tbuckley/cabot-search huggingface dataset:
Interferon release does not add discriminatory value to smear-negative HIV-tuberculosis algorithms
Authors: M.X. Rangaka, H.P. Gideon, K.A. Wilkinson, M. Pai, J. Mwansa-Kambafwile, G. Maartens, J.R. Glynn, A. Boulle, K. Fielding, R. Goliath, R. Titus, S. Mathee, R.J. Wilkinson
Journal: European Respiratory Journal (2011)

Clinical algorithms for evaluating HIV-infected individuals for tuberculosis (TB) prior to isoniazid preventive therapy (IPT) perform poorly, and interferon-γ release assays (IGRAs) have moderate accuracy for active TB. It is unclear whether, when used as adjunct tests, IGRAs add any clinical discriminatory value for active TB diagnosis in the pre-IPT assessment. 779 sputum smear-negative HIV-infected persons, established on or about to commence combined antiretroviral therapy (ART), were screened for TB prior to IPT. Stepwise multivariable logistic regression was used to develop clinical prediction models. The discriminatory ability was assessed by receiver operator characteristic area under the curve (AUC). QuantiFERON®-TB Gold in-tube (QFT-GIT) was evaluated. The prevalence of smear-negative TB by culture was 6.4% (95% CI 4.9–8.4%). Used alone, QFT-GIT and the tuberculin skin test (TST) had comparable performance; the post-test probability of disease based on single negative tests was 3–4%. In a multivariable model, the QFT-GIT test did not improve the ability of a clinical algorithm, which included not taking ART, weight &lt;60 kg, no prior history of TB, any one positive TB symptom/sign (cough ≥2 weeks) and CD4+ count &lt;250 cells per mm 3 , to discriminate smear-negative culture-positive and -negative TB (72% to 74%; AUC comparison p=0.33). The TST marginally improved the discriminatory ability of the clinical model (to 77%, AUC comparison p=0.04). QFT-GIT does not improve the discriminatory ability of current TB screening clinical algorithms used to evaluate HIV-infected individuals for TB ahead of preventive therapy. Evaluation of new TB diagnostics for clinical relevance should follow a multivariable process that goes beyond test accuracy.
How the type of risk reduction influences required sample sizes in randomised clinical trials
Authors: K Bruynesteyn
Journal: Annals of the Rheumatic Diseases (2004)

To increase change between groups, randomised clinical trials (RCT) often include patients with high risk for a particular outcome, by inclusion criteria that select predictors for that outcome. This increases the statistical power, and fewer patients are required for that RCT. The way in which patient selection influences the power, and thus sample size required, depends on how an intervention reduces the individual risk: by an absolute or relative risk reduction model.
Emotional responses to music: The need to consider underlying mechanisms
Authors: Patrik N. Juslin, Daniel Västfjäll
Journal: Behavioral and Brain Sciences (2008)

Research indicates that people value music primarily because of the emotions it evokes. Yet, the notion of musical emotions remains controversial, and researchers have so far been unable to offer a satisfactory account of such emotions. We argue that the study of musical emotions has suffered from a neglect of underlying mechanisms. Specifically, researchers have studied musical emotions without regard to how they were evoked, or have assumed that the emotions must be based on the "default" mechanism for emotion induction, a cognitive appraisal. Here, we present a novel theoretical framework featuring six additional mechanisms through which music listening may induce emotions: (1) brain stem reflexes, (2) evaluative conditioning, (3) emotional contagion, (4) visual imagery, (5) episodic memory, and (6) musical expectancy. We propose that these mechanisms differ regarding such characteristics as their information focus, ontogenetic development, key brain regions, cultural impact, induction speed, degree of volitional influence, modularity, and dependence on musical structure. By synthesizing theory and findings from different domains, we are able to provide the first set of hypotheses that can help researchers to distinguish among the mechanisms. We show that failure to control for the underlying mechanism may lead to inconsistent or non-interpretable findings. Thus, we argue that the new framework may guide future research and help to resolve previous disagreements in the field. We conclude that music evokes emotions through mechanisms that are not unique to music, and that the study of musical emotions could benefit the emotion field as a whole by providing novel paradigms for emotion induction.
The t(8;9)(p22;p24) Is a Recurrent Abnormality in Chronic and Acute Leukemia that Fuses <i>PCM1</i> to <i>JAK2</i>
Authors: Andreas Reiter, Christoph Walz, Ann Watmore, Claudia Schoch, Ilona Blau, Brigitte Schlegelberger, Ute Berger, Nick Telford, Shilani Aruliah, John A. Yin, Danny Vanstraelen, Helen F. Barker, Peter C. Taylor, Aisling O'Driscoll, Fabio Benedetti, Cornelia Rudolph, Hans-Jochem Kolb, Andreas Hochhaus, Rüdiger Hehlmann, Andrew Chase, Nicholas C.P. Cross
Journal: Cancer Research (2005)

