bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlation between carboxylesterase alleles and insecticide resistance in Culex pipiens complex from China
Authors: Liu Yangyang , Zhang Hanying , Qiao Chuanling , Lu Xiping , Cui Feng
Published: December 2011

Background

In China, large amounts of chemical insecticides are applied in fields or indoors every year, directly or indirectly bringing selection pressure on vector mosquitoes. Culex pipiens complex has evolved to be resistant to all types of chemical insecticides, especially organophosphates, through carboxylesterases. Six resistant carboxylesterase alleles (Ester) were recorded previously and sometimes co-existed in one field population, representing a complex situation for the evolution of Ester genes.

Results

In order to explore the evolutionary scenario, we analyzed the data from an historical record in 2003 and a recent investigation on five Culex pipiens pallens populations sampled from north China in 2010. Insecticide bioassays showed that these five populations had high resistance to pyrethroids, medium resistance to organophosphates, and low resistance to carbamates. Six types of Ester alleles, Ester

B1
, Ester

2
, Ester

8
, Ester

9
, Ester

B10
, and Ester

11
were identified, and the overall pattern of their frequencies in geographic distribution was consistent with the report seven years prior to this study. Statistical correlation analysis indicated that Ester

8
and Ester

9
positively correlated with resistance to four insecticides, and Ester

B10
to one insecticide. The occurrences of these three alleles were positively correlated, while the occurrence of Ester

B1
was negatively correlated with Ester

8
, indicating an allelic competition.

Conclusion

Our analysis suggests that one insecticide can select multiple Ester alleles and one Ester allele can work on multiple insecticides. The evolutionary scenario of carboxylesterases under insecticide selection is possibly "one to many".
MEIS1, PREP1, and PBX4 Are Differentially Expressed in Acute Lymphoblastic Leukemia: Association of MEIS1 Expression with Higher Proliferation and Chemotherapy Resistance
Authors: Rosales-Aviña Judith A , Torres-Flores Jorge , Aguilar-Lemarroy Adriana , Gurrola-Díaz Carmen , Hernández-Flores Georgina , Ortiz-Lazareno Pablo C , Lerma-Díaz José M , de Celis Ruth , González-Ramella Óscar , Barrera-Chaires Esperanza , Bravo-Cuellar Alejandro , Jave-Suárez Luis F
Published: December 2011

Background

The Three-amino acid-loop-extension (TALE) superfamily of homeodomain-containing transcription factors have been implicated in normal hematopoiesis and in leukemogenesis and are important survival, differentiation, and apoptosis pathway modulators. In this work, we determined the expression levels ofTALEgenes in leukemic-derived cell lines, in blood samples of patients with Acute lymphoblastic leukemia (ALL), and in the blood samples of healthy donors.

Results

Here we show increased expression ofMEIS1, MEIS2,andPREP1genes in leukemia-derived cell lines compared with blood normal cells. High levels ofMEIS1andPREP1, and low levels ofPBX4expression were also founded in samples of patients with ALL. Importantly, silencing ofMEIS1decreases the proliferation of leukemia-derived cells but increases their survival after etoposide treatment. Etoposide-induced apoptosis induces down-regulation of MEIS1 expression orPREP1up-regulation in chemotherapy-resistant cells.

Conclusions

Our results indicate that up-regulation ofMEIS1is important for sustaining proliferation of leukemic cells and that down-regulation ofMEIS1or up-regulation ofPREP1andPBXgenes could be implicated in the modulation of the cellular response to chemotherapeutic-induced apoptosis.
The Zfx gene is expressed in human gliomas and is important in the proliferation and apoptosis of the human malignant glioma cell line U251
Authors: Zhou Youxin , Su Zuopeng , Huang Yulun , Sun Ting , Chen Sansong , Wu Tingfeng , Chen Guilin , Xie Xueshun , Li Bin , Du Ziwei
Published: December 2011

Background

Zfx is a zinc finger protein of the Zfy family, whose members are highly conserved in vertebrates. Zfx is a shared transcriptional regulator of both embryonic stem cells (ESC) and hematopoietic stem cells (HSC), which suggests a common genetic basis of self-renewal in embryonic and adult stem cells. The level of Zfx expression correlates with aggressiveness and severity in many cancer types, including prostate cancer, breast cancer, and leukemia. However, the importance of Zfx in human glioma is largely unknown. In the present study, we examined the role of Zfx in human glioma.

Methods

We detected expression levels of Zfx mRNA in U251 cells, U87 cells, U373 cells, and A172 cells by semi-quantitative RT-PCR. To analyze the expression of Zfx mRNA in glioma tissues, we performed real-time quantitative PCR on 35 pathologically confirmed glioma samples (Grade I-4cases, Grade II-13cases, Grade III-11cases, and Grade IV-7cases) and on 5 noncancerous brain tissue samples. We used lentivirus-mediated small interfering RNAs (siRNAs) to knock down Zfx expression in the human malignant glioma cell line U251. Changes in Zfx target gene expression were determined by real-time RT-PCR. Cell proliferation was examined by a High Content Screening assay. DNA synthesis in proliferating cells was determined by BrdU incorporation. Cell cycle distribution and apoptosis were detected by flowcytometric analysis.

