Regulation der perizellulären Plasminogenaktivierung durch Shedding des Urokinaserezeptors

Die proteolytische Kaskade der Plasminogenaktivierung nimmt bei der Tumorprogression und Metastasierung während der Überwindung von Gewebsbarrieren eine bedeutende Stellung ein. Durch Shedding des uPAR von der Tumorzelloberfläche mittels der GPI-spezifischen Phospholipase D entsteht löslicher s-uPAR. s-uPAR bindet an ECM-Komponenten in biologisch aktiver Form mit der Folge der Verschiebung lokalisierter Zelloberflächenproteolyse zu einer ausgedehnteren, bindegewebsassoziierten Proteolyse. Zudem induziert die GPI-Hydrolyse durch GPI-PLD eine verstärkte Expression von uPAR an der Zelloberfläche und damit eine Erhöhung der Zelloberflächenproteolyse. Reduzierte GPI-Ankerspaltung durch den Knockdown der GPI-PLD-Expression bewirkte eine Verringerung der uPAR-Expression und Freisetzung von der Zelloberfläche, sowie der s-uPAR-Bindung an die ECM. Als eine Folge resultierte die Reduktion der Oberflächen- und ECM-assoziierten Proteolyse, was Bindegewebsabbau und Tumorinvasion verringern kann

Defining operational strengths and gaps relevant to post licensure Group B Streptococcus vaccine effectiveness studies: an expert stakeholder evaluation of the United Kingdom and Uganda

A future Group B Streptococcal (GBS) vaccine for pregnant women to protect neonates is likely to be licensed based on evidence of vaccine induced protective antibody levels. Post licensure surveillance to monitor the impact of any future vaccine on GBS disease therefore needs to be clearly defined (in both high and low income settings). A priority research gap is understanding health system preparedness for a GBS vaccine evaluation This expert stakeholder evaluation aimed to describe the UK and Uganda's operational strengths and gaps relevant to post-licensure GBS vaccine studies

Evaluation of the long-term treatment efects of intravenous idursulfase in patients with mucopolysaccharidosis II (MPS II) using statistical modeling : data from the Hunter Outcome Survey (HOS)

Background: Mucopolysaccharidosis II (MPS II; Hunter syndrome) is a rare, life-limiting lysosomal storage disease caused by defcient iduronate-2-sulfatase activity. Enzyme replacement therapy (ERT) with intravenous (IV) idursulfase can stabilize or improve many somatic manifestations, but there remains a need for further analysis of long-term treatment outcomes. Using data from patients with MPS II enrolled in the Hunter Outcome Survey (HOS), mixed modeling was performed to evaluate and predict the efects of IV idursulfase treatment on selected clinical parameters for up to 8 years following treatment start. The modeling population comprised male patients followed prospectively in HOS who had received IV idursulfase for at least 5 years and who had data available for two or more time points (at least one post-ERT). Age at ERT start and time since ERT start were included as covariates. Results: In total, 481 patients were eligible for inclusion in at least one model. At 8 years post-ERT start, improvement from baseline was predicted for each age group (–75% in each group), mean left ventricular mass index (decreases of~1 g/m2 ) and mean palpable liver size (decreases of>2 cm). Improvements in mean 6-min walk test distance (increase of>50 m) and stabilization in percent predicted forced vital capacity and forced expiratory volume in 1 s (decreases of~4 and~9 percentage points, respectively) at 8 years post-ERT start were predicted for patients aged≥5 years at ERT start (these assessments are unsuitable for patients aged<5 years). Predicted changes over time were similar across the three age groups; however, overall outcomes were most favorable in children aged<18 months at ERT start. Conclusions: These fndings suggest that the previously reported positive efects of IV idursulfase on the somatic manifestations of MPS II are predicted to be maintained for at least 8 years following ERT initiation and highlight the value of statistical modeling to predict long-term treatment outcomes in patients with rare diseases

Mid-term results of a modified arterial switch operation using the direct reconstruction technique of the pulmonary artery

Background: There is ongoing discussion as to whether it is beneficial to avoid pulmonary sinus augmentation in the arterial switch operation. We report a single-surgeon series of mid-term results for direct pulmonary artery anastomosis during switch operation for transposition of the great arteries (TGA). Methods: This retrospective study includes 17 patients with TGA, combined with an atrial septal defect, patent foramen ovale or ventricular septal defect. Patient data was analyzed from hospital charts, including operative reports, post-operative course, and regular follow-up investigations. The protocol included cardiological examination by a single pediatric cardiologist. Echocardiographic examinations were performed immediately after arrival on the intensive unit, before discharge, and then after three, six, and 12 months, followed by yearly intervals. Pulmonary artery stenosis (PAS) was categorized into three groups according to the Doppler-measured pulmonary gradient: grade I (trivial stenosis) = increased pulmonary flow with a gradient below 25 mm Hg; grade II (moderate stenosis) = a gradient ranging from 25 to 49 mm Hg; and grade III (severe stenosis) = a gradient above 50 mm Hg. Follow-up data was available for all patients. The length of follow-up ranged from 1.2 to 9.7 years, median: 7.5 years (mean 6.1 years &#177; 14 months). Results: During follow-up, 12 patients (70.6%) had no (or only trivial) PAS, five patients (29.4%) had moderate stenosis without progress, and no patient had severe PAS. Cardiac catheterization after arterial switch operation was performed in 11 patients (64.7%) and showed a good correlation with echocardiographic findings. During follow-up there was no reintervention for PAS. Conclusions: Direct reconstruction of the neo-pulmonary artery is a good option in TGA with antero-posterior position of the great vessels, with very satisfactory mid-term results. (Cardiol J 2010; 17, 6: 574-579