Abstract We have identified a t(8;9)(p21-23;p23-24) in seven male patients (mean age 50, range 32-74) with diverse hematologic malignancies and clinical outcomes: atypical chronic myeloid leukemia/chronic eosinophilic leukemia (n = 5), secondary acute myeloid leukemia (n = 1), and pre-B-cell acute lymphoblastic leukemia (n = 1). Initial fluorescence in situ hybridization studies of one patient indicated that the nonreceptor tyrosine kinase Janus-activated kinase 2 (JAK2) at 9p24 was disrupted. Rapid amplification of cDNA ends-PCR identified the 8p22 partner gene as human autoantigen pericentriolar material (PCM1), a gene encoding a large centrosomal protein with multiple coiled-coil domains. Reverse transcription-PCR and fluorescence in situ hybridization confirmed the fusion in this case and also identified PCM1–JAK2 in the six other t(8;9) patients. The breakpoints were variable in both genes, but in all cases the chimeric mRNA is predicted to encode a protein that retains several of the predicted coiled-coil domains from PCM1 and the entire tyrosine kinase domain of JAK2. Reciprocal JAK2–PCM1 mRNA was not detected in any patient. We conclude that human autoantigen pericentriolar material (PCM1)–JAK2 is a novel, recurrent fusion gene in hematologic malignancies. Patients with PCM1–JAK2 disease are attractive candidates for targeted signal transduction therapy.
Computed Tomographic Colonography (Virtual Colonoscopy)
Authors: Peter B. Cotton, Valerie L. Durkalski, Benoit C. Pineau, Yuko Y. Palesch, Patrick D. Mauldin, Brenda Hoffman, David J. Vining, William C. Small, John Affronti, Douglas Rex, Kenyon K. Kopecky, Susan Ackerman, J. Steven Burdick, Cecelia Brewington, Mary A. Turner, Alvin Zfass, Andrew R. Wright, Revathy B. Iyer, Patrick Lynch, Michael V. Sivak, Harold Butler
Journal: JAMA (2004)

ContextConventional colonoscopy is the best available method for detection of colorectal cancer; however, it is invasive and not without risk. Computed tomographic colonography (CTC), also known as virtual colonoscopy, has been reported to be reasonably accurate in the diagnosis of colorectal neoplasia in studies performed at expert centers.ObjectiveTo assess the accuracy of CTC in a large number of participants across multiple centers.Design, Setting, and ParticipantsA nonrandomized, evaluator-blinded, noninferiority study design of 615 participants aged 50 years or older who were referred for routine, clinically indicated colonoscopy in 9 major hospital centers between April 17, 2000, and October 3, 2001. The CTC was performed by using multislice scanners immediately before standard colonoscopy; findings at colonoscopy were reported before and after segmental unblinding to the CTC results.Main Outcome MeasuresThe sensitivity and specificity of CTC and conventional colonoscopy in detecting participants with lesions sized at least 6 mm. Secondary outcomes included detection of all lesions, detection of advanced lesions, possible technical confounders, participant preferences, and evidence for increasing accuracy with experience.ResultsA total of 827 lesions were detected in 308 of 600 participants who underwent both procedures; 104 participants had lesions sized at least 6 mm. The sensitivity of CTC for detecting participants with 1 or more lesions sized at least 6 mm was 39.0% (95% confidence interval [CI], 29.6%-48.4%) and for lesions sized at least 10 mm, it was 55.0% (95% CI, 39.9%-70.0%). These results were significantly lower than those for conventional colonoscopy, with sensitivities of 99.0% (95% CI, 97.1%-&gt;99.9%) and 100%, respectively. A total of 496 participants were without any lesion sized at least 6 mm. The specificity of CTC and conventional colonoscopy for detecting participants without any lesion sized at least 6 mm was 90.5% (95% CI, 87.9%-93.1%) and 100%, respectively, and without lesions sized at least 10 mm, 96.0% (95% CI, 94.3%-97.6%) and 100%, respectively. Computed tomographic colonography missed 2 of 8 cancers. The accuracy of CTC varied considerably between centers and did not improve as the study progressed. Participants expressed no clear preference for either technique.ConclusionsComputed tomographic colonography by these methods is not yet ready for widespread clinical application. Techniques and training need to be improved.
The Putative (Pro)renin Receptor Blocker HRP Fails to Prevent (Pro)renin Signaling
Authors: Sandra Feldt, Ulrike Maschke, Ralf Dechend, Friedrich C. Luft, Dominik N. Muller
Journal: Journal of the American Society of Nephrology (2008)

