bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical and clinicopathologic features of dogs that consumed foodborne hepatotoxic aflatoxins: 72 cases (2005–2006)
Authors: Dereszynski Diane M. , Center Sharon A. , Randolph John F. , Brooks Marjory B. , Hadden Alice G. , Palyada Kiran S. , McDonough Sean P. , Messick Joanne , Stokol Tracy , Bischoff Karyn L. , Gluckman Stuart , Sanders Sara Y.
Published: May 2008

Objective—To characterize clinical signs, clinicopathologic features, treatments, and survival in dogs with naturally acquired foodborne aflatoxicosis.

Design—Retrospective case series.

Animals—72 dogs that consumed aflatoxin-contaminated commercial dog food.

Procedures—Medical records of affected dogs were reviewed. Between December 2005 and March 2006, dogs were identified as having foodborne aflatoxin hepatotoxicosis on the basis of the history of consumption of contaminated food or characteristic histopathologic lesions (subject dog or a recently deceased dog in the same household or kennel). Recorded information included signalment, clinical features, clinicopathologic test results, treatments, and survival. Data were analyzed by survival status.

Results—Most dogs were of large breeds from breeding kennels. No significant differences were found in age or weight between 26 (36%) survivor dogs and 46 (64%) nonsurvivor dogs. Severity of clinical signs varied widely; 7 dogs died abruptly. In order of onset, clinical features included anorexia, lethargy, vomiting, jaundice, diarrhea (melena, hematochezia), abdominal effusion, peripheral edema, and terminal encephalopathy and hemorrhagic diathesis. Common clinicopathologic features included coagulopathic and electrolyte disturbances, hypoproteinemia, increased serum liver enzyme activities, hyperbilirubinemia, and hypocholesterolemia. Cytologic hepatocellular lipid vacuolation was confirmed in 11 dogs examined. In comparisons of clinicopathologic test results between survivor and nonsurvivor dogs, only granular cylindruria (7/21 dogs) consistently predicted death. Best early markers of aflatoxicosis were low plasma activities of anticoagulant proteins (protein C, antithrombin) and hypocholesterolemia. Despite aggressive treatment, many but not all severely affected dogs died.

Conclusions and Clinical Relevance—Serum liver enzyme activities and bilirubin concentration were unreliable early markers of aflatoxin hepatotoxicosis in dogs. Hypocholesterolemia and decreased plasma protein C and antithrombin activities may function as exposure biomarkers.
Clinical and cytogenetic characterization of 13 Dutch patients with deletion 9p syndrome: Delineation of the critical region for a consensus phenotype
Authors: Swinkels Mariëlle E.M. , Simons Annet , Smeets Dominique F. , Vissers Lisenka E. , Veltman Joris A. , Pfundt Rolph , de Vries Bert B.A. , Faas Brigitte H.W. , Schrander‐Stumpel Connie T.R.M. , McCann Emma , Sweeney Elizabeth , May Paul , Draaisma Jos M. , Knoers Nine V. , van Kessel Ad Geurts , van Ravenswaaij‐Arts Conny M.A.
Published: May 2008

The deletion 9p syndrome is caused by a constitutional monosomy of part of the short arm of chromosome 9. It is clinically characterized by dysmorphic facial features (trigonocephaly, midface hypoplasia, and long philtrum), hypotonia and mental retardation. Deletion 9p is known to be heterogeneous and exhibits variable deletion sizes. The critical region for a consensus phenotype has been reported to be located within a ∼4–6 Mb interval on 9p22. In the present study, deletion breakpoints were determined in 13 Dutch patients by applying fluorescence in situ hybridization (FISH) and in some specific cases by array‐based comparative genomic hybridization (array CGH). No clear genotype–phenotype correlation could be established for various developmental features. However, we were able to narrow down the critical region for deletion 9p syndrome to ∼300 kb. A functional candidate gene for trigonocephaly, the CER1 gene, appeared to be located just outside this region. Sequence analysis of this gene in nine additional patients with isolated trigonocephaly did not reveal any pathogenic mutations. © 2008 Wiley‐Liss, Inc.
Primary microcephaly with ASPM mutation shows simplified cortical gyration with antero‐posterior gradient pre‐ and post‐natally
Authors: Desir Julie , Cassart Marie , David Philippe , Van Bogaert Patrick , Abramowicz Marc
Published: May 2008

Primary microcephaly is a disorder of brain development characterized by a congenitally small but normally formed brain, and non‐progressive mild‐to‐moderate mental retardation. Most cases are inherited in an autosomal recessive pattern, with genetic heterogeneity, the ASPM locus being most common. Postnatal imaging data are scarce and prenatal imaging unreported. Microcephaly with simplified gyral pattern shares features with primary microcephaly, but it is not clear whether these disorders are part of a phenotypic continuum. We examined a consanguineous family with a daughter affected with primary microcephaly and an ongoing pregnancy. We performed prenatal and postnatal brain magnetic resonance imaging and genetic analyses in the course of genetic evaluation. The affected daughter and the fetus were homozygous for polymorphic markers linked to the ASPM locus, and we identified a novel, truncating ASPM mutation by direct sequencing of the gene. Imaging at 30 and 35 gestational weeks showed microcephaly with simplified gyration, more severe anteriorly. The antero‐posterior gradient of gyration persisted 1 week after birth. Brain imaging in the affected sister also showed some degree of a predominantly anterior simplification of gyration. Our data suggest that one form of autosomal recessive microcephaly is allelic to at least a subset of microcephaly with simplified gyral pattern, and that the neuronal depletion associated with the ASPM defect predominantly affects the anterior cortex. © 2008 Wiley‐Liss, Inc.
No association between two polymorphisms of the serotonin transporter gene and combined type attention deficit hyperactivity disorder
Authors: Xu X. , Aysimi E. , Anney R. , Brookes K. , Franke B. , Zhou K. , Buschgens C. , Chen W. , Christiansen H. , Eisenberg J. , Gabriëls I. , Manor I. , Marco R. , Müller U.C. , Mulligan A. , Rommelse N. , Thompson M. , Uebel H. , Banaschewski T. , Buitelaar J. , Ebstein R. , Gill M. , Miranda A. , Mulas F. , Oades R.D. , Roeyers H. , Rothenberger A. , Sergeant J. , Sonuga‐Barke E. , Steinhausen H.‐C. , Taylor E. , Faraone S.V. , Asherson P.
Published: May 2008

