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1.  Evolutionary and dispersal history of Eurasian house mice Mus musculus clarified by more extensive geographic sampling of mitochondrial DNA 
Heredity  2013;111(5):375-390.
We examined the sequence variation of mitochondrial DNA control region and cytochrome b gene of the house mouse (Mus musculus sensu lato) drawn from ca. 200 localities, with 286 new samples drawn primarily from previously unsampled portions of their Eurasian distribution and with the objective of further clarifying evolutionary episodes of this species before and after the onset of human-mediated long-distance dispersals. Phylogenetic analysis of the expanded data detected five equally distinct clades, with geographic ranges of northern Eurasia (musculus, MUS), India and Southeast Asia (castaneus, CAS), Nepal (unspecified, NEP), western Europe (domesticus, DOM) and Yemen (gentilulus). Our results confirm previous suggestions of Southwestern Asia as the likely place of origin of M. musculus and the region of Iran, Afghanistan, Pakistan, and northern India, specifically as the ancestral homeland of CAS. The divergence of the subspecies lineages and of internal sublineage differentiation within CAS were estimated to be 0.37–0.47 and 0.14–0.23 million years ago (mya), respectively, assuming a split of M. musculus and Mus spretus at 1.7 mya. Of the four CAS sublineages detected, only one extends to eastern parts of India, Southeast Asia, Indonesia, Philippines, South China, Northeast China, Primorye, Sakhalin and Japan, implying a dramatic range expansion of CAS out of its homeland during an evolutionary short time, perhaps associated with the spread of agricultural practices. Multiple and non-coincident eastward dispersal events of MUS sublineages to distant geographic areas, such as northern China, Russia and Korea, are inferred, with the possibility of several different routes.
doi:10.1038/hdy.2013.60
PMCID: PMC3806020  PMID: 23820581
mitochondrial DNA; cytochrome b; control region; phylogeography; wild house mouse
2.  Crucial role of calbindin-D28k in the pathogenesis of Alzheimer's disease mouse model 
Cell Death and Differentiation  2014;21(10):1575-1587.
Calbindin-D28k (CB), one of the major calcium-binding and buffering proteins, has a critical role in preventing a neuronal death as well as maintaining calcium homeostasis. Although marked reductions of CB expression have been observed in the brains of mice and humans with Alzheimer disease (AD), it is unknown whether these changes contribute to AD-related dysfunction. To determine the pathogenic importance of CB depletions in AD models, we crossed 5 familial AD mutations (5XFAD; Tg) mice with CB knock-out (CBKO) mice and generated a novel line CBKO·5XFAD (CBKOTg) mice. We first identified the change of signaling pathways and differentially expressed proteins globally by removing CB in Tg mice using mass spectrometry and antibody microarray. Immunohistochemistry showed that CBKOTg mice had significant neuronal loss in the subiculum area without changing the magnitude (number) of amyloid β-peptide (Aβ) plaques deposition and elicited significant apoptotic features and mitochondrial dysfunction compared with Tg mice. Moreover, CBKOTg mice reduced levels of phosphorylated mitogen-activated protein kinase (extracellular signal-regulated kinase) 1/2 and cAMP response element-binding protein at Ser-133 and synaptic molecules such as N-methyl-D-aspartate receptor 1 (NMDA receptor 1), NMDA receptor 2A, PSD-95 and synaptophysin in the subiculum compared with Tg mice. Importantly, this is the first experimental evidence that removal of CB from amyloid precursor protein/presenilin transgenic mice aggravates AD pathogenesis, suggesting that CB has a critical role in AD pathogenesis.
doi:10.1038/cdd.2014.67
PMCID: PMC4158683  PMID: 24853300
3.  Multi-profile hidden Markov model for mood, dietary intake, and physical activity in an intervention study of childhood obesity 
Statistics in medicine  2013;32(19):3314-3331.
Motivated by an application to childhood obesity data in a clinical trial, this paper describes a multi-profile hidden Markov model (HMM) that uses several temporal chains of measures respectively related to psychosocial attributes, dietary intake, and energy expenditure behaviors of adolescents in a school setting. Using these psychological and behavioral profiles, the model delineates health states from the longitudinal data set. Furthermore, a two-level regression model that takes into account the clustering effects of students within school is used to assess the effects of school- and community-based interventions and other risk factors on the transition between health states over time. The results from our study suggest that female students tend to decrease their physical activities despite a high level of anxiety about weight. The finding is consistent across intervention and control arms.
doi:10.1002/sim.5719
PMCID: PMC3710544  PMID: 23322318
latent variable; latent Markov model; longitudinal analysis; childhood obesity intervention
4.  Brentuximab vedotin does not cause clinically relevant QTc interval prolongation in patients with CD30-positive hematologic malignancies 
Purpose
Brentuximab vedotin (ADCETRIS®), an antibody–drug conjugate, comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E (MMAE). In vitro studies showed that MMAE does not interfere with hERG K+ channels at clinically relevant concentrations. In pivotal phase 2 clinical trials in patients with relapsed or refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma, brentuximab vedotin has shown substantial efficacy and an acceptable safety profile. This phase 1 open-label study was designed to evaluate the effect of brentuximab vedotin on the duration of cardiac ventricular repolarization.
