Angiotensin II signal transduction pathways

It has been 100 years since the discovery of renin by Tigerstedt and Bergman. Since that time, numerous discoveries have advanced our understanding of the renin-angiotensin system, including the observation that angiotensin II is the effector molecule of this system. A remarkable aspect of angiotensin II is the many different physiological responses this simple peptide induces in different cell types. Here, we focus on the signal transduction pathways that are activated as a consequence of angiotensin II binding to the AT1 receptor. Classical signaling pathways such as the activation of heterotrimeric G proteins by the AT1 receptor are discussed. In addition, recent work examining the role of tyrosine phosphorylation in angiotensin II-mediated signal transduction is also examined. Understanding how these distinct signaling pathways transduce signals from the cell surface will advance our understanding of how such a simple molecule elicits such a wide variety of specific cellular responses.     

Povidone iodine and skin disinfection before initiation of epidural anesthesia

OBJECTIVE: The clinical, mammographic and low grade cytologic features of mucinous carcinoma can make it difficult to diagnose by fine needle aspiration (FNA). Fine needle aspirates of mucinous carcinoma were reviewed with the mammographic findings to improve the diagnostic criteria and specificity for FNA. STUDY DESIGN: All aspirates were reviewed for cytologic criteria and cellularity, atypia and single epithelial cells (SEC). A nuclear grade was assigned to each aspirate. The mammographic findings were correlated with the FNA diagnoses. RESULTS: Forty-five patients with an aspirate and confirmed diagnosis of mucinous carcinoma were identified. The clinical impressions were: benign tissue (5), fibroadenoma (6) and cancer (32). The initial cytologic diagnoses were: adenocarcinoma (32), atypical/suspicious for cancer (11), insufficient (1) and negative (1). The cytologic findings showed smears with increased cellularity (35/45 cases) and minimal atypia. SEC with eccentrically located nuclei and eosinophilic cytoplasm were numerous. The assigned nuclear grade was as follows: grade 1, 16 cases; grade 2, 20 cases; and grade 3, 6 cases. Abundant mucin was present in Papanicolaou-stained slides in 23 cases; focal mucin was observed in 14 cases. The mammograms showed a smoothly outlined to lobulated mass with only slight irregularities identified. CONCLUSION: Mucinous carcinoma has a cytologic pattern that includes increased cellularity, with numerous single cells and abundant mucin. Although the mammographic findings may mimic a benign lesion, in the most patients a specific diagnosis of mucinous carcinoma can be made by FNA.     

The yielding, plastic flow, and fracture behavior of ultra-high molecular weight polyethylene used in total joint replacements

The yielding, plastic flow, and fracture behavior of UHMWPE plays an important role in wear and failure mechanisms of total joint replacement components. The primary objective of this study was to compare the yielding, plastic flow, and fracture behavior of two implantable grades of UHMWPE (GUR 1120 vs 4150 HP). The first part of this work explored the hypothesis that up to the polymer yield point, the monotonic loading behavior of UHMWPE displays similar true stress strain behavior in tension and compression. Uniaxial tension and compression tests were conducted to compare the equivalent true stress vs strain response of UHMWPE up to 0.12 true strain. During monotonic loading, the equivalent true stress strain behavior was similar in tension and compression up to the yield point. However, investigation of the unloading behavior and permanent plastic deformations showed that classical deviatoric rate independent plasticity theory may dramatically overpredict the permanent strains in UHMWPE. A secondary goal of this study was to determine the ultimate true stress and strain for UHMWPE and to characterize the fracture surfaces after failure. Using a fracture mechanics approach, the critical flaw sizes were used in combination with the true ultimate stresses to predict the fracture toughness of the two resins. A custom video-based strain measurement system was developed and validated to characterize the true stress-strain behavior up to failure and to verify the accuracy of the incompressibility assumption in calculating the true stress-strains up to failure. In a detailed uncertainty analysis, theoretical expressions were derived for the relative uncertainty in digital video-based estimates of nominal strain, true strain, homogeneous stress, and true stress. Although the yielding behavior of the two UHMWPE resins was similar, the hardening and plastic flow behavior clearly discriminated between the GUR 1120 and 4150 HP. A statistically significant difference between the fracture toughness of the two resins was also evident. The long-term goal of this research is to provide detailed true stress strain data for UHMWPE under uniaxial tension and compression for future numerical simulations and comparison with more complex multiaxial loading conditions.     

