bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic signature for human risk assessment: Lessons from trichloroethylene
Authors: Shiao Yih‐Horng
Published: November 2008

Trichloroethylene (TCE), an organic solvent commonly used for metal degreasing and as a chemical additive, is a significant environmental contaminant that poses health concerns in humans. The US Environmental Protection Agency (EPA) is currently revising the 2001 TCE human risk assessment draft. The next draft is expected to be ready in 2008. TCE metabolites are detectable in humans and carry varying potencies for induction of cancers in animals. Genomic mechanisms have been explored in animals and humans to link TCE to carcinogenesis. DNA analysis provides an opportunity for detection of unique genetic alterations representing a signature of TCE exposure. These alterations can arise from genotoxic and nongenotoxic pathways at multiple points throughout tumorigenesis. Although fixation of alterations may require several stages of selection and modification, the spectra can be specific to TCE. Only a fraction of these alterations eventually lead to tumor formation and some contribute to tumor progression. Genetic events in two major TCE target organs are reviewed, including the VHL gene in kidney, and the Ras gene and genome‐wide hypomethylation in liver. Attempts to identify a genetic signature of TCE exposure are challenged by inconsistent findings, lack of evidence of promutagenic lesions, biological relevance of specific genomic changes, and likelihood of coexposures. For human risk assessment, genome‐wide screening is useful and is possible with the development of new DNA‐sequencing technologies. Genetic screening for preneoplastic and tumor tissues from high‐risk population is proposed to exclude the noise of passenger mutations and genetic polymorphisms. Environ. Mol. Mutagen., 2009. Published 2008 Wiley‐Liss, Inc.
Comparison of gene expression profiles in HepG2 cells exposed to arsenic, cadmium, nickel, and three model carcinogens for investigating the mechanisms of metal carcinogenesis
Authors: Kawata Koji , Shimazaki Ryuhei , Okabe Satoshi
Published: November 2008

Carcinogenesis is an important chronic toxicity of metals and metalloids, although their mechanisms of action are still unclear. Comparison of gene expression patterns induced by carcinogenic metals, metalloids, and model carcinogens would give an insight into understanding of their carcinogenic mechanisms. In this study, we examined the gene expression alteration in human hepatoma cell line, HepG2, after exposing to two metals (cadmium and nickel), a metalloid (arsenic), and three model carcinogenic chemicalsN‐dimethylnitrosoamine (DMN), 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA), and tetrachloroethylene (TCE) using DNA microarrays with 8,795 human genes. Of the genes altered by As, Cd, and Ni exposures, 31–55% were overlapped with those altered by three model carcinogenic chemical exposures in our experiments. In particular, the metals and metalloid shared certain characteristics with TPA and TCE in remarkable upregulations of the genes associated with progression of cell cycle, which might play a central role in As, Cd, and Ni carcinogenesis. This characteristic of gene expression alteration was partially counteracted by intracellular accumulation of vitamin C in As‐exposed cells, whereas the number of cell‐cycle associated genes was increased in Cd‐ and Ni‐exposed cells. In our experimental conditions, ROS might have an accelerative effect on the cell proliferation mechanisms of As, but have an inhibitory effect on those of other two heavy metals. Furthermore, based on the results of Q‐PCR, the oncogenePTTG1, which was upregulated by all carcinogenic chemical exposures in the array experiments, might be a useful biomarker for evaluation of the carcinogenesis of inorganic carcinogens. Environ. Mol. Mutagen., 2009. © 2008 Wiley‐Liss, Inc.
Bone morphogenetic protein 4 inhibits TGF‐β2 stimulation of extracellular matrix proteins in optic nerve head cells: Role of gremlin in ECM modulation
Authors: Zode Gulab S. , Clark Abbot F. , Wordinger Robert J.
Published: November 2008

The characteristic cupping of the optic nerve head (ONH) in glaucoma is associated with elevated TGF‐β2 and increased synthesis and deposition of extracellular matrix (ECM) proteins. In addition to TGF‐β2, the human ONH also expresses bone morphogenetic proteins (BMPs) and BMP receptors, which are members of the TGF‐β superfamily. We examined the potential effects of BMP4 and the BMP antagonist gremlin on TGF‐β2 induction of ECM proteins in ONH cells. BMP‐4 dose dependently inhibited TGF‐β2‐induced fibronectin (FN) and PAI‐1 expression in ONH astrocytes and lamina cribrosa (LC) cells and also reduced TGF‐β2 stimulation of collagen I, collagen VI, and elastin. Addition of gremlin blocked this BMP‐4 response, increasing cellular and secreted FN as well as PAI‐1 levels in both cell types. Gremlin was expressed in ONH tissues and ONH cells, and gremlin protein levels were significantly increased in the LC region of human glaucomatous ONH tissues. Interestingly, recombinant gremlin dose dependently increased ECM protein expression in cultured ONH astrocytes and LC cells. Gremlin stimulation of ECM required activation of TGF‐β receptor and R‐Smad3. TGF‐β2 increased gremlin mRNA expression and protein levels in ONH cells. Inhibition of either the type I TGF‐β receptor or Smad3 phosphorylation blocked TGF‐β2‐induced gremlin expression. In conclusion, BMP4 blocked the TGF‐β2 induction of ECM proteins in ONH cells. The BMP antagonist gremlin reversed this inhibition, allowing TGF‐β2 stimulation of ECM synthesis. Increased expression of gremlin in the glaucomatous ONH may further exacerbate TGF‐β2 effects on ONH ECM metabolism by inhibiting BMP‐4 antagonism of TGF‐β2 signaling. Modulation of the ECM via gremlin provides a novel therapeutic target for glaucoma. © 2008 Wiley‐Liss, Inc.
The endocannabinoid anandamide inhibits potassium conductance in rat cortical astrocytes
Authors: Vignali M. , Benfenati V. , Caprini M. , Anderova M. , Nobile M. , Ferroni S.
Published: November 2008

