bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetics in Primary Care Practice?
Authors: Farndon Peter
Published: September 2008

Many people expect that future advances in genetic science will result in the availability of tests to identify genetic responses to drug metabolism and susceptibility for common disorders. These are predicted to result in interventions—medical or lifestyle—tailored to a person's genetic make-up. Others are more sceptical. Whatever one's view is about the future, however, it is important to ensure that patients and their families can take full advantage of the benefits that genetic information and testing can offer now.
Recognizing the Common Patterns of Inheritance in Families
Authors: Farndon Peter
Published: September 2008

It is important to identify those families with single gene disorders where genetic testing, surveillance and treatment are currently available to ensure that the family can access specialist opinion and advice if appropriate. Single gene disorders have the highest risk of recurrence within a family. This article is therefore primarily intended to highlight the patterns of affected people which would suggest that a single gene or inherited chromosome disorder might be responsible for the condition in the family.
Communicating Genetics within Primary Care Practice
Authors: Cooley Candy
Published: September 2008

GPs have a wealth of experience in communicating with the families attending their practice. However, many GPs still feel that good communication can be the most difficult part of their role especially when dealing with patients who are fearful of the answers, angry at the outcome of discussions or when the GP feels the answer is not clear or distressing.
Integration of the reticuloendotheliosis virus envelope gene into the poultry fowlpox virus genome is not universal
Authors: Davidson Irit , Shkoda Irena , Perk Shimon
Published: September 2008

Fowlpox virus (FWPV) is found worldwide in poultry and wild birds. FWPV is a natural example of recombination between viruses, as reticuloendotheliosis virus (REV) fragments have been found in all poultry FWPVs and these are implicated in virulence alteration. We aimed to determine the commonality of this phenomenon and analysed FWPVs collected from 128 poultry flocks and birds over the last 10 years. Various fragments of both viruses were amplified and sequenced at the FWPV integration site, located between FWPV open reading frames 201 and 203. Seven isolates were found to contain no REV insertions, including fragments of the REV env, gag and 5′ REV-long terminal repeat (LTR). We demonstrate here for the first time, the existence of poultry FWPVs without REV inserts (two from chickens, one from turkey FWPV and four from wild birds). The REV inserts were heterogeneous in size. In addition to poultry and wild bird isolates, three FWPV vaccine virus strains were examined and found to contain only remnant REV-LTR and no REV envelope gene fragments.
Human cytomegalovirus infection interferes with major histocompatibility complex type II maturation and endocytic proteases in dendritic cells at multiple levels
Authors: Kessler Tobias , Reich Michael , Jahn Gerhard , Tolosa Eva , Beck Alexander , Kalbacher Hubert , Overkleeft Herman , Schempp Susanne , Driessen Christoph
Published: September 2008

Human cytomegalovirus (HCMV) infection suppresses cellular immunity and results in viral persistence. Dendritic cells (DCs) are susceptible to HCMV, and the development and immune function of HCMV-infected DCs are impaired in vitro. HCMV-derived proteins interfere with different aspects of major histocompatibility complex type II (MHC II) maturation and function in genetically engineered cellular models. This study directly analysed the effect of HCMV on the MHC II-associated antigen processing and presentation machinery in HCMV-infected human DCs in vitro. HCMV-infected DCs failed to mature newly synthesized MHC II to the final stage of SDS-stable MHC II αβ dimer/peptide complexes, in contrast to mock-infected controls. MHC II biosynthesis was delayed and reduced, whilst MHC II stability remained unchanged. MHC II surface expression was decreased in the late phase of HCMV infection. In addition, infected DCs decreased the transcription rate of the MHC II-associated proteases cathepsins S, Z, B, H and L and asparagine-specific endopeptidase (AEP). This translated into reduced protein expression of cathepsins H and S, as well as AEP, and less-efficient proteolytic degradation of a peptide substrate by endocytic proteases from HCMV-infected DCs in vitro. Thus, HCMV infection interferes with MHC II biosynthesis and maturation, as well as with the expression and function of endocytic proteases in infected DCs.
A captured viral interleukin 10 gene with cellular exon structure
Authors: Jayawardane Gamini , Russell George C. , Thomson Jackie , Deane David , Cox Helen , Gatherer Derek , Ackermann Mathias , Haig David M. , Stewart James P.
Published: September 2008

We have characterized a novel, captured and fully functional viral interleukin (IL)-10 homologue (OvHVIL-10) from the gammaherpesvirus ovine herpesvirus 2. Unlike IL-10 homologues from other gammaherpesviruses, the OvHVIL-10 peptide sequence was highly divergent from that of the host species. The OvHVIL-10 gene is unique amongst virus captured genes in that it has precisely retained the original cellular exon structure, having five exons of similar sizes to the cellular counterparts. However, the sizes of the introns are dramatically reduced. The OvHVIL-10 protein was shown to be a non-glycosylated, secreted protein of M
r 21 000 with a signal peptidase cleavage site between amino acids 26 and 27 of the nascent peptide. Functional assays showed that OvHVIL-10, in a similar way to ovine IL-10, stimulated mast cell proliferation and inhibited macrophage inflammatory chemokine production. This is the first example of a captured herpesvirus gene retaining the full cellular gene structure.
Trypsin cleavage of the baculovirus occlusion-derived virus attachment protein P74 is prerequisite in per os infection
Authors: Slack Jeffrey M. , Lawrence Susan D. , Krell Peter J. , Arif Basil M.
Published: September 2008

