Early life antibiotic-driven changes in microbiota enhance susceptibility to allergic asthma

Allergic asthma rates have increased steadily in developed countries, arguing for an environmental aetiology. To assess the influence of gut microbiota on experimental murine allergic asthma, we treated neonatal mice with clinical doses of two widely used antibiotics--streptomycin and vancomycin--and evaluated resulting shifts in resident flora and subsequent susceptibility to allergic asthma. Streptomycin treatment had little effect on the microbiota and on disease, whereas vancomycin reduced microbial diversity, shifted the composition of the bacterial population and enhanced disease severity. Neither antibiotic had a significant effect when administered to adult mice. Consistent with the 'hygiene hypothesis', our data support a neonatal, microbiota-driven, specific increase in susceptibility to experimental murine allergic asthma.     

Clinical features and predictors for disease natural progression in adults with Pompe disease: a nationwide prospective observational study

Background

Due partly to physicians’ unawareness, many adults with Pompe disease are diagnosed with great delay. Besides, it is not well known which factors influence the rate of disease progression, and thus disease outcome. We delineated the specific clinical features of Pompe disease in adults, and mapped out the distribution and severity of muscle weakness, and the sequence of involvement of the individual muscle groups. Furthermore, we defined the natural disease course and identified prognostic factors for disease progression.

Methods

We conducted a single-center, prospective, observational study. Muscle strength (manual muscle testing, and hand-held dynamometry), muscle function (quick motor function test), and pulmonary function (forced vital capacity in sitting and supine positions) were assessed every 3–6 months and analyzed using repeated-measures ANOVA.

Results

Between October 2004 and August 2009, 94 patients aged between 25 and 75 years were included in the study. Although skeletal muscle weakness was typically distributed in a limb-girdle pattern, many patients had unfamiliar features such as ptosis (23%), bulbar weakness (28%), and scapular winging (33%). During follow-up (average 1.6 years, range 0.5-4.2 years), skeletal muscle strength deteriorated significantly (mean declines of ?1.3% point/year for manual muscle testing and of ?2.6% points/year for hand-held dynamometry; both p<0.001). Longer disease duration (>15 years) and pulmonary involvement (forced vital capacity in sitting position <80%) at study entry predicted faster decline. On average, forced vital capacity in supine position deteriorated by 1.3% points per year (p=0.02). Decline in pulmonary function was consistent across subgroups. Ten percent of patients declined unexpectedly fast.

Conclusions

Recognizing patterns of common and less familiar characteristics in adults with Pompe disease facilitates timely diagnosis. Longer disease duration and reduced pulmonary function stand out as predictors of rapid disease progression, and aid in deciding whether to initiate enzyme replacement therapy, or when.

     

Ecological aspects of mycorrhizal symbiosis: with special emphasis on the functional diversity of interactions involving the extraradical mycelium

Different symbiotic mycorrhizal associations between plantsand fungi occur, almost ubiquitously, in a wide range of terrestrialecosystems. Historically, these have mainly been consideredwithin the rather narrow perspective of their effects on theuptake of dissolved mineral nutrients by individual plants.More recent research has placed emphasis on a wider, multifunctionalperspective, including the effects of mycorrhizal symbiosison plant and microbial communities, and on ecosystem processes.This includes mobilization of N and P from organic polymers,release of nutrients from mineral particles or rock surfacesvia weathering, effects on carbon cycling, interactions withmyco-heterotrophic plants, mediation of plant responses to stressfactors such as drought, soil acidification, toxic metals, andplant pathogens, as well as a range of possible interactionswith groups of other soil micro-organisms. Mycorrhizal fungiconnect their plant hosts to the heterogeneously distributednutrients required for their growth, enabling the flow of energy-richcompounds required for nutrient mobilization whilst simultaneouslyproviding conduits for the translocation of mobilized productsback to their hosts. In addition to increasing the nutrientabsorptive surface area of their host plant root systems, theextraradical mycelium of mycorrhizal fungi provides a directpathway for translocation of photosynthetically derived carbonto microsites in the soil and a large surface area for interactionwith other micro-organisms. The detailed functioning and regulationof these mycorrhizosphere processes is still poorly understoodbut recent progress is reviewed and potential benefits of improvedunderstanding of mycorrhizosphere interactions are discussed. Key words: Arbuscular mycorrhiza, biotic interactions, carbon flow, ectomycorrhiza, ericoid mycorrhiza, mycelium, nutrient uptake, symbiosis, weathering Received 22 January 2008; Revised 7 February 2008 Accepted 7 February 2008     

Molecular analysis as an aid to assess the public health risk of non-O157 Shiga toxin-producing Escherichia coli strains

Shiga toxin-producing Escherichia coli (STEC) strains are commensal bacteria in cattle with high potential for environmental and zoonotic transmission to humans. Although O157:H7 is the most common STEC serotype, there is growing concern over the emergence of more than 200 highly virulent non-O157 STEC serotypes that are globally distributed, several of which are associated with outbreaks and/or severe human illness such as hemolytic-uremic syndrome (HUS) and hemorrhagic colitis. At present, the underlying genetic basis of virulence potential in non-O157 STEC is unknown, although horizontal gene transfer and the acquisition of new pathogenicity islands are an expected origin. We used seropathotype classification as a framework to identify genetic elements that distinguish non-O157 STEC strains posing a serious risk to humans from STEC strains that are not associated with severe and epidemic disease. We report the identification of three genomic islands encoding non-LEE effector (nle) genes and 14 individual nle genes in non-O157 STEC strains that correlate independently with outbreak and HUS potential in humans. The implications for transmissible zoonotic spread and public health are discussed. These results and methods offer a molecular risk assessment strategy to rapidly recognize and respond to non-O157 STEC strains from environmental and animal sources that might pose serious public health risks to humans.     

