bluuebunny/crossref_metadata_2025 huggingface dataset:
German-Algerian University Exchange from the Perspective of Students and Teachers
Authors: Döring Nicola , Lahmar Kamel , Bouabdallah Mohamed , Bouafia Mohamed , Bouzid Djamel , Gobsch Gerhard , Runge Erich
Published: January 2009

Academic exchange programs provide students and teachers with the opportunity to study or work temporarily at educational institutions abroad. For exchange programs to be successful in promoting intercultural education, they must be designed with their participants in mind. The present study constitutes an investigation of attitudes and expectations of students and teachers with respect to a German—Algerian university exchange program. Germany and Algeria belong to separate cultural spheres—the Western/European and the Arabic/Islamic—and almost no academic exchange has taken place between them to date. The survey’s four participant groups were German ( n = 270) and Algerian students ( n = 214), and German ( n = 24) and Algerian teachers ( n = 43). The study revealed large differences in the hopes and fears that German and Algerian university students and teachers attach to reciprocal academic exchange. The study’s ramifications for the future planning of a German—Algerian university exchange program are discussed.
It's About Time!!!!
Authors: Tosi Henry
Published: January 2009

As anyone who has submitted papers for publication for any period of time knows, there are instances of unconscionable delay in getting reviews back for journals. In this note, some of these reasons are discussed and ways to resolve them are proposed. Perhaps the most radical suggestion is for a process in which reviewers are identified, while authors remain anonymous.
The optimal therapeutic use of ixabepilone in patients with locally advanced or metastatic breast cancer
Authors: Boehnke Michaud Laura
Published: January 2009

Background. The epothilones are a new class of microtubule-stabilizing drugs that exert potent antitumor activity against taxane-resistant and multidrug resistant cell lines. The most clinically advanced member of this class is the semisynthetic epothilone B derivative ixabepilone.

Purpose. This article reviews the preclinical and clinical data on ixabepilone in patients with locally advanced and metastatic breast cancer (MBC) and provides guidance for pharmacists on its optimal use. Data sources. PubMed and conference proceedings through August 2008.

Results. In preclinical studies, ixabepilone has demonstrated potent antitumor activity and low susceptibility to mechanisms that confer tumor resistance. Clinically meaningful benefits have been achieved with ixabepilone monotherapy in phase 2 trials of patients with MBC who have failed previous chemotherapies (anthracyclines, taxanes, or capecitabine). In a randomized, phase 3 trial, the combination of ixabepilone and capecitabine proved more effective than capecitabine alone after the failure of taxane and anthracycline regimens. At the recommended dose and schedule, the therapeutic ratio of ixabepilone is generally favorable, and its adverse effects (notably neutropenia and peripheral neuropathy) are generally manageable and reversible.

Conclusion. Ixabepilone represents an advance in the treatment of anthracycline - and taxane-pretreated MBC. Future studies will define its efficacy in combination with other drugs used in the treatment of MBC, as well as in other types of cancer. J Oncol Pharm Practice (2009) 15: 95—106.
Rapid Infusion Rituximab Changing Practice for Patient Care
Authors: Al Zahrani Ali , Ibrahim Nagwa , Al Eid Ahmed
Published: January 2009

Rituximab is a chimeric anti-CD20 monoclonal antibody. Its intravenous administration is associated with substantial infusion related-toxicity. Recommended infusion durations are prolonged (average 5—6 h for first infusion and 3—4 h for subsequent infusions). We aimed to explore the safety and tolerability of short infusion rituximab, (over 90 min), in Non-Hodgkin’s lymphoma patients at Riyadh Military Hospital. Adult oncology patients diagnosed with Non-Hodgkin’s lymphoma, who were to receive rituximab, were included in the study. The schedule of administration for cycle one was unaltered and delivered according to the product monograph (5—6 h). All subsequent cycles were administered over a total infusion time of 90 min (20% of the dose in the first 30 min then the remaining 80% over 60 min, total dose delivered in 500 mL sodium chloride). All patients were observed for infusion related reactions during the rituximab infusion and for 30 min after the infusion. In addition, all patients were advised to report any reaction occurring within 24 h after rituximab infusion.

From April 2007 to September 2007, 21 patients with non-Hodgkin’s lymphoma were treated with rituximab-based chemotherapy. A total of 126 infusions were administered with average of 6 infusions per patient. The majority of patients were treated with CHOP—Rituximab or CHOP-like regimen. The 90-min Rituximab infusion schedule was well tolerated with no grade 3/4 infusion related adverse events observed. A rapid infusion rituximab over 90 min is well tolerated and safe when administered as the second and subsequent infusions in the course of therapy. This shortened infusion schedule has resulted in a substantial reduction in resource utilization. Our institution has adopted this as routine practice.
Patients’ perspectives and safe handling of oral anticancer drugs at an Asian cancer center
Authors: Chan Alexandre , Leow Yumei Cynthia , Sim Mui Hian
Published: January 2009

Background. In view of the increased usage of oral anticancer drugs in the contemporary treatment of cancer, we aimed to examine cancer patients’ perspectives of oral anticancer drugs, through a survey at an Asian cancer centre. This study also intended to describe patients’ behavior regarding storage, handling, and administration of oral anticancer drugs.