Baculovirus occlusion-derived virions (ODVs) contain a number of infectivity factors essential for the initiation of infection in larval midgut cells. Deletion of any of these factors neutralizes infectivity by the per os route. We have observed that P74 of the group I alphabaculovirus Autographa californica multiple nucleopolyhedrovirus (AcMNPV) is N-terminally cleaved when a soluble form of the protein was incubated with insect midgut tissues under alkaline conditions and that cleavage was prevented by soybean trypsin inhibitor (SBTI). Presently, biological assays were carried out that suggest SBTI inhibits and trypsin enhances baculovirus per os infectivity. We developed a method to rescue per os infectivity of a P74 null virus involving co-transfection of viral DNA with a plasmid that transiently expresses p74. We used this plasmid rescue method to functionally characterize P74. A series of site-directed mutants were generated at the N terminus to evaluate if trypsin cleavage sites were necessary for function. Mutagenesis of R195, R196 and R199 compromised per os infectivity and rendered P74 resistant to midgut trypsin.
Dendritic cells mediate herpes simplex virus infection and transmission through the C-type lectin DC-SIGN
Authors: de Jong Marein A. W. P. , de Witte Lot , Bolmstedt Anders , van Kooyk Yvette , Geijtenbeek Teunis B. H.
Published: September 2008

Dendritic cells (DCs) are essential for the induction of specific immune responses against invading pathogens. Herpes simplex virus (HSV) is a common human pathogen that causes painful but mild infections of the skin and mucosa, and which results in latency and recurrent infections. Of the two HSV subtypes described, HSV-1 causes mainly oral–facial lesions, whilst HSV-2 is associated with genital herpes. DCs are involved in HSV-induced immune suppression, but little is known about the molecular interactions between DCs and HSV. This study demonstrated that HSV-1 and -2 both interact with the DC-specific C-type lectin DC-SIGN. Further analyses demonstrated that DC-SIGN interacts with the HSV glycoproteins gB and gC. Binding of HSV-1 to immature DCs depended on both DC-SIGN and heparan sulfate proteoglycans. Strikingly, HSV-1 infection of DCs was almost completely inhibited by blocking antibodies against DC-SIGN. Thus, DC-SIGN is an important attachment receptor for HSV-1 on immature DCs and enhances infection of DCsin cis. In addition, DC-SIGN captures HSV-1 for transmission to permissive target cells. These data strongly suggest that DC-SIGN is a potential target to prevent HSV infection and virus dissemination. Further studies will show whether these interactions are involved in HSV-induced immune suppression.
RNase-dependent inhibition of extracellular, but not intracellular, dsRNA-induced interferon synthesis by Erns of pestiviruses
Authors: Magkouras Ioannis , Mätzener Philippe , Rümenapf Till , Peterhans Ernst , Schweizer Matthias
Published: September 2008

Recombinant pestivirus envelope glycoprotein Ernshas been shown to interfere with dsRNA-induced interferon (IFN-α/β) synthesis. This study demonstrated that authentic, enzymically active Ernsproduced in mammalian cells prevented a dsRNA-induced IFN response when present in the supernatant of bovine cells. Strikingly, IFN synthesis of cells expressing Ernswas eliminated after extracellular addition, but not transfection, of dsRNA. Importantly, the same applied to cells infected with bovine viral diarrhea virus (BVDV) expressing Ernsbut lacking the N-terminal protease Npro. Free Ernsconcentrations circulating in the blood of animals persistently infected with BVDV were determined to be approximately 50 ng ml−1, i.e. at a similar order of magnitude as that displaying an effect on dsRNA-induced IFN expressionin vitro. Whilst Nproblocks interferon regulatory factor-3-dependent IFN induction in infected cells, Ernsmay prevent constant IFN induction in uninfected cells by dsRNA that could originate from pestivirus-infected cells. This probably contributes to the survival of persistently BVDV-infected animals and maintains viral persistence in the host population.
Altered expression of UVB-induced cytokines in human papillomavirus-immortalized epithelial cells
Authors: Dell'Oste Valentina , Azzimonti Barbara , Mondini Michele , De Andrea Marco , Borgogna Cinzia , Mesturini Riccardo , Accardi Rosita , Tommasino Massimo , Landolfo Santo , Dianzani Umberto , Gariglio Marisa
Published: September 2008

Keratinocytes can be induced to produce cytokines by exogenous stimuli, such as UVB, and dysregulation of this production has been described in various skin diseases, including cancer. In this study, we compared the effect of UVB on the secretion of several cytokines involved in inflammation by human keratinocytes immortalized or not with human papillomavirus (HPV)16 or HPV38 at the mRNA and protein levels. We show that expression of the HPV E6/E7 oncoproteins influences not only the basal cytokine secretion profile of keratinocytes, but also its modulation upon UVB irradiation. In particular, UVB upregulates interleukin (IL)-6, IL-8 and transforming growth factor (TGF)-β in HPV-immortalized cells to a higher extent than in control keratinocytes. Moreover, expression of other pro-inflammatory molecules such as S100A8/9 and interferon (IFN)-κ was downregulated in HPV-immortalized cells. These data support the functional similarity between HPV16 and 38, and suggest an active role of these viruses in modulation of the inflammatory process.
5d and 4f electron configuration of CeB6 at 340 and 535 K
Authors: Makita Ryoko , Tanaka Kiyoaki , Ōnuki Yoshichika
Published: September 2008

