Oscillatory surface rheotaxis of swimming E. coli bacteria

Bacterial contamination of biological conducts, catheters or water resources is a major threat to public health and can be amplified by the ability of bacteria to swim upstream. The mechanisms of this rheotaxis, the reorientation with respect to flow gradients, often in complex and confined environments, are still poorly understood. Here, we follow individual E. coli bacteria swimming at surfaces under shear flow with two complementary experimental assays, based on 3D Lagrangian tracking and fluorescent flagellar labelling and we develop a theoretical model for their rheotactic motion. Three transitions are identified with increasing shear rate: Above a first critical shear rate, bacteria shift to swimming upstream. After a second threshold, we report the discovery of an oscillatory rheotaxis. Beyond a third transition, we further observe coexistence of rheotaxis along the positive and negative vorticity directions. A full theoretical analysis explains these regimes and predicts the corresponding critical shear rates. The predicted transitions as well as the oscillation dynamics are in good agreement with experimental observations. Our results shed new light on bacterial transport and reveal new strategies for contamination prevention.Comment: 12 pages, 5 figure

Allergen-specific immunotherapy provides immediate, long-term and preventive clinical effects in children and adults: the effects of immunotherapy can be categorised by level of benefit -the centenary of allergen specific subcutaneous immunotherapy

Allergen Specific Immunotherapy (SIT) for respiratory allergic diseases is able to significantly improve symptoms as well as reduce the need for symptomatic medication, but SIT also has the capacity for long-term clinical effects and plays a protective role against the development of further allergies and symptoms. The treatment acts on basic immunological mechanisms, and has the potential to change the pathological allergic immune response. In this paper we discuss some of the most important achievements in the documentation of the benefits of immunotherapy, over the last 2 decades, which have marked a period of extensive research on the clinical effects and immunological background of the mechanisms involved. The outcome of immunotherapy is described as different levels of benefit from early reduction in symptoms over progressive clinical effects during treatment to long-term effects after discontinuation of the treatment and prevention of asthma. The efficacy of SIT increases the longer it is continued and immunological changes lead to potential long-term benefits. SIT alone and not the symptomatic treatment nor other avoidance measures has so far been documented as the therapy with long-term or preventive potential. The allergic condition is driven by a subset of T-helper lymphocytes (Th2), which are characterised by the production of cytokines like IL-4, and IL-5. Immunological changes following SIT lead to potential curative effects. One mechanism whereby immunotherapy suppresses the allergic response is through increased production of IgG4 antibodies. Induction of specific IgG4 is able to influence the allergic response in different ways and is related to immunological effector mechanisms, also responsible for the reduced late phase hyperreactivity and ongoing allergic inflammation. SIT is the only treatment which interferes with the basic pathophysiological mechanisms of the allergic disease, thereby creating the potential for changes in the long-term prognosis of respiratory allergy. SIT should not only be recognised as first-line therapeutic treatment for allergic rhinoconjunctivitis but also as secondary preventive treatment for respiratory allergic diseases

Specific immunotherapy by the sublingual route for respiratory allergy

Specific immunotherapy is the only treatment able to act on the causes and not only on the symptoms of respiratory allergy. Sublingual immunotherapy (SLIT) was introduced as an option to subcutaneous immunotherapy (SCIT), the clinical effectiveness of which is partly counterbalanced by the issue of adverse systemic reactions, which occur at a frequency of about 0.2% of injections and 2-5% of the patients and may also be life-threatening. A large number of trials, globally evaluated by several meta-analyses, demonstrated that SLIT is an effective and safe treatment for allergic rhinitis and allergic asthma, severe reactions being extremely rare. The application of SLIT is favored by a good compliance, higher than that reported for SCIT, in which the injections are a major factor for noncompliance because of inconvenience, and by its cost-effectiveness. In fact, a number of studies showed that SLIT may be very beneficial to the healthcare system, especially when its effectiveness persists after treatment withdrawal because of the induced immunologic changes

The Primary Prevention of PTSD in Firefighters: Preliminary Results of an RCT with 12-Month Follow-Up

AIM: To develop and evaluate an evidence-based and theory driven program for the primary prevention of Post-traumatic Stress Disorder (PTSD). DESIGN: A pre-intervention / post-intervention / follow up control group design with clustered random allocation of participants to groups was used. The "control" group received "Training as Usual" (TAU). METHOD: Participants were 45 career recruits within the recruit school at the Department of Fire and Emergency Services (DFES) in Western Australia. The intervention group received a four-hour resilience training intervention (Mental Agility and Psychological Strength training) as part of their recruit training school curriculum. Data was collected at baseline and at 6- and 12-months post intervention. RESULTS: We found no evidence that the intervention was effective in the primary prevention of mental health issues, nor did we find any significant impact of MAPS training on social support or coping strategies. A significant difference across conditions in trauma knowledge is indicative of some impact of the MAPS program. CONCLUSION: While the key hypotheses were not supported, this study is the first randomised control trial investigating the primary prevention of PTSD. Practical barriers around the implementation of this program, including constraints within the recruit school, may inform the design and implementation of similar programs in the future. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12615001362583

SirT1 modulates the estrogen–insulin-like growth factor-1 signaling for postnatal development of mammary gland in mice

