Miracle-dz/UniFAR-FTUs huggingface dataset:
Influence of protein and calorie malnutrition on the pharmacokinetics and pharmacodynamics of bumetanide in rats.

Bumetanide is a loop diuretic that is used for the treatment of edema and hypertension. The rapidly developing syndrome of extracellular fluid overload in some malnourished children has been successfully treated with furosemide, another loop diuretic, and digoxin; however, similar studies with bumetanide have not been conducted to date. Therefore, in the present study, the influence of dietary protein deficiency on the pharmacokinetics and pharmacodynamics of bumetanide was investigated after intravenous (i.v.) bolus and oral administration of bumetanide to male Sprague-Dawley rats fed on 23% (control rats) or 5% [protein and calorie malnutrition (PCM) rats] protein diet ad libitum for 4 weeks. After an i.v. dose of bumetanide, 1 mg/100 g body weight, the mean values of renal clearance and percentages of dose excreted as unchanged bumetanide in an 8-h urine sample were 166 and 154% higher, respectively, in PCM than control rats; however, nonrenal clearance (CLNR) was 28% lower. The decrease in nonrenal clearance in PCM rats might be because of the decrease in nonrenal metabolism of bumetanide in PCM rats. The urine output per 100 g of body weight was not significantly different between the two groups of rats after i.v. administration, although the amount of bumetanide excreted in the 8-h urine sample per 100 g body weight increased significantly in PCM rats. These results could be explained by the fact that the dose of bumetanide used results in urinary excretion rate of bumetanide at the plateau of the concentration-effect relationship. (ABSTRACT TRUNCATED AT 250 WORDS)
The Mode of Bone Morphogenetic Protein (BMP) Receptor Oligomerization Determines Different BMP-2 Signaling Pathways*

Bone morphogenetic proteins (BMPs) are multifunctional proteins regulating cell growth, differentiation, and apoptosis. BMP-2 signals via two types of receptors (BRI and BRII) that are expressed at the cell surface as homomeric as well as heteromeric complexes. Prior to ligand binding, a low but measurable level of BMP-receptors is found in preformed hetero-oligomeric complexes. The major fraction of the receptors is recruited into hetero-oligomeric complexes only after ligand addition. For this, BMP-2 binds first to the high affinity receptor BRI and then recruits BRII into the signaling complex. However, ligand binding to the preformed complex composed of BRII and BRI is still required for signaling, suggesting that it may mediate activating conformational changes. Using several approaches we have addressed the following questions: (i) Are preformed complexes incompetent of signaling in the absence of BMP-2? (ii) Which domains of the BRII receptors are essential for this complex formation? (iii) Are there differences in signals sent from BMP-inducedversus preformed receptor complexes? By measuring the activation of Smads, of p38 MAPK and of alkaline phosphatase, we show that the ability of kinase-deficient BRII receptor mutants to inhibit BMP signaling depends on their ability to form heteromeric complexes with BRI. Importantly, a BRII mutant that is incapable in forming preassembled receptor complexes but recruits into a BMP-induced receptor complex does not interfere with the Smad pathway but does inhibit the induction of alkaline phosphatase as well as p38 phosphorylation. These results indicate that signals induced by binding of BMP-2 to preformed receptor complexes activate the Smad pathway, whereas BMP-2-induced recruitment of receptors activates a different, Smad-independent pathway resulting in the induction of alkaline phosphatase activity via p38 MAPK.
Pharmacokinetic and safety study of doxorubicin-eluting beads in a porcine model of hepatic arterial embolization.

