bluuebunny/crossref_metadata_2025 huggingface dataset:
Multiple distinct molecular mechanisms influence sensitivity and resistance to MDM2 inhibitors in adult acute myelogenous leukemia
Authors: Long Jianting , Parkin Brian , Ouillette Peter , Bixby Dale , Shedden Kerby , Erba Harry , Wang Shaomeng , Malek Sami N.
Published: April 2010

The survival of most patients with acute myelogenous leukemia (AML) remains poor, and novel therapeutic approaches are needed to improve outcomes. Given that the fraction of AML with mutated p53 is small (∼ 10%), it appears rational to study MDM2 inhibitors as therapy for AML. Here, we report results of a detailed characterization of sensitivity and resistance to treatment ex vivo with the MDM2 inhibitor MI219 in AML blasts from 109 patients. In line with previous observations, all AML cases with mutated p53 were resistant to MI219. Importantly, approximately 30% of AML cases with unmutated p53 also demonstrated primary resistance to MI219. Analysis of potential mechanisms associated with MI219 resistance in AML blasts with wild-type p53 uncovered distinct molecular defects, including low or absent p53 protein induction after MDM2 inhibitor treatment or external irradiation. Furthermore, a separate subset of resistant blasts displayed robust p53 protein induction after MI219 treatment, indicative of defective p53 protein function or defects in the apoptotic p53 network. Finally, analysis of very sensitive AML cases uncovered a strong and significant association with mutated Flt3 status (Flt3-ITD), which for the first time identified a clinically high-risk group of AML that may particularly benefit from MDM2 inhibitor treatment.
The outcome of full-intensity and reduced-intensity conditioning matched sibling or unrelated donor transplantation in adults with Philadelphia chromosome–negative acute lymphoblastic leukemia in first and second complete remission
Authors: Marks David I. , Wang Tao , Pérez Waleska S. , Antin Joseph H. , Copelan Edward , Gale Robert Peter , George Biju , Gupta Vikas , Halter Joerg , Khoury H. Jean , Klumpp Thomas R. , Lazarus Hillard M. , Lewis Victor A. , McCarthy Philip , Rizzieri David A. , Sabloff Mitchell , Szer Jeff , Tallman Martin S. , Weisdorf Daniel J.
Published: April 2010

We examined the efficacy of reduced-intensity conditioning (RIC) and compared outcomes of 93 patients older than 16 years after RIC with 1428 patients receiving full-intensity conditioning for allografts using sibling and unrelated donors for Philadelphia-negative acute lymphoblastic leukemia (ALL) in first or second complete remission. RIC conditioning included busulfan 9 mg/kg or less (27), melphalan 150 mg/m2 or less (23), low-dose total body irradiation (TBI; 36), and others (7). The RIC group was older (median 45 vs 28 years, P < .001) and more received peripheral blood grafts (73% vs 43%, P < .001) but had similar other prognostic factors. The RIC versus full-intensity conditioning groups had slightly, but not significantly, less acute grade II-IV graft-versus-host disease (39% vs 46%) and chronic graft-versus-host disease (34% vs 42%), yet similar transplantation-related mortality. RIC led to slightly more relapse (35% vs 26%, P = .08) yet similar age-adjusted survival (38% vs 43%, P = .39). Multivariate analysis showed that conditioning intensity did not affect transplantation-related mortality (P = .92) or relapse risk (P = .14). Multivariate analysis demonstrated significantly improved overall survival with: Karnofsky performance status more than 80, first complete remission, lower white blood count, well-matched unrelated or sibling donors, transplantation since 2001, age younger than 30 years, and conditioning with TBI, but no independent impact of conditioning intensity. RIC merits further investigation in prospective trials of adult ALL.
Comparison of human cord blood engraftment between immunocompromised mouse strains
Authors: McDermott Sean P. , Eppert Kolja , Lechman Eric R. , Doedens Monica , Dick John E.
Published: April 2010

The nonobese diabetic/severe combined immune deficiency (NOD-scid) xenotransplantation model is the “gold standard” for assaying human hematopoietic stem cell activity. Systematic advancements, such as depletion of natural killer cell activity with anti-CD122 antibody, direct intrafemoral injection, and deletion or truncation of IL2Rγ, have improved human cell engraftment; however, questions remain whether these mouse models are equivalent or, if not, which model is superior for assaying hematopoietic stem cell activity. To address this, we compared overall engraftment and multilineage differentiation of near-limiting doses of lineage-depleted human umbilical cord blood cells by direct intrafemoral injection into NOD/Lt-scid, NOD/Shi-scid, NOD/Lt-scid/IL2Rγnull (NSG), and NOD/Shi-scid/IL2Rγnull mice. Transplantation into NSG mice generated moderately higher human engraftment levels in bone marrow compared with other strains. At limiting doses, NSG mice of both sexes were 3.6-fold more sensitive in detecting SCID-repopulating cells compared with NOD/Lt-scid mice. However, NSG females exhibited higher engraftment at limiting cell doses, resulting in an overall increase in SCID-repopulating cell detection of 9-fold. Both NSG and NOD/Shi-scid/IL2Rγnull support significantly improved engraftment in peripheral tissues compared with NOD/Lt-scid and NOD/Shi-scid mice, whereas NSG mice provide greater human engraftment in bone marrow than all other strains, especially at limiting doses.
The evolutionary diversification of LSF and Grainyhead transcription factors preceded the radiation of basal animal lineages
Authors: Traylor-Knowles Nikki , Hansen Ulla , Dubuc Timothy Q , Martindale Mark Q , Kaufman Les , Finnerty John R
Published: April 2010

