bluuebunny/crossref_metadata_2025 huggingface dataset:
Iron reduction by deferoxamine leads to amelioration of adiposity via the regulation of oxidative stress and inflammation in obese and type 2 diabetes KKAy mice
Authors: Tajima Soichiro , Ikeda Yasumasa , Sawada Kaori , Yamano Noriko , Horinouchi Yuya , Kihira Yoshitaka , Ishizawa Keisuke , Izawa-Ishizawa Yuki , Kawazoe Kazuyoshi , Tomita Shuhei , Minakuchi Kazuo , Tsuchiya Koichiro , Tamaki Toshiaki
Published: September 2011

Iron is an essential trace metal for most organisms. However, excess iron causes oxidative stress through production of highly toxic hydroxyl radicals via the Fenton/Haber-Weiss reaction. Iron storage in the body is reported to be associated with fat accumulation and type 2 diabetes mellitus. We investigated the role of iron in adiposity by using KKAy mice and obese and diabetic model mice. Eight-week-old KKAy mice were divided into two groups and treated with deferoxamine (DFO), an iron chelator agent, or a vehicle for 2 wk. DFO treatment diminished fat iron concentration and serum ferritin levels in KKAy mice. Fat weight and adipocyte size were reduced significantly in DFO-treated mice compared with vehicle-treated mice. Macrophage infiltration into fat was also decreased in DFO-treated mice compared with vehicle-treated mice. Superoxide production and NADPH oxidase activity in fat, as well as urinary 8-hydroxy-2′-deoxyguanosine excretion, were decreased in KKAy mice after DFO treatment while p22phox expression in adipose tissue was diminished in such mice. Ferritin expression in the fat of DFO-treated KKAy mice was decreased. In addition, F4/80-positive cells also presented through both p22phox and ferritin expression. The mRNA expression levels of inflammatory cytokines were also reduced in fat tissue of DFO-treated mice. These findings suggest that reduction of iron levels ameliorates adipocyte hypertrophy via suppression of oxidative stress, inflammatory cytokines, and macrophage infiltration, thereby breaking a vicious cycle in obesity.
Leucine or carbohydrate supplementation reduces AMPK and eEF2 phosphorylation and extends postprandial muscle protein synthesis in rats
Authors: Wilson Gabriel J. , Layman Donald K. , Moulton Christopher J. , Norton Layne E. , Anthony Tracy G. , Proud Christopher G. , Rupassara S. Indu , Garlick Peter J.
Published: September 2011

Muscle protein synthesis (MPS) increases after consumption of a protein-containing meal but returns to baseline values within 3 h despite continued elevations of plasma amino acids and mammalian target of rapamycin (mTORC1) signaling. This study evaluated the potential for supplemental leucine (Leu), carbohydrates (CHO), or both to prolong elevated MPS after a meal. Male Sprague-Dawley rats (∼270 g) trained to consume three meals daily were food deprived for 12 h, and then blood and gastrocnemius muscle were collected 0, 90, or 180 min after a standard 4-g test meal (20% whey protein). At 135 min postmeal, rats were orally administered 2.63 g of CHO, 270 mg of Leu, both, or water (sham control). Following test meal consumption, MPS peaked at 90 min and then returned to basal ( time 0) rates at 180 min, although ribosomal protein S6 kinase and eIF4E-binding protein-1 phosphorylation remained elevated. In contrast, rats administered Leu and/or CHO supplements at 135 min postmeal maintained peak MPS through 180 min. MPS was inversely associated with the phosphorylation states of translation elongation factor 2, the “cellular energy sensor” adenosine monophosphate-activated protein kinase-α (AMPKα) and its substrate acetyl-CoA carboxylase, and increases in the ratio of AMP/ATP. We conclude that the incongruity between MPS and mTORC1 at 180 min reflects a block in translation elongation due to reduced cellular energy. Administering Leu or CHO supplements ∼2 h after a meal maintains cellular energy status and extends the postprandial duration of MPS.
Jejunal linoleic acid infusions require GLP-1 receptor signaling to inhibit food intake: implications for the effectiveness of Roux-en-Y gastric bypass
Authors: Dailey Megan J. , Moghadam Alexander A. , Moran Timothy H.
Published: September 2011

Roux-en-Y gastric bypass surgery results in sustained decreases in food intake and weight loss. A key component is likely the direct delivery of nutrients to the jejunum and resulting changes in levels of gut peptide secretion. Prior work modeling this aspect of the surgery has shown that small-volume, prolonged jejunal infusions of linoleic acid (LA) produce sustained decreases in food intake and weight loss. LA infusions also significantly elevate plasma glucagon-like peptide-1 (GLP-1) levels. To assess a role for the increased circulating GLP-1 in the feeding suppression, we examined the effect of prolonged peripheral minipump administration of the GLP-1 receptor antagonist exendin 9–39 (Ex 9) on the feeding suppression produced by jejunal LA. Using a 2 × 2 design, we infused either saline or LA in the jejunum (7 h/day, 11.4 kcal) for 5 days with a subset of animals from each group receiving either saline or Ex 9 (25 pmol·kg−1·min−1) continuously via a minipump. The antagonist alone had no effect on food intake. LA reduced daily food intake greatly in excess of the kilocalories infused. Ex 9 completely blocked the feeding suppression produced by the jejunal LA infusion. Ex 9 also attenuated the increase in plasma GLP-1 induced by jejunal LA infusions. These data demonstrate that endogenous GLP-1 receptor signaling is necessary for the reduction in food intake produced by jejunal LA infusions. Whether increased secretion of additional gut peptides is also necessary for such suppressions remains to be determined.
High-sucrose diet increases ROS generation, FFA accumulation, UCP2 level, and proton leak in liver mitochondria
Authors: Ruiz-Ramírez Angélica , Chávez-Salgado Monserrath , Peñeda-Flores José Antonio , Zapata Estrella , Masso Felipe , El-Hafidi Mohammed
Published: September 2011