Endocannabinoids are a family of endogenous signaling molecules that modulate neuronal excitability in the central nervous system (CNS) by interacting with cannabinoid (CB) receptors. In spite of the evidence that astroglial cells also possess CB receptors, there is no information on the role of endocannabinoids in regulating CNS function through the modulation of ion channel‐mediated homeostatic mechanisms in astroglial cells. We provide electrophysiological evidence that the two brain endocannabinoids anandamide (AEA) and 2‐arachidonylglycerol (2‐AG) markedly depress outward conductance mediated by delayed outward rectifier potassium current (IKDR) in primary cultured rat cortical astrocytes. Pharmacological experiments suggest that the effect of AEA does not result from the activation of known CB receptors. Moreover, neither the production of AEA metabolites nor variations in free cytosolic calcium are involved in the negative modulation of IKDR. We show that the action of AEA is mediated by its interaction with the extracellular leaflet of the plasma membrane. Similar experiments performedin situin cortical slices indicate that AEA downregulates IKDRin complex and passive astroglial cells. Moreover, IKDRis also inhibited by AEA in NG2 glia. Collectively, these results support the notion that endocannabinoids may exert their modulation of CNS function via the regulation of homeostatic function of the astroglial syncytium mediated by ion channel activity. © 2008 Wiley‐Liss, Inc.
Effect of corticosterone on developing hippocampus: Short‐term and long‐term outcomes
Authors: He Wen‐Bin , Zhao Ming , Machida Takeo , Chen Nai‐Hong
Published: November 2008

Many documents implicate that corticosterone plays a negative role in brain function, especially in learning and memory. However, less evidence confirms its direct actions on hippocampal development. In the work reported here, pro treatment, minimum corticosterone administration in infant mice, and con treatment, corticosterone deprivation by adrenalectomy, were used to examine the effects imposed by corticosterone on the structure and function of developing hippocampus. Our study shows that adrenalectomy induces decrease of plasma corticosterone levels and results in the impairment of learning performance and the degenerative changes not in CA regions of hippocampus but in dentate gyrus. Noteworthily, this damage effect is severer in 5‐week‐old mice than that in 10‐week‐old mice. In addition, the short‐term effect of minimum corticosterone administration may accelerate the development of dentate gyrus of 10‐day‐old mice. Moreover, minimum corticosterone administration during infancy contributed to the learning performance and the structural integrity of hippocampal CA regions in different developing stages, while this phenomenon was not observed in dentate gyrus. In conclusion, corticosterone is necessary for the development of dentate gyrus, especially in relatively young individuals, and administration with minimum corticosterone in infancy has a long‐term positive influence on the hippocampal structure and function in different developing stages. © 2008 Wiley‐Liss, Inc.
Low social inclusion in childhood: adjustment and early predictors
Authors: Nyberg Lilianne , Henricsson Lisbeth , Rydell Ann‐Margret
Published: November 2008

The principal aim of the present study was to obtain a deeper understanding than hitherto of the concurrent correlates and prospective predictors of loneliness and poor peer acceptance, both falling under the umbrella term low social inclusion. Problematic and socially competent behaviours were investigated as possible predictors of low social inclusion in grade 6, as defined by self‐rated loneliness and degree of peer non‐acceptance, respectively. In grade 6 808 children participated whereof 323 were followed longitudinally from first grade. Loneliness in grade 6 was distinctively associated with high levels of internalizing problems, concurrently as well as prospectively. Peer acceptance, on the other hand, emerged as a complex, multifaceted aspect, with concurrent, independent predictions from both externalizing and internalizing problem behaviours as well as social competence, although prospective analyses found early externalizing problems to be the strongest predictor of peer acceptance. Moderating effects of social competence were sparse, although peer nominated social competence buffered peer acceptance for children with high levels of aggression in the concurrent analyses and social competence boosted peer acceptance for children with low problem levels in the predictive analyses. Social competence did not appear to buffer the negative impact of early problem behaviours on peer relations. Copyright © 2008 John Wiley & Sons, Ltd.
Who knows best? Preschoolers sometimes prefer child informants over adult informants
Authors: VanderBorght Mieke , Jaswal Vikram K.
Published: November 2008

Do preschoolers think adults know more about everything than children? Or do they recognize that there are some things that children might know more about than adults? Three‐, four‐, and five‐year olds (N=65) were asked to decide whether an adult or child informant would better be able to answer a variety of questions about the nutritional value of foods and about toys. Children at all ages chose to direct the food questions to the adult and the toy questions to the child. Thus, there are some kinds of information for which preschoolers expect that a child would be a better informant than an adult. Copyright © 2008 John Wiley & Sons, Ltd.
Israeli kindergarten children's gender constancy for others' counter‐stereotypic toy play and appearance: the role of sibling gender and relative age
Authors: Karniol Rachel
Published: November 2008

