bluuebunny/crossref_metadata_2025 huggingface dataset:
Elevations in Renal Interstitial Hydrostatic Pressure and 20-Hydroxyeicosatetraenoic Acid Contribute to Pressure Natriuresis
Authors: Williams Jan M. , Sarkis Albert , Lopez Bernardo , Ryan Robert P. , Flasch Averia K. , Roman Richard J.
Published: January 2007

This study examined the role of changes in renal interstitial pressure on the renal levels of cytochrome P450 metabolites of arachidonic acid and compared the effects of inhibition of the formation of 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids with 1-aminobenzotriazole on the pressure-natriuretic response versus that seen after administration of HET0016, a more selective inhibitor of the formation of 20-HETE. Renal interstitial pressure rose by 3.4±0.3 mm Hg, and the levels of 20-HETE in renal cortical tissue doubled when renal perfusion pressure was increased from 100 to 160 mm Hg. Removal of the renal capsule prevented the increase in renal interstitial pressure and 20-HETE levels after an elevation in renal perfusion pressure. Urine flow and sodium excretion increased 5-fold when renal perfusion pressure was increased from 106 to 160 mm Hg. The administration of 1-aminobenzotriazole (50 mg/kg, IP) or HET0016 (10 mg/kg IV bolus plus 1 mg/kg per hour of infusion) decreased the pressure-natriuretic response by 50% and inhibited the renal formation of 20-HETE and epoxyeicosatrienoic acids by 90% and 50%, respectively. Administration of a lower dose of HET0016 (1 mg/kg per hour, IV) selectively reduced the formation of 20-HETE by 80% without inhibiting renal epoxygenase activity and blunted the pressure-natriuretic response by 42%. These results indicate that elevations in renal perfusion pressure increase 20-HETE levels in the kidney secondary to a rise in renal interstitial pressure. They also suggest that 20-HETE, rather than epoxyeicosatrienoic acids, modulates the pressure-natriuretic response, because selective blockade of the formation of 20-HETE with HET0016 blunts the response to the same extent as that seen after inhibition of the formation of 20-HETE and epoxyeicosatrienoic acids with 1-aminobenzotriazole.
Accelerated Mitochondrial Adenosine Diphosphate/Adenosine Triphosphate Transport Improves Hypertension-Induced Heart Disease
Authors: Walther Thomas , Tschöpe Carsten , Sterner-Kock Anja , Westermann Dirk , Heringer-Walther Silvia , Riad Alexander , Nikolic Alen , Wang Yong , Ebermann Linda , Siems Wolf-Eberhard , Bader Michael , Shakibaei Mehdi , Schultheiss Heinz-Peter , Dörner Andrea
Published: January 2007

Background—

Strong evidence suggests that mitochondrial malfunction, which leads to disturbed energy metabolism and stimulated apoptosis, is a linchpin in the induction and manifestation of cardiac failure. An adequate exchange of ATP and ADP over the inner mitochondrial membrane by the adenine nucleotide translocase (ANT) is thereby essential to guarantee the cellular energy supply.

Methods and Results—

To explore the effect of an ameliorated mitochondrial ATP/ADP transportation on cardiac dysfunction, we generated transgenic rats overexpressing ANT1 in the heart (ANT rats) and crossed them with renin-overexpressing rats (REN rats) suffering from hypertension-induced cardiac insufficiency. Cardiac-specific ANT1 overexpression resulted in a higher ATP/ADP transportation and elevated activities of respiratory chain complexes. Increased ANT activity in double-transgenic (ANT/REN) animals did not influence excessive hypertension seen in REN rats. Hypertension-induced cardiac hypertrophy in the REN rats was prevented by parallel ANT1 overexpression, however, and left ventricular function remarkably improved. The ANT1 overexpression led to a reduction in fibrosis and an improvement in cardiac tissue architecture. Consequently, the survival rate of ANT/REN rats was enhanced. Further investigations into the cardioprotective mechanism of ANT1 overexpression revealed improved mitochondrial structure and function and significantly reduced apoptosis in ANT/REN rats, shown by lowered cytosolic/mitochondrial cytochrome c ratio, reduced caspase 3 level, and prevented DNA degradation.

Conclusions—

Myocardial ANT1 overexpression protects against hypertension-induced cardiac pathology. Thus, the improvement in mitochondrial function may be a basic principle for new strategies in treating heart disease.
Cardiac Sodium Channel Dysfunction in Sudden Infant Death Syndrome
Authors: Wang Dao W. , Desai Reshma R. , Crotti Lia , Arnestad Marianne , Insolia Roberto , Pedrazzini Matteo , Ferrandi Chiara , Vege Ashild , Rognum Torleiv , Schwartz Peter J. , George Alfred L.
Published: January 2007

Background—

Mutations in genes responsible for the congenital long-QT syndrome, especially
SCN5A
, have been identified in some cases of sudden infant death syndrome. In a large-scale collaborative genetic screen, several
SCN5A
variants were identified in a Norwegian sudden infant death syndrome cohort (n=201). We present functional characterization of 7 missense variants (S216L, R680H, T1304M, F1486L, V1951L, F2004L, and P2006A) and 1 in-frame deletion allele (delAL586-587) identified by these efforts.

Methods and Results—

Whole-cell sodium currents were measured in tsA201 cells transiently transfected with recombinant wild-type or mutant
SCN5A
cDNA (hH1) coexpressed with the human β1 subunit. All variants exhibited defects in the kinetics and voltage dependence of inactivation. Five variants (S216L, T1304M, F1486L, F2004L, and P2006A) exhibited significantly increased persistent sodium currents (range, 0.5% to 1.7% of peak current) typical of
SCN5A
mutations associated with long-QT syndrome. These same 5 variants also displayed significant depolarizing shifts in voltage dependence of inactivation (range, 5 to 14 mV) and faster recovery from inactivation, but F1486L uniquely exhibits a depolarizing shift in the conductance-voltage relationship. Three alleles (delAL586-587, R680H, and V1951L) exhibited increased persistent current only under conditions of internal acidosis (R680H) or when expressed in the context of a common splice variant (delQ1077), indicating that they have a latent dysfunctional phenotype.