The prorenin/renin receptor is a recently discovered component of the renin-angiotensin system. The effects of aliskiren, a direct inhibitor of human renin, were compared with the handle region decoy peptide (HRP), which blocks the prorenin/renin receptor, in double-transgenic rats overexpressing the human renin and angiotensinogen genes. After 7 wk, all aliskiren-treated rats were alive, whereas mortality was 40% in vehicle-treated and 58% in HRP-treated rats. Aliskiren but not the HRP reduced BP and normalized albuminuria, cystatin C, and neutrophil gelatinase-associated lipocalin, a marker of renal tubular damage, to the levels of nontransgenic controls. In vitro, human renin and prorenin induced extracellular signal-regulated kinase 1/2 phosphorylation, independent of angiotensin II (AngII), in vascular smooth muscle cells. Preincubation with the HRP or aliskiren did not prevent renin- and prorenin-induced extracellular signal-regulated kinase 1/2 phosphorylation, whereas the MAP kinase kinase (MEK1/2) inhibitor PD98059 prevented both. In conclusion, renin inhibition but not treatment with the HRP protects against AngII-induced renal damage in double-transgenic rats. In addition, the in vitro data do not support the use of the HRP to block AngII-independent prorenin- or renin-mediated effects.
Efficacy of Carraguard for prevention of HIV infection in women in South Africa: a randomised, double-blind, placebo-controlled trial
Authors: Stephanie Skoler-Karpoff, Gita Ramjee, Khatija Ahmed, Lydia Altini, Marlena Gehret Plagianos, Barbara Friedland, Sumen Govender, Alana De Kock, Nazira Cassim, Thesla Palanee, Gregory Dozier, Robin Maguire, Pekka Lahteenmaki
Journal: The Lancet (2008)
Human <b> <i>CYP1B1</i> </b> Is Regulated by Estradiol via Estrogen Receptor
Authors: Yuki Tsuchiya, Miki Nakajima, Satoru Kyo, Taro Kanaya, Masaki Inoue, Tsuyoshi Yokoi
Journal: Cancer Research (2004)

Human cytochrome P450 (CYP) 1B1 is a key enzyme in the metabolism of 17beta-estradiol (E2). CYP1B1 is mainly expressed in endocrine-regulated tissues, such as mammary, uterus, and ovary. Because many CYP enzymes are likely to be induced by the substrates themselves, we examined whether the human CYP1B1 expression is regulated by E2 in the present study. Real-time reverse transcription-PCR analysis revealed that treatment with 10 nM E2 for 12 h induced CYP1B1 mRNA expression in estrogen receptor (ER)-positive MCF-7 cells. Luciferase reporter assays using MCF-7 cells showed a significant transactivation up to 7-fold by E2 with a reporter plasmid containing a region from -152 to +25 of the human CYP1B1 gene. A computer-assisted homology search indicated a putative estrogen response element (ERE) between -63 and -49 in the CYP1B1 promoter region. Specific binding of ERalpha to the putative ERE was demonstrated by chromatin immunoprecipitation assays and gel shift analyses. With reporter plasmids containing the wild or mutated putative ERE on the CYP1B1 gene and the wild or mutated ERalpha expression vectors, luciferase assays using Ishikawa cells demonstrated that the putative ERE and ERalpha are essential for the transactivation by E2. Because endometrial tissue is highly regulated by estrogens, the expression pattern of CYP1B1 protein in human endometrial specimens was examined by immunohistochemistry. The staining of CYP1B1 was stronger in glandular epithelial cells during a proliferative phase than those during a secretory phase, consistent with the pattern of estrogen secretion. These findings clearly indicated that the human CYP1B1 is regulated by estrogen via ERalpha. Because 4-hydroxylation of estrogen by CYP1B1 leads to decrease of the estrogenic activity but the produced metabolite is toxicologically active, our findings suggest a clinical significance in the estrogen-regulated CYP1B1 expression for the homeostasis of estrogens as well as estrogen-dependent carcinogenesis.
Sodium Intake and Vascular Smooth Muscle Responsiveness to Norepinephrine and Angiotensin in the Rabbit
Authors: Gordon J. STREWLER, Kathern J. HINRICHS, Linda R. GUIOD, Norman K. HOLLENBERG
Journal: Circulation Research (1972)

