bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of the coupling term in transient elastography
Authors: Sandrin Laurent , Cassereau Didier , Fink Mathias
Published: January 2004

The transient radiation of low-frequency elastic waves through isotropic and homogeneous soft media is investigated using the Green’s function approach. A careful analysis of the coupling term is performed and yields the introduction of a very near field region in which its amplitude behaves as 1/r. To address the calculation of impulse responses, a simplified Green’s function is proposed for semi-infinite media and compared to exact solutions. Impulse response calculations are successfully compared with experimental measurements obtained for circular radiators of different diameters using transient elastography. Results presented in this paper provide a better understanding of the role of the coupling term in elastography and should be used to compensate diffraction and coupling effects observed in transient elastography.
Vowel normalization for accent: An investigation of best exemplar locations in northern and southern British English sentences
Authors: Evans Bronwen G. , Iverson Paul
Published: January 2004

Two experiments investigated whether listeners change their vowel categorization decisions to adjust to different accents of British English. Listeners from different regions of England gave goodness ratings on synthesized vowels embedded in natural carrier sentences that were spoken with either a northern or southern English accent. A computer minimization algorithm adjusted F1, F2, F3, and duration on successive trials according to listeners’ goodness ratings, until the best exemplar of each vowel was found. The results demonstrated that most listeners adjusted their vowel categorization decisions based on the accent of the carrier sentence. The patterns of perceptual normalization were affected by individual differences in language background (e.g., whether the individuals grew up in the north or south of England), and were linked to the changes in production that speakers typically make due to sociolinguistic factors when living in multidialectal environments.
Acoustic properties of naturally produced clear speech at normal speaking rates
Authors: Krause Jean C. , Braida Louis D.
Published: January 2004

Sentences spoken “clearly” are significantly more intelligible than those spoken “conversationally” for hearing-impaired listeners in a variety of backgrounds [Picheny et al., J. Speech Hear. Res. 28, 96–103 (1985); Uchanski et al., ibid.  39, 494–509 (1996); Payton et al., J. Acoust. Soc. Am. 95, 1581–1592 (1994)]. While producing clear speech, however, talkers often reduce their speaking rate significantly [Picheny et al., J. Speech Hear. Res. 29, 434–446 (1986); Uchanski et al., ibid.  39, 494–509 (1996)]. Yet speaking slowly is not solely responsible for the intelligibility benefit of clear speech (over conversational speech), since a recent study [Krause and Braida, J. Acoust. Soc. Am. 112, 2165–2172 (2002)] showed that talkers can produce clear speech at normal rates with training. This finding suggests that clear speech has inherent acoustic properties, independent of rate, that contribute to improved intelligibility. Identifying these acoustic properties could lead to improved signal processing schemes for hearing aids. To gain insight into these acoustical properties, conversational and clear speech produced at normal speaking rates were analyzed at three levels of detail (global, phonological, and phonetic). Although results suggest that talkers may have employed different strategies to achieve clear speech at normal rates, two global-level properties were identified that appear likely to be linked to the improvements in intelligibility provided by clear/normal speech: increased energy in the 1000–3000-Hz range of long-term spectra and increased modulation depth of low frequency modulations of the intensity envelope. Other phonological and phonetic differences associated with clear/normal speech include changes in (1) frequency of stop burst releases, (2) VOT of word-initial voiceless stop consonants, and (3) short-term vowel spectra.
RNA Branching and Debranching in the Yeast Retrovirus-like Element Ty1
Authors: Cheng Zhi , Menees Thomas M.
Published: January 2004

Ty elements of
Saccharomyces cerevisiae
are long terminal repeat (LTR) retroelements related to retroviruses. Normal levels of Ty1 transposition require Dbr1p, a cellular enzyme that cleaves 2′–5′ RNA bonds. We show that Ty1 RNAs lacking identifiable 5′ ends accumulate in virus-like particles (VLPs) in
dbr1
mutants. Debranching this RNA in vitro with Dbr1p creates an uncapped version of the normal Ty1 RNA 5′ end. We show that the 5′ nucleotide (nt) of Ty1 RNA forms a 2′–5′ bond witha nt near the 3′ end of the same RNA, creating a lariat. The properties of the lariat suggest it forms by a novel mechanism and that branching and debranching may play roles in Ty1 reverse transcription at the minus-strand transfer step.
How Enzymes Work: Analysis by Modern Rate Theory and Computer Simulations
Authors: Garcia-Viloca Mireia , Gao Jiali , Karplus Martin , Truhlar Donald G.
Published: January 2004

Advances in transition state theory and computer simulations are providing new insights into the sources of enzyme catalysis. Both lowering of the activation free energy and changes in the generalized transmission coefficient (recrossing of the transition state, tunneling, and nonequilibrium contributions) can play a role. A framework for understanding these effects is presented, and the contributions of the different factors, as illustrated by specific enzymes, are identified and quantified by computer simulations. The resulting understanding of enzyme catalysis is used to comment on alternative proposals of how enzymes work.
Effects of Purifying and Adaptive Selection on Regional Variation in Human mtDNA
Authors: Ruiz-Pesini Eduardo , Mishmar Dan , Brandon Martin , Procaccio Vincent , Wallace Douglas C.
Published: January 2004

