Miracle-dz/UniFAR-FTUs huggingface dataset:
Tadalafil pharmacokinetics in healthy subjects.

AIMS To characterize tadalafil plasma pharmacokinetics in healthy subjects following single and multiple doses. METHODS Noncompartmental parameters were calculated for healthy subjects receiving a single 2.5-20-mg tadalafil dose in 13 clinical pharmacology studies. An integrated statistical analysis of results in 237 subjects provided global averages and an assessment of effects of body mass index (BMI), age, gender and smoking status. Diurnal variation, food effects and proportionality of exposure to dose were analysed in three studies. Multiple-dose pharmacokinetics were evaluated in a separate study in which parallel groups of 15 subjects received 10 or 20 mg tadalafil once daily for 10 days. RESULTS Tadalafil was absorbed rapidly with mean Cmax (378 microg l-1 for 20 mg) observed at 2 h; thereafter, concentrations declined nearly monoexponentially with a mean (5th, 95th percentiles) t1/2 of 17.5 (11.5, 29.6) hours. Mean oral clearance (CL/F) was 2.48 (1.35, 4.35) l h-1 and apparent volume of distribution (Vz/F) was 62.6 (39.5, 92.1) l. No clinically meaningful effect of BMI, age, gender or smoking was identified. Exposure was not substantially affected by time of dosing. Food had negligible effects on bioavailability as assessed by 90% confidence intervals for Cmax and AUC mean ratios. Parameters were proportional to dose, indicating that doubling the dose doubled exposure. Steady state was attained by day 5 following once-daily administration, and accumulation (1.6-fold) was consistent with the t1/2. CONCLUSIONS Tadalafil pharmacokinetics are linear with respect to dose and time, and are not affected by food. Systemic clearance is low relative to other phosphodiesterase 5 inhibitors.
Knowledge-based capital in building regional innovation capacity

Purpose – The purpose of this paper is to investigate the role and the relevance of knowledge‐based capital as a strategic resource and a source of regional innovation capacity. The paper identifies human, relational, structural and social capital as the four main knowledge‐based categories building the knowledge‐based capital of a region. The role of each knowledge‐based category in determining regional innovation capacity is analyzed. Specifically, the authors discuss the relationships among the knowledge‐based categories and a regional innovation capacity.Design/methodology/approach – The paper is based on an in‐depth literature review of the knowledge management and regional innovation research stream. The fundamental underlying research questions that have driven the research are: “What are the knowledge‐based capital categories affecting a region's innovation capacity? ” and “How do knowledge‐based categories influence regional innovation capacity? ”. The paper is conceptual in its nature and aims to .
Pulmonary artery wedge pressure increases with high-intensity exercise in horses.

Using catheter mounted microtip manometers, right atrial, pulmonary artery, and pulmonary artery wedge pressures were studied in 8 horses while they were standing quietly (rest), and during galloping at treadmill speeds of 8, 10, and 13 m/s. At rest, mean (+/- SEM) heart rate, mean right atrial pressure, mean pulmonary artery pressure, and mean pulmonary artery wedge pressure were 37 (+/- 2) beats/min, 8 (+/- 2) mm of Hg, 31 (+/- 2) mm of Hg, and 18 (+/- 2) mm of Hg, respectively. Exercise at treadmill belt speed of 8 m/s resulted in significant (P < 0.05) increments in heart rate, right atrial pressure, pulmonary artery systolic, mean, diastolic and pulse pressures, and pulmonary artery wedge pressure. All these variables registered further significant (P < 0.05) increments as work intensity increased to 10 m/s, and then to 13 m/s. Pulmonary artery diastolic pressure was, however, not different among the 3 work intensities. During exercise at belt speed of 13 m/s, heart rate, mean right atrial pressure, mean pulmonary artery pressure, pulmonary artery pulse pressure, and mean pulmonary artery wedge pressure were 213 (+/- 5) beats/min, 44 (+/- 4) mm of Hg, 89 (+/- 5) mm of Hg, 69 (+/- 4) mm of Hg, and 56 (+/- 4) mm of Hg, respectively. Assuming mean intravascular pulmonary capillary pressure to be halfway between the mean pulmonary arterial and venous pressures, its value during exercise at 13 m/s may have approached 72.5 mm of Hg. Transmural pressure (intravascular minus alveolar pressure) across pulmonary capillaries may be even higher because of the large negative pleural pressure swings in galloping horses. (ABSTRACT TRUNCATED AT 250 WORDS)
Antibody response to a non‐conserved C‐terminal part of human histone deacetylase 3 in colon cancer patients