Methods. This cross sectional survey was conducted at a single site. The interviewer-administered survey was undertaken at the outpatient pharmacy of National Cancer Centre Singapore (NCCS), the largest ambulatory cancer center in Singapore, between January and March 2008. Eligible patients had received at least one cycle of oral anticancer agent treatment or had been taking oral anticancer agents continuously for 3 months.

Results. A total of 126 patients were surveyed. Median age of surveyed patients was 58 years (range 31—85 years). The drugs involved were capecitabine (39.7% of patients), tamoxifen (23.1%), aromatase inhibitors (18.2%), gefitinib (9.1%), and imatinib (3.3%). Over 90% patients self-administered their oral anticancer drugs. The majority of the patients (94.2%) reported no difficulties in adherence to their oral anticancer treatment regimens. Forty per cent of patients reported habitually washing their hands after administering their anticancer drugs. None of the patients, except two patients receiving capecitabine, indicated that they habitually used gloves to handle their oral anticancer medications. Conclusion. The majority of patients receiving oral anticancer agents reported no difficulty in adhering to their oral anticancer treatment regimens as prescribed. However, this survey demonstrated the need to improve patients’ understanding of the requirements for storage, handling and safe administration of oral anticancer drugs.
Free Recall and Learning of Emotional Word Lists in Very Elderly People With and Without Dementia
Authors: Nieuwenhuis-Mark Ruth E. , Schalk Kim , de Graaf Natalie
Published: January 2009

An emotional memory advantage has been found across the life span where recall is better for emotional (as opposed to neutral) stimuli. Our goal was to design emotionally valent word lists for easy use by practitioners and to test whether demented and healthy elderly participants showed an emotional memory advantage with these lists. Three new word lists (a positive, a negative, and a neutral list) were constructed. Thirty-eight controls, 37 with mild cognitive impairment and 20 Alzheimer's dementia participants' free recall was tested. Unsurprisingly, controls had better recall overall. Emotionally valent words were recalled better in comparison to neutral words in all 3 groups. No recall advantage for positive versus negative words emerged. Learning differed among the groups with the Alzheimer's dementia participants showing flatter learning curves. The results tentatively suggest that emotional memory may stay intact longer but that learning of such lists becomes more difficult as dementia progresses.
Has Prolactin a Role in the Hypogonadal Status of HIV-Infected Patients?
Authors: Collazos Julio , Esteban Margarita
Published: January 2009

Most cases of hypogonadism in human immunodeficiency virus (HIV) infection are of hypophyseal— hypothalamic origin, and hyperprolactinemia, also commonly observed in HIV-infected patients, may cause hypogonadism. We studied 188 HIV-infected men who had simultaneous determinations of gonadal and hypophyseal hormones, and we found that prolactin levels were independently predictive of hypogonadism in multivariate analysis.
Return of Memory and Sleep Efficiency Following Moderate to Severe Closed Head Injury
Authors: Makley Michael J. , Johnson-Greene Lisa , Tarwater Patrick M. , Kreuz Andrew J. , Spiro J. , Rao V. , Celnik Pablo A.
Published: January 2009

Objective. Sleep disturbance is common in the subacute recovery phase following brain injury. A previous study from the authors' group found 68% of patients with closed head injury (CHI) had disrupted sleep on a rehabilitation unit. In the present study, the authors investigated whether improvement in sleep efficiency correlates with duration of posttraumatic amnesia (PTA) after CHI. Methods. Fourteen CHI patients were enrolled and followed prospectively. Mechanism of injury included motor vehicle accident, fall, and blunt assault. An actigraph was placed on each subject's wrist within 72 hours of admission to the rehabilitation unit and recorded data for the duration of their stay. A minimum of 7 days of continuous actigraphy data was obtained on all subjects. PTA was measured daily using the Orientation Log (O-LOG). Results. Seventy-eight percent of subjects had mean week-1 sleep efficiency scores of ≤63%. Patients admitted having already cleared PTA had significantly better week-1 sleep efficiency scores than those with ongoing amnesia ( P = .032). For those patients admitted with ongoing PTA, each 10-unit increase in sleep efficiency score correlated with 1 unit increase in O-LOG score ( P = .056). Conclusions. Disrupted sleep is common in the postacute stage following CHI. Improved sleep efficiency correlates with resolution of PTA. Decreased sleep efficiency may negatively affect memory return after traumatic brain injury. Actigraphy is uniquely suited to study the sleep patterns of these patients.
Mature human eosinophils express functional Notch ligands mediating eosinophil autocrine regulation
Authors: Radke Amy L. , Reynolds Lauren E. , Melo Rossana C. N. , Dvorak Ann M. , Weller Peter F. , Spencer Lisa A.
Published: January 2009

