bluuebunny/crossref_metadata_2025 huggingface dataset:
Extracellular RNA mediates endothelial-cell permeability via vascular endothelial growth factor
Authors: Fischer Silvia , Gerriets Tibo , Wessels Carina , Walberer Maureen , Kostin Sawa , Stolz Erwin , Zheleva Kirila , Hocke Andreas , Hippenstiel Stefan , Preissner Klaus T.
Published: June 2007

Cell injury leads to exposure of intracellular material and is associated with increased permeability of vessels in the vicinity of the damage. Here, we demonstrate that natural extracellular RNA as well as artificial RNA (poly-I:C), or single-stranded RNA but not DNA, significantly increased the permeability across brain microvascular endothelial cells in vitro and in vivo. RNA-induced hyperpermeability of tight monolayers of endothelial cells correlated with disintegration of tight junctions and was mediated through vascular endothelial growth factor (VEGF), reminiscent of heparin's activities. Antisense oligonucleotides against VEGF-receptor 2 (VEGF-R2) prevented the permeability-inducing activity of extracellular RNA and heparin completely. Hence, these polyanionic substances can lead to mobilization/stabilization of VEGF with the subsequent activation of VEGF-R2. In accordance with these functional data, strong binding of VEGF as well as other growth factors to RNA was demonstrable. In in vivo rat models of FeCl3-induced sinus sagittal is superior thrombosis and stroke/brain edema, pretreatment of animals with RNase (but not DNase) resulted in a significant reduction of vessel occlusion, infarct volume, and prevention of brain edema formation. Together, these results identify extracellular RNA as a novel natural permeability factor, upstream of VEGF, whereas counteracting RNase treatment may serve as new vessel-protective modality.
Clot busting in kids: less PTS?
Authors: Raffini Leslie
Published: June 2007

Goldenberg and colleagues' retrospective analysis of pediatric patients with high-risk, occlusive lower extremity deep vein thrombosis (DVT) suggests that thrombolytic therapy with tPA (with or without mechanical thrombolysis) may decrease the risk of postthrombotic syndrome (PTS).
Important port for SHIP-1 at Dok-3
Authors: Campbell Kerry S.
Published: June 2007

Dok-3 serves as an inhibitory adaptor protein through recruitment of the 5′-inositol phosphatase, SHIP-1. Ng and colleagues have generated a Dok-3–deficient mouse that exhibits hyperresponsive B cells, thereby implicating the adaptor as an important negative regulator of certain signaling events downstream from the antigen receptor.
Stimulating results with stimulatory antibodies
Authors: Mapara Markus Y.
Published: June 2007

In this issue of Blood, Svegliati and colleagues provide new insights into the mechanisms of chronic GVHD development by demonstrating the presence and functional activity of stimulatory anti–PDGF-R autoantibodies in patients with extensive chronic GVHD.
ROCK and Rho(ll) in bone marrow
Authors: Nurden Alan T.
Published: June 2007

Mutations in the MYH9 gene give rise to May-Hegglin and related giant-platelet syndromes. In this issue of Blood, Chen and colleagues use mouse models to show that Myh9 acts through the Rho-ROCK pathway as a negative regulator of platelet production in the bone marrow.
New criteria to identify risk of progression in monoclonal gammopathy of uncertain significance and smoldering multiple myeloma based on multiparameter flow cytometry analysis of bone marrow plasma cells
Authors: Pérez-Persona Ernesto , Vidriales María-Belén , Mateo Gema , García-Sanz Ramón , Mateos Maria-Victoria , de Coca Alfonso García , Galende Josefina , Martín-Nuñez Guillermo , Alonso José M. , de las Heras Natalia , Hernández José M. , Martín Alejandro , López-Berges Consuelo , Orfao Alberto , San Miguel Jesús F.
Published: June 2007

Monoclonal gammopathy of uncertain significance (MGUS) and smoldering multiple myeloma (SMM) are plasma cell disorders with a risk of progression of approximately 1% and 10% per year, respectively. We have previously shown that the proportion of bone marrow (BM) aberrant plasma cells (aPCs) within the BMPC compartment (aPC/BMPC) as assessed by flow cytometry (FC) contributes to differential diagnosis between MGUS and multiple myloma (MM). The goal of the present study was to investigate this parameter as a marker for risk of progression in MGUS (n = 407) and SMM (n = 93). Patients with a marked predominance of aPCs/BMPC (≥ 95%) at diagnosis displayed a significantly higher risk of progression both in MGUS and SMM (P< .001). Multivariate analysis for progression-free survival (PFS) selected the percentage aPC/BMPC (≥ 95%) as the most important independent variable, together with DNA aneuploidy and immunoparesis, for MGUS and SMM, respectively. Using these independent variables, we have identified 3 risk categories in MGUS (PFS at 5 years of 2%, 10%, and 46%, respectively; P< .001) and SMM patients (PFS at 5 years of 4%, 46%, and 72%, respectively; P < .001). Our results show that multiparameter FC evaluation of BMPC at diagnosis is a valuable tool that could help to individualize the follow-up strategy for MGUS and SMM patients.
Compartmentalised expression of Delta-like 1 in epithelial somites is required for the formation of intervertebral joints
Authors: Teppner Ingeborg , Becker Sonja , de Angelis Martin Hrabé , Gossler Achim , Beckers Johannes
Published: June 2007

Background

Expression of the mouse Delta-like 1 (Dll1) gene in the presomitic mesoderm and in the caudal halves of somites of the developing embryo is required for the formation of epithelial somites and for the maintenance of caudal somite identity, respectively. The rostro-caudal polarity of somites is initiated early on within the presomitic mesoderm in nascent somites. Here we have investigated the requirement of restricted Dll1 expression in caudal somite compartments for the maintenance of rostro-caudal somite polarity and the morphogenesis of the axial skeleton. We did this by overexpressing a functional copy of the Dll1 gene throughout the paraxial mesoderm, in particular in anterior somite compartments, during somitogenesis in transgenic mice.

