bluuebunny/crossref_metadata_2025 huggingface dataset:
Process regime change on a Silurian siliciclastic shelf: controlling influences on deposition of the Gray Sandstone Formation, Pembrokeshire, UK
Authors: Hillier Robert D. , Morrissey Lance B.
Published: July 2009

Shallow marine deposits comprising the Silurian Gray Sandstone Formation (GSF) exhibit pronounced process regime changes through time. The formation was deposited on the southern shelf of the Lower Palaeozoic Welsh Basin (UK), and conformably overlies the Coralliferous Formation. The basal Lithofacies Assemblage A (of Sheinwoodian age) is dominated by a storm‐dominated process regime, comprising shoreface and offshore shelf facies associations. The overlying Lithofacies Assemblage B records a mixed process regime, with units being deposited under both storm‐ and tide‐influenced conditions. Tidal‐influence prevailed during deposition of the overlying Lithofacies Assemblage C, with proximal to distal facies variations across a significant tide‐influenced river delta being observed. A return to storm‐dominated shoreface conditions is seen in the succeeding Lithofacies Assemblage D. Lithofacies Assemblage E (Homerian age) records the return of a tide‐influenced river delta to the area, prior to the conformable transition into the overlying Old Red Sandstone (ORS) Red Cliff Formation (of Ludlow age). Northward thickening of the formation across southern Pembrokeshire into the Musselwick Fault indicates a tectonic control on sedimentation, the formation infilling accommodation space developed in an intra‐shelf half‐graben. Recurring changes in process regime from storm‐ to tide‐influenced sedimentation may be related to the onset and subsequent cessation of tidal resonance in sub‐basins across the shelf area which itself was probably controlled by episodic tectonism. It is proposed that the Coralliferous and Gray Sandstone formations comprise the newly erected Marloes Group. Copyright © 2009 John Wiley & Sons, Ltd.
Changes in the interaction of resting‐state neural networks from adolescence to adulthood
Authors: Stevens Michael C. , Pearlson Godfrey D. , Calhoun Vince D.
Published: July 2009

This study examined how the mutual interactions of functionally integrated neural networks during resting‐state fMRI differed between adolescence and adulthood. Independent component analysis (ICA) was used to identify functionally connected neural networks in 100 healthy participants aged 12–30 years. Hemodynamic timecourses that represented integrated neural network activity were analyzed with tools that quantified system “causal density” estimates, which indexed the proportion of significant Granger causality relationships among system nodes. Mutual influences among networks decreased with age, likely reflecting stronger within‐network connectivity and more efficient between‐network influences with greater development. Supplemental tests showed that this normative age‐related reduction in causal density was accompanied by fewer significant connections to and from each network, regional increases in the strength of functional integration within networks, and age‐related reductions in the strength of numerous specific system interactions. The latter included paths between lateral prefrontal‐parietal circuits and “default mode” networks. These results contribute to an emerging understanding that activity in widely distributed networks thought to underlie complex cognition influences activity in other networks. Hum Brain Mapp 2009. © 2009 Wiley‐Liss, Inc.
Differential force scaling of fine‐graded power grip force in the sensorimotor network
Authors: Keisker Birgit , Hepp‐Reymond Marie‐Claude , Blickenstorfer Armin , Meyer Martin , Kollias Spyros S.
Published: July 2009

Force scaling in the sensorimotor network during generation and control of static or dynamic grip force has been the subject of many investigations in monkeys and human subjects. In human, the relationship between BOLD signal in cortical and subcortical regions and force still remains controversial. With respect to grip force, the modulation of the BOLD signal has been mostly studied for forces often reaching high levels while little attention has been given to the low range for which electrophysiological neuronal correlates have been demonstrated. We thus conducted a whole‐brain fMRI study on the control of fine‐graded force in the low range, using a power grip and three force conditions in a block design. Participants generated on a dynamometer visually guided repetitive force pulses (ca. 0.5 Hz), reaching target forces of 10%, 20%, and 30% of maximum voluntary contraction. Regions of interest analysis disclosed activation in the entire cortical and subcortical sensorimotor network and significant force‐related modulation in several regions, including primary motor (M1) and somatosensory cortex, ventral premotor and inferior parietal areas, and cerebellum. The BOLD signal, however, increased monotonically with force only in contralateral M1 and ipsilateral anterior cerebellum. The remaining regions were activated with force in various nonlinear manners, suggesting that other factors such as visual input, attention, and muscle recruitment also modulate the BOLD signal in this visuomotor task. These findings demonstrate that various regions of the sensorimotor network participate differentially in the production and control of fine‐graded grip forces. Hum Brain Mapp 2009. © 2009 Wiley‐Liss, Inc.
Diminished neural sensitivity to irregular facial expression in first‐episode schizophrenia
Authors: Bleich‐Cohen Maya , Strous Rael D. , Even Raz , Rotshtein Pia , Yovel Galit , Iancu Iulian , Olmer Ahikam , Hendler Talma
Published: July 2009

