bluuebunny/crossref_metadata_2025 huggingface dataset:
Visual Reaction Time and Plethysmography as Measures of Sexual Interest in Child Molesters
Authors: Abel Gene G. , Huffman Jeffrey , Warberg Brent , Holland Clarence L.
Published: June 2008

It is important to determine the sexual interests of those accused of child molestation. Visual reaction time and plethysmography are two means of measuring sexual interest with some objectivity, but there has been no direct comparison of these methodologies. The reliability and validity of visual reaction time and plethysmography were evaluated in groups of individuals with sexual interest in children of various ages and genders. Results showed that both methods of assessment had a high reliability and validity. Visual reaction time has the added advantages that it can be used without nude slides and is a briefer assessment.
Fatigue performance of spot welded and weld bonded advanced high strength steel sheets
Authors: Long X. , Khanna S. K.
Published: June 2008

Fatigue properties and failure characterisation of spot welded and spot weld bonded (WB) high strength steels, such as advanced high strength steels (AHSS) DP600 GI, TRIP600, and high strength low alloy (HSLA) steel HSLA340Y GI have been studied. Tensile shear and coach peel specimens were used in the present study. Both constant amplitude sinusoidal loading and random loading fatigue tests were conducted. The results show that the fatigue strength, under constant amplitude sinusoidal fatigue loading, of spot welded DP600 GI and TRIP600 specimens was approximately the same as that of HSLA340Y GI specimens in the case of tensile shear and coach peel type specimens for both low and high cycle fatigue. However, spot WB specimens show significantly higher fatigue strength than that of spot welded specimens, especially at low load condition (high cycles). Fatigue tests were also conducted on wide width DP600 GI and HSLA340Y GI spot welded specimens and no significant difference in fatigue strength between regular size specimens (39 mm in width) and wide specimens (125 mm in width) was observed. Random loading fatigue tests show that DP600 GI has a lower fatigue strength compared to HSLA340Y GI. Crack initiation and propagation during the fatigue loading history has been experimentally determined and discussed.
Time resolved X-ray diffraction observations of phase transformations in transient arc welds
Authors: Elmer J. W. , Palmer T. A. , Zhang W. , DebRoy T.
Published: June 2008

In situ X-ray diffraction methods have been developed at Lawrence Livermore National Laboratory for direct observation of microstructural evolution under quasi-steady state and transient welding conditions. Using intense highly collimated synchrotron radiation, the crystal structures in the weld heat affected and fusion zones are probed in real time to monitor solidification and solid state phase transformations during welding. Here the authors review recent work on the development and use of the time resolved X-ray diffraction (TRXRD) technique during transient welding and illustrate its unique capabilities to: directly observe the solidification mode; discover, in real time, the definitive sequence of phase transformations that lead to the final microstructure; and provide quantitative kinetic data of phase transformations through synthesis of TRXRD data with the temperature history obtained through heat transfer modelling. The TRXRD technique has been used to investigate welding induced phase transformations in titanium alloys, low alloy steels, and stainless steel alloys. The results show some of the first real time observations of the weld solidification mode and the evolution of equilibrium and non-equilibrium phases during rapid heating and cooling. When combined with numerical modelling, quantitative phase transformation kinetic data are obtained, allowing for its use in a wide variety of isothermal and non-isothermal processing. The potential for future applications of this and similar techniques is also addressed.
Material flow and intermixing during dissimilar friction stir welding
Authors: Gerlich A. , Su P. , Yamamoto M. , North T. H.
Published: June 2008

Material flow and intermixing during dissimilar friction stir spot welding and friction stir seam welding are investigated. During friction stir spot welding, a ribbon of contiguous dissimilar lamellae is produced during each rotation of the tool and the number of intermingled lamellae contained in the intermixed region is determined by the tool rotational speed setting and the dwell time applied. When the rotating tool moves across the component, the ribbon of dissimilar contiguous lamellae continues to be produced and the linear distance in the traversing direction between dissimilar lamellae corresponds with the pitch distance [the travel speed (mm s−1) divided by the tool rotational speed (Hz)]. The material flow pattern produced when a threaded tool moves across a component is therefore a variant of that produced during the touch down period when the rotating tool is held stationary. It is suggested that the onion ring structures observed in similar and dissimilar friction stir seam welds made using threaded tools are produced by material incorporation from the locations beneath the tool shoulder and the bottom of the rotating pin and the creation of a helical vertical rotational flow within the intermixed region formed beside the periphery of the rotating pin.
Ulk1 plays a critical role in the autophagic clearance of mitochondria and ribosomes during reticulocyte maturation
Authors: Kundu Mondira , Lindsten Tullia , Yang Chia-Ying , Wu Junmin , Zhao Fangping , Zhang Ji , Selak Mary A. , Ney Paul A. , Thompson Craig B.
Published: June 2008