Methods
Patients with CD30-positive hematologic malignancies were treated with 1.8 mg/kg brentuximab vedotin by intravenous infusion every 3 weeks for up to 16 cycles. The primary endpoint was the change from baseline to Cycle 1 Days 2, 3, and 4 in the duration of ventricular repolarization using Fridericia's corrected QT interval (QTcF).
Results
There was no clinically meaningful change from baseline in the duration of ventricular repolarization as measured by QTcF in the 46 evaluable patients out of 52 total patients treated with brentuximab vedotin. There was no evidence of treatment-emergent cardiac safety abnormalities. Brentuximab vedotin was generally well tolerated with a response rate and an adverse event profile consistent with prior studies.
Conclusion
There is no significant prolongation of the QT/QTc interval with brentuximab vedotin in patients with CD30-positive hematologic malignancies.
doi:10.1007/s00280-013-2192-z
PMCID: PMC3932653  PMID: 23719719
Brentuximab vedotin; Antibody–drug conjugate; QT interval; CD30-positive hematologic malignancies
5.  Ultrafast 3D spin-echo acquisition improves Gadolinium-enhanced MRI signal contrast enhancement 
Scientific Reports  2014;4:5061.
Long scan times of 3D volumetric MR acquisitions usually necessitate ultrafast in vivo gradient-echo acquisitions, which are intrinsically susceptible to magnetic field inhomogeneities. This is especially problematic for contrast-enhanced (CE)-MRI applications, where non-negligible T2* effect of contrast agent deteriorates the positive signal contrast and limits the available range of MR acquisition parameters and injection doses. To overcome these shortcomings without degrading temporal resolution, ultrafast spin-echo acquisitions were implemented. Specifically, a multiplicative acceleration factor from multiple spin echoes (×32) and compressed sensing (CS) sampling (×8) allowed highly-accelerated 3D Multiple-Modulation-Multiple-Echo (MMME) acquisition. At the same time, the CE-MRI of kidney with Gd-DOTA showed significantly improved signal enhancement for CS-MMME acquisitions (×7) over that of corresponding FLASH acquisitions (×2). Increased positive contrast enhancement and highly accelerated acquisition of extended volume with reduced RF irradiations will be beneficial for oncological and nephrological applications, in which the accurate in vivo 3D quantification of contrast agent concentration is necessary with high temporal resolution.
doi:10.1038/srep05061
PMCID: PMC4034007  PMID: 24863102
6.  Attentional bias modulation by reappraisal in patients with generalized anxiety disorder: an event-related potential study 
Affective states influence subsequent attention allocation. We evaluated emotional negativity bias modulation by reappraisal in patients with generalized anxiety disorder (GAD) relative to normal controls. Event-related potential (ERP) recordings were obtained, and changes in P200 and P300 amplitudes in response to negative or neutral words were noted after decreasing negative emotion or establishing a neutral condition. We found that in GAD patients only, the mean P200 amplitude after negative word presentation was much higher than after the presentation of neutral words. In normal controls, after downregulation of negative emotion, the mean P300 amplitude in response to negative words was much lower than after neutral words, and this was significant in both the left and right regions. In GAD patients, the negative bias remained prominent and was not affected by reappraisal at the early stage. Reappraisal was observed to have a lateralized effect at the late stage.
doi:10.1590/1414-431X20143622
PMCID: PMC4123837  PMID: 24863650
Reappraisal; Generalized anxiety disorder; Event-related potential; P200; P300
7.  Gaussian Mixture Model-based Classification of DCE-MRI data For Identifying Diverse Tumor Microenvironments: Preliminary Results 
NMR in biomedicine  2013;26(5):519-532.