Results

Epithelial somites were generated normally and appeared histologically normal in embryos of two independent Dll1 over-expressing transgenic lines. Gene expression analyses of rostro-caudal marker genes suggested that over-expression of Dll1 without restriction to caudal compartments was not sufficient to confer caudal identity to rostral somite halves in transgenic embryos. Nevertheless, Dll1 over-expression caused dysmorphologies of the axial skeleton, in particular, in morphological structures that derive from the articular joint forming compartment of vertebrae. Accordingly, transgenic animals exhibited missing or reduced intervertebral discs, rostral and caudal articular processes as well as costal heads of ribs. In addition, the midline of the vertebral column did not develop normally. Transgenic mice had open neural arches and split vertebral bodies with ectopic pseudo-growth plates. Endochondral bone formation and ossification in the developing vertebrae were delayed.

Conclusion

The mice overexpressing Dll1 exhibit skeletal dysmorphologies that are also evident in several mutant mice with defects in somite compartmentalisation. The Dll1 transgenic mice demonstrate that vertebral dysmorphologies such as bony fusions of vertebrae and midline vertebral defects can occur without apparent changes in somitic rostro-caudal marker gene expression. Also, we demonstrate that the over-expression of the Dll1 gene in rostral epithelial somites is not sufficient to confer caudal identity to rostral compartments. Our data suggest that the restricted Dll1 expression in caudal epithelial somites may be particularly required for the proper development of the intervertebral joint forming compartment.
Specific expression of lacZ and cre recombinase in fetal thymic epithelial cells by multiplex gene targeting at the Foxn1 locus
Authors: Gordon Julie , Xiao Shiyun , Hughes Bernard , Su Dong-ming , Navarre Samuel P , Condie Brian G , Manley Nancy R
Published: June 2007

Background

Thymic epithelial cells (TECs) promote thymocyte maturation and are required for the early stages of thymocyte development and for positive selection. However, investigation of the mechanisms by which TECs perform these functions has been inhibited by the lack of genetic tools. Since the Foxn1 gene is expressed in all presumptive TECs from the early stages of thymus organogenesis and broadly in the adult thymus, it is an ideal locus for driving gene expression in differentiating and mature TECs.

Results

We generated two knock-in alleles of Foxn1 by inserting IRES-Cre or IRES-lacZ cassettes into the 3' UTR of the Foxn1 locus. We simultaneously electroporated the two targeting vectors to generate the two independent alleles in the same experiment, demonstrating the feasibility of multiplex gene targeting at this locus. Our analysis shows that the knockin alleles drive expression of Cre or lacZ in all TECs in the fetal thymus. Furthermore, the knockin alleles express Cre or lacZ in a Foxn1-like pattern without disrupting Foxn1 function as determined by phenotype analysis of Foxn1 knockin/Foxn1 null compound heterozygotes.

Conclusion

These data show that multiplex gene targeting into the 3' UTR of the Foxn1 locus is an efficient method to express any gene of interest in TECs from the earliest stage of thymus organogenesis. The resulting alleles will make possible new molecular and genetic studies of TEC differentiation and function. We also discuss evidence indicating that gene targeting into the 3' UTR is a technique that may be broadly applicable for the generation of genetically neutral driver strains.
Troponin T isoform expression is modulated during Atlantic Halibut metamorphosis
Authors: Campinho Marco A , Silva Nádia , Nowell Mari A , Llewellyn Lynda , Sweeney Glen E , Power Deborah M
Published: June 2007

Background

Flatfish metamorphosis is a thyroid hormone (TH) driven process which leads to a dramatic change from a symmetrical larva to an asymmetrical juvenile. The effect of THs on muscle and in particular muscle sarcomer protein genes is largely unexplored in fish. The change inTroponin T(TnT), a pivotal protein in the assembly of skeletal muscles sarcomeres and a modulator of calcium driven muscle contraction, during flatfish metamophosis is studied.

Results

In the present study five cDNAs for halibutTnTgenes were cloned; three were splice variants arising from a singlefast TnT(fTnT) gene; a fourth encoded a novel teleost specific fTnT-like cDNA (AfTnT) expressed exclusively in slow muscle and the fifth encoded the teleost specificsTnT2. THs modified the expression of halibutfTnTisoforms which changed from predominantly basic to acidic isoforms during natural and T4 induced metamorphosis. In contrast, expression of red muscle specific genes,AfTnTandsTnT2, did not change during natural metamorphosis or after T4 treatment. Prior to and after metamorphosis no change in the dorso-ventral symmetry or temporal-spatial expression pattern ofTnTgenes and muscle fibre organization occurred in halibut musculature.

Conclusion

Muscle organisation in halibut remains symmetrical even after metamorphosis suggesting TH driven changes are associated with molecular adaptations. We hypothesize that species specific differences inTnTgene expression in teleosts underlies different larval muscle developmental programs which better adapts them to the specific ecological constraints.
Generation and analysis of expressed sequence tags from the ciliate protozoan parasite Ichthyophthirius multifiliis
Authors: Abernathy Jason W , Xu Peng , Li Ping , Xu De-Hai , Kucuktas Huseyin , Klesius Phillip , Arias Covadonga , Liu Zhanjiang
Published: June 2007

Background

The ciliate protozoan Ichthyophthirius multifiliis (Ich) is an important parasite of freshwater fish that causes 'white spot disease' leading to significant losses. A genomic resource for large-scale studies of this parasite has been lacking. To study gene expression involved in Ich pathogenesis and virulence, our goal was to generate expressed sequence tags (ESTs) for the development of a powerful microarray platform for the analysis of global gene expression in this species. Here, we initiated a project to sequence and analyze over 10,000 ESTs.

