A helium-burning white dwarf binary as a supersoft X-ray source.

Type Ia supernovae are cosmic distance indicators1,2, and the main source of iron in the Universe3,4, but their formation paths are still debated. Several dozen supersoft X-ray sources, in which a white dwarf accretes hydrogen-rich matter from a non-degenerate donor star, have been observed5 and suggested as Type Ia supernovae progenitors6-9. However, observational evidence for hydrogen, which is expected to be stripped off the donor star during the supernova explosion10, is lacking. Helium-accreting white dwarfs, which would circumvent this problem, have been predicted for more than 30 years (refs. 7,11,12), including their appearance as supersoft X-ray sources, but have so far escaped detection. Here we report a supersoft X-ray source with an accretion disk whose optical spectrum is completely dominated by helium, suggesting that the donor star is hydrogen-free. We interpret the luminous and supersoft X-rays as resulting from helium burning near the surface of the accreting white dwarf. The properties of our system provide evidence for extended pathways towards Chandrasekhar-mass explosions based on helium accretion, in particular for stable burning in white dwarfs at lower accretion rates than expected so far. This may allow us to recover the population of the sub-energetic so-called Type Iax supernovae, up to 30% of all Type Ia supernovae13, within this scenario.

Sterile granulomatous panuveitis in dogs in the United Kingdom: A review of 33 cases.

PURPOSE: To describe the clinical and histopathological features of a sterile granulomatous panuveitis syndrome in 33 dogs that underwent enucleation and ocular histopathology. METHODS: Retrospective review of the medical records and ocular histopathology reports of 33 cases. Inclusion criteria were enucleation in conjunction with characteristic clinical and histopathological features. RESULTS: Thirteen breeds were represented (including crossbreeds). Panuveitis was acute and fulminating, and secondary glaucoma was common (n = 27). Interval from initial presentation to enucleation was 99 days (median 33 days, range 5-605 days). The mean age at enucleation was 6.7 years. Ocular signs were initially unilateral (n = 18) or bilateral (n = 15). The disease became bilateral in 18/25 cases that initially underwent unilateral enucleation, resulting in enucleation or euthanasia in 9/18 (mean interval of 168 days). Seven out of 59 eyes had a good outcome following topical anti-inflammatory and systemic immunosuppressive therapy. None of the dogs had travel history nor relevant systemic signs from presentation to follow-up (mean 619 days, range 16-3012 days). Histopathology revealed histiocytic and lymphoplasmacytic panuveitis with pigment dispersion, and no infectious agents were identified on light microscopy. CONCLUSION: To the authors' knowledge, this is the first report of a sterile granulomatous panuveitis syndrome in dogs in the UK. The clinical signs are severe, with rapid progression, and can result in bilateral enucleation or euthanasia in affected dogs. There does not appear to be an age or breed predisposition, however further research is necessary in this regard. Early and aggressive intervention, with both topical and systemic immunosuppressive therapy, is recommended to reduce the risk of blindness, enucleation, and euthanasia.

The Stress of Lung Aging: Endoplasmic Reticulum and Senescence Tête-à-Tête.

Beyond the structural changes, features including the dysregulation of endoplasmic reticulum (ER) stress response and increased senescence characterize the lung aging. ER stress response and senescence have been reported to be induced by factors like cigarette smoke. Therefore, deciphering the mechanisms underlying ER and senescent pathways interaction has become a challenge. In this review we highlight the known and unknown regarding ER stress response and senescence and their cross talk in aged lung.

Association between osteoarthritis-related serum biochemical markers over 11 years and knee MRI-based imaging biomarkers in middle-aged adults.

