Miracle-dz/UniFAR-FTUs huggingface dataset:
The influence of cyclooxygenase inhibition on the loss of bronchoconstrictor response to repeated bradykinin challenge in asthma.

Bradykinin is a naturally occurring nonapeptide which may contribute to the pathogenesis of bronchial asthma. When inhaled by asthmatic subjects it is a potent bronchoconstrictor, but with repeated challenge airways responsiveness to the peptide decreases markedly. In vitro studies suggest that loss of bradykinin responsiveness may be due to the secondary generation of relaxant prostanoids. We have used the potent cyclooxygenase inhibitor flurbiprofen to investigate the potential role of prostanoid generation in bradykinin tachyphylaxis in eight asthmatic patients. The effects of oral flurbiprofen (150 mg) and matched placebo were observed on two consecutive dose response studies with inhaled bradykinin and histamine in a double-blind, randomized study. Venous blood was taken to measure the serum concentration of thromboxane B2 (TxB2) as a check on the extent of cyclooxygenase blockade achieved by flurbiprofen. Following recovery from the first challenge with bradykinin, the asthmatic airways showed a reduced response to a second challenge with this nonapeptide, the provocative concentration producing a 20% fall from baseline (PC20) increasing from 0.07 to 0.42 mg.ml-1 (p less than 0.01). The airway response to inhaled histamine after the second bradykinin challenge was not significantly changed. In the presence of demonstrable cyclooxygenase inhibition, flurbiprofen failed to prevent the development of reduced responsiveness to bradykinin observed on the second challenge, the PC20 increasing from 0.10 to 0.48 mg.ml-1 (p less than 0.01). This study demonstrates that repeated exposure to inhaled bradykinin results in loss of the bronchoconstrictor response which appears specific for this agonist and not secondary to the increased generation of protective prostanoids.
Distributions of smokers by stage: international comparison and association with smoking prevalence.

OBJECTIVES The goals of this study were to describe the distribution of smokers by stage of change in Geneva, Switzerland; to compare this result with distributions observed in other countries; and to assess whether, across samples from different countries, the stage distribution of current smokers was associated with the prevalence of smoking. METHODS Two mailed surveys were conducted in Geneva in 1995-1996, in a representative sample of residents (n = 742) and in a representative sample of university members (n = 2,270). A literature review produced seven studies describing the stage distribution in representative samples. RESULTS In the Geneva population, 74% of smokers were in the precontemplation stage, 22% in contemplation, and 4% in preparation. In the university sample, the corresponding figures were 72, 20, and 8%. Our results were similar to other European samples, but less favorable than in American samples, where these distributions were typically 40, 40, and 20%, respectively. Across all samples, a low prevalence of smoking was associated with a more favorable stage distribution (r = 0.88, P = 0.002). CONCLUSIONS Interventions in Europe need to take into account the large proportion of precontemplators repeatedly observed among smokers. A shift to the right of the distribution of current smokers across stages may help increase quit rates and thereby reduce smoking prevalence. This hypothesis should be tested in prospective intervention studies.
Somatosensory responses during selective spatial attention: The N120‐to‐N140 trasition

The somatosensory evoked potential negative components in the 100-150-ms range were studied under conditions where attention was directed either toward or away from the probe stimulus. An N120 component, not sensitive to spatial attention, appeared in all conditions, including the no-task condition. Its distribution was consistent with an origin in the second somatic area. A later N140 response, not recorded in neutral conditions, was highly sensitive to spatial attention and reached its maximum to stimulation of the attended hand; its behavior was consistent with that of a processing negativity. The N140 was bilaterally distributed, but the hemisphere contralateral to stimulation appeared to be involved earlier than the ipsilateral one. Although the exogenous N120 may be influenced by somatosensory awareness and perhaps tactile recognition, the N140 appears linked to the spatial components of attention and results from the activation of several areas in both hemispheres.
Does ABCD2 Score Below 4 Allow More Time to Evaluate Patients With a Transient Ischemic Attack?

