bluuebunny/crossref_metadata_2025 huggingface dataset:
The association between metabolic syndrome, microalbuminuria and impaired renal function in the general population: impact on cardiovascular disease and mortality
Authors: Klausen K. P. , Parving H.‐H. , Scharling H. , Jensen J. S.
Published: August 2007

Objective:  Microalbuminuria and metabolic syndrome are both associated with cardiovascular disease (CVD). The aim of this study was to determine the potential association between numbers of components in the metabolic syndrome, different levels of microalbuminuria and renal function. We also aimed to determine the risk of death and CVD at different levels of microalbuminuria and renal function and numbers of components in the metabolic syndrome.

Design:  Population‐based observational follow‐up study

Setting:  Epidemiological research unit (Copenhagen City Heart Study).

Subjects:  A total of 2696 men and women, 30–70 years of age.

Baseline measures:  Urinary albumin excretion (UAE), creatinine clearance and metabolic risk factors were measured in 1992–1994.

Main outcome measurements:  The participants were followed prospectively by registers until 1999–2000 with respect to CVD, and until 2004 with respect to death.

Results:  We found a strong association between microalbuminuria and the metabolic syndrome: 2% with none and 18% with five metabolic risk factors had microalbuminuria (P < 0.001). No association between impaired renal function defined as creatinine clearance <60 mL min−1 and the metabolic syndrome was found. Microalbuminuria was associated with increased risk of death and CVD to a similar extend as the metabolic syndrome, irrespective of concomitant presence of metabolic syndrome (RR≈2; P < 0.001). Impaired renal function was not associated with increased risk of death and CVD in subjects with the metabolic syndrome.

Conclusions:  Microalbuminuria (UAE >5 μg min−1) confers increased risk of death and CVD to a similar extent as the metabolic syndrome.
Immunomodulation by mesenchymal stem cells and clinical experience
Authors: Le Blanc K. , Ringdén O.
Published: August 2007

Mesenchymal stem cells (MSCs) from adult marrow can differentiate in vitro and in vivo into various cell types, such as bone, fat and cartilage. MSCs preferentially home to damaged tissue and may have therapeutic potential. In vitro data suggest that MSCs have low inherent immunogenicity as they induce little, if any, proliferation of allogeneic lymphocytes. Instead, MSCs appear to be immunosuppressive in vitro. They inhibit T‐cell proliferation to alloantigens and mitogens and prevent the development of cytotoxic T‐cells. In vivo, MSCs prolong skin allograft survival and have several immunomodulatory effects, which are presented and discussed in the present study. Possible clinical applications include therapy‐resistant severe acute graft‐versus‐host disease, tissue repair, treatment of rejection of organ allografts and autoimmune disorders.
Retinol‐binding protein 4 as a plasma biomarker of renal dysfunction and cardiovascular disease in type 2 diabetes
Authors: Cabré A. , Lázaro I. , Girona J. , Manzanares J. , Marimón F. , Plana N. , Heras M. , Masana L.
Published: August 2007

Objective.  The retinol‐binding protein 4 (RBP4) has been linked to the insulin resistance state in obesity and type 2 diabetes in animal studies. Data in humans are controversial and their relationship with organ damage in diabetic patients is lacking. We studied the association of plasma RBP4 with organ complications in type 2 diabetic patients.

Setting.  Sant Joan University Hospital, Reus, Spain.

Subjects.  165 nonsmoker type 2 diabetic subjects according to American Diabetes Association criteria, aged 36–79 years, without proteinuria or severely decreased glomerular filtration rates (MDRD‐GFR <30 mL min−1 1.73 m−2), were included in the study.

Main outcome measure.  Plasma RBP4 concentrations were the primary outcome variable. Statistics were performed in relation to clinical and subclinical arteriosclerosis, renal function parameters and biochemical data.

Results.  Plasma RBP4 concentrations were positively correlated with serum creatinine levels (r = 0.322, P < 0.001) and inversely correlated with MDRD‐GFR (r = −0.468, P = 0.009). Patients with moderately renal dysfunction (MDRD‐GFR <60 mL min−1 1.73 m−2) had higher plasma RBP4 concentrations than those with normal to mildly decreased GFR (55.3 ± 24.6 vs. 40.8 ± 15.4, P <0.001). Patients in the top quartile of RBP4 concentrations had an increased adjusted odds ratio for moderately renal dysfunction compared with lower quartiles (4.68; 95% CI: 1.52–14.36, P = 0.007). The presence of microalbuminuria was not associated with RBP4. Plasma RBP4 concentrations were higher in those subjects with previous clinical arteriosclerosis than in event‐free subjects (48.8 ± 24.2 vs. 40.6 ± 13.9, P = 0.045). The presence of retinopathy or polyneuropathy did not differ across RBP4 quartiles.