X-ray atomic orbital (XAO) analysis revealed that at both temperatures the electrons are transferred from B 2px
(= py
) to Ce 5d and 4f orbitals. At 340 K 5d(j = 5/2)Γ8 orbitals are occupied partially, but 4f(j = 5/2)Γ8 orbitals are more populated than 4f(j = 5/2)Γ7 orbitals, in contrast to our observation at 430 K [Makita et al. (2007). Acta Cryst. B63, 683–692]. At 535 K the XAO analysis revealed clearly that the order of the energy levels of 4f(j = 5/2)Γ8 and Γ7 states reversed again and is the same as that at room temperature. It also limited the possible 5d configurations to three models among the nine possible ones. However, the XAO analysis could not decide which of the three models was the best with the present accuracy of the measurement. Two of them have partially and fully occupied 5d(j = 5/2)Γ7 orbitals and the remaining one has a fully occupied 5d(j = 3/2)Γ8 orbital. Since the lobes of 5d(j = 3/2)Γ8 or 5d(j = 5/2)Γ7 orbitals do not overlap with the 4f(j = 5/2)Γ8 orbitals as well as the 5d(j = 5/2)Γ8 orbitals, the order of the energy levels of the 4f(j = 5/2) orbitals became the same as that at room temperature. These results indicate that the crystal field varies with temperature due to the electron transfer from B 2p to Ce 5d orbitals. The difference densities after the spherical-atom refinement at the three temperatures clearly revealed the different combinations of 4f and 5d orbitals which are occupied. In the present study positive peaks due to the 4f electrons appear near the Ce nucleus and those due to 5d orbitals are found in the area outside the 4f peaks. Between the two areas there is a negative area distributed spherically at 340 K. The negative area produced by the contraction of 4f(j = 5/2)Γ8 orbitals seems to reduce the electron repulsion of the 5d(j = 5/2)Γ8 orbitals and helps the 4f(j = 5/2)Γ8 orbitals to remain as the ground state.
Rapid cold hardening elicits changes in brain protein profiles of the flesh fly, Sarcophaga crassipalpis
Authors: Li A. , Denlinger D. L.
Published: September 2008

Rapid cold hardening (RCH) refers to the enhanced cold tolerance acquired by a brief exposure to a moderately low temperature. Although ecological aspects of this response have been well documented in insects, less is known about the physiological and biochemical mechanisms elicited by RCH. In this study we used two‐dimensional electrophoresis to detect differences in brain protein abundance in pharate adults of the flesh fly Sarcophaga crassipalpis, in response to a 2 h RCH exposure at 0 °C. Fourteen high abundance proteins that responded to RCH were selected for mass spectrometric identification. Three proteins that increased in abundance during RCH included ATP synthase subunit alpha, a small heat shock protein (smHsp), and tropomyosin‐1 isoforms 33/34. Eleven proteins that decreased in abundance or were missing following RCH included several proteins involved in energy metabolism, protein degradation, transcription, actin binding, and cytoskeleton organization. That several proteins increased in abundance during RCH underscores the dynamics of the RCH mechanism and suggests that more than one physiological response likely contribute to RCH. The increase in ATP synthase suggests an elevation of ATP during RCH, and the smHsp increase suggests that at least one of the Hsps is actually mobilized during RCH, rather than after RCH as previously assumed.
Molecular identification and characterization of two new Lepidoptera chemoreceptors belonging to the Drosophila melanogaster OR83b family
Authors: Malpel S. , Merlin C. , François M.‐C. , Jacquin‐Joly E.
Published: September 2008

In insect antennae, olfaction depends on olfactory receptors (ORs) that function through heterodimerization with an unusually highly conserved partner orthologue to the Drosophila melanogaster DOR83b. Here, we report the identification of two cDNAs encoding new DOR83b orthologues that represent the first members, although nonconventional, of the OR families of two noctuid crop pests, the cotton leafworm Spodoptera littoralis and the cabbage armyworm Mamestra brassicae. They both displayed high protein sequence conservation with previously identified DOR83b orthologues. Transcripts were abundantly detected in adult chemosensory organs as well as in fifth instar larvae heads. In adult antennae, the expression patterns of both genes revealed common features with other members of the OR83b subfamily: they appeared to be expressed at the bases of numerous olfactory sensilla belonging to different functional categories, suggesting that both receptors may be co‐expressed with yet unidentified conventional ORs. Bioinformatic analyses predicted the occurrence of seven transmembrane domains and an unusual topology with intracellular N‐termini and extracellular C‐termini, extending to Lepidoptera the hypothesis of an inverted topology for DOR83b orthologues, demonstrated to date only in D. melanogaster.
Comparative analysis of circadian clock genes in insects
Authors: Sandrelli F. , Costa R. , Kyriacou C. P. , Rosato E.
Published: September 2008