To test divergent theoretical predictions as to the impact of having a younger or older, same‐sex sibling or opposite‐sex sibling on other gender constancy, Israeli kindergarten children in two‐child families responded to a gender constancy task in which a male and female picture target engaged in counter‐stereotypic toy play and adopted counter‐stereotypic appearance. Children were also asked whether the target child could change sex at will and to explain the difference between boys and girls. Relative age of sibling, both independently and in interaction with participant sex, was associated with greater gender constancy in the face of counter‐stereotypic toy play. Relative age of sibling and sibling sex was independently associated with greater gender constancy in the face of counter‐stereotypic appearance. In both cases, children with a younger sibling evidenced greater gender constancy. Boys, especially ones with a male sibling, referred most explicitly to target's birth sex in accounting for his or her being unable to change sex at will. Genital and anatomical differences between boys and girls were cited more often by children who referred explicitly to target's birth sex and had a younger sibling. The results were discussed in the context of theories of gender development and the socialization of gender within the family. Copyright © 2008 John Wiley & Sons, Ltd.
Infant‐holding biases in mothers and affective symptoms during pregnancy and after delivery
Authors: Vauclair Jacques , Scola Céline
Published: November 2008

Several authors have reported that participants have a leftward bias when holding a newborn or young infant. Our study of mothers met before and after their infant's birth sought to ascertain whether particular combinations of affective symptoms (depression, anxiety) and holding positions (horizontal versus vertical) were related to holding‐side biases. Our results showed that (a) mothers displayed a significant leftward (71%) holding bias, (b) mothers with affective symptoms held their newborn on the right side and more frequently in the vertical position, and (c) hemispheric specialization for perceiving visual emotions had no significant effect on the holding‐side biases of new mothers. These results suggest that maternal affective symptoms have a dominant effect on the determination of holding‐side preferences, when associated with a particular holding position. Copyright © 2008 John Wiley & Sons, Ltd.
Predicting developmental deficiencies at the age of four based on data from the first seven months of life
Authors: Rostad Anne Margrethe , Nyberg Per , Sivberg Bengt
Published: November 2008

The study examines very young children with the aim of identifying precursors of developmental problems during the first 7 months of age. Information from screening and observations in the birth clinic, in the first level of health care, and from parents was collected on five different occasions. The information that was included concerning the child and family was defined as either optimal or nonoptimal. At the age of 4 years, a clinical group was identified (11.1% of the total population). Logistic regression analyses were performed to detect risk factors. Twenty‐one precursors were used to create a screening questionnaire that provided useful information (sensitivity = 56.1%, specificity = 98.8%) for predicting developmental problems of the children. The contribution of sociodemographic data was significant; medical information was less significant. The highest prediction rate surprisingly was found in the moderate clinical subgroup (62.1%), compared to the group with more severe problems that had a slightly lower rate (46.7%). The conclusion of the study is that it is possible to detect infants in need of early intervention using a continuous process of observation and screening.
Parents' attachment styles, mental representations, and institutionalization of children in Bulgaria
Authors: Markova Galina , Shilkret Robert , Djalev Liubomir
Published: November 2008

We first summarize the history, extent, and characteristics of institutionalization of non‐orphan children in Bulgaria. Then we describe a study of certain psychological characteristics of mothers who use institutionalization compared with mothers similar in ethnicity and close‐to‐poverty circumstances, those using state daycare programs, and those using weekly care programs for their children. Institutionalizing mothers had been institutionalized themselves far more often than had the other mothers. On two attachment measures, as expected, institutionalizing mothers were less secure and more insecure than daycare mothers, with weekly care mothers intermediate. On a parental representation task, results were somewhat more equivocal. Results suggest that psychological characteristics, especially attachment style, are important in decisions to use institutionalization as a means of child care.
Posttraumatic stress symptoms following childbirth and mothers' perceptions of their infants
Authors: Davies John , Slade Pauline , Wright Ingram , Stewart Peter
Published: November 2008

Postpartum psychological distress can adversely affect the early mother–infant relationship; however, this has not been investigated in relation to posttraumatic stress disorder (PTSD) following childbirth. This article explores whether PTSD symptoms relating to labor and delivery are associated with mothers' early perceptions of their infant. Using labor and childbirth as the stressor criterion, 211 women were assessed at 6 weeks' postpartum for symptoms of intrusions, avoidance, and hyperarousal. Their perceptions of their infants, of mother‐to‐infant attachment, and infant behavioral characteristics also were evaluated. In sum, 3.8% of the women fulfilled full diagnostic criteria, and a further 21.3% reported clinically significant symptoms on at least one dimension of PTSD. Those meeting full or partial criteria perceived their attachment relationships to be significantly less optimal and reported more negative maternal representations in terms of their infants being less warm and more invasive. They also rated them as being temperamentally more difficult, prone to distress, and less easy to soothe. However, when the effects of depression were partialled, only the effect for perceived warmth remained. Posttraumatic stress symptoms relating to labor and delivery may adversely influence maternal perceptions of infants, with potentially adverse implications for the developing mother–infant relationship. The overlap with depressive symptoms requires further exploration.
Attachment in foster children associated with caregivers' sensitivity and behavioral problems
Authors: Oosterman Mirjam , Schuengel Carlo
Published: November 2008