Background

The transcription factors of the LSF/Grainyhead (GRH) family are characterized by the possession of a distinctive DNA-binding domain that bears no clear relationship to other known DNA-binding domains, with the possible exception of the p53 core domain. In triploblastic animals, the LSF and GRH subfamilies have diverged extensively with respect to their biological roles, general expression patterns, and mechanism of DNA binding. For example,Grainyhead(GRH) homologs are expressed primarily in the epidermis, and they appear to play an ancient role in maintaining the epidermal barrier. By contrast, LSF homologs are more widely expressed, and they regulate general cellular functions such as cell cycle progression and survival in addition to cell-lineage specific gene expression.

Results

To illuminate the early evolution of this family and reconstruct the functional divergence of LSF and GRH, we compared homologs from 18 phylogenetically diverse taxa, including four basal animals (Nematostella vectensis,Vallicula multiformis,Trichoplax adhaerens, andAmphimedon queenslandica), a choanoflagellate (Monosiga brevicollis) and several fungi. Phylogenetic and bioinformatic analyses of these sequences indicate that (1) the LSF/GRH gene family originated prior to the animal-fungal divergence, and (2) the functional diversification of the LSF and GRH subfamilies occurred prior to the divergence between sponges and eumetazoans. Aspects of the domain architecture of LSF/GRH proteins are well conserved between fungi, choanoflagellates, and metazoans, though within the Metazoa, the LSF and GRH families are clearly distinct. We failed to identify a convincing LSF/GRH homolog in the sequenced genomes of the algaeVolvox carteriandChlamydomonas reinhardtiior the amoebozoanDictyostelium purpureum. Interestingly, the ancestral GRH locus has become split into two separate loci in the sea anemoneNematostella, with one locus encoding a DNA binding domain and the other locus encoding the dimerization domain.

Conclusions

In metazoans, LSF and GRH proteins play a number of roles that are essential to achieving and maintaining multicellularity. It is now clear that this protein family already existed in the unicellular ancestor of animals, choanoflagellates, and fungi. However, the diversification of distinct LSF and GRH subfamilies appears to be a metazoan invention. Given the conserved role of GRH in maintaining epithelial integrity in vertebrates, insects, and nematodes, it is noteworthy that the evolutionary origin of Grh appears roughly coincident with the evolutionary origin of the epithelium.
High-throughput analysis of candidate imprinted genes and allele-specific gene expression in the human term placenta
Authors: Daelemans Caroline , Ritchie Matthew E , Smits Guillaume , Abu-Amero Sayeda , Sudbery Ian M , Forrest Matthew S , Campino Susana , Clark Taane G , Stanier Philip , Kwiatkowski Dominic , Deloukas Panos , Dermitzakis Emmanouil T , Tavaré Simon , Moore Gudrun E , Dunham Ian
Published: April 2010

Background

Imprinted genes show expression from one parental allele only and are important for development and behaviour. This extreme mode of allelic imbalance has been described for approximately 56 human genes. Imprinting status is often disrupted in cancer and dysmorphic syndromes. More subtle variation of gene expression, that is not parent-of-origin specific, termed 'allele-specific gene expression' (ASE) is more common and may give rise to milder phenotypic differences. Using two allele-specific high-throughput technologies alongside bioinformatics predictions, normal term human placenta was screened to find new imprinted genes and to ascertain the extent of ASE in this tissue.

Results

Twenty-three family trios of placental cDNA, placental genomic DNA (gDNA) and gDNA from both parents were tested for 130 candidate genes with the Sequenom MassArray system. Six genes were found differentially expressed but none imprinted. The Illumina ASE BeadArray platform was then used to test 1536 SNPs in 932 genes. The array was enriched for the human orthologues of 124 mouse candidate genes from bioinformatics predictions and 10 human candidate imprinted genes from EST database mining. After quality control pruning, a total of 261 informative SNPs (214 genes) remained for analysis. Imprinting with maternal expression was demonstrated for the lymphocyte imprinted geneZNF331in human placenta. Two potential differentially methylated regions (DMRs) were found in the vicinity ofZNF331. None of the bioinformatically predicted candidates tested showed imprinting except for a skewed allelic expression in a parent-specific manner observed forPHACTR2, a neighbour of the imprintedPLAGL1gene. ASE was detected for two or more individuals in 39 candidate genes (18%).

Conclusions

Both Sequenom and Illumina assays were sensitive enough to study imprinting and strong allelic bias. Previous bioinformatics approaches were not predictive of new imprinted genes in the human term placenta.ZNF331is imprinted in human term placenta and might be a new ubiquitously imprinted gene, part of a primate-specific locus. Demonstration of partial imprinting ofPHACTR2calls for re-evaluation of the allelic pattern of expression for thePHACTR2-PLAGL1locus. ASE was common in human term placenta.
Comparative gene expression in toxic versus non-toxic strains of the marine dinoflagellate Alexandrium minutum
Authors: Yang Ines , John Uwe , Beszteri Sára , Glöckner Gernot , Krock Bernd , Goesmann Alexander , Cembella Allan D
Published: April 2010

Background

The dinoflagellate Alexandrium minutum typically produces paralytic shellfish poisoning (PSP) toxins, which are known only from cyanobacteria and dinoflagellates. While a PSP toxin gene cluster has recently been characterized in cyanobacteria, the genetic background of PSP toxin production in dinoflagellates remains elusive.