Production of a red blood cell's hemoglobin depends on mitochondrial heme synthesis. However, mature red blood cells are devoid of mitochondria and rely on glycolysis for ATP production. The molecular basis for the selective elimination of mitochondria from mature red blood cells remains controversial. Recent evidence suggests that clearance of both mitochondria and ribosomes, which occurs in reticulocytes following nuclear extrusion, depends on autophagy. Here, we demonstrate that Ulk1, a serine threonine kinase with homology to yeast atg1p, is a critical regulator of mitochondrial and ribosomal clearance during the final stages of erythroid maturation. However, in contrast to the core autophagy genes such as atg5 and atg7, expression of ulk1 is not essential for induction of macroautophagy in response to nutrient deprivation or for survival of newborn mice. Together, these data suggest that the ATG1 homologue, Ulk1, is a component of the selective autophagy machinery that leads to the elimination of organelles in erythroid cells rather that an essential mechanistic component of autophagy.
No convincing evidence for a role of CD31-CD38 interactions in the pathogenesis of chronic lymphocytic leukemia
Authors: Tonino Sanne H. , Spijker Rene , Luijks Dieuwertje M.P. , van Oers Marinus H. J. , Kater Arnon P.
Published: June 2008

Although CD38, a marker of poor prognosis in chronic lymphocytic leukemia (CLL), is known primarily as an ecto-enzyme, it has also been ascribed a receptor function. Interaction with its proposed ligand CD31 expressed on nurse-like cells would result in proliferative and survival-signals. Yet, in CLL, both homotypic and heterotypic CD31-CD38 interactions are expected to be rather ubiquitous. We analyzed whether CD38-CD31 interactions result in proliferative and antiapoptotic signals. We found a high expression of CD31 on CLL, irrespective of CD38 expression. Coculture of CD38high CLL with endothelial cells or CD31 transfected fibroblasts, with or without blocking CD31 or CD38 antibodies, did not result in increased survival or proliferation. Analysis of gene expression of most known regulators of apoptosis revealed no influence of coculture with CD31-expressing feeder cells. In conclusion, our data do not support an important contribution of CD38 triggering by CD31 to the proliferative and antiapoptotic state of the leukemic clone.
Immune complexes formed following the binding of anti–platelet factor 4 (CXCL4) antibodies to CXCL4 stimulate human neutrophil activation and cell adhesion
Authors: Xiao Zhihua , Visentin Gian P. , Dayananda Kannayakanahalli M. , Neelamegham Sriram
Published: June 2008

We tested the possibility that immune complexes formed following platelet factor 4 (PF4/CXCL4) binding to anti-PF4 antibody can stimulate neutrophil activation, similar to previous reports with platelets. Monoclonal Abs against PF4 and IgG from a heparin-induced thrombocytopenia (HIT) patient were applied. We observed that although PF4 or anti-PF4 antibody alone did not alter neutrophil function, costimulation with both reagents resulted in approximately 3-fold increase in cell surface Mac-1 expression, enhanced cell adhesion via L-selectin and CD18 integrins, and degranulation of secondary and tertiary granules. The level of Mac-1 up-regulation peaked at an intermediate PF4 dose, suggesting that functional response varies with antigen-antibody stoichiometry. PF4 binding to neutrophils was blocked by chondroitinase ABC. Cell activation was inhibited by both chondroitinase ABC and anti-CD32/FcγRII blocking mAb, IV.3. Confocal microscopy demonstrated that immune complexes colocalize with CD32a. Studies with HIT IgG demonstrated that neutrophils could be activated in the absence of exogenous heparin. These data, together, show that leukocyte surface chondroitin sulfates promote neutrophil activation by enhancing immune-complex binding to CD32a. Studies with recombinant PF4 suggest a role for arginine 49 in stabilizing PF4-chondroitin binding. Neutrophils activated via this mechanism may contribute to thrombosis and inflammation in patients mounting an immune response to PF4-heparin.
Rapid identification of Brucella isolates to the species level by real time PCR based single nucleotide polymorphism (SNP) analysis
Authors: Gopaul Krishna K , Koylass Mark S , Smith Catherine J , Whatmore Adrian M
Published: June 2008

Background

Brucellosis, caused by members of the genus Brucella, remains one of the world's major zoonotic diseases. Six species have classically been recognised within the family Brucella largely based on a combination of classical microbiology and host specificity, although more recently additional isolations of novel Brucella have been reported from various marine mammals and voles. Classical identification to species level is based on a biotyping approach that is lengthy, requires extensive and hazardous culturing and can be difficult to interpret. Here we describe a simple and rapid approach to identification of Brucella isolates to the species level based on real-time PCR analysis of species-specific single nucleotide polymorphisms (SNPs) that were identified following a robust and extensive phylogenetic analysis of the genus.

Results

Seven pairs of short sequence Minor Groove Binding (MGB) probes were designed corresponding to SNPs shown to possess an allele specific for each of the six classical Brucella spp and the marine mammal Brucella. Assays were optimised to identical reaction parameters in order to give a multiple outcome assay that can differentiate all the classical species and Brucella isolated from marine mammals. The scope of the assay was confirmed by testing of over 300 isolates of Brucella, all of which typed as predicted when compared to other phenotypic and genotypic approaches. The assay is sensitive being capable of detecting and differentiating down to 15 genome equivalents. We further describe the design and testing of assays based on three additional SNPs located within the 16S rRNA gene that ensure positive discrimination of Brucella from close phylogenetic relatives on the same platform.

