bluuebunny/crossref_metadata_2025 huggingface dataset:
Transdifferentiation from cornea to lens in Xenopus laevis depends on BMP signalling and involves upregulation of Wnt signalling
Authors: Day Robert C , Beck Caroline W
Published: September 2011

Background

Surgical removal of the lens from larval Xenopus laevis results in a rapid transdifferention of central corneal cells to form a new lens. The trigger for this process is understood to be an induction event arising from the unprecedented exposure of the cornea to the vitreous humour that occurs following lens removal. The molecular identity of this trigger is unknown.

Results

Here, we have used a functional transgenic approach to show that BMP signalling is required for lens regeneration and a microarray approach to identify genes that are upregulated specifically during this process. Analysis of the array data strongly implicates Wnt signalling and the Pitx family of transcription factors in the process of cornea to lens transdifferentiation. Our analysis also captured several genes associated with congenital cataract in humans. Pluripotency genes, in contrast, were not upregulated, supporting the idea that corneal cells transdifferentiate without returning to a stem cell state. Several genes from the array were expressed in the forming lens during embryogenesis. One of these, Nipsnap1, is a known direct target of BMP signalling.

Conclusions

Our results strongly implicate the developmental Wnt and BMP signalling pathways in the process of cornea to lens transdifferentiation (CLT) in Xenopus, and suggest direct transdifferentiation between these two anterior eye tissues.
Comprehensive SNP array study of frequently used neuroblastoma cell lines; copy neutral loss of heterozygosity is common in the cell lines but uncommon in primary tumors
Authors: Kryh Hanna , Carén Helena , Erichsen Jennie , Sjöberg Rose-Marie , Abrahamsson Jonas , Kogner Per , Martinsson Tommy
Published: September 2011

Background

Copy neutral loss of heterozygosity (CN-LOH) refers to a special case of LOH occurring without any resulting loss in copy number. These alterations is sometimes seen in tumors as a way to inactivate a tumor suppressor gene and have been found to be important in several types of cancer.

Results

We have used high density single nucleotide polymorphism arrays in order to investigate the frequency and distribution of CN-LOH and other allelic imbalances in neuroblastoma (NB) tumors and cell lines. Our results show that the frequency of these near-CN-LOH events is significantly higher in the cell lines compared to the primary tumors and that the types of CN-LOH differ between the groups. We also show that the low-risk neuroblastomas that are generally considered to have a "triploid karyotype" often present with a complex numerical karyotype (no segmental changes) with 2-5 copies of each chromosome. Furthermore a comparison has been made between the three related cell lines SK-N-SH, SH-EP and SH-SY5Y with respect to overall genetic aberrations, and several aberrations unique to each of the cell lines has been found.

Conclusions

We have shown that the NB tumors analyzed contain several interesting allelic imbalances that would either go unnoticed or be misinterpreted using other genome-wide techniques. These findings indicate that the genetics underlying NB might be even more complex than previously known and that SNP arrays are important analysis tools. We have also showed that these near-CN-LOH events are more frequently seen in NB cell lines compared to NB tumors and that a set of highly related cell lines have continued to evolve secondary to the subcloning event. Taken together our analysis highlights that cell lines in many cases differ substantially from the primary tumors they are thought to represent, and that caution should be taken when drawing conclusions from cell line-based studies.
Peer-based behavioral health program for drug users in China: a pilot study
Authors: Shen Song-Ying , Zhang Zhou-Bin , Tucker Joseph D , Chang Helena , Zhang Guan-Rong , Lin Ai-Hua
Published: September 2011

Background

Many injection drug users (IDUs) in China have high risk sexual behaviors that contribute to the spread of HIV infection. Although many IDUs in China move through drug rehabilitation centers, this opportunity for sexual health education has largely been overlooked.

Methods

A convenience sample of 667 drug users from two rehabilitation centers in South China was recruited in the study. Two hundred and forty seven drug users from a single Guangdong Province rehabilitation center received the peer-based education intervention, while 420 drug users from another rehabilitation center received routine HIV/STI education and was used as the control. One hundred and eighty nine (22.1%) individuals refused to participate in the study. HIV/STI behavioral and knowledge domains were assessed at 3 months in rehabilitation centers after the intervention (first follow-up) and at 2-23 months in the community after release (second follow-up).

Results

Drug users who completed the intervention reported more frequent condom use with casual sex partners (60.0% vs. 12.5% condom use every time, p = 0.011) and less frequent injection (56.7% vs. 26.4% no injection per day, p = 0.008) at the second follow-up compared to those in the routine education group. Loss to follow up was substantial in both control and intervention groups, and was associated with living far from the detention center and having poor HIV knowledge at baseline.

Conclusions

This study shows that rehabilitation centers may be a useful location for providing behavioral HIV/STI prevention services and referral of individuals to community-based programs upon release. More research is needed on behalf of detained drug users in China who have complex social, medical, and legal needs.
Effect of cinnamon on gastric emptying, arterial stiffness, postprandial lipemia, glycemia, and appetite responses to high-fat breakfast
Authors: Markey Oonagh , McClean Conor M , Medlow Paul , Davison Gareth W , Trinick Tom R , Duly Ellie , Shafat Amir
Published: September 2011

Background

Cinnamon has been shown to delay gastric emptying of a high-carbohydrate meal and reduce postprandial glycemia in healthy adults. However, it is dietary fat which is implicated in the etiology and is associated with obesity, type 2 diabetes and cardiovascular disease. We aimed to determine the effect of 3 g cinnamon (Cinnamomum zeylanicum) on GE, postprandial lipemic and glycemic responses, oxidative stress, arterial stiffness, as well as appetite sensations and subsequent food intake following a high-fat meal.

