bluuebunny/crossref_metadata_2025 huggingface dataset:
The Role of CXCR4 in Maintaining Peripheral B Cell Compartments and Humoral Immunity
Authors: Nie Yuchun , Waite Janelle , Brewer Faraha , Sunshine Mary-Jean , Littman Dan R. , Zou Yong-Rui
Published: November 2004

The chemokine receptor CXCR4 is expressed in B cells at multiple stages of their development. CXCR4 function in humoral immunity has not been fully investigated. We have generated gene-targeted mice in which CXCR4 can be selectively inactivated in B cells and have shown that it is required for retention of B cell precursors in the bone marrow. CXCR4-deficient B cell precursors that migrated prematurely became localized in splenic follicles despite their unresponsiveness to CXCL13. Concomitantly, mature B cell populations were reduced in the splenic marginal zone and primary follicles, and in the peritoneal cavity in the mutant animals, as were T-independent antibody responses. In addition, aberrant B cell follicles formed ectopically in intestinal lamina propria around Peyer's patches. These findings establish an important role for CXCR4 in regulating homeostasis of B cell compartmentalization and humoral immunity.
NF-κB and the Immunoglobulin
κ
Gene Enhancer
Authors: Sen Ranjan
Published: November 2004

Enhancers regulate lineage choice and the developmental timing of antigen receptor gene rearrangements. The transcription factor NF-κB has been implicated as a key component of the recombination and transcription activation potential of the immunoglobulin κ chain gene intronic enhancer. Here, I discuss the implications of the new observation that an NF-κB binding site–mutated enhancer in the correct biological context does not appear to affect κgene expression.
Lysosomal Fusion Is Essential for the Retention of Trypanosoma cruzi Inside Host Cells
Authors: Andrade Luciana O. , Andrews Norma W.
Published: November 2004

Trypomastigotes, the highly motile infective forms of Trypanosoma cruzi, are capable of infecting several cell types. Invasion occurs either by direct recruitment and fusion of lysosomes at the plasma membrane, or through invagination of the plasma membrane followed by intracellular fusion with lysosomes. The lysosome-like parasitophorous vacuole is subsequently disrupted, releasing the parasites for replication in the cytosol. The role of this early residence within lysosomes in the intracellular cycle of T. cruzi has remained unclear. For several other cytosolic pathogens, survival inside host cells depends on an early escape from phagosomes before lysosomal fusion. Here, we show that when lysosome-mediated T. cruzi invasion is blocked through phosophoinositide 3-kinase inhibition, a significant fraction of the internalized parasites are not subsequently retained inside host cells for a productive infection. A direct correlation was observed between the lysosomal fusion rates after invasion and the intracellular retention of trypomastigotes. Thus, formation of a parasitophorous vacuole with lysosomal properties is essential for preventing these highly motile parasites from exiting host cells and for allowing completion of the intracellular life cycle.
Novel and therapeutic effect of caffeic acid and caffeic acid phenyl ester on hepatocarcinoma cells: complete regression of hepatoma growth and metastasis by dual mechanism
Authors: Chung Tae‐Wook , Moon Sung‐Kwon , Chang Young‐Chae , Ko Jeong‐Heon , Lee Young‐Choon , Cho Gun , Kim Soo‐Hyun , Kim Jong‐Guk , Kim Cheorl‐Ho
Published: November 2004

Our previous studies have clearly shown that the angiogenic enzymes, matrix metalloproteinase (MMP) ‐2/9, are directly involved in human hepatic tumorigenesis and metastasis and suggest that the MMP‐2/9 inhibitors, which have dual inhibitory activi¬ties on enzyme activity and transcription, represent the best candidates for achieving tumor regression. Many anti‐cancer drugs have strong cellular cytotoxicity and side effects, indicating that strong anti‐cancer drugs that have no or minimal cytotoxicity and side effects need to be developed. The specific aim of the present study was to develop powerful anti‐cancer drugs with specific tumor regression and anti‐metastatic potential having the dual inhibitory activities of specific MMP‐2 and ‐9 enzyme activities and gene transcription at the molecular level. Caffeic acid (CA), a strong and selective MMP‐9 activity and transcription inhibitor, was isolated from the plant Euonymus alatus and its derivative, caffeic acid phenethyl ester (CAPE), was synthesized. CA and CAPE selectively inhibited MMP‐2 and ‐9 but not ‐1, ‐3, ‐7, or cathepsin K. Treatment of HepG2 cells with CA (100 μg/mL) and CAPE (5 μg/mL) suppressed phorbol 12‐myristate 13‐acetate (PMA) ‐in¬duced MMP‐9 expression by inhibiting the function of NF‐κB, but not AP‐1. We confirmed that CA and CAPE suppressed the growth of HepG2 tumor xenografts in nude mice in vivo. The subcutaneous and oral administrations of CA and CAPE significantly reduced the liver metastasis. These results confirm the therapeutic potential of the compounds and suggest that the antimetastatic and anti‐tumor effects of CA and CAPE are mediated through the selective suppression of MMP‐9 enzyme activity and transcriptional down‐regulation by the dual inhibition of NF‐κB as well as MMP‐9 catalytic activity.—Chung, T.‐W., Moon, S.‐K., Chang, Y.‐C., Ko, J.‐H., Lee, Y.‐C., Cho, G., Kim, S.‐H., Kim, J.‐G., Kim, C.‐H. Novel and therapeutic effect of caffeic acid and caffeic acid phenyl ester on hepatocarcinoma cells: complete regression of hepatoma growth and metastasis by dual mechanism. FASEBJ. 18, 1670–1681 (2004)
The Promoter Targeting Sequence mediates epigenetically heritable transcription memory
Authors: Lin Qing , Chen Qi , Lin Lan , Zhou Jumin
Published: November 2004