Results

We sequenced 10,368 EST clones using a normalized cDNA library made from pooled samples of the trophont, tomont, and theront life-cycle stages, and generated 9,769 sequences (94.2% success rate). Post-sequencing processing led to 8,432 high quality sequences. Clustering analysis of these ESTs allowed identification of 4,706 unique sequences containing 976 contigs and 3,730 singletons. These unique sequences represent over two million base pairs (~10% of Plasmodium falciparum genome, a phylogenetically related protozoan). BLASTX searches produced 2,518 significant (E-value < 10-5) hits and further Gene Ontology (GO) analysis annotated 1,008 of these genes. The ESTs were analyzed comparatively against the genomes of the related protozoa Tetrahymena thermophila and P. falciparum, allowing putative identification of additional genes. All the EST sequences were deposited by dbEST in GenBank (GenBank: EG957858–EG966289). Gene discovery and annotations are presented and discussed.

Conclusion

This set of ESTs represents a significant proportion of the Ich transcriptome, and provides a material basis for the development of microarrays useful for gene expression studies concerning Ich development, pathogenesis, and virulence.
Towards the ictalurid catfish transcriptome: generation and analysis of 31,215 catfish ESTs
Authors: Li Ping , Peatman Eric , Wang Shaolin , Feng Jinian , He Chongbo , Baoprasertkul Puttharat , Xu Peng , Kucuktas Huseyin , Nandi Samiran , Somridhivej Benjaporn , Serapion Jerry , Simmons Micah , Turan Cemal , Liu Lei , Muir William , Dunham Rex , Brady Yolanda , Grizzle John , Liu Zhanjiang
Published: June 2007

Background

EST sequencing is one of the most efficient means for gene discovery and molecular marker development, and can be additionally utilized in both comparative genome analysis and evaluation of gene duplications. While much progress has been made in catfish genomics, large-scale EST resources have been lacking. The objectives of this project were to construct primary cDNA libraries, to conduct initial EST sequencing to generate catfish EST resources, and to obtain baseline information about highly expressed genes in various catfish organs to provide a guide for the production of normalized and subtracted cDNA libraries for large-scale transcriptome analysis in catfish.

Results

A total of 17 cDNA libraries were constructed including 12 from channel catfish (Ictalurus punctatus) and 5 from blue catfish (I. furcatus). A total of 31,215 ESTs, with average length of 778 bp, were generated including 20,451 from the channel catfish and 10,764 from blue catfish. Cluster analysis indicated that 73% of channel catfish and 67% of blue catfish ESTs were unique within the project. Over 53% and 50% of the channel catfish and blue catfish ESTs, respectively, had significant similarities to known genes. All ESTs have been deposited in GenBank. Evaluation of the catfish EST resources demonstrated their potential for molecular marker development, comparative genome analysis, and evaluation of ancient and recent gene duplications. Subtraction of abundantly expressed genes in a variety of catfish tissues, identified here, will allow the production of low-redundancy libraries for in-depth sequencing.

Conclusion

The sequencing of 31,215 ESTs from channel catfish and blue catfish has significantly increased the EST resources in catfish. The EST resources should provide the potential for microarray development, polymorphic marker identification, mapping, and comparative genome analysis.
Detection and mapping of homologous and homoeologous segments in homoeologous groups of allotetraploid cotton by BAC-FISH
Authors: Wang Kai , Guo Wangzhen , Zhang Tianzhen
Published: June 2007

Background

Cotton, as an allopolyploid species, contains homoeologous A and D subgenomes. The study of the homoeologous (duplicated) segments or chromosomes can facilitate insight into the evolutionary process of polyploidy and the development of genomic resources. Fluorescence in situ hybridization (FISH) using bacterial artificial chromosome (BAC) clones as probes has commonly been used to provide a reliable cytological technique for chromosome identification. In polyploids, it also presents a useful approach for identification and localization of duplicated segments. Here, two types of BACs that contained the duplicated segments were isolated and analyzed in tetraploid cotton by FISH.

Results

Homologous and homoeologous BACs were isolated by way of SSR marker-based selection and then used to develop BAC-FISH probes. Duplicated segments in homoeologous chromosomes were detected by FISH. The FISH and related linkage map results followed known reinforced the relationships of homoeologous chromosomes in allotetraploid cotton, and presented a useful approach for isolation of homoeologous loci or segments and for mapping of monomorphic loci. It is very important to find that the large duplicated segments (homologous BACs) do exist between homoeologous chromosomes, so the shot-gun approach for genome sequencing was unavailable for tetraploid cotton. However, without doubt, it will contain more information and promote the research for duplicated segments as well as the genome evolution in cotton.

Conclusion

These findings and the analysis method by BAC-FISH demonstrated the powerful nature and wide use for the genome and genome evolutionary researches in cotton and other polyploidy species.
Brucella suis urease encoded by ure 1 but not ure 2 is necessary for intestinal infection of BALB/c mice
Authors: Bandara Aloka B , Contreras Andrea , Contreras-Rodriguez Araceli , Martins Ana M , Dobrean Victor , Poff-Reichow Sherry , Rajasekaran Parthiban , Sriranganathan Nammalwar , Schurig Gerhardt G , Boyle Stephen M
Published: June 2007

Background

In prokaryotes, the ureases are multi-subunit, nickel-containing enzymes that catalyze the hydrolysis of urea to carbon dioxide and ammonia. The Brucella genomes contain two urease operons designated as ure 1 and ure 2. We investigated the role of the two Brucella suis urease operons on the infection, intracellular persistence, growth, and resistance to low-pH killing.