PURPOSE To present the pathologic and pharmacokinetic findings from hepatic embolization in a porcine model comparing doxorubicin-eluting beads with bland embolization and to correlate these findings with in vitro release kinetics. MATERIALS AND METHODS Drug-eluting beads (DEB; 100-300 microm and 700-900 microm) loaded with 37.5 mg doxorubicin per milliliter hydrated beads were used to embolize the hepatic artery feeding the left lobe of the liver in young adult Yucatan pigs (n = 5 per group). Control animals underwent embolization with bland beads (100-300 microm; n = 5). Systemic plasma levels of doxorubicin were measured and correlated to in vitro drug release. Blood sampling and histopathologic examination were performed during the 90-day follow-up. RESULTS All animals underwent successful embolization, and the treatment was well tolerated. Mean volumes of beads administered were 2.0-3.4 mL, with mean doses of 127.5 mg and 78.7 mg of doxorubicin for the 100- to 300-microm and 700- to 900-microm DEB groups, respectively. Gross pathologic examination revealed no effects on organs other than the liver. There was a transient increase in liver enzyme levels, particularly in the groups of animals who underwent embolization with 100- to 300-microm DEB. Histopathologic study showed mostly nonnecrotic changes with bland beads, whereas the effects of DEB were more severe, with large areas of pannecrosis evident with the 100- to 300-microm DEB. Maximum plasma concentrations were 651 ng/mL and 42.8 ng/mL for the 100- to 300-microm and 700- to 900-microm DEB groups, respectively, observed at 1 minute for both groups. Correlation with in vitro data showed a strong linear relationship. CONCLUSIONS Hepatic arterial embolization with DEB was shown to be safe and well tolerated. The locoregional delivery of doxorubicin from DEB caused targeted tissue damage with minimal systemic impact and could be a promising new approach to transarterial chemoembolization of solid tumors.
Prospective, multicentre validation of a simple, patient-operated electrocardiographic system for the detection of arrhythmias and electrocardiographic changes.

AIMS Electrocardiographic changes, e.g. arrhythmias causing syncope or palpitations, are often transient and therefore difficult to diagnose. Systematic and symptom-activated ECG recordings can increase diagnostic yield in such patients. We evaluated the diagnostic accuracy of a simple, leadless, patient-operated ECG device compared with a standard 12-lead ECG. METHODS AND RESULTS We recorded a standard 12-lead surface ECG and a patient-activated ECG in direct succession in 508 consecutive patients enrolled in four centres. All ECGs were analysed by a single, blinded observer. ECGs were analysable in 505 (99.4%) patients (66% male, age 61 +/- 15 years, and body mass index 27 +/- 4). Analysis of the patient-activated ECG adequately detected a normal ECG (sensitivity 91% and specificity 95%), atrial fibrillation (AF) (sensitivity 99% and specificity 96%), and even T-wave abnormalities (sensitivity 90% and specificity 75%). Diagnostic accuracy for atrioventricular nodal block was moderate (sensitivity 79% and specificity 99%). Continuous parameters correlated well: (r(2) = 0.89 for heart rate, 0.83 for PR interval, 0.78 for QRS duration, and 0.89 for QTc). CONCLUSION Recordings made by this patient-operated ECG device allow to detect arrhythmias and other ECG changes with high accuracy compared with a standard ECG. It may help to improve accurate diagnosis of transient ECG changes such as paroxysmal AF in palpitations or other unexplained cardiac symptoms.
Targeting the JAK2/STAT3 axis in Alzheimer's disease

Background: Amyloid β (Aβ) has long been implicated in the pathogenesis of Alzheimer's disease (AD). Little is known, however, about the intracellular events in neurons which lead to memory loss related to AD. Focusing on the fact that an AD-specific neuroprotective peptide named humanin (HN) inhibits AD-related neurotoxicity by activating the JAK2/STAT3 signaling axis, we recently found that age- and disease-dependent deterioration in the JAK2/STAT3 axis plays a critical role in the pathogenesis of AD. Objective/methods: Here we summarize the neuroprotective effect of HN and its derivative, named colivelin (CLN), and also review the roles of the JAK2/STAT3 axis in memory impairment related to AD. Results/conclusions: The JAK2/STAT3 axis is a major transducer of HN-mediated neuroprotective activity. Aβ-dependent inactivation of the JAK2/STAT3 axis in hippocampal neurons causes cholinergic dysfunction via pre- and post-synaptic mechanisms, which leads to memory impairment related to AD. This provides not only a novel pathological hallmark of AD but also a novel target in AD therapy.
Hypoxia activates 15‐PGDH and its metabolite 15‐KETE to promote pulmonary artery endothelial cells proliferation via ERK1/2 signalling

Dysfunction and injury of endothelial cells in the pulmonary artery play critical roles in the hypertension induced by chronic hypoxia. One consequence of hypoxia is increased activity of 15‐hydroxyprostaglandin dehydrogenase (PGDH). Here, we have explored, in detail, the effects of hypoxia on the proliferation of pulmonary artery endothelial cells.
Psychiatric Referrals within the General Hospital: Comparison with Referrals to General Practitioners

