bluuebunny/crossref_metadata_2025 huggingface dataset:
High susceptibility of human c‐Ha‐ras proto‐oncogene transgenic rats to carcinogenesis: A cancer‐prone animal model
Authors: Tsuda Hiroyuki , Fukamachi Katsumi , Ohshima Yutaka , Ueda Shinobu , Matsuoka Yoichiro , Hamaguchi Tetsuya , Ohnishi Takamasa , Takasuka Nobuo , Naito Akihiro
Published: June 2005

Transgenic animals carrying human c‐Ha‐ras proto‐oncogene, v‐Ha‐ras transgenic mice, pim‐1 transgenic mice and several knockout mice deficient of tumor suppressor genes, such as p53, have been shown to exhibit increased carcinogen susceptibility. As a result, studies into practical application and medium‐term screening of environmental carcinogens are under way. Given the advantages of rat models characterized by larger organ size, abundant information regarding preneoplasias and virus‐free constitution, we have concentrated on the generation of transgenic rats bearing copies of the human c‐Ha‐ras proto‐oncogene and shown the Hras128 strain to be extremely sensitive to the induction of mammary carcinomas, and to a lesser extent, lesions in the urinary bladder, esophagus and skin. In most, if not all, the mammary cancers mutations of the transgene but not the endogenous H‐ras gene are present, appearing to occur early in the process of tumorigenesis, which involves proliferation of cells in TEB and intraductal hyperplasia before carcinomas arise. Preliminary findings suggest that this is independent of endogenous ovarian hormones, although inhibited by soy isoflavones and promoted by atrazine and nonylphenols. Although further studies of the mechanisms are clearly necessary, the model appears to have great potential for screening purposes, not only for modifiers active in the breast, but also other organs where tumors characterized by ras gene mutations develop. (Cancer Sci 2005; 96: 309–316)
First cannabis use: does onset shift to younger ages? Findings from 1988 to 2003 from the Dutch National School Survey on Substance Use
Authors: Monshouwer Karin , Smit Filip , De Graaf Ron , Van Os Jim , Vollebergh Wilma
Published: June 2005

Aims  To investigate the hypothesis that changes in cannabis prevalence among Dutch secondary school students (aged 12–17 years) were paralleled by shifts in the age of first cannabis use.

Design and participants  Data were derived from five waves (1988, 1992, 1996, 1999 and 2003) of the Dutch National School Survey on Substance Use, a nationally representative cross‐sectional study, with a total of 32 777 respondents.

Measurements  Written questionnaires on cannabis, tobacco, alcohol, other drug use and socio‐demographic and behavioural variables were administered in classroom settings.

Findings  Survival analysis showed a strong increase in cumulative incidences by age of first cannabis use from 1988 to 1992, a further increase in 1996 and stabilization in 1999, continuing into 2003. From 1992 to 1996, age of onset shifted towards younger ages. Onset peaked at age 15 in 1992 and age 14 in 1996. The proportion of life‐time cannabis users starting at age 13 or younger increased from 26% in 1992 to 41% in 1996. The overall trend was similar for boys and girls.

Conclusions  The study largely confirmed the expectation that the increase in cannabis use from 1988 to 1996 was paralleled by a decrease in the age of first cannabis use. From 1996 to 2003 age of first cannabis use and prevalence stabilized, possibly occasioned by a change in cannabis policy in the mid‐1990s.
Haematopoietic stem cell transplantation in the treatment of severe autoimmune disease: results from phase I/II studies, prospective randomized trials and future directions
Authors: Tyndall A , Saccardi R
Published: June 2005

Around 700 patients have received an autologous haematopoietic stem cell transplant (HSCT) as treatment for a severe autoimmune disease (AD). The majority of these have been within the context of phase I/II clinical trials and following international guidelines proposed 7 years ago. In general, a positive benefit/risk ratio has led to phase III prospective randomized controlled trials in multiple sclerosis (MS), systemic sclerosis (SSc) and rheumatoid arthritis (RA) in Europe. In the US, similar trials are being planned for SSc, MS and systemic lupus erythematosus (SLE). Transplant related mortality (TRM) has fallen in all disease subgroups since the inception due to more appropriate patient selection, and so far a clear advantage of the more intense myeloablative regimens in terms of remission induction and relapse rate has not emerged. Although each AD has a different profile, over a third of patients have sustained a durable remission, often with no further need for immunosuppressive drugs. In those who relapsed, many responded to agents which pre transplant had been ineffective. The study of immune reconstitution and gene expression pre and post HSCT is being undertaken to further understand the mechanism of autoimmunity.
In vivotumouricidal effects of LAD-1 monoclonal antibody on murine RL-male-1 lymphoma mediated by enhanced phagocytosis
Authors: Ito M , Omoto S , Kato Y , Hayashi T , Mori N , Fujii Y R
Published: June 2005

We have reported previously that the LAD-4 monoclonal antibody (mAb) directed against a fibronectin receptor (FNR) on RL-male-1 T lymphoma cells in BALB/c mice partially inhibited their migration to the liver. In the present study, we examined the mechanism by which another anti-FNR mAb, LAD-1, exerts its antitumourigenic effects. Administration of LAD-1 significantly prolonged survival of BALB/c mice challenged previously with RL-male-1 cells. LAD-1 enhanced phagocytosis of RL-male-1 cells by hepatic macrophages and clodronate-mediated macrophage depletion abrogated the antitumour activity of LAD-1. In vitro experiments revealed that a pan-caspase inhibitor, zVAD-fmk, did not affect the ability of LAD-1 to inhibit the proliferation of RL-male-1 cells. These data suggest that the antitumour effects of LAD-1 may be dependent on stimulation of tumour cell phagocytosis and are apoptosis-independent. Thus, LAD-1-induced phagocytosis of lymphoma cells by hepatic macrophages in mice may, at least in part, be responsible for the prolonged survival of the mice.
Enhanced clearance of Candida albicans from the oral cavities of mice following oral administration of Lactobacillus acidophilus
Authors: Elahi S , Pang G , Ashman R , Clancy R
Published: June 2005

