Inhibitor binding mode and allosteric regulation of Na+-glucose symporters.

Sodium-dependent glucose transporters (SGLTs) exploit sodium gradients to transport sugars across the plasma membrane. Due to their role in renal sugar reabsorption, SGLTs are targets for the treatment of type 2 diabetes. Current therapeutics are phlorizin derivatives that contain a sugar moiety bound to an aromatic aglycon tail. Here, we develop structural models of human SGLT1/2 in complex with inhibitors by combining computational and functional studies. Inhibitors bind with the sugar moiety in the sugar pocket and the aglycon tail in the extracellular vestibule. The binding poses corroborate mutagenesis studies and suggest a partial closure of the outer gate upon binding. The models also reveal a putative Na+ binding site in hSGLT1 whose disruption reduces the transport stoichiometry to the value observed in hSGLT2 and increases inhibition by aglycon tails. Our work demonstrates that subtype selectivity arises from Na+-regulated outer gate closure and a variable region in extracellular loop EL5

Teleparallel Lagrange Geometry and a Unified Field Theory

In this paper, we construct a field theory unifying gravity and electromagnetism in the context of Extended Absolute Parallelism (EAP-) geometry. This geometry combines, within its structure, the geometric richness of the tangent bundle and the mathematical simplicity of Absolute Parallelism (AP-) geometry. The constructed field theory is a generalization of the Generalized Field Theory (GFT) formulated by Mikhail and Wanas. The theory obtained is purely geometric. The horizontal (resp. vertical) field equations are derived by applying the Euler-Lagrange equations to an appropriate horizontal (resp. vertical) scalar Lagrangian. The symmetric part of the resulting horizontal (resp. vertical) field equations gives rise to a generalized form of Einstein's field equations in which the horizontal (resp. vertical) energy-momentum tensor is purely geometric. The skew-symmetric part of the resulting horizontal (resp. vertical) field equations gives rise to a generalized form of Maxwell equations in which the electromagnetic field is purely geometric. Some interesting special cases, which reveal the role of the nonlinear connection in the obtained field equations, are examined. Finally, the condition under which our constructed field equations reduce to the GFT is explicitly established.Comment: Latex file, 33 page

Adverse effects of extra-articular corticosteroid injections: a systematic review

<p>Abstract</p> <p>Background</p> <p>To estimate the occurrence and type of adverse effects after application of an extra-articular (soft tissue) corticosteroid injection.</p> <p>Methods</p> <p>A systematic review of the literature was made based on a PubMed and Embase search covering the period 1956 to January 2010. Case reports were included, as were prospective and retrospective studies that reported adverse events of corticosteroid injection. All clinical trials which used extra-articular corticosteroid injections were examined. We divided the reported adverse events into major (defined as those needing intervention or not disappearing) and minor ones (transient, not requiring intervention).</p> <p>Results</p> <p>The search yielded 87 relevant studies:44 case reports, 37 prospective studies and 6 retrospective studies. The major adverse events included osteomyelitis and protothecosis; one fatal necrotizing fasciitis; cellulitis and ecchymosis; tendon ruptures; atrophy of the plantar fat was described after injecting a neuroma; and local skin effects appeared as atrophy, hypopigmentation or as skin defect. The minor adverse events effects ranged from skin rash to flushing and disturbed menstrual pattern. Increased pain or steroid flare after injection was reported in 19 studies. After extra-articular injection, the incidence of major adverse events ranged from 0-5.8% and that of minor adverse events from 0-81%. It was not feasible to pool the risk for adverse effects due to heterogeneity of study populations and difference in interventions and variance in reporting.</p> <p>Conclusion</p> <p>In this literature review it was difficult to accurately quantify the incidence of adverse effects after extra-articular corticosteroid injection. The reported adverse events were relatively mild, although one fatal reaction was reported.</p

ULTRASTRUCTURE OF MESOTHELIAL REGENERATION AFTER INTRAPERITONEAL INJECTION OF ASBESTOS FIBERS ON RAT OMENTUM

In order to describe the ultrastructural features of the early phases of regenerating mesothelium in rat peritoneum, 69 cases were examined after intraperitoneal injection of 0.05-15 mg crocidolite, chrysotile B and other mineral and synthetic fibers. The findings show the presence of intermediate or transition cells between proliferating submesothelial connective tissue cells bearing the ultrastructural phenotype of myofibroblasts and mature fully regenerated mesothelium. Our results and data accumulated in the literature provide strong support for the hypothesis of submesothelial cell origin for regenerating mesothelium