Large gene complexes frequently use “specialized” DNA elements to ensure proper regulation of gene activities. The Promoter Targeting Sequence (PTS) from the Abdominal-B locus of the Drosophila Bithorax complex overcomes an insulator, and facilitates, yet restricts, distant enhancers to a single promoter. We found that this promoter-targeting activity is independent of an enhancer's tissue or temporal specificity, and can be remembered in all somatic cells in the absence of promoter activation. It requires an insulator for its establishment, but can be maintained by the PTS in the absence of an insulator. More importantly, the promoter-targeting activity can be remembered after the transgene is translocated to new chromosomal locations. These results suggest that promoter targeting is established independent of enhancer activity, and is maintained epigenetically throughout development and subsequent generations.
Pax3:Fkhr interferes with embryonic Pax3 and Pax7 function: implications for alveolar rhabdomyosarcoma cell of origin
Authors: Keller Charles , Hansen Mark S. , Coffin Cheryl M. , Capecchi Mario R.
Published: November 2004

To investigate the role of the translocation-associated gene Pax3:Fkhr in alveolar rhabdomyosarcomas, we generated a Cre-mediated conditional knock-in of Pax3:Fkhr into the mouse Pax3 locus. Exploring embryonic tumor cell origins, we replaced a Pax3 allele with Pax3:Fkhr throughout its expression domain, causing dominant-negative effects on Pax3 and paradoxical activation of the Pax3 target gene, c-Met. Ectopic neuroprogenitor cell proliferation also occurs. In contrast, activation later in embryogenesis in cells that express Pax7 results in viable animals with a postnatal growth defect and a moderately decreased Pax7+ muscle satellite cell pool, phenocopying Pax7 deficiency but remarkably not leading to tumors.
Mitochondrial fission proteins regulate programmed cell death in yeast
Authors: Fannjiang Yihru , Cheng Wen-Chih , Lee Sarah J. , Qi Bing , Pevsner Jonathan , McCaffery J. Michael , Hill R. Blake , Basañez Gorka , Hardwick J. Marie
Published: November 2004

The possibility that single-cell organisms undergo programmed cell death has been questioned in part because they lack several key components of the mammalian cell death machinery. However, yeast encode a homolog of human Drp1, a mitochondrial fission protein that was shown previously to promote mammalian cell death and the excessive mitochondrial fragmentation characteristic of apoptotic mammalian cells. In support of a primordial origin of programmed cell death involving mitochondria, we found that the Saccharomyces cerevisiae homolog of human Drp1, Dnm1, promotes mitochondrial fragmentation/degradation and cell death following treatment with several death stimuli. Two Dnm1-interacting factors also regulate yeast cell death. The WD40 repeat protein Mdv1/Net2 promotes cell death, consistent with its role in mitochondrial fission. In contrast to its fission function in healthy cells, Fis1 unexpectedly inhibits Dnm1-mediated mitochondrial fission and cysteine protease-dependent cell death in yeast. Furthermore, the ability of yeast Fis1 to inhibit mitochondrial fission and cell death can be functionally replaced by human Bcl-2 and Bcl-xL. Together, these findings indicate that yeast and mammalian cells have a conserved programmed death pathway regulated by a common molecular component, Drp1/Dnm1, that is inhibited by a Bcl-2-like function.
Global analysis of transcript and protein levels across the Plasmodium falciparum life cycle
Authors: Le Roch Karine G. , Johnson Jeffrey R. , Florens Laurence , Zhou Yingyao , Santrosyan Andrey , Grainger Munira , Yan S. Frank , Williamson Kim C. , Holder Anthony A. , Carucci Daniel J. , Yates John R. , Winzeler Elizabeth A.
Published: November 2004

To investigate the role of post-transcriptional controls in the regulation of protein expression for the malaria parasite, Plasmodium falciparum, we have compared mRNA transcript and protein abundance levels for seven different stages of the parasite life cycle. A moderately high positive relationship between mRNA and protein abundance was observed for these stages; the most common discrepancy was a delay between mRNA and protein accumulation. Potentially post-transcriptionally regulated genes are identified, and families of functionally related genes were observed to share similar patterns of mRNA and protein accumulation.
The human L1 promoter: Variable transcription initiation sites and a major impact of upstream flanking sequence on promoter activity
Authors: Lavie Laurence , Maldener Esther , Brouha Brook , Meese Eckart U. , Mayer Jens
Published: November 2004