Conclusion

The multiple-outcome assay described represents a new tool for the rapid, simple and unambiguous characterisation of Brucella to the species level. Furthermore, being based on a robust phylogenetic framework, the assay provides a platform that can readily be extended in the future to incorporate newly identified Brucella groups, to further type at the subspecies level, or to include markers for additional useful characteristics.
A novel WFS1 mutation in a family with dominant low frequency sensorineural hearing loss with normal VEMP and EcochG findings
Authors: Bramhall Naomi F , Kallman Jeremy C , Verrall Aimee M , Street Valerie A
Published: June 2008

Background

Low frequency sensorineural hearing loss (LFSNHL) is an uncommon clinical finding. Mutations within three different identified genes (DIAPH1, MYO7A, and WFS1) are known to cause LFSNHL. The majority of hereditary LFSNHL is associated with heterozygous mutations in the WFS1 gene (wolframin protein). The goal of this study was to use genetic analysis to determine if a small American family's hereditary LFSNHL is linked to a mutation in the WFS1 gene and to use VEMP and EcochG testing to further characterize the family's audiovestibular phenotype.

Methods

The clinical phenotype of the American family was characterized by audiologic testing, vestibular evoked myogenic potentials (VEMP), and electrocochleography (EcochG) evaluation. Genetic characterization was performed by microsatellite analysis and direct sequencing of WFS1 for mutation detection.

Results

Sequence analysis of the WFS1 gene revealed a novel heterozygous mutation at c.2054G>C predicting a p.R685P amino acid substitution in wolframin. The c.2054G>C mutation segregates faithfully with hearing loss in the family and is absent in 230 control chromosomes. The p.R685 residue is located within the hydrophilic C-terminus of wolframin and is conserved across species. The VEMP and EcochG findings were normal in individuals segregating the WFS1 c.2054G>C mutation.

Conclusion

We discovered a novel heterozygous missense mutation in exon 8 of WFS1 predicting a p.R685P amino acid substitution that is likely to underlie the LFSNHL phenotype in the American family. For the first time, we describe VEMP and EcochG findings for individuals segregating a heterozygous WFS1 mutation.
Prevalence of dry eye syndrome and diabetic retinopathy in type 2 diabetic patients
Authors: Manaviat Masoud Reza , Rashidi Maryam , Afkhami-Ardekani Mohammad , Shoja Mohammad Reza
Published: June 2008

Background

This study was performed to assess the prevalence of dry eye syndrome and diabetic retinopathy (DR) in type 2 diabetic patients and their contributing factors.

Methods

199 type 2 diabetic patients referred to Yazd Diabetes Research Center were consecutively selected. All Subjects were assessed by questionnaire about other diseases and drugs. Dry eye syndrome was assessed with Tear break up time tests and Schirmer. All the subjects underwent indirect ophthalmoscopy and retinal color photography. DR was graded according to early Treatment Diabetic Retinopathy (ETDRS) criteria.

Results

Of 199 subjects, 108 patients (54.3%) suffer from dry eye syndrome. Although dry eye syndrome was more common in older and female patients, this association was not significant. But there was significantly association between dry eye syndrome and duration of diabetes (P = 0.01). Dry eye syndrome was more frequent in diabetic patients with DR (P = 0.02). DR was found in 140 patients (70.35%), which included 34 patients (17.1%) with mild non proliferative DR (NPDR), 34 patients (17.1%) with moderate NPDR, 22 patients (11.1%) with severe NPDR and 25 patients (25.1%) with proliferative DR (PDR). There were significant relation between age, sex and duration of diabetes and DR.

Conclusion

In this study the prevalence of dry eye syndrome was 54.3%. Diabetes and dry eyes appear to have a common association. Further studies need to be undertaken to establish an etiologic relationship. However, examination for dry eye should be an integral part of the assessment of diabetic eye disease.
Longitudinal study of Plasmodium falciparum and Plasmodium vivax in a Karen population in Thailand
Authors: Phimpraphi Waraphon , Paul Richard E , Yimsamran Surapon , Puangsa-art Supalarp , Thanyavanich Nipon , Maneeboonyang Wanchai , Prommongkol Sutthiporn , Sornklom Samarn , Chaimungkun Wutthichai , Chavez Irwin F , Blanc Herve , Looareesuwan Sornchai , Sakuntabhai Anavaj , Singhasivanon Pratap
Published: June 2008

Background

Clinical case treatment of malaria infections where Plasmodium falciparum and Plasmodium vivax are sympatric has achieved effective reductions in P. falciparum prevalence and incidence rates, but has been less successful for P. vivax. The high transmissibility of P. vivax and its capacity to relapse have been suggested to make it a harder parasite species to control.

Methods

A clinical malaria case treatment programme was carried out over a decade in a Karen community composed of seven hamlets on the Thai-Myanmar border.

Results

From 1994 to 2004, prevalence rates of both P. falciparum and P. vivax decreased by 70–90% in six of the seven study hamlets, but were unchanged in one hamlet. Overall, incidence rates decreased by 72% and 76% for P. falciparum and P. vivax respectively over the period 1999–2004. The age-incidence and prevalence curves suggested that P. vivax was more transmissible than P. falciparum despite a greater overall burden of infection with P. falciparum. Male gender was associated with increased risk of clinical presentation with either parasite species. Children (< 15 years old) had an increased risk of presenting with P. vivax but not P. falciparum.