This study focused on attachment of foster children by examining factors associated with attachment relationships of children raised from birth by the same parents. The sample included 61 children between 26 to 88 months of age and their foster caregivers. Attachment security and caregiver sensitivity were coded on the basis of, respectively, a home‐observation (Attachment Q‐Set) and a laboratory procedure (Three boxes). Other measures included caregiver reports of child externalizing and internalizing behavior problems and symptoms of attachment disorder, including inhibited and disinhibited attachment as well as secure base distortions. For a subsample of children, teacher ratings of behavior problems also were available. Foster parent sensitivity was positively associated with attachment security, but only if symptoms of disordered attachment were partialled out. Symptoms of inhibited and disinhibited attachment as well as secure base distortions were positively related to parent reports of externalizing and internalizing behavior problems whereas attachment security was negatively related to teacher reports of externalizing behavior problems. Attachment theoretical tenets appeared valid with foster parent–child relationships, except for children with symptoms of attachment disorder.
Influences of maternal postpartum depression on fathers and on father–infant interaction
Authors: Goodman Janice H.
Published: November 2008

Maternal postpartum depression (PPD) has been shown to negatively influence mother–infant interaction; however, little research has explored how fathers and father–infant interaction are affected when a mother is depressed. This study examined the influence of maternal PPD on fathers and identified maternal and paternal factors associated with father–infant interaction in families with depressed as compared with nondepressed mothers. A convenience sample of 128 mother–father–infant triads, approximately half of which included women with significant symptoms of PPD at screening, were recruited from a screening sample of 790 postpartum women. Mothers and fathers completed measures of depression, marital satisfaction, and parenting stress at 2 to 3 months' postpartum and were each videotaped interacting with their infants. Results indicate that maternal PPD is associated with increased paternal depression and higher paternal parenting stress. Partners of depressed women demonstrated less optimal interaction with their infants, indicating that fathers do not compensate for the negative effects of maternal depression on the child. Although mother–infant interaction did not influence father–infant interaction, how the mother felt about her relationship with the infant did, even more so than maternal depression. The links between maternal PPD, fathers, and father–infant interaction indicate a need for further understanding of the reciprocal influences between mothers, fathers, and infants.
The p38 mitogen‐activated protein kinase pathway is involved in the regulation of heme oxygenase‐1 by acidic extracellular pH in aortic smooth muscle cells
Authors: Guan Jason , Wu Xinqi , Arons Elena , Christou Helen
Published: November 2008

Extracellular acidosis (EA) regulates Heme Oxygenase‐1 (HO‐1) expression in vascular smooth muscle cells via transcriptional and posttranscriptional mechanisms but the signaling pathways involved are not known. We examined the role of Mitogen‐Activated Protein Kinase (MAPK) pathways in HO‐1 regulation by EA. Primary rat aortic smooth muscle cells were exposed to EA or physiologic pH. Levels of the total and phosphorylated forms of p38, extracellular signal‐regulated protein kinases1/2 (ERK1/2), c‐Jun N‐terminal kinases/stress‐activated protein kinases (JNK1/2), and HO‐1 protein were assessed by Western analysis and HO‐1 mRNA levels were assessed by quantitative PCR. Inhibition of p38 MAPK was achieved with the chemical inhibitor SB203580, or adenoviral infection of a dominant‐negative form of p38α. Phospho p38 MAPK activity was evaluated with an in vitro kinase activity assay. Binding of Activator Protein‐1 (AP‐1), a known target of MAPK pathways, was assessed by Electromobility shift assay (EMSA). EA induced phosphorylation of p38 MAPK in a biphasic manner while total p38 was unchanged. EA did not alter levels of phospho ERK 1/2 and phospho JNK 1/2. There was increased phospho p38 MAPK activity in the setting of EA which preceded the induction of HO‐1. Inhibition of phospho p38 activity with either SB20358 or a dominant negative p38α oligonucleotide abrogated the induction of HO‐1 by EA. Increased specific binding of AP‐1 in the setting of EA was shown by EMSA. Increased phospho p38 activity precedes and likely mediates HO‐1 induction by EA. Increased AP‐1 binding may underlie the transcriptional regulation of HO‐1 by EA. J. Cell. Biochem. 105: 1298–1306, 2008. © 2008 Wiley‐Liss, Inc.
A new method for the gradient‐based optimization of molecular complexes
Authors: Fuhrmann Jan , Rurainski Alexander , Lenhof Hans‐Peter , Neumann Dirk
Published: November 2008