Human L1 elements are non-LTR retrotransposons that comprise ∼17% of the human genome. Their 5′-untranslated region (5′-UTR) serves as a promoter for L1 transcription. Now we find that transcription initiation sites are not restricted to nucleotide +1 but vary considerably in both downstream and upstream directions. Transcription initiating upstream explains additional nucleotides often seen between the 5′-target site duplication and the L1 start site. A higher frequency of G nucleotides observed upstream from the L1 can be explained by reverse transcription of the L1 RNA 5′-CAP, which is further supported by extra Gs seen for full-length HERV-W pseudogenes. We assayed 5′-UTR promoter activities for several full-length human L1 elements, and found that upstream flanking cellular sequences strongly influence the L1 5′-UTR promoter. These sequences either repress or enhance the L1 promoter activity. Therefore, the evolutionary success of a human L1 in producing progeny depends not only on the L1 itself, but also on its genomic integration site. The promoter mechanism of L1 is reminiscent of initiator (Inr) elements that are TATA-less promoters expressing several cellular genes. We suggest that the L1 5′-UTR is able to form an Inr element that reaches into upstream flanking sequence.
Serial segmental duplications during primate evolution result in complex human genome architecture
Authors: Stankiewicz Paweł , Shaw Christine J. , Withers Marjorie , Inoue Ken , Lupski James R.
Published: November 2004

The human genome is particularly rich in low-copy repeats (LCRs) or segmental duplications (5%–10%), and this characteristic likely distinguishes us from lower mammals such as rodents. How and why the complex human genome architecture consisting of multiple LCRs has evolved remains an open question. Using molecular and computational analyses of human and primate genomic regions, we analyzed the structure and evolution of LCRs that resulted in complex architectural features of the human genome in proximal 17p. We found that multiple LCRs of different origins are situated adjacent to one another, whereas each LCR changed at different time points between >25 to 3–7 million years ago (Mya) during primate evolution. Evolutionary studies in primates suggested communication between the LCRs by gene conversion. The DNA transposable element MER1-Charlie3 and retroviral ERVL elements were identified at the breakpoint of the t(4;19) chromosome translocation in Gorilla gorilla, suggesting a potential role for transpositions in evolution of the primate genome. Thus, a series of consecutive segmental duplication events during primate evolution resulted in complex genome architecture in proximal 17p. Some of the more recent events led to the formation of novel genes that in human are expressed primarily in the brain. Our observations support the contention that serial segmental duplication events might have orchestrated primate evolution by the generation of novel fusion/fission genes as well as potentially by genomic inversions associated with decreased recombination rates facilitating gene divergence.
Multiple Genetic Processes Result in Heterogeneous Rates of Evolution within the Major Cluster Disease Resistance Genes in Lettuce[W]
Authors: Kuang Hanhui , Woo Sung-Sick , Meyers Blake C. , Nevo Eviatar , Michelmore Richard W.
Published: November 2004

Resistance Gene Candidate2 (RGC2) genes belong to a large, highly duplicated family of nucleotide binding site–leucine rich repeat (NBS-LRR) encoding disease resistance genes located at a single locus in lettuce (Lactuca sativa). To investigate the genetic events occurring during the evolution of this locus, ∼1.5- to 2-kb 3′ fragments of 126 RGC2 genes from seven genotypes were sequenced from three species of Lactuca, and 107 additional RGC2 sequences were obtained from 40 wild accessions of Lactuca spp. The copy number of RGC2 genes varied from 12 to 32 per genome in the seven genotypes studied extensively. LRR number varied from 40 to 47; most of this variation had resulted from 13 events duplicating two to five LRRs because of unequal crossing-over within or between RGC2 genes at one of two recombination hot spots. Two types of RGC2 genes (Type I and Type II) were initially distinguished based on the pattern of sequence identities between their 3′ regions. The existence of two types of RGC2 genes was further supported by intron similarities, the frequency of sequence exchange, and their prevalence in natural populations. Type I genes are extensive chimeras caused by frequent sequence exchanges. Frequent sequence exchanges between Type I genes homogenized intron sequences, but not coding sequences, and obscured allelic/orthologous relationships. Sequencing of Type I genes from additional wild accessions confirmed the high frequency of sequence exchange and the presence of numerous chimeric RGC2 genes in nature. Unlike Type I genes, Type II genes exhibited infrequent sequence exchange between paralogous sequences. Type II genes from different genotype/species within the genus Lactuca showed obvious allelic/orthologous relationships. Trans-specific polymorphism was observed for different groups of orthologs, suggesting balancing selection. Unequal crossover, insertion/deletion, and point mutation events were distributed unequally through the gene. Different evolutionary forces have impacted different parts of the LRR.
Relative effects of nest size and site on the risk of predation in open nesting passerines
Authors: Weidinger Karel
Published: November 2004

Large nests may incur fitness cost in terms of conspicuousness to predators, but the effect of nest size on predation risk can be confounded by effects of nest site and parental characteristics. I examined relative effects of nest size and placement by experimentally exchanging subsets of inactive nests baited with artificial clutches, among three open‐cup nesting passerine species characterized by different nest size, placement and predation rate. The prediction that increasing nest size (original nest replaced by nest of the larger species) would increase predation, while decreasing nest size (replacement by nest of the smaller species) would decrease predation, relative to control (replacement by conspecific nest) was not supported in any species. The prediction that predation should be higher for large nests compared to small ones, even after exchanging nests among species‐specific sites, was not supported. Predation rate differed among species (combined site/nest effect) before manipulation, whereas only the effect of nest site was significant after manipulation. This means that predation differed between species‐specific nest sites, irrespective of the nest placed at these sites, but not between large (thrush) and small (warbler) nests, irrespective of their placement. Results do not suggest that nest predation selects directionally for smaller nest size. This conclusion could be specific to the study system characterized by high nest densities and high predation rate.
Effects of experimentally increased egg production on female body condition and laying dates in the great skua Stercorarius skua
Authors: Kalmbach Ellen , Griffiths Richard , Crane Jonathan E. , Furness Robert W.
Published: November 2004