The effect of dietary sodium restriction on the responses to norepinephrine and angiotensin was assessed in two vascular smooth muscle preparations in the rabbit. Sodium restriction reduced the response to angiotensin of both the limb vessels in vivo and the aorta in vitro. The response to norepinephrine was potentiated by sodium restriction in both preparations. The effects on angiotensin responsiveness did not appear to be related to tachyphylaxis, changes in extracellular electrolyte composition, or nonspecific depression of smooth muscle function. Probably, the change in sodium intake induced a change in the smooth muscle cell membranes which modified the affinity of their receptors for angiotensin and norepinephrine.
HEPATIC FIBROSIS: Molecular Mechanisms and Drug Targets
Authors: Sophie Lotersztajn, Boris Julien, Fatima Teixeira-Clerc, Pascale Grenard, Ariane Mallat
Journal: The Annual Review of Pharmacology and Toxicology (2004)

▪ Abstract Liver fibrosis is the common response to chronic liver injury, ultimately leading to cirrhosis and its complications, portal hypertension, liver failure, and hepatocellular carcinoma. Efficient and well-tolerated antifibrotic drugs are currently lacking, and current treatment of hepatic fibrosis is limited to withdrawal of the noxious agent. Efforts over the past decade have mainly focused on fibrogenic cells generating the scarring response, although promising data on inhibition of parenchymal injury and/or reduction of liver inflammation have also been obtained. A large number of approaches have been validated in culture studies and in animal models, and several clinical trials are underway or anticipated for a growing number of molecules. This review highlights recent advances in the molecular mechanisms of liver fibrosis and discusses mechanistically based strategies that have recently emerged.
Effect of metformin on maternal and fetal outcomes in obese pregnant women (EMPOWaR): a randomised, double-blind, placebo-controlled trial
Authors: Carolyn Chiswick, Rebecca M Reynolds, Fiona Denison, Amanda J Drake, Shareen Forbes, David E Newby, Brian R Walker, Siobhan Quenby, Susan Wray, Andrew Weeks, Hany Lashen, Aryelly Rodriguez, Gordon Murray, Sonia Whyte, Jane E Norman
Journal: The Lancet Diabetes & Endocrinology (2015)

Background Maternal obesity is associated with increased birthweight, and obesity and premature mortality in adult off spring.The mechanism by which maternal obesity leads to these outcomes is not well understood, but maternal hyperglycaemia and insulin resistance are both implicated.We aimed to establish whether the insulin sensitising drug metformin improves maternal and fetal outcomes in obese pregnant women without diabetes. MethodsWe did this randomised, double-blind, placebo-controlled trial in antenatal clinics at 15 National Health Service hospitals in the UK.Pregnant women (aged ≥16 years) between 12 and 16 weeks' gestation who had a BMI of 30 kg/m² or more and normal glucose tolerance were randomly assigned (1:1), via a web-based computer-generated block randomisation procedure (block size of two to four), to receive oral metformin 500 mg (increasing to a maximum of 2500 mg) or matched placebo daily from between 12 and 16 weeks' gestation until delivery of the baby.Randomisation was stratifi ed by study site and BMI band (30-39 vs ≥40 kg/m²).Participants, caregivers, and study personnel were masked to treatment assignment.The primary outcome was Z score corresponding to the gestational age, parity, and sex-standardised birthweight percentile of liveborn babies delivered at 24 weeks or more of gestation.We did analysis by modifi ed intention to treat.This trial is registered, ISRCTN number 51279843. FindingsBetween Feb 3, 2011, and Jan 16, 2014, inclusive, we randomly assigned 449 women to either placebo (n=223) or metformin (n=226), of whom 434 (97%) were included in the fi nal modifi ed intention-to-treat analysis.Mean birthweight at delivery was 3463 g (SD 660) in the placebo group and 3462 g (548) in the metformin group.The estimated eff ect size of metformin on the primary outcome was non-signifi cant (adjusted mean diff erence -0•029, 95% CI -0•217 to 0•158; p=0•7597).The diff erence in the number of women reporting the combined adverse outcome of miscarriage, termination of pregnancy, stillbirth, or neonatal death in the metformin group (n=7) versus the placebo group (n=2) was not signifi cant (odds ratio 3•60, 95% CI 0•74-17•50; p=0•11).Interpretation Metformin has no signifi cant eff ect on birthweight percentile in obese pregnant women.Further follow-up of babies born to mothers in the EMPOWaR study will identify longer-term outcomes of metformin in this population; in the meantime, metformin should not be used to improve pregnancy outcomes in obese women without diabetes.
SPACE AND ATTENTION IN PARIETAL CORTEX
Authors: Carol L. Colby, Michael E. Goldberg
Journal: Annual Review of Neuroscience (1999)

