bluuebunny/crossref_metadata_2025 huggingface dataset:
Infrared Absorption Induced by Field Effect from a Metal–Insulator–Semiconductor Diode Fabricated with Regioregular Poly(3-hexylthiophene)
Authors: Takao Hiroki , Furukawa Yukio
Published: November 2003

Infrared absorption induced by field effect from a metal–insulator–semiconductor diode with an Au/aluminum oxide/regioregular poly(3-hexylthiophene) structure has been obtained by using a combination of infrared reflection–absorption spectroscopy and the FT-IR difference-spectrum method. The observed bands have been attributed to carriers (positive polarons) injected into the polymer layer and accumulated near the surface of the layer.
Longstanding vulval problems and entry dyspareunia among STD-clinic visitors in Oslo-results from a cross-sectional study
Authors: Edgardh Karin , Abdelnoor Michael
Published: November 2003

An increasing number of women with vulval problems and pain attend Olafiaklinikken, the centre for sexually transmitted infection (STI) in Oslo. The aim of the study was to investigate the prevalence of long-standing vulval problems and entry dyspareunia in a consecutive sample of STI-clinic visitors in Oslo. A self-administered questionnaire was distributed before and independent of the consultation. Response rate was 89.6% (502/560). Mean and median age were 25.9 and 24.0 years respectively, range 16-65 years.

Vulval soreness, burning, dryness and fissures present for at least three months were reported by 23.1% (116/502), entry dyspareunia by 6.9% (34/494). Independent risk factors for dyspareunia were a history of ≥4 treatments for vulvovaginal candidiasis during the last year, reported by 34.6%, odds ratio (OR) 4.45, 95% confidence interval (CI) 1.81-11.0, and a history of bacterial vaginosis, reported by 42.4%, OR 2.34, 95% CI 1.11-4.92. Contraceptive methods, hygienic habits, a history of STIs, depression or sexual abuse were factors unrelated to longstanding symptoms.

Investigation with regard to longstanding vulval problems and entry dyspareunia is required for a certain group of sexually transmitted disease-clinic visitors in Oslo, and referral to a special service for vulva patients would be beneficial for selected patients.
Translational recoding signals between gag and pol in diverse LTR retrotransposons
Authors: GAO XIANG , HAVECKER ERICKA R. , BARANOV PAVEL V. , ATKINS JOHN F. , VOYTAS DANIEL F.
Published: November 2003

Because of their compact genomes, retroelements (including retrotransposons and retroviruses) employ a variety of translational recoding mechanisms to express Gag and Pol. To assess the diversity of recoding strategies, we surveyed gag/pol gene organization among retroelements from diverse host species, including elements exhaustively recovered from the genome sequences of Caenorhabditis elegans, Drosophila melanogaster, Schizosaccharomyces pombe, Candida albicans, and Arabidopsis thaliana. In contrast to the retroviruses, which typically encode pol in the −1 frame relative to gag, nearly half of the retroelements surveyed encode a single gag-pol open reading frame. This was particularly true for the Ty1/copia group retroelements. Most animal Ty3/gypsy retroelements, on the other hand, encode gag and pol in separate reading frames, and likely express Pol through +1 or −1 frameshifting. Conserved sequences conforming to slippery sites that specify viral ribosomal frameshifting were identified among retroelements with pol in the −1 frame. None of the plant retroelements encoded pol in the −1 frame relative to gag; however, two closely related plant Ty3/gypsy elements encode pol in the +1 frame. Interestingly, a group of plant Ty1/copia retroelements encode pol either in a +1 frame relative to gag or in two nonoverlapping reading frames. These retroelements have a conserved stem–loop at the end of gag, and likely express pol either by a novel means of internal ribosomal entry or by a bypass mechanism.
YNMG tetraloop formation by a dyskeratosis congenita mutation in human telomerase RNA
Authors: THEIMER CARLA A. , FINGER L. DAVID , FEIGON JULI
Published: November 2003

Autosomal dominant dyskeratosis congenita (DKC) has been linked to mutations in the RNA component of telomerase, the ribonucleoprotein responsible for telomere maintenance. Recent studies have investigated the role of the GC (107–108) → AG mutation in the conserved P3 helix in the pseudoknot domain of human telomerase RNA. The mutation was found to significantly destabilize the pseudoknot conformation, resulting in a shift in the thermodynamic equilibrium to favor formation of a P2b hairpin intermediate. In the wild-type sequence, the hairpin intermediate was found to form a novel sequence of pyrimidine base pairs in a continuous stem capped by a structured pentaloop. The DKC mutant hairpin was observed to be slightly more stable than the wild-type hairpin, further shifting the pseudoknot-hairpin equilibrium to favor the mutant P2b hairpin. Here we examined the solution structure of the DKC mutant hairpin to identify the reason for this additional stability. We found that the mutant hairpin forms the same stem structure as wild-type and that the additional stabilization observed using optical melting can be explained by the formation of a YNMG-type tetraloop structure, with the last nucleotide of the pentaloop bulged out into the major groove. Our results provide a structural explanation for the increased stability of the mutant hairpin and further our understanding of the effect of this mutation on the structure and stability of the dominant conformation of the pseudoknot domain in this type of DKC.
Analysis of site-specific protein–RNA cross-links in isolated RNP complexes, combining affinity selection and mass spectrometry
Authors: RHODE BRITTA M. , HARTMUTH KLAUS , URLAUB HENNING , LÜHRMANN REINHARD
Published: November 2003

