bluuebunny/crossref_metadata_2025 huggingface dataset:
Representations of the ‘Damaged’ Child: ‘Child Saving’ in a British Children's Charity ad Campaign
Authors: O'Dell Lindsay
Published: August 2008

This article discusses the representation of abused children as ‘damaged’, drawing on a series of three advertising campaigns for a British children's charity. The pictures and text of the advertisements seek to elicit readers’ concern for abused children by portraying them (a) as passive agents in their development and (b) as signifiers of the dangers of the world and the safeness of the home. The portrayal of abused children in the advertisements serves to reinforce a perception of the vulnerability of all children and the need for adult supervision and ‘care’. Without seeking to dismiss the seriousness of abuse or of the work done by children's charities, the article questions the implications of these representations of childhood and ‘damage’, and argues that the dominant representation of abused children drawn on in such campaigns oversimplifies many complexities in the worlds and the lives of children who have been abused.
A Children's Standpoint: Needs in Out‐of‐Home Care
Authors: Mason Jan
Published: August 2008

This article discusses research reported in ‘The Needs of Children in Care’ (Mason and Gibson, 2004) in which children participated in defining their needs in out‐of‐home care. In this study a central research presumption was that children are knowledgeable about their own needs. The methods used to facilitate the involvement in the project of children and adult stakeholders in out‐of‐home care are described. Also described are findings from the research which identified that of prime importance to the children were their connections with others and their agency in their own lives. These findings are compared with findings from the narratives of the adult stakeholder groups. Finally, the implications of the findings, for improving children's participation in decision‐making around their needs in care are considered in the context of broad adult–child social relations in the care system.
Communication and Supervision of Alcohol in the Family: Parental Perspectives
Authors: Sherriff Nigel , Cox Louise , Coleman Lester , Roker Debi
Published: August 2008

It is now well acknowledged that parents can have a central role in supporting sensible alcohol use and reducing alcohol misuse amongst young people. However, little research has considered how communication and supervision in relation to alcohol actually takes place within the family. Drawing upon interviews with the parents of young people aged 13–17 years (n = 40), this article describes the strategies that many parents use in communicating, monitoring, and supervising alcohol use within the family. The findings revealed that many parents lack the guidance needed to convey ‘sensible drinking’ messages to young people, and wish for greater information and support about young people and alcohol.
A multicentre phase II clinical experience with the novel aza‐epothilone Ixabepilone (BMS247550) in patients with relapsed or refractory indolent non‐Hodgkin lymphoma and mantle cell lymphoma
Authors: O’Connor Owen A. , Portlock Carol , Moskowitz Craig , Straus David , Hamlin Paul , Stubblefield Michael , Dumetrescu Otila , Colevas A. Dimitrios , Grant Barbara , Zelenetz Andrew
Published: August 2008

The epothilones represent a novel group of microtubule stabilization agents that appear to retain activity even in chemotherapy‐resistant cell lines and animal models. Because of their ability to overcome chemotherapy resistance, we conducted a phase II study of Ixabepilone in patients with indolent non‐Hodgkin lymphoma and mantle cell lymphoma (MCL). Ixabepilone was given at a dose of 25 mg/m2 weekly for three of four consecutive weeks. Patients were required to have received ≤4 prior chemotherapy regimens, with an interval of at least one month since the last treatment, 3 months from prior rituximab, and 7 d from prior steroids, an absolute neutrophil count >1 × 109/l and a platelet count >50 × 109/l. Dose reductions were allowed. The overall response rate in assessable patients was 27% in this otherwise heavily treated population. One patient with chemotherapy‐refractory follicular lymphoma attained a complete remission that lasted approximately 8 months. Three responses were also seen in refractory MCL and one in small lymphocytic lymphoma. The duration of response ranged from 2 to 8 months. Major toxicities included fatigue, myelosuppression and neuropathy. These data suggest that Ixabepilone has activity in chemotherapy‐refractory lymphoma.
Treating TTP/HUS with plasma exchange: a single centre’s 25‐year experience
Authors: Forzley Brian R. , Sontrop Jessica M. , Macnab Jennifer J. , Chen Salina , Clark William F.
Published: August 2008

Thrombotic thrombocytopenic purpura/Haemolytic uremic syndrome (TTP/HUS) is a thrombotic microangiopathy with a 6‐month mortality rate of 16–29%. The present study described the clinical features, treatment regime and 6‐month all‐cause mortality rate of TTP/HUS patients at the London Health Sciences Centre (LHSC), Canada. Data for this retrospective cohort study were obtained from inpatient and outpatient records for all patients referred for plasma exchange therapy at LHSC, Canada between 1981 and 2006. Patients (n = 110) were categorized as: idiopathic primary (38%) or relapsed (16%), and secondary responsive (30%) or non‐responsive (16%). Mortality data were available for all but three patients. The all‐cause 6‐month mortality rate was 19% overall and was 12% and 26% among idiopathic and secondary TTP/HUS patients, respectively. No mortality events occurred among the 17 idiopathic patients who relapsed. Relapsed patients had the least severe presenting characteristics, the fastest response time, and experienced significant improvement in the severity of clinical features between the first and final presentation. These findings suggest an excellent outcome for relapsed TTP/HUS patients. Patient education, surveillance, and aggressive plasma exchange therapy are hypothesized to improve the likelihood of survival: these hypotheses should be tested in a randomized controlled trial.
Hb Southern Italy: coexistence of two missence mutations (the Hb Sun Prairie α2 130 Ala → Pro and Hb Caserta α2 26 Ala → Thr) in a single HBA2 gene
Authors: Passarello Cristina , Giambona Antonino , Prossomariti Luciano , Ammirabile Massimiliano , Pucci Piero , Renda Disma , Pagano Leonilde , Maggio Aurelio
Published: August 2008

