bluuebunny/crossref_metadata_2025 huggingface dataset:
Fibronectin adsorption and arrangement on copolymer surfaces and their significance in cell adhesion
Authors: Kowalczyńska Hanna M. , Nowak‐Wyrzykowska Małgorzata , Kołos Robert , Dobkowski Jacek , Kamiński Jarosław
Published: December 2004

The adsorption of fibronectin (FN) to (styrene/methyl methacrylate) copolymer surfaces, both sulfonated (hydrophilic) and nonsulfonated (hydrophobic), was studied by means of the radioisotope (125I‐FN) and ELISA assays; the latter employed monoclonal antibodies. It was found that the radioiodination‐derived isotherms did not follow the Langmuir‐type adsorption law within the FN concentration range studied; rather, a quasi‐linear FN surface density versus bulk concentration dependence was observed. These isotherms, and our recent ELISA measurements with polyclonal antibodies, allowed us to estimate saturative FN surface densities, which were, within the experimental error, similar on both types of surfaces. This suggested the amount of adsorbed FN to be not responsible for observed differences in leukaemia L1210 cell adhesion (FN‐coated sulfonated surfaces are far more pro‐adhesive than their nonsulfonated analogues). The presumption that these differences are induced by changes in the FN arrangement was confirmed by the use of monoclonal antibodies directed against distinct FN domains, and by the blocking of α5β1 integrin receptor with the synthetic Gly‐Arg‐Gly‐Asp‐Ser‐Pro (GRGDSP) peptide. The RGD sequence located within the FN cell‐binding domain seems to be masked in the structure adopted on nonsulfonated surfaces, which hinders the integrin–ligand interaction. © 2004 Wiley Periodicals, Inc. J Biomed Mater Res 72A: 228–236, 2005
Raman spectroscopy of phosphates of the variscite mineral group
Authors: Frost Ray L. , Weier Matt L. , Erickson Kristy L. , Carmody Onuma , Mills Stuart J.
Published: December 2004

Raman spectra of phosphates of the variscite mineral group, namely strengite, variscite, metavariscite and phosphosiderite, were obtained at 298 and 77 K using a thermal stage and complemented with selected infrared data using a diamond attenuated total reflection cell. Multiple phosphate stretching bands are observed. Bands for strengite at 1006, 1012 and 1026 cm−1 at 298 K and at 997, 1006, 1014 and 1027 cm−1 at 77 K are observed. Variscite is characterized by PO stretching vibrations at 1023, 1005 and 938 cm−1 and phosphosiderite by bands at 1009 and 993 cm−1. These minerals are readily identified by their Raman spectrum both in the PO stretching region and in the low‐wavenumber region. Multiple bands attributed to the bending modes of PO4 are identified for each of the minerals. A model is proposed involving non‐hydrogen‐bonded PO4 and strongly hydrogen‐bonded PO4 units together with [Al or Fe(OH)2]+ ·(H2PO4)2−‐type species. Raman spectroscopy shows that at the molecular level multiple species of phosphate anions exist for the variscite phosphate minerals. Copyright © 2004 John Wiley & Sons, Ltd.
Transformational leadership, organizational culture, and innovativeness in nonprofit organizations
Authors: Jaskyte Kristina
Published: December 2004

This is an exploratory study of leadership, organizational culture, and organizational innovativeness in a sample of nonprofit human service organizations: Associations of Retarded Citizens. Although leadership has been held out as one of the most important predictors of innovation, this study found it was not correlated with organizational innovativeness. Examination of the relationships between leadership and cultural variables provided some alternative explanations for this finding. Positive relationships among transformational leadership, organizational values, and cultural consensus (degree of agreement among employees on those values) indicate that leadership practices employed in this sample created strong cultural consensus around values that may inhibit innovation. These findings suggest that examining the link between leadership and organizational culture is important for understanding how leadership and innovation are related. This article sets out practical implications, based on the results of the study, that may help nonprofit managers create workplaces supportive of innovation.
Commitment and performance of nonprofit board members
Authors: Preston Jennifer Bright , Brown William A.
Published: December 2004

Boards of nonprofit organizations are entrusted to oversee and ensure that the organization remains true to its mission, functions within the confines of state and federal laws, and operates in a financially responsible manner. This critically important oversight is carried out by volunteers. This study examined the relationships between board member commitment and individual performance. Commitment was assessed using Meyer and Allen's Three‐Component Model of Commitment: Affective, Continuance, and Normative (1991). The population in this study was volunteer board members of midsized, social service nonprofit organizations in the Orange County, California, area. The strongest findings were between affective commitment and performance in board roles. Committed board members reported more involvement and are perceived by the executive to be more engaged and valuable. Analysis revealed that executive judgments of participation are based on both board member behavior and Affective commitment expressed by the board member.
The 30S ribosomal P site: a function of 16S rRNA
Authors: Noller Harry F. , Hoang Lee , Fredrick Kurt
Published: December 2004

The 30S ribosomal P site serves several functions in translation. It must specifically bind initiator tRNA during formation of the 30S initiation complex; bind the anticodon stem–loop of peptidyl‐tRNA during the elongation phase; and help to maintain the translational reading frame when the A site is unoccupied. Early experiments provided evidence that 16S rRNA was an important component of the 30S P site. Footprinting and crosslinking studies later implicated specific nucleotides in interactions with tRNA. The crystal structures of the 30S subunit and 70S ribosome–tRNA complexes confirmed the interactions between 16S rRNA and tRNA, but also revealed contacts between tRNA and the C‐terminal tails of proteins S9 and S13. Deletion of these tails now shows that the 16S rRNA contacts alone are sufficient to support protein synthesis in living cells.
Proteomics strategies for protein identification
Authors: Resing Katheryn A. , Ahn Natalie G.
Published: December 2004

