bluuebunny/crossref_metadata_2025_split huggingface dataset:
In vivo fate-tracing studies using the Scl stem cell enhancer: embryonic hematopoietic stem cells significantly contribute to adult hematopoiesis
Authors: Göthert Joachim R. , Gustin Sonja E. , Hall Mark A. , Green Anthony R. , Göttgens Berthold , Izon David J. , Begley C. Glenn 
Published: December 2004

AbstractEvidence for the lineage relationship between embryonic and adult hematopoietic stem cells (HSCs) in the mouse is primarily indirect. In order to study this relationship in a direct manner, we expressed the tamoxifen-inducible Cre-ERT recombinase under the control of the stem cell leukemia (Scl) stem-cell enhancer in transgenic mice (HSC-SCL-Cre-ERT). To determine functionality, HSC-SCL-Cre-ERT transgenics were bred with Cre reporter mice. Flow cytometric and transplantation studies revealed tamoxifen-dependent recombination occurring in more than 90% of adult long-term HSCs, whereas the targeted proportion within mature progenitor populations was significantly lower. Moreover, the transgene was able to irreversibly tag embryonic HSCs on days 10 and 11 of gestation. These cells contributed to bone marrow hematopoiesis 5 months later. In order to investigate whether the de novo HSC generation is completed during embryogenesis, HSC-SCL-Cre-ERT–marked fetal liver cells were transplanted into adult recipients. Strikingly, the proportion of marked cells within the transplanted and the in vivo–remaining HSC compartment was not different, implying that no further HSC generation occurred during late fetal and neonatal stages of development. These data demonstrate for the first time the direct lineage relationship between midgestation embryonic and adult HSCs in the mouse. Additionally, the HSC-SCL-Cre-ERT mice will provide a valuable tool to achieve temporally controlled genetic manipulation of HSCs.
Ly49Q defines 2 pDC subsets in mice
Authors: Kamogawa-Schifter Yumiko , Ohkawa Jun , Namiki Sahori , Arai Naoko , Arai Ken-ichi , Liu YongJun 
Published: December 2004

AbstractPlasmacytoid dendritic cells (pDCs) play an important primary role for antiviral innate immunity by rapidly producing large amounts of type 1 interferon (IFN) upon viral infection. To study pDC biology, we generated a monoclonal antibody, termed 2E6, that recognizes pDCs. Molecular cloning of a cDNA encoding the 2E6 antigen revealed that it is a type II C-type lectin, Ly49Q, that consists of 247 amino acids with high homology to the natural killer (NK) receptor family Ly49, with an immunoreceptor tyrosine-based inhibitory motif in the cytoplasmic domain. Ly49Q is expressed on pDCs but not on NK cells or myeloid dendritic cells. B220+, CD11c+, CD11b– pDCs in bone marrow were divided into Ly49Q+ and Ly49Q– subsets. While both subsets produced IFN-α upon cytosine-phosphate-guanosine (CpG) and herpes simplex virus stimulation, Ly49Q– pDCs responded poorly to influenza virus. In addition, Ly49Q– pDCs produced inflammatory cytokines such as interleukin 6 (IL-6), IL-12, and tumor necrosis factor α (TNF-α) upon stimulation at lower levels than those produced by Ly49Q+ pDCs. In contrast to bone marrow, Ly49Q+ pDCs were only found in peripheral blood, lymph nodes, and spleen. These results indicate that Ly49Q is a specific marker for peripheral pDCs and that expression of Ly49Q defines 2 subsets of pDCs in bone marrow.
Microarray analysis of bicalutamide action on telomerase activity, p53 pathway and viability of prostate carcinoma cell lines
Authors: Bouchal Jan , Baumforth Karl R N , Šváchová Michaela , Murray Paul G , von Angerer Erwin , Kolár̂ Zdenêk 
Published: December 2004

