bluuebunny/crossref_metadata_2025 huggingface dataset:
The Leaning Tower Illusion is Not a Simple Perspective Illusion
Authors: Maniatis Lydia M
Published: November 2008

The Learning Tower illusion has been explained as a simple perspective illusion. I suggest that it is a variant of the Jastrow illusion, applied to perspective tilt, and that the original explanation is inconsistent with its own implicit assumptions and with the visual resolution of pictorial stimuli in general.
Blurry Means Good Focus: Myopia and Visual Attention
Authors: McKone Elinor , Davies Anne Aimola , Fernando Dinusha
Published: November 2008

A correlation between myopia and visuo-spatial attention is reported. More severe myopia was found to be associated with better ability to quickly narrow the focus of visual attention to a small region of space (assessed via interference from spatial proximity of to-be-ignored inverted half-faces), in a task where local focus was explicitly required. There was no myopia association with size of the default attentional window, when the need to respond to either small local or larger global regions was equally likely (in a particular Navon figure task). Results suggest that myopics might allocate attention more narrowly than individuals with normal eyesight in certain functionally important visual tasks (eg reading) but not others (eg driving).
Kv Channel Gating Requires a Compatible S4-S5 Linker and Bottom Part of S6, Constrained by Non-interacting Residues
Authors: Labro Alain J. , Raes Adam L. , Grottesi Alessandro , Van Hoorick Diane , Sansom Mark S.P. , Snyders Dirk J.
Published: November 2008

Voltage-dependent K+ channels transfer the voltage sensor movement into gate opening or closure through an electromechanical coupling. To test functionally whether an interaction between the S4-S5 linker (L45) and the cytoplasmic end of S6 (S6T) constitutes this coupling, the L45 in hKv1.5 was replaced by corresponding hKv2.1 sequence. This exchange was not tolerated but could be rescued by also swapping S6T. Exchanging both L45 and S6T transferred hKv2.1 kinetics to an hKv1.5 background while preserving the voltage dependence. A one-by-one residue substitution scan of L45 and S6T in hKv1.5 further shows that S6T needs to be α-helical and forms a “crevice” in which residues I422 and T426 of L45 reside. These residues transfer the mechanical energy onto the S6T crevice, whereas other residues in S6T and L45 that are not involved in the interaction maintain the correct structure of the coupling.
Regulation of Bestrophin Cl Channels by Calcium: Role of the C Terminus
Authors: Xiao Qinghuan , Prussia Andrew , Yu Kuai , Cui Yuan-yuan , Hartzell H. Criss
Published: November 2008

Human bestrophin-1 (hBest1), which is genetically linked to several kinds of retinopathy and macular degeneration in both humans and dogs, is the founding member of a family of Cl− ion channels that are activated by intracellular Ca2+. At present, the structures and mechanisms responsible for Ca2+ sensing remain unknown. Here, we have used a combination of molecular modeling, density functional–binding energy calculations, mutagenesis, and patch clamp to identify the regions of hBest1 involved in Ca2+ sensing. We identified a cluster of a five contiguous acidic amino acids in the C terminus immediately after the last transmembrane domain, followed by an EF hand and another regulatory domain that are essential for Ca2+ sensing by hBest1. The cluster of five amino acids (293–308) is crucial for normal channel gating by Ca2+ because all but two of the 35 mutations we made in this region rendered the channel incapable of being activated by Ca2+. Using homology models built on the crystal structure of calmodulin (CaM), an EF hand (EF1) was identified in hBest1. EF1 was predicted to bind Ca2+ with a slightly higher affinity than the third EF hand of CaM and lower affinity than the second EF hand of troponin C. As predicted by the model, the D312G mutation in the putative Ca2+-binding loop (312–323) reduced the apparent Ca2+ affinity by 20-fold. In addition, the D312G and D323N mutations abolished Ca2+-dependent rundown of the current. Furthermore, analysis of truncation mutants of hBest1 identified a domain adjacent to EF1 that is rich in acidic amino acids (350–390) that is required for Ca2+ activation and plays a role in current rundown. These experiments identify a region of hBest1 (312–323) that is involved in the gating of hBest1 by Ca2+ and suggest a model in which Ca2+ binding to EF1 activates the channel in a process that requires the acidic domain (293–308) and another regulatory domain (350–390). Many of the ∼100 disease-causing mutations in hBest1 are located in this region that we have implicated in Ca2+ sensing, suggesting that these mutations disrupt hBest1 channel gating by Ca2+.
Regularity of growth and the class 𝒮: Correction
Authors: Drasin D.
Published: November 2008

This corrects some errors in formulas which appear in the author’s paper in this journal, vol. 11, pp. 90–100 (2007).
A multivariate test of association
Authors: Ferreira Manuel A. R. , Purcell Shaun M.
Published: November 2008

Summary: Although genetic association studies often test multiple, related phenotypes, few formal multivariate tests of association are available. We describe a test of association that can be efficiently applied to large population-based designs.

Availability: A C++ implementation can be obtained from the authors.

