bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics and systemic endocrine effects of the phyto‐oestrogen 8‐prenylnaringenin after single oral doses to postmenopausal women
Authors: Rad M. , Hümpel M. , Schaefer O. , Schoemaker R. C. , Schleuning W‐D. , Cohen A. F. , Burggraaf J. 
Published: April 2006

AimsPre‐clinical data suggest that the racemic phyto‐oestrogen 8‐prenylnaringenin (8‐PN) may have beneficial effects in postmenopausal women and may become an alternative to classical hormone replacement therapy (HRT) treatment regimes. The aim of this study was to investigate the pharmacokinetics, endocrine effects and tolerability of chemically synthesized 8‐PN in postmenopausal women.MethodsThe study was performed using a randomized, double‐blind, placebo‐controlled, dose‐escalation design with three groups of eight healthy postmenopausal women. In each group six subjects received 8‐PN and two subjects placebo. 8‐PN was given orally in doses of 50, 250 or 750 mg. Drug concentrations in serum, urine and faeces were measured up to 48 h and follicle‐stimulating hormone/luteinizing hormone (LH) concentrations up to 24 h.ResultsAll treatments were well tolerated and associated with a low incidence of (drug unrelated) adverse events. Serum concentrations of free 8‐PN showed rapid drug absorption and secondary peaks suggestive of marked enterohepatic recirculation. Independent of the treatment group, approximately 30% of the dose was recovered in excreta as free compound or conjugates over the 48‐h observation period. The first Cmax and AUC0−48 h showed dose linearity with ratios of 1 : 4.5 : 13.6 (Cmax) and 1 : 5.2 : 17.1 (AUC). The750‐ mg dose decreased LH concentrations by 16.7% (95% confidence interval 0.5, 30.2).ConclusionSingle oral doses of up to 750 mg 8‐PN were well tolerated by postmenopausal women. The pharmacokinetic profile of 8‐PN was characterized by rapid and probably complete enteral absorption, high metabolic stability, pronounced enterohepatic recirculation and tight dose linearity. The decrease in LH serum concentrations found after the highest dose demonstrates the ability of 8‐PN to exert systemic endocrine effects in postmenopausal women.
Influence of a single dose of 20 mg tadalafil, a phosphodiesterase 5 inhibitor, on ambulatory blood pressure in subjects with hypertension
Authors: Patterson Dean , McInnes Gordon T. , Webster John , Mitchell Malcolm M. , MacDonald Thomas M. 
Published: April 2006

AimsTo test the non‐inferiority of a single dose of tadalafil 20 mg compared with placebo with respect to 26‐h mean ambulatory systolic and diastolic blood pressure in treated and untreated hypertensive subjects.MethodsA multicentre, randomized, double‐blind, placebo‐controlled crossover study in 114 subjects with hypertension (36 subjects on no therapy with daytime mean ambulatory blood pressure ≥ 140/85 mmHg; 38 subjects on two to four classes of antihypertensive agents with daytime mean ambulatory blood pressure ≥140/85 mmHg and 40 subjects on two to four classes of antihypertensive agents with ambulatory blood pressure < 140/85 mmHg).ResultsOverall tadalafil reduced mean ambulatory blood pressure monitor systolic and diastolic blood pressure by 4.8 mmHg [95% confidence interval (Cl) 3.7, 5.9; P < 0.01] and 2.9 mmHg (95% CI 1.9, 3.6; P < 0.01), respectively, compared with placebo. In hypertensive subjects with uncontrolled blood pressure on two to four classes of antihypertensive agents (n = 36) tadalafil reduced mean ABPM systolic and diastolic blood pressure by 7.5 mmHg (95% CI 5.4, 9.6; P < 0.01) and 4.3 mmHg (95% CI 6.1, 8.9; P < 0.01) compared with placebo.ConclusionsIn patients with uncontrolled hypertension on multiple agents the addition of tadalafil 20 mg lowered mean 26‐h blood pressure.
Hydroxychloroquine potentiates Fas-mediated apoptosis of rheumatoid synoviocytes
Authors: Kim W-U , Yoo S-A , Min S-Y , Park S-H , Koh H-S , Song S-W , Cho C-S 
Published: April 2006

