tbuckley/cabot-search huggingface dataset:
Risk Information Provided to Prospective Oocyte Donors in a Preliminary Phone Call
Authors: A D Gurmankin
Journal: The American Journal of Bioethics (2001)

In order to accommodate for the present shortage of oocyte donors, oocyte-donation programs place ads in college newspapers and provide large monetary compensation to encourage participation. Large compensation acts as a strong incentive for young women to undergo the potentially risky procedure of donation. In this enticing situation, it is particularly important for programs to fully inform prospective donors of the risks of the procedure so that they can accurately weigh the costs and benefits of donating. However, because oocyte-donor programs must alleviate the shortage of donors if they wish to maintain a financially viable business, there is reason to fear that they may minimize or misrepresent risks when recruiting egg donors. In this pilot study, the risk information provided by programs (n=19) to prospective oocyte donors in a preliminary phone call inquiry was investigated. The majority of the programs provided incomplete and/or inaccurate risk information. Policy changes are recommended to reduce the potential for undue influence and to standardize and regulate the risk information provided to prospective egg donors.
Inflammatory Bowel Disease Genetics: Nod2
Authors: Judy H. Cho, Clara Abraham
Journal: Annual Review of Medicine (2006)

The inflammatory bowel diseases (IBD) are comprised of two major subphenotypes, Crohn's disease (CD) and ulcerative colitis (UC). A significant role for genetic factors in IBD was established from epidemiologic studies and, more recently, the identification of well-established disease associations, notably the association of Nod2 (CARD15) polymorphisms with CD. The mapping to CD of Nod2 variants that alter protein function represents one of the earliest, most well-established, associations in complex genetic disorders. Since the initial discovery, genotype-phenotype correlations, definition of Nod2 expression and signaling pathways, association studies in other, related disorders, and features of Nod2 deficiency in murine models have been reported. Taken together, the Nod2 association to CD provides an illustrative model of the role of single gene variants in disease pathogenesis for common, complex multigenic disorders. Here we review general aspects of IBD genetics with particular focus on the role of Nod2 in CD.
High -catenin/Tcf-4 activity confers glioma progression via direct regulation of AKT2 gene expression
Authors: J. Zhang, K. Huang, Z. Shi, J. Zou, Y. Wang, Z. Jia, A. Zhang, L. Han, X. Yue, N. Liu, T. Jiang, Y. You, P. Pu, C. Kang
Journal: Neuro-Oncology (2011)

Recent data suggest that the b-catenin/Tcf-4 signaling pathway plays an important role in human cancer tumorigenesis.However, the mechanism of b-catenin/ Tcf-4 signaling in tumorigenesis is poorly understood.In this study, we show that Tcf-4 protein levels were significantly elevated in high-grade gliomas in comparison with low-grade gliomas and that Tcf-4 levels correlated with levels of AKT2.Reduction of b-catenin/Tcf-4 activity inhibited glioma cell proliferation and invasion in vitro and tumor growth in vivo.This effect of bcatenin/Tcf-4 activity was mediated by AKT2, and in vivo binding of b-catenin/Tcf-4 to the AKT2 promoter was validated using the chromatin immunoprecipitation assay and luciferase reporter assays.Taken together, we have demonstrated that Tcf-4 is associated with glioma progression and that AKT2 is a new member of the genes that are regulated by b-catenin/Tcf-4.
THE LANGUAGE OF HEALTH CARE: Funding and the NEJM
Authors: N. Ross
Journal: Journal of the Royal Society of Medicine (2006)

Richard Smith, who knows a thing or two about editing medical journals, makes a persuasive case that they are often an extension of the marketing arm of pharmaceutical companies. If Jeffrey Drazen persists in his denial and believes his NEJM is above such things, perhaps he would agree to declare in each edition the Journal's sources of income, including the numbers of reprints sold and to whom. Then we could judge for ourselves. Meanwhile, as a journalist, I can tell you that Dr Drazen's belief in trusting his sources is misplaced to the point of naivety, whether in science or in any other field of human endeavour. On the other hand his reluctance to apologise quickly for getting things wrong makes him a very professional journalist indeed.
Molecular evolution of the Sex-Ratio inversion complex in Drosophila pseudoobscura: analysis of the Esterase-5 gene region
Authors: C. S. Babcock, W. W. Anderson
Journal: Molecular Biology and Evolution (1996)

