Safety and Efficacy of Elosulfase Alfa in Australian Patients with Morquio a Syndrome: A Phase 3b Study

Abstract The safety and efficacy of elosulfase alfa were evaluated in a multicenter, open-label, phase 3b study in Australian Morquio A patients, consisting of a 49-week initial phase and an extension phase until elosulfase alfa was government funded. Thirteen patients (1-27 years) were enrolled. No new safety concerns were identified over 138 weeks. Most drug-related adverse events were mild or moderate in severity; none led to study discontinuation. After 49 weeks of treatment, median improvements from baseline were seen in the 6-minute walk test (+41.0 m), 3-minute stair climb test (+14.0 stairs/min), forced vital capacity (+16.4%), forced expiratory volume in 1 second (+14.1%), urine keratan sulfate (-7.1 µg/mg creatinine), and pain intensity. Growth, cardiac function, sleep, and quality of life results were mixed or stable. These results provide further evidence of the acceptable safety/tolerability profile of elosulfase alfa. The improvements in endurance, pulmonary function, and pain support findings from previous studies.

Marijuana use is associated with inattention in men and sleep quality in women with Attention-Deficit/Hyperactivity Disorder: a preliminary study.

The study examined the association between marijuana use, Attention-Deficit/Hyperactivity Disorder (ADHD) symptoms, and sleep quality in 56 men and 20 women with ADHD. Participants, ages 18-45, were assessed with the Assessment of Hyperactivity and Attention, drug use survey, and Pittsburgh Sleep Quality Index. Moderate to strong correlations were found between marijuana use and inattentive symptoms in men, and marijuana use and decreased sleep quality in women. Men and women with ADHD may use marijuana for different reasons.

Filtration, adsorption and immunodetection of virus using polyelectrolyte multilayer-modified paper.

A new method for detection of viruses has been developed. The entire assay can be performed within 2h, and consists of a polyelectrolyte-multilayer-modified cellulosic filter paper combined with immunodetection. The M13 bacteriophage was used as a model virus. A visual colour-based detection system, anti-M13 horseradish peroxidase (HRP) conjugate and 3,3',5,5'-tetramethylbenzidine (TMB), was selected to allow semi-quantitative assessment by human eye, or quantitative assessment using a digital scanner. By filtering a volume of 0.50 ml, it was possible to visually detect a concentration of 10(6) pfu/ml. The detection limit was improved to 5×10(4) pfu/ml by increasing the volume of the sample to 100ml. For comparison, it was only possible to detect a concentration of 10(7) pfu/ml using conventional sandwich enzyme-linked immunosorbent assay (ELISA) with the same detection system.

uPA binding to PAI-1 induces corneal myofibroblast differentiation on vitronectin.

PURPOSE: Vitronectin (VN) in provisional extracellular matrix (ECM) promotes cell migration. Fibrotic ECM also includes VN and, paradoxically, strongly adherent myofibroblasts (Mfs). Because fibrotic Mfs secrete elevated amounts of urokinase plasminogen activator (uPA), we tested whether increased extracellular uPA promotes the persistence of Mfs on VN. METHODS: Primary human corneal fibroblasts (HCFs) were cultured in supplemented serum-free medium on VN or collagen (CL) with 1 ng/mL transforming growth factor ß1 (TGFß1). Adherent cells were quantified using crystal violet. Protein expression was measured by Western blotting and flow cytometry. Transfection of short interfering RNAs was performed by nucleofection. Mfs were identified by α-smooth muscle actin (α-SMA) stress fibers. Plasminogen activator inhibitor (PAI-1) levels were quantified by ELISA. RESULTS: TGFß1-treated HCFs secreted PAI-1 (0.5 uM) that bound to VN, competing with αvß3/αvß5 integrin/VN binding, thus promoting cell detachment from VN. However, addition of uPA to cells on VN increased Mf differentiation (9.7-fold), cell-adhesion (2.2-fold), and binding by the VN integrins αvß3 and -ß5 (2.2-fold). Plasmin activity was not involved in promoting these changes, as treatment with the plasmin inhibitor aprotinin had no effect. A dominant negative PAI-1 mutant (PAI-1R) that binds to VN but does not inhibit uPA prevented the increase in uPA-stimulated cell adhesion and reduced uPA-stimulated integrin αvß3/αvß5 binding to VN by 73%. CONCLUSIONS: uPA induction of TGFß1-dependent Mf differentiation on VN supports the hypothesis that elevated secretion of uPA in fibrotic tissue may promote cell adhesion and the persistence of Mfs. By blocking uPA-stimulated cell adhesion, PAI-1R may be a useful agent in combating corneal scarring.