INTRODUCTION: Estrogen and insulin-like growth factor-1 (IGF-1) play important roles in mammary gland development and breast cancer. SirT1 is a highly conserved protein deacetylase that can regulate the insulin/IGF-1 signaling in lower organisms, as well as a growing number of transcription factors, including NF-κB, in mammalian cells. Whether SirT1 regulates the IGF-1 signaling for mammary gland development and function, however, is not clear. In the present study, this role of SirT1 was examined by studying SirT1-deficient mice. METHODS: SirT1-deficient (SirT1(ko/ko)) mice were generated by crossing a new strain of mice harboring a conditional targeted mutation in the SirT1 gene (SirT1(co/co)) with CMV-Cre transgenic mice. Whole mount and histology analyses, immunofluorescence staining, immunohistochemistry, and western blotting were used to characterize mammary gland development in virgin and pregnant mice. The effect of exogenous estrogen was also examined by subcutaneous implantation of a slow-releasing pellet in the subscapular region. RESULTS: Both male and female SirT1(ko/ko )mice can be fertile despite the growth retardation phenotype. Virgin SirT1(ko/ko )mice displayed impeded ductal morphogenesis, whereas pregnant SirT1(ko/ko )mice manifested lactation failure due to an underdeveloped lobuloalveolar network. Estrogen implantation was sufficient to rescue ductal morphogenesis. Exogenous estrogen reversed the increased basal level of IGF-1 binding protein-1 expression in SirT1(ko/ko )mammary tissues, but not that of IκBα expression, suggesting that increased levels of estrogen enhanced the production of local IGF-1 and rescued ductal morphogenesis. Additionally, TNFα treatment enhanced the level of the newly synthesized IκBα in SirT1(ko/ko )cells. SirT1 deficiency therefore affects the cellular response to multiple extrinsic signals. CONCLUSION: SirT1 modulates the IGF-1 signaling critical for both growth regulation and mammary gland development in mice. SirT1 deficiency deregulates the expression of IGF-1 binding protein-1 and attenuates the effect of IGF-1 signals, including estrogen-stimulated local IGF-1 signaling for the onset of ductal morphogenesis. These findings suggest that the enzymatic activity of SirT1 may influence both normal growth and malignant growth of mammary epithelial cells

ARIA-Versorgungspfade für die Allergenimmuntherapie 2019 = 2019 ARIA Care pathways for allergen immunotherapy

Allergen immunotherapy (MT) is a proven therapeutic option for the treatment of allergic rhinitis and/or asthma. Many guidelines or national practice guidelines have been produced but the evidence- based method varies, many are complex and none propose care pathways. This paper reviews care pathways for AIT using strict criteria and provides simple recommendations that can be used by all stakeholders including health professionals. The decision to prescribe MT for the patient should be individualized and based on the relevance of the allergens, the persistence of symptoms despite appropriate medications according to guidelines as well as on the availability of good-quality and efficacious extracts. Allergen extracts cannot be regarded as generics. Immunotherapy is selected by specialists for stratified patients. There are no currently available validated biomaikers that can predict MT success. In adolescents and adults, AIT should be reserved for patients with moderate/severe rhinitis or for those with moderate asthma who, despite appropriate phannacotherapy and adherence, continue to exhibit exacerbations that appear to be related to allergen exposure, except in some specific cases. Immunotherapy may be even more advantageous in patients with multimorbidity. In children, AIT may prevent asthma onset in patients with rhinitis. mHealth tools are promising for the stratification and follow up of patients

Allergen Immunotherapy in Children User’s Guide

Allergen immunotherapy is a cornerstone in the treatment of allergic children. The clinical efficiency relies on a well-defined immunologic mechanism promoting regulatory T cells and downplaying the immune response induced by allergens. Clinical indications have been well documented for respiratory allergy in the presence of rhinitis and/or allergic asthma, to pollens and dust mites. Patients who have had an anaphylactic reaction to hymenoptera venom are also good candidates for allergen immunotherapy. Administration of allergen is currently mostly either by subcutaneous injections or by sublingual administration. Both methods have been extensively studied and have pros and cons. Specifically in children, the choice of the method of administration according to the patient's profile is important. Although allergen immunotherapy is widely used, there is a need for improvement. More particularly, biomarkers for prediction of the success of the treatments are needed. The strength and efficiency of the immune response may also be boosted by the use of better adjuvants. Finally, novel formulations might be more efficient and might improve the patient's adherence to the treatment. This user's guide reviews current knowledge and aims to provide clinical guidance to healthcare professionals taking care of children undergoing allergen immunotherapy

Chronic Obstructive Pulmonary Disease and Lung Cancer: Underlying Pathophysiology and New Therapeutic Modalities

Chronic obstructive pulmonary disease (COPD) and lung cancer are major lung diseases affecting millions worldwide. Both diseases have links to cigarette smoking and exert a considerable societal burden. People suffering from COPD are at higher risk of developing lung cancer than those without, and are more susceptible to poor outcomes after diagnosis and treatment. Lung cancer and COPD are closely associated, possibly sharing common traits such as an underlying genetic predisposition, epithelial and endothelial cell plasticity, dysfunctional inflammatory mechanisms including the deposition of excessive extracellular matrix, angiogenesis, susceptibility to DNA damage and cellular mutagenesis. In fact, COPD could be the driving factor for lung cancer, providing a conducive environment that propagates its evolution. In the early stages of smoking, body defences provide a combative immune/oxidative response and DNA repair mechanisms are likely to subdue these changes to a certain extent; however, in patients with COPD with lung cancer the consequences could be devastating, potentially contributing to slower postoperative recovery after lung resection and increased resistance to radiotherapy and chemotherapy. Vital to the development of new-targeted therapies is an in-depth understanding of various molecular mechanisms that are associated with both pathologies. In this comprehensive review, we provide a detailed overview of possible underlying factors that link COPD and lung cancer, and current therapeutic advances from both human and preclinical animal models that can effectively mitigate this unholy relationship

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability