bluuebunny/crossref_metadata_2025 huggingface dataset:
Phylogeny, evolution, and biogeography of Asiatic Salamanders (Hynobiidae)
Authors: Zhang Peng , Chen Yue-Qin , Zhou Hui , Liu Yi-Fei , Wang Xiu-Ling , Papenfuss Theodore J. , Wake David B. , Qu Liang-Hu
Published: April 2006

We sequenced 15 complete mitochondrial genomes and performed comprehensive molecular phylogenetic analyses to study the origin and phylogeny of the Hynobiidae, an ancient lineage of living salamanders. Our phylogenetic analyses show that the Hynobiidae is a clade with well resolved relationships, and our results contrast with a morphology-based phylogenetic hypothesis. These salamanders have low vagility and are limited in their distribution primarily by deserts, mountains, and oceans. Our analysis suggests that the relationships among living hynobiids have been shaped primarily by geography. We show that four-toed species assigned to
Batrachuperus
do not form a monophyletic group, and those that occur in Afghanistan and Iran are transferred to the resurrected
Paradactylodon
. Convergent morphological characters in different hynobiid lineages are likely produced by similar environmental selective pressures. Clock-independent molecular dating suggests that hynobiids originated in the Middle Cretaceous [≈110 million years ago (Mya)]. We propose an “out of North China” hypothesis for hynobiid origins and hypothesize an ancestral stream-adapted form. Given the particular distributional patterns and our molecular dating estimates, we hypothesize that: (
i
) the interior desertification from Mongolia to Western Asia began ≈50 Mya; (
ii
) the Tibetan plateau (at least on the eastern fringe) experienced rapid uplift ≈40 Mya and reached an altitude of at least 2,500 m; and (
iii
) the Ailao–Red River shear zone underwent the most intense orogenic movement ≈24 Mya.
Subcellular localization and functions of the barley stem rust resistance receptor-like serine/threonine-specific protein kinase Rpg1
Authors: Nirmala Jayaveeramuthu , Brueggeman Robert , Maier Christina , Clay Christine , Rostoks Nils , Kannangara C. Gamini , von Wettstein Diter , Steffenson Brian J. , Kleinhofs Andris
Published: April 2006

The
Rpg1
gene confers resistance to many pathotypes of the stem rust fungus
Puccinia graminis
f. sp.
tritici
and has protected barley from serious disease losses for over 60 years.
Rpg1
encodes a constitutively expressed protein with two tandem kinase domains. Fractionation by differential centrifugation and aqueous two-phase separation of the microsome proteins located Rpg1 mainly in the cytosol but also in the plasma membrane and intracellular membranes. Recombinant Rpg1 autophosphorylates
in vitro
intramolecularly only serine and threonine amino acids with a preference for Mn
2+
cations and a

K
m

of 0.15 and a

V
max

of 0.47 nmol·min
−1
·mg
−1
protein. The inability of wild-type Rpg1 to transphosphorylate a recombinant Rpg1 inactivated by site-directed mutation confirmed that Rpg1 autophosphorylation proceeds exclusively via an intramolecular mechanism. Site-directed mutagenesis of the two adjacent lysine residues in the ATP anchor of the two-kinase domains established that the first of the two tandem kinase domains is nonfunctional and that lysine 461 of the second domain is the catalytically active residue. Transgenic barley, expressing Rpg1 mutated in either the kinase 1 or 2 domains, were fully susceptible to
P. graminis
f. sp.
tritici
revealing requirement of both kinase domains for resistance.
In planta
-expressed Rpg1 mutant protein confirmed that mutation in domain 2, but not 1, rendered the protein incapable of autophosphorylation.
An essential role for the
DXPas34
tandem repeat and
Tsix
transcription in the counting process of X chromosome inactivation
Authors: Vigneau Sébastien , Augui Sandrine , Navarro Pablo , Avner Philip , Clerc Philippe
Published: April 2006

A counting process senses the X chromosome/autosome ratio and ensures that X chromosome inactivation (XCI) initiates in the early female (XX) embryo and in differentiating female ES cells but not in their male (XY) counterparts. Counting depends on the X inactivation center (
Xic
), which contains the
Xist
gene encoding a nuclear RNA, which coats the inactive X chromosome and induces gene silencing. A 37-kb sequence lying 3′ to the
Xist
gene is known to prevent initiation of XCI in male differentiating ES cells. This region contains the major and minor promoters of the
Tsix
gene, which runs antisense to
Xist
, and the
DXPas34
tandem repeat lying close to the
Tsix
major promoter. We have addressed the role of these elements in counting by using male ES cells. Targeted deletion of
DXPas34
impaired recruitment of RNA-polymerase II and TFIIB at the
Tsix
major promoter, resulting in low levels of
Tsix
expression in ES cells and moderate ectopic initiation of XCI upon differentiation. A deletion extending 3′ to
Xist
and including the
Tsix
major promoter resulted in almost complete impairment of
Tsix
transcription and in efficient ectopic XCI upon differentiation of male ES cells. Internal deletions within the
Tsix
gene did not affect significantly the level of antisense transcription within
Xist
and had only minor effects upon differentiation. Our results identify a function for
DXPas34
in murine XCI and demonstrate the critical role of
Tsix
transcription in preventing XCI in differentiating male ES cells and in normal functioning of the counting pathway.
The circadian basis of winter depression
Authors: Lewy Alfred J. , Lefler Bryan J. , Emens Jonathan S. , Bauer Vance K.
Published: April 2006