Antibodies to cancer antigens can often be detected in the sera of patients, although the mechanism of the underlying humoral immune response is poorly understood. Using immunoscreening of tumor‐derived cDNA expression libraries (SEREX), we identified human histone deacetylase 3 (HDAC3) as serologically defined antigen in colon cancer. Closely related HDAC1 and HDAC2 do not elicit humoral response in colon cancer patients. We show that the C‐terminal region of HDAC3 protein lacking the homology to other Class I HDAC contains at least 3 distinct B‐cell epitopes that are recognized by the serum antibodies. HDAC3 in combination with other SEREX antigens may become a useful molecular biomarker with diagnostic or prognostic value for a subset of colon cancer patients. Supplementary material for this article can be found on the International Journal of Cancer website at http://www.interscience. wiley.com/jpages/0020‐7136/suppmat/index.html. © 2005 Wiley‐Liss, Inc.
The effect of antibiotics on elevated serum prostate specific antigen in patients with urinary symptoms and negative digital rectal examination: a pilot study.

INTRODUCTION AND OBJECTIVES 65-70% of patients with abnormal prostate specific antigen (PSA) do not have cancer on prostate needle biopsy. Prostate biopsy is a potentially morbid procedure. Prostatitis is commonly reported on needle biopsies. To cut down on the number of unnecessary prostate biopsies we evaluated the effect of antibiotic on PSA level in patients with lower urinary tract symptoms (LUTS), normal digital rectal examination (DRE), normal urinalysis and elevated PSA. MATERIAL AND METHODS 48 selected patients with LUTS, normal DRE, normal urinalysis and elevated PSA (range 5.0-28.5 ng/ml), that usually will undergo prostate biopsy, received 2 weeks of Ciprofloxacin. An alpha-blocker was added if the patient was bothered. PSA was repeated and prostate biopsy was performed if PSA did not drop. RESULTS 25/48 patients (52%) dropped their PSA (median of 42% drop), with 80% improvement in LUTS, were not biopsied. 23/48 patients (48%) did not drop their PSA, with 65% improvement in LUTS, were biopsied. 9/23 patients (39%) had prostate cancer. CONCLUSION Almost 50% of patients with LUTS, normal DRE and elevated PSA will drop their PSA following 2 weeks of Ciprofloxacin thus by avoiding prostate biopsy. This needs to be done in a very strict manner with careful follow-up of those patients dropping their PSA especially not to normal levels.
Molecular biodiversity and population structure in common ash (Fraxinus excelsior L.) in Britain: implications for conservation

Current forestry policy promotes the use of local seed for new plantings, on the assumption that local material may be better adapted to local conditions. However, landscape‐scale genetic studies which are necessary to underpin conservation and breeding strategies are often lacking. We investigated molecular diversity in common ash (Fraxinus excelsior L.) sampled from 42 British and six French sites with microsatellites. Chloroplast haplotype H04 was the most common and widespread in Britain, although rare and localized individuals with H02 and H09 were also detected. In addition, three new chloroplast haplotypes were identified, and these were rare and highly localized. In terms of nuclear microsatellite markers, allelic richness differed between sites and decreased in an east to west direction. Differentiation between sites was often very low (mean FST 0.025), indicating few differences between the majority of sites. There was a clear excess of homozygotes (mean HO 0.669, mean HE 0.818) and a relatively high FIS (mean 0.182), suggests a consistent level of inbreeding or a widespread Wahlund effect in many F. excelsior sites. Gene pool ancestry analysis suggested that the majority of British F. excelsior belongs to a single meta‐population which covers mainland western and central Europe. Three northern and western sites diverged markedly from the dominant population, and may represent remnants of two late potential Ice Age refugia in northern Britain. The data provide new information which will aid development of appropriate conservation policies for ash and other wind pollinated tree species.
Histologic Features of Postnatal Development of Immune System Organs in the Sprague-Dawley Rat