An important aspect of the assembly of RNPs, and in particular of spliceosomes, is the succession of proteins bound to any given site on the RNA. Protein–RNA cross-linking is a well-established technique for investigating this, but the identification of a cross-linked protein has so far relied upon the availability of antibodies for immunoprecipitation or Western blot studies. To facilitate identification of proteins independent of these techniques, site-specific protein–RNA cross-links were purified in a large scale, which were then used for mass spectrometry (MS). This approach was carried out by the use of a minimal pre-mRNA construct containing a single photoactivatable azidophenacyl group and an adjacent biotin-dT tag for affinity purification of the cross-linked product. To test the feasibility of the method, we purified cross-links to nucleotide 9 downstream of the 5′ splice site of pre-mRNA in the spliceosomal complexes A (“pre-spliceosome”) and H. By this method, we were able to identify several proteins by MS; the hnRNP proteins A2/B1 were cross-linked to the pre-mRNA in complex A, and FUSE 2/FBP (a homolog of the intronic splicing enhancer KSRP) was cross-linked in complex H.
Inhibition of Escherichia coli RNase P by oligonucleotide directed misfolding of RNA
Authors: CHILDS JESSICA L. , POOLE ALEX W. , TURNER DOUGLAS H.
Published: November 2003

Oligonucleotide directed misfolding of RNA (ODMiR) uses short oligonucleotides to inhibit RNA function by exploiting the ability of RNA to fold into different structures with similar free energies. It is shown that the 2′-O-methyl oligonucleotide, m(CAGCCUACCCGG), can trap Escherichia coli RNase P RNA (M1 RNA) in a nonfunctional structure in a transcription mixture containing RNase P protein (C5 protein). At about 200 nM, the 12-mer thus inhibits 50% of pre-tRNA processing by RNase P. Roughly 10-fold more 12-mer is required to inhibit RNase P containing full-length, renatured RNase P RNA. Diethyl pyrocarbonate modification in the presence of 12-mer reveals increased modification of sites in and interacting with P4, suggesting a structural rearrangement of a large pseudoknot important for catalytic activity. Thus, the ODMiR method can be applied to RNAs even when folding is facilitated by a cognate protein.
Quantification of alternatively spliced FGFR2 RNAs using the RNA invasive cleavage assay
Authors: WAGNER ERIC J. , CURTIS MICHELLE L. , ROBSON NICOLE D. , BARANIAK ANDREW P. , EIS PEGGY S. , GARCIA-BLANCO MARIANO A.
Published: November 2003

The regulated splicing of fibroblast growth factor receptor-2 (FGFR2) transcripts leads to tissue-specific expression of distinct receptor isoforms. These isoforms contain two different versions of the ligand binding Ig-like domain III, which are encoded by exon IIIb or exon IIIc. The mutually exclusive use of exon IIIb and exon IIIc can be recapitulated in tissue culture using DT3 and AT3 rat prostate carcinoma cells. We used this well-characterized system to evaluate the precision and accuracy of the RNA invasive cleavage assay to specifically measure FGFR2 alternative splicing outcomes. Experiments presented here demonstrated that the RNA invasive cleavage assay could specifically detect isoforms with discrimination levels that ranged from 1 in 5 × 103 to 1 in 105. Moreover the assay could detect close to 0.01 amole of FGFR2 RNAs. The assay detected the expected levels of transcripts containing either exon IIIb or IIIc, but, surprisingly, it detected high levels of IIIb-IIIc double inclusion transcripts. This finding, which has important implications for the role of exon silencing and of mRNA surveillance mechanisms, had been missed by RT-PCR. Additionally, we used the RNA invasive cleavage assay to demonstrate a novel function for the regulatory element IAS2 in repressing exon IIIc inclusion. We also show here that purification of RNA is not necessary for the invasive cleavage assay, because crude cell lysates could be used to accurately measure alternative transcripts. The data presented here indicate that the RNA invasive cleavage assay is an important addition to the repertoire of techniques available for the study of alternative splicing.
Glimepiride Pharmacokinetics in Obese Versus Non-Obese Diabetic Patients
Authors: Shukla Umesh A , Chi Eric M , Lehr Karl-Heinz
Published: November 2003

BACKGROUND:

Type 2 diabetes is a global concern, accounting for the vast majority of cases of diabetes. Type 2 diabetes is associated with insulin deficiency and insulin resistance and, increasingly, with patients who are overweight or obese. Glimepiride is a popular choice of oral antidiabetic agent for patients with Type 2 diabetes since it increases both insulin secretion and insulin sensitivity and, unlike some other oral agents, is associated with weight neutrality or even weight loss.

OBJECTIVE:

To assess the pharmacokinetic characteristics of glimepiride and its metabolites in normal-weight and morbidly obese patients with type 2 diabetes to determine whether the pharmacokinetics of glimepiride are altered by obesity.

METHODS:

Normal-weight (n = 14) and morbidly obese (n = 14) men and women (in a 1:1 ratio) with type 2 diabetes received a single oral dose of glimepiride 8 mg following an overnight fast. Serum concentrations of glimepiride and its metabolites, cyclohexyl hydroxymethyl derivative (MI) and carboxyl derivative (MII), and urinary concentrations of these metabolites were measured.

RESULTS:

There was no significant difference between the 2 patient groups for glimepiride in terms of mean peak concentration (Cmax) (p = 0.0807), time to reach Cmax (tmax) (p = 0.9916), AUC0–24 (p = 0.2609), AUC0–∞ (p = 0.1275), or terminal half-life (p = 0.3076). Mean tmax values and relative total clearances for the 2 groups were also equivalent. Some differences were noted with respect to the pharmacokinetics of metabolites between the groups. In particular, over a 24-hour period, the morbidly obese group excreted statistically significantly greater amounts of MI (p = 0.0430) and MII (p = 0.0051) compared with the normal-weight group. However, none of the differences was considered clinically significant since these metabolites do not have meaningful pharmacologic activity.

