EFFICACY AND SAFETY OF RADIATION SYNOVECTOMY WITH YTTRIUM-90: A RETROSPECTIVE LONG-TERM ANALYSIS OF 164 APPLICATIONS IN 82 PATIENTS

In this long term retrospective study of radiation synovectomy with Yttrium-90 (Y90), we evaluated the results of 164 applications in 82 patients with RA, OA with synovitis, ankylosing spondylitis and psoriatic arthritis. Radiation synovectomy with Y90 has an overall success rate of approximately 50% and is therefore an effective alternative to surgical synovectomy in chronic synovitis which fails to respond to conservative treatment. Elbow and knee responded significantly better than shoulder and ankle joints. Patients with radiological stages from 0 to 2 showed a significantly better success rate than those with stage 3 changes. In responders, repeat therapy for recurrence of symptoms or treatment of a symptomatic corresponding symmetrical joint is advisable. Repeat therapy in a previous non-responder is associated with an unacceptably high failure rate. Therefore, when a joint fails to respond after 6 months, arthroscopy should be performed to evaluate further treatment procedures. A successful result was found in only 11 of 25 joints treated with arthroscopic synovectomy followed by radiation synovectomy within 2 weeks, indicating no benefit of this combinatio

Endotension is Influenced by Wall Compliance in a Latex Aneurysm Model

AbstractObjectives. Even though endovascular aneurysm repair (EVAR) creates a closed chamber except for patent branches, the intra-sac pressure is never zero. This study was designed to investigate whether, and to what extent, aneurysm wall compliance influences intra-sac pressure.Design. In vitro experimental study.Methods. Aneurysm models with six and 12 latex layers were produced, resulting in elastic and stiff circumferential compliance (3.5±0.5 and 0.9±0.3%/100 mmHg, respectively). The models with an 18 mm internal neck and maximum aneurysm diameter of 60 mm were inserted into an in vitro circulation system. The systemic mean pressure (SPmean) was varied from 50 to 120 mmHg. After the aneurysm was excluded with a knitted polyethylene graft, aneurysm sac mean pressure (ASPmean) and aneurysm sac pulse pressure (ASPpulse) were measured. Data are presented as mean±SD. Statistics were performed using repeated measurements of variance; p<0.05 was considered significant.Results. In the model EVAR created a closed chamber without endoleak, but with an aneurysm sac pressure related to wall compliance. In the elastic aneurysm model with six latex coats the aneurysm sac mean pressure (ASPmean) and the aneurysm sac pulse pressure (ASPpulse) at all systemic pressures were significantly lower than they were in the stiffer model with 12 latex coats (p<0.05). At a SPmean of 90 mmHg, the ASPmean was 21.0±0.9 mmHg (six latex coats) and 26.0±0.2 mmHg (12 latex coats) (p<0.05), the ASPpulse was 5.7±0.2 mmHg (six latex coats) and 8.8±0.3 mmHg (12 latex coats) (p<0.05).Conclusions. This in vitro model demonstrated that the aneurysm sac mean pressure (ASPmean) and the aneurysm sac pulse pressure (ASPpulse) were significantly influenced by the compliance of the aneurysm wall. These data highlight the need for further studies regarding endotension

The mammalian phosphatidylinositol 3-phosphate 5-kinase (PIKfyve) regulates endosome-to-TGN retrograde transport

The yeast gene fab1 and its mammalian orthologue Pip5k3 encode the phosphatidylinositol 3-phosphate [PtdIns(3)P] 5-kinases Fab1p and PIKfyve, respectively, enzymes that generates phosphatidylinositol 3,5-bisphosphate [PtdIns(3,5)P(2)]. A shared feature of fab1Delta yeast cells and mammalian cells overexpressing a kinase-dead PIKfyve mutant is the formation of a swollen vacuolar phenotype: a phenotype that is suggestive of a conserved function for these enzymes and their product, PtdIns(3,5)P(2), in the regulation of endomembrane homeostasis. In the current study, fixed and live cell imaging has established that, when overexpressed at low levels in HeLa cells, PIKfyve is predominantly associated with dynamic tubular and vesicular elements of the early endosomal compartment. Moreover, through the use of small interfering RNA, it has been shown that suppression of PIKfyve induces the formation of swollen endosomal structures that maintain their early and late endosomal identity. Although internalisation, recycling and degradative sorting of receptors for epidermal growth factor and transferrin was unperturbed in PIKfyve suppressed cells, a clear defect in endosome to trans-Golgi-network (TGN) retrograde traffic was observed. These data argue that PIKfyve is predominantly associated with the early endosome, from where it regulates retrograde membrane trafficking to the TGN. It follows that the swollen endosomal phenotype observed in PIKfyve-suppressed cells results primarily from a reduction in retrograde membrane fission rather than a defect in multivesicular body biogenesis