Abstract
Bicalutamide is a non-steroidal anti-androgen commonly used in the treatment of prostate carcinoma. We analysed the transcriptional response to bicalutamide treatment with the aim of explaining the inhibition of telomerase in the androgen-sensitive cell line LNCaP and the effects of bicalutamide on the androgen-insensitive cell line DU145. Cells treated with 80 μm bicalutamide in steroid-depleted medium for 1 day were analysed in duplicate by Affymetrix Human Genome Focus Arrays. Response to bicalutamide in LNCaP cells was represented by downregulation of androgen-regulated genes, activation of the p53 pathway and inhibition of telomerase, which was associated with downregulation of v-myc avian myelocytomatosis viral oncogene homologue (MYC) and telomerase reverse transcriptase subunit. In DU145 cells we observed the influence of cell density on bicalutamide effectivity such that highly confluent cells showed lesser sensitivity than low confluent ones. In conclusion, we provide an explanation for telomerase inhibition after androgen receptor blockade in LNCaP cells and we also report activation of the p53 pathway in LNCaP cells and in-vitro sensitivity to bicalutamide of low confluent androgen-insensitive DU145 cells. These findings might have implications for both experimental and clinical research into prostate cancer. In particular, activation of the p53 pathway after treatment with 80 μm bicalutamide could justify usage of bicalutamide dosages higher than 150 mg daily in androgen-sensitive carcinoma therapy.
Prey capture kinematics of ant-eating lizards
Authors: Meyers Jay J. , Herrel Anthony 
Published: December 2004

SUMMARYWhile morphological and behavioral feeding specializations are obvious in many vertebrate groups, among lizards there appear to be few dietary specialists. By comparing the prey capture kinematics and overall feeding behavior in two highly specialized ant-eating lizards (Moloch horridus and Phrynosoma platyrhinos) with those of two closely related dietary generalists (Pogona vitticeps and Uma notata), we investigate whether dietary specialization has been accompanied by changes in the function and use of the feeding system. We quantified kinematic variables from high-speed video recordings (200-250 frames s-1) of each species feeding on ants. Prey capture was strikingly different in M. horridus to that of other species, being characterized by a suite of unusual behaviors including the lack of a body lunge, faster tongue protrusion, reduced prey processing and, most notably,the ability to modulate the slow open phase of the gape cycle. In concert,these traits make a single feeding event in M. horridus faster than that in any other iguanian lizard studied to date. Prey capture behavior in P. platyrhinos is kinematically more similar to U. notataand P. vitticeps than to M. horridus, but the ant specialists are similar in that both lack distinct prey processing behaviors,resulting in faster overall capture and feeding events. While ant feeding in P. vitticeps is faster than feeding on other prey, the duration of a single feeding event is still four times longer than in either ant specialist,because of extensive prey processing. Additionally, a phylogenetic comparison of ant specialist lizards with dietary generalists revealed that ant-eating lizards require significantly less time to capture and process prey. Thus there are not only significant behavioral modifications in these ant-eating lizards, but also multiple strategies among specialists, suggesting differing selective pressures or phylogenetic constraints in the evolution of ant eating in lizards.
Persistence with Antihypertensives Related to Formulation: The Case of Nifedipine
Authors: Breekveldt-Postma Nancy S , Herings Ron MC 
Published: December 2004

