bluuebunny/crossref_metadata_2025 huggingface dataset:
Evolution of aptamers with a new specificity and new secondary structures from an ATP aptamer
Authors: HUANG ZHEN , SZOSTAK JACK W.
Published: November 2003

Small changes in target specificity can sometimes be achieved, without changing aptamer structure, through mutation of a few bases. Larger changes in target geometry or chemistry may require more radical changes in an aptamer. In the latter case, it is unknown whether structural and functional solutions can still be found in the region of sequence space close to the original aptamer. To investigate these questions, we designed an in vitro selection experiment aimed at evolving specificity of an ATP aptamer. The ATP aptamer makes contacts with both the nucleobase and the sugar. We used an affinity matrix in which GTP was immobilized through the sugar, thus requiring extensive changes in or loss of sugar contact, as well as changes in recognition of the nucleobase. After just five rounds of selection, the pool was dominated by new aptamers falling into three major classes, each with secondary structures distinct from that of the ATP aptamer. The average sequence identity between the original aptamer and new aptamers is 76%. Most of the mutations appear to play roles either in disrupting the original secondary structure or in forming the new secondary structure or the new recognition loops. Our results show that there are novel structures that recognize a significantly different ligand in the region of sequence space close to the ATP aptamer. These examples of the emergence of novel functions and structures from an RNA molecule with a defined specificity and fold provide a new perspective on the evolutionary flexibility and adaptability of RNA.
Fish Oil Interaction with Warfarin
Authors: Buckley Mitchell S , Goff Angela D , Knapp Walter E
Published: November 2003

OBJECTIVE:

To report a case of elevated international normalized ratio (INR) in a patient taking fish oil and warfarin.

CASE SUMMARY:

A 67-year-old white woman had been taking warfarin for 11/2 years due to recurrent transient ischemic attacks. Her medical history included hypothyroidism, hyperlipidemia, osteopenia, hypertension, and coronary artery disease. She also experienced an inferior myocardial infarction in 1995 requiring angioplasty, surgical repair of her femoral artery in 1995, and hernia repair in 1996. This patient has her INR checked in the anticoagulation clinic and is followed monthly by the clinical pharmacist. Prior to the interaction, her INR was therapeutic for 5 months while she was taking warfarin 1.5 mg/d. The patient admitted to doubling her fish oil dose from 1000 to 2000 mg/d. Without dietary, lifestyle, or medication changes, the INR increased from 2.8 to 4.3 within 1 month. The INR decreased to 1.6 one week after subsequent fish oil reduction, necessitating a return to the original warfarin dosing regimen.

DISCUSSION:

Fish oil supplementation could have provided additional anticoagulation with warfarin therapy. Fish oil, an omega-3 polyunsaturated fatty acid, consists of eicosapentaenoic acid and docosahexaenoic acid. This fatty acid may affect platelet aggregation and/or vitamin K—dependent coagulation factors. Omega-3 fatty acids may lower thromboxane A2 supplies within the platelet as well as decrease factor VII levels. Although controversial, this case report illustrates that fish oil can provide additive anticoagulant effects when given with warfarin.

CONCLUSIONS:

This case reveals a significant rise in INR after the dose of concomitant fish oil was doubled. Patients undergoing anticoagulation therapy with warfarin should be educated about and monitored for possible drug—herb interactions. Pharmacists can play a crucial role in identifying possible drug interactions by asking patients taking warfarin about herbal and other alternative medicine product use.
Role of C-Reactive Protein in Cardiovascular Disease
Authors: Backes James M , Howard Patricia A , Moriarty Patrick M
Published: November 2003

OBJECTIVE:

To discuss the role of C-reactive protein (CRP) in cardiovascular disease as a predictor of vascular events and identify key factors that increase or decrease this inflammatory marker.

DATA SOURCES:

Articles were identified through searches of MEDLINE (1966–July 2003), International Pharmaceutical Abstracts (1970–June 2003), and bibliographies of selected articles. Search terms included C-reactive protein, HMG-CoA reductase inhibitors, fenofibrate, niacin, aspirin, estrogen, thiazolidinediones, and raloxifene.

DATA SELECTION AND DATA EXTRACTION:

All studies relevant to CRP and cardiovascular disease or the effects of pharmacologic and nonpharmacologic interventions on CRP levels were evaluated. All information deemed relevant to this review was included.

DATA SYNTHESIS:

Numerous studies have shown a strong association between CRP levels and future vascular events (i.e., coronary, cerebrovascular, peripheral vascular disease), with minimal correlation to low-density-lipoprotein cholesterol. Clinical guidelines have recently been published indicating that CRP levels of <1, 1–3, and >3 mg/L correspond to low, moderate, and high risk, respectively, for future vascular events. Drugs including statins, fibrates, niacin, thiazolidinediones, and antiplatelet agents, as well as weight loss and exercise, have demonstrated efficacy in lowering CRP levels.

CONCLUSIONS:

CRP appears to be a valuable tool for predicting future vascular events in patients striving for primary or secondary prevention of cardiovascular disease. While several pharmacologic and nonpharmacologic interventions have been shown to lower CRP levels, the impact on clinical outcomes requires further study.
Recruitment of mesenchymal stem cells and expression of TGF‐β1 and VEGF in the early stage of shock wave‐promoted bone regeneration of segmental defect in rats
Authors: Chen Yeung‐Jen , Wurtz Tilmann , Wang Ching‐Jen , Kuo Yur‐Ren , Yang Kuender D. , Huang Hue‐Chen , Wang Feng‐Sheng
Published: November 2003