Contact:  manuel.ferreira@qimr.edu.au

Supplementary information:  Supplementary figures are available at Bioinformatics online.
Hemostatic Agent Microporous Polysaccharide Hemospheres (MPH) Does Not Affect Healing or Intact Sinus Mucosa
Authors: Antisdel Jastin L. , Janney Christine G. , Long John P. , Sindwani Raj
Published: November 2008

Objectives/Hypothesis: Absorbable hemostatic agents are used routinely following sinus surgery. Recent studies suggest that current biomaterials, such as FloSeal Matrix Hemostatic Sealant (Fusion Medical Technologies, Mountain View, CA) may interfere with mucosal regeneration. This study was designed to evaluate the effects of Microporous Polysaccharide Hemospheres (MPH, Medafor, Inc., Minneapolis, MN), a novel rapidly‐absorbing hemostatic powder, on healing and intact sinus mucosa.

Study Design: Prospective, controlled study using the rabbit model.

Methods: Both maxillary sinuses of 14 New Zealand white rabbits were surgically opened. The mucosa of 10 rabbits were stripped bilaterally, and the left sinus of each was then treated with either MPH or FloSeal. The mucosa of four additional rabbits were incised but otherwise remained undisturbed. Again, the left sinus of each of the four additional rabbits was treated with either MPH or FloSeal. The right sinus served as an untreated control (stripped or intact) in both arms of the study. Animals were recovered and euthanized 2 weeks later. Specimens were examined by a blinded pathologist using light microscopy.

Results: Untreated regenerated mucosa showed expected areas of sparse cilia, mild serous gland reduction, and fibrosis. MPH‐treated sinuses showed no significant changes compared to respective controls, and no MPH substance was identified. In contrast, regenerating mucosa treated with FloSeal showed extensive loss of cilia, inflammation, and fibrosis. Residual FloSeal particles were present within the sinus cavity and grossly incorporated within healing mucosa. Unexpectedly, intact mucosa exposed to FloSeal showed similar findings.

Conclusions: Absorbable hemostatic materials have starkly different effects on mucosal healing. Unlike other agents, MPH is rapidly cleared and has no negative effects on healing or intact sinus mucosa.
The Theory and Practice of Consultation-Liaison (CL) Psychiatry in Trinidad and Tobago with Reference to Suicidal Behavior
Authors: Maharajh Hari D. , Abdool Petal , Mohammed-Emamdee Rehanna
Published: November 2008

Consultation-Liaison Psychiatry (CL Psychiatry) is not a well-established discipline in developing countries. It is a multifaceted area that incorporates clinical, teaching, and research activities both within the hospital and extramurally in community health services. Our purpose was first to define the role of CL Psychiatry, to review essential steps in the process, and to advise on how to set up services. Second, a 1-year retrospective analysis was conducted on all patients referred. A total of 708 persons were referred for psychiatric consultation, of which 41% (291) were referred because of suicidal behavior. Sixty-six percent were female and there was an over-representation of Indo-Trinidadians (67%). Twenty-six percent of all cases of suicidal behavior were diagnosed with clinical depression, 3% were suffering from a psychotic illness (schizophrenia), and 8% (24/291) were under the influence of alcohol. The most vulnerable group was the 25- to 35-year-old age group, accounting for 27% (78/291) of attempters, with the largest number of female attempters. The 36- to 55-year-old males were most likely to attempt suicide (35/99). Ingestion of a toxic substance was the most popular method among all races, genders, and age groups. Of all referrals, 95% originated from medical wards. The most common reason cited for attempts was depressed mood, secondary to a domestic dispute with a family member or significant other. Among Caribbean countries, Trinidad and Tobago has high rates of suicide and suicidal behavior, depression, and alcoholism. CL psychiatrists have a major role to play in the delivery of services to these groups, facilitating the transition of care from admission in the emergency room to discharge and follow-up in the community.
Tissue-Specific Expression Patterns of Arabidopsis NF-Y Transcription Factors Suggest Potential for Extensive Combinatorial Complexity
Authors: Siefers Nicholas , Dang Kristen K. , Kumimoto Roderick W. , Bynum William Edwards , Tayrose Gregory , Holt Ben F.
Published: November 2008

All aspects of plant and animal development are controlled by complex networks of transcription factors. Transcription factors are essential for converting signaling inputs, such as changes in daylength, into complex gene regulatory outputs. While some transcription factors control gene expression by binding to cis-regulatory elements as individual subunits, others function in a combinatorial fashion. How individual subunits of combinatorial transcription factors are spatially and temporally deployed (e.g. expression-level, posttranslational modifications and subcellular localization) has profound effects on their control of gene expression. In the model plant Arabidopsis (Arabidopsis thaliana), we have identified 36 Nuclear Factor Y (NF-Y) transcription factor subunits (10 NF-YA, 13 NF-YB, and 13 NF-YC subunits) that can theoretically combine to form 1,690 unique complexes. Individual plant subunits have functions in flowering time, embryo maturation, and meristem development, but how they combine to control these processes is unknown. To assist in the process of defining unique NF-Y complexes, we have created promoter:β-glucuronidase fusion lines for all 36 Arabidopsis genes. Here, we show NF-Y expression patterns inferred from these promoter:β-glucuronidase lines for roots, light- versus dark-grown seedlings, rosettes, and flowers. Additionally, we review the phylogenetic relationships and examine protein alignments for each NF-Y subunit family. The results are discussed with a special emphasis on potential roles for NF-Y subunits in photoperiod-controlled flowering time.
Molecular background of α‐fetoprotein in liver cancer cells as revealed by global RNA expression analysis
Authors: Saito Shigeru , Ojima Hidenori , Ichikawa Hitoshi , Hirohashi Setsuo , Kondo Tadashi
Published: November 2008