Tumor hypoxia develops heterogeneously and affects radiation sensitivity and development of metastases. Prognostic information derived from the in vivo characterisation of the spatial distribution of hypoxic areas in solid tumors can be of value for radiation therapy planning and for monitoring early treatment response. Tumor hypoxia is caused by an imbalance between the supply and consumption of oxygen. Tumor oxygen supply is inherently linked to its vasculature and perfusion which can be evaluated by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) using the contrast agent Gd-DTPA. Thus we hypothesize that DCE-MRI data may provide surrogate information regarding tumor hypoxia. In this study, DCE-MRI data from a rat prostate tumor model were analysed with a Gaussian Mixture Model (GMM)-based classification to identify perfused, hypoxic, and necrotic areas for a total of ten tumor slices from six rats, of which one slice was used as training data for GMM classifications. The results of pattern recognition analyses were validated by comparison to corresponding Akep maps defining the perfused area (0.84±0.09 overlap), hematoxylin/eosin (H&E) stained tissue sections defining necrosis (0.64±0.15 overlap), and pimonidazole-stained sections defining hypoxia (0.72±0.17 overlap), respectively. Our preliminary data indicate the feasibility of a GMM-based classification to identify tumor hypoxia, necrosis, and perfusion/permeability from non-invasively acquired, in vivo DCE-MRI data alone, possibly obviating the need for invasive procedures, such as biopsies, or exposure to radioactivity, such as in PET exams.
doi:10.1002/nbm.2888
PMCID: PMC3706205  PMID: 23440683
DCE-MRI; hypoxia; Gaussian mixture model; preclinical prostate model; tumor microenvironments; radiation therapy
8.  Validity of the Remote Food Photography Method (RFPM) for estimating energy and nutrient intake in near real-time 
Obesity (Silver Spring, Md.)  2011;20(4):891-899.
Two studies are reported; a pilot study to demonstrate feasibility followed by a larger validity study. Study 1’s objective was to test the effect of two ecological momentary assessment (EMA) approaches that varied in intensity on the validity/accuracy of estimating energy intake with the Remote Food Photography Method (RFPM) over six days in free-living conditions. When using the RFPM, Smartphones are used to capture images of food selection and plate waste and to send the images to a server for food intake estimation. Consistent with EMA, prompts are sent to the Smartphones reminding participants to capture food images. During Study 1, energy intake estimated with the RFPM and the gold standard, doubly labeled water (DLW), were compared. Participants were assigned to receive Standard EMA Prompts (n=24) or Customized Prompts (n=16) (the latter received more reminders delivered at personalized meal times). The RFPM differed significantly from DLW at estimating energy intake when Standard (mean±SD = −895±770 kcal/day, p<.0001), but not Customized Prompts (−270±748 kcal/day, p=.22) were used. Error (energy intake from the RFPM minus that from DLW) was significantly smaller with Customized vs. Standard Prompts. The objectives of Study 2 included testing the RFPM’s ability to accurately estimate energy intake in free-living adults (N=50) over six days, and energy and nutrient intake in laboratory-based meals. The RFPM did not differ significantly from DLW at estimating free-living energy intake (−152±694 kcal/day, p=0.16). During laboratory-based meals, estimating energy and macronutrient intake with the RFPM did not differ significantly compared to directly weighed intake.
doi:10.1038/oby.2011.344
PMCID: PMC3975169  PMID: 22134199
Food Intake; Energy Intake; Dietary Intake; Dietary Assessment; Eating Behaviors
9.  Drainage Failure Because of Spontaneous Fracture of the Peritoneal Dialysis Catheter 
doi:10.3747/pdi.2012.00045
PMCID: PMC3598116  PMID: 23478378
Peritoneal dialysis catheter; spontaneous catheter fracture; drainage failure
10.  Herbicide resistance-endowing ACCase gene mutations in hexaploid wild oat (Avena fatua): insights into resistance evolution in a hexaploid species 
Heredity  2012;110(3):220-231.
Many herbicide-resistant weed species are polyploids, but far too little about the evolution of resistance mutations in polyploids is understood. Hexaploid wild oat (Avena fatua) is a global crop weed and many populations have evolved herbicide resistance. We studied plastidic acetyl-coenzyme A carboxylase (ACCase)-inhibiting herbicide resistance in hexaploid wild oat and revealed that resistant individuals can express one, two or three different plastidic ACCase gene resistance mutations (Ile-1781-Leu, Asp-2078-Gly and Cys-2088-Arg). Using ACCase resistance mutations as molecular markers, combined with genetic, molecular and biochemical approaches, we found in individual resistant wild-oat plants that (1) up to three unlinked ACCase gene loci assort independently following Mendelian laws for disomic inheritance, (2) all three of these homoeologous ACCase genes were transcribed, with each able to carry its own mutation and (3) in a hexaploid background, each individual ACCase resistance mutation confers relatively low-level herbicide resistance, in contrast to high-level resistance conferred by the same mutations in unrelated diploid weed species of the Poaceae (grass) family. Low resistance conferred by individual ACCase resistance mutations is likely due to a dilution effect by susceptible ACCase expressed by homoeologs in hexaploid wild oat and/or differential expression of homoeologous ACCase gene copies. Thus, polyploidy in hexaploid wild oat may slow resistance evolution. Evidence of coexisting non-target-site resistance mechanisms among wild-oat populations was also revealed. In all, these results demonstrate that herbicide resistance and its evolution can be more complex in hexaploid wild oat than in unrelated diploid grass weeds. Our data provide a starting point for the daunting task of understanding resistance evolution in polyploids.