Results

We constructed and analysed an expressed sequence tag (EST) library of A. minutum, which contained 15,703 read sequences yielding a total of 4,320 unique expressed clusters. Of these clusters, 72% combined the forward-and reverse reads of at least one bacterial clone. This sequence resource was then used to construct an oligonucleotide microarray. We analysed the expression of all clusters in three different strains. While the cyanobacterial PSP toxin genes were not found among the A. minutum sequences, 192 genes were differentially expressed between toxic and non-toxic strains.

Conclusions

Based on this study and on the lack of identified PSP synthesis genes in the two existent Alexandrium tamarense EST libraries, we propose that the PSP toxin genes in dinoflagellates might be more different from their cyanobacterial counterparts than would be expected in the case of a recent gene transfer. As a starting point to identify possible PSP toxin-associated genes in dinoflagellates without relying on a priori sequence information, the sequences only present in mRNA pools of the toxic strain can be seen as putative candidates involved in toxin synthesis and regulation, or acclimation to intracellular PSP toxins.
GPR30, but not estrogen receptor-α, is crucial in the treatment of experimental autoimmune encephalomyelitis by oral ethinyl estradiol
Authors: Yates Melissa A , Li Yuexin , Chlebeck Peter J , Offner Halina
Published: April 2010

Background

Remission of multiple sclerosis during periods of high ovarian hormone secretion (such as pregnancy) has led to a great deal of interest in the potential for estrogens to treat autoimmune disease. Previous work has established that 17β-estradiol can inhibit onset of experimental autoimmune encephalomyelitis (EAE), while ethinyl estradiol (EE) can reduce the severity of established disease. In the current study, the influence of estrogen receptor-α (ERα) and the G-protein coupled estrogen receptor (GPR30 or GPER) on EE's ability to treat EAE was explored.

Results

EE reduced disease severity in wild-type and ERα knockout (ERKO) mice, but did not alter disease in the GPR30KO group. Production of anti-inflammatory IL-10 increased in EE-ERKO mice (which showed reduced disease) but not in EE-GPR30KO mice (who did not have improved disease).

Conclusions

Differential production of IL-10 following EE treatment in ERKO and GPR30KO animals may be responsible for the distinctly different effects on disease severity. Increased IL-10 in ERKO-EE compared to ERKO-Controls is likely to be an important factor in reducing established disease. The inability of EE to reduce disease in GPR30KO mice indicates an important but still undefined role for GPR30 in regulating immune reactivity.
Transcriptional profiles underlying parent-of-origin effects in seeds of Arabidopsis thaliana
Authors: Tiwari Sushma , Spielman Melissa , Schulz Reiner , Oakey Rebecca J , Kelsey Gavin , Salazar Andres , Zhang Ke , Pennell Roger , Scott Rod J
Published: April 2010

Background

Crossing plants of the same species but different ploidies can have dramatic effects on seed growth, but little is known about the alterations to transcriptional programmes responsible for this. Parental genomic imbalance particularly affects proliferation of the endosperm, with an increased ratio of paternally to maternally contributed genomes ('paternal excess') associated with overproliferation, while maternal excess inhibits endosperm growth. One interpretation is that interploidy crosses disrupt the balance in the seed of active copies of parentally imprinted genes. This is supported by the observation that mutations in imprinted FIS-class genes of Arabidopsis thaliana share many features of the paternal excess phenotype. Here we investigated gene expression underlying parent-of-origin effects in Arabidopsis through transcriptional profiling of siliques generated by interploidy crosses and FIS-class mutants.

Results

We found that fertilized fis1 mutant seeds have similar profiles to seeds with paternal excess, showing that the shared phenotypes are underpinned by similar patterns of gene expression. We identified genes strongly associated with enhanced or inhibited seed growth; this provided many candidates for further investigation including MADS-box transcription factors, cell cycle genes, and genes involved in hormone pathways.

Conclusions

The work presented here is a step towards understanding the effects on seed development of the related phenomena of parental genome balance and imprinting.
Essential role of the N-terminal region of TFII-I in viability and behavior
Authors: Lucena Jaume , Pezzi Susana , Aso Ester , Valero Maria C , Carreiro Candelas , Dubus Pierre , Sampaio Adriana , Segura Maria , Barthelemy Isabel , Zindel Marc Y , Sousa Nuno , Barbero José L , Maldonado Rafael , Pérez-Jurado Luis A , Campuzano Victoria
Published: April 2010

Background

GTF2Icodes for a general intrinsic transcription factor and calcium channel regulator TFII-I, with high and ubiquitous expression, and a strong candidate for involvement in the morphological and neuro-developmental anomalies of the Williams-Beuren syndrome (WBS). WBS is a genetic disorder due to a recurring deletion of about 1,55-1,83 Mb containing 25-28 genes in chromosome band 7q11.23 includingGTF2I. Completed homozygous loss of either theGtf2iorGtf2ird1function in mice provided additional evidence for the involvement of both genes in the craniofacial and cognitive phenotype. Unfortunately nothing is now about the behavioral characterization of heterozygous mice.

