tbuckley/cabot-search huggingface dataset:
Hypercoagulability in adolescent girls on oral contraceptives-global coagulation profile and estrogen receptor polymorphisms
Authors: Ayesha Zia, Michael U. Callaghan, Joseph H. Callaghan, Anju Sawni, Heather Bartlett, Alcesa Backos, Sharon Marshall, Meera Chitlur, Madhvi Rajpurkar
Journal: American Journal of Hematology (2015)

Oral contraceptive (OCP) induced changes on coagulation are complex with high inter-individual variability. The precise reason for differences in this variability is unknown. We hypothesized that global coagulation assays better delineate these changes and variability in hypercoagulability may be the result of differences in estrogen metabolism and thrombophilia. Fifty-two adolescents initiating OCPs were prospectively enrolled; 33 subjects completed the study. Samples were analyzed prior to and after OCPs for procoagulant and anticoagulant factor activities and thrombin generation (TG) +/-thrombomodulin. Participants were genotyped for common thrombophilia and estrogen receptor-α (ESR-α) single nucleotide polymorphisms (SNPs). SNP genotypes were compared to coagulation parameters; TG parameters and differences pre and post OCPs were examined. At baseline, a striking finding was elevated FVIII levels. FVL was absent in all and F2 G20210A was present in one participant. The ESR-α polymorphism was present in heterozygous state in 59% and homozygous state in 21% participants. There were no differences in VWF levels andC after being on OCPs. Protein S levels decreased with OCPs. Sixty percent of participants showed evidence of hypercoagulability on TG testing on OCPs. Higher thrombin peak and endogenous thrombin potential (ETP) were seen on TG after OCPs. With thrombomodulin, ETP and thrombin peak did not decrease after OCPs, signifying 'thrombomodulin resistance'. We demonstrated that OCPs induce a state of "variable" hypercoagulability in adolescents, predominantly through the protein S pathway. Genetic and nongenetic factors may account for the variable increase in hypercoagulability. Further research is needed to understand this.
<i>BRAF</i> Mutation in Endometrial Carcinoma and Hyperplasia: Correlation with <i>KRAS</i> and <i>p53</i> Mutations and Mismatch Repair Protein Expression
Authors: Yu-Zhen Feng, Tanri Shiozawa, Tsutomu Miyamoto, Hiroyasu Kashima, Miyuki Kurai, Akihisa Suzuki, Ikuo Konishi
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Although several gene abnormalities have been reported in endometrial carcinoma, the genetic alterations have not fully been elucidated. Recent studies have revealed frequent activating mutations of the gene for BRAF, an effector of Ras protein in the mitogen-activated protein kinase pathway, in several malignancies. However, the prevalence and significance of BRAF mutations in endometrial carcinoma remain unclear. Experimental Design: We examined BRAF mutations in exons 11 and 15 in 97 cases of endometrial carcinoma (endometrioid type, 78; nonendometrioid type, 19), 9 cases of atypical endometrial hyperplasia, and 20 cases of normal endometrium by direct sequencing. In addition, mutations of KRAS and p53 and the immunohistochemical expression of hMLH1 and hMSH2 were also examined. Results: Of the 97 carcinomas and 9 hyperplasias, 20 (21%) and 1 (11%) had BRAF mutations, most of them at previously unreported sites. Twenty samples of normal endometrium and 21 samples of normal endometrium obtained from sites adjacent to neoplastic lesions had no BRAF mutations. There was no apparent difference in the prevalence of BRAF mutation among stages, histologic subtypes, or grades. Mutations of KRAS and p53 were found in 18 (19%) and 22 (23%) cases, and 65 (67%) and 92 (95%) cases showed positive immunostaining for hMLH1 and hMSH2, respectively. BRAF mutation was more frequently found in hMLH1-negative cases (12 of 32, 41%) than in hMLH1-positive cases (7 of 65, 11%; P = 0.008), suggesting that it is associated with an abnormal mismatch repair function. Conclusions: These findings suggest that mutations of the BRAF gene are partly involved in the malignant transformation of the endometrium.
Crystal Surface Adhesion Explains the Pathological Activity of Calcium Oxalate Hydrates in Kidney Stone Formation
Authors: Xiaoxia Sheng, Michael D. Ward, Jeffrey A. Wesson
Journal: Journal of the American Society of Nephrology (2005)