SummaryInadequate apoptosis may contribute to the synovial hyperplasia associated with rheumatoid arthritis (RA). The Fas-associated death domain protein (FADD)-like interleukin (IL)-1β-converting enzyme (FLICE)-inhibitory protein (FLIP), which is an apoptotic inhibitor, has been implicated in the resistance to Fas-mediated apoptosis of synoviocytes. This study investigated whether hydroxychloroquine (HCQ), an anti-rheumatic drug, induces the apoptosis of rheumatoid synoviocytes, and modulates the expression of FLIP. Fibroblast-like synoviocytes (FLS) were prepared from the synovial tissues of RA patients, and were cultured with various concentrations of HCQ in the presence or absence of the IgM anti-Fas monoclonal antibodies (mAb) (CH11). Treatment with HCQ, ranging from 1 to 100 µM, induced the apoptosis of FLS in a dose- and time-dependent manner. The increase in synoviocytes apoptosis by HCQ was associated with caspase-3 activation. A combined treatment of HCQ and anti-Fas mAb increased FLS apoptosis and caspase-3 activity synergistically, compared with either anti-Fas mAb or HCQ alone. The Fas expression level in the FLS was not increased by the HCQ treatment, while the FLIP mRNA and protein levels were decreased rapidly by the HCQ treatment. Moreover, time kinetics analysis revealed that the decreased expression of FLIP by HCQ preceded the apoptotic event that was triggered by HCQ plus anti-Fas mAb. Taken together, HCQ increases the apoptosis of rheumatoid synoviocytes by activating caspase-3, and also sensitizes rheumatoid synoviocytes to Fas-mediated apoptosis. Our data suggest that HCQ may exert its anti-rheumatic effect in rheumatoid joints through these mechanisms.
A rare RET gene exon 8 mutation is found in two Greek kindreds with familial medullary thyroid carcinoma: implications for screening
Authors: Kaldrymides Philippos , Mytakidis Nikolaos , Anagnostopoulos Theodore , Vassiliou Manolis , Tertipi Athanasia , Zahariou Maria , Rampias Theodoros , Koutsodontis Giorgos , Konstantopoulou Irene , Ladopoulou Angela , Bei Thalia , Yannoukakos Drakoulis 
Published: April 2006

SummaryObjective  Familial medullary thyroid carcinoma (FMTC) is caused by germ‐line mutations in the RET proto‐oncogene. These mutations concern mainly cysteine residues in exons 10 and 11, whereas noncysteine mutations in exons 13–16 are rare. Mutations in other exons have been reported only in isolated families. In this study we have analysed the RET gene in two FMTC families negative for mutations in the above exons.Design  We have analysed exons 7–19 and 21 in one index patient from each family using DNA sequencing.Patients  Twenty‐eight subjects from both families were clinically assessed and subsequently molecularly analysed for the presence of RET gene mutations.Results  We have found the mutation c.1597G→T (Gly533Cys) in two Greek families with FMTC. The mutation was detected in all seven MTC patients of both families as well as in 13 asymptomatic relatives in the heterozygote state, although one of the patients was also a homozygote due to consanguinity. The mutation shows a wide clinical heterogeneity, as there are carrier patients with age of diagnosis ranging from 23 to 88 years.Conclusions  It is likely that this mutation causes FMTC, as no other mutation was found in the RET gene, the mutation co‐segregates with FMTC, and family members without the mutation are clinically unaffected. As the same point mutation was previously found in a large Brazilian family, it may be present in other populations as well. Therefore, exon 8 of RET should be screened in FMTC families with no identified common RET mutations.
E‐learning for healthcare students: developing the communities of practice framework
Authors: Moule Pam 
Published: April 2006

Aim.  This paper presents research considering whether healthcare students were able to develop characteristics of communities of practice when engaged in an online module.Background.  Little is known about whether the communities of practice framework can be applied to online learning, with no previous consideration of its potential use within healthcare education.Methods.  Using a case study approach the research, completed in 2004, had two phases. A questionnaire was administered to a group of 109 healthcare students to gain information on which to base sampling for the subsequent phase. Phase 2 employed three strands of data collection: five students completed an online diary, the online interactions of seven students were captured on a discussion board and three students were interviewed. Data were analysed using a form of pattern matching.Findings.  Students were able to develop essential elements of communities of practice: mutual engagement, joint enterprise and shared repertoire, though this was not uniformly seen. Particular issues emerged for the online community, including enabling access to the online environment to support mutual engagement. The development of trust was also threatened by difficulties of presenting identities online. Joint enterprise was hampered by the online situation, although the virtual classroom proved essential for supporting endeavour. Not all students were committed to their groups. There was some evidence of group members developing shared repertoire, as routines of group working emerged. Professional understanding and computer skills were also enhanced.Conclusion.  The framework can be applied to supporting online learning internationally amongst students and has applicability to professional groups. Those intending to employ the framework should ensure that students can gain access to the community and have the computer skills to engage. Course design should be considered to ensure support for developing the essential components of communities of practice.
Microclimate, light adaptation and desiccation tolerance of epiphytic bryophytes in two Venezuelan cloud forests
Authors: León‐Vargas Yelitza , Engwald Stefan , Proctor Michael C. F. 
Published: April 2006