We present a novel method for the local optimization of molecular complexes. This new approach is especially suited for usage in molecular docking. In molecular modeling, molecules are often described employing a compact representation to reduce the number of degrees of freedom. This compact representation is realized by fixing bond lengths and angles while permitting changes in translation, orientation, and selected dihedral angles. Gradient‐based energy minimization of molecular complexes using this representation suffers from well‐known singularities arising during the optimization process. We suggest an approach new in the field of structure optimization that allows to employ gradient‐based optimization algorithms for such a compact representation. We propose to use exponential mapping to define the molecular orientation which facilitates calculating the orientational gradient. To avoid singularities of this parametrization, the local minimization algorithm is modified to change efficiently the orientational parameters while preserving the molecular orientation, i.e. we perform well‐defined jumps on the objective function. Our approach is applicable to continuous, but not necessarily differentiable objective functions. We evaluated our new method by optimizing several ligands with an increasing number of internal degrees of freedom in the presence of large receptors. In comparison to the method of Solis and Wets in the challenging case of a non‐differentiable scoring function, our proposed method leads to substantially improved results in all test cases, i.e. we obtain better scores in fewer steps for all complexes. © 2008 Wiley Periodicals, Inc. J Comput Chem, 2009
Mineralization of bisphenol A by advanced oxidation processes
Authors: Rivas F. Javier , Encinas Ángel , Acedo Benito , Beltrán Fernando J.
Published: November 2008

BACKGROUND: Endocrine disruptors, as in the case of bisphenol A (BPA), are increasingly found in aqueous effluents. The degree of mineralization of a bisphenol A (BPA) aqueous solution after applying several oxidation treatments has been investigated.

RESULTS: UV‐C photolysis of BPA allowed calculation of the quantum yield, ϕλ=254 = 0.045 ± 0.005 mol Einstein−1 but only 15% of the initial organic carbon content (TOC) was eliminated. Better results (80% conversion) were obtained after TiO2 addition. Ozone inmediately reacts with BPA. Again, TiO2 addition in the presence of O3 was capable of increasing the mineralization level (60%). The photolytic ozonation of BPA was capable of completely eliminating TOC. The presence of activated carbon in the O3/UV and O3/UV/TiO2 systems significantly enhanced the TOC removal reaction rate (100% conversion in 20 min).

CONCLUSIONS: Processes such as ozonation or photolysis are capable of efficiently removing BPA from water however, mineralization levels are rather low. Addition of TiO2 to O3 or UV‐C significantly enhances TOC removal. The remaining organics still account for an average 20–40% of the initial organic carbon. The combination of O3/UV‐C is capable of completely mineralizing BPA. Activated carbon and/or TiO2 addition to the system O3/UV‐C improves the TOC depletion rate. Copyright © 2008 Society of Chemical Industry
Perturbation training prior to ACL reconstruction improves gait asymmetries in non‐copers
Authors: Hartigan Erin , Axe Michael J. , Snyder‐Mackler Lynn
Published: November 2008

We investigated whether preoperative perturbation training would help anterior cruciate ligament (ACL) deficient individuals who complain of knee instability (“non‐copers”) regain quadriceps strength and walk normally after ACL reconstruction. Nineteen non‐copers with acute ACL injury were randomly assigned into a perturbation group (PERT) or a strengthening group (STR). The PERT group received specialized neuromuscular training and progressive quadriceps strength training, whereas the STR group received progressive quadriceps strength training only. We compared quadriceps strength indexes and knee excursions during the mid‐stance phase of gait preoperatively to data collected 6 months after ACL reconstruction. Analyses of Variance with repeated measures (time/limb) were conducted to compare quadriceps strength index values over time (time × group) and differences in knee excursions in limbs between groups over time (limb × time × group). If significance was found, post hoc analyses were performed using paired and independent t‐tests. Quadriceps strength indexes before intervention (Pert: 87.2%; Str: 75.8%) improved 6 months after ACL reconstruction in both groups (Pert: 97.1%; Str: 94.4%). Non‐copers who received perturbation training preoperatively had no differences in knee excursions between their limbs 6 months after ACL reconstruction (p = 0.14), whereas those who received just strength training continued to have smaller knee excursions during the mid‐stance phase of gait (p = 0.007). Non‐copers strength and knee excursions were more symmetrical 6 months postoperatively in the group that received perturbation training and progressive quadriceps strength training than the group who received strength training alone. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27: 724–729, 2009
Host‐derived neoangiogenesis with short‐term immunosuppression allows incorporation and remodeling of vascularized diaphyseal allogeneic rabbit femur transplants
Authors: Giessler Goetz A. , Zobitz Mark , Friedrich Patricia F. , Bishop Allen T.
Published: November 2008

The purpose of this study was to demonstrate that living bone allotransplants can incorporate, remodel, and maintain mechanical properties without long‐term immunosuppression in a fashion comparable to living autotransplants. For this, viability is maintained by repair of nutrient vessels and neovascularization from implanted host‐derived vasculature. Microsurgically revascularized femoral diaphysis allotransplants were transferred from young male New‐Zealand‐White (NZW) into 4 groups of male Dutch‐Belted (DB) rabbits. Short‐term immunosuppression by tacrolimus (IS, groups 4 and 5) and host‐derived neovascularization (NV) from implanted fascial flaps was used to maintain viability (groups 3 and 5) as independent variables. Group 2 received neither IS nor NV. Vascularized pedicled autotransplants were orthotopically transplanted in group 1. After 16 weeks, transplants were evaluated using radiologic, histologic, biomechanical, and histomorphometric parameters. Vascularized bone allotransplants treated with both short‐term IS and host‐derived NV (group 5) healed in a fashion similar to pedicled autotransplants (group 1). Their radiographic scores were higher than other groups. Groups with patent fascial flaps (3 and 5) showed significantly greater neoangiogenesis than ligated controls (2 and 4). Tacrolimus administration did not affect neoangiogenesis. Elastic modulus and ultimate stress were significantly greater in autogenous bone than in allotransplanted femora. Biomechanical properties were not significantly different among allotransplants. Bone turnover was decreased with IS, but increased with NV by the implanted fascial flaps. Living allogeneic femoral allotransplants treated with short‐term IS and host‐derived neoangiogenesis can lead to stable transplant incorporation in this rabbit model. The combination of both factors optimizes bone healing. Transplant mineralization is improved with neoangiogenesis but diminished with IS. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27: 763–770, 2009
Prostaglandin E2 inhibits BMP signaling and delays chondrocyte maturation
Authors: Clark Christine A. , Li Tian‐Fang , Kim Kyung‐Ok , Drissi Hicham , Zuscik Michael J. , Zhang Xinping , O'Keefe Regis J.
Published: November 2008