The immune system of the rat undergoes substantial functional and morphological development during the postnatal period. Some aspects of this development are genetically predetermined, while other aspects depend on environmental influences. Detailed information on postnatal development is important in the interpretation of histopathologic findings in juvenile toxicology and pubertal assay studies, as well as other studies conducted in juvenile rats. Studies were conducted to provide detailed characterization of histologic features of the major functional compartments of immune system organs in male and female Sprague-Dawley rats at weekly intervals from the day of birth through postnatal day (PND) 42. Maturation of the individual immune system organs occurred across a range of ages, with histologic maturation of T-cell-related compartments typically occurring prior to maturation of B-cell-related compartments. The sequence of histologic maturation was bone marrow and thymus on PND 14, mesenteric lymph node on PND 21, Peyer’s patches and bronchus-associated lymphoid tissue on PND 28, mandibular lymph node, nasopharynx-associated lymphoid tissue, and diffuse mucosal mononuclear cell population of small intestine on PND 35, and spleen on PND 42. An estimation of functional maturation can be made based on the morphological indications of maturity of each compartment of immune system organs, but histologic indications of maturity do not confirm functional immunocompetence.
Video-Assisted Versus Open Anterior Lumbar Spine Fusion Surgery: A Comparison of Four Techniques and Complications in 135 Patients

Study Design. A retrospective review involved 135 patients undergoing anterior interbody fusion using four different approaches: transperitoneal video-assisted surgery with insufflation, retroperitoneal endoscopic video-assisted surgery, minilaparotomy retroperitoneal surgery, and traditional oblique muscle-splinting retroperitoneal surgery. Objective. To describe and compare the operative procedure and perioperative complications of four different interbody fusion techniques. Summary of Background Data. Although anterior lumbar interbody fusion surgery has a long history, several new and innovative approaches have been introduced recently. In contrast to the traditional oblique muscle-splitting retroperitoneal flank incision, the following have been used: a “minilaparotomy” open extraperitoneal approach through a small midline incision, a transperitoneal video-assisted insufflation technique, and a video-assisted gasless retroperitoneal endoscopic technique. Methods. A retrospective review was performed using the hospital records, operating room records, and clinic charts of 135 consecutive patients (50 men and 85 women) who underwent surgery between December 1993 and February 1998. Cases were included if either bone grafts alone or cylindrical cages with bone graft inside were used. Cases with anterior instrumentation using plates or rods were excluded. Diagnoses included degenerative disc disease, spondylolisthesis, or pseudarthrosis of a previous lumbosacral fusion. Patients with tumors or infection were excluded. The patients all were adults ranging in age from 17 to 83 years. Among the 135 patients, 12 had undergone previous anterior spine fusion surgery and 64 had undergone prior abdominal surgery. Results. The onset of new radicular pain or numbness, not experienced by the patient before surgery, occurred in six patients (18%; all with transperitoneal video-assisted surgery using insufflation). Vascular problems occurred in five patients (3.7% overall): two in the transperitoneal video-assisted group (5.9% of the group) and three in the minilaparotomy group (8.7% of the group). Retrograde ejaculation occurred in 4 of the 50 male patients (8% of the group): three in the transperitoneal video-assisted group (25% of the group) and one in the minilaparotomy group (2% of the group). Two patients had ureteral injuries (1.5% overall): one each in the retroperitoneal endoscopic and minilaparotomy groups. Conversion to open procedures was performed in seven patients (11% of the video-assisted procedures). The reasons for conversion included two major vessel lacerations and five peritoneal tears in the retroperitoneal video-assisted group. Conclusions. A comparative analysis of four techniques for approaching the lower lumbar spine to perform arthrodesis in 135 patients showed an incidence of complications consistent with the literature for video-assisted techniques, but higher than for open techniques. For these and other reasons, the video-assisted approaches have been abandoned by the surgeons of this report.
Public engagement with emerging infectious disease: The case of MRSA in Britain

As a route to providing a framework for elucidating the content of public thinking concerning emerging and re-emerging infectious diseases (EID), this article examines public engagement with methicillin-resistant Staphylococcus aureus (MRSA). It explores how British lay publics represent MRSA utilising a social representations framework. For this group, MRSA is associated primarily with dirty National Health Service (NHS) hospitals that have been neglected due to management culture having superseded the matron culture that dominated the putative golden age of the NHS. Furthermore, MRSA represents a transgression of the purpose of a hospital as a clean and curative institution. While this widely shared picture is accompanied by a strong sense of general concern, the respondents associate contracting MRSA with other identities, such as hospitalised, young and old people. These associations are linked to feelings of personal invulnerability. There is also blame of foreigners – especially cleaners and nurses – for MRSA's spread. Thus, the data corroborate a key pattern of response found in relation to myriad EID – that of othering. However, the identities associated with contracting MRSA are mutable; therefore, the threat cannot be distanced unequivocally. Beyond developing an understanding of the relationship between epidemics and identities, this article proposes a fitting theory with which to explore EID-related public thinking.
Regulation of Human Macrophage M1–M2 Polarization Balance by Hypoxia and the Triggering Receptor Expressed on Myeloid Cells-1