This study describes a new molecular condition in the α2‐globin gene (HBA2) found in six unrelated families from Southern Italy (Campania and Sicily). This new double mutant form of haemoglobin is called Hb Southern Italy and originated from the coexistence of two known mutations occurring in the same globin gene, HBA2 26 G→A (Hb Caserta) and HBA2 130 G→C (Hb Sun Prairie). Hb Sun Prairie was originally observed in Indian patients in either the homozygous state, with severe hemolytic anemia, and in the heterozygous state with microcytosis, or in asymptomatic cases as an α‐thalassemia carrier phenotype. Hb Caserta was observed for the first time in a Casertian family (South Italy) that displayed a slowmigrating haemoglobin upon investigation. We report the clinical phenotype and molecular study of this new double mutant form of haemoglobin in heterozygous and homozygous subjects, as well as in association with α° delectional thalassemia.
Predictors of survival in patients with systemic light‐chain amyloidosis and cardiac involvement initially ineligible for stem cell transplantation and treated with oral melphalan and dexamethasone
Authors: Lebovic D. , Hoffman J. , Levine B. M. , Hassoun H. , Landau H. , Goldsmith Y. , Maurer M. S. , Steingart R. M. , Cohen A. D. , Comenzo R. L.
Published: August 2008

The treatment of systemic light‐chain (AL) amyloidosis with symptomatic cardiac involvement at diagnosis remains a challenge. We report the results of 40 consecutive newly diagnosed AL cardiac patients who were not candidates for stem cell transplant and therefore received monthly oral melphalan and dexamethasone. Median survival was 10·5 months and baseline predictors of survival included gender, troponin I and interventricular septal thickness. The most significant predictor of survival was response to therapy. The haematological response rate was 58% (23/40) with 13% (5/40) complete responses; most responses were noted in <3 cycles. Achievement of a rapid response to therapy extends survival.
Depletion of CD4+CD25+CD127lo regulatory T cells does not increase allergen‐driven T cell activation
Authors: Skrindo I. , Farkas L. , Kvale E. O. , Johansen F.‐E. , Jahnsen F. L.
Published: August 2008

Background
It has been suggested that allergic diseases are caused by defective suppression of allergen‐specific Th2 cells by CD4+CD25+ regulatory T cells. However, such studies have been hampered by the difficulty in distinguishing regulatory T cells from CD25‐expressing activated T cells. Recently, it was shown that conventional T cells expressed high levels of CD127, whereas regulatory T cells were CD127lo, allowing discrimination between these distinct T cell subpopulations.

Objective
The aim of this study was to study whether the putative regulatory subset defined as CD4+CD25+CD127lo was involved in grass pollen‐reactive T cell responses.

Methods
Peripheral blood mononuclear cells (PBMCs) were obtained from allergic donors and non‐atopic controls out of season. Grass pollen‐induced cytokine production and proliferation were compared in cultures of undepleted cells and cells depleted of CD4+CD25+, CD4+CD25+CD127hi or CD4+CD25+CD127lo T cells.

Results
Undepleted cell cultures from allergic patients showed significantly increased proliferation and Th2 cytokine production compared with non‐atopic controls. Depletion of all CD25+ T cells did not increase cytokine production or proliferation, and more importantly, no increase in Th2 cytokine production or proliferation was observed in cell cultures depleted of CD4+CD25+CD127lo cells (putative regulatory T cells) compared with undepleted PBMCs in both the allergic and the non‐atopic group.

Conclusion
Our study showed that T cells from grass pollen‐allergic patients and non‐atopic controls responded very differently to grass pollen extract, but this difference could not be explained by differences in regulatory T cell function. Further studies are needed to understand the importance of regulatory T cells in allergy.
Thyroid function and the natural history of depression: findings from the Caerphilly Prospective Study (CaPS) and a meta‐analysis
Authors: Williams M. D. , Harris R. , Dayan C. M. , Evans J. , Gallacher J , Ben‐Shlomo Y.
Published: August 2008

Objective   Low thyroid function has been associated with depression in clinical populations. We have examined whether thyroid function in the normal range is associated with minor psychiatric morbidity.

Design   Prospective cohort study of 2269 middle aged men (45–59 years) with thyroid function (total T4 only, TSH unavailable) measured between 1979 and 1983 and with repeat measures of minor psychiatric morbidity (GHQ‐30) over a mean of 12·3 years follow‐up. We also undertook a systematic review and meta‐analysis of population‐based studies examining thyroid function and mood.

Results   There was a positive association between total T4 and chronic psychiatric morbidity (odds ratio 1·21, 95% CI 1·02–1·43, P= 0·03), but this was consistent with chance after adjusting for social class, alcohol and smoking behaviours. The association with incident and recovery from psychiatric morbidity was weaker and consistent with chance.

We identified seven eligible studies, from our systematic review and included six studies, including our own, in a meta‐analysis. The pooled estimate showed a positive association (odds ratio 1·12, 95% CI 1·02–1·22, P‐value = 0·01) between depression and T4 and an inverse association with TSH (odds ratio 0·92, 95% CI 0·88–0·97, P= 0·0007) with no evidence of heterogeneity or publication bias.