A 15-year perspective of the fabry outcome survey

The Fabry Outcome Survey (FOS) is an international long-term observational registry sponsored by Shire for patients diagnosed with Fabry disease who are receiving or are candidates for therapy with agalsidase alfa (agala). Established in 2001, FOS provides long-term data on agala safety/efficacy and collects data on the natural history of Fabry disease, with the aim of improving clinical management. The FOS publications have helped establish prognostic and severity scores, defined the incidence of specific disease variants and implications for clinical management, described clinical manifestations in special populations, confirmed the high prevalence of cardiac morbidity, and demonstrated correlations between ocular changes and Fabry disease severity. These FOS data represent a rich resource with utility not only for description of natural history/therapeutic effects but also for exploratory hypothesis testing and generation of tools for diagnosis/management, with the potential to improve future patient outcomes

Role of human milk oligosaccharides in Group B Streptococcus colonisation.

Group B Streptococcus (GBS) infection is a major cause of morbidity and mortality in infants. The major risk factor for GBS disease is maternal and subsequent infant colonisation. It is unknown whether human milk oligosaccharides (HMOs) protect against GBS colonisation. HMO production is genetically determined and linked to the Lewis antigen system. We aimed to investigate the association between HMOs and infant GBS colonisation between birth and postnatal day 90. Rectovaginal swabs were collected at delivery, as well as colostrum/breast milk, infant nasopharyngeal and rectal swabs at birth, 6 days and days 60-89 postpartum from 183 Gambian mother/infant pairs. GBS colonisation and serotypes were determined using culture and PCR. (1)H nuclear magnetic resonance spectroscopy was used to characterise the mother's Lewis status and HMO profile in breast milk. Mothers who were Lewis-positive were significantly less likely to be colonised by GBS (X (2)=12.50, P<0.001). Infants of Lewis-positive mothers were less likely GBS colonised at birth (X (2)=4.88 P=0.03) and more likely to clear colonisation between birth and days 60-89 than infants born to Lewis-negative women (P=0.05). There was no association between Secretor status and GBS colonisation. In vitro work revealed that lacto-N-difucohexaose I (LNDFHI) correlated with a reduction in the growth of GBS. Our results suggest that HMO such as LNDFHI may be a useful adjunct in reducing maternal and infant colonisation and hence invasive GBS disease. Secretor status offers utility as a stratification variable in GBS clinical trials

Effects of Renal Denervation on Insulin Sensitivity and Inflammatory Markers in Nondiabetic Patients with Treatment-Resistant Hypertension

Increased sympathetic activity is important in the pathogenesis of hypertension and insulin resistance. Afferent signaling from the kidneys elevates the central sympathetic drive. We investigated the effect of catheter-based renal sympathetic denervation (RDN) on glucose metabolism, inflammatory markers, and blood pressure in nondiabetic patients with treatment-resistant hypertension. Eight subjects were included in an open-labelled study. Each patient was studied before and 6 months after RDN. Endogenous glucose production was assessed by a 3-3H glucose tracer, insulin sensitivity was examined by hyperinsulinemic euglycemic clamp, hormones and inflammatory markers were analyzed, and blood pressure was measured by office blood pressure readings and 24-hour ambulatory blood pressure monitoring. Insulin sensitivity (M-value) increased nonsignificantly from 2.68 ± 0.28 to 3.07 ± 0.41 (p=0.12). A significant inverse correlation between the increase in M-value and BMI 6 months after RDN (p=0.03) was found, suggesting beneficial effects on leaner subjects. Blood pressure decreased significantly, but there were no changes in hormones, inflammatory markers, or endogenous glucose production. Our results indicate that RDN may improve insulin sensitivity in some patients with treatment-resistant hypertension, albeit confirmation of these indications of beneficial effects on leaner subjects awaits the outcome of larger randomized controlled studies

Development and validation of the predicted heat strain model

Abstract Eight laboratories participated in a concerted research project on the assessment of hot working conditions. The objectives were, among others, to co-ordinate the work of the main European research teams in the field of thermal factors and to improve the methods available to assess the risks of heat disorders at the workplace, and in particular the "Required Sweat Rate" model as presented in International Standard ISO 7933 Standard (1989). The scientific bases of this standard were thoroughly reviewed and a revised model, called "Predicted Heat Strain" (PHS), was developed. This model was then used to predict the minute by minute sweat rates and rectal temperatures during 909 laboratory and field experiments collected from the partners. The Pearson correlation coefficients between observed and predicted values were equal to 0.76 and 0.66 for laboratory experiments and 0.74 and 0.59 for field experiments, respectively, for the sweat rates and the rectal temperatures. The change in sweat rate with time was predicted more accurately by the PHS model than by the required sweat rate model. This suggests that the PHS model would provide an improved basis upon which to determine allowable exposure times from the predicted heat strain in terms of dehydration and increased core temperature

Considerations for post-licensure group B streptococcus vaccine effectiveness studies.

Post-licensure studies of a Group B streptococcal vaccines for pregnant women in low and middle-income countries will require investment in electronic health records