BACKGROUND: Controlled-release dosage forms may enhance persistence with therapy because of reduced dosing frequency and fewer adverse effects. OBJECTIVE: To assess the differences in persistent use of nifedipine between once-daily nifedipine gastrointestinal therapeutic system (GITS) and twice-daily nifedipine retard formulations. METHODS: Incident nifedipine users were selected from January 1992 to December 2001 from the PHARMO database, including drug-dispensing records and hospital records of more than one million subjects in the Netherlands. Patients with unaltered formulation and dosing frequency of nifedipine in the first year of follow-up with at least 2 prescriptions were included in the cohort. Persistence with different formulations was assessed using Cox's proportional hazard analyses. Covariates included in the analysis were, among others, hospitalizations and comedication for cardiovascular diseases. RESULTS: In total, 5889 incident users of nifedipine were included. The median duration of the first treatment episode was 133 days for nifedipine retard and 262 days for nifedipine GITS. One-year persistence with nifedipine increased from 32% in patients using retard formulations to 44% in patients using nifedipine GITS. Multivariate analyses showed that patients using nifedipine GITS were 1.3 times (RR 1.33; 95% CI 1.22 to 1.46) more persistent than those using retard formulations of nifedipine. Persistent patients more often used other antihypertensive drugs and were more often hospitalized for cardiovascular diseases. CONCLUSIONS: Patients using once-daily nifedipine GITS are more persistent with therapy than patients using twice-daily retard formulations.
Disabilities of the Arm, Shoulder and Hand (Dash) Questionnaire: Determining Functional Activity Profiles in Patients with Upper Extremity Disorders
Authors: JESTER A. , HARTH A. , WIND G. , GERMANN G. , SAUERBIER M. 
Published: December 2004

The Disability of Arm, Shoulder and Hand (DASH) questionnaire is a standardized measure which captures the patients’ own perspective of their upper extremity health status. Based on the scores of the DASH modules: symptoms, function and sport, this follow-up study of 590 hand-injured subjects from 11 diagnostic groups evaluated impairments and disabilities perceived 2 to 5 years postoperatively. Secondly, we explored the relationships between the diagnostic groups at the individual DASH item level. Exploratory testing of statistical significance showed that the DASH modules differentiated well among the groups (ANOVA P-value 0.001) and further differences existed at the item level, so that functional activity problem profiles could be developed for each diagnostic group. Our findings confirm that the DASH is a useful instrument for outcome evaluation. Moreover, in view of the continuing challenge to provide comprehensive care which meets patients’ needs in the shortest space of time, we consider that DASH has potential in the development of patient-centred treatment programmes which are tailored to the individual patients’ requirements and have relevance to their daily activities.
Ibuprofen pharmacokinetics in preterm infants with patent ductus arteriosus
Authors: Van Overmeire Bart , Touw Daan , Schepens Paul J. C. , Kearns Gregory L. , van den Anker John N. 
Published: December 2004

ObjectiveOur objective was to study the pharmacokinetics of ibuprofen in premature infants with patent ductus arteriosus on day 3 and day 5 after birth.MethodsIbuprofen was administered on days 3, 4, and 5 by a 15‐minute intravenous infusion of 10, 5, and 5 mg/kg, respectively, with the aim of closing the ductus arteriosus. Blood samples were drawn at time zero and at 0.5, 1, 2, 4, 12, and 24 hours after the first and third doses. Ibuprofen plasma concentrations were assayed by HPLC.ResultsA total of 27 premature infants were included (gestational age, 28.6 ±1.9 weeks; birth weight, 1250 ±460 g; values are mean ±standard deviation). Ibuprofen pharmacokinetics followed a 2‐compartment open model. Between the first and third doses (day 3 and day 5) there was a significant decrease of the volume of distribution of the central compartment (Vdc) (0.244 versus 0.171 L/kg; P = .03) and area under the plasma concentration‐time curve (524 versus 447 mg · h/L; P = .01). The decrease in Vdc was most pronounced in patients with a closing ductus. Total body clearance and plasma half‐life did not change significantly. No significant differences were observed in ibuprofen peak plasma concentrations after the first and third doses in relation to ductal status after treatment.ConclusionIbuprofen pharmacokinetics showed a large interindividual variation in premature infants during treatment for patent ductus arteriosus, and significant changes may occur between day 3 and day 5 after birth in those infants with a closing ductus. These findings may have implications for the treatment schedule with ibuprofen in patients with patent ductus arteriosus.Clinical Pharmacology & Therapeutics (2001) 70, 336–343; doi: 10.1016/S0009‐9236(01)13478‐8
The human pharmacology of monocyte cyclooxygenase 2 inhibition by cortisol and synthetic glucocorticoids
Authors: Santini Giovanna , Patrignani Paola , Sciulli Maria G. , Seta Francesca , Tacconelli Stefania , Panara Maria R. , Ricciotti Emanuela , Capone Marta L. , Patrono Carlo 
Published: December 2004