Conclusion   The results from CaPS and our meta‐analysis are consistent and suggest that, if anything, higher levels of thyroxine in the normal range are associated with increased risk of depression. The effects of thyroid hormone on mood may differ in normal populations and patients with clinical thyroid dysfunction.
Polymorphisms of the SHBG gene contribute to the interindividual variation of sex steroid hormone blood levels in young, middle‐aged and elderly men
Authors: Vanbillemont Griet , Bogaert Veerle , De Bacquer Dirk , Lapauw Bruno , Goemaere Stefan , Toye Kaatje , Van Steen Kristel , Taes Youri , Kaufman Jean‐Marc
Published: August 2008

Objective  In men there is a large interindividual variation of SHBG levels and consequently of testosterone (T) and E2 levels. Family and twin studies suggested a strong genetic contribution, besides metabolic and hormonal influences. The aim of this study was to examine the influence of a missense mutation in exon 8 (Asp327Asn) and a (TAAAA)n‐repeat in the promoter region of the SHBG gene, on SHBG and sex steroid serum concentrations in a population of healthy men.

Design  SHBG and hormone levels were measured in 1485 men, contributed by three independent cohort studies and representing three different age groups (young, middle‐aged and elderly men). The number of TAAAA‐repeats was determined by fragment‐analysis; carriers of the Asn327‐allele were identified using restriction fragment length polymorphism analysis.

Results  In the different age groups, carriers of six TAAAA‐repeats presented with higher SHBG (young 19%, middle‐aged 20% and elderly 26%; P < 0·001) and T (young 9%, middle‐aged 22% and elderly 21%; P < 0·05) levels compared to non‐carriers. For free T, a modest increase was found for carriers in the middle‐aged group, but not for the young and elderly group. E2 and free E2 did not differ between carriers and non‐carriers in the different age‐groups. The Asn327‐allele was associated with higher mean SHBG (14·20%, P < 0·001) and T levels (7·33%; P = 0·01) in the middle‐aged group only.

Conclusions  Our findings show that and the (TAAAA)n‐repeat and the Asp327Asn polymorphism contribute to the genetically determined interindividual variation in total serum T levels in healthy men through variation in SHBG concentrations.
Expanding clinical spectrum of non‐autoimmune hyperthyroidism due to an activating germline mutation, p.M453T, in the thyrotropin receptor gene
Authors: Supornsilchai Vichit , Sahakitrungruang Taninee , Wongjitrat Nattakarn , Wacharasindhu Suttipong , Suphapeetiporn Kanya , Shotelersuk Vorasuk
Published: August 2008

Objective  To describe clinical and genetic features of a Thai family with non‐autoimmune hyperthyroidism (NAH) caused by an activating germline mutation in the thyrotropin receptor (TSHR) gene.

Patients  Three affected individuals from the same family (a father and his two children) were studied. Clinical and imaging findings were reviewed and compared.

Genetic analysis  Genomic DNA was extracted from peripheral blood leukocytes and mutation analysis of the entire coding sequence of the TSHR gene was performed in both children and their parents by direct DNA sequencing.

Results  A heterozygous germline T to C transition in exon 10 of the TSHR gene (c.1358T→C) resulting in the substitution of methionine (ATG) by threonine (ACG) at codon 453 (p.M453T) was identified in the father and his two children. They presented with different clinical severity and variable age of onset. In addition to hyperthyroidism, ventriculomegaly and bilateral shortening of the fifth metacarpal bones and the middle phalanges of the fifth fingers were consistently found in all affected individuals.

Conclusions  Ventriculomegaly and bilateral shortening of the fifth metacarpal bones and the middle phalanges of the fifth fingers might be characteristic features of NAH because of an activating TSHR germline mutation. In addition, the shortening of the middle phalanges of the fifth fingers has never been previously described, expanding the phenotypic spectrum of the disease.
SDHC mutation in an elderly patient without familial antecedents
Authors: López‐Jiménez Elena , De Campos José M. , Kusak Elena M. , Landa Iñigo , Leskelä Susanna , Montero‐Conde Cristina , Leandro‐García Luis J. , Vallejo Luis A. , Madrigal Beatriz , Rodríguez‐Antona Cristina , Robledo Mercedes , Cascón Alberto
Published: August 2008

Head and neck paragangliomas are usually asymptomatic and benign tumours arising mainly from the carotid body and the vagal, tympanic or jugular glomus. The majority of patients develop sporadic masses, and around 30% of cases harbour germline mutations in one of the succinate dehydrogenase genes: SDHB, SDHC or SDHD. In these hereditary cases, the presence of familial antecedents of the disease, multiplicity/bilaterality, young age at onset, and more recently, presence of gastrointestinal stromal tumours, are main factors to be considered. Here we describe a new mutation (c.256–257insTTT) affecting the SDHC gene in a 60‐year‐old‐patient with a single head and neck paraganglioma, and without familial antecedents of the disease. In silico splice site analysis showed that this variant created a cryptic splice acceptor site and loss of heterozygosity (LOH) supported the pathogenic role of the mutation. Control population analyses did not detect this variant but revealed a novel SDHC polymorphism that exhibited a frequency of 0·3% (3/1020). This latter finding highlights the importance of assessing the clinical relevance of variants of unknown significance by means of analysing sufficient controls. Despite having found a germline mutation in an older, apparently sporadic patient, we consider that the high costs of analysing all susceptibility genes related to the disease support the recommendation of screening for mutations only in patients fulfilling the above criteria.
BCL11A is a SUMOylated protein and recruits SUMO‐conjugation enzymes in its nuclear body
Authors: Kuwata Takeshi , Nakamura Takuro
Published: August 2008