Orally administered live Lactobacillus acidophilus was assessed for its capacity to enhance clearance from the oral cavity of DBA/2 mice shown previously to be ‘infection prone’. L. acidophilus fed to DBA/2 mice significantly shortened the duration of colonization of the oral cavity compared to controls. Enhanced clearance of Candida albicans correlated with both early mRNA gene expression for interleukin (IL)-4 and interferon (IFN)-γ and expression of their secreted products in cultures of cervical lymph nodes stimulated with Candida antigen. In addition rapid clearance correlated with higher levels of IFN-γ and nitric oxide in saliva. Delayed clearance, less pronounced levels of the cytokine response, saliva IFN-γ and nitric oxide, and later mRNA expression for IL-4 and IFN-γ relative to feeding with the L. acidophilus isolate were noted in mice fed a different Lactobacillus isolate (L. fermentum). These observations indicate significant variations in individual isolates to activate the common mucosal system.
Increased expression of plasma and cell surface co-stimulatory molecules CTLA-4, CD28 and CD86 in adult patients with allergic asthma
Authors: Wong C K , Lun S W M , Ko F W S , Ip W K , Hui D S C , Lam C W K
Published: June 2005

The co-stimulatory interactions of the B7 family molecules CD80 and CD86 on antigen-presenting cells, together with their T cell counter receptors CD28 and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), modulate T lymphocyte-mediated immune responses in a reciprocal manner. To investigate whether there is altered expression and the clinical significance of soluble co-stimulatory molecules in asthmatic patients, plasma concentrations of sCTLA-4, sCD28, sCD80 and sCD86 in 51 adult allergic asthmatic adults with or without steroid treatment, and 35 sex- and age-matched control subjects were measured by enzyme-linked immunosorbent assay (ELISA). Cell surface expression of CTLA-4 and CD28 on peripheral blood mononuclear cells (PBMC) were analysed by flow cytometry. Results showed that the plasma sCTLA-4 concentration was significantly higher in all asthmatic patients while sCD28 and sCD86 concentrations were significantly higher in steroid and non-steroid treated asthmatic patients, respectively, compared with control subjects (all P < 0·01). Significantly increased cell surface expression of CD28 but not CTLA-4 on PBMC was found in asthmatic patients compared with controls (P < 0·05). The plasma concentration and cell surface expression of CTLA-4 were found to exhibit positive and significant correlations with those of CD28 (both P < 0·05). Serum total IgE concentration correlated positively and significantly with sCTLA-4 and sCD28 concentrations in allergic asthmatic patients (both P < 0·05). The increased expression of these soluble co-stimulatory molecules may reflect the dysregulation of T cell activation, thereby contributing to the immunopathogenesis of allergic asthma.
The distribution of body size in a stream community: one system, many patterns
Authors: STEAD TRACEY K. , SCHMID‐ARAYA JENNY M. , SCHMID PETER E. , HILDREW ALAN G.
Published: June 2005

We investigated abundance–size spectra and body size–density allometry using an exceptionally detailed data set from a stony stream. The body size distribution of the whole metazoan community was expressed in terms of both density and biomass over a 14‐month survey, and the relationships of body size with population density and taxon richness were also evaluated.

The distribution of density among size classes varied considerably between sampling occasions, although that of biomass was rather more consistent. This suggests that the body size distribution is dynamic and does not always fall into any single pattern or category, as has been assumed hitherto.

Analysis of the modes in the density–body size distribution in individual sample‐units revealed small‐scale spatial variation, with little consistency in the number or position of modes in any one month.

This stream community did not conform to the −0·75 (or indeed to any other significant regression) relationship between body size and population density, although such patterns are very sensitive to methodological details.

In data aggregated over the whole study, most metazoan taxa fell into the size range < 10–100 µg. The annual average density– and biomass–body size spectra appeared tri‐ and bimodal, respectively (on log–log scales), with minor troughs in the density spectrum at about 100 and 0·1 µg body mass. This could indicate, at this scale of analysis, discontinuities in the way in which benthic species exploit their environment.

Spatial and temporal heterogeneity in size spectra, and the lack of clear density–body size allometry, could be due to biotic or physicochemical fluctuations and environmental change (including seasonal and longer‐term changes in acidity) that cause rapid species turnover and changes in density and distribution, particularly among the meiofauna. Small and rare species may thus be in the process of colonization or decline and the pattern would indicate a lack of equilibrium, particularly among organisms in the smallest size classes, at this temporal scale of the study.
Expanding on Watson's framework for classifying patches: when is an island not an island?
Authors: Shepherd U. L. , Brantley S. L.
Published: June 2005

Aim  The aims were: (1) evaluate the potential of Watson's framework for studying species composition in fragments and islands for a specific landscape type: cryptobiotic crust systems in the arid south‐western US; (2) expand Watson's original model to include ephemeral/non‐equilibrium systems by revising his categories of patch age and matrix contrast; and (3) examine the interplay between patch dynamics and species autecology, demonstrating the need for more work on ephemeral patchy systems.