Results

We discovered that Zfx mRNA was expressed in U251 cells, U87 cells, U373 cells, and A172 cells. The expression level of Zfx is significantly higher in gliomas compared to noncancerous brain tissue. Using a lentivirus-based RNAi approach, Zfx expression was significantly inhibited in human glioblastoma U251 cells. The effects of Zfx knockdown on cell proliferation, cell cycle distribution, and apoptosis were assessed. Inhibition of Zfx expression in U251 cells by RNAi significantly impaired cell proliferation, increased apoptosis, and arrested cells in S phase.

Conclusions

The results of our study demonstrate that the Zfx gene is highly expressed in glioma tissue and in glioma cell lines. Furthermore, Zfx may play a critical role in cell proliferation, cell cycle distribution, and apoptosis of human malignant glioma cells.
The synthetic Tie2 agonist peptide vasculotide protects against vascular leakage and reduces mortality in murine abdominal sepsis
Authors: Kümpers Philipp , Gueler Faikah , David Sascha , Van Slyke Paul , Dumont Daniel J , Park Joon-Keun , Bockmeyer Clemens L , Parikh Samir M , Pavenstädt Hermann , Haller Hermann , Shushakova Nelli
Published: December 2011

Introduction

Angiopoietin-1 (Angpt1), the natural agonist ligand for the endothelial Tie2 receptor, is a non-redundant endothelial survival and vascular stabilization factor that reduces endothelial permeability and inhibits leukocyte-endothelium interactions. Here we evaluate the efficacy of a novel polyethylene glycol (PEG)-clustered Tie2 agonist peptide, vasculotide (VT), to protect against vascular leakage and mortality in a murine model of polymicrobial abdominal sepsis.

Methods

Polymicrobial abdominal sepsis in C57BL6 mice was induced by cecal-ligation-and-puncture (CLP). Mice were treated with different dosages of VT or equal volume of phosphate-buffered saline (PBS). Sham-operated animals served as time-matched controls.

Results

Systemic administration of VT induced long-lasting Tie2 activation in vivo. VT protected against sepsis-induced endothelial barrier dysfunction, as evidenced by attenuation of vascular leakage and leukocyte transmigration into the peritoneal cavity. Histological analysis revealed that VT treatment ameliorated leukocyte infiltration in kidneys of septic mice, probably due to reduced endothelial adhesion molecule expression. VT-driven effects were associated with significantly improved organ function and reduced circulating cytokine levels. The endothelial-specific action of VT was supported by additional in vitro studies showing no effect of VT on either cytokine release from isolated peritoneal macrophages, or migratory capacity of isolated neutrophils. Finally, administration of VT pre-CLP (hazard ratio 0.39 [95% confidence interval 0.19-0.81] P < 0.001) and post-CLP reduced mortality in septic mice (HR 0.22 [95% CI 0.06-0.83] P < 0.05).

Conclusions

We provide proof of principle in support of the efficacious use of PEGylated VT, a drug-like Tie2 receptor agonist, to counteract microvascular endothelial barrier dysfunction and reduce mortality in a clinically relevant murine sepsis model. Further studies are needed to pave the road for clinical application of this therapeutic concept.
The relationship between proteome size, structural disorder and organism complexity
Authors: Schad Eva , Tompa Peter , Hegyi Hedi
Published: December 2011

Background

Sequencing the genomes of the first few eukaryotes created the impression that gene number shows no correlation with organism complexity, often referred to as the G-value paradox. Several attempts have previously been made to resolve this paradox, citing multifunctionality of proteins, alternative splicing, microRNAs or non-coding DNA. As intrinsic protein disorder has been linked with complex responses to environmental stimuli and communication between cells, an additional possibility is that structural disorder may effectively increase the complexity of species.

Results

We revisited the G-value paradox by analyzing many new proteomes whose complexity measured with their number of distinct cell types is known. We found that complexity and proteome size measured by the total number of amino acids correlate significantly and have a power function relationship. We systematically analyzed numerous other features in relation to complexity in several organisms and tissues and found: the fraction of protein structural disorder increases significantly between prokaryotes and eukaryotes but does not further increase over the course of evolution; the number of predicted binding sites in disordered regions in a proteome increases with complexity; the fraction of protein disorder, predicted binding sites, alternative splicing and protein-protein interactions all increase with the complexity of human tissues.

Conclusions

We conclude that complexity is a multi-parametric trait, determined by interaction potential, alternative splicing capacity, tissue-specific protein disorder and, above all, proteome size. The G-value paradox is only apparent when plants are grouped with metazoans, as they have a different relationship between complexity and proteome size.
Accurate proteome-wide protein quantification from high-resolution 15N mass spectra
Authors: Khan Zia , Amini Sasan , Bloom Joshua S , Ruse Cristian , Caudy Amy A , Kruglyak Leonid , Singh Mona , Perlman David H , Tavazoie Saeed
Published: December 2011

In quantitative mass spectrometry-based proteomics, the metabolic incorporation of a single source of 15N-labeled nitrogen has many advantages over using stable isotope-labeled amino acids. However, the lack of a robust computational framework for analyzing the resulting spectra has impeded wide use of this approach. We have addressed this challenge by introducing a new computational methodology for analyzing 15N spectra in which quantification is integrated with identification. Application of this method to an Escherichia coli growth transition reveals significant improvement in quantification accuracy over previous methods.
K12/SECTM1, an interferon-γ regulated molecule, synergizes with CD28 to costimulate human T cell proliferation
Authors: Wang Tao , Huang Catherine , Lopez-Coral Alfonso , Slentz-Kesler Kimberly A , Xiao Min , Wherry E John , Kaufman Russel E
Published: December 2011

