Improving patient involvement in the lifecycle of medicines : insights from the EUPATI BE survey

EUPATI Belgium (EUPATI.be) is an informal gathering of local partners who are interested in improving patient involvement in healthcare innovation and medicines research and development. EUPATI.be brings together various stakeholders from different areas related to healthcare including patients, academia and industry. In doing so, we create an innovative collaborative approach where actors from different backgrounds work toward improving patient involvement in medical research, and putting the patient at the center of the Belgian healthcare system. Previously, we performed in-depth interviews with a small group of stakeholders on patient involvement. Here, we elaborate on our previous findings by using a nation-wide survey to inquire into Belgian stakeholders' perception on patient involvement. To this end, an electronic survey was available in French, Dutch and English, and accessible for 11 months. Twelve questions were asked, including 11 multiple choice questions and 1 open question. The latter was thematically analyzed according to the framework method. A total of 117 responses were registered and descriptive statistics were performed. The majority of respondents could be categorized into patient, academia and industry, whereas policy makers, payers, and healthcare professionals were underrepresented. We identified several barriers that hamper patient involvement, which were sometimes more reported by specific stakeholder groups. Next, we found that various stakeholders still consider patient involvement as a passive role, i.e., medical subject in a clinical trial. Respondents also reported that the role of the various stakeholders needed more clarification; this was also confirmed by the level of trust amongst the various stakeholders. Existing and the wish for more collaboration with the various stakeholders was reported by almost all respondents. Based on this survey, we can define the potential of involving patients in the medical research and development in the Belgian landscape. Our results will help to understand and tackle the various barriers that currently hamper patient involvement, whilst highlighting the need for a collaborative landscape from the multi-stakeholder perspective

A damped oscillator imposes temporal order on posterior gap gene expression in Drosophila.

Insects determine their body segments in two different ways. Short-germband insects, such as the flour beetle Tribolium castaneum, use a molecular clock to establish segments sequentially. In contrast, long-germband insects, such as the vinegar fly Drosophila melanogaster, determine all segments simultaneously through a hierarchical cascade of gene regulation. Gap genes constitute the first layer of the Drosophila segmentation gene hierarchy, downstream of maternal gradients such as that of Caudal (Cad). We use data-driven mathematical modelling and phase space analysis to show that shifting gap domains in the posterior half of the Drosophila embryo are an emergent property of a robust damped oscillator mechanism, suggesting that the regulatory dynamics underlying long- and short-germband segmentation are much more similar than previously thought. In Tribolium, Cad has been proposed to modulate the frequency of the segmentation oscillator. Surprisingly, our simulations and experiments show that the shift rate of posterior gap domains is independent of maternal Cad levels in Drosophila. Our results suggest a novel evolutionary scenario for the short- to long-germband transition and help explain why this transition occurred convergently multiple times during the radiation of the holometabolan insects.MINECO BFU2009-10184/BFU2012-33775/SEV-2012-0208 European Commission FP7/KBBE-2011/5/289434 La Caixa Savings Bank (PhD fellowship to BV) KLI Klosterneuburg (PhD Writing-up & Postdoctoral Fellowships to BV) Wissenschaftskolleg zu Berlin (Wiko) (Fellowships to JJ and AC

In-vitro growth characteristics of commercial probiotic strains and their potential for inhibition of Clostridium difficile and Clostridium perfringens