The Sex-Ratio chromosome in Drosophila pseudoobscura is subject to meiotic drive. It is associated with a series of three nonoverlapping paracentric inversions on the right arm of the X chromosome. The esterase-5 gene region has been localized to section 23 within the subbasal inversion of the Sex-Ratio inversion complex, making esterase-5 a convenient locus for molecular evolutionary analyses of the Sex-Ratio inversion complex and the associated drive system. A 504-bp fragment of noncoding, intergenic DNA from the esterase-5 gene region was amplified and sequenced from 14 Sex-Ratio and 14 Standard X chromosomes of D. pseudoobscura, and from 9 X chromosomes of its two sibling species, Drosophila persimilis and Drosophila miranda. There is extensive sequence differentiation between the Sex-Ratio and Standard chromosomal types. The common Standard chromosome is highly polymorphic, while, as expected from either the neutral mutation theory or the selective sweep hypothesis, the rarer Sex-Ratio chromosome has much less within-chromosome nucleotide polymorphism. We estimate that the Standard and Sex-Ratio chromosomes in D. pseudoobscura diverged between 700,000 and 1.3 Mya, or at least 2 million generations ago. The clustering of D. pseudoobscura Sex-Ratio chromosomes in a neighbor-joining phylogeny indicates a fairly old, monophyletic origin in this species. It appears from these data that Sex-Ratio genes were present prior to the divergence of D. pseudoobscura and D. persimilis and that both the Standard and Sex-Ratio chromosomes of D. persimilis were derived from the Standard chromosome of D. pseudoobscura after the inversion events that isolated the D. pseudoobscura Sex-Ratio chromosome.
Spectral Analysis Identifies Sites of High-Frequency Activity Maintaining Atrial Fibrillation in Humans
Authors: Prashanthan Sanders, Omer Berenfeld, Mélèze Hocini, Pierre Jaïs, Ravi Vaidyanathan, Li-Fern Hsu, Stéphane Garrigue, Yoshihide Takahashi, Martin Rotter, Fréderic Sacher, Christophe Scavée, Robert Ploutz-Snyder, José Jalife, Michel Haïssaguerre
Journal: Circulation (2005)

The identification of sites of dominant activation frequency during atrial fibrillation (AF) in humans and the effect of ablation at these sites have not been reported.Thirty-two patients undergoing AF ablation (19 paroxysmal, 13 permanent) during ongoing arrhythmia were studied. Electroanatomic mapping was performed, acquiring 126+/-13 points per patient throughout both atria and coronary sinus. At each point, 5-second electrograms were obtained to determine the highest-amplitude frequency on spectral analysis and to construct 3D dominant frequency (DF) maps. The temporal stability of the recording interval was confirmed in a subset. Ablation was performed with the operator blinded to the DF maps. The effect of ablation at sites with or without high-frequency DF sites (maximal frequencies surrounded by a decreasing frequency gradient > or =20%) was evaluated by determining the change in AF cycle length (AFCL) and the termination and inducibility of AF. The spatial distribution of the DF sites was different in patients with paroxysmal and permanent AF; paroxysmal AF patients were more likely to harbor the DF site within the pulmonary vein, whereas in permanent AF, atrial DF sites were more prevalent. Ablation at a DF site resulted in significant prolongation of the AFCL (180+/-30 to 198+/-40 ms; P<0.0001; kappa=0.77), whereas in the absence of a DF site, there was no change in AFCL (169+/-22 to 170+/-22 ms; P=0.4). AF terminated during ablation in 17 of 19 patients with paroxysmal and 0 of 13 with permanent AF (P<0.0001). When 2 patients with nonsustained AF during mapping were excluded, 13 of 15 (87%) had AF termination at DF sites (54% at the initially ablated DF site): 11 pulmonary veins and 2 atrial. In addition, AF could no longer be induced in 69% with termination of AF at a DF site. There were no significant differences in the number or percentage of DF sites detected (5.4+/-1.6 versus 4.9+/-2.1; P=0.3) and ablated (1.9+/-1.0 versus 2.4+/-1.0; P=0.3) in those with and without AF termination. The duration of radiofrequency ablation to achieve termination was significantly shorter than that delivered in those with persisting AF (34.8+/-24.0 versus 73.5+/-22.9 minutes; P=0.0002). All patients with persisting AF had additional DF sites outside the ablated zones.Spectral analysis and frequency mapping identify localized sites of high-frequency activity during AF in humans with different distributions in paroxysmal and permanent AF. Ablation at these sites results in prolongation of the AFCL and termination of paroxysmal AF, indicating their role in the maintenance of AF.
Tolvaptan plus Pasireotide Shows Enhanced Efficacy in a PKD1 Model
Authors: Katharina Hopp, Cynthia J. Hommerding, Xiaofang Wang, Hong Ye, Peter C. Harris, Vicente E. Torres
Journal: Journal of the American Society of Nephrology (2014)