Introduction: Blunted, inappropriate affective‐social behavior is a hallmark of early schizophrenia, possibly corresponding to reduced ability to recognize and express emotions. It is yet unknown if this affective deficiency relates to disturbed neural sensitivity to facial expressions or to overall face processing. In a previous imaging study, healthy subjects showed less suppression of the fusiform gyrus (FG) to repeated presentation of the same transfigured‐bizarre face relative to regular face. We assumed that the FG in schizophrenia will show reduced repetition related sensitivity to transfigured‐bizarre faces, while having overall normal response to faces. Methods: Ten first‐episode patients with schizophrenia and 10 controls rated the bizarreness of upright and inverted faces. In an fMRI study, another group of 17 first‐episode patients with schizophrenia and 12 controls viewed regular and transfigured‐bizarre faces in blocks. Each block contained regular‐ or transfigured‐bizarre faces of either different or same individual, presented in an upright or inverted orientation. Results: Patients in comparison with controls rated irregular faces as less bizarre. The FG, in patients and controls exhibited similar response to inverted faces, suggesting normal face processing. In contrast, the FG only in patients, showed similar suppression to repeated transfigured‐bizarre and regular faces. Finally, the FG in patients compared with controls showed reduced functional connectivity with the amygdala and prefrontal cortex. Conclusion: Patients with schizophrenia already at first‐episode, showed reduced behavioral and neural sensitivity to bizarre facial expressions. Possibly, this deficiency is related to disturbed modulations of emotion‐related face processing in the FG by the amygdala and prefrontal cortex. Hum Brain Mapp 2009. © 2009 Wiley‐Liss, Inc.
Activated region fitting: A robust high‐power method for fMRI analysis using parameterized regions of activation
Authors: Weeda Wouter D. , Waldorp Lourens J. , Christoffels Ingrid , Huizenga Hilde M.
Published: July 2009

An important issue in the analysis of fMRI is how to account for the spatial smoothness of activated regions. In this article a method is proposed to accomplish this by modeling activated regions with Gaussian shapes. Hypothesis tests on the location, spatial extent, and amplitude of these regions are performed instead of hypothesis tests of individual voxels. This increases power and eases interpretation. Simulation studies show robust hypothesis tests under misspecification of the shape model, and increased power over standard techniques especially at low signal‐to‐noise ratios. An application to real single‐subject data also indicates that the method has increased power over standard methods. Hum Brain Mapp 2009. © 2009 Wiley‐Liss, Inc.
Volume and iron content in basal ganglia and thalamus
Authors: Péran Patrice , Cherubini Andrea , Luccichenti Giacomo , Hagberg Gisela , Démonet Jean‐François , Rascol Olivier , Celsis Pierre , Caltagirone Carlo , Spalletta Gianfranco , Sabatini Umberto
Published: July 2009

Magnetic resonance imaging (MRI) studies have highlighted the possibility to investigate brain iron content in vivo. In this study, we combined T2* relaxometry and automatic segmentation of basal ganglia based on T1‐weighted images in healthy subjects, with the aim of characterizing age related changes in volume and iron‐related relaxivity values (R2*) of these structures. Thirty healthy subjects underwent MR imaging at 3 Tesla. Mean R2* values and volumes were calculated for the selected subcortical structures (pallidum, putamen, thalamus and caudate nucleus). Our results showed a correlation between R2* values and iron concentration as calculated from published post‐mortem data. Furthermore, we observed a shrinkage/iron increase with a different pattern in the anatomical regions selected in this work, suggesting that the age‐related changes on these MR parameters are specific to the subcortical structure considered. In particular, the putamen demonstrated a decrease of volume and an increase of iron level, with the posterior region of this structure appearing more disposed to iron deposition. Our work suggests that combining volumetry and iron estimation in MRI permits to investigate in vivo neurophysiological and neuropathological changes of basal ganglia. Hum Brain Mapp 2009. © 2009 Wiley‐Liss, Inc.
Effects of different viewing perspectives on somatosensory activations during observation of touch
Authors: Schaefer Michael , Xu Benjamin , Flor Herta , Cohen Leonardo G.
Published: July 2009

Previous studies showed that neurons in the monkey premotor cortex became active when performing a particular action and also when observing the same action performed by others. These findings suggest a mirror system for action observation. Recently, bimodal neurons, sensitive both to visual and tactile stimulation, were reported in the parietal cortex, suggesting a potential mirror neuron system for observing and experiencing tactile stimulation. Subsequently, a mirror neuron system for observed touch has been suggested. The current study was designed to determine whether the activation of a sensory mirror system during touch observation is affected by possible attributions of the observed touch to oneself (subjective view) or to somebody else (objective view). In the study, healthy volunteers observed video clips of a touched or nontouched hand either in an egocentric or in an allocentric perspective during functional magnetic resonance imaging. Results showed activation of somatosensory cortices when observing the hand being touched in egocentric as well as in the allocentric perspectives. Moreover, somatosensory responses differed depending on the perspective of the observed touch. We discuss the results in terms of a possible mirror neuron system for observed and experienced touch. Hum Brain Mapp 2009. © 2009 Wiley‐Liss, Inc.
Exploring the relationship between white matter and gray matter damage in early primary progressive multiple sclerosis: An in vivo study with TBSS and VBM
Authors: Bodini Benedetta , Khaleeli Zhaleh , Cercignani Mara , Miller David H. , Thompson Alan J. , Ciccarelli Olga
Published: July 2009