A phylogenetic analysis of 1125 global human mitochondrial DNA (mtDNA) sequences permitted positioning of all nucleotide substitutions according to their order of occurrence. The relative frequency and amino acid conservation of internal branch replacement mutations was found to increase from tropical Africa to temperate Europe and arctic northeastern Siberia. Particularly highly conserved amino acid substitutions were found at the roots of multiple mtDNA lineages from higher latitudes. These same lineages correlate with increased propensity for energy deficiency diseases as well as longevity. Thus, specific mtDNA replacement mutations permitted our ancestors to adapt to more northern climates, and these same variants are influencing our health today.
Neural Systems Underlying the Suppression of Unwanted Memories
Authors: Anderson Michael C. , Ochsner Kevin N. , Kuhl Brice , Cooper Jeffrey , Robertson Elaine , Gabrieli Susan W. , Glover Gary H. , Gabrieli John D. E.
Published: January 2004

Over a century ago, Freud proposed that unwanted memories can be excluded from awareness, a process called repression. It is unknown, however, how repression occurs in the brain. We used functional magnetic resonance imaging to identify the neural systems involved in keeping unwanted memories out of awareness. Controlling unwanted memories was associated with increased dorsolateral prefrontal activation, reduced hippocampal activation, and impaired retention of those memories. Both prefrontal cortical and right hippocampal activations predicted the magnitude of forgetting. These results confirm the existence of an active forgetting process and establish a neurobiological model for guiding inquiry into motivated forgetting.
Dendrite Development Regulated by CREST, a Calcium-Regulated Transcriptional Activator
Authors: Aizawa Hiroyuki , Hu Shu-Ching , Bobb Kathryn , Balakrishnan Karthik , Ince Gulayse , Gurevich Inga , Cowan Mitra , Ghosh Anirvan
Published: January 2004

The lasting effects of neuronal activity on brain development involve calcium-dependent gene expression. Using a strategy called transactivator trap, we cloned a calcium-responsive transactivator called CREST (for calcium-responsive transactivator). CREST is a SYT-related nuclear protein that interacts with adenosine 3′,5′-monophosphate (cAMP) response element–binding protein (CREB)–binding protein (CBP) and is expressed in the developing brain. Mice that have a targeted disruption of the
crest
gene are viable but display defects in cortical and hippocampal dendrite development. Cortical neurons from
crest
mutant mice are compromised in calcium-dependent dendritic growth. Thus, calcium activation of CREST-mediated transcription helps regulate neuronal morphogenesis.
14
C Activity and Global Carbon Cycle Changes over the Past 50,000 Years
Authors: Hughen K. , Lehman S. , Southon J. , Overpeck J. , Marchal O. , Herring C. , Turnbull J.
Published: January 2004

A series of
14
C measurements in Ocean Drilling Program cores from the tropical Cariaco Basin, which have been correlated to the annual-layer counted chronology for the Greenland Ice Sheet Project 2 (GISP2) ice core, provides a high-resolution calibration of the radiocarbon time scale back to 50,000 years before the present. Independent radiometric dating of events correlated to GISP2 suggests that the calibration is accurate. Reconstructed
14
C activities varied substantially during the last glacial period, including sharp peaks synchronous with the Laschamp and Mono Lake geomagnetic field intensity minimal and cosmogenic nuclide peaks in ice cores and marine sediments. Simulations with a geochemical box model suggest that much of the variability can be explained by geomagnetically modulated changes in
14
C production rate together with plausible changes in deep-ocean ventilation and the global carbon cycle during glaciation.
Periodic Pulsing of Characteristic Microearthquakes on the San Andreas Fault
Authors: Nadeau Robert M. , McEvilly Thomas V.
Published: January 2004

Deep fault slip information from characteristically repeating microearthquakes reveals previously unrecognized patterns of extensive, large-amplitude, long-duration, quasiperiodic repetition of aseismic events along much of a 175-kilometer segment of the central San Andreas fault.Pulsing occurs both in conjunction with and independent of transient slip from larger earthquakes.It extends to depths of ∼10 to 11 kilometers but may be deeper, and it may be related to similar phenomena occurring in subduction zones.Over much of the study area, pulse onset periods also show a higher probability of larger earthquakes, which may provide useful information for earthquake forecasting.
Abiotic Forcing of Plankton Evolution in the Cenozoic
Authors: Schmidt Daniela N. , Thierstein Hans R. , Bollmann Jörg , Schiebel Ralf
Published: January 2004

We characterize the evolutionary radiation of planktic foraminifera by the test size distributions of entire assemblages in more than 500 Cenozoic marine sediment samples, including more than 1 million tests. Calibration of Holocene size patterns with environmental parameters and comparisons with Cenozoic paleoproxy data show a consistently positive correlation between test size and surface-water stratification intensity. We infer that the observed macroevolutionary increase in test size of planktic foraminifera through the Cenozoic was an adaptive response to intensifying surface-water stratification in low latitudes, which was driven by polar cooling.
Widespread Intense Turbulent Mixing in the Southern Ocean
Authors: Garabato Alberto C. Naveira , Polzin Kurt L. , King Brian A. , Heywood Karen J. , Visbeck Martin
Published: January 2004