Obesity, a risk factor for insulin resistance, contributes to the development of type 2 diabetes and cardiovascular diseases. The relationship between increased levels of free fatty acids in the liver mitochondria, mitochondrial function, and ROS generation in rat model of obesity induced by a high-sucrose diet was not sufficiently established. We determined how the bioenergetic functions and ROS generation of the mitochondria respond to a hyperlipidemic environment. Mitochondria from sucrose-fed rats generated H2O2at a higher rate than the control mitochondria. Adding fatty acid-free bovine serum albumin to mitochondria from sucrose-fed rats significantly reduced the rate of H2O2generation. In contrast, adding exogenous oleic or linoleic acid exacerbated the rate of H2O2generation in both sucrose-fed and control mitochondria, and the mitochondria from sucrose-fed rats were more sensitive than the control mitochondria. The increased rate of H2O2generation in sucrose-fed mitochondria corresponded to decreased levels of reduced GSH and vitamin E and increased levels of Cu/Zn-SOD in the intermembrane space. There was no difference between the levels of lipid peroxidation and protein carbonylation in the two types of mitochondria. In addition to the normal activity of Mn-SOD, GPX and catalase detected an increased activity of complex II, and upregulation of UCP2 was observed in mitochondria from sucrose-fed rats, all of which may accelerate respiration rates and reduce generation of ROS. In turn, these effects may protect the mitochondria of sucrose-fed rats from oxidative stress and preserve their function and integrity. However, in whole liver these adaptive mechanisms of the mitochondria were inefficient at counteracting redox imbalances and inhibiting oxidative stress outside of the mitochondria.
Multistate proteomics analysis reveals novel strategies used by a hibernator to precondition the heart and conserve ATP for winter heterothermy
Authors: Grabek Katharine R. , Karimpour-Fard Anis , Epperson L. Elaine , Hindle Allyson , Hunter Lawrence E. , Martin Sandra L.
Published: September 2011

The hibernator's heart functions continuously and avoids damage across the wide temperature range of winter heterothermy. To define the molecular basis of this phenotype, we quantified proteomic changes in the 13-lined ground squirrel heart among eight distinct physiological states encompassing the hibernator's year. Unsupervised clustering revealed a prominent seasonal separation between the summer homeotherms and winter heterotherms, whereas within-season state separation was limited. Further, animals torpid in the fall were intermediate to summer and winter, consistent with the transitional nature of this phase. A seasonal analysis revealed that the relative abundances of protein spots were mainly winter-increased. The winter-elevated proteins were involved in fatty acid catabolism and protein folding, whereas the winter-depleted proteins included those that degrade branched-chain amino acids. To identify further state-dependent changes, protein spots were re-evaluated with respect to specific physiological state, confirming the predominance of seasonal differences. Additionally, chaperone and heat shock proteins increased in winter, including HSPA4, HSPB6, and HSP90AB1, which have known roles in protecting against ischemia-reperfusion injury and apoptosis. The most significant and greatest fold change observed was a disappearance of phospho-cofilin 2 at low body temperature, likely a strategy to preserve ATP. The robust summer-to-winter seasonal proteomic shift implies that a winter-protected state is orchestrated before prolonged torpor ensues. Additionally, the general preservation of the proteome during winter hibernation and an increase of stress response proteins, together with dephosphorylation of cofilin 2, highlight the importance of ATP-conserving mechanisms for winter cardioprotection.
Therapeutic Use of Botulinum Toxin in Neurorehabilitation
Authors: Intiso Domenico
Published: September 2011

The botulinum toxins (BTX), type A and type B by blocking vesicle acetylcholine release at neuro-muscular and neuro-secretory junctions can result efficacious therapeutic agents for the treatment of numerous disorders in patients requiring neuro-rehabilitative intervention. Its use for the reduction of focal spasticity following stroke, brain injury, and cerebral palsy is provided. Although the reduction of spasticity is widely demonstrated with BTX type A injection, its impact on the improvement of dexterity and functional outcome remains controversial. The use of BTX for the rehabilitation of children with obstetrical brachial plexus palsy and in treating sialorrhea which can complicate the course of some severe neurological diseases such as amyotrophic lateral sclerosis and Parkinson's disease is also addressed. Adverse events and neutralizing antibodies formation after repeated BTX injections can occur. Since impaired neurological persons can have complex disabling feature, BTX treatment should be viewed as adjunct measure to other rehabilitative strategies that are based on the individual's residual ability and competence and targeted to achieve the best functional recovery. BTX therapy has high cost and transient effect, but its benefits outweigh these disadvantages. Future studies must clarify if this agent alone or adjunctive to other rehabilitative procedures works best on functional outcome.
PGC1α Promotes Tumor Growth by Inducing Gene Expression Programs Supporting Lipogenesis
Authors: Bhalla Kavita , Hwang Bor Jang , Dewi Ruby E. , Ou Lihui , Twaddel William , Fang Hong-bin , Vafai Scott B. , Vazquez Francesca , Puigserver Pere , Boros Laszlo , Girnun Geoffrey D.
Published: September 2011

