Phylobioactive hotspots in plant resources used to treat Chagas disease

Globally, more than six million people are infected with Trypanosoma cruzi, the causative protozoan parasite of the vector-borne Chagas disease (CD). We conducted a cross-sectional ethnopharmacological field study in Bolivia among different ethnic groups where CD is hyperendemic. A total of 775 extracts of botanical drugs used in Bolivia in the context of CD and botanical drugs from unrelated indications from the Mediterranean De Materia Medica compiled by Dioscorides two thousand years ago were profiled in a multidimensional assay uncovering different antichagasic natural product classes. Intriguingly, the phylobioactive anthraquinone hotspot matched the antichagasic activity of Senna chloroclada, the taxon with the strongest ethnomedical consensus for treating CD among the Izoceño-Guaraní. Testing common 9,10-anthracenedione derivatives in T. cruzi cellular infection assays demarcates hydroxyanthraquinone as a potential antichagasic lead scaffold. Our study systematically uncovers in vitro antichagasic phylogenetic hotspots in the plant kingdom as a potential resource for drug discovery based on ethnopharmacological hypotheses

Daphnia revisited: Local stability and bifurcation theory for physiologically structured population models explained by way of an example

We consider the interaction between a general size-structured consumer population and an unstructured resource. We show that stability properties and bifurcation phenomena can be understood in terms of solutions of a system of two delay equations (a renewal equation for the consumer population birth rate coupled to a delay differetial equation for the resource concentration). As many results for such systems are available, we can draw rigorous conclusions concerning dynamical behaviour from an analysis of a characteristic equation. We derive the characteristic equation for a fairly general class of population models, including those based on the Kooijman-Metz Daphnia model and a model introduced by Gurney-Nisbet and Jones et al., and next obtain various ecological insights by analytical or numerical studies of special cases

Sublethal toxicant effects with dynamic energy budget theory: model formulation

We develop and test a general modeling framework to describe the sublethal effects of pollutants by adding toxicity modules to an established dynamic energy budget (DEB) model. The DEB model describes the rates of energy acquisition and expenditure by individual organisms; the toxicity modules describe how toxicants affect these rates by changing the value of one or more DEB parameters, notably the parameters quantifying the rates of feeding and maintenance. We investigate four toxicity modules that assume: (1) effects on feeding only; (2) effects on maintenance only; (3) effects on feeding and maintenance with similar values for the toxicity parameters; and (4) effects on feeding and maintenance with different values for the toxicity parameters. We test the toxicity modules by fitting each to published data on feeding, respiration, growth and reproduction. Among the pollutants tested are metals (mercury and copper) and various organic compounds (chlorophenols, toluene, polycyclic aromatic hydrocarbons, tetradifon and pyridine); organisms include mussels, oysters, earthworms, water fleas and zebrafish. In most cases, the data sets could be adequately described with any of the toxicity modules, and no single module gave superior fits to all data sets. We therefore propose that for many applications, it is reasonable to use the most general and parameter sparse module, i.e. module 3 that assumes similar effects on feeding and maintenance, as a default. For one example (water fleas), we use parameter estimates to calculate the impact of food availability and toxicant levels on the long term population growth rate

Interleukin-2/interferon-α2a/13-retinoic acid-based chemoimmunotherapy in advanced renal cell carcinoma: results of a prospectively randomised trial of the German Cooperative Renal Carcinoma Chemoimmunotherapy Group (DGCIN)

We performed a prospectively randomised clinical trial to compare the efficacy of four subcutaneous interleukin-2-(sc-IL-2) and sc interferon-α2a (sc-IFN-α2a)-based outpatient regimens in 379 patients with progressive metastatic renal cell carcinoma. Patients with lung metastases, an erythrocyte sedimentation rate ⩽70 mm h−1 and neutrophil counts ⩽6000 μl−1 (group I) were randomised to arm A: sc-IL-2, sc-IFN-α2a, peroral 13-cis-retinoic acid (po-13cRA) (n=78), or arm B: arm A plus inhaled-IL-2 (n=65). All others (group II) were randomised to arm C: arm A plus intravenous 5-fluorouracil (iv-5-FU) (n=116), or arm D: arm A plus po-Capecitabine (n=120). Median overall survival (OS) was 22 months (arm A; 3-year OS: 29.7%) and 18 months (arm B; 3-year OS: 29.2%) in group I, and 18 months (arm C; 3-year OS: 25.7%) and 16 months (arm D; 3-year OS: 32.6%) in group II. There were no statistically significant differences in OS, progression-free survival, and objective response between arms A and B, and between arms C and D, respectively. Given the known therapeutic efficacy of sc-IL-2/sc-INF-α2a/po-13cRA-based outpatient chemoimmunotherapies, our results did not establish survival advantages in favour of po-Capecitabine vs iv-5-FU, and in favour of short-term inhaled-IL-2 in patients with advanced renal cell carcinoma receiving systemic cytokines