Several independent studies have reported association between serotonin transporter gene (SLC6A4) polymorphisms and attention deficit hyperactivity disorder (ADHD). Five studies found evidence for association between the long‐allele of a 44‐bp insertion/deletion polymorphism (5‐HTTLPR) and ADHD. Another two studies corroborated this finding while a further six studies did not find such an association. For a second polymorphism within the gene, a variable number tandem repeat (VNTR) within intron 2, one study demonstrated that the 12/12 genotype was significantly less frequent in ADHD cases compared to controls, while a second study found that the 12‐allele was preferentially transmitted to offspring affected with ADHD. To provide further clarification of the reported associations, we investigated the association of these two markers with ADHD in a sample of 1,020 families with 1,166 combined type ADHD cases for the International Multi‐Centre ADHD Genetics project, using the Transmission Disequilibrium Test. Given the large body of work supporting the association of the promoter polymorphism and mood disorders, we further analyzed the group of subjects with ADHD plus mood disorder separately. No association was found between either of the two markers and ADHD in our large multisite study or with depression within the sample of ADHD cases. © 2008 Wiley‐Liss, Inc.
Association and linkage analysis of candidate genes GRP, GRPR, CRHR1, and TACR1 in panic disorder
Authors: Hodges Laura M. , Weissman Myrna M. , Haghighi Fatemeh , Costa Ramiro , Bravo Oscar , Evgrafov Oleg , Knowles James A. , Fyer Abby J. , Hamilton Steven P.
Published: May 2008

Panic disorder (PD) is a debilitating anxiety disorder, characterized by recurrent episodes of intense fear that are accompanied by autonomic and psychological symptoms leading to behavioral impairment. Basic research implicates neuropeptide‐signaling genes in the modulation of anxiety and stress. The genes encoding corticotropin releasing hormone receptor 1 (CRHR1), tachykinin receptor 1 (TACR1), gastrin releasing peptide (GRP), and gastrin releasing peptide receptor (GRPR) were selected as candidates for PD based on their biology. Linkage and association analysis in 120 multiplex U.S. PD pedigrees was performed using 21 single nucleotide polymorphisms (SNPs). Parametric and non‐parametric linkage tests in pedigrees, for single point and multipoint analysis, revealed limited support for genetic linkage to TACR1 (parametric and non‐parametric lod scores ∼1). The family‐based association test (FBAT) generated nominal support for allelic association in TACR1 (P = 0.02), and GRP (P = 0.02), findings which must be considered in the light of multiple comparisons. Further exploration of the GRP and TACR1 findings in large case‐control PD samples may provide more definitive evidence implicating these loci in the genetic etiology of PD. © 2008 Wiley‐Liss, Inc.
Analysis of five single nucleotide polymorphisms in the ESR1 gene in cryptorchidism
Authors: Wang Yanping , Barthold Julia , Figueroa Ernesto , González Ricardo , Noh Paul H. , Wang Miao , Manson Jeanne
Published: May 2008

BACKGROUND

Recent findings suggest that a specific haplotype, including five single nucleotide polymorphisms (SNPs) in the 3′‐terminal region of the estrogen receptor α gene (ESR1), is associated with the risk for cryptorchidism, but results have been conflicting in different populations. The goal of this study was to further define the association between this specific ESR1 haplotype and the risk for nonsyndromic cryptorchidism in a multiracial American population including Caucasian, African American, and Asian American subjects.

METHODS

Applied Biosystems TaqMan SNP Genotyping Assays were used to identify the genotypes of the five SNPs in ESR1 in 152 nonsyndromic cryptorchidism cases and 160 healthy controls.

RESULTS

For the five SNPs, there were no significant differences in genotype frequencies between cases and controls. The four estimated haplotypes at the 3′ region of ESR1 gene were also not associated with the occurrence of cryptorchidism, but the haplotype AGATC was associated with the severity of cryptorchidism. SNP12 (rs6932902) in ESR1 was not associated with cryptorchidism per se, but was associated with increasing severity of cryptorchidism. Severe cases were more likely to have GG genotype (93%) than moderate (54%) cases (p = .04), and this association was in recessive mode (p = .02). The allele distribution of this SNP was also significantly different between moderate and severe cases: 97% of severe cases had the G allele while only 76% of moderate cases had the G allele (p = .03).