After a slow start, the comparative analysis of clock genes in insects has developed into a mature area of study in recent years. Brain transplant or surgical interventions in larger insects defined much of the early work in this area, before the cloning of clock genes became possible. We discuss the evolution of clock genes, their key sequence differences, and their likely modes of regulation in several different insect orders. We also present their expression patterns in the brain, focusing particularly on Diptera, Lepidoptera, and Orthoptera, the most common non‐genetic model insects studied. We also highlight the adaptive involvement of clock molecules in other complex phenotypes which require biological timing, such as social behaviour, diapause and migration.
CAG repeat variation in the mtDNA polymerase γ is not associated with oligoasthenozoospermia
Authors: Rani Deepa Selvi , Carlus S. Justin , Poongothai J. , Jyothi Amara , Pavani Kadupa , Gupta Nalini J. , Reddy Alla G. , Rajan M. Mamtha , Rao Kamini , Chakravarty Baidyanath , Singh Lalji , Thangaraj Kumarasamy
Published: September 2008

Variations in the trinucleotide‐CAG repeat number of the catalytic subunit of the mitochondrial DNA polymerase gamma(POLG)have been speculated to be associated with male infertility. The ten CAG repeats (10/10) were found to be the most common allele (88%), absence of which was found to be associated with male infertility. As no study on Indian population was conducted so far to support this view, we investigated the distribution of thePOLG‐CAG repeats in 509 oligoasthenozoospermic and 241 normozoospermic control Indian men from the same ethnic background. Our study suggested that the distribution of common allele (10/10) was almost similar in both infertile (75%) and normozoospermic (75.5%) men. Further, we had analysed the CAG repeat number in as many as 1306 Indian men belonging to different ethnic, geographical and linguistic backgrounds and found the common allele 10/10 at a frequency of 78.4%. Our study, therefore, suggests that the 10‐CAG repeat is the most common allele present in Indian populations, but its absence and the occurrence of the other mutant homozygous (non 10/non 10) genotype should not be understood as being specific to infertility. It, thus, suggests that thePOLG‐CAG repeat variation is not associated with male infertility in Indian populations, and hence is not a useful marker for screening infertile men.
Evaluation of testicular biopsies for carcinoma in situ: immunohistochemistry is mandatory
Authors: Van Casteren N. J. , De Jong J. , Stoop H. , Steyerberg E. W. , De Bekker‐Grob E. W. , Dohle G. R. , Oosterhuis J. W. , Looijenga L. H. J.
Published: September 2008

Carcinoma in situ (CIS) is the common precursor of all type II testicular germ cell tumors (TGCTs), i.e. seminomas and non‐seminomas, which can be diagnosed using a surgical biopsy. The objective of this study was to investigate the additional value of immunohistochemistry for the diagnosis of CIS in assessing testicular biopsies taken in the context of infertility. A series of 21 infertile patients were retrieved from the Dutch pathological database (PALGA), being diagnosed with an invasive TGCT, while a matched previously obtained testicular biopsy was diagnosed as non‐malignant. From 20 patients, both the invasive tumors as well as the biopsies were revised using morphology and immunohistochemistry for OCT3/4, placental‐like alkaline phosphatase and c‐KIT, all known established markers for CIS. The presence of CIS or invasive malignancies was scored. There are no interventions. Morphological criteria alone allowed an experienced pathologist in TGCTs to diagnose CIS in five and an invasive tumor in two cases (total n = 7, 35%). Application of immunohistochemistry resulted in the identification of an additional four cases of CIS (total n = 11, 55%, additional value of 20%). The initial correct diagnosis of CIS could have prevented a second gonadectomy in four patients (20%). This study, for the first time, really shows that time of progression from CIS to seminoma is longer than to non‐seminoma. Our study demonstrates that immunohistochemistry should be performed for the diagnosis of CIS of the testis on single biopsies obtained because of infertility, resulting in an extra diagnostic yield of at least 20%. Application of this protocol will allow early diagnosis, and therefore prevent any adverse anti‐cancer treatment sequelae including gonadectomy, and requiring life long androgen supplementation in some patients.
AtCIPK8, a CBL‐interacting protein kinase, regulates the low‐affinity phase of the primary nitrate response
Authors: Hu Heng‐Cheng , Wang Ya‐Yun , Tsay Yi‐Fang
Published: September 2008

Nitrate, the major nitrogen source for most plants, is not only a nutrient but also a signaling molecule. For almost two decades, it has been known that nitrate can rapidly induce transcriptional expression of several nitrate‐related genes, a process that is referred to as the primary nitrate response. However, little is known about how plants actually sense nitrate and how the signal is transmitted in this pathway. In this study, a calcineurin B‐like (CBL) ‐interacting protein kinase (CIPK) gene, CIPK8, was found to be involved in early nitrate signaling. CIPK8 expression was rapidly induced by nitrate. Analysis of two independent knockout mutants and a complemented line showed that CIPK8 positively regulates the nitrate‐induced expression of primary nitrate response genes, including nitrate transporter genes and genes required for assimilation. Kinetic analysis of nitrate induction levels of these genes in wild‐type plants indicated that there are two response phases: a high‐affinity phase with a Km of approximately 30 μm and a low‐affinity phase with a Km of approximately 0.9 mm. As cipk8 mutants were defective mainly in the low‐affinity response, the high‐affinity and low‐affinity nitrate signaling systems are proposed to be genetically distinct, with CIPK8 involved in the low‐affinity system. In addition, CIPK8 was found to be involved in long‐term nitrate‐modulated primary root growth and nitrate‐modulated expression of a vacuolar malate transporter. Taken together, our results indicate that CBL–CIPK networks are responsible not only for stress responses and potassium shortage, but also for nitrate sensing.
Do different stakeholder groups share mental health research priorities? A four‐arm Delphi study
Authors: Owens Christabel , Ley Ann , Aitken Peter
Published: September 2008

Background  Despite considerable investment in research priority setting within diverse fields of healthcare, little is known about the extent to which different stakeholder groups share research priorities. Conflicting priorities may jeopardize stakeholder engagement in research.