OBJECTIVE: To describe the associations between osteoarthritis (OA)-related biochemical markers (COMP, MMP-3, HA) and MRI-based imaging biomarkers in middle-aged adults over 10-13 years. METHODS: Blood serum samples collected during the Childhood Determinants of Adult Health (CDAH)-1 study (year:2004-06; n = 156) and 10-13 year follow-up at CDAH-3 (n = 167) were analysed for COMP, MMP-3, and HA using non-isotopic ELISA. Knee MRI scans obtained during the CDAH-knee study (year:2008-10; n = 313) were assessed for cartilage volume and thickness, subchondral bone area, cartilage defects, and BML. RESULTS: In a multivariable linear regression model describing the association of baseline biochemical markers with MRI-markers (assessed after 4-years), we found a significant negative association of standardised COMP with medial femorotibial compartment cartilage thickness (ß:-0.070; 95%CI:-0.138,-0.001), and standardised MMP-3 with patellar cartilage volume (ß:-141.548; 95%CI:-254.917,-28.179) and total bone area (ß:-0.729; 95%CI:-1.340,-0.118). In multivariable Tobit regression model, there was a significant association of MRI-markers with biochemical markers (assessed after 6-9 years); a significant negative association of patellar cartilage volume (ß:-0.001; 95%CI:-0.002,-0.00004), and total bone area (ß:-0.158; 95%CI-0.307,-0.010) with MMP-3, and total cartilage volume (ß:-0.001; 95%CI:-0.001,-0.0001) and total bone area (ß:-0.373; 95%CI:-0.636,-0.111) with COMP. No significant associations were observed between MRI-based imaging biomarkers and HA. CONCLUSION: COMP and MMP-3 levels were negatively associated with knee cartilage thickness and volume assessed 4-years later, respectively. Knee cartilage volume and bone area were negatively associated with COMP and MMP-3 levels assessed 6-9 years later. These results suggest that OA-related biochemical markers and MRI-markers are interrelated in early OA.

Human lung extracellular matrix hydrogels resemble the stiffness and viscoelasticity of native lung tissue.

Chronic lung diseases such as idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) are associated with changes in extracellular matrix (ECM) composition and abundance affecting the mechanical properties of the lung. This study aimed to generate ECM hydrogels from control, severe COPD [Global Initiative for Chronic Obstructive Lung Disease (GOLD) IV], and fibrotic human lung tissue and evaluate whether their stiffness and viscoelastic properties were reflective of native tissue. For hydrogel generation, control, COPD GOLD IV, and fibrotic human lung tissues were decellularized, lyophilized, ground into powder, porcine pepsin solubilized, buffered with PBS, and gelled at 37°C. Rheological properties from tissues and hydrogels were assessed with a low-load compression tester measuring the stiffness and viscoelastic properties in terms of a generalized Maxwell model representing phases of viscoelastic relaxation. The ECM hydrogels had a greater stress relaxation than tissues. ECM hydrogels required three Maxwell elements with slightly faster relaxation times (τ) than that of native tissue, which required four elements. The relative importance (Ri) of the first Maxwell element contributed the most in ECM hydrogels, whereas for tissue the contribution was spread over all four elements. IPF tissue had a longer-lasting fourth element with a higher Ri than the other tissues, and IPF ECM hydrogels did require a fourth Maxwell element, in contrast to all other ECM hydrogels. This study shows that hydrogels composed of native human lung ECM can be generated. Stiffness of ECM hydrogels resembled that of whole tissue, while viscoelasticity differed.

Crystal structure of NucB, a biofilm-degrading endonuclease.

Bacterial biofilms are a complex architecture of cells that grow on moist interfaces, and are held together by a molecular glue of extracellular proteins, sugars and nucleic acids. Biofilms are particularly problematic in human healthcare as they can coat medical implants and are thus a potential source of disease. The enzymatic dispersal of biofilms is increasingly being developed as a new strategy to treat this problem. Here, we have characterized NucB, a biofilm-dispersing nuclease from a marine strain of Bacillus licheniformis, and present its crystal structure together with the biochemistry and a mutational analysis required to confirm its active site. Taken together, these data support the categorization of NucB into a unique subfamily of the ßßα metal-dependent non-specific endonucleases. Understanding the structure and function of NucB will facilitate its future development into an anti-biofilm therapeutic agent.