Conclusion

There was a considerable reduction in incidence rates of both P. vivax and P. falciparum over a decade following implementation of a case treatment programme. The concern that intervention methods would inadvertently favour one species over another, or even lead to an increase in one parasite species, does not appear to be fulfilled in this case.
Development and validation of a Greek language version of the Manchester Foot Pain and Disability Index
Authors: Kaoulla Patricia , Frescos Nicoletta , Menz Hylton B
Published: June 2008

Background

The Manchester Foot Pain and Disability Index (MFPDI) is a 19 item questionnaire used to assess the severity and impact of foot pain. The aim of this study was to develop a Greek-language version of the MFPDI and to assess the instrument's psychometric properties.

Methods

The MFPDI was translated into Greek by three bilingual content experts and two bilingual language experts, and then back-translated into English to assess for equivalence. The final Greek version was administered, along with a questionnaire consisting medical history and the Medical Outcomes Study Short Form 36 (SF-36), to 104 Greek-speaking, community-dwelling people (64 female, 40 male), aged between 64 and 90 years (mean 73.00, SD 5.26) with disabling foot pain.

Results

The Greek translation of the MFPDI was found to have high internal consistency (Cronbach's α= 0.89, and item-total correlation coefficients from 0.33 to 0.72). Principal components analysis revealed a four-factor structure representing the constructs of functional limitation, pain intensity, concern with appearance and activity restriction, which explained 60.8% of the variance, with 38.9% of the variance explained by the first construct (functional limitation). Six items demonstrated different factor loadings to the original English version.

Conclusion

The Greek-language version of the MFPDI appears to be a valid tool in assessing foot pain in Greek-speaking older people. The total MFPDI scores are comparable between the Greek and English version, however due to differences in the factor loadings of some items, between-language comparisons of MFPDI should be undertaken with some caution.
Resource supply and the evolution of public-goods cooperation in bacteria
Authors: Brockhurst Michael A , Buckling Angus , Racey Dan , Gardner Andy
Published: June 2008

Background

Explaining public-goods cooperation is a challenge for evolutionary biology. However, cooperation is expected to more readily evolve if it imposes a smaller cost. Such costs of cooperation are expected to decline with increasing resource supply, an ecological parameter that varies widely in nature. We experimentally tested the effect of resource supply on the evolution of cooperation using two well-studied bacterial public-good traits: biofilm formation by Pseudomonas fluorescens and siderophore production by Pseudomonas aeruginosa.

Results

The frequency of cooperative bacteria increased with resource supply in the context of both bacterial public-good traits. In both cases this was due to decreasing costs of investment into public-goods cooperation with increasing resource supply.

Conclusion

Our empirical tests with bacteria suggest that public-goods cooperation is likely to increase with increasing resource supply due to reduced costs of cooperation, confirming that resource supply is an important factor in the evolution of cooperation.
Comparison of p53 and the PDZ domain containing protein MAGI-3 regulation by the E6 protein from high-risk human papillomaviruses
Authors: Ainsworth Julia , Thomas Miranda , Banks Lawrence , Coutlee Francois , Matlashewski Greg
Published: June 2008

Central to cellular transformation caused by human papillomaviruses (HPVs) is the ability of E6 proteins to target cellular p53 and proteins containing PDZ domains, including MAGI-3, for degradation. The aim of this study was to compare E6-mediated degradation of p53 and MAGI-3 under parallel experimental conditions and further with respect to the involvement of proteasomes and ubiquitination. We also compared the degradation of p53 and MAGI-3 by E6 from several HPV types including different variants from HPV-33. All of the E6 genes from different HPV types displayed similar abilities to mediate the degradation of both p53 and MAGI-3 although there may be subtle differences observed with the different 33E6 variants. There were however differences in E6 mediated degradation of p53 and MAGI-3. Proteasome inhibition assays partially protected p53 from E6 mediated degradation, but did not protect MAGI-3. In addition, under conditions where p53 was ubiquitinated by E6 and MDM2 in vivo, ubiquitination of MAGI-3 was not detected. These results imply that although both p53 and MAGI-3 represent effective targets for oncogenic E6, the mechanisms by which E6 mediates p53 and MAGI-3 degradation are distinct with respect to the involvement of ubiquitination prior to proteasomal degradation.
Herpes simplex virus type-1(HSV-1) oncolytic and highly fusogenic mutants carrying the NV1020 genomic deletion effectively inhibit primary and metastatic tumors in mice
Authors: Israyelyan Anna , Chouljenko Vladimir N , Baghian Abolghasem , David Andrew T , Kearney Michael T , Kousoulas Konstantin G
Published: June 2008

Background

The NV1020 oncolytic herpes simplex virus type-1 has shown significant promise for the treatment of many different types of tumors in experimental animal models and human trials. Previously, we described the construction and use of the NV1020-like virus OncSyn to treat human breast tumors implanted in nude mice. The syncytial mutation gKsyn1 (Ala-to-Val at position 40) was introduced into the OncSyn viral genome cloned into a bacterial artificial chromosome using double-red mutagenesis in E. coli to produce the OncdSyn virus carrying syncytial mutations in both gB(syn3) and gK(syn1).

