Structural Studies of Lanthanide Double Perovskites

This project focuses on the examination of the structures of lanthanide containing double perovskites of the type Ba2LnB'O6-d (Ln = lanthanide or Y3+ and B' = Nb5+, Ta5+, Sb5+ and/or Sn4+) using synchrotron X-ray and neutron powder diffraction. The first part of this project examined the relative stability of R3 rhombohedral and I4/m tetragonal structures as the intermediate phase adopted by the series Ba2LnB'O6 (Ln = lanthanide (III) or Y3+ and B' = Nb5+, Ta5+ or Sb5+). It was found that I4/m tetragonal symmetry was favoured when B' was a transition metal with a small number of d electrons, such as Nb5+ or Ta5+. This is due to the presence of p-bonding in these compounds. In the Ba2LnNbO6 and Ba2LnTaO6 series R3 rhombohedral symmetry was, however, favoured over I4/m tetragonal symmetry when Ln = La3+ or Pr3+ due to the larger ionic radius of these cations. The incompatibility of the d0 and d10 B'-site cations in this family of compounds was indicated by significant regions of phase segregation in the two series Ba2Eu1-xPrxNb1-xSbxO6 and Ba2NdNb1-xSbxO6. In the second part of this project the compounds in the series Ba2LnSnxB'1-xO6-d (Ln = Pr, Nd or Tb and B' = Nb5+ or Sb5+) were examined to understand the relative stability of oxygen vacancies in these materials compared to the oxidation of the lanthanide cations and to determine if any oxygen vacancy ordering occurred. It was found, using a combination of structural characterisation, X ray Absorption Near Edge Structure and Ultra-Violet, Visible and Near Infrared spectroscopies, that with Ln = Pr or Tb increased Sn4+ doping results in a change in the oxidation state of the Ln3+ cations to Ln4+. This leads to those series containing little or no oxygen vacancies. A loss of B site cation ordering was found to accompany this oxidation state change and phase segregation was found to occur in the Ba2PrSnxSb1-xO6-d series most likely due to the Pr3+ and Pr4+ cations segregating into different phases. The Nd3+ cations in the series Ba2NdSnxSb1-xO6-d, however, can not oxidise to the tetravalent state so the number of oxygen vacancies rises with increasing x. It was found that oxygen vacancies concentrate onto the axial site of the compounds with x = 0.6 and 0.8 at ambient temperature. In Ba2Sn0.6Sb0.4O5.7 the oxygen vacancies were found to change to concentrating on the equatorial site at higher temperatures and it is suggested that this oxygen vacancy ordering plays a role in the adoption of I2/m monoclinic symmetry

The effectiveness of "Exercise on Prescription" in stimulating physical activity among women in ethnic minority groups in the Netherlands: protocol for a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Lack of physical activity is an important risk factor for overweight, diabetes, cardiovascular disease and other chronic conditions. In the Netherlands, ethnic minority groups are generally less physically active and rate their own health poorer compared to ethnic Dutch. This applies in particular to women. For this reason women from ethnic minority groups are an important target group for interventions to promote physical activity.</p> <p>In the Netherlands, an exercise referral program ("Exercise on Prescription") seems successful in reaching women from ethnic minority groups, in particular because of referral by the general practitioner and because the program fits well with the needs of these women. However, the effect of the intervention on the level of physical activity and related health outcomes has not been formally evaluated within this population. This paper describes the study design for the evaluation of the effect of "Exercise on Prescription" on level of physical activity and related health outcomes.</p> <p>Methods</p> <p>The randomized controlled trial will include 360 inactive women from ethnic minority groups, with the majority having a non-Western background, aged between 18 and 65 years old, with regular visits to their general practitioner. Participants will be recruited at healthcare centres within a deprived neighbourhood in the city of The Hague, the Netherlands.</p> <p>An intervention group of 180 women will participate in an exercise program with weekly exercise sessions during 20 weeks. The control group (n = 180) will be offered care as usual. Measurements will take place at baseline, and after 6 and 12 months. Main outcome measure is minutes of self reported physical activity per week. Secondary outcomes are the mediating motivational factors regarding physical activity, subjective and objective health outcomes (including wellbeing, perceived health, fitness and body size) and use of (primary) health care. Attendance and attrition during the program will be determined.</p> <p>Conclusion</p> <p>This trial will provide information on the effectiveness of an exercise referral scheme on the short and long term among women from ethnic minority groups, mainly non-Western, in the Netherlands. The results of this study will contribute to the evidence base for interventions in ethnic minority populations.</p> <p>Trial registration</p> <p>Dutch Trial register: NTR1294</p

