RpoN (sigma54) controls production of antifungal compounds and biocontrol activity in Pseudomonas fluorescens CHA0.

Pseudomonas fluorescens CHA0 is an effective biocontrol agent of root diseases caused by fungal pathogens. The strain produces the antibiotics 2,4-diacetylphloroglucinol (DAPG) and pyoluteorin (PLT) that make essential contributions to pathogen suppression. This study focused on the role of the sigma factor RpoN (sigma54) in regulation of antibiotic production and biocontrol activity in P. fluorescens. An rpoN in-frame-deletion mutant of CHAO had a delayed growth, was impaired in the utilization of several carbon and nitrogen sources, and was more sensitive to salt stress. The rpoN mutant was defective for flagella and displayed drastically reduced swimming and swarming motilities. Interestingly, the rpoN mutant showed a severalfold enhanced production of DAPG and expression of the biosynthetic gene phlA compared with the wild type and the mutant complemented with monocopy rpoN+. By contrast, loss of RpoN function resulted in markedly lowered PLT production and plt gene expression, suggesting that RpoN controls the balance of the two antibiotics in strain CHA0. In natural soil microcosms, the rpoN mutant was less effective in protecting cucumber from a root rot caused by Pythium ultimum. Remarkably, the mutant was not significantly impaired in its root colonization capacity, even at early stages of root infection by Pythium spp. Taken together, our results establish RpoN for the first time as a major regulator of biocontrol activity in Pseudomonas fluorescens.

The environmental roots of non-communicable diseases (NCDs) and the epigenetic impacts of globalization

BACKGROUND: Non-communicable diseases (NCDs) are increasing worldwide. We hypothesize that environmental factors (including social adversity, diet, lack of physical activity and pollution) can become "embedded" in the biology of humans. We also hypothesize that the "embedding" partly occurs because of epigenetic changes, i.e., durable changes in gene expression patterns. Our concern is that once such factors have a foundation in human biology, they can affect human health (including NCDs) over a long period of time and across generations. OBJECTIVES: To analyze how worldwide changes in movements of goods, persons and lifestyles (globalization) may affect the "epigenetic landscape" of populations and through this have an impact on NCDs. We provide examples of such changes and effects by discussing the potential epigenetic impact of socio-economic status, migration, and diet, as well as the impact of environmental factors influencing trends in age at puberty. DISCUSSION: The study of durable changes in epigenetic patterns has the potential to influence policy and practice; for example, by enabling stratification of populations into those who could particularly benefit from early interventions to prevent NCDs, or by demonstrating mechanisms through which environmental factors influence disease risk, thus providing compelling evidence for policy makers, companies and the civil society at large. The current debate on the '25 × 25 strategy', a goal of 25% reduction in relative mortality from NCDs by 2025, makes the proposed approach even more timely. CONCLUSIONS: Epigenetic modifications related to globalization may crucially contribute to explain current and future patterns of NCDs, and thus deserve attention from environmental researchers, public health experts, policy makers, and concerned citizens.

Imagerie des atteintes inflammatoires rachidiennes [Imaging in inflammatory spine diseases]

There is a mean delay of 5 to 8 years between the onset of symptoms and the diagnosis of ankylosing spondylitis. This is due to the fact that radiographic sacroiliitis is delayed. The purpose of an earlier diagnosis is emphasized by the need for better management, the new diagnostic method including magnetic resonance imaging and by the efficacy of anti-TNF therapy. The current criteria are classification but not diagnostic criteria. Their sensitivity is insufficient for an early diagnosis of ankylosing spondylitis. MRI criteria allow to differentiate inflammatory signs from degenerative signs in patients sent for aspecific low back pain. The aims of this article are to illustrate the different stages of the disease from early inflammatory involvement to ankylosis and to discuss the role of imaging in the management of affected patients.

De Novo Production of Metabolites by Fungal Co-culture of Trichophyton rubrum and Bionectria ochroleuca.