We investigated the relationship between the damage occurring in the brain normal‐appearing white matter (NAWM) and in the gray matter (GM) in patients with early Primary Progressive multiple sclerosis (PPMS), using Tract‐Based Spatial Statistics (TBSS) and an optimized voxel‐based morphometry (VBM) approach. Thirty‐five patients with early PPMS underwent diffusion tensor and conventional imaging and were clinically assessed. TBSS and VBM were employed to localize regions of lower fractional anisotropy (FA) and lower GM volume in patients compared with controls. Areas of anatomical and quantitative correlation between NAWM and GM damage were detected. Multiple regression analyses were performed to investigate whether NAWM FA or GM volume of regions correlated with clinical scores independently from the other and from age and gender. In patients, we found 11 brain regions that showed an anatomical correspondence between reduced NAWM FA and GM atrophy; of these, four showed a quantitative correlation (i.e., the right sensory motor region with the adjacent corticospinal tract, the left and right thalamus with the corresponding thalamic radiations and the left insula with the adjacent WM). Either the NAWM FA or the GM volume in each of these regions correlated with disability. These results demonstrate a link between the pathological processes occurring in the NAWM and in the GM in PPMS in specific, clinically relevant brain areas. Longitudinal studies will determine whether the GM atrophy precedes or follows the NAWM damage. The methodology that we described may be useful to investigate other neurological disorders affecting both the WM and the GM. Hum Brain Mapp 2009. © 2009 Wiley‐Liss, Inc.
A method for accurate group difference detection by constraining the mixing coefficients in an ICA framework
Authors: Sui Jing , Adali Tülay , Pearlson Godfrey D. , Clark Vincent P. , Calhoun Vince D.
Published: July 2009

Independent component analysis (ICA) is a promising method that is increasingly used to analyze brain imaging data such as functional magnetic resonance imaging (fMRI), structural MRI, and electroencephalography and has also proved useful for group comparison, e.g., differentiating healthy controls from patients. An advantage of ICA is its ability to identify components that are mixed in an unknown manner. However, ICA is not necessarily robust and optimal in identifying between‐group effects, especially in highly noisy situations. Here, we propose a modified ICA framework for multigroup data analysis that incorporates prior information regarding group membership as a constraint into the mixing coefficients. Our approach, called coefficient‐constrained ICA (CC‐ICA), prioritizes identification of components that show a significant group difference. The performance of CC‐ICA via synthetic and hybrid data simulations is evaluated under different hypothesis testing assumptions and signal to noise ratios (SNRs). Group analysis is also conducted on real multitask fMRI data. Results show that CC‐ICA improves the estimation accuracy of the independent components greatly, especially those that have different patterns for different groups (e.g., patients vs. controls); In addition, it enhances the data extraction sensitivity to group differences by ranking components with P value or J‐divergence more consistently with the ground truth. The proposed algorithm performs quite well for both group‐difference detection and multitask fMRI data fusion, which may prove especially important for the identification of relevant disease biomarkers. Hum Brain Mapp 2009. © 2009 Wiley‐Liss, Inc.
Advanced time‐series analysis of MEG data as a method to explore olfactory function in healthy controls and Parkinson's disease patients
Authors: Boesveldt Sanne , Stam Cornelis J. , Knol Dirk L. , Verbunt Jeroen P.A. , Berendse Henk W.
Published: July 2009

Objectives:

To determine whether time‐series analysis of magnetoencephalography (MEG) data is a suitable method to study brain activity related to olfactory information processing, and to detect differences in odor‐induced brain activity between patients with Parkinson's disease (PD) and controls.

Methods:

Whole head 151‐channel MEG recordings were obtained in 21 controls and 20 patients with PD during a 10‐min olfactory stimulus paradigm, consisting of 10 alternating rest‐stimulus cycles (30 s each), using phenylethyl alcohol administered by means of a Burghart olfactometer. Relative spectral power and synchronization likelihood (SL; an unbiased measure of functional connectivity) were calculated for delta, theta, alpha1, alpha2, beta, and gamma frequency bands.

Results:

In controls, olfactory stimulation produced an increase in theta power and a decrease in beta power. In patients with PD, there was a decrease in alpha1 power. No significant interaction between group and condition was found for spectral power. SL analysis revealed a significantly different response to olfactory stimulation in patients with PD compared to controls. In controls, the odor stimulus induced a decrease in local beta band SL. The response in patients with PD involved a decrease in intrahemispheric alpha2 band SL.

Conclusion:

This is the first study to show that time‐series analysis of MEG data, including spectral power and SL, can be used to detect odor‐induced changes in brain activity. In addition, differences in odor‐induced brain activity were found between patients with PD and controls using analysis of SL, but not of spectral power. Hum Brain Mapp 2009. © 2009 Wiley‐Liss, Inc.
Test–retest reliability of fMRI verbal episodic memory paradigms in healthy older adults and in persons with mild cognitive impairment
Authors: Clément Francis , Belleville Sylvie
Published: July 2009

This study investigated test–retest functional magnetic resonance imaging (fMRI) reproducibility in 10 healthy older adults and in 10 mild cognitive impairment (MCI) persons using a two‐condition (encoding and retrieval) verbal episodic memory task as well as a two‐condition (with and without a motor response) phonological processing task. Reproducibility measures included an overlap ratio with four different thresholds, statistical comparisons of the condition contrasts across sessions (test–retest contrasts), ANCOVAs, and intraclass correlation (ICC) on selected regions of interests (ROIs). In all four conditions and for all reproducibility measures, MCI individuals showed fMRI test–retest reproducibility indices that were comparable to those of healthy older adults. At the group level, the comparison of the test–retest condition contrasts yielded very few differences in the areas and level of activation and those differences tended to show a slight reduction of activation in the second session. In addition, the results from the ANCOVAs showed that the fMRI signal measured at the group level does not vary significantly from one session to another. Overlap ratios, however, showed that the fMRI signal failed to produce a reliable pattern of significantly activated voxels across sessions. ICC analyses on selected ROIs indicated that there is high within‐subject variability, suggesting reduced reliability at the individual level. Overall, these findings indicate that MCI individuals show fMRI test–retest reproducibility comparable to those of healthy controls and hence that MCI do not alter fMRI reproducibility. Furthermore, they indicate that monitoring treatment effects is reliable when comparing groups but reduced when comparing single individuals. These results have precise implications for the design of longitudinal studies relying on fMRI measures in older adults. Hum Brain Mapp, 2009. © 2009 Wiley‐Liss, Inc.
Caring for mom and neglecting yourself? The health effects of caring for an elderly parent
Authors: Coe Norma B. , Van Houtven Courtney Harold
Published: July 2009