CD7 is a cell-surface molecule, expressed on T lymphocytes and NK cells, which functions as a costimulatory receptor for T cell proliferation. SECTM1 has been proposed as a ligand for CD7. However, the expression pattern of this molecule in human immune cells and role in human T cell function remain unclear. In the present study, using human rSECTM1, we demonstrate that SECTM1 strongly costimulates CD4 and CD8 T cell proliferation and induces IFN-γ production, likely via a CD7-dependent mechanism. In addition, SECTM1 synergizes with suboptimal anti-CD28 to strongly augment T cell functions. We found a robust induction of IL-2 production when SECTM1 and anti-CD28 signals were present with TCR ligation. Furthermore, addition of SECTM1 into a MLR significantly enhanced proliferation of alloantigen-activated T cells, whereas blockade of SECTM1 inhibited T cell proliferation in a two-way MLR assay. Simultaneously blocking the effect of SECTM1, along with CTLA-4/Fc, diminishes two-way MLR. Finally, we demonstrated that expression of SECTM1 is not detected in monocytes and imMoDCs at the protein level. However, it is strongly induced by IFN-γ in monocytes and imMoDCs, and this induction is STAT1-dependent. These results indicate that SECTM1 is a broadly expressed, IFN-γ-inducible molecule, which functions as a potent costimulatory ligand for T cell activation and is synergistic with anti-CD28.
Longitudinal Assessment of Chemotherapy-Induced Structural Changes in Cerebral White Matter and Its Correlation With Impaired Cognitive Functioning
Authors: Deprez Sabine , Amant Frederic , Smeets Ann , Peeters Ronald , Leemans Alexander , Van Hecke Wim , Verhoeven Judith S. , Christiaens Marie-Rose , Vandenberghe Joris , Vandenbulcke Mathieu , Sunaert Stefan
Published: December 2011

Purpose

To uncover the neural substrate of cognitive impairment related to adjuvant chemotherapy, we studied cerebral white matter (WM) integrity before and after chemotherapy by using magnetic resonance diffusion tensor imaging (DTI) in combination with detailed cognitive assessment.

Patients and Methods

Thirty-four young premenopausal women with early-stage breast cancer who were exposed to chemotherapy underwent neuropsychologic testing and DTI before the start of chemotherapy (t1) and 3 to 4 months after treatment (t2). Sixteen patients not exposed to chemotherapy and 19 age-matched healthy controls underwent the same assessment at matched intervals. In all groups, we used paired t tests to study changes in neuropsychologic test scores and whole-brain voxel-based paired t tests to study changes in WM fractional anisotropy (FA; a DTI measure that reflects WM tissue organization), with depression scores and intelligence quotient as included covariates. We correlated changes of neuropsychologic test scores with the mean change of FA for regions that survived the paired t tests in patients treated with chemotherapy.

Results

In contrast to controls, the chemotherapy-treated group performed significantly worse on attention tests, psychomotor speed, and memory at t2 compared with t1 (P < .05). In the chemotherapy-treated group, we found significant decreases of FA in frontal, parietal, and occipital WM tracts after treatment (familywise error P < .05), whereas for both control groups, FA values were the same between t1 and t2. Furthermore, performance changes in attention and verbal memory correlated with mean regional FA changes in chemotherapy-treated patients (P < .05).

Conclusion

We report evidence of longitudinal changes in cognitive functioning and cerebral WM integrity after chemotherapy as well as an association between both.
Phase I/II Trial and Pharmacokinetic Study of Cixutumumab in Pediatric Patients With Refractory Solid Tumors and Ewing Sarcoma: A Report From the Children's Oncology Group
Authors: Malempati Suman , Weigel Brenda , Ingle Ashish M. , Ahern Charlotte H. , Carroll Julie M. , Roberts Charles T. , Reid Joel M. , Schmechel Stephen , Voss Stephan D. , Cho Steven Y. , Chen Helen X. , Krailo Mark D. , Adamson Peter C. , Blaney Susan M.
Published: December 2011

Purpose

A phase I/II study of cixutumumab (IMC-A12) in children with refractory solid tumors was conducted. This study was designed to assess the toxicities, pharmacokinetics, and pharmacodynamics of cixutumumab in children to determine a recommended phase II dose and to assess antitumor activity in Ewing sarcoma (ES).

Patients and Methods

Pediatric patients with relapsed or refractory solid tumors were treated with cixutumumab as a 1-hour intravenous infusion once per week. Two dose levels—6 and 9 mg/kg—were evaluated using a standard three-plus-three cohort design. Patients with refractory ES were treated in an expanded phase II cohort at each dose level.

Results

Forty-seven eligible patients with a median age of 15 years (range, 4 to 28 years) were enrolled. Twelve patients were treated in the dose-finding phase. Hematologic and nonhematologic toxicities were generally mild and infrequent. Dose-limiting toxicities included grade 4 thrombocytopenia at 6 mg/kg and grade 3 dehydration at 9 mg/kg. Mean trough concentration (± standard deviation) at 9 mg/kg was 106 ± 57 μg/mL, which exceeded the effective trough concentration of 60 μg/mL observed in xenograft models. Three patients with ES had confirmed partial responses: one of 10 at 6 mg/kg and two of 20 at 9 mg/kg. Serum insulin-like growth factor I (IGF-I) levels consistently increased after one dose of cixutumumab. Tumor IGF-I receptor expression by immunohistochemistry did not correlate with response in patients with ES.