Conclusions—

Our present results greatly expand the spectrum of functionally characterized
SCN5A
variants associated with sudden infant death syndrome and provide further biophysical correlates of arrhythmia susceptibility in this syndrome.
Cardiac and Systemic Hemodynamic Characteristics of Hypertension and Prehypertension in Adolescents and Young Adults
Authors: Drukteinis Jennifer S. , Roman Mary J. , Fabsitz Richard R. , Lee Elisa T. , Best Lyle G. , Russell Marie , Devereux Richard B.
Published: January 2007

Background—

The epidemic of overweight is increasing the prevalence of both prehypertension and early-onset hypertension, but few population-based data exist on their impact on cardiac structure and function in adolescents and young adults.

Methods and Results—

We analyzed clinical characteristics, hemodynamic parameters, and left ventricular structure and function in 1940 participants, 14 to 39 years of age, in the Strong Heart Study. Hypertension occurred in 294 participants (15%), who were more often men (70% versus 30%), older (age, 31±7 versus 25±8 years), and more commonly diabetic (23% versus 4.5%; all
P
<0.001) than their normotensive counterparts. Prehypertension occurred in 675 (35%) of participants with similar trends in gender, age, and diabetes status. After adjustment for covariates, both hypertensive and prehypertensive participants had higher left ventricular wall thickness (0.83 and 0.78 versus 0.72 cm), left ventricular mass (182 and 161 versus 137 g), and relative wall thickness (0.30 and 0.29 versus 0.28 cm) and 3- and 2-fold-higher prevalences of left ventricular hypertrophy than their normotensive counterparts (all
P
<0.001). Hypertension and prehypertension also were associated with higher mean pulse pressure/stroke volume index (1.24 and 1.15 versus 1.02 mm Hg/mL · m
2
) and total peripheral resistance index (3027 and 2805 versus 2566 dynes · s · cm
−5
· m
2
; all
P
<0.001).

Conclusions—

In a population with high prevalences of obesity and diabetes, hypertension and prehypertension are associated with increases in both cardiac output and peripheral resistance index. Despite the young age of participants with hypertension and prehypertension, they had prognostically adverse preclinical cardiovascular disease, including left ventricular hypertrophy and evidence of increased arterial stiffness.
Joseph Ratzingers Apologie des Christentums: Bibeldeutung auf der Basis einer spiritualistischen Metaphysik
Authors: Albert Hans
Published: January 2007

Ratzinger's Apology of Christianity can be characterized as an interpretation of the Bible based on spiritualist metaphysics. This paper is a critical analysis of the central theses and arguments of his book against the background of critical rationalism.
Sand, Fish and Sea: A Legal Reflection on Islands—From Orkney to Vanuatu
Authors: Farran Sue
Published: January 2007

It might be thought that the Orkney and Shetland Islands to the north of Scotland have little in common with the tropical islands in the South Pacific region. This article demonstrates that islands across time and space can share many similar concerns by reflecting on a number of legal issues which either have been or are pertinent to islands in both hemispheres, taking into account the role and relevance of customary or traditional law, the influence of introduced or colonial law, and the legal consequences of political domination of one group by another. In particular the article looks at the challenges presented where there is more than one system of law or set of rules applicable to questions of ownership of the sea, the seashore and fishing, and the consequences this can have for management and control of marine resources.
X-linked gray platelet syndrome due to a GATA1 Arg216Gln mutation
Authors: Tubman Venée N. , Levine Jason E. , Campagna Dean R. , Monahan-Earley Rita , Dvorak Ann M. , Neufeld Ellis J. , Fleming Mark D.
Published: January 2007

We identified a family with gray platelet syndrome (GPS) segregating as a sex-linked trait. Affected males had a mild bleeding disorder, thrombocytopenia, and large agranular platelets characteristic of GPS, while obligate carrier females were asymptomatic but had dimorphic platelets on peripheral smear. Associated findings included mild erythrocyte abnormalities in affected males. Linkage analysis revealed a 63 cM region on the X chromosome between markers G10578 and DXS6797, which segregated with the platelet phenotype and included the GATA1 gene. Sequencing of GATA1 revealed a G-to-A mutation at position 759 corresponding to amino acid change Arg216Gln. This mutation was previously described as a cause of X-linked thrombocytopenia with thalassemia (XLTT) but not of gray platelet syndrome. Our findings suggest that XLTT is within a spectrum of disorders constituting the gray platelet syndrome, and we propose that GATA1 is an upstream regulator of the genes required for platelet α-granule biogenesis.
A sequence variation scan of the coagulation factor VIII (FVIII) structural gene and associations with plasma FVIII activity levels
Authors: Viel Kevin R. , Machiah Deepa K. , Warren Diane M. , Khachidze Manana , Buil Alfonso , Fernstrom Karl , Souto Juan C. , Peralta Juan M. , Smith Todd , Blangero John , Porter Sandra , Warren Stephen T. , Fontcuberta Jordi , Soria Jose M. , Dana Flanders W. , Almasy Laura , Howard Tom E.
Published: January 2007