Background and Purpose— The National Institute for Clinical Excellence (NICE) recommends that patients with a transient ischemic attack and ABCD2 score ≥4 and those with >2 transient ischemic attacks within 1 week be admitted for urgent complete etiologic evaluation within 24 hours and that those with an ABCD2 score <4 be evaluated less urgently within 1 week. Methods— Using data from 1176 patients with a definite or possible transient ischemic attack or minor stroke included in the SOS-TIA registry (January 2003 to June 2007), we studied the usefulness of the conventional ABCD2 score cutoff as well as the NICE criteria for urgent admission to a stroke unit defined as presence of symptomatic internal carotid artery stenosis ≥50%, symptomatic intracranial artery stenosis ≥50%, or major cardiac source of embolism. Results— Among 697 patients with an ABCD2 score <4, 20% required immediate consideration for emergency treatment (eg, symptomatic internal carotid stenosis ≥50% in 9.1% of patients, symptomatic intracranial stenosis in 5.0%, atrial fibrillation in 5.9%, other major cardiac source of embolism in 2.1%) in comparison to 31.6% of 497 patients with an ABCD2 score ≥4. The sensitivity and specificity of ABCD2 score ≥4 or NICE criteria for discriminating between patients requiring admission or not were <62% with low positive predictive values (<30%) and high negative predictive values (≥80%). Conclusions— One in 5 patients with an ABCD2 score <4 had high-risk disease requiring urgent treatment decision-making. When triaging on an ABCD2 score, we recommend adding systematic carotid ultrasound (or a default angiographic CT scan) and electrocardiography within 24 hours before postponing complete transient ischemic attack evaluation.
Significant Pharmacokinetic and Pharmacodynamic Interaction of Warfarin With the NO‐Independent sGC Activator HMR1766

HMR1766 is a new nitric oxide (NO)–independent activator of soluble guanylyl cyclase (sGC) in development for the treatment of cardiovascular diseases and chronic heart failure. A significant fraction of patients to be treated with HMR1766 is expected to be maintained on warfarin. Because HMR1766 is an inhibitor and warfarin a substrate of CYP2C9, the authors studied whether warfarin pharmacokinetics and pharmacodynamics are influenced by HMR1766. Eighteen healthy males were to receive a single oral dose of 20 mg warfarin each under steady‐state conditions of HMR1766 or placebo. Plasma concentrations of HMR1766, (R)‐ and (S)‐warfarin, and its 7‐hydroxy‐metabolites were determined using high‐performance liquid chromatography and prothrombin time, and the international standardized ratio was determined by the nephelometric method. (S)‐Warfarin AUCinf and t1/2 were 106 471 h·μg/L and 82.92 hours versus 33 148 h·μg/L under HMR1766 and 31.72 hours under placebo, and the maximum decrease in prothrombin time values after warfarin dosing was 58.75% versus 39.94%. These data demonstrate a CYP2C9‐mediated pharmacokinetic interaction with pharmacodynamic, clinically relevant consequences, which might require warfarin dose adjustment.
The Option Market Reaction to Bank Loan Announcements

In this study, we examine the options market reaction to bank loan announcements for the population of US firms with traded options and loan announcements during 1996-2010. We get evidence on a significant options market reaction to bank loan announcements in terms of levels and changes in short-term implied volatility and its term structure, and observe significant decreases in short-term implied volatility, and significant increases in the slope of its term structure as a result of loan announcements. Our findings appear to be more pronounced for firms with more information asymmetry, lower credit ratings and loans with longer maturities and higher spreads. Evidence is consistent with loan announcements providing reassurance for investors in the short-term, however, over longer time horizons, the increase in the TSIV slope indicates that investors become increasingly unsure over the potential risks of loan repayment or uses of the proceeds.
The Discovery of Acquaintance Rape

Over the past 20 years, research has uncovered the many types of sexual victimizations women experience. Findings regarding the victim-offender relationship in such incidents have undoubtedly been among the most striking. Particularly salient is the revelation that the sexual abuse of and violence against women—including rape—most often are perpetrated not by a stranger but by someone known to the victim. Without the innovation and implementation of victimization surveys with behaviorally specific questions, this knowledge may have remained unknown. Instead, armed with such knowledge, prevention and education efforts can be fashioned to address sexual victimizations committed by someone known to the victim. In this article, we address these issues related to key developments in sexual victimization research.
Evaluation of normal human foveal development using optical coherence tomography and histologic examination.

