bluuebunny/crossref_metadata_2025 huggingface dataset:
Preservation of motor skill learning in patients with multiple sclerosis
Authors: Tomassini Valentina , Johansen-Berg Heidi , Leonardi Laura , Paixão Luis , Jbabdi Saad , Palace Jackie , Pozzilli Carlo , Matthews Paul M
Published: September 2010

Background:Several studies have demonstrated benefits of rehabilitation in multiple sclerosis (MS). However, the neuroscientific foundations for rehabilitation in MS are poorly established.

Objectives:As rehabilitation and motor learning share similar mechanisms of brain plasticity, we test whether the dynamics of skill learning are preserved in MS patients relative to controls.

Methods:MS patients and controls learned a repeating sequence of hand movements and were assessed for short-term learning. Long-term learning was tested in another cohort of patients and controls practising the same sequence daily for two weeks.

Results:Despite differences in baseline performance, the dynamics and extent of improvements were comparable between MS and control groups for both the short- and long-term learning. Even the most severely damaged patients were capable of performance improvements of similar magnitude to that seen in controls. After one week of training patients performed as well as the controls at baseline.

Conclusions:Mechanisms for short- and long-term plasticity may compensate for impaired functional connectivity in MS to mediate behavioural improvements. Future studies are needed to define the neurobiological substrates of this plasticity and the extent to which mechanisms of plasticity in patients may be distinct from those used for motor learning in controls.
Prospective evaluation of two recruitment strategies for a randomized controlled cancer prevention trial
Authors: Chlebowski Rowan T , Menon Rashmi , Chaisanguanthum Roslyn M , Jackson D Marie
Published: September 2010

Purpose To evaluate two recruitment strategies used during the full-scale randomized, placebo-controlled Selenium and Vitamin E Cancer Prevention Trial (SELECT) at one clinical center.

Background Recruitment of participants to cancer prevention trials is challenging and costly and more efficient methods are needed.

Methods SELECT participants were males ≥60 years old who were solicited with two recruitment strategies. In the control strategy, potential participants, identified through purchased mailing lists, were sent a SELECT invitation letter. In the ‘spouse’ strategy, letters were sent to married postmenopausal women already participating in the Women’s Health Initiative (WHI) at our clinical center asking them to provide an enclosed SELECT invitation letter (identical to the one in the control strategy) to the ‘man in her life’. Our hypothesis was that SELECT recruitment of men would be enhanced by this indirect mailing to their spouses already participating in a similar program.

Results In the control strategy, 183,315 invitation letters were mailed to 60,000 men; cumulative response was 2.16%; 600 men ultimately enrolled in SELECT (15.1% of respondents) for a mailing recruitment cost of $259 per participant. In the spouse strategy, 800 women participating in WHI clinical studies had husbands; of the 2214 invitation letters mailed to this group of women, cumulative response was 2.75%; 34 men ultimately enrolled in SELECT (55.7% of respondents) for a mailing recruitment cost of $59 per participant.

Limitation Process information on how invitation letters were handled in the spouse strategy was not collected.

Conclusion A direct mail recruitment strategy was successful in recruiting men to a cancer prevention trial. A recruitment strategy involving indirect mailing to married women participating in a similar research program in the same center did not increase initial response substantially, but a higher proportion of respondents ultimately entered the prevention trial.
Progenitor cell dose determines the pace and completeness of engraftment in a xenograft model for cord blood transplantation
Authors: Liu Congxiao , Chen Benny J. , DeOliveira Divinomar , Sempowski Gregory D. , Chao Nelson J. , Storms Robert W.
Published: September 2010

Two critical concerns in clinical cord blood transplantation are the initial time to engraftment and the subsequent restoration of immune function. These studies measured the impact of progenitor cell dose on both the pace and strength of hematopoietic reconstitution by transplanting nonobese diabetic/severe combined immunodeficiency/interleukin-2 receptor-gamma–null (NSγ) mice with lineage-depleted aldehyde dehydrogenase-bright CD34+ human cord blood progenitors. The progress of each transplant was monitored over an extended time course by repeatedly analyzing the peripheral blood for human hematopoietic cells. In vivo human hematopoietic development was complete. After long-term transplantation assays (≥ 19 weeks), human T-cell development was documented within multiple tissues in 16 of 32 NSγ mice. Human T-cell differentiation was active within NSγ thymuses, as documented by the presence of CD4+ CD8+ T-cell progenitors as well as T-cell receptor excision circles. It is important to note that although myeloid and B-cell engraftment was detected as early as 4 weeks after transplantation, human T-cell development was exclusively late onset. High progenitor cell doses were associated with a robust human hematopoietic chimerism that accelerated both initial time to engraftment and subsequent T-cell development. At lower progenitor cell doses, the chimerism was weak and the human hematopoietic lineage development was frequently incomplete.
Loss of Cxcl12/Sdf-1 in adult mice decreases the quiescent state of hematopoietic stem/progenitor cells and alters the pattern of hematopoietic regeneration after myelosuppression
Authors: Tzeng Yi-Shiuan , Li Hung , Kang Yuan-Lin , Chen Wen-Cheng , Cheng Wei-Cheng , Lai Dar-Ming
Published: September 2010

