Femoral vein thrombosis and total hip replacement.

Of 160 patients who underwent total hip replacement, 81 developed venographic evidence of thrombi in the operated leg. In 46 cases (57%) the thrombus originated from the femoral vein, and in 43 of these the exact site of origin was defined by venography. In 34 cases (74%) the thrombus arose from the wall of the femoral vein at the level of the lesser trochanter. This region was studied by intraoperative venography in eight patients undergoing total hip replacement, and in every case severe distortion of the common femoral vein was observed, producing almost total occlusion. We suggest that intraoperative damage to the femoral vein results from manipulation of the leg, and that this is one reason why the operation is followed by a high incidence of deep vein thrombosis in the upper femoral region.     

The intestinal loops of bluegill fish, Lepomis macrochirus

The structural configurations of the intestinal loops of bluegill fish (Lepomis macrochirus) and a correlation of their probable functional significance have been investigated. The bluegill fish accommodates its relatively large intestine in its smaller body cavity by developing two intestinal loops. Regional variations in the intestinal wall exist due to the presence of the intestinal loops. The structural complexity of the intestine by loop formation has apparently created a problem by posing an obstruction as well as deviation to the smooth flow of food. In order to solve this problem structural modifications in the walls of the intestinal loops are needed, as is observed by the variation in muscle thickness of greater and lesser curvature of both the intestinal loops.     

T11 target structure exerts effector function by activating immune cells in CNS against glioma where cytokine modulation provide favorable microenvironment

Glycoprotein T 11 target structure (T11TS), derived from sheep erythrocyte membrane, directly interacts with T cells to activate them to enter in the brain. When untreated, glioma exerts an immune-suppressive environment in its vicinity by secreting prostaglandin E2 (PGE2), IL-10, tumor growth factor beta, gangliosides etc. to dampen the immune attack. But exogenous administration of T11TS reverses the situation to pro-inflammatory immune active state by expressing enhanced IL-12 and tumor necrosis factor alpha (TNF-alpha) production and suppression of IL-4 and IL-10 levels. The T11TS activated lymphocytic accumulation along the capillary endothelium in brain and their penetration in the matrix was evident from histological sections. IL-6 with TNF-alpha facilitates leukocyte migration to glioma site to exert cytotoxic effector function. Brain infiltrated lymphocytes offer cytotoxic proximity to neoplastic glial cells, which lead them to apoptosis. In the Th1 dominated microenvironment microglial cells was found with enhanced phagocytic functions. Initially infiltrated lymphocytes with microglia showed increased production of TNF-alpha, interferon gamma (IFN-gamma) to facilitate their effector actions. Repeated dosing of T11TS shows glioma abrogation in rat model, but also a resurgence of anti-inflammatory cytokine environment found with increased IL-4, IL-10 and decreased IL-12, IL-6, TNF-alpha. This is a unique homeostatic regulation of total immune system after T11TS mediated carnage of glioma. The resultant balance of cytokines between interacting glioma cells, T cells and microglia in T11TS induced condition determines the success of its immunotherapeutic effect in glioma.     

Further delineation of hydrophobic binding sites in dopamine D2/D3 receptors for N-4 substituents on the piperazine ring of the hybrid template 5/7-{[2-(4-aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ol

Here we report a structure–activity relationship (SAR) study of analogues of 5/7-{[2-(4-aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ol. Our SAR is focused on introduction of various substitutions in the piperazine ring of the hybrid template. The goal behind this study is to delineate the nature of the binding pocket for N-aryl substitution in the piperazine ring by observing the effect of various hydrophobic and other heteroaromatic substitutions on binding affinity (K_i), as measured with tritiated spiperone and HEK-293 cells expressing either D₂ or D₃ receptors. Functional activity of selected compounds was assessed with the GTPγS binding assay. Compound 8d was the most selective for the D₃ receptor in the spiperone binding assay. An interesting similarity in binding affinity was observed between isoquinoline derivative D-301 and the 2-substituted pyridine derivative 8d, suggesting the importance of relative spatial relationships between the N-atom of the ligand and the molecular determinants of the binding pocket in D₂/D₃ receptors. Functional activity assays demonstrated high potency and selectivity of (+)-8a and (?)-28b (D₂/D₃ (ratio of EC₅₀): 105 and 202, respectively) for the D₃ receptor and both compounds were more selective compared to the reference drug ropinirole (D₂/D₃ (ratio of EC₅₀): 29.5).     

Structural determination of biomolecular interfaces by nuclear magnetic resonance of proteins with reduced proton density

Protein interactions are important for understanding many molecular mechanisms underlying cellular processes. So far, interfaces between interacting proteins have been characterized by NMR spectroscopy mostly by using chemical shift perturbations and cross-saturation via intermolecular cross-relaxation. Although powerful, these techniques cannot provide unambiguous estimates of intermolecular distances between interacting proteins. Here, we present an alternative approach, called REDSPRINT (REDduced/Standard PRoton density INTerface identification), to map protein interfaces with greater accuracy by using multiple NMR probes. Our approach is based on monitoring the cross-relaxation from a source protein (or from an arbitrary ligand that need not be a protein) with high proton density to a target protein (or other biomolecule) with low proton density by using isotope-filtered nuclear Overhauser spectroscopy (NOESY). This methodology uses different isotropic labeling for the source and target proteins to identify the source-target interface and also determine the proton density of the source protein at the interface for protein-protein or protein-ligand docking. Simulation indicates significant gains in sensitivity because of the resultant relaxation properties, and the utility of this technique, including a method for direct determination of the protein interface, is demonstrated for two different protein–protein complexes.     

The present perspective of astaxanthin with reference to biosynthesis and pharmacological importance

Astaxanthin is an important natural pigment, a diketo carotenoid that besides being a food ingredient has importance as a nutraceutical. Astaxanthin is a fat-soluble nutrient with a molecular weight of 596.8 Da (Dalton) and a molecular formula of C₄₀H₅₂O_4. It is water insoluble and lipophilic. Organisms that produce astaxanthin include the basidiomycetous yeast; Phaffia rhodozyma, the green alga; Haematococcus pluvialis and the Gram-negative bacteria; Agrobacterium aurantiacum, Paracoccus marcusii, P. carotinifaciens, Paracoccus sp. strain MBIC 01143, and P. haeundaensis. Xanthophyllomyces dendrorhous and Haematococcus pluvialis, which are potential sources of astaxanthin. The antioxidant properties of astaxanthin are believed to have a key role in the medicinal, pharmaceutical, and food industries. Astaxanthin acts as a free-radical scavenger and an immunomodulator. It is a medicinal ingredient against degenerative diseases such as cancer, skin related illness, and heart disease. Presently, this carotenoid is used as a major pigmentation source and a feed supplement in aquaculture, primarily salmon, trout, crabs, shrimp, chickens, and red sea bream. The present review focuses on the pharmacological connotations of astaxanthin and specifies the natural sources and pathways of its production along with other relevant aspects.     

Design,synthesis, and pharmacological evaluation of phenoxy pyridyl derivatives as dual norepinephrine reuptake inhibitors and 5-HT1A partial agonists

Preclinical studies suggest that compounds with dual norepinephrine reuptake inhibitor (NRI) and 5-HT_1A partial agonist properties may provide an important new therapeutic approach to ADHD, depression, and anxiety. Reported herein is the discovery of a novel chemical series with a favorable NRI and 5-HT_1A partial agonist pharmacological profile as well as excellent selectivity for the norepinephrine transporter over the dopamine transporter.