AbstractAim  Analysis of microclimate factors and physiological responses determining survival and growth of epiphytic bryophytes in the lower canopy and trunk space of north‐Andean cloud forests.Location  Two cloud forests at 2000–2400 m in the northern Andes near Mérida, Venezuela.Methods  Data‐logging of dry and wet‐season temperature, relative humidity (r.h.) and photosynthetically‐active radiation (PAR) for month‐long periods, and laboratory measurements of desiccation tolerance and light responses of selected epiphytic bryophytes.Results  Rainfall averages 20 mm or less in January and February, and 200 mm or more from August to October, but is very variable at all seasons. The proportion of time ‘wet’ (continuous 100% r.h.) in the months sampled ranged from 8.5% to 52.2% or more; a dry/wet‐season range between 20% and 40% is probably commoner. The length of ‘wet’ and ‘dry’ periods approximated log‐normal distributions, with mid‐points for wet periods ranging from 2.8 to 10.7 h, and dry periods from 6.2 to 17.1 h. The longest recorded dry period was 143 h. Humidity typically rose during the night to > 90% r.h., reaching 100% for significant periods (implying cloudwater (fog) deposition) on about one night in two in all seasons. Of six bryophytes of pendulous growth form, all survived periods of at least a few days’ desiccation; most recovered better from high than low humidities. Measured 95% light‐saturation values ranged from 110 to 256 μmol m−2 s−1, somewhat but not greatly higher than ambient light levelsMain conclusions  Environmental conditions in the cloud forests are probably near‐optimal for epiphytic bryophytes, but in even the wettest forest these plants must tolerate at least short periods of drying at any time of year, and longer periods seasonally. Interception of cloudwater droplets from moving air is likely to be an important source of water for bryophytes of pendant and other diffuse life forms, especially in periods of low rainfall. Absorption of water from near‐saturated air is probably of little physiological significance. Bryophytes of these life‐forms are notably conspicuous in tropical‐montane cloud forests. They remain prominent into humid temperate regions such as southern Chile, New Zealand and Macaronesia, but progressively disappear at higher latitudes with the stresses of increasing seasonality.
Dependence of Hyperpolarisation‐Activated Cyclic Nucleotide‐Gated Channel Activity on Basal Cyclic Adenosine Monophosphate Production in Spontaneously Firing GH3 Cells
Authors: Kretschmannova K. , Gonzalez‐Iglesias A. E. , Tomić M. , Stojilkovic S. S. 
Published: April 2006

AbstractThe hyperpolarisation‐activated cyclic nucleotide‐gated (HCN) channels play a distinct role in the control of membrane excitability in spontaneously active cardiac and neuronal cells. Here, we studied the expression and role of HCN channels in pacemaking activity, Ca2+ signalling, and prolactin secretion in GH3 immortalised pituitary cells. Reverse transcriptase‐polymerase chain reaction analysis revealed the presence of mRNA transcripts for HCN2, HCN3 and HCN4 subunits in these cells. A hyperpolarisation of the membrane potential below − 60 mV elicited a slowly activating voltage‐dependent inward current (Ih) in the majority of tested cells, with a half‐maximal activation voltage of −89.9 ± 4.2 mV and with a time constant of 1.4 ± 0.2 s at −120 mV. The bath application of 1 mM Cs+, a commonly used inorganic blocker of Ih, and 100 µM ZD7288, a specific organic blocker of Ih, inhibited Ih by 90 ± 4.1% and 84.3 ± 1.8%, respectively. Receptor‐ and nonreceptor‐mediated activation of adenylyl and soluble guanylyl cyclase and the addition of a membrane permeable cyclic adenosine monophosphate (cAMP) analogue, 8‐Br‐cAMP, did not affect Ih. Inhibition of basal adenylyl cyclase activity, but not basal soluble guanylyl cyclase activity, led to a reduction in the peak amplitude and a leftward shift in the activation curve of Ih by 23.7 mV. The inhibition of the current was reversed by stimulation of adenylyl cyclase with forskolin and by the addition of 8‐Br‐cAMP, but not 8‐Br‐cGMP. Application of Cs+ had no significant effect on the resting membrane potential or electrical activity, whereas ZD7288 exhibited complex and Ih‐independent effects on spontaneous electrical activity, Ca2+ signalling, and prolactin release. These results indicate that HCN channels in GH3 cells are under tonic activation by basal level of cAMP and are not critical for spontaneous firing of action potentials.
Role of FNR and FNR‐regulated, sugar fermentation genes in Neisseria meningitidis infection
Authors: Bartolini Erika , Frigimelica Elisabetta , Giovinazzi Serena , Galli Giuliano , Shaik Yazdani , Genco Caroline , Welsch Jo Anne , Granoff Dan M. , Grandi Guido , Grifantini Renata 
Published: April 2006