The information from genome sequencing provides new approaches for systems‐wide understanding of protein networks and cellular function. DNA microarray technologies have advanced to the point where nearly complete monitoring of gene expression is feasible in several organisms. An equally important goal is to comprehensive survey cellular proteomes and profile protein changes under different cellular states. This presents a complex analytical problem, due to the chemical variability between proteins and peptides. Here, we discuss strategies to improve accuracy and sensitivity of peptide identification, distinguish represented protein isoforms, and quantify relative changes in protein abundance.
Holocene geoarchaeology of the Sixteen Mile Beach barrier dunes in the Western Cape, South Africa
Authors: Compton John S. , Franceschini Giuliana
Published: December 2004

Holocene evolution and human occupation of the Sixteen Mile Beach barrier dunes on the southwest coast of South Africa between Yzerfontein and Saldanha Bay are inferred from the radiocarbon ages of calcareous dune sand, limpet shell (Patella spp.) manuports and gull-dropped white mussel shells (Donax serra). A series of coast-parallel dunes have prograded seaward in response to an overall marine regression since the mid-Holocene with dated shell from relict foredunes indicating periods of shoreline progradation that correspond to drops in sea level at around 5900, 4500 and 2400 calibrated years before the present (cal yr B.P.). However, the active foredune, extensively covered by a layer of gull-dropped shell, has migrated 500 m inland by the recycling of eroded dune sand in response to an approximate 1 m sea level rise over the last 700 yr. Manuported limpet shells from relict blowouts on landward vegetated dunes indicate human occupation of coastal dune sites at 6200 and 6000 cal yr B.P. and help to fill the mid-Holocene gap in the regional archaeological record. Coastal midden shells associated with small hearth sites exposed in blowouts on the active foredune are contemporaneous (1600–500 cal yr B.P.) with large midden sites on the western margin of Langebaan Lagoon and suggest an increase in marine resource utilisation associated with the arrival of pastoralism in the Western Cape.
Stereoselective pharmacokinetics of ketamine: R(−)‐Ketamine inhibits the elimination of S(+)‐ketamine
Authors: Ihmsen Harald , Geisslinger Gerd , Schüttler Jürgen
Published: December 2004

Objective

We investigated the pharmacokinetics of ketamine with special regard to enantiomer‐specific differences.

Methods

Ten healthy young male volunteers (mean age, 28 ± 4 years; mean weight, 79 ± 11 kg) received racemic ketamine and S(+)‐ketamine in a randomized double‐blind crossover study. Drugs were administered by a computer‐controlled device. Two infusion cycles with linearly increasing targets [slope, 0.1 μg · ml−1 · min−1 for S(+)‐ketamine and 0.2 μg · ml−1 · min−1 for racemic ketamine] were administered. Concentrations of the ketamine enantiomers were determined from arterial blood, and pharmacokinetic parameters were estimated with a 2‐ and 3‐compartment model.

Results

The total doses needed to reach defined end points were 271 ± 80 mg and 409 ± 75 mg for S(+)‐ketamine and racemic ketamine, respectively (P < .05). S(+)‐ketamine showed a significantly higher clearance (26.3 ± 3.5 ml · kg−1 · min−1) compared with racemic ketamine (14.8 ±1.7 ml · kg−1 · min−1; P < .05) and R(−)‐ketamine (13.8 ±1.3 ml · kg−1 · min−1; P < .05). Furthermore, the clearance of the S(+)‐ketamine was smaller in the racemate (18.5 ±0.7 ml · kg−1 · min−1; P < .05) than for the pure isomer.

Conclusions

These results demonstrate that R(−)‐ketamine inhibits the elimination of S(+)‐ketamine.

Clinical Pharmacology & Therapeutics (2001) 70, 431–438; doi: 10.1016/S0009‐9236(01)06321‐4
Impaired cognitive function and compliance with antihypertensive drugs in elderly: The Rotterdam Study
Authors: Salas Maribel , In't Veld Bas A. , van der Linden Paul D. , Hofman Albert , Breteler Monique , Stricker Bruno H.
Published: December 2004

Background

To our knowledge, there are no epidemiologic studies on the association between cognitive impairment and noncompliance with antihypertensive therapy. We studied compliance with antihypertensive treatment in elderly patients with cognitive impairment.

Methods

The Rotterdam Study is a prospective community‐based cohort study of 7983 residents ≥55 years old. We studied 1979 participants in the study who had 2 consecutive Mini Mental State Examination (MMSE) assessments in the period from 1991 to 1996, who did not have dementia at baseline, and who had received 3 or more consecutive antihypertensive prescriptions for at least 6 months. We compared persons with MMSE scores ≤25 on both assessments to persons with MMSE scores >25 on both occasions. Compliance was estimated by dividing the number of days the subjects took antihypertensive drugs by the follow‐up period in days, and it was expressed as a ratio between 0 and 1. We defined patients as compliant if they had a compliance ratio ≥0.80 and as noncompliant if they had a compliance ratio ≤0.50 during the study period.

Results

We followed‐up on 1573 patients (mean age, 68 years) during an average period of 1609 days. The risk of noncompliance in cognitively impaired elderly subjects was 2.0 (95% confidence interval, 1.4 to 2.8) after adjustment for age, sex, education, income, living situation, and smoking. Stratification by living situation showed that the risk increase predominantly occurred in those who lived alone (odds ratio, 2.9; 95% confidence interval, 1.2 to 7.5).

Conclusions

Cognitive function is an independent predictor of compliance with antihypertensive drugs in elderly patients who are living alone.