Conclusions.  Plasma RBP4 concentration might be a biomarker of nephropathy and cardiovascular disease in type 2 diabetic subjects.
Regulation of inflammation‐related genes in human adipose tissue
Authors: Clement K. , Langin D.
Published: August 2007

The identification of a moderate increase in circulating inflammatory factors in obese subjects, the description of changes in inflammatory gene expression in adipose tissue (AT) and the discovery that macrophage cells infiltrate AT are observations contributing to the concept that human obesity is a chronic inflammatory illness. This concept has led to some revision of the physiopathology of obesity and of its related metabolic and cardiovascular co‐morbidities. Low‐grade inflammation in the AT and the subsequent production of specific biomarkers could actually link expanded fat mass to obesity complications. This review aims at providing an overview of the current knowledge brought up by human gene expression studies, notably those performed on a large scale in AT depots. The regulation of specific biomarkers related to inflammation and putative new candidates (i.e. cathepsins and serum amyloid A) is discussed in the context of weight loss programmes based on calorie restriction and physical exercise. The foreseen clinical and technological challenges are also summarized.
The role of endothelial cells in inflamed adipose tissue
Authors: Sengenès C. , Miranville A. , Lolmède K. , Curat C. A. , Bouloumié A.
Published: August 2007

In recent years, the general concept has emerged that chronic low‐grade inflammation can be the condition linking excessive development of adipose tissue (AT) and obesity‐associated pathologies such as type II diabetes and atherosclerosis. Moreover, the evidence that the growth of the fat mass was associated with an accumulation of adipose tissue macrophages (ATM) has raised the hypothesis that the development of an inflammatory process within the growing fat mass is a primary event involved in the genesis of systemic metabolic and vascular alterations. As ATM originate from the bone marrow/blood compartment, enhanced macrophage recruitment to growing AT is suspected. However, the mechanisms responsible for attracting the blood cells and their entry into the fat mass remain to be clearly defined. The present review highlights the key role of endothelial cells in the control of the inflammatory process and describes the potential involvement of AT‐endothelial cells as well as the factors involved in the regulation of their phenotype in the ‘inflamed fat tissue’.
Tumour necrosis factor‐α in human adipose tissue – from signalling mechanisms to clinical implications
Authors: Rydén M. , Arner P.
Published: August 2007

From its initial implication in the development of cachexia in the early 1980s, it is now almost 15 years ago that tumour necrosis factor‐alpha (TNF‐α) was first shown to be involved in the development of insulin resistance in obesity. Since the original findings in mice, a wealth of data has been obtained in a variety of settings and species. This intensive research has demonstrated both similarities and differences between rodents and humans regarding the molecular mechanisms and metabolic consequences of TNF‐α overexpression. This review will focus on the role of TNF‐α in human white adipose tissue with particular emphasis on its regulation of lipolysis – an important pathway in adipocytes which is linked to insulin‐resistant phenotypes in obesity and the metabolic syndrome.
A pilot study of 2 years of interferon treatment in patients with chronic delta hepatitis
Authors: Yurdaydın C. , Bozkaya H. , Karaaslan H. , Önder F. O. , Erkan Ö. E. , Yalçın K. , Değertekin H. , Bozdayı A. M. , Uzunalimoğlu Ö.
Published: August 2007

Summary.  High dose interferon treatment for 1 year is the only established treatment for chronic hepatitis D, but it is associated with a high relapse rate after treatment discontinuation. In this study, patients were treated with 10 MU interferon alpha 2b, thrice weekly for 2 years. Twenty‐three patients were recruited and 15 completed the 2‐year treatment and 6 months follow‐up periods. Treatment response was assessed biochemically [normal alanine aminotransferase (ALT)], virologically (undetectable hepatitis D virus RNA) and histologically (at least 2 point decrease in the Knodell score) at the end of treatment (EOT) and at the end of follow‐up. Out of 15 patients who finished the 2‐year treatment period, seven patients (47%) had a biochemical response but only two (13%) had a normal ALT after follow‐up. ALT decreased from the baseline value of 143.1 ± 121.7 (mean ± SD) to 39.7 ± 20.6 (P < 0.01) at EOT. Virological response was observed in six patients at EOT and in two patients at follow‐up. Two patients lost hepatitis B surface antigen. Of the 12 patients with paired liver biopsies, a histological improvement was observed in eight patients. Interferon treatment leads to a complete or partial response in a substantial number of patients but 2 years of treatment does not appear to increase sustained response rates over 1 year treatment.
Association of TLR7 single nucleotide polymorphisms with chronic HCV‐infection and response to interferon‐a‐based therapy
Authors: Schott E. , Witt H. , Neumann K. , Bergk A. , Halangk J. , Weich V. , Müller T. , Puhl G. , Wiedenmann B. , Berg T.
Published: August 2007

Summary.  An efficient immune response against hepatitis C virus (HCV) is necessary to clear infection. As HCV is a single‐stranded RNA virus, a role for TLR7 in the immune response against HCV is possible, and early clinical studies have demonstrated an antiviral effect of TLR7 stimulation. We tested the hypothesis that genetic variations of TLR7 are associated with chronic HCV‐infection and outcome of therapy. The prevalence of three TLR7 variations was analysed in 978 patients with chronic HCV‐infection, 898 patients with chronic liver disease of other aetiologies, and in 203 healthy controls. The prevalence of TLR7 variations was correlated with the response to interferon‐α‐based treatment in 544 patients with chronic HCV‐infection. We analysed TLR7 polymorphisms by melting curve analysis and reconstructed haplotypes. The c.32A>T variation was over‐represented in female patients with chronic HCV‐infection compared to patients with other chronic liver diseases and to healthy controls (P < 0.05). In contrast, c.2403 G>A was less prevalent in male patients with chronic HCV‐infection (P < 0.05). No association was observed for the third variant, c.1‐120T>G. Haplotype analysis confirmed the differential distribution of TLR7 variants between the groups. Within the group of female patients with chronic HCV‐infection, c.32T was predictive of an unfavourable outcome of interferon‐α therapy (P < 0.05). This study reports the association of TLR7 variants with chronic HCV‐infection and with the response to interferon‐α therapy in patients with chronic HCV‐infection. Our results suggest that variations of TLR7 impair the immune response to HCV and imply a gender‐specific effect of this X‐chromosomal variation.
Niche partitioning of closely related symbiotic dinoflagellates
Authors: SAMPAYO EUGENIA M. , FRANCESCHINIS LORENZO , HOEGH‐GULDBERG OVE , DOVE SOPHIE
Published: August 2007