doi:10.1038/hdy.2012.69
PMCID: PMC3668648  PMID: 23047200
ACCase mutation;  Acc1 ; herbicide resistance; hexaploid wild oat (Avena fatua); polyploidy; resistance evolution
11.  Galectin-1 stimulates motility of human umbilical cord blood-derived mesenchymal stem cells by downregulation of smad2/3-dependent collagen 3/5 and upregulation of NF-κB-dependent fibronectin/laminin 5 expression 
Cell Death & Disease  2014;5(2):e1049-.
Galectin-1 (Gal-1) belongs to a family of endogenous lectins with conserved carbohydrate recognition domains binding β-galactosidase sugars and plays a vital role in regulating stem cell functions including determination of cell fate. However, our understanding of the functional roles of Gal-1 in human umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) is still fragmentary and incomplete. Gal-1 significantly increased motility after a 24-h incubation, and this effect was inhibited by β-lactose. We analyzed 17 extracellular matrix (ECM) genes in UCB-MSCs. Gal-1 decreased the expression of collagen genes COL3A1 (COL-3) and COL5A1 (COL-5) but increased the expression of fibronectin (FN) and laminin 5 (LM-5), that were reversed by β-lactose. Gal-1 increased protein kinase C (PKC), c-Src, and caveolin-1 (Cav-1) phosphorylation that was attenuated by β-lactose and the Src inhibitor PP2. In addition, pretreatment with the lipid raft disruptor Mβ-CD and the PKC inhibitors inhibited Gal-1-induced UCB-MSC motility. In addition, Gal-1 reduced smad2/3 phosphorylation and induced nuclear factor (NF)-κB phosphorylation. Pretreatment with Mβ-CD attenuated Gal-1-reduced smad2/3 phosphorylation, COL-3, and COL-5 expression but did not affect NF-κB phosphorylation, FN, or LM-5 expression. In contrast, PKC inhibitors only attenuated NF-κB phosphorylation, FN, and LM-5 expression. Reconstructing Gal-1-induced genetic changes by replacing it with siRNA specific for COL-3 or COL-5, or treatment of the cells with FN and LM-5 proteins, increased motility and its related proteins such as focal adhesion kinase, Akt, Erk, integrins, and matrix metalloproteinase-2. A combined treatment with COL-3/COL-5 siRNA or FN/LM-5 compared with that of single treatments was synergistic. However, a single Gal-1 treatment maximally stimulated motility and related protein phosphorylation/expression. These results demonstrate that Gal-1 stimulated human UCB-MSC motility by decreasing COL-3/COL-5 expression and increasing FN/LM-5 expression through a PKC-dependent NF-κB and c-Src/Cav-1-dependent smad2/3 pathway that was critical for governing the activation of FAK, Akt, Erk, integrins, and MMP2.
doi:10.1038/cddis.2014.3
PMCID: PMC3944255  PMID: 24503541
umbilical cord blood-derived mesenchymal stem cells; galectin-1; extracellular matrix proteins; motility
13.  Netrin-1 protects hypoxia-induced mitochondrial apoptosis through HSP27 expression via DCC- and integrin α6β4-dependent Akt, GSK-3β, and HSF-1 in mesenchymal stem cells 
Cell Death & Disease  2013;4(3):e563-.