Observations of internal wave velocity fluctuations show that enhanced turbulent mixing over rough topography in the Southern Ocean is remarkably intense and widespread. Mixing rates exceeding background values by a factor of 10 to 1000 are common above complex bathymetry over a distance of 2000 to 3000 kilometers at depths greater than 500 to 1000 meters. This suggests that turbulent mixing in the Southern Ocean may contribute crucially to driving the upward transport of water closing the ocean's meridional overturning circulation, and thus needs to be represented in numerical simulations of the global ocean circulation and the spreading of biogeochemical tracers.
Transgenic RNAi Reveals Essential Function for CTCF in
H19
Gene Imprinting
Authors: Fedoriw Andrew M. , Stein Paula , Svoboda Petr , Schultz Richard M. , Bartolomei Marisa S.
Published: January 2004

The imprinted regulation of
H19
and
Insulin-like growth factor 2
expression involves binding of the vertebrate insulator protein, CCCTC binding factor (CTCF), to the maternally hypomethylated differentially methylated domain (DMD). Howthis hypomethylated state is maintained during oogenesis and the role of CTCF, if any, in this process are not understood. With the use of a transgenic RNA interference (RNAi)–based approach to generate oocytes with reduced amounts of CTCF protein, we found increased methylation of the
H19
DMD and decreased developmental competence of CTCF-deficient oocytes. Our results suggest that CTCF protects the
H19
DMD from de novo methylation during oocyte growth and is required for normal preimplantation development.
Regulation of Bone Mass in Mice by the Lipoxygenase Gene
Alox15
Authors: Klein Robert F. , Allard John , Avnur Zafrira , Nikolcheva Tania , Rotstein David , Carlos Amy S. , Shea Marie , Waters Ruth V. , Belknap John K. , Peltz Gary , Orwoll Eric S.
Published: January 2004

The development of osteoporosis involves the interaction of multiple environmental and genetic factors. Through combined genetic and genomic approaches, we identified the lipoxygenase gene
Alox15
as a negative regulator of peak bone mineral density in mice. Crossbreeding experiments with
Alox15
knockout mice confirmed that 12/15-lipoxygenase plays a role in skeletal development. Pharmacologic inhibitors of this enzyme improved bone density and strength in two rodent models of osteoporosis. These results suggest that drugs targeting the 12/15-lipoxygenase pathway merit investigation as a therapy for osteoporosis.
Constraining Webs
Authors: Carrel James E.
Published: January 2004

Spiderwebs and Silk
Tracing Evolution from Molecules to Genes to Phenotypes. by Catherine L. Craig. Oxford University Press, New York, 2003. 256 pp. $59.95, £40. ISBN 0-19-512916-4.

Weaving together findings from biochemistry, molecular genetics, cellular physiology, ecology, and behavior, Craig explores the links between the molecular evolution of silk proteins and the evolution, diversity, and ecology of spiders.
Reflectins: The Unusual Proteins of Squid Reflective Tissues
Authors: Crookes Wendy J. , Ding Lin-Lin , Huang Qing Ling , Kimbell Jennifer R. , Horwitz Joseph , McFall-Ngai Margaret J.
Published: January 2004

A family of unusual proteins is deposited in flat, structural platelets in reflective tissues of the squid
Euprymna scolopes
. These proteins, which we have named reflectins, are encoded by at least six genes in three subfamilies and have no reported homologs outside of squids. Reflectins possess five repeating domains, which are highly conserved among members of the family. The proteins have a very unusual composition, with four relatively rare residues (tyrosine, methionine, arginine, and tryptophan) comprising ∼57% of a reflectin, and several common residues (alanine, isoleucine, leucine, and lysine) occurring in none of the family members. These protein-based reflectors in squids provide a marked example of nanofabrication in animal systems.
Global Assessment of Organic Contaminants in Farmed Salmon
Authors: Hites Ronald A. , Foran Jeffery A. , Carpenter David O. , Hamilton M. Coreen , Knuth Barbara A. , Schwager Steven J.
Published: January 2004

The annual global production of farmed salmon has increased by a factor of 40 during the past two decades. Salmon from farms in northern Europe, North America, and Chile are now available widely year-round at relatively low prices. Salmon farms have been criticized for their ecological effects, but the potential human health risks of farmed salmon consumption have not been examined rigorously. Having analyzed over 2 metric tons of farmed and wild salmon from around the world for organochlorine contaminants, we show that concentrations of these contaminants are significantly higher in farmed salmon than in wild. European-raised salmon have significantly greater contaminant loads than those raised in North and South America, indicating the need for further investigation into the sources of contamination. Risk analysis indicates that consumption of farmed Atlantic salmon may pose health risks that detract from the beneficial effects of fish consumption.
Boron Nitride Nanomesh
Authors: Corso Martina , Auwärter Willi , Muntwiler Matthias , Tamai Anna , Greber Thomas , Osterwalder Jürg
Published: January 2004

A highly regular mesh of hexagonal boron nitride with a 3-nanometer periodicity and a 2-nanometer hole size was formed by self-assembly on a Rh(111) single crystalline surface. Two layers of mesh cover the surface uniformly after high-temperature exposure of the clean rhodium surface to borazine (HBNH)
3
. The two layers are offset in such a way as to expose a minimum metal surface area. Hole formation is likely driven by the lattice mismatch of the film and the rhodium substrate. This regular nanostructure is thermally very stable and can serve as a template to organize molecules, as is exemplified by the decoration of the mesh by C
60
molecules.
Virus-Based Toolkit for the Directed Synthesis of Magnetic and Semiconducting Nanowires
Authors: Mao Chuanbin , Solis Daniel J. , Reiss Brian D. , Kottmann Stephen T. , Sweeney Rozamond Y. , Hayhurst Andrew , Georgiou George , Iverson Brent , Belcher Angela M.
Published: January 2004