Eosinophil chemotaxis and survival within tissues are key components in the development of tissue eosinophilia and subsequent effector responses. In this study, we demonstrate a novel mechanism of eosinophil autoregulation affecting migration and survival mediated through Notch signaling. We show for the first time that human blood eosinophils express Notch receptors and Notch ligands, expressions of which are influenced by the presence of eosinophil-activating granulocyte-macrophage colony-stimulating factor (GM-CSF). Evidence of Notch receptor activation and subsequent transcription of the Notch-responsive gene HES1 were observed in GM-CSF–stimulated eosinophils, confirming functionality of eosinophil-expressed Notch-signaling components. Moreover, by inhibiting Notch signaling with γ-secretase inhibitors or Notch receptor–specific neutralizing antibodies, we demonstrate that autocrine Notch signaling enhances stimulus-mediated actin rearrangement and eosinophil chemokinesis, and impairs eosinophil viability. Taken together, these data suggest autocrine Notch signaling, enhanced in response to tissue- or inflammatory-derived signals, influences eosinophil activity and longevity, which may ultimately contribute to the development of tissue eosinophilia and exacerbation or remediation of eosinophil effector functions.
C1q enhances IFN-γ production by antigen-specific T cells via the CD40 costimulatory pathway on dendritic cells
Authors: Baruah Paramita , Dumitriu Ingrid E. , Malik Talat H. , Cook H. Terence , Dyson Julian , Scott Diane , Simpson Elizabeth , Botto Marina
Published: January 2009

Dendritic cells (DCs) are known to produce C1q, the initiator of the classical complement pathway. We demonstrate that murine DCs deficient in C1q (C1qa−/−) are poorer than wild-type (WT) DCs at eliciting the proliferation and Th1 differentiation of antigen-specific T cells. These defects result from decreased production of IL-12p70 by C1qa−/− DCs and impaired expression of costimulatory molecules CD80 and CD86 in response to CD40 ligation. The defective production of IL-12p70 and the reduced expression of CD80 and CD86 by C1qa−/− DCs were specifically mediated via CD40 ligation, as normal levels of IL-12p70 and CD80/86 were observed after ligation of Toll-like receptors (TLRs) on C1qa−/− DCs. CD40 ligation on C1qa−/− DCs, but not TLR ligation, results in decreased phosphorylation of p38 and ERK1/2 kinases. A strong colocalization of CD40 and C1q was observed by confocal microscopy upon CD40 ligation (but not TLR ligation) on DCs. Furthermore, human DCs from 2 C1q-deficient patients were found to have impaired IL-12p70 production in response to CD40L stimulation. Our novel data suggest that C1q augments the production of IL-12p70 by mouse and human DCs after CD40 triggering and plays important roles in sustaining the maturation of DCs and guiding the activation of T cells.
ICSBP-mediated immune protection against BCR-ABL–induced leukemia requires the CCL6 and CCL9 chemokines
Authors: Nardi Valentina , Naveiras Olaia , Azam Mohammad , Daley George Q.
Published: January 2009

Interferon (IFN) is effective at inducing complete remissions in patients with chronic myelogenous leukemia (CML), and evidence supports an immune mechanism. Here we show that the type I IFNs (alpha and beta) regulate expression of the IFN consensus sequence-binding protein (ICSBP) in BCR-ABL–transformed cells and as shown previously for ICSBP, induce a vaccine-like immunoprotective effect in a murine model of BCR-ABL–induced leukemia. We identify the chemokines CCL6 and CCL9 as genes prominently induced by the type I IFNs and ICSBP, and demonstrate that these immunomodulators are required for the immunoprotective effect of ICSBP expression. Insights into the role of these chemokines in the antileukemic response of IFNs suggest new strategies for immunotherapy of CML.
Clinical relevance of Wilms tumor 1 gene mutations in childhood acute myeloid leukemia
Authors: Hollink Iris H. I. M. , van den Heuvel-Eibrink Marry M. , Zimmermann Martin , Balgobind Brian V. , Arentsen-Peters Susan T. C. J. M. , Alders Marielle , Willasch Andre , Kaspers Gertjan J. L. , Trka Jan , Baruchel Andre , de Graaf Siebold S. N. , Creutzig Ursula , Pieters Rob , Reinhardt Dirk , Zwaan C. Michel
Published: January 2009

Wilms tumor 1 (WT1) mutations have recently been identified in approximately 10% of adult acute myeloid leukemia (AML) with normal cytogenetics (CN-AML) and are associated with poor outcome. Using array-based comparative genome hybridization in pediatric CN-AML samples, we detected a WT1 deletion in one sample. The other WT1 allele was mutated. This prompted us to further investigate the role of WT1 aberrations in childhood AML. Mutations were found in 35 of 298 (12%) diagnostic pediatric AML samples. In 19 of 35 (54%) samples, more than one WT1 aberration was found: 15 samples had 2 different mutations, 2 had a homozygous mutation, and 2 had a mutation plus a WT1 deletion. WT1 mutations clustered significantly in the CN-AML subgroup (22%; P < .001) and were associated with FLT3/ITD (43 vs 17%; P < .001). WT1 mutations conferred an independent poor prognostic significance (WT1 mutated vs wild-type patients: 5-year probability of overall survival [pOS] 35% vs 66%, P = .002; probability of event-free survival 22% vs 46%, P < .001; and cumulative incidence of relapse or regression 70% vs 44%, P < .001). Patients with both a WT1 mutation and a FLT3/ITD had a dismal prognosis (5-year pOS 21%). WT1 mutations occur at a significant rate in childhood AML and are a novel independent poor prognostic marker.
Double CEBPA mutations, but not single CEBPA mutations, define a subgroup of acute myeloid leukemia with a distinctive gene expression profile that is uniquely associated with a favorable outcome
Authors: Wouters Bas J. , Löwenberg Bob , Erpelinck-Verschueren Claudia A. J. , van Putten Wim L. J. , Valk Peter J. M. , Delwel Ruud
Published: January 2009