Renal tubular fluid in the distal nephron of the kidney is supersaturated with calcium oxalate (CaOx), which crystallizes in the tubules as either calcium oxalate monohydrate (COM) or calcium oxalate dihydrate (COD). Kidney stones are aggregates, most commonly containing microcrystals of COM as the primary inorganic constituent. Stones also contain small amounts of embedded proteins, which are thought to play an adhesive role in these aggregates, and they often are found attached to the tip of renal papilla, presumably through adhesive contacts. Voided urine, however, often contains COD in the form of single micron-sized crystals. This suggests that COD formation protects against stone disease because of its reduced capacity to form stable aggregates and strong adhesion contacts to renal epithelial cells. Using atomic force microscopy configured with tips modified with biologically relevant functional groups, we have compared the adhesion strengths of the morphologically important faces of COM and COD. These measurements provide direct experimental evidence, at the near molecular level, for poorer adhesion at COD crystal faces, which explains the benign character of COD and has implications for resolving one of the mysteries of kidney stone formation.
Cardiomyocytes as effectors of nitric oxide signalling
Authors: M SEDDON, A SHAH, B CASADEI
Journal: Cardiovascular Research (2007)

Nitric oxide (NO) generated constitutively within the heart has long been known to influence myocardial function; however, the precise nature of these effects has been controversial--at least in part--because of the experimental use of non-isoform-selective inhibitors of NO synthases (NOS) and unwarranted extrapolation from results obtained with NO donors. Recent studies using NOS-selective inhibitors and genetically modified models are beginning to redress the balance. It is well established that agonist-stimulated release of NO from eNOS in the coronary endothelium exerts paracrine effects on cardiomyocytes, predominantly affecting the timing of relaxation as well as myocardial oxygen consumption. A significant recent advance has been the finding that both eNOS and nNOS are constitutively expressed in distinct subcellular locations within cardiomyocytes. The relative autocrine role of these isoforms in the cardiomyocyte remains to be fully clarified but evidence suggests that the autocrine effects of nNOS may include the modulation of basal inotropy and relaxation, beta-adrenergic responsiveness, and the force-frequency relationship. Myocardial eNOS, on the other hand, may be involved in mediating the inotropic response to sustained stretch. These effects may change significantly in the diseased heart where the expression, activity and/or coupling of NOS isoforms to downstream effectors may be altered. In this article, we review the current understanding of this important but complex field, focussing particularly on contractile function and on recent advances in knowledge regarding the autocrine functions of nNOS-derived NO.
Identification of FGF7 as a novel susceptibility locus for chronic obstructive pulmonary disease
Authors: J. M. Brehm, K. Hagiwara, Y. Tesfaigzi, S. Bruse, T. J. Mariani, S. Bhattacharya, N. Boutaoui, J. P. Ziniti, M. E. Soto-Quiros, L. Avila, M. H. Cho, B. Himes, A. A. Litonjua, F. Jacobson, P. Bakke, A. Gulsvik, W. H. Anderson, D. A. Lomas, E. Forno, S. Datta, E. K. Silverman, J. C. Celedon
Journal: Thorax (2011)

<h3>Rationale</h3> Traditional genome-wide association studies (GWASs) of large cohorts of subjects with chronic obstructive pulmonary disease (COPD) have successfully identified novel candidate genes, but several other plausible loci do not meet strict criteria for genome-wide significance after correction for multiple testing. <h3>Objectives</h3> The authors hypothesise that by applying unbiased weights derived from unique populations we can identify additional COPD susceptibility loci. <h3>Methods</h3> The authors performed a homozygosity haplotype analysis on a group of subjects with and without COPD to identify regions of conserved homozygosity haplotype (RCHHs). Weights were constructed based on the frequency of these RCHHs in case versus controls, and used to adjust the p values from a large collaborative GWAS of COPD. <h3>Results</h3> The authors identified 2318 RCHHs, of which 576 were significantly (p&lt;0.05) over-represented in cases. After applying the weights constructed from these regions to a collaborative GWAS of COPD, the authors identified two single nucleotide polymorphisms (SNPs) in a novel gene (fibroblast growth factor-7 (<i>FGF7</i>)) that gained genome-wide significance by the false discovery rate method. In a follow-up analysis, both SNPs (rs12591300 and rs4480740) were significantly associated with COPD in an independent population (combined p values of 7.9E–7 and 2.8E–6, respectively). In another independent population, increased lung tissue <i>FGF7</i> expression was associated with worse measures of lung function. <h3>Conclusion</h3> Weights constructed from a homozygosity haplotype analysis of an isolated population successfully identify novel genetic associations from a GWAS on a separate population. This method can be used to identify promising candidate genes that fail to meet strict correction for multiple testing.
Rupture of the Perinaeum: Perineorraphy
Authors: A. W. Williams
Journal: BMJ (1886)

