in the last few years argue
Contemporary Clinical Profile and Outcome of Prosthetic Valve Endocarditis
Authors: Andrew Wang
Journal: JAMA (2007)

HEART VALVE REPLACEMENT surgery is performed in more than 150 000 patients per year in the United States and Europe, 1,2 and the number of prosthetic valve implantations continues to increase. 3Infection of a heart valve prosthesis, or prosthetic valve endocarditis (PVE), is an uncommon but potentially lethal complication of heart valve replacement surgery.Despite ad-
Randomized, Controlled Trial of Glucose-Sparing Peritoneal Dialysis in Diabetic Patients
Authors: Philip K.T. Li, Bruce F. Culleton, Amaury Ariza, Jun-Young Do, David W. Johnson, Mauricio Sanabria, Ty R. Shockley, Ken Story, Andrey Vatazin, Mauro Verrelli, Alex W. Yu, Joanne M. Bargman
Journal: Journal of the American Society of Nephrology (2013)

Glucose-containing peritoneal dialysis solutions may exacerbate metabolic abnormalities and increase cardiovascular risk in diabetic patients. Here, we examined whether a low-glucose regimen improves metabolic control in diabetic patients undergoing peritoneal dialysis. Eligible patients were randomly assigned in a 1:1 manner to the control group (dextrose solutions only) or to the low-glucose intervention group (IMPENDIA trial: combination of dextrose-based solution, icodextrin and amino acids; EDEN trial: a different dextrose-based solution, icodextrin and amino acids) and followed for 6 months. Combining both studies, 251 patients were allocated to control (n=127) or intervention (n=124) across 11 countries. The primary endpoint was change in glycated hemoglobin from baseline. Mean glycated hemoglobin at baseline was similar in both groups. In the intention-to-treat population, the mean glycated hemoglobin profile improved in the intervention group but remained unchanged in the control group (0.5% difference between groups; 95% confidence interval, 0.1% to 0.8%; P=0.006). Serum triglyceride, very-low-density lipoprotein, and apolipoprotein B levels also improved in the intervention group. Deaths and serious adverse events, including several related to extracellular fluid volume expansion, increased in the intervention group, however. These data suggest that a low-glucose dialysis regimen improves metabolic indices in diabetic patients receiving peritoneal dialysis but may be associated with an increased risk of extracellular fluid volume expansion. Thus, use of glucose-sparing regimens in peritoneal dialysis patients should be accompanied by close monitoring of fluid volume status.
Plitidepsin Has a Cytostatic Effect in Human Undifferentiated (Anaplastic) Thyroid Carcinoma
Authors: Susana B. Bravo, María E.R. García-Rendueles, Rafael Seoane, Vanesa Dosil, José Cameselle-Teijeiro, Luis López-Lázaro, Juan Zalvide, Francisco Barreiro, Celia M. Pombo, Clara V. Álvarez
Journal: Clinical Cancer Research (2005)

Abstract Undifferentiated (anaplastic) thyroid carcinoma is a highly aggressive human cancer with very poor prognosis. Although there have been a few studies of candidate treatments, the fact that it is an infrequent tumor makes it very difficult to design clinical trials. A strong association has been observed between undifferentiated thyroid carcinoma and TP53 mutations in numerous molecular genetic and expression studies. Plitidepsin (Aplidin, PharmaMar, Madrid, Spain) is a novel anticancer compound obtained from a sea tunicate. This compound has been reported to induce apoptosis independently of TP53 status. We investigated the actions of plitidepsin in human thyroid cancer cells. In initial experiments using primary cultured cells from a differentiated (papillary) carcinoma, we found that 100 nmol/L plitidepsin induced apoptosis, whereas lower doses were cytostatic. Because our aim was to study the effects of plitidepsin at clinically relevant concentrations, subsequent experiments were done with a dosage regimen reflecting plasma concentrations observed in previously reported clinical trials: 100 nmol/L for 4 hours, followed by 10 nmol/L for 20 hours (4100/2010 plitidepsin). This plitidepsin dosage regimen blocked the proliferation of a primary undifferentiated/anaplastic thyroid carcinoma culture obtained in our laboratory and of a commercial cell line (8305C) obtained from an undifferentiated thyroid carcinoma; however, it did not induce apoptosis. The proportion of cells in the G1 phase of the cell cycle was greatly increased and the proportion in the S/G2-M phases greatly reduced, suggesting that plitidepsin blocks G1-to-S transition. Levels of the cyclin D1/cyclin-dependent kinase 4/p21 complex proteins were decreased and, in line with this, the levels of unphosphorylated Rb1 increased. The decrease in cell cycle proteins correlated with hypoacetylation of histone H3. Finally, we did experiments to assess how rapidly tumor cells return to their initial pretreatment proliferative behavior after 4100/2010 plitidepsin treatment. Cells from undifferentiated tumors needed more than 3 days to recover logarithmic growth, and after 7 days, cell number was still significantly lower than in control cultures. 4100/2010 plitidepsin inhibited the growth in soft agar. Together, our data show that plitidepsin is able to block in vitro cell cycle progression at concentrations similar to serum concentrations observed in vivo, and that this effect is persistent for several days after plitidepsin removal. Whether plitidepsin will prove to be clinically useful in the treatment of undifferentiated thyroid cancers remains to be established. However, our results raise the possibility that plitidepsin might be effective alone or in combination with radiotherapy and/or other drug treatments.
Treatment of Prostate Cancer With Intermittent Versus Continuous Androgen Deprivation: A Systematic Review of Randomized Trials
Authors: Saroj Niraula, Lisa W. Le, Ian F. Tannock
Journal: Journal of Clinical Oncology (2013)