Location  Cryptobiotic crust systems in two piñon‐juniper sites in Central New Mexico, western North America.

Results  Watson's patch age designation was not applicable to our system because of its ephemeral or non‐equilibrial nature. Based on this result, we constructed what we refer to as a ‘speed key’ that includes equilibrium and non‐equilibrium patches of all kinds. For this model we maintained one of Watson's original traits: patch origin, and amended two others to describe persistence and permeability across the matrix. Importantly, persistence and matrix permeability must be evaluated as functions of the organisms under consideration. Systems that may be in equilibrium for one taxon may well be non‐equilibrial (ephemeral) for another. A patch that appears to be in high contrast with its intervening matrix may actually be in low contrast, depending on the dispersal ability of the organism through that matrix.

Main conclusions  To improve substantially on our understanding of patchy systems (whether islands or fragments) it is important to account explicitly for relevant organismal life‐history traits in the designation of those systems. Too often, patches are defined by how the researcher views them from his/her own spatio‐temporal viewpoint. Once we move to an organism‐centred understanding of these patches we may find surprising and novel comparisons that allow us to move across scales and inform our view of ecological patterns and processes. By incorporating non‐equilibrium systems into a model of insularity, this work has general implications that go beyond the scope of cryptobiotic crusts to add to the current dialogue in biogeography.
Histidine nutrition and genotype affect cataract development in Atlantic salmon, Salmo salar L.
Authors: Breck O , Bjerkås E , Campbell P , Rhodes J D , Sanderson J , Waagbø R
Published: June 2005

The aim of this study was to investigate effects of dietary levels of histidine (His) and iron (Fe) on cataract development in two strains of Atlantic salmon monitored through parr‐smolt transformation. Three experimental diets were fed: (i) a control diet (CD) with 110 mg kg−1 Fe and 11.7 g kg−1 His; (ii) CD supplemented with crystalline His to a level of 18 g kg−1 (HD); and (iii) HD with added iron up to 220 mg kg−1 (HID). A cross‐over design, with two feeding periods was used. A 6‐week freshwater (FW) period was followed by a 20‐week period, of which the first three were in FW and the following 17 weeks in sea water (SW). Fish were sampled for weighing, cataract assessment and tissue analysis at five time points. Cataracts developed in all groups in SW, but scores were lower in those fed high His diets (P < 0.05). This effect was most pronounced when HD or HID was given in SW, but was also observed when these diets were given in FW only. Histidine supplementation had a positive effect on growth performance and feed conversion ratio (P < 0.05), whereas this did not occur when iron was added. Groups fed HD or HID had higher lens levels of His and N‐acetyl histidine (NAH), the latter showing a marked increase post‐smoltification (P < 0.05). The HD or HID groups also showed higher muscle concentrations of the His dipeptide anserine (P < 0.05). There was a strong genetic influence on cataract development in the CD groups (P < 0.001), not associated with tissue levels of His or NAH. The role of His and His‐related compounds in cataractogenesis is discussed in relation to tissue buffering, osmoregulation and antioxidation.
Fluorescence resonance energy transfer (FRET) measurement by gradual acceptor photobleaching
Authors: VAN MUNSTER E. B. , KREMERS G. J. , ADJOBO‐HERMANS M. J. W. , GADELLA T. W. J.
Published: June 2005

Fluorescence resonance energy transfer (FRET) is an extremely effective tool to detect molecular interaction at suboptical resolutions. One of the techniques for measuring FRET is acceptor photobleaching: the increase in donor fluorescence after complete acceptor photobleaching is a measure of the FRET efficiency. However, in wide‐field microscopy, complete acceptor photobleaching is difficult due to the low excitation intensities. In addition, the method is sensitive to inadvertent donor bleaching, autofluorescence and bleed‐through of excitation light. In the method introduced in this paper, donor and acceptor intensities are monitored continuously during acceptor photobleaching. Subsequently, curve fitting is used to determine the FRET efficiency. The method was demonstrated on cameleon (YC2.1), a FRET‐based Ca2+ indicator, and on a CFP‐YFP fusion protein expressed in HeLa cells. FRET efficiency of cameleon in the presence of 1 mm Ca2+ was 31 ± 3%. In the absence of Ca2+ a FRET efficiency of 15 ± 2% was found. A FRET efficiency of 28% was found for the CFP‐YFP fusion protein in HeLa cells. Advantages of the method are that it does not require complete acceptor photobleaching, it includes correction for spectral cross‐talk, donor photobleaching and autofluorescence, and is relatively simple to use on a normal wide‐field microscope.
Evaluation of neonatal verbal autopsy using physician review versus algorithm‐based cause‐of‐death assignment in rural Nepal
Authors: Freeman James V. , Christian Parul , Khatry Subarna K. , Adhikari Ramesh K. , LeClerq Steven C. , Katz Joanne , Darmstadt Gary L.
Published: June 2005

Verbal autopsy (VA) is used to ascertain cause‐specific neonatal mortality using parental/familial recall. We sought to compare agreement between causes of death obtained from the VA by physician review vs. computer‐based algorithms. Data were drawn from a cluster‐randomised trial involving 4130 live‐born infants and 167 neonatal deaths in the rural Sarlahi District of Nepal. We examined the agreement between causes ascertained by physician review and algorithm assignment by the kappa (κ) statistic. We also compared responses to identical questions posed posthumously during neonatal VA interviews with those obtained during maternal interviews and clinical examinations regarding condition of newborns soon after birth.