Results

The OncdSyn virus caused extensive virus-induced cell fusion in cell culture. The oncolytic potential of the OncSyn and OncdSyn viruses was tested in the highly metastatic syngeneic mouse model system, which utilizes 4T1 murine mammary cancer cells implanted within the interscapular region of Balb/c mice. Mice were given three consecutive intratumor injections of OncSyn, OncdSyn, or phosphate buffered saline four days apart. Both OncSyn and OncdSyn virus injections resulted in significant reduction of tumor sizes (p < 0.05) compared to control tumors. Virus treated mice but not controls showed a marked reduction of metastatic foci in lungs and internal organs. Mouse weights were not significantly impacted by any treatment during the course of the entire study (p = 0.296).

Conclusion

These results show that the attenuated, but highly fusogenic OncSyn and OncdSyn viruses can effectively reduce primary and metastatic breast tumors in immuncompetent mice. The available bac-cloned OncSyn and OncdSyn viral genomes can be rapidly modified to express a number of different anti-tumor and immunomodulatory genes that can further enhance their anti-tumor potency.
Context and strain-dependent behavioral response to stress
Authors: Nosek Katarzyna , Dennis Kristen , Andrus Brian M , Ahmadiyeh Nasim , Baum Amber E , Woods Leah C Solberg , Redei Eva E
Published: June 2008

Background

This study posed the question whether strain differences in stress-reactivity lead to differential behavioral responses in two different tests of anxiety. Strain differences in anxiety-measures are known, but strain differences in the behavioral responses to acute prior stress are not well characterized.

Methods

We studied male Fisher 344 (F344) and Wistar Kyoto (WKY) rats basally and immediately after one hour restraint stress. To distinguish between the effects of novelty and prior stress, we also investigated behavior after repeated exposure to the test chamber. Two behavioral tests were explored; the elevated plus maze (EPM) and the open field (OFT), both of which are thought to measure activity, exploration and anxiety-like behaviors. Additionally, rearing, a voluntary behavior, and grooming, a relatively automatic, stress-responsive stereotyped behavior were measured in both tests.

Results

Prior exposure to the test environment increased anxiety-related measures regardless of prior stress, reflecting context-dependent learning process in both tests and strains. Activity decreased in response to repeated testing in both tests and both strains, but prior stress decreased activity only in the OFT which was reversed by repeated testing. Prior stress decreased anxiety-related measures in the EPM, only in F344s, while in the OFT, stress led to increased freezing mainly in WKYs.

Conclusion

Data suggest that differences in stressfulness of these tests predict the behavior of the two strains of animals according to their stress-reactivity and coping style, but that repeated testing can overcome some of these differences.
Identification of immune genes and proteins involved in the response of bovine mammary tissue to Staphylococcus aureus infection
Authors: Lutzow Ylva C Strandberg , Donaldson Laurelea , Gray Christian P , Vuocolo Tony , Pearson Roger D , Reverter Antonio , Byrne Keren A , Sheehy Paul A , Windon Ross , Tellam Ross L
Published: June 2008

Background

Mastitis in dairy cattle results from infection of mammary tissue by a range of micro-organisms but principally coliform bacteria and Gram positive bacteria such asStaphylococcus aureus. The former species are often acquired by environmental contamination whileS. aureusis particularly problematic due to its resistance to antibiotic treatments and ability to reside within mammary tissue in a chronic, subclinical state. The transcriptional responses within bovine mammary epithelial tissue subjected to intramammary challenge withS. aureusare poorly characterised, particularly at the earliest stages of infection. Moreover, the effect of infection on the presence of bioactive innate immune proteins in milk is also unclear. The nature of these responses may determine the susceptibility of the tissue and its ability to resolve the infection.

Results

Transcriptional profiling was employed to measure changes in gene expression occurring in bovine mammary tissues sampled from three dairy cows after brief and graded intramammary challenges withS. aureus. These limited challenges had no significant effect on the expression pattern of the gene encoding β-casein but caused coordinated up-regulation of a number of cytokines and chemokines involved in pro-inflammatory responses. In addition, the enhanced expression of two genes, S100 calcium-binding protein A12 (S100A12) and Pentraxin-3 (PTX3) corresponded with significantly increased levels of their proteins in milk from infected udders. Both genes were shown to be expressed by mammary epithelial cells grown in culture after stimulation with lipopolysaccharide. There was also a strong correlation between somatic cell count, a widely used measure of mastitis, and the level of S100A12 in milk from a herd of dairy cows. Recombinant S100A12 inhibited growth ofEscherichia coliin vitro and recombinant PTX3 bound toE. colias well as C1q, a subunit of the first component of the complement cascade.