Plasma factor VIII coagulant activity (FVIII:C) level is a highly heritable quantitative trait that is strongly correlated with thrombosis risk. Polymorphisms within only 1 gene, the ABO blood-group locus, have been unequivocally demonstrated to contribute to the broad population variability observed for this trait. Because less than 2.5% of the structural FVIII gene (F8) has been examined previously, we resequenced all known functional regions in 222 potentially distinct alleles from 137 unrelated nonhemophilic individuals representing 7 racial groups. Eighteen of the 47 variants identified, including 17 single-nucleotide polymorphisms (SNPs), were previously unknown. As the degree of linkage disequilibrium across F8 was weak overall, we used measured-genotype association analysis to evaluate the influence of each polymorphism on the FVIII:C levels in 398 subjects from 21 pedigrees known as the Genetic Analysis of Idiopathic Thrombophilia project (GAIT). Our results suggested that 92714C>G, a nonsynonymous SNP encoding the B-domain substitution D1241E, was significantly associated with FVIII:C level. After accounting for important covariates, including age and ABO genotype, the association persisted with each C-allele additively increasing the FVIII:C level by 14.3 IU dL−1 (P = .016). Nevertheless, because the alleles of 56010G>A, a SNP within the 3′ splice junction of intron 7, are strongly associated with 92714C>G in GAIT, additional studies are required to determine whether D1241E is itself a functional variant.
ABT-869, a multitargeted receptor tyrosine kinase inhibitor: inhibition of FLT3 phosphorylation and signaling in acute myeloid leukemia
Authors: Shankar Deepa B. , Li Junling , Tapang Paul , Owen McCall J. , Pease Lori J. , Dai Yujia , Wei Ru-Qi , Albert Daniel H. , Bouska Jennifer J. , Osterling Donald J. , Guo Jun , Marcotte Patrick A. , Johnson Eric F. , Soni Niru , Hartandi Kresna , Michaelides Michael R. , Davidsen Steven K. , Priceman Saul J. , Chang Jenny C. , Rhodes Katrin , Shah Neil , Moore Theodore B. , Sakamoto Kathleen M. , Glaser Keith B.
Published: January 2007

In 15% to 30% of patients with acute myeloid leukemia (AML), aberrant proliferation is a consequence of a juxtamembrane mutation in the FLT3 gene (FMS-like tyrosine kinase 3–internal tandem duplication [FLT3-ITD]), causing constitutive kinase activity. ABT-869 (a multitargeted receptor tyrosine kinase inhibitor) inhibited the phosphorylation of FLT3, STAT5, and ERK, as well as Pim-1 expression in MV-4-11 and MOLM-13 cells (IC50 approximately 1-10 nM) harboring the FLT3-ITD. ABT-869 inhibited the proliferation of these cells (IC50 = 4 and 6 nM, respectively) through the induction of apoptosis (increased sub-G0/G1 phase, caspase activation, and PARP cleavage), whereas cells harboring wild-type (wt)–FLT3 were less sensitive. In normal human blood spiked with AML cells, ABT-869 inhibited phosphorylation of FLT3 (IC50 approximately 100 nM), STAT5, and ERK, and decreased Pim-1 expression. In methylcellulose-based colony-forming assays, ABT-869 had no significant effect up to 1000 nM on normal hematopoietic progenitor cells, whereas in AML patient samples harboring both FLT3-ITD and wt-FLT3, ABT-869 inhibited colony formation (IC50 = 100 and 1000 nM, respectively). ABT-869 dose-dependently inhibited MV-4-11 and MOLM-13 flank tumor growth, prevented tumor formation, regressed established MV-4-11 xenografts, and increased survival by 20 weeks in an MV-4-11 engraftment model. In tumors, ABT-869 inhibited FLT3 phosphorylation, induced apoptosis (transferase-mediated dUTP nick-end labeling [TUNEL]) and decreased proliferation (Ki67). ABT-869 is under clinical development for AML.
Inhibition of HIV-1 infection by viral chemokine U83A via high-affinity CCR5 interactions that block human chemokine-induced leukocyte chemotaxis and receptor internalization
Authors: Catusse Julie , Parry Chris M. , Dewin David R. , Gompels Ursula A.
Published: January 2007

HIV-1 strains use C-C-chemokine receptor 5, CCR5, as a coreceptor for host transmission. Human CCR5 chemokine ligands inhibit binding and infection, whereas CCR5 mutations also inhibit infection by preventing surface expression, resulting in delayed progression to AIDS. Here, we describe a human herpesvirus 6 (HHV-6A) chemokine, U83A, which binds CCR5 with higher affinity than human chemokines, displacing their binding and leading to inhibition of chemotaxis of human leukocytes. Similarly, U83A inhibits infection by HIV-1 strains which use CCR5, but not the CXCR4, coreceptor. Unlike human CCR5 chemokine ligands which induce rapid CCR5 internalization mediated via clathrin, treatment with U83A prevents internalization. A spliced truncated U83A isoform, U83A-N, also binds CCR5 albeit with lower affinity, and this correlates with lower HIV-1 infection inhibition, whereas further truncation abolishes binding and any inhibition. Confocal microscopy confirms CCR5 internalization inhibition by U83A treatment, whereas labeled transferrin uptake shows that endocytosis via clathrin is unaltered. Previous results show that, although U83A-N is an antagonist, U83A is an agonist for CCR1, CCR4, CCR6, and CCR8 present on immune effector and antigen-presenting cells and here also shown for CCR5. Thus, U83A could act as a novel inhibitor of HIV-1 infection while also stimulating local immunity to the virus.
Cladribine in a weekly versus daily schedule for untreated active hairy cell leukemia: final report from the Polish Adult Leukemia Group (PALG) of a prospective, randomized, multicenter trial
Authors: Robak Tadeusz , Jamroziak Krzysztof , Gora-Tybor Joanna , Blonski Jerzy Z. , Kasznicki Marek , Dwilewicz-Trojaczek Jadwiga , Wiater Elzbieta , Zdunczyk Andrzej , Dybowicz Jacek , Dmoszynska Anna , Wojtaszko Maria , Zdziarska Barbara , Calbecka Malgorzata , Kostyra Aleksandra , Hellmann Andrzej , Lewandowski Krzysztof , Stella-Holowiecka Beata , Sulek Kazimierz , Gawronski Krzysztof , Skotnicki Aleksander B. , Nowak Wieslaw , Zawilska Krystyna , Molendowicz-Portala Lucyna , Kloczko Janusz , Sokolowski Jarosław , Warzocha Krzysztof , Seferyńska Ilona , Ceglarek Bernardeta , Konopka Lech ,   for the Polish Adult Leukemia Group
Published: January 2007