Mutations in CCAAT/enhancer binding protein α (CEBPA) are seen in 5% to 14% of acute myeloid leukemia (AML) and have been associated with a favorable clinical outcome. Most AMLs with CEBPA mutations simultaneously carry 2 mutations (CEBPAdouble-mut), usually biallelic, whereas single heterozygous mutations (CEBPAsingle-mut) are less frequently seen. Using denaturing high-performance liquid chromatography and nucleotide sequencing, we identified among a cohort of 598 newly diagnosed AMLs a subset of 41 CEBPA mutant cases (28 CEBPAdouble-mut and 13 CEBPAsingle-mut cases). CEBPAdouble-mut associated with a unique gene expression profile as well as favorable overall and event-free survival, retained in multivariable analysis that included cytogenetic risk, FLT3-ITD and NPM1 mutation, white blood cell count, and age. In contrast, CEBPAsingle-mut AMLs did not express a discriminating signature and could not be distinguished from wild-type cases as regards clinical outcome. These results demonstrate significant underlying heterogeneity within CEBPA mutation-positive AML with prognostic relevance.
Th-1 polarization is regulated by dendritic-cell comparison of MHC class I and class II antigens
Authors: Decker William K. , Xing Dongxia , Li Sufang , Robinson Simon N. , Yang Hong , Steiner David , Komanduri Krishna V. , Shpall Elizabeth J.
Published: January 2009

In the control of T-helper type I (Th-1) polarization, dendritic cells (DCs) must interpret a complex array of stimuli, many of which are poorly understood. Here we demonstrate that Th-1 polarization is heavily influenced by DC-autonomous phenomena triggered by the loading of DCs with antigenically matched major histocompatibility complex (MHC) class I and class II determinants, that is, class I and II peptide epitopes exhibiting significant amino acid sequence overlap (such as would be physiologically present during infectious processes requiring Th-1 immunity for clearance). Data were derived from 13 independent antigenic models including whole-cell systems, single-protein systems, and 3 different pairs of overlapping class I and II binding epitopes. Once loaded with matched class I and II antigens, these “Th-1 DCs” exhibited differential cytokine secretion and surface marker expression, a distinct transcriptional signature, and acquired the ability to enhance generation of CD8+ T lymphocytes. Mechanistically, tRNA-synthetases were implicated as components of a putative sensor complex involved in the comparison of class I and II epitopes. These data provide rigorous conceptual explanations for the process of Th-1 polarization and the antigenic specificity of cognate T-cell help, enhance the understanding of Th-1 responses, and should contribute to the formulation of more effective vaccination strategies.
Expression of the leukemia oncogene Lmo2 is controlled by an array of tissue-specific elements dispersed over 100 kb and bound by Tal1/Lmo2, Ets, and Gata factors
Authors: Landry Josette-Renée , Bonadies Nicolas , Kinston Sarah , Knezevic Kathy , Wilson Nicola K. , Oram S. Helen , Janes Mary , Piltz Sandie , Hammett Michelle , Carter Jacinta , Hamilton Tina , Donaldson Ian J. , Lacaud Georges , Frampton Jonathan , Follows George , Kouskoff Valerie , Göttgens Berthold
Published: January 2009

The Lmo2 gene encodes a transcriptional cofactor critical for the development of hematopoietic stem cells. Ectopic LMO2 expression causes leukemia in T-cell acute lymphoblastic leukemia (T-ALL) patients and severe combined immunodeficiency patients undergoing retroviral gene therapy. Tightly controlled Lmo2 expression is therefore essential, yet no comprehensive analysis of Lmo2 regulation has been published so far. By comparative genomics, we identified 17 highly conserved noncoding elements, 9 of which revealed specific acetylation marks in chromatin-immunoprecipitation and microarray (ChIP-chip) assays performed across 250 kb of the Lmo2 locus in 11 cell types covering different stages of hematopoietic differentiation. All candidate regulatory regions were tested in transgenic mice. An extended LMO2 proximal promoter fragment displayed strong endothelial activity, while the distal promoter showed weak forebrain activity. Eight of the 15 distal candidate elements functioned as enhancers, which together recapitulated the full expression pattern of Lmo2, directing expression to endothelium, hematopoietic cells, tail, and forebrain. Interestingly, distinct combinations of specific distal regulatory elements were required to extend endothelial activity of the LMO2 promoter to yolk sac or fetal liver hematopoietic cells. Finally, Sfpi1/Pu.1, Fli1, Gata2, Tal1/Scl, and Lmo2 were shown to bind to and transactivate Lmo2 hematopoietic enhancers, thus identifying key upstream regulators and positioning Lmo2 within hematopoietic regulatory networks.
Regulation of macrophage function in tumors: the multifaceted role of NF-κB
Authors: Hagemann Thorsten , Biswas Subhra K. , Lawrence Toby , Sica Antonio , Lewis Claire E.
Published: January 2009