Regulating, Measuring, and Modeling the Viscoelasticity of Bacterial Biofilms

Biofilms occur in a broad range of environments under heterogeneous physicochemical conditions, such as in bioremediation plants, on surfaces of biomedical implants, and in the lungs of cystic fibrosis patients. In these scenarios, biofilms are subjected to shear forces, but the mechanical integrity of these aggregates often prevents their disruption or dispersal. Biofilms' physical robustness is the result of the multiple biopolymers secreted by constituent microbial cells which are also responsible for numerous biological functions. A better understanding of the role of these biopolymers and their response to dynamic forces is therefore crucial for understanding the interplay between biofilm structure and function. In this paper, we review experimental techniques in rheology, which help quantify the viscoelasticity of biofilms, and modeling approaches from soft matter physics that can assist our understanding of the rheological properties. We describe how these methods could be combined with synthetic biology approaches to control and investigate the effects of secreted polymers on the physical properties of biofilms. We argue that without an integrated approach of the three disciplines, the links between genetics, composition, and interaction of matrix biopolymers and the viscoelastic properties of biofilms will be much harder to uncover.

Importance of Water-Volume on the Release of Microplastic Fibers from Laundry.

The influence of laundry washing parameters on the release of microfibers (MF) from polyester textiles was studied. These fibers are an important type of microplastic pollution. However, the factors which affect MF release during laundry are poorly understood and more rigorous methods for quantifying this release are needed. A novel method was therefore developed using a tergotometer with eight 1000 mL washing vessels and the CIELab color space measure of lightness (L*). L* was related to the mass of released MFs by creating a calibration curve to quantify the amounts of MFs released from textiles during washing. This method was used to investigate the effect of water-volume, agitation, temperature, and duration of the wash on MF release. Counterintuitively, increased water-volume, characteristic of European "delicate" cycles, resulted in the greatest release of MFs. Full-scale testing was then carried out using domestic washing machines with real consumer cycles to determine the effect of cycle type on MF release. In the first wash, delicate wash cycles released 800 000 more MFs (94 mg/kg) per wash than a lower water-volume standard wash and also increased MF release in subsequent washing cycles (P < 0.05). These results indicate that a high water-volume-to-fabric ratio is the most influential factor for MF release, rather than agitation as previously thought. Therefore, consumers can reduce MF release by avoiding high water-volume washes (delicate cycles), transitioning to appliances that use a lower water-volume (North American high-efficiency washing machines), and ensuring that full wash loads are used.

Association between the age of solid food introduction and eczema: A systematic review and a meta-analysis.

INTRODUCTION: Eczema is a common childhood ailment responsible for a considerable disease burden. Both timing of introduction to solid food and allergenic food are believed to be related to childhood eczema. Despite the growing body of evidence, the relationship between timing of any solid food introduction (allergenic and/or non-allergenic) and development of eczema has not previously been systematically reviewed. METHODS: PubMed and EMBASE databases were searched using food and eczema terms. Two authors selected papers according to the inclusion criteria and extracted information on study characteristics and measures of association. Meta-analyses were performed after grouping studies according to the age and type of exposure. RESULTS: A total of 17 papers met the inclusion criteria, reporting results from 16 study populations. Of these, 11 were cohort studies, 2 case-controls, 1 cross-sectional study and 2 randomized controlled trials. Limited meta-analyses were performed due to heterogeneity between studies. Timing of solid food introduction was not associated with eczema. One randomized controlled trial provided weak evidence of an association between early allergenic (around 4 months) food introduction and reduced risk of eczema. CONCLUSIONS: The available evidence is currently insufficient to determine whether the timing of introduction of any solid food influences the risk of eczema.

Silver Diamine Fluoride: A Successful Anticarious Solution with Limits.