Reef‐building corals are fundamental to the most diverse marine ecosystems, yet a detailed understanding of the processes involved in the establishment, persistence and ecology of the coral–dinoflagellate association remains largely unknown. This study explores symbiont diversity in relation to habitat by employing a broad‐scale sampling regime using ITS2 and denaturing gradient gel electrophoresis. Samples from Pocillopora damicornis, Stylophora pistillata and Seriatopora hystrix all harboured host‐specific clade C symbiont types at Heron Island (Great Barrier Reef, Australia). While Ser. hystrix associated with a single symbiont profile along its entire depth distribution, both P. damicornis and Sty. pistillata associated with multiple symbiont profiles that showed a strong zonation with depth. It is shown that, with an increased sampling effort, previously identified ‘rare’ symbiont types within this group of host species are in fact environmental specialists. A multivariate approach was used to expand on the common distinction of symbionts by a single genetic identity. It shows merit in its capacity not only to include all the variability present within the marker region but also to reliably represent ecological diversification of symbionts. Furthermore, the cohesive species concept is explored to explain how niche partitioning may drive diversification of closely related symbiont lineages. This study provides thus evidence that closely related symbionts are ecologically distinct and fulfil their own niche within the ecosystem provided by the host and external environment.
Risk of ectoparasitism and genetic diversity in a wild lesser kestrel population
Authors: ORTEGO JOAQUÍN , APARICIO JOSE MIGUEL , CALABUIG GUSTAU , CORDERO PEDRO J.
Published: August 2007

Parasites and infectious diseases are major determinants of population dynamics and adaptive processes, imposing fitness costs to their hosts and promoting genetic variation in natural populations. In the present study, we evaluate the role of individual genetic diversity on risk of parasitism by feather liceDegeeriella rufain a wild lesser kestrel population (Falco naumanni). Genetic diversity at 11 microsatellite loci was associated with risk of parasitism by feather lice, with more heterozygous individuals being less likely to be parasitized, and this effect was statistically independent of other nongenetic parameters (colony size, sex, location, and year) which were also associated with lice prevalence. This relationship was nonlinear, with low and consistent prevalences among individuals showing high levels of genetic diversity that increased markedly at low levels of individual heterozygosity. This result appeared to reflect a genome‐wide effect, with no single locus contributing disproportionably to the observed effect. Thus, overall genetic variation, rather than linkage of markers to genes experiencing single‐locus heterosis, seems to be the underlying mechanism determining the association between risk of parasitism and individual genetic diversity in the study host–parasite system. However, feather lice burden was not affected by individual heterozygosity; what suggest that differences in susceptibility, rather than variation in defences once the parasite has been established, may shape the observed pattern. Overall, our results highlight the role of individual genetic diversity on risk of parasitism in wild populations, what has both important evolutionary implications and major consequences for conservation research on the light of emerging infectious diseases that may endanger genetically depauperated populations.
Nuclear vs. plastid data: complex Pleistocene history of a circumpolar key species
Authors: EIDESEN P. B. , ALSOS I. G. , POPP M. , STENSRUD Ø. , SUDA J. , BROCHMANN C.
Published: August 2007

To fully understand the contemporary genetic structure of plants, both nuclear and plastid markers are needed. Three chloroplast DNA (cpDNA) lineages, which probably diverged before the major Pleistocene glaciations, have been identified in the circumpolar/circumborealVaccinium uliginosum. Here we investigate its nuclear DNA variation using nuclear ribosomal internal transcribed spacer (ITS) sequences, DNA ploidy level measurements and amplified fragment length polymorphisms (AFLPs). We also extend the cpDNA dataset. Two ITS lineages, corresponding to diploids and tetraploids, respectively, were identified. However, both main sequence types apparently occurred in most individual plants but showed ploidy‐biased homogenization and possibly reflect paralogy predating the origin ofV.uliginosum. The ploidy levels were largely consistent with the cpDNA lineages, suggesting that the initial cpDNA divergence followed early polyploidizations. Five main AFLP groups were identified, consistent with recent glacial refugia in Beringia, western Siberia, the southern European mountains and areas south/east of the Scandinavian and Laurentide ice sheets. Except from the southern European mountains, there has been extensive expansion from all refugia, resulting in several contact zones. Surprisingly, the presumably older ploidy and cpDNA patterns were partly inconsistent with the main AFLP groups and more consistent with AFLP subgroups. A likely major driver causing the inconsistencies is recent nuclear gene flow via unreduced pollen from diploids to tetraploids. This may prevent cytoplasmic introgression and result in overlayed patterns formed by processes dominating at different time scales. The data also suggest more recent polyploidizations, as well as several chloroplast capture events, further complicating this scenario. This study highlights the importance of combining different marker systems to unravel intraspecific histories.
Role of inbreeding depression and purging in captive breeding and restoration programmes
Authors: LEBERG PAUL L. , FIRMIN BRIGETTE D.
Published: August 2007