The C-X-C-type chemokine Cxcl12, also known as stromal cell–derived factor-1, plays a critical role in hematopoiesis during fetal development. However, the functional requirement of Cxcl12 in the adult hematopoietic stem/progenitor cell (HSPC) regulation was still unclear. In this report, we developed a murine Cxcl12 conditional deletion model in which the target gene can be deleted at the adult stage. We found that loss of stroma-secreted Cxcl12 in the adult led to expansion of the HSPC population as well as a reduction in long-term quiescent stem cells. In Cxcl12-deficient bone marrow, HSPCs were absent along the endosteal surface, and blood cell regeneration occurred predominantly in the perisinusoidal space after 5-fluorouracil myelosuppression challenge. Our results indicate that Cxcl12 is required for HSPC homeostasis regulation and is an important factor for osteoblastic niche organization in adult stage bone marrow.
In pediatric patients, age has more impact on dosing of vitamin K antagonists than VKORC1 or CYP2C9 genotypes
Authors: Nowak-Göttl Ulrike , Dietrich Kevin , Schaffranek Daria , Eldin Noha Sharaf , Yasui Yutaka , Geisen Christof , Mitchell Lesley G.
Published: September 2010

Anticoagulation with vitamin K antagonists (VKAs) is problematic because of difficulties in safely managing dosing. Polymorphisms in cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase genes (VKORC1) have been shown to affect VKA dosing in adults. The association of these polymorphisms on VKA dosing in children has not been investigated. The objective of the study was to assess associations of CYP2C9 and VKORC1 polymorphisms and clinical variables on VKA dosing in children. A nonselected cohort of pediatric patients receiving VKA were tested for CYP2C9 and VKORC1 polymorphisms, and clinical data were collected. Multiple linear regression modeling was used to assess relationships of VKA dose with genetic and clinical variables. Fifty-nine patients were recruited; 55.9% were receiving warfarin, and 44.1% were on phenprocoumon. There was a negative association of age with VKA dose (P < .001). Comparing VKORC1 genotypes, the AA group required significantly lower daily doses than GG group (P = .011). In the full model including age, VKORC1 and CYP2C9 genotypes accounted for 38% of dose variation. Age explained 28.3% of VKA dose variations; VKORC1 and CYP2C9 explained only 3.7% and 0.4%, respectively. In children, the most critical factor in determining VKA dose is age. VKORC1/CYP2C9 genotypes only marginally explain dose variations.
Sequence variation at multiple loci influences red cell hemoglobin concentration
Authors: Peters Luanne L. , Shavit Jordan A. , Lambert Amy J. , Tsaih Shirng-Wern , Li Qian , Su Zhiguang , Leduc Magalie S. , Paigen Beverly , Churchill Gary A. , Ginsburg David , Brugnara Carlo
Published: September 2010

A substantial genetic contribution underlies variation in baseline peripheral blood counts. We performed quantitative trait locus/loci analyses to identify chromosome regions harboring genes influencing red cell hemoglobin concentration using the cell hemoglobin concentration mean (CHCM), a directly measured parameter analogous to the mean cell hemoglobin concentration. Fourteen significant loci (gene symbols Chcmq1-Chcmq14) were detected. Seven of these influenced CHCM in a sex-specific fashion, and 2 showed significant interactive effects (epistasis). For quantitative trait locus/loci detected in multiple crosses, confidence intervals were narrowed using statistical and bioinformatic approaches. Two strong candidate genes emerged and were further analyzed: adult β-globin (Hbb) for Chcmq3 on Chr 7, and transferrin (Trf) for Chcmq2 on Chr 9. High and low allele parental strains in crosses detecting Chcmq3 segregate 100% with the known ancestral haplotype blocks, hemoglobin (Hb) diffuse (Hbbd) and Hb single (Hbbs), respectively. Hbbd consists of nonidentical major and minor polypeptides and exhibits an increased positive charge relative to Hbbs due to the net loss of 2 negative residues in the Hbbdminor polypeptide, resulting in a pI of 7.85 versus 7.13. Thus, as shown in human erythrocytes, positively charged Hbs are associated with cell dehydration and increased CHCM in mouse erythrocytes.
Adaptation to anemia in hemoglobin E-β thalassemia
Authors: Allen Angela , Fisher Christopher , Premawardhena Anuja , Peto Timothy , Allen Stephen , Arambepola Mahinda , Thayalsutha Vivekanandan , Olivieri Nancy , Weatherall David
Published: September 2010

Hemoglobin E β thalassemia is the commonest form of severe thalassemia in many Asian countries. Its remarkably variable clinical phenotype presents a major challenge to determining its most appropriate management. In particular, it is not clear why some patients with this condition can develop and function well at very low hemoglobin levels. Here, we demonstrate that patients with hemoglobin Eβ thalassemia have a significant decrease in the oxygen affinity of their hemoglobin, that is an increased P50 value, in response to anemia. This may in part reflect the lower level of hemoglobin F in this condition compared with other forms of β thalassemia intermedia. The ability to right-shift the oxygen dissociation curve was retained across the spectrum of mild and severe phenotypes, despite the significantly higher levels of hemoglobin F in the former, suggesting that efforts directed at producing a modest increase in the level of hemoglobin F in symptomatic patients with this disease should be of therapeutic value.
Efficacy of tyrosine kinase inhibitors (TKIs) as third-line therapy in patients with chronic myeloid leukemia in chronic phase who have failed 2 prior lines of TKI therapy
Authors: Ibrahim Amr R. , Paliompeis Christos , Bua Marco , Milojkovic Dragana , Szydlo Richard , Khorashad Jamshid S. , Foroni Letizia , Reid Alistair , de Lavallade Hugues , Rezvani Katayoun , Dazzi Francesco , Apperley Jane F. , Goldman John M. , Marin David
Published: September 2010