Community analysis of arbuscular mycorrhizal fungi and bacteria in the maize mycorrhizosphere in a long-term fertilization trial

In this study, we investigated the impact of organic and mineral fertilizers on the community composition of arbuscular mycorrhizal (AM) fungi and bacteria in the mycorrhizosphere of maize in a field experiment established in 1956, in south-east Sweden. Roots and root-associated soil aggregates were sampled four times during the growing season in 2005, in control plots and in plots amended with calcium nitrate, ammonium sulphate, green manure, farmyard manure or sewage sludge. Fungi in roots were identified by cloning and sequencing, and bacteria in soil aggregates were analysed by terminal-restriction fragment length polymorphism, cloning and sequencing. The community composition of AM fungi and bacteria was significantly influenced by the different fertilizers. Changes in microbial community composition were mainly correlated with changes in pH induced by the fertilization regime. However, other factors, including phosphate and soil carbon content, also contributed significantly to these changes. Changes in bacterial community composition and a reduction in bacterial taxon richness throughout the growing season were also manifest. The results of this study highlight the importance and significant effects of the long-term application of different fertilizers on edaphic factors and specific groups of fungi and bacteria playing a key role in arable soils.     

Glycogen Synthase Kinase-3 regulates IGFBP-1 gene transcription through the Thymine-rich Insulin Response Element

Background  

Hepatic expression of several gene products involved in glucose metabolism, including phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase) and insulin-like growth factor binding protein-1 (IGFBP-1), is rapidly and completely inhibited by insulin. This inhibition is mediated through the regulation of a DNA element present in each of these gene promoters, that we call the Thymine-rich Insulin Response Element (TIRE). The insulin signalling pathway that results in the inhibition of these gene promoters requires the activation of phosphatidylinositol 3-kinase (PI 3-kinase). However, the molecules that connect PI 3-kinase to these gene promoters are not yet fully defined. Glycogen Synthase Kinase 3 (GSK-3) is inhibited following activation of PI 3-kinase. We have shown previously that inhibitors of GSK-3 reduce the activity of two TIRE-containing gene promoters (PEPCK and G6Pase), whose products are required for gluconeogenesis.     

Autoantibody systems in rheumatoid arthritis: specificity, sensitivity and diagnostic value

This review focuses on the mechanisms of stress response in the synovial tissue of rheumatoid arthritis. The major stress factors, such as heat stress, shear stress, proinflammatory cytokines and oxidative stress, are discussed and reviewed, focusing on their potential to induce a stress response in the synovial tissue. Several pathways of stress signalling molecules are found to be activated in the synovial membrane of rheumatoid arthritis; of these the most important examples are heat shock proteins, mitogen-activated protein kinases, stress-activated protein kinases and molecules involved in the oxidative stress pathways. The expression of these pathways in vitro and in vivo as well as the consequences of stress signalling in the rheumatoid synovium are discussed. Stress signalling is part of a cellular response to potentially harmful stimuli and thus is essentially involved in the process of synovitis. Stress signalling pathways are therefore new and promising targets of future anti-rheumatic therapies.     

Nramp1 modifies the fusion of Salmonella typhimurium-containing vacuoles with cellular endomembranes in macrophages.

Salmonella survive and replicate within mammalian cells by becoming secluded within specialized membrane-bound vacuoles inaccessible to the host defense mechanisms. Delayed acidification of the vacuole and its incomplete fusion with lysosomes have been implicated in intracellular Salmonella survival. Nramp1 confers to macrophages resistance to a variety of intracellular pathogens, including Salmonella, but its precise mode of action is not understood. We investigated whether Nramp1 affects the maturation and acidification of Salmonella-containing vacuoles (SCV). A mouse-derived macrophage line (RAW/Nramp1(-)) devoid of Nramp1 and therefore susceptible to infection was compared with isogenic clones stably transfected with Nramp1 (RAW/Nramp1(+)). Intravacuolar pH, measured in situ, was similar in Nramp1-expressing and -deficient cells. SCV acquired LAMP1 and fused with preloaded fluid-phase markers in both cell types. In contrast, although few vacuoles in RAW/Nramp1(-) acquired mannose 6-phosphate receptor, many more contained M6PR in RAW/Nramp1(+) cells. Shortly after closure, SCV in RAW/Nramp1(-) became inaccessible to extracellular markers, suggesting inability to fuse with newly formed endosomes. Expression of Nramp1 markedly increased the access to extracellularly added markers. We propose that Nramp1 counteracts the ability of Salmonella to become secluded in a compartment that limits access of bactericidal agents, allowing the normal degradative pathway of the macrophage to proceed.