CONCLUSIONS

SNP12 in ESR1 is not associated with the occurrence of cryptorchidism but is associated with the severity of cryptorchidism. Birth Defects Research (Part A), 2008. © 2008 Wiley‐Liss, Inc.
Refinement of 2q and 7p loci in a large multiplex NTD family
Authors: Stamm Demetra S. , Siegel Deborah G. , Mehltretter Lorraine , Connelly Jessica J. , Trott Alison , Ellis Nathen , Zismann Victoria , Stephan Dietrich A. , George Timothy M. , Vekemans Michel , Ashley‐Koch Allison , Gilbert John R. , Gregory Simon G. , Speer Marcy C. ,   NTD Collaborative Group
Published: May 2008

BACKGROUND: NTDs are considered complex disorders that arise from an interaction between genetic and environmental factors. NTD family 8776 is a large multigenerational Caucasian family that provides a unique resource for the genetic analysis of NTDs. Previous linkage analysis using a genome‐wide SNP screen in family 8776 with multipoint nonparametric mapping methods identified maximum LOD* scores of ∼3.0 mapping to 2q33.1–q35 and 7p21.1–pter. METHODS: We ascertained an additional nuclear branch of 8776 and conducted additional linkage analysis, fine mapping, and haplotyping. Expression data from lymphoblast cell lines were used to prioritize candidate genes within the minimum candidate intervals. Genomic copy number changes were evaluated using BAC tiling arrays and subtelomeric fluorescent in situ hybridization probes. RESULTS: Increased evidence for linkage was observed with LOD* scores of ∼3.3 for both regions. Haplotype analyses narrowed the minimum candidate intervals to a 20.3 Mb region in 2q33.1–q35 between markers rs1050347 and D2S434, and an 8.3 Mb region in 7p21.1–21.3 between a novel marker 7M0547 and rs28177. Within these candidate regions, 16 genes were screened for mutations; however, no obvious causative NTD mutation was identified. Evaluation of chromosomal aberrations using comparative genomic hybridization arrays, subtelomeric fluorescent in situ hybridization, and copy number variant detection techniques within the 2q and 7p regions did not detect any chromosomal abnormalities. CONCLUSIONS: This large NTD family has identified two genomic regions that may harbor NTD susceptibility genes. Ascertainment of another branch of family 8776 and additional fine mapping permitted a 9.1 Mb reduction of the NTD candidate interval on chromosome 7 and 37.3 Mb on chromosome 2 from previously published data. Identification of one or more NTD susceptibility genes in this family could provide insight into genes that may affect other NTD families. Birth Defects Research (Part A), 2008. © 2008 Wiley‐Liss, Inc.
Effect of low frequency modulated microwave exposure on human EEG: Individual sensitivity
Authors: Hinrikus Hiie , Bachmann Maie , Lass Jaanus , Karai Deniss , Tuulik Viiu
Published: May 2008

The aim of this study was to evaluate the effect of modulated microwave exposure on human EEG of individual subjects. The experiments were carried out on four different groups of healthy volunteers. The 450 MHz microwave radiation modulated at 7 Hz (first group, 19 subjects), 14 and 21 Hz (second group, 13 subjects), 40 and 70 Hz (third group, 15 subjects), 217 and 1000 Hz (fourth group, 19 subjects) frequencies was applied. The field power density at the scalp was 0.16 mW/cm2. The calculated spatial peak SAR averaged over 1 g was 0.303 W/kg. Ten cycles of the exposure (1 min off and 1 min on) at fixed modulation frequencies were applied. All subjects completed the experimental protocols with exposure and sham. The exposed and sham‐exposed subjects were randomly assigned. A computer also randomly assigned the succession of modulation frequencies. Our results showed that microwave exposure increased the EEG energy. Relative changes in the EEG beta1 power in P3‐P4 channels were selected for evaluation of individual sensitivity. The rate of subjects significantly affected is similar in all groups except for the 1000 Hz group: in first group 3 subjects (16%) at 7 Hz modulation; in second group 4 subjects (31%) at 14 Hz modulation and 3 subjects (23%) at 21 Hz modulation; in third group 3 subjects (20%) at 40 Hz and 2 subjects (13%) at 70 Hz modulation; in fourth group 3 subjects (16%) at 217 Hz and 0 subjects at 1000 Hz modulation frequency. Bioelectromagnetics 29:527–538, 2008. © 2008 Wiley‐Liss, Inc.
Development of a benzene vapour sensor utilizing chemiluminescence on Y2O3
Authors: Rao Zhiming , Liu Linjie , Xie Jingyi , Zeng Yuyun
Published: May 2008

Chemiluminescence (CL) was observed when benzene vapour passed through the surface of Y2O3, TiO2, Y2O3–V2O5, TiO2–Y2O3, Y2O3–Cr2O3, Y2O3–Al2O3 and TiO2–Al2O3, with air as the carrier gas. The strongest CL intensity was found with Y2O3 as the catalyst. A novel benzene sensor based on this kind of CL was developed. Quantitative analysis was performed at the wavelength of 425 nm. Under optimal conditions, CL intensity was directly proportional to the concentration of benzene vapour. The linear range was 4–7018 mg/m3 (r = 0.9981, n = 11), with a detection limit of 1 mg/m3 (the signal:noise ratio was 3). This gas sensor can work continuously for >80 h and has been successfully applied to the real‐time determination of benzene vapour. Copyright © 2008 John Wiley & Sons, Ltd.
Neural correlates of verbal episodic memory in patients with MCI and Alzheimer's disease––a VBM study
Authors: Leube Dirk T. , Weis Susanne , Freymann Kathrin , Erb Michael , Jessen Frank , Heun Reinhard , Grodd Wolfgang , Kircher Tilo T.
Published: May 2008

Objective

The hippocampus is a key area for episodic memory processes. Hippocampal atrophy is a hallmark feature of Alzheimer's disease (AD). We used a new and automatized morphometric technique to better characterize brain atrophy in subjects with different levels of cognitive deficit.

Methods

In this study 21 participants with Mild Cognitive Impairment (MCI), 12 patients with early AD and 29 elderly control subjects were subjected to high resolution MRI and a neuropsychological test battery. Brain volume across participants, measured by voxel‐based morphometry (VBM), was correlated with verbal memory capacity, measured with a verbal memory test (VLMT).

Results

Atrophy in the anterior hippocampus, the ento‐ and perirhinal cortex as well as the parahippocampal gyrus, middle temporal gyrus and anterior cingulate cortex correlated closely with episodic memory performance.