Clinical Pharmacology & Therapeutics (2001) 70, 561–566; doi: 10.1016/S0009‐9236(01)14469‐3
Losartan attenuates symptomatic and hormonal responses to hypoglycemia in humans
Authors: Deininger Eva , Oltmanns Kerstin M. , Wellhoener Peter , Fruehwald‐Schultes Bernd , Kern Werner , Heuer Bettina , Dominiak Peter , Born Jan , Fehm Horst L. , Peters Achim
Published: December 2004

Objective

Reduced awareness of hypoglycemic symptoms and compromised hormonal counterregulation increase the risk of severe hypoglycemia in people with diabetes mellitus. Up to the present, angiotensin 1 receptor blockers, which play an important role in controlling diabetic complications, have not been known to increase the risk of hypoglycemia. Nevertheless, we observed 3 cases of diabetic patients complaining of reduced awareness of hypoglycemic symptoms while they were under treatment with losartan in our outpatients clinic. We therefore investigated the effects of losartan on symptomatic and hormonal responses to hypoglycemia in humans.

Research design and methods

We carried out a randomized, double‐blind, crossover study including 16 healthy men. The subjects received losartan 50 mg/d versus placebo. Treatment periods lasted for 7 days and were followed by a stepwise hypoglycemic clamp session (4.5 to 3.8 to 3.1 to 2.4 mmol/L) with measurement of counterregulatory hormones (epinephrine, norepinephrine, adrenocorticotropin, cortisol, glucagon), symptoms, and hemodynamic parameters (blood pressure, heart rate).

Results

Losartan attenuated the hypoglycemia‐induced rise in plasma epinephrine (6480 ± 490 pmol/L versus placebo 8970 ± 790 pmol/L; P < .001) and the rise in plasma adrenocorticotropin (21 ± 2 pmol/L versus 26 ± 3 pmol/L; P < .01). Losartan also reduced symptom scores during hypoglycemia (P < .05).

Conclusion

We conclude that short‐term treatment with losartan slightly attenuates symptomatic and hormonal responses to hypoglycemia. At present, for patients who are unaware of hypoglycemia and who require antihypertensive or nephroprotective treatment, we would recommend caution concerning treatment with losartan.

Clinical Pharmacology & Therapeutics (2001) 70, 362–369; doi: 10.1016/S0009‐9236(01)26448‐0
Effect of high‐dose lansoprazole on intragastic pH in subjects who are homozygous extensive metabolizers of cytochrome P4502C19
Authors: Furuta Takahisa , Shirai Naohito , Xiao Fang , Ohashi Kyoichi , Ishizaki Takashi
Published: December 2004

Backgrounds and Aim

Lansoprazole is mainly metabolized by cytochrome P4502C19 (CYP2C19) in the liver. The effect of lansoprazole is assumed to be insufficient in subjects who are homozygous extensive metabolizers of CYP2C19. This study aimed to examine whether the CYP2C19 genotype status affected the acid‐inhibitory effects of lansoprazole and to develop a strategy to overcome this pharmacogenetic problem.

Methods

Eighteen Helicobacter pylori3‐negative healthy volunteers, whose CYP2C19 genotypic status had been assessed, participated in the study. They consisted of 7 subjects who were homozygous extensive metabolizers, 7 subjects who were heterozygous extensive metabolizers, and 4 subjects who were poor metabolizers of CYP2C19, who took a placebo or lansoprazole 30 mg once daily in the morning for 8 days. On day 8 of dosing, 24‐hour intragastric pH values were recorded. Five of the homozygous extensive metabolizer subjects underwent the 24‐hour intragastric pH monitoring on day 8 of dosing of lansoprazole 30 mg 4 times daily.

Results

When lansoprazole 30 mg was given once daily, the mean 24‐hour intragastric pH values in the subjects who were homozygous extensive metabolizers, heterozygous extensive metabolizers, and poor metabolizers were 4.5, 4.9, and 5.5, respectively (P < .005). On day 8 of dosing of lansoprazole 30 mg 4 times daily in subjects who were homozygous extensive metabolizers, the mean 24‐hour intragastric pH value was 7.4.

Conclusion

The effect of lansoprazole on intragastric pH depended significantly on CYP2C19 genotype status. Complete acid inhibition could be achieved by the frequent administration of lansoprazole (eg, 30 mg 4 times daily) in subjects who were homozygous extensive metabolizers. A genotyping test of CYP2C19 status appears useful for prescribing an optimal dosing scheme of lansoprazole.

Clinical Pharmacology & Therapeutics (2001) 70, 484–492; doi: 10.1016/S0009‐9236(01)28055‐2
Early postoperative erythromycin breath test correlates with hepatic cytochrome P4503A activity in liver transplant recipients
Authors: Schmidt Lars E. , Olsen Anette Kristensen , Stentoft Karen , Rasmussen Allan , Kirkegaard Preben , Dalhoff Kim
Published: December 2004

Background

Interindividual variation in the pharmacokinetics of the immunosuppressive agents cyclosporine (INN, ciclosporin) and tacrolimus may result from differences in the activity of cytochrome P4503A (CYP3A). The erythromycin breath test is an in vivo assay of hepatic CYP3A activity, but the method has never been directly validated. The aim of the study was to investigate whether an early post‐operative erythromycin breath test correlated with the hepatic CYP3A protein level and catalytic activity in liver transplant recipients.

Methods

In 18 liver transplant recipients, the erythromycin breath test was performed within 2 hours after transplantation. A graft biopsy was obtained during surgery and analyzed for the CYP3A protein level by Western blotting and for CYP3A activity with erythromycin demethylation and testosterone 6β‐hydroxylation assays.