BCL11A/EVI9 is a zinc‐finger protein predominantly expressed in brain and hematopoietic cells. Previous studies show that BCL11A is involved in acute myelomonocytic leukemia and chronic lymphoid leukemia in mouse and human, respectively. Moreover, BCL11A is localized in the characteristic nuclear body in which BCL6 is co‐localized. However, the significance of BCL11A in leukemogenesis and nuclear function remains unknown. In this study we show that BCL11A interacts with UBC9, a small ubiquitin‐like modifier (SUMO) E2 conjugating enzyme, and recruits SUMO1 into the nuclear body. A lysine residue at amino acid 634 of BCL11A is SUMOylated but not required for the SUMO1 recruitment. The N‐terminal region of BCL11A is responsible for SUMO1 recruitment as well as its nuclear body formation. We also show that SENP2, a SUMO specific peptidase, is co‐localized in the nuclear body. These results suggest that BCL11A could be involved in the SUMO conjugation system, and that BCL11A might play an important role in protein modification.
Specificity of Atonal and Scute bHLH factors: analysis of cognate E box binding sites and the influence of Senseless
Authors: Powell Lynn M. , Deaton Aimée M. , Wear Martin A. , Jarman Andrew P.
Published: August 2008

The question of how proneural bHLH transcription factors recognize and regulate their target genes is still relatively poorly understood. We previously showed that Scute (Sc) and Atonal (Ato) target genes have different cognate E box motifs, suggesting that specific DNA interactions contribute to differences in their target gene specificity. Here we show that Sc and Ato proteins (in combination with Daughterless) can activate reporter gene expression via their cognate E boxes in a non‐neuronal cell culture system, suggesting that the proteins have strong intrinsic abilities to recognize different E box motifs in the absence of specialized cofactors. Functional comparison of E boxes from several target genes and site‐directed mutagenesis of E box motifs suggests that specificity and activity require further sequence elements flanking both sides of the previously identified E box motifs. Moreover, the proneural cofactor, Senseless, can augment the function of Sc and Ato on their cognate E boxes and therefore may contribute to proneural specificity.
Phylogenetic analyses and molecular epidemiology of European salmonid alphaviruses (SAV) based on partial E2 and nsP3 gene nucleotide sequences
Authors: Fringuelli E , Rowley H M , Wilson J C , Hunter R , Rodger H , Graham D A
Published: August 2008

Sequence data were generated for portions of the E2 and nsP3 genes of 48 salmonid alphaviruses from farmed Atlantic salmon (AS), Salmo salar L., and rainbow trout (RT), Oncorhynchus mykiss (Walbaum), in marine and freshwater environments, respectively, from the Republic of Ireland, Northern Ireland, England, Scotland, Norway, France, Italy and Spain between 1991 and 2007. Based on these sequences, and those of six previously published reference strains, phylogenetic trees were constructed using the parsimony method. Trees generated with both gene segments were similar. Clades corresponding to the three previously recognized subtypes were generated and in addition, two further new clades of viruses were identified. A single further strain (F96‐1045) was found to be distinct from all of the other strains in the study. The percentage of nucleotide divergence within clades was generally low (0–4.8% for E2, 0–6.6% for nsP3). Interclade divergence tended to be higher (3.4–19.7% for E2, 6.5–28.1% for nsP3). Based on these results and using current SAV terminology, the two new clades and F96‐1045 were termed SAV subtypes 4, 5 and 6, respectively. SAV4 contained AS strains from Ireland and Scotland, while SAV5 contained only Scottish AS strains. Recently identified SAV strains from RT in Italy and Spain were shown to belong to SAV2. In addition, marine AS strains belonging to SAV2 were identified for the first time. Analysis of the origin of several clusters of strains with identical E2 and nsP3 sequences strongly support horizontal transmission of virus between farms and aquaculture companies. Evidence in support of vertical transmission was not found.
Genetic diversity of Flavobacterium psychrophilum recovered from commercially raised rainbow trout, Oncorhynchus mykiss (Walbaum), and spawning coho salmon, O. kisutch (Walbaum)
Authors: Chen Y‐C , Davis M A , LaPatra S E , Cain K D , Snekvik K R , Call D R
Published: August 2008

Flavobacterium psychrophilum is the aetiological agent of rainbow trout fry syndrome and bacterial cold water disease. This study examined the genetic diversity of F. psychrophilum isolates retrieved from multiple epizootics at rainbow trout, Oncorhynchus mykiss, rearing facilities and from spawning coho salmon, O. kisutch. A total of 139 isolates were confirmed as F. psychrophilum by PCR assay and were further typed using pulsed‐field gel electrophoresis (PFGE). Multiple epizootics at three proximally located rainbow trout rearing facilities were numerically dominated by three PFGE profiles, which accounted for 76% of all trout isolates. In coho salmon, 19 PFGE profiles were differentiated by PFGE and four numerically dominant PFGE profiles represented 56% of all coho salmon isolates. PFGE analysis also indicated that the average similarity of macrorestriction patterns of F. psychrophilum isolates was greater in rainbow trout than in coho salmon (88% vs. 70%). Furthermore, it was not unusual to isolate multiple PFGE profiles from a single coho salmon sample whereas only two PFGE profiles were shared between two sample dates separated by 1 month. It is clear that the domestic rainbow trout aquaculture facilities studied here were primarily affected by a complex of genetically related strains whereas spawning coho salmon supported a much more genetically diverse collection of F. psychrophilum.
The first report of viral haemorrhagic septicaemia in farmed rainbow trout, Oncorhynchus mykiss (Walbaum), in the United Kingdom
Authors: Stone D M , Ferguson H W , Tyson P A , Savage J , Wood G , Dodge M J , Woolford G , Dixon P F , Feist S W , Way K
Published: August 2008