Inbreeding depression is a major force affecting the evolution and viability of small populations in captive breeding and restoration programmes. Populations that experience small sizes may be less susceptible to future inbreeding depression because they have been purged of deleterious recessive alleles. We review issues related to purging, as they apply to the management of small populations, and discuss an experiment we conducted examining purging in populations of mosquitofish (Gambusia affinis). Purging is an important process in many small populations, but the literature contains a diversity of responses to purging both within and among studies. With the exception that slow inbreeding results in more purging and less threat to population viability, there seem to be few consistent trends that aid in prediction of how a purging event will affect a population. In our examination of purging on population viability in mosquitofish, single or multiple bottlenecks do not appear to have resulted in any purging of the influence of genetic load on population growth. Rather, serial bottlenecks resulted in a marked decline in population growth and an increase in extinction. Our results, taken together with those of reviewed studies, suggest that in small populations there is great uncertainty regarding the success of any single purging event in eliminating inbreeding depression, together with the high likelihood that purging will depress population viability through the fixation of deleterious alleles. In management of captive breeding and restoration programmes, the common practice of avoiding inbreeding and small population sizes should be followed whenever possible.
Genetic consequences of interbreeding between farmed and wild Atlantic salmon: insights from the transcriptome
Authors: ROBERGE CHRISTIAN , NORMANDEAU ÉRIC , EINUM SIGURD , GUDERLEY HELGA , BERNATCHEZ LOUIS
Published: August 2007

Large annual escapees of farmed Atlantic salmon enhance the risk of extinction of wild populations through genetic and ecological interactions. Recently, we documented evolutionary change in gene transcription between farmed and wild Atlantic salmon after only five generations of artificial selection. While differences for most quantitative traits are expected to gradually dilute through repeated backcrossing to wild populations, the genetic basis of gene transcription has been shown to be largely nonadditive and hybrid crosses may display unexpected inheritance patterns. This makes it difficult to predict to what extent interbreeding between farmed and wild individuals will change the genetic makeup of wild salmon populations. Here, we compare the genome‐wide gene transcription profiles of Norwegian wild salmon to that of a second generation hybrid cross [backcross: (Farmed X Wild) X Wild]. Over 6% (298, q‐value < 0.01) of the detected genes exhibited highly significantly different transcription levels, and the range and average magnitude of those differences was strikingly higher than previously described between pure farmed and wild strains. Most differences appear to result from nonadditive gene interactions. These results suggest that interbreeding of fugitive farmed salmon and wild individuals could substantially modify the genetic control of gene transcription in natural populations exposed to high migration from fish farms, resulting in potentially detrimental effects on the survival of these populations. This further supports the idea that measures to considerably reduce the number of escaped farmed salmon and their reproduction in the wild are urgently needed.
Comparative estimation of effective population sizes and temporal gene flow in two contrasting population systems
Authors: FRASER DYLAN J. , HANSEN MICHAEL M. , ØSTERGAARD SIRI , TESSIER NATHALIE , LEGAULT MICHEL , BERNATCHEZ LOUIS
Published: August 2007

Estimation of effective population sizes (Ne) and temporal gene flow (Nem, m) has many implications for understanding population structure in evolutionary and conservation biology. However, comparative studies that gauge the relative performance of Ne, Nem or m methods are few. Using temporal genetic data from two salmonid fish population systems with disparate population structure, we (i) evaluated the congruence in estimates and precision of long‐ and short‐term Ne, Nem and m from six methods; (ii) explored the effects of metapopulation structure on Ne estimation in one system with spatiotemporally linked subpopulations, using three approaches; and (iii) determined to what degree interpopulation gene flow was asymmetric over time. We found that long‐term Ne estimates exceeded short‐term Ne within populations by 2–10 times; the two were correlated in the system with temporally stable structure (Atlantic salmon, Salmo salar) but not in the highly dynamic system (brown trout, Salmo trutta). Four temporal methods yielded short‐term Ne estimates within populations that were strongly correlated, and these were higher but more variable within salmon populations than within trout populations. In trout populations, however, these short‐term Ne estimates were always lower when assuming gene flow than when assuming no gene flow. Linkage disequilibrium data generally yielded short‐term Ne estimates of the same magnitude as temporal methods in both systems, but the two were uncorrelated. Correlations between long‐ and short‐term geneflow estimates were inconsistent between methods, and their relative size varied up to eightfold within systems. While asymmetries in gene flow were common in both systems (58–63% of population‐pair comparisons), they were only temporally stable in direction within certain salmon population pairs, suggesting that gene flow between particular populations is often intermittent and/or variable. Exploratory metapopulation Ne analyses in trout demonstrated both the importance of spatial scale in estimating Ne and the role of gene flow in maintaining genetic variability within subpopulations. Collectively, our results illustrate the utility of comparatively applying Ne, Nem and m to (i) tease apart processes implicated in population structure, (ii) assess the degree of continuity in patterns of connectivity between population pairs and (iii) gauge the relative performance of different approaches, such as the influence of population subdivision and gene flow on Ne estimation. They further reiterate the importance of temporal sampling replication in population genetics, the value of interpreting Neor m in light of species biology, and the need to address long‐standing assumptions of current Ne, Nem or m models more explicitly in future research.
In vitro transposition of ISY100, a bacterial insertion sequence belonging to the Tc1/mariner family
Authors: Feng Xiaofeng , Colloms Sean D.
Published: August 2007