Results

The erythromycin breath test values ranged from 0.14% to 1.65% of carbon 14 per hour, and the CYP3A protein level ranged from 732 to 7822 as measured by optical density. The in vitro catalytic activity determined by the erythromycin demethylation assay ranged from 94 to 902 disintegrations per minute per 5 minutes per milligram of protein, and the activity determined by testosterone 6β‐hydroxylation ranged from 0.030 to 0.627 nmol per minute per milligram of protein. Significant correlation was demonstrated between the erythromycin breath test and both the erythromycin demethylation (Spearman correlation coefficient: R = 0.76, R2 = 0.57; P = .0004) and the testosterone 6β‐hydroxylation (Spearman correlation coefficient: R = 0.79, R2 = 0.63; P = .0001) assays. The erythromycin breath test also correlated with the CYP3A protein level (Spearman correlation coefficient: R = 0.60, R2 = 0.36; P = .01).

Conclusion

Our data support the erythromycin breath test as a specific in vivo assay of CYP3A activity in humans. The test is applicable in liver transplant recipients in the early postoperative phase. Future studies should evaluate the clinical usefulness of an early postoperative erythromycin breath test as a predictor of cyclosporine‐tacrolimus pharmacokinetics in liver transplantation.

Clinical Pharmacology & Therapeutics (2001) 70, 446–454; doi: 10.1016/S0009‐9236(01)36203‐3
Use of the erythromycin breath test for in vivo assessments of cytochrome P4503A activity and dosage individualization
Authors: Chiou Win L. , Jeong Hyun Young , Wu Ta C. , Ma Chien
Published: December 2004

Clinical Pharmacology & Therapeutics (2001) 70, 305–310; doi: 10.1016/S0009‐9236(01)45600‐1
Fluvoxamine‐theophylline interaction: Gap between in vitro and in vivo inhibition constants toward cytochrome P4501A2
Authors: Yao Caiping , Kunze Kent L. , Kharasch Evan D. , Wang Yi , Trager William F. , Ragueneau Isabelle , Levy René H.
Published: December 2004

Objective

Several reports indicate that fluvoxamine decreases the clearance of cytochrome P4501A2 (CYP1A2) substrates. This study compared in vitro and in vivo inhibition potencies of fluvoxamine toward CYP1A2 with an approach based on inhibition constants (Ki) determined in vitro and in vivo.

Methods

In vitro inhibition constant values were determined with human liver microsomes and complementary deoxyribonucleic acid‐expressed CYP1A2 (supersomes). Fluvoxamine in vivo inhibition constants (Kiiv) for CYP1A2 were obtained from an investigation of single‐dose theophylline (250 mg) disposition in 9 healthy volunteers receiving steady‐state (9 days) fluvoxamine at 3 doses (0, 25, or 75 mg/d) in a randomized crossover design.

Results

In vitro Ki values based on total inhibitor concentrations were 177 ±56 nmol/L, 121 ±21 nmol/L, and 52 ±13 nmol/L in human liver microsomes with 1 mg/ml protein and 0.5 mg/ml protein and in supersomes with 0.3 mg/ml protein, respectively. The corresponding in vitro Ki values based on unbound fluvoxamine concentrations were 35 nmol/L, 36 nmol/L, and 36 nmol/L. The ratio of 1‐methyluric acid formation clearances (control/inhibited) in 8 subjects was positively correlated with fluvoxamine concentration (r2 = 0.87; P < .001) with an intercept near 1. Mean values for Kiiv based on total and unbound plasma concentrations at steady state were 25.3 nmol/L (range, 14–39 nmol/L) and 3.6 nmol/L (range, 2.4–5.9 nmol/L), respectively.

Conclusion

Comparison of in vitro and in vivo Ki values based on unbound fluvoxamine concentrations suggests that fluvoxamine inhibition potency is approximately 10 times greater in vivo than in vitro.

Clinical Pharmacology & Therapeutics (2001) 70, 415–424; doi: 10.1016/S0009‐9236(01)62844‐3
Red wine decreases cyclosporine bioavailability
Authors: Tsunoda Shirley M. , Harris Robert Z. , Christians Uwe , Velez Rebecca L. , Freeman Richard B. , Benet Leslie Z. , Warshaw Abigail
Published: December 2004

Background

Many commonly ingested substances such as grapefruit juice and Hypericum perforatum (St John's wort) have been found to interact with important therapeutic agents such as cyclosporine (INN, ciclosporin). The mechanism for these interactions is thought to involve modulation of the activity of the drug‐metabolizing enzyme cytochrome P4503A4 (CYP3A4) and/or the drug transport protein P‐glycoprotein. In vitro data suggest that red wine may interact with CYP3A4 substrates such as cyclosporine.

Methods

We conducted a randomized, 2‐way crossover study of 12 healthy individuals. Subjects received a single 8‐mg/kg dose of oral cyclosporine with water (control) and with 12 oz of red wine (Blackstone Merlot 1996; Blackstone Winery, Graton, Calif). Whole blood was analyzed for cyclosporine and 6 metabolites by specific fluorescence polarization immunoassay and tandem liquid chromatography‐mass spectrometry. Blood levels of cyclosporine were compared between the 2 arms.

Results

Red wine caused a 50% increase in the oral clearance of cyclosporine. Systemic exposure as measured by the area under the concentration‐versus‐time curve (AUC) and peak concentration (Cmax) were significantly decreased by red wine. However, half‐life was not affected, suggesting that red wine decreased cyclosporine absorption. In vitro, the solubility of cyclosporine in red wine appeared to be lower than in water.