Autosomal dominant polycystic kidney disease (ADPKD) is a leading cause of ESRD. A central defect associated with ADPKD pathology is elevated levels of 3', 5'-cyclic AMP (cAMP). Compounds such as tolvaptan and pasireotide, which indirectly reduce adenylyl cyclase 6 (AC6) activity, have hence proven effective in slowing cyst progression. Here, we tested the efficacy of these compounds individually and in combination in a hypomorphic PKD1 model, Pkd1(R3277C/R3277C) (Pkd1(RC/RC)), in a 5-month preclinical trial. Initially, the Pkd1(RC/RC) model was inbred into the C57BL/6 background, minimizing disease variability, and the pathogenic effect of elevating cAMP was confirmed by treatment with the AC6 stimulant desmopressin. Treatment with tolvaptan or pasireotide alone markedly reduced cyst progression and in combination showed a clear additive effect. Furthermore, combination treatment significantly reduced cystic and fibrotic volume and decreased cAMP to wild-type levels. We also showed that Pkd1(RC/RC) mice experience hepatic hypertrophy that can be corrected by pasireotide. The observed additive effect reinforces the central role of AC6 and cAMP in ADPKD pathogenesis and highlights the likely benefit of combination therapy for patients with ADPKD.
Carotid Endarterectomy for Elderly Patients: Predicting Complications
Authors: R H Brook, R E Park, M R Chassin, J Kosecoff, J Keesey, D H Solomon
Journal: Annals of Internal Medicine (1990)

Objective: To determine whether the complication or death rate from carotid endarterectomy can be predicted from hospital and physician structural variables, such as the hospital's teaching status or the number of endarterectomies done by the surgeon per year. Design: Survey of medical records. After controlling for the severity of the patient's condition on the basis of data in the medical record at the time of the endarterectomy, regression analyses were used to predict the postoperative stroke, heart attack, and 30-day death rate as a function of patient, physician, and hospital characteristics. Setting: Three geographic areas (states or large parts of states; average population, 3 million) in the United States. Patients: Random sample of 1302 patients 65 years of age or older having carotid endarterectomy in 1981. Intervention: Carotid endarterectomy. Measurements and Main Results: Of 1302 patients, 11.3% had a postoperative stroke or heart attack or died within 30 days of the operation. Patient age, race, income, and gender; physician volume, board certification status, and age; and hospital size, for-profit status, ownership, and teaching status were not significantly related to the postoperative complication or death rate. If the surgeon was a graduate of a foreign, but not a Western European or Canadian, medical school, however, the average complication or death rate rose from 10.4% to 19.6% (P < 0.05). Conclusions: The effectiveness of carotid endarterectomy depends heavily on its complication rate. Because complications after surgery cannot, in general, be predicted from structural variables, referring physicians cannot rely solely on the surgeon's experience and qualifications when recommending a carotid endarterectomy. The surgeon's and the hospital's actual postoperative complication and death rate should be considered.
The Majority of Recent Short DNA Insertions in the Human Genome Are Tandem Duplications
Authors: P. W. Messer, P. F. Arndt
Journal: Molecular Biology and Evolution (2007)

