Glial Heterotopia of the orbit: A rare presentation

<p>Abstract</p> <p>Background</p> <p>Glial heterotopias are rare, benign, congenital, midline, non-teratomatous extracranial glial tissue. They may masquerade as encephalocoele or dermoid cyst and mostly present in nose. Herein, we present an unusual case of glial heterotopia of the orbit with unilateral blindness.</p> <p>Case presentation</p> <p>A 6 year-old-boy presented with a progressive painless mass over the nose and medial aspect of the left eye noticed since birth. On examination, the globe was displaced laterally by a firm, regular, mobile, non-pulsatile and non-tender medial mass. The affected eye had profound loss of vision. Computed tomography scan showed a large hypodense mass in the extraconal space with no intracranial connectivity and bony erosion. The child underwent total surgical excision of the mass and histopathological examination confirmed glial heterotopia of the orbit.</p> <p>Conclusion</p> <p>Though the incidence of this condition is rare, the need of appropriate diagnosis and management of such mass to prevent the visual and cosmetic deterioration is warranted. To our knowledge this is the first reported case of Glial heterotopia of orbit causing unilateral blindness.</p

Further characterization of ADAMTS-13 inactivation by thrombin

Background: The multimeric size and platelet-tethering function of von Willebrand factor (VWF) are modulated by the plasma metalloprotease, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13). In vitro ADAMTS-13 is susceptible to proteolytic inactivation by thrombin. Objectives: In this study, we aimed to characterize the inactivation of ADAMTS-13 by thrombin and to assess its physiological significance. Methods and results: By N-terminal sequencing of cleavage products, and by mutagenesis, we identified the principal thrombin cleavage sites in ADAMTS-13 as R257 and R1176. Using a library of 76 thrombin mutants, we highlighted the functional importance of exosite I on thrombin in the proteolysis of ADAMTS-13. Proteolysis of ADAMTS-13 by thrombin caused an 8-fold reduction in its affinity for VWF that contributed to its loss of VWF-cleaving function. Intriguingly, thrombin-cleaved ADAMTS-13 both bound and proteolyzed a short recombinant VWF A2 domain substrate (VWF115) normally. Following activation of coagulation in normal plasma, endogenous ADAMTS-13, but not added ADAMTS-13, appeared resistant to coagulation-induced fragmentation. An estimation of the Km for ADAMTS-13 proteolysis by thrombin was appreciably higher than the physiological concentration of ADAMTS-13. This was corroborated by the comparatively low affinity of ADAMTS-13 for thrombin (KD 95 nm). Conclusions: Together, our data suggest that ADAMTS-13 is protected from rapid proteolytic inactivation by thrombin in normal plasma. Whether this remains the case under pathological situations involving elevated/sustained generation of thrombin remains unclear

Pelvic tenderness is not limited to the prostate in chronic prostatitis/chronic pelvic pain syndrome (CPPS) type IIIA and IIIB: comparison of men with and without CP/CPPS

Background: We wished to determine if there were differences in pelvic and non-pelvic tenderness between men with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) Type III and men without pelvic pain. Methods: We performed the Manual Tender Point Survey (MTPS) as described by the American College of Rheumatology on 62 men with CP/CPPS Type IIIA and IIIB and 98 men without pelvic pain. We also assessed tenderness of 10 external pelvic tender points (EPTP) and of 7 internal pelvic tender points (IPTP). All study participants completed the National Institutes of Health Chronic Prostatitis Symptom Inventory (NIH CPSI). Results: We found that men with CPPS were significantly more tender in the MTPS, the EPTPS and the IPTPS. CPSI scores correlated with EPTP scale but not with IPTP scale or prostate tenderness. Prostatic tenderness was present in 75% of men with CPPS and in 50% of men without CPPS. Expressed prostatic fluid leukocytosis was not associated with prostatic tenderness. Conclusion: Men with CP/CPPS have more tenderness compared to men without CPPS. Tenderness in men with CPPS is distributed throughout the pelvis and not specific to the prostate

Multiple FadD Acyl-CoA Synthetases Contribute to Differential Fatty Acid Degradation and Virulence in Pseudomonas aeruginosa