We examine the physical and mental health effects of providing care to an elderly mother on the adult child caregiver. We address the endogeneity of the selection in and out of caregiving using an instrumental variable approach, using the death of the care recipient and sibling characteristics. We also carefully control for baseline health and work status of the adult child. We explore flexible specifications, such as Arellano–Bond estimation techniques. Continued caregiving over time increases depressive symptoms and decreases self‐rated health for married women and married men. In addition, the increase in depressive symptoms is persistent for married women. While depressive symptoms for single men and women are not affected by continued caregiving, there is evidence of increased incidence of heart conditions for single men, and that these effects are persistent. Robustness checks indicate that these health changes can be directly attributable to caregiving behavior, and not due to a direct effect of the death of the mother. The initial onset of caregiving has modest immediate negative effects on depressive symptoms for married women and no immediate effects on physical health. Negative physical health effects emerge 2 years later, however, suggesting that there are delayed effects on health that would be missed with a short recall period. Initial caregiving does not affect health of married men. Published in 2009 by John Wiley & Sons, Ltd.
The impact of health on individual retirement plans: self‐reported versus diagnostic measures
Authors: Datta Gupta Nabanita , Larsen Mona
Published: July 2009

We reassess the impact of health on retirement plans of older workers using a unique survey‐register match‐up which allows comparing the retirement effects of potentially biased survey self‐reports of health to those of unbiased register‐based diagnostic measures. The aim is to investigate whether even for narrowly defined health measures a divergence exists in the impacts of health on retirement between self‐reported health and objective physician‐reported health. Our sample consists of older workers and retirees drawn from a Danish panel survey from 1997 and 2002, merged to longitudinal register data. Estimation of measurement error‐reduced and selection‐corrected pooled OLS and fixed effects models of retirement show that receiving a medical diagnosis is an important determinant of retirement planning for both men and women, in fact more important than economic factors. The type of diagnosis matters, however. For men, the largest reduction in planned retirement age occurs for a diagnosis of lung disease while for women it occurs for musculo‐skeletal disease. Except for cardiovascular disease, diagnosed disease is more influential in men's retirement planning than in women's. Our study provides evidence that men's self‐report of myalgia and back problems and women's self‐report of osteoarthritis possibly yield biased estimates of the impact on planned retirement age, and that this bias ranges between 1.5 and 2 years, suggesting that users of survey data should be wary of applying self‐reports of health conditions with diffuse symptoms to the study of labor market outcomes. On the other hand, self‐reported cardiovascular disease such as high blood pressure does not appear to bias the estimated impact on planned retirement. Copyright © 2009 John Wiley & Sons, Ltd.
Model‐based projections for deriving up‐to‐date cancer survival estimates: An international evaluation
Authors: Gondos Adam , Holleczek Bernd , Janssen‐Heijnen Maryska , Brewster David H. , Bray Freddie , Rosso Stefano , Hakulinen Timo , Brenner Hermann
Published: July 2009

Model‐based projections were shown to be useful for deriving most up‐to‐date population‐based cancer survival estimates. However, the performance of these projections, which can be derived by various approaches, has only been evaluated in very few cancer patient populations. Using incidence and follow‐up data for 22 common cancers from 9 long‐standing population‐based cancer registries from diverse parts of Europe, we compared the performance of model‐based period and cohort analysis for predicting 5‐year relative survival of patients diagnosed in 1996–2000 against standard survival analysis approaches (cohort, complete and period analysis). Overall, model‐based predictions provided a best estimate of the later observed actual survival in 135 of 198 occasions, compared to 25, 18 and 33 occasions for cohort, complete and period analysis, respectively. Projections based on cohort and period type modeling performed essentially equally well on average, and their performance was better for more common cancers, in registries with larger population bases, and for cancers subjected to continuous clinical progress and/or ongoing screening efforts. Projections from model‐based analysis may contribute to improved timeliness of monitoring of concurrent trends in population‐based cancer survival in cancer registries operating in different populations and socioeconomic environments. © 2009 UICC
Consistent genomic alterations in carcinoma in situ of the urinary bladder confirm the presence of two major pathways in bladder cancer development
Authors: Zieger Karsten , Marcussen Niels , Borre Michael , Ørntoft Torben F. , Dyrskjøt Lars
Published: July 2009