CONCLUSIONS:

Overall, the results presented here indicate that no intrinsic difference is observed in the oral clearance of glimepiride in obese patients compared with non-obese patients. Given that the dosage is titrated to achieve optimal fasting glucose levels, no special dose consideration is required for the use of glimepiride in the treatment of obese patients with type 2 diabetes.
Zur Bestimmung von Alters- effekten bei der subjektiven Beurteilung des Schlafes
Authors: Schulz Peter , Schlotz Wolff , Hellhammer Juliane
Published: November 2003

Zusammenfassung: Selbstauskunftsdaten zum Schlaf älterer Menschen werden von altersabhängigen, altersassoziierten und altersunabhängigen Faktoren beeinflusst. Diese Faktoren werden einleitend hinsichtlich ihrer Relevanz zur Bestimmung von Alterseffekten auf den Schlaf diskutiert. Ziel der vorliegenden Arbeit ist es, die Effekte der altersunabhängigen Faktoren chronischer Stress, Persönlichkeit und Gesundheitsverhalten auf den Zusammenhang zwischen Alter und subjektiver Beurteilung des Schlafes, d.h. Schlafqualität (SQ) und Gefühl des Erholtseins durch den Schlaf (GES), zu prüfen. In einer ersten Analyse wird für vier Stichproben (N = 958) geprüft, wie stark SQ und GES zusammenhängen und ob die Alterseffekte bei der SQ bzw. dem GES unterschiedlich ausfallen. Es zeigt sich, dass die berichtete SQ bei älteren Menschen zwar niedriger ist, sie sich dennoch am Morgen erholter fühlen. In einer zweiten Analyse (N = 277) werden Variablen identifiziert und ausgewählt, die zur Bestimmung von Alterseffekten auf die SQ kontrolliert werden sollten. In einer dritten Analyse wird abschließend die Beziehung zwischen Alter und Schlafparametern unter Kontrolle dieser Faktoren geprüft. Ohne Berücksichtigung konfundierender Faktoren wird der Alterseffekt auf die SQ stichprobenbedingt erheblich unterschätzt und auf das GES überschätzt. Die positive Korrelation zwischen Alter und GES nimmt bei Kontrolle konfundierender Variablen stark ab. Die Ergebnisse dieser Analysen werden ausführlich diskutiert.
Traumatische Lebens- erfahrungen und heutige Belastungsstörungen pflege- bedürftiger alter Menschen
Authors: Teegen Frauke , Cizmic Lucas-David
Published: November 2003

Zusammenfassung: Ziel der Studie war es, pflegebedürftige Senioren zu Erinnerungen an traumatische Lebenserfahrungen (TLEQ) zu befragen und ein Screening zu Symptomen der Posttraumatischen Belastungsstörung (PCL-C), komorbiden Beschwerden (SCL-90-R) und emotional-kognitiven Bewältigungsstrategien (FAPK, 3; TAS-20; SOC-13) durchzuführen. An der Erhebung beteiligten sich 37 Personen, die im Mittel 81 Jahre alt waren und im Zusammenhang mit körperlichen Erkrankungen einen ambulanten Pflegedienst in Anspruch nahmen. 65% litten unter intrusiven Symptomen, die häufig mit traumatischen Erfahrungen während des II.Weltkrieges assoziiert waren. Bei 11% wurde eine Posttraumatische Belastungsstörung (PTBS) und bei weiteren 32% eine partielle PTBS festgestellt. Im Vergleich zu geringer belasteten TeilnehmerInnen berichteten Senioren mit (voller oder partieller) PTBS signifikant häufiger über komorbide Beschwerden (vor allem Depressivität), Defizite der emotionalen Kompetenz, Alexithymie und ein geringeres Kohärenzgefühl.
Online- versus paper-pencil-version of a high potential intelligence test
Authors: Preckel Franzis , Thiemann Helge
Published: November 2003

Up to now there are hardly any studies available that examine the feasibility of online ability assessment. In the present study, a figural matrices test for the assessment of intellectual giftedness was applied as an online- and as a paper and pencil-version. The data was analyzed by classical test theory and by modern item response theory. Item design was based on a rule taxonomy and assessed by multiple regression analyses. Due to the reduction in experimental control in online data collection, the comparison of both data sets was limited to the aspects of qualitative equivalence. It could be shown that reliable and valid data can be collected online and that both test versions are comparable with regard to the contribution of the features of item design to task difficulty.
Social identification and interpersonal attraction in MUDs
Authors: Utz Sonja
Published: November 2003

In social psychology, two forms of attachment to groups are distinguished: interpersonal attraction and social identification. A web experiment was conducted to examine whether these two forms of attachment can also be differentiated in virtual communities, more precisely, MUDs (multi-user-dungeons). Both forms of attachment occurred. As expected, the concepts were functionally independent from each other. Whereas interpersonal attraction became stronger with increased duration of group membership and was fostered by physical life contacts, social identification was independent from these factors. Instead, social identification was related to more cognitive indicators of self-categorization. In contrast to interpersonal attraction, social identification was influenced by situational context and predicted group behavior such as ingroup bias.
Altitude‐extended equatorial spread F observed near sunrise terminator over Indonesia
Authors: Fukao S. , Ozawa Y. , Yamamoto M. , Tsunoda R. T.
Published: November 2003