Extracorporeal shock wave (ESW) treatment has recently been established as a method to enhance bone repair. Here, we reported that ESW‐promoted healing of segmental defect via stimulation of mesenchymal stem cell recruitment and differentiation into bone forming cells. Rats with a segmental femoral defect were exposed to a single ESW treatment (0.16 mJ/mm2, 1 Hz, 500 impulses). Cell morphology and histological changes in the defect region were assessed 3, 7, 14, and 28 days post‐treatment. Presence of mesenchymal stem cell was assayed by immuno‐staing for RP59, a recently discovered marker, and also production of TGF‐β1 and VEGF was monitored. ESW treatment increased total cell density and the proportion of RP59 positive cells in the defect region. High numbers of round‐ and cuboidal‐shaped cells strongly expressing RP59 were initially found. Later, the predominant cell type was spindle‐shaped fibroblastic cells, subsequently, aggregates of osteogenic and chondrogenic cells were observed. Histological observation suggested that bone marrow stem cells were progressively differentiated into osteoblasts and chondrocytes. RP59 staining was initially intense and decreased with the appearance of expression depended on the differentiation states of osteogenic and chondrogenic cells during the regeneration phase. Mature chondrocytes and osteoblasts exhibited only slight RP59 immunoreactivity. Expression of TGF‐β1 and VEGF‐A mRNA in the defect tissues was also significantly increased (P < 0.05) after ESW treatment as determined by RT‐PCR. Intensive TGF‐β1 immuno‐reactivity was induced immediately, whereas a lag period was observed for VEGF‐A. Chondrocytes and osteoblasts at the junction of ossified cartilage clearly exhibited VEGF‐A expression. Our findings suggest that recruitment of meseoblasts at the junction of ossified cartilage clearly exhibited mesenchymal stem cells is a critical step in bone reparation that is enhanced by ESW treatment. TGF‐β1 and VEGF‐A are proposed to play a chemotactic and mitogenic role in recruitment and differentiation of mesenchymal stem cells. © 2003 Orthopaedic Research Society. Published by Elsevier Ltd. All rights reserved.
Bedingungen der Erhaltung und Förderung von Selbstständigkeit im höheren Lebensalter (SIMA)
Authors: Gunzelmann Thomas , Oswald Wolf D. , Hagen Bernd , Rupprecht Roland
Published: November 2003

Zusammenfassung: Im Rahmen der 1991 begonnenen Längsschnittstudie SIMA wurde die Mortalität der Teilnehmer zwischen 1991 und 1998 verfolgt. Die Teilnehmer lebten bei Studienbeginn selbstständig und waren zwischen 75 und 93 Jahren bzw. im Mittel 79.5±3.5 Jahre alt. Bis Ende 1998 verstarben von 340 Teilnehmern 99 (29.1%). In multivariaten Risikoanalysen (Cox Regression) wurden signifikante medizinische und psychologische Risikofaktoren bestätigt, wobei es sich auf der medizinischen Seite jeweils um Diagnosen, auf der psychologischen Seite um Leistungen unter dem Median der Gesamtgruppe handelte. Bei Studienbeginn war das höchste Mortalitätsrisiko verbunden mit Rauchen, geringer Aktivität beim Selbstständigbleiben, Diabetes mellitus, subjektiv als eingeschränkt bewerteter Gesundheit, geringer körperlicher Leistungsfähigkeit, koronarer Herzerkrankung, reduzierter kognitiver Geschwindigkeit und hoher Multimorbidität. Das heißt, eine hohe Multimorbidität oder einzelne typische Erkrankungen waren nicht die ausschließlichen Mortalitätsrisiken im höheren Lebensalter. Insbesondere Defizite in geistig-körperlichen Aktivitäten und eine ausgeprägte kognitive Verlangsamung erwiesen sich für eine Erhöhung des Mortalitätsrisikos als ebenso bedeutsam.
LOGPAT: A semi-automatic way to analyze hypertext navigation behavior
Authors: Richter Tobias , Naumann Johannes , Noller Stephan
Published: November 2003

In hypertext research, log files represent a useful source of information about users’ navigational behavior. Since log files can contain enormous amounts of data, methods for data reduction with a minimum loss of information are needed. In this paper, LOGPAT (Log file Pattern Analysis) is presented, a Web-based tool for analyzing log files. With LOGPAT, single-unit, sequential, and graph-theoretic measures (including distance matrices) for the description of user navigation can be computed. The paper gives an overview of these methods and discusses their value for psychological research on hypertext. Components and analysis options of LOGPAT are described in detail. The program’s basic options are illustrated by data from a study on learning with hypertext.
Who owns a personal home page?
Authors: Schütz Astrid , Machilek Franz
Published: November 2003

Research on personal home pages is still rare. Many studies to date are exploratory, and the problem of drawing a sample that reflects the variety of existing home pages has not yet been solved. The present paper discusses sampling strategies and suggests a strategy based on the results retrieved by a search engine. This approach is used to draw a sample of 229 personal home pages that portray private identities. Findings on age and sex of the owners and elements characterizing the sites are reported.
Time series study of CFC concentrations in the Labrador Sea during deep and shallow convection regimes (1991–2000)
Authors: Azetsu‐Scott Kumiko , Jones E. Peter , Yashayaev Igor , Gershey Robert M.
Published: November 2003

Annual measurements of concentrations of chlorofluorocarbons (CFCs) along the Labrador Sea WOCE repeat section (AR7W) during 1991–2000 revealed increasing CFC‐12 concentrations in the surface layer (<100 m), the newly ventilated Labrador Seawater (LSW), North East Atlantic Deep Water (NEADW), and Denmark Strait Overflow Water (DSOW). In newly ventilated LSW, CFC concentrations were influenced less by CFC concentrations in the atmosphere than by convection regimes, including the deep convection years of 1991–1994 and the shallow convection years of 1995–2000. The average saturation levels for CFC‐12 and CFC‐11 in the newly ventilated LSW also showed large variations between two convection regimes, which would suggest using caution in estimating ventilation ages for the LSW away from the source. A time series of the CFC‐12 inventory in the Labrador Sea demonstrated the enhanced storage of CFC‐12 during the years of deep convection, while a lower rate of inventory increase was observed during the shallow convection period of late 1990s. This suggests that a periodic renewal of intermediate and deep waters by deep convection influences the uptake of anthropogenic gases such as CFC‐12 and presumably anthropogenic carbon dioxide.
Dust impacts at Comet P/Borrelly
Authors: Tsurutani B. T. , Clay D. R. , Zhang L. D. , Dasgupta B. , Brinza D. , Henry M. , Mendis A. , Moses S. , Glassmeier K.‐H. , Musmann G. , Richter I.
Published: November 2003