Conclusions

These brain areas are known to subserve episodic encoding of verbal material. The data contribute to a better understanding of atrophic brain processes in subjects at risk for AD. A combination of neuropsychological testing and voxel‐based morphometry may serve as a diagnostic tool in the future. Copyright © 2008 John Wiley & Sons, Ltd.
HMGA2 gene is a promising target for ovarian cancer silencing therapy
Authors: Malek Anastasia , Bakhidze Elena , Noske Aurelia , Sers Christine , Aigner Achim , Schäfer Reinhold , Tchernitsa Oleg
Published: May 2008

Ovarian cancer is one of the most lethal gynecological malignancies and the small success rate of routine therapeutic methods justifies efforts to develop new approaches. Evaluation of targets for effective inhibition of ovarian cancer cell growth should precipitate clinical application of gene silencing therapy. In our previous work, we showed upregulation of HMGA2 gene expression as a result of Ras‐induced rat ovarian surface epithelial cell transformation. This gene codes the HMGA2 protein, a member of the high‐mobility group AT‐hook (HMGA) family of nonhistone chromatin proteins. Genome‐wide studies revealed upregulation of the HMGA2 gene in human ovarian carcinomas. Herein we have evaluated over‐expression of the HMGA2 gene, relevant to ovarian cancer, in subsets of human specimens and cell lines by in situ RNA hybridization and RT‐PCR. Transient silencing of HMGA2 gene by means of siRNA inhibited proliferation of those ovarian cancer cells, which over‐express this gene initially. Growth suppression was mediated by cell‐cycle arrest. Stable silencing of highly expressed HMGA2 gene by shRNAi in A27/80, Ovcar‐3 and OAW‐42 ovarian cancer cell lines resulted in growth inhibition because of G1 arrest and increase of apoptosis as well. The tumor growth inhibition effect of HMGA2 silencing for Ovcar‐3 cells was validated in vivo. Our findings revealed that the HMGA2 gene represents a promising target for gene silencing therapy in ovarian cancer. © 2008 Wiley‐Liss, Inc.
Investigating Black‐White differences in prostate cancer prognosis: A systematic review and meta‐analysis
Authors: Evans Simon , Metcalfe Chris , Ibrahim Fowzia , Persad Raj , Ben‐Shlomo Yoav
Published: May 2008

The case‐fatality rate following a diagnosis of prostate cancer is higher for Black men compared to White men. How this elevated rate arises is uncertain, with differences in disease biology, presentation, treatment and comorbidity having been suggested. A systematic search was conducted for articles that reported ethnic differences in overall‐survival, prostate cancer specific survival (PSS) or biochemical recurrence. 48 articles met the inclusion criteria. Black men had worse overall survival (risk ratio 1.35, 95% CI 1.23–1.48) but this was not due to comorbidity alone as PSS and risk of biochemical recurrence were also elevated (1.29, 95% CI 1.13–1.47 and 1.34, 95% CI 1.23–1.46, respectively). Studies adjusting for clinical predictors and socioeconomic variables no longer supported a difference in overall survival (1.01, 95% CI 0.88–1.16), but continued to find an increased risk amongst Black men for PSS (1.13, 95% CI 1.00–1.27) and biochemical recurrence (1.25, 95% CI 1.11–1.41). Similar results were seen for studies from the pre‐PSA era and free‐health care settings. In contrast to others, studies of metastatic cancer did not find evidence of Black‐White differences (p for interaction = 0.01). In conclusion, Black men had a poorer prognosis which was not fully explained by comorbidity, PSA screening, or access to free health care, although few studies measure these factors well. Either management differences for local disease and/or biological differences may be behind Black‐White differences in prostate cancer prognosis. © 2008 Wiley‐Liss, Inc.
Potentiation of chemotherapeutic drugs by energy metabolism inhibitors 2‐deoxyglucose and etomoxir
Authors: Hernlund Emma , Ihrlund Linda Strandberg , Khan Omar , Ates Yildiz Ozlem , Linder Stig , Panaretakis Theocharis , Shoshan Maria C.
Published: May 2008

Inhibition of energy production as a strategy for potentiation of anticancer chemotherapy was investigated using 1 glycolysis inhibitor and 1 fatty acid β‐oxidation inhibitor—2‐deoxyglucose and etomoxir, respectively, both known to be clinically well tolerated. Eighteen anticancer drugs were screened for potentiation by these inhibitors. 2‐deoxyglucose potentiated acute apoptosis (24 hr) induced mainly by some, but not all, genotoxic drugs, whereas etomoxir had effect only on cisplatin. By contrast, etomoxir did potentiate the overall, 48 hr effects of some genotoxic drugs, and was in addition more efficient than deoxyglucose in potentiating the overall effects of several non‐genotoxic drugs. Both types of potentiation were largely lost in the absence of p53. Because cisplatin was potentiated by both energy inhibitors in both types of assay, it was investigated at additional concentrations and over longer time. Both energy inhibitors strongly potentiated non‐apoptotic concentrations of cisplatin in p53‐wildtype as well as in p53‐deficient, cisplatin‐resistant HCT116 colon carcinoma cells. Reduced ATP levels correlated with, but were not sole determinants, the antiproliferative effects. We conclude that the long‐term effects of cisplatin potentiation are important and either p53‐independent or improved by a lack of p53. We also conclude that although the potentiated drugs as yet have no obvious mechanistic factor in common, the strategy holds promise with genotoxic as well non‐genotoxic anticancer drugs. © 2008 Wiley‐Liss, Inc.
Involvement of endoplasmic reticulum in paclitaxel‐induced apoptosis
Authors: Liao Pei‐Chun , Tan Sai‐Koong , Lieu Chien‐Hui , Jung Hsuan‐Kuang
Published: May 2008

