Antimicrobial Peptides and Skin: A Paradigm of Translational Medicine

Antimicrobial peptides (AMPs) are small, cationic, amphiphilic peptides with broad-spectrum microbicidal activity against both bacteria and fungi. In mammals, AMPs form the first line of host defense against infections and generally play an important role as effector agents of the innate immune system. The AMP era was born more than 6 decades ago when the first cationic cyclic peptide antibiotics, namely polymyxins and tyrothricin, found their way into clinical use. Due to the good clinical experience in the treatment of, for example, infections of mucus membranes as well as the subsequent understanding of mode of action, AMPs are now considered for treatment of inflammatory skin diseases and for improving healing of infected wounds. Based on the preclinical findings, including pathobiochemistry and molecular medicine, targeted therapy strategies are developed and first results indicate that AMPs influence processes of diseased skin. Importantly, in contrast to other antibiotics, AMPs do not seem to propagate the development of antibiotic-resistant micro-organisms. Therefore, AMPs should be tested in clinical trials for their efficacy and tolerability in inflammatory skin diseases and chronic wounds. Apart from possible fields of application, these peptides appear suited as an example of the paradigm of translational medicine for skin diseases which is today seen as a `two-way road' - from bench to bedside and backwards from bedside to bench. Copyright (c) 2012 S. Karger AG, Base

Ecological implications of a flower size/number trade-off in tropical forest trees

Peer reviewedPublisher PD

Modulation of epithelial immunity by mucosal fluid

Mucosal epithelial cells, including those at the ocular surface, resist infection by most microbes in vivo but can be susceptible to microbial virulence in vitro. While fluids bathing mucosal surfaces (e.g. tears) contain antimicrobials, potentially pathogenic microbes often thrive in these fluids, suggesting that additional mechanisms mediate epithelial resistance in vivo. Here, tear fluid acted directly upon epithelial cells to enhance their resistance to bacterial invasion and cytotoxicity. Resistance correlated with tear fluid-magnified activation of NFκB and AP-1 transcription factors in epithelial cells in response to bacterial antigens, suggesting priming of innate defense pathways. Further analysis revealed differential regulation of potential epithelial cell defense genes by tears. siRNA knockdown confirmed involvement of at least two factors, RNase7 and ST-2, for which tears increased mRNA levels, in protection against bacterial invasion. Thus, the role of mucosal fluids in defense can include modulation of epithelial immunity, in addition to direct effects on microbes

Legionella pneumophila induces human beta Defensin-3 in pulmonary cells

<p>Abstract</p> <p>Background</p> <p><it>Legionella pneumophila </it>is an important causative agent of severe pneumonia in humans. Human alveolar epithelium and macrophages are effective barriers for inhaled microorganisms and actively participate in the initiation of innate host defense. The beta defensin-3 (hBD-3), an antimicrobial peptide is an important component of the innate immune response of the human lung. Therefore we hypothesize that hBD-3 might be important for immune defense towards <it>L. pneumophila</it>.</p> <p>Methods</p> <p>We investigated the effects of <it>L. pneumophila </it>and different TLR agonists on pulmonary cells in regard to hBD-3 expression by ELISA. Furthermore, siRNA-mediated inhibition of TLRs as well as chemical inhibition of potential downstream signaling molecules was used for functional analysis.</p> <p>Results</p> <p><it>L. pneumophila </it>induced release of hBD-3 in pulmonary epithelium and alveolar macrophages. A similar response was observed when epithelial cells were treated with different TLR agonists. Inhibition of TLR2, TLR5, and TLR9 expression led to a decreased hBD-3 expression. Furthermore expression of hBD-3 was mediated through a JNK dependent activation of AP-1 (c-Jun) but appeared to be independent of NF-κB. Additionally, we demonstrate that hBD-3 elicited a strong antimicrobial effect on <it>L. pneumophila </it>replication.</p> <p>Conclusions</p> <p>Taken together, human pulmonary cells produce hBD-3 upon <it>L. pneumophila </it>infection via a TLR-JNK-AP-1-dependent pathway which may contribute to an efficient innate immune defense.</p

Predictors of overweight and obesity in five to seven-year-old children in Germany: Results from cross-sectional studies

BACKGROUND: Childhood obesity is a serious public health problem and epidemiological studies are important to identify predictive factors. It is the aim of this study to analyse factors associated with overweight/obesity in samples of German children. METHODS: 35,434 five to seven year-old children (50.9% boys) participated in cross-sectional studies between 1991 and 2000 in several rural and urban areas in East and West Germany. Weight and height were measured and body mass index was calculated. International cut-off points, recommended by the International Obesity Task Force, were used to classify childhood overweight and obesity. Predictive modelling was employed to analyse independently associated factors, using logistic regression to adjust for confounding. RESULTS: 15.5% were overweight, and 4.3% were obese. Female sex, other than German nationality, smoking in the living place and increasing birth weight were found to increase the odds of overweight and obesity, while increasing educational level, living space > 75 m2 and breastfeeding for more than three months were inversely associated. CONCLUSION: The findings add to the evidence informing public health action, both through health promotion strategies (promoting breastfeeding, tackling smoking) and wider societal change management (addressing children from migrant families and families with low educational level)