Cladribine (2-chlorodeoxyadenosine, 2-CdA) treatment-associated infections may shorten potentially long-term survival in hairy cell leukemia (HCL). In search of the optimal mode of 2-CdA administration, 132 patients with untreated HCL were randomized to receive either standard 5-day 2-CdA protocol or a novel schedule of 6 weekly 2-CdA infusions suggested to be less toxic. Analysis of treatment response confirmed similar complete remission rates, overall response rates, progression-free survival, and overall survival in both 2-CdA protocols. However, we did not observe lower toxicity in the weekly schedule. Of special interest, no significant differences were found in the rate of grade 3/4 infections (18% for daily and 26% for weekly protocol, difference −8.2%; 95% confidence interval [CI] −23.2% to 6.9%; P = .28) and the rate of septic deaths (3% for daily and 2% for weekly protocol, difference 1.4%; 95% CI −4.3% to 7.0%; P = .64). In conclusion, HCL treatment with weekly 2-CdA infusions is equally effective but no safer than the standard 5-day 2-CdA protocol.
Vitamin A potentiates CpG-mediated memory B-cell proliferation and differentiation: involvement of early activation of p38MAPK
Authors: Ertesvag Aase , Aasheim Hans-Christian , Naderi Soheil , Blomhoff Heidi Kiil
Published: January 2007

Foreign CpG-DNA from viruses and bacteria can activate memory B cells through binding to toll-like receptor 9, and this pathway has been hypothesized to be involved in the continuous activation of memory B cells ensuring life-long humoral immunity. In this study, we demonstrate that retinoic acid (RA) is a potent coactivator of this pathway in human B cells. RA enhanced the CpG-mediated proliferation of CD27+ memory B cells, and the proliferative response was accompanied by increased immunoglobulin (Ig) secretion indicative of plasma-cell formation. The RA-induced proliferation was preceded by enhanced expression of cyclin D3, and both the expression of cyclin D3 and the induced Ig secretion were found to be dependent on IL-10. Of importance, RA increased the CpG-induced phosphorylation of ERK1/2, p38MAPK, and IκB as early as 30 minutes after stimulation. By using specific inhibitors, all the RA-mediated events, including proliferation, cyclin D3 expression, IL-10 secretion, and Ig secretion, were shown to be dependent on p38MAPK. Hence, we propose that RA can strengthen humoral immunity by promoting CpG-mediated stimulation of CD27+ B cells via activation of p38MAPK resulting in increased proliferation and differentiation to Ig-secreting plasma cells.
Mapping early conformational changes in αIIb and β3 during biogenesis reveals a potential mechanism for αIIbβ3 adopting its bent conformation
Authors: Beau Mitchell W. , Li Jihong , Murcia Marta , Valentin Nathalie , Newman Peter J. , Coller Barry S.
Published: January 2007

Current evidence supports a model in which the low-affinity state of the platelet integrin αIIbβ3 results from αIIbβ3 adopting a bent conformation. To assess αIIbβ3 biogenesis and how αIIbβ3 initially adopts the bent conformation, we mapped the conformational states occupied by αIIb and β3 during biogenesis using conformation-specific monoclonal antibodies (mAbs). We found that αIIbβ3 complex formation was not limited by the availability of either free pro-αIIb or free β3, suggesting that other molecules, perhaps chaperones, control complex formation. Five β3-specific, ligand-induced binding site (LIBS) mAbs reacted with much or all free β3 but not with β3 when in complex with mature αIIb, suggesting that β3 adopts its mature conformation only after complex formation. Conversely, 2 αIIb-specific LIBS mAbs directed against the αIIb Calf-2 region adjacent to the membrane reacted with only minor fractions of free pro-αIIb, raising the possibility that pro-αIIb adopts a bent conformation early in biogenesis. Our data suggest a working model in which pro-αIIb adopts a bent conformation soon after synthesis, and then β3 assumes its bent conformation by virtue of its interaction with the bent pro-αIIb.
A sequence based synteny map between soybean and Arabidopsis thaliana
Authors: Shultz Jeffry L , Ray Jeffery D , Lightfoot David A
Published: January 2007

Background

Soybean (Glycine max, L. Merr.) is one of the world's most important crops, however, its complete genomic sequence has yet to be determined. Nonetheless, a large body of sequence information exists, particularly in the form of expressed sequence tags (ESTs). Herein, we report the use of the model organism Arabidopsis thaliana (thale cress) for which the entire genomic sequence is available as a framework to align thousands of short soybean sequences.

Results

A series of JAVA-based programs were created that processed and compared 341,619 soybean DNA sequences against A. thaliana chromosomal DNA. A. thaliana DNA was probed for short, exact matches (15 bp) to each soybean sequence, and then checked for the number of additional 7 bp matches in the adjacent 400 bp region. The position of these matches was used to order soybean sequences in relation to the A. thaliana genome.