Viral haemorrhagic septicaemia (VHS) was diagnosed in rainbow trout in the UK in May 2006. VHS virus (VHSV) was isolated from fingerlings showing typical histopathological lesions at a single rainbow trout farm site experiencing high mortality. The virus was confirmed as VHSV by serological and molecular biological tests. Phylogenetic analysis based on the complete glycoprotein gene sequence revealed that the isolate was closely related (99% nucleotide identity) to several Danish isolates from 1991 to 2000 and was assigned to VHSV genogroup Ia. The pathogenicity of the isolate was determined in infection experiments using rainbow trout fry. Following waterborne challenge, cumulative mortalities reached 96.67–100% by 12 days post‐infection. This represents the first isolation of a pathogenic freshwater VHSV in the UK.
The effects of repeated heat‐pressing on properties of pressable glass‐ceramics
Authors: CHUNG K‐H. , LIAO J‐H. , DUH J‐G. , CHAN D. C‐N.
Published: August 2008

Summary  The aim of this study was to evaluate the properties of four heat‐pressed glass‐ceramic materials after repeated heat‐pressing. Two commercially available heat‐pressed glass‐ceramic systems [Optimal pressable glass‐ceramics (OPC® and 3G™) and Empress pressable glass‐ceramics (Empress® and Empress®2)] were selected. Disc samples (14 mm × 1·4 mm) of each tested material were heat‐pressed and used as controls. Sprue and button parts of the pressed groups were retrieved and used for repeated heat‐pressing to construct specimens of re‐pressed group. All the heat‐pressed casting procedures were performed according to the manufacturers’ instructions. A biaxial flexural strength (BFS) test (ISO 6872) was performed to determine the strength of pressed and re‐pressed glass‐ceramic disc specimens (n = 10) at a crosshead speed of 0·5 mm min−1. Ions eluted from etching procedure were collected and examined using inductively coupled plasma mass spectrometer. Surface characteristics were examined with electron probe microanalysis, X‐ray diffraction and secondary electron imaging (SEI). The data were analysed statistically (anova + Tukey’s HSD post hoc test, P < 0·05). The BFS values obtained ranged from 123·5 ± 18·5 to 365·9 ± 35·5 MPa. The re‐pressed Empress®2 group had a statistically significant higher BFS mean than the pressed control group (P < 0·05). The SEI micrographs of the lithium disilicate‐reinforced glass‐ceramic material (Empress®2) showed a densely packed, interlocking microstructure and an increase in size with preferred orientation of the lithium disilicate crystals after repeated heat‐pressing. Repeated heat‐pressing treatment produced a statistically significant increase in the flexural strength of Empress®2 glass‐ceramic material.
Farnesol induces the transcriptional accumulation of the Aspergillus nidulans Apoptosis‐Inducing Factor (AIF)‐like mitochondrial oxidoreductase
Authors: Savoldi Marcela , Malavazi Iran , Soriani Frederico Marianetti , Capellaro José Luiz , Kitamoto Katsuhiko , da Silva Ferreira Márcia Eliana , Goldman Maria Helena S. , Goldman Gustavo Henrique
Published: August 2008

Farnesol (FOH) is a non‐sterol isoprenoid produced by dephosphorylation of farnesyl pyrophosphate, a catabolite of the cholesterol biosynthetic pathway. These isoprenoids inhibit proliferation and induce apoptosis. It has been shown previously that FOH triggers morphological features characteristic of apoptosis in the filamentous fungus Aspergillus nidulans. Here, we investigate which pathways are influenced through FOH by examining the transcriptional profile of A. nidulans exposed to this isoprenoid. We observed decreased mRNA abundance of several genes involved in RNA processing and modification, transcription, translation, ribosomal structure and biogenesis, amino acid transport and metabolism, and ergosterol biosynthesis. We also observed increased mRNA expression of genes encoding a number of mitochondrial proteins and characterized in detail one of them, the aifA, encoding the Apoptosis‐Inducing Factor (AIF)‐like mitochondrial oxidoreductase. The ΔaifA mutant is more sensitive to FOH (about 8.0% and 0% survival when exposed to 10 and 100 μM FOH respectively) than the wild type (about 97% and 3% survival when exposed to 10 and 100 μM FOH respectively). These results suggest that AifA is possibly important for decreasing the effects of FOH and reactive oxygen species. Furthermore, we showed an involvement of autophagy and protein kinase C in A. nidulans FOH‐induced apoptosis.
RloC: a wobble nucleotide‐excising and zinc‐responsive bacterial tRNase
Authors: Davidov Elena , Kaufmann Gabriel
Published: August 2008

The conserved bacterial protein RloC, a distant homologue of the tRNALys anticodon nuclease (ACNase) PrrC, is shown here to act as a wobble nucleotide‐excising and Zn++‐responsive tRNase. The more familiar PrrC is silenced by a genetically linked type I DNA restriction‐modification (R‐M) enzyme, activated by a phage anti‐DNA restriction factor and counteracted by phage tRNA repair enzymes. RloC shares PrrC's ABC ATPase motifs and catalytic ACNase triad but features a distinct zinc‐hook/coiled‐coil insert that renders its ATPase domain similar to Rad50 and related DNA repair proteins. Geobacillus kaustophilus RloC expressed in Escherichia coli exhibited ACNase activity that differed from PrrC's in substrate preference and ability to excise the wobble nucleotide. The latter specificity could impede reversal by phage tRNA repair enzymes and account perhaps for RloC's more frequent occurrence. Mutagenesis and functional assays confirmed RloC's catalytic triad assignment and implicated its zinc hook in regulating the ACNase function. Unlike PrrC, RloC is rarely linked to a type I R‐M system but other genomic attributes suggest their possible interaction in trans. As DNA damage alleviates type I DNA restriction, we further propose that these related perturbations prompt RloC to disable translation and thus ward off phage escaping DNA restriction during the recovery from DNA damage.
The Vibrio harveyi master quorum‐sensing regulator, LuxR, a TetR‐type protein is both an activator and a repressor: DNA recognition and binding specificity at target promoters
Authors: Pompeani Audra J. , Irgon Joseph J. , Berger Michael F. , Bulyk Martha L. , Wingreen Ned S. , Bassler Bonnie L.
Published: August 2008