The Synechocystis sp. PCC6803 insertion sequence ISY100 (ISTcSa) belongs to the Tc1/mariner/IS630 family of transposable elements. ISY100 transposase was purified and shown to promote transposition in vitro. Transposase binds specifically to ISY100 terminal inverted repeat sequences via an N‐terminal DNA‐binding domain containing two helix–turn–helix motifs. Transposase is the only protein required for excision and integration of ISY100. Transposase made double‐strand breaks on a supercoiled DNA molecule containing a mini‐ISY100 transposon, cleaving exactly at the transposon 3′ ends and two nucleotides inside the 5′ ends. Cleavage of short linear substrates containing a single transposon end was less precise. Transposase also catalysed strand transfer, covalently joining the transposon 3′ end to the target DNA. When a donor plasmid carrying a mini‐ISY100 was incubated with a target plasmid and transposase, the most common products were insertions of one transposon end into the target DNA, but insertions of both ends at a single target site could be recovered after transformation into Escherichia coli. Insertions were almost exclusively into TA dinucleotides, and the target TA was duplicated on insertion. Our results demonstrate that there are no fundamental differences between the transposition mechanisms of IS630 family elements in bacteria and Tc1/mariner elements in higher eukaryotes.
The staphylococcal respiratory response regulator SrrAB induces ica gene transcription and polysaccharide intercellular adhesin expression, protecting Staphylococcus aureus from neutrophil killing under anaerobic growth conditions
Authors: Ulrich Martina , Bastian Mike , Cramton Sarah E. , Ziegler Katrin , Pragman Alexa A. , Bragonzi Alessandra , Memmi Guido , Wolz Christiane , Schlievert Patrick M. , Cheung Ambrose , Döring Gerd
Published: August 2007

In anaerobic environments, Staphylococcus aureus increases the transcription of the intercellular adhesin (ica) cluster, leading to increased polysaccharide intercellular adhesin (PIA) production. The regulatory mechanisms involved in this phenotypic change are mostly unknown. Here we show that the staphylococcal respiratory response regulator, SrrAB, significantly increases icaA transcription under anaerobic growth in S. aureus. Phosphorylated SrrA preferentially bound to a 100 bp DNA sequence located upstream of ica, and dot blot assays revealed little or no PIA expression in S. aureus srrAB deletion‐replacement mutants of strains Sa113 and SH1000, grown anaerobically. The biological relevance of SrrAB for S. aureus was assessed in a phagocytosis assay employing human neutrophils. Sixty‐eight per cent of PIA producing wild‐type cells, but only 19% of srrAB mutant cells survived under anaerobic conditions, suggesting that PIA protected S. aureus against non‐oxidative killing mechanisms of the neutrophils. No protection was observed when S. aureus or S. epidermidis strains, producing PIA also under aerobic conditions, were subjected to phagocytosis under aerobic conditions. These results demonstrate that SrrAB is a major activator of ica expression and PIA production in anaerobic environments, where it contributes to the protection of S. aureus against non‐oxidative defence mechanisms.
Root growth dynamics of Nicotiana attenuata seedlings are affected by simulated herbivore attack
Authors: HUMMEL GRÉGOIRE M. , NAUMANN MARIA , SCHURR ULRICH , WALTER ACHIM
Published: August 2007

Many studies demonstrate resource‐based trade‐offs between growth and defence on a large timescale. Yet, the short‐term dynamics of this growth reaction are still completely unclear, making it difficult to explain growth‐defence trade‐offs mechanistically. In this study, image‐based non‐destructive methods were used to quantify root growth reactions happening within hours following simulated herbivore attack. The induction of wound reactions in Nicotiana attenuata in the seedling stage led to transiently decreased root growth rates. Application of the oral secretion of the specialist herbivore Manduca sexta to the leaves led to a transient decrease in root growth that was more pronounced than if a mere mechanical wounding was imposed. Root growth reduction was more pronounced than leaf growth reduction. When fatty acid–amino acid conjugates (FACs) were applied to wounds, root growth reduction occurred in the same intensity as when oral secretion was applied. Timing of the transient growth reduction coincided with endogenous bursts of jasmonate (JA) and ethylene emissions reported in literature. Simulation of a wound response by applying methyl jasmonate (MeJA) led to more prolonged negative effects on root growth. Increased nicotine concentrations, trichome lengths and densities were observed within 72 h in seedlings that were treated with MeJA or that were mechanically wounded. Overall, these reactions indicate that even in a very early developmental stage, the diversion of plant metabolism from primary (growth‐sustaining) to secondary (defence‐related) metabolism can cause profound alterations of plant growth performance.
TERE; a novel cis‐element responsible for a coordinated expression of genes related to programmed cell death and secondary wall formation during differentiation of tracheary elements
Authors: Pyo Hyunjin , Demura Taku , Fukuda Hiroo
Published: August 2007