Netrin (Ntn) has the potential to be successfully applied as an anti-apoptotic agent with a high affinity for tissue, for therapeutic strategies of umbilical cord blood-derived mesenchymal stem cells (UCB-MSC), although the mechanism by which Ntn-1 protects hypoxic injury has yet to be identified. Therefore, the present study examined the effect of Ntn-1 on hypoxia-induced UCB-MSC apoptosis, as well as the potential underlying mechanisms of its protective effect. Hypoxia (72 h) reduced cell viability (MTT reduction, and [3H]-thymidine incorporation) and cell number, and induced apoptosis (annexin and/or PI positive), which were reversed by Ntn-1 (10 ng/ml). Moreover, Ntn-1 decreased the increase of hypoxia-induced Bax, cleaved caspase-9, and -3, but blocked the decrease of hypoxia-reduced Bcl-2. Next, in order to examine the Ntn-1-related signaling cascade in the protection of hypoxic injury, we analyzed six Ntn receptors in UCB-MSC. We identified deleted in colorectal cancer (DCC) and integrin (IN) α6β4, except uncoordinated family member (UNC) 5A–C, and neogenin. Among them, IN α6β4 only was detected in lipid raft fractions. In addition, Ntn-1 induced the dissociation of DCC and APPL-1 complex, thereby stimulating the formation of APPL-1 and Akt2 complex. Ntn-1 also reversed the hypoxia-induced decrease of Akt and glycogen synthase kinase 3β (GSK-3β) phosphorylation, which is involved in heat shock factor-1 (HSF-1) expression. Ntn-1-induced phospho-Akt and -GSK-3β were inhibited by DCC function-blocking antibody, IN a6b4 function-blocking antibody, and the Akt inhibitor. Hypoxia and/or Ntn-1 stimulated heat shock protein (HSP)27 expression, which was blocked by HSF-1-specific small interfering RNA (siRNA). Furthermore, HSP27-specific siRNA reversed the Ntn-1-induced increase of phospho-Akt. Additionally, HSP27-specific siRNA attenuated the Ntn-1-reduced loss of mitochondrial membrane injury via the inhibition of cytochrome c (cyt c) release and formation of cyt c and HSP27 complex. Moreover, the inhibition of each signaling protein attenuated Ntn-1-induced blockage of apoptosis. In conclusion, Ntn-1-induced HSP27 protected hypoxic injury-related UCB-MSC apoptosis through DCC- and IN α6β4-dependent Akt, GSK-3β, and HSF-1 signaling pathways.
doi:10.1038/cddis.2013.94
PMCID: PMC3615739  PMID: 23538444
umbilical cord blood-derived mesenchymal stem cell; netrin-1; hypoxic injury; apoptosis; cytoprotection; heat shock protein
14.  Effect of an Environmental School-based Obesity Prevention Program On Changes in Body Fat and Body Weight: A Randomized Trial 
Obesity (Silver Spring, Md.)  2012;20(8):1653-1661.
This study tested the efficacy of two school-based programs for prevention of body weight/fat gain in comparison to a control group, in all participants and in overweight children. The Louisiana (LA) Health study utilized a longitudinal, cluster randomized 3-arm controlled design, with 28 months of follow-up. Children (N=2060; M age = 10.5 years, SD = 1.2) from rural communities in Grades 4 to 6 participated in the study. 17 school clusters (M = 123 children/cluster) were randomly assigned to one of three prevention arms: 1) Primary Prevention (PP), an environmental modification program, 2) Primary + Secondary Prevention (PP+SP), the environmental program with an added classroom and internet education component, or 3) Control (C). Primary outcomes were changes in percent body fat and body mass index z scores. Secondary outcomes were changes in behaviors related to energy balance. Comparisons of PP, PP+SP, and C on changes in body fat and BMI z scores found no differences. PP and PP+SP study arms were combined to create an environmental modification arm (EM). Relative to C, EM decreased body fat for boys (−1.7% ± 0.38% versus −0.14% ± 0.69%) and attenuated fat gain for girls (2.9% ± 0.22% versus 3.93% ± 0.37%), but standardized effect sizes were relatively small (< 0.30). In conclusion, this school-based environmental modification programs had modest beneficial effects on changes in percent body fat. Addition of a classroom/internet program to the environmental program did not enhance weight/fat gain prevention, but did impact physical activity and social support in overweight children.
doi:10.1038/oby.2012.60
PMCID: PMC3374922  PMID: 22402733
15.  Targeting the Myostatin Signaling Pathway to Treat Muscle Wasting Diseases 
Purpose of review
To understand mechanisms of muscle wasting and how inhibiting myostatin signaling affects them.
Recent findings
Myostatin signaling is critical for understanding the pathogenesis of muscle wasting since blocking it mitigates muscle losses in rodent models of catabolic diseases including cancer, chronic kidney or heart failure.
Summary
Muscle wasting increases the risks of morbidity and mortality. But, the reliability of estimates of the degree of muscle wasting is controversial as are definitions of terms like cachexia. Much has been learned about the pathophysiology of muscle wasting, including the major role of the ubiquitin-proteasome system (UPS) which along with other proteases degrades protein and limits protein synthesis. In contrast, few successful strategies for reversing muscle loss have been tested.