Despite the role of aerobic glycolysis in cancer, recent studies highlight the importance of the mitochondria and biosynthetic pathways as well. PPARγ coactivator 1α (PGC1α) is a key transcriptional regulator of several metabolic pathways including oxidative metabolism and lipogenesis. Initial studies suggested that PGC1α expression is reduced in tumors compared with adjacent normal tissue. Paradoxically, other studies show that PGC1α is associated with cancer cell proliferation. Therefore, the role of PGC1α in cancer and especially carcinogenesis is unclear. Using Pgc1α−/− and Pgc1α+/+ mice, we show that loss of PGC1α protects mice from azoxymethane-induced colon carcinogenesis. Similarly, diethylnitrosamine-induced liver carcinogenesis is reduced in Pgc1α−/− mice as compared with Pgc1α+/+ mice. Xenograft studies using gain and loss of PGC1α expression showed that PGC1α also promotes tumor growth. Interestingly, while PGC1α induced oxidative phosphorylation and tricarboxylic acid cycle gene expression, we also observed an increase in the expression of two genes required for de novo fatty acid synthesis, ACC and FASN. In addition, SLC25A1 and ACLY, which are required for the conversion of glucose into acetyl-CoA for fatty acid synthesis, were also increased by PGC1α, thus linking the oxidative and lipogenic functions of PGC1α. Indeed, using stable 13C isotope tracer analysis, we show that PGC1α increased de novo lipogenesis. Importantly, inhibition of fatty acid synthesis blunted these progrowth effects of PGC1α. In conclusion, these studies show for the first time that loss of PGC1α protects against carcinogenesis and that PGC1α coordinately regulates mitochondrial and fatty acid metabolism to promote tumor growth. Cancer Res; 71(21); 6888–98. ©2011 AACR.
Targeting the Immunoregulator SRA/CD204 Potentiates Specific Dendritic Cell Vaccine-Induced T-cell Response and Antitumor Immunity
Authors: Yi Huanfa , Guo Chunqing , Yu Xiaofei , Gao Ping , Qian Jie , Zuo Daming , Manjili Masoud H. , Fisher Paul B. , Subjeck John R. , Wang Xiang-Yang
Published: September 2011

Although dendritic cell (DC) vaccines offer promise as cancer immunotherapy, further improvements are needed to amplify their clinical therapeutic efficacy. The pattern recognition scavenger receptor SRA/CD204 attenuates the ability of DCs to activate CD8+ T-cell responses. Therefore, we examined the impact of SRA/CD204 on antitumor responses generated by DC vaccines and we also evaluated the feasibility of enhancing DC vaccine potency by SRA/CD204 blockade. DCs from SRA/CD204-deficient mice were more immunogenic in generating antitumor responses to B16 melanoma, compared with DCs from wild-type mice. Similarly, siRNA-mediated knockdown of SRA/CD204 by lentiviral vectors improved the ability of wild-type DCs to stimulate the expansion and activation of CD8+ T cells specific for idealized or established melanoma antigens in mice. Using SRA/CD204-silenced DCs to generate antigen-targeted vaccines, we documented a marked increase in the level of antitumor immunity achieved against established B16 tumors and metastases. This increase was associated with enhanced activation of antigen specific CTLs, greater tumor infiltration by CD8+ T cells and NK cells, and increased intratumoral ratios of both CD4+ and CD8+ T-effector cells to CD4+CD25+ T-regulatory cells. Our studies establish that downregulating SRA/CD204 strongly enhances DC-mediated antitumor immunity. In addition, they provide a rationale to enhance DC vaccine potency through SRA/CD204-targeting approaches that can improve clinical outcomes in cancer treatment. Cancer Res; 71(21); 6611–20. ©2011 AACR.
A Hypermethylated Phenotype Is a Better Predictor of Survival than MGMT Methylation in Anaplastic Oligodendroglial Brain Tumors: A Report from EORTC Study 26951
Authors: van den Bent Martin J. , Gravendeel Lonneke A. , Gorlia Thierry , Kros Johan M. , Lapre Lariesa , Wesseling Pieter , Teepen Johannes L. , Idbaih Ahmed , Sanson Marc , Smitt Peter A.E. Sillevis , French Pim J.
Published: September 2011

Purpose: The MGMT promoter methylation status has been suggested to be predictive for outcome to temozolomide chemotherapy in patients with glioblastoma (GBM). Subsequent studies indicated that MGMT promoter methylation is a prognostic marker even in patients treated with radiotherapy alone, both in GBMs and in grade III gliomas.

Experimental Design: To help determine the molecular mechanism behind this prognostic effect, we have conducted genome-wide methylation profiling and determined the MGMT promoter methylation status, 1p19q LOH, IDH1 mutation status, and expression profile on a series of oligodendroglial tumors [anaplastic oligodendrogliomas (AOD) and anaplastic oligoastrocytomas (AOA)] within EORTC study 26951. The series was expanded with tumors of the same histology and treatment from our own archive.

Results: Methylation profiling identified two main subgroups of oligodendroglial brain tumors of which survival in the CpG island hypermethylation phenotype (CIMP+) subgroup was markedly better than the survival of the unmethylated (CIMP−) subgroup (5.62 vs. 1.24 years; P < 0.0001). CIMP status correlated with survival, MGMT promoter methylation, 1p19q LOH, and IDH1 mutation status. CIMP status strongly increases the predictive accuracy of survival in a model including known clinical prognostic factors such as age and performance score. We validated our results on an independent data set from the Cancer Genome Atlas (TCGA).

