bluuebunny/crossref_metadata_2025 huggingface dataset:
Bcl-2, Bcl-xL, and Bcl-w are not equivalent targets of ABT-737 and navitoclax (ABT-263) in lymphoid and leukemic cells
Authors: Mérino Delphine , Khaw Seong L. , Glaser Stefan P. , Anderson Daniel J. , Belmont Lisa D. , Wong Chihunt , Yue Peng , Robati Mikara , Phipson Belinda , Fairlie Walter D. , Lee Erinna F. , Campbell Kirsteen J. , Vandenberg Cassandra J. , Cory Suzanne , Roberts Andrew W. , Ludlam Mary J. C. , Huang David C. S. , Bouillet Philippe
Published: April 2012

The BH3-mimetic ABT-737 and an orally bioavailable compound of the same class, navitoclax (ABT-263), have shown promising antitumor efficacy in preclinical and early clinical studies. Although both drugs avidly bind Bcl-2, Bcl-xL, and Bcl-w in vitro, we find that Bcl-2 is the critical target in vivo, suggesting that patients with tumors overexpressing Bcl-2 will probably benefit. In human non-Hodgkin lymphomas, high expression of Bcl-2 but not Bcl-xL predicted sensitivity to ABT-263. Moreover, we show that increasing Bcl-2 sensitized normal and transformed lymphoid cells to ABT-737 by elevating proapoptotic Bim. In striking contrast, increasing Bcl-xL or Bcl-w conferred robust resistance to ABT-737, despite also increasing Bim. Cell-based protein redistribution assays unexpectedly revealed that ABT-737 disrupts Bcl-2/Bim complexes more readily than Bcl-xL/Bim or Bcl-w/Bim complexes. These results have profound implications for how BH3-mimetics induce apoptosis and how the use of these compounds can be optimized for treating lymphoid malignancies.
DNA-binding factor CTCF and long-range gene interactions in V(D)J recombination and oncogene activation
Authors: Ribeiro de Almeida Claudia , Stadhouders Ralph , Thongjuea Supat , Soler Eric , Hendriks Rudi W.
Published: April 2012

Regulation of V(D)J recombination events at immunoglobulin (Ig) and T-cell receptor loci in lymphoid cells is complex and achieved via changes in substrate accessibility. Various studies over the last year have identified the DNA-binding zinc-finger protein CCCTC-binding factor (CTCF) as a crucial regulator of long-range chromatin interactions. CTCF often controls specific interactions by preventing inappropriate communication between neighboring regulatory elements or independent chromatin domains. Although recent gene targeting experiments demonstrated that the presence of the CTCF protein is not required for the process of V(D)J recombination per se, CTCF turned out to be essential to control order, lineage specificity and to balance the Ig V gene repertoire. Moreover, CTCF was shown to restrict activity of κ enhancer elements to the Ig κ locus. In this review, we discuss CTCF function in the regulation of V(D)J recombination on the basis of established knowledge on CTCF-mediated chromatin loop domains in various other loci, including the imprinted H19-Igf2 locus as well as the complex β-globin, MHC class II and IFN-γ loci. Moreover, we discuss that loss of CTCF-mediated restriction of enhancer activity may well contribute to oncogenic activation, when in chromosomal translocations Ig enhancer elements and oncogenes appear in a novel genomic context.
Metabolic classification of microbial genomes using functional probes
Authors: Lee Chi-Ching , Lo Wei-Cheng , Lai Szu-Ming , Chen Yi-Ping Phoebe , Tang Chuan Yi , Lyu Ping-Chiang
Published: April 2012

Background

Microorganisms able to grow under artificial culture conditions comprise only a small proportion of the biosphere's total microbial community. Until recently, scientists have been unable to perform thorough analyses of difficult-to-culture microorganisms due to limitations in sequencing technology. As modern techniques have dramatically increased sequencing rates and rapidly expanded the number of sequenced genomes, in addition to traditional taxonomic classifications which focus on the evolutionary relationships of organisms, classifications of the genomes based on alternative points of view may help advance our understanding of the delicate relationships of organisms.

Results

We have developed a proteome-based method for classifying microbial species. This classification method uses a set of probes comprising short, highly conserved amino acid sequences. For each genome, in silico translation is performed to obtained its proteome, based on which a probe-set frequency pattern is generated. Then, the probe-set frequency patterns are used to cluster the proteomes/genomes.

Conclusions

Features of the proposed method include a high running speed in challenge of a large number of genomes, and high applicability for classifying organisms with incomplete genome sequences. Moreover, the probe-set clustering method is sensitive to the metabolic phenotypic similarities/differences among species and is thus supposed potential for the classification or differentiation of closely-related organisms.
In vitro study of uptake and synthesis of creatine and its precursors by cerebellar granule cells and astrocytes suggests some hypotheses on the physiopathology of the inherited disorders of creatine metabolism
Authors: Carducci Claudia , Carducci Carla , Santagata Silvia , Adriano Enrico , Artiola Cristiana , Thellung Stefano , Gatta Elena , Robello Mauro , Florio Tullio , Antonozzi Italo , Leuzzi Vincenzo , Balestrino Maurizio
Published: April 2012

Background

The discovery of the inherited disorders of creatine (Cr) synthesis and transport in the last few years disclosed the importance of blood Cr supply for the normal functioning of the brain. These putatively rare diseases share a common pathogenetic mechanism (the depletion of brain Cr) and similar phenotypes characterized by mental retardation, language disturbances, seizures and movement disorders. In the effort to improve our knowledge on the mechanisms regulating Cr pool inside the nervous tissue, Cr transport and synthesis and related gene transcripts were explored in primary cultures of rat cerebellar granule cells and astrocytes.