The participation of the mitochondrial pathway in paclitaxel‐induced apoptosis has been well documented. After addition of paclitaxel to U937 cells, however, we observed an early expression of five endoplasmic reticulum (ER) stress response genes that preceded the release of cytochrome c from the mitochondria and the cleavage of the caspases. Involvement of the ER was supported by the following evidence. Paclitaxel treatment not only activated calpain and caspase‐4, but also induced a gradual increase in the cytosolic Ca2+ concentration at 3–6 h. Paclitaxel‐induced apoptosis can be inhibited by the calpain inhibitor calpeptin and IP3 receptor inhibitors. Either buffering of the cytosolic Ca2+ or inhibition of mitochondrial calcium uptake reduced BiP expression. These inhibitors also reduced mitochondrial apoptotic signals, such as mitochondrion membrane potential disruption, cytochrome c release and eventually reduced the death of U937 cells. Paclitaxel‐induced Bax/Bak translocation to the ER and Bax dimerization on the ER membrane occurred within 3 h, which led to a Ca2+ efflux into cytosol. Moreover, we found that cytochrome c translocated to the ER after releasing from mitochondria and then interacted with the IP3 receptor at 12–15 h. This phenomenon has been known to amplify apoptotic signaling. Taken together, ER would seem to contribute to paclitaxel‐induced apoptosis via both the early release of Ca2+ and the late amplification of mitochondria‐mediated apoptotic signals. J. Cell. Biochem. 104: 1509–1523, 2008. © 2008 Wiley‐Liss, Inc.
Increased intracellular [dATP] enhances cardiac contraction in embryonic chick cardiomyocytes
Authors: Schoffstall Brenda , Chase P. Bryant
Published: May 2008

Although ATP is the physiological substrate for cardiac contraction, cardiac contractility is significantly enhanced in vitro when only 10% of ATP substrate is replaced with 2′‐deoxy‐ATP (dATP). To determine the functional effects of increased intracellular [dATP] ([dATP]i) within living cardiac cells, we used hypertonic loading with varying exogenous dATP/ATP ratios, but constant total nucleotide concentration, to elevate [dATP]i in contractile monolayers of embryonic chick cardiomyocytes. The increase in [dATP]i was estimated from dilution of dye added in parallel with dATP. Cell viability, average contractile amplitude, rates of contraction/relaxation, spontaneous beat frequency, and Ca2+ transient amplitude and kinetics were examined. At total [dATP]i above ∼70 µM, spontaneous contractions ceased, and above ∼100 µM [dATP]i, membrane blebbing was also observed, consistent with apoptosis. Interestingly, [dATP]i of ∼60 µM (∼40% increase over basal [dATP]i levels) enhanced both amplitude of contraction and the rates of contraction and relaxation without affecting beat frequency. With total [dATP]i of ∼60 µM or less, we found no significant change in Ca2+ transients. These data indicate that there is an “optimal” concentration of exogenously loaded [dATP]i that under controlled conditions can enhance contractility in living cardiomyocytes without affecting beat frequency or Ca2+ transients. J. Cell. Biochem. 104: 2217–2227, 2008. © 2008 Wiley‐Liss, Inc.
Differential expression of the two distinct replication protein A subunits from Cryptosporidium parvum
Authors: Rider Stanley Dean , Zhu Guan
Published: May 2008

Apicomplexan parasites differ from their host by possessing at least two distinct types (long and short) of replication protein A large subunits (RPA1). Different roles for the long and short types of RPA1 proteins have been implied in early biochemical studies, but certain details remained to be elucidated. In the present study, we have found that the Cryptosporidium parvum short‐type RPA1 (CpRPA1A) was highly expressed at S‐phase in parasites during the early stage of merogony (a cell multiplication process unique to this group of parasites), but otherwise present in the cytosol at a much lower level in other cell‐cycle stages. This observation indicates that CpRPA1A is probably responsible for the general DNA replication of the parasite. On the other hand, the long‐type CpRPA1B protein was present in a much lower level in the early life cycle stages, but elevated at later stages involved in sexual development, indicating that CpRPA1B may play a role in DNA recombination. Additionally, CpRPA1B could be up‐regulated by UV exposure, indicating that this long‐type RPA1 is probably involved in DNA repair. Collectively, our data implies that the two RPA1 proteins in C. parvum are performing different roles during DNA replication, repair and recombination in this parasite. J. Cell. Biochem. 104: 2207–2216, 2008. © 2008 Wiley‐Liss, Inc.
Desirability‐based multiobjective optimization for global QSAR studies: Application to the design of novel NSAIDs with improved analgesic, antiinflammatory, and ulcerogenic profiles
Authors: Cruz‐Monteagudo Maykel , Borges Fernanda , Cordeiro M. Natália D. S.
Published: May 2008

Up to now, very few reports have been published concerning the application of multiobjective optimization (MOOP) techniques to quantitative structure–activity relationship (QSAR) studies. However, none reports the optimization of objectives related directly to the desired pharmaceutical profile of the drug. In this work, for the first time, it is proposed a MOOP method based on Derringer's desirability function that allows conducting global QSAR studies considering simultaneously the pharmacological, pharmacokinetic and toxicological profile of a set of molecule candidates. The usefulness of the method is demonstrated by applying it to the simultaneous optimization of the analgesic, antiinflammatory, and ulcerogenic properties of a library of fifteen 3‐(3‐methylphenyl)‐2‐substituted amino‐3H‐quinazolin‐4‐one compounds. The levels of the predictor variables producing concurrently the best possible compromise between these properties is found and used to design a set of new optimized drug candidates. Our results also suggest the relevant role of the bulkiness of alkyl substituents on the C‐2 position of the quinazoline ring over the ulcerogenic properties for this family of compounds. Finally, and most importantly, the desirability‐based MOOP method proposed is a valuable tool and shall aid in the future rational design of novel successful drugs. © 2008 Wiley Periodicals, Inc. J Comput Chem, 2008
The calcium binding protein S100A9 is essential for pancreatic leukocyte infiltration and induces disruption of cell–cell contacts
Authors: Schnekenburger Jürgen , Schick Verena , Krüger Burkhard , Manitz Marie Pierre , Sorg Clemens , Nacken Wolfgang , Kerkhoff Claus , Kahlert Andreas , Mayerle Julia , Domschke Wolfram , Lerch Markus M.
Published: May 2008