Objective  To identify the research priorities of different stakeholder groups within mental health care and examine the extent and nature of agreement between them.

Design  Using a Delphi technique, we conducted parallel consultation processes within four different stakeholder groups. Each group process consisted of three rounds.

Setting and participants  The study was carried out within a mental health and learning disabilities trust in southern England. Participants were recruited from the following groups: mental health service users (34), informal carers (26), mental health practitioners (35) and service managers (23).

Findings  There were striking differences between the four groups in respect of their ability and willingness to make priority decisions. These differences notwithstanding, there was considerable overlap in respect of their research interests. All groups identified and attached high importance to issues relating to the promotion of independence, self‐esteem and recovery. The quality of in‐patient care, the place of psychological therapies and the relationship between physical and mental health also emerged across the board.

Conclusions  The confluence of four different stakeholder groups around a number of clear themes is highly encouraging, providing a framework within which to construct a research agenda and suggesting that mental health research can be built on solid partnerships.
Body mass index in Belgian schoolchildren and its relationship with sensitization and allergic symptoms
Authors: Van Gysel D. , Govaere E. , Verhamme K. , Doli E. , De Baets F.
Published: September 2008

Results of studies of the influence of body mass index (BMI) on the allergic status are controversial. As a part of the Aalst Allergy Study, we assessed the prevalence of the different BMI categories (underweight, normal weight, overweight, and obesity) and a possible association between BMI and atopy in 1576 unselected Belgian schoolchildren, aged from 3.4 to 14.8 yr. BMI was used to determine weight status. Skin prick testing with the most common aeroallergens was performed. A parental questionnaire documented data on respiratory and allergic disorders, demographic characteristics and other potential risk factors for sensitization. Among the total children, 4.1% of the children were underweight, 14.5% were overweight, and 7.4% were obese. More girls than boys were overweight (p = 0.015). In the group of children older than 12 yr, we found more overweight (p = 0.03) and obese (p = 0.004) girls, and more obese boys (p = 0.004) than in the younger age groups. In contrast with reports in the literature, an increased prevalence of allergic sensitization in underweight girls only [adjusted odd ratio (ORadj) = 2.9, 95% confidence interval (CI): 1.3–6.4] was documented. A strong association between obesity and exercise‐induced respiratory symptoms was found in both boys (ORadj = 14.5, 95% CI: 2.9–73.3) and girls (ORadj = 4.9, 95% CI: 1.3–17.4). No correlations with allergic respiratory symptoms, eczema, or rhinoconjunctivitis could be documented.
Signaling pathways activated by epidermal growth factor receptor or fibroblast growth factor receptor differentially regulate branching morphogenesis in fetal mouse submandibular glands
Authors: Koyama Noriko , Hayashi Toru , Ohno Kenji , Siu Larry , Gresik Edward W. , Kashimata Masanori
Published: September 2008

Although growth factor signaling is required for embryonic development of organs, individual signaling mechanisms regulating these organotypic processes are just beginning to be defined. We compared signaling activated in fetal mouse submandibular glands (SMGs) by three growth factors, epidermal growth factor (EGF), fibroblast growth factor (FGF) 7, or FGF10, and correlated it with specific events of branching morphogenesis. Immunoblotting showed that EGF strongly stimulated phosphorylation of extracellular signal‐regulated kinase‐1/2 (ERK‐1/2) and weakly stimulated phosphorylation of phospholipase Cγ1 (PLCγ1) and phosphatidylinositol‐3 kinase (PI3K) in cultured E14 SMG. However, FGF7 and FGF10 stimulated phosphorylation of both PLCγ1 and PI3K, but elicited only minimal phosphorylation of ERK‐1/2. Morphological study of mesenchyme‐free SMG epithelium cultured in Matrigel revealed that EGF induced cleft formation of endpieces, that FGF7 stimulated both cleft formation and stalk elongation, but that FGF10 induced only stalk elongation. In mesenchyme‐free SMG epithelium cultured with EGF, FGF7 and FGF10, U0126 (MEK inhibitor) completely blocked cleft formation, whereas U73122 (PLCγ1 inhibitor) suppressed stalk elongation. These finding suggest that EGF stimulates cleft formation and drives branch formation via ERK‐1/2, and that FGF7 stimulates both cleft formation and stalk elongation via PLCγ1 and partly via ERK‐1/2, but that FGF10 stimulates stalk elongation mainly via PLCγ1.
Non-Parametric Heteroscedastic Transformation Regression Models for Skewed Data With an Application to Health Care Costs
Authors: Zhou Xiao-Hua , Lin Huazhen , Johnson Eric
Published: September 2008