Spatial structure of a post‐sunrise backscatter plume associated with a plasma bubble has been observed for the first time with the 47–MHz Equatorial Atmosphere Radar (EAR) in West Sumatra, Indonesia (0.20°S, 100.32°E; dip latitude 10.36°N). This plume is likely associated with a geomagnetic storm. It extended from what appears to be the base of the F layer into the topside ionosphere and differed from all plumes previously observed. It was also extended in longitude (i.e., in the east‐west direction), and appeared to involve two spatially separated regions. The plume was first observed around sunrise, close to 200–250 km altitude, but at a time when the E region was not yet sunlit. Spatial maps of the line‐of‐sight Doppler velocity show that there was upward development and westward drift of backscatter regions, indicative of daytime drift conditions. The observations remain puzzling because the plume continued for approximately two hours after E region sunrise.
A mechanistic model for compaction of granular aggregates moderated by pressure solution
Authors: Yasuhara Hideaki , Elsworth Derek , Polak Amir
Published: November 2003

A model is presented for the compaction of granular aggregates that accommodates the serial processes of grain‐contact dissolution, grain‐boundary diffusion, and precipitation at the pore wall. The progress of compaction and the evolution of the mass concentration of the pore fluids may be followed with time, for arbitrary mean stress, fluid pressure, and temperature conditions, for hydraulically open or closed systems, and accommodating arbitrary switching in dominant processes, from dissolution, to diffusion, to precipitation. Hindcast comparisons for compaction of quartz sands [] show excellent agreement for rates of change of porosity, the asymptotic long‐term porosity, and for the development of silica concentrations in the pore fluid with time. Predictions may be extended to hydraulically open systems where flushing by meteoric fluids affects the compaction response. For basins at depths to a few kilometers, at effective stresses of 35 MPa, and temperatures in the range 75°–300°C, rates of porosity reduction and ultimate magnitudes of porosity reduction increase with increased temperature. Ultimate porosities asymptote to the order of 15% (300°C) to 25% (75°C) at the completion of dissolution‐mediated compaction and durations are accelerated from a few centuries to a fraction of a year as the temperature is increased. Where the system is hydraulically open, flushing elevates the final porosity, has little effect on evolving strain in these precipitation‐controlled systems, and depresses pore fluid concentrations. These effects are greatest at lower temperatures.
Mixtures of pollution, dust, sea salt, and volcanic aerosol during ACE‐Asia: Radiative properties as a function of relative humidity
Authors: Carrico Christian M. , Kus Pinar , Rood Mark J. , Quinn Patricia K. , Bates Timothy S.
Published: November 2003

The Ron Brown cruise during ACE‐Asia (March–April 2001) encountered complex aerosol that at times was dominated by marine, polluted, volcanic, and dust aerosols. Average total light scattering coefficients (σsp for Dp <10 μm, relative humidity (RH) = 19%, and λ = 550 nm) ranged from 23 (marine) to 181 Mm−1 (dust). Aerosol hygroscopicity ranged from deliquescent with hysteresis (marine frequently and polluted variably) to hygroscopic without hysteresis (volcanic) to nearly hygrophobic (dust‐dominated). Average deliquescence and crystallization RH were 77 ± 2% and 42 ± 3%, respectively. The ambient aerosol was typically on the upper branch of the hysteresis loop for marine and polluted air masses and the lower branch for dust‐dominated aerosols. Average f(RH = ambient), defined as σsp (RH = ambient)/σsp (RH = 19%), ranged from 1.25 (dust) to 2.88 (volcanic). Average h(RH ∼60%), defined as f(RH)upper branch/f(RH)lower branch, were 1.6, 1.3, 1, and 1.25 for marine, polluted, volcanic, and dust, demonstrating an importance of hysteresis to optical properties. Hemispheric backscatter fraction (b) at ambient RH ranged from 0.077 (marine) to 0.111 (dust), while single scattering albedo (ω) at ambient RH ranged from 0.94 (dust and polluted) to 0.99 (marine).
Applications of Fuzzy Regression in Actuarial Analysis
Authors: De Andrés Sánchez Jorge , Terceño Gómez Antonio
Published: November 2003

Abstract

In this article, we propose several applications of fuzzy regression techniques for actuarial problems. Our main analysis is motivated, on the one hand, by the fact that several articles in the financial and actuarial literature suggest using fuzzy numbers to model interest rate uncertainty but do not explain how to quantify these rates with fuzzy numbers. Likewise, actuarial literature has recently focused some of its attention in analyzing the Term Structure of Interest Rates (TSIR) because this is a key instrument for pricing insurance contracts. With these two ideas in mind, we show that fuzzy regression is suitable for adjusting the TSIR and discuss how to apply a fuzzy TSIR when pricing life insurance contracts and property‐liability policies. Finally, we reflect on other actuarial applications of fuzzy regression and develop with this technique the London Chain Ladder Method for obtaining Incurred But Not Reported Reserves.
Pulmonary drug delivery. Part I: Physiological factors affecting therapeutic effectiveness of aerosolized medications
Authors: Labiris N. R. , Dolovich M. B.
Published: November 2003

As the end organ for the treatment of local diseases or as the route of administration for systemic therapies, the lung is a very attractive target for drug delivery. It provides direct access to disease in the treatment of respiratory diseases, while providing an enormous surface area and a relatively low enzymatic, controlled environment for systemic absorption of medications. As a major port of entry, the lung has evolved to prevent the invasion of unwanted airborne particles from entering into the body. Airway geometry, humidity, mucociliary clearance and alveolar macrophages play a vital role in maintaining the sterility of the lung and consequently are barriers to the therapeutic effectiveness of inhaled medications. In addition, a drug's efficacy may be affected by where in the respiratory tract it is deposited, its delivered dose and the disease it may be trying to treat.
Genetic polymorphisms of CYP2C9 and CYP2C19 in the Beninese and Belgian populations
Authors: Allabi Aurel C. , Gala Jean‐Luc , Desager Jean‐Pierre , Heusterspreute Michel , Horsmans Yves
Published: November 2003

Aims  To investigate the distribution of cytochrome P450 2C9 (CYP2C9) and 2C19 (CYP2C19) genotype frequencies in the Beninese and Belgian Caucasian populations.