Silver diamine fluoride (SDF) is a solution containing ionic silver, fluoride, and ammonia that arrests the progress of carious lesions and prevents the development of future caries. The silver particle extends into the dentin tubules and could create some bonding problems for subsequent composite resin restorations placed over SDF-treated darkened tooth structures. The fluoride penetrates deeper into the tooth with SDF as compared with other fluoride solutions, creating a fluoride reservoir in the tooth structure. The fluoride component of SDF contributes to remineralization and fluorapatite formation, producing harder, more caries-resistant tooth structures. The silver provides the antimicrobial activity for the material and inhibits biofilm formation. It has been evaluated in >20 clinical studies and reviewed in systemic reviews. The material was recently approved by the Food and Drug Administration for desensitizing cold-sensitive teeth and has been used off-label to treat carious lesions. SDF will produce a caries lesion darker (brown to black) than the original, which is the major criticism of the material. A nanoparticle-sized silver material was recently developed that may retain the antimicrobial properties of the larger-sized ion silver material without the discoloring effects. The application of SDF is easily adapted for field use. The lesion is isolated, and the solution is painted onto the clean caries lesion and dried. This simple application process requires little equipment, and its low cost per application makes the material ideal for large populations.

The promise of marine molecules as cosmetic active ingredients.

The marine environment represents an underexploited resource for the discovery of novel products, despite its high level of biological and chemical diversity. With increasing awareness of the harmful effects of chronic ultraviolet exposure, and a universal desire to improve cosmetic appearance, the market for new cosmetic ingredients is growing, and current trends have generated a greater demand for products sourced from the environment. A growing number of novel molecules from marine flora and fauna exhibit potent and effective dermatological activities. Secondary metabolites isolated from macroalgae, including carotenoids and polyphenols, have demonstrated antioxidant, anti-ageing and anti-inflammatory activities. In addition, marine extremophilic bacteria have recently been shown to produce bioactive exopolymeric molecules, some of which have been commercialized. Available data on their activities show significant antioxidant, moisturizing and anti-ageing activities, but a more focussed investigation into their mechanisms and applications is required. This review surveys the reported biological activities of an emerging and growing portfolio of marine molecules that show promise in the treatment of cosmetic skin problems including ultraviolet damage, ageing and cutaneous dryness.

Latrophilin receptors: novel bronchodilator targets in asthma.

BACKGROUND: Asthma affects 300 million people worldwide. In asthma, the major cause of morbidity and mortality is acute airway narrowing, due to airway smooth muscle (ASM) hypercontraction, associated with airway remodelling. However, little is known about the transcriptional differences between healthy and asthmatic ASM cells. OBJECTIVES: To investigate the transcriptional differences between asthmatic and healthy airway smooth muscle cells (ASMC) in culture and investigate the identified targets using in vitro and ex vivo techniques. METHODS: Human asthmatic and healthy ASMC grown in culture were run on Affymetrix_Hugene_1.0_ST microarrays. Identified candidates were confirmed by PCR, and immunohistochemistry. Functional analysis was conducted using in vitro ASMC proliferation, attachment and contraction assays and ex vivo contraction of mouse airways. RESULTS: We suggest a novel role for latrophilin (LPHN) receptors, finding increased expression on ASMC from asthmatics, compared with non-asthmatics in vivo and in vitro, suggesting a role in mediating airway function. A single nucleotide polymorphism in LPHN1 was associated with asthma and with increased LPHN1 expression in lung tissue. When activated, LPHNs regulated ASMC adhesion and proliferation in vitro, and promoted contraction of mouse airways and ASMC. CONCLUSIONS: Given the need for novel inhibitors of airway remodelling and bronchodilators in asthma, the LPHN family may represent promising novel targets for future dual therapeutic intervention.

Temporal trends in thyroid-stimulating hormone (TSH) and thyroid peroxidase antibody (ATPO) testing across two phases of iodine fortification in Tasmania (1995-2013).