Prevalence and Predictors of Vitamin D Insufficiency in Children: A Great Britain Population Based Study

Objectives To evaluate the prevalence and predictors of vitamin D insufficiency (VDI) in children In Great Britain. Design A nationally representative cross-sectional study survey of children (1102) aged 4–18 years (999 white, 570 male) living in private households (January 1997–1998). Interventions provided information about dietary habits, physical activity, socio-demographics, and blood sample. Outcome measures were vitamin D insufficiency (<50 nmol/L). Results Vitamin D levels (mean = 62.1 nmol/L, 95%CI 60.4–63.7) were insufficient in 35%, and decreased with age in both sexes (p<0.001). Young People living between 53–59 degrees latitude had lower levels (compared with 50–53 degrees, p = 0.045). Dietary intake and gender had no effect on vitamin D status. A logistic regression model showed increased risk of VDI in the following: adolescents (14–18 years old), odds ratio (OR) = 3.6 (95%CI 1.8–7.2) compared with younger children (4–8 years); non white children (OR = 37 [95%CI 15–90]); blood levels taken December-May (OR = 6.5 [95%CI 4.3–10.1]); on income support (OR = 2.2 [95%CI 1.3–3.9]); not taking vitamin D supplementation (OR = 3.7 [95%CI 1.4–9.8]); being overweight (OR 1.6 [95%CI 1.0–2.5]); <1/2 hour outdoor exercise/day/week (OR = 1.5 [95%CI 1.0–2.3]); watched >2.5 hours of TV/day/week (OR = 1.6[95%CI 1.0–2.4]). Conclusion We confirm a previously under-recognised risk of VDI in adolescents. The marked higher risk for VDI in non-white children suggests they should be targeted in any preventative strategies. The association of higher risk of VDI among children who exercised less outdoors, watched more TV and were overweight highlights potentially modifiable risk factors. Clearer guidelines and an increased awareness especially in adolescents are needed, as there are no recommendations for vitamin D supplementation in older children

Hard Habits to Break: Investigating Coastal Resource Utilisations and Management Systems in Sulawesi, Indonesia.

This research investigates the paradox that many coastal communities in developing countries are resource rich but income poor. Another aspect of this paradox is the belief that local communities possess traditional knowledge that respects nature. This belief contrasts the fact that major tropical coastal ecosystems, namely coral reefs and mangroves, are being destroyed at rapid and increasing rates, in many cases by the people whose livelihoods depend on them. These paradoxical circumstances lead to a central question: if the sustainability of coastal resources is vital for the livelihood of local communities, why are these resources being degraded, often to the point of complete destruction? This study explores the motives and consequences of destructive methods of coastal resource utilisation and examines the potential for sustainable livelihoods based on coastal resources currently under threat from destructive use patterns. The analysis is based on a field study conducted in 2006 and 2008 in eleven sites around the island of Sulawesi, Indonesia. This area is characterised by great biodiversity, including one of the highest marine biodiversities in the Asia-Pacific region. Coral and mangrove ecosystem resource use was found to be driven by different processes and activities; hence the destructive practices impacting both ecosystems were also different. Blast and poison fishing were the most widespread destructive resource use methods found for coral reefs whereas large-scale habitat conversion was responsible for mangrove ecosystem reduction. In the field both resources were found to be under enormous anthropogenic pressures, with published data suggesting that only 5.8% of Indonesian coral reefs are currently in excellent condition and only 38% of mangrove cover remaining in Sulawesi relative to that of 25 years ago. The dynamics of these coastal resources, and of their destruction, are classic examples of the ’tragedy of the commons’. Research findings further indicate that formal institutions tasked with managing these resources have not been able to promote their effective conservation. An array of competing demands and conflicting interests, coupled with inefficient institutional arrangements and under-investment, have rendered inadequate many resource management efforts, including the externally-imposed concepts, allowing destructive patterns of resource utilization to persist. Local communities are disempowered when confronted with (1) the intricate network of destructive-fishing actors targeting coral reefs, or (2) large company-government bureaucracy collusions allowing mangrove conversion. The existence of this collusive network must be considered in any effort to address problems of effective management. Empirical insights suggest that conservation at local level has to face the challenges of market-driven resource extraction at a global scale. Only when a coastal community manages to overcome the dilemma in managing common-pool resource, conservation measures can be implemented and a degree of sustainability attained. Findings from this research have important implications for the discourses on coastal resource policy and research. This research advances the discussions to the area where the core of conflict of interests among stakeholders took place, and yet has rarely been addressed previously. The synthesis from this study provides a strong basis to understand the nature of asymmetric relations amongst the resource stakeholders, and therefore will help in generating effective policies for a fairer coastal resource management regime