Conclusion

The transcriptional responses in infected bovine mammary tissue, even at low doses of bacteria and short periods of infection, probably reflect the combined contributions of gene expression changes resulting from the activation of mammary epithelial cells and infiltrating immune cells. The secretion of a number of proinflammatory cytokines and chemokines from mammary epithelial cells stimulated by the bacteria serves to trigger the recruitment and activation of neutrophils in mammary tissue. The presence of S100A12 and PTX3 in milk from infected udder quarters may increase the anti-bacterial properties of milk thereby helping to resolve the mammary tissue infection as well as potentially contributing to the maturation of the newborn calf epithelium and establishment of the newborn gut microbial population.
Multiple functions of the von Willebrand Factor A domain in matrilins: secretion, assembly, and proteolysis
Authors: Zhang Yue , Wang Zheng-ke , Luo Jun-ming , Kanbe Katsuaki , Chen Qian
Published: June 2008

The von Willebrand Factor A (vWF A) domain is one of the most widely distributed structural modules in cell-matrix adhesive molecules such as intergrins and extracellular matrix proteins. Mutations in the vWF A domain of matrilin-3 cause multiple epiphyseal dysplasia (MED), however the pathological mechanism remains to be determined. Previously we showed that the vWF A domain in matrilin-1 mediates formation of a filamentous matrix network through metal-ion dependent adhesion sites in the domain. Here we show two new functions of the vWF A domain in cartilage-specific matrilins (1 and 3). First, vWF A domain regulates oligomerization of matrilins. Insertion of a vWF A domain into matrilin-3 converts the formation of a mixture of matrilin-3 tetramer, trimer, and dimer into a tetramer only, while deletion of a vWF A domain from matrilin-1 converts the formation of the native matrilin-1 trimer into a mixture of trimer and dimer. Second, the vWF A domain protects matrilin-1 from proteolysis. We identified a latent proteolytic site next to the vWF A2 domain in matrilin-1, which is sensitive to the inhibitors of matrix proteases. Deletion of the abutting vWF A domain results in degradation of matrilin-1, presumably by exposing the adjacent proteolytic site. In addition, we also confirmed the vWF A domain is vital for the secretion of matrilin-3. Secretion of the mutant matrilin-3 harbouring a point mutation within the vWF A domain, as occurred in MED patients, is markedly reduced and delayed, resulting from intracellular retention of the mutant matrilin-3. Taken together, our data suggest that different mutations/deletions of the vWF A domain in matrilins may lead to distinct pathological mechanisms due to the multiple functions of the vWF A domain.
Acute bilateral anterior circulation stroke due to anomalous cerebral vasculature: a case report
Authors: Menezes Brian F. , Cheserem Beverley , Kandasamy Jothy , O'Brien Donnacha
Published: June 2008

Introduction

Simultaneous bilateral cerebrovascular infarction is relatively rare and its initial presentation as a space-occupying lesion is extremely uncommon. However, bilateral infarction can result from unilateral occlusion of anomalous cerebral vasculature.

Case presentation

We report the case of a man presenting with lower limb weakness and aphasia of acute onset with initial computerised tomography suggesting bifrontal neoplasm. However, further investigation confirmed bilateral anterior cerebral artery territory infarction with a hypoplastic left anterior cerebral artery with the right anterior cerebral artery supplying both frontal lobes (an anatomical variant). We present the clinical and diagnostic features of this presentation and attempt to ascertain, by reviewing existent medical literature, the frequency and patterns of structural variations in cerebral vasculature.

Conclusion

Simultaneous bilateral cerebral infarction can be the result of a unilateral cerebral artery occlusion and this can potentially mimic a space-occupying lesion. Anomalies of cerebral vasculature are not as rare as is usually believed and this should be borne in mind when investigating unusual presentations of cerebrovascular infarction.
Markers for Microscopic Imaging of Lymphangiogenesis and Angiogenesis
Authors: Baluk Peter , McDonald Donald M.
Published: June 2008

Imaging of lymphangiogenesis and angiogenesis requires robust and unambiguous markers of lymphatic and blood vessels. Although much progress has been made in recent years in identifying molecules specifically expressed on lymphatic and blood vessels, no perfect marker has been found that works reliably in all species, tissues, vascular beds, and in all physiological and pathologic conditions. The heterogeneity of expression of markers in both blood and lymphatic vessels reflects underlying differences in the phenotype of endothelial cells. Use of only one marker can lead to misleading interpretations, but these pitfalls can usually be avoided by use of multiple markers and three‐dimensional whole‐mount preparations. LYVE‐1, VEGFR‐3, Prox1, and podoplanin are among the most useful markers for microscopic imaging of lymphatic vessels, but, depending on histologic location, each marker can be expressed by other cell types, including vascular endothelial cells. Other markers, including CD31, junctional proteins, and receptors, such as VEGF‐2, are shared by lymphatic and blood vessels.
Peptide Targeting of Tumor Lymph Vessels
Authors: Laakkonen Pirjo , Zhang Lianglin , Ruoslahti Erkki
Published: June 2008

In addition to having a blood vasculature, most normal organs and pathologic conditions involve a second vascular system, the lymphatic vasculature, and many tumors induce the growth of new lymphatic vessels. However, compared to the blood vasculature, very little is known about the lymphatic vessels in tumors. We have used thein vivophage display technology to map tumor‐specific differences in the lymphatic vasculature, and identified peptides that specifically home to tumor lymphatics. Each of these peptides recognizes lymphatic vessels in a different set of tumors, and some of them also recognize tumor cells. Furthermore, these peptides can differentiate lymphatic vasculature of a premalignant lesion from that of a full‐blown tumor, indicating tumor stage–specific differences in the lymphatic vessels. None of the lymphatic homing peptides recognizes blood endothelial cells, nor do they home to any normal organ. Of interest, some of our homing peptides are able to penetrate the target cells in a cell type–specific manner. These peptides appear to be able to concentrate in the target tissue, making them particularly efficient delivery vectors for the targeting of therapeutic moieties and imaging agents. Conjugation of the lymphatic homing peptides to drugs provides an opportunity to specifically deliver therapeutic agents into tumors using a route not previously exploited. The surprising degree of selectivity of these lymphatic homing peptides suggests extensive molecular specialization of tumor lymphatic vessels, positing the existence of a molecular lymphatic “zip code” system, as has been previously demonstrated for the tumor blood vasculature.
The Link between Lymphatic Function and Adipose Biology
Authors: Harvey Natasha L.
Published: June 2008