Conclusions

Administration of cyclosporine with red wine causes a significant decrease in cyclosporine exposure. Because cyclosporine is a narrow therapeutic range compound, caution may be warranted with concomitant intake of red wine and cyclosporine.

Clinical Pharmacology & Therapeutics (2001) 70, 462–467; doi: 10.1016/S0009‐9236(01)70992‐7
Effect of gemfibrozil on the pharmacokinetics and pharmacodynamics of glimepiride
Authors: Niemi Mikko , Neuvonen Pertti J. , Kivistö Kari T.
Published: December 2004

Objective

Our objective was to study the effects of gemfibrozil on the pharmacokinetics and pharmacodynamics of glimepiride, a new sulfonylurea antidiabetic drug and a substrate of cytochrome P4502C9 (CYP2C9).

Methods

In a randomized, 2‐phase crossover study, 10 healthy volunteers were treated for 2 days with 600 mg oral gemfibrozil or placebo twice daily. On day 3, they received a single dose of 600 mg gemfibrozil or placebo and 1 hour later a single dose of 0.5 mg glimepiride orally. Plasma glimepiride, serum insulin, and blood glucose concentrations were measured up to 12 hours.

Results

Gemfibrozil increased the mean total area under the plasma concentration‐time curve of glimepiride by 23% (range, 6%–56%; P < .005). The mean elimination half‐life of glimepiride was prolonged from 2.1 to 2.3 hours (P < .05) by gemfibrozil. No statistically significant differences were found in the serum insulin or blood glucose variables between the two phases.

Conclusions

Gemfibrozil modestly increases the plasma concentrations of glimepiride. This may be caused by inhibition of CYP2C9.

Clinical Pharmacology & Therapeutics (2001) 70, 439–445; doi: 10.1016/S0009‐9236(01)84578‐1
Deficient C‐oxidation of nicotine continued
Authors: Benowitz Neal L. , Griffin Chandi , Tyndale Rachel
Published: December 2004

Clinical Pharmacology & Therapeutics (2001) 70, 567–567; doi: 10.1016/S0009‐9236(01)90120‐1
Erythromycin breath test
Authors: Rivory Laurent P. , Watkins Paul B.
Published: December 2004

Clinical Pharmacology & Therapeutics (2001) 70, 395–397; doi: 10.1016/S0009‐9236(01)90132‐8
QT interval lengthening in premature infants treated with doxapram
Authors: Maillard Christine , Boutroy Marie‐Jeanne , Fresson Jeanne , Barbé Françoise , Hascoët Jean‐Michel
Published: December 2004

Objective

Doxapram, routinely used in premature infants treated for apnea of prematurity unresponsive to methylxanthines, has been related to cardiac conduction disorders. This study was designed to evaluate doxapram cardiac and general tolerance and its relationship to drug plasma concentrations in very premature infants.

Methods

Forty infants (mean ±SEM, 28.9 ±0.3 weeks of gestation) who were given intravenous doxapram, 0.5 to 1 mg/kg per hour, at 15.9 ±2.4 days of life were evaluated prospectively. Electrocardiograms were monitored before and during the first 3 days of treatment. QT interval corrected for heart rate (QTc) longer than 440 ms was regarded as clinically pertinent, given that it is considered a significant risk of conduction disorder leading to torsades de pointes and sudden death. Other side effects were recorded. Toxic plasma concentration of doxapram and ketodoxapram was set at >4 mg/L.

Results

A statistically significant but moderate lengthening of QTc interval has been observed from 394 ±4 ms before doxapram to 409 ±4 ms at 48 and 72 hours of treatment (P = .0065). For 6 patients, QTc interval became longer than 440 ms without any other rhythm or conduction disorder. Digestive disorders were observed in 20 infants but 9 presented with concomitant septicemia. No relationship was found between presence or absence of adverse effects and drug plasma concentrations.

Conclusion

Our study enlightened the lengthening effect of doxapram on QTc interval in premature infants with a risk of exceeding the 440 ms threshold that is considered life‐threatening. This finding emphasizes the need for electrocardiogram follow‐up when using doxapram in neonates.

Clinical Pharmacology & Therapeutics (2001) 70, 540–545; doi: 10.1016/S0009‐9236(01)95877‐1
How Smart Is my Dummy? Time Series Tests for the Influence of Politics
Authors: Caporale Tony , Grier Kevin
Published: December 2004

Of necessity, many tests for political influence on policies or outcomes involve the use of dummy variables. However, it is often the case that the hypothesis against which the political dummies are tested is the null hypothesis that the intercept is otherwise constant throughout the sample. This simple null can cause inference problems if there are (nonpolitical) intercept shifts in the data and the political dummies are correlated with these unmodeled shifts. Here we present a method for more rigorously testing the significance of political dummy variables in single equation models estimated with time series data. Our method is based on recent work on detecting multiple regime shifts by Bai and Perron. The article illustrates the potential problem caused by an overly simple null hypothesis, exposits the Bai and Perron model, gives a proposed methodology for testing the significance of political dummy variables, and illustrates the method with two examples.