The differentiation of water‐conducting tracheary elements (TEs) is the result of the orchestrated construction of secondary wall structure, including lignification, and programmed cell death (PCD), including cellular autolysis. To understand the orchestrated regulation of differentiation of TEs, we investigated the regulatory mechanism of gene expression directing TE differentiation. Detailed loss‐of‐function and gain‐of‐function analyses of the ZCP4 (Zinniacysteine protease 4) promoter, which confers TE‐specific expression, demonstrated that a novel 11‐bp cis‐element is necessary and sufficient for the immature TE‐specific promoter activity. The 11‐bp cis‐element‐like sequences were found in promoters of many Arabidopsis TE differentiation‐related genes. A gain‐of‐function analysis with similar putative cis‐elements from secondary wall formation or modification‐related genes as well as PCD‐related genes indicated that the cis‐elements are also sufficient for TE‐specific expression of genes. These results demonstrate that a common sequence, designated as the tracheary‐element‐regulating cis‐element, confers TE‐specific expression to both genes related to secondary wall formation or modification and PCD.
Maximum Likelihood Estimation in Semiparametric Regression Models with Censored Data
Authors: Zeng D. , Lin D. Y.
Published: August 2007

Semiparametric regression models play a central role in formulating the effects of covariates on potentially censored failure times and in the joint modelling of incomplete repeated measures and failure times in longitudinal studies. The presence of infinite dimensional parameters poses considerable theoretical and computational challenges in the statistical analysis of such models. We present several classes of semiparametric regression models, which extend the existing models in important directions. We construct appropriate likelihood functions involving both finite dimensional and infinite dimensional parameters. The maximum likelihood estimators are consistent and asymptotically normal with efficient variances. We develop simple and stable numerical techniques to implement the corresponding inference procedures. Extensive simulation experiments demonstrate that the inferential and computational methods proposed perform well in practical settings. Applications to three medical studies yield important new insights. We conclude that there is no reason, theoretical or numerical, not to use maximum likelihood estimation for semiparametric regression models. We discuss several areas that need further research.
HLA Dr‐Dq haplotypes and the TNFA‐308 polymorphism: associations with asthma and allergy
Authors: Munthe‐Kaas M. C. , Carlsen K. L. , Carlsen K. H. , Egeland T. , Håland G. , Devulapalli C. S. , Akselsen H. , Undlien D.
Published: August 2007

Background:  The HLA (human leukocyte antigen) class II genes DQB1 and DRB1 and the Tumor Necrosis Factor α gene (TNFA) within the HLA complex (chromosome 6p21) have been associated with asthma and allergy. Due to the strong linkage disequilibrium characterizing this complex and the multiple asthma/allergy expressions, we aimed to determine which of these genes were primarily involved in specific asthma/allergy traits.

Methods:  The DRB1–DQB1 alleles and TNFA‐308 polymorphism were genotyped in 959 children from the Environment and Childhood Asthma study and analyzed for possible associations with allergic and non‐allergic asthma (with/without at least one positive skin prick test for allergens) and specific allergic sensitization, as well as bronchial hyperresponsiveness and total IgE, using both allele and extended haplotype analyses.

Results:  Different genes within the HLA complex were associated with separate asthma and allergy traits. Nonallergic asthma was associated with both the TNFA‐308A allele [Odds ratio (OR) 1.7 (1.3–2.3)] and DRB1*03 allele [OR 1.6(1–2.6)], but extended DRB1*03‐TNFA‐308 haplotype analysis suggested that the DRB1–DQB1 association was secondary to linkage disequilibrium with the TNFA‐308 polymorphism. Allergies were associated with HLA class II alleles only; birch sensitization with DQB1*0603‐DRB1*13 [OR 2.3 (1.4–4.0)] and mugwort sensitization with DQB1*0609‐DRB1*13 [OR 7.1 (1.9–27.0)] and DQB1*0501‐DRB1*01 [OR 2.0 (1.0–4.0)].

Conclusions:  Our data suggests that asthma is not associated with DRB1 or DQB1 but rather TNFA or a gene(s) in linkage disequilibrium, while sensitization to specific allergens is associated with particular alleles at the DQ and/or DR loci. A novel association between DQB1*0603‐DRB1*13 and birch allergy is identified.
Bronchial hyperresponsiveness in young children with allergic rhinitis and its risk factors
Authors: Choi S. H. , Yoo Y. , Yu J. , Rhee C.‐S. , Min Y.‐G. , Koh Y. Y.
Published: August 2007

Background:  Subjects with allergic rhinitis but no clinical evidence of asthma have greater bronchial hyperresponsiveness (BHR), and several factors have been implicated as its determinants. However, studies in young children are lacking. The aims of this study were to evaluate the prevalence of BHR in young children with allergic rhinitis and to investigate its risk factors.

Methods:  Methacholine bronchial challenges were performed in 4‐ to 6‐year‐old nonasthmatic children with allergic rhinitis (n = 83) and in healthy nonatopic controls (n = 32), using a modified auscultation method. The end‐point was defined as the appearance of wheezing and/or oxygen desaturation. Subjects were considered to have BHR when they had end‐point concentrations of methacholine ≤8 mg/mL. Clinical and laboratory data in allergic rhinitis patients and a history of allergic diseases in their parents were collected.