We report a virus-based scaffold for the synthesis of single-crystal ZnS, CdS, and freestanding chemically ordered CoPt and FePt nanowires, with the means of modifying substrate specificity through standard biological methods. Peptides (selected through an evolutionary screening process) that exhibit control of composition, size, and phase during nanoparticle nucleation have been expressed on the highly ordered filamentous capsid of the M13 bacteriophage. The incorporation of specific, nucleating peptides into the generic scaffold of the M13 coat structure provides a viable template for the directed synthesis of semiconducting and magnetic materials. Removal of the viral template by means of annealing promoted oriented aggregation-based crystal growth, forming individual crystalline nanowires. The unique ability to interchange substrate-specific peptides into the linear self-assembled filamentous construct of the M13 virus introduces a material tunability that has not been seen in previous synthetic routes. Therefore, this system provides a genetic toolkit for growing and organizing nanowires from semiconducting and magnetic materials.
RAD51C Is Required for Holliday Junction Processing in Mammalian Cells
Authors: Liu Yilun , Masson Jean-Yves , Shah Rajvee , O'Regan Paul , West Stephen C.
Published: January 2004

During genetic recombination and the recombinational repair of chromosome breaks, DNA molecules become linked at points of strand exchange. Branch migration and resolution of these crossovers, or Holliday junctions (HJs), complete the recombination process. Here, we show that extracts from cells carrying mutations in the recombination/repair genes
RAD51C
or
XRCC3
have reduced levels of HJresolvase activity. Moreover, depletion of RAD51C from fractionated human extracts caused a loss of branch migration and resolution activity, but these functions were restored by complementation with a variety of RAD51 paralog complexes containing RAD51C. We conclude that the RAD51 paralogs are involved in HJprocessing in human cells.
INCREMENTAL EVOLUTION OF CELLULAR AUTOMATA FOR RANDOM NUMBER GENERATION
Authors: GUAN SHENG-UEI , ZHANG SHU
Published: January 2004

Cellular automata (CA) have been used in pseudorandom number generation for over a decade. Recent studies show that controllable CA (CCA) can generate better random sequences than conventional one-dimensional (1D) CA and compete with two-dimensional (2D) CA. Yet the structural complexity of CCA is higher than that of 1D programmable cellular automata (PCA). It would be good if CCA can attain a good randomness quality with the least structural complexity. In this paper, we evolve PCA/CCA to their lowest complexity level using genetic algorithms (GAs). Meanwhile, the randomness quality and output efficiency of PCA/CCA are also evolved. The evolution process involves two algorithms — a multi-objective genetic algorithm (MOGA) and an algorithm for incremental evolution. A set of PCA/CCA are evolved and compared in randomness, complexity, and efficiency. The results show that without any spacing, the CCA could generate good random number sequences that could pass DIEHARD. To obtain the same randomness quality, the structural complexity of the CCA is not higher than that of 1D CA. Furthermore, the methodology developed could be used to evolve other CA or serve as a yardstick to compare different types of CA.
STRUCTURAL FEATURES AND ENERGETICS OF ZnkCdl MICROCLUSTERS
Authors: AMIROUCHE LYNDA , ERKOÇ ŞAKIR
Published: January 2004

An empirical many-body potential energy function has been developed to investigate the structural features and energetics of Zn k Cd l (k+l=3, 4) microclusters. The most stable structures were found to be triangular for the three-atom clusters and tetrahedral for the four-atom clusters. The present results are in good agreement with available literature values.
SELF-ORGANIZED CRITICALITY, OPTIMIZATION AND BIODIVERSITY
Authors: ONODY ROBERTO N. , DE CASTRO PAULO A.
Published: January 2004

By driving to extinction species that are less or poorly adapted, the Darwinian evolutionary theory is intrinsically an optimization theory. We investigate two optimization algorithms with such evolutionary characteristics: the Bak–Sneppen and the Extremal Optimization. By comparing their mean fitness in the steady state regime, we conclude that the Bak–Sneppen dynamics is more efficient than the Extremal Optimization if the parameter τ is in the interval [0, 0.86]. The determination of the spatial correlation and the probability distribution of the avalanches show that the Extremal Optimization dynamics does not lead the system into a critical self-organized state. Through a discrete form of the Bak–Sneppen model we argue that biodiversity is an essential prerequisite to preserve the self-organized criticality.
A NEW APPROACH TO DYNAMIC FINITE-SIZE SCALING
Authors: DİLAVER MEHMET , GÜNDÜÇ SEMRA , AYDIN MERAL , GÜNDÜÇ YİĞİT
Published: January 2004

In this work we have considered the Taylor series expansion of the dynamic scaling relation of the magnetization with respect to small initial magnetization values in order to study the dynamic scaling behavior of two- and three-dimensional Ising models. We have used the literature values of the critical exponents and of the new dynamic exponent x0 to observe the dynamic finite-size scaling behavior of the time evolution of the magnetization during early stages of the Monte Carlo simulation. For the three-dimensional Ising model we have also presented that this method opens the possibility of calculating z and x0 separately. Our results show good agreement with the literature values. Measurements done on lattices with different sizes seem to give very good scaling.
SPECIATION AND NEUTRAL MOLECULAR EVOLUTION IN ONE-DIMENSIONAL CLOSED POPULATION
Authors: SEMOVSKI SERGEI V. , BUKIN YURI S. , SHERBAKOV DMITRY Yu.
Published: January 2004