Methods

A single-blind randomized crossover study assessed nine healthy, young subjects. GE rate of a high-fat meal supplemented with 3 g cinnamon or placebo was determined using the 13C octanoic acid breath test. Breath, blood samples and subjective appetite ratings were collected in the fasted and during the 360 min postprandial period, followed by an ad libitum buffet meal. Gastric emptying and 1-day fatty acid intake relationships were also examined.

Results

Cinnamon did not change gastric emptying parameters, postprandial triacylglycerol or glucose concentrations, oxidative stress, arterial function or appetite (p < 0.05). Strong relationships were evident (p < 0.05) between GE Thalf and 1-day palmitoleic acid (r = -0.78), eiconsenoic acid (r = -0.84) and total omega-3 intake (r = -0.72). The ingestion of 3 g cinnamon had no effect on GE, arterial stiffness and oxidative stress following a HF meal.

Conclusions

3 g cinnamon did not alter the postprandial response to a high-fat test meal. We find no evidence to support the use of 3 g cinnamon supplementation for the prevention or treatment of metabolic disease. Dietary fatty acid intake requires consideration in future gastrointestinal studies.

Trial registration

Trial registration number: at http://www.clinicaltrial.gov: NCT01350284
Recent increase of genetic diversity in Plasmodium vivax population in the Republic of Korea
Authors: Honma Hajime , Kim Jung-Yeon , Palacpac Nirianne MQ , Mita Toshihiro , Lee Wonja , Horii Toshihiro , Tanabe Kazuyuki
Published: September 2011

Background

The reemergence of Plasmodium vivax in South Korea since 1993 represents a serious public health concern. Despite the importance in understanding genetic diversity for control strategies, however, studies remain inconclusive with the general premise that due to low rate of malaria transmission, there is generally low genetic diversity with very few strains involved. In this study, the genetic diversity and population structure of P. vivax in South Korea were explored by analysing microsatellite polymorphism.

Methods

Sequences for 13 microsatellite loci distributed across the twelve chromosomes of P. vivax were obtained from 58 South Korean isolates collected during two sampling periods, namely 1997-2000 and 2007. The sequences were used for the analysis of expected heterozygosity and multilocus genotype diversity. Population structure was evaluated using STRUCTURE version 2.3.2. Linkage disequilibrium was also analysed to investigate the extent of outbreeding in the P. vivax population.

Results

Mean expected heterozygosity significantly increased from 0.382 in 1997-2000 to 0.545 in 2007 (P < 0.05). The number of multilocus genotypes was 7 and 27; and genotype diversity was statistically significant (P < 0.01) at 0.661 and 0.995 in 1997-2000 and 2007, respectively. Analysis by STRUCTURE showed a more complex population structure in 2007 than in 1997-2000. Linkage disequilibrium between 13 microsatellites, although significant in both time points, was notably lower in 2007.

Conclusions

The present microsatellite analysis clearly showed recent increase of genetic diversity and recent relaxation of the strong population structure observed in 1997-2000. These results suggest that multiple genotypes not present previously recently migrated into South Korea, accompanied by substantial outbreeding between different genotypes.
Identification of H-2d Restricted T Cell Epitope of Foot-and-mouth Disease Virus Structural Protein VP1
Authors: Liu Xin-Sheng , Wang Yong-Lu , Zhang Yong-Guang , Fang Yu-Zhen , Pan Li , Lu Jian-Liang , Zhou Peng , Zhang Zhong-Wang , Jiang Shou-Tian
Published: September 2011

Background

Foot-and-mouth disease (FMD) is a highly contagious and devastating disease affecting livestock that causes significant financial losses. Therefore, safer and more effective vaccines are required against Foot-and-mouth disease virus(FMDV). The purpose of this study is to screen and identify an H-2d restricted T cell epitope from the virus structural protein VP1, which is present with FMD. We therefore provide a method and basis for studying a specific FMDV T cell epitope.

Results

A codon-optimized expression method was adopted for effective expression of VP1 protein in colon bacillus. We used foot-and-mouth disease standard positive serum was used for Western blot detection of its immunogenicity. The VP1 protein was used for immunizing BALB/c mice, and spleen lymphocytes were isolated. Then, a common in vitro training stimulus was conducted for potential H-2Dd, H-2Kd and H-2Ld restricted T cell epitope on VP1 proteins that were predicted and synthesized by using a bioinformatics method. The H-2Kd restricted T cell epitope pK1 (AYHKGPFTRL) and the H-2Dd restricted T cell epitope pD7 (GFIMDRFVKI) were identified using lymphocyte proliferation assays and IFN-γ ELISPOT experiments.