Methods

By gene targeting we have generated a mutant mice with a deletion of the first 140 amino-acids of TFII-I. mRNA and protein expression analysis were used to document the effect of the study deletion. We performed behavioral characterization of heterozygous mutant mice to documentin vivoimplications of TFII-I in the cognitive profile of WBS patients.

Results

Homozygous and heterozygous mutant mice exhibit craniofacial alterations, most clearly represented in homozygous condition. Behavioral test demonstrate that heterozygous mutant mice exhibit some neurobehavioral alterations and hyperacusis or odynacusis that could be associated with specific features of WBS phenotype. Homozygous mutant mice present highly compromised embryonic viability and fertility. Regarding cellular model, we documented a retarded growth in heterozygous MEFs respect to homozygous or wild-type MEFs.

Conclusion

Our data confirm that, although additive effects of haploinsufficiency at several genes may contribute to the full craniofacial or neurocognitive features of WBS, correct expression ofGTF2Iis one of the main players. In addition, these findings show that the deletion of the fist 140 amino-acids of TFII-I altered it correct function leading to a clear phenotype, at both levels, at the cellular model and at thein vivomodel.
Increased expression of urokinase plasminogen activator and its cognate receptor in human seminomas
Authors: Ulisse Salvatore , Baldini Enke , Mottolese Marcella , Sentinelli Steno , Gargiulo Patrizia , Valentina Brancato , Sorrenti Salvatore , Di Benedetto Anna , De Antoni Enrico , D'Armiento Massimino
Published: April 2010

Background

The urokinase plasminogen activating system (uPAS) is implicated in neoplastic progression and high tissue levels of uPAS components correlate with a poor prognosis in different human cancers. Despite that, relative few studies are available on the expression and function of the uPAS components in human seminomas. In the present study we characterized the expression of the urokinase plasminogen activator (uPA), its cognate receptor (uPAR) and the uPA inhibitors PAI-1 and PAI-2 in normal human testis and seminomas.

Methods

The expression of the above genes was evaluated by means of quantitative RT-PCR, western blot, zymographic analysis and immunohistochemistry.

Results

Quantitative RT-PCR analysis of 14 seminomas demonstrated that uPA and uPAR mRNAs were, with respect to control tissues, increased in tumor tissues by 3.80 ± 0.74 (p < 0.01) and 6.25 ± 1.18 (p < 0.01) fold, respectively. On the other hand, PAI-1 mRNA level was unchanged (1.02 ± 0.24 fold), while that of PAI-2 was significantly reduced to 0.34 ± 0.18 (p < 0.01) fold. Western blot experiments performed with protein extracts of three seminomas and normal tissues from the same patients showed that uPA protein levels were low or undetectable in normal tissues and induced in tumor tissues. On the same samples, zymographic analysis demonstrated increased uPA activity in tumor tissue extracts. Western blot experiments showed that also the uPAR protein was increased in tumor tissues by 1.83 ± 0.15 fold (p < 0.01). The increased expression of uPA and uPAR was further confirmed by immunohistochemical staining performed in 10 seminomas and autologous uninvolved peritumoral tissues. Finally, variation in the mRNA level of PAI-1 significantly correlated with tumor size.

Conclusions

We demonstrated the increased expression of uPA and uPAR in human seminomas with respect to normal testis tissues, which may be relevant in testicular cancer progression.
A simple fluorescence based assay for quantification of human immunodeficiency virus particle release
Authors: Hermle Johannes , Anders Maria , Heuser Anke-Mareil , Müller Barbara
Published: April 2010

Background

The assembly and release of human immunodeficiency virus (HIV) particles from infected cells represent attractive, but not yet exploited targets for antiretroviral therapy. The availability of simple methods to measure the efficiency of these replication steps in tissue culture would facilitate the identification of host factors essential for these processes as well as the screening for lead compounds acting as specific inhibitors of particle formation. We describe here the development of a rapid cell based assay for quantification of human immunodeficiency virus type 1 (HIV-1) particle assembly and/or release.

Results

Using a fluorescently labelled HIV-derivative, which carries an eYFP domain within the main viral structural protein Gag in the complete viral protein context, the release of virus like particles could be monitored by directly measuring the fluorescence intensity of the tissue culture supernatant. Intracellular Gag was quantitated in parallel by direct fluorescence analysis of cell lysates, allowing us to normalize for Gag expression efficiency. The assay was validated by comparison with p24 capsid ELISA measurements, a standard method for quantifying HIV-1 particles. Optimization of conditions allowed the robust detection of particle amounts corresponding to 50 ng p24/ml in medium by fluorescence spectroscopy. Further adaptation to a multi-well format rendered the assay suitable for medium or high throughput screening of siRNA libraries to identify host cell factors involved in late stages of HIV replication, as well as for random screening approaches to search for potential inhibitors of HIV-1 assembly or release.