Models are presented suitable for a description of speciation processes arising due to reproductive isolation depending on genetic distance. The main attention is paid to the model of a one-dimensional closed population, which describes the evolution of littoral benthic organisms. In order to correspond the modeling results to the results obtained in the course of experimental phylogenetic studies, all individual-based models described here involve neutrally evolving and maternally inherited DNA sequence. Sub-samples of the resulting sequences were used for a posteriori phylogenetic inferences which then were compared to the "true" evolutionary histories.
Renal Dopamine and Salt Sensitivity of Blood Pressure in IgA Nephropathy
Authors: Pestana Manuel , Santos Joana , Santos Alejandro , Coroas Andreia , Correia Flora , Serrão Paula , Valbuena Carmen , Soares-da-Silva Patrício
Published: January 2004

Background: Patients with chronic glomerulonephritis exhibit salt-sensitive (SS) hypertension. In the early stage, however, the exact characteristics are still unclear. A decrease in renal dopamine production under basal conditions or after a sodium load has been reported in a subset of patients with SS primary hypertension. Aims: The present study examined 17 untreated IgA-N patients with near-normal renal function, to determine whether salt sensitivity appears before hypertension and whether this sensitivity is related to renal dopamine production. Methods: Daily urinary excretion of dopamine, the amine precursor – L-DOPA, and metabolites was monitored in conditions of basal sodium ingestion, followed by three consecutive 5-day periods of 100, 20 and 350 mmol/day sodium intake. The sodium sensitivity index (SSI) was evaluated in each patient. In addition, the patients were considered SS when showing an increase ≧5 mm Hg in 24-hour mean BP when they changed from a 20- to a 350-mmol/day sodium diet. Results: Urinary dopamine output was lower in SS than in salt-resistant patients throughout the study (p < 0.001). This was accompanied by lower creatinine clearance values and higher urinary protein excretion in SS IgA-N patients. A strong negative relationship was observed in these 17 IgA-N patients between the SSI and the daily urinary excretion of dopamine in conditions of both 20 mmol/day sodium intake (r2 = 0.592; p = 0.0003) and 350 mmol/day sodium diet (r2 = 0.352; p = 0.01). However, urinary dopamine output varied appropriately throughout the study in SS patients, in agreement with changes in sodium intake. Conclusion: We conclude that in IgA-N patients, a rightward shift in the ‘pressure natriuresis’ can appear before hypertension and is related with a reduced renal production of dopamine. It is suggested that decreased renal dopamine synthesis in SS IgA-N patients results from acquired tubulointerstitial injury. In contrast to what has been found in SS primary hypertension, renal dopamine may behave appropriately in SS IgA-N patients, as a compensatory hormone.
Reduction, Regrowth, and de novo Formation of Abdominal Adhesions after Laparoscopic Adhesiolysis: A Prospective Analysis
Authors: Swank D.J. , Hop W.C.J. , Jeekel J.
Published: January 2004

Aim: A significant reduction of abdominal adhesions at second-look relaparoscopy after adhesiolysis in patients with chronic abdominal pain. Methods: 368 patients underwent laparoscopic adhesiolysis because of chronic abdominal pain. Regrowth and de novo abdominal adhesions were determined in a qualitative and quantitative way in 24 patients who underwent a second-look re-laparoscopy because of recurrent pain after a mean period of 16 months after the first laparoscopic adhesiolysis. Reduction of incidence, extent, type, and severity of abdominal adhesions between organs and abdominal wall and de novo adhesion formation were determined. Results: Incidence (40 vs. 26), extent, type, and severity of abdominal adhesions between organs and abdominal wall are significantly reduced after laparoscopic adhesiolysis. After adhesiolysis of adhesions between organs themselves, no significant reduction could be demonstrated (incidence 40 vs. 32). De novo adhesions were present in 5 (5/24) patients. Conclusion: Laparoscopic adhesiolysis results in a significant reduction of adhesions between organs and abdominal wall, despite the occurrence of de novo adhesions in about 20% of the patients.
Thrombolysis for Ischemic Stroke in Patients with Old Microbleeds on Pretreatment MRI
Authors: Derex Laurent , Nighoghossian Norbert , Hermier Marc , Adeleine Patrice , Philippeau Frédéric , Honnorat Jérôme , Yilmaz Hasan , Dardel Pascal , Froment Jean-Claude , Trouillas Paul
Published: January 2004

Background: Old asymptomatic microbleeds (MBs) visualized on T2-weighted MRI are indicative of microangiopathy. They may be a marker of increased risk of intracerebral hemorrhage (ICH) following thrombolysis. However, data regarding this potential risk are limited. Methods: A retrospective analysis of pretreatment T2-weighted MRI was performed in consecutive stroke patients who received intravenous tissue plasminogen activator (tPA). We aimed to assess the impact of MBs on the risk of cerebral bleeding. The frequency and location of MBs were assessed and compared with the location of ICH after thrombolysis. Results: Forty-four patients were studied. MBs were present on pretreatment MRI in 8 cases (18.2%). At day 1, symptomatic ICH occurred in none of 8 patients with MBs versus 1 of 36 patients without (NS). At day 1, ICH occurred in 3 of 8 patients with MBs versus 10 of 36 patients without (NS). At day 7, symptomatic ICH occurred in 1 of 8 patients with MBs versus 2 of 36 patients without (NS). At day 7, ICH occurred in 5 of 8 patients with MBs versus 12 of 36 patients without (NS). No ICH occurred at the site of an MB. ICH occurred within the ischemic area in all patients who bled. Conclusions: Our study suggests that stroke patients with a small number of MBs on pretreatment MRI could be treated safely with thrombolysis. Larger prospective studies are needed to address the predictive value of detection of MBs with regard to the risk of tPA-induced ICH.
Topical Application of FK506 (Tacrolimus) Ointment Inhibits Mite Antigen-Induced Dermatitis by Local Action in NC/Nga Mice
Authors: Sasakawa Tatsuya , Higashi Yasuyuki , Sakuma Shozo , Hirayama Yoshitaka , Sasakawa Yuka , Ohkubo Yoshitaka , Mutoh Seitaro
Published: January 2004