We investigated the effects of increased egg production on body condition as well as on measures of reproductive performance in great skuas, Stercorarius skua, over two subsequent years. We experimentally increased egg production from the normal two to six eggs. Six eggs might also be produced under natural circumstances after repeated clutch loss. After the production of the last egg we measured: (i) body mass, (ii) pectoral muscle, and (iii) haematocrit, total red blood cell count and mean corpuscular volume, as indicators of body condition. We took the same measurements of control females who had produced the normal clutch of two eggs. The measurements were repeated one year after the manipulation, and survival, laying dates, clutch sizes and hatching success were recorded for up to three consecutive years. After producing six eggs, females were lighter, had smaller pectoral muscles and lower haematological values than control females. Hatching success of eggs was significantly reduced. Even one year after the experiment there were still differences in body condition. Annual survival was not affected by the manipulations, although there was an indication that survival costs depended on whether chicks were raised after the increased egg production. While pair bonds and egg sizes were not affected in the post‐experimental year, females started breeding significantly later than in the previous year. Two years after the experiment laying dates had advanced again and were not different from those of control females. This pattern of maintaining survival and egg sizes, but delaying breeding in the post‐experimental year was found for two independent groups of females which had both been subjected to increased egg production. These results present evidence that increased egg production can have long‐term effects on female body condition and aspects of reproduction. However, although present, the costs of extra eggs appear to have been relatively small in the great skua in comparison to the two other bird species for which inter‐annual effects have been reported.
Nest cavity orientation in black‐capped chickadees Poecile atricapillus: do the acoustic properties of cavities influence sound reception in the nest and extra‐pair matings?
Authors: Mennill Daniel J. , Ratcliffe Laurene M.
Published: November 2004

Birds that nest in cavities may regulate nest microclimate by orienting their nest entrance relative to the sun or prevailing winds. Alternatively, birds may orient their nest entrance relative to conspecific individuals around them, especially if the acoustic properties of cavities permit nesting birds to better hear individuals in front of their nest. We measured the cavity entrance orientation of 132 nests and 234 excavations in a colour‐banded population of black‐capped chickadees Poecile atricapillus for which the reproductive behaviour of nesting females was known. Most chickadees excavated cavities in rotten birch Betula papyrifera, aspen Populus tremuloides and maple Acer saccharum. Nest cavities showed random compass orientation around 360° demonstrating that chickadees do not orient their cavities relative to the sun or prevailing winds. We also presented chickadees with nest boxes arranged in groups of four, oriented at 90° intervals around the same tree. Nests constructed in these nest box quartets also showed random compass orientation. To test the acoustic properties of nest cavities, we conducted a sound transmission experiment using a microphone mounted inside a chickadee nest. Re‐recorded songs demonstrate that chickadee nest cavities have directional acoustic properties; songs recorded with the cavity entrance oriented towards the loudspeaker were louder than songs recorded with the cavity entrance oriented away from the loudspeaker. Thus, female chickadees, who roost inside their nest cavity in the early morning during their fertile period, should be better able to hear males singing the dawn chorus in front of their nest cavity. Using GIS analyses we tested for angular‐angular correlation between actual nest cavity orientation and the azimuth from the nest tree to the territories and nest cavities of nearby males. In general, nest cavity entrances showed no angular‐angular correlation with neighbourhood territory features. However, among birds who followed a mixed reproductive strategy and nested in the soft wood of birch and aspen trees, nest cavity entrances were oriented towards their extra‐pair partners. We conclude that nest cavity orientation in birds may be influenced by both ecological and social factors.
Male song sparrows Melospiza melodia do not announce their female's fertility
Authors: Turner Wendy C. , Barber Colleen A.
Published: November 2004

We tested the fertility announcement hypothesis, whereby male song during a female's fertile period functions as both a paternity guard and an advertisement for extra‐pair copulations, in an eastern population of song sparrows Melospiza melodia over two broods within a breeding season. Our results did not support one of its main predictions: male song rate was not significantly higher in the female's fertile period than in her post‐fertile period. Song rate peaked prior to pairing, when males were establishing territories and trying to attract females. Once paired, song rate dropped by a factor of about ten, and was consistently low through all stages of the nesting cycle. Males who failed to pair continued singing at high rates throughout the breeding season. Our results do not support the fertility announcement hypothesis, therefore song rate is not used primarily as a paternity assurance strategy by song sparrows.
Colorful songbirds metabolize carotenoids at the integument
Authors: McGraw Kevin J.
Published: November 2004

