Extracellular matrix defects in aneurysmal Fibulin-4 mice predispose to lung emphysema

Background: In this study we set out to investigate the clinically observed relationship between chronic obstructive pulmonary disease (COPD) and aortic aneurysms. We tested the hypothesis that an

Triple antimalarial drug combinations for the treatment of falciparum malaria

Artemisinin-based Combination Therapies (ACTs), in which an artemisinin component is combined with a slowly eliminated partner drug such as piperaquine, mefloquine, lumefantrine, amodiaquine or sulphadoxine-pyrimethamine, are the recommended first-line treatment for Plasmodium falciparum in all malaria endemic countries. Artemisinin resistance, which was first identified between 2006 and 2009 in western Cambodia, results in a high number of parasites surviving the initial 3 days of artemisinin exposure. As a result, a large number of parasites is exposed to a partner drug with a limited potency for an extended time, providing ideal conditions for the selection of partner drug resistance. The threat of artemisinin and partner drug resistance spreading out of Southeast Asia and the threat of independent emergence in other areas underlines the need for treatments that are effective against multidrug resistant malaria and are less likely to fall to resistance. A potential strategy to prolong the utility of existing antimalarials is combining an artemisinin with two partner drugs in the form of a Triple Artemisinin-based Combination Therapy. This thesis describes the current extent of antimalarial resistance in Plasmodium falciparum malaria and assesses the safety, tolerability and efficacy of Triple Antimalarial Combination Therapies. In addition, this thesis explores potential barriers and outstanding questions that will need to be addressed to enable widescale implementation of Triple Antimalarial Combination Therapies

Body mass index is not associated with cytokine induction during experimental human endotoxemia

A higher body mass index (BMI) appears to be associated with lower mortality in critically ill patients, possibly explained by an altered innate immune response. However, the precise relationship between BMI and the innate immune response in humans in vivo is unknown. We investigated the relationship between BMI and the systemic cytokine response during experimental human endotoxemia. Endotoxemia was induced in 112 healthy male volunteers by intravenous administration of 2 ng/kg Escherichia coli endotoxin. Plasma concentrations of TNF-alpha, IL-6, IL-10 and IL-1RA were serially determined. The relationship between BMI and the cytokine response, as well as body temperature, was investigated. The BMIs of the participants ranged from 18.3 to 33.6 kg/m(2), (median: 22.7 kg/m(2)). All participants showed a marked increase in plasma cytokine levels [median (interquartile range)] peak levels: TNF-alpha 509 (353-673) pg/ml; IL-6 757 (522-1098) pg/ml; IL-10 271 (159-401) pg/ml; IL-1RA 4882 (3927-6025) pg/ml; and an increase in body temperature [1.8(1.4-2.2)] during endotoxemia. No significant correlations were found between BMI and levels of any of the cytokines or body temperature. No relationship between BMI and the cytokine response was found in healthy volunteers subjected to experimental endotoxemia. These data question the relationship between BMI and cytokine responses in critical illness

The effect of iron loading and iron chelation on the innate immune response and subclinical organ injury during human endotoxemia: a randomized trial

In this double-blind randomized placebo-controlled trial involving 30 healthy male volunteers we investigated the acute effects of iron loading (single dose of 1.25 mg/kg iron sucrose) and iron chelation therapy (single dose of 30 mg/kg deferasirox) on iron parameters, oxidative stress, the innate immune response, and subclinical organ injury during experimental human endotoxemia. The administration of iron sucrose induced a profound increase in plasma malondialdehyde 1 h after administration (433+/-37% of baseline; P<0.0001), but did not potentiate the endotoxemia-induced increase in malondialdehyde, as was seen 3 h after endotoxin administration in the placebo group (P=0.34) and the iron chelation group (P=0.008). Endotoxemia resulted in an initial increase in serum iron levels and transferrin saturation that was accompanied by an increase in labile plasma iron, especially when transferrin saturation reached levels above 90%. Thereafter, serum iron decreased to 51.6+/-9.7% of baseline at T=8 h in the placebo group versus 84+/-15% and 60.4+/-8.9% of baseline at 24 h in the groups treated with iron sucrose and deferasirox, respectively. No significant differences in the endotoxemia-induced cytokine response (TNF-alpha, IL-6, IL-10 and IL-1RA), subclinical vascular injury and kidney injury were observed between groups. However, vascular reactivity to noradrenalin was impaired in the 6 subjects in whom labile plasma iron was elevated during endotoxemia as opposed to those in whom no labile plasma iron was detected (P=0.029). In conclusion, a single dose of iron sucrose does not affect the innate immune response in a model of experimental human endotoxemia, but may impair vascular reactivity when labile plasma iron is formed. (Clinicaltrials.gov identifier:01349699)

Extracellular Matrix Defects in Aneurysmal Fibulin-4 Mice Predispose to Lung Emphysema

Cardiovascular Aspects of Radiolog

The methodological quality of clinical guidelines of the European Society of Human Reproduction and Embryology (ESHRE).

Contains fulltext : 70713.pdf (publisher's version ) (Closed access)BACKGROUND: Clinical practice guidelines bridge the gap between the evidence from literature and clinical practice, and they may provide guidance in ethical, legal and societal dilemmas. To explore the potentials for future international guideline development within the field of human reproduction and embryology, we assessed the quality of existing guidelines produced by the European Society of Human Reproduction and Embryology (ESHRE). METHODS: We systematically searched for the ESHRE guidelines produced after 1996 in electronic databases and on the Internet. Subsequently, we assessed the methodological quality of these guidelines using the validated Appraisal of Guidelines for Research and Evaluation (AGREE) Instrument. RESULTS: The overall methodological quality of most of the 11 selected ESHRE guidelines was poor. Most of the guidelines scored <30% in the domains of 'stakeholder involvement', 'rigour of development', 'applicability' and 'editorial independence'. Only one guideline was rated 'strongly recommended'. CONCLUSIONS: The methodological quality of the guidelines produced under the auspices of ESHRE can be improved. We suggest a systematic, up-to-date methodology, investment in guideline development specialists, systematic quality control and the incorporation of indicator development. Furthermore, attention should be paid to the document nomenclature, and an ESHRE guidelines' summary on a special part of the ESHRE website would be a good initiative

The impact of targeted malaria elimination with mass drug administrations on falciparum malaria in southeast Asia: A cluster randomised trial

10.1371/journal.pmed.1002745PLoS Medicine162e100274

Pf7: an open dataset of Plasmodium falciparum genome variation in 20,000 worldwide samples

We describe the MalariaGEN Pf7 data resource, the seventh release of Plasmodium falciparum genome variation data from the MalariaGEN network.  It comprises over 20,000 samples from 82 partner studies in 33 countries, including several malaria endemic regions that were previously underrepresented.  For the first time we include dried blood spot samples that were sequenced after selective whole genome amplification, necessitating new methods to genotype copy number variations.  We identify a large number of newly emerging crt mutations in parts of Southeast Asia, and show examples of heterogeneities in patterns of drug resistance within Africa and within the Indian subcontinent.  We describe the profile of variations in the C-terminal of the csp gene and relate this to the sequence used in the RTS,S and R21 malaria vaccines.  Pf7 provides high-quality data on genotype calls for 6 million SNPs and short indels, analysis of large deletions that cause failure of rapid diagnostic tests, and systematic characterisation of six major drug resistance loci, all of which can be freely downloaded from the MalariaGEN website