safe in these cases, for the silk is apt to cut through the succulent broad ligaments and cause hnmorrhage.But the operation is safer than it looks ; there is no need to seek out bleeding points and tie them, packing with sponges, and the subsequent use of a drainage- tube (which may be safely withdrawn in twenty-four hours) being all that is necessary.There is very little reaction, and complete restoration to health is a matter of two or three weeks.
The brain basis of emotion: A meta-analytic review
Authors: Kristen A. Lindquist, Tor D. Wager, Hedy Kober, Eliza Bliss-Moreau, Lisa Feldman Barrett
Journal: Behavioral and Brain Sciences (2012)

Researchers have wondered how the brain creates emotions since the early days of psychological science. With a surge of studies in affective neuroscience in recent decades, scientists are poised to answer this question. In this target article, we present a meta-analytic summary of the neuroimaging literature on human emotion. We compare the locationist approach (i.e., the hypothesis that discrete emotion categories consistently and specifically correspond to distinct brain regions) with the psychological constructionist approach (i.e., the hypothesis that discrete emotion categories are constructed of more general brain networks not specific to those categories) to better understand the brain basis of emotion. We review both locationist and psychological constructionist hypotheses of brain-emotion correspondence and report meta-analytic findings bearing on these hypotheses. Overall, we found little evidence that discrete emotion categories can be consistently and specifically localized to distinct brain regions. Instead, we found evidence that is consistent with a psychological constructionist approach to the mind: A set of interacting brain regions commonly involved in basic psychological operations of both an emotional and non-emotional nature are active during emotion experience and perception across a range of discrete emotion categories.
Protein Kinase B/Akt-Dependent Phosphorylation of Glycogen Synthase Kinase-3β in Irradiated Vascular Endothelium
Authors: Jiahua Tan, Ling Geng, Eugenia M. Yazlovitskaya, Dennis E. Hallahan
Journal: Cancer Research (2006)

Abstract The vascular endothelium plays a critical role in the response of cancer to ionizing radiation. Activation of the phosphoinositide-3-kinase/Akt pathway is one initial signaling event in irradiated endothelial cells. Specifically, a low dose of ionizing radiation (3 Gy) induces phosphorylation of Akt at Ser473 in the vascular endothelium within minutes of irradiation. However, signaling events that are downstream of Akt have not been well defined. Here, we show that phosphorylation of the Akt downstream target glycogen synthase kinase-3β (GSK-3β) at Ser9 also occurred within minutes of exposure to ionizing radiation. In addition, ionizing radiation caused the dissociation of GSK-3β from the cell membrane, consistent with the inactivation of GSK-3β enzyme activity. Overexpression of the dominant negative mutant Akt attenuated GSK-3β phosphorylation at Ser9 and enhanced radiation-induced apoptosis. X-irradiated endothelial cells formed capillaries in both in vitro and in vivo models, whereas overexpression of the dominant negative mutant Akt inhibited capillary tubule formation. Studies using GSK-3β antagonists showed that GSK-3β activity was required for apoptosis in endothelial cells treated simultaneously with Akt antagonists and radiation. In mouse vascular models, radiation-induced microvascular destruction in response to Akt antagonists also required GSK-3β function. These data indicate that on exposure of vascular endothelium to ionizing radiation, activation of Akt signaling contributes to GSK-3β inhibition, which in turn promotes endothelial cell survival and capillary formation. Thus, pharmacologic regulation of Akt/GSK-3β signaling may present a new approach to the radiation response in the tumor microvasculature. (Cancer Res 2006; 66(4): 2320-7)
Two cilengitide regimens in combination with standard treatment for patients with newly diagnosed glioblastoma and unmethylated MGMT gene promoter: results of the open-label, controlled, randomized phase II CORE study
Authors: L. Burt Nabors, Karen L. Fink, Tom Mikkelsen, Danica Grujicic, Rafal Tarnawski, Do Hyun Nam, Maria Mazurkiewicz, Michael Salacz, Lynn Ashby, Vittorina Zagonel, Roberta Depenni, James R. Perry, Christine Hicking, Martin Picard, Monika E. Hegi, Benoit Lhermitte, David A. Reardon
Journal: Neuro-Oncology (2015)