The following test of the circadian phase-shift hypothesis for patients with winter depression (seasonal affective disorder, or SAD) uses low-dose melatonin administration in the morning or afternoon/evening to induce phase delays or phase advances, respectively, without causing sleepiness. Correlations between depression ratings and circadian phase revealed a therapeutic window for optimal alignment of circadian rhythms that also appears to be useful for phase-typing SAD patients for the purpose of administering treatment at the correct time. These analyses also provide estimates of the circadian component of SAD that may apply to the antidepressant mechanism of action of appropriately timed bright light exposure, the treatment of choice. SAD may be the first psychiatric disorder in which a physiological marker correlates with symptom severity before, and in the course of, treatment in the same patients. The findings support the phase-shift hypothesis for SAD, as well as suggest a way to assess the circadian component of other psychiatric, sleep, and chronobiologic disorders.
Microfabricated bioprocessor for integrated nanoliter-scale Sanger DNA sequencing
Authors: Blazej Robert G. , Kumaresan Palani , Mathies Richard A.
Published: April 2006

An efficient, nanoliter-scale microfabricated bioprocessor integrating all three Sanger sequencing steps, thermal cycling, sample purification, and capillary electrophoresis, has been developed and evaluated. Hybrid glass–polydimethylsiloxane (PDMS) wafer-scale construction is used to combine 250-nl reactors, affinity-capture purification chambers, high-performance capillary electrophoresis channels, and pneumatic valves and pumps onto a single microfabricated device. Lab-on-a-chip-level integration enables complete Sanger sequencing from only 1 fmol of DNA template. Up to 556 continuous bases were sequenced with 99% accuracy, demonstrating read lengths required for
de novo
sequencing of human and other complex genomes. The performance of this miniaturized DNA sequencer provides a benchmark for predicting the ultimate cost and efficiency limits of Sanger sequencing.
SirT2 is a histone deacetylase with preference for histone H4 Lys 16 during mitosis
Authors: Vaquero Alejandro , Scher Michael B. , Lee Dong Hoon , Sutton Ann , Cheng Hwei-Ling , Alt Frederick W. , Serrano Lourdes , Sternglanz Rolf , Reinberg Danny
Published: April 2006

The mammalian cytoplasmic protein SirT2 is a member of the Sir2 family of NAD+-dependent protein deacetylases involved in caloric restriction-dependent life span extension. We found that SirT2 and its yeast counterpart Hst2 have a strong preference for histone H4K16Ac in their deacetylation activity in vitro and in vivo. We have pinpointed the decrease in global levels of H4K16Ac during the mammalian cell cycle to the G2/M transition that coincides with SirT2 localization on chromatin. Mouse embryonic fibroblasts (MEFs) deficient for SirT2 show higher levels of H4K16Ac in mitosis, in contrast to the normal levels exhibited by SirT1-deficient MEFs. The enzymatic conversion of H4K16Ac to its deacetylated form may be pivotal to the formation of condensed chromatin. Thus, SirT2 is a major contributor to this enzymatic conversion at the time in the cell’s life cycle when condensed chromatin must be generated anew.
Phosphorus and Aluminum Interactions in Soybean in Relation to Aluminum Tolerance. Exudation of Specific Organic Acids from Different Regions of the Intact Root System
Authors: Liao Hong , Wan Huiyan , Shaff Jon , Wang Xiurong , Yan Xiaolong , Kochian Leon V.
Published: April 2006

Aluminum (Al) toxicity and phosphorus (P) deficiency often coexist in acid soils that severely limit crop growth and production, including soybean (Glycine max). Understanding the physiological mechanisms relating to plant Al and P interactions should help facilitate the development of more Al-tolerant and/or P-efficient crops. In this study, both homogeneous and heterogeneous nutrient solution experiments were conducted to study the effects of Al and P interactions on soybean root growth and root organic acid exudation. In the homogenous solution experiments with a uniform Al and P distribution in the bulk solution, P addition significantly increased Al tolerance in four soybean genotypes differing in P efficiency. The two P-efficient genotypes appeared to be more Al tolerant than the two P-inefficient genotypes under these high-P conditions. Analysis of root exudates indicated Al toxicity induced citrate exudation, P deficiency triggered oxalate exudation, and malate release was induced by both treatments. To more closely mimic low-P acid soils where P deficiency and Al toxicity are often much greater in the lower soil horizons, a divided root chamber/nutrient solution approach was employed to impose elevated P conditions in the simulated upper soil horizon, and Al toxicity/P deficiency in the lower horizon. Under these conditions, we found that the two P-efficient genotypes were more Al tolerant during the early stages of the experiment than the P-inefficient lines. Although the same three organic acids were exuded by roots in the divided chamber experiments, their exudation patterns were different from those in the homogeneous solution system. The two P-efficient genotypes secreted more malate from the taproot tip, suggesting that improved P nutrition may enhance exudation of organic acids in the root regions dealing with the greatest Al toxicity, thus enhancing Al tolerance. These findings demonstrate that P efficiency may play a role in Al tolerance in soybean. Phosphorus-efficient genotypes may be able to enhance Al tolerance not only through direct Al-P interactions but also through indirect interactions associated with stimulated exudation of different Al-chelating organic acids in specific roots and root regions.
Aging in Legume Symbiosis. A Molecular View on Nodule Senescence in Medicago truncatula
Authors: Van de Velde Willem , Guerra Juan Carlos Pérez , Keyser Annick De , De Rycke Riet , Rombauts Stéphane , Maunoury Nicolas , Mergaert Peter , Kondorosi Eva , Holsters Marcelle , Goormachtig Sofie
Published: April 2006