We analyzed a cohort of 26 patients with chronic myeloid leukemia who had failed imatinib and a second tyrosine kinase inhibitor but were still in first chronic phase and identified prognostic factors for response and outcomes. The achievement of a prior cytogenetic response on imatinib or on second-line therapy were the only independent predictors for the achievement of complete cytogenetic responses on third-line therapy. Younger age and the achievement of a cytogenetic response on second line were the only independent predictors for overall survival (OS). At 3 months, the 9 patients who had achieved a cytogenetic response had better 30-month probabilities of complete cytogenetic responses and OS than the patients who had failed to do so. Factors measurable before starting treatment with third line therapy and cytogenetic responses at 3 months can accurately predict subsequent outcome and thus guide clinical decisions.
Characterization of tetracycline modifying enzymes using a sensitive in vivo reporter system
Authors: Yu Zhou , Reichheld Sean E , Cuthbertson Leslie , Nodwell Justin R , Davidson Alan R
Published: September 2010

Background

Increasing our understanding of antibiotic resistance mechanisms is critical. To enable progress in this area, methods to rapidly identify and characterize antibiotic resistance conferring enzymes are required.

Results

We have constructed a sensitive reporter system in Escherichia coli that can be used to detect and characterize the activity of enzymes that act upon the antibiotic, tetracycline and its derivatives. In this system, expression of the lux operon is regulated by the tetracycline repressor, TetR, which is expressed from the same plasmid under the control of an arabinose-inducible promoter. Addition of very low concentrations of tetracycline derivatives, well below growth inhibitory concentrations, resulted in luminescence production as a result of expression of the lux genes carried by the reporter plasmid. Introduction of another plasmid into this system expressing TetX, a tetracycline-inactivating enzyme, caused a marked loss in luminescence due to enzyme-mediated reduction in the intracellular Tc concentration. Data generated for the TetX enzyme using the reporter system could be effectively fit with the known K
m and k
cat values, demonstrating the usefulness of this system for quantitative analyses.

Conclusion

Since members of the TetR family of repressors regulate enzymes and pumps acting upon almost every known antibiotic and a wide range of other small molecules, reporter systems with the same design as presented here, but employing heterologous TetR-related proteins, could be developed to measure enzymatic activities against a wide range of antibiotics and other compounds. Thus, the assay described here has far-reaching applicability and could be adapted for high-throughput applications.
Alterations in Vitamin D signalling and metabolic pathways in breast cancer progression: a study of VDR, CYP27B1 and CYP24A1 expression in benign and malignant breast lesions Vitamin D pathways unbalanced in breast lesions
Authors: Lopes Nair , Sousa Bárbara , Martins Diana , Gomes Madalena , Vieira Daniella , Veronese Luiz A , Milanezi Fernanda , Paredes Joana , Costa José L , Schmitt Fernando
Published: September 2010

Background

Breast cancer is a heterogeneous disease associated with different patient prognosis and responses to therapy. Vitamin D has been emerging as a potential treatment for cancer, as it has been demonstrated that it modulates proliferation, apoptosis, invasion and metastasis, among others. It acts mostly through the Vitamin D receptor (VDR) and the synthesis and degradation of this hormone are regulated by the enzymes CYP27B1 and CYP24A1, respectively. We aimed to study the expression of these three proteins by immunohistochemistry in a series of breast lesions.

Methods

We have used a cohort comprising normal breast, benign mammary lesions, carcinomas in situ and invasive carcinomas and assessed the expression of the VDR, CYP27B1 and CYP24A1 by immunohistochemistry.

Results

The results that we have obtained show that all proteins are expressed in the various breast tissues, although at different amounts. The VDR was frequently expressed in benign lesions (93.5%) and its levels of expression were diminished in invasive tumours (56.2%). Additionally, the VDR was strongly associated with the oestrogen receptor positivity in breast carcinomas. CYP27B1 expression is slightly lower in invasive carcinomas (44.6%) than in benign lesions (55.8%). In contrast, CYP24A1 expression was augmented in carcinomas (56.0% in in situ and 53.7% in invasive carcinomas) when compared with that in benign lesions (19.0%).

Conclusions

From this study, we conclude that there is a deregulation of the Vitamin D signalling and metabolic pathways in breast cancer, favouring tumour progression. Thus, during mammary malignant transformation, tumour cells lose their ability to synthesize the active form of Vitamin D and respond to VDR-mediated Vitamin D effects, while increasing their ability to degrade this hormone.
'ZP domain' of human zona pellucida glycoprotein-1 binds to human spermatozoa and induces acrosomal exocytosis
Authors: Ganguly Anasua , Bansal Pankaj , Gupta Tripti , Gupta Satish K
Published: September 2010

Background

The human egg coat, zona pellucida (ZP), is composed of four glycoproteins designated as zona pellucida glycoprotein-1 (ZP1), -2 (ZP2), -3 (ZP3) and -4 (ZP4) respectively. The zona proteins possess the archetypal 'ZP domain', a signature domain comprised of approximately 260 amino acid (aa) residues. In the present manuscript, attempts have been made to delineate the functional significance of the 'ZP domain' module of human ZP1, corresponding to 273-551 aa fragment of human ZP1.