Conclusion

Cixutumumab is well tolerated in children with refractory solid tumors. The recommended phase II dose is 9 mg/kg. Limited single-agent activity of cixutumumab was seen in ES.
Racial Disparities in Stage-Specific Colorectal Cancer Mortality Rates From 1985 to 2008
Authors: Robbins Anthony S. , Siegel Rebecca L. , Jemal Ahmedin
Published: December 2011

Purpose

Since the early 1980s, colorectal cancer (CRC) mortality rates for whites and blacks in the United States have been diverging as a result of earlier and larger reductions in death rates for whites. We examined whether this mortality pattern varies by stage at diagnosis.

Methods

The Incidence-Based Mortality database of the Surveillance, Epidemiology, and End Results (SEER) Program was used to examine data from the nine original SEER regions. Our main outcome measures were changes in stage-specific mortality rates by race.

Results

From 1985 to 1987 to 2006 to 2008, CRC mortality rates decreased for each stage in both blacks and whites, but for every stage, the decreases were smaller for blacks, particularly for distant-stage disease. For localized stage, mortality rates decreased 30.3% in whites compared with 13.2% in blacks; for regional stage, declines were 48.5% in whites compared with 34.0% in blacks; and for distant stage, declines were 32.6% in whites compared with 4.6% in blacks. As a result, the black-white rate ratios increased from 1.17 (95% CI, 0.98 to 1.39) to 1.41 (95% CI, 1.21 to 1.63) for localized disease, from 1.03 (95% CI, 0.93 to 1.14) to 1.30 (95% CI, 1.17 to 1.44) for regional disease, and from 1.21 (95% CI, 1.10 to 1.34) to 1.72 (95% CI, 1.58 to 1.86) for distant-stage disease. In absolute terms, the disparity in distant-stage mortality rates accounted for approximately 60% of the overall black-white mortality disparity.

Conclusion

The black-white disparities in CRC mortality increased for each stage of the disease, but the overall disparity in overall mortality was largely driven by trends for late-stage disease. Concerted efforts to prevent or detect CRC at earlier stages in blacks could improve the worsening black- white disparities.
Anaplastic Lymphoma Kinase Aberrations in Rhabdomyosarcoma: Clinical and Prognostic Implications
Authors: van Gaal J. Carlijn , Flucke Uta E. , Roeffen Melissa H.S. , de Bont Eveline S.J.M. , Sleijfer Stefan , Mavinkurve-Groothuis Annelies M.C. , Suurmeijer Albert J.H. , van der Graaf Winette T.A. , Versleijen-Jonkers Yvonne M.H.
Published: December 2011

Purpose

The aim of this study is to investigate anaplastic lymphoma kinase (ALK) protein expression and underlying genetic aberrations in rhabdomyosarcoma (RMS), with special attention to clinical and prognostic implications.

Patients and Methods

A total of 189 paraffin-embedded RMS tumor specimens from 145 patients were collected on tissue microarray. ALK protein expression was evaluated by immunohistochemistry. ALK gene (2p23) copy number and translocations were determined by in situ hybridization. cDNA sequencing of the receptor tyrosine kinase domain of the ALK gene was assessed in 43 samples.

Results

Strong cytoplasmic ALK protein expression was more frequently observed in alveolar RMS (ARMS) than in embryonal RMS (ERMS) (81% v 32%, respectively; P < .001). ALK gene copy number gain was detected in the vast majority of ARMS (88%), compared with 52% of ERMS (P < .001). ALK copy number correlated with protein expression in primary tumors (n = 107). We identified one point mutation (2%) and seven tumors harboring whole exon deletions (16%). In ERMS, specific ALK gain in the primary tumor correlated with metastatic disease (100% in metastatic disease v 29% in nonmetastatic disease; P = .004) and poor disease-specific survival (5-year disease-specific survival: 62% v 82% for nonspecific or no gain; P = .046).

Conclusion

Because ALK aberrations on genomic and protein levels are frequently found in RMSs, in particular ARMS, and are associated with disease progression and outcome in ERMS, ALK may play a role in tumor biology and may provide a potential therapeutic target for these tumors. Future research should aim at the oncogenic role of ALK and the potential effect of ALK inhibitors in RMS.
Sox2 and Mitf cross-regulatory interactions consolidate progenitor and melanocyte lineages in the cranial neural crest
Authors: Adameyko Igor , Lallemend Francois , Furlan Alessandro , Zinin Nikolay , Aranda Sergi , Kitambi Satish Srinivas , Blanchart Albert , Favaro Rebecca , Nicolis Silvia , Lübke Moritz , Müller Thomas , Birchmeier Carmen , Suter Ueli , Zaitoun Ismail , Takahashi Yoshiko , Ernfors Patrik
Published: December 2011

The cellular origin and molecular mechanisms regulating pigmentation of head and neck are largely unknown. Melanocyte specification is controlled by the transcriptional activity of Mitf, but no general logic has emerged to explain how Mitf and progenitor transcriptional activities consolidate melanocyte and progenitor cell fates. We show that cranial melanocytes arise from at least two different cellular sources: initially from nerve-associated Schwann cell precursors (SCPs) and later from a cellular source that is independent of nerves. Unlike the midbrain-hindbrain cluster from which melanoblasts arise independently of nerves, a large center of melanocytes in and around cranial nerves IX-X is derived from SCPs, as shown by genetic cell-lineage tracing and analysis of ErbB3-null mutant mice. Conditional gain- and loss-of-function experiments show genetically that cell fates in the neural crest involve both the SRY transcription factor Sox2 and Mitf, which consolidate an SCP progenitor or melanocyte fate by cross-regulatory interactions. A gradual downregulation of Sox2 in progenitors during development permits the differentiation of both neural crest- and SCP-derived progenitors into melanocytes, and an initial small pool of nerve-associated melanoblasts expands in number and disperses under the control of endothelin receptor B (Ednrb) and Wnt5a signaling.
A photoactivatable small-molecule inhibitor for light-controlled spatiotemporal regulation of Rho kinase in live embryos
Authors: Morckel Allison R. , Lusic Hrvoje , Farzana Laila , Yoder Jeffrey A. , Deiters Alexander , Nascone-Yoder Nanette M.
Published: December 2011