OBJECTIVE To assess outer retinal layer maturation during late gestation and early postnatal life using optical coherence tomography and histologic examination. METHODS Thirty-nine participants 30 weeks' postmenstrual age or older were imaged using a handheld optical coherence tomography system, for a total of 102 imaging sessions. Foveal images from 16 participants (21 imaging sessions) were normal and evaluated for inner retinal excavation and the presence of outer retinal reflective bands. Reflectivity profiles of central, parafoveal, and parafoveal retina were extracted and were compared with age-matched histologic sections. RESULTS The foveal pit morphologic structure in infants was generally distinguishable from that in adults. Reflectivity profiles showed a single hyperreflective band at the fovea in all the infants younger than 42 weeks' postmenstrual age. Multiple bands were distinguishable in the outer retina at the peri fovea by 32 weeks' postmenstrual age and at the fovea by 3 months' postterm. By 17 months' postnatal, the characteristic appearance of 4 hyperreflective bands was evident across the foveal region. These features are consistent with previous results from histologic examinations. A "temporal divot" was present in some infants, and the foveal pit morphologic structure and the extent of inner retinal excavation were variable. CONCLUSIONS Handheld optical coherence tomography is a viable technique for evaluating neonatal retinas. In premature infants who do not develop retinopathy of prematurity, the foveal region seems to follow a developmental time course similar to that associated with in utero maturation. CLINICAL RELEVANCE As pediatric optical coherence tomography becomes more common, a better understanding of normal foveal and macular development is needed. Longitudinal imaging offers the opportunity to track postnatal foveal development among preterm infants in whom poor visual outcomes are anticipated or to follow up treatment outcomes in this population.
Quantitative analysis of the velopharyngeal sphincter function during speech.

OBJECTIVE This study reports a new concept for quantitative analysis of velopharyngeal function using electromagnetic articulography and simultaneous transoral video endoscopy. PARTICIPANTS The velopharyngeal closure mechanism was studied in 16 healthy German subjects during production of the vowel-consonant-vowel sequences /afa/ and /apa/. DESIGN Velar movements in the sagittal and vertical direction were measured by electromagnetic articulography (EMA) while video endoscopy was used for recording in the sagittal and transverse directions. MAIN OUTCOME MEASURE A transverse sagittal quotient (TSQ) was defined after the measurement of sagittal and transverse diameters of the velopharyngeal port (VPP) in the video-endoscopic pictures on the basis of a frame-by-frame analysis. RESULTS The sphincter morphology was objectively determined with the TSQ base value. A terminal sphincter deformation (TSD) for closure phases of articulatory movement was revealed by a qualitative shape analysis of the TSQ curves. CONCLUSIONS The assessment of the TSQ of velopharyngeal port diameters and the TSD in the terminal closure period lead to a new dynamic interpretation of velopharyngeal closure patterns.
Mechanism of action of purine analogues in chronic lymphocytic leukaemia

Fludarabine and chlorodeoxyadenosine are deaminationresistant analogues of deoxyadenosine (dAdo) that induce apoptosis in normal and malignant lymphocytes and have important therapeutic activity in chronic lymphocytic leukaemia (CLL). Both drugs are converted intracellularly to cytotoxic 5¢-phosphorylated derivatives through the action of deoxycytidine kinase. Phosphorylated purine analogues are substrates for several enzymes involved in DNA synthesis and repair. In proliferating cells, cytotoxicity seems to require incorporation of purine analogue into DNA. In resting lymphocytes, killing has been attributed to inhibition of DNA repair, accumulation of unrepaired DNA breaks and NAD ⁄ATP depletion due to sustained activation of poly(ADP-ribose) polymerase. Although this mechanism is demonstrable in occasional patients with CLL, p53-mediated apoptosis and direct induction of mitochondrial depolarization are probably more important. Caspase activation is not required for the induction of cell killing but determines whether death occurs by apoptosis or necrosis. Purine analogue resistance in CLL is associated with P53 mutation ⁄ deletion, relative over-expression of antiapoptotic Bcl-2 family proteins and a low capacity for nucleoside phosphorylation. To overcome drug resistance, strategies are required that target these points of blockade.
LA AFLUENCIA DE VISITANTES A LOS PARQUES NATURALES DE CASTILLA Y LEÓN: UNA CUESTIÓN PROBLEMÁTICA *