Results

The deduced amino acid sequence of urease-α subunits of operons-1 and -2 exhibited substantial identity with the structural ureases of alpha- and beta-proteobacteria, Gram-positive and Gram-negative bacteria, fungi, and higher plants. Four ure deficient strains were generated by deleting one or more of the genes encoding urease subunits of B. suis strain 1330 by allelic exchange: strain 1330Δure 1K (generated by deleting ureD and ureA in ure 1 operon), strain 1330Δure 2K (ureB and ureC in ure 2 operon), strain 1330Δure 2C (ureA, ureB, and ureC in ure 2 operon), and strain 1330Δure 1KΔure 2C (ureD and ureA in ure 1 operon and ureA, ureB, and ureC in ure 2 operon). When grown in urease test broth, strains 1330, 1330Δure 2K and 1330Δure 2C displayed maximal urease enzyme activity within 24 hours, whereas, strains 1330Δure 1K and 1330Δure 1KΔure 2C exhibited zero urease activity even 96 h after inoculation. Strains 1330Δure 1K and 1330Δure 1KΔure 2C exhibited slower growth rates in tryptic soy broth relative to the wild type strain 1330. When the BALB/c mice were infected intraperitoneally with the strains, six weeks after inoculation, the splenic recovery of the ure deficient strains did not differ from the wild type. In contrast, when the mice were inoculated by gavage, one week after inoculation, strain 1330Δure 1KΔure 2C was cleared from livers and spleens while the wild type strain 1330 was still present. All B. suis strains were killed when they were incubated in-vitro at pH 2.0. When the strains were incubated at pH 2.0 supplemented with 10 mM urea, strain 1330Δure 1K was completely killed, strain 1330Δure 2C was partially killed, but strains 1330 and 1330Δure 2K were not killed.

Conclusion

These findings suggest that the ure 1 operon is necessary for optimal growth in culture, urease activity, resistance against low-pH killing, and in vivo persistence of B. suis when inoculated by gavage. The ure 2 operon apparently enhances the resistance to low-pH killing in-vitro.
Restricted cell elongation in Arabidopsishypocotyls is associated with a reduced average pectin esterification level
Authors: Derbyshire Paul , McCann Maureen C , Roberts Keith
Published: June 2007

Background

Cell elongation is mainly limited by the extensibility of the cell wall. Dicotyledonous primary (growing) cell walls contain cellulose, xyloglucan, pectin and proteins, but little is known about how each polymer class contributes to the cell wall mechanical properties that control extensibility.

Results

We present evidence that the degree of pectin methyl-esterification (DE%) limits cell growth, and that a minimum level of about 60% DE is required for normal cell elongation inArabidopsishypocotyls. When the average DE% falls below this level, as in two gibberellic acid (GA) mutantsga1-3andgai, and plants expressing pectin methyl-esterase (PME1) fromAspergillus aculeatus, then hypocotyl elongation is reduced.

Conclusion

Low average levels of pectin DE% are associated with reduced cell elongation, implicating PMEs, the enzymes that regulate DE%, in the cell elongation process and in responses to GA. At high average DE% other components of the cell wall limit GA-induced growth.
Transcriptional activation and localization of expression of Brassica juncea putative metal transport protein BjMTP1
Authors: Muthukumar Balasubramaniam , Yakubov Bakhtiyor , Salt David E
Published: June 2007

Background

Metal hyperaccumulators, including various Thlaspi species, constitutively express the putative metal transporter MTP1 to high levels in shoots. Here we present data on the transcriptional regulation and localization of expression of the homologous gene BjMTP1 in Brassica juncea. Though B. juncea lacks the ability to hyperaccumulate metals, its relatively high biomass, rapid growth and relatedness to true metal hyperaccumulating plants makes it a promising starting point for the development of plants for phytoremediation. Our goal in this study is to determine the transcriptional regulation of MTP1 in order to start to better understanding the physiological role of MTP1 in B. juncea.

Results

Steady-state mRNA levels of BjMTP1 were found to be enhanced 8.8, 5.9, and 1.6-fold in five-day-old B. juncea seedlings after exposure to Ni2+, Cd2+ or Zn2+, respectively. This was also reflected in enhanced GUS activity in B. juncea seedlings transformed with BjMTP1 promoter::GUSPlus after exposure to these metals over a similar range of toxicities from mild to severe. However, no increase in GUS activity was observed after exposure of seedlings to cold or heat stress, NaCl or hydrogen peroxide. GUS expression in Ni2+ treated seedlings was localized in roots, particularly in the root-shoot transition zone. In four- week- old transgenic plants BjMTP1 promoter activity also primarily increased in roots in response to Ni2+ or Cd2+ in plants transformed with either GUS or mRFP1 as reporter genes, and expression was localized to the secondary xylem parenchyma. In leaves, BjMTP1 promoter activity in response to Ni2+ or Cd2+ spiked after 24 h then decreased. In shoots GUS expression was prominently present in the vasculature of leaves, and floral parts.