The co-cultivation of fungi has recently been described as a promising strategy to induce the production of novel metabolites through possible gene activation. A large screening of fungal co-cultures in solid media has identified an unusual long-distance growth inhibition between Trichophyton rubrum and Bionectria ochroleuca. To study metabolite induction in this particular fungal interaction, differential LC-MS-based metabolomics was performed on pure strain cultures and on their co-cultures. The comparison of the resulting fingerprints highlighted five de novo induced compounds, which were purified using software-oriented semipreparative HPLC-MS. One metabolite was successfully identified as 4″-hydroxysulfoxy-2,2″-dimethylthielavin P (a substituted trimer of 3,5-dimethylorsellinic acid). The nonsulfated form, as well as three other related compounds, were found in the pure strain culture of B. ochroleuca.

Management of faecal incontinence and constipation in adults with central neurological diseases.

BACKGROUND: People with neurological disease have a much higher risk of both faecal incontinence and constipation than the general population. There is often a fine line between the two conditions, with any management intended to ameliorate one risking precipitating the other. Bowel problems are observed to be the cause of much anxiety and may reduce quality of life in these people. Current bowel management is largely empirical with a limited research base. OBJECTIVES: To determine the effects of management strategies for faecal incontinence and constipation in people with neurological diseases affecting the central nervous system. SEARCH STRATEGY: We searched the Cochrane Incontinence Group Specialised Trials Register (searched 26 January 2005), the Cochrane Central Register of Controlled Trials (Issue 2, 2005), MEDLINE (January 1966 to May 2005), EMBASE (January 1998 to May 2005) and all reference lists of relevant articles. SELECTION CRITERIA: All randomised or quasi-randomised trials evaluating any types of conservative or surgical measure for the management of faecal incontinence and constipation in people with neurological diseases were selected. Specific therapies for the treatment of neurological diseases that indirectly affect bowel dysfunction were also considered. DATA COLLECTION AND ANALYSIS: Two reviewers assessed the methodological quality of eligible trials and two reviewers independently extracted data from included trials using a range of pre-specified outcome measures. MAIN RESULTS: Ten trials were identified by the search strategy, most were small and of poor quality. Oral medications for constipation were the subject of four trials. Cisapride does not seem to have clinically useful effects in people with spinal cord injuries (three trials). Psyllium was associated with increased stool frequency in people with Parkinson's disease but did not alter colonic transit time (one trial). Prucalopride, an enterokinetic did not demonstrate obvious benefits in this patient group (one study). Some rectal preparations to initiate defaecation produced faster results than others (one trial). Different time schedules for administration of rectal medication may produce different bowel responses (one trial). Mechanical evacuation may be more effective than oral or rectal medication (one trial). There appears to be a benefit to patients in one-off educational interventions from nurses. The clinical significance of any of these results is difficult to interpret. AUTHORS' CONCLUSIONS: There is still remarkably little research on this common and, to patients, very significant condition. It is not possible to draw any recommendation for bowel care in people with neurological diseases from the trials included in this review. Bowel management for these people must remain empirical until well-designed controlled trials with adequate numbers and clinically relevant outcome measures become available.

Prolonged fluconazole exposure leads to a shift to Candida species with decreased susceptibility in breakthrough candidemia: prospective survey of the Fungal Infection Network of Switzerland