Classical/nonclassical hybrid cannabinoids: southern aliphatic chain-functionalized C-6beta methyl, ethyl, and propyl analogues

The stereoelectronic requirements for interaction of the southern aliphatic hydroxyl of cannabimimetic pharmacophores with the CB1 and CB2 receptors are explored. The stereoselective syntheses of three series of classical/nonclassical hybrid cannabinoids are described. These compounds were designed to investigate the importance of the southern aliphatic hydroxyl (SAH) pharmacophore for cannabimimetic activity. Variation in the chain length of the SAH moiety in these 6beta-(hydroxyalkyl)dihydrobenzopyran analogues, from 6beta-hydroxymethyl to 6beta-(omega-hydroxyethyl) and 6beta-(omega-hydroxypropyl), and the effects of replacing the hydroxyl functionality by hydride and iodide are reported. Our results indicate that the SAH pharmacophore has less pronounced effects than the C-3 aliphatic chain on cannabinoid activity. Furthermore, it appears that this southern molecular component is capable of interacting with two different subsites on the receptor and that the nature of this interaction is determined by the terminal substituent on the C-6beta alkyl group. One of the subsites can accommodate the relatively polar SAH pharmacophore, while the second subsite interacts with more hydrophobic C-6beta substituents and can accommodate large spherical pharmacophores separated by three methylene carbons from the tricyclic cannabinoid template.     

Testicular plasmacytoma following chemical orchiectomy: potential role of hypogonadism in myeloma proliferation

We present a case of a 55 year old man with multiple myeloma who underwent autologous stem cell transplantation and subsequently developed testicular myeloma. Testicular enlargement was observed only after treatment of an incidental prostatic adenocarcinoma with chemical orchidectomy at a time when myeloma was controlled systemically. A subsequent bilateral surgical orchiectomy revealed plasmacytoma in both testis. Enhanced production of B-lymphocytes after castration has been reported and implicates testosterone as a possible negative regulator of B-cell production. We propose that the androgen deficient state may have contributed to the development of plasmacytoma of the testes in our patient. The regulatory role of sex steroids in B-cell development is discussed.     

Targeting of active sialyltransferase to the plant Golgi apparatus

Glycosyltransferases in the Golgi apparatus synthesize cell wall polysaccharides and elaborate the complex glycans of glycoproteins. To investigate the targeting of this type of enzyme to plant Golgi compartments, we generated transgenic Arabidopsis plants expressing alpha-2,6-sialyltransferase, a glycosyltransferase of the mammalian trans-Golgi cisternae and the trans-Golgi network. Biochemical analysis as well as immunolight and immunoelectron microscopy of these plants indicate that the protein is targeted specifically to the Golgi apparatus. Moreover, the protein is predominantly localized to the cisternae and membranes of the trans side of the organelle. When supplied with the appropriate substrates, the enzyme has significant alpha-2,6-sialyltransferase activity. These results indicate a conservation of glycosyltransferase targeting mechanisms between plant and mammalian cells and also demonstrate that glycosyltransferases can be subcompartmentalized to specific cisternae of the plant Golgi apparatus.     