To uncover the molecular mechanisms of embryonic development, the ideal loss-of-function strategy would be capable of targeting specific regions of the living embryo with both temporal and spatial precision. To this end, we have developed a novel pharmacological agent that can be light activated to achieve spatiotemporally limited inhibition of Rho kinase activity in vivo. A new photolabile caging group, 6-nitropiperonyloxymethyl (NPOM), was installed on a small-molecule inhibitor of Rho kinase, Rockout, to generate a ‘caged Rockout’ derivative. Complementary biochemical, cellular, molecular and morphogenetic assays in both mammalian cell culture and Xenopus laevis embryos validate that the inhibitory activity of the caged compound is dependent on exposure to light. Conveniently, this unique reagent retains many of the practical advantages of conventional small-molecule inhibitors, including delivery by simple diffusion in the growth medium and concentration-dependent tuneability, but can be locally activated by decaging with standard instrumentation. Application of this novel tool to the spatially heterogeneous problem of embryonic left-right asymmetry revealed a differential requirement for Rho signaling on the left and right sides of the primitive gut tube, yielding new insight into the molecular mechanisms that generate asymmetric organ morphology. As many aromatic/heterocyclic small-molecule inhibitors are amenable to installation of this caging group, our results indicate that photocaging pharmacological inhibitors might be a generalizable technique for engendering convenient loss-of-function reagents with great potential for wide application in developmental biology.
A rodent model of rapid-onset diabetes (ROD) induced by glucocorticoids and high-fat feeding
Authors: Shpilberg Yaniv , Beaudry Jacqueline L. , D'Souza Anna , Campbell Jonathan E. , Peckett Ashley , Riddell Michael C.
Published: December 2011

Glucocorticoids (GC) are potent pharmacological agents used to treat a number of immune conditions. GCs are also naturally occurring steroid hormones (e.g. cortisol, corticosterone) produced in response to stressful conditions that are thought to increase the preference for calorie dense “comfort” foods. If chronically elevated, GCs may contribute to the development of type 2 diabetes mellitus (T2DM), although mechanisms are not entirely clear. The present study proposes a new rodent model to investigate the combined metabolic effects of elevated GCs and high-fat feeding on ectopic fat deposition and various indexes of insulin resistance that induces rapid-onset diabetes (ROD). Male Sprague-Dawley rats (aged 4 weeks) received exogenous corticosterone or wax (placebo) (4 x 100 mg each) pellets, implanted subcutaneously, and fed either a standard chow diet (SD) or a 60% high-fat diet (HFD) for 16 days (n= 8-10). Animals given corticosterone and a HFD (cort-HFD) had lower body weight (226.1±9.05 versus 358.9±5.57 g, mean ± SEM, p<0.05) and smaller relative glycolytic muscle mass (0.14±0.01 versus 0.09±0.02 g/kg body mass for the epitroclearis muscle, p<0.05), but increased relative epididymal mass (9.81±1.65 versus 4.56±0.54 g/kg, p<0.05), compared to controls (placebo-SD). Cort-HFD rats exhibited severe hepatic steatosis and increased muscle lipid deposition compared to placebo-SD animals. Moreover, cort-HFD animals were found to exhibit severe fasting hyperglycemia (60% increase), hyperinsulinemia (80% increase), insulin resistance (60% increase) and impaired beta cell response (20% decrease) to oral glucose load compared to placebo-SD animals. Thus, a metabolic syndrome/T2DM phenotype can be rapidly induced in young Sprague-Dawley rats by using exogenous GCs if a HFD is consumed. This finding may be valuable in examining the physiological and molecular mechanisms of GC-induced metabolic disease.
Radiological catheter placement for transcatheter arterial steroid injection therapy to treat severe acute hepatic failure: technical feasibility and efficacy
Authors: Ushijima Yasuhiro , Tajima Tsuyoshi , Yoshimitsu Kengo , Irie Hiroyuki , Nishie Akihiro , Hirakawa Masakazu , Ishigami Kousei , Okamoto Daisuke , Kotoh Kazuhiro , Honda Hiroshi
Published: December 2011

Background

Severe acute hepatic failure (SAHF), which progresses to fulminant form in some cases, is a life-threatening disease.

Purpose

To assess the technical feasibility and the efficacy of transcatheter arterial steroid injection therapy (TASIT) for SAHF.

Material and Methods

Twenty-seven patients with SAHF, 10 of whom had variant anatomy of the hepatic artery, underwent radiologic placement of an indwelling catheter in the hepatic artery, and TASIT was subsequently performed for three days. The tips of the catheters were inserted as follows: common hepatic artery ( n = 18), proper hepatic artery ( n = 4), and replaced right hepatic artery ( n = 5). The clinical success rate of TASIT and the prognosis after TASIT were evaluated.