Objectives: To compare the clinical characteristics, species distribution and antifungal susceptibility of Candida bloodstream isolates (BSI) in breakthrough (BTC) vs. non-breakthrough candidemia (NBTC) and to study the effect of prolonged vs. short fluconazole (F) exposure in BTC.Methods: Candida BSI were prospectively collected during 2004- 2006 from 27 hospitals (seven university, 20 affiliated) of the FUNGINOS network. Susceptibility to F, voriconazole (V) and caspofungin (C) was tested in the FUNGINOS mycology reference laboratory by microtitre broth dilution method with the Sensititre YeastOneTM test panel. Clinical data were collected using standardized CRFs. BTC was defined as occurring during antifungal treatment/prophylaxis of at least three days duration prior to the candidemia. Susceptibility of BSI was defined according to 2010/2011 CLSI clinical breakpoints.Results: Out of 567 candidemia episodes, 550 Candida BSI were available. Of these, 43 (7.6%) were from BTC (37/43, 86% were isolated after F exposure). 38 BTC (88.4%) and 315 NBTC (55.6%) occurred in university hospitals (P < 0.001). The majority of patients developing BTC were immunocompromised: higher proportions of haematological malignancies (62.8% in BTC vs. 47.1% in NBTC, P < 0.001), neutropenia (37.2% vs. 11.8%, P < 0.001), acute GvHD (14% vs. 0.2%, P < 0.001), immunosuppressive drugs (74.4% vs. 7.8%, P < 0.001), and mucositis (32.6% vs. 2.3%, P < 0.001) were observed. Other differences between BTC and NBTC were higher proportions of patients with central venous catheters in the 2 weeks preceding candidemia (95.3% vs. 83.4%, P = 0.047) and receiving total parenteral nutrition (62.8% vs. 35.9%, P < 0.001), but a lower proportion of patients treated with gastric proton pump inhibitors (23.3% vs. 72.1%, P < 0.001). Overall mortality of BTC and NBTC was not different (34.9% vs. 31.7%, P = 0.73), while a trend to higher attributable mortality in BTC was found (13.9% vs. 6.9%, P = 0.12). Species identification showed a majority of C. albicans in both groups (51.2% in BTC vs. 62.9% in NBTC, P = 0.26), followed by C. glabrata (18.6% vs. 18.5%), C. tropicalis (2.3% vs. 6.3%) and C. parapsilosis (7.0% vs. 4.7%). Significantly more C. krusei were detected in BTC versus NBTC (11.6% vs. 1.6%, P = 0.002). The geometric mean MIC for F, V and C between BTC and NBTC isolates was not significantly different. However, in BTC there was a significant association between duration of F exposure and the Candida spp.: >10 days of F was associated with a significant shift from susceptible Candida spp. (C. albicans, C. parapsilosis, C. tropicalis, C. famata) to non-susceptible species (C. glabrata, C. krusei, C. norvegensis). Among 21 BTC episodes occurring after £10 days of F, 19% of the isolates were non-susceptible, in contrast to 68.7% in 16 BTC episodes occurring after >10 days of F (P = 0.003).Conclusions: Breakthrough candidemia occurred more often in immunocompromised hosts. Fluconazole administered for >10 days was associated with a shift to non-susceptible Candida spp.. Length of fluconazole exposure should be taken into consideration for the choice of empirical antifungal treatment.

Calcitic nanofibers in soils and caves : a putative fungal contribution to carbonatogenesis

The origin of soil mineralized nanofibres remains controversial. It is attributed to either biogenic factors or physicochemical processes. Scanning electron microscope and transmission electron microscope observations show that nanofibres could originate from the breakdown of fungal hyphae, especially its cell wall. It is hypothesized that during the decay of organic matter, cell wall microfibrils are released in the soil where they are exposed to mineralizing pore fluids, leading to their calcitic pseudomorphosis and/or are used as a template for calcite precipitation. When associated with needle fibre calcite bundles, nanofibres could indicate the relict of an organic sheath in which calcite has precipitated. This paper emphasizes the important roles of both organic matter and fungi in carbonatogenesis, and consequently in the soil carbon cycle.

Affections pulmonaires et attitude [High altitude and preexisting lung diseases].

Today, a growing number of people, some of them suffering from lung diseases, travel to high altitude resorts. It is sometimes not easy for the general practitioner to adequately counsel these patients. Based on our knowledge of physiopathology and clinical studies, the present paper addresses the effects of high altitude in patients with preexisting lung diseases and provides recommendations in order to optimize the sojourn at high altitude.

Detection of metabolite induction in fungal co-cultures on solid media by high-throughput differential ultra-high pressure liquid chromatography-time-of-flight mass spectrometry fingerprinting.