Conclusion

Our studies establish that a 983 bp DNA fragment upstream of the BjMTP1 translational start site is sufficient for the specific activation by Ni2+ and Cd2+ of BjMTP1 expression primarily in roots. Activation of expression by both metals in roots is primarily localized to the xylem parenchyma cells. This study is the first to identify specific Ni2+ and Cd2+ transcriptional regulation and tissue localization of BjMTP1.
Integration in primary community care networks (PCCNs): examination of governance, clinical, marketing, financial, and information infrastructures in a national demonstration project in Taiwan
Authors: Lin Blossom Yen-Ju
Published: June 2007

Background

Taiwan's primary community care network (PCCN) demonstration project, funded by the Bureau of National Health Insurance on March 2003, was established to discourage hospital shopping behavior of people and drive the traditional fragmented health care providers into cooperate care models. Between 2003 and 2005, 268 PCCNs were established. This study profiled the individual members in the PCCNs to study the nature and extent to which their network infrastructures have been integrated among the members (clinics and hospitals) within individual PCCNs.

Methods

The thorough questionnaire items, covering the network working infrastructures – governance, clinical, marketing, financial, and information integration in PCCNs, were developed with validity and reliability confirmed. One thousand five hundred and fifty-seven clinics that had belonged to PCCNs for more than one year, based on the 2003–2005 Taiwan Primary Community Care Network List, were surveyed by mail. Nine hundred and twenty-eight clinic members responded to the surveys giving a 59.6 % response rate.

Results

Overall, the PCCNs' members had higher involvement in the governance infrastructure, which was usually viewed as the most important for establishment of core values in PCCNs' organization design and management at the early integration stage. In addition, it found that there existed a higher extent of integration of clinical, marketing, and information infrastructures among the hospital-clinic member relationship than those among clinic members within individual PCCNs. The financial infrastructure was shown the least integrated relative to other functional infrastructures at the early stage of PCCN formation.

Conclusion

There was still room for better integrated partnerships, as evidenced by the great variety of relationships and differences in extent of integration in this study. In addition to provide how the network members have done for their initial work at the early stage of network forming in this study, the detailed surveyed items, the concepts proposed by the managerial and theoretical professionals, could be a guide for those health care providers who have willingness to turn their business into multi-organizations.
Power for tests of interaction: effect of raising the Type I error rate
Authors: Marshall Stephen W
Published: June 2007

Background

Power for assessing interactions during data analysis is often poor in epidemiologic studies. This is because epidemiologic studies are frequently powered primarily to assess main effects only. In light of this, some investigators raise the Type I error rate, thereby increasing power, when testing interactions. However, this is a poor analysis strategy if the study is chronically under-powered (e.g. in a small study) or already adequately powered (e.g. in a very large study). To demonstrate this point, this study quantified the gain in power for testing interactions when the Type I error rate is raised, for a variety of study sizes and types of interaction.

Methods

Power was computed for the Wald test for interaction, the likelihood ratio test for interaction, and the Breslow-Day test for heterogeneity of the odds ratio. Ten types of interaction, ranging from sub-additive through to super-multiplicative, were investigated in the simple scenario of two binary risk factors. Case-control studies of various sizes were investigated (75 cases & 150 controls, 300 cases & 600 controls, and 1200 cases & 2400 controls).

Results

The strategy of raising the Type I error rate from 5% to 20% resulted in a useful power gain (a gain of at least 10%, resulting in power of at least 70%) in only 7 of the 27 interaction type/study size scenarios studied (26%). In the other 20 scenarios, power was either already adequate (n = 8; 30%), or else so low that it was still weak (below 70%) even after raising the Type I error rate to 20% (n = 12; 44%).

Conclusion

Relaxing the Type I error rate did not usefully improve the power for tests of interaction in many of the scenarios studied. In many studies, the small power gains obtained by raising the Type I error will be more than offset by the disadvantage of increased "false positives". I recommend investigators should not routinely raise the Type I error rate when assessing tests of interaction.
Solitary fibrous tumor of the thigh with epithelioid features: a case report
Authors: Martorell Miguel , Pérez-Vallés Ana , Gozalbo Francisco , Garcia-Garcia Jose Angel , Gutierrez Jair , Gaona John
Published: June 2007

Background

Extrapleural Solitary Fibrous tumors (SFTs) have been increasingly reported. The retroperitoneum, deep soft tissues of proximal extremities, abdominal cavity, trunk, head and neck are the most common extraserosal locations reported. Microscopically they show a wide range of morphological features, and so the differential diagnosis is extensive. Immunohistochemically, they commonly express CD34, vimentin, bcl-2 and CD99. Epithelial membrane antigen (EMA) and smooth muscle actin (SMA) may occasionally be expressed. Epithelioid morphology in extrapleural SFT has only very occasionally been described (five cases reported), some of them with biphasic pattern and others with malignant characteristics.

Case presentation

A SFT of the thigh with epithelioid areas in a 63 year old woman is reported. Microscopically the tumor showed areas hypo and hipercellular. At the periphery of the hipercellular areas there were nodules composed of epithelioid cells. Immunohistochemically both the spindle and epithelioid cells were positive for CD34, vimentin, bcl-2 and CD99. Epithelial, neural and muscular markers were negative. Molecular study was done and ruled out a synovial sarcoma.

Conclusion

Ten cases of SFT of the thigh have been reported but to our knowledge this is the first case with epithelioid morphology affecting the extremities. Identification of this pattern of SFT is of importance, to avoid misdiagnosis with other more aggressive conditions in soft tissue.
Genetic background influences murine prostate gene expression: implications for cancer phenotypes
Authors: Bianchi-Frias Daniella , Pritchard Colin , Mecham Brigham H , Coleman Ilsa M , Nelson Peter S
Published: June 2007

Background

Cancer of the prostate is influenced by both genetic predisposition and environmental factors. The identification of genes capable of modulating cancer development has the potential to unravel disease heterogeneity and aid diagnostic and prevention strategies. To this end, mouse models have been developed to isolate the influences of individual genetic lesions in the context of consistent genotypes and environmental exposures. However, the normal prostatic phenotypic variability dictated by a genetic background that is potentially capable of influencing the process of carcinogenesis has not been established.