RESUMEN Se va a estudiar la afl uencia a los parques naturales de Castilla y Leon. Sin embargo, esta resulta una cuestion problematica debido a la escasez de recuentos de visitantes y a una debil dotacion de centros de visitantes, asi como a una ubicacion no siempre idonea. Se ha intentado esbozar una posible explicacion en la escasa planifi cacion ambiental de la Junta de Castilla y Leon, no solo en materia de uso publico, sino tambien en instrumentos clave como los Planes de Uso y Gestion, y en una politica cambiante sin una direccion clara. Ademas, existe el problema de que la mayor parte de los parques naturales son recientes y que ni los instrumentos de planifi cacion ni los equipamientos se han desarrollado convenientemente, lo que hace que los resultados no sean concluyentes. Por ello, se insta a desarrollar la planifi cacion en materia de uso publico para preservar los valores que merecieron la declaracion de los parques naturales y a hacer estudios sobre los visitantes para adecuar la oferta a la demanda. Palabras clave: parques naturales, planifi cacion, uso publico, visitantes, afl uencia. The visitors’ infl ow to natural parks of Castilla y Leon: a problematic question
Granular matter and the marginal rigidity state

Model experiments are reported on the build-up of granular piles in two dimensions. These show that, as the initial density of falling grains is increased, the resulting pile has decreasing final density and its coordination number approaches the low value predicted for the theoretical marginal rigidity state. This provides the first direct experimental evidence for this state of granular matter. We trace the decrease in the coordination number to the dynamics within an advancing yield front between the consolidated pile and the falling grains. We show that the front’s size diverges as the marginal rigidity state is approached, suggesting a critical phenomenon.
GABAergic Inhibition Regulated Pain Sensitization through STEP61 Signaling in Spinal Dorsal Horn of Mice

Background:The reduction of &ggr;-aminobutyric acid (GABA) type A receptor–mediated inhibition has long been implicated in spinal sensitization of nociceptive responses. However, it is largely unknown which signaling cascades in spinal dorsal horn neurons are initiated by the reduced inhibition to trigger pain hypersensitivity. Methods:GABAergic inhibition was manipulated by intrathecal application of GABA type A receptor antagonist bicuculline in intact mice or by GABA type A receptor agonist muscimol in complete Freund’s adjuvant–injected mice. Immunoblotting, coimmunoprecipitation, immunohistochemistry, and behavioral tests were used to explore the signaling pathways downstream of the altered GABAergic tone. Results:The study data revealed that the 61-kD isoform of striatal-enriched protein phosphatase (STEP61) was a key molecule that relayed the signals from GABAergic neurotransmission. The authors found that STEP61 was highly expressed in dorsal horn neurons. Under physiological conditions, STEP61 tonically interacted with and negatively controlled the activities of extracellular signal–regulated kinase and Src-family protein tyrosine kinases member Fyn, two critical kinases involved in spinal sensitization. Once GABAergic inhibition was impaired, STEP61 interaction with its substrates was substantially disturbed, allowing for activation of extracellular signal–regulated kinase and Fyn (n = 4 to 6). The hyperactivities of extracellular signal–regulated kinase and Fyn, along with STEP61 dysregulation, caused the tyrosine phosphorylation and synaptic accumulation of GluN2B subunit-containing N-methyl-D-aspartate subtype of glutamate receptors (n = 6), leading to GluN2B receptor-dependent pain hypersensitivity. Overexpression of wild-type STEP61 to resume its enzymatic activity significantly blocked the mechanical allodynia evoked by bicuculline and more importantly, alleviated chronic inflammatory pain (n = 6 in each group). Conclusion:These data identified STEP61 as a key intermediary for GABAergic inhibition to regulate pain sensitization.
A Clinicopathological Study of Necrotizing Fasciitis