The increase in referrals to a new consultant psychiatrist within a teaching hospital was documented. During 1987/88 there were 279 consecutive referrals from physicians and surgeons (159 out-patients and 120 ward-consultation requests) which were compared with 184 consecutive GP referrals over the same period. Hospital referrals tended to be older, and less socially disadvantaged, but with psychiatric disorder of similar severity to GP referrals. They were more likely to have a concurrent physical diagnosis, and demonstrate somatisation. The latter was not confined to patients without physical disorder; half of the patients classified as ‘psychological reaction to physical disorder’ showed somatisation. ICD–10 appeared to perform better than ICD–9 or DSM–III for somatoform disorders, but a comprehensive classification system is still needed for liaison psychiatry. Personal discussion with the referring doctor was most common among the ward-consultation requests; in this situation the referring doctor usually continued primary management of the patient.
The Contribution of Antismoking Advertising to Quitting: Intra- and Interpersonal Processes

This study explored the roles of transportability—the tendency to become absorbed in a narrative—and interpersonal discussion in the use of televised antismoking advertising in attempts to quit smoking. We used data from a representative population survey of adults (n = 2,999), examining responses from current smokers (n = 594) and former smokers who had quit in the last 5 years (n = 167). Logistic regression analysis revealed that current and former smokers higher in transportability were more likely to recall an antismoking ad (OR = 1.08, p < .001), and to perceive they had been helped by antismoking advertising in their attempts to quit smoking (OR = 1.05, p < .01). Transportability also was related to the recall of narrative antismoking advertisements (OR = 1.06, p < .05). Among current smokers, those who engaged in interpersonal discussion about any antismoking advertising were more likely to have made a quit attempt (OR = 2.76, p < .001). Finally, individuals were most likely to discuss advertising containing information about the negative health consequences of smoking using graphic images or simulations of bodily processes. These results suggest that the effectiveness of antismoking advertising is dependent upon both intra- and interpersonal processes that are triggered by the advertisements.
Protein and mRNA expression of folic acid-associated enzymes as biomarkers for the cytotoxicity of the thymidylate synthase-targeted drugs, pemetrexed and S-1, in non-small cell lung cancer

The thymidylate synthase (TS)-targeted drugs, pemetrexed and S-1, exert an important role in advanced non-small cell lung cancer (NSCLC) treatment; folic acid-associated enzymes are expected to behave as biomarkers, although their role has yet to be fully elucidated. In the present study, a single-institutional prospective analysis, in which the mRNA and protein expression levels of five folic acid-associated enzymes were evaluated with surgical specimens of NSCLC, was performed. Drug sensitivity was evaluated using a collagen gel droplet-embedded culture drug sensitivity test (CD-DST) in vitro. A total of 50 patients with NSCLC were enrolled, and the mRNA and protein expression levels of five enzymes were assessed in 47 and 46 patients, respectively. A significant association was identified between mRNA and protein expression in TS (r=0.6266), but the correlation between mRNA and protein expression levels for the other four enzymes was poor. TS mRNA expression was significantly higher in poorly differentiated tumors compared with moderately differentiated tumors (P=0.0399). TS protein expression was significantly higher in patients with pleural invasion or lymphatic invasion compared with those lacking them (P=0.027 and 0.030, respectively). CD-DST revealed that none of the tumors that were sensitive to pemetrexed, but not to S-1, were well differentiated, whereas none of the tumors that were sensitive to S-1, but not to pemetrexed, were poorly differentiated. More prominent vascular invasion was observed in the tumors that were sensitive to S-1. The only factors that exhibited the potential to discriminate the cytotoxicity of pemetrexed from S-1 were tumor differentiation grade and vascular invasion.
Umbilical cord blood concentrations of IL-6, IL-8, and MMP-8 in pregnancy complicated by preterm premature rupture of the membranes and histological chorioamnionitis.