Results

In this study we used microarray analysis to quantify transcript levels in the prostates of five commonly studied inbred mouse strains. We applied a multiclass response t-test and determined that approximately 13% (932 genes) exhibited differential expression (range 1.3-190-fold) in any one strain relative to other strains (false discovery rate ≤10%). Expression differences were confirmed by quantitative RT-PCR, or immunohistochemistry for several genes previously shown to influence cancer progression, such as Psca, Mmp7, and Clusterin. Analyses of human prostate transcripts orthologous to variable murine prostate genes identified differences in gene expression in benign epithelium that correlated with the differentiation state of adjacent tumors. For example, the gene encoding apolipoprotein D, which is known to enhance resistance to cell stress, was expressed at significantly greater levels in benign epithelium associated with high-grade versus low-grade cancers.

Conclusion

These studies support the concept that the cellular, tissue, and organismal context contribute to oncogenesis and suggest that a predisposition to a sequence of events leading to pathology may exist prior to cancer initiation.
ABCC transporter inhibition reduces zymosan-induced peritonitis
Authors: Leite Daniela F P , Echevarria-Lima Juliana , Ferreira Samira Cardoso , Calixto João B , Rumjanek Vivian M
Published: June 2007

Inflammatory mediators are released from injured tissues being responsible for the first steps of inflammatory processes. Multidrug efflux transporters, members of the ATP-binding cassette (ABC) family, are ubiquitously expressed. ABCC molecules transport several endogenous substances, including leukotriene C4 (LTC4) and PGE2, which are involved in zymosan-induced inflammation. The present study investigated the role played by ABCC transporters on zymosan-induced peritonitis in mice. Most of the resident peritoneal cells were macrophages, based on their morphology and membrane-activated complex 3 expression. RT-PCR demonstrated that these cells expressed ABCC, and ABCC activity was analyzed in vivo via the s.c. injection of ABCC inhibitors [probenecid (PROB) 200 mg/kg or MK571 20 mg/kg], followed by an i.v. injection of carboxyfluorescein diacetate (CFDA), an ABCC fluorescent substrate. Both inhibitors increased CFDA accumulation, suggesting ABCC impairment. Moreover, ABCC reversors decreased zymosan-induced plasma exudation by 86.6 ± 7.4 and 97.6 ± 2.3%, a feature related to a diminished secretion of LTC4 (65.1±11 and 47.8±9.9%) and PGE2 (under basal levels). Cell migration was inhibited similarly. Furthermore, PROB and MK571 inhibited IL-1ß by 83.4 ± 13 and 71.2 ± 13.4% and TNF-α content by 47 ± 4.5 and 28.9 ± 0.8%, respectively. NO metabolites and reactive oxygen species production were also reduced. The present results suggest that ABCC molecules have a relevant role in the acute inflammatory response produced by zymosan in mice.
6-Methylprednisolone down-regulates IRAK-M in human and murine osteoclasts and boosts bone-resorbing activity: a putative mechanism for corticoid-induced osteoporosis
Authors: Soares-Schanoski Alessandra , Gómez-Piña Vanesa , De l Fresno Carlos , Rodríguez-Rojas Alexandro , García Felipe , Glaría Alberto , Sánchez Miriam , Vallejo-Cremades María Teresa , Baos Rosa , Fuentes-Prior Pablo , Arnalich Francisco , López-Collazo Eduardo
Published: June 2007

Osteoclasts are large, multinucleated cells, which originate from the fusion of macrophages. They play a central role in bone development and remodeling via the resorption of bone and are thus important mediators of bone loss, which leads to osteoporosis. IL-1R-associated kinase (IRAK)-M is a pseudokinase, which acts as a negative modulator of innate immune responses mediated by TLRs and IL-1R. Recently, it has been reported that IRAK-M also participates in the control of macrophage differentiation into osteoclasts. In addition, it was shown that IRAK-M knockout mice develop a strong osteoporosis phenotype, suggesting that down-regulation of this molecule activates osteoclast-mediated bone resorption. We studied the effect of the osteoporosis-inducing glucocorticoid, 6-methylprednisolone (6-MP), on IRAK-M expression in osteoclasts. Our results showed that osteoclasts, derived from THP-1 and RAW cells as well as human blood monocytes, differentiated into osteoclasts, express high levels of IRAK-M at mRNA and protein levels. In addition, 6-MP down-regulates IRAK-M expression, which correlates with an increased activation of bone resorption. These findings suggest a mechanism of corticosteroid-induced osteoporosis and open new avenues for treating this endemic disease of Western societies.
Performance of Severity of Illness Scoring Systems in Emergency Department Patients with Infection
Authors: Howell Michael D. , Donnino Michael W. , Talmor Daniel , Clardy Peter , Ngo Long , Shapiro Nathan I.
Published: June 2007

ObjectivesTo validate the Mortality in Emergency Department Sepsis (MEDS) score, the Confusion, Urea nitrogen, Respiratory rate, Blood pressure, 65 years of age and older (CURB‐65) score, and a modified Rapid Emergency Medicine Score (mREMS) in patients with suspected infection.

MethodsThis was a prospective cohort study. Adult patients with clinically suspected infection admitted from December 10, 2003, to September 30, 2004, in an urban emergency department with approximately 50,000 annual visits were eligible. The MEDS and CURB‐65 scores were calculated as originally described, but REMS was modified in neurologic scoring because a full Glasgow Coma Scale score was not uniformly available. Discrimination of each score was assessed with the area under the receiver operating characteristics curve (AUC).