Before the curse of statistics fell upon mankind we lived a happy, innocent life

—Hilaire Belloc,On Statistics
Analyzing the 2000 National Election Study
Authors: Bowers Jake , Burns Nancy , Ensley Michael J. , Kinder Donald R.
Published: December 2004

In an earlier report, two of us (Bowers and Ensley, 2003, National Election Studies Technical Report, www.umich.edu/~nes) provided a general framework for understanding the particular strategy outlined by Fogarty et al. (in this issue). Fogarty et al.'s strategy is to make the face-to-face variables more like the random digit dial (RDD) telephone variables by trimming the ends in order to reduce the variance of the face-to-face (FTF) variables. Perhaps some scholars will want the FTF variables to look like the RDD variables, but that would be a fix for a specific research question. Given the significant differences in the representativeness of the samples, the processes of survey nonresponse, and the quality and character of the responses between data taken from a National Area Probability sample in person and data taken from an RDD telephone sample, research questions involving comparisons with other years in the 50-year time series will require different remedies.
Reorganization and in Vivo Dynamics of Microtubules during Arabidopsis Root Hair Development
Authors: Van Bruaene Nathalie , Joss Greg , Van Oostveldt Patrick
Published: December 2004

Root hairs emerge from epidermal root cells (trichoblasts) and differentiate by highly localized tip growth. Microtubules (MTs) are essential for establishing and maintaining the growth polarity of root hairs. The current knowledge about the configuration of the MT cytoskeleton during root hair development is largely based on experiments on fixed material, and reorganization and in vivo dynamics of MTs during root hair development is at present unclear. This in vivo study provides new insights into the mechanisms of MT (re)organization during root hair development in Arabidopsis (Arabidopsis thaliana). Expression of a binding site of the MT-associated protein-4 tagged with green fluorescent protein enabled imaging of MT nucleation, growth, and shortening and revealed distinct MT configurations. Depending on the dynamics of the different MT populations during root hair development, either repeated two-dimensional (x, y, t) or repeated three-dimensional (x, y, z, t) scanning was performed. Furthermore, a new image evaluation tool was developed to reveal important data on MT instability. The data show how MTs reorient after apparent contact with other MTs and support a model for MT alignment based on repeated reorientation of dynamic MT growth.
Ca2+-Permeable Channels in the Plasma Membrane of Arabidopsis Pollen Are Regulated by Actin Microfilaments
Authors: Wang Yong-Fei , Fan Liu-Min , Zhang Wen-Zheng , Zhang Wei , Wu Wei-Hua
Published: December 2004

Cytosolic free Ca2+ and actin microfilaments play crucial roles in regulation of pollen germination and tube growth. The focus of this study is to test the hypothesis that Ca2+ channels, as well as channel-mediated Ca2+ influxes across the plasma membrane (PM) of pollen and pollen tubes, are regulated by actin microfilaments and that cytoplasmic Ca2+ in pollen and pollen tubes is consequently regulated. In vitro Arabidopsis (Arabidopsis thaliana) pollen germination and tube growth were significantly inhibited by Ca2+ channel blockers La3+ or Gd3+ and F-actin depolymerization regents. The inhibitory effect of cytochalasin D (CD) or cytochalasin B (CB) on pollen germination and tube growth was enhanced by increasing external Ca2+. Ca2+ fluorescence imaging showed that addition of actin depolymerization reagents significantly increased cytoplasmic Ca2+ levels in pollen protoplasts and pollen tubes, and that cytoplasmic Ca2+ increase induced by CD or CB was abolished by addition of Ca2+ channel blockers. By using patch-clamp techniques, we identified the hyperpolarization-activated inward Ca2+ currents across the PM of Arabidopsis pollen protoplasts. The activity of Ca2+-permeable channels was stimulated by CB or CD, but not by phalloidin. However, preincubation of the pollen protoplasts with phalloidin abolished the effects of CD or CB on the channel activity. The presented results demonstrate that the Ca2+-permeable channels exist in Arabidopsis pollen and pollen tube PMs, and that dynamic actin microfilaments regulate Ca2+ channel activity and may consequently regulate cytoplasmic Ca2+.
Promoter Analysis of the Barley Pht1;1 Phosphate Transporter Gene Identifies Regions Controlling Root Expression and Responsiveness to Phosphate Deprivation
Authors: Schünmann Petra H.D. , Richardson Alan E. , Vickers Claudia E. , Delhaize Emmanuel
Published: December 2004

Previous studies have shown that the promoter from the barley (Hordeum vulgare) phosphate transporter gene, HvPht1;1, activates high levels of expression in rice (Oryza sativa) roots and that the expression level was induced by up to 4-fold in response to phosphorus (P) deprivation. To identify promoter regions controlling gene regulation specificities, successive promoter truncations were made and attached to reporter genes. Promoters of between 856 and 1,400 nucleotides activated gene expression in a number of cell types but with maximal expression in trichoblast (root hair) cells. For shorter promoters the trichoblast specificity was lost, but in other tissues the distribution pattern was unchanged. The low P induction response was unaffected by promoter length. Domain exchange experiments subsequently identified that the region between −856 and −547 nucleotides (relative to the translational start) is required for epidermal cell expression. A second region located between 0 and −195 nucleotides controls root-tip expression. The HvPht1;1 promoter contains one PHO-like motif and three motifs similar to the dicot P1BS element. Analysis of promoters from which the PHO-like element was eliminated (by truncation) showed no change in the gene induction response to P deficiency. In contrast, mutation of the P1BS elements eliminated any induction of gene expression in response to low P. An internal HvPht1;1 promoter fragment, incorporating a single P1BS element, had an increased response to P deprivation in comparison with the unmodified promoter (containing three elements). Together these findings further our understanding of the regulation of the HvPht1;1 gene and provide direct evidence for a functional role of the P1BS element in the expression of P-regulated genes.
Characterization of Anion Channels in the Plasma Membrane of Arabidopsis Epidermal Root Cells and the Identification of a Citrate-Permeable Channel Induced by Phosphate Starvation
Authors: Diatloff Eugene , Roberts Michael , Sanders Dale , Roberts Stephen K.
Published: December 2004