Results

In one patient, intimal injury of the left hepatic artery was encountered; however, TASIT could be resumed and completed via intrahepatic arterial collaterals. In two patients, the catheter tip placement was corrected on the following day because of dislocation. Finally, TASIT could be carried out in all patients. Twenty-two patients (81.5%) responded to TASIT but five patients (18.5%) did not. Among the five non-responders, two patients were transferred to liver transplantation and survived, and three patients died. There was no significant difference in the response rates to TASIT among locations of catheter tip ( P > 0.05) and extent of drug distribution in the liver ( P > 0.05).

Conclusion

TASIT is a feasible and efficient treatment option for SAHF regardless of the anatomic variation of the hepatic artery. Careful manipulation during the procedure to prevent injury of the hepatic artery may be the most essential factor not only for successful TASIT but also for liver transplantation, which may be performed on TASIT non-responders.
Diffusion-weighted imaging in the diagnosis of enterovirus 71 encephalitis
Authors: Lian Zhou-yang , Huang Biao , He Shao-ru , Liang Chang-hong , Guo Yu-xiong
Published: December 2011

Background

In the early phase of viral encephalitis, conventional MRI may appear normal. Diffusion-weighted imaging (DWI) is a sensitive tool for detecting early changes in cellular function in the central nervous system.

Purpose

To investigate the usefulness of DWI in the diagnosis of enterovirus 71 (EV71) encephalitis, and to determine whether DWI is superior to conventional MR sequences.

Material and Methods

MRI scans in 26 patients were retrospectively evaluated for distribution of lesions on T1-weighted images (T1WI), T2-weighted images (T2WI), fluid-attenuated inversion recovery (FLAIR), and DWI. Contrast-to-noise ratios (CNRs) were calculated for all regions on each sequence and differences in the four MRI sequences were assessed using CNRs. Apparent diffusion coefficient (ADC) values were measured for all regions to look for true restriction of diffusion.

Results

Fifteen out of 26 cases showed positive findings on MR imaging. The brain stem was involved in 11 patients, cortex and subcortical white matter in four patients. DWI was more sensitive in detecting the abnormalities (89.7%) compared to T2WI (48.7%), FLAIR (41.0%), and T1WI (35.9%), and the positive ratio of DWI was significantly higher compared to other sequences. Furthermore, no significant difference was found between T2WI and FLAIR ( P = 0.649). The corresponding mean CNRs were 8.73 ± 2.57, 83.59 ± 29.28, 24.22 ± 6.22, and 132.27 ± 78.32 on T1WI, T2WI, FLAIR, and DWI, respectively. The absolute values of CNRs of lesions on DWI were significantly greater than those on other sequences.

Conclusion

DWI appears to be more sensitive in detecting EV71 encephalitis than conventional MRI sequences. This capability may improve the accuracy in diagnosing EV71 encephalitis, especially at the early stage.
Adaptation to tRNA acceptor stem structure by flexible adjustment in the catalytic domain of class I tRNA synthetases
Authors: Liu Cuiping , Sanders Jeffrey M. , Pascal John M. , Hou Ya-Ming
Published: December 2011

Class I aminoacyl-tRNA synthetases (aaRSs) use a Rossmann-fold domain to catalyze the synthesis of aminoacyl-tRNAs required for decoding genetic information. While the Rossmann-fold domain is conserved in evolution, the acceptor stem near the aminoacylation site varies among tRNA substrates, raising the question of how the conserved protein fold adapts to RNA sequence variations. Of interest is the existence of an unpaired C-A mismatch at the 1-72 position unique to bacterial initiator tRNAfMetand absent from elongator tRNAs. Here we show that the class I methionyl-tRNA synthetase (MetRS) ofEscherichia coliand its close structural homolog cysteinyl-tRNA synthetase (CysRS) display distinct patterns of recognition of the 1-72 base pair. While the structural homology of the two enzymes in the Rossmann-fold domain is manifested in a common burst feature of aminoacylation kinetics, CysRS discriminates against unpaired 1-72, whereas MetRS lacks such discrimination. A structure-based alignment of the Rossmann fold identifies the insertion of an α-helical motif, specific to CysRS but absent from MetRS, which docks on 1-72 and may discriminate against mismatches. Indeed, substitutions of the CysRS helical motif abolish the discrimination against unpaired 1-72. Additional structural alignments reveal that with the exception of MetRS, class I tRNA synthetases contain a structural motif that docks on 1-72. This work demonstrates that by flexible insertion of a structural motif to dock on 1-72, the catalytic domain of class I tRNA synthetases can acquire structural plasticity to adapt to changes at the end of the tRNA acceptor stem.
Mechanisms of activation and repression by the alternative splicing factors RBFOX1/2
Authors: Sun Shuying , Zhang Zuo , Fregoso Oliver , Krainer Adrian R.
Published: December 2011