We develop a new non-parametric heteroscedastic transformation regression model for predicting the expected value of the outcome of a patient with given patient's covariates when the distribution of the outcome is highly skewed with a heteroscedastic variance. In our model, we allow both the transformation function and the error distribution function to be unknown. We show that under some regularity conditions the estimators for regression parameters, the expected value of the original outcome and the transformation function converge to their true values at the rate n−1/2. In our simulation studies, we demonstrate that our proposed non-parametric method is robust with little loss of efficiency. Finally, we apply our model to a study on health care costs.
Estimation of Controlled Direct Effects
Authors: Goetgeluk Sylvie , Vansteelandt Stijn , Goetghebeur Els
Published: September 2008

When regression models adjust for mediators on the causal path from exposure to outcome, the regression coefficient of exposure is commonly viewed as a measure of the direct exposure effect. This interpretation can be misleading, even with a randomly assigned exposure. This is because adjustment for post-exposure measurements introduces bias whenever their association with the outcome is confounded by more than just the exposure. By the same token, adjustment for such confounders stays problematic when these are themselves affected by the exposure. Robins accommodated this by introducing linear structural nested direct effect models with direct effect parameters that can be estimated by using inverse probability weighting by a conditional distribution of the mediator. The resulting estimators are consistent, but inefficient, and can be extremely unstable when the mediator is absolutely continuous. We develop direct effect estimators which are not only more efficient but also consistent under a less demanding model for a conditional expectation of the outcome. We find that the one estimator which avoids inverse probability weighting altogether performs best. This estimator is intuitive, computationally straightforward and, as demonstrated by simulation, competes extremely well with ordinary least squares estimators in settings where standard regression is valid.
CAPITAL INFLOW UNDER VOLUNTARY EXPORT RESTRAINT
Authors: Chakraborty Brati Sankar
Published: September 2008

This paper investigates the welfare consequence of exogenous capital inflow for the host country when the source country implements ‘voluntary export restraint’. In an imperfectly competitive market with an increasing returns to scale (IRS) sector, we show the possibility of welfare immiserization. Two channels are identified leading to immiserization. First, and this is direct, resource reallocation following capital inflow can squeeze the underproduced sector and reduce welfare. Second, contraction of the IRS sector can raise the return to capital, even when the price of the capital‐intensive importable falls unambiguously. Thus, even with an improvement in commodity terms of trade, the factor terms of trade can worsen and reduce welfare.
Fallen or Unfallen? Christ's Human Nature and the Ontology of Human Sinfulness
Authors: McFARLAND IAN A.
Published: September 2008

Abstract:  Because Christ's sinlessness is a matter of virtual consensus among Christians, debates over whether the human nature he assumed was fallen or unfallen turn on the ontological conditions of his being ‘without sin’ (Heb. 4:15). The claim that Christ assumed a fallen nature can be defended by distinguishing between fallenness and sinfulness as properties of nature and hypostasis, respectively. Moreover, by highlighting the peculiar place of the will in human nature, this christological analysis helps counter the charge that an Augustinian understanding of original sin entails a dualism inconsistent with belief in the goodness of creation and human moral accountability.
Binocular Rivalry in Migraine
Authors: Wilkinson F , Karanovic O , Wilson HR
Published: September 2008

Cortical hyperexcitability in migraine could arise from abnormally weak inhibition or from strengthened intracortical excitatory mechanisms. The present study employed binocular rivalry to differentiate between these possibilities. Rivalry between static oriented grating patterns was examined in migraine with aura (MA), migraine without aura (MoA) and headache-free control participants. A non-significant trend toward elevated mean dominance intervals (monocular percepts, in seconds) was seen in both migraine groups at all contrasts. Second, significant interocular differences in rivalry dominance durations were seen in the MoA group compared with controls; this difference also approached significance in the MA group. Finally, both MA and MoA exhibited significantly greater visual discomfort than the control group in the presence of both static stripes and flickering visual stimuli. The rivalry results provide no support for weakened intracortical inhibition in migraine. Optical or neural precortical differences in the eyes' input strengths paired with enhanced recurrent cortical excitation can explain these findings.
New Powerful Approaches for Family‐based Association Tests with Longitudinal Measurements
Authors: Ding Xiao , Lange Christoph , Xu Xin , Laird Nan
Published: September 2008

We discuss several new powerful family‐based approaches for testing genetic association when the traits are obtained from longitudinal or repeated measurement studies. The popular approach FBAT‐PC is based on a linear combination of the individual traits. We propose a one‐sided modification, FBAT‐PCM, which has a closed‐form expression and is always more powerful. We also present two approaches FBAT‐LC and FBAT‐LCC based on linear combination of the univariate test statistics. Furthermore, all three approaches are shown to be unified to a general form. Through simulation studies, we compare the power of these tests under different models of genetic effect sizes. Compared to original FBAT‐PC, our modification achieves a power gain of up to 50%. In addition, all three new approaches gain substantial power compared to the ordinary approach of Bonferroni correction, with the relative performance depending upon the underlying model. Application of these approaches for testing an association between Body Mass Index and a previously reported candidate SNP confirms our results.
Relationship of asymmetric dimethylarginine with flow‐mediated dilatation in subjects with newly detected severe hypercholesterolemia
Authors: Vladimirova‐Kitova L. , Deneva T. , Angelova E. , Nikolov F. , Marinov B. , Mateva N.
Published: September 2008

Background:  Little is know about the relationship between asymmetric dimethylarginine (ADMA) and percent flow‐mediated dilatation (%FMD) in subjects with severe hypercholesterolemia (HH).