Rhizobia reside as symbiosomes in the infected cells of legume nodules to fix atmospheric nitrogen. The symbiotic relation is strictly controlled, lasts for some time, but eventually leads to nodule senescence. We present a comprehensive transcriptomics study to understand the onset of nodule senescence in the legume Medicago truncatula. Distinct developmental stages with characteristic gene expression were delineated during which the two symbiotic partners were degraded consecutively, marking the switch in nodule tissue status from carbon sink to general nutrient source. Cluster analysis discriminated an early expression group that harbored regulatory genes that might be primary tools to interfere with pod filling-related or stress-induced nodule senescence, ultimately causing prolonged nitrogen fixation. Interestingly, the transcriptomes of nodule and leaf senescence had a high degree of overlap, arguing for the recruitment of similar pathways.
Phosphorus Deficiency Decreases Cell Division and Elongation in Grass Leaves
Authors: Kavanová Monika , Lattanzi Fernando Alfredo , Grimoldi Agustín Alberto , Schnyder Hans
Published: April 2006

Leaf growth in monocotyledons results from the flux of newly born cells out of the division zone and into the adjacent elongation-only zone, where cells reach their final length. We used a kinematic method to analyze the effect of phosphorus nutrition status on cell division and elongation parameters in the epidermis of Lolium perenne. Phosphorus deficiency reduced the leaf elongation rate by 39% due to decreases in the cell production rate (−19%) and final cell length (−20%). The former was solely due to a lower average cell division rate (0.028 versus 0.046 cell cell−1 h−1) and, thus, a lengthened average cell cycle duration (25 versus 15 h). The number of division cycles of the initial cell progeny (five to six) and, as a result, the number of meristematic cells (32–64) and division zone length were independent of phosphorus status. Accordingly, low-phosphorus cells maintained meristematic activity longer. Lack of effect of phosphorus deficiency on meristematic cell length implies that a lower division rate was matched to a lower elongation rate. Phosphorus deficiency did not affect the elongation-only zone length, thus leading to longer cell elongation duration (99 versus 75 h). However, the substantially reduced postmitotic average relative elongation rate (0.045 versus 0.064 mm mm−1 h−1) resulted in shorter mature cells. In summary, phosphorus deficiency did not affect the general controls of cell morphogenesis, but, by slowing down the rates of cell division and expansion, it slowed down its pace.
High Light Response of the Thylakoid Proteome in Arabidopsis Wild Type and the Ascorbate-Deficient Mutant vtc2-2. A Comparative Proteomics Study
Authors: Giacomelli Lisa , Rudella Andrea , van Wijk Klaas Jan
Published: April 2006

The thylakoid proteome of chloroplasts contains multiple proteins involved in antioxidative defense, protein folding, and repair. To understand this functional protein network, we analyzed the quantitative response of the thylakoid-associated proteome of Arabidopsis (Arabidopsis thaliana) wild type and the ascorbate-deficient mutant vtc2-2 after transition to high light (HL; 1,000 μmol photons m−2 s−1). The soluble thylakoid proteomes of wild type and vtc2-2 were compared after 0, 1, 3, and 5 d of HL using two-dimensional gels with three independent experiments, followed by a multivariant statistical analysis and tandem mass spectrometry. After 5 d of HL, both wild-type and vtc2-2 plants accumulated anthocyanins, increased their total ascorbate content, and lost 10% of photosystem II efficiency, but showed no bleaching. Anthocyanin and total ascorbate concentrations in vtc2-2 were respectively 34% and 20% of wild type, potentially leading to enhanced oxidative stress in vtc2-2. Forty-five protein spots significantly changed as a consequence of genotype, light treatment, or both. Independent confirmation was obtained from western blots. The most significant response was the up-regulation of thylakoid YCF37 likely involved in photosystem I assembly, and specific fibrillins, a flavin reductase-like protein, and an aldolase, each located in thylakoid-associated plastoglobules. Fe-superoxide dismutase was down-regulated in vtc2-2, while Cu,Zn-superoxide dismutase was up-regulated. vtc2-2 also showed a systematic up-regulation of a steroid dehydrogenase-like protein. A number of other stress-related proteins, several thylakoid proteases, and lumenal isomerases did not change, while PsbS increased in wild type upon light stress. These findings are discussed in terms of plastid metabolism and oxidative stress defense, and emphasize that understanding of the chloroplast stress-response network must include the enzymatic role of plastoglobules.
Maintenance of DNA Methylation during theArabidopsisLife Cycle Is Essential for Parental Imprinting
Authors: Jullien Pauline E. , Kinoshita Tetsu , Ohad Nir , Berger Frédéric
Published: April 2006

Imprinted genes are expressed predominantly from either their paternal or their maternal allele. To date, all imprinted genes identified in plants are expressed in the endosperm. In Arabidopsis thaliana, maternal imprinting has been clearly demonstrated for the Polycomb group gene MEDEA (MEA) and for FWA. Direct repeats upstream of FWA are subject to DNA methylation. However, it is still not clear to what extent similar cis-acting elements may be part of a conserved molecular mechanism controlling maternally imprinted genes. In this work, we show that the Polycomb group gene FERTILIZATION-INDEPENDENT SEED2 (FIS2) is imprinted. Maintenance of FIS2 imprinting depends on DNA methylation, whereas loss of DNA methylation does not affect MEA imprinting. DNA methylation targets a small region upstream of FIS2 distinct from the target of DNA methylation associated with FWA. We show that FWA and FIS2 imprinting requires the maintenance of DNA methylation throughout the plant life cycle, including male gametogenesis and endosperm development. Our data thus demonstrate that parental genomic imprinting in plants depends on diverse cis-elements and mechanisms dependent or independent of DNA methylation. We propose that imprinting has evolved under constraints linked to the evolution of plant reproduction and not by the selection of a specific molecular mechanism.
The effect of red light in the high irradiance reaction of phytochrome:
Authors: JOHNSON C. B.
Published: April 2006