Leukocyte infiltration is an early and critical event in the development of acute pancreatitis. However, the mechanism of leukocyte transmigration into the pancreas and the function of leukocytes in initiating acute pancreatitis are still poorly understood. Here, we studied the role of S100A9 (MRP14), a calcium binding protein specifically released by polymorph nuclear leukocytes (PMN), in the course of acute experimental pancreatitis. Acute pancreatitis was induced by repeated supramaximal caerulein injections in S100A9 deficient or S100A9 wild‐type mice. We then determined S100A9 expression, trypsinogen activation peptide (TAP) levels, serum amylase and lipase activities, and tissue myeloperoxidase (MPO) activity. Cell–cell contact dissociation was analyzed in vitro with biovolume measurements of isolated acini after incubation with purified S100A8/A9 heterodimers, and in vivo as measurement of Evans Blue extravasation after intravenous application of S100A8/A9. Pancreatitis induced increased levels of S100A9 in the pancreas. However, infiltration of leukocytes and MPO activity in the lungs and pancreas during acute pancreatitis was decreased in S100A9‐deficient mice and associated with significantly lower serum amylase and lipase activities as well as reduced intrapancreatic TAP‐levels. Incubation of isolated pancreatic acini with purified S100A8/A9‐heterodimers resulted in a rapid dissociation of acinar cell–cell contacts which was highly calcium‐dependent. Consistent with these findings, in vivo application of S100A8/A9 in mice was in itself sufficient to induce pancreatic cell–cell contract dissociation as indicated by Evans Blue extravasation. These data show that the degree of intrapancreatic trypsinogen activation is influenced by the extent of leukocyte infiltration into the pancreas which, in turn, depends on the presence of S100A9 that is secreted from PMN. S100A9 directly affects leukocyte tissue invasion and mediates cell contact dissociation via its calcium binding properties. J. Cell. Physiol. 216: 558–567, 2008. © 2008 Wiley‐Liss, Inc.
RAGE recycles at the plasma membrane in S100B secretory vesicles and promotes Schwann cells morphological changes
Authors: Perrone Lorena , Peluso Gianfranco , Melone Mariarosa AB
Published: May 2008

RAGE is a multiligand receptor of the immunoglobulin superfamily involved in regeneration of injured peripheral nerve and cell motility. RAGE is implicated in the development of various chronic diseases, such as neurodegenerative disorders, inflammatory responses, and diabetic complications. The correlation between RAGE endocytic trafficking and RAGE function is still uninvestigated. S100B is one of the ligands of RAGE. The molecular mechanisms responsible of S100B translocation in exocytic vesicles are still poorly investigated. In the present study we elucidate the role of RAGE endocytic trafficking in promoting S100B secretion in Schwann cells. Here we show that RAGE‐induced secretion of S100B requires phosphorylated caveolin1‐dependent endocytosis of RAGE. Endocytosis of RAGE in response to ligand binding promotes the fusion of endosomes with S100B‐positive secretory vesicles. Src promotes the fusion of endosomes with S100B‐secretory vesicles. Inhibition of src induces RAGE degradation. RAGE‐mediated src activation induces cav1 phosphorylation and relocalization in the perinuclear compartment. RAGE signaling and recycling are required for S100‐induced Schwann cells morphological changes and are inhibited by high‐glucose, suggesting a possible link between diabetes and peripheral nerve injury. Indeed, high glucose inhibits RAGE‐mediated src activation. Src inhibition blocks RAGE recycling, S100B secretion, and morphological changes. In summary, we identified a novel pathway of vesicular trafficking required for the amplification of RAGE signaling and cytoskeleton dynamics that is potentially involved in the regeneration of injured peripheral nerve. J. Cell. Physiol. 217: 60–71, 2008. © 2008 Wiley‐Liss, Inc.
New insights into the morphology of Trypanosoma cruzi reservosome
Authors: Sant'Anna Celso , Pereira Miria G. , Lemgruber Leandro , de Souza Wanderley , Cunha e Silva Narcisa L.
Published: May 2008

Reservosomes are late endosomes present only in members of the Schizotrypanum subgenus of the Trypanosoma genus and are defined as the site of storage of endocytosed macromolecules and lysosomal enzymes. They have been extensively described in Trypanosoma cruzi epimastigote: are bounded by a membrane unit, present an electron‐dense protein matrix with electron‐lucent lipid inclusions, being devoid of inner membranes. Here we performed a detailed ultrastructural analysis of these organelles using a variety of electron microscopy techniques, including ultrathin sectioning, uranyl acetate stained preparations, and freeze fracture, either in intact epimastigotes or in isolated reservosomes. New informations were obtained. First, both isolated and in situ reservosomes presented small profiles of inner membranes that are morphologically similar to the membrane surrounding the organelle. In uranyl acetate stained preparations, internal membrane profiles turned out to be longer than they appeared in ultrathin section images and traversed the organelle diameter. Internal vesicles were also found. Second, endocytosed cargo are not associated with internal vesicles and reach reservosomes on board of vesicles that fuse with the boundary membrane, delivering cargo directly into reservosome lumen. Third, electron‐lucent bodies with saturated lipid core surrounded by a membrane monolayer and with unusual rectangular shape were also observed. Fourth, it was possible to demonstrate the presence of intramembranous particles on the E face of both internal vesicles and the surrounding membrane. Collectively, these results indicate that reservosomes have a complex internal structure, which may correlate with their multiple functions. Microsc. Res. Tech., 2008. © 2008 Wiley‐Liss, Inc.
Analysis of industrial tasks as a tool for the inclusion of people with disabilities in the work market
Authors: Simonelli Angela Paula , Camarotto João Alberto
Published: May 2008