Methods

Cr uptake and synthesis were explored in vitro by incubating monotypic primary cultures of rat type I astrocytes and cerebellar granule cells with: a) D3-Creatine (D3Cr) and D3Cr plus β-guanidinopropionate (GPA, an inhibitor of Cr transporter), and b) labelled precursors of Guanidinoacetate (GAA) and Cr (Arginine, Arg; Glycine, Gly). Intracellular D3Cr and labelled GAA and Cr were assessed by ESI-MS/MS. Creatine transporter (CT1), L-arginine:glycine amidinotransferase (AGAT), and S-adenosylmethionine:guanidinoacetate N-methyltransferase (GAMT) gene expression was assessed in the same cells by real time PCR.

Results

D3Cr signal was extremely high in cells incubated with this isotope (labelled/unlabelled Cr ratio reached about 10 and 122, respectively in cerebellar granule cells and astrocytes) and was reduced by GPA. Labelled Arg and Gly were taken up by the cells and incorporated in GAA, whose concentration paralleled that of these precursors both in the extracellular medium and inside the cells (astrocytes). In contrast, the increase of labelled Cr was relatively much more limited since labelled Cr after precursors' supplementation did not exceed 2,7% (cerebellar granule cells) and 21% (astrocytes) of unlabelled Cr. Finally, AGAT, GAMT and SLC6A8 were expressed in both kind of cells.

Conclusions

Our results confirm that both neurons and astrocytes have the capability to synthesize and uptake Cr, and suggest that at least in vitro intracellular Cr can increase to a much greater extent through uptake than through de novo synthesis. Our results are compatible with the clinical observations that when the Cr transporter is defective, intracellular Cr is absent despite the brain should be able to synthesize it. Further research is needed to fully understand to what extent our results reflect the in vivo situation.
Distinct muscarinic acetylcholine receptor subtypes mediate pre- and postsynaptic effects in rat neocortex
Authors: Gigout Sylvain , Jones Gareth A , Wierschke Stephan , Davies Ceri H , Watson Jeannette M , Deisz Rudolf A
Published: April 2012

Background

Cholinergic transmission has been implicated in learning, memory and cognition. However, the cellular effects induced by muscarinic acetylcholine receptors (mAChRs) activation are poorly understood in the neocortex. We investigated the effects of the cholinergic agonist carbachol (CCh) and various agonists and antagonists on neuronal activity in rat neocortical slices using intracellular (sharp microelectrode) and field potential recordings.

Results

CCh increased neuronal firing but reduced synaptic transmission. The increase of neuronal firing was antagonized by pirenzepine (M1/M4 mAChRs antagonist) but not by AF-DX 116 (M2/M4 mAChRs antagonist). Pirenzepine reversed the depressant effect of CCh on excitatory postsynaptic potential (EPSP) but had marginal effects when applied before CCh. AF-DX 116 antagonized the depression of EPSP when applied before or during CCh. CCh also decreased the paired-pulse inhibition of field potentials and the inhibitory conductances mediated by GABAA and GABAB receptors. The depression of paired-pulse inhibition was antagonized or prevented by AF-DX 116 or atropine but only marginally by pirenzepine. The inhibitory conductances were unaltered by xanomeline (M1/M4 mAChRs agonist), yet the CCh-induced depression was antagonized by AF-DX 116. Linopirdine, a selective M-current blocker, mimicked the effect of CCh on neuronal firing. However, linopirdine had no effect on the amplitude of EPSP or on the paired-pulse inhibition, indicating that M-current is involved in the increase of neuronal excitability but neither in the depression of EPSP nor paired-pulse inhibition.

Conclusions

These data indicate that the three effects are mediated by different mAChRs, the increase in firing being mediated by M1 mAChR, decrease of inhibition by M2 mAChR and depression of excitatory transmission by M4 mAChR. The depression of EPSP and increase of neuronal firing might enhance the signal-to-noise ratio, whereas the concomitant depression of inhibition would facilitate long-term potentiation. Thus, this triade of effects may represent a “neuronal correlate” of attention and learning.
Race-ethnic differences in the association of genetic loci with HbA1c levels and mortality in U.S. adults: the third National Health and Nutrition Examination Survey (NHANES III)
Authors: Grimsby Jonna L , Porneala Bianca C , Vassy Jason L , Yang Quanhe , Florez José C , Dupuis Josée , Liu Tiebin , Yesupriya Ajay , Chang Man-Huei , Ned Renee M , Dowling Nicole F , Khoury Muin J , Meigs James B ,   the MAGIC Investigators
Published: April 2012

Background

Hemoglobin A1c (HbA1c) levels diagnose diabetes, predict mortality and are associated with ten single nucleotide polymorphisms (SNPs) in white individuals. Genetic associations in other race groups are not known. We tested the hypotheses that there is race-ethnic variation in 1) HbA1c-associated risk allele frequencies (RAFs) for SNPs near SPTA1, HFE, ANK1, HK1, ATP11A, FN3K, TMPRSS6, G6PC2, GCK, MTNR1B; 2) association of SNPs with HbA1c and 3) association of SNPs with mortality.

Methods

We studied 3,041 non-diabetic individuals in the NHANES (National Health and Nutrition Examination Survey) III. We stratified the analysis by race/ethnicity (NHW: non-Hispanic white; NHB: non-Hispanic black; MA: Mexican American) to calculate RAF, calculated a genotype score by adding risk SNPs, and tested associations with SNPs and the genotype score using an additive genetic model, with type 1 error = 0.05.