Physician reviewers assigned prematurity or acute lower respiratory infection (ALRI) as causes of 48% of neonatal deaths; 41% were assigned as uncertain. The algorithm approach assigned sepsis (52%), ALRI (31%), birth asphyxia (29%), and prematurity (24%) as the most common causes of neonatal death. Physician review and algorithm assignment of causes of death showed high κ for prematurity (0.73), diarrhoea (0.81) and ALRI (0.68), but was low for congenital malformation (0.44), birth asphyxia (0.17) and sepsis (0.00). Sensitivity and specificity of VA interview questions varied by symptom, with positive predictive values ranging from 50% to 100%, when compared with maternal interviews and examinations of neonates soon after birth. Analysis of the VA data by physician review and computer‐based algorithms yielded disparate results for some causes but not for others. We recommend an analysis technique that combines both methods, and further validation studies to improve performance of the VA for assigning causes of neonatal death.
The search for genenotype/phenotype associations and the phenome scan
Authors: Jones Richard , Pembrey Marcus , Golding Jean , Herrick David
Published: June 2005

All the approaches to the search for genotype/phenotype associations have their share of problems. Comparing the genome scan and candidate gene approaches, the former makes fewer assumptions at the genetic level or about mechanism but has greater statistical difficulties while the latter partially solves the statistical problem but makes more assumptions at both genetic and mechanistic levels. Among current difficulties is a lack of information about the nature of gene variant/phenotype associations: the frequency with which different classes of gene or sequence are involved; the type of genetic variation most commonly involved; the appropriate genetic models to apply to analysis. The overarching problem is that of multiple testing, one solution to which is to integrate genetic information to create a smaller number of compound variables. At the other end of the scale, decisions about the level of complexity at which to pitch the identification of phenotypes also affect the multiple testing problem: whether to pitch them at the level of disease outcomes, or at any of the multiple levels of intermediate phenotypes or traits. The third issue is how best to deal with gene/gene or gene/environment interactions, or whether to ignore them. Only as more genotype/phenotype associations emerge, by whatever means, will the numbers of results allow these questions to be answered. We describe here a new approach to genotype/phenotype association studies, the phenome scan, in which dense phenotypic information in human cohorts is scanned for associations with individual genetic variants. We believe that this approach can generate data that will be useful in answering generic questions about genotype/phenotype associations as well as in discovering novel ones.
The effect of terminations of pregnancy for fetal abnormalities on trends in mortality to one year of age in Western Australia
Authors: Bourke Jenny , Bower Carol , Blair Eve , Charles Adrian , Knuiman Matthew
Published: June 2005

Many studies documenting the decline in all‐cause infant mortality rates over the past 20 years have highlighted the contribution of birth defects. Over this time there has also been an increasing number of terminations of pregnancy for fetal abnormality. However, the effect of these terminations on mortality rates in Australia has not yet been estimated. The Western Australian Birth Defects Registry (BDR) records all birth defects that are diagnosed in stillbirths, livebirths and in pregnancies terminated because of a fetal abnormality. All cases on the BDR over the period 1980–98 were categorised into one of eight main birth defect groups and analysed in four time periods to show trends. Linkage provided information on deaths to one year of age, defined as perinatal plus postneonatal deaths. The proportion of terminations for fetal abnormality that would have resulted in a death before one year of age was estimated in two ways. The first method used the proportion of births with a birth defect in each diagnostic category that resulted in a death. The second method involved determination of likelihood of survival to one year of all terminations for fetal abnormality through independent review by two experts. Whilst mortality to one year of age for all birth defects has declined from 4.36/1000 births in 1980–84 to 2.75/1000 births in 1995–98, terminations of pregnancies for fetal abnormalities increased from 1.19/1000 births to 4.70/1000 births. After including the estimated mortality associated with terminations for fetal abnormality, the decline in mortality to one year of age associated with birth defects from 1980 to 1998 changed from a 37% reduction to a 15% reduction based on observed mortality 1980–84, and an 11% increase in mortality based on individual case review, highlighting the importance of considering terminations in mortality analyses.
Multilingual home environment and specific language impairment: a case–control study in Chinese children
Authors: Cheuk Daniel Ka Leung , Wong Virginia , Leung Gabriel Matthew
Published: June 2005

Specific language impairment (SLI) is a common developmental disorder in young children. To investigate the association between multilingual home environment and SLI, we conducted a case–control study in Hong Kong Chinese children over a 4‐year period in the Duchess of Kent Children's Hospital. Consecutive medical records of all new referrals below 5 years of age were reviewed and children diagnosed with SLI (case) were compared with those referred with other developmental and behavioural problems who had been assessed as having normal language and overall development (control) using the Griffiths Mental Developmental Scale. SLI was defined as those with a language quotient more than one standard deviation below the mean and below the general developmental quotient in children with normal general developmental quotient, but without neurological or other organic diseases. We used binary and ordinal logistic regression to assess any association between SLI and multilingual exposure at home, adjusting for age and gender of subjects, parental age, education level and occupational status, number of siblings, family history of language delay and main caregiver at home. Multivariable linear regression was used to examine the effect of covariates on the language comprehension and expression standard scores assessed by the Reynell Developmental Language Scale.