OBJECTIVE To determine whether umbilical cord blood concentrations of interleukin-6 (IL-6), interleukin-8 (IL-8), and matrix metalloproteinase-8 (MMP-8) are of value in the diagnosis of histological chorioamnionitis (HCA) and funisitis in patients with preterm premature rupture of membranes (PPROM). SETTING Department of Obstetrics and Gynaecology, Charles University in Prague, Faculty of Medicine Hradec Kralove, University Hospital Hradec Kralove, Czech Republic. METHODS We compared umbilical cord blood IL-6, IL-8, and MMP-8 concentrations in 83 women with PPROM between 24th and 36th gestational weeks with the presence and the absence of HCA/funisitis using nonparametric tests (Mann-Whitney U test), given the non-normal distribution of analyte. Comparisons of proportions were performed the D'Agostino and Pearson omnibus normality test and the Shapiro-Wilk test. RESULTS Patients with HCA had a significantly higher median umbilical cord blood IL-6 concentration than patients without histological signs of inflammation (12.0 pg/mL [2.1-138.3] versus 2.7 pg/mL [0.1-12.4]; p=0.004) but did not have significantly higher median umbilical cord IL-8 (29.9 pg/mL [14.0-186.3]; versus 18.9 pg/mL [7.9-89.4]; p=0.13) and MMP-8 (2.9 pg/mL [0.5-25.2] versus 0.5 ng/mL [0.5-7.9]; p=0.18). Patients with HCA and funisitis had a significantly higher median umbilical cord blood IL-6 (222 pg/mL [95.3-411.7] versus 6.1 pg/mL [1.3-18.5]; p<0.0001) and IL-8 (20.9 pg/mL [8.4-37.7] versus 190.7 pg/mL [83.8-554.2]; p=0.0004) concentration than patients with HCA alone. Differences were not found in MMP-8 concentrations (3.7 ng/mL [0.5-21.4] versus 2.4 ng/mL [0.5-88.1]; p=0.7). CONCLUSION HCA was associated with a significant increase in umbilical cord blood IL-6 concentration. In patients with HCA and funisitis, umbilical cord blood IL-6 and IL-8 were significantly higher than those without histological signs of inflammation.
Purification and Characterization of Colicin D

Colicin D-CA23, obtained by sonic treatment of mitomycin C-induced cells of Escherichia coli K-12 W1485 (colD), was purified by ammonium sulfate precipitation, gel filtration on Sephadex G200, ion-exchange chromatography on diethylaminoethyl cellulose, and isoelectrofocusing. Polyacrylamide-gel electrophoresis, sedimentation velocity analysis, and antigenic analysis indicated that the preparation was homogeneous. Colicin D is composed entirely of amino acids and hence is a simple protein uncomplexed with lipid or lipopolysaccharide. It contains six residues of cysteine per molecule. The molecular weight of colicin D is approximately 92,000, as determined by sodium dodecyl sulfate-polyacrylamide-gel electrophoresis and gel filtration on Sephadex G200. Its sedimentation coefficient is 4.41S. The behavior of colicin D in solutions of sodium dodecyl sulfate and 2-mercaptoethanol indicates that it does not consist of subunits and exists as a single polypeptide chain. Its high molecular weight and presence of six cysteine residues per molecule distinguish colicin D from all colicins previously described. Although colicins D and E3 have similar modes of action, their gross molecular properties are entirely different.
Are kids too busy?: early adolescents' perceptions of discretionary activities, overscheduling, and stress.

BACKGROUND The activity patterns of children, especially after-school patterns, are receiving more professional attention. However, evidence regarding the value of various activities in children's lives is contradictory. The purpose of this study was to assess perceptions of discretionary activities, overscheduling, and levels of stress from adolescents' perspective. METHODS A sample of 882 children, ages 9 to 13, recruited at 9 health education centers in the United States was selected for this study. Children answered questionnaires using remote, handheld devices. Data were analyzed using descriptive statistics and multivariate logistic regression. The outcomes of interest were activity-based stress and desire for more free time. RESULTS The primary predictor for the desire for more free time was hours of screen time (television, computer, video games): those who reported 3 or more hours were nearly 3 times more likely to desire more free time. Further, children who chose their own activities experienced more activity-related stress than those who shared decisions with parents. The single greatest predictor of activity-related stress was the reported number of hours spent on homework. Students who averaged at least 2 hours on homework per night were nearly twice as likely to report frequent activity-related stress. CONCLUSION Parents of school-aged children should assess activity-related stress and the degree to which children perceive they are busy. Teachers, school counselors, and school administrators should be aware of these perceptions as they are making decisions regarding school schedules and should teach personal skills such as time management and stress control.
USING ICT IN SECONDARY SCHOOL SCIENCE TEACHING – WHAT STUDENTS AND TEACHERS IN TRINIDAD AND TOBAGO SAY?