Results:  BHR was observed in 27 subjects with allergic rhinitis (32.5%) and three controls (9.4%). Among subjects with allergic rhinitis, serum total IgE, the number and pattern of skin‐prick test responses, blood eosinophil markers, and parental history of allergic rhinitis and atopic dermatitis were not different between the BHR(+) and BHR(−) groups, whereas the persistent type of rhinitis and parental history of asthma were more frequent in the BHR(+) group than in the BHR(−) group. These associations remained significant in a multivariable logistic regression.

Conclusions:  Young children with allergic rhinitis alone showed an increased prevalence of BHR. Both persistent type of rhinitis and parental history of asthma were significant and independent risk factors for BHR in these children.
Nasal epithelial cells express IL‐10 at levels that negatively correlate with clinical symptoms in patients with house dust mite allergy
Authors: Muller B. , De Groot E. J. J. , Kortekaas I. J. M. , Fokkens W. J. , Van Drunen C. M.
Published: August 2007

Background:  Despite constant exposure to micro‐organisms and other immunogenic environmental factors, relatively very few immunological responses are initiated in the nasal mucosa. Although several mechanisms could play a role in maintaining this immune suppressive milieu, none of them have been validated. Previous data from our group suggested that locally produced interleukin (IL)‐10 could be involved in maintaining local homeostasis.

Methods:  To investigate the role of epithelial IL‐10 expression in the manifestation of allergic symptoms, we used immunohistochemistry to study the expression of IL‐10 in the nasal epithelium of healthy individuals and house dust mite allergic patients. In the allergic patients, we determined potential correlations of epithelial expression with allergic symptoms, both at baseline and after allergen provocation.

Results:  IL‐10 is expressed in the basal and differentiated epithelial cells of both healthy individuals and allergic rhinitis patients. In the allergic individuals, there is a strong negative correlation at baseline between the epithelial expression level of IL‐10 and rhinorrhoea and sneezing, but not between that expression level and nasal blockage or peak nasal inspiratory flow (PNIF). This correlation disappears with steroid treatment or after allergen provocation, although the expression at baseline seems to predict PNIF scores after provocation.

Conclusions:  Our data not only reveals IL‐10 expression by human nasal epithelial cells, but also suggests that nasal epithelial IL‐10 regulates allergic symptoms. Targeting the regulation mechanisms affecting IL‐10 or targeting the regulation mechanism affected by IL‐10 could constitute new options for the treatment of allergic disease.
Effects of pollen and nasal glucocorticoid on FOXP3+, GATA‐3+ and T‐bet+ cells in allergic rhinitis
Authors: Malmhäll C. , Bossios A. , Pullerits T. , Lötvall J.
Published: August 2007

Background:  T‐regulatory cells (Treg) affect the balance of TH2 and TH1 cells. Treg, TH2 and TH1 cells are regulated by the FOXP3, GATA‐3 and T‐bet transcription factors respectively. Our aim was to determine the number of FOXP3+, GATA‐3+ and T‐bet+ cells in nasal mucosa in symptom‐free allergic rhinitis (AR) patients vs healthy controls, as well as the effects of natural pollen exposure and concomitant nasal glucocorticoid treatment on these cells.

Methods:  Nasal biopsies were taken from healthy controls and patients with grass‐pollen AR preseason. The AR patients were randomized to receive treatment with either fluticasone propionate (FP) or a placebo, and additional biopsies were taken during the pollen season. FOXP3+, GATA‐3+ and T‐bet+ cells in nasal mucosa were quantified by immunohistochemistry.

Results:  The number of FOXP3+ and GATA‐3+ cells, but not T‐bet+ cells, was significantly higher in AR patients vs controls preseason. The number of FOXP3+ cells remained unchanged in the former group after the pollen season but decreased significantly in the nasal mucosa as a result of FP treatment. The pollen season substantially increased the number of GATA‐3+ cells, which was inhibited by FP. The number of T‐bet+ cells was not affected by pollen or FP.

Conclusion:  These data suggest that nasal glucocorticoids attenuate the allergic inflammation partly by reducing the number of TH2 cells, but not by means of local upregulation of Treg cells. The local relationship between TH1 and TH2 cells as well as between Treg and TH2 is maintained by nasal glucocorticoid treatment.
Today’s allergic rhinitis patients are different: new factors that may play a role
Authors: Mösges R. , Klimek L.
Published: August 2007

Most of today’s patients suffering from allergic rhinitis (AR) are sensitized to more than one trigger and suffer from persistent and moderate/severe symptoms, which severely impair their quality of life (QOL). The objective of this article was to review the data on the effect of increased air pollution, changes in indoor environment/lifestyle/affluence, exposure to new allergens and psychologically stressful lifestyles, as also to explore their potential in the development of this more ‘aggressive’ form of disease.

Increased fossil fuel‐generated air pollution may increase the risk of allergic sensitization, airway responsiveness to allergens, and allergenicity and the bioavailability of airborne allergens. Changes in indoor environment/lifestyle/affluence appear to have led to more time being spent indoors and resulted in perennial exposure to indoor allergens, changes in sensitization patterns, and polysensitization to a variety of novel cross‐reacting exotic food and pet allergens. Although evidence suggests an association between psychological stress and increased risk for atopy and allergic disease, further studies are required to demonstrate this unequivocally.