α‐Fetoprotein (AFP) is considered to be a diagnostic and prognostic biomarker in hepatocellular carcinoma (HCC). However, the role of AFP in the development of HCC is presently obscure. We hypothesized that a certain set of genes is expressed in a manner coordinate with AFP, and that these genes essentially contribute to the malignant characteristics of AFP‐producing HCC. To address this hypothesis, we carried out global mRNA expression analysis of 21 liver cancer cell lines that produce varying levels of AFP. We identified 213 genes whose mRNA expression levels were significantly correlated with that of AFP (P < 0.0001). These included liver‐specific transcription factors for AFP and other albumin family genes. Eighteen HCC‐associated genes and 11 genes associated with malignancies other than HCC showed significant correlations with AFP production levels. Genes involved in lipid catabolism, blood coagulation, iron metabolism, angiogenesis, and the Wnt and mitogen‐activated protein kinase pathways were also identified. Text data mining revealed that participation in the transcription factor network could explain the connection between 78 of the identified genes. Glypican 3, which is a component of the Wnt pathway and contributes to HCC development, had the fifth highest correlation coefficient with AFP. Reactivity to specific antibodies confirmed the significant correlation between AFP and glypican 3 expression in HCC tissues. These observations suggest that AFP‐producing liver cancer cells may have a unique molecular background consisting of cancer‐associated genes. From this genome‐wide association study, novel aspects of the molecular background of AFP were revealed, and thus may lead to the identification of novel biomarker candidates. (Cancer Sci 2008; 99: 2402–2409)
Involvement of thioredoxin‐binding protein 2 in the antitumor activity of CD437
Authors: Matsuoka Saori , Tsuchiya Hiroyuki , Sakabe Tomohiko , Watanabe Yumi , Hoshikawa Yoshiko , Kurimasa Akihiro , Itamochi Hiroaki , Harada Tasuku , Terakawa Naoki , Masutani Hiroshi , Yodoi Junji , Shiota Goshi
Published: November 2008

The present authors previously reported that a synthetic retinoid, CD437, induces endoplasmic reticulum stress‐mediated apoptosis in ovarian adenocarcinoma cells in spite of no response to natural retinoids. However, the precise mechanism of its proapoptotic action has not been fully determined. The present study herein demonstrates that apoptosis induction of ovarian adenocarcinoma SKOV3 cells by CD437 involves the upregulation of thioredoxin‐binding protein 2 (TBP2) by a mechanism that is dependent on the intracellular calcium concentration. TBP2 is known to bind to and suppress thioredoxin (TRX) activity whereas TRX has an anti‐apoptotic effect by inhibiting apoptosis signal‐regulating kinase 1 (ASK1). The activation of ASK1 and its downstream molecule, c‐Jun N‐terminal kinase, was observed after induction of TBP2 by CD437. Interestingly, CD437 induced the association of TBP2 with TRX and, in turn, facilitated the dissociation of ASK1 from TRX. Moreover, blockade of TBP2 induction by small interfering RNA (siRNA) significantly attenuated the cytotoxic effect of CD437. These results suggest that TBP2 plays a critical role in the mechanism by which CD437 exerts proapoptotic action against SKOV3 cells. (Cancer Sci 2008; 99: 2485–2490)
Loss of estrogen receptor β isoform expression and its correlation with aberrant DNA methylation of the 5′‐untranslated region in human epithelial ovarian carcinoma
Authors: Suzuki Fumihiko , Akahira Jun‐ichi , Miura Ikumi , Suzuki Takashi , Ito Kiyoshi , Hayashi Shin‐ichi , Sasano Hironobu , Yaegashi Nobuo
Published: November 2008

Evidence exists that sex steroids such as estrogens affect epithelial ovarian cancer. The expression profiles of the estrogen receptors (ER) and ERβ in particular have not been fully described. Therefore, in our present study, we examined the methylation status of the promoters 0K and 0N, and the expression of ERβ isoforms in human epithelial ovarian carcinoma. We then correlated methylation status with ER expression status. Twelve ovarian carcinoma cell lines, six primary cultures of ovarian surface epithelial cells (OSE), and 64 cases of ovarian carcinoma tissues were examined. Bisulfite sequencing and quantitative reverse transcription–polymerase chain reaction were used to evaluate methylation status and expression of ERβ isoforms. The relative abundance of exon 0N, ERβ1, ERβ2, and ERβ4 mRNA was significantly lower in ovarian cancer cell lines and tissues than in their corresponding normal counterparts. However, ERβ5 mRNA level was relatively higher in the cancers, in clear cell adenocarcinoma in particular, than in the normal ovary. Bisulfite sequencing analysis demonstrated that the two promoters of the ERβ gene exhibited distinct methylation patterns. Promoter 0N was unmethylated in OSE, rarely methylated in normal ovarian tissues, and extensively methylated in ovarian cancer cell lines and tissues (11/15 cell lines and 18/32 cancer tissues were extensively methylated). The promoter 0K was, however, unmethylated in both normal and malignant ovarian cells and tissues. A significant correlation between promoter 0N hypermethylation and the loss of exon 0N, ERβ1, ERβ2, and ERβ4 mRNA expression was detected in ovarian carcinoma cells and tissues. Treatment of ovarian carcinoma cells with 5‐aza‐2′ deoxycytidine resulted in reexpression of the ERβ gene. The results of our present study suggest that ERβ is inactivated mainly through aberrant DNA methylation. This process may play an important role in the pathogenesis of epithelial ovarian cancer. (Cancer Sci 2008; 99: 2365–2372)
A genome‐screen experiment to detect quantitative trait loci affecting resistance to facial eczema disease in sheep
Authors: Phua S. H. , Dodds K. G. , Morris C. A. , Henry H. M. , Beattie A. E. , Garmonsway H. G. , Towers N. R. , Crawford A. M.
Published: November 2008