Conclusions

The results of this study lay foundation for studying the FMDV immune process, vaccine development, among other things. These results also showed that, to identify viral T cell epitopes, the combined application of bioinformatics and molecular biology methods is effective.
Heterologous prime-boost-boost immunisation of Chinese cynomolgus macaques using DNA and recombinant poxvirus vectors expressing HIV-1 virus-like particles
Authors: Bridge Simon H , Sharpe Sally A , Dennis Mike J , Dowall Stuart D , Getty Brian , Anson Donald S , Skinner Michael A , Stewart James P , Blanchard Tom J
Published: September 2011

Background

There is renewed interest in the development of poxvirus vector-based HIV vaccines due to the protective effect observed with repeated recombinant canarypox priming with gp120 boosting in the recent Thai placebo-controlled trial. This study sought to investigate whether a heterologous prime-boost-boost vaccine regimen in Chinese cynomolgus macaques with a DNA vaccine and recombinant poxviral vectors expressing HIV virus-like particles bearing envelopes derived from the most prevalent clades circulating in sub-Saharan Africa, focused the antibody response to shared neutralising epitopes.

Methods

Three Chinese cynomolgus macaques were immunised via intramuscular injections using a regimen composed of a prime with two DNA vaccines expressing clade A Env/clade B Gag followed by boosting with recombinant fowlpox virus expressing HIV-1 clade D Gag, Env and cholera toxin B subunit followed by the final boost with recombinant modified vaccinia virus Ankara expressing HIV-1 clade C Env, Gag and human complement protein C3d. We measured the macaque serum antibody responses by ELISA, enumerated T cell responses by IFN-γ ELISpot and assessed seroneutralisation of HIV-1 using the TZM-bl β-galactosidase assay with primary isolates of HIV-1.

Results

This study shows that large and complex synthetic DNA sequences can be successfully cloned in a single step into two poxvirus vectors: MVA and FPV and the recombinant poxviruses could be grown to high titres. The vaccine candidates showed appropriate expression of recombinant proteins with the formation of authentic HIV virus-like particles seen on transmission electron microscopy. In addition the b12 epitope was shown to be held in common by the vaccine candidates using confocal immunofluorescent microscopy. The vaccine candidates were safely administered to Chinese cynomolgus macaques which elicited modest T cell responses at the end of the study but only one out of the three macaques elicited an HIV-specific antibody response. However, the antibodies did not neutralise primary isolates of HIV-1 or the V3-sensitive isolate SF162 using the TZM-bl β-galactosidase assay.

Conclusions

MVA and FP9 are ideal replication-deficient viral vectors for HIV-1 vaccines due to their excellent safety profile for use in humans. This study shows this novel prime-boost-boost regimen was poorly immunogenic in Chinese cynomolgus macaques.
Deciphering the role of Epstein-Barr virus in the pathogenesis of T and NK cell lymphoproliferations
Authors: Fox Christopher P , Shannon-Lowe Claire , Rowe Martin
Published: September 2011

Epstein-Barr virus (EBV) is a highly successful herpesvirus, colonizing more than 90% of the adult human population worldwide, although it is also associated with various malignant diseases. Primary infection is usually clinically silent, and subsequent establishment of latency in the memory B lymphocyte compartment allows persistence of the virus in the infected host for life. EBV is so markedly B-lymphotropic when exposed to human lymphocytesin vitrothat the association of EBV with rare but distinct types of T and NK cell lymphoproliferations was quite unexpected. Whilst relatively rare, these EBV-associated T and NK lymphoproliferations can be therapeutically challenging and prognosis for the majority of patients is dismal. In this review, we summarize the current knowledge on the role of EBV in the pathogenesis of these tumours, and the implications for treatment.
Quantifying the effect of environment stability on the transcription factor repertoire of marine microbes
Authors: Kostadinov Ivaylo , Kottmann Renzo , Ramette Alban , Waldmann Jost , Buttigieg Pier Luigi , Glöckner Frank Oliver
Published: September 2011

Background

DNA-binding transcription factors (TFs) regulate cellular functions in prokaryotes, often in response to environmental stimuli. Thus, the environment exerts constant selective pressure on the TF gene content of microbial communities. Recently a study on marine Synechococcus strains detected differences in their genomic TF content related to environmental adaptation, but so far the effect of environmental parameters on the content of TFs in bacterial communities has not been systematically investigated.

Results

We quantified the effect of environment stability on the transcription factor repertoire of marine pelagic microbes from the Global Ocean Sampling (GOS) metagenome using interpolated physico-chemical parameters and multivariate statistics. Thirty-five percent of the difference in relative TF abundances between samples could be explained by environment stability. Six percent was attributable to spatial distance but none to a combination of both spatial distance and stability. Some individual TFs showed a stronger relationship to environment stability and space than the total TF pool.

Conclusions

Environmental stability appears to have a clearly detectable effect on TF gene content in bacterioplanktonic communities described by the GOS metagenome. Interpolated environmental parameters were shown to compare well to in situ measurements and were essential for quantifying the effect of the environment on the TF content. It is demonstrated that comprehensive and well-structured contextual data will strongly enhance our ability to interpret the functional potential of microbes from metagenomic data.
Age, Breast Cancer Subtype Approximation, and Local Recurrence After Breast-Conserving Therapy
Authors: Arvold Nils D. , Taghian Alphonse G. , Niemierko Andrzej , Abi Raad Rita F. , Sreedhara Meera , Nguyen Paul L. , Bellon Jennifer R. , Wong Julia S. , Smith Barbara L. , Harris Jay R.
Published: September 2011

Purpose

Prior results of breast-conserving therapy (BCT) have shown substantial rates of local recurrence (LR) in young patients with breast cancer (BC).