Abstract. A proposal has recently been made (Johnson & Tasker, 1979) that phytochrome acts through the multiplicative effect of two components of the phytochrome system, only one of them being Pfr and the other a product of the photoconversion reaction Pr→Pfr. It has been shown previously that HIR action spectra based on this assumption show a good resemblance to the observed responses with the possible exception of the red region of the spectrum. There, a greater response is predicted than is often observed and fluence rate dependency is predicted, on which matter there is disagreement in the literature.

The experiments reported here show that, because chlorophyll is formed in red light but not in far‐red, chlorophyll screening lowers the effective fluence rate in red light with respect to phytochrome. When such screening is eliminated the observed responses show strong fluence rate dependency, as predicted. Evidence is also presented to support the conclusion that the two proposed effectors must act together multiplicatively.
Sodium fluxes in corn roots: comparison to Cl and K fluxes, and to Na‐fluxes in barley
Authors: JACOBY B. , RUDICH B.
Published: April 2006

Abstract. Carbonylcyanide, m‐chlorophenyl hydra‐zone (CCCP) decreased the ATP content of barley and corn roots by 80% within 5 min. The protonophore inhibited K and Cl absorption by largely unvacuolated root tips, and vacuolated root segments of barley and corn. The protonophore also inhibited Na absorption by root segments and Na extrusion by root tips of barley; it did not affect these Na fluxes in corn root tips and segments, and Na Influx in barley root tips. It was concluded that corn roots lack a metabolic mechanism for Na extrusion from the cytoplasm to the external solution or vacuole, which is functional in barley roots.
Phloem sap exudation in Ricinus communis: elastic responses and anatomical implications
Authors: KALLARACKAL J. , MILBURN J. A.
Published: April 2006

Abstract. Ricinus communis plants have an unusually high capacity to exude considerable quantities of phloem sap from bark incisions. We have used Ricinus as an experimental system to study different aspects of sap exudation. Dimensional changes in the bark, monitored by a displacement transducer, showed that pressure release in the sieve tubes was accompanied by elastic shrinkage. The rate of exudation was also controlled by the degree of pressurization and elastic properties of the sieve tubes. A displacement transducer was used to measure the elastic modulus (ɛ) of phloem samples by immersing them in a range of different osmotica. The cells had a low elastic modulus (ɛ= 1.62 ± 0.41 MPa at full turgor). ɛ of phloem tissue in massage pretreated bark, from which exudation was enhanced, was not significantly different from that of unmassaged bark in contrast with the suggestion of Lee (1981). However, anatomical studies showed that massage pretreatment has a stimulating influence on the cambial cell division, which increased the phloem tissue cross‐section up to 160%. The newly‐formed sieve tubes were ‘spliced’ into existing ones in the unmassaged zone to re‐establish vascular continuity. Plants with a greater capacity to exude phloem sap from a given stem location had a greater cross‐sectional area of sieve tubes in the vicinity.

The significance of observations with respect to other sap exudation phenomenon is discussed. The importance of the present work in understanding the technique of palm tapping, on which the palm sugar industry depends, is also considered.
The evolutionary relationship between stomatal mechanism, crassulacean acid metabolism and C4 photosynthesis
Authors: COCK BURN W.
Published: April 2006

Abstract. All of the features of crassulacean acid metabolism (CAM) and most characteristics of C4 photosynthesis are exhibited by stomatal guard cells. It is proposed that CAM and possibly also C4 photosynthesis result from the expression in photosynthetic cells of genetic information which is expressed only in guard cells of C3 plants.
Chloroplast ultrastructure in two Crassulacean species and an F1 hybrid with differing biomass δ13C values
Authors: TEERI J. A. , OVERTON J.
Published: April 2006

Abstract. The chloroplasts of two species of the Crassulaceae and their F1 hybrid were compared by electron microscopy. The two species had contrasting leaf tissue δ13C values of −25°/∞ (Sedum greggii) and −13°/∞ (Cremnophila linguifolia), and the F1 hybrid had a value of − 18°/∞. S. greggii had a mean of 8.9 thylakoids per granum in contrast to C. linguifolia which had a mean of only 3.8 thylakoids per granum. The F1 hybrid had a mean of 6.4 thylakoids per granum. Crystaloids were observed in S. greggii and the hybrid but not in C. linguifolia
Time‐dependent changes in the responsiveness to light of phytochrome‐mediated anthocyanin synthesis
Authors: SCHMIDT R. , MOHR H.
Published: April 2006

Abstract. It is well established that seedlings of mustard (Sinapis alba L.) synthesize juvenile anthocyanin only if treated with light pulses or continuous light. The light effects are considered to be due to the operation of phytochrome. Here we show that the responsiveness of anthocyanin synthesis to a saturating red light pulse or to continuous far‐red light varies as a function of time and is strongly influenced by a light pretreatment prior to competence. Competence appears approximately 25 h after sowing. The starting point of anthocyanin synthesis, which is 27 h after sowing, and the lag‐ phase of this response, which is 2 h, are not affected by light pretreatments prior to competence. It is concluded that quantitative interpretations of phytochrome responses based entirely on properties of phytochrome can no longer be considered adequate.
Phytochrome‐mediated responses in light‐grown corn showing rapid, reverse reciprocity failure*
Authors: GORTON HOLLY L. , BRIGGS WINSLOW R.
Published: April 2006