RBFOX1 and RBFOX2 are alternative splicing factors that are predominantly expressed in the brain and skeletal muscle. They specifically bind the RNA element UGCAUG, and regulate alternative splicing positively or negatively in a position-dependent manner. The molecular basis for the position dependence of these and other splicing factors on alternative splicing of their targets is not known. We explored the mechanisms of RBFOX splicing activation and repression using an MS2-tethering assay. We found that the Ala/Tyr/Gly-rich C-terminal domain is sufficient for exon activation when tethered to the downstream intron, whereas both the C-terminal domain and the central RRM are required for exon repression when tethered to the upstream intron. Using immunoprecipitation and mass spectrometry, we identified hnRNP H1, RALY, and TFG as proteins that specifically interact with the C-terminal domain of RBFOX1 and RBFOX2. RNA interference experiments showed that hnRNP H1 and TFG modulate the splicing activity of RBFOX1/2, whereas RALY had no effect. However, TFG is localized in the cytoplasm, and likely modulates alternative splicing indirectly.
QuarterWatch Signals for Two Newly Approved Drugs: Dabigatran and Dalfampridine/Include Purpose on Rx/Use of Two Pumps Allows Bypass of Drug Library/Anesthesia Patient Safety Foundation Tackles Postoperative Opioid Monitoring/Lilly Updates Humulin R U-500 Label
Authors: Michael R. Cohen , Judy L. Smetzer
Published: December 2011

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

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

Errors, close calls, or hazardous conditions may be reported directly to ISMP through the ISMP Web site ( www.ismp.org ), by calling 800-FAIL-SAFE, or via e-mail at ismpinfo@ismp.org . ISMP guarantees the confidentiality and security of the information received and respects reporters' wishes as to the level of detail included in publications.
Dabigatran-lnduced Rash/Type B Lactic Acidosis Associated with Carboplatin Therapy/Sunitinib-Induced Hyperammonemic Encephalopathy/Virilization from Partner's Use of Topical Androgen/Psychosis Associated with Synthetic Cannabinoid Agonists/Drug-Induced Yawning Cardiovascular Medications and Risk of Cancer
Authors: Joel Shuster
Published: December 2011

The purpose of this feature is to heighten awareness of specific adverse drug reactions (ADRs), discuss methods of prevention, and promote reporting of ADRs to the US Food and Drug Administration's (FDA's) MEDWATCH program (800-FDA-1088). If you have reported an interesting, preventable ADR to MEDWATCH, please consider sharing the account with our readers.
Nitroglycerin (Ointment): Low Bone Density or Osteoporosis in Postmenopausal Women
Authors: Joyce A. Generali , Dennis J. Cada
Published: December 2011

This Hospital Pharmacy feature is extracted from Off-Label Drug Pacts, a quarterly publication available from Wolters Kluwer Health. Off-Label Drug Pacts is a practitioner-oriented resource for information about specific drug uses that are unapproved by the US Food and Drug Administration. This new guide to the literature enables the health care professional or clinician to quickly identify published studies on off-label uses and determine if a specific use is rational in a patient care scenario. References direct the reader to the full literature for more comprehensive information before patient care decisions are made. Direct questions or comments regarding Off-Label Drug Uses to jgeneral@kumc.edu .
Drug Shortages: Process for Evaluating Impact on Patient Safety
Authors: Elyse A. MacDonald , Erin R. Fox , Linda S. Tyler
Published: December 2011

Purpose

Drug shortages can seriously impact patient safety. The objective of this study was to develop safety assessment checklists for use during a drug shortage, whether the same drug is available or an alternative is required.

Methods

A failure modes and effects analysis (FMEA) was conducted following the Institute for Healthcare Improvement's FMEA tool. Each step of the medication use process was reviewed for the potential impact of a shortage-related event. The likelihood of occurrence, likelihood of detection, and severity of potential harm were determined and rated by a multidisciplinary team. To supplement the results of the FMEA, a survey focusing on the perception of patient safety during a drug shortage was developed and sent to various e-mail lists. These data were used to develop the safety assessment checklists.

Results

Common safety concerns associated with drug shortages in multiple areas of the medication use process include possible look-alike sound-alike issues and delays in patient care. The FMEA and survey results noted that unfamiliarity with an alternative agent was a high vulnerability during a shortage where an alternative is required. The potential for incorrect doses was the greatest concern during a shortage where the same drug is available, but in a different concentration or presentation.

Conclusion

Drug shortages create patient safety risks. Safety assessment checklists for use when the same drug is available and when an alternative is required during a drug shortage were developed to aid institutions in preventing patient safety impacts.
Cephalosporins for Patients with a History of Penicillin Allergy: The Safety of an Oral Test Dose
Authors: Mamta Sharma , Pramodini B. Kale-Pradhan , Jason Taylor , Riad Khatib
Published: December 2011

Background

Cephalosporins are often avoided in patients labeled with penicillin allergy due to potential cross-reaction. We describe the utility of an oral cephalosporin test dose in patients with penicillin allergy.

Method

A retrospective review of all inpatients labeled with penicillin allergy who received a single oral cephalosporin dose, identified through the pharmacy records between April 1, 2004 and October 30, 2008.

Results

Ninety-seven inpatients met our selection criteria. Type of penicillin reaction was described as rash/hives/pruritis, anaphylaxis, angioedema, and unknown in 53 (54.7%), 10 (10.3%), 7 (7.2%), and 27 (27.8%) cases, respectively. The test dose used was cephalexin 250 mg (56.7%) or 125 mg (35.1%) and cefuroxime axetil 125 mg (8.2%). Reaction to the test dose was noted in 5 (5.2%) patients, including rash (n=2), breathing difficulty (n=2), and asymptomatic eosinophilia (n=1). Breathing difficulty resolved with diphenhydramine/corticosteroids in one case and without any therapy in the other. Cephalosporin therapy was initiated within 3 hours (interquartile range, 2-6 hours) after test dose in 90/93 patients without test-dose reaction. Two (2.2 %) patients developed reaction during treatment: rash (n=1) and angioedema (n=1). One case complained of anxiety, and therapy was interrupted. Test-dose and treatment reactions were transient and easily managed.