Conclusion

Reported associations between soybean sequences and A. thaliana were within a 95% confidence interval of e-30 – e-100. In addition, the clustering of soybean expressed sequence tags (ESTs) based on A. thaliana sequence was accurate enough to identify potential single nucleotide polymorphisms (SNPs) within the soybean sequence clusters. An EST, bacterial artificial chromosome (BAC) end sequence and marker amplicon sequence synteny map of soybean and A. thaliana is presented. In addition, all JAVA programs used to create this map are available upon request and on the WEB.
Ashbya Genome Database 3.0: a cross-species genome and transcriptome browser for yeast biologists
Authors: Gattiker Alexandre , Rischatsch Riccarda , Demougin Philippe , Voegeli Sylvia , Dietrich Fred S , Philippsen Peter , Primig Michael
Published: January 2007

Background

The Ashbya Genome Database (AGD) 3.0 is an innovative cross-species genome and transcriptome browser based on release 40 of the Ensembl developer environment.

Description

AGD 3.0 provides information on 4726 protein-encoding loci and 293 non-coding RNA genes present in the genome of the filamentous fungus Ashbya gossypii. A synteny viewer depicts the chromosomal location and orientation of orthologous genes in the budding yeast Saccharomyces cerevisiae. Genome-wide expression profiling data obtained with high-density oligonucleotide microarrays (GeneChips) are available for nearly all currently annotated protein-coding loci in A. gossypii and S. cerevisiae.

Conclusion

AGD 3.0 hence provides yeast- and genome biologists with comprehensive report pages including reliable DNA annotation, Gene Ontology terms associated with S. cerevisiae orthologues and RNA expression data as well as numerous links to external sources of information. The database is accessible at http://agd.vital-it.ch/.
FM1-43 is a Permeant Blocker of Mechanosensitive Ion Channels in Sensory Neurons and Inhibits Behavioural Responses to Mechanical Stimuli
Authors: Drew Liam J , Wood John N
Published: January 2007

The molecular identity and pharmacological properties of mechanically gated ion channels in sensory neurons are poorly understood. We show that FM1-43, a styryl dye used to fluorescently label cell membranes, permeates mechanosensitive ion channels in cultured dorsal root ganglion neurons, resulting in blockade of three previously defined subtypes of mechanically activated currents. Blockade and dye uptake is voltage dependent and regulated by external Ca2+. The structurally related larger dye FM3-25 inhibited mechanically activated currents to a lesser degree and did not permeate the channels. In vivo, FMI-43 decreases pain sensitivity in the Randall-Selitto test and increases the withdrawal threshold from von Frey hairs, together suggesting that the channels expressed at the cell body in culture mediate mechanosensation in the intact animal. These data give further insight into the mechanosensitive ion channels expressed by somatosensory neurons and suggest FM dyes are an interesting tool for studying them.
Analysis of the thiol status of peripheral blood leukocytes in rheumatoid arthritis patients
Authors: Pedersen-Lane Joan H , Zurier Robert B , Lawrence David A
Published: January 2007

Although the exact etiology of rheumatoid arthritis (RA) remains unknown, there is increasing evidence that reactive oxygen species and a pro-oxidant/antioxidant imbalance are an important part of the pathogenesis of joint tissue injury. Flow cytometry was used to evaluate the thiol status [surface-thiols and intracellular glutathione (iGSH)] of leukocytes from RA patients and controls. Levels of surface-thiols and iGSH of leukocytes from RA patients were significantly lower than of leukocytes from controls. CD53, a glycoprotein of the tetraspanin superfamily, which coprecipitates with the GSH recycling enzyme γ-glutamyl transpeptidase, was elevated significantly on leukocytes from RA patients compared with leukocytes from controls. Surface-thiols and GSH play important roles in redox buffering of cells, providing protection from oxidative stress. The chronic inflammation of RA has been associated with oxidative stress, which is shown to cause a decline in the levels of cellular antioxidant sulfhydryls (R-SH). As antioxidant-protective levels also decline with age, the problem is compounded in older RA patients, who did have fewer R-SH. Chronic stress can also have an effect on telomere lengths, determining cell senescence and longevity. Although telomeres shorten with increasing age, our flow cytometry studies indicate that accelerated shortening in telomere lengths occurs with increasing age of RA patients, suggesting premature cellular aging. The paradox is that lymphocytes from RA patients are believed to resist apoptosis, and we suggest that the elevated expression of CD53, which results from the increased oxidative stress, may protect against apoptosis.
Interaction analysis of theCBLBandCTLA4genes in type 1 diabetes
Authors: Payne Felicity , Cooper Jason D , Walker Neil M , Lam Alex C , Smink Luc J , Nutland Sarah , Stevens Helen E , Hutchings Jayne , Todd John A
Published: January 2007

Gene-gene interaction analyses have been suggested as a potential strategy to help identify common disease susceptibility genes. Recently, evidence of a statistical interaction between polymorphisms in two negative immunoregulatory genes, CBLB and CTLA4, has been reported in type 1 diabetes (T1D). This study, in 480 Danish families, reported an association between T1D and a synonymous coding SNP in exon 12 of the CBLB gene (rs3772534 G>A; minor allele frequency, MAF=0.24; derived relative risk, RR for G allele=1.78; P=0.046). Furthermore, evidence of a statistical interaction with the known T1D susceptibility-associated CTLA4 polymorphism rs3087243 (laboratory name CT60, G>A) was reported (P<0.0001), such that the CBLB SNP rs3772534 G allele was overtransmitted to offspring with the CTLA4 rs3087243 G/G genotype. We have, therefore, attempted to obtain additional support for this finding in both large family and case-control collections. In a primary analysis, no evidence for an association of the CBLB SNP rs3772534 with disease was found in either sample set (2162 parent-child trios, P=0.33; 3453 cases and 3655 controls, P=0.69). In the case-only statistical interaction analysis between rs3772534 and rs3087243, there was also no support for an effect (1994 T1D affected offspring, and 3215 cases, P=0.92). These data highlight the need for large, well-characterized populations, offering the possibility of obtaining additional support for initial observations owing to the low prior probability of identifying reproducible evidence of gene-gene interactions in the analysis of common disease-associated variants in human populations.
Physical modeling and analysis of P-wave attenuation anisotropy in transversely isotropic media
Authors: Zhu Yaping , Tsvankin Ilya , Dewangan Pawan , Wijk Kasper van
Published: January 2007