A total of 326 cases and 304 controls were included. The mean ages of cases and controls were 2.56 and 2.89 years respectively. Boys predominated in both groups (cases, 75.2%; controls, 60.2%). The children were exposed to between one and four languages at home, the major ones being Cantonese Chinese followed by English. The adjusted odds ratio (OR) of SLI was 2.94; [95% confidence interval (CI) 1.82, 4.74] for multilingual compared with monolingual exposure. A significant linear dose–response relationship was found (OR of SLI = 2.58 [1.72, 3.88] for each additional language to which the child was exposed). Male gender (OR = 1.88 [1.24, 2.87]), positive family history (OR = 2.01 [1.17, 3.47]), lower education levels of parents (P = 0.028 for father,P = 0.038 for mother) and lower occupational status of father (P = 0.005) were also risk factors for SLI. Multilingual exposure also significantly reduced the language quotient (P = 0.012) and language comprehension standard score (P = 0.016) of children with SLI, but not of normal children.

We concluded that multilingual home environment is associated with SLI with a dose‐response relationship. Exposure to multiple languages might adversely affect subsequent language ability.
Characterization of Fusarium oxysporum f. sp. radicis‐cucumerinum attacking melon under natural conditions in Greece
Authors: Vakalounakis D. J. , Doulis A. G. , Klironomou E.
Published: June 2005

A severe root and stem rot disease of melon was observed during the 2001 growing season on four glasshouse crops in Heraklio, Greece. A total of 43 isolates of F. oxysporum, obtained in Crete from glasshouse‐grown melon and showing fusarium wilt or root and stem rot symptoms, were characterized by pathogenicity and vegetative compatibility. The majority of these isolates was also fingerprinted via amplified fragment length polymorphic (AFLP) analysis. Of the total number of isolates, 22 were identified by pathogenicity tests as F. oxysporum f. sp. melonis, 20 as F. oxysporum f. sp. radicis‐cucumerinum, while one isolate was nonpathogenic on cucumber, melon, sponge gourd and pumpkin. All 22 isolates of F. oxysporum f. sp. melonis were assigned to vegetative compatibility group (VCG) 0134, and all 20 isolates of F. oxysporum f. sp. radicis‐cucumerinum to VCG 0260. Isolates of F. oxysporum f. sp. radicis‐cucumerinum were incompatible with isolates of F. oxysporum f. sp. melonis. AFLP fingerprinting allowed for the clustering of the isolates of the two formae speciales of F. oxysporum along two separate phenetic groups: f. sp. melonis to AFLP major haplotype I, and f. sp. radicis‐cucumerinum to AFLP major haplotype II. Overall, pathogenicity, vegetative compatibility grouping and AFLP analysis were correlated and effectively distinguished isolates of F. oxysporum from melon. This appears to be the first report of natural infection of melon by F. oxysporum f. sp. radicis‐cucumerinum worldwide.
Variation in pathogen aggressiveness within a metapopulation of the Cakile maritima–Alternaria brassicicola host–pathogen association
Authors: Thrall P. H. , Barrett L. G. , Burdon J. J. , Alexander H. M.
Published: June 2005

Variation in aggressiveness and its consequences for disease epidemiology were studied in the Cakile maritima–Alternaria brassicicola host–pathogen association. Variability in pathogen growth rates and spore production in vitro, as well as disease severity and lesion growth rate on C. maritima in glasshouse inoculation trials, were investigated. Substantial variation was found in growth rates among individual A. brassicicola isolates, as well as among pathogen populations. A significant trade‐off also existed between growth and spore production, such that faster‐growing isolates produced fewer spores per unit area. While there was little evidence for a link between growth in vitro and either disease severity or lesion development among fast‐ vs slow‐growth isolate classes at the individual isolate level, the results suggest that variation in pathogen fitness components associated with aggressiveness may influence disease dynamics in nature. An analysis using an independent data set of disease prevalence in the associated host populations found a significant positive relationship between the average growth rate of pathogen populations in vitro and disease progress over the growing season in wild host populations. Trade‐offs such as those demonstrated between growth rate and spore production may contribute to the maintenance of variation in quantitatively based host–pathogen interactions.
Normal ICOS, ICOSL and AID Alleles in Danish Patients with Common Variable Immunodeficiency
Authors: Ohm‐Laursen L. , Schjebel L. , Jacobsen K. , Permin H. , Svejgaard A. , Barington T.
Published: June 2005

Common variable immunodeficiency, CVID, is a primary antibody deficiency characterized by decreased levels of serum immunoglobulin G (IgG), decreased IgA and/or IgM and recurrent infections. It is assumed to be heterogeneous group of disorders caused by different genetic defects. Some patients have decreased levels of class switched memory B cells and/or decreased levels of somatic hypermutation which points to defects in the germinal centre (GC) reactions as cause of the disease in these patients. The inducible costimulator, ICOS, and its' ligand, ICOSL, are both involved in and necessary for the GC reaction and so is activation‐induced cytidine deaminase, AID. Therefore, we sequenced the ICOS, ICOSL and AID genes in a cohort of 34 Danish CVID patients. We found 13 new single nucleotide polymorphisms (SNP) in the intron regions of the ICOSL gene as well as one SNP in exon 3. However, none of these polymorphisms were associated with CVID. We did not find a previously reported CVID‐causing ICOS gene deletion or any other unique mutations in the ICOS or AID genes.
Infection of Human Endothelial Cells with Staphylococcus aureus Induces Transcription of Genes Encoding an Innate Immunity Response
Authors: Matussek A. , Strindhall J. , Stark L. , Rohde M. , Geffers R. , Buer J. , Kihlström E. , Lindgren P.‐E. , Löfgren S.
Published: June 2005