CONTEXT: Tasmania is an island state of the Australian Commonwealth with a well-documented history of mild iodine deficiency. Between 2001 and 2009, Tasmania experienced two incremental phases of iodine fortification. OBJECTIVE: To examine trends in thyroid-stimulating hormone (TSH) and thyroid peroxidase antibody (ATPO) testing and their relationship to different phases of iodine nutrition in the Tasmanian population between 1995 and 2013. DESIGN: Retrospective longitudinal study. SETTING AND PARTICIPANTS: The major primary care and largest public hospital pathology providers in Tasmania submitted data for all TSH and ATPO tests performed between 1995 and 2013. Data linkage methodology was used to determine trends in TSH and ATPO testing. RESULTS: A total of 1.66 million TSH assessments, involving 389,910 individual patients, were performed in Tasmania between 1995 and 2013. There was approximately a fourfold increase in the overall rate of TSH testing during this period with the rate of incident TSH assessment remaining relatively stable over the study period. The incidence of overt suppression and elevation of TSH (TSH≤0.1 mIU/L and ≥10 mIU/L) declined 62.3% and 59.7%, respectively, with a trend for increased incidence of borderline TSH elevation ≥4.0 mIU/L. The incidence of thyroid autoimmunity as determined by the proportion of abnormal ATPO results remained stable, with the absolute number of positive test results increasing during the study period. CONCLUSION: Iodine supplementation of this mildly iodine-deficient population was not associated with an obvious increase in incidence of overt thyroid dysfunction or autoimmunity. Whilst the volume of TSH testing increased over the study period, the increase was driven by patients undergoing follow-up TSH assessments.

Utility of FDG-PET imaging in screening for succinate dehydrogenase B and D mutation-related lesions.

OBJECTIVE: Mutations of the genes encoding succinate dehydrogenase B and D (SDHB, SDHD) are associated with highly penetrant phenotypes, including paragangliomas and phaeochromocytomas. Patients with these mutations require lifelong surveillance; however, there is currently ambiguity regarding the optimal screening regimen. We sought to determine the utility of fluorodeoxyglucose (18F) positron emission tomography (18F-FDG PET) imaging, compared to other modalities for detecting SDHB and SDHD mutation-related lesions. DESIGN: A retrospective audit of patients with SDHB or SDHD mutation. PATIENTS: All adult patients with confirmed SDHB and SDHD mutations who underwent 18F-FDG PET/CT at our institution between 1 July 2011 and 30 May 2015. MEASUREMENTS: 18F-FDG PET/computed tomography (CT) performed during surveillance of patients with SDHB and SDHD mutations. Lesion numbers and locations detected by 18F-FDG PET were compared to those identified on the CT component, as well as other imaging modalities and histology when available. RESULTS: Thirty-one 18F-FDG PET/CT studies were completed on 22 patients. For SDHB (20 patients), there were five positive and 21 negative studies. There were no false-negative 18F-FDG PET studies. Positive 18F-FDG PET findings correlated with magnetic resonance imaging (MRI), CT and [68 Ga]-DOTA(0)-Tyr(3)-octreotate (68 Ga DOTATATE PET/CT) imaging with no missed lesions; the only potential false-positive result relating to nonspecific postoperative changes (sensitivity 100·0%, specificity 95·5%). For SDHD (two patients), lesions were detected on 18F-FDG PET and correlated with other imaging in three of five studies. Metastatic lesions were incompletely visualized on 18F-FDG PET but were detected on the noncontrast fusion CT. CONCLUSIONS: 18F-FDG PET/CT is suitable for detecting SDHB and SDHD mutation-related lesions and may be considered effective for periodic surveillance of patients with these mutations.

Exposure to 'farming' and objective markers of atopy: a systematic review and meta-analysis.