Patients and Methods

We studied 1,434 consecutive patients with invasive BC who received BCT from December 1997 to July 2006. Ninety-one percent received adjuvant systemic therapy; no patients received trastuzumab. Five BC subtypes were approximated: estrogen receptor (ER) or progesterone receptor (PR) positive, HER2 negative, and grades 1 to 2 (ie, luminal A); ER positive or PR positive, HER2 negative, and grade 3 (ie, luminal B); ER or PR positive, and HER2 positive (ie, luminal HER2); ER negative, PR negative, and HER2 positive (ie, HER2); and ER negative, PR negative, and HER2 negative (ie, triple negative). Actuarial rates of LR were calculated by using the Kaplan-Meier method.

Results

Median follow-up was 85 months. Overall 5-year cumulative incidence of LR was 2.1% (95% CI, 1.4% to 3.0%). The 5-year cumulative incidence of LR was 5.0% (95% CI, 3.0% to 8.3%) for age quartile 23 to 46 years; 2.2% (95% CI, 1.0% to 4.6%) for ages 47 to 54 years; 0.9% (95% CI, 0.3% to 2.6%) for ages 55 to 63 years; and 0.6% (95% CI, 0.1% to 2.2%) for ages 64 to 88 years. The 5-year cumulative incidence of LR was 0.8% (95% CI, 0.4% to 1.8%) for luminal A; 2.3% (95% CI, 0.8% to 5.9%) for luminal B; 1.1% (95% CI, 0.2% 7.4%) for luminal HER2; 10.8% (95% CI, 4.6% to 24.4%) for HER2; and 6.7% (95% CI, 3.6% to 12.2%) for triple negative. On multivariable analysis, increasing age was associated with decreased risk of LR (adjusted hazard ratio, 0.97; 95% CI, 0.94 to 0.99; P = .009).

Conclusion

In the era of systemic therapy and BC subtyping, age remains an independent prognostic factor after BCT. However, the risk of LR for young women appears acceptably low.
Diacerhein Improves Glucose Tolerance and Insulin Sensitivity in Mice on a High-Fat Diet
Authors: Tobar Natália , Oliveira Alexandre G. , Guadagnini Dioze , Bagarolli Renata A. , Rocha Guilherme Z. , Araújo Tiago G. , Santos-Silva Junia C. , Zollner Ricardo L. , Boechat Luiz H. B. , Carvalheira José B. C. , Prada Patrícia O. , Saad Mario J. A.
Published: September 2011

Obesity and type 2 diabetes are characterized by insulin resistance, and the common basis of these events is a chronic and systemic inflammatory process marked by the activation of the c-Jun N-terminal kinase (JNK) and inhibitor-κB kinase (IKKβ)/nuclear factor-κB (NFκB) pathways, up-regulated cytokine synthesis, and endoplasmic reticulum dysfunction. The aim of this study was to evaluate the effects of diacerhein administration, an antiinflammatory drug that reduces the levels of inflammatory cytokines, on insulin sensitivity and signaling in diet-induced obese (DIO) mice. Swiss mice were fed with conventional chow (control group) or a high-fat diet (DIO group). Later, DIO mice were randomly subdivided into a new subgroup (DAR) that received 20 mg/kg diacerhein for 10 d. Western blotting was used to quantify the expression and phosphorylation of insulin receptor, insulin receptor substrate 1, and Akt and of inflammatory mediators that modulate insulin signaling in a negative manner (IKKβ, JNK, and inducible nitric oxide synthase). We show here, for the first time, that the administration of diacerhein in DIO mice improved endoplasmic reticulum stress, reduced JNK and IKKβ phosphorylation, and resulted in a marked improvement in fasting glucose, a decrease in macrophage infiltration in adipose tissue, and a reduced expression and activity of proinflammatory mediators accompanied by an improvement in the insulin signaling mainly in the liver and adipose tissue. Taken together, these results indicate that diacerhein treatment improves insulin sensitivity in obesity, mediated by the reversal of subclinical inflammation, and that this drug may be an alternative therapy for insulin resistance.
The control of developmental phase transitions in plants
Authors: Huijser Peter , Schmid Markus
Published: September 2011

Plant development progresses through distinct phases: vegetative growth, followed by a reproductive phase and eventually seed set and senescence. The transitions between these phases are controlled by distinct genetic circuits that integrate endogenous and environmental cues. In recent years, however, it has become evident that the genetic networks that underlie these phase transitions share some common factors. Here, we review recent advances in the field of plant phase transitions, highlighting the role of two microRNAs – miR156 and miR172 – and their respective targets during these transitions. In addition, we discuss the evolutionary conservation of the functions of these miRNAs in regulating the control of plant developmental phase transitions.
Transmembrane protein 2 (Tmem2) is required to regionally restrict atrioventricular canal boundary and endocardial cushion development
Authors: Smith Kelly A. , Lagendijk Anne K. , Courtney Andrew D. , Chen Huijun , Paterson Scott , Hogan Benjamin M. , Wicking Carol , Bakkers Jeroen
Published: September 2011