The pivotal role of tumor-associated macrophages (TAMs) in tumor progression is now well established. TAMs have been shown to influence multiple steps in tumor development including the growth, survival, invasion, and metastasis of tumor cells as well as angiogenesis and lymphangiogenesis in tumors. The molecular circuits that polarize TAMs toward such a protumoral phenotype are now the focus of intense investigation. The transcription factor, nuclear factor–κB (NF-κB), is a master regulator of many cellular processes and been shown to regulate various pathways that impact on the function of TAMs. Much evidence for this has come from the use of elegant transgenic murine tumor models in which modification of single components of the NF-κB signaling pathway has been shown to regulate the pro-tumor repertoire of TAMs. Here, we outline this evidence and attempt to reconcile the various views that have emerged recently over the exact role of NF-κB in this phenomenon.
Assessment of codivergence of Mastreviruses with their plant hosts
Authors: Wu Beilei , Melcher Ulrich , Guo Xingyi , Wang Xifeng , Fan Longjiang , Zhou Guanghe
Published: January 2009

Background

Viruses that have spent most of their evolutionary time associated with a single host lineage should have sequences that reflect codivergence of virus and host. Several examples for RNA viruses of host-virus tree congruence are being challenged. DNA viruses, such as mastreviruses, are more likely than RNA viruses to have maintained a record of host lineage association.

Results

The full genomes of 28 isolates of Wheat dwarf virus (WDV), a member of the Mastrevirus genus, from different regions of China were sequenced. The analysis of these 28 entire genomes and 18 entire genome sequences of cereal mastreviruses from other countries support the designation of wheat, barley and oat mastrevirus isolates as separate species. They revealed that relative divergence times for the viruses WDV, Barley dwarf virus (BDV), Oat dwarf virus (ODV) and Maize streak virus (MSV) are proportional to divergence times of their hosts, suggesting codivergence. Considerable diversity among Chinese isolates was found and was concentrated in hot spots in the Rep A, SIR, LIR, and intron regions in WDV genomes. Two probable recombination events were detected in Chinese WDV isolates. Analysis including further Mastrevirus genomes concentrated on coding regions to avoid difficulties due to recombination and hyperdiversity. The analysis demonstrated congruence of trees in two branches of the genus, but not in the third. Assuming codivergence, an evolutionary rate of 10-8 substitutions per site per year was calculated. The low rate implies stronger constraints against change than are obtained by other methods of estimating the rate.

Conclusion

We report tests of the hypothesis that mastreviruses have codiverged with their monocotyledonous hosts over 50 million years of evolution. The tests support the hypothesis for WDV, BDV and ODV, but not for MSV and other African streak viruses.
Genome and gene alterations by insertions and deletions in the evolution of human and chimpanzee chromosome 22
Authors: Volfovsky Natalia , Oleksyk Taras K , Cruz Kristine C , Truelove Ann L , Stephens Robert M , Smith Michael W
Published: January 2009

Background

Understanding structure and function of human genome requires knowledge of genomes of our closest living relatives, the primates. Nucleotide insertions and deletions (indels) play a significant role in differentiation that underlies phenotypic differences between humans and chimpanzees. In this study, we evaluated distribution, evolutionary history, and function of indels found by comparing syntenic regions of the human and chimpanzee genomes.

Results

Specifically, we identified 6,279 indels of 10 bp or greater in a ~33 Mb alignment between human and chimpanzee chromosome 22. After the exclusion of those in repetitive DNA, 1,429 or 23% of indels still remained. This group was characterized according to the local or genome-wide repetitive nature, size, location relative to genes, and other genomic features. We defined three major classes of these indels, using local structure analysis: (i) those indels found uniquely without additional copies of indel sequence in the surrounding (10 Kb) region, (ii) those with at least one exact copy found nearby, and (iii) those with similar but not identical copies found locally. Among these classes, we encountered a high number of exactly repeated indel sequences, most likely due to recent duplications. Many of these indels (683 of 1,429) were in proximity of known human genes. Coding sequences and splice sites contained significantly fewer of these indels than expected from random expectations, suggesting that selection is a factor in limiting their persistence. A subset of indels from coding regions was experimentally validated and their impacts were predicted based on direct sequencing in several human populations as well as chimpanzees, bonobos, gorillas, and two subspecies of orangutans.

Conclusion

Our analysis demonstrates that while indels are distributed essentially randomly in intergenic and intronic genomic regions, they are significantly under-represented in coding sequences. There are substantial differences in representation of indel classes among genomic elements, most likely caused by differences in their evolutionary histories. Using local sequence context, we predicted origins and phylogenetic relationships of gene-impacting indels in primate species. These results suggest that genome plasticity is a major force behind speciation events separating the great ape lineages.
Low frequency of CD4+CD25+ Treg in SLE patients: a heritable trait associated with CTLA4 and TGFβ gene variants
Authors: Barreto Marta , Ferreira Ricardo C , Lourenço Lara , Moraes-Fontes Maria F , Santos Eugénia , Alves Miguel , Carvalho Cláudia , Martins Berta , Andreia Rita , Viana João F , Vasconcelos Carlos , Mota-Vieira Luísa , Ferreira Carlos , Demengeot Jocelyne , Vicente Astrid M
Published: January 2009

Background

CD4+CD25+regulatory T cells play an essential role in maintaining immune homeostasis and preventing autoimmunity. Therefore, defects in Treg development, maintenance or function have been associated with several human autoimmune diseases including Systemic Lupus Erythematosus (SLE), a systemic autoimmune disease characterized by loss of tolerance to nuclear components and significantly more frequent in females.