Nucleotide substitutions, insertions, and deletions constitute the principal molecular mechanisms generating genetic variation on small length scales. In contrast to substitutions, the nature of short DNA insertions and deletions (indels) is far less understood. With the recent availability of whole-genome multiple alignments between human and other primates, detailed investigations on indel characteristics and origin have come within reach. Here, we show that the majority of short (1-100 bp) DNA insertions in the human lineage are tandem duplications of directly adjacent sequence segments with conserved polarity. Indels in microsatellites comprise only a small fraction. The underlying molecular processes generating indels do not necessarily rely on the presence of preexisting duplicates, as would be expected for unequal crossing over, as well as replication slippage. Instead, our findings point toward a mechanism that preferentially occurs in the male germline and is not recombination-mediated. Surprisingly, nonframeshifting tandem duplications and deletions in coding regions still occur at approximately 50% of their genomic background rates. As is already well established in the context of gene and segmental duplications, our results demonstrate that duplications are also likely to constitute the predominant process for rapid generation of new genetic material and function on smaller scales.
Enhancement of T-cell–Mediated Antitumor Response: Angiostatic Adjuvant to Immunotherapy against Cancer
Authors: Ruud P.M. Dings, Kieng B. Vang, Karolien Castermans, Flavia Popescu, Yan Zhang, Mirjam G.A. oude Egbrink, Matthew F. Mescher, Michael A. Farrar, Arjan W. Griffioen, Kevin H. Mayo
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Tumor-released proangiogenic factors suppress endothelial adhesion molecule (EAM) expression and prevent leukocyte extravasation into the tumor. This is one reason why immunotherapy has met with limited success in the clinic. We hypothesized that overcoming EAM suppression with angiogenesis inhibitors would increase leukocyte extravasation and subsequently enhance the effectiveness of cellular immunotherapy. Experimental Design: Intravital microscopy, multiple color flow cytometry, immunohistochemistry, and various tumor mouse (normal and T-cell deficient) models were used to investigate the temporal dynamics of cellular and molecular events that occur in the tumor microenvironment during tumor progression and angiostatic intervention. Results: We report that while EAM levels and T-cell infiltration are highly attenuated early on in tumor growth, angiostatic therapy modulates these effects. In tumor models with normal and T-cell–deficient mice, we show the active involvement of the adaptive immune system in cancer and differentiate antiangiogenic effects from antiangiogenic mediated enhancement of immunoextravasation. Our results indicate that a compromised immune response in tumors can be obviated by the use of antiangiogenic agents. Finally, with adoptive transfer studies in mice, we show that a phased combination of angiostatic therapy and T-cell transfer significantly (P &amp;lt; 0.0013) improves tumor growth inhibition. Conclusions: This research contributes to understand the cellular mechanism of action of angiostatic agents and the immune response within the tumor microenvironment, in particular as a consequence of the temporal dynamics of EAM levels. Moreover, our results suggest that adjuvant therapy with angiogenesis inhibitors holds promise for cellular immunotherapy in the clinic. Clin Cancer Res; 17(10); 3134–45. ©2011 AACR.
Differential Effects of a Mutation on the Normal and Promiscuous Activities of Orthologs: Implications for Natural and Directed Evolution
Authors: Akhil Khanal, Sean Yu McLoughlin, Jamie P. Kershner, Shelley D. Copley
Journal: Molecular Biology and Evolution (2014)

Neutral drift occurring over millions or billions of years results in substantial sequence divergence among enzymes that catalyze the same reaction. Although natural selection maintains the primary activity of orthologous enzymes, there is, by definition, no selective pressure to maintain physiologically irrelevant promiscuous activities. Thus, the levels and the evolvabilities of promiscuous activities may vary among orthologous enzymes. Consistent with this expectation, we have found that the levels of a promiscuous activity in nine gamma-glutamyl phosphate reductase (ProA) orthologs vary by about 50-fold. Remarkably, a single amino acid change from Glu to Ala near the active site appeared to be critical for improvement of the promiscuous activity in every ortholog. The effects of this change varied dramatically. The improvement in the promiscuous activity varied from 50- to 770-fold, and, importantly, was not correlated with the initial level of the promiscuous activity. The decrease in the original activity varied from 190- to 2,100-fold. These results suggest that evolution of a novel enzyme may be possible in some microbes, but not in others. Further, these results underscore the importance of using multiple orthologs as starting points for directed evolution of novel enzyme activities.
Interleukin-15, a leukocyte activator and growth factor, is produced by cortical tubular epithelial cells.
Authors: M Weiler, B Rogashev, T Einbinder, M J Hausmann, J Kaneti, C Chaimovitz, A Douvdevani
Journal: Journal of the American Society of Nephrology (1998)