Methods  Beninese (n = 111) and Belgian (n = 121) were genotyped for CYP2C9*2, *3, *4, *5, and *11 as well as for CYP2C19*2 and*3.

Results  The distribution of alleles was: CYP2C9*1: 95.5 vs. 82.2% (P < 0.001); CYP2C9*2: 0 vs. 10% (P < 0.001); CYP2C9*3: 0 vs. 7.4% (P < 0.01); CYP2C9*4: both 0%; CYP2C9*5: 1.8 vs. 0% (P = 0.05); and CYP2C9*11: 2.7 vs. 0.4% (P < 0.05). The frequencies of the CYP2C19*2 allele were 13 vs. 9.1%, respectively. CYP2C19*3 was not detected in either population. The 95% confidence intervals for the differences of frequencies of CYP2C9*1, CYP2C9*2, CYP2C9*3, CYP2C9*4, CYP2C9*5, CYP2C9*11, CYP2C19*1, CYP2C19*2 and CYP2C19*3 between  Belgian  and  Beninese  were  7%,  19%;  − 14%,  − 6%;  − 11%, − 4%; − 1%, 1%; 0%, 4%; 0%, 5%; − 10%, 2%; − 2%, 10%; − 1%; respectively. The distributions of CYP2C9 genotypes in the Beninese and Belgian individuals were: CYP2C9*1/*1: 91 vs. 67% (P < 0.00001); CYP2C9*1/*2: 0 vs. 18.2% (P < 0.0001); CYP2C9*1/*3: 0 vs. 11.6% (P < 0.001); CYP2C9*1/*5: 3.6 vs. 0% (P = 0.05); CYP2C9*1/*11: 5.4 vs. 0.8% (P = 0.05); CYP2C9*2/*3: 0 vs. 1.6% (NS); CYP2C9*3/*3: 0 vs. 0.8% (NS). The distributions of CYP2C19 genotypes between these ethnic groups were: CYP2C19*1/*1: 73.9 vs. 83.5% (NS); CYP2C19*1/*2: 26.1 vs. 14.9% (P < 0.05); CYP2C9*2/*2: 0 vs. 1.6% (NS).

Conclusions  Differences of allele frequencies between Beninese and Belgian populations were statistically significant for CYP2C9*2, *3, *5 and *11, but not for CYP2C9*4 or for CYP2C19*2 and *3.
Bioavailability of dexmedetomidine after extravascular doses in healthy subjects
Authors: Anttila Markku , Penttilä Jani , Helminen Antti , Vuorilehto Lauri , Scheinin Harry
Published: November 2003

Aim  To determine the absolute bioavailability of extravascularly administered dexmedetomidine, a novel a2‐adrenoceptor agonist, in healthy subjects.

Methods  Single 2 µg kg−1 doses of dexmedetomidine were given intravenously, intramuscularly, perorally and buccally (where the solution is not swallowed) to 12 healthy male subjects. The drug concentration‐time data were analysed using linear one‐compartment (buccal and peroral data), or two‐compartment modelling (intravenous data), or noncompartmental methods (intramuscular data).

Results  Mean (95% CI) absolute bioavailability after peroral, buccal and intramuscular administration was 16% (12–20%), 82% (73–92%) and 104% (96–112%), respectively.

Conclusion  Dexmedetomidine is well absorbed systemically through the oral mucosa, and therefore buccal dosing may provide an effective, noninvasive route to administer the drug.
Population pharmacokinetic modelling of darifenacin and its hydroxylated metabolite using pooled data, incorporating saturable first‐pass metabolism, CYP2D6 genotype and formulation‐dependent bioavailability
Authors: Kerbusch Thomas , Wählby Ulrika , Milligan Peter A. , Karlsson Mats O.
Published: November 2003

Aims  A model describing the population pharmacokinetics of darifenacin and its hydroxylated metabolite was developed from a combined analysis of 18 studies. The relationships between explanatory covariates and pharmacokinetic parameters were explored.

Methods  Plasma concentration data from 337 individuals were pooled from 17 Phase 1 studies (median 28/33 darifenacin/metabolite observations per healthy subject), and one Phase 2 study (median 7/7 darifenacin/metabolite observations per subject) encompassing one intravenous and five different oral formulations (1–45 mg).

Results  Non‐linear Mixed Effects Models (NONMEM Version VI) described both the population pharmacokinetics of darifenacin and its hydroxylated metabolite with a two‐compartment disposition model with first order absorption. The values (mean ± standard error of the mean) for clearance (CL) and volume of distribution of the central compartment were 40.2 ± 2.0 l h−1 and 34.7 ± 4.6 l h−1, respectively, in a typical male CYP2D6 homozygote‐extensive metabolizer (Hom‐EM). The absolute bioavailability (F) of darifenacin in a Hom‐EM after doses of 7.5, 15 or 30 mg extended release formulation (CR) was 15, 19 and 25%, respectively. Factors influencing F were formulation (70–110% higher for CR compared with immediate release following equivalent daily doses), CYP2D6 genotype [heterozygote‐extensive metabolizers (Het‐EM) and poor metabolizers (PM) experienced 40 and 90%, respectively, higher exposure than Hom‐EM irrespective of dose administered] and saturable first‐pass metabolism (dose nonlinearity 1.05–1.43‐fold). Race affected F, which was 56% lower in Japanese males. The CYP3A4 inhibitors ketoconazole and erythromycin increased F to approximately 100% and ketoconazole decreased CL by 67.5%. CL was 31% lower in females and 10% lower at night. Formulation affected the metabolite absorption/formation rate. Ketoconazole and erythromycin administration resulted in a decrease of 61.2 and 28.8% in exposure to the metabolite, respectively. The covariates race, gender and circadian rhythm accounted for only approximately half of the variability in the estimated exposures to darifenacin.