Conclusions

The fast and simple fluorescence based quantification of HIV particle release yielded reproducible results which were comparable to the well established ELISA measurements, while in addition allowing the parallel determination of intracellular Gag expression. The protocols described here can be used for screening of siRNA libraries or chemical compounds, respectively, for inhibition of HIV in a 96-well format.
Socio-demographic disparity in oral health among the poor: a cross sectional study of early adolescents in Kilwa district, Tanzania
Authors: Mashoto Kijakazi O , Astrom Anne N , Skeie Marit S , Masalu Joyce R
Published: April 2010

Background

There is a lack of studies considering social disparity in oral health emanating from adolescents in low-income countries. This study aimed to assess socio-demographic disparities in clinical- and self reported oral health status and a number of oral health behaviors. The extent to which oral health related behaviors might account for socio-demographic disparities in oral health status was also examined.

Methods

A cross-sectional study was conducted in Kilwa district in 2008. One thousand seven hundred and forty five schoolchildren completed an interview and a full mouth clinical examination. Caries experience was recorded using WHO criteria, whilst type of treatment need was categorized using the ART approach.

Results

The majority of students were caries free (79.8%) and presented with a low need for dental treatment (89.3%). Compared to their counterparts in opposite groups, rural residents and those from less poor households presented more frequently with caries experience (DMT>0), high need for dental treatment and poor oral hygiene behavior, but were less likely to report poor oral health status. Stepwise logistic regressions revealed that social and behavioral variables varied systematically with caries experience, high need for dental treatment and poor self reported oral health. Socio-demographic disparities in oral health outcomes persisted after adjusting for oral health behaviors.

Conclusions

Socio-demographic disparities in oral health outcomes and oral health behaviors do exist. Socio-demographic disparities in oral health outcomes were marginally accounted for by oral health behaviors. Developing policies and programs targeting both social and individual determinants of oral health should be an urgent public health strategy in Tanzania.
Alpha-tocopherol transfer protein disruption confers resistance to malarial infection in mice
Authors: Herbas Maria S , Ueta Yoshiko Y , Ichikawa Chie , Chiba Mayumi , Ishibashi Kana , Shichiri Mototada , Fukumoto Shinya , Yokoyama Naoaki , Takeya Motohiro , Xuan Xuenan , Arai Hiroyuki , Suzuki Hiroshi
Published: April 2010

Background

Various factors impact the severity of malaria, including the nutritional status of the host. Vitamin E, an intra and extracellular anti-oxidant, is one such nutrient whose absence was shown previously to negatively affect Plasmodium development. However, mechanisms of this Plasmodium inhibition, in addition to means by which to exploit this finding as a therapeutic strategy, remain unclear.

Methods

α-TTP knockout mice were infected with Plasmodium berghei NK65 or Plasmodium yoelii XL-17, parasitaemia, survival rate were monitored. In one part of the experiments mice were fed with a supplemented diet of vitamin E and then infected. In addition, parasite DNA damage was monitored by means of comet assay and 8-OHdG test. Moreover, infected mice were treated with chloroquine and parasitaemia and survival rate were monitored.

Results

Inhibition of α-tocopherol transfer protein (α-TTP), a determinant of vitamin E concentration in circulation, confers resistance to malarial infection as a result of oxidative damage to the parasites. Furthermore, in combination with the anti-malarial drug chloroquine results were even more dramatic.

Conclusion

Considering that these knockout mice lack observable negative impacts typical of vitamin E deficiency, these results suggest that inhibition of α-TTP activity in the liver may be a useful strategy in the prevention and treatment of malaria infection. Moreover, a combined strategy of α-TTP inhibition and chloroquine treatment might be effective against drug resistant parasites.
School-based participatory health education for malaria control in Ghana: engaging children as health messengers
Authors: Ayi Irene , Nonaka Daisuke , Adjovu Josiah K , Hanafusa Shigeki , Jimba Masamine , Bosompem Kwabena M , Mizoue Tetsuya , Takeuchi Tsutomu , Boakye Daniel A , Kobayashi Jun
Published: April 2010

Background

School children have been increasingly recognized as health messengers for malaria control. However, little evidence is available. The objective of this study was to determine the impact of school-based malaria education intervention on school children and community adults.

Methods

This study was conducted in the Dangme-East district of the Greater Accra Region, Ghana, between 2007 and 2008. Trained schoolteachers designed participatory health education activities and led school children to disseminate messages related to malaria control to their communities. Three schools and their respective communities were chosen for the study and assigned to an intervention group (one school) and a control group (two schools). Questionnaire-based interviews and parasitological surveys were conducted before and after the intervention, with the intervention group (105 children, 250 community adults) and the control group (81 children, 133 community adults). Chi-square and Fisher's Exact tests were used to analyse differences in knowledge, practices, and parasite prevalence between pre- and post-intervention.

Results

After the intervention, the misperception that malaria has multiple causes was significantly improved, both among children and community adults. Moreover, the community adults who treated a bed net with insecticide in the past six months, increased from 21.5% to 50.0% (p < 0.001). Parasite prevalence in school children decreased from 30.9% to 10.3% (p = 0.003). These positive changes were observed only in the intervention group.