There is growing interest in the 'farm effect' on the spectrum of allergy. Evidence concerning the farm effect on asthma, eczema, and allergic rhinitis has been systematically synthesized, but without a specific focus on objective markers of sensitization. This focus is important, as farm exposures may be related to allergy but not to non-allergic phenotypes of disease. We aimed to systematically review and meta-analyse literature that has investigated associations between farm exposure at any age and objective measures of atopy, that is serum IgE or skin prick tests results. Using predefined inclusion and exclusion criteria, we identified 29 articles for review. IgE levels were measured in either childhood or adulthood by eighteen studies, while skin prick testing was performed in sixteen studies. Newcastle-Ottawa Scale quality assessments indicated that the majority of these studies demonstrated a representative sample of selected participants. Due to significant heterogeneity in study measures and methodology between studies, only few were meta-analysed. This meta-analysis showed a significant protective effect of farm exposure before 1 year of life on allergic sensitization (OR = 0.60 [0.52-0.70]). Farm exposure during childhood was also associated with a reduced risk of sensitization to cat or timothy (OR = 0.60 [0.51-0.70]; OR=0.46 [0.41-0.51]). Studies investigating the effect of farm exposure in adult life could not be meta-analysed, and their results were inconsistent. Insufficient studies investigated food sensitization as an outcome to allow synthesis. The majority of studies included in this review investigated childhood farm exposure, finding evidence to support a protective childhood 'farm effect' against subsequent atopy. There is inconsistent evidence on the association between farm exposure in adulthood and allergic sensitization. Further studies are needed to tease out the exact exposures and timing associated with farming environments that protect against allergic disease.

Shewanella electrodiphila sp. nov., a psychrotolerant bacterium isolated from Mid-Atlantic Ridge deep-sea sediments.

Strains MAR441(T) and MAR445 were isolated from Mid-Atlantic Ridge sediments from a depth of 2734 m, and were found to belong to the genus Shewanella. The strains were rod-shaped, pigmented, non-motile and capable of anaerobic growth either by fermentation of carbohydrates or by anaerobic respiration. The strains utilized a variety of electron acceptors, including nitrate and ferric compounds, and could utilize peptone when grown anaerobically in a two-chambered microbial fuel cell, which used carbon cloth electrodes and delivered a stable power output of ,150-200 mW m(-2). The major fatty acids were typical of the genus Shewanella, with major components C13 : 0, iso-C13 : 0, iso-C15 : 0, C16 : 0, C16 : 1ω7c, C18 : 1ω7c and C20 : 5ω3 fatty acids. The DNA G+C content of strains MAR441(T) and MAR445 was 42.4 mol%. 16S rRNA gene sequence analysis indicated that strains MAR441(T) and MAR445 were most closely related to Shewanella olleyana (sequence similarities 97.9% to the type strain). DNA-DNA hybridization demonstrated only 15.6-37.2% relatedness between strain MAR441(T) and the type strains of related species of the genus Shewanella. Phenotypic characteristics confirmed that these isolates constituted a novel species of the genus Shewanella, for which the name Shewanella electrodiphila sp. nov. is proposed; the type strain is MAR441(T) (5ATCC BAA-2408(T) = DSM 24955(T)).

A limit on the variation of the speed of light arising from quantum gravity effects.

A cornerstone of Einstein's special relativity is Lorentz invariance-the postulate that all observers measure exactly the same speed of light in vacuum, independent of photon-energy. While special relativity assumes that there is no fundamental length-scale associated with such invariance, there is a fundamental scale (the Planck scale, l(Planck) approximately 1.62 x 10(-33) cm or E(Planck) = M(Planck)c(2) approximately 1.22 x 10(19) GeV), at which quantum effects are expected to strongly affect the nature of space-time. There is great interest in the (not yet validated) idea that Lorentz invariance might break near the Planck scale. A key test of such violation of Lorentz invariance is a possible variation of photon speed with energy. Even a tiny variation in photon speed, when accumulated over cosmological light-travel times, may be revealed by observing sharp features in gamma-ray burst (GRB) light-curves. Here we report the detection of emission up to approximately 31 GeV from the distant and short GRB 090510. We find no evidence for the violation of Lorentz invariance, and place a lower limit of 1.2E(Planck) on the scale of a linear energy dependence (or an inverse wavelength dependence), subject to reasonable assumptions about the emission (equivalently we have an upper limit of l(Planck)/1.2 on the length scale of the effect). Our results disfavour quantum-gravity theories in which the quantum nature of space-time on a very small scale linearly alters the speed of light.