Several catabolic conditions are characterized by inflammation, increased glucocorticoid production and impaired intracellular signaling in response to insulin and IGF-1. These characteristics lead to activation of the UPS and other proteases producing muscle wasting. Another potential initiator of muscle wasting is myostatin and its expression is increased in muscles of animal models and patients with certain catabolic conditions. Myostatin is a member of the TGF-β family; it suppresses muscle growth and its absence stimulates muscle growth substantially. Recently, pharmacologic suppression of myostatin was found to counteract inflammation, increased glucocorticoids and impaired insulin/IGF-1 signaling and most importantly, prevents muscle wasting in rodent models of cancer and kidney failure. Myostatin antagonism as a therapy for patients with muscle wasting should become a topic of clinical investigation.
doi:10.1097/SPC.0b013e32834bddf9
PMCID: PMC3273421  PMID: 22025090
Myostatin; activin A; ActRIIB; Smad; Foxo; muscle wasting; cancer; chronic kidney disease; heart failure; ubiquitin-proteasome system; muscle protein breakdown; protein degradation
16.  Establishment of Eimeria tenella (local isolate) in chicken embryos 
Development of an in vitro Eimeria (E.) tenella model could be valuable as a tool for vaccine, coccidiostats or molecular biology research. 1.0 × 104 sporozoites per 0.1 mL were inoculated into the allantoic cavity of ten-day-old chicken embryos. The complete lifecycle of E. tenella was accomplished in eight-nine days at 37 °C and 70% humidity. The addition of 100 U insulin to the embryos could remarkably improve the output of oocysts. The development of the parasite within the embryos was systematically observed, allowing guidelines to be set regarding the appropriate times at which different developmental stages of the parasite may be sampled.
doi:10.1051/parasite/2012193285
PMCID: PMC3671444  PMID: 22910673
Eimeria tenella; chicken; embryo; in vitro cultivation; vaccine; Eimeria tenella; poulet; embryon; culture in vitro; vaccin
17.  Neuromuscular pharmacodynamics of mivacurium in adults with major burns 
BJA: British Journal of Anaesthesia  2011;106(5):675-679.
Background
Mivacurium is metabolized by plasma pseudocholinesterase (PChE) enzyme, which is decreased in burns. We tested whether the decreased metabolism of mivacurium due to decreased PChE activity can overcome the pharmacodynamic resistance to non-depolarizing relaxants previously seen in major burns.
Methods
Thirty adults with 35 (13)% [mean (sd)] burn were studied at 5–91 post-burn days and 31 non-burns matched controls. Mivacurium 0.2 mg kg−1 was administered as a single bolus. Neuromuscular block was monitored with single-twitch response using TOF-Watch™. Onset time (drug administration to maximal twitch suppression) and spontaneous recovery were measured.
Results
Onset time was significantly prolonged in burns when compared with non-burns (115 vs 90 s; P<0.001). The PChE levels were lower in burns [1432 (916) vs 2866 (731) IU litre−1; P<0.001] and the neuromuscular recovery to 50% of baseline twitch height was prolonged in burns (41 vs 26 min; P<0.001). There was a significant correlation between PChE and time to 50% recovery for the whole group together (r=−0.6; P<0.001). The dibucaine numbers were not different.
Conclusions
The prolonged onset time suggests resistance to neuromuscular effects, whereas the prolonged recovery suggests increased sensitivity. This divergent response can be explained by qualitative and quantitative changes in acetylcholine receptor expression causing resistance and decreased PChE activity causing sensitivity. Despite using a relatively large dose of mivacurium (0.2 mg kg−1) in the presence of decreased PChE levels, this did not overcome the resistance resulting from up-regulated receptors.
doi:10.1093/bja/aer023
PMCID: PMC3077750  PMID: 21354998
neuromuscular relaxants, mivacurium; pharmacodynamics; trauma, burns
18.  Longitudinal Study of Body Weight Changes in Children: Who is Gaining and Who is Losing Weight 
Obesity (Silver Spring, Md.)  2010;19(3):667-670.
Cross-sectional studies have reported significant temporal increases in prevalence of childhood obesity in both genders and various racial groups, but recently the rise has subsided. Childhood obesity prevention trials suggest that, on average, overweight/obese children lose body weight and non-overweight children gain weight. This investigation tested the hypothesis that overweight children lose body weight/fat and non-overweight children gain body weight/fat using a longitudinal research design that did not include an obesity prevention program. The participants were 451 children in 4th to 6th grades at baseline. Height, weight, and body fat were measured at Month 0 and Month 28. Each child’s body mass index (BMI) percentile score was calculated specific for their age, gender and height. Higher BMI percentile scores and percent body fat at baseline were associated with larger decreases in BMI and percent body fat after 28 months. The BMI percentile mean for African-American girls increased whereas BMI percentile means for white boys and girls and African-American boys were stable over the 28 month study period. Estimates of obesity and overweight prevalence were stable because incidence and remission were similar. These findings support the hypothesis that overweight children tend to lose body weight and non-overweight children tend to gain body weight.
doi:10.1038/oby.2010.221
PMCID: PMC3026913  PMID: 20885393
childhood obesity; longitudinal study; prevalence; incidence; remission
19.  Accelerometry measured ethnic differences in activity in rural adolescents 
Background
To determine if there are differences in time spent in physical activity and sedentary behavior between African American and Caucasian children.