Facial eczema (FE) is a secondary photosensitization disease arising from liver cirrhosis caused by the mycotoxin sporidesmin. The disease affects sheep, cattle, deer and goats, and costs the New Zealand sheep industry alone an estimated NZ$63M annually. A long‐term sustainable solution to this century‐old FE problem is to breed for disease‐resistant animals by marker‐assisted selection. As a step towards finding a diagnostic DNA test for FE sensitivity, we have conducted a genome‐scan experiment to screen for quantitative trait loci (QTL) affecting this trait in Romney sheep. Four F1 sires, obtained from reciprocal matings of FE resistant and susceptible selection‐line animals, were used to generate four outcross families. The resulting half‐sib progeny were artificially challenged with sporidesmin to phenotype their FE traits measured in terms of their serum levels of liver‐specific enzymes, namely gamma‐glutamyl transferase and glutamate dehydrogenase. In a primary screen using selective genotyping on extreme progeny of each family, a total of 244 DNA markers uniformly distributed over all 26 ovine autosomes (with an autosomal genome coverage of 79–91%) were tested for linkage to the FE traits. Data were analysed using Haley–Knott regression. The primary screen detected one significant and one suggestive QTL on chromosomes 3 and 8 respectively. Both the significant and suggestive QTL were followed up in a secondary screen where all progeny were genotyped and analysed; the QTL on chromosome 3 was significant in this analysis.
Novel polymorphisms in the bovine β‐lactoglobulin gene and their effects on β‐lactoglobulin protein concentration in milk
Authors: Ganai N. A. , Bovenhuis H. , Van Arendonk J. A. M. , Visker M. H. P. W.
Published: November 2008

The aim of our study was to detect new polymorphisms in the bovine β‐lactoglobulin (β‐LG) gene with significant effects on β‐LG protein concentration. Genomic DNA samples from 22 proven bulls were screened for polymorphisms in the coding and promoter regions of the β‐LG gene. In total, 50 polymorphisms were detected. Two single nucleotide polymorphisms (SNPs) (g.1772G>A and g.3054C>T) lead to amino acid changes and are the causal genetic polymorphisms of β‐LG protein variants A and B. Forty‐two polymorphisms were in complete linkage disequilibrium (LD) with β‐LG protein variants A and B. Any of these 42 polymorphisms can be involved in the differential expression of the respective A and B alleles of the β‐LG gene. The eight polymorphisms not in complete LD with β‐LG protein variants A and B and the two polymorphisms causing the amino acid changes were genotyped in a set of 208 cows: 106 animals homozygous for β‐LG protein variant A and 102 animals homozygous for β‐LG protein variant B. Of these eight polymorphisms, six SNPs segregated only within the cows homozygous for β‐LG protein variant A and two SNPs segregated only within the cows homozygous for β‐LG protein variant B. One of the eight polymorphisms had a significant effect on β‐LG protein concentration. This SNP, g.‐731G>A, segregated only within the 106 cows homozygous for β‐LG protein variant A. Within these cows, adjusted relative β‐LG protein concentration was reduced by 1.22% (w/w) in animals homozygous g.‐731AA compared with animals homozygous g.‐731GG.
How well are general practice trainees prepared for paediatric prescribing?
Authors: Isa N. M. , Taylor Michael W. , Helms Peter J. , McLay James S.
Published: November 2008

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Children make up a significant proportion of a general practitioner's (GP's) prescribing workload.

• The realisation that children cannot be assumed to be little adults and may require specialized prescribing and therapeutic knowledge is relatively recent.

• Off‐label medicines, which have been associated with an increased frequency of adverse drug reactions, are commonly prescribed by GPs to children.

WHAT THIS STUDY ADDS

• The majority of GP trainees believe that their undergraduate and postgraduate training in paediatric therapeutics is insufficient for their coming requirements in primary care.

• Approximately one‐third of GP trainees do not undertake any paediatrics training prior to starting work as a GP.

• Off‐label and unlicensed prescribing are the most poorly covered areas of paediatric therapeutics in universities/university hospitals.

• Those trainees who do undergo paediatric training during their vocational years report increased paediatric prescribing confidence.

AIMS AND METHODOLOGY We invited 232 General Practice Trainees to complete an on‐line questionnaire to assess how they rated their training for the task of paediatric prescribing and therapeutics in the community.

RESULTS Of the 166 (71%) respondents who completed the questionnaire, 26.5% recalled specific teaching about paediatric prescribing and 59.6% covering one or more relevant topic during their undergraduate years. Undertaking a paediatric post during vocational training was associated with greater prescribing confidence (P < 0.001); however, 35% of respondents were not intending to undertake such a post.