Conclusions

This study suggests that the participatory health education intervention contributed to the decreased malaria prevalence among children. It had a positive impact not only on school children, but also on community adults, through the improvement of knowledge and practices. This strategy can be applied as a complementary approach to existing malaria control strategies in West African countries where school health management systems have been strengthened.
Selection in spatial stochastic models of cancer: Migration as a key modulator of fitness
Authors: Thalhauser Craig J , Lowengrub John S , Stupack Dwayne , Komarova Natalia L
Published: April 2010

Background

We study the selection dynamics in a heterogeneous spatial colony of cells. We use two spatial generalizations of the Moran process, which include cell divisions, death and migration. In the first model, migration is included explicitly as movement to a proximal location. In the second, migration is implicit, through the varied ability of cell types to place their offspring a distance away, in response to another cell's death.

Results

In both models, we find that migration has a direct positive impact on the ability of a single mutant cell to invade a pre-existing colony. Thus, a decrease in the growth potential can be compensated by an increase in cell migration. We further find that the neutral ridges (the set of all types with the invasion probability equal to that of the host cells) remain invariant under the increase of system size (for large system sizes), thus making the invasion probability a universal characteristic of the cells selection status. We find that repeated instances of large scale cell-death, such as might arise during therapeutic intervention or host response, strongly select for the migratory phenotype.

Conclusions

These models can help explain the many examples in the biological literature, where genes involved in cell's migratory and invasive machinery are also associated with increased cellular fitness, even though there is no known direct effect of these genes on the cellular reproduction. The models can also help to explain how chemotherapy may provide a selection mechanism for highly invasive phenotypes.

Reviewers

This article was reviewed by Marek Kimmel and Glenn Webb.
The evolutionary impact of androgen levels on prostate cancer in a multi-scale mathematical model
Authors: Eikenberry Steffen E , Nagy John D , Kuang Yang
Published: April 2010

Background

Androgens bind to the androgen receptor (AR) in prostate cells and are essential survival factors for healthy prostate epithelium. Most untreated prostate cancers retain some dependence upon the AR and respond, at least transiently, to androgen ablation therapy. However, the relationship between endogenous androgen levels and cancer etiology is unclear. High levels of androgens have traditionally been viewed as driving abnormal proliferation leading to cancer, but it has also been suggested that low levels of androgen could induce selective pressure for abnormal cells. We formulate a mathematical model of androgen regulated prostate growth to study the effects of abnormal androgen levels on selection for pre-malignant phenotypes in early prostate cancer development.

Results

We find that cell turnover rate increases with decreasing androgen levels, which may increase the rate of mutation and malignant evolution. We model the evolution of a heterogeneous prostate cell population using a continuous state-transition model. Using this model we study selection for AR expression under different androgen levels and find that low androgen environments, caused either by low serum testosterone or by reduced 5α-reductase activity, select more strongly for elevated AR expression than do normal environments. High androgen actually slightly reduces selective pressure for AR upregulation. Moreover, our results suggest that an aberrant androgen environment may delay progression to a malignant phenotype, but result in a more dangerous cancer should one arise.

Conclusions

The model represents a useful initial framework for understanding the role of androgens in prostate cancer etiology, and it suggests that low androgen levels can increase selection for phenotypes resistant to hormonal therapy that may also be more aggressive. Moreover, clinical treatment with 5α-reductase inhibitors such as finasteride may increase the incidence of therapy resistant cancers.

Reviewers

This article was reviewed by Ariosto S. Silva (nominated by Marek Kimmel) and Marek Kimmel.
Surveillance and simulation of bovine spongiform encephalopathy and scrapie in small ruminants in Switzerland
Authors: Häusermann Chantal , Schwermer Heinzpeter , Oevermann Anna , Nentwig Alice , Zurbriggen Andreas , Heim Dagmar , Seuberlich Torsten
Published: April 2010

Background

After bovine spongiform encephalopathy (BSE) emerged in European cattle livestock in 1986 a fundamental question was whether the agent established also in the small ruminants' population. In Switzerland transmissible spongiform encephalopathies (TSEs) in small ruminants have been monitored since 1990. While in the most recent TSE cases a BSE infection could be excluded, for historical cases techniques to discriminate scrapie from BSE had not been available at the time of diagnosis and thus their status remained unclear. We herein applied state-of-the-art techniques to retrospectively classify these animals and to re-analyze the affected flocks for secondary cases. These results were the basis for models, simulating the course of TSEs over a period of 70 years. The aim was to come to a statistically based overall assessment of the TSE situation in the domestic small ruminant population in Switzerland.

Results

In sum 16 TSE cases were identified in small ruminants in Switzerland since 1981, of which eight were atypical and six were classical scrapie. In two animals retrospective analysis did not allow any further classification due to the lack of appropriate tissue samples. We found no evidence for an infection with the BSE agent in the cases under investigation. In none of the affected flocks, secondary cases were identified. A Bayesian prevalence calculation resulted in most likely estimates of one case of BSE, five cases of classical scrapie and 21 cases of atypical scrapie per 100'000 small ruminants. According to our models none of the TSEs is considered to cause a broader epidemic in Switzerland. In a closed population, they are rather expected to fade out in the next decades or, in case of a sporadic origin, may remain at a very low level.

