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© F e r r a t a S t o r t i F o u n d a t i o nMedicines Agency (EMA) for the treatment and prevention of bleeding episodes and in surgery or invasive procedures in GT patients with antibodies to GPIIb/IIIa and/or HLA, and a past or present history of platelet refractoriness to platelet transfusions. 20 To date, for GT patients who are not refractory, platelets are used as the first-line treatment.As part of the approval, the EMA required the collection of post-marketing pharmacovigilance data on rFVIIa in GT. The observational, international, multicenter, webbased Glanzmann's Thrombasthenia Registry (GTR) was, therefore, launched to prospectively gather and evaluate information on the different treatment modalities and their outcomes in "real-world" clinical practice. 21 Collection of such registry data is key to improving the understanding and management of rare diseases such as GT, for which randomized clinical trials are difficult to perform.This paper reports new, clinically relevant effectiveness and safety data on rFVIIa, as well as the other therapeutic options available (antifibrinolytics and platelets), for the treatment of non-surgical bleeds in patients with GT, using data obtained from the largest observational study of GT patients, the GTR. Methods PatientsFrom May 10, 2007, to December 16, 2011, prospectively collected online data were entered into the GTR on the effectiveness and safety (including thromboembolic events) of systemic hemostatic treatments used in clinics in patients with GT, including rFVIIa, platelet transfusions (P), and antifibrinolytics (AF) alone or in combination with other agents. All patients were treated according to local practices in an open-label manner, and no drugs were supplied for this registry. The main features of the GTR include: (i) standardized data collection using a customized webbased tool; (ii) a protocol-based registry conducted in accordance with general data protection laws and any local country requirements for conducting observational studies; and (iii) centralized data management overseen by an external expert panel composed of four physicians and by the international medical director of Novo Nordisk (the study sponsor). Protocol definitions and outcomes specified by the study sponsor, and post hoc classifications of bleed severity employed by the external expert panel (in response to requests by the EMA), are reported in Online Supplementary Table S1.Only patients with a diagnosis of congenital GT were included in the GTR (see Online Supplementary Table S1). Patients with acquired thrombasthenic states caused by autoimmune disorders or medications were excluded. Refractoriness and the presence of antibodies were coded initially and assessed periodically as deemed important by the investigator. As tests for antibodies may not have been available at all centers, antibodies may also have been present in some patients classified as having refractoriness only. Data handlingAs this was an observational study, treatment was based on local practice ...

The aim of this study was to design and evaluate a modified Ussing chamber, that makes use of constant air suction (modified Ussing air suction chamber, MUAS) for fixation of biopsy specimens. Standard size forceps biopsies were taken from the descending part of duodenum from patients undergoing endoscopy. Short circuit current (SCC) and conductance (G) were measured during basal conditions and after addition of different sugars and secretagogues. Histologic examination was performed to determine the degree of tissue damage after study in the chamber. Basal SCC was 54.7 +/- 4.3 microA x cm(-2) and G was 58.7 +/- 4.7 mS x cm(-2) (mean +/- SEM, n=48) and steady values of these parameters were observed for at least 2 h. Reproducible and steady responses in SCC were obtained with D-glucose (SCCmax=172 +/- 22.1 microA x cm(-2); EC50=6.9 +/- 0.7 mM, n=5) and D-galactose (SCCmax=233 +/- 55.7 microA x cm(-2); EC50=9.2 +/- 0.7 mM, n=3), and secretory responses with 5-hydroxytryptamine, 100 microM (DeltaSCC= 16.1 +/- 3.8 microA x cm(-2), n=10), histamine, 100 microM (DeltaSCC=24.0 +/- 4.1 microA x cm(-2), n=10) and prostaglandin E2, 1 microM (DeltaSCC=30.3 +/- 5.4 microA x cm(-2), n=6). Experimental biopsy specimens showed intact surface epithelium by histologic examination and did not differ from controls apart from minor indications of edge damage. No difference in basal electrical parameters and D-glucose fluxes were found between Helicobacter pylori positive and negative patients. Our data suggests that the MUAS chamber represents a promising alternative approach to measure transport processes in intestinal endoscopic biopsies.

Summary.We have studied the effect of d-c currents and osmotic gradients on the conductance and ultrastructure of the frog gallbladder. Passing current across the epithelium produces three voltage transients which are due to (i) the membrane capacitance, (ii) ion polarization effects, and (iii) changes in membrane resistance. The direction and magnitude of these resistance changes depended on (i) the direction of the current pulse, (ii) the current density, (iii) the ion selectivity of the epithelium, (iv) the thickness of the unstirred layers, and (v) the presence or absence of osmotic gradients across the tissue. Osmotic gradients also change the resistance of the gallbladder. These resistance changes are accompanied by changes in cell structure. Resistance increases are associated with the collapse of the lateral intercellular spaces. We conclude that osmotic and electrical gradients increase tissue resistance by narrowing the spaces and thereby increasing their resistance. On the other hand, we believe that the drop in resistance brought about by both current and osmotic gradients is not fully accounted for by dilation of the spaces, but is related to changes within the epithelial membranes similar to those in high resistance tissues.