Conclusion: The strong association between CIMP status and MGMT promoter methylation suggests that the MGMT promoter methylation status is part of a more general, prognostically favorable genome-wide methylation profile. Methylation profiling therefore may help identify AODs and AOAs with improved prognosis. Clin Cancer Res; 17(22); 7148–55. ©2011 AACR.
The NEDD8-Activating Enzyme Inhibitor, MLN4924, Cooperates with TRAIL to Augment Apoptosis through Facilitating c-FLIP Degradation in Head and Neck Cancer Cells
Authors: Zhao Liqun , Yue Ping , Lonial Sagar , Khuri Fadlo R. , Sun Shi-Yong
Published: September 2011

TNF-related apoptosis-inducing ligand (TRAIL) is a tumor-selective cytokine with potential anticancer activity and is currently under clinical testing. Head and neck squamous cell carcinoma (HNSCC), like other cancer types, exhibits varied sensitivity to TRAIL. MLN4924 is a newly developed investigational small molecule inhibitor of NEDD8-activating enzyme with potent anticancer activity. This study reveals a novel function of MLN4924 in synergizing with TRAIL to induce apoptosis in HNSCC cells. MLN4924 alone effectively inhibited the growth of HNSCC cells and induced apoptosis. When combined with TRAIL, synergistic effects on decreasing the survival and inducing apoptosis of HNSCC cells occurred. MLN4924 decreased c-FLIP levels without modulating death receptor 4 and death receptor 5 expression. Enforced expression of c-FLIP substantially attenuated MLN4924/TRAIL–induced apoptosis. Thus c-FLIP reduction plays an important role in mediating MLN4924/TRAIL–induced apoptosis. Moreover, MLN4924 decreased c-FLIP stability, increased c-FLIP ubiquitination, and facilitated c-FLIP degradation, suggesting that MLN4924 decreases c-FLIP levels through promoting its degradation. MLN4924 activated c-jun-NH2-kinase (JNK) signaling, evidenced by increased levels of phospho-c-Jun in MLN4924-treated cells. Chemical inhibition of JNK activation not only prevented MLN4924-induced c-FLIP reduction, but also inhibited MLN4924/TRAIL–induced apoptosis, suggesting that JNK activation mediates c-FLIP downregulation and subsequent enhancement of TRAIL-induced apoptosis by MLN4924. Because knockdown of NEDD8 failed to activate JNK signaling and downregulate c-FLIP, it is likely that MLN4924 reduces c-FLIP levels and enhances TRAIL-induced apoptosis independent of NEDD8 inhibition. Mol Cancer Ther; 10(12); 2415–25. ©2011 AACR.
The Bcl-2/Bcl-XL/Bcl-w Inhibitor, Navitoclax, Enhances the Activity of Chemotherapeutic Agents In Vitro and In Vivo
Authors: Chen Jun , Jin Sha , Abraham Vivek , Huang Xiaoli , Liu Bernard , Mitten Michael J. , Nimmer Paul , Lin Xiaoyu , Smith Morey , Shen Yu , Shoemaker Alexander R. , Tahir Stephen K. , Zhang Haichao , Ackler Scott L. , Rosenberg Saul H. , Maecker Heather , Sampath Deepak , Leverson Joel D. , Tse Chris , Elmore Steven W.
Published: September 2011

The ability of a cancer cell to avoid apoptosis is crucial to tumorigenesis and can also contribute to chemoresistance. The Bcl-2 family of prosurvival proteins (Bcl-2, Bcl-XL, Bcl-w, Mcl-1, and A1) plays a key role in these processes. We previously reported the discovery of ABT-263 (navitoclax), a potent small-molecule inhibitor of Bcl-2, Bcl-XL, and Bcl-w. While navitoclax exhibits single-agent activity in tumors dependent on Bcl-2 or Bcl-XL for survival, the expression of Mcl-1 has been shown to confer resistance to navitoclax, most notably in solid tumors. Thus, therapeutic agents that can downregulate or neutralize Mcl-1 are predicted to synergize potently with navitoclax. Here, we report the activity of navitoclax in combination with 19 clinically relevant agents across a panel of 46 human solid tumor cell lines. Navitoclax broadly enhanced the activity of multiple therapeutic agents in vitro and enhanced efficacy of both docetaxel and erlotinib in xenograft models. The ability of navitoclax to synergize with docetaxel or erlotinib corresponded to an altered sensitivity of the mitochondria toward navitoclax, which was associated with the downmodulation of Mcl-1 and/or upregulation of Bim. These data provide a rationale to interrogate these combinations clinically. Mol Cancer Ther; 10(12); 2340–9. ©2011 AACR.
Chemoprevention of Colon Cancer in a Rat Carcinogenesis Model Using a Novel Nanotechnology-Based Combined Treatment System
Authors: Chaudhary Abhishek , Sutaria Dhruvitkumar , Huang Ying , Wang Jeffrey , Prabhu Sunil
Published: September 2011

Colorectal cancer (CRC) is the third most common cause of cancer death in the United States, accounting for approximately 51,000 deaths each year. We have previously shown in vitro chemopreventive effects of mixtures of aspirin, folic acid, and calcium (AFAC) on colon cancer cell lines. The objective of the present study was to evaluate the in vivo effects of orally administered, colon targeted chemopreventive combination regimens on the inhibition of aberrant crypt foci (ACF) in a rat model of colon carcinogenesis using (i) unmodified (free drug) combinations of AFAC and (ii) nanoparticle-encapsulated combinations of the same agents. A 14-week animal study was conducted in three phases to determine an optimal effective dose from AFAC combinations and evaluate the efficacy of nanotechnology-based chemopreventive regimens administered in combined (mixtures) and individual (single entity) forms. ACF inhibition when compared with azoxymethane-treated rat control group was significant in both the unmodified and the modified nanoparticle-mediated chemopreventive regimens, showing a range of 31% to 38% (P < 0.05) and 50% to 75% (P < 0.001) reduction, respectively, in the number of ACFs. In addition, the nanoparticulate combination regimens of AFAC showed a 2-fold increase in suppression of ACF compared with free drug mixtures. Individual administration of nanoparticle-encapsulated drugs showed no significant effect on the reduction of ACF. Histochemical analysis provided further confirmation of chemopreventive effects, showing a significant reduction in cell nuclear proliferation. Overall, our results provide a strong proof of concept using nanoparticle-mediated combination treatment in the chemoprevention of colon cancer. Cancer Prev Res; 4(10); 1655–64. ©2011 AACR.
Novel Biomarkers Do Not Correlate with Severity of Vascular Stiffness in CKD Patients with Severe Co-Morbid Disease
Authors: Weber Catherine , Sigrist Mhairi , Romann Alexandra , Chiarelli Giusy , Levin Adeera
Published: September 2011

