Compliance with guidelines is related to better local recurrence-free survival in ductal carcinoma in situ

The aim was to study the effect of compliance with guidelines on local recurrence (LR)-free survival in patients treated for ductal carcinoma in situ (DCIS). From January 1992 to December 2003, 251 consecutive patients had been treated for DCIS in two hospitals in the North Netherlands. Every case in this two-hospital sample was reviewed in retrospect for its clinical and pathological parameters. It was determined whether treatment had been carried out according to clinical guidelines, and outcomes in follow-up were assessed. In addition, all patients treated for DCIS in this region (n=1389) were studied regarding clinical parameters, in order to determine whether the two-hospital sample was representative of the entire region. In the two-hospital sample, 31.4% (n=79) of the patients had not been treated according to the guidelines. Positive margins were associated with LR (hazard ratio (HR)=4.790, 95% confidence interval (CI) 1.696–13.531). Breast-conserving surgery and deviation from the guidelines were independent predictors of LR (HR=7.842, 95% CI 2.126–28.926; HR=2.778, 95% CI 0.982–6.781, respectively). Although the guidelines changed over time, time was not a significant factor in predicting LRs (HR=1.254, 95% CI 0.272–5.776 for time period 1992–1995 and HR=1.976, 95% CI 0.526–7.421 for time period 1996–1999). Clinical guidelines for the treatment of patients with DCIS have been developed and updated from existing literature and best evidence. Compliance with the guidelines was an independent predictor of disease-free survival. These findings support the application of guidelines in the treatment of DCIS

A series of Fas receptor agonist antibodies that demonstrate an inverse correlation between affinity and potency

Receptor agonism remains poorly understood at the molecular and mechanistic level. In this study, we identified a fully human anti-Fas antibody that could efficiently trigger apoptosis and therefore function as a potent agonist. Protein engineering and crystallography were used to mechanistically understand the agonistic activity of the antibody. The crystal structure of the complex was determined at 1.9 Å resolution and provided insights into epitope recognition and comparisons with the natural ligand FasL (Fas ligand). When we affinity-matured the agonist antibody, we observed that, surprisingly, the higher-affinity antibodies demonstrated a significant reduction, rather than an increase, in agonist activity at the Fas receptor. We propose and experimentally demonstrate a model to explain this non-intuitive impact of affinity on agonist antibody signalling and explore the implications for the discovery of therapeutic agonists in general

Effects of Hepatocyte CD14 Upregulation during Cholestasis on Endotoxin Sensitivity

Cholestasis is frequently related to endotoxemia and inflammatory response. Our previous investigation revealed a significant increase in plasma endotoxin and CD14 levels during biliary atresia. We therefore propose that lipopolysacharides (LPS) may stimulate CD14 production in liver cells and promote the removal of endotoxins. The aims of this study are to test the hypothesis that CD14 is upregulated by LPS and investigate the pathophysiological role of CD14 production during cholestasis. Using Western blotting, qRT-PCR, and promoter activity assay, we demonstrated that LPS was associated with a significant increase in CD14 and MD2 protein and mRNA expression and CD14 promoter activity in C9 rat hepatocytes but not in the HSC-T6 hepatic stellate cell line in vitro. To correlate CD14 expression and endotoxin sensitivity, in vivo biliary LPS administration was performed on rats two weeks after they were subjected to bile duct ligation (BDL) or a sham operation. CD14 expression and endotoxin levels were found to significantly increase after LPS administration in BDL rats. These returned to basal levels after 24 h. In contrast, although endotoxin levels were increased in sham-operated rats given LPS, no increase in CD14 expression was observed. However, mortality within 24 h was more frequent in the BDL animals than in the sham-operated group. In conclusion, cholestasis and LPS stimulation were here found to upregulate hepatic CD14 expression, which may have led to increased endotoxin sensitivity and host proinflammatory reactions, causing organ failure and death in BDL rats

Serum Lipopolysaccharide Binding Protein Levels Predict Severity of Lung Injury and Mortality in Patients with Severe Sepsis

Background: There is a need for biomarkers insuring identification of septic patients at high-risk for death. We performed a prospective, multicenter, observational study to investigate the time-course of lipopolysaccharide binding protein (LBP) serum levels in patients with severe sepsis and examined whether serial serum levels of LBP could be used as a marker of outcome. Methodology/Principal Findings: LBP serum levels at study entry, at 48 hours and at day-7 were measured in 180 patients with severe sepsis. Data regarding the nature of infections, disease severity, development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), and intensive care unit (ICU) outcome were recorded. LBP serum levels were similar in survivors and non-survivors at study entry (117.4±75.7 µg/mL vs. 129.8±71.3 µg/mL, P = 0.249) but there were significant differences at 48 hours (77.2±57.0 vs. 121.2±73.4 µg/mL, P<0.0001) and at day-7 (64.7±45.8 vs. 89.7±61.1 µg/ml, p = 0.017). At 48 hours, LBP levels were significantly higher in ARDS patients than in ALI patients (112.5±71.8 µg/ml vs. 76.6±55.9 µg/ml, P = 0.0001). An increase of LBP levels at 48 hours was associated with higher mortality (odds ratio 3.97; 95%CI: 1.84–8.56; P<0.001). Conclusions/Significance: Serial LBP serum measurements may offer a clinically useful biomarker for identification of patients with severe sepsis having the worst outcomes and the highest probability of developing sepsis-induced ARDS