Bladder cancer develops through different pathways, provisionally entitled “papillary” and “invasive.” Carcinoma in situ (CIS) is thought to be the precursor of invasive bladder cancer. However, little is known about chromosomal alterations of these clinically important lesions, and the relationship between chromosomal alterations and the different pathways. We laser‐microdissected 12 CIS and 4 dysplasia samples concomitant to invasive bladder cancer. We determined genome‐wide chromosome copy number changes and loss of heterozygosity (LOH) using Mapping 10K SNP microarrays. We further examined 48 high‐risk non‐muscle‐invasive bladder cancers using SNP microarrays to reveal characteristic changes correlated with the CIS‐phenotype. DNA copy‐number changes were further validated using QPCR in 77 independent tumor samples. CIS was found to be chromosomal unstable in 8 of 12 cases. Characteristic chromosomal changes were copy number gains of chromosomes 5p, 6p22.3, 10p15.1 and losses/LOH of chromosome 5q and 13q13‐q14. Tumor samples with these alterations were significantly associated with CIS. Using FGFR3 mutations as markers of the opposing papillary phenotype, we found 5p gains and FGFR3 mutations mutually exclusive. No FGFR3 mutations were found in 23 CIS and dysplasia samples. Based on this, we classified high‐risk non‐muscle‐invasive bladder tumors according to FGFR3 mutations and chromosomal changes into papillary and CIS‐type tumors with high correlation to CIS status (p = 0.001). Furthermore, we found significant correlation to the results of molecular classifiers based on gene‐expression. We concluded that chromosomal changes may be used to characterize different pathways in bladder cancer development. © 2009 UICC
The reduction of cell death and proliferation by p27Kip1 minimizes DNA damage in an experimental model of genotoxicity
Authors: Ranchal Isidora , González Raúl , Bello Rosario I. , Ferrín Gustavo , Hidalgo Ana B. , Linares Clara I. , Aguilar‐Melero Patricia , González‐Rubio Sandra , Barrera Pilar , Marchal Trinidad , Nakayama Keiichi I. , de la Mata Manuel , Muntané Jordi
Published: July 2009

Hepatocellular carcinoma (HCC) is the fifth most commonly occurring cancer worldwide. The expression of p27 has been related to reduced severity of tumor grade and recurrence of HCC. The study assessed the role of p27 on the cell proliferation and death, and DNA mutagenesis in experimental genotoxicity induced by aflatoxin B1 (AFB1) in cultured hepatocytes obtained from control and p27Kip1 deficient mice. The overexpression of p27 was assessed with wild type p27Kip1 expression vector in HepG2 cells. The expression of p27, p21 and p53 was assessed in well and poorly‐differentiated liver tumors. DNA damage and cell death induced by AFB1 were related to a reduction of p27 and p21 expression in cultured hepatocytes. AFB1‐induced nuclear phosphorylated (Ser 10) p27 degradation was related to a rise of nuclear KIST, Rsk‐1 and Rsk‐2 expression and cytoplasm phosphorylated (Thr 198) p27 expression. The overexpression of p27 reduced cell proliferation, cell death and DNA damage in AFB1‐treated hepatocytes. The enhanced survival of patients with well differentiated compared to poorly‐differentiated tumors was related to high expression of p27, p21 and p53 in liver sections. The study showed that the p27 reduced cell proliferation and death, as well as the accumulation of DNA damage in hepatocarcinogenesis. © 2009 UICC
Identification of modifier genes for cutaneous malignant melanoma in melanoma‐prone families with and without CDKN2A mutations
Authors: Yang Xiaohong Rose , Pfeiffer Ruth M. , Wheeler William , Yeager Meredith , Chanock Stephen , Tucker Margaret A. , Goldstein Alisa M.
Published: July 2009

CDKN2A is a major susceptibility gene for cutaneous malignant melanoma (CMM), but the variable penetrance and clinical manifestations among mutation carriers suggest the existence of modifier factors. The goal of this study was to identify modifier genes for CMM in CMM‐prone families with or without CDKN2A mutations. We genotyped 537 individuals (107 CMM) from 28 families (19 CDKN2A+, 9 CDKN2A−) for 1,536 SNPs in 152 genes involved in DNA repair, apoptosis and immune response pathways. We used conditional logistic regression to account for family ascertainment and differences in disease prevalence among families. Pathway‐ and gene‐based permutation analyses were used to assess the risk of CMM associated with genes in the 5 pathways (DNA repair, apoptosis, TNF/NFκB, TH1:TH2 and other immune regulation). Our analyses identified some candidate genes such as FAS, BCL7A, CASP14, TRAF6, WRN, IL9, IL10RB, TNFSF8, TNFRSF9 and JAK3 that were associated with CMM risk (p < 0.01, gene‐based test). After correction for multiple comparisons, IL9 remained significant (Bonferroni p < 0.05). The effects of some genes were stronger in CDKN2A‐positive families (BCL7A and IL9), while some were stronger in CDKN2A‐negative families (BCL2L1). Our findings support the hypothesis that common genetic polymorphisms in DNA repair, apoptosis and immune response pathways may modify the risk of CMM in CMM‐prone families with or without CDKN2A mutations. Published 2009 UICC.
IGF2R polymorphisms and risk of esophageal and gastric adenocarcinomas
Authors: Hoyo Cathrine , Schildkraut Joellen M. , Murphy Susan K. , Chow Wong‐Ho , Vaughan Thomas L. , Risch Harvey , Marks Jeffrey R. , Jirtle Randy L. , Calingeart Brian , Mayne Susan , Fraumeni Joseph , Gammon Marilie D.
Published: July 2009