Background/Aims: Novel biomarkers may help explain the pathobiology of vascular disease in chronic kidney disease, and thus set the stage for identification of therapeutic targets, potential reversibility, and improved outcomes in this population. Methods: 124 subjects with GFR <60 ml/min or on renal replacement therapy underwent measurement of inflammatory, vascular and cardiac biomarkers as well as aortic pulse wave velocity (PWV) testing. A subset of patients (n = 60) had repeat PWV measured at 6 months. Results: Thirty-four percent of the patients were diabetic, and 50% had a history of cardiovascular disease or congestive heart failure. Median PWV was 9.8 (IQR 8.3–12.7) m/s. No significant correlations between the measured biomarkers and baseline PWV was observed. An increase in PWV (>1.5 m/s) over 6 months was observed in those subjects with diabetes, a higher brain natriuretic peptide level, lower cholesterol and lower phosphate level. Age (HR 1.086, p = 0.0028), fetuin (0.024, p = 0.0448), and interleukin-10 (top tertile HR 4.720, p = 0.0359) were associated with mortality. Conclusions: In this cohort of patients with chronic kidney disease and diabetes and/or heart disease, we were unable to demonstrate that select biomarkers can inform processes leading to vascular disease. Biomarkers do appear to have utility in predicting future events in this population.
Relationship between Fat Mass and Serum High-Sensitivity C-Reactive Protein Levels in Prevalent Hemodialysis Patients
Authors: Ishimura Eiji , Okuno Senji , Tsuboniwa Naoki , Shoji Shigeichi , Yamakawa Tomoyuki , Nishizawa Yoshiki , Inaba Masaaki
Published: September 2011

Background/Aims: Little is known about the relationship between fat mass distribution and chronic inflammation in dialysis patients, in whom chronic inflammation is related to morbidity and mortality. Methods: The fat and lean masses (truncal and nontruncal) of 452 hemodialysis patients (age: 64 ± 11 years; hemodialysis duration: 89 ± 77 months; 37% diabetics) were measured by dual X-ray absorptiometry and their association with high-sensitivity C-reactive protein (hsCRP) was examined. Results: The fat mass of the high hsCRP group (n = 106) was significantly higher than that of the normal hsCRP group (n = 346; p < 0.05); there were no significant differences in lean mass between the two groups. Truncal fat mass of the former group was significantly greater than that of the latter (p < 0.05), but there was no significant difference in nontruncal fat mass between the two groups. In multiple regression analysis, truncal fat mass (β = 0.227, p < 0.01) was significantly and independently associated with serum hsCRP levels after adjustment for age, gender and serum albumin (R2 = 0.137, p < 0.01), whereas nontruncal fat mass was not. Conclusion: Fat mass, particularly truncal fat mass, but not lean body mass, was significantly associated with serum hsCRP levels. The results suggest that truncal fat mass exhibits a distinct effect on chronic inflammation in hemodialysis patients.
Association of Cocaine- and Amphetamine-Related Transcript, Leptin and Leptin Receptor Gene Polymorphisms with Anthropometric Obesity Phenotype Indicators in South African Learners
Authors: Yako Y.Y. , Fanampe B.L. , Hassan M.S. , Erasmus R.T. , van der Merwe L. , van Rensburg S.J. , Matsha T.E.
Published: September 2011

Background/Aims: Obesity has increased rapidly in South African children and adolescents. Genes involved in appetite regulation have been extensively studied worldwide, but their role in the obesity phenotype in South African Black and mixed-ancestry school adolescents is unknown. Methods: Seven common polymorphisms in LEP, GHRL, CART and LEPR were analysed for genotype and haplotype association with anthropometric obesity phenotype indicators in South African Black and mixed-ancestry adolescent school learners. Results: The CART c.517A→G polymorphism was significantly associated with obesity susceptibility. The LEPR Lys109Arg G allele was associated with an average reduction of 2.36 kg/m2 in body mass index (BMI), 5.66 cm in waist circumference (WC) and 1.61 cm in mid-upper-arm circumference (MUAC). This was confirmed by haplotype analysis. Additionally, a haplotype of the LEP polymorphisms significantly increased BMI, MUAC and hip circumference, while LEPR haplotypes were associated with differences in MUAC. Conclusion: Our findings suggest that c.517A→G and Lys109Arg contribute to the variation in anthropometric obesity phenotype indicators observed among Black African and mixed-ancestry South African learners. Furthermore, haplotypes of LEP, LEPR and GHRL polymorphisms were associated with varying measurements of weight, BMI and WC. Further studies are required to confirm our results in a larger and homogeneous study population group.
Does Growth Hormone Treatment Influence Pubertal Development in Short Children?
Authors: Albin Anna-Karin , Ankarberg-Lindgren Carina , Tuvemo Torsten , Jonsson Björn , Albertsson-Wikland Kerstin , Ritzén E. Martin ,   on behalf of the study group
Published: September 2011