Organic-acid secretion from higher plant roots into the rhizosphere plays an important role in nutrient acquisition and metal detoxification. In this study we report the electrophysiological characterization of anion channels in Arabidopsis (Arabidopsis thaliana) root epidermal cells and show that anion channels represent a pathway for citrate efflux to the soil solution. Plants were grown in nutrient-replete conditions and the patch clamp technique was applied to protoplasts isolated from the root epidermal cells of the elongation zone and young root hairs. Using SO42− as the dominant anion in the pipette, voltage-dependent whole-cell inward currents were activated at membrane potentials positive of −180 mV exhibiting a maximum peak inward current (Ipeak) at approximately −130 mV. These currents reversed at potentials close to the equilibrium potential for SO42−, indicating that the inward currents represented SO42− efflux. Replacing intracellular SO42− with Cl− or NO3− resulted in inward currents exhibiting similar properties to the SO42− efflux currents, suggesting that these channels were also permeable to a range of inorganic anions; however when intracellular SO42− was replaced with citrate or malate, no inward currents were ever observed. Outside-out patches were used to characterize a 12.4-picoSiemens channel responsible for these whole-cell currents. Citrate efflux from Arabidopsis roots is induced by phosphate starvation. Thus, we investigated anion channel activity from root epidermal protoplasts isolated from Arabidopsis plants deprived of phosphate for up to 7 d after being grown for 10 d on phosphate-replete media (1.25 mm). In contrast to phosphate-replete plants, protoplasts from phosphate-starved roots exhibited depolarization-activated voltage-dependent citrate and malate efflux currents. Furthermore, phosphate starvation did not regulate inorganic anion efflux, suggesting that citrate efflux is probably mediated by novel anion channel activity, which could have a role in phosphate acquisition.
State Transitions in Chlamydomonas reinhardtii. The Role of the Mehler Reaction in State 2-to-State 1 Transition
Authors: Forti Giorgio , Caldiroli Giovanni
Published: December 2004

The light intensity-dependent transition to state 1 of dark-adapted anaerobic state 2 Chlamydomonas reinhardtii cells is stimulated by oxygen and by other electron acceptors for photosystem I, such as oxaloacetate and methylviologen. This suggests that the transition to state 1 requires the oxidation of the intersystem chain by photosystem I photochemistry. On the other hand, the mere oxidation in the dark of the chain—by addition of O2—leads only to a slow and incomplete transition. The light-driven stimulation by O2 of the state 1 transition is saturated at an O2 concentration of 15 to 20 μ  m, definitely higher than that of respiration. We suggest that this may represent the affinity for oxygen of the Mehler reaction, a conclusion that is confirmed by the observations that mitochondrial respiration is apparently not involved in modulating state 2-to-state 1 transition. The catalysis of the state 2-to-state 1 transition upon illumination of anaerobically adapted algae might represent, therefore, a relevant physiological role of this process in C. reinhardtii.
A Green Fluorescent Protein Fusion to Actin-Binding Domain 2 of Arabidopsis Fimbrin Highlights New Features of a Dynamic Actin Cytoskeleton in Live Plant Cells
Authors: Sheahan Michael B. , Staiger Chris J. , Rose Ray J. , McCurdy David W.
Published: December 2004

The actin cytoskeleton coordinates numerous cellular processes required for plant development. The functions of this network are intricately linked to its dynamic arrangement, and thus progress in understanding how actin orchestrates cellular processes relies on critical evaluation of actin organization and turnover. To investigate the dynamic nature of the actin cytoskeleton, we used a fusion protein between green fluorescent protein (GFP) and the second actin-binding domain (fABD2) of Arabidopsis (Arabidopsis thaliana) fimbrin, AtFIM1. The GFP-fABD2 fusion protein labeled highly dynamic and dense actin networks in diverse species and cell types, revealing structural detail not seen with alternative labeling methods, such as the commonly used mouse talin GFP fusion (GFP-mTalin). Further, we show that expression of the GFP-fABD2 fusion protein in Arabidopsis, unlike GFP-mTalin, has no detectable adverse effects on plant morphology or development. Time-lapse confocal microscopy and fluorescence recovery after photobleaching analyses of the actin cytoskeleton labeled with GFP-fABD2 revealed that lateral-filament migration and sliding of individual actin filaments or bundles are processes that contribute to the dynamic and continually reorganizing nature of the actin scaffold. These new observations of the dynamic actin cytoskeleton in plant cells using GFP-fABD2 reveal the value of this probe for future investigations of how actin filaments coordinate cellular processes required for plant development.
Nitric Oxide Block of Outward-Rectifying K+ Channels Indicates Direct Control by Protein Nitrosylation in Guard Cells
Authors: Sokolovski Sergei , Blatt Michael R.
Published: December 2004

Recent work has indicated that nitric oxide (NO) and its synthesis are important elements of signal cascades in plant pathogen defense and are a prerequisite for drought and abscisic acid responses in Arabidopsis (Arabidopsis thaliana) and Vicia faba guard cells. Nonetheless, its mechanism(s) of action has not been well defined. NO regulates inward-rectifying K+ channels of Vicia guard cells through its action on Ca2+ release from intercellular Ca2+ stores, but alternative pathways are indicated for its action on the outward-rectifying K+ channels (I  K,out), which are Ca2+ insensitive. We report here that NO affects I  K,out when NO is elevated above approximately 10 to 20 nm. NO action on I  K,out was consistent with oxidative stress and was suppressed by several reducing agents, the most effective being British anti-Lewisite (2,3-dimercapto-1-propanol). The effect of NO on the K+ channel was mimicked by phenylarsine oxide, an oxidizing agent that cross-links vicinal thiols. Neither intracellular pH buffering nor the phosphotyrosine kinase antagonist genistein affected NO action on I  K,out, indicating that changes in cytosolic pH and tyrosine phosphorylation are unlikely to contribute to NO or phenylarsine oxide action in this instance. Instead, our results strongly suggest that NO directly modifies the K+ channel or a closely associated regulatory protein, probably by nitrosylation of cysteine sulfhydryl groups.
Genotypic and Developmental Evidence for the Role of Plasmodesmatal Regulation in Cotton Fiber Elongation Mediated by Callose Turnover
Authors: Ruan Yong-Ling , Xu Shou-Min , White Rosemary , Furbank Robert T.
Published: December 2004