The mannose‐6‐phosphate/insulin‐like growth factor 2 receptor (M6P/IGF2R) encodes a protein that plays a critical role in tumor suppression, in part by modulating bioavailability of a potent mitogen, insulin‐like growth factor‐2 (IGF2). We tested the hypothesis that the common nonsynonymous genetic variants in M6P/IGF2R c.901C > G (Leu > Val) in exon 6 and c.5002G > A (Gly > Arg) in exon 34 are associated with risk of esophageal and gastric cancers. Study participants in this population‐based study comprise 197 controls and 182 cases, including 105 with esophageal‐gastric cardia adenocarcinoma (EGA), 57 with noncardia gastric adenocarcinoma and 20 with esophageal squamous (ES) cell carcinoma. Among white males, odds ratios (ORs) were elevated in relation to carrying at least 1 c.901C > G allele for EGA [OR = 1.9; 95% confidence intervals (CIs) = 1.0–3.6] and noncardia gastric cancer (OR = 2.5; 95% CI = 1.2–5.5), but not ES. Exploratory subgroup analyses suggested that associations between EGA and this variant were stronger among irregular or nonusers of nonsteroidal anti‐inflammatory drugs (NSAIDs) (OR = 2.3; 95% CI = 1.2–4.2) and cigarette smokers (OR = 2.1; 95% CI = 1.0–4.2). An association between carrying the c.5002G > A genotype and EGA was not evident. These findings suggest that nonsynonymous polymorphisms in M6P/IGF2R may contribute to the risks of EGA and noncardia adenocarcinomas. Larger studies are required to confirm these findings. © 2009 UICC
The novel tumor‐suppressor Mel‐18 in prostate cancer: Its functional polymorphism, expression and clinical significance
Authors: Wang Wei , Yuasa Takeshi , Tsuchiya Norihiko , Ma Zhiyong , Maita Shinya , Narita Shintaro , Kumazawa Teruaki , Inoue Takamitsu , Tsuruta Hiroshi , Horikawa Yohei , Saito Mitsuru , Hu Weilie , Ogawa Osamu , Habuchi Tomonori
Published: July 2009

Mel‐18 is a member of the polycomb group (PcG) proteins, which are chromatin regulatory factors and play important roles in development and oncogenesis. This study was designed to investigate the clinical and prognostic significance of Mel‐18 in patients with prostate cancer. A total of 539 native Japanese subjects consisting of 393 prostate cancer patients and 146 controls were enrolled in this study. Mel‐18 genotyping was analyzed using a PCR‐RFLP method and an automated sequencer using the GENESCAN software. Immunohistochemistry revealed that Mel‐18 expression was diminished in high grade and high stage prostate cancers. Moreover, patients with positive Mel‐18 expression had significantly longer PSA recurrence‐free survival than patients negative for Mel‐18 expression (p = 0.038). A Mel‐18 1805A/G SNP was located in the 3' untranslated region and was predicted to alter the secondary structure of the mRNA. Mel‐18 mRNA expression of the 1805A allele was clearly higher than expression of the 1805G allele by allele specific quantitative RT‐PCR. In multivariate analysis, a homozygous G allele genotype and negative Mel‐18 expression were independent risk factors predicting high PSA recurrence after radical prostatectomy, with HRs of 2.757 (p = 0.022) and 2.271 (p = 0.045), respectively. Moreover, the G allele was also an independent predictor of poor cancer‐specific survival with an HR of 4.658 (p = 0.019) for patients with stage D2 prostate cancer. This is the first study to provide important evidence demonstrating that Mel‐18 is a tumor suppressor and possible therapeutic target, as well as a diagnostic marker for poor prognosis in prostate cancer patients. © 2009 UICC
Response surface analysis of microwave‐assisted extraction of polysaccharides from cultured Cordyceps militaris
Authors: Song Jiang‐Feng , Li Da‐Jing , Liu Chun‐Quan
Published: July 2009

BACKGROUND: Microwave‐assisted extraction was employed to extract polysaccharides from cultured Cordyceps militaris. The optimal conditions for polysaccharide extraction were determined by response surface methodology. Box–Behnken design was applied to evaluate the effects of three independent variables (microwave power, extraction time and ratio of solution to solid) on the polysaccharide yield of C. militaris.

RESULTS: Correlation analysis of the mathematical‐regression model indicated that a quadratic polynomial model could be employed to optimize the microwave‐assisted extraction of polysaccharide. Response surface plots showed that microwave power, extraction time and ratio of solution to solid exhibited independent and interactive effects on the extraction of polysaccharide. The optimal conditions to obtain the highest polysaccharide yield of C. militaris were a microwave power of 744.8 W, an extraction time of 4.2 min and a ratio of solution to solid of 31.1 mL g−1.

CONCLUSION: Under these optimal conditions, the experimental values agreed with the predicted values, using analysis of variance, indicating the goodness of fit of the model used and the success of response surface methodology for optimizing microwave‐assisted extraction of polysaccharide from C. militaris. Copyright © 2009 Society of Chemical Industry
Depletion of CD4+CD25+ T cells exacerbates experimental autoimmune encephalomyelitis induced by mouse, but not rat, antigens
Authors: Akirav Eitan M. , Bergman Cheryl M. , Hill Myriam , Ruddle Nancy H.
Published: July 2009

A key question in the field of autoimmunity concerns the fact that experimental disease is generally induced more easily with closely related, but not completely identical, tissue‐restricted antigens. Here, the possibility that naturally occurring regulatory T cells (Tregs) for self‐antigens are more potent than those for related antigens was investigated. The self‐antigen specificity of naturally occurring Tregs was tested in experimental autoimmune encephalomyelitis (EAE) induced with mouse (self) or closely related (rat) myelin oligodendrocyte glycoproteins (MOGs). Surprisingly, Treg depletion increased EAE severity in mice immunized with mouse, but not rat, MOG. This increase was associated with increased T‐cell activation and infiltration of the central nervous system, as well as increased interleukin (IL)‐17 production and a higher ratio of interferon‐γ‐ to IL‐10‐producing cells. These data suggest that Tregs are specific for self‐antigen and do not “cross‐protect” against autoimmunity even when disease is induced with closely related foreign antigens. © 2009 Wiley‐Liss, Inc.
A novel method for isolating Schwann cells using the extracellular domain of Necl1
Authors: Spiegel Ivo , Peles Elior
Published: July 2009