Methods

Baculovirus-expressed, nickel-nitrilotriacetic acid affinity chromatography purified 'ZP domain' of human ZP1 was employed to assess its capability to bind and subsequently induce acrosomal exocytosis in capacitated human spermatozoa using tetramethyl rhodamine isothiocyanate conjugated Pisum sativum Agglutinin in absence or presence of various pharmacological inhibitors. Binding characteristics of ZP1 'ZP domain' were assessed employing fluorescein isothiocyanate (FITC) labelled recombinant protein.

Results

SDS-PAGE and immunoblot characterization of the purified recombinant protein (both from cell lysate as well as culture supernatant) revealed a doublet ranging from ~35-40 kDa. FITC- labelled 'ZP domain' of ZP1 binds primarily to the acrosomal cap of the capacitated human spermatozoa. A dose dependent increase in acrosomal exocytosis was observed when capacitated sperm were incubated with recombinant 'ZP domain' of human ZP1. The acrosome reaction mediated by recombinant protein was independent of Gi protein-coupled receptor pathway, required extra cellular calcium and involved both T- and L-type voltage operated calcium channels.

Conclusions

Results described in the present study suggest that the 'ZP domain' module of human ZP1 has functional activity and may have a role during fertilization in humans.
Role of surface charge and oxidative stress in cytotoxicity of organic monolayer-coated silicon nanoparticles towards macrophage NR8383 cells
Authors: Bhattacharjee Sourav , de Haan Laura HJ , Evers Nynke M , Jiang Xue , Marcelis Antonius TM , Zuilhof Han , Rietjens Ivonne MCM , Alink Gerrit M
Published: September 2010

Background

Surface charge and oxidative stress are often hypothesized to be important factors in cytotoxicity of nanoparticles. However, the role of these factors is not well understood. Hence, the aim of this study was to systematically investigate the role of surface charge, oxidative stress and possible involvement of mitochondria in the production of intracellular reactive oxygen species (ROS) upon exposure of rat macrophage NR8383 cells to silicon nanoparticles. For this aim highly monodisperse (size 1.6 ± 0.2 nm) and well-characterized Si core nanoparticles (Si NP) were used with a surface charge that depends on the specific covalently bound organic monolayers: positively charged Si NP-NH2, neutral Si NP-N3 and negatively charged Si NP-COOH.

Results

Positively charged Si NP-NH2 proved to be more cytotoxic in terms of reducing mitochondrial metabolic activity and effects on phagocytosis than neutral Si NP-N3, while negatively charged Si NP-COOH showed very little or no cytotoxicity. Si NP-NH2 produced the highest level of intracellular ROS, followed by Si NP-N3 and Si NP-COOH; the latter did not induce any intracellular ROS production. A similar trend in ROS production was observed in incubations with an isolated mitochondrial fraction from rat liver tissue in the presence of Si NP. Finally, vitamin E and vitamin C induced protection against the cytotoxicity of the Si NP-NH2 and Si NP-N3, corroborating the role of oxidative stress in the mechanism underlying the cytotoxicity of these Si NP.

Conclusion

Surface charge of Si-core nanoparticles plays an important role in determining their cytotoxicity. Production of intracellular ROS, with probable involvement of mitochondria, is an important mechanism for this cytotoxicity.
Mechanisms of oxidative stress and alterations in gene expression by Libby six-mix in human mesothelial cells
Authors: Hillegass Jedd M , Shukla Arti , MacPherson Maximilian B , Lathrop Sherrill A , Alexeeva Vlada , Perkins Timothy N , van der Vliet Albert , Vacek Pamela M , Gunter Mickey E , Mossman Brooke T
Published: September 2010

Background

Exposures to an amphibole fiber in Libby, Montana cause increases in malignant mesothelioma (MM), a tumor of the pleural and peritoneal cavities with a poor prognosis. Affymetrix microarray/GeneSifter analysis was used to determine alterations in gene expression of a human mesothelial cell line (LP9/TERT-1) by a non-toxic concentration (15×106μm2/cm2) of unprocessed Libby six-mix and negative (glass beads) and positive (crocidolite asbestos) controls. Because manganese superoxide dismutase (MnSOD; SOD2) was the only gene upregulated significantly (p < 0.05) at both 8 and 24 h, we measured SOD protein and activity, oxidative stress and glutathione (GSH) levels to better understand oxidative events after exposure to non-toxic (15×106μm2/cm2) and toxic concentrations (75×106μm2/cm2) of Libby six-mix.