Abstract.Three responses (mesocotyl and coleoptile elongation and anthocyanin accumulation in the coleoptile) to end‐ of‐day far‐red irradiation in light‐grown corn show rapid failure of the reciprocity law such that short, high fluence rate irradiations are much more effective than long, low fluence rate ones of the same fluence (reverse reciprocity failure). The reciprocity failure cannot be explained by escape from photoreversibility, a change in sensitivity to Pfr, reciprocity failure for photoconversion, or a high irradiance response taking over for long irradiation times. Fluence–response curves measured by varying irradiation time at a low fluence rate show the threshold fluence shifted to higher energy in comparison with fluence–response curves obtained at a high fluence rate. Red reversal of these responses also shows rapid reciprocity failure in the same direction, a process which can be only partially explained by escape.

These responses to end‐of‐day far‐red and red illumination are distinguished from high irradiance reactions by their low fluence requirements and ready reversibility. These same characteristics are similar to those of classical phytochrome‐ mediated, induction‐reversion responses in etiolated tissue, but it is difficult to explain the rapid, reverse reciprocity failure in terms of standard phytochrome dogma.
Rapid, reverse reciprocity failure for phytochrome control of its own accumulation*
Authors: GORTON HOLLY L. , BRIGGS WINSLOW R.
Published: April 2006

Abstract. Fluence–response curves have been obtained for end‐of‐day far‐red stimulation and red reversal of phytochrome accumulation in leaves of light‐grown corn during darkness following a white‐light period. The response to end‐of‐day far‐red, but not to R, shows rapid, reverse reciprocity failure which cannot be explained by escape from photoreversibility. Because the Pfr/Ptot established by long, low fluence rate and short, high fluence rate exposures of the same total fluence is the same and can lead to vastly different responses, explanations for this phenomenon based simply on Pfr levels or Pfr/Ptot are inadequate. Reciprocity failure for end‐of‐day far‐red is not necessarily coupled to reciprocity failure for red reversal of the far‐red effect. The two phenomena must stem from different causes.
A new method of measuring water potential in tree stems by water injection
Authors: EDWARDS W. R. N. , JARVIS P. G.
Published: April 2006

Abstract. A new method of measuring xylem water potential in the stems of trees is described. The flow rate of water injected into the xylem at two or more known pressures is measured. The xylem water potential is derived either graphically from the relationship between flow rate and applied pressure, or from the solution of simultaneous flow equations.
Safety and efficacy of two dose formulations of alicaforsen enema compared with mesalazine enema for treatment of mild to moderate left‐sided ulcerative colitis: a randomized, double‐blind, active‐controlled trial
Authors: MINER P. B. , WEDEL M. K. , XIA S. , BAKER B. F.
Published: April 2006

Background

Alicaforsen is an antisense oligonucleotide inhibitor of intercellular adhesion molecule 1 protein expression with activity in subjects with ulcerative colitis and pouchitis.

Aim

To compare the effects of alicaforsen enema to standard of care mesalazine (mesalamine) enema in subjects with mild to moderate active left‐sided ulcerative colitis.

Method

A randomized, double‐blind, active‐controlled multicentre clinical trial. Subjects received a nightly enema of 120 mg alicaforsen (n = 55), 240 mg alicaforsen (n = 50), or 4 g mesalazine (n = 54) for 6 weeks, followed by a 24‐week monitoring period. The primary end point was Disease Activity Index at week 6. Clinical improvement, remission and relapse were secondary end points.

Results

No significant difference was observed between treatment arms in the primary end point. However, the median duration of response to alicaforsen enema treatment was two‐ to threefold longer (128 and 146 days) in comparison with mesalazine (54 days). Complete mucosal healing occurred in 24% of the 240 mg alicaforsen group, when compared with 17% in the mesalazine.

Conclusions

Alicaforsen enema demonstrated an acute response and safety profile similar to mesalazine enema, but was differentiated by a more durable response. The extended length of remission suggests that alicaforsen enema treatment may have a disease modifying effect.
Efficacy and safety of bisacodyl in the acute treatment of constipation: a double‐blind, randomized, placebo‐controlled study
Authors: KIENZLE‐HORN S. , VIX J.‐M. , SCHUIJT C. , PEIL H. , JORDAN C. C. , KAMM M. A.
Published: April 2006

Background

Although laxatives are a first‐line treatment for constipation, there are few randomized placebo‐controlled trials assessing their efficacy.

Aim

To determine the effect and safety of oral bisacodyl on stool frequency and consistency in patients with idiopathic constipation.

Methods

55 patients (age 19–89 years) with idiopathic constipation were recruited from eight primary care practices and randomized to receive bisacodyl, 10 mg once daily, or placebo, on three successive days following a 3‐day run‐in period. Patients recorded stool frequency and consistency and adverse events.

Results

In each treatment group, 27 patients were evaluable for efficacy. The mean number of stools per day was significantly greater in the bisacodyl‐treated group (1.8/day) compared with placebo (0.95/day) over the treatment phase (P = 0.0061). Mean stool consistency score improved from ‘hard’ (run‐in) to between ‘soft’ and ‘well‐formed’ during bisacodyl treatment, remaining between ‘moderately hard’ and ‘hard’ for placebo treatment (P < 0.0001). The investigator's global efficacy score was superior for the bisacodyl group compared with placebo. Both treatments were well tolerated. Serum electrolyte levels and incidence of adverse events were comparable between treatment groups.