Aim: To study the influence of growth hormone (GH) treatment on the initiation and progression of puberty in short children. Methods: This prospective, randomized, controlled study included 124 short children (33 girls) who received GH treatment (Genotropin®; Pfizer Inc.) from a mean age of 11 years until near adult height [intent-to-treat (ITT) population]. Children were randomized into three groups: controls (n = 33), GH 33 µg/kg/day (n = 34) or GH 67 µg/kg/day (n = 57). Prepubertal children at study start constituted the per-protocol (PP) population (n = 101). Auxological measurements were made and puberty was staged every 3 months. Serum sex-steroid concentrations were assessed every 6 months. Results: No significant differences were found between the groups, of both PP and ITT populations, in time elapsed from start of treatment until either onset of puberty, age at start of puberty or age at final pubertal maturation in either sex. In the ITT population, pubertal duration was significantly longer in GH-treated girls, and maximum mean testicular volume was significantly greater in GH-treated boys than controls, but there were no differences in testosterone levels between the groups. Conclusion: GH treatment did not influence age at onset of puberty and did not accelerate pubertal development. In boys, GH treatment appeared to increase testicular volume.
Analysis of FOXG1 Is Highly Recommended in Male and Female Patients with Rett Syndrome
Authors: Van der Aa N. , Van den Bergh M. , Ponomarenko N. , Verstraete L. , Ceulemans B. , Storm K.
Published: September 2011

We screened a cohort of 5 male and 20 female patients with a Rett spectrum disorder for mutations in the coding region of FOXG1, previously shown to cause the congenital variant of Rett syndrome. Two de novo mutations were identified. The first was a novel missense mutation, p.Ala193Thr (c.577G>A), in a male patient with congenital Rett syndrome, and the second was the p.Glu154GlyfsX301 (c.460dupG) truncating mutation in a female with classical Rett syndrome, a mutation that was previously reported in an independent patient. The overall rate of FOXG1 mutations in our cohort is 8%. Our findings stress the importance of FOXG1 analysis in male patients with Rett syndrome and in female patients when mutations in the MECP2 and CDKL5 genes have been excluded.
Whole Xp Deletion in a Girl with Mental Retardation, Epilepsy, and Biochemical Features of OTC Deficiency
Authors: Joost K. , Tammur P. , Teek R. , Žilina O. , Peters M. , Kreile M. , Lace B. , Žordania R. , Talvik I. , Õunap K.
Published: September 2011

Background: Females with a total or partial deletion of the short arm of the X chromosome have variable features of Turner syndrome, but mental retardation (MR) rarely occurs. The haploinsufficiency of deleted genes that escape X-inactivation may explain the occurrence of MR and autism. Ornithine transcarbamylase (OTC) deficiency is the most common urea cycle disorder and is inherited in an X-linked semi-dominant trait, and the OTC gene maps to Xp21. Methods: We report on a girl with MR, epilepsy and biochemical changes characteristic of OTC deficiency but no identifiable point mutation in the OTC gene. Standard G-banding cytogenetic analysis, whole genome karyotyping, and X-inactivation studies were performed to determine the genetic etiology of the OTC deficiency in the patient. Results: Cytogenetic analysis and molecular karyotyping using SNP array revealed a deletion of the whole short arm of the X chromosome (Xp22.33–p11.1). Inactivation studies also revealed a completely skewed X-inactivation. Conclusion: Our patient presented with MR, epilepsy, and some evidence of reduced OTC activity, but performed genetic studies gave no explanation for this phenotype. We hope that this case report contributes to the understanding of the underlying genetic factors of the manifestation of X-linked disorders in female patients.
Reference Frame of Human Medial Intraparietal Cortex in Visually Guided Movements
Authors: Ogawa Kenji , Inui Toshio
Published: September 2011

Visually guided reaching involves the transformation of a spatial position of a target into a body-centered reference frame. Although involvement of the posterior parietal cortex (PPC) has been proposed in this visuomotor transformation, it is unclear whether human PPC uses visual or body-centered coordinates in visually guided movements. We used a delayed visually guided reaching task, together with an fMRI multivoxel pattern analysis, to reveal the reference frame used in the human PPC. In experiments, a target was first presented either to the left or to the right of a fixation point. After a delay period, subjects moved a cursor to the position where the target had previously been displayed using either a normal or a left–right reversed mouse. The activation patterns of normal sessions were first used to train the classifier to predict movement directions. The activity patterns of the reversed sessions were then used as inputs to the decoder to test whether predicted directions correspond to actual movement directions in either visual or body-centered coordinates. When the target was presented before actual movement, the predicted direction in the medial intraparietal cortex was congruent with the actual movement in the body-centered coordinates, although the averaged signal intensities were not significantly different between two movement directions. Our results indicate that the human medial intraparietal cortex uses body-centered coordinates to encode target position or movement directions, which are crucial for visually guided movements.
The Role of Left Ventrolateral Prefrontal Cortex during Episodic Decisions: Semantic Elaboration or Resolution of Episodic Interference?
Authors: Han Sanghoon , O'Connor Akira R. , Eslick Andrea N. , Dobbins Ian G.
Published: September 2011