Initial microbial spectrum in severe secondary peritonitis and relevance for treatment

This study aims to determine whether abdominal microbial profiles in early severe secondary peritonitis are associated with ongoing infection or death. The study is performed within a randomized study comparing two surgical treatment strategies in patients with severe secondary peritonitis (n = 229). The microbial profiles of cultures retrieved from initial emergency laparotomy were tested with logistic regression analysis for association with ‘ongoing infection needing relaparotomy’ and in-hospital death. No microbial profile or the presence of yeast or Pseudomonas spp. was related to the risk of ongoing infection needing relaparotomy. Resistance to empiric therapy for gram positive cocci and coliforms was moderately associated with ongoing abdominal infection (OR 3.43 95%CI 0.95–12.38 and OR 7.61, 95%CI 0.75–76.94). Presence of only gram positive cocci, predominantly Enterococcus spp, was borderline independently associated with in-hospital death (OR 3.69, 95%CI 0.99–13.80). In secondary peritonitis microbial profiles do not predict ongoing abdominal infection after initial emergency laparotomy. However, the moderate association of ongoing infection with resistance to the empiric therapy compels to more attention for resistance when selecting empiric antibiotic coverage

Hormonal crises following receptor radionuclide therapy with the radiolabeled somatostatin analogue [177Lu-DOTA0,Tyr3]octreotate

textabstractIntroduction: Receptor radionuclide therapy is a promising treatment modality for patients with neuroendocrine tumors for whom alternative treatments are limited. The aim of this study was to investigate the incidence of hormonal crises after therapy with the radiolabeled somatostatin analogue [177Lu-DOTA0,Tyr3]octreotate (177Lu-octreotate). Materials and methods: All177Lu- octreotate treatments between January 2000 and January 2007 were investigated. Four hundred seventy-six patients with gastroenteropancreatic neuroendocrine tumors and three patients with metastatic pheochromocytoma were included for analysis. Results: Four hundred seventy-nine patients received a total of 1,693 administrations of177Lu-octreotate. Six of 479 patients (1%) developed severe symptoms because of massive release of bioactive substances after the first cycle of177Lu-octreotate. One patient had a metastatic hormone-producing small intestinal carcinoid; two patients had metastatic, hormone-producing bronchial carcinoids; two patients had vasoactive intestinal polypeptide-producing pancreatic endocrine tumors (VIPomas); and one patient had a metastatic pheochromocytoma. With adequate treatment, all patients eventually recovered. Conclusion: Hormonal crises after177Lu- octreotate therapy occur in 1% of patients. Generally,177Lu- octreotate therapy is well tolerated

Factors associated with posttraumatic stress symptoms in a prospective cohort of patients after abdominal sepsis:A nomogram

Objective: To determine to what extent patients who have survived abdominal sepsis suffer from symptoms of posttraumatic stress disorder (PTSD) and depression, and to identify potential risk factors for PTSD symptoms. Design and setting: PTSD and depression symptoms were measured using the Impact of Events Scale-Revised (IES-R), the Post-Traumatic Symptom Scale 10 (PTSS-10) and the Beck Depression Inventory II (BDI-II). Patients and participants: A total of 135 peritonitis patients were eligible for this study, of whom 107 (80%) patients completed the questionnaire. The median APACHE-II score was 14 (range 12-16), and 89% were admitted to the ICU.Measurements and results: The proportion of patients with "moderate" PTSD symptom scores was 28% (95% CI 20-37), whilst 10% (95% CI 6-17) of patients had "high" PTSD symptom scores. Only 5% (95% CI 2-12) of the patients expressed severe depression symptoms. Factors associated with increased PTSD symptoms in a multivariate ordinal regression model were younger age (0.74 per 10 years older, p = 0.082), length of ICU stay (OR = 1.4 per doubling of duration, p = 0.003) and having some (OR = 4.9, p = 0.06) or many (OR = 55.5, p &lt; 0.001) traumatic memories of the ICU or hospital stay. Conclusion: As many as 38% of patients after abdominal sepsis report elevated levels of PTSD symptoms on at least one of the questionnaires. Our nomogram may assist in identifying patients at increased risk for developing symptoms of PTSD.</p