For decades, carotenoids have attracted attention for their roles as vitamin‐A precursors, antioxidants, and immunostimulants, but we still understand very little about the metabolic processes that accompany these compounds. Animals like birds use carotenoids to color their feathers and bare parts to become sexually attractive. They commonly metabolically derive their body colorants from dietary sources of carotenoids, but the sites of pigment metabolism remain unidentified. Here I test the hypothesis that songbirds manufacture their colorful feather and beak carotenoids directly at these tissues. I offer two lines of evidence to support this idea: (1) in a study of 11 colorful species from three passerine families, metabolically derived feather and beak carotenoids were found neither in the liver (a purported site of carotenoid metabolism), nor in the bloodstream (the means by which metabolites would be transported to colorful tissues from anywhere else in the body) at the time when pigments were being deposited into keratinized tissue, and (2) in a more detailed study of pigmentation in the American goldfinch Carduelis tristis, carotenoids sampled from the lipid fractions of maturing feather follicles yielded a mix of dietary and synthetic carotenoids, suggesting that this is the metabolically active site for feather‐pigment production. This fresh perspective on carotenoid metabolism in animals should aid our efforts to characterize the responsible enzymes and to better understand the localized biological functions of these pigments.
A prospective, randomized‐controlled pilot study of ursodeoxycholic acid combined with mycophenolate mofetil in the treatment of primary sclerosing cholangitis
Authors: Sterling R. K. , Salvatori J. J. , Luketic V. A. , Sanyal A. J. , Fulcher A. S. , Stravitz R. T. , Contos M. J. , Mills A. S. , Shiffman M. L.
Published: November 2004

Background : Ursodeoxycholic acid has been ineffective in the treatment of primary sclerosing cholangitis. Because the pathogenesis of primary sclerosing cholangitis is related to immune destruction of bile duct epithelium, several immune suppressive agents have been evaluated. Mycophenolate mofetil is a potent immunosuppressant that is now widely used in organ transplantation.

Aim : In this pilot study to determine if mycophenolate mofetil when combined with ursodeoxycholic acid could prevent evidence of clinical progression and improve the biochemical, histological and/or cholangiographic features of primary sclerosing cholangitis compared with patients treated with ursodeoxycholic acid alone.

Methods : Twenty‐five patients with well‐defined primary sclerosing cholangitis were randomized to ursodeoxycholic acid (13–15 mg/kg/day) with or without mycophenolate mofetil (1000 mg b.d.). Cholangiography and liver biopsy were performed at study entry and after 2 years of treatment. Symptoms, clinical features of liver disease and biochemical tests were monitored at 3‐month intervals.

Results : The mean age 44 years, 58% male, 84% Caucasian and 64% had ulcerative colitis. After 2 years, there were no differences in laboratory values, histological stage or cholangiograms between patients treated with ursodeoxycholic acid alone and those treated with mycophenolate mofetil + ursodeoxycholic acid.

Conclusions : Mycophenolate mofetil combined with ursodeoxycholic acid does not appear to provide additional benefit compared with standard doses of ursodeoxycholic acid alone in the treatment of primary sclerosing cholangitis.
A single dose of ranitidine 150 mg modulates oesophageal acid sensitivity in patients with functional heartburn
Authors: Rodriguez‐Stanley S. , Ciociola A. A. , Zubaidi S. , Proskin H. M. , Miner P. B.
Published: November 2004

Background : The rapid onset and symptomatic response to histamine‐2 receptor antagonists prior to the pharmacological effect on acid secretion suggests a different mechanism of action.

Aim : To determine if ranitidine decreases oesophageal sensitivity to chemical and mechanical stimulation, potentially via oesophageal histamine receptors.

Methods : A total of 18 patients with functional heartburn received oral ranitidine 150 mg b.d. or placebo for 7 consecutive days in a double‐blind randomized crossover design and underwent Barostat balloon distention and Bernstein acid infusion on study day 1 (90 min postdose) and study day 7. First sensation and pain were recorded and pain severity was rated on a 5‐point Likert scale and a 100 mm visual analogue scale. Least square mean values were generated and one‐tailed t‐tests were performed.

Results : After a single dose of ranitidine 150 mg, time to pain with oesophageal acid infusion was increased by 29% (P < 0.05) and visual analogue scale and Likert scores were decreased by 20% (P < 0.06) and 23% (P < 0.02), respectively compared with placebo. After 1 week of ranitidine, positive alterations in sensory parameters persisted. Balloon distention sensory parameters were not altered by ranitidine.

Conclusions : Ranitidine significantly decreased oesophageal sensitivity to acid. Failure of ranitidine to improve balloon sensory parameters supports existence of multiple sensory pathways in the oesophagus.
Behaviour of the bowel wall during the first year after surgery is a strong predictor of symptomatic recurrence of Crohn's disease: a prospective study
Authors: Parente F. , Sampietro G. M. , Molteni M. , Greco S. , Anderloni A. , Sposito C. , Danelli P. G. , Taschieri A. M. , Gallus S. , Bianchi Porro G.
Published: November 2004

Background : Recurrences after surgery for Crohn's disease are frequent and unpredictable. To date, there is little agreement as to which factors increase a patient risk of early recurrence.

Aim : To assess whether the post‐operative behaviour of diseased bowel walls, as determined by ultrasound, may be a useful predictor of relapse.

Methods : A total of 127 Crohn's disease patients were monitored after surgery by means of bowel ultrasound as well as by clinical and laboratory evaluations for a median follow‐up of 41.0 months. Bowel wall thickness of diseased loops measured at ultrasound during follow‐up was compared with the presurgery values. Multivariable survival analysis was performed to elucidate predictors of early post‐operative recurrence. Receiver operating characteristic curves were also constructed taking into account bowel wall thickness for selecting Crohn's disease patients with high risk of clinical/surgical recurrence.