Staphylococcus aureus is a gram‐positive bacterium frequently isolated from patients with bloodstream infections. Endothelial cells (EC) play an important role in host defence against bacteria, and recent reports have shown that infection of EC with S. aureus induces expression of cytokines and cell surface receptors involved in activating the innate immune response. The ability of S. aureus to invade nonphagocytic cells, including EC, has been documented. However, the knowledge of the role of EC in pathogenesis of S. aureus infection is still limited. In this study, we investigate the gene‐expression program in human EC initiated by internalized S. aureus, using microarray analysis. We found 156 genes that were differentially regulated at least threefold, using arrays representing 14,239 genes. Many of the upregulated genes code for proteins involved in innate immunity, such as cytokines, chemokines and cell adhesion proteins. Other upregulated genes encode proteins involved in antigen presentation, cell signalling and metabolism. Furthermore, intracellular bacteria survived for days without inducing EC death.
Quantifying velocity and turbulence structure in depositing sustained turbidity currents across breaks in slope
Authors: GRAY THOMAS E. , ALEXANDER JAN , LEEDER MIKE R.
Published: June 2005

Two‐dimensional experiments investigating sediment transport and turbulence structure in sustained turbidity currents that cross breaks in slope are presented as analogue illustrations for natural flows. The results suggest that in natural flows, turbulence generation at slope breaks may account for increased sand transport into basins and that the formation of a hydraulic jump may not be necessary to explain features such as the occurrence of submarine plunge pools and the deposition of coarser‐grained beds in the bottomsets of Gilbert‐type fan deltas. Experimental flows were generated on 0°, 3°, 6° and 9° slopes of equal length which terminated abruptly on a horizontal bed. Two‐component velocities were measured on the slope, at the slope break and downstream of the slope break. Flows were depositional and non‐uniform, visibly slowing and thickening with distance downstream. One‐dimensional continuous wavelet transforms of velocity time series were used to produce time‐period variance maps. Peaks in variance were tested against a background red‐noise spectrum at the 95% level; a significant period banding occurs in the cross‐wavelet transform at the slope break, attributed to increased formation of coherent flow structures (Kelvin–Helmholtz billows). Variance becomes distributed at progressively longer periods and the shape of the bed‐normal‐velocity spectral energy distribution changes with distance downstream. This is attributed to a shift towards larger turbulent structures caused by wake stretching. Mean velocity, Reynolds shear stress and turbulent kinetic energy profiles illustrate the mean distribution of turbulence through the currents. A turbulent kinetic energy transfer balance shows that flow non‐uniformity arises through the transfer of mean streamwise slowing to mean bed‐normal motion through the action of Reynolds normal stresses. Net turbulence production through the action of normal stresses is achieved on steeper slopes as turbulence dissipation due to mean bed‐normal motion is limited. At the slope break, an imbalance between the production and dissipation of turbulence occurs because of the contrasting nature of the wall and free‐shear boundaries at the bottom and top of the flows, respectively. A rapid reduction in mean streamwise velocity predominately affects the base of the flows and steeper proximal slope flows have to slow more at the break in slope. The increased turbulent kinetic energy, limited bed‐normal motion and strong mixing imposed by steep proximal slopes means rapid slowing enhances turbulence production at the break in slope by focusing energy into coherent flow structures at a characteristic period. Thus, mean streamwise slowing is transferred into turbulence production at the slope break that causes increased transport of sediment and a decrease in deposit mass downstream of the slope break. The internal effects of flow non‐uniformity therefore can be separated from the external influence of the slope break.
AUXIN RESPONSE FACTOR 2 (ARF2): a pleiotropic developmental regulator
Authors: Okushima Yoko , Mitina Irina , Quach Hong L. , Theologis Athanasios
Published: June 2005

AUXIN RESPONSE FACTORS (ARFs) regulate auxin‐mediated transcriptional activation/repression. They are encoded by a gene family in Arabidopsis, and each member is thought to play a central role in various auxin‐mediated developmental processes. We have characterized three arf2 mutant alleles, arf2‐6, arf2‐7 and arf2‐8. The mutants exhibit pleiotropic developmental phenotypes, including large, dark green rosette leaves, delayed flowering, thick and long inflorescence, abnormal flower morphology and sterility in early formed flowers, large organ size and delayed senescence and abscission, compared with wild‐type plants. In addition, arf2 mutant seedlings have elongated hypocotyls with enlarged cotyledons under various light conditions. The transcription of ACS2, ACS6 and ACS8 genes is impaired in the developing siliques of arf2‐6. The phenotypes of all three alleles are similar to those of the loss‐of‐function mutants obtained by RNA interference or co‐suppression. There is no significant effect of the mutation on global auxin‐regulated gene expression in young seedlings, suggesting that ARF2 does not participate in auxin signaling at that particular developmental stage of the plant life cycle. Because ARF2 is thought to function as a transcriptional repressor, the prospect arises that its pleiotropic effects may be mediated by negatively modulating the transcription of downstream genes in signaling pathways that are involved in cell growth and senescence.
Spontaneously occurring mutations in the cyclobutane pyrimidine dimer photolyase gene cause different sensitivities to ultraviolet‐B in rice
Authors: Hidema Jun , Teranishi Mika , Iwamatsu Yutaka , Hirouchi Tokuhisa , Ueda Tadamasa , Sato Tadashi , Burr Benjamin , Sutherland Betsy M. , Yamamoto Kazuo , Kumagai Tadashi
Published: June 2005