Conclusions  The pooled analysis provided a descriptive integration of all characteristics and covariates of the pharmacokinetics of darifenacin and its metabolite, enabling interpolation and extrapolation of these key factors.
The pharmacokinetics and safety of intravenous voriconazole – a novel wide‐spectrum antifungal agent
Authors: Purkins Lynn , Wood Nolan , Greenhalgh Katie , Eve Malcolm D. , Oliver Stuart D. , Nichols Don
Published: November 2003

Aims  Voriconazole is a new triazole with broad‐spectrum antifungal activity against clinically significant and emerging pathogens. These studies evaluated the pharmacokinetics and safety of intravenous voriconazole in healthy male volunteers.

Methods  Two single‐blind, placebo‐controlled studies were conducted. In Study A, 12 subjects were randomized to voriconazole (3 mg kg−1) or placebo, administered once daily on days 1 and 12, and every 12 h on days 3–11. In Study B, 18 subjects were randomized to voriconazole or placebo, with voriconazole being administered as a loading dose at 6 mg kg−1 twice on day 1, then at 3 mg kg−1 twice daily on days 2–9, and once at 3 mg kg−1 on day 10.

Results  In both studies, the plasma concentrations of voriconazole increased rapidly following the initiation of dosing. Minimum observed plasma concentration (Cmin) values at steady state were above the in vitro minimum inhibitory concentrations (MICs) for most fungal pathogens (Cmin > 0.8 µg ml−1). The use of a loading dose in Study B resulted in a shorter time to steady‐state Cmin values than was observed in Study A. Values of the final day plasma pharmacokinetic parameters in Studies A and B were similar: maximum observed plasma concentration (Cmax) 3621 and 3063 ng ml−1; areas under the plasma concentration–time curve from time zero to the end of the dosing interval (AUCτ) 16 535 and 13 245 ng·h  ml−1, and terminal elimination phase half‐lives (t1/2) 6.5 and 6.7 h, respectively. On multiple dosing, voriconazole accumulated (AUCτ accumulation ratio 2.53–3.17, Study A) at a level that was not predictable from single‐dose data. The mean concentration–time profiles for voriconazole in saliva were similar to those in plasma. Multiple doses of voriconazole were well tolerated and no subject discontinued from either study. Seven cases of possibly drug‐related visual disturbance were reported in three subjects (Study B).

Conclusions  Administration of a loading dose of 6 mg kg−1 i.v. voriconazole on the first day of treatment followed by 3 mg kg−1 i.v. twice daily achieves steady state by the third day of dosing. This dosage regimen results in plasma levels of the drug that rapidly exceed the minimum inhibitory concentrations (MICs) against important fungal pathogens, including Aspergillus spp.
No clinically significant effect of erythromycin or azithromycin on the pharmacokinetics of voriconazole in healthy male volunteers
Authors: Purkins Lynn , Wood Nolan , Ghahramani Parviz , Kleinermans Diane , Layton Gary , Nichols Don
Published: November 2003

Aims  The antibiotic erythromycin is a potent inhibitor of cytochrome P450 CYP3A4 metabolism. As CYP isozymes, including CYP3A4, are involved in the metabolism of the new triazole voriconazole, this study investigated the effects of multiple‐dose erythromycin or azithromycin on the steady‐state pharmacokinetics of voriconazole in healthy male subjects.

Methods  In an open, randomized, parallel‐group, single‐centre study, 30 healthy male subjects aged 20–41 years received oral voriconazole 200 mg twice daily for 14 days plus either erythromycin (1 g twice daily on days 8–14), azithromycin (500 mg once daily on days 12–14) or placebo (twice daily on days 8–14). Only morning doses were administered on day 14. Plasma concentrations of voriconazole were measured up to 12 h postdose on days 7 and 14, and plasma pharmacokinetic parameters were calculated. Adverse events and standard laboratory test results were recorded before and throughout the study.

Results  Comparison of the voriconazole Cmax day 14/day 7 ratio for the voriconazole + erythromycin group with that of the voriconazole + placebo group yielded a ratio of 107.7%[90% confidence interval (CI) 90.6, 128.0]; for the voriconazole + azithromycin group, the ratio was 117.5% (90% CI 98.8, 139.7). Comparison of the voriconazole AUCτ day 14/day 7 ratios of the voriconazole + erythromycin and voriconazole + azithromycin groups with that of the voriconazole + placebo group showed ratios of 101.2% (90% CI 89.1, 114.8) and 107.9% (90% CI 95.1, 122.4), respectively. For voriconazole tmax, the differences between the day 14–day 7 calculations for the voriconazole + erythromycin or the voriconazole + azithromycin groups and that of the voriconazole + placebo group were − 0.2 h (90% CI − 0.8, 0.3) and − 0.1 h (90% CI − 0.7, 0.5), respectively. None of these changes was considered clinically relevant. The study drugs were well tolerated by subjects in all groups; the most common study drug‐related adverse events were visual disturbances, reported in all groups, and abdominal pain, present in the voriconazole + erythromycin group.