SummaryWhile it is generally accepted that anaerobic metabolism is required during infection, supporting experimental data have only been described in a limited number of studies. To provide additional evidence on the role of anaerobic metabolism in bacterial pathogens while invading mammalian hosts, we analysed the effect of the inactivation of FNR, the major regulatory protein involved in the adaptation to oxygen restrictive conditions, and of two of the FNR‐regulated genes on the survival of Neisseria meningitidis serogroup B (MenB) in vivo. We found that fnr deletion resulted in more than 1 log reduction in the meningococcal capacity to proliferate both in infant rats and in mice. To identify which of the FNR‐regulated genes were responsible for this attenuated phenotype, we defined the FNR regulon by combining DNA microarray analysis and FNR–DNA binding studies. Under oxygen‐restricted conditions, FNR positively controlled the transcription of nine transcriptional units, the most upregulated of which were the two operons NMB0388‐galM and mapA‐pgmβ implicated in sugar metabolism and fermentation. When galM and mapA were knocked out, the mutants were attenuated by 2 and 3 logs respectively. As the operons are controlled by FNR, from these data we conclude that MenB survival in the host anatomical sites where oxygen is limiting is supported by sugar fermentation.
The CBF1‐dependent low temperature signalling pathway, regulon and increase in freeze tolerance are conserved in Populus spp.
Authors: BENEDICT CATHERINE , SKINNER JEFFREY S. , MENG RENGONG , CHANG YONGJIAN , BHALERAO RISHIKESH , HUNER NORMAN P. A. , FINN CHAD E. , CHEN TONY H. H. , HURRY VAUGHAN 
Published: April 2006

ABSTRACTThe meristematic tissues of temperate woody perennials must acclimate to freezing temperatures to survive the winter and resume growth the following year. To determine whether the C‐repeat binding factor (CBF) family of transcription factors contributing to this process in annual herbaceous species also functions in woody perennials, we investigated the changes in phenotype and transcript profile of transgenic Populus constitutively expressing CBF1 from Arabidopsis (AtCBF1). Ectopic expression of AtCBF1 was sufficient to significantly increase the freezing tolerance of non‐acclimated leaves and stems relative to wild‐type plants. cDNA microarray experiments identified genes up‐regulated by ectopic AtCBF1 expression in Populus, demonstrated a strong conservation of the CBF regulon between Populus and Arabidopsis and identified differences between leaf and stem regulons. We studied the induction kinetics and tissue specificity of four CBF paralogues identified from the Populus balsamifera subsp. trichocarpa genome sequence (PtCBFs). All four PtCBFs are cold‐inducible in leaves, but only PtCBF1 and PtCBF3 show significant induction in stems. Our results suggest that the central role played by the CBF family of transcriptional activators in cold acclimation of Arabidopsis has been maintained in Populus. However, the differential expression of the PtCBFs and differing clusters of CBF‐responsive genes in annual (leaf) and perennial (stem) tissues suggest that the perennial‐driven evolution of winter dormancy may have given rise to specific roles for these ‘master‐switches’ in the different annual and perennial tissues of woody species.
Exogenous supply of glutamine and active cytokinin to the roots reduces NO3–uptake rates in poplar
Authors: DLUZNIEWSKA PAULINA , GESSLER ARTHUR , KOPRIVA STANISLAV , STRNAD MIROSLAV , NOVÁK ONDŘEJ , DIETRICH HENRIETTE , RENNENBERG HEINZ 
Published: April 2006