Context memory retrieval tasks often implicate the left ventrolateral pFC (LVPFC) during functional imaging. Although this region has been linked to controlled semantic processing of materials, it may also play a more general role in selecting among competing episodic representations during demanding retrieval tasks. Thus, the LVPFC response during context memory retrieval may reflect either semantic processing of memoranda or adjudication of interfering episodic memories evoked by memoranda. To distinguish between these hypotheses, we contrasted context and item memory retrieval tasks for meaningful and nonmeaningful memoranda using fMRI. Increased LVPFC activation during context compared with item memory only occurred for meaningful memory probes. In contrast, even demanding context retrieval for nonmeaningful materials failed to engage LVPFC. These data demonstrate that the activation previously seen during episodic tasks likely reflects semantic processing of the probes during episodic retrieval attempt, not the selection among competing elicited episodic representations. Posterior middle temporal gyrus and the body/head of the caudate demonstrated the same selective response as LVPFC, although resting state functional connectivity analyses suggested that these two regions likely shared separate functional relationships with the LVPFC.
When Sounds Become Actions: Higher-order Representation of Newly Learned Action Sounds in the Human Motor System
Authors: Ticini Luca F. , Schütz-Bosbach Simone , Weiss Carmen , Casile Antonino , Waszak Florian
Published: September 2011

In the absence of visual information, our brain is able to recognize the actions of others by representing their sounds as a motor event. Previous studies have provided evidence for a somatotopic activation of the listener's motor cortex during perception of the sound of highly familiar motor acts. The present experiments studied (a) how the motor system is activated by action-related sounds that are newly acquired and (b) whether these sounds are represented with reference to extrinsic features related to action goals rather than with respect to lower-level intrinsic parameters related to the specific movements. TMS was used to measure the correspondence between auditory and motor codes in the listener's motor system. We compared the corticomotor excitability in response to the presentation of auditory stimuli void of previous motor meaning before and after a short training period in which these stimuli were associated with voluntary actions. Novel cross-modal representations became manifest very rapidly. By disentangling the representation of the muscle from that of the action's goal, we further showed that passive listening to newly learnt action-related sounds activated a precise motor representation that depended on the variable contexts to which the individual was exposed during testing. Our results suggest that the human brain embodies a higher-order audio-visuo-motor representation of perceived actions, which is muscle-independent and corresponds to the goals of the action.
Hearing Shapes Our Perception of Time: Temporal Discrimination of Tactile Stimuli in Deaf People
Authors: Bolognini Nadia , Cecchetto Carlo , Geraci Carlo , Maravita Angelo , Pascual-Leone Alvaro , Papagno Costanza
Published: September 2011

Confronted with the loss of one type of sensory input, we compensate using information conveyed by other senses. However, losing one type of sensory information at specific developmental times may lead to deficits across all sensory modalities. We addressed the effect of auditory deprivation on the development of tactile abilities, taking into account changes occurring at the behavioral and cortical level. Congenitally deaf and hearing individuals performed two tactile tasks, the first requiring the discrimination of the temporal duration of touches and the second requiring the discrimination of their spatial length. Compared with hearing individuals, deaf individuals were impaired only in tactile temporal processing. To explore the neural substrate of this difference, we ran a TMS experiment. In deaf individuals, the auditory association cortex was involved in temporal and spatial tactile processing, with the same chronometry as the primary somatosensory cortex. In hearing participants, the involvement of auditory association cortex occurred at a later stage and selectively for temporal discrimination. The different chronometry in the recruitment of the auditory cortex in deaf individuals correlated with the tactile temporal impairment. Thus, early hearing experience seems to be crucial to develop an efficient temporal processing across modalities, suggesting that plasticity does not necessarily result in behavioral compensation.
Drug-Induced Discoloration of Teeth
Authors: Kumar Arun , Kumar Vijay , Singh Janardhan , Hooda Anita , Dutta Samir
Published: September 2011

The problem of tooth discoloration is emerging in our society because of the poor oral hygiene, physical agents, environmental chemicals, mouth rinses, some dental procedures, general systemic conditions, and drugs. Other common causes of tooth discoloration include excessive use of tea, coffee, tobacco smoking and chewing, chewing of betel morsel (piper betel, paan), and so on. Drug-induced tooth discoloration can be prevented by avoiding prescriptions of well-known offender drugs known to cause tooth discoloration during pregnancy and in young children. This review describes some important groups of drugs that cause tooth discoloration.
Childhood Rhabdomyosarcoma
Authors: Wang C.
Published: September 2011

Rhabdomyosarcoma (RMS) is a morphologically and clinically heterogeneous group of malignant tumors that resemble developing skeletal muscle and is the most common soft-tissue sarcoma in children and adolescents. The most prominent sites involve head and neck structures (~40%), genito-urinary track (~25%), and extremities (~20%). Embryonal (ERMS) and alveolar (ARMS) are the two major RMS subtypes that are distinct in their morphology and genetic make-up. The prognosis for this cancer depends strongly on tumor size, location, staging, and child’s age. In general, ERMS has a more favorable outcome, whereas the mortality rate remains high in patients with ARMS, because of its aggressive and metastatic nature. Over the past two decades, researchers have made concerted efforts to delineate genetic and epigenetic changes associated with RMS pathogenesis. These molecular signatures have presented golden opportunities to design targeted therapies for treating this aggressive cancer. This article highlights recent advances in understanding the molecular pathogenesis of RMS, and addresses promising research areas for further exploration.
Post-natal Effect of Overexpressed DKK1 on Mandibular Molar Formation
Authors: Han X.L. , Liu M. , Voisey A. , Ren Y.S. , Kurimoto P. , Gao T. , Tefera L. , Dechow P. , Ke H.Z. , Feng J.Q.
Published: September 2011