The effect of catheter material on intravenous catheterisation complications in horses are unknown. This study evaluated the presence of bacterial colonisation on Teflon® and polyurethane short term intravenous catheters in healthy adult horses undergoing elective surgery. Horses on admission for elective surgery were randomly allocated according to catheter type. Sixteen horses received Teflon® catheters and 19 received polyurethane. Aseptic catheter placement and removal was standardised, however systemic antibiotic treatment was case dependant and at the clinician’s discretion. To simulate routine clinical practice, face masks were not worn during placement nor were the catheters bandaged. Catheters were maintained for 74 hours and assessed for clinical evidence of catheter site reaction, phlebitis or thrombosis twice daily. Bacteria were cultured from 69% of Teflon® and 89% of polyurethane catheters. Multiple isolates were found in 31% of Teflon® and 42% of polyurethane catheters The Fisher exact test showed no difference between the proportion of catheters with colonisation (P=0.28) or multiple isolates (P=0.76). The microbes cultured were predominantly gram positive, similar to other equine and human studies. Multiple-drug resistance was seen regularly, regardless of antibiotic treatment. Despite this, no clinical evidence of phlebitis or thrombosis occurred in any horse. It was concluded, that was no clear association between bacterial colonisation of Teflon® or polyurethane catheters (0.9<RR<1.87). The unexpected large proportion of bacterial isolates in the absence of clinical signs was also evaluated and suggests that the equine immune system plays a role in the development of septic phlebitis or thrombosis

Decreased soluble guanylate cyclase contributes to cardiac dysfunction induced by chronic doxorubicin treatment in mice

Aims: The use of doxorubicin, a potent chemotherapeutic agent, is limited by cardiotoxicity. We tested the hypothesis that decreased soluble guanylate cyclase (sGC) enzyme activity contributes to the development of doxorubicin-induced cardiotoxicity. Results: Doxorubicin administration (20 mg/kg, intraperitoneally [IP]) reduced cardiac sGC activity in wild-type (WT) mice. To investigate whether decreased sGC activity contributes to doxorubicin-induced cardiotoxicity, we studied mice with cardiomyocyte-specific deficiency of the sGC alpha 1-subunit (mice with cardiomyocyte-specific deletion of exon 6 of the sGC alpha 1 allele [sGC alpha 1(-/-CM)]). After 12 weeks of doxorubicin administration (2 mg/kg/week IP), left ventricular (LV) systolic dysfunction was greater in sGC alpha 1(-/-CM) than WT mice. To further assess whether reduced sGC activity plays a pathogenic role in doxorubicin-induced cardiotoxicity, we studied a mouse model in which decreased cardiac sGC activity was induced by cardiomyocyte-specific expression of a dominant negative sGC alpha 1 mutant (DNsGC alpha 1) upon doxycycline removal (Tet-off). After 8 weeks of doxorubicin administration, DNsGC alpha 1(tg/+), but not WT, mice displayed LV systolic dysfunction and dilatation. The difference in cardiac function and remodeling between DNsGC alpha 1(tg/+) and WT mice was even more pronounced after 12 weeks of treatment. Further impairment of cardiac function was attenuated when DNsGC alpha 1 gene expression was inhibited (beginning at 8 weeks of doxorubicin treatment) by administering doxycycline. Furthermore, doxorubicin-associated reactive oxygen species generation was higher in sGC alpha 1-deficient than WT hearts. Innovation and Conclusion: These data demonstrate that a reduction in cardiac sGC activity worsens doxorubicin-induced cardiotoxicity in mice and identify sGC as a potential therapeutic target. Various pharmacological sGC agonists are in clinical development or use and may represent a promising approach to limit doxorubicin-associated cardiotoxicity

Dietary cholesterol withdrawal reduces vascular inflammation and induces coronary plaque stabilization in miniature pigs