CONCLUSION This study suggests that many GP trainees perceive their paediatric prescribing training as inadequate.
Screening and treatment for heritable thrombophilia in pregnancy failure: inconsistencies among UK early pregnancy units
Authors: Norrie Gillian , Farquharson Roy G. , Greaves Mike
Published: November 2008

The significance of heritable thrombophilia in pregnancy failure is controversial. We surveyed all UK Early Pregnancy Units and 70% responded. The majority test routinely for heritable thrombophilias; 80%, 76% and 88% undertook at least one screening test in late miscarriage, recurrent miscarriage and placental abruption, respectively. The range of thrombophilias sought is inconsistent: testing for proteins C and S deficiency and F5 R506Q (factor V Leiden) is most prevalent. Detection of heritable thrombophilia frequently leads to administration of antithrombotics in subsequent pregnancies. Thus, thrombophilia testing and use of antithrombotics are widespread in the UK despite controversies regarding the role of heritable thrombophilia in the pathogenesis of pregnancy complications, and the lack of robust evidence for the efficacy of antithrombotic therapy.
Short stature: increased in children with severe learning disability
Authors: Abdullah N. , Drummond P. , Gray N. , Al‐Khalidi O. , Barry R. , Cheetham T.
Published: November 2008

Introduction  ‘Health for all children’ recommends that children should be screened for growth disorders at school entry with a 0.4th centile ‘cut‐off’. Following the diagnosis of growth hormone deficiency in four children attending local special schools, our aim was to compare the height distribution of children attending special schools with mainstream schools.

Methods  Children at two local special schools were measured using a Leicester height measurer and values converted to standard deviation scores (SDS). Children were categorized according to whether there were known factors that could affect height. The data were compared with those collected from local mainstream schools.

Results  In total, 242 children were registered at the two special schools and 192 children were measured. The mean height SDS of children in mainstream school (n = 2301) was similar to national standards at −0.09 (SD 1.02). The mean height SDS distribution of the 192 children in special schools (age range 3.2–18.4 years; median age 11.3 years) was −0.73; 95%CI −0.9 to −0.5. In those with no established diagnosis to explain altered growth (n = 120) this was −0.613; 95%CI −0.8 to −0.4. Both pre‐pubertal (n = 37) and pubertal (n = 83) children were short and eight (6.7%) had a height less than the 0.4th centile.

Conclusions  Children attending special school with severe or profound learning disability were shorter than those attending mainstream school. This is still the case following the exclusion of children with a known cause for abnormal growth. This underlines the importance of each child being assessed by professionals with a refined knowledge of normal and abnormal growth.
Screening for faecal contamination in primary schools in Crete, Greece
Authors: Kyriacou A. , Drakopoulou S. , Georgaki I. , Fountoulakis M. , Mitsou E. , Lasaridi K. E. , Manios Y. , Manios T.
Published: November 2008

Background  Hygienic conditions in primary schools are a major concern for both governmental organizations and families. Particularly, the occurrence of faecal indicators on children's hands and various school surfaces has been associated with increased risk of diarrhoeal diseases. The presence of faecal streptococci on environmental surfaces and children's hands and the possible correlation with socio‐economic factors were examined.

Methods  Overall, 1956 samples from hands and 1470 samples from surfaces were collected from 20 primary schools in Heraklion, Crete, Greece.

Results  Faecal streptococci were found at 52.9% of children's hands and at 16.7% of other surfaces. Children, who had parents with the highest education level (>12 years), had the lowest percentage (48.8%) of faecal contamination on their hands. Furthermore, boys exhibited higher levels of hands contamination compared with girls. Among the environmental surfaces examined, the school canteen reception was the most contaminated area.

Conclusion  High faecal contamination was detected in primary schools in the examined region. Children's hands were highly infected (52.9%), while boys exhibited higher levels of contamination. The educational level of parents correlated well with the contamination of children's hands.
A comparison of father–infant interaction between primary and non‐primary care giving fathers
Authors: Lewis S. N. , West A. F. , Stein A. , Malmberg L.‐E. , Bethell K. , Barnes J. , Sylva K. , Leach P. ,   The Families, Children and Child Care (FCCC) project team
Published: November 2008

Background  This study examined the socio‐demographic characteristics and attitudes of primary care giving fathers and non‐primary care giving fathers and the quality of their interaction with their infants.

Method  Two groups of fathers of 11.9‐month old infants were compared – 25 primary care giving fathers (20 h per week or more of sole infant care) and 75 non‐primary care giving fathers – with regard to socio‐demographic characteristics, attitudinal differences and father–infant interaction during play and mealtimes. The quality of father–child interaction in relation to the total number of hours of primary care provided by fathers was also examined.

Results  Primary care giving fathers had lower occupational status and earned a smaller proportion of the family income but did not differ in educational level or attitudes compared with non‐primary care giving fathers. There were no differences between the partners of the two groups of fathers on any variables, and their infants did not differ in temperament. Primary care giving fathers and their infants exhibited more positive emotional tone during play than non‐primary care giving fathers, although fathers did not differ in responsivity. There were no differences between the groups during mealtimes. There was a positive association between total number of child care hours provided by all fathers and infant positive emotional tone.