While cyclooxygenases are important in endochondral bone formation during fracture healing, mechanisms involved in prostaglandin E2 (PGE2) regulation of chondrocyte maturation are incompletely understood. The present study was undertaken to determine if PGE2 effects on chondrocyte differentiation are related to modulation of the bone morphogenetic protein (BMP) signaling pathway. In primary murine sternal chondrocytes, PGE2 differentially regulated genes involved in differentiation. PGE2 induced type II collagen and MMP‐13, had minimal effects on alkaline phosphatase, and inhibited the expression of the maturational marker, type X collagen. In BMP‐2–treated cultures, PGE2 blocked the induction of type X collagen. All four EP receptors were expressed in chondrocytes and tended to be inhibited by BMP‐2 treatment. RCJ3.1C5.18 chondrocytes transfected with the protein kinase A (PKA) responsive reporter, CRE‐luciferase, showed luciferase induction following exposure to PGE2, consistent with activation of PKA signaling and the presence of the EP2 and EP4 receptors. Both PGE2 and the PKA agonist, dibutyryl cAMP, blocked the induction of the BMP‐responsive reporter, 12XSBE, by BMP‐2 in RCJ3.1C5.18 chondrocytes. In contrast, PGE2 increased the ability of TGF‐β to activate the TGF‐β‐responsive reporter, 4XSBE. Finally, PGE2 down‐regulated BMP‐mediated phosphorylation of Smads 1, 5, and 8 in RCJ3.1C5.18 cells and in primary murine sternal chondrocytes. Altogether, the findings show that PGE2 regulates chondrocyte maturation in part by targeting BMP/Smad signaling and suggest an important role for PGE2 in endochondral bone formation. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27: 785–792, 2009
Reproducibility of 31P cardiac magnetic resonance spectroscopy at 3 T
Authors: Tyler D. J. , Emmanuel Y. , Cochlin L. E. , Hudsmith L. E. , Holloway C. J. , Neubauer S. , Clarke K. , Robson M. D.
Published: November 2008

The purpose of this work was to take advantage of the new clinical field strength of 3 T to implement and optimize a chemical shift imaging (CSI) acquisition protocol to produce spectra of high quality with high specificity to the myocardium within a clinically feasible scan time. Further, an analysis method was implemented dependent purely on anatomical location of spectra, and as such free from any potential user bias caused by inference from spectral information. Twenty healthy male subjects were scanned on two separate occasions using the optimized CSI protocol at 3 T. Data were analyzed for intra‐ and inter‐subject variability, as well as intra‐ and inter‐observer variability. The average phosphocreatine (PCr)/adenosine triphosphate (ATP) value for scan 1 was 2.07 ± 0.38 and for scan 2 was 2.14 ± 0.46, showing no significant difference between scans. Intra‐subject variability was 0.43 ± 0.35 (percentage difference 20%) and the inter‐subject coefficient of variation was 18%. The intra‐observer variability, assessed as the absolute difference between analyses of the data by a single observer, was 0.14 ± 0.24 with no significant difference between analyses. The inter‐observer variability showed no significant differences between the PCr/ATP value measured by four different observers as demonstrated by an intra‐class correlation coefficient of 0.763. The increased signal available at 3 T has improved spatial resolution and thereby increased myocardial specificity without any significant decrease in reproducibility over previous studies at 1.5 T. We present an acquisition protocol that routinely provides high quality spectra and a robust analysis method that is free from potential user bias. Copyright © 2008 John Wiley & Sons, Ltd.
High‐resolution MRI of internal field diffusion‐weighting in trabecular bone
Authors: Sigmund E.E. , Cho H. , Song Y.‐Q.
Published: November 2008