Background: Necrotizing fasciitis is a relatively common infection with high morbidity and mortality, as they often present late in their clinical course. Quick and aggressive surgical treatment improves survival and decreases hospital stay. Methods: A prospective study of 50 consecutive patients of necrotizing fasciitis who were admitted in our hospital over a period of 342 days between May 2007 and April 2008. The study includes clinical presentation, biochemical parameters, bacteriology, predisposing factors, associated co-morbid conditions, time interval between admission and first surgical intervention and outcome of this life threatening infection. Results: 50 patients of necrotizing fasciitis were studied over a period of 342 days. The mean age of the patients were 44.5 ± 8.36 years and male: female ratio was 3.17 : 1. Diabetes mellitus was the most common co-morbid condition (42%). Alcoholism was the commonest addiction (34%). Regarding predisposing conditions majority (48%) of the cases were idiopathic. History of trivial trauma was present in (38%) patients. Mean duration of symptoms was 5.16 ± 0.902 days. Perineum was the commonest site involved (52%) followed by the lower extremity (40%). The commonest bacteria isolated was E.coli (42%). The culture was polymicrobial in (78%) patients. Mean number of surgical debridement were 3.84 ± 0.809. Secondary surgical procedures included mobilization and suturing (48%) and skin grafting (42%). Average duration of hospital stay was 33.04 ± 7.99 days. Mortality was 10%. Conclusions: Necrotizing fasciitis is more common in middle aged males. Diabetes mellitus is the most common co-morbid condition associated with necrotizing fasciitis. The perineum is commonly affected. The presence of multiple co- morbid conditions reduces the survival. Early diagnosis and aggressive surgical debridement reduces mortality.
Eleven-year Management of Prostate Cancer Patients on Active Surveillance: What have We Learned?

Purpose To evaluate the outcomes of active surveillance (AS) on patients with low-risk prostate cancer (PCa) and to identify predictors of disease reclassification. Methods In 2005, we defined an institutional AS protocol (Sorveglianza Attiva Istituto Nazionale Tumori [SAINT]), and we joined the Prostate Cancer Research International: Active Surveillance (PRIAS) study in 2007. Eligibility criteria included clinical stage ≤T2a, initial prostate-specific antigen (PSA) <10 ng/mL, and Gleason Pattern Score (GPS) ≤3 + 3 (both protocols); ≤25% positive cores with a maximum core length containing cancer ≤50% (SAINT); and ≤2 positive cores and PSA density <0.2 ng/mL/cm3 (PRIAS). Switching to active treatment was advised for a worsening of GPS, increased positive cores, or PSA doubling time <3 years. Active treatment-free survival (ATFS) was assessed using the Kaplan-Meier method. Factors associated with ATFS were evaluated with a multivariate Cox proportional hazards model. Results A total of 818 patients were included: 200 in SAINT, 530 in PRIAS, and 88 in personalized AS monitoring. Active treatment-free survival was 50% after a median follow-up of 60 months. A total of 404/818 patients (49.4%) discontinued AS: 274 for biopsy-related reclassification, 121/404 (30%) for off-protocol reasons, 9/404 (2.2%) because of anxiety. Biopsy reclassification was associated with PSA density (hazard ratio [HR] 1.8), maximum percentage of core involvement (HR 1.5), positive cores at diagnostic biopsy (HR 1.6), older age (HR 1.5), and prostate volume (HR 0.6) (all p<0.01). Patients from SAINT were significantly more likely to discontinue AS than were the patients from PRIAS (HR 1.65, p<0.0001). Conclusions Five years after diagnosis, 50% of patients with early PCa were spared from active treatment. Wide inclusion criteria are associated with lower ATFS. However, at preliminary analysis, this does not seem to affect the probability of unfavorable pathology.
Self-Concept Differentiation and Self-Concept Clarity across Adulthood: Associations with Age and Psychological Well-Being

This study focused on the identification of conceptually meaningful groups of individuals based on their joint self-concept differentiation (SCD) and self-concept clarity (SCC) scores. Notably, we examined whether membership in different SCD-SCC groups differed by age and also was associated with differences in psychological well-being (PWB). Cluster analysis revealed five distinct SCD-SCC groups: a self-assured, unencumbered, fragmented-only, confused-only, and fragmented and confused group. Individuals in the self-assured group had the highest mean scores for positive PWB and the lowest mean scores for negative PWB, whereas individuals in the fragmented and confused group showed the inverse pattern. Findings showed that it was psychologically advantageous to belong to the self-assured group at all ages. As hypothesized, older adults were more likely than young adults to be in the self-assured cluster, whereas young adults were more likely to be in the fragmented and confused cluster. Thus, consistent with extant theorizing, age was positively associated with psychologically adaptive self-concept profiles.