Quorum sensing is the process of cell‐to‐cell communication by which bacteria communicate via secreted signal molecules called autoinducers. As cell population density increases, the accumulation of autoinducers leads to co‐ordinated changes in gene expression across the bacterial community. The marine bacterium, Vibrio harveyi, uses three autoinducers to achieve intra‐species, intra‐genera and inter‐species cell–cell communication. The detection of these autoinducers ultimately leads to the production of LuxR, the quorum‐sensing master regulator that controls expression of the genes in the quorum‐sensing regulon. LuxR is a member of the TetR protein superfamily; however, unlike other TetR repressors that typically repress their own gene expression and that of an adjacent operon, LuxR is capable of activating and repressing a large number of genes. Here, we used protein binding microarrays and a two‐layered bioinformatics approach to show that LuxR binds a 21 bp consensus operator with dyad symmetry. In vitro and in vivo analyses of two promoters directly regulated by LuxR allowed us to identify those bases that are critical for LuxR binding. Together, the in silico and biochemical results enabled us to scan the genome and identify novel targets of LuxR in V. harveyi and thus expand the understanding of the quorum‐sensing regulon.
A new Vibrio cholerae sRNA modulates colonization and affects release of outer membrane vesicles
Authors: Song Tianyan , Mika Franziska , Lindmark Barbro , Liu Zhi , Schild Stefan , Bishop Anne , Zhu Jun , Camilli Andrew , Johansson Jörgen , Vogel Jörg , Wai Sun Nyunt
Published: August 2008

We discovered a new small non‐coding RNA (sRNA) gene, vrrA of Vibrio cholerae O1 strain A1552. A vrrA mutant overproduces OmpA porin, and we demonstrate that the 140 nt VrrA RNA represses ompA translation by base‐pairing with the 5′ region of the mRNA. The RNA chaperone Hfq is not stringently required for VrrA action, but expression of the vrrA gene requires the membrane stress sigma factor, σE, suggesting that VrrA acts on ompA in response to periplasmic protein folding stress. We also observed that OmpA levels inversely correlated with the number of outer membrane vesicles (OMVs), and that VrrA increased OMV production comparable to loss of OmpA. VrrA is the first sRNA known to control OMV formation. Moreover, a vrrA mutant showed a fivefold increased ability to colonize the intestines of infant mice as compared with the wild type. There was increased expression of the main colonization factor of V. cholerae, the toxin co‐regulated pili, in the vrrA mutant as monitored by immunoblot detection of the TcpA protein. VrrA overproduction caused a distinct reduction in the TcpA protein level. Our findings suggest that VrrA contributes to bacterial fitness in certain stressful environments, and modulates infection of the host intestinal tract.
Association between perceived security of the neighbourhood and small‐for‐gestational‐age birth
Authors: Auger Nathalie , Daniel Mark , Platt Robert W. , Wu Yuquan , Luo Zhong‐Cheng , Choinière Robert
Published: August 2008

Evidence points to an association between a mother's place of residence and her newborn's health, independent of individual characteristics. Neighbourhood constructs such as immigrant density, deprivation and crime have all been separately associated with birth outcomes. Little research has considered the joint influence of variables representing a spectrum of neighbourhood constructs. Subjective vs. objective measures of neighbourhood constructs (e.g. reported vs. perceived crime) are often not considered. We sought to evaluate the relationship between neighbourhood measures of reported crime, neighbourhood perceived security, immigrant density, material/social deprivation, residential stability and the odds of small‐for‐gestational‐age (SGA) birth in an urban setting in Canada. Neighbourhood was defined as police districts (n = 49). We linked Montreal livebirths 1997–2001 (n = 98 330) to police district crime measures, survey data on perceived security, and 2001 census data. We used multi‐level analysis to calculate odds ratios (OR) for neighbourhood effects on SGA birth accounting for individual characteristics.

Mothers residing in neighbourhoods with the most favourable perception had a lower odds of SGA birth than neighbourhoods with the least favourable perception [OR 0.87, 95% CI 0.77, 0.97]. Mothers in neighbourhoods with lower proportions of immigrants had lower odds of SGA birth relative to neighbourhoods with the highest proportion of immigrants. Reported crime, residential stability and material/social deprivation (accounting for neighbourhood perception) were not associated with SGA birth. Immigrant density and subjective perceptions of neighbourhood security are associated with SGA birth. Public health strategies to improve fetal growth should target neighbourhoods with low perceived security and high immigrant density.
Diagnostic accuracy of verbal autopsies in ascertaining the causes of stillbirths and neonatal deaths in rural Ghana
Authors: Edmond Karen M. , Quigley Maria A. , Zandoh Charles , Danso Samuel , Hurt Chris , Agyei Seth Owusu , Kirkwood Betty R.
Published: August 2008

This study evaluated the diagnostic accuracy of a verbal autopsy (VA) tool in ascertaining the causes of stillbirths and neonatal deaths in rural Ghana and was nested within a community‐based maternal vitamin A supplementation trial (ObaapaVitA trial). All stillbirths and neonatal deaths between 1 January 2003 and 30 June 2004 were prospectively included. Community VAs were carried out within 6 months of death and were classified with a primary cause of death by three experienced paediatricans. The reference standard diagnosis was obtained by the study paediatrician in 4 district hospitals in the study area.