BackgroundWe studied the concentration dependence of the inhibitory effects of cortisol, 6‐methylprednisolone, and dexamethasone on cyclooxygenase‐2 (COX‐2) expression and activity in human monocytes in response to lipopolysaccharide (LPS) in vitro. Moreover, we characterized the time and dose dependence of the inhibitory effects of 6‐methylprednisolone, administered to healthy subjects, on LPS‐inducible prostaglandin E2 (PGE2) biosynthesis in whole blood ex vivo.MethodsHeparinized whole‐blood samples obtained from healthy subjects and patients with rheumatoid arthritis were incubated with LPS (10 μg/ml) for 24 hours at 37°C, and PGE2 was measured in plasma as an index of monocyte COX‐2 activity. Comparative experiments were performed in LPS‐stimulated isolated monocytes. The levels of COX‐2‐like immunoreactivity in monocyte lysates were measured by a specific Western blot technique. PGE2 was evaluated by radioimmunoassay.ResultsNanomolar concentrations of cortisol, 6‐methylprednisolone, and dexamethasone suppressed LPS‐induced PGE2 biosynthesis both in whole blood and in isolated monocytes in vitro with relative potencies similar to those reported for their anti‐inflammatory effects in vivo. The administration of single oral doses (4, 8, or 16 mg) of 6‐methylprednisolone caused a dose‐ and time‐dependent inhibition of whole‐blood COX‐2 activity. Whole‐blood samples obtained from patients with rheumatoid arthritis treated with comparable maintenance doses of glucocorticoids produced significantly lower levels of LPS‐inducible PGE2 than were found in untreated patients.ConclusionsTherapeutic plasma levels of synthetic glucocorticoids down‐regulate inducible prostanoid biosynthesis in circulating monocytes. This effect may represent a readily measurable surrogate marker of their clinical efficacy for dose‐finding studies.Clinical Pharmacology & Therapeutics (2001) 70, 475–483; doi: 10.1016/S0009‐9236(01)14130‐5
Influence of hepatic impairment on everolimus pharmacokinetics: Implications for dose adjustment
Authors: Kovarik John M. , Sabia Helene D. , Figueiredo Joaquim , Zimmermann Heidrun , Reynolds Christine , Dilzer Stacy C. , Lasseter Kenneth , Rordorf Christiane 
Published: December 2004

ObjectiveWe assessed the influence of hepatic impairment on the pharmacokinetics of the immunosuppressant everolimus to provide dose recommendations for clinical use.MethodsIn this open‐label, single‐dose, case‐control study, 8 subjects with liver cirrhosis classed as moderate hepatic impairment (Child‐Pugh score, 7–9) and 8 demographically matched healthy control subjects received a single oral 2‐mg dose of everolimus. Routine safety assessments were made, and blood samples were taken for determination of everolimus concentrations and protein binding.ResultsThe apparent clearance of everolimus was significantly reduced by 53% in subjects with moderate hepatic impairment compared with healthy subjects (9.1 ± 3.1 versus 19.4 ± 5.8 L/h). This was manifested by a 115% higher area under the blood concentration‐time curve (AUC) (245 ± 91 versus 114 ± 45 ng · h/ml) and 84% prolonged half‐life (79 ±42 versus 43 ± 18 hours) in subjects with hepatic impairment. The rate of absorption of everolimus was not altered by hepatic impairment on the basis of the maximum blood concentration (Cmax) and time to reach Cmax (tmax). Protein binding was similar in the two groups (73.8% ± 3.6% versus 73.5% ± 2.4%). A significant positive correlation of the everolimus AUC with bilirubin level (r = 0.86) and a significant negative correlation with albumin concentration (r = 0.72) was observed.ConclusionsThe dose of everolimus should initially be reduced by half in patients with mild and moderate hepatic impairment on the basis of the Child‐Pugh classification. Therapeutic monitoring would be a helpful adjunct to subsequent titration of everolimus exposure in this subpopulation. Everolimus has not been assessed in patients with severe hepatic impairment.Clinical Pharmacology & Therapeutics (2001) 70, 425–430; doi: 10.1016/S0009‐9236(01)15633‐X
Pharmacokinetics and metabolism of intravenous midazolam in preterm infants
Authors: de Wildt S. N. , Kearns G. L. , Hop W. C. J. , Murry D. J. , Abdel‐Rahman S. M. , van den Anker J. N. 
Published: December 2004