A close interconnection between nutrient metabolism and virulence factor expression contributes to the pathophysiology of Pseudomonas aeruginosa as a successful pathogen. P. aeruginosa fatty acid (FA) degradation is complicated with multiple acyl-CoA synthetase homologs (FadDs) expressed in vivo in lung tissue during cystic fibrosis infections. The promoters of two genetically linked P. aeruginosa fadD genes (fadD1 and fadD2) were mapped and northern blot analysis indicated they could exist on two different transcripts. These FadDs contain ATP/AMP signature and FA-binding motifs highly homologous to those of the Escherichia coli FadD. Upon introduction into an E. coli fadD-/fadR- double mutant, both P. aeruginosa fadDs functionally complemented the E. coli fadD-/fadR- mutant, allowing degradation of different chain-length FAs. Chromosomal mutagenesis, growth analysis, induction studies, and determination of kinetic parameters suggested that FadD1 has a substrate preference for long-chain FAs while FadD2 prefers shorter-chain FAs. When compared to the wild type strain, the fadD2 mutant exhibited decreased production of lipase, protease, rhamnolipid and phospholipase, and retardation of both swimming and swarming motilities. Interestingly, fadD1 mutant showed only increased swarming motility. Growth analysis of the fadD mutants showed noticeable deficiencies in utilizing FAs and phosphatidylcholine (major components of lung surfactant) as the sole carbon source. This defect translated into decreased in vivo fitness of P. aeruginosa in a BALB/c mouse lung infection model, supporting the role of lipids as a significant nutrient source for this bacterium in vivo

Downregulation of TFPI in breast cancer cells induces tyrosine phosphorylation signaling and increases metastatic growth by stimulating cell motility

<p>Abstract</p> <p>Background</p> <p>Increased hemostatic activity is common in many cancer types and often causes additional complications and even death. Circumstantial evidence suggests that tissue factor pathway inhibitor-1 (TFPI) plays a role in cancer development. We recently reported that downregulation of TFPI inhibited apoptosis in a breast cancer cell line. In this study, we investigated the effects of TFPI on self-sustained growth and motility of these cells, and of another invasive breast cancer cell type (MDA-MB-231).</p> <p>Methods</p> <p>Stable cell lines with TFPI (both α and β) and only TFPIβ downregulated were created using RNA interference technology. We investigated the ability of the transduced cells to grow, when seeded at low densities, and to form colonies, along with metastatic characteristics such as adhesion, migration and invasion.</p> <p>Results</p> <p>Downregulation of TFPI was associated with increased self-sustained cell growth. An increase in cell attachment and spreading was observed to collagen type I, together with elevated levels of integrin α2. Downregulation of TFPI also stimulated migration and invasion of cells, and elevated MMP activity was involved in the increased invasion observed. Surprisingly, equivalent results were observed when TFPIβ was downregulated, revealing a novel function of this isoform in cancer metastasis.</p> <p>Conclusions</p> <p>Our results suggest an anti-metastatic effect of TFPI and may provide a novel therapeutic approach in cancer.</p

Granular Assembly of α-Synuclein Leading to the Accelerated Amyloid Fibril Formation with Shear Stress

α-Synuclein participates in the Lewy body formation of Parkinson's disease. Elucidation of the underlying molecular mechanism of the amyloid fibril formation is crucial not only to develop a controlling strategy toward the disease, but also to apply the protein fibrils for future biotechnology. Discernable homogeneous granules of α-synuclein composed of approximately 11 monomers in average were isolated in the middle of a lag phase during the in vitro fibrillation process. They were demonstrated to experience almost instantaneous fibrillation during a single 12-min centrifugal membrane-filtration at 14,000×g. The granular assembly leading to the drastically accelerated fibril formation was demonstrated to be a result of the physical influence of shear force imposed on the preformed granular structures by either centrifugal filtration or rheometer. Structural rearrangement of the preformed oligomomeric structures is attributable for the suprastructure formation in which the granules act as a growing unit for the fibril formation. To parallel the prevailing notion of nucleation-dependent amyloidosis, we propose a double-concerted fibrillation model as one of the mechanisms to explain the in vitro fibrillation of α-synuclein, in which two consecutive concerted associations of monomers and subsequent oligomeric granular species are responsible for the eventual amyloid fibril formation

Angiogenesis inhibitors in the treatment of prostate cancer

Prostate cancer remains a significant public health problem, with limited therapeutic options in the setting of castrate-resistant metastatic disease. Angiogenesis inhibition is a relatively novel antineoplastic approach, which targets the reliance of tumor growth on the formation of new blood vessels. This strategy has been used successfully in other solid tumor types, with the FDA approval of anti-angiogenic agents in breast, lung, colon, brain, and kidney cancer. The application of anti-angiogenic therapy to prostate cancer is reviewed in this article, with attention to efficacy and toxicity results from several classes of anti-angiogenic agents. Ultimately, the fate of anti-angiogenic agents in prostate cancer rests on the eagerly anticipated results of several key phase III studies