Budesonide foam versus budesonide enema in active ulcerative proctitis and proctosigmoiditis

Background: Rectal budesonide is an effective treatment of active ulcerative proctitis or proctosigmoiditis. Aim: To compare the therapeutic efficacy, tolerability and safety, and patient's preference of budesonide foam vs. budesonide enema. Methods: Patients with active ulcerative proctitis or proctosigmoiditis (clinical activity index >4 and endoscopic index ≥4) were eligible for this double-blind, double-dummy, randomized, multicentre study. They received 2 mg/25 mL budesonide foam and placebo enema (n = 265), or 2 mg/100 mL budesonide enema and placebo foam (n = 268) for 4 weeks. Primary endpoint was clinical remission (clinical activity index ≤4) at the final/withdrawal visit (per protocol). Results: A total of 541 patients were randomized - 533 were evaluable for intention-to-treat analysis and 449 for per protocol analysis. Clinical remission rates (per protocol) were 60% for budesonide foam and 66% for budesonide enema (P = 0.02362 for non-inferiority of foam vs. enema within a predefined non-inferiority margin of 15%). Both formulations were safe and no drug-related serious adverse events were observed. Because of better tolerability and easier application most patients preferred foam (84%). Conclusion: Budesonide foam is as effective as budesonide enema in the treatment of active ulcerative proctitis or proctosigmoiditis. Both budesonide formulations are safe, and most patients prefer foam.publishersversionPeer reviewe

Platelets Alter Gene Expression Profile in Human Brain Endothelial Cells in an In Vitro Model of Cerebral Malaria

Platelet adhesion to the brain microvasculature has been associated with cerebral malaria (CM) in humans, suggesting that platelets play a role in the pathogenesis of this syndrome. In vitro co-cultures have shown that platelets can act as a bridge between Plasmodium falciparum-infected red blood cells (pRBC) and human brain microvascular endothelial cells (HBEC) and potentiate HBEC apoptosis. Using cDNA microarray technology, we analyzed transcriptional changes of HBEC in response to platelets in the presence or the absence of tumor necrosis factor (TNF) and pRBC, which have been reported to alter gene expression in endothelial cells. Using a rigorous statistical approach with multiple test corrections, we showed a significant effect of platelets on gene expression in HBEC. We also detected a strong effect of TNF, whereas there was no transcriptional change induced specifically by pRBC. Nevertheless, a global ANOVA and a two-way ANOVA suggested that pRBC acted in interaction with platelets and TNF to alter gene expression in HBEC. The expression of selected genes was validated by RT-qPCR. The analysis of gene functional annotation indicated that platelets induce the expression of genes involved in inflammation and apoptosis, such as genes involved in chemokine-, TREM1-, cytokine-, IL10-, TGFβ-, death-receptor-, and apoptosis-signaling. Overall, our results support the hypothesis that platelets play a pathogenic role in CM

Inefficacy of different strategies to improve guideline awareness – 5-year follow-up of the hypertension evaluation project (HEP)