BackgroundMidazolam, a benzodiazepine, is finding expanded use in neonatal intensive care units. We studied the pharmacokinetics and metabolism of midazolam after a single intravenous dose in preterm infants.MethodsThe pharmacokinetics of midazolam and its hydroxylated metabolite (1‐OH‐midazolam) after a single 0.1 mg/kg intravenous dose of midazolam were determined in 24 preterm infants (gestational age, 26 to 34 weeks; postnatal age, 3 to 11 days). Blood samples were obtained before drug administration and at 0.5, 1, 2, 4, 6, 12, and 24 hours after the start of the infusion. Midazolam and 1‐OH‐midazolam concentrations were determined by use of gas chromatography‐mass spectrometry.ResultsTotal body clearance, apparent volume of distribution, and plasma half‐life of midazolam were (median [range]): 1.8 (0.7–6.7) ml/kg per min, 1.1 (0.4–4.2) L/kg, and 6.3 (2.6–17.7) h, respectively. In 19 of 24 preterm infants, 1‐OH‐midazolam concentrations could be detected: 1‐OH‐midazolam (1‐OH‐M) maximal concentration of drug in plasma (Cmax), time to reach Cmax (Tmax), and 1‐OH‐M/M area under the concentration‐time curve from time zero to the last sampling time point (AUC0−t) ratio were [median (range)]: 8.2 (<0.5–68.2) ng/ml, 6 (1–12) h, and 0.09 (<0.001–1), respectively. Midazolam plasma clearance was increased in those infants who had indomethacin (INN, indometacin) exposure.DiscussionConsequent to immature hepatic cytochrome P450 3A4 (CYP3A4) activity, midazolam clearance and 1‐OH‐midazolam concentrations are reduced markedly in preterm infants as compared to concentrations in previous reports from studies in older children and adults. Indomethacin exposure and its apparent impact on midazolam clearance support alteration of drug disposition produced by a patent ductus arteriosus or by the direct effects of indomethacin on hemodynamic or renal function.Clinical Pharmacology & Therapeutics (2001) 70, 525–531; doi: 10.1016/S0009‐9236(01)15882‐0
Pathogenetic role of cyclooxygenase‐2 in hyperprostaglandin E syndrome/antenatal bartter syndrome: Therapeutic use of the cyclooxygenase‐2 inhibitor nimesulide
Authors: Nüsing Rolf M. , Reinalter Stephan C. , Peters Melanie , Kömhoff Martin , Seyberth Hannsjörg W. 
Published: December 2004