Dickkopf-related protein 1 (DKK1) is a potent inhibitor of Wnt/β-catenin signaling. Dkk1-null mutant embryos display severe defects in head induction. Conversely, targeted expression of Dkk1 in dental epithelial cells leads to the formation of dysfunctional enamel knots and subsequent tooth defects during embryonic development. However, its role in post-natal dentinogenesis is largely unknown. To address this issue, we studied the role of DKK1 in post-natal dentin development using 2.3-kb Col1a1- Dkk1 transgenic mice, with the following key findings: (1) The Dkk1 transgene was highly expressed in pulp and odontoblast cells during post-natal developmental stages; (2) the 1st molar displayed short roots, an enlarged pulp/root canal region, and a decrease in the dentin formation rate; (3) a small malformed second molar and an absent third molar; (4) an increase of immature odontoblasts, few mature odontoblasts, and sharply reduced dentinal tubules; and (5) a dramatic change in Osx and nestin expression. We propose that DKK1 controls post-natal mandibular molar dentin formation either directly or indirectly via the inhibition of Wnt signaling at the following aspects: (i) post-natal dentin formation, (ii) formation and/or maintenance of the dentin tubular system, (iii) mineralization of the dentin, and (iv) regulation of molecules such as Osx and nestin.
The Use of Mouse Models to Investigate Shear Bond Strength in Amelogenesis Imperfecta
Authors: Pugach M.K. , Ozer F. , Li Y. , Sheth K. , Beasley R. , Resnick A. , Daneshmehr L. , Kulkarni A.B. , Bartlett J.D. , Gibson C.W. , Lindemeyer R.G.
Published: September 2011

Patients with amelogenesis imperfecta (AI) have defective enamel; therefore, bonded restorations of patients with AI have variable success rates. To distinguish which cases of AI may have good clinical outcomes with bonded materials, we evaluated etching characteristics and bond strength of enamel in mouse models, comparing wild-type (WT) with those having mutations in amelogenin (Amelx) and matrix metalloproteinase-20 (Mmp20), which mimic 2 forms of human AI. Etched enamel surfaces were compared for roughness by scanning electron microscopy (SEM) images. Bonding was compared through shear bond strength (SBS) studies with 2 different systems (etch-and-rinse and self-etch). Etched enamel surfaces of incisors from Amelx knock-out ( AmelxKO) mice appeared randomly organized and non-uniform compared with WT. Etching of Mmp20KO surfaces left little enamel, and the etching pattern was indistinguishable from unetched surfaces. SBS results were significantly different when AmelxKO and Mmp20KO enamel surfaces were compared. A significant increase in SBS was measured for all samples when the self-etch system was compared with the etch-and-rinse system. We have developed a novel system for testing shear bond strength of mouse incisors with AI variants, and analysis of these data may have important clinical implications for the treatment of patients with AI.
The Paradox of Better Subjective Oral Health in Older Age
Authors: Slade G.D. , Sanders A.E.
Published: September 2011

We analyzed data from the 2004-06 Australian National Survey of Adult Oral Health to investigate the paradoxical relationship of better subjective oral health in older adults compared with young or middle-aged adults. In interviews with 14,092 adults, prevalence of problems with eating or appearance was not significantly associated with age among dentate people with no denture(s). In contrast, among dentate denture-wearers, prevalence ranged from 18.7% in ≥ 65-year-olds to 46.7% in 25- to 34-year-olds (p < 0.01). Dentate interviewees (n = 3,724) underwent oral epidemiological examinations and completed the 14-item Oral Health Impact Profile (OHIP-14) questionnaire, evaluating adverse impacts of oral conditions. In multivariable analysis, mean OHIP-14 scores were only weakly associated with age among people who had none of 5 clinical conditions [≥ 5 missing teeth, denture(s), untreated decay, moderate/severe periodontitis, toothache]. However, for people with ≥ 2 clinical conditions, there was a three-fold, inverse association between age and mean OHIP-14 scores (p < 0.01). The findings show that experience of oral disease is more deleterious to subjective oral health when it occurs early in adulthood than when it occurs in old age, a pattern that likely reflects high expectations of young generations and, conversely, great resilience in Australia’s oldest generation.
Acceptance-Versus Change-Based Pain Management
Authors: Blacker Kara J. , Herbert James D. , Forman Evan M. , Kounios John
Published: September 2011

This study compared two theoretically opposed strategies for acute pain management: an acceptance-based and a change-based approach. These two strategies were compared in a within-subjects design using the cold pressor test as an acute pain induction method. Participants completed a baseline pain tolerance assessment followed by one of the two interventions and another pain tolerance test. The alternate strategy was presented in a separate, but otherwise identical, experimental session. On average, both interventions significantly increased pain tolerance relative to baseline, with no significant difference between the two intervention conditions. Baseline psychological acceptance emerged as a significant moderator of intervention efficacy; individuals with a high level of acceptance benefited significantly more from the acceptance intervention, whereas those with a low level of acceptance benefited more from the change-based intervention. Implications for increasing the effectiveness of psychotherapeutic treatments based on individual differences are discussed.
MHUI-max: An efficient algorithm for discovering high-utility itemsets from data streams
Authors: Li Hua-Fu
Published: September 2011

Online mining of utility itemsets from data streams is one of the most interesting research issues in stream data mining. Although a number of relevant approaches have been proposed in recent years, they have the drawback of producing a large number of candidate itemsets for high-utility itemset mining. In this paper, an efficient algorithm, called MHUI-max (Mining High-Utility Itemsets based on LexTree-maxHTU), is proposed for mining high-utility itemsets from data streams with fewer candidates. Based on the framework of the MHUI-max algorithm, an effective representation of item information, called TID-list, and a new lexicographical tree-based data structure, called LexTree-maxHTU, has been developed to improve the efficiency of discovering high-utility itemsets with positive profits from data streams. Experimental results show that the proposed algorithm, MHUI-max, outperforms the existing approaches, MHUI-TID and THUI-Mine, for mining high-utility itemsets from data streams over transaction-sensitive sliding windows.