This article describes the application of a model for analyzing industrial tasks that was developed to identify jobs that could potentially be filled by people with disabilities (DP) and to serve as a guideline for a company hiring policy. In Brazil, Law No. 8213/91 makes it obligatory to hire DP based on quotas that are established according to the number of employees in a public and private company. Using a set of methods and techniques based on ergonomic work analysis and on occupational therapy, we sought to build a model to indicate the skills required to perform industrial tasks. The model was applied at 19 workstations at a Brazilian aircraft manufacturer in 2002. The task supervisor and the operator performing the task were interviewed, the work activity was filmed, a kinesiological analysis was done, the task was observed and a checklist was applied to help recognize and systematize the skills involved in performing the job task. The last step consisted of correlating the skills required to perform the task to the potential skills of the various types of disability. It was found that 100% of the jobs could be filled by workers with low‐level paraplegia, 89% by workers with general paraplegia, 0% with low‐level tetraplegia, 47% with auditory impairment, 42% with hemiplegia, 68% with upper limb amputees wearing adequate prostheses, and 89% handicapped wheelchair users. The company hired 14 DP based on the results of this model. The model proved adequate for analyzing industrial tasks with a view to the inclusion of DP, and it can be applied to other sectors of industrial production. Copyright © 2008 John Wiley & Sons, Ltd.
Influence of antidepressants on glycaemic control in patients with diabetes mellitus
Authors: Knol M. J. , Derijks H. J. , Geerlings M. I. , Heerdink E. R. , Souverein P. C. , Gorter K. J. , Grobbee D. E. , Egberts A. C. G.
Published: May 2008

Purpose

Anecdotal evidence suggests that antidepressants (ADs) may complicate glycaemic control. The objective of this longitudinal study was to investigate the influence of ADs on glycaemic control within diabetes patients.

Methods

From the pharmacy registry database PHARMO, we selected insulin users who did not use oral antidiabetics. The study population comprised: 133 patients with at least 12 months insulin use before and 6 months during an AD episode, including 56 patients with an additional 6 months of insulin use after the AD episode; 180 patients with 24 months insulin use without an AD episode. Glycaemic control was measured as the amount of insulin used, which was calculated intra‐individually in 3‐month periods. We stratified for selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs).

Results

Mean age (s.d.) of the subjects was 53.9 (19) years; 46.9% were men. Overall, the amount of insulin used did not change during or after AD use. No‐AD users showed an increase of 16% in amount of insulin used over a period of 2 years (p < 0.001). SSRI users showed a decrease of 13% in amount of insulin used during the AD episode (p = 0.029), while no change was seen in TCA users. Notable was the large intra‐ and interindividual variation in amount of insulin used across all groups.

Conclusions

Overall, AD use did not influence glycaemic control in diabetes patients. The tendency for a difference between SSRIs and TCAs is suggestive for a pharmacologic effect of ADs rather than a general effect of depression on glycaemic control. Copyright © 2008 John Wiley & Sons, Ltd.
Anti‐apoptotic Bcl‐XL protein in complex with BH3 peptides of pro‐apoptotic Bak, Bad, and Bim proteins: Comparative molecular dynamics simulations
Authors: Lama Dilraj , Sankararamakrishnan Ramasubbu
Published: May 2008

The Bcl‐2 family of proteins plays a central role in the regulation of mitochondrial outer‐membrane permeabilization, a critical step in apoptosis. Heterodimerization between the pro‐ and anti‐apoptotic members of Bcl‐2 family is a key event in this process. Anti‐apoptotic proteins have high levels of expression in many cancers and they have different affinities for different pro‐apoptotic proteins. Experimentally determined structures of all members of Bcl‐2 proteins have remarkably similar helical fold despite poor amino acid sequence identity. Peptides representing BH3 region of pro‐apoptotic proteins have been shown to bind the hydrophobic cleft of anti‐apoptotic proteins and this segment is responsible in modulating the apoptotic pathways in living cells. Understanding the molecular basis of protein–protein recognition is required to develop inhibitors specific to a particular anti‐apoptotic protein. We have carried out molecular dynamics simulations on the anti‐apoptotic Bcl‐XL protein in complex with three different BH3 peptides derived from pro‐apoptotic Bak, Bad and Bim proteins. Each complex structure was simulated for a period of 50 ns after 2.5 ns equilibration. Analysis of the simulation results showed that in the Bcl‐XL protein, the helix containing the BH3 region is more flexible than other helices in all three simulations. A network of strong hydrophobic interactions exists between four of the six helices and they contribute significantly to the stability of this helix bundle protein. Analysis of Bcl‐XL‐BH3 peptide interactions reveals the role of loop residues in the protein–peptide interactions in all three simulations. Bad and Bim peptides maintain strong hydrophobic and hydrophilic interactions with the helix preceding the central hydrophobic helix. Residues from this helix interact with an Arg residue in Bad and Bim peptides. This Arg residue is next to the conserved Leu residue and is replaced by Ala in Bak. Absence of these interactions and the helix propensity are likely to be the cause for Bak peptide's weaker binding affinity with the Bcl‐XL protein. The results of this study have implications in the design of Bcl‐XL‐specific inhibitors. Proteins 2008. © 2008 Wiley‐Liss, Inc.
Usefulness and Application of the Liver Hanging Maneuver for Anatomical Liver Resections
Authors: Nanashima Atsushi , Sumida Yorihisa , Abo Takafumi , Nagayasu Takeshi , Sawai Terumitsu
Published: May 2008

Background

To achieve complete anatomic hepatectomy, hepatic transection by an anterior approach is useful. The liver hanging maneuver is a useful procedure for transection of adequate cut plane in anatomical liver resections and may reduce intraoperative bleeding and transection time.