Myelinating cocultures of Schwann cells and dorsal root ganglion neurons are a powerful experimental system for probing the molecular mechanisms of axon–Schwann cell interaction. The isolation of a pure population of myelination‐competent Schwann cells is a prerequisite for this experimental system. We describe here a protocol for a FACS‐based isolation of Schwann cells utilizing a specific affinity reagent (Necl1‐Fc) and the use of these isolated cells in myelinating cocultures. An advantage of the myelinating coculture system is that Schwann cells and the neurons can be genetically manipulated before they are cocultured. We further show that our method allows the isolation of virally transduced Schwann cells in a single purification step. This protocol for the FACS‐based isolation of myelination‐competent Schwann cells by Necl1‐Fc and the use of these cells in myelinating cocultures should significantly facilitate future studies aimed at delineation of the molecular mechanisms of axon–Schwann cell interactions and myelination. © 2009 Wiley‐Liss, Inc.
Effect of exogenous IGF‐1 on chondrocyte apoptosis in a rabbit intraarticular osteotomy model
Authors: Higgins Thomas F. , Johnson Brian D.
Published: July 2009

Insulin‐like growth factor‐1 (IGF‐1) has been shown to protect chondrocytes from apoptosis in vitro. IGF‐1 expression may also assist in maintaining a fully differentiated chondrocyte phenotype. Theoretically, posttraumatic administration of IGF‐1 may inhibit chondrocyte apoptosis. This study is to determine if administration of IGF‐1 after fracture inhibits apoptosis in vivo. Twenty‐four mature female New Zealand white rabbits were randomized to control and IGF‐1 groups. All subjects underwent standardized medial femoral condyle fracture and repair. Fibrin clot was administered in all subjects, with 25 mcg/ml IGF‐1 in the clot in half the subjects. Half of the animals in each group were sacrificed at 2 weeks and half at 4 weeks, specimens were fixed and underwent TUNEL staining. Two‐week controls showed significantly higher rate of apoptosis than 2‐week IGF‐1 subjects (21 ± 6 vs. 12 ± 6, p = 0.04). Likewise, 4‐week controls showed significantly higher rate of apoptosis than 2‐week IGF‐1 subjects (23 ± 7 vs. 10 ± 2, p = 0.01). There was no significant administration difference between 2‐week control and 4‐week control subjects, or between 2‐week IGF‐1 and 4‐week IGF‐1 subjects. Intraarticular IGF‐1 at the time of fracture repair appears to inhibit chondrocyte apoptosis in vivo, as judged by TUNEL staining, in this animal model. If administration of IGF‐1 inhibits human chondrocyte apoptosis in vivo, this may lead to interventions that may reduce posttraumatic arthritis after fracture. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:125–130, 2010
k‐t PCA: Temporally constrained k‐t BLAST reconstruction using principal component analysis
Authors: Pedersen Henrik , Kozerke Sebastian , Ringgaard Steffen , Nehrke Kay , Kim Won Yong
Published: July 2009

The k‐t broad‐use linear acquisition speed‐up technique (BLAST) has become widespread for reducing image acquisition time in dynamic MRI. In its basic form k‐t BLAST speeds up the data acquisition by undersampling k‐space over time (referred to as k‐t space). The resulting aliasing is resolved in the Fourier reciprocal x‐f space (x = spatial position, f = temporal frequency) using an adaptive filter derived from a low‐resolution estimate of the signal covariance. However, this filtering process tends to increase the reconstruction error or lower the achievable acceleration factor. This is problematic in applications exhibiting a broad range of temporal frequencies such as free‐breathing myocardial perfusion imaging. We show that temporal basis functions calculated by subjecting the training data to principal component analysis (PCA) can be used to constrain the reconstruction such that the temporal resolution is improved. The presented method is called k‐t PCA. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.
High dynamic‐range magnetic resonance spectroscopy (MRS) time‐domain signal analysis
Authors: Hutton William C. , Bretthorst G. Larry , Garbow Joel R. , Ackerman Joseph J.H.
Published: July 2009

In the absence of water signal suppression, the proton magnetic resonance spectroscopy (1H MRS) in vivo water resonance signal‐to‐noise ratio (SNR) is orders of magnitude larger than the SNR of all the other resonances. In this case, because the high‐SNR water resonance dominates the data, it is difficult to obtain reliable parameter estimates for the low SNR resonances. Herein, a new model is described that offers a solution to this problem. In this model, the time‐domain signal for the low SNR resonances is represented as the conventional sum of exponentially decaying complex sinusoids. However, the time‐domain signal for the high SNR water resonance is assumed to be a complex sinusoid whose amplitude is slowly varying from pure exponential decay and whose phase is slowly varying from a constant frequency. Thus, the water resonance has only an instantaneous amplitude and frequency. The water signal is neither filtered nor subtracted from the data. Instead, Bayesian probability theory is used to simultaneously estimate the frequencies, decay‐rate constants, and amplitudes for all the low SNR resonances, along with the water resonance's time‐dependent amplitude and phase. While computationally intensive, this approach models all of the resonances, including the water and the metabolites of interest, to within the noise level. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.
CSF protein biomarkers for proximal axonal damage improve prognostic accuracy in the acute phase of Guillain‐Barré syndrome
Authors: Petzold A. , Brettschneider J. , Jin K. , Keir G. , Murray N.M.F. , Hirsch N.P. , Itoyama Y. , Reilly M.M. , Takeda A. , Tumani H.
Published: July 2009