Conclusions

In summary, these data indicate that despite a significant epidemic of BSE in cattle, there is no evidence that BSE established in the small ruminant population in Switzerland. Classical and atypical scrapie both occur at a very low level and are not expected to escalate into an epidemic. In this situation the extent of TSE surveillance in small ruminants requires reevaluation based on cost-benefit analysis.
Laparoscopic adjustable gastric band in an obese unrelated living donor prior to kidney transplantation: a case report
Authors: Koshy Anoop N , Wilkinson Stephen , Coombes Jeff S , Fassett Robert G
Published: April 2010

Introduction

Obese living donors who undergo donor nephrectomy have higher rates of intra-operative and post-operative complications. Many centres exclude obese donors from living donor transplant programs. Diet, exercise and medication are often ineffective weight loss interventions for donors, hence bariatric surgery should be considered.

Case presentation

We report the case of a 53-year-old Caucasian woman who underwent laparoscopically adjustable gastric banding. The procedure enabled her to lose sufficient weight to gain eligibility for kidney donation. After losing weight, she had an uncomplicated laparoscopic donor nephrectomy surgery, and the recipient underwent successful kidney transplantation.

Conclusion

Laparoscopically adjustable gastric banding should be considered for obese potential living kidney donors whenever transplantation units restrict access to donor nephrectomy based on the increased surgical risk for donors.
Imported and travelling dogs as carriers of canine vector-borne pathogens in Germany
Authors: Menn Brigitte , Lorentz Susanne , Naucke Torsten J
Published: April 2010

Background

With the import of pets and pets taken abroad, arthropod-borne diseases have increased in frequency in German veterinary practices. This is reflected by 4,681 dogs that have been either travelled to or relocated from endemic areas to Germany. The case history of these dogs and the laboratory findings have been compared with samples collected from 331 dogs living in an endemic area in Portugal. The various pathogens and the seroprevalences were examined to determine the occurrence of, and thus infection risk, for vector-borne pathogens in popular travel destinations.

Results

4,681 dogs were examined serological for Leishmania infantum, Babesia canis and Ehrlichia canis. Buffy coats were detected for Hepatozoon canis and blood samples were examined for microfilariae via the Knott's test. The samples were sent in from animal welfare organizations or private persons via veterinary clinics. Upon individual requests, dogs were additionally examined serological for Anaplasma phagocytophilum, Borrelia burgdorferi and Rickettsia conorii. Overall B. canis was the most prevalent pathogen detected by antibody titers (23.4%), followed by L. infantum (12.2%) and E. canis (10.1%). Microfilariae were detected in 7.7% and H. canis in 2.7% of the examined dogs. In 332/1862 dogs A. phagocytophilum, in 64/212 B. burgdorferi and in 20/58 R. conorii was detected. Of the 4,681 dogs, in total 4,226 were imported to Germany from endemic areas. Eighty seven dogs joined their owners for a vacation abroad. In comparison to the laboratory data from Germany, we examined 331 dogs from Portugal. The prevalence of antibodies/pathogens we detected was: 62.8% to R. conorii, 58% to B. canis, 30.5% to A. phagocytophilum, 24.8% to E. canis, 21.1% to H. canis (via PCR), 9.1% to L. infantum and 5.3% to microfilariae.

Conclusions

The examination of 4,681 dogs living in Germany showed pathogens like L. infantum that are non-endemic in Germany. Furthermore, the German data are similar in terms of multiple pathogen infection to the data recorded for dogs from Portugal. Based on these findings the importation of dogs from endemic predominantly Mediterranean regions to Germany as well as travelling with dogs to these regions carries a significant risk of acquiring an infection. Thus we would conclude that pet owners seek advice of the veterinarians prior to importing a dog from an endemic area or travel to such areas. In general, it might be advisable to have a European recording system for translocation of dogs.
Histone variant macroH2A1 deletion in mice causes female-specific steatosis
Authors: Boulard Mathieu , Storck Sébastien , Cong Rong , Pinto Rodrigo , Delage Hélène , Bouvet Philippe
Published: April 2010

Background

Vertebrate heterochromatin contains a non-allelic variant of the histone H2A called macroH2A1, which has the characteristic of being three times the size of the canonical H2A. The macroH2A1 C-terminal extension can recruit onto chromatin the poly-ADP-ribose polymerase (PARP)1, which is crucial for DNA repair. This led to the speculation that macroH2A1 could be essential for genome surveillance; however, no experimental evidence supported this hypothesis. Because macroH2A1 has been found to be enriched on the inactive X-chromosome in females, it is thought to play a role in sex chromosome dosage compensation through its ability to regulate gene expression. However, more genetic data are needed to further understand the function of macroH2A1 in mammals.

Results

Deletion of the murine geneH2afy, which encodes for macroH2A1, resulted in lipid accumulation in liver. Hepatic steatosis caused byH2afydisruption occurred specifically in homozygous mutant females. The metabolic disorder constantly affected half of the number of homozygote females. Given the mixed genetic background of the mutants, an unreported genetic modifier is likely to influence the penetrance of the phenotype. In addition, the X-linkedthyroxine-binding globulin(Tbg) gene was specifically upregulated in steatotic livers. Chromatin immunoprecitation indicated that macroH2A1 is enriched at theTbgpromoter in wild-type female animals, indicating that increasedTbgexpression inH2afynull mutants is likely to be a direct consequence of the absence of macroH2A1. Furthermore, male mice, which are not prone to the metabolic disorder, had a reduced level of macroH2A1 incorporated into theTbgpromoter.