Background: FK506 ointment (tacrolimus ointment, protopic) is a new drug therapeutically effective for patients with atopic dermatitis (AD). However, the mechanism of action of FK506 ointment on AD is not fully understood. Methods: We examined the effect of FK506 ointment on mite antigen-induced dermatitis in NC/Nga mice. Clinical symptoms and ear thickness were recorded, and histopathological studies and in vitro analyses were performed. Results: Topical application of FK506 ointment (0.03–0.3%) suppressed the development of dermatitis. In the lesional skin, both interleukin (IL)-4 and interferon (IFN)-γ were detected, even though the IL-4+/IFN-γ– T helper 2 (Th2) population was predominant in the regional lymph nodes (LNs). Topical application of FK506 treatment reduced the elevated level of both IL-4 and IFN-γ in the skin, but did not decrease the expansion of the Th2 population in the LNs. Conclusions: Topical application of FK506 ointment suppresses dermatitis by inhibiting the activation of inflammatory cells locally, without systemic immune suppression, in this AD model.
Secondary Lymphoid Tissue Chemokine (CCL21) Is Upregulated in Allergic Contact Dermatitis
Authors: Serra Horacio Marcelo , Eberhard Yanina , Martín Andrea Paula , Gallino Norberto , Gagliardi Julio , Baena-Cagnani Carlos Eduardo , Lascano Alejandro Ruiz , Ortiz Susana , Mariani Ana Lía , Uguccioni Mariagrazia
Published: January 2004

Chemokines are important players in the development of allergic contact dermatitis (ACD). The participation of secondary lymphoid tissue chemokine (CCL21) is essential in the induction of the disease due to its expression in lymphatic vessels and in secondary lymphoid organs. Since there is no information about its participation during the effector phase of ACD, we studied this chemokine in patients already diagnosed with ACD, who were challenged with the relevant positive and negative (control) antigens. All patients showed a specific antigen-induced immune response characterized by early expression of inflammatory markers in blood endothelial cells followed by dermal accumulation of mononuclear cells with an important increase in infiltration of CXCR3+ but not of CCR7+ cells. In situ hybridization and immunohistochemistry showed low levels of CCL21 in lymphatic vessels at 2 h, whereas they were significantly increased at 10 and 48 h in all positive patch tests. In contrast, very low expression of this chemokine was observed in skin biopsies from the control site at 48 h. In addition, Langerin+ cells, which were present in dermis from positive patch tests at 2 h, were diminished in number at 10 and 48 h, but a significant number of those cells was still present in dermal areas of the control site at 48 h. We demonstrate for the first time that CCL21, a constitutively expressed chemokine, is strongly upregulated in human lymphatic vessels during a Th1/Tc1 allergic inflammatory response. This can provide the signal required for CCR7+ cells to leave the skin through CCL21-positive lymphatic vessels.
B Lymphocyte Selection and Survival in Systemic Lupus
Authors: Liossis Stamatis-Nick C. , Zouali Moncef
Published: January 2004

B lymphocytes are an essential element in the body’s immune system. Engagement of the B cell receptor is responsible for initiating the signaling events that can activate, inactivate or physically eliminate B cells, depending on the magnitude and duration of the signal. Control of B cell signaling occurs through both positive and negative regulation, as well as through the actions of molecular scaffolds that contribute to the formation of signaling complexes. Inactivation of genes encoding signaling molecules was shown to result in clinical manifestations reminiscent of systemic autoimmunity in experimental animals. Aberrant expression of some signaling molecules was also observed in patients with systemic autoimmune diseases. Understanding the mechanisms that subvert B cell receptor transduction pathways is likely to aid in the development of therapeutic agents to treat autoimmune diseases.
Do Mouse Models of Allergic Asthma Mimic Clinical Disease?
Authors: Epstein Michelle M.
Published: January 2004