Macrophages (Mf) are a heterogeneous population of tissue-resident professional phagocytes and a major component of the leukocyte infiltrate at sites of inflammation, infection, and tumor growth. They can undergo diverse forms of activation in response to environmental factors, polarizing into specialized functional subsets. A common hallmark of the pathologic environment is represented by hypoxia. The impact of hypoxia on human Mf polarization has not been fully established. The objective of this study was to elucidate the effects of a hypoxic environment reflecting that occurring in vivo in diseased tissues on the ability of human Mf to polarize into classically activated (proinflammatory M1) and alternatively activated (anti-inflammatory M2) subsets. We present data showing that hypoxia hinders Mf polarization toward the M1 phenotype by decreasing the expression of T cell costimulatory molecules and chemokine homing receptors and the production of proinflammatory, Th1-priming cytokines typical of classical activation, while promoting their acquisition of phenotypic and secretory features of alternative activation. Furthermore, we identify the triggering receptor expressed on myeloid cells (TREM)-1, a member of the Ig-like immunoregulatory receptor family, as a hypoxia-inducible gene in Mf and demonstrate that its engagement by an agonist Ab reverses the M2-polarizing effect of hypoxia imparting a M1-skewed phenotype to Mf. Finally, we provide evidence that Mf infiltrating the inflamed hypoxic joints of children affected by oligoarticular juvenile idiopatic arthritis express high surface levels of TREM-1 associated with predominant M1 polarization and suggest the potential of this molecule in driving M1 proinflammatory reprogramming in the hypoxic synovial environment.
A Randomized Controlled Trial on the Effect of Needle Gauge on the Pain and Anxiety Experienced during Radial Arterial Puncture

Background Arterial punctures for assessment of arterial blood-gases can be a painful procedure. Lidocaine can be used to reduce pain prior to needle insertion but it is not a widely accepted practice. The purpose of this study was to determine whether a large size needle induces more pain compared to a smaller size needle for radial arterial puncture and to assess the anxiety associated with radial arterial punctures. Methods We conducted a prospective, double-blind, randomized, controlled, monocentric study including all outpatients who had a planned assessment of arterial blood gas analysis. Patients were randomized to have the arterial puncture performed with a 23 or a 25 G needle. The main judgement criteria was pain during arterial puncture. Visual analogue scale for pain (VAS-P) and visual analogue scale for anxiety (VAS-A) were used to assess pain and anxiety during radial arterial puncture. Results Two hundred consecutive patients were randomized. The 25 G needle was as painful as the 23 G needle (6.63 mm [0–19 mm] vs. 5.21 mm [0–18.49 mm], respectively, p = 0.527). Time for arterial puncture was longer with the 25 G needle than with the 23 G needle (42 s [35–55 s] vs. 33 s [24.5–35 s], respectively, p = 0.002). There was a correlation between the level of anxiety prior to the arterial puncture and the pain experienced by the patients (p: 0.369, p<0.0001). There was a correlation between the pain experienced by patients and the anxiety experienced in anticipation of another arterial puncture (p: 0.5124, p<0.0001). Conclusions The use of 23 G needle allows quicker arterial sampling and is not associated with increased pain and symptoms. Anxiety was correlated with the pain experienced by patients during arterial punctures. Trial Registration Clinicaltrials.gov: NCT02320916
Design, development and characterization of ACT017, a humanized Fab that blocks platelet's glycoprotein VI function without causing bleeding risks