Results

To investigate the involvement of Treg in SLE pathogenesis, we determined the frequency of CD4+CD25+CD45RO+T cells, which encompass the majority of Treg activity, in the PBMC of 148 SLE patients (76 patients were part of 54 families), 166 relatives and 117 controls. SLE patients and their relatives were recruited in several Portuguese hospitals and through the Portuguese Lupus Association. Control individuals were blood donors recruited from several regional blood donor centers. Treg frequency was significantly lower in SLE patients than healthy controls (z = -6.161,P< 0.00001) and intermediate in the relatives' group. Remarkably, this T cell subset was also lower in females, most strikingly in the control population (z = 4.121,P< 0.001). We further ascertained that the decreased frequency of Treg in SLE patients resulted from the specific reduction ofbona fideFOXP3+CD4+CD25+Treg. Treg frequency was negatively correlated with SLE activity index (SLEDAI) and titers of serum anti-dsDNA antibodies. Both Treg frequency and disease activity were modulated by IVIg treatment in a documented SLE case. The segregation of Treg frequency within the SLE families was indicative of a genetic trait. Candidate gene analysis revealed that specific variants ofCTLA4andTGFβwere associated with the decreased frequency of Treg in PBMC, whileFOXP3gene variants were associated with affection status, but not with Treg frequency.

Conclusion

SLE patients have impaired Treg production or maintenance, a trait strongly associated with SLE disease activity and autoantibody titers, and possibly resulting from the inability to convert FOXP3+CD25-into FOXP3+CD25+T cells. Treg frequency is highly heritable within SLE families, with specific variants of theCTLA4andTGFβgenes contributing to this trait, whileFOXP3contributes to SLE through mechanisms not involving a modulation of Treg frequency. These findings establish that the genetic components in SLE pathogenesis include genes related to Treg generation or maintenance.
Ultrastructure and molecular phylogeny of Calkinsia aureus: cellular identity of a novel clade of deep-sea euglenozoans with epibiotic bacteria
Authors: Yubuki Naoji , Edgcomb Virginia P , Bernhard Joan M , Leander Brian S
Published: January 2009

Background

The Euglenozoa is a large group of eukaryotic flagellates with diverse modes of nutrition. The group consists of three main subclades – euglenids, kinetoplastids and diplonemids – that have been confirmed with both molecular phylogenetic analyses and a combination of shared ultrastructural characteristics. Several poorly understood lineages of putative euglenozoans live in anoxic environments, such asCalkinsia aureus, and have yet to be characterized at the molecular and ultrastructural levels. Improved understanding of these lineages is expected to shed considerable light onto the ultrastructure of prokaryote-eukaryote symbioses and the associated cellular innovations found within the Euglenozoa and beyond.

Results

We collectedCalkinsia aureusfrom core samples taken from the low-oxygen seafloor of the Santa Barbara Basin (580 – 592 m depth), California. These biflagellates were distinctively orange in color and covered with a dense array of elongated epibiotic bacteria. Serial TEM sections through individually prepared cells demonstrated thatC. aureusshares derived ultrastructural features with other members of the Euglenozoa (e.g. the same paraxonemal rods, microtubular root system and extrusomes). However,C. aureusalso possessed several novel ultrastructural systems, such as modified mitochondria (i.e. hydrogenosome-like), an "extrusomal pocket", a highly organized extracellular matrix beneath epibiotic bacteria and a complex flagellar transition zone. Molecular phylogenies inferred from SSU rDNA sequences demonstrated thatC. aureusgrouped strongly within the Euglenozoa and with several environmental sequences taken from low-oxygen sediments in various locations around the world.

Conclusion

Calkinsia aureuspossesses all of the synapomorphies for the Euglenozoa, but lacks traits that are specific to any of the three previously recognized euglenozoan subgroups. Molecular phylogenetic analyses ofC. aureusdemonstrate that this lineage is a member of a novel euglenozoan subclade consisting of uncharacterized cells living in low-oxygen environments. Our ultrastructural description ofC. aureusestablishes the cellular identity of a fourth group of euglenozoans, referred to as the "Symbiontida".
The tep1 gene of Sinorhizobium meliloti coding for a putative transmembrane efflux protein and N-acetyl glucosamine affect nod gene expression and nodulation of alfalfa plants
Authors: van Dillewijn Pieter , Sanjuán Juan , Olivares José , Soto María José
Published: January 2009

Background

Soil bacteria collectively known as Rhizobium, characterized by their ability to establish beneficial symbiosis with legumes, share several common characteristics with pathogenic bacteria when infecting the host plant. Recently, it was demonstrated that a fadD mutant of Sinorhizobium meliloti is altered in the control of swarming, a type of co-ordinated movement previously associated with pathogenicity, and is also impaired in nodulation efficiency on alfalfa roots. In the phytopathogen Xanthomonas campestris, a fadD homolog (rpfB) forms part of a cluster of genes involved in the r egulation of p athogenicity f actors. In this work, we have investigated the role in swarming and symbiosis of SMc02161, a S. meliloti fadD-linked gene.

Results

The SMc02161 locus in S. meliloti shows similarities with members of the Major Facilitator Superfamily (MFS) of transporters. A S. meliloti null-mutant shows increased sensitivity to chloramphenicol. This indication led us to rename the locus tep1 for t ransmembrane e fflux p rotein. The lack of tep1 does not affect the appearance of swarming motility. Interestingly, nodule formation efficiency on alfalfa plants is improved in the tep1 mutant during the first days of the interaction though nod gene expression is lower than in the wild type strain. Curiously, a nodC mutation or the addition of N-acetyl glucosamine to the wild type strain lead to similar reductions in nod gene expression as in the tep1 mutant. Moreover, aminosugar precursors of Nod factors inhibit nodulation.