Results : The estimated 5 years survival probability of symptomatic Crohn's disease recurrence were 90% and 33%, respectively for unchanged/worsened bowel wall thickness vs. improved bowel wall thickness at 12 months from surgery. The hazard ratio for unchanged/worsened bowel wall thickness at 12 months was 8.9 (95% CI: 3.4–23.2). Receiver operating characteristic curve identified a bowel wall thickness > 6.0 mm at 12 months from surgery as directly associated with the risk of having a Crohn's disease recurrence (hazard ratio was 6.5, 95% CI: 2.8–15.4).

Conclusions : Systematic ultrasound follow‐up of diseased bowel walls after conservative surgery allows the early identification of patients at high risk of clinical/surgical recurrence.
Evaluation of the clinical value of pharmacists’ modifications of prescription errors
Authors: Buurma Henk , De Smet Peter A. G. M. , Leufkens Hubert G. M. , Egberts Antoine C. G.
Published: November 2004

Aims

Our objective was to examine the clinical value of pharmacists’ interventions to correct prescription errors.

Methods

In this study, we reviewed a random sample of prescriptions that had been modified in pharmacies. These prescriptions were collected on one predetermined day between 25th February and 12th March 1999 from 141 Dutch community pharmacies. Each prescription modification was evaluated by a panel of reviewers, including representatives of five groups of health care professionals. After generally rating each modification as positive, negative, or neutral, the reviewers assessed its outcome (in terms of prevention of an adverse drug reaction [ADR], an improvement in effectiveness, both, or other), the probability and importance of improvements in effectiveness and/or the probability and seriousness of an ADR in the case of a nonintervention. Our analyses included 144 interventions from the first general assessment and a selection of 90 consistently rated ‘positive’ interventions (from all assessments).

Results

On average, one in 200 prescriptions (0.49%) was found to have been positively modified by Dutch community pharmacists. About half of these interventions (49.8%) were aimed at preventing ADRs; 29.2% were rated as a positive modification in the effectiveness of pharmacotherapy and 8.6% affected both effectiveness and ADR. Reviewers’ ratings varied widely between different categories of drug‐related problems (DRPs). The impact of individual interventions (n = 83) varied, and for 53% of these interventions it was estimated to be relatively high.

Conclusions

Pharmacists’ interventions led to modification of prescriptions for an array of DRPs. Such interventions can contribute positively to the quality of pharmacotherapy. By extrapolating our data, we estimated a daily occurrence of approximately 2700 positive interventions in all Dutch pharmacies (1.6 per pharmacy per day). Reviewers rated the impact of interventions on a patient's health as significant in a substantial number of cases.
Effect of oral linezolid on the pressor response to intravenous tyramine
Authors: Cantarini Mireille V. , Painter Catherine J. , Gilmore Elaine M. , Bolger Catherine , Watkins Claire L. , Hughes Andrew M.
Published: November 2004

Aims

To investigate the effect of monoamine oxidase A inhibition from a single oral dose of linezolid on the pressor response to intravenous (i.v.) tyramine, using positive and negative controls to validate the methodology.

Methods

This placebo‐controlled, three‐period crossover study was conducted in 12 healthy male volunteers. Each volunteer received either one oral dose of moclobemide (300 mg), linezolid (600 mg), or placebo tablet followed by an i.v. tyramine pressor test until an increase in systolic blood pressure of at least 30 mmHg above baseline occurred. Each study day was separated by a 7‐day washout period. The dose of tyramine required to raise the blood pressure by 30 mmHg (TYR30) was calculated for each oral treatment by linear interpolation between log‐transformed doses of i.v. tyramine. The influence of body mass index (BMI) on TYR30 was also investigated.

Results

The tyramine sensitivity factor (ratio of the geometric least square mean TYR30 for placebo and active oral treatment) was 1.8 [90% confidence interval (CI) 1.6, 2.0, P < 0.0001] for linezolid and 2.1 (90% CI 1.8, 2.4, P < 0.0001) for the positive control moclobemide. BMI had a statistically significant effect on TYR30.

Conclusions

There was a significant difference in the pressor response to i.v. tyramine between linezolid and placebo. Moclobemide (positive control) and linezolid have a similar pressor response to i.v. tyramine. The statistically significant effect of BMI on TYR30 underlines the advantage of within‐individual comparisons of treatments in order to reduce variability and provide more accurate treatment estimates.
Association between adherence to statin therapy and lipid control in Hong Kong Chinese patients at high risk of coronary heart disease
Authors: Cheng Caroline W. R. , Woo Kam‐sang , Chan Juliana C. N. , Tomlinson Brian , You Joyce H. S.
Published: November 2004

Aims

To examine the pattern of adherence to statin therapy and to determine the association of adherence to statin therapy and the control of serum low‐density lipoprotein (LDL)‐cholesterol in a cohort of Hong Kong Chinese patients at high risk of coronary heart disease (CHD).

Methods

This was a prospective observational cohort study conducted at the outpatient clinics of a public teaching hospital in Hong Kong. Patients at high risk of CHD who had been initiated on statin monotherapy for < 12 months were recruited. The statin prescription was dispensed in a bottle with the Medication Event Monitoring System (MEMS). Adherence was assessed in two dimensions: dose‐count was defined as the percentage of doses taken, and dose‐time was defined as the percentage of doses taken within the suggested time interval. Lipid profiles were obtained at baseline and during two follow‐up visits at month 3 and month 6.