Results

RAFs varied widely and at six loci race-ethnic differences in RAF were significant (p < 0.0002), with NHB usually the most divergent. For instance, at ATP11A, the SNP RAF was 54% in NHB, 18% in MA and 14% in NHW (p < .0001). The mean genotype score differed by race-ethnicity (NHW: 10.4, NHB: 11.0, MA: 10.7, p < .0001), and was associated with increase in HbA1c in NHW (β = 0.012 HbA1c increase per risk allele, p = 0.04) and MA (β = 0.021, p = 0.005) but not NHB (β = 0.007, p = 0.39). The genotype score was not associated with mortality in any group (NHW: OR (per risk allele increase in mortality) = 1.07, p = 0.09; NHB: OR = 1.04, p = 0.39; MA: OR = 1.03, p = 0.71).

Conclusion

At many HbA1c loci in NHANES III there is substantial RAF race-ethnic heterogeneity. The combined impact of common HbA1c-associated variants on HbA1c levels varied by race-ethnicity, but did not influence mortality.
Extragonadal mixed germ cell tumor of the right arm: description of the first case in the literature
Authors: Benali Hicham Ait , Lalya lssam , Allaoui Mohamed , Benmansour Aniss , Elkhanoussi Basma , Benjelloun Samir , Benjaafar Noureddine , Elyaacoubi Mourad
Published: April 2012

Background

Extragonadal localization of germ cell tumors (GCTs) is rare; to the best of our knowledge, a location in the soft tissue of the arm has never been previously reported in the literature.

Case presentation

We report the case of a 37-year-old man who presented with a primary malignant mixed non-seminomatous GCT (teratocarcinoma variety) in the right arm, treated by a combination of cisplatin-based chemotherapy and surgery. After 18 months of close follow-up, no locoregional recurrence or distant metastases have been detected.

Conclusions

A combination of chemotherapy and surgery is the most appropriate treatment strategy for extragonadal GCTs, to ensure both local and systemic control.
Expression of the T regulatory cell transcription factor FoxP3 in peri-implantation phase endometrium in infertile women with endometriosis
Authors: Chen Shufang , Zhang Jian , Huang Changxiao , Lu Wen , Liang Yan , Wan Xiaoping
Published: April 2012

Background

Endometriosis (EM) is highly associated with infertility. The precise mechanism underlying EM-associated infertility remains controversial. This study aimed to investigate the pathogenesis of infertility in women with EM by comparing FoxP3+ T regulatory cells (Tregs) expression in the eutopic endometrium of infertile women with EM and endometrium from healthy fertile women.

Methods

As a marker of Tregs, FoxP3 expression was analyzed in eutopic endometrium during the peri-implantation phase in infertile women with mild EM (n = 7), advanced EM (n = 20), and normally fertile women without EM (n = 20). FoxP3 mRNA expression was analyzed by quantitative real-time RT-PCR. FoxP3 protein expression was assessed by immunohistochemistry.

Results

FoxP3 mRNA expression in all infertile patients with EM was significantly higher than the control group (P < 0.05) by non-parametric Mann–Whitney U-test. Further analysis based on the extent of EM revealed that FoxP3 mRNA expression in infertile patients with advanced EM was significantly higher than the mild EM group and the control group (P < 0.05). Immunohistochemistry analysis showed predominant positive staining for FoxP3 protein in the endometrial stroma. In addition, the number of FoxP3+ cells in the eutopic endometrium of infertile women with advanced EM was marginally higher than the mild EM group and the control group, although the differences were not statistically significant (P > 0.05) by two-tailed t-tests.

Conclusions

These findings suggest that FoxP3+ Tregs in the peri-implantation endometrium might participate in the pathogenesis of advanced EM. However, they are not directly involved in the pathogenesis of advanced EM associated with infertility. The differential expression of FoxP3 in infertile women with mild EM and advanced EM implicates that notable differences in the uterine immune status are likely involved in the pathogenesis of mild EM associated with infertility in the peri-implantation endometrium.
Fabrication of palladium/graphene oxide composite by plasma reduction at room temperature
Authors: Yu Yue , Li Yingzhi , Pan Yunxiang , Liu Chang-jun
Published: April 2012

Pd nanoparticles were fabricated on graphene oxide (GO) using a deposition-precipitation method with a glow discharge plasma reduction at room temperature. Argon was employed as the plasma-generating gas. The novel plasma method selectively reduces the metal ions. The graphene oxide has no change with this plasma reduction according to the Fourier transform infrared analysis. The Pd nanoparticles on the GO were uniformly distributed with an average diameter of 1.6 nm. The functional groups on the GO not only prevent Pd nanoparticles from further aggregation but also provide a strong hydrophilic property to the Pd/GO composite, which can form stable colloidal dispersions in water.
An improved method for the removal of ring artifacts in high resolution CT imaging
Authors: Rashid Sabrina , Lee Soo Yeol , Hasan Md Kamrul
Published: April 2012

In high resolution computed tomography (CT) using flat panel detectors, imperfect or defected detector elements cause stripe artifacts in sinogram which results in concentric ring artifacts in the image. Such ring artifacts obscure image details in the regions of interest of the image. In this article, novel techniques are proposed for the detection, classification, and correction of ring artifacts in the sinogram domain. The proposed method is suitable for multislice CT with parallel or fan beam geometry. It can also be employed for ring artifact removal in 3D cone beam volume CT by adopting a sinogram by sinogram processing technique. The detection algorithm is based on applying data driven thresholds on the mean curve and difference curve of the sinogram. The ring artifacts are classified into three types and a separate correction algorithm is used for each class. The performance of the proposed techniques is evaluated on a number of real micro-CT images. Experimental results corroborate that the proposed algorithm can remove ring artifacts from micro-CT images more effectively as compared to other recently reported techniques in the literature.
UBXN7 docks on neddylated cullin complexes using its UIM motif and causes HIF1α accumulation
Authors: Bandau Susanne , Knebel Axel , Gage Zoe O , Wood Nicola T , Alexandru Gabriela
Published: April 2012