Despite observations of a link between lymphatic vessels and lipids that date as far back as 300, a link between lymphatic vessels and adipose tissue has only recently been recognized. This review will summarize documented evidence that supports a close relationship between lymphatic vessels and adipose tissue biology. Lymphatic vessels mediate lipid absorption and transport, share an intimate spatial association with adipose tissue, and regulate the traffic of immune cells that rely on specialized adipose tissue depots as a reservior of energy deployed to fight infection. Important links between inflammation and adipose tissue biology will also be discussed in this article, as will recent evidence connecting lymphatic vascular dysfunction with the onset of obesity. There seems little doubt that future research in this topical field will ensure that the link between lymphatic vascular function and adipose tissue is firmly established.
Molecular Regulation of Lymphatic Contractility
Authors: Muthuchamy Mariappan , Zawieja David
Published: June 2008

The lymphatic system plays critical roles in body fluid and macromolecular homeostasis, lipid absorption, immune function, and metastasis. To accomplish these tasks, the lymphatics must move lymph and its contents from the interstitial space through the lymph vessels and nodes and into the great veins. Contrary to popular belief, lymph does not passively “drain” down this pathway, because the net pressure gradients oppose flow. Instead, the lymphatics must act as both the conduits that direct and regulate lymph flow and the pumps that generate the lymph flow. Thus, to regulate lymph transport and function, both lymphatic pumping and flow resistance must be controlled. Both of these processes occur via regulation of lymphatic muscle contractions, which are classically thought to occur via the interaction of cell calcium with regulatory and contractile proteins. However, our knowledge of this regulation of lymphatic contractile function is far from complete. In this chapter we review our understanding of the important molecular mechanisms, the calcium regulation, and the contractile/regulatory proteins that control lymphatic contractions. A better understanding of these mechanisms could provide the basis for the development of better diagnostic and treatment modalities for lymphatic dysfunction. While progress has been made in our understanding of the molecular biology of lymphangiogenesis as a result of the development of potential lymphangiogenic therapeutic targets, there are currently no therapeutic agents that specifically modulate lymphatic pump function and lymph flow via lymphatic muscle. However, their development will not be possible until the molecular basis of lymphatic contractility is more fully understood.
Contractility Patterns of Human Leg Lymphatics in Various Stages of Obstructive Lymphedema
Authors: Olszewski Waldemar L.
Published: June 2008

In healthy human leg, lymphatics contract spontaneously, rhythmically propelling lymph. The pressures generated by lymphatic contractions constitute the main force for lymph flow. This mechanism is of utmost importance during night rest, anesthesia, and immobilization, as well as in those with damaged peripheral motor neurons. Under physiological conditions, limb muscular activity and position only slightly change lymph flow. In obstructive lymphedema, lymphatic wall muscular fibers become damaged and the spontaneous contractility becomes ineffective in lymph transport because of low generated pressures and lymphatic valve insufficiency. The lymph‐propelling task is taken over by leg muscle contractions. Measuring intralymphatic pressures and flow gives some insight into the mechanism of lymph flow in healthy limbs and loss of this function in lymphedema. This knowledge will be useful in the derivation of rational treatments for lymphedema.
Lymphatics in Lung Disease
Authors: El‐Chemaly Souheil , Levine Stewart J. , Moss Joel
Published: June 2008

The lymphatic circulation appears to be a vital component in lung biology in health and in disease. Animal models have established the role of the lymphatic circulation in neoplastic and inflammatory diseases of the lung, such as asthma and cancer, and allowed for the understanding of the molecular controls of lymphangiogenesis in normal lung development. Understanding the role of lymphatics in human lung disease appears likely to contribute to the understanding of the pathogenesis of disease and the development of novel therapeutic targets.
Molecular Control of Lymphatic Metastasis
Authors: Achen Marc G. , Stacker Steven A.
Published: June 2008

The metastatic spread of tumor cells is the most lethal aspect of cancer and often occurs via the lymphatic vasculature. Both experimental tumor models and human clinicopathologic data indicate that growth of lymphatic vessels (lymphangiogenesis) near solid tumors is often associated with lymph node metastasis. Changes in the adhesive properties of lymphatic endothelium near tumors may also facilitate metastatic spread via the lymphatics. Lymphangiogenic growth factors have been identified that promote formation of tumor lymphatics and metastatic spread of tumor cells to lymph nodes. These include the secreted glycoproteins vascular endothelial growth factor‐C (VEGF‐C) and VEGF‐D, which act via their cognate receptor tyrosine kinase VEGF receptor‐3 (VEGFR‐3) located on lymphatic endothelial cells. Other signaling molecules that have been reported to promote lymphangiogenesis and/or lymphatic metastasis in cancer include VEGF‐A, platelet‐derived growth factor‐BB, and hepatocyte growth factor. However, the quantitative contribution of these proteins to tumor lymphangiogenesis and lymphatic metastasis in different tumor types requires further investigation. In addition, chemokines are thought to play a role in attracting tumor cells and lymphatic vessels to each other. Moreover, it has recently been shown that lymphangiogenic growth factors secreted from a primary tumor can induce lymphangiogenesis in nearby lymph nodes, even before arrival of tumor cells, which may facilitate further metastasis. This article provides an overview of the molecular mechanisms that control lymphatic metastasis and discusses potential therapeutic approaches for inhibiting this process in human cancer.
Gorham's Disease
Authors: Radhakrishnan Kavita , Rockson Stanley G.
Published: June 2008