<p>Abstract</p> <p>Background</p> <p>In spite of numerous guidelines for evidence based diagnostic and therapy adequate knowledge of current recommendations is disappointingly low. In the Hypertension Evaluation Project (HEP I) we showed that awareness of national hypertension guidelines under German practitioners was less than 25% in the year 2000. This indicates the need for efficient strategies to relevantly improve guideline awareness.</p> <p>Methods</p> <p>To asses different tools for amending guideline knowledge we used three strategies (guideline in print, interactive guideline, expert seminars) to train 8325 randomised physicians, who had participated in the HEP I trial. Guideline knowledge of the trained physicians was again tested with the HEP questionnaire and compared to a control group of HEP I physicians.</p> <p>Results</p> <p>The return rate of questionnaires was 57.9% without a significant distinction between the groups. Overall guideline awareness was still low but remarkably improved compared to the results of HEP I (37.1% vs. 23.7%, p < 0.0001). There was no difference between the trained physicians and the control group (35.8% and 35.9% vs. 39.7%, p = n.s.).</p> <p>Conclusion</p> <p>We investigated the influence of different strategies to improve guideline awareness among German physicians. None of our interventions (guideline in print, interactive guideline, expert seminars) brought a notable benefit compared to control group. However, overall knowledge of guideline contents increased from 23.7% to 37.1% over five years. Therefore, other probably multimodal interventions are necessary to significantly improve guideline awareness beyond spontaneous advancement.</p> <p>Trial Registration</p> <p>ISRCTN53383289</p

The amyloid precursor protein controls PIKfyve function

While the Amyloid Precursor Protein (APP) plays a central role in Alzheimer's disease, its cellular function still remains largely unclear. It was our goal to establish APP function which will provide insights into APP's implication in Alzheimer's disease. Using our recently developed proteo-liposome assay we established the interactome of APP's intracellular domain (known as AICD), thereby identifying novel APP interactors that provide mechanistic insights into APP function. By combining biochemical, cell biological and genetic approaches we validated the functional significance of one of these novel interactors. Here we show that APP binds the PIKfyve complex, an essential kinase for the synthesis of the endosomal phosphoinositide phosphatidylinositol-3,5-bisphosphate. This signalling lipid plays a crucial role in endosomal homeostasis and receptor sorting. Loss of PIKfyve function by mutation causes profound neurodegeneration in mammals. Using C. elegans genetics we demonstrate that APP functionally cooperates with PIKfyve in vivo. This regulation is required for maintaining endosomal and neuronal function. Our findings establish an unexpected role for APP in the regulation of endosomal phosphoinositide metabolism with dramatic consequences for endosomal biology and important implications for our understanding of Alzheimer's disease

Reference values for methacholine reactivity (SAPALDIA study)

BACKGROUND: The distribution of airway responsiveness in a general population of non-smokers without respiratory symptoms has not been established, limiting its use in clinical and epidemiological practice. We derived reference equations depending on individual characteristics (i.e., sex, age, baseline lung function) for relevant percentiles of the methacholine two-point dose-response slope. METHODS: In a reference sample of 1567 adults of the SAPALDIA cross-sectional survey (1991), defined by excluding subjects with respiratory conditions, responsiveness during methacholine challenge was quantified by calculating the two-point dose-response slope (O'Connor). Weighted L1-regression was used to estimate reference equations for the 95(th ), 90(th ), 75(th )and 50(th )percentiles of the two-point slope. RESULTS: Reference equations for the 95(th ), 90(th ), 75(th )and 50(th )percentiles of the two-point slope were estimated using a model of the form a + b* Age + c* FEV(1 )+ d* (FEV(1))(2 ), where FEV(1 )corresponds to the pre-test (or baseline) level of FEV(1). For the central half of the FEV(1 )distribution, we used a quadratic model to describe the dependence of methacholine slope on baseline FEV(1). For the first and last quartiles of FEV(1), a linear relation with FEV(1 )was assumed (i.e., d was set to 0). Sex was not a predictor term in this model. A negative linear association with slope was found for age. We provide an Excel file allowing calculation of the percentile of methacholine slope of a subject after introducing age – pre-test FEV(1 )– and results of methacholine challenge of the subject. CONCLUSION: The present study provides equations for four relevant percentiles of methacholine two-point slope depending on age and baseline FEV(1 )as basic predictors in an adult reference population of non-obstructive and non-atopic persons. These equations may help clinicians and epidemiologists to better characterize individual or population airway responsiveness