Background

The proteins from the UBA-UBX family interact with ubiquitylated proteins via their UBA domain and with p97 via their UBX domain, thereby acting as substrate-binding adaptors for the p97 ATPase. In particular, human UBXN7 (also known as UBXD7) mediates p97 interaction with the transcription factor HIF1α that is actively ubiquitylated in normoxic cells by a CUL2-based E3 ligase, CRL2. Mass spectrometry analysis of UBA-UBX protein immunoprecipitates showed that they interact with a multitude of E3 ubiquitin-ligases. Conspicuously, UBXN7 was most proficient in interacting with cullin-RING ligase subunits. We therefore set out to determine whether UBXN7 interaction with cullins was direct or mediated by its ubiquitylated targets bound to the UBA domain.

Results

We show that UBXN7 interaction with cullins is independent of ubiquitin- and substrate-binding. Instead, it relies on the UIM motif in UBXN7 that directly engages the NEDD8 modification on cullins. To understand the functional consequences of UBXN7 interaction with neddylated cullins, we focused on HIF1α, a CUL2 substrate that uses UBXD7/p97 as a ubiquitin-receptor on its way to proteasome-mediated degradation. We find that UBXN7 over-expression converts CUL2 to its neddylated form and causes the accumulation of non-ubiquitylated HIF1α. Both of these effects are strictly UIM-dependent and occur only when UBXN7 contains an intact UIM motif. We also show that HIF1α carrying long ubiquitin-chains can recruit alternative ubiquitin-receptors, lacking p97's ATP-dependent segregase activity.

Conclusions

Our study shows that independently of its function as a ubiquitin-binding adaptor for p97, UBXN7 directly interacts with neddylated cullins and causes the accumulation of the CUL2 substrate HIF1α. We propose that by sequestering CUL2 in its neddylated form, UBXN7 negatively regulates the ubiquitin-ligase activity of CRL2 and this might prevent recruitment of ubiquitin-receptors other than p97 to nuclear HIF1α.
Metabolic network analysis predicts efficacy of FDA-approved drugs targeting the causative agent of a neglected tropical disease
Authors: Chavali Arvind K , Blazier Anna S , Tlaxca Jose L , Jensen Paul A , Pearson Richard D , Papin Jason A
Published: April 2012

Background

Systems biology holds promise as a new approach to drug target identification and drug discovery against neglected tropical diseases. Genome-scale metabolic reconstructions, assembled from annotated genomes and a vast array of bioinformatics/biochemical resources, provide a framework for the interrogation of human pathogens and serve as a platform for generation of future experimental hypotheses. In this article, with the application of selection criteria for both Leishmania major targets (e.g. in silico gene lethality) and drugs (e.g. toxicity), a method (MetDP) to rationally focus on a subset of low-toxic Food and Drug Administration (FDA)-approved drugs is introduced.

Results

This metabolic network-driven approach identified 15 L. major genes as high-priority targets, 8 high-priority synthetic lethal targets, and 254 FDA-approved drugs. Results were compared to previous literature findings and existing high-throughput screens. Halofantrine, an antimalarial agent that was prioritized using MetDP, showed noticeable antileishmanial activity when experimentally evaluated in vitro against L. major promastigotes. Furthermore, synthetic lethality predictions also aided in the prediction of superadditive drug combinations. For proof-of-concept, double-drug combinations were evaluated in vitro against L. major and four combinations involving the drug disulfiram that showed superadditivity are presented.

Conclusions

A direct metabolic network-driven method that incorporates single gene essentiality and synthetic lethality predictions is proposed that generates a set of high-priority L. major targets, which are in turn associated with a select number of FDA-approved drugs that are candidate antileishmanials. Additionally, selection of high-priority double-drug combinations might provide for an attractive and alternative avenue for drug discovery against leishmaniasis.
Therapeutic efficacy of milbemycin oxime/praziquantel oral formulation (Milbemax®) against Thelazia callipaeda in naturally infested dogs and cats
Authors: Motta Bruna , Schnyder Manuela , Basano Fabrizio Solari , Nägeli Fabio , Nägeli Catherine , Schiessl Brigitte , Mallia Egidio , Lia Riccardo P , Dantas-Torres Filipe , Otranto Domenico
Published: April 2012

Background

Over the last few decades, canine and feline thelaziosis caused byThelazia callipaedaeye worms has gained the attention of the veterinary community due to the spread of this ocular infestation in geographical areas previously regarded as non endemic. The therapeutic efficacy of milbemycin oxime/praziquantel tablets (Milbemax®) againstT. callipaedawas tested in naturally infested dogs and cats.

Methods

From January 2009 to July 2011 a placebo controlled and randomized field study was conducted inT. callipaedaendemic areas of Switzerland (CH) and Italy (ITA) involving client-owned animals. Dogs (n = 56) and cats (n = 31) were physically examined at enrolment Day 0 (D0) and twice afterwards (D7 and D14). Infested animals were orally treated with Milbemax® or with placebo tablets on D0 and, if an animal was found still infested withT. callipaeda, also on D7. On D14 nematodes were flushed from the conjunctiva, identified and counted.