Anisotropic attenuation can provide sensitive attributes for fracture detection and lithology discrimination. This paper analyzes measurements of the P-wave attenuation coefficient in a transversely isotropic sample made of phenolic material. Using the spectral-ratio method, we estimate the group (effective) attenuation coefficient of P-waves transmitted through the sample for a wide range of propagation angles (from [Formula: see text] to [Formula: see text]) with the symmetry axis. Correction for the difference between the group and phase angles and for the angular velocity variation help us to obtain the normalized phase attenuation coefficient [Formula: see text] governed by the Thomsen-style attenuation-anisotropy parameters [Formula: see text] and [Formula: see text]. Whereas the symmetry axis of the angle-dependent coefficient [Formula: see text] practically coincides with that of the velocity function, the magnitude of the attenuation anisotropy far exceeds that of the velocity anisotropy. The quality factor [Formula: see text] increases more than tenfold from the symmetry axis (slow direction) to the isotropy plane (fast direction). Inversion of the coefficient [Formula: see text] using the Christoffel equation yields large negative values of the parameters [Formula: see text] and [Formula: see text]. The robustness of our results critically depends on several factors, such as the availability of an accurate anisotropic velocity model and adequacy of the homogeneous concept of wave propagation, as well as the choice of the frequency band. The methodology discussed here can be extended to field measurements of anisotropic attenuation needed for AVO (amplitude-variation-with-offset) analysis, amplitude-preserving migration, and seismic fracture detection.
A separable-kernel decomposition method for approximating the DSR continuation operator
Authors: Chen Jing-Bo , Liu Hong , Zhang Zhi-Fu
Published: January 2007

We develop a separable-kernel decomposition method for approximating the double-square-root (DSR) continuation operator in one-way migrations in this paper. This new approach is a further development of separable approximations of the single-square-root (SSR) operator. The separable approximation of the DSR operator generally involves solving a complicated nonlinear system of integral equations. Instead of solving this nonlinear system directly, our new method consists of repeatedly applying the separable-kernel technique developed for the two-variable SSR operator to the multivariable DSR operator. Numerical experiments demonstrate the efficiency of the proposed method. We illustrate the fast convergence of the obtained separable approximation. We also demonstrate the capability of this novel approximation for imaging an area with geologic complexities through synthetic data.
Degrees of homogeneity of potential fields and structural indices of Euler deconvolution
Authors: Stavrev Petar , Reid Alan
Published: January 2007

Homogeneity is a well-known property of the potential fields of simple point sources used in field inversion. We find that the analytical expressions of potential fields created by sources of complicated shape and constant or variable density or magnetization also show this property. This is true if all variables of length dimension are involved in the test of homogeneity. The coordinates of observation points and the source coordinates and sizes form an extended set of variables, in relation to which the field expression is homogeneous. In this case, the principal definition of homogeneity applied to a potential field can be treated as an operator of a space transform of similarity. The ratio between the transformed and original fields determines the value and sign of the degree of homogeneity [Formula: see text]. The latter may take on positive, zero, or negative values. The degree of homogeneity depends on the type of field and on the assumed physical parameter of the field source, and can be nonunique for a given field element. We analyze the potential field of one singular point as the simplest case of homogeneity. Thus, we deduce results for the structural index, [Formula: see text], in Euler deconvolution. The structural index can also be positive, zero, or negative, but it has a unique value. Analytical considerations, as well as numerical tests on the gravity contact model, confirm the proposed physical interpretation of [Formula: see text], and lead to an extended version of Euler’s differential equation for potential fields.
Obestatin Is Not Elevated or Correlated with Insulin in Children with Prader-Willi Syndrome
Authors: Park Won Hah , Oh Yoo Joung , Kim Gae Young , Kim Sang Eun , Paik Kyung-Hoon , Han Sun Ju , Kim An Hee , Chu Su Hyun , Kwon Eun Kyung , Kim Seon Woo , Jin Dong-Kyu
Published: January 2007

Context: Obestatin is a peptide hormone derived from the proteolytic cleavage of ghrelin preprohormone. In Prader-Willi syndrome (PWS), the levels of total ghrelin (TG) and acylated ghrelin (AG) are increased, and these hormones are regulated by insulin.

Objective: Our objective was to analyze the changes in the obestatin levels after glucose loading and to characterize the correlations of obestatin with TG, AG, and insulin.

Design: Plasma obestatin, TG, AG, and insulin levels were measured in PWS children (n = 15) and controls (n = 18) during an oral glucose tolerance test.

Setting: All subjects were admitted to the Samsung Medical Center.

Interventions: An oral glucose tolerance test was performed after an overnight fast.

Main Outcome Measures: The plasma levels of obestatin, TG, AG, and serum insulin were measured at 0, 30, 60, 90, and 120 min after glucose challenge, and areas under the curves (AUCs) were calculated.