Gorham's disease, also known as massive osteolysis, Gorham–Stout disease, vanishing bone disease, or, phantom bone disease is a rare disorder of the musculoskeletal system. The disease is characterized by osteolysis in bony segments, with localized proliferation of lymphatic channels. The presence of abundant, leaky systemic lymphatic vessels is often accompanied by chylous ascites. There is no standardized treatment available for Gorham's disease, and its molecular mechanisms remain unclear. Future strategies for understanding Gorham's disease should emphasize its apparent identity as a disease of disordered lymphangiogenesis. Breakthroughs in lymphatic research have identified several lymphangiogenic pathways that may play a relevant role in Gorham's disease.
Imatinib for Newly Diagnosed Patients With Chronic Myeloid Leukemia: Incidence of Sustained Responses in an Intention-to-Treat Analysis
Authors: de Lavallade Hugues , Apperley Jane F. , Khorashad Jamshid S. , Milojkovic Dragana , Reid Alistair G. , Bua Marco , Szydlo Richard , Olavarria Eduardo , Kaeda Jaspal , Goldman John M. , Marin David
Published: June 2008

Purpose

Imatinib is remarkably effective in treating newly diagnosed patients with chronic myeloid leukemia (CML) in chronic phase (CP). To date, most of the available data come from a single multicenter study in which some of the patients were censored for diverse reasons. Here, we report our experience in treating patients at a single institution in a setting where all events were recorded.

Patients and Methods

A total of 204 consecutive adult patients with newly diagnosed CML in CP received imatinib from June 2000 until August 2006. Response (hematologic, cytogenetic, and molecular), progression-free survival (PFS) and survival were evaluated.

Results

At 5 years, cumulative incidences of complete cytogenetic response (CCyR) and major molecular response (MMR) were 82.7% and 50.1%, respectively. Estimated overall survival and PFS were 83.2% and 82.7%, respectively. By 5 years, 25% of patients had discontinued imatinib treatment because of an unsatisfactory response and/or toxicity. The 5-year probability of remaining in major cytogenetic response while still receiving imatinib was 62.7%. Patients achieving a CCyR at 1 year had a better PFS and overall survival than those failing to reach CCyR, but achieving a MMR conferred no further advantage. The identification of a kinase domain mutation was the only factor predicting for loss of CCyR.

Conclusion

Imatinib is highly effective in most patients with CML-CP; patients who respond are likely to live substantially longer than those treated with earlier therapies. Achieving CCyR correlated with PFS and overall survival, but achieving MMR had no further predictive value. However, approximately one third of patients still need better therapy.
Early Detection of Pompe Disease by Newborn Screening Is Feasible: Results From the Taiwan Screening Program
Authors: Chien Yin-Hsiu , Chiang Shu-Chuan , Zhang Xiaokui Kate , Keutzer Joan , Lee Ni-Chung , Huang Ai-Chu , Chen Chun-An , Wu Mei-Hwan , Huang Pei-Hsin , Tsai Fu-Jen , Chen Yuan-Tsong , Hwu Wuh-Liang
Published: June 2008

OBJECTIVE. Pompe disease is an autosomal recessive lysosomal storage disorder that is caused by deficient acid α-glucosidase activity and results in progressive, debilitating, and often life-threatening symptoms involving the musculoskeletal, respiratory, and cardiac systems. Recently, enzyme replacement therapy with alglucosidase α has become possible, but the best outcomes in motor function have been achieved when treatment was initiated early. The aim of this study was to test the feasibility of screening newborns in Taiwan for Pompe disease by using a fluorometric enzymatic assay to determine acid α-glucosidase activity in dried blood spots.

METHODS. We conducted a large-scale newborn screening pilot program between October 2005 and March 2007. The screening involved measuring acid α-glucosidase activity in dried blood spots of ∼45% of newborns in Taiwan. The unscreened population was monitored as a control.

RESULTS. Of the 132 538 newborns screened, 1093 (0.82%) repeat dried blood-spot samples were requested and retested, and 121 (0.091%) newborns were recalled for additional evaluation. Pompe disease was confirmed in 4 newborns. This number was similar to the number of infants who received a diagnosis of Pompe disease in the control group (n = 3); however, newborn screening resulted in an earlier diagnosis of Pompe disease: patients were <1 month old compared with 3 to 6 months old in the control group.

CONCLUSIONS. To our knowledge, this is the first large-scale study to show that newborn screening for Pompe disease is feasible. Newborn screening allows for earlier diagnosis of Pompe disease and, thus, for assessment of the value of an earlier start of treatment.