ResultsOf 2,132 patients, 3.9% (95% confidence interval [CI] = 3.1% to 4.7%) died. Mortality stratified by the MEDS score was as follows: 0–4 points, 0.4% (95% CI = 0.0 to 0.7%); 5–7 points, 3.3% (95% CI = 1.7% to 4.9%); 8–12 points, 6.6% (95% CI = 4.4% to 8.8%); and ≥13 points, 31.6% (95% CI = 22.4% to 40.8%). Mortality stratified by CURB‐65 was as follows: 0 points, 0% (0 of 457 patients); 1 point, 1.6% (95% CI = 0.6% to 2.6%); 2 points, 4.1% (95% CI = 2.3% to 6.0%); 3 points, 4.9% (95% CI = 2.8% to 6.9%); 4 points, 18.1% (95% CI = 11.9% to 24.3%); and 5 points, 28.0% (95% CI = 10.4% to 45.6%). Mortality stratified by the mREMS was as follows: 0–2 points, 0.6% (95% CI = 0 to 1.2%); 3–5 points, 2.0% (95% CI = 0.8% to 3.1%); 6–8 points, 2.3% (95% CI = 1.1% to 3.5%); 9–11 points, 7.1% (95% CI = 4.2% to 10.1%); 12–14 points, 20.0% (95% CI = 12.5% to 27.5%); and ≥15 points, 40.0% (95% CI = 22.5% to 57.5%). The AUCs were 0.85, 0.80, and 0.79 for MEDS, mREMS, and CURB‐65, respectively.

ConclusionsIn this large cohort of patients with clinically suspected infection, MEDS, mREMS, and CURB‐65 all correlated well with 28‐day in‐hospital mortality.
Ziprasidone, Diazepam, or the Combination for Prevention of Cocaine Toxicity in a Mouse Model
Authors: Cleveland Nathan R. , Krier Shay , Heard Kennon
Published: June 2007

BackgroundAcute cocaine poisoning is a common problem in the United States. Sedation with benzodiazepines is the standard treatment, but animal studies have suggested that ziprasidone is also protective.

ObjectivesTo assess whether the combination of these two medications would offer more protection than either treatment alone.

MethodsThis was a randomized, blinded, placebo‐controlled trial in CF‐1 mice. The authors administered intraperitoneal injections of 2 mg/kg diazepam (group D), 4 mg/kg ziprasidone (group Z), the same dose of both drugs (group DZ), or saline 15 minutes before intraperitoneal administration of 105 mg/kg cocaine (an estimated lethal dose to 70%). The number of animals with seizures and apparent lethality over the following 30 minutes was recorded.

ResultsAll treatments increased survival relative to placebo (relative risk: D = 2.6, Z = 2.3, DZ = 2.9) and decreased seizures (relative risk: D = 0.5, Z = 0.3, DZ = 0.02).

ConclusionsThis study suggests that diazepam and ziprasidone have efficacy for preventing lethality from cocaine poisoning in an animal model but that the combination offers little addition to either therapy alone. However, the combination may be more effective for prevention of cocaine‐induced seizures.
Impact of Randomized Clinical Trial Results in the National Comprehensive Cancer Network on the Use of Tamoxifen After Breast Surgery for Ductal Carcinoma in Situ
Authors: Yen Tina W.F. , Kuerer Henry M. , Ottesen Rebecca A. , Rouse Layla , Niland Joyce C. , Edge Stephen B. , Theriault Richard L. , Weeks Jane C.
Published: June 2007

Purpose

The National Surgical Adjuvant Breast and Bowel Project B-24 trial, published in June 1999, demonstrated that tamoxifen after breast-conserving surgery (BCS) and radiotherapy for ductal carcinoma in situ (DCIS) reduced the absolute occurrence of ipsilateral and contralateral breast cancer. We assessed the impact of B-24 on practice patterns at selected National Comprehensive Cancer Network (NCCN) centers.

Patients and Methods

Tamoxifen use after surgery was examined among 1,622 patients presenting for treatment of unilateral DCIS between July 1997 and December 2003 at eight NCCN centers. Associations of clinicopathologic and treatment factors with tamoxifen use were assessed in univariate and multivariable logistic regression analyses.

Results

Overall, 41% of patients (665 of 1,622) received tamoxifen. The proportion increased from 24% before July 1, 1999, to 46% on or after July 1, 1999. Factors significantly associated with receipt of tamoxifen included diagnosis on or after July 1, 1999 (odds ratio [OR], 3.85; P < .0001), BCS in patients younger than 70 years (OR, 3.21; P = .0073), no history of cerebrovascular or peripheral vascular disease (OR, 3.13; P = .0071), receipt of radiotherapy (OR, 1.82; P = .0009), and previous hysterectomy (OR, 1.34; P = .0459). Tamoxifen use varied significantly by center, from 34% to 74% after BCS and 17% to 53% after mastectomy (P < .0001).

Conclusion

Tamoxifen use after surgery for DCIS at NCCN centers increased after presentation of the B-24 results. Rates varied substantially by institution, suggesting that physicians differ in how they weigh the modest reduction in breast cancer risk with tamoxifen against its potential adverse effects in this population.
American Society of Clinical Oncology Clinical Evidence Review on the Ongoing Care of Adult Cancer Survivors: Cardiac and Pulmonary Late Effects
Authors: Carver Joseph R. , Shapiro Charles L. , Ng Andrea , Jacobs Linda , Schwartz Cindy , Virgo Katherine S. , Hagerty Karen L. , Somerfield Mark R. , Vaughn David J.
Published: June 2007

Purpose

To review the evidence on the incidence of long-term cardiac or pulmonary toxicity secondary to chemotherapy, radiotherapy, or trastuzumab in symptomatic and asymptomatic cancer survivors.