ABSTRACTThe present study shows for the first time the influence of exogenously applied amino acids and cytokinin on the physiological and molecular aspects of N metabolism in poplar trees. In a short‐term feeding experiment, glutamine ortrans‐zeatin riboside (tZR) was added directly to the nutrient solution. NO3–net uptake declined significantly in response to both treatments. Feeding with glutamine brought about an increase in concentrations of different amino compounds in the roots (glutamine, glutamate, alanine,γ‐amino butyric acid (GABA) and NH4+, which negatively correlated with the net NO3–uptake. The plants showed a reduction of cytosolic glutamine synthetase 1 (GS1) transcript level in the roots. In addition, glutamine feeding changed the root‐to‐shoot distribution on N assimilation in favour of the leaves and plant internal N cycling.tZR treatment resulted in expansion of zeatin‐type (Z‐type) cytokinins in the roots and increased nitrate reductase (NR)–mRNA level. The results indicate that both particular amino acids and active cytokinins are involved in the feedback regulation of N uptake and metabolism in poplar. We propose that inhibition of N uptake by cytokinins in poplar is more complex than that mediated by amino compounds, and other effectors are involved in this regulation.
Two‐hybrid protein–protein interaction analysis in Arabidopsis protoplasts: establishment of a heterodimerization map of group C and group S bZIP transcription factors
Authors: Ehlert Andrea , Weltmeier Fridtjof , Wang Xuan , Mayer Caroline S. , Smeekens Sjef , Vicente‐Carbajosa Jesús , Dröge‐Laser Wolfgang 
Published: April 2006

Summary In vivo protein–protein interactions are frequently studied by means of yeast two‐hybrid analysis. However, interactions detected in yeast might differ considerably in the plant system. Based on GAL4 DNA‐binding (BD) and activation domains (AD) we established an Arabidopsis protoplast two‐hybrid (P2H) system. The use of Gateway®‐compatible vectors enables the high‐throughput screening of protein–protein interactions in plant cells. The efficiency of the system was tested by examining the homo‐ and heterodimerization properties of basic leucine zipper (bZIP) transcription factors. A comprehensive heterodimerization matrix of Arabidopsis thaliana group C and group S bZIP transcription factors was generated by comparing the results of yeast and protoplast two‐hybrid experiments. Surprisingly, almost no homodimerization but rather specific and selective heterodimerization was detected. Heterodimers were preferentially formed between group C members (AtbZIP9, ‐10, ‐25, ‐63) and members of group S1 (AtbZIP1, ‐2, ‐11, ‐44, ‐53). In addition, significant but low‐affinity interactions were detected inside group S1, S2 or C AtbZIPs, respectively. As a quantitative approach, P2H identified weak heterodimerization events which were not detected in the yeast system. Thus, in addition to cell biological techniques, P2H is a valuable tool for studying protein–protein interaction in living plant cells.
Highly salted food and mountain herbs elevate the risk for stomach cancer death in a rural area of Japan
Authors: Kurosawa Michiko , Kikuchi Shogo , Xu Jun , Inaba Yutaka 
Published: April 2006

AbstractBackground:  Although many case–control and experimental studies have shown that highly salted foods are risk factors for stomach cancer, only a few cohort studies have supported the relationship.Methods:  In a cohort study conducted in a rural area of Japan, 8035 residents aged over 30 years (approx. 55% were female) filled out a questionnaire. Seventy‐six of them died from stomach cancer during an 11‐year follow‐up period. In the questionnaire, intake frequencies of 29 food items, smoking and drinking habits were investigated. Tsukemono (pickled vegetables) and tsukudani (foods deep boiled in soy sauce) are highly salted foods in the area. Frequency of each food item intake was classified into three levels, and age‐ and sex‐adjusted risks were calculated using proportional hazard models.Results:  In the final model obtained by backward elimination, frequent intake of tsukemono and tsukudani and that of mountain herbs remained as significant risk factors. Compared with the least frequent intake, risk (95% confidence interval) of the most frequent intake was 5.4 (1.8–16.3) for highly salted foods (P for trend < 0.01) and 3.7 (1.4–9.6) for mountain herbs (P for trend = 0.04).Conclusion:  Highly salted foods and mountain herbs were important risk factors for death from stomach cancer.