Conclusions  Primary and non‐primary care giving fathers were similar in many respects, but primary care giving fathers and their infants were happier during play. This suggests a possible link between the involvement of fathers in the care of their children and their children's emotional state. The finding of a trend towards increased paternal happiness with increased hours of child care suggests that there may also be a gain for fathers who are more involved in the care of their infants. Further research is needed to determine whether these differences ultimately have an effect on children's development.
Proinsulin peptide immunotherapy in type 1 diabetes: report of a first-in-man Phase I safety study
Authors: Thrower S L , James L , Hall W , Green K M , Arif S , Allen J S , Van-Krinks C , Lozanoska-Ochser B , Marquesini L , Brown S , Wong F S , Dayan C M , Peakman M
Published: November 2008

Immunotherapeutic strategies under consideration for type 1 diabetes include modification of the autoimmune response through antigen-specific routes. Administration of short peptides representing T cell epitopes targeted by patients with the disease represents one approach. This study evaluated safety and mechanistic outcomes during first-in-man intradermal administration of a human leucocyte antigen-DR4 (HLA-DR4)-restricted peptide epitope of proinsulin (C19-A3). This randomized, open-label study assessed two major theoretical risks of peptide immunotherapy, namely induction of allergic hypersensitivity and exacerbation of the proinflammatory autoimmune response, using clinical assessment and mechanistic assays in vitro. Patients with long-standing type 1 diabetes and HLA-DRB1*0401 genotype received 30 µg (n = 18) or 300 µg (n = 18) of peptide in three equal doses at 0, 1 and 2 months or no intervention (n = 12). Proinsulin peptide immunotherapy in the dosing regimen used is well tolerated and free from risk of systemic hypersensitivity and induction/reactivation of proinsulin-specific, proinflammatory T cells. Peptide-specific T cells secreting the immune suppressive cytokine interleukin (IL)-10 were observed at month 3 in four of 18 patients in the low-dose group (versus one of 12 in the control group; P = not significant). Mean IL-10 response to peptide in the low-dose group increased between 0 and 3 months (P = 0·05 after stimulation with 5 µM peptide in vitro) and then declined to baseline levels between 3 and 6 months (P = 0·01 at 10 µM peptide in vitro). These studies pave the way for future investigations in new-onset patients designed to examine whether proinsulin peptide immunotherapy has beneficial effects on markers of T cell autoimmunity and preservation of β cell mass.
Effects of tropism and virulence ofLeishmaniaparasites on cytokine production by infected human monocytes
Authors: Meddeb-Garnaoui A , Zrelli H , Dellagi K
Published: November 2008

The nature of early interactions between Leishmania and macrophages which determine the outcome of infection can be related directly to parasite biological properties. Here we compared the capacity of L. major (Lm) strains, reported to be high (LmHV) and low virulent and (LmLV) in the mouse model and L. infantum (Li) strains, dermotropic (LiD) and viscerotropic (LiV), to infect and modulate cytokine production in human peripheral blood derived monocytes. Monocytes were infected with metacyclic promastigotes for 24, 48 and 72 h. Parasite burden was significantly higher in Lm- than in Li-infected monocytes. LmHV and LiD induced a significantly higher parasite burden than LmLV and LiV respectively. Cytokine production was evaluated in monocytes infected for 24 h. Contrary to interleukin (IL)-12p70, monocyte chemotactic protein-1 and transforming growth factor-β production was increased significantly in infected monocytes with no differences between strains. Lm isolates induced significantly higher quantities of tumour necrosis factor (TNF)-α than Li isolates. Low levels of IL-10 were induced by all Leishmania strains and, interestingly, co-stimulation with lipopolysaccharide (LPS) was accompanied by a dramatic increase in IL-10 production by infected monocytes. In conclusion, Lm isolates displaying different levels of virulence in mice exhibited significant differences in parasite burden but similar abilities to modulate cytokine production in human monocytes. Li strains showed weaker infectivity and TNF-α inducing-capacity compared with Lm strains. The dramatic increase of IL-10 production in infected monocytes co-stimulated by LPS may play a role in disease progression considering the presence of LPS during bacterial superinfections observed during human leishmaniasis.
Spatiotemporal fire occurrence in Borneo over a period of 10 years
Authors: LANGNER ANDREAS , SIEGERT FLORIAN
Published: November 2008

South‐east Asia's tropical rainforests are experiencing the highest rate of deforestation worldwide and fire is one of the most important drivers of forest loss and subsequent carbon dioxide emissions. In this study, we analyzed all fire events in Borneo recorded by satellites over a period of 10 years. About 16.2 Mha, which corresponds to 21% of the land surface, have been affected by fire at least once and 6% more than one time. During El Niño conditions, which cause prolonged droughts in the region, the fire‐affected area was on average three times larger than during normal weather conditions. Similarly, fires in forests affected 0.3 Mha in normal years and 1 Mha during El Niño years. Carbon rich peat swamp forest ecosystems were most severely affected. There is a pronounced difference in fire occurrence between different countries and provinces in Borneo although ecosystem and land use are very similar across the island. Compared with Sarawak, Sabah (Malaysia) and Brunei the relative annual fire‐affected area in Kalimantan, the Indonesian part of Borneo, was on average five times larger. During El Niño conditions the fire‐affected area increased only in Kalimantan and not in Brunei and the Malaysia. A similar pattern was observed in National Parks. This suggests, that El Niño related droughts are not the only cause of increased fire occurrence and do not necessarily lead to a higher number of fire events. These results improve our understanding of existing fire regimes and drivers of fire in SE Asian tropical ecosystems and may help to better protect the remaining rainforests.
The role of dendritic cells in the mechanism of action of a peptide that ameliorates lupus in murine models
Authors: Sela Uri , Sharabi Amir , Dayan Molly , Hershkoviz Rami , Mozes Edna
Published: November 2008