Over the last decade and a half, classrooms have become swamped with a range of electronic devices. Technology will continue to be more efficient, more versatile and indeed more abundant in schools and in classrooms. This study explores the views of students and teachers on the effectiveness of ICT in science teaching in terms of (i) levels of enjoyment derived by students, and (ii) usefulness of ICTs to teachers for their teaching. A questionnaire was used to elicit the views of students and teachers in respect of a range of ICT-based classroom activities. Qualitative and quantitative data collected through the questionnaires from 12 teachers and 100 students involved in science teaching and learning at a selected secondary school in Trinidad were analyzed. The results show that students enjoy ICT interventions in their lessons and teachers rank it high in many respects but, both students and teachers agree that ICT loses its appeal when its use is arbitrary and ill-planned. Article visualizations:
In vivo dynamics of glycolysis in Escherichia coli shows need for growth‐rate dependent metabolome analysis

Metabolomics emerges to become an important profiling technique in bio(techno)logical systems. In addition to intracellular metabolite concentrations at (quasi) stationary conditions, stimulus‐response experiments provide information on the dynamic behavior of metabolic pathways. These data are relevant for bioprocess analysis on the level of metabolism and for application of metabolic engineering principles aiming at a metabolic redesign of producer cells. However, even for the well‐studied bacteria Escherichia coli only limited growth‐rate dependent intracellular metabolite information is currently available, thereby impeding comprehensive metabolome analysis. Here, we present intracellular metabolite concentration data of representative glycolytic intermediates in E. coli cultivated in glucose‐limited chemostats, (i) at systematic variation of growth‐rate (D = 0.1, 0.2, 0.3, and 0.4 h−1) and (ii) at both steady‐state and after a glucose pulse applying a recently introduced integrated sampling procedure and LC‐MS analytical method. Whereas intracellular steady‐state concentrations of upper part glycolytic intermediates FBP and DHAP+GAP increased 2.3‐fold, respectively 2.8‐fold, when specific growth‐rate is raised from μ = 0.1 h−1 to μ = 0.4 h−1, the opposite trend was observed for 2PG+3PG and PEP pools with a decrease by a factor of 2.1, respectively 1.9. In glucose pulse experiments FBP and DHAP+GAP showed a 3.3 (1.8)‐fold, respectively 2.8 (2.0)‐fold, increase relative to the steady‐state level at μ = 0.1 (0.4) h−1. Also, the dynamics changed with growth‐rate for these two metabolite pools. In contrast, 2PG+3PG and PEP were characterized by decreased concentrations in response to a glucose pulse and the relative changes related to steady‐state values were significantly smaller compared with FBP and DHAP+GAP. The observed growth‐rate dependency of our data clearly indicates the necessity for metabolome studies covering a broader range of physiological growth conditions.
A missing link in thymic dendritic cell development

Negative selection in the thymus prevents the generation of self‐reactive T cells through the deletion of thymocytes with high affinity for self‐antigens. Within the thymus, self‐antigens are presented by thymic epithelial cells and DCs. Both cell types can mediate negative selection, although the relative contribution of each cell type remains elusive. Similar to DCs of other lymphoid organs, thymic DCs come in different flavors. Over the past years, various lines of evidence have emerged that either favor a common origin for some thymic DCs and thymocytes or, conversely, indicate the existence of separate intrathymic T lineage and DC precursors. In this issue of the European Journal of Immunology, a study reports the identification of an intrathymic DC precursor that is likely to be unrelated to the earliest physiological T‐cell progenitors. Thus this intrathymic DC precursor may constitute a “missing link” between extrathymic DC precursor‐types, which are able to generate DCs in secondary lymphoid organs and intrathymic DCs, and supports the notion that intrathymic DCs and thymocytes arise from different precursors.