Sensitivity to ultraviolet‐B (UVB) radiation (280–320 nm) varies widely among rice cultivars. We previously indicated that UV‐resistant rice cultivars are better able to repair cyclobutane pyrimidine dimers (CPDs) through photorepair than are UV‐sensitive cultivars. In this paper, we report that UVB sensitivity in rice, in part, is the result of defective CPD photolyase alleles. Surjamkhi (indica) exhibited greater sensitivity to UVB radiation and was more deficient in CPD photorepair ability compared with UV‐resistant Sasanishiki (japonica). The deficiency in CPD photorepair in Surjamkhi resulted from changes in two nucleotides at positions 377 and 888 in the photolyase gene, causing alterations of two deduced amino acids at positions 126 and 296 in the photolyase enzyme. A linkage analysis in populations derived from Surjamkhi and Sasanishiki showed that UVB sensitivity is a quantitative inherited trait and that the CPD photolyase locus is tightly linked with a quantitative trait locus that explains a major portion of the genetic variation for this trait. These results suggest that spontaneously occurring mutations in the CPD photolyase gene cause different degrees of sensitivity to UVB in rice, and that the resistance of rice to UVB radiation could be increased by increasing the photolyase function through conventional breeding or bioengineering.
Repression of light signaling by Arabidopsis SPA1 involves post‐translational regulation of HFR1 protein accumulation
Authors: Yang Jianping , Lin Rongcheng , Hoecker Ute , Liu Bolin , Xu Ling , Wang Haiyang
Published: June 2005

Arabidopsis uses two major classes of photoreceptors to mediate seedling de‐etiolation. The cryptochromes (cry1 and cry2) absorb blue/ultraviolet‐A light, whereas the phytochromes (phyA–phyE) predominantly regulate responses to red/far‐red light. Arabidopsis COP1 represses light signaling by acting as an E3 ubiquitin ligase in the nucleus, and is responsible for targeted degradation of a number of photomorphogenesis‐promoting factors, including HY5, LAF1, phyA, and HFR1. Distinct light signaling pathways initiated by multiple photoreceptors (including both phytochromes and cryptochromes) eventually converge on COP1, causing its inactivation and nuclear depletion. Arabidopsis SPA1, which encodes a protein structurally related to COP1, also represses light signaling under various light conditions. In this study, we present genetic evidence supporting that HFR1, which encodes a photomorphogenesis‐promoting bHLH transcription factor, acts downstream of SPA1 and is required for different subsets of branch pathways of light signaling controlled by SPA1 under different light conditions. We show that SPA1 physically interacts with HFR1 in a yeast two‐hybrid assay and an in vitro co‐immunoprecipitation assay. We demonstrate that higher levels of HFR1 protein accumulate in the spa1 mutant background under various light conditions, including far‐red, red, blue, and white light, whereas a marginal increase in HFR1 transcript level is only seen in dark‐ and far‐red light‐grown spa1‐100 mutants. Together, our data suggest that repression of light signaling by Arabidopsis SPA1 likely involves post‐translational regulation of HFR1 protein accumulation.
Arabidopsis IQD1, a novel calmodulin‐binding nuclear protein, stimulates glucosinolate accumulation and plant defense
Authors: Levy Maggie , Wang Qiaomei , Kaspi Roy , Parrella Michael P. , Abel Steffen
Published: June 2005

Glucosinolates are a class of secondary metabolites with important roles in plant defense and human nutrition. To uncover regulatory mechanisms of glucosinolate production, we screened Arabidopsis thaliana T‐DNA activation‐tagged lines and identified a high‐glucosinolate mutant caused by overexpression of IQD1 (At3g09710). A series of gain‐ and loss‐of‐function IQD1 alleles in different accessions correlates with increased and decreased glucosinolate levels, respectively. IQD1 encodes a novel protein that contains putative nuclear localization signals and several motifs known to mediate calmodulin binding, which are arranged in a plant‐specific segment of 67 amino acids, called the IQ67 domain. We demonstrate that an IQD1‐GFP fusion protein is targeted to the cell nucleus and that recombinant IQD1 binds to calmodulin in a Ca2+‐dependent fashion. Analysis of steady‐state messenger RNA levels of glucosinolate pathway genes indicates that IQD1 affects expression of multiple genes with roles in glucosinolate metabolism. Histochemical analysis of tissue‐specific IQD1::GUS expression reveals IQD1 promoter activity mainly in vascular tissues of all organs, consistent with the expression patterns of several glucosinolate‐related genes. Interestingly, overexpression of IQD1 reduces insect herbivory, which we demonstrated in dual‐choice assays with the generalist phloem‐feeding green peach aphid (Myzus persicae), and in weight‐gain assays with the cabbage looper (Trichoplusia ni), a generalist‐chewing lepidopteran. As IQD1 is induced by mechanical stimuli, we propose IQD1 to be novel nuclear factor that integrates intracellular Ca2+ signals to fine‐tune glucosinolate accumulation in response to biotic challenge.
In vitro metabolism of progesterone by canine hair follicle cells
Authors: BAMBERG ELMAR , AICHINGER AMANDA , WÜNSCH GERDA
Published: June 2005