Increased Intestinal Permeability Correlates with Sigmoid Mucosa alpha-Synuclein Staining and Endotoxin Exposure Markers in Early Parkinson's Disease

Parkinson's disease (PD) is the second most common neurodegenerative disorder of aging. The pathological hallmark of PD is neuronal inclusions termed Lewy bodies whose main component is alpha-synuclein protein. The finding of these Lewy bodies in the intestinal enteric nerves led to the hypothesis that the intestine might be an early site of PD disease in response to an environmental toxin or pathogen. One potential mechanism for environmental toxin(s) and proinflammatory luminal products to gain access to mucosal neuronal tissue and promote oxidative stress is compromised intestinal barrier integrity. However, the role of intestinal permeability in PD has never been tested. We hypothesized that PD subjects might exhibit increased intestinal permeability to proinflammatory bacterial products in the intestine. To test our hypothesis we evaluated intestinal permeability in subjects newly diagnosed with PD and compared their values to healthy subjects. In addition, we obtained intestinal biopsies from both groups and used immunohistochemistry to assess bacterial translocation, nitrotyrosine (oxidative stress), and alpha-synuclein. We also evaluated serum markers of endotoxin exposure including LPS binding protein (LBP). Our data show that our PD subjects exhibit significantly greater intestinal permeability (gut leakiness) than controls. In addition, this intestinal hyperpermeability significantly correlated with increased intestinal mucosa staining for E. coli bacteria, nitrotyrosine, and alpha-synuclein as well as serum LBP levels in PD subjects. These data represent not only the first demonstration of abnormal intestinal permeability in PD subjects but also the first correlation of increased intestinal permeability in PD with intestinal alpha-synuclein (the hallmark of PD), as well as staining for gram negative bacteria and tissue oxidative stress. Our study may thus shed new light on PD pathogenesis as well as provide a new method for earlier diagnosis of PD and suggests potential therapeutic targets in PD subjects.Clinicaltrials.gov NCT01155492

Strong Host-Feeding Preferences of the Vector Triatoma infestans Modified by Vector Density: Implications for the Epidemiology of Chagas Disease

Chagas disease is a complex zoonosis with more than 150 mammalian host species, nearly a dozen blood-sucking triatomine species as main vectors, and 9–11 million people infected with Trypanosoma cruzi (its causal agent) in the Americas. Triatoma infestans, a highly domesticated species and one of the main vectors, feeds more often on domestic animals than on humans in northern Argentina. The question of whether there are host-feeding preferences among dogs, cats, and chickens is crucial to estimating transmission risks and predicting the effects of control tactics targeting them. This article reports the first host choice experiments of triatomine bugs conducted in small huts under natural conditions. The results demonstrate that T. infestans consistently preferred dogs to chickens or cats, with host shifts occurring more frequently at higher vector densities. Combined with earlier findings showing that dogs have high infection rates, are highly infectious, and have high contact rates with humans and domestic bugs, our results reinforce the role of dogs as the key reservoirs of T. cruzi. The strong bug preference for dogs can be exploited to target dogs with topical lotions or insecticide-impregnated collars to turn them into baited lethal traps or use them as transmission or infestation sentinels

Roles of spatial scale and rarity on the relationship between butterfly species richness and human density in South Africa

Wildlife and humans tend to prefer the same productive environments, yet high human densities often lead to reduced biodiversity. Species richness is often positively correlated with human population density at broad scales, but this correlation could also be caused by unequal sampling effort leading to higher species tallies in areas of dense human activity. We examined the relationships between butterfly species richness and human population density at five spatial resolutions ranging from 2′ to 60′ across South Africa. We used atlas-type data and spatial interpolation techniques aimed at reducing the effect of unequal spatial sampling. Our results confirm the general positive correlation between total species richness and human population density. Contrary to our expectations, the strength of this positive correlation did not weaken at finer spatial resolutions. The patterns observed using total species richness were driven mostly by common species. The richness of threatened and restricted range species was not correlated to human population density. None of the correlations we examined were particularly strong, with much unexplained variance remaining, suggesting that the overlap between butterflies and humans is not strong compared to other factors not accounted for in our analyses. Special consideration needs to be made regarding conservation goals and variables used when investigating the overlap between species and humans for biodiversity conservation