Results

Exposure to 15×106μm2/cm2Libby six-mix elicited significant (p < 0.05) upregulation of one gene (SOD2; 4-fold) at 8 h and 111 gene changes at 24 h, including a 5-fold increase inSOD2. Increased levels of SOD2 mRNA at 24 h were also confirmed in HKNM-2 normal human pleural mesothelial cells by qRT-PCR. SOD2 protein levels were increased at toxic concentrations (75×106μm2/cm2) of Libby six-mix at 24 h. In addition, levels of copper-zinc superoxide dismutase (Cu/ZnSOD; SOD1) protein were increased at 24 h in all mineral groups. A dose-related increase in SOD2 activity was observed, although total SOD activity remained unchanged. Dichlorodihydrofluorescein diacetate (DCFDA) fluorescence staining and flow cytometry revealed a dose- and time-dependent increase in reactive oxygen species (ROS) production by LP9/TERT-1 cells exposed to Libby six-mix. Both Libby six-mix and crocidolite asbestos at 75×106μm2/cm2caused transient decreases (p < 0.05) in GSH for up to 24 h and increases in gene expression of heme oxygenase 1 (HO-1) in LP9/TERT-1 and HKNM-2 cells.

Conclusions

Libby six-mix causes multiple gene expression changes in LP9/TERT-1 human mesothelial cells, as well as increases in SOD2, increased production of oxidants, and transient decreases in intracellular GSH. These events are not observed at equal surface area concentrations of nontoxic glass beads. Results support a mechanistic basis for the importance of SOD2 in proliferation and apoptosis of mesothelial cells and its potential use as a biomarker of early responses to mesotheliomagenic minerals.
Evaluation of multicomponent recombinant vaccines against Actinobacillus pleuropneumoniae in mice
Authors: Shao Meili , Wang Yong , Wang Chunlai , Guo Yang , Peng Yonggang , Liu Jiandong , Li Guangxing , Liu Huifang , Liu Siguo
Published: September 2010

Background

Porcine contagious pleuropneumonia (PCP) is a highly contagious disease that is caused byActinobacillus pleuropneumoniae(APP) and characterized by severe fibrinous necrotizing hemorrhagic pleuropneumonia, which is a severe threat to the swine industry. In addition to APP RTX-toxins I (ApxI), APP RTX-toxin II (ApxII), APP RTX-toxin III (ApxIII) and Outer membrane protein (OMP), there may be other useful antigens that can contribute to protection. In the development of an efficacious vaccine against APP, the immunogenicities of multicomponent recombinant subunit vaccines were evaluated.

Methods

Six major virulent factor genes of APP, i.e.,apxI,apxII,apxIII, APP RTX-toxins IV (apxIV),ompand type 4 fimbrial structural (apfa) were expressed. BALB/c mice were immunized with recombinant ApxI ( rApxI), recombinant ApxII (rApxII), recombinant ApxIII (rApxIII) and recombinant OMP (rOMP) (Group I); rApxI, rApxII, rApxIII, recombinant ApxIV (rApxIV), recombinant Apfa (rApfa) and rOMP (Group II); APP serotype 1 (APP1) inactivated vaccine (Group III); or phosphate-buffered saline (PBS) (Control group), respectively. After the first immunization, mice were subjected to two booster immunizations at 2-week intervals, followed by challenge with APP1 Shope 4074 and APP2 S1536.

Results

The efficacy of the multicomponent recombinant subunit vaccines was evaluated on the basis of antibody titers, survival rates, lung lesions and indirect immunofluorescence (IIF) detection of APP. The antibody level of Group I was significantly higher than those of the other three groups (P< 0.05). The survival rate of Group I was higher than that of Groups II and III (P< 0.05) and the control (P< 0.01). Compared with the other three groups, the lungs of Group I did not exhibit obvious hemorrhage or necrosis, and only showed weak and scattered fluorescent dots by IIF detection.

Conclusion

The result indicates that the multicomponent recombinant subunit vaccine composed of rApxI, rApxII, rApxIII and rOMP can provide effective cross-protection against homologous and heterologous APP challenge.
Leucine-rich alpha-2-glycoprotein-1 is upregulated in sera and tumors of ovarian cancer patients
Authors: Andersen John D , Boylan Kristin LM , Jemmerson Ronald , Geller Melissa A , Misemer Benjamin , Harrington Katherine M , Weivoda Starchild , Witthuhn Bruce A , Argenta Peter , Vogel Rachel Isaksson , Skubitz Amy PN
Published: September 2010

Background

New biomarkers that replace or are used in conjunction with the current ovarian cancer diagnostic antigen, CA125, are needed for detection of ovarian cancer in the presurgical setting, as well as for detection of disease recurrence. We previously demonstrated the upregulation of leucine-rich alpha-2-glycoprotein-1 (LRG1) in the sera of ovarian cancer patients compared to healthy women using quantitative mass spectrometry.

Methods

LRG1 was quantified by ELISA in serum from two relatively large cohorts of women with ovarian cancer and benign gynecological disease. The expression of LRG1 in ovarian cancer tissues and cell lines was examined by gene microarray, reverse-transcriptase polymerase chain reaction (RT-PCR), Western blot, immunocytochemistry and mass spectrometry.

Results

Mean serum LRG1 was higher in 58 ovarian cancer patients than in 56 healthy women (89.33 ± 77.90 vs. 42.99 ± 9.88 ug/ml; p = 0.0008) and was highest among stage III/IV patients. In a separate set of 193 pre-surgical samples, LRG1 was higher in patients with serous or clear cell ovarian cancer (145.82 ± 65.99 ug/ml) compared to patients with benign gynecological diseases (82.53 ± 76.67 ug/ml, p < 0.0001). CA125 and LRG1 levels were moderately correlated (r = 0.47, p < 0.0001).LRG1mRNA levels were higher in ovarian cancer tissues and cell lines compared to their normal counterparts when analyzed by gene microarray and RT-PCR. LRG1 protein was detected in ovarian cancer tissue samples and cell lines by immunocytochemistry and Western blotting. Multiple iosforms of LRG1 were observed by Western blot and were shown to represent different glycosylation states by digestion with glycosidase. LRG1 protein was also detected in the conditioned media of ovarian cancer cell culture by ELISA, Western blotting, and mass spectrometry.