ABSTRACT Glycoprotein VI is a platelet-specific collagen receptor critical for in vivo formation of arterial thrombosis. It is also considered as an attractive target for the development of anti-thrombotic drugs because blocking glycoprotein (GP)VI inhibits platelet aggregation without inducing detrimental effects on physiologic hemostasis. Here, we present data on the identification, in vitro and ex vivo pharmacology of a humanized Fab fragment designated as ACT017. ACT017 was selected out of 15 humanized variants based upon structural and functional properties. It was produced under GMP-like conditions followed by detailed physico-chemical analysis and functional characterization indicating high antigen-binding specificity and affinity. In addition, we demonstrate, in a dose-escalation study, that ACT017 has a high capacity to specifically inhibit collagen-induced platelet aggregation ex vivo after injection to the macaque without inducing thrombocytopenia, GPVI depletion or bleeding side effects as is the case for conventional anti-platelets. Therefore, ACT017 is a promising therapeutic candidate for the development of a new generation of safe and efficient anti-thrombotic drugs.
Neutrophil Adherence to Rat Cardiac Myocyte by Proinflammatory Cytokines

Summary: Cytokine induction of intercellular adhesion molecule-1 (ICAM-1) in cardiac myocytes may be a critical step in inflammation associated with ischemia–reperfusion injury. We investigated the involvement of tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), and interleukin 8 (IL-8) on neutrophil-myocyte adhesion; These cytokines are increased in plasma of patients with acute myocardial infarction (AMI). ICAM-1 expression on cultured neonatal rat cardiac myocytes was determined through immunohistochemical and enzyme-linked immunosorbent assay (ELISA) analysis. ICAM-1 mRNA expression in myocytes was investigated by Northern blot hybridization. Rat neutrophils isolated from peripheral blood (PB) were used for adherence assay. In immunohistochemical study, cultured neonatal rat cardiac myocytes constitutively expressed ICAM-1 molecules. In ELISA analysis, ICAM-1 molecule expression on myocytes was significantly stimulated by TNF-α (100 U/ml), but not by IL-6 (100 U/ml) or IL-8 (100 ng/ml) dose dependently. The effect of TNF-α was observed as early as 6 h after stimulation. Levels of ICAM-1 mRNA were very low or almost undetectable in unstimulated myocytes, but its expression was markedly induced after exposure to TNF-α for 3 h. IL-6 and IL-8 showed no effect on ICAM-1 mRNA accumulation. Adhesion of rat neutrophils to myocytes was stimulated by TNF-α, and the effect of TNF-α on adherence was significantly inhibited by an anti-ICAM-1 monoclonal antibody (MoAb). These results show that TNF-α, but not IL-6 and IL-8, promotes neutrophil-myocyte adhesion through ICAM-1 expression, suggesting involvement of TNF-α in inflammation associated with ischemia–reperfusion injury.
A Prospective Evaluation of Systemic Biomarkers and Cognitive Function Associated with Carotid Revascularization

Objective: To determine factors affecting cognition and identify predictors of long-term cognitive impairment following carotid revascularization procedures. Background: Cognitive impairment is common in older patients with carotid occlusive diseases. Methods: Patients undergoing carotid intervention for severe occlusive diseases were prospectively recruited. Patients received neurocognitive testing before, 1, and 6 months after carotid interventions. Plasma samples were also collected within 24 hours after carotid intervention and inflammatory cytokines were analyzed. Univariate and multivariate logistic regressions were performed to identify risk factors associated with significant cognitive deterioration (>10% decline). Results: A total of 98 patients (48% symptomatic) were recruited, including 55 patients receiving carotid stenting and 43 receiving endarterectomy. Mean age was 69 (range 54–91 years). Patients had overall improvement in cognitive measures 1 month after revascularization. When compared with carotid stenting, endarterectomy patients demonstrated postoperative improvement in cognition at 1 and 6 months compared with baseline. Carotid stenting (odds ratio 6.49, P = 0.020) and age greater than 80 years (odds ratio 12.6, P = 0.023) were associated with a significant long-term cognitive impairment. Multiple inflammatory cytokines also showed significant changes after revascularization. On multivariate analysis, after controlling for procedure and age, IL-12p40 (P = 0.041) was associated with a higher risk of significant cognitive impairment at 1 month; SDF1-&agr; (P = 0.004) and tumor necrosis factor alpha (P = 0.006) were independent predictors of cognitive impairment, whereas interleukin-6 (P = 0.019) demonstrated cognitive protective effects at 6 months after revascularization. Conclusions: Carotid interventions affect cognitive function. Systemic biomarkers can be used to identify patients at risk of significant cognitive decline postprocedures that benefit from targeted cognitive training.