The more persistent and moderate/severe nature of the disease suggests a need for modification of current treatment strategies and advocacy of the use from the outset of agents, which are both efficacious and safe in managing severe and persistent AR symptoms and in improving the QOL of affected individuals.
Assessment of combined symptom and medication scores for rhinoconjunctivitis immunotherapy clinical trials
Authors: Clark J. , Schall R.
Published: August 2007

Background:  In randomized, double‐blind, placebo‐controlled clinical trials the efficacy of immunotherapy for allergic rhinoconjunctivitis is evaluated using the Average Rhinoconjunctivitis Total Symptom Score (ARTSS). Effective treatment is associated with lower ARTSS relative to placebo. For ethical reasons patients are provided with registered rescue medication, which may alleviate symptoms and thus reduce symptom scores. This effect biases the mean difference in ARTSS between effective treatment and placebo towards zero. Therefore, when rescue medication is taken by a patient, the ARTSS needs to be adjusted appropriately.

Methods:  We considered five outcome measures: ARTSS, Average Rescue Medication Score (ARMS), and three combined symptom and RMSs. To assess the different outcome measures regarding their power to discriminate between effective treatment and placebo, we calculated their effect size when applied to data from a clinical trial of immunotherapy for allergic rhinoconjunctivitis.

Results:  Of the five outcome measures considered, the average of the ARTSS and ARMS was associated with the largest effect size, and thus with the highest power to show treatment efficacy. Discriminant and multivariate analyses suggest that this average is approximately optimal among all weighted sums of ARTSS and ARMS.

Conclusion:  Our findings support recommendations made in a World Allergy Organisation document on methodological aspects of immunotherapy trials. The average of the ARTSS and ARMS should be considered as a primary efficacy variable in clinical trials of immunotherapy for allergic rhinoconjunctivitis.
Relationship between ARIA classification and drug treatment in allergic rhinitis and asthma
Authors: Antonicelli L. , Micucci C. , Voltolini S. , Senna G. E. , Di Blasi P. , Visonà G. , De Marco R. , Bonifazi F.
Published: August 2007

Introduction:  The Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines provide a stepwise treatment to rhinitis, which classifies the disease according to its duration and severity.

Objectives:  The aim of the study was to verify whether these variables influence drug prescriptions for rhinitis and asthma.

Methods:  A multi‐centre cross‐sectional pharmaco‐epidemiological survey was carried out on 1610 allergic rhinitis patients and the relationship between the clinical features of rhinitis and drug therapy for rhinitis and asthma was evaluated.

Results:  A total of 1321 adult patients were enrolled. Mild intermittent rhinitis was diagnosed in 7.7%of the patients, moderate/severe intermittent in 17.1%, mild persistent in 11.6%, and moderate/severe persistent in 63.6%. A high level of rhinitis‐asthma comorbidity (616/1321 = 46.6%) was found. The majority of patients [1060 (80.24%)] were treated. Significant associations between the severity of rhinitis and the presence of therapy (P = 0.008), the use of oral antihistamines (P < 0.001), topical nasal steroids (P = 0.020) and systemic steroids (P = 0.005) were found. A weak association was found between the features of rhinitis and the therapy for asthma, and vice versa the comorbidity with asthma increases the prescription of inhalant (P < 0.001) and oral steroids (P = 0.015) to treat rhinitis.

Conclusion:  The severity of rhinitis influences patient request for rhinitis therapy and the type of medication more than the duration. These features of rhinitis seem to poorly influence asthma therapy. As the ARIA classification is able to reveal a relevant impairment notwithstanding therapy, its role in treated patients merits further study.
Molecular analysis and long‐term clinical evaluation of three siblings with Alström syndrome
Authors: Özgül RK , Satman I , Collin GB , Hinman EG , Marshall JD , Kocaman O , Tütüncü Y , Yılmaz T , Naggert JK
Published: August 2007

Alström syndrome is a rare, autosomal recessive disorder characterized by a wide spectrum of clinical features including early‐onset retinal degeneration leading to blindness, sensorineural hearing loss, short stature, obesity, type 2 diabetes, hyperlipidemia and dilated cardiomyopathy. Renal, hepatic and pulmonary dysfunction may occur in the later phases of the disease. The three affected sisters, from a consanguineous Turkish family, with the characteristic features of Alström syndrome, were clinically diagnosed in 1987 and followed for 20 years. DNA sequence analysis of ALMS1, the causative gene in Alström syndrome, identified a novel homozygous disease‐causing mutation, c.8164C>T, resulting in a premature termination codon in exon 10 in each of the three affected sisters. Furthermore, we describe the longitudinal disease progression in this family and report new clinical findings likely associated with Alström syndrome, such as pes planus and hyperthyroidism.
Movement and mood disorder in two brothers with Gaucher disease
Authors: Raja M , Azzoni A , Giona F , Regis S , Grossi S , Filocamo M , Sidransky E
Published: August 2007

Gaucher disease (GD) is a lysosomal storage disorder with a wide spectrum of phenotypic presentations. We report the case histories of two adult brothers with GD who developed both parkinsonism and psychiatric symptoms. Direct sequencing and real‐time polymerase chain reaction were used to establish that the patients were homozygous for mutation L444P. While parkinsonism has been described previously in GD, these patients had atypical features, including a complicated mood disorder. The comorbidity of GD and a mood disorder is a new finding, as psychiatric manifestations of GD have been described rarely. The etiology of the mental illness could be related to the processes contributing to the development of parkinsonism.