Results

Eighty‐three patients completed the study. The median adherence to dose‐count and to dose‐time were 95% (25‐75th percentile = 87–99%) and 78% (25–75th percentile = 17–92%), respectively. Both dose‐count and dose‐time adherence declined slightly over the first 6 months of therapy. Living with family [relative risk (RR) = 0.79, 95% confidence interval (CI) 0.63, 0.91] and duration of therapy (RR = 0.99, 95% CI 0.98, 1.00) were negative predictors while number of family members (among those living with family) (RR = 1.05, 95% CI 1.00, 1.08) was a positive predictor for adherence to dose‐count. Monthly household income (RR = 1.01, 95% CI 1.00, 1.02) and angina (RR = 1.29, 95% CI 1.05, 1.58) were positive predictors while living with family (RR = 0.74, 95% CI 0.55, 0.90) was a negative predictor for dose‐time adherence. Percent reduction in serum LDL‐cholesterol was correlated to dose‐count (P < 0.001) and dose‐time (P = 0.047) adherence. Statistically significant correlations were observed between adherence to dose‐count and LDL reduction (R2 = 0.130; P = 0.001), and between dose‐time adherence and LDL reduction (R2 = 0.048; P = 0.047).

Conclusion

High adherence to statin therapy was found in a cohort of Chinese patients at high risk of CHD and the adherence declined slightly over time. A weak association between adherence to statin dose‐count and LDL reduction and a marginal association between dose‐time adherence and LDL reduction were observed.
Effect of itraconazole on the pharmacokinetics and pharmacodynamics of a single oral dose of brotizolam
Authors: Osanai T. , Ohkubo T. , Yasui N. , Kondo T. , Kaneko S.
Published: November 2004

Aims

To assess the effect of itraconazole, a potent inhibitor of cytochrome P450 (CYP)3A4, on the single oral dose pharmacokinetics and pharmacodynamics of brotizolam.

Methods

In this randomized, double‐blind, cross‐over trial 10 healthy male subjects received either itraconazole 200 mg or matched placebo once daily for 4 days. On day 4, a single 0.5 mg dose of brotizolam was administered orally. Plasma concentrations of brotizolam were followed up to 24 h, together with assessment of psychomotor function measured by the digit symbol substitution test (DSST), visual analogue scales and UKU side‐effect rating scale.

Results

Itraconazole significantly (P < 0.001) decreased the apparent oral clearance (CL/F) (16.47 ± 4.3 vs 3.91 ± 2.1), increased the area under the concentration‐time curves (AUC) from 0 h to 24 h (28.37 ± 10.8 vs 68.71 ± 24.1 ng ml h−1), and prolonged the elimination half‐life (4.56 ± 1.4 vs 23.27 ± 10.3 h) of brotizolam. The AUC(0,24 h) of the DSST (P < 0.001) and the item ‘sleepiness’ of UKU (P < 0.05) were significantly decreased.

Conclusions

Itraconazole increases plasma concentrations of brotizolam probably via its inhibitory effect on CYP3A4 brotizolam metabolism.
Breast cancer resistance protein (BCRP/MXR/ABCG2) in adult acute lymphoblastic leukaemia: frequent expression and possible correlation with shorter disease‐free survival
Authors: Suvannasankha Attaya , Minderman Hans , O'Loughlin Kieran L. , Nakanishi Takeo , Ford Laurie A. , Greco William R. , Wetzler Meir , Ross Douglas D. , Baer Maria R.
Published: November 2004

Drugs used in treatment of adult acute lymphoblastic leukaemia (ALL) are substrates for breast cancer resistance protein (BCRP, MXR, ABCG2), which may thus play a role in resistance in this disease. Pretreatment blasts from 30 adult ALL patients were studied for BCRP mRNA by quantitative reverse transcription polymerase chain reaction analysis, BCRP protein by immunophenotyping with three antibodies and BCRP function by fumitremorgin C modulation of intracellular mitoxantrone retention, measured by flow cytometry. BCRP mRNA in all cases encoded wild type protein (BCRPR482), which mediates mitoxantrone and methotrexate resistance, but only low‐level anthracycline resistance. The BXP‐21, BXP‐34 and anti‐ABCG2 antibodies stained blasts in 13, 11 and 14 cases (43%, 37% and 47%); BXP‐21 correlated well with BXP‐34 and anti‐ABCG2, but BXP‐34 and anti‐ABCG2 did not correlate, and antibody staining did not correlate with mRNA levels. BCRP function was seen in 21 cases (70%), but correlated poorly with antibody staining. An exploratory statistical analysis indicated that BXP‐21 staining was predictive of shorter disease‐free survival (DFS) (P = 0·0374) in this small patient population. Poor correlations between mRNA, protein and function indicate the complex biology of BCRP in adult ALL, and the possible correlation of BCRP expression with DFS should be studied in larger series.
Erythropoietin treatment of the anaemia of myelofibrosis with myeloid metaplasia: results in 20 patients and review of the literature
Authors: Cervantes Francisco , Alvarez‐Larrán Alberto , Hernández‐Boluda Juan‐Carlos , Sureda Ana , Torrebadell Montserrat , Montserrat Emili
Published: November 2004