Conclusions

An oral cephalosporin test dose was safe in patients labeled with penicillin allergy and predicted subsequent cephalosporin tolerance in nearly 90% of patients.
The Information Appliance of Choice
Authors: Bill G. Felkey , Brent I. Fox
Published: December 2011

Where portability was once a luxury, it is now a requirement in today's pharmacy technology world. The perfect information appliance for one pharmacist is not necessarily ideal for another pharmacist. The determination of “perfection” as it relates to information appliances is based on appliance characteristics and user preferences. In this installment, we address appliance characteristics and user preferences, focusing on mobile appliances.
Strategies for Staff Recognition
Authors: Scott M. Mark , Hany S. Edward , Robert J. Weber
Published: December 2011

The Director's Forum series is written and edited by Robert J. Weber and Scott M. Mark and is designed to guide pharmacy leaders in establishing patient-centered services in hospitals and health systems. Developing an effective practice model depends on recruiting and sustaining a highly qualified workforce of pharmacists and technicians. Recognition of that workforce is a vital communication tool that reinforces and rewards the most important endpoints in the workplace. When staff are recognized effectively, they are encouraged to continue their “good” actions. An effective staff recognition program should be simple, consistent, individualized, and conducive to good behavior. A recognition program is beneficial for both the organization and the staff. Pharmacy directors should consider their department's strategies for making their staff feel appreciated and an integral part of the practice model. Implementing staff recognition strategies will result in a motivated pharmacy staff whose commitment will be realized in an effective pharmacy practice model.
Recent Publications on Medications and Pharmacy
Authors: Flint Russett
Published: December 2011

Hospital Pharmacy presents this feature to keep pharmacists abreast of new publications in the medical/pharmacy literature. Articles of interest regarding a broad scope of topics are abstracted monthly.
Scientific Basis of Hyponatremia and Its Clinical Presentations
Authors: Adams Kirkwood F.
Published: December 2011

Purpose

To describe causes, pathophysiologic mechanisms, and classifications of hyponatremia, and to describe clinical symptoms and underlying disease states associated with different levels of hyponatremia.

The key to comprehending hyponatremia is to understand body water content and plasma osmolality and accurately assess arterial volume. Hyponatremia results from sodium dilution because of retained water or sodium depletion because of electrolyte loss in excess of water loss. Body sodium, water, and extracellular fluid (ECF) volume are tightly regulated by mechanisms that act to maintain a closely controlled concentration of solutes in the ECF. These forces act to regulate water content and sodium excretion to maintain normal intravascular volume. The body closely defends normal plasma osmolality within a narrow range primarily by controlling the release of arginine vasopressin (AVP) and via the thirst mechanism. A number of factors can stimulate inappropriate AVP release and cause or worsen hyponatremia. Dysregulation of AVP plays an important role in heart failure and cirrhosis, common causes of hypervolemic hyponatremia.

Conclusion

Body water content and plasma osmolality are tightly regulated by the action of AVP. A variety of disease states are associated with hyponatremia related to inappropriate AVP release. The cause of the electrolyte disturbance must be determined, because it can have profound implications for treatment. Differential diagnosis can be guided by observation of the rapidity of onset as well as volume status changes. If untreated or treated inappropriately, hyponatremia can impact morbidity and mortality.
Cost Issues in Hyponatremia
Authors: Rhoney Denise H.
Published: December 2011

Purpose

To describe the morbidity and mortality associated with hyponatremia and its impact on health care costs and outcomes in the United States, describe the role of pharmacists in the overall management of hyponatremia, and identify and address cost and resource allocation issues.

Hyponatremia places a significant burden on overall hospital and health care costs. Underrecognition of the disorder and inappropriate hospital management can lead to worse outcomes, impacting length of stay (LOS), need for intensive care unit (ICU) admission, and clinical outcomes. Risk of mortality rises with increasing severity of hyponatremia, but even mild hyponatremia is associated with increased in-hospital mortality. The association with mortality is particularly robust in patients admitted to the hospital with cardiovascular disease and metastatic cancer. For patients admitted to the ICU, severe hyponatremia is a predictor of mortality. Elderly patients with admission hyponatremia face an especially poor prognosis. Resolving hyponatremia during hospitalization decreases the risk of mortality, suggesting that improved identification and aggressive monitoring may lead to more appropriate treatment. Pharmacoeconomic data can be utilized to support clinical decision-making in the management of hyponatremia by evaluating drug therapy and by monitoring hyponatremia development and therapeutic outcomes.

Conclusion:

Prompt recognition and optimal management of hyponatremia in hospitalized patients may reduce mortality and symptom severity, allow for less intensive care, decrease LOS and associated costs, and improve treatment of underlying comorbid conditions and quality of life. Pharmacists have a key role in optimizing the management of hyponatremia.
Agent-noun polysemy in a cross-linguistic perspective
Authors: Luschützky Hans Christian , Rainer Franz
Published: December 2011

According to a widely held opinion, agent-instrument polysemy in derivational morphology is the result of semantic extension from agent to instrument meaning. In the present paper we set out to explore the cross-linguistic distribution of patterns of polysemy along the agent-instrument axis. It turns out that about forty percent in a sample of 82 languages expressing both agent and instrument meaning by derivational morphology have markers that are polysemous for the categories in question. A closer look at the data reveals, however, that many of these prima-facie cases of agent-instrument polysemy have arisen not by semantic extension from agent to instrument meaning, but in a number of different ways.