Conclusions

Serum LRG1 was significantly elevated in women with ovarian cancer compared to healthy women and women with benign gynecological disease, and was only moderately correlated with CA125. Ovarian cancer cells secrete LRG1 and may contribute directly to the elevated levels of LRG1 observed in the serum of ovarian cancer patients. Future studies will determine whether LRG1 may serve as a biomarker for presurgical diagnosis, disease recurrence, and/or as a target for therapy.
It takes nerves to fight infections: insights on neuro-immune interactions fromC. elegans
Authors: Kawli Trupti , He Fanglian , Tan Man-Wah
Published: September 2010

The innate immune response is evoked as a consequence of interactions between invading foreign infectious agents and host immune cells. A successful innate immune response is pivotal in maintaining the delicate balance between health and disease; an insufficient response results in infection, whereas an excessive response results in prolonged inflammation and tissue damage. Alterations in the state and function of the nervous system influence the immune response. The nervous system regulates innate immune responses through the release of neurotransmitters, neuropeptides and neurohormones. However, many questions related to the molecular and cellular mechanisms involved, the physiological role of the link between the immune and the nervous system, and the biological significance of neuro-immune interactions remain unresolved. The interactions between the nematode Caenorhabditis elegans and its pathogens provide insights into mechanisms of neuroendocrine regulation of immunity and address many outstanding issues related to neuro-immune interactions.
Genetic and chemical modulation of spastin-dependent axon outgrowth in zebrafish embryos indicates a role for impaired microtubule dynamics in hereditary spastic paraplegia
Authors: Butler Richard , Wood Jonathan D. , Landers Jennifer A. , Cunliffe Vincent T.
Published: September 2010

Mutations in the SPAST (SPG4) gene, which encodes the microtubule-severing protein spastin, are the most common cause of autosomal dominant hereditary spastic paraplegia (HSP). Following on from previous work in our laboratory showing that spastin is required for axon outgrowth, we report here that the related microtubule-severing protein katanin is also required for axon outgrowth in vivo. Using confocal time-lapse imaging, we have identified requirements for spastin and katanin in maintaining normal axonal microtubule dynamics and growth cone motility in vivo, supporting a model in which microtubule severing is required for concerted growth of neuronal microtubules. Simultaneous knockdown of spastin and katanin caused a more severe phenotype than did individual knockdown of either gene, suggesting that they have different but related functions in supporting axon outgrowth. In addition, the microtubule-destabilising drug nocodazole abolished microtubule dynamics and growth cone motility, and enhanced phenotypic severity in spast-knockdown zebrafish embryos. Thus, disruption of microtubule dynamics might underlie neuronal dysfunction in this model, and this system could be used to identify compounds that modulate microtubule dynamics, some of which might have therapeutic potential in HSP.
Uncertainties Associated with Strain-Measuring Systems Using Resistance Strain Gauges
Authors: Montero W , Farag R , Díaz V , Ramirez M , Boada B L
Published: September 2010

Resistance strain gauges have been used for the measurement of strain for more than 50 years; however, research to quantify the inherent uncertainty in a strain-measuring system has been scarce hitherto. Nevertheless, resistive strain gauges are the most widely used tool to measure strain owing to their simplicity, apparent accuracy, low cost, and ease of use. In spite of this, at times they are used improperly, and the sources of error are neglected. Every type of measurement has an uncertainty associated with it. As it is impossible to eliminate error completely, the goal must be to quantify it and to reduce it to a value that is acceptable for the purposes of the measurement being taken. The novelty of the present research is to put forward a new methodology for determining the uncertainty in a strain gauge measuring system. To achieve this, the principal sources of error that influence the measuring system are formulated in order to develop an error model. Subsequently, the law of propagation of uncertainty is applied, together with a type A and B evaluation approach to determine the combined uncertainty of the entire measuring system, taking into consideration the correlation between variables, when applicable. The new methodology is then applied to a series of strain measurements taken on an aluminium flat bar subject to a bending load, and the results are discussed.
A New Mixed-Mode Fracture Criterion for Orthotropic Materials, Based on Strength Properties
Authors: Anaraki A R Gowhari , Fakoor M
Published: September 2010

In this paper, a new methodology for modelling the fracture process zone in cracked wooden structures has been proposed. Implementing this method for modelling the crack tip damage zone could help to establish a new criterion applicable for assessing the fracture of cracked wood specimens under combined mode I/II loading. This criterion involves a damage factor representing the material softening effect due to microcrack existence and growth in the fracture process zone. For calculation of this damage factor, it is not necessary to investigate the complex and non-linear analysis of material behaviour in the damage zone. The approach proposed makes it possible to express an analytical relation for the damage factor as a function of tensile strength along and across the wood fibres. The novelty of this work is that the given method enables not only the arbitrary orientation effects of the original crack with respect to wood fibres but also the T-stress effects in crack growth initiation to be considered. To demonstrate the effectiveness of this method, different case studies have been investigated, and the results obtained by applying the new criterion are compared with available experimental data.
Controlled Fracture Test for Brittle Ceramics
Authors: García-Prieto A , Hernández J , López M , Baudín C
Published: September 2010