Patients with hyperprostaglandin E syndrome/antenatal Bartter syndrome typically have renal salt wasting, hypercalciuria with nephrocalcinosis, and secondary hyperaldosteronism. Antenatally, these patients have fetal polyuria, leading to polyhydramnios and premature birth. Hyperprostaglandin E syndrome/antenatal Bartter syndrome is accompanied by a pathologically elevated synthesis of prostaglandin E2, thought to be responsible for aggravation of clinical symptoms such as salt and water loss, vomiting, diarrhea, and failure to thrive. In this study administration of the cyclooxygenase‐2 (COX‐2) specific inhibitor nimesulide to patients with hyperprostaglandin E syndrome/antenatal Bartter syndrome blocked renal prostaglandin E2 formation and relieved the key parameters hyperprostaglandinuria, secondary hyperaldosteronism, and hypercalciuria. Partial suppression of serum thromboxane B2 synthesis resulting from platelet COX‐1 activity and complete inhibition of urinary 6‐keto‐prostaglandin F1α, reflecting endothelial COX‐2 activity, indicate preferential inhibition of COX‐2 by nimesulide. Amelioration of the clinical symptoms by use of nimesulide indicates that COX‐2 may play an important pathogenetic role in hyperprostaglandin E syndrome/antenatal Bartter syndrome. Moreover, on the basis of our data we postulate that COX‐2‐derived prostaglandin E2 is an important mediator for stimulation of the renin‐angiotensin‐aldosterone system in the kidney.Clinical Pharmacology & Therapeutics (2001) 70, 384–390; doi: 10.1016/S0009‐9236(01)21861‐X
A pilot evaluation of alfentanil‐induced miosis as a noninvasive probe for hepatic cytochrome P450 3A4 (CYP3A4) activity in humans
Authors: Phimmasone Somphane , Kharasch Evan D. 
Published: December 2004

ObjectiveThe opioid alfentanil is a CYP3A4 substrate whose plasma clearance depends exclusively on hepatic CYP3A4 activity. Alfentanil clearance is an excellent in vivo probe for hepatic CYP3A4 activity and drug interactions in humans. However, such pharmacokinetic studies are invasive and time‐consuming, and they require extensive analytical effort. This investigation tested the hypothesis that alfentanil‐induced miosis (drug effect) can be used as a surrogate measure for alfentanil plasma concentrations and that alfentanil effect clearance will reflect plasma clearance; thus alfentanil can serve as a noninvasive probe for hepatic CYP3A4.MethodsSix healthy volunteers were studied in a 3‐way randomized crossover design. Each volunteer received 1 mg intravenous midazolam, followed 1 hour later by 15 μg/kg intravenous alfentanil, after CYP3A4 induction (rifampin [INN, rifampicin]), CYP3A4 inhibition (troleandomycin), and control. Dark‐adapted pupil diameter and dynamic light response were measured coincident with venous blood sampling for up to 8 hours. Midazolam and alfentanil were quantified by gas chromatography‐mass spectrometry. Plasma concentrations of alfentanil and midazolam (an additional CYP3A4 probe) and pupil diameter versus time data were analyzed by use of noncompartmental modeling. Pupil diameter change was analyzed analogously to determine the area under the alfentanil effect (miosis)‐time curve (AUEC), effect clearance (CLmiosis), and effect half‐time.ResultsCompared with control, CYP3A4 induction and inhibition significantly altered the clearances of alfentanil (2.8 ±1.4, 5.3 ±1.0, and 0.42 ±0.1 ml/kg/min, respectively;P < .05 versus control) and midazolam. Dark‐adapted resting diameter (in millimeters) was the best measure of alfentanil pupil effects. Alfentanil‐dependent miosis was significantly altered by CYP3A4 modulation, and log(diameter0 — diametert) versus time curves resembled alfentanil plasma disposition. AUEC∞ values after control, CYP3A4 induction, and inhibition were 280 ±150, 120 ±22, and 1030 ±240 mm · min, respectively (P < .05 versus control). Effect clearances (CLmiosis) were 4.2 ±1.3, 8.8 ±2.4, and 1.2 ±0.8 μg/mm · min, respectively, and effect half‐times were 62 ±23, 34 ±27, and 211 ±35 minutes, respectively (P < .05 versus control). CLmiosis was significantly correlated with plasma clearances of alfentanil (r = 0.77, P < .001) and midazolam (r = 0.80; P < .001).ConclusionsAlfentanil effect (miosis) may be a sensitive and reliable surrogate for plasma alfentanil concentrations. Alfentanil effect kinetics may be used as a noninvasive surrogate for conventional pharmacokinetics. CLmiosis appears to be a suitable noninvasive in vivo probe for hepatic CYP3A4 activity, and it merits further investigation.Clinical Pharmacology & Therapeutics (2001) 70, 505–517; doi: 10.1016/S0009‐9236(01)23711‐4