Bacterial Biodiversity-Ecosystem Functioning Relations Are Modified by Environmental Complexity

Peer reviewedPublisher PD

Determinants of rapid weight gain during infancy: baseline results from the NOURISH randomised controlled trial

Background: Rapid weight gain in infancy is an important predictor of obesity in later childhood. Our aim was to determine which modifiable variables are associated with rapid weight gain in early life.Methods: Subjects were healthy infants enrolled in NOURISH, a randomised, controlled trial evaluating an intervention to promote positive early feeding practices. This analysis used the birth and baseline data for NOURISH. Birthweight was collected from hospital records and infants were also weighed at baseline assessment when they were aged 4-7 months and before randomisation. Infant feeding practices and demographic variables were collected from the mother using a self administered questionnaire. Rapid weight gain was defined as an increase in weight-for-age Z-score (using WHO standards) above 0.67 SD from birth to baseline assessment, which is interpreted clinically as crossing centile lines on a growth chart. Variables associated with rapid weight gain were evaluated using a multivariable logistic regression model.Results: Complete data were available for 612 infants (88% of the total sample recruited) with a mean (SD) age of 4.3 (1.0) months at baseline assessment. After adjusting for mother's age, smoking in pregnancy, BMI, and education and infant birthweight, age, gender and introduction of solid foods, the only two modifiable factors associated with rapid weight gain to attain statistical significance were formula feeding [OR = 1.72 (95%CI 1.01-2.94), P = 0.047] and feeding on schedule [OR = 2.29 (95%CI 1.14-4.61), P = 0.020]. Male gender and lower birthweight were non-modifiable factors associated with rapid weight gain.Conclusions: This analysis supports the contention that there is an association between formula feeding, feeding to schedule and weight gain in the first months of life. Mechanisms may include the actual content of formula milk (e.g. higher protein intake) or differences in feeding styles, such as feeding to schedule, which increase the risk of overfeeding.Trial Registration: Australian Clinical Trials Registry ACTRN12608000056392

Capecitabine plus oxaliplatin as first-line treatment in patients with advanced biliary system adenocarcinoma: a prospective multicentre phase II trial

This prospective multicentre phase II study characterises the toxicity and activity of first-line capecitabine and oxaliplatin combination therapy (CAPOX) in advanced biliary system adenocarcinomas. Patients received oxaliplatin (130 mg m−2, day 1) plus capecitabine (1000 mg m−2 b.i.d., days 1–14) every 3 weeks. Patients were stratified prospectively into two groups based on location of the primary (gallbladder carcinoma (GBC) or extrahepatic cholangiocarcinoma (ECC) versus intrahepatic mass-forming type cholangiocarcinoma (ICC)). Sixty-five patients were evaluable. The response rate in 47 patients with GBC/ECC was 27% (4% complete responses), and in 23 patients (49%) stable disease (SD) was encountered. In 18 patients with ICC, we observed no objective responses, but 6 patients (33%) had SD. Median survival was 12.8 months (95% CI, 10.0–15.6) for patients with GBC or ECC (GBC: 8.2 months; 95% CI, 4.3–11.7; ECC: 16.8 months; 95% CI, 12.7–20.5), and 5.2 months (95% CI, 0.6–9.8) for ICC patients. In both cohorts, therapy was well tolerated. The most common grade 3–4 toxicity was peripheral sensory neuropathy (11 patients). Our data suggest that the CAPOX regimen is a well-tolerated and active treatment option for advanced ECC and GBC but might produce poorer results for ICC

Modifiable risk factors predicting major depressive disorder at four year follow-up: a decision tree approach

<p>Abstract</p> <p>Background</p> <p>Relative to physical health conditions such as cardiovascular disease, little is known about risk factors that predict the prevalence of depression. The present study investigates the expected effects of a reduction of these risks over time, using the decision tree method favoured in assessing cardiovascular disease risk.</p> <p>Methods</p> <p>The PATH through Life cohort was used for the study, comprising 2,105 20-24 year olds, 2,323 40-44 year olds and 2,177 60-64 year olds sampled from the community in the Canberra region, Australia. A decision tree methodology was used to predict the presence of major depressive disorder after four years of follow-up. The decision tree was compared with a logistic regression analysis using ROC curves.</p> <p>Results</p> <p>The decision tree was found to distinguish and delineate a wide range of risk profiles. Previous depressive symptoms were most highly predictive of depression after four years, however, modifiable risk factors such as substance use and employment status played significant roles in assessing the risk of depression. The decision tree was found to have better sensitivity and specificity than a logistic regression using identical predictors.</p> <p>Conclusion</p> <p>The decision tree method was useful in assessing the risk of major depressive disorder over four years. Application of the model to the development of a predictive tool for tailored interventions is discussed.</p