The NASA DS1 spacecraft flew past comet P/Borrelly on September 22, 2001, on the sunward side of the comet. Dust impacts were detected by sharp increases (or decreases) in electric fields measured by the plasma wave dipole antennae. Electric pulses from as small as 0.014 Vm−1 to saturation (∼±0.8 Vm−1) were detected. Pulse overshoots were noted in the largest electric pulses. No simultaneous dc magnetic signatures >1 nT were detected in the magnetometer data. Assuming that cometary dust grains propagating in the sunward direction were decelerated by solar radiation pressure, arguments are made that the size of the earliest dust particles detected were probably ∼0.4 μm in radius. Elaboration of the characteristics of these electric pulses and pulse overshoots and their interpretations will be reserved for a subsequent work.
Bashful ballerina: Southward shifted heliospheric current sheet
Authors: Mursula K. , Hiltula T.
Published: November 2003

It is known since long [Rosenberg and Coleman, 1969] that one of the two sectors of the interplanetary magnetic field (IMF) observed at the Earth's orbit dominates at high heliographic latitudes during solar minimum times, reflecting the poloidal structure of the global solar magnetic field at these times. Here we find that while this latitudinal variation of the dominant IMF sector around the solar equator is valid for both solar hemispheres during the last four solar minima covered by direct observations, it is systematically more strongly developed in the northern heliographic hemisphere. This implies that the average heliospheric current sheet is shifted or coned southward during solar minimum times, suggesting that the temporary southward shift of the heliosheet found earlier by Ulysses observations in 1995 is a persistent pattern. This also implies that the open solar magnetic field is north‐south asymmetric at these times, suggesting that the solar dynamo has an asymmetric component. Accordingly, the Sun with the heliosheet is like a bashful ballerina who is repeatedly trying to push her excessively high flaring skirt downward. However, the effective shift at 1 AU is only a few degrees, allowing the Rosenberg‐Coleman rule to be valid, on an average, in both hemispheres during solar minima.
Climate‐related variations in lead concentrations and sources in Vostok Antarctic ice from 65,000 to 240,000 years BP
Authors: Hong Sungmin , Kim Yeadong , Boutron Claude F. , Ferrari Christophe P. , Petit Jean Robert , Barbante Carlo , Rosman Kevin , Lipenkov Vladimir Y.
Published: November 2003

Pb has been measured in various sections of the 3,623‐m Vostok deep Antarctic ice core dated from 65,000 to 240,000 years BP, i.e. back to the beginning of the penultimate ice age and the preceding interglacial (isotopic stage 7.5). Pb concentrations were highly variable during this time interval, with low values down to ∼0.5 pg/g during warm climatic stages and much higher values up to ∼20 pg/g during cold climatic stages, especially isotopic stages 4.2 and 6.2 to 6.6. Rock and soil dust accounts for virtually 100% of Pb measured in the ice during cold climatic stages, while the contribution from volcanoes might be significant during warm stages.
A generalized single‐channel method for retrieving land surface temperature from remote sensing data
Authors: Jiménez‐Muñoz Juan C. , Sobrino José A.
Published: November 2003

Many papers have developed algorithms to retrieve land surface temperature from at‐sensor and land surface emissivity data. These algorithms have been specified for different thermal sensors on board satellites, i.e., the algorithm used for one thermal sensor (or a combination of thermal sensors) cannot be used for other thermal sensor. The main goal of this paper is to propose a generalized single‐channel algorithm that only uses the total atmospheric water vapour content and the channel effective wavelength (assuming that emissivity is known), and can be applied to thermal sensors characterized with a FWHM (Full‐Width Half‐Maximum) of around 1 μm actually operative on board satellites. The main advantage of this algorithm compared with the other single‐channel methods is that in‐situ radiosoundings or effective mean atmospheric temperature values are not needed, whereas the main advantage of this algorithm compared with split‐window and dual‐angle methods is that it can be applied to different thermal sensors using the same equation and coefficients. The validation for different test sites shows root mean square deviations lower than 2 K for AVHRR channel 4 (λ ≈ 10.8 μm) and ATSR‐2 channel 2 (λ ≈ 11 μm), and lower than 1.5 K for Landsat Thematic Mapper (TM) band 6 (λ ≈ 11.5 μm).
Bonus‐Malus Scales in Segmented Tariffs With Stochastic Migration Between Segments
Authors: Brouhns Natacha , Guillén Montserrat , Denuit Michel , Pinquet Jean
Published: November 2003

Abstract

This article proposes a computer‐intensive methodology to build bonus‐malus scales in automobile insurance. The claim frequency model is taken from Pinquet, Guillén, and Bolancé (2001). It accounts for overdispersion, heteroskedasticity, and dependence among repeated observations. Explanatory variables are taken into account in the determination of the relativities, yielding an integrated automobile ratemaking scheme. In that respect, it complements the study of Taylor (1997).
An Economic Analysis of Auto Compensation Systems: Choice Experiences From New Jersey and Pennsylvania
Authors: Schmit Joan T. , Yeh Jia‐Hsing
Published: November 2003