Thrombospondins in the heart: potential functions in cardiac remodeling

Cardiac remodeling after myocardial injury involves inflammation, angiogenesis, left ventricular hypertrophy and matrix remodeling. Thrombospondins (TSPs) belong to the group of matricellular proteins, which are non-structural extracellular matrix proteins that modulate cell–matrix interactions and cell function in injured tissues or tumors. They interact with different matrix and membrane-bound proteins due to their diverse functional domains. That the expression of TSPs strongly increases during cardiac stress or injury indicates an important role for them during cardiac remodeling. Recently, the protective properties of TSP expression against heart failure have been acknowledged. The current review will focus on the biological role of TSPs in the ischemic and hypertensive heart, and will describe the functional consequences of TSP polymorphisms in cardiac disease

The role of SPARC in extracellular matrix assembly

SPARC is a collagen-binding matricellular protein. Expression of SPARC in adult tissues is frequently associated with excessive deposition of collagen and SPARC-null mice fail to generate a robust fibrotic response to a variety of stimuli. This review summarizes recent advancements in the characterization of the binding of SPARC to collagens and describes the results of studies that implicate a function for SPARC in the regulation of the assembly of basal lamina and fibrillar collagen in the ECM. Potential cellular mechanisms that underlie SPARC activity in ECM deposition are also explored

Cardiomyopathy and Response to Enzyme Replacement Therapy in a Male Mouse Model for Fabry Disease

Fabry disease is an X-linked disorder of glycosphingolipid metabolism that results in progressive accumulation of neutral glycosphingolipids, (predominately globotriaosylceramide; GL-3) in lysosomes, as well as other cellular compartments and the extracellular space. Our aim was to characterize the cardiac phenotype of male knock-out mice that are deficient in alpha-galactosidase A activity, as a model for Fabry disease and test the efficacy of Enzyme Replacement Therapy with agalsidase-beta. Male mice (3–4 months of age) were characterized with awake blood pressure and heart rate measurements, cardiac echocardiography and electrocardiography measurements under light anesthesia, histological studies and molecular studies with real-time polymerase chain reaction. The Fabry knock-out mouse has bradycardia and lower blood pressure than control wild type (CB7BL/6J) mice. In Fabry knock-out mice, the cardiomyopathy associated mild hypertrophy at echography with normal systolic LV function and mild diastolic dysfunction. Premature atrial contractions were more frequent in without conduction defect. Heart weight normalized to tibial length was increased in Fabry knock-out mice. Ascending aorta dilatation was observed. Molecular studies were consistent with early stages of cardiac remodeling. A single dose of agalsidase-beta (3 mg/kg) did not affect the LV hypertrophy, function or heart rate, but did improve the mRNA signals of early cardiac remodeling. In conclusion, the alpha-galactosidase A deficient mice at 3 to 4 months of age have cardiac and vascular alterations similar to that described in early clinical stage of Fabry disease in children and adolescents. Enzyme replacement therapy affects cardiac molecular remodeling after a single dose

Orally Inhaled Flecainide for Conversion of Atrial Fibrillation to Sinus Rhythm: INSTANT Phase 2 Trial.

BACKGROUND: INSTANT (INhalation of flecainide to convert recent-onset SympTomatic Atrial fibrillatioN to sinus rhyThm) was a multicenter, open-label, single-arm study of flecainide acetate oral inhalation solution (FlecIH) for acute conversion of recent-onset (≤48 hours) symptomatic atrial fibrillation (AF) to sinus rhythm. OBJECTIVES: This study investigated the efficacy and safety in 98 patients receiving a single dose of FlecIH delivered via oral inhalation. METHODS: Patients self-administered FlecIH over 8 minutes in a supervised medical setting using a breath-actuated nebulizer and were continuously monitored for 90 minutes using a 12-lead Holter. RESULTS: Mean age was 60.5 years, mean body mass index was 27.0 kg/m2, and 34.7% of the patients were women. All patients had ≥1 AF-related symptoms at baseline, and 87.8% had AF symptoms for ≤24 hours. The conversion rate was 42.6% (95% CI: 33.0%-52.6%) with a median time to conversion of 14.6 minutes. The conversion rate was 46.9% (95% CI: 36.4%-57.7%) in a subpopulation that excluded predose flecainide exposure for the current AF episode. Median time to discharge among patients who converted was 2.5 hours, and only 2 patients had experienced AF recurrence by day 5. In the conversion-no group, 44 (81.5%) patients underwent electrical cardioversion by day 5. The most common adverse events were related to oral inhalation of flecainide (eg, cough, oropharyngeal irritation/pain), which were mostly of mild intensity and limited duration. CONCLUSIONS: The risk-benefit of orally inhaled FlecIH for acute cardioversion of recent-onset AF appears favorable. FlecIH could provide a safe, effective, and convenient first-line therapeutic option. (INhalation of Flecainide to Convert Recent Onset SympTomatic Atrial Fibrillation to siNus rhyThm [INSTANT]; NCT03539302)