Conclusion

tep1 putatively encodes a transmembrane protein which can confer chloramphenicol resistance in S. meliloti by expelling the antibiotic outside the bacteria. The improved nodulation of alfalfa but reduced nod gene expression observed in the tep1 mutant suggests that Tep1 transports compounds which influence nodulation. In contrast to Bradyrhizobium japonicum, we show that in S. meliloti there is no feedback regulation of nodulation genes. Moreover, the Nod factor precursor, N-acetyl glucosamine reduces nod gene expression and nodulation efficiency when present at millimolar concentrations. A role for Tep1 in the efflux of Nod factor precursors could explain the phenotypes associated with tep1 inactivation.
Improper excess light energy dissipation in Arabidopsis results in a metabolic reprogramming
Authors: Frenkel Martin , Külheim Carsten , Jänkänpää Hanna Johansson , Skogström Oskar , Dall'Osto Luca , Ågren Jon , Bassi Roberto , Moritz Thomas , Moen Jon , Jansson Stefan
Published: January 2009

Background

Plant performance is affected by the level of expression of PsbS, a key photoprotective protein involved in the process of feedback de-excitation (FDE), or the qE component of non-photochemical quenching, NPQ.

Results

In studies presented here, under constant laboratory conditions the metabolite profiles of leaves of wild-type Arabidopsis thaliana and plants lacking or overexpressing PsbS were very similar, but under natural conditions their differences in levels of PsbS expression were associated with major changes in metabolite profiles. Some carbohydrates and amino acids differed ten-fold in abundance between PsbS-lacking mutants and over-expressers, with wild-type plants having intermediate amounts, showing that a metabolic shift had occurred. The transcriptomes of the genotypes also varied under field conditions, and the genes induced in plants lacking PsbS were similar to those reportedly induced in plants exposed to ozone stress or treated with methyl jasmonate (MeJA). Genes involved in the biosynthesis of JA were up-regulated, and enzymes involved in this pathway accumulated. JA levels in the undamaged leaves of field-grown plants did not differ between wild-type and PsbS-lacking mutants, but they were higher in the mutants when they were exposed to herbivory.

Conclusion

These findings suggest that lack of FDE results in increased photooxidative stress in the chloroplasts of Arabidopsis plants grown in the field, which elicits a response at the transcriptome level, causing a redirection of metabolism from growth towards defence that resembles a MeJA/JA response.
Prevalence of tuberculosis drug resistance in 10 provinces of China
Authors: He Guang Xue , Zhao Yan Lin , Jiang Guang Lu , Liu Yu Hong , Xia Hui , Wang Sheng Fen , Wang Li Xia , Borgdorff Martien W , van der Werf Marieke J , van den Hof Susan
Published: January 2009

Background

The emergence of drug-resistant tuberculosis (TB) hampers TB control. Ten provinces in China performed drug resistance surveys among tuberculosis (TB) patients in 1996–2004 to assess levels of drug resistance.

Methods

Provincial drug resistance surveys included all isolates from newly diagnosed, smear-positive TB patients. Drug susceptibility testing (DST) against isoniazid, rifampicin, streptomycin and ethambutol was carried out in the provincial laboratories. For purposes of quality assurance, a random sample (11.6%) was re-tested by the national reference laboratory (NRL).

Results

Of 14,059 patients tested 11,052 (79%) were new TB cases. The weighted mean prevalence of multi-drug resistant tuberculosis (MDR-TB) among all cases was 9.3% (range 2.2%–10.4%); 5.4% (range 2.1% – 10.4%) among new cases and 25.6% (range 11.7%–36.9%) among previously treated cases. Adjusting the drug resistance proportions using the re-testing results did not change the estimated national mean prevalence significantly. However, in some individual provinces the estimated resistance proportions were greatly influenced, especially among re-treatment patients.

Conclusion

MDR-TB levels varied greatly between provinces in China, but on average were high compared to the global estimated average of 4.8%. This study shows the importance of quality-assured laboratory performance. Programmatic management of drug-resistant TB, including high quality DST for patients at high risk of resistance and treatment with second-line drugs, should become the standard, especially in high MDR-TB settings.
A randomised controlled trial evaluating the effect of an individual auditory cueing device on freezing and gait speed in people with Parkinson's disease
Authors: Ledger Sean , Galvin Rose , Lynch Deirdre , Stokes Emma K
Published: January 2009

Background

Parkinson's disease is a progressive neurological disorder resulting from a degeneration of dopamine producing cells in the substantia nigra. Clinical symptoms typically affect gait pattern and motor performance. Evidence suggests that the use of individual auditory cueing devices may be used effectively for the management of gait and freezing in people with Parkinson's disease. The primary aim of the randomised controlled trial is to evaluate the effect of an individual auditory cueing device on freezing and gait speed in people with Parkinson's disease.

Methods

A prospective multi-centre randomised cross over design trial will be conducted. Forty-seven subjects will be randomised into either Group A or Group B, each with a control and intervention phase. Baseline measurements will be recorded using the Freezing of Gait Questionnaire as the primary outcome measure and 3 secondary outcome measures, the 10 m Walk Test, Timed "Up & Go" Test and the Modified Falls Efficacy Scale. Assessments are taken 3-times over a 3-week period. A follow-up assessment will be completed after three months. A secondary aim of the study is to evaluate the impact of such a device on the quality of life of people with Parkinson's disease using a qualitative methodology.