Uncertainty exists regarding benefits of intermittent androgen deprivation (IAD) compared with continuous androgen deprivation (CAD) for treatment of prostate cancer. On the basis of a systematic review of evidence, our aim was to formulate a recommendation for either IAD or CAD to treat relapsing, locally advanced, or metastatic prostate cancer.We searched literature published up to September 2012 from MEDLINE, EMBASE, the Cochrane Library, and major conference proceedings. We included randomized controlled trials comparing IAD and CAD if they reported overall survival (OS) or biochemical/radiologic time to disease progression.Nine studies with 5,508 patients met our criteria. There were no significant differences in time-to-event outcomes between the groups in any studies. The pooled hazard ratio (HR) for OS was 1.02 (95% CI, 0.94 to 1.11) for IAD compared with CAD, and the HR for progression-free survival was 0.96 (95% CI, 0.76 to 1.20). More prostate cancer-related deaths with IAD tended to be balanced by more deaths not related to prostate cancer with CAD. Superiority of IAD for sexual function, physical activity, and general well-being was observed in some trials. Median cost savings with IAD was estimated to be 48%.There is fair evidence to recommend use of IAD instead of CAD for the treatment of men with relapsing, locally advanced, or metastatic prostate cancer who achieve a good initial response to androgen deprivation. This recommendation is based on evidence against superiority of either strategy for time-to-event outcomes and substantial decrease with IAD in exposure to androgen deprivation, resulting in less cost, inconvenience, and potential toxicity.
End-of-Life Decision Making in the Intensive Care Unit
Authors: John M. Luce
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Increasingly in the United States and other countries, medical decisions, including those at the end of life, are made using a shared decision-making model. Under this model, physicians and other clinicians help patients clarify their values and reach consensus about treatment courses consistent with them. Because most critically ill patients are decisionally impaired, family members and other surrogates must make end-of-life decisions for them, ideally in accord with a substituted judgment standard. Physicians generally make decisions for patients who lack families or other surrogates and have no advance directives, based on a best interests standard and occasionally in consultation with other physicians or with review by a hospital ethics committee. End-of-life decisions for patients with surrogates usually are made at family conferences, the functioning of which can be improved by several methods that have been demonstrated to improve communications. Facilitative ethics consultations can be helpful in resolving conflicts when physicians and families disagree in end-of-life decisions. Ethics committees actually are allowed to make such decisions in one state when disagreements cannot be resolved otherwise.
GRAFT-VS.-HOST REACTION IN TISSUE CULTURE
Authors: Robert Auerbach, M. R. Shalaby
Journal: The Journal of Experimental Medicine (1973)

The primary purpose of this study has been to validate the in vitro graft-vs.-host reaction as an experimental system. Time-dose studies have been presented for cells obtained from spleen, thymus, cortisone-treated thymus, inguinal lymph node, mesenteric lymph node, thoracic duct, and bone marrow cells. Both the degree of splenomegaly and the onset of spleen enlargement were found to be dependent on the number and source of cells tested. The effect of several immunosuppressive agents was examined. Amantadine was found to suppress completely the graft-vs.-host reaction in vitro when present at a concentration of 75 microg/ml. Pretreatment of effector cells with mitomycin C prevented their subsequent ability to cause a graft-vs.-host reaction. The effect of X irradiation on immunocompetence of spleen cells in vitro paralleled the known effect of irradiation on in vivo immunocompetence. Preimmunization did not increase the number or effectiveness of immunocompetent cells when measured under standard in vitro conditions. Preimmunization did, however, permit persistence of immunocompetence after immunosuppressive doses of X irradiation. Studies using congenic lines, moreover, indicated that the preimmunization effect could be demonstrated in strain combinations differing only in factors determined by the H-2 complex of genes. A weak graft-vs.-host reaction could be detected in strain combinations not involving differences at the H-2 locus. The potential of the in vitro graft-vs.-host reaction as a highly reproducible, quantifiable, internally controlled, and experimentally accessible system for study of such critical problems as cell differentiation and cell interactions is discussed.