Interleukin-12 is required for control of the growth of attenuated aromatic-compound-dependent salmonellae in BALB/c mice: role of gamma interferon and macrophage activation

The attenuated S. typhimurium SL3261 (aroA) strain causes mild infections in BALB/c mice. We were able to exacerbate the disease by administering anti-interleukin-12 (IL-12) antibodies, resulting in bacterial counts in the spleens and livers of anti-IL-12-treated mice that were 10- to 100-fold higher than the ones normally observed in premortem mice; yet the animals showed only mild signs of illness. Nevertheless, they eventually died of a slow, progressive disease. Mice infected with salmonellae become hypersusceptible to endotoxin. We found that IL-12 neutralization prevented the death of infected mice following subcutaneous injection of lipopolysaccharide. Granulomatous lesions developed in the spleens and livers of control animals, as opposed to a widespread infiltration of mononuclear cells seen in the organs of anti-IL-12-treated mice. In the latter (heavily infected), salmonellae were seen within mononuclear cells, indicating an impairment of the bactericidal or bacteriostatic ability of the phagocytes in the absence of biologically active IL-12. Gamma interferon (IFN-gamma) levels were reduced in the sera and tissue homogenates from anti-IL-12-treated mice compared to those in control animals. Furthermore, fluorescence-activated cell sorter analysis on spleen cells showed that IL-12 neutralization impaired the upregulation of I-Ad/I-Ed antigens on macrophages from infected mice. Inducible nitric oxide synthase and IFN-gamma mRNA production was down-regulated in anti-IL-12-treated mice, which also showed an increased production of IL-10 mRNA and a decrease in nitric oxide synthase activity in the tissues. Administration of recombinant IFN-gamma to anti-IL-12-treated mice was able to restore host resistance, granuloma formation, and expression of major histocompatibility complex class II antigens in F4/80(+) and CD11b+ spleen cells.     

Abciximab therapy and unplanned coronary stent deployment: favorable effects on stent use, clinical outcomes, and bleeding complications. EPILOG Trial Investigators

BACKGROUND: Recent studies indicate that eradication of Helicobacter pylori might prevent peptic ulcer formation in patients treated with non-steroidal anti-inflammatory drugs (NSAIDs). On the other hand, gastric adaptation after repeated exposures to aspirin (ASA) is well documented but the influence of H. pylori on this process remains to be elucidated. AIM: To compare gastric damage and adaptation following repeated exposures to ASA in a group of patients with H. pylori infection, before and after eradication of the bacterium, and in H. pylori-negative controls. METHODS: Eight healthy volunteers without H. pylori infection and eight patients with duodenal ulcer (DU) history and H. pylori infection before and after H. pylori eradication were given ASA 2 g/day for a period of 14 days. Mucosal damage was evaluated by endoscopy and histology of biopsy samples. Gastric microbleeding, DNA synthesis in the gastric mucosa and mucosal expression, as well as luminal content of transforming growth factor-alpha (TGFalpha) were determined on days 0, 3, 7 and 14 of the ASA course. RESULTS: In all patients aspirin-induced gastric damage reached a maximum on day 3. In H. pylori-positive patients, this damage was maintained at a similar level up to day 14, whereas in H. pylori-negative controls and H. pylori-eradicated patients this damage significantly lessened on day 14 and was accompanied by elevated DNA synthesis as well as increased mucosal expression and luminal release of TGFalpha.     

Determination of aspirin and salicylic acid in transdermal perfusates

A high-performance liquid chromatographic (HPLC) method has been developed for the simultaneous determination of aspirin and salicylic acid in transdermal perfusates. The compounds were separated on a C8 Nucleosil column (5 microm, 250x4.6 mm) using a mobile phase containing a mixture of water-acetonitrile-orthophosphoric acid (650:350:2, v/v/v) and a flow-rate of 1 ml/min. The transdermal samples were in phosphate-buffered saline (PBS) and could be injected directly onto the HPLC system. The method was reproducible with inter-day R.S.D. values of no greater than 3.46 and 2.60% for aspirin and salicylic acid, respectively. The method was linear over the concentration range 0.2-5.0 microg/ml and had a limit of detection of 0.05 microg/ml for both compounds. For certain samples, it was necessary to ensure that no transmembrane leakage of the aspirin prodrugs had occurred. In these cases, a gradient was introduced by increasing the acetonitrile content of the mobile phase after the salicylic acid had eluted. The method has been applied to the determination of aspirin and salicylic acid in PBS following in vitro application of the compounds to mouse skin samples.