Methods
Children wore accelerometers for three weekdays. The students were randomly selected from a larger sample of children participating in a weight gain prevention intervention. Usable data was obtained from 272 of the 310 students who agreed to participate. The outcome data included counts per minute (CPM), time spent in moderate to vigorous (MVPA), light (LPA), and sedentary (SED) activity. The equation and cutoff used to analyze national accelerometry data were utilized for the current study.
Results
The sample had an average age of 10.4 (1.1) years and 76% were African American. Lower SES African American boys had more CPM (p = .012) and spent more time in MVPA (p = .008) compared to middle SES African American and lower SES Caucasian children. Lower SES African American children also spent fewer minutes in SED activity (p = .044) compared to middle SES African American children.
Conclusions
These findings support recent results that also used objective activity measures. Children appeared less active and more sedentary than a national sample, warranting interventions in minority and rural populations.
PMCID: PMC3074436  PMID: 21415456
Activity monitors; African American; children; exercise; sedentary
20.  Myostatin blockage using actRIIB antagonism in mice bearing the Lewis lung carcinoma results in the improvement of muscle wasting and physical performance 
Background
Cachexia is a multiorganic syndrome associated with cancer, characterized by body weight loss, muscle and adipose tissue wasting and inflammation.
Methods
The aim of this investigation was to examine the effect of the soluble receptor antagonist of myostatin (sActRIIB) in cachectic tumor-bearing animals analyzing changes in muscle proteolysis and in quality of life.
Results
Administration of sActRIIB resulted in an improvement in body and muscle weights. Administration of the soluble receptor antagonist of myostatin also resulted in an improvement in the muscle force.
Conclusions
These results suggest that blocking myostatin pathway could be a promising therapeutic strategy for the treatment of cancer cachexia.
doi:10.1007/s13539-011-0049-z
PMCID: PMC3302990  PMID: 22450815
Myostatin; Cancer cachexia; Skeletal muscle; Physical activity; Muscle force; Ubiquitin
21.  Myostatin blockage using actRIIB antagonism in mice bearing the Lewis lung carcinoma results in the improvement of muscle wasting and physical performance 
Background
Cachexia is a multiorganic syndrome associated with cancer, characterized by body weight loss, muscle and adipose tissue wasting and inflammation.
Methods
The aim of this investigation was to examine the effect of the soluble receptor antagonist of myostatin (sActRIIB) in cachectic tumor-bearing animals analyzing changes in muscle proteolysis and in quality of life.
Results
Administration of sActRIIB resulted in an improvement in body and muscle weights. Administration of the soluble receptor antagonist of myostatin also resulted in an improvement in the muscle force.
Conclusions
These results suggest that blocking myostatin pathway could be a promising therapeutic strategy for the treatment of cancer cachexia.
doi:10.1007/s13539-011-0049-z
PMCID: PMC3302990  PMID: 22450815
Myostatin; Cancer cachexia; Skeletal muscle; Physical activity; Muscle force; Ubiquitin
22.  Change in food cravings, food preferences, and appetite during a low-carbohydrate and low-fat diet 
Obesity (Silver Spring, Md.)  2011;19(10):1963-1970.
The study objective was to evaluate the effect of prescribing a low-carbohydrate diet (LCD) and a low-fat diet (LFD) on food cravings, food preferences, and appetite. Obese adults were randomly assigned to a LCD (n=134) or a LFD (n=136) for two years. Cravings for specific types of foods (sweets, high-fats, fast-food fats, carbohydrates/starches); preferences for high-sugar, high-carbohydrate, and low-carbohydrate/high-protein foods; and appetite were measured during the trial and evaluated during this secondary analysis of trial data. Differences between the LCD and LFD on change in outcome variables were examined with mixed linear models. Compared to the LFD, the LCD had significantly larger decreases in cravings for carbohydrates/starches and preferences for high-carbohydrate and high-sugar foods. The LCD group reported being less bothered by hunger compared to the LFD group. Compared to the LCD group, the LFD group had significantly larger decreases in cravings for high-fat foods and preference for low-carbohydrate/high-protein foods. Men had larger decreases in appetite ratings compared to women. Prescription of diets that promoted restriction of specific types of foods resulted in decreased cravings and preferences for the foods that were targeted for restriction. The results also indicate that the LCD group was less bothered by hunger compared to the LFD group and that men had larger reductions in appetite compared to women.