Results

Out of 56 dogs, 43 were included in the statistical analysis, whereas 13 were excluded because the products under investigation were not administered with food, as required by the label. On D7 and D14, 72.7% and 90.9% of treated dogs were eye worm free, whereas in the placebo group 95.2% and 76.2% still harbored nematodes, resulting in a mean percentage worm count reduction for the Milbemax® group of 86.1% and 96.8%, respectively. Both results were significantly higher (p = 0.0001) than the placebo group. Out of the 31 cats included in the study at D7 and D14, 53.3% and 73.3% treated with Milbemax® were free ofT. callipaeda, while 81.3% and 73.3 in the placebo group were still harbouring eye worms, resulting in a mean percentage worm count reduction for the treated group of 62.2% and 80.0%, respectively. Both results were significantly higher (p = 0.0106 andp = 0.0043) than the placebo group.

Conclusions

The commercial formulation of milbemycin oxime at the minimal dose of 0.5 mg/kg and 2 mg/k in dogs and cats, respectively, showed a high therapeutic efficacy in curingT. callipaedainfestations. The advantages of an oral application are additionally increased by the large spectrum of activity of praziquantel and milbemycin oxime against Cestodes and Nematodes infesting dogs and cats.
Autogenous osteochondral graft transplantation for steroid-induced osteonecrosis of the femoral condyle: A report of three young patients
Authors: Fujita Norifumi , Matsumoto Tomoyuki , Kubo Seiji , Matsushita Takehiko , Ishida Kazunari , Hoshino Yuichi , Nishimoto Koji , Kurosaka Masahiro , Kuroda Ryosuke
Published: April 2012

Steroid-induced osteonecrosis of the femoral condyle is a relatively uncommon condition and is often difficult to select appropriate treatment especially in young patients. Three young men (aged 25, 18, and 24) presented with severe pain and dysfunction of the knee diagnosed as steroid-induced osteonecrosis of the femoral condyle by magnetic resonance imaging (MRIs). Full-thickness cartilage defects sized 20 × 10, 15 × 10, and 30 × 20 mm respectively were classified as International Cartilage Repair Society Grade IV lesions and treated with osteochondral autograft transplantation. They were treated successfully with osteochondral autograft transplantation certificated by post-operative MRI and second look arthroscopy.
Therapeutic potential of targeting IL‐17 and IL‐23 in sepsis
Authors: Bosmann Markus , Ward Peter A
Published: April 2012

Severe sepsis is a major concern of public health in industrialized countries. It is estimated that in the United States 200,000‐400,000 cases occur annually and resulting in an extensive burden for the health care systems. To date, no FDA‐approved pharmacologic agents for the treatment or prevention of human sepsis are available. The current modalities of therapy in sepsis include the standard arsenal of supportive interventions in critical care medicine and pharmacotherapy, with use of antibiotics and catecholamines. Despite such efforts, the mortality rates of sepsis have remained around 30‐50 %. Extensive scientific studies have utilized animal models of disease and aimed for a better understanding of the pathophysiologic mechanisms during sepsis. Members of the IL‐17 family of cytokines, as well as the functionally related IL‐23, have been identified as new players in the molecular events during sepsis. Strategies for targeting these mediators with neutralizing antibodies during experimental sepsis in rodents have demonstrated efficacy, resulting in improved survival outcomes. Currently, it is not clear whether such findings can be translated to human sepsis. This review highlights the current knowledge on the biology of IL‐17 isoforms and IL‐23 as well as potential applications to clinical medicine.
Water quality legislation in Palestine over the past century
Authors: Marie Amer , Khayat Saed , Dajani Muna
Published: April 2012

Background

This paper deals with the water quality legislation that has been enforced in Palestine over the past century, from the Ottoman era through the British Mandate and Jordanian reign, to the Israeli occupation and current Palestinian autonomy.

Results

The study reveals that, due to the instability and the short interrupted spans of these regimes, apart from the Ottoman era, the successive ruling administrations were unable to draft water legislation in the interest of the Palestinian population, though the more stable Jordanian rule is an exception to this. Moreover, the study shows that the subject of the enacted legislations has depended on the circumstances that the population is subjected to or simply as reaction that deals instantly with a certain problem without taking into account any planning or future socioeconomic development. However, major concerns over the quality of accessible water gained momentum with an ever-increasing demand for limited water resources and the need for water treatment.

Conclusions

Investments in legislation and its enforcement will lead to significant economic development and public health and environmental quality enhancement through equitable and reasonable management of shared water resources and community empowerment and awareness.
Routine chest x-rays in intensive care units: a systematic review and meta-analysis
Authors: Ganapathy Anusoumya , Adhikari Neill KJ , Spiegelman Jamie , Scales Damon C
Published: April 2012

Introduction

Chest x-rays (CXRs) are the most frequent radiological tests performed in the intensive care unit (ICU). However, the utility of performing daily routine CXRs is unclear.

Methods

We searched Medline and Embase (1948 to March 2011) for randomized and quasi-randomized controlled trials (RCTs) and before-after observational studies comparing a strategy of routine CXRs to a more restrictive approach with CXRs performed to investigate clinical changes among critically ill adults or children. In duplicate, we extracted data on the CXR strategy, study quality and clinical outcomes (ICU and hospital mortality; duration of mechanical ventilation and ICU and hospital stay).