Results: No significant difference in AUC of the plasma obestatin was found between the PWS children and normal obese controls (P = 0.885), although AUC of AG (P = 0.002) and TG (P = 0.003) were increased in the PWS children. Moreover, There was a negative correlation between the AUC of AG and AUC of insulin both in PWS (r = −0.432; P = 0.049) and in controls (r = −0.507; P = 0.016). However, AUC of obestatin was not significantly correlated with AUC of insulin (in PWS, r = 0.168 and P = 0.275; in controls, r = −0.331 and P = 0.09).

Conclusions: Our results indicate that plasma obestatin is not elevated in PWS children and is not regulated by insulin both in PWS children and in obese controls.
Fat Mass Is Not Beneficial to Bone in Adolescents and Young Adults
Authors: Janicka Agnieszka , Wren Tishya A. L. , Sanchez Monique M. , Dorey Frederick , Kim Paul S. , Mittelman Steven D. , Gilsanz Vicente
Published: January 2007

Context: Although muscle mass is beneficial to bone, studies on the effect of fat mass on bone have yielded conflicting results.

Objective: The aim of this study was to assess the relations between lean and fat mass and bone structure.

Design: This study was cross-sectional.

Setting: The study was conducted in a general community.

Subjects: Subjects included 300 healthy sexually mature adolescents and young adults (150 males and 150 females) between the ages of 13 and 21 yr.

Main Outcome Measure: We investigated the relation between dual-energy x-ray absorptiometry (DXA) measures of total body fat and lean mass and bone values obtained with DXA (legs and lumbar spine bone mineral density and bone mineral content) and computed tomography (CT) (cross-sectional and cortical bone areas of the femurs and cross-sectional area and cancellous bone density of the vertebrae).

Results: Simple and multiple linear regression analyses showed significant positive relations between DXA lean mass and all CT and DXA measures of bone in the axial and appendicular skeletons (all P < 0.005). In contrast, whereas Pearson correlations between DXA measures of fat mass and bone parameters were generally positive, multiple regression analyses showed that fat mass, after accounting for lean mass, trunk height/leg length, had a negative, or no, correlation with CT and DXA values for bone.

Conclusions: Our findings provide compelling evidence that, despite increased mechanical loading and independent of lean mass, adipose tissue is not beneficial to bone structure.
Thyroid Hormone Synthesis and Secretion in Humans after 80 Milligrams of Iodine for 15 Days and Subsequent Withdrawal
Authors: Theodoropoulou Anastasia , Vagenakis Apostolos G. , Makri Maria , Markou Kostas B.
Published: January 2007

Context: In animals, acute iodine administration results in acute intrathyroidal inhibition of iodinations followed by escape of the inhibition if the excessive iodine intake continues. In humans, the intrathyroidal nonhormonal and hormonal iodine concentration after exposure to large doses of iodine for a relatively long period of time is not known.

Objective: To determine whether, in human thyroid, administration of large doses of iodine for a relatively long time results in alterations of intrathyroidal hormonal (HI) T4 and T3 and total iodine (TI) content, as well as whether changes in serum concentration of thyroid hormones and TSH would occur after iodine administration or discontinuation.

Design: In 33 euthyroid patients with single thyroid nodule or hyperparathyroidism, Lugol solution (80 mg iodine) was administered for 15 d before operation. Groups of six to eight patients underwent operation 0, 5, 10, and 15 d after iodine withdrawal. TI, HI in a sample of thyroid tissue, and serum concentration of T4, T3, and TSH were measured. In 21 normal euthyroid subjects who did not undergo operation, a similar protocol was used and serial blood measurements were taken.

Main Outcome Measure: Intrathyroidal TI, HI, and serum thyroid hormone and TSH measurements were the main outcome measure.

Results: Intrathyroidal HI content and serum T4 and T3 were unchanged during and after iodine discontinuation. TI was increased during iodine administration and returned to control values 5 d after discontinuation of iodine. The ratio of HI/TI was decreased and returned to control values 15 d after the iodine was discontinued. Serum TSH was increased during iodine administration and returned to control values 10 d after iodine withdrawal.

Conclusions: In humans, administration of iodine for a relatively long period of time was accompanied by increased intrathyroidal TI, but no changes in HI or demonstrable increases of serum T4 and T3 were observed. It is hypothesized that the maintenance of normal intrathyroidal HI is the result of the combined inhibitory effect of iodine on thyroid hormone synthesis and on the release of T4 and T3 from the thyroid.
Gestational Age Correlates to Genotype in Girls with CYP21 Deficiency
Authors: Gidlöf Sebastian , Wedell Anna , Nordenström Anna
Published: January 2007

Context: The mechanisms behind onset of labor and prolongation of pregnancy are not fully understood, but steroid hormones are thought to contribute. 17-Hydroxyprogesterone has been shown to prolong pregnancy in humans. Male fetuses have been reported to have longer gestation than females.

Objective: The objective of the study was to investigate whether severity of 21-hydroxylase gene (CYP21) deficiency in fetuses with congenital adrenal hyperplasia (CAH) correlates with length of pregnancy.

Design and Subjects: The gestational age (GA) of a cohort of CAH patients born between 1978 and 2004 was studied retrospectively. The GA was correlated to the severity of disease indicated by CYP21 genotype in 114 patients. The results were compared with respect to sex and the normal Swedish population data.

Results: In female fetuses with CAH, we found a correlation between GA and CYP21 genotype. Females with the most severe form of the disease, null mutation, had the longest GA and differed significantly from the normal population. No difference between the sexes was detected for fetuses with CAH as a group. There were no significant differences between CYP21 genotype groups for males.