Abstract  Dermal papilla cells (DPC) and dermal fibroblasts (DFB) derived from hair follicles from two different body sites (head, flank) of four male, castrated beagle dogs were incubated for 24 h with radioactive progesterone (P4). Thin‐layer chromatography was used for separation and autoradiography for identification of the radioactive metabolites. In DFB the main metabolites were cortisol and 4‐pregnene‐11β‐ol‐3,20‐dione, whereas in DPC they were 5α‐pregnane‐3,20‐dione and cortisol. The highest percentage of metabolism of P4 was found in DFB of the head. Smaller amounts of other metabolites were found in both cell types of both locations.
Comparison of the clinical efficacy of oral terbinafine and ketoconazole combined with cephalexin in the treatment ofMalasseziadermatitis in dogs – a pilot study
Authors: ROSALES MILLIE S. , MARSELLA ROSANNA , KUNKLE GAIL , HARRIS BRADLEY L. , NICKLIN CONSTANCE F. , LOPEZ JENNIFER
Published: June 2005

Abstract The purpose of this randomized, single blinded clinical trial was to evaluate cytologically and clinically the efficacy of oral cephalexin alone and its combination with terbinafine or ketoconazole for the treatment ofMalasseziadermatitis in dogs. Twenty‐two client‐owned dogs withMalasseziadermatitis completed the 3‐week study. All received cephalexin (generic, 250 mg or 500 mg) at 22–30 mg kg−1twice daily. Eight dogs received terbinafine at 30 mg kg−1once daily and seven dogs received ketoconazole (generic, 200 mg) at 5–10 mg kg−1twice daily. The remaining seven dogs received cephalexin alone. At week 0 (visit 1) and week 3 (visit 2), mean yeast counts were determined from three affected areas using tape‐strip cytology, a clinical index score (CIS) was assigned to the affected areas, and owners evaluated pruritus using a visual analogue scale. All groups showed reduction in mean yeast counts, CIS and pruritus. There was an 86.8%, 80.2% and 28.8% reduction in mean yeast counts from visit 1 to visit 2 for the terbinafine, ketoconazole and cephalexin‐only groups, respectively. However, within treatment group comparisons a significant reduction in mean yeast count was only evident for the terbinafine (P < 0.002) and ketoconazole (P < 0.01) groups. Pruritus reduction was only significant for the terbinafine group. These preliminary results suggest that terbinafine should be further assessed for the treatment of canineMalasseziadermatitis.
The morphological compensatory change of peritubular capillary network in chronic allograft rejection
Authors: Nishi Shinichi , Imai Naofumi , Alchi Bassam , Iguchi Seitaro , Ueno Mitsuhiro , Fukase Sachiko , Mori Honami , Arakawa Masaaki , Saito Kazuhide , Takahashi Kota , Gejyo Fumitake
Published: June 2005

Abstract:  To clarify the compensatory hemodynamic alterations in the interstitium of renal allograft biopsies with chronic rejection, we evaluated the morphological changes in the peritubular capillary (PTC) network. Seven renal biopsy specimens from recipients with chronic rejection presenting with elevation of serum creatinine of 1.9 ± 0.5 mg/dL were examined. Renal biopsy specimens from their counterpart donors were used as normal controls. In each specimen, non‐pathological interstitial areas without fibrosis, tubular atrophy or cell infiltration were compared with pathological areas (PA) showing fibrosis and/or tubular atrophy using a computer image analysis. Morphological measurements revealed that the mean cut surface area of the PTC in the non‐pathological and pathological interstitial areas in the recipient biopsies were significantly larger than that of the normal controls (p < 0.001 and 0.001, respectively). In the recipient biopsies, both of the mean cut surface areas of the tubules and PTC in the non‐pathological areas were significantly higher than those in the PA (p < 0.001). The mean glomerular diameter in the recipient biopsies was also significantly higher than that of the donors (p < 0.01). In this study, we provided pathological evidence for the compensatory interstitial and glomerular hemodynamic alterations in kidney graft with chronic rejection and the condition as single kidney.
Post‐transplant early recurrent proteinuria in patients with focal glomerulosclerosis‐ Angiotensin II immunostaining and treatment outcome
Authors: Mizuiri Sonoo , Kawamura Takeshi , Miyagi Moriatsu , Arai Kenji , Sakai Ken , Aikawa Atsushi , Ohara Takehiro , Shibuya Kazutoshi , Ishikawa Yukio , Kawamura Sadao , Hasegawa Akira
Published: June 2005

Abstract:  We reviewed the transplantation data and results of histopathological studies with additional angiotensin II (AII) immunostaining of renal graft biopsies of nine cases (10 grafts) with recurrent proteinuria and three controls without recurrent proteinuria that received renal transplantation for primary focal segmental glomerulosclerosis (FSGS) between 1986 and 2002. Recurrent FSGS was confirmed in six grafts from nine cases by light microscopy. In cases with recurrent proteinuria, loss of graft function was noted in all six renal grafts received between 1986 and early 1992 but in none of four grafts received between late 1992 and 2002. Two of four patients of the late group but none of those of the early group received angiotensin converting enzyme (ACEI) or angiotensin II receptor blocker (ARB) with plasma exchange (PE). In control cases without proteinuria, AII immunostaining was detected in tubules but not in glomeruli in 1‐hour biopsies as well as later on. In cases with recurrent proteinuria, AII immunostaining was detected in both tubules and glomeruli, although glomerular AII staining was not observed in 1‐hour biopsies. Our results suggest that effective treatment of post‐transplantation recurrent FSGS requires ACEI or ARB with PE in the absence of another etiology.