Experimental mouse models of allergic asthma established almost 10 years ago offered new opportunities to study disease pathogenesis and to develop new therapeutics. These models focused on the factors governing the allergic immune response, on modeling clinical behavior of allergic asthma, and led to insights into pulmonary pathophysiology. Although mouse models rarely completely reproduce all the features of human disease, after sensitization and respiratory tract challenges with antigen, wild-type mice develop a clinical syndrome that closely resembles allergic asthma, characterized by eosinophilic lung inflammation, airway hyperresponsiveness (AHR), increased IgE, mucus hypersecretion, and eventually, airway remodeling. There are, however, differences between mouse and human physiology that threaten to limit the value of mouse models. Three examples of such differences relate to both clinical manifestations of disease and underlying pathogenesis. First, in contrast to patients who have increased methacholine-induced AHR even when they are symptom-free, mice exhibit only transient methacholine-induced AHR following allergen exposure. Second, chronic allergen exposure in patients leads to chronic allergic asthma, whereas repeated exposures in sensitized mice causes suppression of disease. Third, IgE and mast cells, in humans, mediate early- and late-phase allergic responses, though both are unnecessary for the generation of allergic asthma in mice. Taken together, these observations suggest that mouse models of allergic asthma are not exact replicas of human disease and thus, question the validity of these models. However, observations from mouse models of allergic asthma support many existing paradigms, although some novel discoveries in mice have yet to be verified in patients. This review presents an overview of the clinical aspects of disease in mouse models of allergic asthma emphasizing (1) the factors influencing the pathophysiological responses during the initiation and perpetuation of disease, (2) the utility of mouse models for studying clinical manifestations of disease, and (3) the applicability of mouse models for testing new treatments for allergic asthma.
Altered Distribution of the Debrisoquine Oxidative Phenotypes in Children with Type 1 Diabetes mellitus
Authors: Madácsy L. , Barkai L. , Sánta A. , Krikovszky D.
Published: January 2004

Objective: The recently observed increase in the incidence of type 1 diabetes mellitus (Type 1 DM) suggests a major role of environmental factors in the etiopathogenesis of the disease. The individual variation in cytochrome P450IID6 may influence the individual susceptibility to environmentally linked diseases. We aimed to evaluate the prevalence of cytochrome P450IID6 phenotypes in Hungarian children with Type 1 DM (n = 69) compared to healthy controls (n = 100). Methods: Debrisoquine was administered orally and debrisoquine hydroxylation phenotype was determined as a metabolic ratio of urinary recovered debrisoquine and 4-hydroxydebrisoquine. Results: Eight of the 100 healthy subjects (8%) and 15 of the 69 diabetic children (22%) (p < 0.05) had cytochrome P450IID6 poor metabolizer phenotype (metabolic ratio ≧12.6). Conclusion: Cytochrome P450IID6’s activity may play a role in the development of Type 1 DM.
Progressing Stroke: Towards an Internationally Agreed Definition
Authors: Birschel Philip , Ellul John , Barer David
Published: January 2004

Background: The study of early neurological deterioration (progression) in acute stroke has been hampered by a lack of standardisation in the terminology or assessment procedures. An international panel was therefore convened, to agree on robust operational definitions for future studies and to validate them in an observational study involving 10 centres from the European Stroke Database Collaboration. Methods: Standardised neurological assessments were performed daily for the first 3 days on patients with acute stroke, consecutively admitted within 24 h of onset, using the Scandinavian Stroke Scale (SSS) scoring system. An early deterioration episode (EDE) was defined as a ≧2 SSS-point worsening in either conscious level, arm, leg or eye movement scores, and/or a ≧3 SSS-point worsening in speech score, between consecutive neurological assessments. Stroke progression (SP) was defined as a similar neurological worsening comparing the day 3 assessment with the baseline assessment, or death occurring within 72 h of onset. The ability of SP to predict poor outcome (death or a Barthel ADL score <15/20 at 3 months), independently of initial stroke severity or other prognostic factors, was compared with possible alternative definitions, including one based on the Canadian Stroke Scale. Results: The occurrence of EDEs and SP within the first 3 days of admission could be determined in 563 cases. EDEs occurred in 33% and SP in 26% of cases. Both were strong independent predictors of poor outcome. The prognostic efficiency of the European Progressing Stroke Study (EPSS) definition of SP was better than any of the alternatives examined, and clearly better than a definition based on changes in the total SSS score. Conclusions: The EPSS definitions of EDEs and SP have good construct and prognostic validity. They can be recommended as a standard for future studies on the aetiology and mechanisms of this common and important phenomenon.
G Protein–Coupled Receptor Oligomerization
Authors: Breitwieser Gerda E.
Published: January 2004

The cardiovascular system is richly endowed with G protein–coupled receptors (GPCRs), members of the largest family of plasma membrane-localized receptors. During the last 10 years, it has become increasingly clear that many, if not all, GPCRs function in oligomeric complexes, as either homo- or hetero-oligomers. This review explores the mechanistic implications of GPCR dimerization and/or oligomerization on receptor activation and interactions with G proteins. The effects of GPCR oligomerization on receptor pharmacology, GPCR-mediated signaling, and potential contributions to GPCR crosstalk will be considered in the context of receptors important in the cardiovascular system. Our evolving understanding of the structural and functional consequences of GPCR oligomerization may provide novel and more selective sites for pharmacological tuning of cardiovascular function.
JNK activation is a mediator of arsenic trioxide-induced apoptosis in acute promyelocytic leukemia cells
Authors: Davison Kelly , Mann Koren K. , Waxman Samuel , Miller Wilson H.
Published: January 2004