Results

Nine studies (39,358 CXRs; 9,611 patients) were included in the meta-analysis. Three trials (N = 870) of moderate to good quality provided information on the safety of a restrictive routine CXR strategy; only one trial systematically assessed for missed findings. Pooled data from trials showed no evidence of effect of a restrictive approach on ICU mortality (risk ratio [RR] 1.04, 95% confidence interval [CI] 0.84 to 1.28, P = 0.72; two trials, N = 776), hospital mortality (RR 0.98, 95% CI 0.68 to 1.41, P = 0.91; two trials, N = 259), ICU length of stay (weighted mean difference [WMD] -0.86 days, 95% CI -2.38 to 0.66 days, P = 0.27; three trials, N = 870), hospital length of stay (WMD -2.50 days, 95% CI -6.62 to 1.61 days, P = 0.23; two trials, N = 259), or duration of mechanical ventilation (WMD -0.30 days, 95% CI -1.48 to 0.89 days, P = 0.62; three trials, N = 705). Adding data from six observational studies, one of which systematically screened for missed findings, gave similar results.

Conclusions

This meta-analysis did not detect any harm associated with a restrictive chest radiograph strategy. However, confidence intervals were wide and harm was not rigorously assessed. Therefore, the safety of abandoning routine CXRs in patients admitted to the ICU remains uncertain.
Neural basis of autobiographical memory retrieval in schizophrenia
Authors: Cuervo-Lombard Christine , Lemogne Cédric , Gierski Fabien , Béra-Potelle Céline , Tran Eric , Portefaix Christophe , Kaladjian Arthur , Pierot Laurent , Limosin Frédéric
Published: April 2012

Background

Autobiographical memory retrieval is impaired in schizophrenia.

Aims

To determine the neural basis of this impairment.

Method

Thirteen patients with schizophrenia and 14 healthy controls performed an autobiographical memory retrieval task based on cue words during functional magnetic resonance imaging. Patients were selected on the basis of their ability to perform the task and all participants received training.

Results

Although patients and controls activated a similar brain network during autobiographical memory retrieval, patients displayed decreased activation in several of these regions, including the anterior cingulate cortex, left lateral prefrontal cortex, right cerebellum and ventral tegmental area (k ≥ 10, P < 0.001, uncorrected). In addition, activation of the caudate nuclei was negatively correlated with retrieval performance in controls but positively correlated with performance in patients.

Conclusions

The autobiographical memory retrieval brain network is impaired in schizophrenia. Patients with schizophrenia display decreased activation of the cognitive control network during retrieval, possibly due to aberrant functioning of the dorsal striatum.
Vitamin D3 Therapy Corrects the Tissue Sensitivity to Angiotensin II Akin to the Action of a Converting Enzyme Inhibitor in Obese Hypertensives: An Interventional Study
Authors: Vaidya Anand , Sun Bei , Larson Carol , Forman John P. , Williams Jonathan S.
Published: April 2012

Context:

Vitamin D deficiency and obesity are associated with increased tissue renin-angiotensin system (RAS) activity.

Objective:

The objective of the study was to evaluate whether vitamin D3 therapy in obesity reduces tissue-RAS activity, as indicated by an increase in tissue sensitivity to angiotensin II (AngII).

Participants:

Participants included obese subjects with hypertension and 25-hydroxyvitamin D less than 25 ng/ml.

Design:

Subjects were studied before and after 1 month of vitamin D3 15,000 IU/d, while in dietary sodium balance, and off all interfering medications. Fourteen subjects successfully completed all study procedures.

Setting:

The study was conducted at a clinical research center.

Outcome Measures:

At each study visit, tissue sensitivity to AngII was assessed by measuring renal plasma flow (RPF), mean arterial pressure (MAP), and adrenal secretion of aldosterone during an infusion of AngII. Subjects were then given captopril, and a second AngII infusion to evaluate the effect of captopril on tissue-RAS activity.

Results:

Vitamin D3 therapy increased 25-hydroxyvitamin D (18 to 52 ng/ml) and basal RPF (+5%) and lowered supine MAP (−3%) (all P < 0.01). There was a greater decline in RPF and higher stimulation of aldosterone with AngII infusion after vitamin D3 therapy (both P < 0.05). As anticipated, captopril increased the renal-vascular, MAP, and adrenal sensitivity to AngII, but this effect was much smaller after vitamin D3 therapy, indicating that vitamin D3 therapy corrected the tissue sensitivity to AngII akin to captopril.

Conclusions:

Vitamin D3 therapy in obese hypertensives modified RPF, MAP, and tissue sensitivity to AngII similar to converting enzyme inhibition. Whether chronic vitamin D3 therapy abrogates the development of diseases associated with excess RAS activity warrants investigation.
SNP Array Profiling of Childhood Adrenocortical Tumors Reveals Distinct Pathways of Tumorigenesis and Highlights Candidate Driver Genes
Authors: Letouzé Eric , Rosati Roberto , Komechen Heloisa , Doghman Mabrouka , Marisa Laetitia , Flück Christa , de Krijger Ronald R. , van Noesel Max M. , Mas Jean-Christophe , Pianovski Mara A. D. , Zambetti Gerard P. , Figueiredo Bonald C. , Lalli Enzo
Published: April 2012

Context:

Childhood adrenocortical tumors (ACT) are rare malignancies, except in southern Brazil, where a higher incidence rate is associated to a high frequency of the founder R337H TP53 mutation. To date, copy number alterations in these tumors have only been analyzed by low-resolution comparative genomic hybridization.

Objective:

We analyzed an international series of 25 childhood ACT using high-resolution single nucleotide polymorphism arrays to: 1) detect focal copy number alterations highlighting candidate driver genes; and 2) compare genetic alterations between Brazilian patients carrying the R337H TP53 mutation and non-Brazilian patients.