Abstract

Nearly since the first automobile traveled on U.S. soil, questions about how best to compensate people injured by their use have been raised. As early as in 1932, in fact, the tort system of imposing costs on negligent drivers was strongly criticized, and a system of compensation without regard to negligence recommended. Yet despite various efforts to identify and implement improved systems during the past more than 70 years, no clear best compensation mechanism has been found. Current discussions have focused on the “choice” system, under which insureds are allowed to select either a tort system or a no‐fault system of compensation at the time of insurance purchase. New Jersey and Pennsylvania, which implemented very similar choice programs in 1989 and 1990, respectively, offer an opportunity to observe the effects of choice on outcomes such as: use of attorneys, speed of payment, and consistency (equity) of payment. Our results indicate outcomes consistent with expectations in New Jersey (NJ), which switched from no‐fault to choice, but inconsistent with expectations in Pennsylvania (PA), which switched from tort to choice. Furthermore, analysis of tort versus no‐fault selectors postchoice in New Jersey and Pennsylvania does not offer clear evidence of no‐fault's lower administrative costs and speedier, more equitable payment in these jurisdictions.
Bootstrap Methodology in Claim Reserving
Authors: Pinheiro Paulo J. R. , Andrade e Silva João Manuel , De Lourdes Centeno Maria
Published: November 2003

Abstract

In this article, we use the bootstrap technique to obtain prediction errors for different claim‐reserving methods, namely, the chain ladder technique and methods based on generalized linear models. We discuss several forms of performing the bootstrap and illustrate the different solutions using the data set from Taylor and Ashe (1983), which has already been used by several authors.
A “Small Great National State”: An Analysis of the Cultural and Political Factors that shaped Danish Nationalism 1760–1870
Authors: Brincker Benedikte
Published: November 2003

Abstract  This article provides an analysis of the cultural and political factors that shaped Danish nationalism in the late eighteenth and nineteenth century. Throughout the analysis of the development of Danish nationalism, parallels are drawn to nationalism in late eighteenth and nineteenth century Britain. Finally, consideration is given to the question of whether studies of nationalism can contribute to an understanding of national states’ attitudes towards and willingness to engage in international cooperation.
Increased finger arterial blood pressure after exercise detraining in women with parental hypertension: autonomic tasks
Authors: BUCKWORTH J. , CONVERTINO V. A. , CURETON K. J. , DISHMAN R.K.
Published: November 2003

The effects of exercise detraining on resting finger arterial blood pressure (BP), the carotid‐cardiac vagal baroreflex, and BP and heart rate (HR) responses to mental arithmetic and forehead cold exposure were studied in young (19 ± 1.1 years) normotensive women with parental history of hypertension. Following 8 weeks of aerobic exercise for 25 min, 3 days week−1 at an intensity of 60% V˙O2 peak, subjects ceased training for 6–8 weeks. After detraining, V˙O2 peak (mL kg−1 min−1) was reduced by 11.5% (41.1 ± 6.9 to 36.4 ± 4.8) coincident with an ≈ 10 %increase in submaximal exercise heart rate. Responses to the laboratory tasks were then compared. Detraining was accompanied by increases (P <0.05) in resting systolic (SBP) (113.6 ± 8.9 to 121.2 ± 9.0), diastolic (DBP) (63.0 ± 8.4 to 68.3 ± 6.8), and mean arterial (MAP) (78.7 ±8.4 to 84.2 ± 7.3) BP (mmHg). None of the above changes occurred in sedentary matched‐control subjects. Systolic blood pressure was elevated during forehead cold exposure and MAP was elevated during mental arithmetic after detraining, but the rates of response and recovery for SBP, DBP and MAP were not altered by detraining. Despite higher submaximal exercise HR after detraining, HR responses to autonomic challenges, including the carotid‐cardiac vagal baroreflex, were unchanged between training and detraining. Our results indicate that exercise detraining increases resting finger arterial BP in young normotensive women at risk for hypertension with no effects on the rate of response or recovery of heart rate and BP during autonomic tasks known to elicit sympathetic and carotid‐cardiac vagal activities in this population. The use of auscultatory brachial artery pressures in a similar study of women diagnosed with hypertension will clarify the clinical meaning of our findings.
The goat mammary gland as a target organ for atrial natriuretic peptide
Authors: CVEK K. , GERSTBERGER R. , SCHÜTZ H. , OLSSON K.
Published: November 2003

Milk secretion represents a major route for electrolyte and water excretion in the dairy goat. The aims of this study were to investigate whether the mammary gland is a target site for atrial natriuretic peptide (ANP) in the goat and whether ANP affects mammary sodium and water secretion. Receptor autoradiography using 125I‐ANP as radioligand revealed specific binding sites in the secretory tissue of the mammary gland. The radioligand was totally displaced by unlabelled ANP, but not by brain natriuretic peptide or the ANP fragment c‐ANP4–23, indicative of ANP‐A receptor preference. To elucidate the role of ANP in milk secretion, ANP (30 ng kg−1min−1; 120 min) or 0.15 m NaCl (control) were administered in vivo. The ANP infusions caused haemoconcentration, but did not change milk flow or the concentrations of sodium, potassium, lactose, fat and protein in the milk. The results show that the mammary gland of the goat expresses ANP‐specific binding sites, however, a physiological role of ANP in goat mammary gland function remains to be elucidated.
Effect of inhibition of pentagastrin‐stimulated acid secretion on gastric mucosal gland luminal pressure
Authors: SYNNERSTAD I. , PERSSON A. E. G. , HOLM L.
Published: November 2003