Admission blood glucose predicts mortality and length of stay in patients admitted through the emergency department.

BACKGROUND: Hyperglycaemia has been associated with adverse outcomes in several different hospital populations. AIM: The aim of this study was to investigate the relationship between admission blood glucose level (BGL) and outcomes in all patients admitted through the emergency department. METHODS: This study was a retrospective observational cohort study from an Australian tertiary referral hospital. Patients admitted in the first week of each month from April to October 2012 had demographic data, co-morbidities, BGL, intensive care unit admission, length of stay and dates of death recorded. Factors associated with outcomes were assessed by multi-level mixed-effects linear regression. RESULTS: Admission BGL was recorded for 601 admissions with no diagnosis of diabetes and for 219 admissions diagnosed with type 2 diabetes (T2DM). In patients with no diagnosis of diabetes, admission BGL was associated with in-hospital and 90-day mortality (P < 0.001). After multivariate analysis, BGL greater than 11.5 mmol/L was significantly associated with increased mortality at 90 days (P < 0.05). In patients with T2DM increased BGL on admission was not associated with in-hospital or 90-day mortality but was associated with length of hospital stay (ß: 0.22 days/mmol/L; 95% confidence interval 0.09-0.35; P < 0.001), although this association was lost on multivariable analysis. In patients with T2DM, increased coefficient of variation of BGL was also positively associated with length of hospital stay in an almost dose-dependent fashion (P < 0.001). CONCLUSION: Admission BGL was independently associated with increased mortality in patients with no diagnosis of diabetes. Glycaemic variability was associated with increased length of hospital stay in patients with T2DM.

Atopic dermatitis and the atopic march revisited.

Atopic dermatitis (AD) has become a significant public health problem because of increasing prevalence, together with increasing evidence that it may progress to other allergic phenotypes. While it is now acknowledged that AD commonly precedes other allergic diseases, a link termed 'the atopic march', debate continues as to whether this represents a causal relationship. An alternative hypothesis is that this association may be related to confounding by familial factors or phenotypes that comanifest, such as early-life wheeze and sensitization. However, there is increasing evidence from longitudinal studies suggesting that the association between AD and other allergies is independent of confounding by comanifest allergic phenotypes. The hypotheses on plausible biological mechanisms for the atopic march focus on defective skin barrier function and overexpression of inflammatory mediators released by the skin affected by AD (including thymic stromal lymphopoietin). Both human and animal studies have provided evidence supporting these potential biological mechanisms. Evidence from prevention trials is now critical to establishing a causal nature of the atopic march. An emerging area of research is investigation into environmental modifiers of the atopic march. Such information will assist in identifying secondary prevention strategies to arrest the atopic march. Despite much research into the aetiology of allergies, little progress has been made in identifying effective strategies to reduce the burden of allergic conditions. In this context, the atopic march remains a promising area of investigation.

CD14 polymorphisms, microbial exposure and allergic diseases: a systematic review of gene-environment interactions.

Asthma and allergy may develop as a result of interactions between environmental factors and the genetic characteristics of an individual. This review aims to summarize the available evidence for, and potential effects of, an interaction between polymorphisms of the CD14 gene and exposure to microbes on the risk of asthma and allergic diseases. We searched PubMed, MEDLINE and Global Health databases, finding 12 articles which met inclusion criteria. Most studies reported a significant interaction between CD14 polymorphisms and microbial exposure. When stratified by age at microbial exposure (early life vs adult life), there was evidence of a protective effect of gene-environment interaction against atopy in children, but not adults. We also found different effects of interaction depending on the type of microbial exposures. There was no strong evidence for asthma and eczema. Future studies should consider a three-way interaction between CD14 gene polymorphisms, microbial exposures and the age of exposure.