Cotton fibers are single-celled hairs that elongate to several centimeters long from the seed coat epidermis of the tetraploid species (Gossypium hirsutum and Gossypium barbadense). Thus, cotton fiber is a unique system to study the mechanisms of rapid cell expansion. Previous work has shown a transient closure of plasmodesmata during fiber elongation (Y.-L. Ruan, D.J. Llewellyn, R.T. Furbank [2001] Plant Cell 13: 47–60). To examine the importance of this closure in fiber elongation, we compared the duration of the plasmodesmata closure among different cotton genotypes differing in fiber length. Confocal imaging of the membrane-impermeant fluorescent molecule carboxyfluorescein revealed a genotypic difference in the duration of the plasmodesmata closure that positively correlates with fiber length among three tetraploid genotypes and two diploid progenitors. In all cases, the closure occurred at the rapid phase of elongation. Aniline blue staining and immunolocalization studies showed that callose deposition and degradation at the fiber base correlates with the timing of plasmodesmata closure and reopening, respectively. Northern analyses showed that the expression of a fiber-specific β-1,3-glucanase gene, GhGluc1, was undetectable when callose was deposited at the fiber base but became evident at the time of callose degradation. Genotypically, the level of GhGluc1 expression was high in the short fiber genotype and weak in the intermediate and long fiber genotypes. The data provide genotypic and developmental evidence that (1) plasmodesmata closure appears to play an important role in elongating cotton fibers, (2) callose deposition and degradation may be involved in the plasmodesmata closure and reopening, respectively, and (3) the expression of GhGluc1 could play a role in this process by degrading callose, thus opening the plasmodesmata.
Exploring the Temperature-Stress Metabolome of Arabidopsis
Authors: Kaplan Fatma , Kopka Joachim , Haskell Dale W. , Zhao Wei , Schiller K. Cameron , Gatzke Nicole , Sung Dong Yul , Guy Charles L.
Published: December 2004

Metabolic profiling analyses were performed to determine metabolite temporal dynamics associated with the induction of acquired thermotolerance in response to heat shock and acquired freezing tolerance in response to cold shock. Low-Mr polar metabolite analyses were performed using gas chromatography-mass spectrometry. Eighty-one identified metabolites and 416 unidentified mass spectral tags, characterized by retention time indices and specific mass fragments, were monitored. Cold shock influenced metabolism far more profoundly than heat shock. The steady-state pool sizes of 143 and 311 metabolites or mass spectral tags were altered in response to heat and cold shock, respectively. Comparison of heat- and cold-shock response patterns revealed that the majority of heat-shock responses were shared with cold-shock responses, a previously unknown relationship. Coordinate increases in the pool sizes of amino acids derived from pyruvate and oxaloacetate, polyamine precursors, and compatible solutes were observed during both heat and cold shock. In addition, many of the metabolites that showed increases in response to both heat and cold shock in this study were previously unlinked with temperature stress. This investigation provides new insight into the mechanisms of plant adaptation to thermal stress at the metabolite level, reveals relationships between heat- and cold-shock responses, and highlights the roles of known signaling molecules and protectants.
ArabidopsisFHY3/FAR1Gene Family and Distinct Roles of Its Members in Light Control of Arabidopsis Development
Authors: Lin Rongcheng , Wang Haiyang
Published: December 2004

FHY3 (far-red elongated hypocotyls 3) and FAR1 (far-red-impaired response) are two homologous proteins essential for phytochrome A controlled far-red responses in Arabidopsis (Arabidopsis thaliana). There are 12 additional FHY3/FAR1-related genes in the Arabidopsis genome. The predicted sizes of this family of proteins range from 531 amino acids to 851 amino acids, and they share 12.0% to 82.4% amino acid identities over their entire lengths. In addition, most FRS proteins contain one to three coiled-coil domains and one or two putative nuclear localization signals. Semiquantitative reverse transcription-polymerase chain reaction analyses revealed that all FRS genes except FRS10 are expressed in all tissues examined, including rosette leaves, cauline leaves, inflorescence stems, flowers, and siliques. Analyses of gene specific promoter∷GUS fusion reporter gene expression revealed that all FRS genes except FRS1 are expressed in hypocotyls, and their expression in hypocotyl is induced by far-red light treatment. Transient expression of green fluorescent protein tagged FRS fusion proteins in onion (Allium cepa) epidermal cells revealed that all FRS proteins are targeted into the nucleus. T-DNA knockout frs6 and frs8 mutants flowered early under both long-day and short-day conditions (with much more drastic effects under short-day conditions), suggesting that FRS6 and FRS8 regulate flowering time. In addition, FRS9 RNAi transgenic plants showed a specific hypersensitivity to red light inhibition of hypocotyl elongation and light-regulated gene expression, indicating that FRS9 is a specific negative regulator of phyB signaling mediating seedling deetiolation. In summary, our results support the notion that FRS family members play distinct roles in light control of Arabidopsis development, most likely by regulating nuclear gene expression.