There were 20 317 deliveries, 661 stillbirths and 590 neonatal deaths with a VA diagnosis in the study population. A total of 311 stillbirths and 191 neonatal deaths had both a VA and a hospital reference standard diagnosis. The VA performed poorly for stillbirth diagnoses such as congenital abnormalities and maternal haemorrhage. Accuracy was higher for intrapartum obstetric complications and antepartum maternal disease. For neonatal deaths, sensitivity was >60% for all major causes; specificity was 76% for birth asphyxia but >85% for prematurity and infection. Overall, VA diagnostic accuracy was higher than expected in this rural African setting. Our classification system was based on the expected public health importance of the individual causes of death, differing implications for intervention and the ability to distinguish between the individual causes in low‐resource settings. We believe this system was easier to use than traditional approaches and resulted in high precision and accuracy. However, further simplifications are needed to allow use of the World Health Organisation VA in routine child health programmes. The diagnostic accuracy of the VA tool should also be assessed in other regions and in multicentre studies.
Multiple alien Phytophthora taxa discovered on diseased ornamental plants in Spain
Authors: Moralejo E. , Pérez‐Sierra A. M. , Álvarez L. A. , Belbahri L. , Lefort F. , Descals E.
Published: August 2008

The plant trade is unwittingly accelerating the worldwide spread of well‐known and new or undescribed Phytophthora species and creating novel niches for emerging pathogens. The results of a survey carried out from 2001 to 2006 in garden centres and nurseries of the Balearic Islands and eastern Spain combined with the analysis of samples received from ornamental nurseries from northern Spain reflected the extent of this global issue at the local scale. A total of 125 Phytophthora isolates were obtained from 37 different host species and 17 putative species identified on morphological features and direct sequencing of the internal transcribed spacer and four mitochondrial and nuclear genes. Five species, P. ramorum, P. hedraiandra, P. ‘niederhauserii’, P. ‘kelmania’ and P. ‘taxon Pgchlamydo’ were formally unknown to science prior to 2001. In addition, 37 new host/pathogen combinations were first records for Spain, highlighting the risk of non‐coevolved organisms from different biogeographic origins coming into contact under managed environments. The problem generated by new or rare taxa of Phytophthora found in nurseries for which no prior information on natural habitat and ecology is available for pest risk analysis is discussed.
Development of protocols for detection of Colletotrichum acutatum and monitoring of strawberry anthracnose using real‐time PCR
Authors: Garrido C. , Carbú M. , Fernández‐Acero F. J. , Boonham N. , Colyer A. , Cantoral J. M. , Budge G.
Published: August 2008

Real‐time PCR (TaqMan®) assays were developed for the specific detection and discrimination of Colletotrichum spp., C. acutatum and C. gloeosporioides causing anthracnose in strawberry using the most divergent area of the internal transcribed spacers (ITS1 and ITS2) and 5·8S ribosomal RNA (rRNA) gene region. The specificity of the new assays was tested using DNA from six species of Colletotrichum and nine fungal species commonly found associated with strawberry material, and additionally by comparing the sequences with those from databases using a blast search. The sequences only showed identity with homologous sequences from the desired target organisms. The new assays were 10–100 times more sensitive than conventional PCR methods previously published for the diagnosis of strawberry anthracnose. When real‐time PCR was compared with ELISA methods, PCR improved the sensitivity of the identification by obtaining positive results for samples of strawberry plant material that tested negative with ELISA. The development of C. acutatum was monitored using artificially infected strawberry crowns from two strawberry cultivars (Camarosa and Ventana) and a real‐time PCR assay specific for this species between January and June 2006. The amount of C. acutatum detected using real‐time PCR varied significantly by month (P < 0·001), but not by cultivar (P = 0·394). The new assays were shown to be useful tools for rapid detection and identification of these pathogens and to allow rapid and accurate assessment of the casual agents of anthracnose in strawberry.
A New Strategy to Induce Effective Antitumour Response In Vitro and In Vivo
Authors: Wang M. , Xie Z. , Shi M. , Lu H. , Yu M. , Hu M. , Lu F. , Ma Y. , Shen B. , Guo N.
Published: August 2008

To induce Her2‐specific cell immune response, we used xenogeneic antigen rat neu L2–S2 domains as the vaccine antigen. The antigenic protein was engineered as a chimeric protein with human IgG1 Fc region (neu‐Fc). Neu‐Fc could stimulate the cell proliferation in mixed lymphocyte reaction effectively. Simultaneous neu‐Fc and IFN‐γ stimulation dramatically elevated IL‐12 secretion and reduced IL‐10 production in PBMC. To further augment the activating effects on Th1‐type response, Bacille Calmette–Guerin (BCG) was utilized as a non‐specific stimulus. Neu‐Fc, IFN‐γ and BCG costimulation exhibited the most conspicuous effects on the reversal of the Th1‐type inhibitory effects by MCF‐7 cell supernatant compared with neu‐Fc alone or IFN‐γ and BCG costimulation. The lytic activity of effector cells to Her2 overexpressing cells was greatly promoted by neu‐Fc, IFN‐γ and BCG stimulation simultaneously. Neu‐Fc led to considerable retardation in EMT6/Her2 tumour growth in Balb/c mice. IFN‐γ and BCG efficiently enhanced the antitumour activity. A large amount of inflammatory cells were found to be accumulated in the tumour tissues or surrounded tumours in mice treated with neu‐Fc, IFN‐γ and BCG but no inflammatory cell infiltration was observed in control tumours, indicating that the strategy is potent enough to support the initiation and propagation of tumour‐specific immune response in an established tumour and generate a proinflammatory environment.
The Liver Mediates Apoptotic Cell‐Induced Immune Regulation
Authors: Wang Y. , Gao Y. , Yuan X. , Xia W. , Luo Y. , Sun E. , Chen Z. K.
Published: August 2008