Survival outcomes for patients with glioblastoma remain poor, particularly for patients with unmethylated O6-methylguanine-DNA methyltransferase (MGMT) gene promoter. This phase II, randomized, open-label, multicenter trial investigated the efficacy and safety of 2 dose regimens of the selective integrin inhibitor cilengitide combined with standard chemoradiotherapy in patients with newly diagnosed glioblastoma and an unmethylated MGMT promoter. Overall, 265 patients were randomized (1:1:1) to standard cilengitide (2000 mg 2×/wk; n = 88), intensive cilengitide (2000 mg 5×/wk during wk 1−6, thereafter 2×/wk; n = 88), or a control arm (chemoradiotherapy alone; n = 89). Cilengitide was administered intravenously in combination with daily temozolomide (TMZ) and concomitant radiotherapy (RT; wk 1−6), followed by TMZ maintenance therapy (TMZ/RT→TMZ). The primary endpoint was overall survival; secondary endpoints included progression-free survival, pharmacokinetics, and safety and tolerability. Median overall survival was 16.3 months in the standard cilengitide arm (hazard ratio [HR], 0.686; 95% CI: 0.484, 0.972; P = .032) and 14.5 months in the intensive cilengitide arm (HR, 0.858; 95% CI: 0.612, 1.204; P = .3771) versus 13.4 months in the control arm. Median progression-free survival assessed per independent review committee was 5.6 months (HR, 0.822; 95% CI: 0.595, 1.134) and 5.9 months (HR, 0.794; 95% CI: 0.575, 1.096) in the standard and intensive cilengitide arms, respectively, versus 4.1 months in the control arm. Cilengitide was well tolerated. Standard and intensive cilengitide dose regimens were well tolerated in combination with TMZ/RT→TMZ. Inconsistent overall survival and progression-free survival outcomes and a limited sample size did not allow firm conclusions regarding clinical efficacy in this exploratory phase II study.
Pulmonary function studies in bird breeder's lung
Authors: P. Dinda, S. S. Chatterjee, W. D. Riding
Journal: Thorax (1969)

Pulmonary function studies were performed at the time of diagnosis in 10 patients, aged between 11 and 51 years, with bird breeder9s lung due to exposure of between 9 months and 42 years. The studies were repeated after a varying interval in nine of these patients, following removal from exposure. In initial tests, diffusing capacity was impaired in eight patients and the arterial oxygen tension at rest was below 80 mm. Hg in seven. Five patients had a low vital capacity and three showed evidence of airway obstruction. One patient continued to breed pigeons, against medical advice, and his pulmonary function, repeated after nine months, showed further deterioration. The others with abnormal pulmonary function showed significant improvement on repeat studies. Pulmonary function studies appear to be helpful in the diagnosis, irrespective of radiographic changes, and in the follow-up of patients.
Detrimental Effects of Tumor Progression on Cognitive Function of Patients With High-Grade Glioma
Authors: Paul D. Brown, Ashley W. Jensen, Sara J. Felten, Karla V. Ballman, Paul L. Schaefer, Kurt A. Jaeckle, Jane H. Cerhan, Jan C. Buckner
Journal: Journal of Clinical Oncology (2006)

There is growing recognition that the primary cause of cognitive deficits in adult patients with primary brain tumors is the tumor itself and more significantly, tumor progression. To assess the cognitive performance of high-grade glioma patients, prospectively collected cognitive performance data were analyzed.We studied 1,244 high-grade brain tumor patients entered onto eight consecutive North Central Cancer Treatment Group treatment trials that used radiation and nitrosourea-based chemotherapy. Imaging studies and Folstein Mini-Mental State Examination (MMSE) scores recorded at baseline, 6, 12, 18, and 24 months were analyzed to assess tumor status and cognitive function over time.The proportion of patients without tumor progression who experienced clinically significant cognitive deterioration compared with baseline was stable at 6, 12, 18, and 24 months (18%, 16%, 14%, and 13%, respectively). In patients without radiographic evidence of progression, clinically significant deterioration in MMSE scores was a strong predictor of a more rapid time to tumor progression and death. At evaluations preceding interval radiographic evidence of progression, there was significant deterioration in MMSE scores for patients who were to experience progression, whereas the scores remained stable for the patients who did not have tumor progression.The proportion of high-grade glioma patients with cognitive deterioration over time is stable, most consistent with the constant pressure of tumor progression over time. Although other factors may contribute to cognitive decline, the predominant cause of cognitive decline seems to be subclinical tumor progression that precedes radiographic changes.
Community football players’ attitudes towards protective equipment—a pre-season measure
Authors: R A Braham, C F Finch, A McIntosh, P McCrory
Journal: British Journal of Sports Medicine (2004)