Early predictors of prognosis in Guillain‐Barré syndrome (GBS) are needed to identify patients who are likely to make a poor recovery and to guide therapeutic decision‐making in the acute phase. Here we investigate whether axonal protein biomarkers released into the cerebrospinal fluid (CSF) following proximal axonal damage improve the early prognostic accuracy in GBS. A prospective multicenter study including 132 patients (38 GBS, 38 neurological controls, 42 headaches, 14 chronic inflammatory demyelinating neuropathy). CSF levels of axonal [neurofilament (NfH) and tau] and glial (S100B and glial fibrillary acidic protein) protein biomarkers were measured on admission. Nerve conduction studies were performed at the time of lumbar puncture and patients were classified according to neurophysiological criteria. Outcome was assessed on the Hughes functional score (F‐score). Poor outcome was defined as the inability to walk independently (F‐score ≥3). High NfH levels (>0.73 ng/ml) predicted poor outcome (P = 0.01) with an odds ratio of 7.3 and correlated with the outcome F‐score (R = 0.51, P < 0.01), as did hTau levels (R = 0.47, P < 0.01). Patients with poor outcome had significantly higher CSF NfH (median 1.78 ng/ml) when compared to those with good outcome (0.03 ng/ml) or all of the control groups (neurological controls 0.18 ng/ml, headaches 0.06 ng/ml, chronic inflammatory demyelinating neuropathy 0.05 ng/ml). Except for age (P < 0.05) and need for ventilatory support (P < 0.05), none of the other features reliably predicted outcome. Improved prognostic accuracy in the acute phase of GBS seems possible using CSF NfH levels. Muscle Nerve 40: 42–49, 2009
Fiber density of the motor units recruited at high and low force output
Authors: Lukács Miklós , Vécsei László , Beniczky Sándor
Published: July 2009

Motor units (MUs) are recruited according to the size principle. At low force output, macro‐motor unit potentials (macro‐MUPs) with small amplitude and area are recorded; MUs with large electrical size fire at high force output. Our objective was to elucidate whether this difference is caused by a higher fiber density (FD) of the MUs recruited at high force output. We measured the FD and respectively the amplitude and the area of the macro‐MUPs via single‐fiber macro electromyography (EMG) recorded at low and high force output in 48 healthy subjects. The macro‐MUPs were significantly larger at high force output than at low force. The FD did not differ at the two force levels. Our findings suggest that the larger electrical size of the high recruitment threshold MUs is due not to a higher FD, but to a larger territory. FD is a robust EMG parameter, independent of the level of the force output. Muscle Nerve 40: 112–114, 2009
Motor unit number estimation in the rat tail using a modified multipoint stimulation technique
Authors: Kasselman Lora J. , Shefner Jeremy M. , Rutkove Seward B.
Published: July 2009

Motor unit number estimation (MUNE) of the rodent hindlimb has been used mainly for following the progression of motor neuron disorders. By performing MUNE in the tail, however, progression of axonal neuropathy could also be assessed, as both proximal and distal regions would be available for study. In this investigation, three raters performed a modified multipoint stimulation MUNE technique in the tails of 14 healthy adult rats. The technique was straightforward to perform, with a relatively narrow range of motor unit number estimates of 40 ± 16 (standard deviation) for the proximal tail and 21 ± 11 for the distal tail. Intrarater reliability coefficients were 0.31 (P = 0.033) and 0.32 (P = 0.028) for the proximal and distal tail, respectively. Interrater reliability coefficients were 0.22 (P = 0.086) and 0.44 (P = 0.004). These reliability assessments, along with the relatively low motor unit estimates and narrow range of values, support the idea that rat tail MUNE may have utility in the evaluation of rodent models of neuromuscular disease, including length‐dependent neuropathy. Muscle Nerve 40: 115–121, 2009
Torque‐based triggering improves stimulus timing precision in activation tests
Authors: Krishnan Chandramouli , Allen Eric J. , Williams Glenn N.
Published: July 2009

The aim of this study was to assess whether automated torque‐based stimulator triggering could improve precision in delivering stimuli near peak torque during voluntary activation tests. The quadriceps activation test was used as a test model in 11 volunteers. Automated torque‐based triggering reduced stimulus delivery timing errors by 75% when compared with conventional automated time‐based triggering. Torque‐based stimulator triggering is recommended as an alternative to automated time‐based triggering in voluntary activation tests, as it improves stimulus timing precision and thereby reduces measurement error. Muscle Nerve 40: 130–133, 2009
Thymic carcinoma in myasthenia gravis developing years after thymectomy
Authors: Katzberg Hans D. , Miller Robert G. , Katz Jonathan
Published: July 2009

We report two patients with myasthenia gravis (MG) who underwent thymectomy but developed thymic carcinoma years after the initial surgery. In one patient, the initial thymic pathology was normal, whereas the other had an encapsulated benign thymoma that was found only on pathological assessment. These cases demonstrate that MG may occur as part of a “new” paraneoplastic syndrome even after thymectomy. The late appearance of metastatic thymoma raises questions about monitoring for these patients. Muscle Nerve 40: 137–138, 2009