Allogeneic apoptotic cells have been demonstrated to induce allograft tolerance, but the mechanisms for this remain unclear. The study presented here investigates organs in which the tolerogenic immune responses may occur. Distribution of live or apoptotic CFSE+ splenocytes in recipients’ organs and phagocytosis by liver antigen‐presenting cells (APC) were investigated by fluorescence microscopy and flow cytometry, and cytokine expression was analysed by Multiplex and ELISA. It was found that allogeneic or autogenic apoptotic cells preferentially accumulated in the liver within 30 min, peaked at 60 min, and disappeared at 12 h after infusion, whereas these cells scarcely appeared in the spleen. The accumulation in the liver was apoptotic cell‐specific as both allogeneic and autogenic live splenocytes were completely deposited in the spleen. Liver phagocytes, including Kupffer cells, liver sinusoidal endothelial cells and dendritic cells, all efficiently phagocytized apoptotic cells in vitro and in vivo. Although a Th1 cytokine profile found both in the spleen and liver in the recipients of allogeneic apoptotic cells, a rapid and consistent Th2 cytokine profile specifically was initiated in the liver. From this, we conclude that liver APC phagocytize donor apoptotic cells and induce liver‐specific Th2 cytokines, which may contribute to the mechanisms of allograft tolerance induced by donor apoptotic cells.
The Long‐term Impaired Macrophages Functions are Already Observed Early after High‐dose Ethanol Administration
Authors: Andrade M. C. , Martins‐Filho O. A. , Coelho‐Neto J. , Mesquita O. N. , Faria A. M. C.
Published: August 2008

Herein, we described an experimental model of high‐dose ethanol (EtOH) administration, able to induce in vitro impairment in macrophage phagocytic capacity, already observed at 24 h after the last EtOH administration. This phenomenon was characterized by enlarged time required for adhesion and internalization events. Parallel studies documented an overall impaired production of interleukin (IL)‐6 and nitric oxide (NO) production by peritoneal macrophages in EtOH‐treated mice following interferon (IFN)‐γ and lipopolysaccharide (LPS) stimuli. Although the impaired IL‐6 response could not be restored by any of the experimental conditions tested, the lower NO response to INF‐γ and LPS was overturned by simultaneous IFN‐γ/LPS stimuli. It was interesting to notice that high‐dose EtOH administration drives peritoneal macrophages towards long‐term impairment in phagocytosis capacity with slower adhesion time, but with no impact on the time required for internalization. Moreover, 30 days after the last EtOH administration, lower IL‐6 response to INF‐γ and impaired NO production were still observed in response to IFN‐γ/LPS stimuli, with the IL‐6 response to IFN‐γ being restored by IFN‐γ/LPS stimuli. Histological studies showed that high‐dose EtOH administration led to long‐term in vivo impairment of antigen‐clearance following OVA‐driven delayed‐type‐hypersensitivity induction, characterized by the presence of a large amount of unprocessed OVA surrounded by dermal inflammatory infiltrate, suggesting defective activity of antigen‐presenting cells. Together, these findings supported our hypothesis that the poor antigen clearance in vivo may be related to the impaired macrophage function in vitro. These observations in the murine experimental model may reflect some of the consequences of EtOH consumption by humans.
Effect of HLA Genotype or CTLA‐4 Polymorphism on Cytokine Response in Healthy Children
Authors: Walldén J. , Ilonen J. , Roivainen M. , Ludvigsson J. , Vaarala O. ,   & the ABIS Study Group
Published: August 2008

Type 1 diabetes (T1D) is considered to be a T‐cell‐mediated autoimmune disease in which genetic predisposition is affected by HLA class II alleles and polymorphisms in cytotoxic T‐lymphocyte‐associated antigen‐4 (CTLA‐4) gene. We tested the hypothesis whether these T1D‐related gene polymorphisms modulate cytokine response and thus contribute to the development of autoimmunity. The study includes 67 non‐diabetic children, typed for HLA class II alleles and CTLA‐4 polymorphisms (+49A/G, CT60A/G, CTBC217_1C/T). We measured cytokine secretion of peripheral blood mononuclear cells after stimulation with tetanus toxoid (TT), polio virus, coxsackie virus B4, pertussis toxin (PT) and phytohemagglutinin (PHA). We saw higher IL‐13 response to TT in individuals with DR3–DQ2 haplotype (P = 0.002). HLA class II protective haplotype, DR2–DQ6, showed association with increased production of IFN‐γ (P < 0.001) and IL‐2 (P = 0.005) in response to polio virus. In children with the autoimmunity‐related homozygous genotypes CTLA‐4 +49G/G, CT60G/G and CTBC217_1T/T, we found enhanced PT‐ and PHA‐induced IFN‐γ production (P < 0.05). The cytokine responses to studied antigens were weakly modified by HLA class II risk haplotypes, and children with T1D‐associated HLA risk haplotypes are not specifically inclined to develop an immune response in general. Higher IFN‐γ and IL‐2 response to enterovirus in children with HLA class II protective haplotype DR2‐DQ6 could be of importance in the protection from T1D‐associated enterovirus infections. All autoimmunity related CTLA‐4 polymorphisms were associated with enhanced IFN‐γ. This suggests impaired downregulation of cellular immunity by these CTLA‐4 polymorphisms.