Systemic lupus erythematosus (SLE) is characterized in its early stages by the expansion of autoreactive T cells that trigger B‐cell activation with subsequent multi‐organ injury. Dendritic cells (DCs) in lupus were found to display an aberrant phenotype with higher expression of the maturation markers major histocompatibility complex (MHC) class II, CD80 and CD86, as well as higher production of proinflammatory cytokines including interleukin‐12 (IL‐12), resulting in an increased ability to activate T cells. A peptide (hCDR1) based on the complementarity determining region‐1 of an anti‐DNA antibody ameliorated SLE in both induced and spontaneous lupus models by downregulating T‐cell functions. Our objectives were to determine whether DCs play a role in promoting the beneficial effects of hCDR1. We showed here that treatment with hCDR1 lowered the expression levels of MHC class II, CD80 and CD86 on DCs. The latter effect was associated with downregulation of messenger RNA expression and secretion of IL‐12, a cytokine that upregulated T‐cell proliferation and interferon‐γ (IFN‐γ) secretion. Moreover, DCs derived from hCDR1‐treated mice downregulated proliferation and IFN‐γ secretion by T cells from untreated mice. Upregulation of transforming growth factor‐β (TGF‐β) secretion by T cells, following treatment with hCDR1, resulted in downregulation of IFN‐γ production and contributed to the phenotypic changes and magnitude of IL‐12 secretion by DCs. The ameliorating effects of hCDR1 are therefore mediated at least partially by the upregulated secretion of TGF‐β by T cells that contribute to the induction of DCs with immature phenotype and suppressed functions. The resulting DCs further downregulate autoreactive T‐cell functions.
Transcriptional and functional defects of dendritic cells derived from the MUTZ‐3 leukaemia line
Authors: Rasaiyaah Jane , Noursadeghi Mahdad , Kellam Paul , Chain Benjamin
Published: November 2008

Dendritic cells (DC) generated from MUTZ‐3, an immortalized acute myeloid leukaemia‐derived cell line, have potential application as a model for the study of human DC, and as a tool with which to stimulate immunotherapeutic responses to cancer. However, the relationship of MUTZ‐3 DC to their non‐transformed counterparts remains incompletely understood. Immunoselected CD14+ MUTZ‐3 cells were used to generate a homogeneous population of DC (M3DC). These cells had a cell surface phentoype and morphology characteristic of conventional monocyte‐derived DC (MDDC). Whole genome transcriptome comparison of M3DC and MDDC however, revealed extensive differences between these two cell types. Functional ontology‐based data analysis revealed three enriched clusters of genes downregulated in M3DC, with functions in pathogen recognition, DC maturation and cytokine/chemokine signalling. Downregulation of protein expression was confirmed for several of these genes. The molecular differences were accompanied by a profoundly impaired phenotypic and functional response of M3DC to microbial stimulation. The immortalized phenotype of MUTZ‐3 therefore reflects not only deregulated proliferative capacity, but substantial perturbation of normal antigen‐presenting cell function. These results have important implications for studies using MUTZ‐3 as a model of MDDC or for cancer immunotherapy.
Human leucocyte antigen (HLA) expression of primary trophoblast cells and placental cell lines, determined using single antigen beads to characterize allotype specificities of anti‐HLA antibodies
Authors: Apps Richard , Murphy Shawn P. , Fernando Raymond , Gardner Lucy , Ahad Tashmeeta , Moffett Ashley
Published: November 2008

Human trophoblast cells express an unusual repertoire of human leucocyte antigen (HLA) molecules which has been difficult to define. Close homology between and extreme polymorphism at the classical HLA class‐I (HLA‐I) loci has made it difficult to generate locus‐specific monoclonal antibodies (mAbs). The problem of defining an antibody’s reactivity against the thousands of existing HLA‐I allotypes has often made it impossible to determine the HLA bound by a mAb in biological samples from a normal outbred population. Here we have used commercially available beads coated with individual HLA‐I to characterize experimentally the reactivity of nine mAb against 96 common HLA‐I allotypes. In conjunction with donor HLA‐I genotyping, we could then define the specific HLA molecules bound by these antibodies in normal individuals. We used this approach to analyse the HLA expression of primary trophoblast cells from normal pregnancies; the choriocarcinoma cells JEG‐3 and JAR; and the placental cell lines HTR‐8/SVneo, Swan‐71 and TEV‐1. We confirm that primary villous trophoblast cells are HLA null whereas extravillous trophoblast cells express HLA‐C, HLA‐G and HLA‐E, but not HLA‐A, HLA‐B or HLA‐DR molecules in normal pregnancy. Tumour‐derived JEG‐3 and JAR cells reflect extravillous and villous trophoblast HLA phenotypes, respectively, but the HLA repertoire of the in vitro derived placental cell lines is not representative of either in vivo trophoblast phenotype. This study raises questions regarding the validity of using the placental cell lines that are currently available as model systems for immunological interactions between fetal trophoblast and maternal leucocytes bearing receptors for HLA molecules.
Elevation of interleukin‐18 in chronic hepatitis C: implications for hepatitis C virus pathogenesis
Authors: Sharma Arpita , Chakraborti Anuradha , Das Ashim , Dhiman Radha Krishan , Chawla Yogesh
Published: November 2008