doi:10.1038/oby.2011.62
PMCID: PMC3139783  PMID: 21494226
low-carbohydrate diet; weight loss; diet; hunger; macronutrient composition
23.  Cell Imaging and Analysis Network (CIAN)—Multi-Platform Resources and Services 
The Cell Imaging and Analysis Network (CIAN) provides services and tools to researchers in the field of cell biology from within or outside Montreal's McGill University community. CIAN is composed of six scientific platforms: Cell Imaging (confocal and fluorescence microscopy; walk-up), Proteomics (2-D, DiGE and fluorescent protein analysis; walk-up), Automation and High throughput screening (Pinning robot and liquid handler; full service), Protein expression and antibody production (in collaboration with local animal facilities; full service), Genomics (real-time PCR; walk-up), and Data storage/analysis (cluster, server and workstations). Users get in-depth consultation for proposed projects, and can obtain training in any of the walk-up aspects of the facility, or take advantage of the full-service platforms. CIAN is designed to facilitate training, enhance interactions, as well as share and maintain resources and expertise.
PMCID: PMC3186647
24.  Body Image Changes Associated with Participation in an Intensive Lifestyle Weight Loss Intervention 
Obesity (Silver Spring, Md.)  2010;19(6):1290-1295.
The primary aim of this study was to test for changes in body image in men and women enrolled in the Look AHEAD trial. Look AHEAD (Action for Health in Diabetes) is a multi-center, randomized controlled trial designed to test whether intentional weight loss reduces cardiovascular morbidity and mortality in overweight individuals with type 2 diabetes. Participants included 157 adults at one site (Pennington Biomedical Research Center) of the Look AHEAD study. At baseline, the mean body mass index (BMI) of the female participants was 36.4, and the mean BMI for males was 33.5. Following baseline assessment, participants were randomly assigned to the Intensive Lifestyle intervention (ILI, n = 81) or Diabetes Support and Education (DSE, n = 76). The Body Morph Assessment version 2.0 (BMA 2.0) was used to assess estimates of perceived current body size, ideal body size, acceptable body size, and body image dissatisfaction at baseline and one year. Over the 1 year, participants in the ILI group had significantly greater reductions in weight (10.1% for men and 8.9% for women) than those in the DSE group (+ 0.8% for men and −0.2%, for women). Perceived current body size was reduced significantly more in both men and women in the ILI group, relative to DSE. There were also significantly greater reductions in body image dissatisfaction in the ILI group, relative to the DSE group for men and women. The results of this study indicate that body image dissatisfaction improved following participation in an intensive behavioral weight loss program.
doi:10.1038/oby.2010.276
PMCID: PMC3102126  PMID: 21151020
Body Image; Obesity; Diabetes; Weight loss; Lifestyle Intervention
25.  High performance liquid chromatographic analysis and anticancer potential of Oplopanax horridus: Comparison of stem and berry extracts 
Fitoterapia  2009;81(2):132.
Oplopanax horridus or devil’s club is a herbal medicine distributed in North America. The constituents and pharmacological activities of O. horridus (OPH) are largely unknown. In this study, we assayed OPH stem and berry extracts using high performance liquid chromatography (HPLC). The anticancer potentials of extracts on different human cancer cell lines (SW-480, HCT-116, HT-29, MCF-7 and NSCLC) were determined by MTS method. The effect of stem extract on cancer cell cycle, expression of cyclin A, and apoptosis were assayed using flow cytometry. HPLC data showed that the composition of OPH stem extract is more complicated than the berry extract. The wavelength of maximum absorption of the major constituent in stem and berry is 196.0 nm and 201.9 nm, respectively. Compared to the berry extract, the stem extract showed significant potent antiproliferative effect on all the studied cell lines. The stem extract at 0.1 mg/ml arrested cancer cells in S- and G2/M-phases, and significantly induced expression of cyclin A. After treatment with 0.1 mg/ml of stem extract for 72 h, apoptotic cells were increased to 45.2%, while control was 9.6%. The cell cycle arrest and induction of apoptosis may play a critical role in cancer chemoprevention by Oplopanax horridus stem extract.
doi:10.1016/j.fitote.2009.08.003
PMCID: PMC2814987  PMID: 19686820
Oplopanax horridus; devil’s club; HPLC analysis; cancer chemoprevention; cell cycle; apoptosis

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