We demonstrated previously that hydrochloric acid secreted from the gastric glands traverses the mucus layer in channels above the gland openings. The driving force for creation of these channels is most probably the hydrostatic pressure generated in the gastric gland lumen during stimulation of acid secretion. Here we investigated the effect of total inhibition of acid secretion on gland luminal pressure. Glandular pressure was measured in vivo with a pressure‐sensitive microelectrode technique in Inactin®‐anaesthetized Sprague Dawley or Lewis × DA F1 rats. Glandular pressure was significantly reduced after ranitidine inhibition of acid secretion, from 17.2 ± 2.1 mmHg during pentagastrin stimulation to 11.2 ± 1.2 mmHg. This was also true when pentagastrin infusion was continued after inhibition of secretion with ranitidine. Omeprazole, however, did not significantly alter gland luminal pressure although it totally inhibited acid secretion. With continuation of pentagastrin infusion after omeprazole inhibition, glandular pressure increased significantly from 17.6 ± 3.4 to 20.1 ± 3.3 mmHg. In conclusion, total inhibition of acid secretion with ranitidine reduces but does not abolish gland luminal pressure. After omeprazole inhibition of acid secretion the gastric gland luminal pressure persisted or even increased. Since the volume secretion is lower after omeprazole administration than during pentagastrin stimulation, the outflow resistance most probably had increased after omeprazole injection. Suggestions for increased outflow resistance are narrowing in the upper part of the gland lumen by conformational changes of the cells or muscle contractions, and/or an increase in mucus secretion or viscosity.
Middle cerebral artery blood velocity, arterial diameter and muscle sympathetic nerve activity during post‐exercise muscle ischaemia
Authors: POTT F. , RAY C. A. , OLESEN H. L. , IDE K. , SECHER N. H.
Published: November 2003

During exercise the transcranial Doppler determined mean blood velocity (Vmean) increases in the middle cerebral artery (MCA) and reflects cerebral blood flow when the diameter at the site of investigation remains constant. Sympathetic activation could induce MCA vasoconstriction and in turn elevate Vmean at an unchanged cerebral blood flow. In 12 volunteers we evaluated whether Vmean relates to muscle sympathetic nerve activity (MSNA) in the peroneal nerve during rhythmic handgrip and post‐exercise muscle ischaemia (PEMI). The luminal diameter of the dorsalis pedis artery (AD) was taken to reflect the MSNA influence on a peripheral artery. Rhythmic handgrip increased heart rate (HR) from 74 ± 20 to 92 ± 21 beats min−1 and mean arterial pressure (MAP) from 87 ± 7 to 105 ± 9 mmHg (mean ± SD; P <  0.05). During PEMI, HR returned to pre‐exercise levels while MAP remained elevated (101 ± 9 mmHg). During handgrip contralateral MCA Vmean increased from 65 ± 10 to 75 ± 13 cm s−1 and this was more than on the ipsilateral side (from 63 ± 10 to 68 ± 10 cm s−1; P <  0.05). On both sides of the brain Vmean returned to baseline during PEMI. MSNA did not increase significantly during handgrip (from 56 ± 24 to 116 ± 39 units) but the elevation became statistically significant during PEMI (135 ± 86 units, P <  0.05), while AD did not change. Taken together, during exercise and PEMI, Vmean changed independent of an elevation of MSNA by more than 140% and the dorsalis pedis artery diameter was stable. The results provide no evidence for a vasoconstrictive influence of sympathetic nerve activity on medium size arteries of the limbs and the brain during rhythmic handgrip and post‐exercise muscle ischaemia.
Pressure‐volume relationship for rat dermis: compression studies
Authors: BERT J. L. , REED R. K.
Published: November 2003

The relationship between tissue hydrostatic pressure and fluid content is an important determinant of the response of the microvascular exchange system to perturbations. However, only a limited number of studies relating these parameters have been reported. To add to this body of information, fully swollen rat dermis in vitro was subjected to successive compressive loads in an apparatus in which tissue thickness changes were monitored. At steady‐state the mechanical load on the tissue was balanced by the interstitial fluid pressure within the tissue while the fluid content of the tissue was determined from the unstressed tissue fluid content and changes in tissue thickness. The range of conditions investigated was from moderate overhydration through normal tissue fluid content to significant dehydration. From the relationship between interstitial fluid pressure and tissue fluid content (expressed as mass of fluid per mass of fat‐free dry tissue) the tissue compliance was determined. Compliance, defined as the rate of change of the tissue fluid content with changes in interstitial pressure, increased with tissue hydration. The compliance determined using compressive loads and steady‐state response of tissue thickness compares favourably with the limited amount of information available about this tissue property which is critical in the determination of tissue fluid balance. Compliance ranged over one order of magnitude for the conditions studied and at normal hydration, tissue fluid volume changed by about 6.6% per mmHg in tissue hydrostatic pressure.
Nitrate tolerance and the links with endothelial dysfunction and oxidative stress
Authors: Fayers Katherine E. , Cummings Michael H. , Shaw Kenneth M. , Laight David W.
Published: November 2003

Identification of nitric oxide as the molecule responsible for endothelial dependant vasodilatation has led to an explosion of interest in endothelial function. Oxidative stress has been identified as an important factor in the development of tolerance to organic nitrates. This review examines the evidence supporting this recently developed theory and how mechanisms of nitrate tolerance may link with the wider picture of primary nitric oxide resistance.
Voriconazole, a novel wide‐spectrum triazole: oral pharmacokinetics and safety
Authors: Purkins Lynn , Wood Nolan , Greenhalgh Katie , Allen Michael J. , Oliver Stuart D.
Published: November 2003

Aims  Voriconazole is a potent new triazole with broad‐spectrum antifungal activity against clinically significant and emerging pathogens. The present study evaluated the safety, toleration, and pharmacokinetics of oral voriconazole after single and multiple dosing.

Methods  Sixty‐four healthy subjects were randomized to receive treatment and 56 completed the study. Groups of eight subjects each received voriconazole doses of 2 mg kg−1 twice daily, 4 mg kg−1 once daily, 2 mg kg−1 three times daily, or 3 mg kg−1 twice daily. Eleven subjects received 1.5 mg kg−1 three times daily, and 21 subjects were administered placebo.