The outcome of hepatitis C virus (HCV) infection is determined by the interplay between the virus and the host immune response. Interleukin (IL)‐18, an interferon‐γ‐inducing factor, plays a critical role in the T helper type 1 (Th1) response required for host defence against viruses, and antibodies to IL‐18 have been found to prevent liver damage in a murine model. The present study was conducted to investigate the possible role of IL‐18 in the pathogenesis and persistence of HCV. IL‐18 levels were measured in sera of 50 patients at various stages of HCV infection (resolved, chronic and cirrhosis) and compared with those of normal controls. IL‐18 gene expression was studied in peripheral blood mononuclear cells (PBMC) from each group, and in liver biopsy tissue from patients with chronic hepatitis C. The mean levels of IL‐18 in sera were markedly elevated in patients with chronic hepatitis and cirrhosis, and were reduced in patients with resolved HCV infection. The serum IL‐18 concentrations were related to the Child–Pugh severity of liver disease in cirrhotic patients. There also existed a strong positive correlation of IL‐18 levels with histological activity score and necrosis. IL‐18 mRNA expression was significantly up‐regulated in the PBMC of cirrhotic patients when compared with other groups, while in the liver, higher levels of IL‐18 transcripts were expressed in patients with chronic hepatitis C. The results of our study indicate that IL‐18 levels reflect the severity and activity of HCV infection, and may contribute to the pathogenesis and progression of liver disease associated with HCV.
Selected commensal‐related bacteria and Toll‐like receptor 3 agonist combinatorial codes synergistically induce interleukin‐12 production by dendritic cells to trigger a T helper type 1 polarizing programme
Authors: Baba Nobuyasu , Samson Sandrine , Bourdet‐Sicard Raphaëlle , Rubio Manuel , Sarfati Marika
Published: November 2008

Enteric infections remain a major health problem causing millions of deaths in developing countries. The interplay among the host intestinal epithelium, the mucosa‐associated immune system and microbiota performs an essential role in gut homeostasis and protection against infectious diseases. Dendritic cells (DCs) play a key role in orchestrating protective immunity and tolerance in the gut. The mechanisms by which DCs adapt their responses and discriminate between virulent microbes and trillions of innocuous bacteria remain ill‐defined. Here we investigated the effect of cross‐talk between commensal‐related bacteria (CB) and Toll‐like receptor (TLR) agonists on DC activation and the outcome of the in vitro T helper response. Human monocyte‐derived DCs were exposed to eight different Gram‐positive or Gram‐negative CB strains prior to activation with five different TLR agonists. The key polarizing cytokines interleukin (IL)‐12p70, IL‐10, IL‐1β and IL‐6 were quantified and the fate of naïve T‐cell differentiation was evaluated. We identified a unique combination of Lactobacillus casei and TLR3 signals that acted in synergy to selectively increase IL‐12p70 secretion. Exposure to poly(I:C) converted L. casei‐treated DCs into potent promoters of T helper type 1 (Th1) responses. We propose that DCs can integrate harmless and dangerous non‐self signals delivered by viral products, to mount robust Th1 responses. Thus, in vivo DC targeting with selective probiotics may improve strategies for the management of enteric diseases.
Indicators of pain in neonates at risk for neurological impairment
Authors: Stevens Bonnie , McGrath Patrick , Dupuis Annie , Gibbins Sharyn , Beyene Joseph , Breau Lynn , Camfield Carol , Allen Finley Gordon , Franck Linda S. , Howlett Alexandra , Johnston Celeste , McKeever Patricia , O’Brien Karel , Ohlsson Arne , Yamada Janet
Published: November 2008

Title.  Indicators of pain in neonates at risk for neurological impairment.

Aim.  This paper is a report of a study to compare the importance and usefulness ratings of physiological and behavioural indicators of pain in neonates at risk for neurological impairment by nurse clinicians and pain researchers.

Background.  Neonates at risk for neurological impairment have not been systematically included in neonatal pain measure development and how clinicians and researchers view pain indicators in these infants is unknown.

Methods.  Data triangulation was undertaken in three Canadian Neonatal Intensive Care Units using data from: (a) 149 neonates at high, moderate and low risk for neurological impairment, (b) 95 nurse clinicians from the three units where infant data were collected and (c) 14 international pain researchers. Thirteen indicators were assessed following heel lance in neonates and 39 indicators generated from nurse clinicians and pain researchers were assessed for importance and accuracy. Data were collected between 2004 and 2005.

Results.  Across risk groups, indicators with the highest accuracy for discriminating ‘pain’ among neonates were: brow bulge (77–83%), eye squeeze (75–84%), nasolabial furrow (79–81%), and total facial expression (78–83%). Correlations between nurse ratings and neonatal accuracy scores ranged from moderate to none (mild risk r = 0·52, P = 0·07; moderate r = 0·43, P = 0·15; high r = −0·12, P = 0·69). Researchers demonstrated a better understanding of the importance of pain indicators (mild risk, r = 0·91, P < 0·001; moderate 0·85, P < 0·001; 0·0002; high r = 0·64, P = 0·019) than nurse clinicians.

Conclusion/Discussion.  Facial actions were rated as the most important indicators of neonatal pain. However, as neurological impairment risk increased, physiological indicators were rated more important by nurse clinicians and pain researchers, opposite to pain indicators demonstrated by neonates.