Conclusions  Coadministration of erythromycin or azithromycin does not affect the steady‐state pharmacokinetics of voriconazole in a clinically relevant manner in healthy male subjects.
Bone marrow transplantation for chronic myeloid leukaemia: the effects of differing criteria for defining chronic phase on probabilities of survival and relapse
Authors: Savage David G. , Szydlo Richard M. , Chase Andrew , Apperley Jane F. , Goldman John M.
Published: November 2003

We studied actuarial survival and relapse in 251 patients with chronic myeloid leukaemia (CML) treated by bone marrow transplantation (BMT) from HLA‐identical sibling donors at a single institution. According to the institutional criteria used to define disease phase at the time of BMT, the 5‐year probabilities of survival were 58.1% (95% confidence interval 50–66%) for 205 chronic‐phase patients and 21.5% (95%CI 12–37%) for 46 advanced‐phase patients (P < 0.00001); the corresponding values for relapse were 34.8% (95%CI 27–44%) versus 72.7% (95%CI 46–89%). When disease phase was defined strictly according to the criteria of the International Bone Marrow Transplant Registry, the survival for 154 chronic‐phase patients increased to 60.1% (95%CI 51–69%) and that for 97 advanced‐phase patients increased to 37.6% (95%CI 28–48%). There was a parallel change in probabilities of relapse in the two patient groups (33.9% [95%CI 25–44%] and 51.3% [95%CI 37–66%], respectively). We also observed that patients transplanted in advanced phase had a higher incidence of grades III–IV acute graft‐versus‐host disease (P = 0.001) and transplant‐related mortality (P = 0.02) than those undergoing BMT for chronic‐phase disease. We recommend that transplant centres reporting results of BMT should always specify the precise criteria used for defining disease phase in order to ensure that results between different centres are strictly comparable.
The effects of anagrelide on human megakaryocytopoiesis
Authors: Solberg Jr Lawrence A. , Tefferi Ayalew , Oles Karl J. , Tarach Jerzy S. , Petitt Robert M. , Forstrom Lee A. , Silverstein Murray N.
Published: November 2003

Anagrelide, an inhibitor of platelet aggregation, decreases the number of platelets in normal subjects and in patients with myeloproliferative disorders. We describe studies aimed at discovering the general mechanism(s) by which anagrelide acts. We examined three hypotheses: (1) anagrelide shortens platelet survival, (2) anagrelide inhibits the proliferation of megakaryocytic‐committed progenitor cells (CFU‐M), and (3) anagrelide inhibits maturation of megakaryocytes. We observed that anagrelide did not shorten platelet survival. Proliferation of CFU‐M in vivo was not affected by anagrelide, although high concentrations of anagrelide inhibited CFU‐M in vitro. In‐vivo and in‐vitro anagrelide altered the maturation of megakaryocytes, causing a decrease in their size and changing other morphometric features. We conclude that anagrelide decreases the number of platelets primarily by interfering with the maturation of megakaryocytes.
Fludarabine is effective in the treatment of splenic lymphoma with villous lymphocytes
Authors: Bolam Simon , Orchard Jenny , Oscier David
Published: November 2003

We report on the use of fludarabine in four patients with splenic lymphoma with villous lymphocytes (SLVL). All four had relapsed after, or failed to respond to, recommended first‐line therapies. In each case fludarabine resulted in a complete clinico‐haematological response with minimal toxicity, which, in the two patients with long‐term follow‐up, proved durable. Fludarabine is effective in the treatment of SLVL and should be considered as both a first‐line therapeutic option as well as salvage therapy in this condition.
Sibling allogeneic bone marrow transplantation in a patient with type I Glanzmann's thrombasthenia
Authors: McColl M. D. , Gibson B. E. S.
Published: November 2003

Glanzmann's thrombasthenia is a rare inherited bleeding disorder caused by either quantitative or qualitative abnormalities of the platelet membrane glycoprotein (Gp) IIb/IIIa complex. Bleeding is usually mucocutaneous in origin and may be of a severe nature. We report the use of allegeneic bone marrow transplantation in a 5‐year‐old child with homozygous type I Glanzmann's thrombasthenia, using the patient's younger brother as marrow donor. Engraftment was successful and has resulted in a resolution of bleeding episodes. We conclude that allogeneic BMT is a potentially curative option for those with Glanzmann's thrombasthenia associated with severe bleeding symptoms.
Effect of hepatocyte growth factor on early human haemopoietic cell development
Authors: Ratajczak Mariusz Z. , Marlicz Woytek , Ratajczak Janina , Wasik Mariusz , Machalinski Bogdan , Carter Anna , Gewirtz Alan M.
Published: November 2003

Hepatocyte growth factor (HGF) stimulates cell proliferation, differentiation and migration by binding to its receptor, MET R. Whether the HGF/MET R axis plays an important regulatory role in human haemopoietic cell growth is an unresolved issue. To investigate this situation, we employed several complementary strategies including RT‐PCR, FACS analysis, and mRNA perturbation with oligodeoxynucleotides (ODN). We found that very primitive, FACS sorted, CD34+ Kit+ marrow mononuclear cells (MNC) failed to express RT‐PCR detectable MET R mRNA. In contrast, MET R expression was easily detectable by RT‐PCR in marrow stroma fibroblasts, in cells isolated from BFU‐E and CFU‐GM colonies, and in unselected normal MNC. Subsequent FACS analysis revealed that MET R protein was detectable on ∼5% of the latter cells. HGF, at concentrations of 1–50 ng/ml, had no demonstrable effect on survival or cloning efficiency of normal CD34+ MNC in serum‐free cultures. Antisense ODN mediated perturbation of MET R mRNA expression in normal CD34+ MNC, with FACS documented decline in protein expression, had no effect on the ability of these cells to give rise to haemopoietic colonies of any lineage. We also examined the biology of HGF/MET R expression in malignant haemopoietic cells. Using the strategies described above, we found that MET R mRNA was expressed in many human haemopoietic cell lines, and that the protein was expressed at high levels on HTLV transformed T lymphocytes. Wild‐type CML and AML blast cells also expressed MET mRNA, and HGF was able to co‐stimulate CFU‐GM colony formation in ∼20% of cases studied. Therefore, although the HGF/MET R axis appears to be dispensable for normal haemopoietic cell growth, it may play a role in the growth of malignant haemopoietic progenitor cells.
Frequent deletion of chromosome 12p12.3 in children with acute lymphoblastic leukaemia
Authors: Baccichet A. , Sinnett D.
Published: November 2003