Conclusions

Bisacodyl is effective and safe in improving stool frequency and consistency in acute treatment of idiopathic constipation.
Basiliximab for the treatment of steroid‐resistant ulcerative colitis: further experience in moderate and severe disease
Authors: CREED T. J. , PROBERT C. S. J. , NORMAN M. N. , MOORGHEN M. , SHEPHERD N. A. , HEARING S. D. , DAYAN C. M. ,   THE BASBUC INVESTIGATORS
Published: April 2006

Background

Preliminary data have suggested that interleukin‐2 receptor blockade with basiliximab may increase steroid sensitivity. We have previously reported a small case series demonstrating the potential of basiliximab as a novel agent for the treatment of steroid‐resistant ulcerative colitis.

Aim

To report further experience of the efficacy and safety of treatment with the interleukin‐2 receptor blocking monoclonal antibody basiliximab, in addition to steroids, for the treatment of severe and moderate steroid‐resistant ulcerative colitis.

Methods

Twenty patients were enrolled – 13 patients with moderate steroid‐resistant ulcerative colitis (Ulcerative Colitis Symptom Score: ≥6) and seven patients with severe steroid‐resistant ulcerative colitis. All were given a single dose of 40 mg basiliximab plus standard steroid therapy in an open‐label, uncontrolled trial. Primary end point was clinical remission within 8 weeks (Ulcerative Colitis Symptom Score: ≤2).

Results

Within 8 weeks, 10 of 20 (50%) patients achieved clinical remission (seven of 13 moderate, and three of seven severe). At 24 weeks, 13 of 20 (65%) patients were in clinical remission. Five patients required colectomy (four severe, one moderate ulcerative colitis) and one required rescue ciclosporin (moderate ulcerative colitis). Two patients developed herpes zoster, but treatment was generally well tolerated.

Conclusions

Basiliximab appears to promote prolonged remission after a single treatment. Taken in combination with previously reported data, basiliximab shows particular promise in moderate steroid‐resistant ulcerative colitis.
Oats in the treatment of childhood coeliac disease: a 2‐year controlled trial and a long‐term clinical follow‐up study
Authors: HOLM K. , MÄKI M. , VUOLTEENAHO N. , MUSTALAHTI K. , ASHORN M. , RUUSKA T. , KAUKINEN K.
Published: April 2006

Background

The exclusion of oats from the diet in coeliac disease is controversial.

Aim

To study the long‐term safety of oats in the treatment of children with coeliac disease.

Methods

Altogether 32 children with coeliac disease were enrolled in a 2‐year controlled trial. Twenty‐three children in remission were randomized either to oats or gluten challenge; when small bowel histological relapse was evident after gluten challenge, a gluten‐free diet including oats was started. Furthermore, nine newly detected coeliac patients adopted an oat‐containing gluten‐free diet. Small bowel mucosal morphology, CD3+, αβ+ and γδ+ intraepithelial lymphocytes, human leucocyte antigen (HLA) DR expression and coeliac serology were determined. After the trial, the children were allowed to eat oats freely; follow‐up was extended up to 7 years.

Results

In coeliac children in remission, oats had no detrimental effect on intestinal histology or serology during the 2‐year trial. In contrast, the gluten‐challenge group relapsed after 3–12 months. Complete recovery from the disease was accomplished in all relapsed and newly detected patients on an oat‐containing gluten‐free diet. After the trial, 86% of the children preferred to consume oats and they all remained in remission.

Conclusion

In most children with coeliac disease, long‐term consumption of oats is well tolerated, and it does not result in small bowel mucosal deterioration or immune activation.
A Phase II dose ranging, double‐blind, placebo‐controlled study of alicaforsen enema in subjects with acute exacerbation of mild to moderate left‐sided ulcerative colitis
Authors: VAN DEVENTER S. J. H. , WEDEL M. K. , BAKER B. F. , XIA S. , CHUANG E. , MINER P. B.
Published: April 2006

Background

Alicaforsen is an antisense oligonucleotide designed to inhibit expression of human intercellular adhesion molecule 1. Previous clinical studies have demonstrated activity of alicaforsen enema in ulcerative colitis and pouchitis.

Aim

To determine the minimally effective dosing regimen of alicaforsen enema in subjects with mild to moderate left‐sided ulcerative colitis.

Methods

Randomized, placebo‐controlled, double‐blind, two‐dose ranging multicentre study. One hundred and twelve subjects were equally randomized to receive one of four alicaforsen enema regimens or placebo daily for 6 weeks. Primary end point was Disease Activity Index at week 6. Secondary end points included evaluation of clinical improvement, relapse rates and durability of response. Analysis of data were performed on the intent‐to‐treat population.

Results

No significant difference was observed between treatment arms and placebo in the primary end point. A prolonged reduction in mean% Disease Activity Index relative to baseline was observed in the daily 240 mg alicaforsen enema treatment arm in comparison with placebo from week 18 (51% vs. 18%, P = 0.04) to week 30 (50% vs. 11%, P = 0.03).

Conclusions

Alicaforsen enema was safe and well tolerated at all doses studied. The durability of the response to alicaforsen enema treatment may suggests a disease‐modifying effect.
Sub‐optimal proton pump inhibitor dosing is prevalent in patients with poorly controlled gastro‐oesophageal reflux disease
Authors: GUNARATNAM N. T. , JESSUP T. P. , INADOMI J. , LASCEWSKI D. P.
Published: April 2006

Background

Proton pump inhibitors are the most potent drug treatment for gastro‐oesophageal reflux disease. Premeal dosing maximizes efficacy while sub‐optimal dose timing may limit efficacy.