Controlled fracture tests that ensure the full conversion of supplied energy into crack surface energy are required for the accurate determination of the toughness parameters of materials. In this work, a new experimental configuration to perform three-point-bending single-edge V-notch beam stable fracture tests controlled by the crack mouth opening displacement (CMOD) is presented. The CMOD is chosen as the control variable because it is the only parameter that increases throughout the whole fracture process. Results obtained by applying the proposed approach to a fine-grained test sample of the spinel-structured phase of magnesium aluminium oxide are presented. The results obtained demonstrate that the proposed configuration allows stable fracture tests to be performed on extremely brittle ceramics.
The need for developing an effective and acceptable engineering response to terrorist attacks on railway systems
Authors: Powell J , Fletcher D
Published: September 2010

In recent years, terrorism has affected rail transport in Europe and elsewhere in the world. This article gives a brief historical review of terrorist attacks on rail systems and the counter-terrorism security measures that have evolved in response. The possibilities for ‘designing-in’ resilience to a terrorist attack are examined, and some inputs by which engineering may have a positive long-term impact on the security of rail systems are identified. The article reviews media articles, academic papers and reports, government material, and the results of interviews with security managers on rail systems. It considers the required performance of counter-terrorism measures with regard to the safety of passengers and staff, the physical processes taking place during a bomb explosion, and also highlights several issues that will affect how counter-terrorist measures are ‘designed-in’, including public and business acceptability, reduction of threat and cost effectiveness.
A novel hybrid methodology combining back propagation neural network with rough set and its application
Authors: Deng W , Chen R , Liu Y Q
Published: September 2010

In the increasingly complex world, decision makers need assistance in making informed transportation planning decisions. This article describes the application of rough set (RS) and back propagation neural network (BPNN) in the development of a novel hybrid intelligent model for forecasting the railway passenger traffic demand. The model intends to exploit the respective advantages of both RS and BPNN methods, but to avoid their respective weak points. The basic idea is to think of RS as the pre-treatment unit for BPNN that can mine knowledge from historical data. To do so, RS was used in data pre-treatment and constructing the decision table, and obtaining the minimum rule set from the decision table reduced by discretizing continuous attributes through a hybrid hierarchical k-means clustering. Input such rule set to the BPNN, trained on a sample dataset to determine parameters by using the Levenberg–Marquardt algorithm and the golden section algorithm. A hybrid intelligent forecasting model based on RS and BPNN is thus constructed and applied to forecast railway passenger traffic demand with pre-treated forecasting data. In the experiment, the railway passenger traffic data in China from 1991 to 2008 are selected as learning samples and testing samples, and the effectiveness of this method is verified in comparison to the linear recursive method.
The Bio-Tribological Characteristics of Synthetic Tissue Grafts
Authors: Thomas J M C , Beevers D , Dowson D , Jones M D , King P , Theobald P S
Published: September 2010

The use of synthetic connective tissue grafts became popular in the mid-1980s, particularly for anterior cruciate ligament reconstruction; however, this trend was soon changed given the high failure rate due to abrasive wear. More than 20 years later, a vast range of grafts are available to the orthopaedic surgeon for augmenting connective tissue following rupture or tissue loss. While the biomechanical properties of these synthetic grafts become ever closer to the natural tissue, there have been no reports of their bio-tribological (i.e. bio-friction) characteristics. In this study, the bio-tribological performance of three clinically available synthetic tissue grafts, and natural tendon, was investigated. It was established that the natural tissue exhibits fluid-film lubrication characteristics and hence is highly efficient when sliding against opposing tissues. Conversely, all the synthetic tissues demonstrated boundary or mixed lubrication regimes, resulting in surface—surface contact, which will subsequently cause third body wear. The tribological performance of the synthetic tissue, however, appeared to be dependent on the macroscopic structure. This study indicates that there is a need for synthetic tissue designs to have improved frictional characteristics or to use a scaffold structure that encourages tissue in-growth. Such a development would optimize the bio-tribological properties of the synthetic tissue and thereby maximize longevity.
The Effects of Disc Degeneration and Muscle Dysfunction on Cervical Spine Stability from a Biomechanical Study
Authors: Cheng C-H , Chen P-J , Kuo Y-W , Wang J-L
Published: September 2010