Methods

An American Society of Clinical Oncology Panel reviewed pertinent information from the literature through February 2006.

Results

Few studies directly addressing the benefits of screening for long-term cardiac or pulmonary toxicity in asymptomatic cancer survivors who received chemotherapy, radiotherapy, or trastuzumab were identified. The reviewed literature included primarily retrospective and cross-sectional studies describing the incidence of cardiac and pulmonary late effects. Anatomic and/or functional abnormalities have been associated with use of all currently available anthracyclines and their derivatives. Trastuzumab-related cardiac dysfunction rarely causes death, and in most cases is reversible with improvement in cardiac function on drug discontinuation and/or treatment with cardiac medications. The estimated aggregate incidence of radiation-induced cardiac disease is 10% to 30% by 5 to 10 years post-treatment, although the incidence may be lower with modern techniques. Radiation pneumonitis is reported in 5% to 15% of lung cancer patients receiving definitive external-beam radiation therapy. A minority of patients may develop progressive pulmonary fibrosis; late complications include cor pulmonale and respiratory failure. Bleomycin-induced pneumonitis is an acute rather than late effect of treatment. Late pulmonary complications in bone marrow or stem cell transplantation patients who develop interstitial pneumonitis include idiopathic pneumonia syndrome and bronchiolitis obliterans.

Conclusion

An increased incidence of cardiac and/or pulmonary dysfunction is observed in cancer survivors. Research is needed to identify high-risk patients, and to determine the optimal screening strategies and subsequent treatment.
Primary Treatment of Waldenström Macroglobulinemia With Dexamethasone, Rituximab, and Cyclophosphamide
Authors: Dimopoulos Meletios Athanasios , Anagnostopoulos Athanasios , Kyrtsonis Marie-Christine , Zervas Konstantinos , Tsatalas Constantinos , Kokkinis Garyfallia , Repoussis Panagiotis , Symeonidis Argyris , Delimpasi Souzana , Katodritou Eirini , Vervessou Elina , Michali Evridiki , Pouli Anastasia , Gika Dimitra , Vassou Amalia , Terpos Evangelos , Anagnostopoulos Nikolaos , Economopoulos Theophanis , Pangalis Gerasimos
Published: June 2007

Purpose

Alkylating agents and the anti-CD20 monoclonal antibody rituximab are among appropriate choices for the primary treatment of symptomatic patients with Waldenström macroglobulinemia (WM), and they induce at least a partial response in 30% to 50% of patients. To improve these results, we designed a phase II study that included previously untreated symptomatic patients with WM who received a combination of dexamethasone, rituximab, and cyclophosphamide (DRC).

Patients and Methods

Seventy-two patients were treated with dexamethasone 20 mg intravenously followed by rituximab 375 mg/m2 intravenously on day 1 and cyclophosphamide 100 mg/m2 orally bid on days 1 to 5 (total dose, 1,000 mg/m2). This regimen was repeated every 21 days for 6 months. Patients' median age was 69 years and many had features of advanced disease such as anemia (57%), hypoalbuminemia (40%), and elevated serum beta2-microglobulin (43%).

Results

On an intent-to-treat basis, 83% of patients (95% CI, 73% to 91%) achieved a response, including 7% complete, 67% partial, and 9% minor responses. The median time to response was 4.1 months. The 2-year progression-free survival rate for all patients was 67%; for patients who responded to DRC, it was 80%. The 2-year disease-specific survival rate was 90%. Treatment with DRC was well tolerated, with 9% of patients experiencing grade 3 or 4 neutropenia and approximately 20% of patients experiencing some form of toxicity related to rituximab.

Conclusion

Our large, multicenter trial showed that the non–stem-cell toxic DRC regimen is an active, well-tolerated treatment for symptomatic patients with WM.
Are DIT scores empirically distinct from measures of political identification and intellectual ability? A test using post‐9/11 data
Authors: Michael Crowson H. , DeBacker Teresa K. , Thoma Stephen J.
Published: June 2007

Emler, Renwick, and Malone (1983) argued against a developmental interpretation of the Defining Issues Test (DIT), suggesting instead that it actually measures a social psychological phenomenon – political identification. On the other hand, Sanders, Lubinski, and Benbow (1995) have argued that DIT scores measure intellectual ability. In this study, we pitted the DIT against measures of political identification and intellectual ability in order to test its ability to incrementally predict variation in post‐9/11 attitudes. We found that both DIT‐2 scores and political identification were significant predictors of attitudes toward restricting human rights/civil liberties, while our index of intellectual ability (i.e. ACT scores) was not. DIT‐2 scores, political identification and intellectual ability each accounted for significant variation in attitudes toward President George W. Bush in our undergraduate college sample during the spring of 2004.
Preadolescents' categorization of gender and ethnicity at the subgroup level in memory
Authors: Susskind Joshua E.
Published: June 2007

The statement matching paradigm was used to examine how 10‐ to 13‐year‐olds categorized adults when both ethnicity and gender varied across targets. Forty‐seven children watched a PowerPoint presentation of a conversation involving two Black men, two Black women, two White men and two White women. Each slide displayed the speaker's picture, name and the statement made. The children then were asked to determine who made each statement. The pattern of errors in their assignments was examined to assess how they spontaneously categorized the adults. More within‐ethnicity within‐gender errors (e.g. assigning a statement made by a White woman to the other White woman) were made than any other type of error. This implies that the targets were categorized at the subgroup level. In contrast to findings for adults, the children did not also categorize at the more global level of gender above and beyond the subgroup categorization.