Aim:  The aim the present study was the evaluation of the relationship of ADMA to %FMD, as well as to lipid parameters and other markers of endothelial dysfunction in newly detected subjects with severe HH.

Methods:  One hundred and twenty asymptomatic patients with severe, newly detected HH and 100 controls were evaluated. The plasma level of ADMA was tested by ELISA and total homocysteine (tHcy) – through fluid chromatographic analysis. The %FMD was evaluated by the diameter of brachial artery with 7·5 MHz transducer of HP SONOS 5500.

Results:  Significant difference was found between patients and controls, (P<0·05) regarding lipid total cholesterol, triglycerides, high‐density lipoprotein, low‐dencity lipoprotein, atherogenic indices) and non‐lipid markers (ADMA, sICAM‐1, sVCAM‐1), as well as the endothelium dependent %FMD in contrast to flow independent vasodilation. (P>0·05) No significant difference was found between the groups with respect to tHcy, P‐selectine and E‐selectine. (P>0·05) A strong negative correlation was found between %FMD and ADMA. (rxy = −0·895; P<0·001), Apolipoprotein‐B (rxy = −0·687; P<0·0001, tHcy (rxy = −0·560; P<0·001) and Apolipoprotein index –B/A1 (rxy = −0·518; P<0·001). The subsequent linear and multiple regression analysis selected ADMA as the most significant factor in relation to %FMD.

Conclusion:  It is concluded that ADMA is the basic modulator of %FMD among all tested atherogenic risk biomarkers in in newly detected subjects with severe HH.
Association of findings in flow‐volume spirometry with high‐resolution computed tomography signs in asbestos‐exposed male workers
Authors: Piirilä Päivi , Kivisaari Leena , Huuskonen Olli , Kaleva Simo , Sovijärvi Anssi , Vehmas Tapio
Published: September 2008

Introduction:  Disorders of pulmonary tissue and pleura are visualized by findings in high‐resolution computed tomography (HRCT), and the impairment caused by these findings is assessed by pulmonary function tests. Our aim was to determine how some commonly used spirometric variables are related to certain HRCT signs, in order to find out which HRCT signs are associated with restrictive and which with obstructive ventilatory impairment.

Methods:  Altogether 590 asbestos‐exposed workers, 95% of whom were smokers or ex‐smokers, were studied with HRCT; 19 pathological signs were scored. Forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), FEV1/FVC ratio, forced expiratory flow at 50% of FVC (MEF50) and total lung capacity (TLC) were measured, and their relationship with HRCT signs was examined with bivariate correlations and multiple regression analysis.

Results:  FVC and TLC were negatively correlated with fibrosis score, parenchymal bands, extent of pleural thickenings and positively with widened retrosternal space. FEV1/FVC ratio was negatively correlated with emphysema types and widened retrosternal space and positively with parenchymal bands and subpleural nodules. Thickened bronchial walls did not separate between restrictive and obstructive ventilatory function.

Conclusions:  HRCT signs showed distinctive patterns in restrictive and obstructive ventilatory impairment. These results can be used to help to analyse the lung function of patients simultaneously exposed to asbestos and smoking, when this relationship requires elucidation. In addition, the results may be helpful in explaining some radiological findings.
Nest‐Site Selection in Individual Loggerhead Turtles and Consequences for Doomed‐Egg Relocation
Authors: PFALLER JOSEPH B. , LIMPUS COLIN J. , BJORNDAL KAREN A.
Published: September 2008

Abstract:  Relocation of eggs is a common strategy for conservation of declining reptilian populations around the world. If individuals exhibit consistency in their nest‐site selection and if nest‐site selection is a heritable trait, relocating eggs deposited in vulnerable locations may impose artificial selection that would maintain traits favoring unsuccessful nest‐site selection. Conversely, if most individuals scatter their nesting effort and individuals that consistently select unsuccessful nest sites are uncommon, then artificial selection would be less of a concern. During the 2005 nesting season of loggerhead turtles (Caretta caretta) at Mon Repos beach, Queensland, Australia, we measured the perpendicular distance from the original nest site to a stationary dune baseline for in situ (unrelocated) and relocated clutches of eggs. We observed the fate of in situ clutches and predicted what would have been the fate of relocated clutches if they had not been moved by mapping tidal inundation and storm erosion lines. In 2005 turtles deposited an average of 3.84 nests and did not consistently select nest sites at particular distances from the stationary dune baseline. Selection of unsuccessful nest sites was distributed across the nesting population; 80.3% of the turtles selected at least one unsuccessful nest site and when previous breeding seasons were included, 97% selected at least one unsuccessful nest site. Females with nesting experience selected more successful nest sites than females with little or no experience. Relocating eggs vulnerable to tidal inundation and erosion saves the progeny from a large percentage of the population and the progeny from individuals who may in subsequent years nest successfully. Our results suggest that doomed‐egg relocation does not substantially distort the gene pool in the eastern Australian loggerhead stock and should not be abandoned as a strategy for the conservation of marine turtle populations.
Inferring National and Regional Declines of Rare Orchid Species with Probabilistic Models
Authors: DUFFY KARL J. , KINGSTON NAOMI E. , SAYERS BRENDAN A. , ROBERTS DAVID L. , STOUT JANE C.
Published: September 2008