Methods

We examined the records of 71 patients who underwent anatomic hepatic resection with (n = 24, between 2001 and September 2007) or without liver hanging maneuver (LHM) (n = 47, between 2000 and 2003). Groups were historically compared in terms of patient demographics, preoperative hepatic function, surgical records, and outcome. LHM was conducted according to the Belghiti’s original method.

Results

LHM could be performed not only in hemihepatectomy but also in right and left trisectionectomy. Demographics and preoperative hepatic function tests were not significantly different between the LHM and non‐LHM groups. Although intraoperative bleeding, blood transfusion, and operating time were not significantly different between groups, the time required for liver parenchymal transection was significantly shorter in the LHM group (36.5 ± 9.9 vs. 48.1 ± 12.7 min, P = 0.004). Postoperative liver function, morbidity, and mortality were not significantly different between the groups. In other hepatectomy with cut plane along the right hepatic vein, the transection time tended to be shorter in the LHM group (n = 5, 32.4 ± 6.1 min) than in the non‐LHM group (n = 5, 44.4 ± 8.3 min), albeit insignificantly (P = 0.06).

Conclusion

LHM can reduce the transection time at the cut plane in hepatic resections. Our results emphasized the advantages and usefulness of LHM in anatomical liver resections.
Changes in HIV Testing Policies and the Implications for Women
Authors: Maman Suzanne , King Elizabeth
Published: May 2008

The US Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) together with the Joint United Nations Programme on HIV/AIDS (UNAIDS) recently released new guidelines for HIV testing in health care settings. Both sets of guidelines recommend eliminating individual informed consent in favor of an opt‐out approach that requires clients to actively decline the HIV test after a pretest information session. The revised guidelines also recommend reducing the amount of counseling that accompanies the HIV test. Women are more likely than men to be affected by efforts to expand access to HIV testing in health care settings because of women's increased vulnerability to HIV and greater contact with the health care system. Women may also be more susceptible to changes to the consent and counseling process for HIV testing because of their marginalized social status in many settings. More research is needed to document women's experiences with provider‐initiated, opt‐out HIV testing. Understanding women's experiences will help to formulate feasible and effective strategies to support women and ensure they gain access to HIV treatment services.
The Quadrivalent Human Papillomavirus Vaccine: Potential Factors in Effectiveness
Authors: Zonfrillo Nancy J. , Hackley Barbara
Published: May 2008

Cervical cancer, caused by human papillomavirus (HPV) infection, is the second most common female cancer in the world, causing over a quarter of a million deaths worldwide every year. The quadrivalent HPV vaccine (Gardasil) has the potential to significantly reduce morbidity and mortality associated with cervical disease. However, a variety of factors affect the vaccine's success, including exposure to HPV prior to vaccination, duration of protection provided by the vaccine, the in vivo interaction between HPV serotypes, and variation in HPV serotype prevalence worldwide. This article describes the pathophysiology of HPV infection, efficacy and safety of the quadrivalent HPV vaccine, factors that may influence the vaccine's effectiveness in reducing cervical cancer rates, and recommendations for maximizing this effectiveness.
Antibiotic Resistance: A Guide for Effective Prescribing in Women's Health
Authors: Roe Valerie A.
Published: May 2008

Current national and international trends in antibiotic resistance are becoming a public health crisis. Multi‐drug resistant organisms are more prevalent in hospital settings and, alarmingly, are now being identified in the community. Over‐reliance on broad‐spectrum antibiotics, as well as inappropriate prescribing practices, play a significant role in encouraging the emergence of resistant organisms. This article reviews the mechanisms of bacterial resistance, current trends in national and international antibiotic resistance, and examines approaches to combat pathogens while sparing benign microbes.
Listeriosis in Pregnancy
Authors: Delgado Ana R.
Published: May 2008

M.G., a 24‐year‐old, healthy, gravida 2, para 1001 had an uncomplicated prenatal course, with a normal first trimester ultrasound and normal values on all routine prenatal labs. At 18 weeks' gestation, she presented to her midwife on labor and delivery complaining of severe abdominal pain and a sudden onset of fever. She was found to be febrile with a temperature of 38.5°C and tachycardic with a pulse of 120 bpm. Using Doppler ultrasound, her nurse identified fetal heart tones. Her midwife noted fetal membranes bulging into the vagina through a dilated cervix on speculum exam. M.G. received fentanyl 100 mcg intravenously for pain. The midwife paged her consulting physician who arrived within 30 minutes. Shortly thereafter, M.G. gave birth to a normally formed fetus appropriate for 18 weeks gestation. The placenta delivered within a few minutes and was sent to the pathology department for culture. The placenta was noted to have a fibrous, exudative coating. M.G. received routine postpartum care and follow‐up for a second‐trimester abortion, including grief counseling. Her febrile illness resolved spontaneously within a day following the birth. The pathology report stated that the placenta had signs of chorioamnionitis and the culture grew Listeria monocytogenes. During postpartum follow‐up, M.G. denied exposure to any of the foods known to be at high risk for L monocytogenes contamination.