Results  Voriconazole exhibited nonlinear (dose‐ and time‐dependent) pharmacokinetics. This deviation from linear pharmacokinetics was confirmed by linearity ratios of > 1 and decreasing kel values on multiple dosing, with a consequent increase in the terminal phase t1/2. There was also notable intersubject variability in Cmax and AUCτ. The absorption of voriconazole was rapid (mean tmax=  0.9–1.7 h) after single and multiple dosing and the decline in plasma concentration–time curves after tmax was generally biphasic. By day 12, the Cmax, AUCτ, tmax, and t1/2 values for the 3 mg kg−1 twice‐daily group were 2356 ng ml−1, 11 170 ng·h  ml−1, 1.1 h, and 6.4 h, respectively. The observed accumulation of voriconazole after multiple dosing was greater than predicted from single‐dose data. Accumulation ratios for Cmax and AUCτ, which were 1.97 and 3.55, respectively, for the group given voriconazole 3 mg kg−1 twice daily, varied between treatment groups and appeared to be influenced by total daily dose and the frequency and duration of dosing. Visual inspection of Cmin values together with statistical analyses of Cmax and AUCτ values suggest that steady‐state levels were achieved by the fifth to sixth day of multiple dosing. Plasma concentrations of voriconazole were well above the minimum inhibitory concentrations (MICs) for Aspergillus spp., Candida spp., and for most emerging fungal pathogens (Cmin > 0.8 µg ml−1). Voriconazole was well tolerated: most treatment‐related adverse events (abnormal vision, headache, dizziness) were mild and resolved within an hour of dosing.

Conclusions  The oral dosing regimen selected for subsequent Phase II/III clinical trials on the basis of these results was 200 mg twice daily, equivalent to 3 mg kg−1 twice daily.
Voriconazole potentiates warfarin‐induced prothrombin time prolongation
Authors: Purkins Lynn , Wood Nolan , Kleinermans Diane , Nichols Don
Published: November 2003

Aims  Voriconazole is a novel triazole with broad‐spectrum antifungal activity. It is likely that some patients receiving voriconazole may also require treatment with the anticoagulant warfarin. Cytochrome P450 isoenzymes are important in the metabolism of both these drugs. This study investigated the effect of voriconazole on the pharmacodynamics of warfarin by measuring prothrombin time, and also evaluated the safety and tolerability of the coadministered drugs.

Methods  This was a double‐blind, placebo‐controlled, two‐way crossover study in which healthy male subjects received either 300 mg voriconazole or placebo twice daily on days 1–12, plus a single oral dose of 30 mg warfarin on day 7 of each study period. Volunteers were randomized to one of the following treatment sequences: voriconazole + warfarin followed by placebo + warfarin or placebo + warfarin followed by voriconazole + warfarin. There was a washout of at least of 7 days between treatment periods.

Results  The mean Cmax, AUCτ and tmax for voriconazole were 3736 ng ml−1, 25 733 ng·h  ml−1, and 1.66 h, respectively. Both the mean maximum change from baseline prothrombin time and the mean area under the effect curve (AUEC) for prothrombin time during coadministration with voriconazole (17 s and 3211 s·h , respectively) were statistically significantly greater than the mean values observed during the placebo period (8 s and 2282 s·h ). Prothrombin times were still increased by a mean value of 5.4 s 144 h post warfarin dose following coadministration with voriconazole compared with a mean value of 0.6 s in the placebo treatment period.

Conclusions  Coadministration of voriconazole and warfarin potentiates warfarin‐induced prothrombin time prolongation. Regular monitoring of prothrombin time is recommended if these drugs are coadministered, with appropriate adjustment of the dose of warfarin.
Coadministration of voriconazole and phenytoin: pharmacokinetic interaction, safety, and toleration
Authors: Purkins Lynn , Wood Nolan , Ghahramani Parviz , Love Edward R. , Eve Malcolm D. , Fielding Anitra
Published: November 2003

Aims  Voriconazole is a new triazole antifungal agent, and is metabolized by the cytochrome P450 isoenzymes CYP2C9, CYP2C19, and, to a lesser extent, by CYP3A4. Phenytoin is an inducer of CYP3A4 activity, and a substrate and inducer of CYP2C9 and CYP2C19. The present studies investigated the pharmacokinetic interactions of voriconazole and phenytoin when coadministered.

Methods  Two placebo‐controlled parallel‐group studies were conducted in healthy male volunteers. Study A was an open‐label study and investigated the effect of phenytoin (300 mg once daily) on the steady‐state pharmacokinetics of voriconazole (200 mg and 400 mg twice daily). Study B was a double‐blind randomized study to investigate the effects of voriconazole (400 mg twice daily) on the steady‐state pharmacokinetics of phenytoin (300 mg once daily). Cmax and AUCτ were compared at days 7, 21, and 28 (Study A), and at days 7 and 17 (Study B). All adverse events were recorded.

Results  Study A: 21 subjects were evaluable (10 voriconazole + phenytoin, 11 voriconazole + placebo). For subjects receiving voriconazole (200 mg twice daily) plus phenytoin, the day 21/day 7 ratios for voriconazole Cmax and AUCτ were 60.7%[90% confidence interval (CI) 50.1, 73.6] and 35.9% (90% CI 29.7, 43.3), respectively. Adjusted for voriconazole + placebo, the ratios between the means were 50.7% (90% CI 38.8, 66.1) and 30.6% (90% CI 23.5, 39.7), respectively. When the dose of voriconazole was increased to 400 mg twice daily, the day 28/day 7 ratios for voriconazole Cmax and AUCτ were 134% (90% CI 89.2, 200) and 139% (90% CI 97.3, 199), respectively. Study B: 15 subjects were evaluable for pharmacokinetic assessments (six phenytoin + voriconazole, nine phenytoin + placebo). The ratios between the means for phenytoin + voriconazole/phenytoin + placebo on day 17 vs. day 7 were: phenytoin Cmax 167% (90% CI 144, 193) and phenytoin AUCτ 181% (90% CI 156, 210). All treatments were well tolerated: most adverse events were mild/moderate and transient.