Cytogenetic deletions of the short arm of chromosome 12 are common recurring alterations found in a wide range of haematological neoplasias, including childhood acute lymphoblastic leukaemia (ALL), the most frequent paediatric malignancy. Such a loss of genetic material suggests the presence of a tumour suppressor gene which plays an important role in growth regulation or in the differentiation of haemopoietic stem cells. To substantiate this hypothesis and to determine more precisely the chromosomal location of this putative gene, we applied a deletion mapping strategy based on the detection of loss of heterozygosity (LOH) at specific genomic loci in tumour cells. 13 polymorphic markers were used to screen DNA samples from 20 children with ALL. LOHs at 12p12.3 were observed in almost 50% of informative B‐cell precursor ALL patients analysed. This is one of the most frequent genetic alterations found in this disease. A common region of LOH was delimited by the markers D12S89 (distal) and D12S358 (proximal), separated by a genetic interval of approximately 3 cM. We refined the position of the putative 12p tumour suppressor gene to a physical interval of <1.3 Mb, a crucial step towards the identification of candidate genes. A yeast artificial chromosome clone contig that spans the entire critically deleted region includes two known genes: TEL, a member of the ets family of transcription factors, and p27KIP1, a cyclin‐dependent kinase inhibitor.
Stages of activation of hepatic stellate cells: effects of ellagic acid, an inhibiter of liver fibrosis, on their differentiation in culture
Authors: Buniatian G. H.
Published: November 2003

Abstract. To further explore that hepatic stellate cell (HSC) activation results in physiological protection against environmental insult, the profile of differentiation of HSC has been examined upon treatment with ellagic acid (EA), a plant‐derived antioxidant that shows multiple protective effects during liver disease. Sparse rat liver cell cultures were grown in media containing EA (3, 6, 30 and 100 µg/ml) and, as controls, without EA, and inspected until day 7 in culture. The cells were double‐labelled with antibodies against glial fibrillary acidic protein (GFAP) and smooth muscle alpha‐actin (SMAA), marker proteins of quiescent and activated HSC, respectively. In EA‐free culture conditions, the quiescent (SMAA−/GFAP+) HSC transiently acquired a semi‐activated (SMAA+/GFAP+), phenotype and were further transformed into activated (SMAA+/GFAP−), pleomorphic HSC. Up to a concentration of 30 µg/ml, EA induced an early synthesis of SMAA in all HSC and inhibited their morphologic differentiation and individual growth throughout the culture period. At a concentration of 6 µg/ml, EA supported the semi‐activated (SMAA+/GFAP+) phenotype of HSC throughout the culture period, whereas treatment with high EA concentrations (30 µg/ml) resulted in an early loss of GFAP expression. In conclusion: (i) the uniform response of HSC to EA by mild activation adds functional significance to cellular features preceding the transformation of HSC to myofibroblasts; (ii) the high sensitivity of HSC to EA treatment suggests their involvement in any mechanisms of protection by this antioxidant; (iii) the maintenance of HSC morphology might be one of the factors playing a role in the prevention or slowing down of liver fibrosis; (iv) because the effects of EA are concentration‐ and time‐dependent, an arbitrary usage of this antioxidant is a matter of potential concern; (v) the various patterns of HSC activation observed might correspond to distinct activities of these cells, which, in turn, might lead to different outcomes of liver fibrosis.
Exploring sexual and relationship possibilities for people with psychosis – a review of the literature
Authors: MCCANN E.
Published: November 2003

This review examines the literature on sex and relationship issues in the context of serious and persistent mental health problems. It identifies gaps in the research and highlights key issues needing further investigation. The available published documents have been identified, which contain information, ideas, data and evidence on the topic. A critical analysis of the subject, through the examination of the various documents, is provided. The main themes that emerged included HIV/AIDS, medication and sexual dysfunction, sexuality needs, intimate relationships, family planning, policies and sex education. Several subthemes are discussed and include needs assessment, stigma and loneliness. The key findings highlight the lack of systematic studies in the UK, especially regarding the subjective views of patients in determining need and the subsequent development of appropriate plans of care. The author argues that future mental health research needs to go beyond investigating perceived ‘risky’ behaviours and should include potential therapeutic responses in all areas of sexuality. Further recommendations are made in terms of nurse education particularly the inclusion of psychosexual aspects in future pre‐ and postregistration curricula. This paper may be of interest to service users, mental health practitioners working alongside people with serious and persistent mental health problems as well as educators, researchers and policy makers.
Experiencing psychiatric diagnosis: client perspectives on being named mentally ill*
Authors: HAYNE Y. M.
Published: November 2003

In this article is reported result of a phenomenological study whereby privileged view was gained into the lives of persons who had experienced receiving a diagnosis which named ‘severe and enduring mental illness’. Thematic analysis yielded the four essential themes of diagnosis as the experience of ‘a knowledge that knows’, ‘destructive (gift) of difference’, ‘making visible the invisible’ and ‘making knowledge knowledgeable’. Each of the themes is discussed under its own heading in this paper as a means for describing the nature of ‘experiencing psychiatric diagnosis’. Effort is made to provide glimpse into the ‘lifeworld’ of being diagnosed mentally ill, and the reader's attention is directed to a particular kind of power that exists in the medical language of diagnoses. Discernment is highlighted as most consequential to an ‘action sensitive practice’ and a case is made for care‐providers in psychiatric‐mental health care to be sensitized to how medical terminology is experienced and the need to strive for balance within the ‘economy of power’ contained in these specialized words.