Background: The Australian football injury prevention project (AFIPP) was a randomised controlled trial examining the effects of protective equipment on injury rates in Australian Football. Objective: To present the results of the AFIPP baseline survey of community football players’ attitudes towards protective equipment. Methods: Teams of players were recruited from the largest community football league in Victoria, Australia, during the 2001 playing season; 301 players were enrolled in the study and all were surveyed before the season began about their attitudes towards protective headgear and mouthguards. Results: Almost three quarters of the players (73.6%) reported wearing mouthguards during the previous playing season (year 2000) compared with only 2.1% wearing headgear. The most common reasons for not wearing headgear and mouthguards (in non-users) were: “I don’t like wearing it” (headgear: 44.8%; mouthguards: 30.6%), and “It is too uncomfortable” (headgear: 40.7%; mouthguards: 45.8%). Conclusions: The higher mouthguard usage reflects the favourable attitudes towards mouthguards by Australian football players generally. Similarly, the low headgear usage reflects the low acceptance of this form of protection in this sport. Further research should be directed towards establishing the reasons why players seem to believe that headgear plays a role in injury prevention yet few wear it.
Spending Differences Associated With the Medicare Physician Group Practice Demonstration
Authors: Carrie H. Colla, David E. Wennberg, Ellen Meara, Jonathan S. Skinner, Daniel Gottlieb, Valerie A. Lewis, Christopher M. Snyder, Elliott S. Fisher
Journal: JAMA (2012)

<h3>Context</h3>The Centers for Medicare &amp; Medicaid Services (CMS) recently launched accountable care organization (ACO) programs designed to improve quality and slow cost growth. The ACOs resemble an earlier pilot, the Medicare Physician Group Practice Demonstration (PGPD), in which participating physician groups received bonus payments if they achieved lower cost growth than local controls and met quality targets. Although evidence indicates the PGPD improved quality, uncertainty remains about its effect on costs.<h3>Objective</h3>To estimate cost savings associated with the PGPD overall and for beneficiaries dually eligible for Medicare and Medicaid.<h3>Design</h3>Quasi-experimental analyses comparing preintervention (2001-2004) and postintervention (2005-2009) trends in spending of PGPD participants to local control groups. We compared estimates using several alternative approaches to adjust for case mix.<h3>Setting</h3>Ten physician groups from across the United States.<h3>Patients and Participants</h3>The intervention group was composed of fee-for-service Medicare beneficiaries (n = 990 177) receiving care primarily from the physicians in the participating medical groups. Controls were Medicare beneficiaries (n = 7 514 453) from the same regions who received care largely from non-PGPD physicians. Overall, 15% of beneficiaries were dually eligible for Medicare and Medicaid.<h3>Main Outcome Measure</h3>Annual spending per Medicare fee-for-service beneficiary.<h3>Results</h3>Annual savings per beneficiary were modest overall (adjusted mean $114, 95% CI, $12-$216). Annual savings were significant in dually eligible beneficiaries (adjusted mean $532, 95% CI, $277-$786), but were not significant among nondually eligible beneficiaries (adjusted mean $59, 95% CI, $166 in savings to $47 in additional spending). The adjusted mean spending reductions were concentrated in acute care (overall, $118, 95% CI, $65-$170; dually eligible: $381, 95% CI, $247-$515; nondually eligible: $85, 95% CI, $32-$138). There was significant variation in savings across practice groups, ranging from an overall mean per-capita annual saving of $866 (95% CI, $815-$918) to an increase in expenditures of $749 (95% CI, $698-$799) . Thirty-day medical readmissions decreased overall (−0.67%, 95% CI, −1.11% to −0.23%) and in the dually eligible (−1.07%, 95% CI, −1.73% to −0.41%), while surgical readmissions decreased only for the dually eligible (−2.21%, 95% CI, −3.07% to −1.34%). Estimates were sensitive to the risk-adjustment method.<h3>Conclusions</h3>Substantial PGPD savings achieved by some participating institutions were offset by a lack of saving at other participating institutions. Most of the savings were concentrated among dually eligible beneficiaries.