Conclusions

Because TBG is the main carrier of the thyroid hormone T4, which regulates energy metabolism, we propose that overexpression of TBG is responsible for the fat accumulation observed inH2afy-deficient liver. Moreover, our results suggest that the sexual dimorphism of the steatotic phenotype is probably due to the different incorporation of macroH2A1 in males and females. In combination with previous studies, our data demonstrate a role for macroH2A1 in regulating homeostasis in a sex-dependent manner, subject to genetic background.
Neurocognitive impairment among HIV‐positive individuals in Botswana: a pilot study
Authors: Lawler Kathy , Mosepele Mosepele , Ratcliffe Sarah , Seloilwe Esther , Steele Katherine , Nthobatsang Rudo , Steenhoff Andrew
Published: April 2010

Background

The primary objective of this study was to determine the prevalence of neurocognitive impairment among HIV‐positive individuals in Botswana, using the International HIV Dementia Scale (IHDS). We also compared performance on the IHDS with performance on tests of verbal learning/memory and processing speed, and investigated the association between performance on the IHDS and such variables as depression, age, level of education and CD4 count.

Methods

We conducted a cross‐sectional study of 120 HIV‐positive individuals randomly selected from an outpatient HIV clinic in Gaborone, Botswana. Patients provided a detailed clinical history and underwent neuropsychological testing; measures of depression, daily activities and subjective cognitive complaints were recorded.

Results

Despite the fact that 97.5% of subjects were receiving highly active antiretroviral therapy (HAART), 38% met criteria for dementia on the IHDS, and 24% were diagnosed with major depressive disorder. There was a significant association between neurocognitive impairment as measured by the IHDS and performance on the other two cognitive measures of verbal learning/memory and processing speed. Level of education significantly affected performance on all three cognitive measures, and age affected processing speed and performance on the IHDS. Depression and current CD4 count did not affect performance on any of the cognitive measures.

Conclusions

The prevalence of neurocognitive impairment in HIV‐positive individuals in Botswana is higher than expected, especially since almost all of the subjects in this study were prescribed HAART. This suggests the need to reconsider the timing of introduction of antiretroviral therapy in developing countries where HAART is generally not administered until the CD4 cell count has dropped to 200/mm3 or below. The contribution of other factors should also be considered, such as poor central nervous system penetration of some antiretrovirals, drug resistance, potential neurotoxicity, and co‐morbidities. Memory impairment and poor judgment may be underlying causes for behaviours that contribute to the spread of HIV and to poor adherence. It is important to identify these neurobehavioural complications of HIV so that effective treatments can be developed.
Inhaled activated protein C protects mice from ventilator-induced lung injury
Authors: Maniatis Nikolaos A , Letsiou Eleftheria , Orfanos Stylianos E , Kardara Matina , Dimopoulou Ioanna , Nakos Georgios , Lekka Marilena E , Roussos Charalambos , Armaganidis Apostolos , Kotanidou Anastasia
Published: April 2010

Introduction

Activated Protein C (APC), an endogenous anticoagulant, improves tissue microperfusion and endothelial cell survival in systemic inflammatory states such as sepsis, but intravenous administration may cause severe bleeding. We have thus addressed the role of APC delivered locally by inhalation in preventing acute lung injury from alveolar overdistention and the subsequent ventilator-induced lung injury (VILI). We also assessed the effects of APC on the activation status of Extracellular- Regulated Kinase 1/2 (ERK) pathway, which has been shown to be involved in regulating pulmonary responses to mechanical stretch.

Methods

Inhaled APC (12.5 μg drotrecogin-α × 4 doses) or saline was given to tracheotomized C57/Bl6 mice starting 20 min prior to initiation of injurious mechanical ventilation with tidal volume 25 mL/Kg for 4 hours and then hourly thereafter; control groups receiving inhaled saline were ventilated with 8 mL/Kg for 30 min or 4 hr. We measured lung function (respiratory system elastance H), arterial blood gases, surrogates of vascular leak (broncho-alveolar lavage (BAL) total protein and angiotensin-converting enzyme (ACE)-activity), and parameters of inflammation (BAL neutrophils and lung tissue myeloperoxidase (MPO) activity). Morphological alterations induced by mechanical ventilation were examined in hematoxylin-eosin lung tissue sections. The activation status of ERK was probed in lung tissue homogenates by immunoblotting and in paraffin sections by immunohistochemistry. The effect of APC on ERK signaling downstream of the thrombin receptor was tested on A549 human lung epithelial cells by immunoblotting. Statistical analyses were performed using ANOVA with appropriate post-hoc testing.

Results

In mice subjected to VILI without APC, we observed hypoxemia, increased respiratory system elastance and inflammation, assessed by BAL neutrophil counts and tissue MPO activity. BAL total protein levels and ACE activity were also elevated by VILI, indicating compromise of the alveolo-capillary barrier. In addition to preserving lung function, inhaled APC prevented endothelial barrier disruption and attenuated hypoxemia and the inflammatory response. Mechanistically, we found a strong activation of ERK in lung tissues by VILI, which was prevented by APC, suggestive of pathogenetic involvement of the Mitogen-Activated Kinase pathway. In cultured human lung epithelial cells challenged by thrombin, APC abrogated the activation of ERK and its downstream effector, cytosolic Phospholipase A2.

Conclusions

Topical application of APC by inhalation may effectively reduce lung injury induced by mechanical ventilation in mice.