Many renal diseases, including transplant rejection, are mediated by mononuclear cells. Interleukin-15 (IL-15) has been recently described as a cytokine with IL-2-like activity. IL-15 is an effective leukocyte growth factor, activator, and chemoattractant. In rejected human kidney allografts, elevated IL-15, but not IL-2, mRNA is expressed, suggesting a role for IL-15 in the rejection process. The aim of this study was to investigate whether human cortical tubular epithelial cells (HTC) are able to produce IL-15 and whether IL-15 expression is regulated by inflammatory mediators. HTC were isolated and characterized, and IL-15 expression was analyzed by reverse transcription-PCR, enzyme-linked immunosorbent assay, and bioactivity. It was found that HTC constitutively express IL-15. Upon stimulation of HTC with interferon-gamma (IFN gamma), the levels of both mRNA and protein increased up to twofold. In contrast, lipopolysaccharide, IL-1, IL-2, and tumor necrosis factor-alpha had no detectable effect. IFN gamma action on HTC was dose-dependent from concentrations of 5 U/ml, reaching a plateau at 50 U/ml. HTC supernatants induced proliferation of the T cell line CTLD, which could be partially blocked (50%) by specific IL-15 antibodies. This study shows that IL-15 is secreted by HTC and that the Th1-cytokine IFN gamma upregulates IL-15 expression. This suggests that HTC play a role in cell-mediated renal diseases by releasing IL-15.
Platelet aggregation in the cerebral microcirculation: effect of aspirin and other agents.
Authors: W I Rosenblum, F El-Sabban
Journal: Circulation Research (1977)

After a certain period of time filtered ultraviolet light produces platelet aggregation in microvessels on the cerebral surface of the mouse, but only when sodium fluorescein is first injected intravascularly to provide a light-absorbing, heat-generating target. The platelet aggregates fluoresce. They occur only in the illuminated field and adhere to arteriolar and venular walls. Vasoconstriction is not detected prior to or up to 30 seconds after aggregation. Electron microscopy reveals damaged endothelium and undamaged red cells, as well as aggregates consisting almost exclusively of platelets in varying stages of aggregation, pseudopod formation, and degranulation. The time between onset of the noxious stimulus and recognition of the first aggregate can be measured as the vessels are observed microscopically. This "time of aggregation" is prolonged by pentobarbital as opposed to urethane anesthesia, and also is related to time elapsed after craniotomy. We also found that aspirin and indomethacin significantly prolong time to first aggregate, but only on the arteriolar side of the circulation. This is so even though the composition of the aggregates is the same on both the arteriolar and venular sides. Heparin has no effect.
PWE-077 Altered Epithelial Tight Junction Expression and Elevated Il 6 Levels in Pouchitis
Authors: J Landy, H O Al-Hassi, E R Mann, S T Peake, P J Ciclitira, S K Clark, J Nicholls, S C Knight, A L Hart
Journal: Gut (2013)

<h3>Introduction</h3> Intestinal epithelial barrier function limits the interactions between microbial antigens and the mucosal immune system. In IBD, epithelial barrier function is impaired with altered expression of tight junctions. We aimed to assess epithelial tight junction expression and mucosal cytokines in acute and chronic pouchitis and non-inflamed pouches of patients with ulcerative colitis. <h3>Methods</h3> Mucosal biospy samples were taken from ulcerative colitis patients with pouchitis (chronic pouchitis n = 9, acute pouchitis n = 4) and those without pouchitis (n = 11). Epithelial cells were isolated from biopsy tissue after incubation with DTT and EDTA. Eptihelial cell expression of ZO-1, claudin 1 and claudin 2 were measured by multicolour flow cytometry. Cytokines were assessed by multiplex ELISA of biopsy supernatants. The t-test was used for statistical analysis. <h3>Results</h3> In acute pouchitis ZO-1 was elevated compared with both chronic pouchitis and non-pouchitis (p = 0.008), whilst in chronic pouchtis ZO-1 expression was reduced compared with non pouchitis (p = 0.006). Claudin 1 expression was reduced in chronic pouchitis (p = 0.04), but was not significantly reduced in acute pouchitis. In acute pouchitis, claudin 2 expression was elevated (p≤0.001), but was not increased in chronic pouchitis. IL6 levels were elevated in chronic pouchitis compared with non pouchitis patients (p = 0.01). <h3>Conclusion</h3> Epithelial tight junction expression was altered in pouchitis in association with increased IL6 levels. Increased claudin 2 expression in acute, but not chronic pouchitis may represent early pathological changes in the development of pouch inflammation. In chronic inflammation the tight junction complex was deranged with reduced expression of both claudin 1 and ZO-1. Increased epithelial barrier permeability due to altered tight junction expression may be a critical mechanism in the development and perpetuation of pouch inflammation. <h3>Disclosure of Interest</h3> None Declared.