Trabecular bone structure is known to play a crucial role in the overall strength, and thus fracture risk, of such areas of the skeleton as the vertebrae, spine, femur, tibiae, or radius. Several MR methods devoted to probing this structure depend upon the susceptibility difference between the solid bone matrix and the intervening fluid/marrow/fat, usually in the context of a linewidth (1/T2′) measurement or mapping technique. A recently demonstrated new approach to this system involves using internal gradients to encode diffusion weighting, and extracting structural information (e.g., surface‐to‐volume ratio) from the resulting signal decay. This contrast method has been demonstrated in bulk measurements on cleaned, water‐saturated bovine trabecular bone samples. In the present work, microscopic imaging (0.156 mm in‐plane resolution) is performed in order to spatially resolve this contrast on the trabecular level, and confirm its interpretation for the bulk measurements. It is found that the local rate of decay due to diffusion in the internal field (DDIF) is maximal close to the trabecular surfaces. The overall decay rate in a lower resolution scan probes the abundance of these surfaces, and provides contrast beyond that found in conventional proton density weighted or T1‐weighted imaging. Furthermore, a microscopic calculation of internal field distributions shows a qualitative distinction between the structural sensitivities of DDIF and T2′. DDIF contrast is highly localized around trabecular walls than is the internal field itself, making it a less sensitive but more specific measure of such important properties as trabecular number. Copyright © 2008 John Wiley & Sons, Ltd.
Analysis of the clonal architecture of the human small intestinal epithelium establishes a common stem cell for all lineages and reveals a mechanism for the fixation and spread of mutations
Authors: Gutierrez‐Gonzalez Lydia , Deheragoda Maesha , Elia George , Leedham Simon J , Shankar Arjun , Imber Charles , Jankowski Janusz A , Turnbull Douglass M , Novelli Marco , Wright Nicholas A , McDonald Stuart AC
Published: November 2008

Little is known about the clonal structure or stem cell architecture of the human small intestinal crypt/villus unit, or how mutations spread and become fixed. Using mitochondrial DNA (mtDNA) mutations as a marker of clonal expansion of stem cell progeny, we aimed to provide answers to these questions. Enzyme histochemistry (for cytochrome c oxidase and succinate dehydrogenase) was performed on frozen sections of normal human duodenum. Laser‐capture microdissected cells were taken from crypts/villi. The entire mitochondrial genome was amplified using a nested PCR protocol; sequencing identified mutations and immunohistochemistry demonstrated specific cell lineages. Cytochrome c oxidase‐deficient small bowel crypts were observed within all sections: negative crypts contained the same clonal mutation and all differentiated epithelial lineages were present, indicating a common stem cell origin. Mixed crypts were also detected, confirming the existence of multiple stem cells. We observed crypts where Paneth cells were positive but the rest of the crypt was deficient. We have demonstrated patches of deficient crypts that shared a common mutation, suggesting that they have divided by fission. We have shown that all cells within a small intestinal crypt are derived from one common stem cell. Partially‐mutated crypts revealed some novel features of Paneth cell biology, suggesting that either they are long‐lived or a committed Paneth cell‐specific long‐lived progenitor was present. We have demonstrated that mutations are fixed in the small bowel by fission and this has important implications for adenoma development. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
3q27 aberrations in a childhood ovary teratoma with associated malignant germ cell component
Authors: Brassesco María Sol , Castro‐Gamero Angel Mauricio , Valera Elvis Terci , Neder Luciano , Elias Jorge , Tone Luiz Gonzaga
Published: November 2008

Cytogenetic studies of childhood ovary tumors have been poorly described. In the present article, the cytogenetic findings of an ovarian teratoma with malignant germ cell (yolk‐sac) component occurring in an 8‐year‐old female are detailed. GTG‐banding showed a karyotype of 46,XX, t(3;20)(q27;q13.3) [4]/46,XX, del3q27 [3]/46,XX [30]. Previous studies have demonstrated common sites of loss of heterozygosity at 3q27‐q28 region in different types of cancer, suggesting the presence of tumor suppressor genes within this region. Pediatr Blood Cancer 2009;52:398–401. © 2008 Wiley‐Liss, Inc.
Self‐esteem and suicide rates in 55 Nations
Authors: Chatard Armand , Selimbegović Leila , Konan Paul N'Dri
Published: November 2008

Using recent data from the International Sexuality Description Project (ISDP), we examined whether national differences in self‐esteem across 55 nations are reflected in suicide rates. Results indicate that suicide is especially common in nations with relatively low levels of self‐esteem. This relation is consistent across sex lines, age of suicide and independent from several other relevant factors such as economic affluence, transition, individualism, subjective well‐being, and neuroticism. These findings provide support for the predictive validity of self‐esteem scores as assessed in the ISDP survey. They also contribute to a growing body of research documenting negative consequences associated with low self‐esteem. Possible implications for suicide prevention strategies are discussed. Copyright © 2008 John Wiley & Sons, Ltd.
Mindfulness‐based stress reduction and cancer: a meta‐analysis
Authors: Ledesma Dianne , Kumano Hiroaki
Published: November 2008

Objective: This meta‐analysis was conducted to investigate the effects of mindfulness‐based stress reduction (MBSR) on the mental and physical health status of various cancer patients.

Methods: Ten studies (randomized‐controlled trials and observational studies) were found to be eligible for meta‐analysis. Individual study results were categorized into mental and physical variables and Cohen's effect size d was computed for each category.

Results: MBSR may indeed be helpful for the mental health of cancer patients (Cohen's effect size d=0.48); however, more research is needed to show convincing evidence of the effect on physical health (Cohen's effect size d=0.18).