Aim

To determine the prevalence of sub‐optimal proton pump inhibitor dosing in a community‐based gastro‐oesophageal reflux disease population.

Materials and methods

One hundred patients on proton pump inhibitors referred for persistent gastro‐oesophageal reflux disease symptoms were questioned about their proton pump inhibitor dosing habits and classified as optimal or sub‐optimal dosers. Optimal dosers took proton pump inhibitors with or up to 60 min before meals. Sub‐optimal dosers took proton pump inhibitors >60 min before meals, after meals, as needed, or at bedtime.

Results

Forty‐six percent dosed optimally. Fifty‐four percent dosed sub‐optimally with 21 of 54 (39%) dosing >60 min before meals, 16 (30%) after meals, 15 (28%) at bedtime and two (4%) as needed. Only 6% of the subjects on once‐daily proton pump inhibitor regimens and 33% of subjects taking proton pump inhibitors two‐ to three times daily dosed in a manner that maximized acid suppression (15–30 min before a meal).

Conclusions

In this study, 54% of patients dosed proton pump inhibitors sub‐optimally and only 12% dosed in a manner that maximized acid suppression. As sub‐optimal proton pump inhibitor dose timing can limit efficacy, patients with refractory symptoms should be asked about dose timing to avoid inappropriate and costly dose escalations.
Increased intestinal permeability and NOD2 variants in familial and sporadic Crohn's disease
Authors: D'INCÀ R. , ANNESE V. , DI LEO V. , LATIANO A. , QUAINO V. , ABAZIA C. , VETTORATO M. G. , STURNIOLO G. C.
Published: April 2006

Background

Abnormal barrier function may be genetically determined in Crohn's disease.

Aim

To examine the role of abnormal intestinal permeability in genetic predisposition in multiplex vs. sporadic Crohn's disease families.

Methods

Intestinal permeability was measured in patients, relatives and partners by means of lactulose/mannitol test. Healthy subjects from the hospital staff served as controls. CARD15 mutations were investigated in sporadic and familial Crohn's disease patients and in a group of blood donors.

Results

The median lactulose/mannitol ratio was increased significantly in Crohn's disease patients vs. their relatives [0.03 (0.01–0.24) vs. 0.01 (0.003–0.19), P = 0.005]. The percentage of abnormal tests was significantly higher in familial vs. sporadic first‐degree relatives of Crohn's disease patients (29% vs. 11%, P = 0.0281). Abnormal permeability occurred significantly more frequent in patients with familial Crohn's disease carrying the frameshift mutation. The frameshift mutation 3020insC was associated with increased permeability in 75% in the multiplex and in 61% of the sporadic CD patients. One partner had abnormal lactulose/mannitol ratio.

Conclusion

Intestinal permeability is raised in Crohn's disease patients and relatives, with higher rates in familial vs. sporadic healthy relatives. CARD15 mutations are associated with abnormal permeability in ileal Crohn's disease.
Systemic eosinophil response induced by respiratory syncytial virus
Authors: Lindemans C A , Kimpen J L L , Luijk B , Heidema J , Kanters D , Van Der Ent C K , Koenderman L
Published: April 2006

Respiratory syncytial virus (RSV) is a common cause of lower respiratory tract disease (LRTD) in infants. Eosinophils have been suggested to play a role in the disease pathogenesis of LRTD. Inflammation can induce functional and morphological alterations of peripheral blood granulocytes. In patients with RSV LRTD, we aimed to investigate the eosinophil activation status by analysing surface markers. In vitro stimulation of eosinophils with cytokines leads to up-regulation of CD11b and priming markers recognized by the recently developed priming markers A17 and A27, whereas interleukin (IL)-5Rα is being down-regulated. In 51 patients and 10 controls we examined the expression of these surface markers on eosinophils in moderate to severe RSV-induced LRTD patients at the time of admission and 6 weeks later during the convalescence phase. RSV-patients were characterized by a higher eosinophil CD11b expression compared to controls. Although basal A17 and A27 expression was not increased, we observed a significantly higher expression of these priming epitopes on N-formyl-methionyl-leucyl-phenylalanine (fMLP)-stimulated cells of RSV patients compared with cells of controls, indicative of prior in vivo priming. Furthermore, IL-5Rα expression was down-regulated on peripheral blood eosinophils of these patients. Follow-up blood samples showed normalization of all markers but CD11b, which was persistently increased. Utilizing cellular markers, we observed that peripheral blood eosinophils from infants with RSV LRTD are in a more activated state compared to eosinophils of controls, which normalizes only partially during convalescence.
Polyclonal expansion of large granular lymphocytes in common variable immunodeficiency − association with neutropenia
Authors: Holm A M , Tjønnfjord G , Yndestad A , Beiske K , Müller F , Aukrust P , Frøland S S
Published: April 2006

Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency disease, characterized by low levels of circulating immunoglobulins and recurrent bacterial infections, particularly of the respiratory tract. T cell dysfunction is often present, and lymphoproliferative and autoimmune disorders as well as haematological cytopenias are frequently observed. In this study, we report a polyclonal expansion of large granular lymphocytes (LGL) in a substantial proportion of CVID patients, associated with splenomegaly, increased numbers of CD8+ T cells, inverted CD4 : CD8 T cell ratios and neutropenia. CVID patients who had both increased numbers of LGL and granulocytopenia had elevated levels of soluble Fas ligand (sFasL). Our observations indicate that CVID may be added to the list of inflammatory diseases associated with increased numbers of LGL. Furthermore, our findings suggest common pathogenic mechanisms of granulocytopenia in CVID and lymphoproliferative disease of granular lymphocytes.
The relationship between the first Fresnel zone and the normalized geometrical spreading factor1
Authors: Sun Jianguo
Published: April 2006