Results:

We identified 16 significantly recurrent chromosomal alterations (q-value < 0.05), the most frequent being −4q34, +9q33-q34, +19p, loss of heterozygosity (LOH) of chromosome 17 and 11p15. Focal amplifications and homozygous deletions comprising well-known oncogenes (MYC, MDM2, PDGFRA, KIT, MCL1, BCL2L1) and tumor suppressors (TP53, RB1, RPH3AL) were identified. In addition, eight focal deletions were detected at 4q34, defining a sharp peak region around the noncoding RNA LINC00290 gene. Although non-Brazilian tumors with a mutated TP53 were similar to Brazilian tumors, those with a wild-type TP53 displayed distinct genomic profiles, with significantly fewer rearrangements (P = 0.019). In particular, three alterations (LOH of chromosome 17, +9q33-q34, and −4q34) were significantly more frequent in TP53-mutated samples. Finally, two of four TP53 wild-type tumors displayed as sole rearrangement a copy-neutral LOH of the imprinted region at 11p15, supporting a major role for this region in ACT development.

Conclusions:

Our findings highlight potential driver genes and cellular pathways implicated in childhood ACT and demonstrate the existence of different oncogenic routes in this pathology.
Regulation of microRNA-375 by cAMP in Pancreatic β-Cells
Authors: Keller David M. , Clark Elizabeth A. , Goodman Richard H.
Published: April 2012

MicroRNA-375 (miR-375) is necessary for proper formation of pancreatic islets in vertebrates and is necessary for the development of β-cells in mice, but regulation of miR-375 in these cells is poorly understood. Here, we show that miR-375 is transcriptionally repressed by the cAMP-protein kinase A (PKA) pathway and that this repression is mediated through a block in RNA polymerase II binding to the miR-375 promoter. cAMP analogs that are PKA selective repress miR-375, as do cAMP agonists and the glucagon-like peptide-1 receptor agonist, exendin-4. Repression of the miR-375 precursor occurs rapidly in rat insulinoma INS-1 832/13 cells, within 15 min after cAMP stimulation, although the mature microRNA declines more slowly due to the kinetics of RNA processing. Repression of miR-375 in isolated rat islets by exendin-4 also occurs slowly, after several hours of stimulation. Glucose is another reported antagonist of miR-375 expression, although we demonstrate here that glucose does not target the microRNA through the PKA pathway. As reported previously, miR-375 negatively regulates insulin secretion, and attenuation of miR-375 through the cAMP-PKA pathway may boost the insulin response in pancreatic β-cells.
Calcium adjustment equations in neonates and children
Authors: Jassam Nuthar , Gopaul Shireen , McShane Philip , McHugh Anna , Coleman Robert , Thompson Douglas , Barth Julian H
Published: April 2012

Background

Calcium exists in human blood in a free form and in a form bound to plasma proteins, principally albumin. Since it is the ionized form that is biologically active, it has long been common practice to present calcium adjusted on the basis of serum albumin concentration. The concept of adjusted calcium has only been evaluated in adults. In this study, we evaluated the use of the adult-adjusted equation to report calcium in children.

Methods

We searched the laboratory information system over three teaching hospitals for young patients aged between newborn and 18 years old with a request for calcium and albumin analysis but with no evidence of disturbances of calcium homeostasis. These data were organized on the basis of age and was separated into four age groups (birth to 1 month old, 1 month to 1 year old, 1 to 5 years old and 5 to 18 years old). These data were subjected to regression analysis to derive the calcium-adjusted equation for each age group.

Results

There is an inverse relationship between the bias value and the age. The younger the age, the higher the difference between the adjusted calcium calculated by the adult equation and that calculated by the age-specific equation. This pattern was maintained on all sites.

Conclusion

For all sites, the adult-adjusted calcium equation may be used to calculate the adjusted calcium for children aged one year old and above.
The relative impact on leg symptoms of fears of getting varicose veins and of great saphenous vein reflux
Authors: Blaettler W , Amsler F , Mendoza E
Published: April 2012

Objective:

To assess possible links between fears of getting varicose veins and unknown great saphenous vein reflux with the prevalence and features of leg symptoms in healthy people and patients with varicose veins.

Methods:

Questionnaire and venous ultrasound in healthy volunteers and patients with great saphenous vein (GSV) incompetence.

Results:

Intensity of feelings of swelling and heaviness (S&H; scale 0–3) was 0.26 (±0.51) in healthy people without fears of varicose veins ( n = 162), 0.56 (±0.72) in the presence of GSV reflux ( n = 39, P = 0.001), 0.73 (±0.77) in the presence of fears of varicose veins ( n = 43, P, 0.001), 0.95 (±0.98) in the presence of both findings ( n = 10, P = 0.002) and 0.73 (±0.91) in patients ( n = 40, P < 0.001). Intensity of S&H was higher in women ( P < 0.001) and in the presence of a family history of varicose veins ( P = 0.003). Fears had a large influence on S&H ( F = 12.38, P < 0.001) while GSV reflux was less important ( F = 4.58, P = 0.033). Fears and GSV reflux were not related to each other ( r = 20.01, P = 0.933). The prevalence of a crawling sensation was equal in all study groups and cramps were more frequent in volunteers than in patients with GSV reflux ( P < 0.001).

