Dimethylarginine dimethylaminohydrolase I enhances tumour growth and angiogenesis

Angiogenesis is a prerequisite for tumour progression and is highly regulated by growth factors and cytokines a number of which also stimulate the production of nitric oxide. Asymmetric dimethylarginine is an endogenous inhibitor of nitric oxide synthesis. Asymmetric dimethylarginine is metabolised by dimethylarginine dimethylaminohydrolase. To study the effect of dimethylarginine dimethylaminohydrolase on tumour growth and vascular development, the rat C6 glioma cell line was manipulated to overexpress the rat gene for dimethylarginine dimethylaminohydrolase I. Enhanced expression of dimethylarginine dimethylaminohydrolase I increased nitric oxide synthesis (as indicated by a two-fold increase in the production of cGMP), expression and secretion of vascular endothelial cell growth factor, and induced angiogenesis in vitro. Tumours derived from these cells grew more rapidly in vivo than cells with normal dimethylarginine dimethylaminohydrolase I expression. Immunohistochemical and magnetic resonance imaging measurements were consistent with increased tumour vascular development. Furthermore, dimethylarginine dimethylaminohydrolase activity was detected in a series of human tumours. This data demonstrates that dimethylarginine dimethylaminohydrolase plays a pivotal role in tumour growth and the development of the tumour vasculature by regulating the concentration of nitric oxide and altering vascular endothelial cell growth factor production

Structural basis of the leukocyte integrin Mac-1 I-domain interactions with the platelet glycoprotein Ib

Cell-surface receptor interactions between leukocyte integrin macrophage-1 antigen (Mac-1, also known as CR3, aMb2, CD11b/CD18) and platelet glycoprotein Iba (GPIba) are critical to vascular in?ammation. To de?ne the key residues at the binding interface, we used nuclear magnetic resonance (NMR) to assign the spectra of the mouse Mac-1 I-domain and mapped the residues contacting the mouse GPIba N-terminal domain (GPIbaN) to the locality of the integrin metal ion-dependant adhesion site (MIDAS) surface. We next determined the crystal structures of the mouse GPIbaN and Mac-1 I-domain to 2 ?A and 2.5 ?A resolution, respectively. The mouse Mac-1 I-domain crystal structure reveals an active conformation that is stabilized by a crystal contact from the a7-helix with a glutamatesidechaincompletingtheoctahedralcoordinationsphereoftheMIDASMg21 ion. The amino acid sequence of the a7-helix and disposition of the glutamic acid matches the C-terminal capping region a-helix of GPIba effectively acting as a ligand mimetic. Using these crystal structures in combination with NMR measurements and docking analysis, we developed a model whereby an acidic residue from the GPIba leucine-rich repeat (LRR) capping a-helix coordinates directly to the Mac-1 MIDAS Mg21 ion. The Mac-1:GPIbaN complex involves additional interactions consolidated by an elongated pocket ?anking the GPIbaN LRR capping a-helix. The GPIbaN a-helix has an HxxxE motif, which is equivalent by homology to RxxxD from the human GPIbaN. Subsequent mutagenesis of residues at this interface, coupled with surface plasmon resonance studies, con?rmed the importance of GPIbaN residues H218, E222, and the Mac-1 MIDAS residue T209 to formation of the complex

Electrophysiology of Inhibitory Control in the Context of Emotion Processing in Children With Autism Spectrum Disorder

Autism Spectrum Disorder (ASD) is an increasingly common developmental disorder that affects 1 in 59 children. Despite this high prevalence of ASD, knowledge regarding the biological basis of its associated cognitive difficulties remains scant. In this study, we aimed to identify altered neurophysiological responses underlying inhibitory control and emotion processing difficulties in ASD, together with their associations with age and various domains of cognitive and social function. This was accomplished by assessing electroencephalographic recordings during an emotional go/nogo task alongside parent rating scales of behavior. Event related potential (ERP) N200 component amplitudes were reduced in children with ASD compared to typically developing (TD) children. No group differences were found, however, for task performance, P300 amplitude or latency, or N170 amplitude or latency, suggesting that individuals with ASD may only present conflict monitoring abnormalities, as reflected by the reduced N200 component, compared to TD individuals. Consistent with previous findings, increased age correlated with improved task performance scores and reduced N200 amplitude in the TD group, indicating that as these children develop, their neural systems become more efficient. These associations were not identified in the ASD group. Results also showed significant associations between increased N200 amplitudes and improved executive control abilities and decreased autism traits in TD children only. The newly discovered findings of decreased brain activation in children with ASD, alongside differences in correlations with age compared to TD children, provide a potential neurophysiological indicator of atypical development of inhibitory control mechanisms in these individuals

Abscess Formation Following Spilled Gallstones During Laparoscopic Cholecystectomy

A review of the English literature concerning spilled gallstones during laparoscopic cholecystectomy is compared with one institution's experience of four cases during 1,726 laparoscopic cholecystectomies performed over a four-year period. Strategies regarding management and treatment are discussed