Recombinant human erythropoietin (rHuEPO) is an effective treatment for the anaemia that occurs secondary to various conditions, but its role in myelofibrosis with myeloid metaplasia (MMM) is not well established. rHuEPO, at an initial dose of 10 000 U thrice a week, was given to 20 patients with MMM and anaemia. Complete response (CR) was defined as transfusion cessation with normal haemoglobin (Hb) levels and partial response (PR) as a transfusion decrease ≥50% and Hb > 10 g/dl maintained for at least 8 weeks. Nine patients (45%) showed a favourable response to treatment, including four CR and five PR, four of whom have maintained their response at a median follow‐up of 12·5 months (range: 4–21 months) from the start of treatment. The pretreatment factors associated with a favourable response were lack of transfusion requirement (P = 0·002) and higher Hb at start treatment of (P = 0·01). An analysis of the present series (n = 20) and 31 patients from the literature identified 28 (55%) favourable responses to rHuEPO, including 16 CR and 12 PR. In the multivariate analysis, serum erythropoietin level <125 U/l was found to be associated with a favourable response to rHuEPO, whereas lack of transfusional support had borderline significance.
Maternal soluble tumour necrosis factor receptor type 2 (sTNFR2) and adiponectin are both related to blood pressure during gestation and infant's birthweight
Authors: López‐Bermejo A. , Fernández‐Real J. M. , Garrido E. , Rovira R. , Brichs R. , Genaró P. , Bach C. , Cabrero D. , Kihara S. , Funahashi T. , Vendrell J. , Ricart W.
Published: November 2004

objective  Tumour necrosis factor alpha (TNF‐α) and adiponectin are strongly related to insulin sensitivity; insulin resistance of pregnancy is a major determinant of infant's birthweight. We aimed to study the contributions of maternal serum concentrations of soluble TNF‐α receptors (sTNFR1 and sTNFR2) and adiponectin to infant's birthweight.

design  Cross‐sectional, hospital‐based study of insulin sensitivity during gestation.

patients  Fifty‐one healthy women with uncomplicated pregnancy and delivery (except for elective Caesarian section) and their healthy newborn infants.

measurements  Maternal blood levels of glucose, insulin, glycosylated haemaglobin (HbA1c), sTNFR1, sTNFR2 and adiponectin at delivery; cord‐blood levels of sTNFR1, sTNFR2 and adiponectin.

results  At delivery, maternal sTNFR2 correlated with systolic blood pressure (SBP; r = 0·38, P = 0·005). In multiple regression analyses, SBP and HbA1c were independent predictors of sTNFR2, explaining 18 and 7% of its variance, respectively; insulin resistance index (HOMA‐IR), body mass index at delivery and SBP were independent predictors of adiponectin, explaining 15, 8 and 7% of its variance, respectively. Both maternal sTNFR2 and SBP were negatively correlated with infant's birthweight (r = −0·28, P = 0·04 and r = −0·36, P = 0·01 respectively, adjusted for sex and gestational age). In multivariate regression analyses, infant's sex and either maternal sTNFR2 or adiponectin were independent predictors of infant's birthweight, each explaining between 6 and 9% of birthweight variance. Further addition of maternal SBP to these models revealed that this variable was the main predictor of infant's birthweight, explaining 13% of its variance.

conclusions  Maternal sTNFR2 and adiponectin are independently related to both maternal blood pressure and infant's birthweight in uncomplicated pregnancy. The contributions of the TNF‐α system and adiponectin to hypertensive disorders of pregnancy and fetal growth merit further studies.
Testosterone increases bone mineral density in female‐to‐male transsexuals: a case series of 15 subjects
Authors: Turner Adrian , Chen Tai C. , Barber Tom W. , Malabanan Alan O. , Holick Michael F. , Tangpricha Vin
Published: November 2004

objective  Testosterone therapy for osteoporosis has not been studied extensively in women because of its potential to cause virilization. Female‐to‐male transsexuals are genetic females who suffer from gender dysphoria and thus take supra‐physiologic doses of testosterone to change from the female to male phenotype. The aim of this study is to examine the effects of testosterone treatment on the genetic female skeleton.

patients and design  A group of 15 female‐to‐male transsexuals was prospectively enrolled for observation over a 2‐year period. The subjects had a mean age of 37·0 ± 3·0 years. All of the subjects self‐administered testosterone esters intramuscularly at a mean dose of 70·7 ± 4·5 mg weekly.

measurements  The subjects had measurements of bone mineral density (BMD) by dual X‐ray absorptiometry (DXA) of the femoral neck and spine (L2–L4) at 12‐month intervals. They had determinations of serum oestradiol, testosterone, soluble RANKL (sRANKL), osteoprotegerin (OPG) and urine N‐telopeptide (NTX) at the date of enrolment and at the end of 2 years.

results  There was a significant positive increase in mean BMD of 7·8% at the femoral neck and a nonsignificant increase in mean BMD of 3·1% at the spine over 2 years. The levels of testosterone reached the upper normal range for males and the levels of oestradiol declined to near the postmenopausal range. sRANKL levels decreased significantly in female‐to‐male transsexuals who newly initiated testosterone therapy. There was no significant change in urine NTX or serum OPG during the study.

conclusions  We conclude that supra‐physiologic testosterone therapy increases BMD at the hip while maintaining BMD at the spine in female‐to‐male transsexuals. The effects of testosterone may be the result of testosterone hormone directly acting on the bone or indirectly through aromatization to oestradiol. Lower RANKL levels coupled with unchanged OPG levels results in an increased OPG/RANKL ratio, which may be beneficial to the bone by inhibiting osteoclastogenesis.