Conclusion

The Apple iPod-Shuffle™ and similar devices provide a cost effective and an innovative platform for integration of individual auditory cueing devices into clinical, social and home environments and are shown to have immediate effect on gait, with improvements in walking speed, stride length and freezing. It is evident that individual auditory cueing devices are of benefit to people with Parkinson's disease and the aim of this randomised controlled trial is to maximise the benefits by allowing the individual to use devices in both a clinical and social setting, with minimal disruption to their daily routine.

Trial registration

The protocol for this study is registered with the US NIH Clinical Trials Registry (NCT00727467).
Characterization of SV-40 Tag rats as a model to study prostate cancer
Authors: Harper Curt E , Patel Brijesh B , Cook Leah M , Wang Jun , Shirai Tomoyuki , Eltoum Isam A , Lamartiniere Coral A
Published: January 2009

Background

Prostate cancer is the second most frequently diagnosed cancer in men. Animal models that closely mimic clinical disease in humans are invaluable tools in the fight against prostate cancer. Recently, a Simian Virus-40 T-antigen (SV-40 Tag) targeted probasin promoter rat model was developed. This model, however, has not been extensively characterized; hence we have investigated the ontogeny of prostate cancer and determined the role of sex steroid receptor and insulin-like growth factor-1 (IGF-1) signaling proteins in the novel SV-40 Tag rat.

Methods

The SV-40 Tag rat was histopathologically characterized for time to tumor development, incidence and multiplicity and in the ventral, dorsal, lateral and anterior lobes of the prostate. Immunoassay techniques were employed to measure cell proliferation, apoptosis, and sex steroid receptor and growth factor signaling-related proteins. Steroid hormone concentrations were measured via coated well enzyme linked immunosorbent assay (ELISA) kits.

Results

Prostatic intraepithelial neoplasia (PIN) and well-differentiated prostate cancer developed as early as 2 and 10 weeks of age, respectively in the ventral prostate (VP) followed by in the dorsolateral (DLP). At 8 weeks of age, testosterone and dihydrotestosterone (DHT) concentrations in SV-40 Tag rats were increased when compared to non-transgenic rats. High cell proliferation and apoptotic indices were found in VP and DLP of transgenic rats. Furthermore, we observed increased protein expression of androgen receptor, IGF-1, IGF-1 receptor, and extracellular signal-regulated kinases in the prostates of SV-40 Tag rats.

Conclusion

The rapid development of PIN and prostate cancer in conjunction with the large prostate size makes the SV-40 Tag rat a useful model for studying prostate cancer. This study provides evidence of the role of sex steroid and growth factor proteins in prostate cancer development and defines appropriate windows of opportunity for preclinical trials and aids in the rational design of chemoprevention, intervention, regression, and therapeutic studies using prostate cancer rodent models.
Investigation of G72 (DAOA) expression in the human brain
Authors: Benzel Isabel , Kew James NC , Viknaraja Ramya , Kelly Fiona , de Belleroche Jacqueline , Hirsch Steven , Sanderson Thirza H , Maycox Peter R
Published: January 2009

Background

Polymorphisms at the G72/G30 locus on chromosome 13q have been associated with schizophrenia or bipolar disorder in more than ten independent studies. Even though the genetic findings are very robust, the physiological role of the predicted G72 protein has thus far not been resolved. Initial reports suggested G72 as an activator of D-amino acid oxidase (DAO), supporting the glutamate dysfunction hypothesis of schizophrenia. However, these findings have subsequently not been reproduced and reports of endogenous human G72 mRNA and protein expression are extremely limited. In order to better understand the function of this putative schizophrenia susceptibility gene, we attempted to demonstrate G72 mRNA and protein expression in relevant human brain regions.

Methods

The expression of G72 mRNA was studied by northern blotting and semi-quantitative SYBR-Green and Taqman RT-PCR. Protein expression in human tissue lysates was investigated by western blotting using two custom-made specific anti-G72 peptide antibodies. An in-depth in silico analysis of the G72/G30 locus was performed in order to try and identify motifs or regulatory elements that provide insight to G72 mRNA expression and transcript stability.

Results

Despite using highly sensitive techniques, we failed to identify significant levels of G72 mRNA in a variety of human tissues (e.g. adult brain, amygdala, caudate nucleus, fetal brain, spinal cord and testis) human cell lines or schizophrenia/control post mortem BA10 samples. Furthermore, using western blotting in combination with sensitive detection methods, we were also unable to detect G72 protein in a number of human brain regions (including cerebellum and amygdala), spinal cord or testis. A detailed in silico analysis provides several lines of evidence that support the apparent low or absent expression of G72.

Conclusion

Our results suggest that native G72 protein is not normally present in the tissues that we analysed in this study. We also conclude that the lack of demonstrable G72 expression in relevant brain regions does not support a role for G72 in modulation of DAO activity and the pathology of schizophrenia via a DAO-mediated mechanism. In silico analysis suggests that G72 is not robustly expressed and that the transcript is potentially labile. Further studies are required to understand the significance of the G72/30 locus to schizophrenia.