Arsenic trioxide induces c-jun N-terminal kinase (JNK) activation and apoptosis in acute promyelocytic leukemia (APL), where it has major clinical activity, but whether JNK is necessary to induce apoptosis is unknown. To clarify this necessity, we established 2 arsenic trioxide (As2O3)-resistant subclones of the APL cell line, NB4. Both resistant lines showed little activation of JNK1 following treatment with As2O3, even at doses sufficient to elicit robust activation in NB4 cells. One mechanism of resistance in these cells is up-regulated glutathione (GSH) content, and GSH depletion by l-buthionine-[S,R]-sulfoximine (BSO) restores JNK activation and As2O3 sensitivity. This correlation between JNK activation and apoptosis led us to test whether inhibition of JNK would protect cells from As2O3-induced apoptosis. SEK1-/- mouse embryo fibroblasts (MEFs) showed diminished JNK activation following As2O3 treatment and were protected from As2O3-induced but not doxorubicin-induced apoptosis. Furthermore, treatment of arsenic trioxide-sensitive APL cells with the JNK inhibitor, dicumarol, significantly increased growth and survival in response to As2O3 but did not protect cells from doxorubicin. Together, these data support an essential role for JNK signaling in the induction of growth inhibition and apoptosis by As2O3 and suggest that activating JNK may provide a therapeutic advantage in the treatment of cancers that do not respond to arsenic alone. (Blood. 2004;103:3496-3502)
A pilot study of alemtuzumab (anti-CD52 monoclonal antibody) therapy for patients with relapsed or chemotherapy-refractory peripheral T-cell lymphomas
Authors: Enblad Gunilla , Hagberg Hans , Erlanson Martin , Lundin Jeanette , MacDonald Anja Porwit , Repp Roland , Schetelig Johannes , Seipelt Gernot , Österborg Anders
Published: January 2004

Patients with peripheral T-cell lymphomas (PTLs) have an extremely poor prognosis when relapsed or refractory to conventional chemotherapy. We have studied alemtuzumab, a humanized anti-CD52 monoclonal antibody, as therapy for patients with heavily pretreated and refractory PTL. Fourteen patients entered the study. All had clinical stage III or IV disease. Patients received a rapidly escalating dosage of alemtuzumab during the first week and, thereafter, 30 mg intravenously 3 times per week for a maximum of 12 weeks. Trimethoprim/sulphamethoxazole and valaciclovir prophylaxis was given to all patients. The overall response rate was 36% (5 of 14). Three patients achieved a complete remission (CR) and 2 patients a partial remission. The durations of the CRs were 2, 6, and 12 months, respectively. Toxicity included cytomegalovirus reactivation in 6 patients, which was successfully treated with ganciclovir or foscarnet; pulmonary aspergillosis in 2 patients; and pancytopenia in 4 patients. Epstein-Barr virus–related hemophagocytosis was observed in 2 patients. Five patients died of causes related to the treatment, in combination with advanced disease. We conclude that alemtuzumab is active when used in patients with advanced, heavily pretreated PTL, although it is associated with significant hematologic toxicity and infectious complications. Further studies are warranted in younger patients and patients with less advanced disease. (Blood. 2004;103: 2920-2924)
Case-control study ofStenotrophomonas maltophiliaacquisition in cystic fibrosis patients
Authors: Marchac V. , Equi A. , Le Bihan-Benjamin C. , Hodson M. , Bush A.
Published: January 2004

The aims of this case-control study were to describe the characteristics of cystic fibrosis (CF) patients who isolatedStenotrophomonas maltophiliain sputum, to determine risk factors for acquisition, to assess persistence of the organism and clinical outcomes postacquisition.

Data were collected from 1991–1999. CF patients and controls (who had never isolatedS. maltophilia) were matched for age (±1 yr), sex and forced expiratory volume in one second (±10%). Data were collected from the year prior and for 2 yrs postacquisition ofS. maltophilia.

The prevalence ofS. maltophiliaincreased from 3.3% to 15%. Factors associated withS. maltophiliaacquisition were more than two courses of intravenous antibiotics, isolation ofAspergillus fumigatusin sputum and oral steroid use. The effect ofA. fumigatuswas independent of steroid use. Clinical status did not change postacquisition. The majority of patients cleared the organism from the sputum.

Long-term infection or an accelerated deterioration in lung function or nutrition is not likely post-Stenotrophomonas maltophiliaacquisition in cystic fibrosis. This is the first documentation of an association betweenAspergillus fumigatusisolation andStenotrophomonas maltophiliaacquisition in cystic fibrosis, independently of steroid therapy.
Home mechanical ventilation in Hong Kong
Authors: Chu C.M. , Yu W.C. , Tam C.M. , Lam C.W. , Hui D.S.C. , Lai C.K.W.
Published: January 2004

Home mechanical ventilation (HMV) is increasingly used to treat chronic respiratory failure. This present study was aimed to examine the trend, the disease categories treated and the outcomes of HMV use in Hong Kong.

In the year 2002, all adult respiratory units in Hong Kong were invited to report to a multicentre retrospective survey of HMV use. A total of 249 patients (156 males, mean age 62.7±13.8 yrs) were treated since 1980, with 197 (79%) continuing with HMV at the time of the survey.

Cumulative number of HMV grew as a cubic function of time since 1980. Currently, there are 2.9 users per 100,000 population. The predominant mode of HMV was noninvasive ventilation by bilevel pressure support ventilators (n=236). Chronic obstructive pulmonary disease accounted for 48.6% of all cases. The overall 3‐yr HMV continuation rate was 66.2%. Death was the main reason for discontinuation.

A rapidly rising trend of home mechanical ventilation use is observed in Hong Kong. In contrast to other series, chronic obstructive pulmonary disease was the major group treated and bilevel pressure support ventilation was the predominant mode chosen. Most patients tolerate home mechanical ventilation reasonably well, with approximately two-thirds continuing with its use at 36 months.