Conclusions:

Healthy people with fears of getting varicose veins experience feelings of leg S&H as frequently as subjects with previously unknown GSV incompetence and patients with manifest varicose veins.
Plasma Prolylcarboxypeptidase (Angiotensinase C) Is Increased in Obesity and Diabetes Mellitus and Related to Cardiovascular Dysfunction
Authors: Xu Shengyuan , Lind Lars , Zhao Linshu , Lindahl Bertil , Venge Per
Published: April 2012

BACKGROUND

Prolylcarboxypeptidase (PRCP) (angiotensinase C) has 3 major targets, angiotensin II, prekallikrein, and α-melanocyte stimulating hormone1–13. The truncation of the latter leads to loss in appetite regulation and obesity in experimental animals. The objectives of this study were to purify PRCP from a native source, establish a sensitive immunoassay for PRCP, and relate plasma PRCP concentrations to signs and symptoms of obesity, diabetes mellitus, and cardiovascular dysfunction.

METHODS

Purification of PRCP from human neutrophils and establishment of a sensitive ELISA was carried out with the use of samples from study participants. Three cohorts were studied: healthy individuals (n = 40); a chest pain cohort (Fast Assessment of Thoracic Pain by Neural Networks) (n = 165); and a community-based cohort [Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS)] (n = 1004).

RESULTS

PRCP was purified to homogeneity. Mean (SD) plasma concentrations in healthy individuals were 12.9 (3.2) μg/L and were increased in patients with chest pain and in patients with obesity and/or diabetes mellitus (P < 0.0001). In the PIVUS cohort the concentrations were related to several measures of arterial plaque formation, thickness of arterial intima media and posterior wall of the heart (P = 0.04–0.000005); the Framingham score (r = 0.14, P < 0.0001); and concentrations of C-reactive protein (r = 0.16, P < 0.0001) and N-terminal pro B-type natriuretic peptide (r = −0.13, P < 0.0001).

CONCLUSIONS

Plasma concentrations of PRCP may be used to reflect metabolic conditions in individuals with obesity and diabetes mellitus. The associations of PRCP concentrations with signs of cardiovascular dysfunction and cardiovascular abnormalities suggest a pivotal role of the enzyme in disease.
Corporate Political Donations: Investment or Agency?
Authors: Aggarwal Rajesh K. , Meschke Felix , Wang Tracy Yue
Published: April 2012

We examine corporate donations to political candidates for federal offices in the United States from 1991 to 2004. Firms that donate have operating characteristics consistent with the existence of a free cash flow problem, and donations are negatively correlated with returns. A $10,000 increase in donations is associated with a reduction in annual excess returns of 7.4 basis points. Worse corporate governance is associated with larger donations. Even after controlling for corporate governance, donations are associated with lower returns. Donating firms engage in more acquisitions and their acquisitions have significantly lower cumulative abnormal announcement returns than non-donating firms. We find virtually no support for the hypothesis that donations represent an investment in political capital. Instead, political donations are symptomatic of agency problems within firms. Our results are particularly useful in light of the Citizens United ruling, which is likely to greatly increase the use of corporate funds for political donations.
Three-Dimensional Flamelet Simulation of Polycyclic Aromatic Hydrocarbons Formation in DI-Diesel Engines
Authors: Zhong Beijing , Dang Shuai , Xi Jun
Published: April 2012

In this study, numerical simulations for an n-heptane fueled Chaochai 6102bzl direct injection diesel engine are performed in order to predict the chemical details of the combustion process and resulting polycyclic aromatic hydrocarbons (such as benzene, naphthalene, phenanthrene and pyrene) formation. The diesel geometry and reduced kinetic mechanism of n-heptane oxidation, which includes only 86 reactions and 57 species, have been developed and incorporated into the computational fluid dynamics code, FLUENT. The diesel unsteady laminar flamelet model, turbulence model and spray model have been employed in the numerical simulations. The numerical simulation results showed that the polycyclic aromatic hydrocarbons were firstly increased with the increase of diesel crank angel and then decreased, which was mostly located at the bottom of diesel combustion chamber wall.
Production of Acid Silica Sols and Gels by Using a Y-shaped Reactor and Dilution Technique
Authors: Saeki Takashi , Kikuchi Saori , Ishida Masahiro , Kaide Aya
Published: April 2012

Silica sols were produced continuously by using a Y-shaped reactor. Diluted sodium silicate and sulfuric acid were forced to collide with each other at the intersection of the reactor. The produced silica sols gradually increase in the viscosity and finally form silica gels. In this study, the gelation process of silica sols was considered by rheological measurements. The onset time of gelling was strongly affected by both the concentration of SiO2 and the excessive rate of sulfuric acid. Also, the gelation time can be controlled by the addition of appropriate amount of water of sulfuric acid solution.
Membrane Contactor as Reactor for CO2 Capture
Authors: Lu Jian-Gang , Fan Fan , Liu Cong , Ji Yan , Zhang Hui
Published: April 2012

A novel composite solution consisting of N-methylmonoethanolamine (MM-EA) and 2-amino-2-methyl-1-propanol (AMP) as a CO2 absorbent was proposed. Coupling process of membrane contactor and the composite solution was investigated. The performance of the coupling was experimentally compared between the single and composite solution. Overall mass transfer coefficients were determined. Effects of various factors, such as flow rates and operation temperatures on mass transfer of membrane contactor, were studied. Comparison of prediction for overall mass transfer coefficients using a resistance in series model with experimental values was performed. Results show that performance of the composite solution is evidently better than that of the single MMEA solution. The overall mass transfer coefficient with the composite solution is much higher than that with the single MMEA solution. Higher operation temperature can enhance mass transfer of membrane contactor. Operation parameters such as flow rates can promote mass transfer, but the promotion is limited. Enhance of mass transfer relies essentially on chemical reaction. Model values are in good agreement with experimental ones.