Objective: To study the effect of dietary cholesterol withdrawal on size and composition of LDL-hypercholesterolemia-induced coronary plaques in miniature pigs. Methods: Pigs were on normal chow (control group), on a cholesterol-rich diet for 37 weeks (hypercholesterolemic group) or on a cholesterol-rich diet followed by normal chow for 26 weeks (cholesterol withdrawal group). Endothelial function was assessed with quantitative angiography after intracoronary infusion of acetylcholine, plaque load with intra-coronary ultrasound and plaque composition with image analysis of cross-sections. The effect of porcine serum on coronary smooth muscle cell (SMC) function was studied in vitro. Results: Cholesterol-rich diet caused LDL-hypercholesterolemia, increased plasma levels of oxidized LDL (ox-LDL) and C-reactive protein (CRP), and induced endothelial dysfunction and coronary atherosclerosis. Dietary cholesterol withdrawal lowered LDL, ox-LDL and CRP. It restored endothelial function, did not affect plaque size but decreased lipid, ox-LDL and macrophage content. Smooth muscle cells and collagen accumulated within the plaque. Increased smoothelin-to-α-smooth muscle actin ratio indicated a more differentiated SMC phenotype. Cholesterol lowering reduced proliferation and apoptosis. In vitro, hypercholesterolemic serum increased SMC apoptosis and decreased SMC migration compared to non-hypercholesterolemic serum. Conclusions: Cholesterol lowering induced coronary plaque stabilization as evidenced by a decrease in lipids, ox-LDL, macrophages, apoptosis and cell proliferation, and an increase in differentiated SMC and collagen. Increased migration and decreased apoptosis of SMC may contribute to the disappearance of the a-cellular core after lipid lowerin

A role for Phospholipase D in Drosophila embryonic cellularization

BACKGROUND: Cellularization of the Drosophila embryo is an unusually synchronous form of cytokinesis in which polarized membrane extension proceeds in part through incorporation of new membrane via fusion of apically-translocated Golgi-derived vesicles. RESULTS: We describe here involvement of the signaling enzyme Phospholipase D (Pld) in regulation of this developmental step. Functional analysis using gene targeting revealed that cellularization is hindered by the loss of Pld, resulting frequently in early embryonic developmental arrest. Mechanistically, chronic Pld deficiency causes abnormal Golgi structure and secretory vesicle trafficking. CONCLUSION: Our results suggest that Pld functions to promote trafficking of Golgi-derived fusion-competent vesicles during cellularization

FlyMine: an integrated database for Drosophila and Anopheles genomics.

FlyMine is a data warehouse that addresses one of the important challenges of modern biology: how to integrate and make use of the diversity and volume of current biological data. Its main focus is genomic and proteomics data for Drosophila and other insects. It provides web access to integrated data at a number of different levels, from simple browsing to construction of complex queries, which can be executed on either single items or lists

Increased Cardiac Myocyte PDE5 Levels in Human and Murine Pressure Overload Hypertrophy Contribute to Adverse LV Remodeling

Background: The intracellular second messenger cGMP protects the heart under pathological conditions. We examined expression of phosphodiesterase 5 (PDE5), an enzyme that hydrolyzes cGMP, in human and mouse hearts subjected to sustained left ventricular (LV) pressure overload. We also determined the role of cardiac myocyte-specific PDE5 expression in adverse LV remodeling in mice after transverse aortic constriction (TAC). Methodology/Principal Findings: In patients with severe aortic stenosis (AS) undergoing valve replacement, we detected greater myocardial PDE5 expression than in control hearts. We observed robust expression in scattered cardiac myocytes of those AS patients with higher LV filling pressures and BNP serum levels. Following TAC, we detected similar, focal PDE5 expression in cardiac myocytes of C57BL/6NTac mice exhibiting the most pronounced LV remodeling. To examine the effect of cell-specific PDE5 expression, we subjected transgenic mice with cardiac myocyte-specific PDE5 overexpression (PDE5-TG) to TAC. LV hypertrophy and fibrosis were similar as in WT, but PDE5-TG had increased cardiac dimensions, and decreased dP/dtmax and dP/dtmin with prolonged tau (P<0.05 for all). Greater cardiac dysfunction in PDE5-TG was associated with reduced myocardial cGMP and SERCA2 levels, and higher passive force in cardiac myocytes in vitro. Conclusions/Significance: Myocardial PDE5 expression is increased in the hearts of humans and mice with chronic pressure overload. Increased cardiac myocyte-specific PDE5 expression is a molecular hallmark in hypertrophic hearts with contractile failure, and represents an important therapeutic target