The atrioventricular canal (AVC) physically separates the atrial and ventricular chambers of the heart and plays a crucial role in the development of the valves and septa. Defects in AVC development result in aberrant heart morphogenesis and are a significant cause of congenital heart malformations. We have used a forward genetic screen in zebrafish to identify novel regulators of cardiac morphogenesis. We isolated a mutant, named wickham (wkm), that was indistinguishable from siblings at the linear heart tube stage but exhibited a specific loss of cardiac looping at later developmental stages. Positional cloning revealed that the wkm locus encodes transmembrane protein 2 (Tmem2), a single-pass transmembrane protein of previously unknown function. Expression analysis demonstrated myocardial and endocardial expression of tmem2 in zebrafish and conserved expression in the endocardium of mouse embryos. Detailed phenotypic analysis of the wkm mutant identified an expansion of expression of known myocardial and endocardial AVC markers, including bmp4 and has2. By contrast, a reduction in the expression of spp1, a marker of the maturing valvular primordia, was observed, suggesting that an expansion of immature AVC is detrimental to later valve maturation. Finally, we show that immature AVC expansion in wkm mutants is rescued by depleting Bmp4, indicating that Tmem2 restricts bmp4 expression to delimit the AVC primordium during cardiac development.
Secreted frizzled-related proteins are required for Wnt/β-catenin signalling activation in the vertebrate optic cup
Authors: Esteve Pilar , Sandonìs Africa , Ibañez Carmen , Shimono Akihiko , Guerrero Isabel , Bovolenta Paola
Published: September 2011

Secreted frizzled-related proteins (Sfrps) are considered Wnt signalling antagonists but recent studies have shown that specific family members enhance Wnt diffusion and thus positively modulate Wnt signalling. Whether this is a general and physiological property of all Sfrps remains unexplored. It is equally unclear whether disruption of Sfrp expression interferes with developmental events mediated by Wnt signalling activation. Here, we have addressed these questions by investigating the functional consequences of Sfrp disruption in the canonical Wnt signalling-dependent specification of the mouse optic cup periphery. We show that compound genetic inactivation of Sfrp1 and Sfrp2 prevents Wnt/β-catenin signalling activation in this structure, which fails to be specified and acquires neural retina characteristics. Consistent with a positive role of Sfrps in signalling activation, Wnt spreading is impaired in the retina of Sfrp1–/–;Sfrp2–/– mice. Conversely, forced expression of Sfrp1 in the wing imaginal disc of Drosophila, the only species in which the endogenous Wnt distribution can be detected, flattens the Wg gradient, suppresses the expression of high-Wg target genes but expands those typically activated by low Wg concentrations. Collectively, these data demonstrate that, in vivo, the levels of Wnt signalling activation strongly depend on the tissue distribution of Sfrps, which should be viewed as multifunctional regulators of Wnt signalling.
TRB3 interacts with SMAD3 promoting tumor cell migration and invasion
Authors: Hua Fang , Mu Rong , Liu Jinwen , Xue Jianfei , Wang Ziyan , Lin Heng , Yang Hongzhen , Chen Xiaoguang , Hu Zhuowei
Published: September 2011

Tribbles homolog 3 (TRB3, also known as TRIB3, NIPK and SKIP3), a human homolog of Drosophila Tribbles, has been found to interact with a variety of signaling molecules to regulate diverse cellular functions. Here, we report that TRB3 is a novel SMAD3-interacting protein. Expression of exogenous TRB3 enhanced the transcriptional activity of SMAD3, whereas knocking down endogenous TRB3 reduced the transcriptional activity of SMAD3. The kinase-like domain (KD) of TRB3 was responsible for the interaction with SMAD3 and the regulation of SMAD3-mediated transcriptional activity. In addition, TGF-β1 stimulation or overexpression of SMAD3 enhanced the TRB3 promoter activity and expression, suggesting that there is a positive feedback loop between TRB3 and TGF-β–SMAD3 signaling. Mechanistically, TRB3 was found to trigger the degradation of SMAD ubiquitin regulatory factor 2 (Smurf2), which resulted in a decrease in the degradation of SMAD2 and phosphorylated SMAD3. Moreover, TRB3–SMAD3 interaction promoted the nuclear localization of SMAD3 because of the interaction of TRB3 with the MH2 domain of SMAD3. These effects of TRB3 were responsible for potentiating the SMAD3-mediated activity. Furthermore, knockdown of endogenous TRB3 expression inhibited the migration and invasion of tumor cells in vitro, which were associated with an increase in the expression of E-cadherin and a decrease in the expression of Twist-1 and Snail, two master regulators of epithelial-to-mesenchymal transition, suggesting a crucial role for TRB3 in maintaining the mesenchymal status of tumor cells. These results demonstrate that TRB3 acts as a novel SMAD3-interacting protein to participate in the positive regulation of TGF-β–SMAD-mediated cellular biological functions.
Chronic hypoxia stimulates an enhanced response to immune challenge without evidence of an energetic tradeoff
Authors: Baze Monica M. , Hunter Kenneth , Hayes Jack P.
Published: September 2011