Conclusions  Repeat dose administration of phenytoin decreased the mean steady‐state Cmax and AUCτ of voriconazole by approximately 50% and 70%, respectively. Increasing the dose of voriconazole from 200 mg to 400 mg b.d. compensated for this effect. Repeat dose administration of 400 mg b.d. voriconazole increased the mean steady‐state Cmax and AUCτ of phenytoin by approximately 70% and 80%, respectively. It is therefore recommended that plasma phenytoin concentrations are monitored and the dose adjusted as appropriate when phenytoin is coadministered with voriconazole.
Effect of omeprazole on the steady‐state pharmacokinetics of voriconazole
Authors: Wood Nolan , Tan Keith , Purkins Lynn , Layton Gary , Hamlin Julia , Kleinermans Diane , Nichols Don
Published: November 2003

Aims  Voriconazole, a novel triazole antifungal agent, is metabolized by the cytochrome P450 isoenzymes CYP2C19, CYP2C9, and to a lesser extent by CYP3A4. Omeprazole, a proton pump inhibitor used widely for the treatment of gastric and duodenal ulcers, is predominantly metabolized by CYP2C19 and CYP3A4. The aim of this study was to determine the effects of omeprazole on the steady‐state pharmacokinetics of voriconazole. A secondary objective was to characterize the pharmacokinetic profile of an oral loading dose regimen of 400 mg twice‐daily voriconazole on day 1.

Methods  This was an open, randomized, placebo‐controlled, two‐way crossover study of 18 healthy male volunteers. Subjects received oral voriconazole (400 mg twice daily on day 1 followed by 200 mg twice daily on days 2–9 and a single 200‐mg dose on day 10) with either omeprazole (40 mg once daily) or matched placebo for 10 days. There was a minimum 7‐day washout between treatment periods.

Results  Mean Cmax and AUCτ of voriconazole were increased by 15%[90% confidence interval (CI) 5, 25] and 41% (90% CI 29, 55), respectively, with no effect on tmax during coadministration of omeprazole. Visual inspection of predose plasma concentrations (Cmin) indicated that steady‐state plasma concentrations were achieved following the second loading dose. One subject withdrew from the study during the voriconazole + omeprazole treatment period because of treatment‐related abnormal liver function test values. All other treatment‐related adverse events resolved without intervention.

Conclusions  Omeprazole had no clinically relevant effect on voriconazole exposure, suggesting that no voriconazole dosage adjustment is necessary for patients in whom omeprazole therapy is initiated. Administration of a 400‐mg twice‐daily oral loading dose regimen on day 1 resulted in steady‐state plasma levels of voriconazole being achieved following the second loading dose.
No clinically significant pharmacokinetic interactions between voriconazole and indinavir in healthy volunteers
Authors: Purkins Lynn , Wood Nolan , Kleinermans Diane , Love Edward R.
Published: November 2003

Aims  Voriconazole is a new triazole antifungal agent, and is metabolized by the cytochrome P450 isoenzymes CYP2C9, CYP2C19 and to a lesser extent by CYP3A4. Protease inhibitors, such as indinavir, are also metabolized by cytochrome P450 (mainly CYP3A4). As these drugs are likely to be coadministered, these studies were performed to assess the pharmacokinetic interactions, safety and toleration of these drugs when taken together.

Methods  Two randomized placebo‐controlled studies were conducted in healthy male volunteers. Study A was an open parallel‐group study of the effect of indinavir on the steady‐state pharmacokinetics of voriconazole in 18 volunteers (nine subjects in each group). Subjects received voriconazole 200 mg twice daily (days 1–7), then voriconazole 200 mg twice daily + indinavir 800 mg or placebo three times daily (days 8–17). Study B was a double‐blind, randomized, two‐way crossover study of the effect of voriconazole on the steady‐state pharmacokinetics of indinavir in 14 volunteers. They received indinavir 800 mg three times daily + voriconazole 200 mg or placebo twice daily for two 7‐day treatment periods separated by a washout period of at least 7 days. Pharmacokinetic parameters were compared within treatment groups at days 7 and 17 in Study A and between treatment groups on day 7 of each period in Study B. All adverse events were recorded.

Results  Study A: Seventeen subjects were evaluable for pharmacokinetic analysis (eight voriconazole + indinavir, nine voriconazole + placebo). The day 17/day 7 ratios for Cmax and AUCτ were estimated as 102%[90% confidence interval (CI) 91, 114] and 107% (90% CI 98, 118), respectively. Study B: Fourteen subjects were evaluable for pharmacokinetic analysis in each treatment period. The ratios between the geometric means for indinavir + voriconazole vs. indinavir + placebo were: Cmax, 91% (90% CI 83, 101), AUCτ, 87% (90% CI 77, 100), and Cmin, 101% (90% CI 82, 125). Trough plasma concentrations of indinavir were above the concentration required to inhibit HIV replication (IC95) in both treatment periods. Voriconazole coadministered with indinavir was well tolerated in both studies.