Abstract:  Fragmentation of natural habitats can increase numbers of rare species. Conservation of rare species requires experts and resources, which may be lacking for many species. In the absence of regular surveys and expert knowledge, historical sighting records can provide data on the distribution of a species. Numerous models have been developed recently to make inferences regarding the threat status of a taxon on the basis of variation in trends of sightings over time. We applied 5 such models to national and regional (county) data on 3 red‐listed orchid species (Cephalanthera longifolia, Hammarbya paludosa, and Pseudorchis albida) and 1 species that has recently come to the attention of conservation authorities (Neotinea maculata) in the Republic of Ireland. In addition, we used an optimal linear estimate to calculate the time of extinction for each species overall and within each county. To account for bias in recording effort over time, we used rarefaction analysis. On the basis of sighting records, we inferred that these species are not threatened with extinction and, although there have been declines, there is no clear geographical pattern of decline in any species. Most counties where these orchid species occurred had a low number of sightings; hence, we were cautious in our interpretation of output from statistical models. We suggest the main drivers of decline in these species in Ireland are modification of habitats for increased agricultural production and lack of appropriate management. Our results show that the application of probabilistic models can be used even when sighting data are scarce, provided multiple models are used simultaneously and rarefaction is used to account for bias in recording effort among species over time. These models could be used frequently when making an initial conservation assessment of species in a region, particularly if there is a relatively constant recording rate and some knowledge of the underlying recording process. Regional‐scale analyses, such as ours, complement World Conservation Union criteria for assessment of the extinct category and are useful for highlighting areas of under recording and focusing conservation efforts of rare and endangered species.
Sensitivity Analyses of Spatial Population Viability Analysis Models for Species at Risk and Habitat Conservation Planning
Authors: NAUJOKAITIS‐LEWIS ILONA R. , CURTIS JANELLE M. R. , ARCESE PETER , ROSENFELD JORDAN
Published: September 2008

Abstract: Population viability analysis (PVA) is an effective framework for modeling species‐ and habitat‐recovery efforts, but uncertainty in parameter estimates and model structure can lead to unreliable predictions. Integrating complex and often uncertain information into spatial PVA models requires that comprehensive sensitivity analyses be applied to explore the influence of spatial and nonspatial parameters on model predictions. We reviewed 87 analyses of spatial demographic PVA models of plants and animals to identify common approaches to sensitivity analysis in recent publications. In contrast to best practices recommended in the broader modeling community, sensitivity analyses of spatial PVAs were typically ad hoc, inconsistent, and difficult to compare. Most studies applied local approaches to sensitivity analyses, but few varied multiple parameters simultaneously. A lack of standards for sensitivity analysis and reporting in spatial PVAs has the potential to compromise the ability to learn collectively from PVA results, accurately interpret results in cases where model relationships include nonlinearities and interactions, prioritize monitoring and management actions, and ensure conservation‐planning decisions are robust to uncertainties in spatial and nonspatial parameters. Our review underscores the need to develop tools for global sensitivity analysis and apply these to spatial PVA.
Threatened Species and the Potential Loss of Phylogenetic Diversity: Conservation Scenarios Based on Estimated Extinction Probabilities and Phylogenetic Risk Analysis
Authors: FAITH DANIEL P.
Published: September 2008

Abstract:  New species conservation strategies, including the EDGE of Existence (EDGE) program, have expanded threatened species assessments by integrating information about species' phylogenetic distinctiveness. Distinctiveness has been measured through simple scores that assign shared credit among species for evolutionary heritage represented by the deeper phylogenetic branches. A species with a high score combined with a high extinction probability receives high priority for conservation efforts. Simple hypothetical scenarios for phylogenetic trees and extinction probabilities demonstrate how such scoring approaches can provide inefficient priorities for conservation. An existing probabilistic framework derived from the phylogenetic diversity measure (PD) properly captures the idea of shared responsibility for the persistence of evolutionary history. It avoids static scores, takes into account the status of close relatives through their extinction probabilities, and allows for the necessary updating of priorities in light of changes in species threat status. A hypothetical phylogenetic tree illustrates how changes in extinction probabilities of one or more species translate into changes in expected PD. The probabilistic PD framework provided a range of strategies that moved beyond expected PD to better consider worst‐case PD losses. In another example, risk aversion gave higher priority to a conservation program that provided a smaller, but less risky, gain in expected PD. The EDGE program could continue to promote a list of top species conservation priorities through application of probabilistic PD and simple estimates of current extinction probability. The list might be a dynamic one, with all the priority scores updated as extinction probabilities change. Results of recent studies suggest that estimation of extinction probabilities derived from the red list criteria linked to changes in species range sizes may provide estimated probabilities for many different species. Probabilistic PD provides a framework for single‐species assessment that is well‐integrated with a broader measurement of impacts on PD owing to climate change and other factors.