Conclusion: The results suggest that MBSR may improve cancer patients' psychosocial adjustment to their disease. Copyright © 2008 John Wiley & Sons, Ltd.
A peptide‐centric approach to breast cancer biomarker discovery utilizing label‐free multiple reaction monitoring mass spectrometry
Authors: Metodieva Gergana , Greenwood Christina , Alldridge Louise , Sauven Paul , Metodiev Metodi
Published: November 2008

We report an approach for multiplex analysis of cancer biomarkers based on the measurement of diagnostic peptides in whole tissue protein digests. Label‐free quantitation with MS3 multiple reaction monitoring (MRM) was developed to afford accurate analysis of prospective marker peptides in a panel of breast tumors. This approach provides an economical and robust alternative to stable isotope‐based methods. It is equally applicable to the analysis of samples derived from tissue biopsy, aspirate, or plasma and can be easily translated to clinic.
Charting online OMICS resources: A navigational chart for clinical researchers
Authors: Vizcaíno Juan Antonio , Mueller Michael , Hermjakob Henning , Martens Lennart
Published: November 2008

The life sciences have sprouted several popular and successful OMICS technologies that span all levels of biological information transfer. Ever since the start of the Human Genome Project, the then revolutionary idea to make all resulting data publicly available has been central to all of the efforts across OMICS technologies. As a result, a great variety of publicly available data repositories and resources is currently available to the research community. This widespread availability of data does come at the price of increased confusion on the part of the users, especially for those that see the OMICS technologies as tools to help unravel a larger biological or clinical question. We therefore provide a comprehensive overview of the available resources across OMICS fields, with a special emphasis on those databases that are relevant to the study of proteins. Additionally, we also describe various integrative systems that have been established, and highlight new developments in the field that can revolutionize the way in which live data integration is achieved over the internet.
Proteomic analysis of breast cancer tissue reveals upregulation of actin‐remodeling proteins and its relevance to cancer invasiveness
Authors: Kim Dong‐Hyun , Bae Jinhee , Lee Jong Won , Kim Seon‐Young , Kim Yong‐Hak , Bae Ji‐Yeon , Yi Jae Kyo , Yu Myeong‐Hee , Noh Dong‐Young , Lee Cheolju
Published: November 2008

There is an emerging interest in protein expression profiling with the aim of identifying novel diagnostic markers and therapeutic targets in breast cancer. We analyzed breast cancer tissues by 2‐D DIGE using a narrow range IPG strip (pH 5.5–6.7) after the immunodepletion of serum albumin and Ig. Sixty‐three protein spots were detected with more than ±1.8‐fold differences (p <0.05 for three technical replicates) from a set of tissue samples in which three tumor and three nontumor samples were randomly selected from six breast cancer subjects and pooled separately. Of these, 53 proteins were successfully identified by MS. Among the proteins whose levels were increased, we identified three novel WD‐repeat‐motif‐bearing proteins that have been known to be involved in actin remodeling: Arp2/3 complex subunit 2 (p34‐Arc), coronin‐1A and WD‐repeat protein 1 (Wdr1). Significantly increased amounts of p34‐Arc and coronin‐1A in breast cancer were also shown by Western blot analysis of matched tumor and nontumor tissue samples (N = 11, p <0.05), and were consistent with the mRNA levels retrieved from publicly available microarray databases. The siRNA knockdown of p34‐Arc attenuated the invasion of SK‐BR3 breast cancer cells into Matrigel. In contrast, the overexpression of coronin‐1A increased this invasive activity. Taken together, the cellular levels of p34‐Arc and coronin‐1A were linked to cancer development and migration. The data obtained from the present study provides new insight into the management of breast cancer.
Atlas of dihydrotestosterone actions on the transcriptome of prostate in vivo
Authors: Ma Ci , Yoshioka Mayumi , Boivin André , Gan Lin , Takase Yasukazu , Labrie Fernand , St‐Amand Jonny
Published: November 2008

BACKGROUND

Using serial analysis of gene expression (SAGE), we studied the transcriptomic changes in vivo by dihydrotestosterone (DHT) treatment in mice to better understand androgen effects in the prostate.

METHODS

Approximately 872,000 SAGE tags were isolated from intact and castrated (GDX) mice with and without DHT injection.

RESULTS

GDX significantly altered 431 transcripts, including 110 transcripts restored by DHT, and 146 potentially new transcripts. Totally, 187 transcripts were significantly affected by DHT treatment, of which 124 were induced and 63 were repressed. Interestingly and consistent with the prostate's secretory role, DHT up‐regulated the expression of many genes involved in various steps of protein metabolism such as synthesis, folding, and secretion. GDX modulated the expression of genes which induce cell apoptosis and inhibit cell proliferation through polyamine biosynthesis, retinoid X receptor actions as well as several signaling pathways and some related factors. These results clarify DHT effects on prostate transcriptome in the areas of protein metabolism, cell proliferation and apoptosis. In addition, we detected gene expression changes in metabolic pathways, cytoskeleton, immunity and endoplasmic reticulum stress. Furthermore, knockdown of S‐adenosylmethionine decarboxylase 1 in LNCaP cells confirmed the importance of androgen‐regulated genes (ARGs) in prostate cancer cell growth.

CONCLUSION

Our data support the idea that ARGs are essential for the normal development of the prostate and can also be responsible for the pathogenesis of the prostate cancer. Prostate 69:293–316, 2009. © 2008 Wiley‐Liss, Inc.