Access to new biological sources is a key element of natural product research. A particularly large number of biologically active molecules have been found to originate from microorganisms. Very recently, the use of fungal co-culture to activate the silent genes involved in metabolite biosynthesis was found to be a successful method for the induction of new compounds. However, the detection and identification of the induced metabolites in the confrontation zone where fungi interact remain very challenging. To tackle this issue, a high-throughput UHPLC-TOF-MS-based metabolomic approach has been developed for the screening of fungal co-cultures in solid media at the petri dish level. The metabolites that were overexpressed because of fungal interactions were highlighted by comparing the LC-MS data obtained from the co-cultures and their corresponding mono-cultures. This comparison was achieved by subjecting automatically generated peak lists to statistical treatments. This strategy has been applied to more than 600 co-culture experiments that mainly involved fungal strains from the Fusarium genera, although experiments were also completed with a selection of several other filamentous fungi. This strategy was found to provide satisfactory repeatability and was used to detect the biomarkers of fungal induction in a large panel of filamentous fungi. This study demonstrates that co-culture results in consistent induction of potentially new metabolites.

Country actions to meet UN commitments on non-communicable diseases: a stepwise approach.

Strong leadership from heads of state is needed to meet national commitments to the UN political declaration on non-communicable diseases (NCDs) and to achieve the goal of a 25% reduction in premature NCD mortality by 2025 (the 25 by 25 goal). A simple, phased, national response to the political declaration is suggested, with three key steps: planning, implementation, and accountability. Planning entails mobilisation of a multisectoral response to develop and support the national action plan, and to build human, financial, and regulatory capacity for change. Implementation of a few priority and feasible cost-effective interventions for the prevention and treatment of NCDs will achieve the 25 by 25 goal and will need only few additional financial resources. Accountability incorporates three dimensions: monitoring of progress, reviewing of progress, and appropriate responses to accelerate progress. A national NCD commission or equivalent, which is independent of government, is needed to ensure that all relevant stakeholders are held accountable for the UN commitments to NCDs.

Chaperones and proteases: cellular fold-controlling factors of proteins in neurodegenerative diseases and aging.

The formation of toxic protein aggregates is a common denominator to many neurodegenerative diseases and aging. Accumulation of toxic, possibly infectious protein aggregates induces a cascade of events, such as excessive inflammation, the production of reactive oxygen species, apoptosis and neuronal loss. A network of highly conserved molecular chaperones and of chaperone-related proteases controls the fold-quality of proteins in the cell. Most molecular chaperones can passively prevent protein aggregation by binding misfolding intermediates. Some molecular chaperones and chaperone-related proteases, such as the proteasome, can also hydrolyse ATP to forcefully convert stable harmful protein aggregates into harmless natively refoldable, or protease-degradable, polypeptides. Molecular chaperones and chaperone-related proteases thus control the delicate balance between natively folded functional proteins and aggregation-prone misfolded proteins, which may form during the lifetime and lead to cell death. Abundant data now point at the molecular chaperones and the proteases as major clearance mechanisms to remove toxic protein aggregates from cells, delaying the onset and the outcome of protein-misfolding diseases. Therapeutic approaches include treatments and drugs that can specifically induce and sustain a strong chaperone and protease activity in cells and tissues prone to toxic protein aggregations.

Calcineurin as a Multifunctional Regulator: Unraveling Novel Functions in Fungal Stress Responses, Hyphal Growth, Drug Resistance, and Pathogenesis.

Calcineurin signaling plays diverse roles in fungi in regulating stress responses, morphogenesis and pathogenesis. Although calcineurin signaling is conserved among fungi, recent studies indicate important divergences in calcineurin-dependent cellular functions among different human fungal pathogens. Fungal pathogens utilize the calcineurin pathway to effectively survive the host environment and cause life-threatening infections. The immunosuppressive calcineurin inhibitors (FK506 and cyclosporine A) are active against fungi, making targeting calcineurin a promising antifungal drug development strategy. Here we summarize current knowledge on calcineurin in yeasts and filamentous fungi, and review the importance of understanding fungal-specific attributes of calcineurin to decipher fungal pathogenesis and develop novel antifungal therapeutic approaches.