There is broad interest in whether there is a tradeoff between energy metabolism and immune function, and how stress affects immune function. Under hypoxic stress, maximal aerobic metabolism is limited, and other aspects of energy metabolism of animals may be altered as well. Although acute hypoxia appears to enhance certain immune responses, the effects of chronic hypoxia on immune function are largely unstudied. We tested: (1) whether chronic hypoxia affects immune function and (2) whether hypoxia affects the metabolic cost of immune function. First, flow cytometry was used to monitor the peripheral blood immunophenotype of mice over the course of 36 days of hypoxic exposure. Second, hypoxic and normoxic mice were subjected to an adaptive immune challenge via keyhole limpet hemocyanin (KLH) or to an innate immune challenge via lipopolysaccharide (LPS). The resting metabolic rates of mice in all immune challenge treatments were also measured. Although hypoxia had little effect on the peripheral blood immunophenotype, hypoxic mice challenged with KLH or LPS had enhanced immunological responses in the form of higher antibody titers or increased TNF-α production, respectively. Initially, mice exposed to hypoxia had lower metabolic rates, but this response was transitory and resting metabolic rates were normal by the end of the experiment. There was no effect of either immune challenge on resting metabolic rate, suggesting that mounting either the acute phase response or a humoral response is not as energetically expensive as previously thought. In addition, our results suggest that immune responses to chronic and acute hypoxia are concordant. Both forms of hypoxia appear to stimulate both innate and adaptive immune responses.
Aerobic capacity in wild satin bowerbirds: repeatability and effects of age, sex and condition
Authors: Chappell Mark A. , Savard Jean-Francois , Siani Jennifer , Coleman Seth W. , Keagy Jason , Borgia Gerald
Published: September 2011

Individual variation in aerobic capacity has been extensively studied, especially with respect to condition, maturity or pathogen infection, and to gain insights into mechanistic foundations of performance. However, its relationship to mate competition is less well understood, particularly for animals in natural habitats. We examined aerobic capacity [maximum rate of O2 consumption () in forced exercise] in wild satin bowerbirds, an Australian passerine with a non-resource based mating system and strong intermale sexual competition. We tested for repeatability of mass and , differences among age and sex classes, and effects of several condition indices. In adult males, we examined interactions between aerobic performance and bower ownership (required for male mating success). There was significant repeatability of mass and within and between years, but between-year repeatability was lower than within-year repeatability. varied with an overall scaling to mass0.791, but most variance in was not explained by mass. Indicators of condition (tarsus and wing length asymmetry, the ratio of tarsus length to mass) were not correlated to . Ectoparasite counts were weakly correlated to across all age–sex classes but not within any class. Adult males, the cohort with the most intense levels of mating competition, had higher than juvenile birds or adult females. However, there was no difference between the of bower-owning males and that of males not known to hold bowers. Thus one major factor determining male reproductive success was not correlated to aerobic performance.
No evidence for DPOAEs in the mechanical motion of the locust tympanum
Authors: Moir Hannah M. , Jackson Joseph C. , Windmill James F. C.
Published: September 2011

Distortion-product otoacoustic emissions (DPOAEs) are present in non-linear hearing organs, and for low-intensity sounds are a by-product of active processes. In vertebrate ears they are considered to be due to hair cell amplification of sound in the cochlea; however, certain animals lacking a cochlea and hair cells are also reported to be capable of DPOAEs. In the Insecta, DPOAEs have been recorded from the locust auditory organ. However, the site of generation of these DPOAEs and the physiological mechanisms causing their presence in the locust ear are not yet understood, despite there being a number of potential places in the tympanal organ that could be capable of generating DPOAEs. This study aimed to record locust tympanal membrane vibration using a laser Doppler vibrometer in order to identify a distinct place of DPOAE generation on the membrane. Two species of locust were investigated over a range of frequencies and levels of acoustic stimulus, mirroring earlier acoustic recording studies; however, the current experiments were carried out in an open acoustic system. The laser measurements did not find any evidence of mechanical motion on the tympanal membrane related to the expected DPOAE frequencies. The results of the current study therefore could not confirm the presence of DPOAEs in the locust ear through the mechanics of the tympanal membrane. Experiments were also carried out to test how membrane behaviour altered when the animals were in a state of hypoxia, as this was previously found to decrease DPOAE magnitude, suggesting a metabolic sensitivity. However, hypoxia did not have any significant effect on the membrane mechanics. The location of the mechanical generation of DPOAEs in the locust's ear, and therefore the basis for the related physiological mechanisms, thus remains unknown.
Causes and consequences of stolon regression in a colonial hydroid
Authors: Vogt Kimberly S. Cherry , Harmata Katherine L. , Coulombe Hilary L. , Bross Lori S. , Blackstone Neil W.
Published: September 2011

A cnidarian colony can be idealized as a group of feeding polyps connected by tube-like stolons. Morphological variation ranges from runner-like forms with sparse polyp and stolon development to sheet-like forms with dense polyp and stolon development. These forms have typically been considered in a foraging context, consistent with a focus on rates of polyp development relative to stolon elongation. At the same time, rates of stolon regression can affect this morphological variation; several aspects of regression were investigated in this context. More sheet-like forms were produced by periodic peroxide treatment, which induced high rates of stolon regression. Caspase inhibitors altered the effects of regression induced by peroxide or vitamin C. These inhibitors generally diminished physical regression and the abundance of associated reactive oxygen species. Caspase inhibitors also altered cellular ultrastructure, resulting in features suggestive of necrosis rather than apoptosis. At the same time, caspase inhibitors had little effect on reactive nitrogen species that are also associated with regression. Although regression is most easily triggered by pharmacological perturbations related to reactive oxygen species (e.g. peroxide or vitamin C), a variety of environmental effects, particularly restricted environments and an interaction between feeding and temperature, can also induce regression. Stolon regression may thus be a factor contributing to natural variation between runners and sheets.
Scaling of resting and maximum hopping metabolic rate throughout the life cycle of the locust Locusta migratoria
Authors: Snelling Edward P. , Seymour Roger S. , Matthews Philip G. D. , Runciman Sue , White Craig R.
Published: September 2011