▪ Abstract The space around us is represented not once but many times in parietal cortex. These multiple representations encode locations and objects of interest in several egocentric reference frames. Stimulus representations are transformed from the coordinates of receptor surfaces, such as the retina or the cochlea, into the coordinates of effectors, such as the eye, head, or hand. The transformation is accomplished by dynamic updating of spatial representations in conjunction with voluntary movements. This direct sensory-to-motor coordinate transformation obviates the need for a single representation of space in environmental coordinates. In addition to representing object locations in motoric coordinates, parietal neurons exhibit strong modulation by attention. Both top-down and bottom-up mechanisms of attention contribute to the enhancement of visual responses. The saliance of a stimulus is the primary factor in determining the neural response to it. Although parietal neurons represent objects in motor coordinates, visual responses are independent of the intention to perform specific motor acts.
Diagnosis and management of heritable thrombophilias
Authors: P. MacCallum, L. Bowles, D. Keeling
Journal: BMJ (2014)

#### Summary points

The term thrombophilia refers to an abnormality of blood coagulation that increases the risk of thrombosis. Such abnormalities represent one component of the triad (along with stasis and abnormalities of the vessel wall) put forward by Virchow in the 19th century to explain why thrombosis occurs.

#### Sources and selection criteria

We searched PubMed and the Cochrane Collaboration for recent systematic reviews and meta-analyses on thrombophilia and its epidemiology, pathophysiology, and management. We supplemented these with recent largely UK based national guidelines and with further references obtained through PubMed and through personal archives of references. Evidence on the management of symptomatic or asymptomatic people with heritable thrombophilia is weak and largely based on extrapolation from observational studies.

Thrombophilic abnormalities may be heritable (the topic of this review) or acquired, although both genetic and environmental factors influence activity within the coagulation system and may interact to provoke thrombotic events.1 Clinicians in primary and secondary care may need to counsel or manage asymptomatic people or patients with venous thromboembolism (VTE) who have either a family history of venous thrombosis or a known heritable thrombophilia. …
Identification of PVR (CD155) and Nectin-2 (CD112) as Cell Surface Ligands for the Human DNAM-1 (CD226) Activating Molecule
Authors: Cristina Bottino, Roberta Castriconi, Daniela Pende, Paola Rivera, Marina Nanni, Barbara Carnemolla, Claudia Cantoni, Jessica Grassi, Stefania Marcenaro, Nicolas Reymond, Massimo Vitale, Lorenzo Moretta, Marc Lopez, Alessandro Moretta
Journal: The Journal of Experimental Medicine (2003)

Human natural killer (NK) cells express a series of activating receptors and coreceptors that are involved in recognition and killing of target cells. In this study, in an attempt to identify the cellular ligands for such triggering surface molecules, mice were immunized with NK-susceptible target cells. On the basis of a functional screening, four mAbs were selected that induced a partial down-regulation of the NK-mediated cytotoxicity against the immunizing target cells. As revealed by biochemical analysis, three of such mAbs recognized molecules of ∼70 kD. The other mAb reacted with two distinct molecules of ∼65 and 60 kD, respectively. Protein purification followed by tryptic digestion and mass spectra analysis, allowed the identification of the 70 kD and the 65/60 kD molecules as PVR (CD155) and Nectin-2 δ/α (CD112), respectively. PVR-Fc and Nectin-2-Fc soluble hybrid molecules brightly stained COS-7 cells transfected with the DNAM-1 (CD226) construct, thus providing direct evidence that both PVR and Nectin-2 represent specific ligands for the DNAM-1 triggering receptor. Finally, the surface expression of PVR or Nectin-2 in cell transfectants resulted in DNAM-1–dependent enhancement of NK-mediated lysis of these target cells. This lysis was inhibited or even virtually abrogated upon mAb-mediated masking of DNAM-1 (on NK cells) or PVR or Nectin-2 ligands (on cell transfectants).
Cardiac resynchronization therapy may benefit patients with left ventricular ejection fraction &gt;35%: a PROSPECT trial substudy
Authors: Eugene S. Chung, Rodolphe P. Katra, Stefano Ghio, Jeroen Bax, Bart Gerritse, Kathryn Hilpisch, Brett J. Peterson, David S. Feldman, William T. Abraham
Journal: European Journal of Heart Failure (2010)