Conclusions: Female patients with severe CYP21 deficiency had longer GA than patients with the milder form of the disease, indicating that androgen excess, increased 17-hydroxyprogesterone levels, or cortisol deficiency or a combination of these factors is of importance for prolongation of pregnancy. The same correlation was not observed for male patients. The results of this study support the notion that steroid hormones affect the prolongation of pregnancy or onset of labor or both.
Acute Effects of Triiodothyronine on Endothelial Function in Human Subjects
Authors: Napoli Raffaele , Guardasole Vincenzo , Angelini Valentina , Zarra Emanuela , Terracciano Daniela , D’Anna Carolina , Matarazzo Margherita , Oliviero Ugo , Macchia Vincenzo , Saccà Luigi
Published: January 2007

Context: Thyroid hormone regulates several cardiovascular functions, and low T3 levels are frequently associated with cardiovascular diseases. Whether T3 exerts any acute and direct effect on endothelial function in humans is unknown.

Objective: Our objective was to clarify whether acute changes in serum T3 concentration affect endothelial function.

Design, Setting, and Subjects: Ten healthy subjects (age, 24 ± 1 yr) participated in a double-blind, placebo-controlled trial at a university hospital.

Interventions: T3 (or placebo) was infused for 7 h into the brachial artery to raise local T3 to levels observed in moderate hyperthyroidism. Vascular reactivity was tested by intraarterial infusion of vasoactive agents.

Main Outcome Measures: We assessed changes in forearm blood flow (FBF) measured by plethysmography.

Results: FBF response to the endothelium-dependent vasodilator acetylcholine was enhanced by T3 (P = 0.002 for the interaction between T3 and acetylcholine). The slopes of the dose-response curves were 0.41 ± 0.06 and 0.23 ± 0.04 ml/dl·min/μg in the T3 and placebo study, respectively (P = 0.03). T3 infusion had no effect on the FBF response to sodium nitroprusside. T3 potentiated the vasoconstrictor response to norepinephrine (P = 0.006 for the interaction). Also, the slopes of the dose-response curves were affected by T3 (1.95 ± 0.77 and 3.83 ± 0.35 ml/dl·min/mg in the placebo and T3 study, respectively; P < 0.05). The increase in basal FBF induced by T3 was inhibited by NG-monomethyl-l-arginine.

Conclusions: T3 exerts direct and acute effects on the resistance vessels by enhancing endothelial function and norepinephrine-induced vasoconstriction. The data may help clarify the vascular impact of the low T3 syndrome and point to potential therapeutic strategies.
Accuracy of paediatric echocardiographic transmission via telemedicine
Authors: Lewin Mark , Xu Cathy , Jordan Mary , Borchers Heidi , Ayton Catherine , Wilbert Dennis , Melzer Sanford
Published: January 2007

We evaluated the accuracy of realtime echocardiography studies conducted via telemedicine (at 384 kbit/s) and prerecorded video studies, by comparing the results with subsequent in-person echocardiography examination performed at follow-up. Between January 2002 and December 2004, there were 769 paediatric echo studies of patients aged one day to 19 years by telemedicine. There were three cases (0.4%) in which the study could not be successfully transmitted in realtime due to ISDN line or equipment failure. These were recorded, then transmitted and reviewed within 24 h. A normal heart was demonstrated in 272 studies (35%). A non-urgent congenital heart defect (CHD) was detected in 311 studies (41%). A critical cardiac abnormality was identified in 25 studies (3% of the total). Sixty-seven studies were repeated in person at the tertiary centre. All but one of the follow-up echocardiograms confirmed our initial telemedicine diagnosis (99% sensitivity). There were 655 videorecorded studies delivered to the tertiary centre between February 2002 and November 2003. Thirty-two patients had a repeated echocardiogram performed there. There were either discrepancies or lack of diagnostic clarity in 12 studies (38%) compared with on-site echo evaluations. This suggests that echocardiography evaluation using videorecordings may be less accurate than via realtime telemedicine.
Experience with asynchronous medical teleconsultation in the Alliance of the Italian Hospitals Worldwide
Authors: Costanzo G , Monari P
Published: January 2007

A store-and-forward teleconsultation system was established for 36 Italian hospitals located in 22 different countries. Referrals were made to a network of 33 health centres in Italy via a management centre (MC). The MC was equipped with a server to manage the service. The participating hospitals used client workstations with special software. The referring centres generated teleconsultation requests, which were sent to the MC and allocated manually by the latter to the most appropriate specialist on the basis of information provided in the message. From 1 June 2005 to 15 March 2006, 187 enquiries out of 221 were answered. The median response time was two days. A service satisfaction survey was conducted among the users and about 90% of the responses were positive. The teleconsultation system represents a mechanism for providing equitable access to health care for all the referring doctors.
Randomized controlled trial of the effectiveness of an intervention to implement evidence-based patient decision support in a nursing call centre
Authors: Stacey Dawn , O'Connor Annette M , Graham Ian D , Pomey Marie-Pascale
Published: January 2007

We evaluated the effect of an intervention on call centre nurses' knowledge of decision support and skills in coaching callers facing value-sensitive health decisions. Forty-one registered nurses at a health call centre were randomly assigned to an intervention or control group. The intervention was a coaching protocol, online tutorial, skills building workshop and performance feedback. The main outcome measures were: knowledge test; blinded quality assessment of coaching skills during simulated calls and call duration. Compared with controls, nurses in the intervention group had better knowledge (74 versus 60%, P = 0.007) and decision coaching skills (81 versus 44%, P < 0.001), particularly in assessing decisional needs (information, values clarity, support, stage and timing of decision) and addressing support issues. Call duration did not differ (18.5 versus 16.7 min, P = 0.73). The coaching protocol was rated as compatible with nurses' views on decision-making and more advantageous compared with their usual practices. The intervention improved the quality of nurses' decision coaching without affecting call duration.