The hemimetabolous migratory locust Locusta migratoria progresses through five instars to the adult, increasing in size from 0.02 to 0.95 g, a 45-fold change. Hopping locomotion occurs at all life stages and is supported by aerobic metabolism and provision of oxygen through the tracheal system. This allometric study investigates the effect of body mass (Mb) on oxygen consumption rate (, μmol h–1) to establish resting metabolic rate (), maximum metabolic rate during hopping () and maximum metabolic rate of the hopping muscles () in first instar, third instar, fifth instar and adult locusts. Oxygen consumption rates increased throughout development according to the allometric equations , , and, if adults are excluded, and . Increasing body mass by 20–45% with attached weights did not increase mass-specific significantly at any life stage, although mean mass-specific hopping was slightly higher (ca. 8%) when juvenile data were pooled. The allometric exponents for all measures of metabolic rate are much greater than 0.75, and therefore do not support West, Brown and Enquist's optimised fractal network model, which predicts that metabolism scales with a ¾-power exponent owing to limitations in the rate at which resources can be transported within the body.
Parents' Role in Critical Events during a Child's Hospitalization Nplate Has a Confusing Label
Authors: Cohen Michael R. , Smetzer Judy L.
Published: September 2011

These medication errors have occurred in health care facilities at least once. They will happen again—perhaps where you work. Through education and alertness of personnel and procedural safeguards, they can be avoided. You should consider publishing accounts of errors in your newsletters and/or presenting them at your inservice training programs.

Your assistance is required to continue this feature. The reports described here were received through the Institute for Safe Medication Practices (ISMP) National Medication Errors Reporting Program. Any reports published by ISMP will be anonymous. Comments are also invited; the writers' names will be published if desired. ISMP may be contacted at the address shown below.

Errors, close calls, or hazardous conditions may be reported directly to ISMP through the ISMP Web site ( www.ismp.org ), by calling 800-FAIL-SAFE, or via e-mail at ismpinfo@ismp.org . ISMP guarantees the confidentiality and security of the information received and respects reporters' wishes as to the level of detail included in publications.
Anorgasmia with Gabapentin: Toxic Effects of Levamisole in a Cocaine User: Acute Generalized Exanthematous Pustulosis: Bisphosphonate-Related Subtrochanteric Femoral Fractures: Mirtazapine-Induced Hepatocellular-Type Liver Injury: Pregabalin-Induced Hepatotoxicity: Potentially Inappropriate Medications in the Elderly
Authors: Shuster Joel
Published: September 2011

The purpose of this feature is to heighten awareness of specific adverse drug reactions (ADRs), discuss methods of prevention, and promote reporting of ADRs to the US Food and Drug Administration's (FDA's) MedWatch program (800-FDA-1088). If you have reported an interesting, preventable ADR to MedWatch, please consider sharing the account with our readers.
Linagliptin
Authors: Cada Dennis J. , Baker Danial E. , Levien Terri L.
Published: September 2011

Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are sent in print and are also available on-line. Monographs can be customized to meet the needs of a facility. Subscribers to The Formulary Monograph Service also receive access to a pharmacy bulletin board, The Formulary Information Exchange (The F.I.X.). All topics pertinent to clinical and hospital pharmacy are discussed on The F.I.X. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. For more information about The Formulary Monograph Service or The F.I.X., call The Formulary at 800-322-4349. The September 2011 monograph topics are on rivaroxaban, ezogabine, fentanyl nasal spray, belatacept, and nitroglycerin ointment 0.4%. The DUE/MUE is on rivaroxaban.
New Drugs Approved by the FDA New Dosage Forms and Indications Approved by the FDA Agents Pending FDA Approval New Drug/Biologics License Applications Filed by Manufacturer Supplemental Actions Filed by Manufacturer Significant Labeling Changes or “Dear Health Professional” Letters Related to Safety
Authors: Baker Danial E.
Published: September 2011

This monthly feature will help readers keep current on new drugs, new indications, dosage forms, and safety-related changes in labeling or use. Efforts have been made to ensure the accuracy of this information; however, if there are any questions, please let me know at bakerdan@wsu.edu .
Pharmacy e-Health Information Technology Collaborative
Authors: Fox Brent I. , Felkey Bill G.
Published: September 2011

Today's health care environment is dynamic. The national attention on patient safety, cost, and efficiency has highlighted the role of health information technology as a key method to address today's challenges. This technology briefing introduces and describes a pharmacy group that is focused on the pharmacist's role in health information technology and improving patient care.
Practice Models: What Are Other Professions Doing?
Authors: Storey Michael , White Sara , Weber Robert J.
Published: September 2011