The impact of a cancer Survivorship Care Plan on gynecological cancer patient and health care provider reported outcomes (ROGY Care): study protocol for a pragmatic cluster randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>There is a need for improvement of information provision and post-treatment care for cancer survivors. A Survivorship Care Plan (SCP) is recommended by the American Institute of Medicine and the Dutch Health Council, which is a summary of patients' course of treatment as a formal document, and includes recommendations for subsequent cancer surveillance, management of late effects, and strategies for health promotion. Until now, evidence on the effects of implementing the SCP in clinical practice is lacking. The rationale and study design of a pragmatic cluster randomized trial, aiming to assess the impact of SCP care in routine clinical practice, is presented.</p> <p>Methods/Design</p> <p>A web-based patient registration system 'Registrationsystem Oncological GYnecology' (ROGY) is used by gynecologists in the South of the Netherlands since 2006. A personalized SCP can automatically be generated out of ROGY. In this pragmatic cluster randomized controlled trial, 12 hospitals are randomized to either 'usual care' or 'SCP care'. In patients with 'usual care', the gynecologist provides care as usual. In patients with 'SCP care', information about the tumor stage and treatment is personally discussed with the patient and a document is handed to the patient. Prospectively, all patients diagnosed with endometrial or ovarian cancer in the participating hospitals will be approached for study participation. Patients will complete questionnaires after surgery, and before additional treatment, and after 6, 12, 18 and 24 months. In addition, health care providers will be asked their opinion about implementation of SCP care. Primary outcome is defined as patient satisfaction with information provision and care. Secondary outcomes are illness perception, health-related quality of life, health care use, prevalence, course and referral rate of survivors with psychosocial distress, and health care providers' evaluation of SCP care.</p> <p>Discussion</p> <p>The ROGY Care trial will help to gain insight into the impact of SCP care on patient reported outcomes, and on the evaluation of cancer survivors and health care providers of the different elements of the SCP. Therefore, results will contribute to efforts to improve quality of care for cancer survivors.</p> <p>Trial registration</p> <p>Trial Registration: <url>http://www.ClinicalTrials.gov</url>. Identifier: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01185626">NCT01185626</a></p> <p>Medical Research Ethics Committee Reference Number: NL33429.008.10 Grant Reference Number: UVT2010-4743</p

Conservative versus invasive strategy in elderly patients with non-ST-elevation myocardial infarction: insights from the international POPular age registry

This registry assessed the impact of conservative and invasive strategies on major adverse clinical events (MACE) in elderly patients with non-ST-elevation myocardial infarction (NSTEMI). Patients aged ≥75 years with NSTEMI were prospectively registered from European centers and followed up for one year. Outcomes were compared between conservative and invasive groups in the overall population and a propensity score-matched (PSM) cohort. MACE included cardiovascular death, acute coronary syndrome, and stroke. The study included 1190 patients (median age 80 years, 43% female). CAG was performed in 67% (N = 798), with two-thirds undergoing revascularization. Conservatively treated patients had higher baseline risk. After propensity score matching, 319 patient pairs were successfully matched. MACE occurred more frequently in the conservative group (total population 20% vs. 12%, adjHR 0.53, 95% CI 0.37–0.77, p = 0.001), remaining significant in the PSM cohort (18% vs. 12%, adjHR 0.50, 95% CI 0.31–0.81, p = 0.004). In conclusion, an early invasive strategy was associated with benefits over conservative management in elderly patients with NSTEMI. Risk factors associated with ischemia and bleeding should guide strategy selection rather than solely relying on age

MicroRNA Involvement in Immune Activation During Heart Failure

Heart failure is one of the common end stages of cardiovascular diseases, the leading cause of death in developed countries. Molecular mechanisms underlying the development of heart failure remain elusive but there is a consistent observation of chronic immune activation and aberrant microRNA (miRNA) expression that is present in failing hearts. This review will focus on the interplay between the immune system and miRNAs as factors that play a role during the development of heart failure. Several studies have shown that heart failure patients can be characterized by a sustained innate immune activation. The role of inflammatory signaling is discussed and TLR4 signaling, IL-1β, TNFα and IL-6 expression appears to coincide with the development of heart failure. Furthermore, we describe the implication of the renin angiotensin aldosteron system in immunity and heart failure. In the past decade microRNAs (miRNAs), small non-coding RNAs that translationally repress protein synthesis by binding to partially complementary sequences of mRNA, have come to light as important regulators of several kinds of cardiovascular diseases including cardiac hypertrophy and heart failure. The involvement of differentially expressed miRNAs in the inflammation that occurs during the development of heart failure is still subject of investigation. Here, we summarize and comment on the first studies in this field and hypothesize on the putative involvement of certain miRNAs in heart failure. MicroRNAs have been shown to be critical regulators of cardiac function and inflammation. Future research will have to point out if dampening the immune response, and the miRNAs associated with it, during the development of heart failure is a therapeutically plausible route to follow