Conventionally, the Fresnel zone and the geometrical spreading factor are investigated separately, because they belong to different theories of wave propagation. However, if the paraxial ray method is used for establishing the Fresnel–Kirchhoff diffraction formula for a laterally inhomogeneous multilayered medium, it can be shown that the normalized geometrical spreading factor is inversely proportional to the area of the first Fresnel zone associated with the reflection point. Therefore, if no diffracting edge cuts the first Fresnel zone, the geometrical optics approximation represents the principal part of the wavefield obtained by Fresnel–Kirchhoff diffraction theory. Otherwise, the geometrical optics approximation has to be corrected by adding edge diffractions. It is also shown that Kirchhoff‐type migration and geometrical spreading factor correction both reduce the first Fresnel zone to a zone with unit area.
Practical techniques for 3D resistivity surveys and data inversion1
Authors: Loke M.H. , Barker R.D.
Published: April 2006

Techniques to reduce the time needed to carry out 3D resistivity surveys with a moderate number (25 to 100) of electrodes and the computing time required to interpret the data have been developed. The electrodes in a 3D survey are normally arranged in a square grid and the pole‐pole array is used to make the potential measurements. The number of measurements required can be reduced to about one‐third of the maximum possible number without seriously degrading the resolution of the resulting inversion model by making measurements along the horizontal, vertical and 45° diagonal rows of electrodes passing through the current electrode. The smoothness‐constrained least‐squares inversion method is used for the data interpretation. The computing time required by this technique can be greatly reduced by using a homogeneous half‐space as the starting model so that the Jacobian matrix of partial derivatives can be calculated analytically. A quasi‐Newton updating method is then used to estimate the partial derivatives for subsequent iterations. This inversion technique has been tested on synthetic and field data where a satisfactory model is obtained using a modest amount of computer time. On an 80486DX2/66 microcomputer, it takes about 20 minutes to invert the data from a 7 by 7 electrode survey grid. using the techniques described below, 3D resistivity surveys and data inversion can be carried out using commercially available field equipment and an inexpensive microcomputer.
The magnetotelluric response over 2D media with resistivity frequency dispersion1
Authors: Mauriello P. , Patella D. , Siniscalchi A.
Published: April 2006

We investigate the magnetotelluric response of two‐dimensional bodies, characterized by the presence of low‐frequency dispersion phenomena of the electrical parameters. The Cole‐Cole dispersion model is assumed to represent the frequency dependence of the ‘impedivity’ complex function, defined as the inverse of Stoyer's ‘admittivity’ complex parameter. To simulate real geological situations, we consider three structural models, representing a sedimentary basin, a geothermal system and a magma chamber, assumed to be partially or totally dispersive. From a detailed study of the frequency and space behaviours of the magnetotelluric parameters, taking known non‐dispersive results as reference, we outline the main peculiarities of the local distortion effects, caused by the presence of dispersion in the target media. Finally, we discuss the interpretative errors which can be made by neglecting the dispersion phenomena. The apparent dispersion function, which was defined in a previous paper to describe similar effects in the one‐dimensional case, is again used as a reliable indicator of location, shape and spatial extent of the dispersive bodies. The general result of this study is a marked improvement in the resolution power of the magnetotelluric method.
Estimation of multivalued arrivals in 3D models using wavefront construction—Part I1
Authors: Vinje V. , Iversen E. , Åstebøl K. , Gjøystdal H.
Published: April 2006

A new 3D wavefield modelling approach based on dynamic ray tracing is presented. This approach is called wavefront construction, and it can be used in 3D models with constant or smoothly varying material properties (S‐ and P‐velocity and density) separated by smooth interfaces. Wavefronts consisting of rays arranged in a triangular network are propagated stepwise through the model. At each time step, the differences in a number of parameters are checked between each pair of rays on the wavefront. New rays are interpolated whenever this difference between pairs of rays exceeds some predefined maximum value. A controlled sampling of the wavefront at all time steps is thus obtained. Receivers are given multiple‐event values by interpolation when the wavefronts pass them. The strength of the wavefront construction method is that it is robust and efficient.
Part II: Tracing and interpolation1
Authors: Vinje V. , Iversen E. , Åstebøl K. , Gjøystdal H.
Published: April 2006

The numerical tracing of short ray segments and interpolation of new rays between these ray segments are central constituents of the wavefront construction method. In this paper the details of the ray tracing and ray‐interpolation procedures are described. The ray‐tracing procedure is based on classical ray theory (high‐frequency approximation) and it is both accurate and efficient. It is able to compute both kinematic and dynamic parameters at the endpoint of the ray segments, given the same set of parameters at the starting point of the ray. Taylor series are used to approximate the raypath so that the kinematic parameters (new position and new ray tangent) may be found, while a staggered finite‐difference approximation gives the dynamic parameters (geometrical spreading).

When divergence occurs in some parts of the wavefront, new rays are interpolated. The interpolation procedure uses the kinematic and dynamic parameters of two parent rays to estimate the initial parameters of a new ray on the wavefront between the two rays. Third‐order (cubic) interpolation is used for interpolation of position, ray tangent and take‐off vector from the source) while linear interpolation is used for the geometrical spreading parameters.