The Director's Forum series is written and edited by Robert J. Weber and Scott M. Mark and is designed to guide pharmacy leaders in establishing patient-centered services in hospitals and health systems. During the next several years, much will be written and presented on implementing the recommendations of the American Society of Health-System Pharmacists' Pharmacy Practice Model Initiative (PPMI). Developing a practice model vision is not unique to pharmacy. Nursing, medicine, and others have developed their vision of new practice models in responding to the challenges of health care. A pharmacy director implementing practice model change can successfully use the lessons learned from the professional practice models of other health care professions. Pharmacy directors all too often take a myopic view of their department, focusing only on issues impacting their daily operations. By gaining a further understanding of other professional practice models, pharmacy directors can maximize the benefits of their practice model changes to best focus on meeting the medication needs of patients.
Recent Publications on Medications and Pharmacy
Authors: Russett Flint
Published: September 2011

Hospital Pharmacy presents this feature to keep pharmacists abreast of new publications in the medical/pharmacy literature. Articles of interest regarding a broad scope of topics are abstracted monthly.
Ofatumumab: A Novel Anti-CD20 Monoclonal Antibody for Treatment of Refractory Chronic Lymphocytic Leukemia
Authors: Nightingale Ginah
Published: September 2011

Objective:

To present the current clinical evidence on ofatumumab for use in refractory chronic lymphocytic leukemia (CLL).

Data Sources:

A literature search was performed using MEDLINE and PubMed (both 1966-May 2011), as well as the American Society of Hematology abstracts (2000-May 2011), using the primary search terms ofatumumab and HuMax-CD20,

Study Selection and Data Extraction:

Clinical studies and abstracts available in the English language, describing the pharmacology, pharmacokinetics, clinical activity, and safety of ofatumumab in CLL were included in this review.

Data Synthesis:

Ofatumumab is a human immunoglobulin monoclonal antibody that binds to B-lymphocytes expressing CD-20 cell surface antigens. Ofatumumab was granted accelerated approval by the Food and Drug Administration in October 2009 for the treatment of CLL refractory to fludarabine and alemtuzumab. A Phase 1/2 trial has established the safety and tolerability of single-agent ofatumumab at an initial dose of 300 mg intravenously on week 1, followed by 2000 mg once weekly for 7 doses (weeks 2–8), followed by 2000 mg once every 4 weeks for 4 doses (weeks 9–12), for a total of 12 doses. The final analysts of a pivotal international multicenter trial has shown promising activity in patients with CLL refractory to fludarabine and alemtuzumab, demonstrating overall response rates of 44–51 %, with prolonged progress ion-free and overall survival. Ofatumumab activity has also been shown in a variety of other malignant and nonmalignant conditions, including non-Hodgkin lymphoma, rheumatoid arthritis, and multiple sclerosis. The most common adverse effect is grade 1 and 2 infusion reactions. Other adverse effects include infection, neutropenia, anemia, rash, fever, and diarrhea.

Conclusions:

Clinical evidence suggests that ofatumumab is an effective agent in patients with CLL refractory to fludarabine and alemtuzumab. Data are awaited comparing ofatumumab to other salvage regimens. Until results of head-to-head trials are conducted comparing ofatumumab to existing regimens, it cannot be said whether ofatumumab is more efficacious or tolerable than currently available therapies.
Relaxation Increases Monetary Valuations
Authors: Pham Michel Tuan , Hung Iris W. , Gorn Gerald J.
Published: September 2011

This research documents an intriguing empirical phenomenon whereby states of relaxation increase the monetary valuation of products. The authors demonstrate this phenomenon in six experiments involving two methods of inducing relaxation, a large number of products of different types, and various methods of assessing monetary valuation. In all six experiments, participants who were put into a relaxed affective state reported higher monetary valuations than participants who were put into an equally pleasant but less relaxed state. This effect seems to be caused by differences in relaxed and nonrelaxed people's mental construals of the value of the products. Specifically, compared with less relaxed people, relaxed people seem to represent the value of products at a higher level of abstraction, which increases their perceptions of these products' value. The phenomenon appears to reflect an inflation of value by relaxed people rather than a deflation of value by less relaxed people.
Mental Simulation and Product Evaluation: The Affective and Cognitive Dimensions of Process versus Outcome Simulation
Authors: Zhao Min , Hoeffler Steve , Zauberman Gal
Published: September 2011

In this research, the authors examine the role of process versus outcome simulation in product evaluation and demonstrate how manipulating the type of information-processing mode (cognitive vs. affective) leads to unique effects in process and outcome simulation. The article begins with the premise that when consumers do not have well-formed preferences for a product, they tend to focus on the usage process. The authors predict and find that outcome simulation is more effective than process simulation in increasing product evaluation under a cognitive mode, whereas process simulation is more effective than outcome simulation under an affective mode. Establishing boundary conditions, the authors further show the effect of two important moderators that alter consumers' focus on/away from the product's usage process. Specifically, they show a reversal of the effect for each type of mental simulation for hedonic products, for which product benefits are the more salient aspect (vs. the usage process). Furthermore, a distant-future (vs. near-future) evaluation frame shifts people's focus away from the usage process toward product benefits and reverses the effect of each type of simulation. The authors conclude with a discussion of theoretical and managerial implications.