Disc degeneration and muscle dysfunction are common spinal degenerations in the elderly. This in vitro study was carried out to investigate the effects of these two degenerative changes on spinal stability. The stability of nine porcine cervical spines (C2–T1) with mechanically simulated cervical muscles (sternocleidomastoid (SCM), splenius capitis (SPL), semispinalis capitis (SSC)) was tested before and after experiment-induced disc degeneration. The patterns of muscle recruitments included: no muscle recruitment, normal recruitment of SCM/SPL/SSC, and SCM/SPL/SSC muscle dysfunctions. The neutral zone (NZ) and the range of motion (ROM) in the sagittal plane were measured to determine spinal stability. The results showed that the NZ and the ROM of a degenerative spine were larger than those of an intact spine under no muscle recruitment, but not under muscle recruitments. For both intact and degenerative spines, the NZ and the ROM were greatest under no muscle recruitment, followed by SSC dysfunction, SCM dysfunction, and SPL dysfunction, and smallest under normal muscle recruitment. In conclusion, muscle recruitments stabilize both intact and degenerative cervical spines, while dysfunctional muscles do not maintain stability efficiently as normal muscles do. Thus, spinal stability is more significantly affected by muscle dysfunction than by disc degeneration. Muscle training is suggested for the elderly with spinal degeneration to improve stability.
Periodontal regeneration: A challenge for the tissue engineer?
Authors: Hughes F J , Ghuman M , Talal A
Published: September 2010

Periodontitis affects around 15 per cent of human adult populations. While periodontal treatment aimed at removing the bacterial cause of the disease is generally very successful, the ability predictably to regenerate the damaged tissues remains a major unmet objective for new treatment strategies. Existing treatments include the use of space-maintaining barrier membranes (guided tissue regeneration), use of graft materials, and application of bioactive molecules to induce regeneration, but their overall effects are relatively modest and restricted in application. The periodontal ligament is rich in mesenchymal stem cells, and the understanding of the signalling molecules that may regulate their differentation has increased enormously in recent years. Applying these principles for the development of new tissue engineering strategies for periodontal regeneration will require further work to determine the efficacy of current experimental preclinical treatments, including pharmacological application of growth factors such as bone morphogenetic proteins (BMPs) or Wnts, use of autologous stem cell reimplantation strategies, and development of improved biomaterial scaffolds. This article describes the background to this problem, addresses the current status of periodontal regeneration, including the background biology, and discusses the potential for some of these experimental therapies to achieve the goal of clinically predictable periodontal regeneration.
Osteoblasts in bone tissue engineering
Authors: Jayakumar P , Di Silvio L
Published: September 2010

Osteoblasts are integral to the development, growth, function, repair and maintenance of bone. The osteoblast forms organic, non-mineralized bone matrix and is involved in complex interactions with a variety of factors, mediators and cell types. Degeneration, pathology, and trauma cause disruption and destruction of the normal skeletal environment and may lead to bone loss.

There is a rise in active populations involved in trauma, elderly patients with fragility fractures and an overall increase in primary, revision and reconstructive bone and joint surgery. Despite the rapid evolution of implant technologies and bone grafting techniques, there is still a great demand for novel bone replacement strategies.

Bone tissue engineering is the state of the art science with the potential to regenerate bone with natural form and function. This review presents the biology of osteoblasts and their current applications in bone tissue engineering biotechnologies and role in stem cell, bioactive factor, recombinant signalling molecule and gene therapy research.
Composite membranes of native silk fibroin powder and biomedical polyurethane for controlled release of heparin
Authors: Yang H-J , Xu H-Y , Zhu G-C , Ouyang C-X , Wang X-G , Xu W-L
Published: September 2010

Native silk fibroin powder (NSFP) carrying heparin was blended with biomedical polyurethane (BPU) to fabricate novel composite membranes for the controlled release of heparin. The NSFP/BPU composite membranes exhibited excellent hydrophilicity, water vapour permeability, and water absorption. The release of heparin from the composite membranes was evaluated by immersing the membranes in phosphate-buffered saline at 37 °C. The release of heparin from the composite membrane could be controlled by adjusting the blend ratios of NSFP and BPU, the amount of heparin in the membrane, and the membrane thickness. The bioactivity of heparin released from the composite membrane (NSFP/BPU 30/70, thickness 110 µm, length 2 cm, width 0.5 cm) with different amounts of heparin was evaluated by immersing the novel release system (composite membranes) in 0.5 mL of platelet-poor plasma for 1 h at 37 °C. The thrombin time, activated partial thromboplastin time, and prothrombin time were measured, the three parameters all exceeding the measurement limit of the clot detection instrument. The results suggest that heparin has excellent bioactivity, and the novel heparin release system can improve the blood compatibility of BPU.
The Development of a New Mandibular Osteosynthesis Plate: An Application of the Ashby Approach
Authors: Kovan V
Published: September 2010

Mandible fractures are among the most common bone injuries in facial traumas. Currently, mandibular fracture repair is carried out with an appropriate osteosynthesis plate. These osteosynthesis plates are also used to provide mastication function as soon as possible after operation. Therefore, the plates employed should ensure functional, mechanical, and morphological rehabilitation. Many researchers have reported that the titanium osteosynthesis plates currently used for mandibular defects are often subject to excessive stress. This excessive stress may lead to unexpected fractures of the plates. Unexpected fractures have been indicated as a mechanical weakness of titanium osteosynthesis plates. The aim of the present study is to investigate the mechanical stability and deformation behaviour of commercially available titanium mandibular osteosynthesis plates, as well as to design and develop a new osteosynthesis plate with better mechanical stability. In the first stage of this investigation, an analytical study was carried out to determine the optimum cross-sectional shape for the new plates. Subsequently, the cross-sectional shapes for the new plates were validated by numerical methods. Finally, the project was completed by manufacturing the plates and conducting static mechanical experiments of the developed plates. The mandibular osteosynthesis plates developed here are shown to exhibit improved mechanical stability.