Conclusions  The coadministration of voriconazole and indinavir in healthy volunteers had no clinically significant effect on the pharmacokinetics of either voriconazole or indinavir.
Survival of patients with chronic myelogenous leukaemia relapsing after bone marrow transplantation: comparison with patients receiving conventional chemotherapy
Authors: Zhang Mei‐Jie , Baccarani Michele , Gale Robert Peter , McGlave Philip B. , Atkinson Kerry , Champlin Richard E. , Dicke Karel A. , Giralt Sergio , Gluckman Eliane , Goldman John M. , Klein John P. , Herzig Roger H. , Masaoka Tohru , O'Reilly Richard J. , Rozman Ciril , Rowlings Philip A. , Sobocinski Kathleen A. , Speck Bruno , Zwaan Ferry E. , Horowitz Mary M.
Published: November 2003

Treatment with busulphan and/or hydroxyurea rarely produces remission in patients with chronic myelogenous leukaemia (CML) in chronic phase. HLA‐identical sibling transplants almost always produce remission, and only about 20% of patients relapse post‐transplant. The increased anti‐leukaemic efficacy of transplants results from intensive pretransplant treatment and immune‐mediated anti‐leukaemia effects. We studied 433 patients surviving  2 years after diagnosis of CML to determine if patients who have relapsed after a transplant in chronic phase have longer survival from diagnosis than comparable subjects receiving chemotherapy. The chemotherapy cohort included 344 adults < 50 years of age treated on consecutive trials of the Italian Cooperative Study Group on CML between 1973 and 1986. The transplant cohort included 89 patients reported to the International Bone Marrow Transplant Registry who relapsed after an HLA‐identical sibling bone marrow transplant carried out between 1978 and 1992. Survivals in the two groups were compared using Cox proportional hazards regression to adjust for prognostic variables. Median survival was 65 months in the chemotherapy cohort and 86 months in the transplant cohort. The 7‐year probability (95% confidence interval) of survival was 34% (28–39%) in the chemotherapy cohort and 57% (43–70%) in the transplant cohort (P=0.003). There was no difference in survival of patients relapsing after T‐cell depleted and non‐T‐cell‐depleted transplants. We conclude that patients who relapse after an HLA‐identical sibling bone marrow transplant for CML in chronic phase have longer survival from diagnosis than comparable patients receiving chemotherapy. This effect is most likely to be the result of intensive chemotherapy and/or radiation given for pretransplant conditioning.
Minimal residual disease in acute myelogenous leukaemia and myelodysplastic syndromes: a follow‐up of patients in clinical remission
Authors: Engel Heike , Goodacre Angela , Keyhani Afsaneh , Jiang Shuwei , Van Nguyen T. , Kimmel Marek , Sanchez‐Williams Gisela , Andreeff Michael
Published: November 2003

The majority of patients with acute myelogenous leukaemia (AML) and myelodysplastic syndromes (MDS) relapse, especially those with unfavourable cytogenetics.

This study was designed to investigate the presence and frequency of minimal residual disease (MRD) in patients with AML or MDS (n = 35) and numerical abnormalities of chromosomes 6, 7, 8, 9, 10, 17 and 18 in clinical remission by using a combination of fluorescence activated cell sorting (FACS), fluorescence in‐situ hybridization (FISH) and labelling with bromodeoxyuridine (BUdR). The technique enables the detection of as few as three leukaemic cells in 105 normal cells.

MRD was detected in 33/35 patients in complete remission (CR). 16 patients relapsed (8/11 with monosomy 7, 4/17 with trisomy 8, and 4/7 with other cytogenetic abnormalities) after a median of 4.8 months (range 3–13). Levels of MRD (P = 0.007) and proliferation index (P = 0.011) were significantly higher in patients with monosomy 7 than in patients with trisomy 8 or other cytogenetic abnormalities. The percentage of cells in S‐phase, the number of abnormal cells and cytogenetic class were related to time to relapse (P = 0.001) with S‐phase being the single most important prognostic factor (P = 0.0001).

We conclude that the combination of FACS/FISH/BUdR, which determines the number, phenotype and proliferation rate of very rare leukaemic cells in patients with AML or MDS in clinical remission, provides information that is useful in the identification of patients with high and low likelihood of relapse.
Fludarabine ability to down‐regulate Bcl‐2 gene product in CD5+ leukaemic B cells: in vitro/in vivo correlations
Authors: Gottardi D. , De Leo A. M. , Alfarano A. , Stacchini A. , Circosta P. , Gregoretti M. G. , Bergui L. , Aragno M. , Caligaris‐Cappio F.
Published: November 2003

CD5+ B‐chronic lymphocytic leukaemia (B‐CLL) and mantle cell lymphoma (MCL) in leukaemic phase are characterized by defects in cell death induction that primarily involves the Bcl‐2 family of genes. Fludarabine (9‐β‐D‐arabinofuranosyl‐2‐fluoradenine, F‐ara‐A) is a potent inducer of apoptosis in CLL cells. This study aimed to determine whether F‐ara‐A‐induced apoptosis might be related to Bcl‐2 modifications and to evaluate in vitro/in vivo correlations.  Peripheral blood lymphocytes from eight B‐CLL and four leukaemic MCL were cultured in the presence of different concentrations of F‐ara‐A ±methylprednisolone (MP). F‐ara‐A down‐regulated the expression of Bcl‐2 in 5/12 cases. mRNA down‐regulation was maximal at 48 h; protein down‐regulation was prominent after 48 h. Both events were dose‐dependent. The amount of apoptosis was significantly higher in the samples treated with F‐ara‐A than in those exposed to MP alone. In the seven remaining cases, no Bcl‐2 down‐regulation was observed after exposure to F‐ara‐A and the degree of F‐ara‐A‐induced apoptosis overlapped that induced by MP.  The in vivo outcome after treatment with three to six courses of F‐ara‐A was evaluable in 10 patients: 4/5 cases, whose cells had shown in vitro Bcl‐2 down‐regulation and prominent apoptosis after exposure to F‐ara‐A, had a complete response (CR) and a partial response (PR) was observed in the remaining patient. Of the five patients whose cells had shown no in vitro Bcl‐2 modulation after exposure to F‐ara‐A, two had a PR, but the other three did not show any in vivo clinical response.