Effect of a nitric oxide-releasing naproxen derivative on hypertension and gastric damage induced by chronic nitric oxide inhibition in the rat

NSAIDs can elevate blood pressure through mechanisms such as renal vasoconstriction and sodium retention. These effects are particularly evident in hypertensive individuals. Nitric oxide-releasing NSAID derivatives have been shown to have greatly reduced toxicity in the gastrointestinal tract and kidney. We therefore evaluated the effects of a 4 week treatment with either naproxen or its nitric oxide-releasing derivative (NO-naproxen) on systemic arterial blood pressure and gastric damage in rats in which hypertension was induced by L-NAME. Rats received either L-NAME dissolved in the drinking water (400 mg/L) or tap water (control). Vehicle, naproxen (10 mg/kg) or an equimolar dose of NO-naproxen (14.5 mg/kg) were administered orally each day. After 4 weeks, blood pressure was measured, blood samples were taken for measurement of thromboxane synthesis, and gastric damage was evaluated by blind, macroscopic scoring. Both naproxen and NO-naproxen inhibited systemic cyclooxygenase activity by >90%. NO-naproxen-treated rats exhibited no significant gastric damage. The gastric damage produced by L-NAME alone was potentiated by naproxen but prevented by NO-naproxen. L-NAME treatment significantly increased blood pressure. In the absence of L-NAME, the naproxen group had significantly higher blood pressure than both the control and NO-naproxen groups. In rats receiving L-NAME, the same conclusions apply, but the concomitant administration of NO-naproxen was able to significantly reduce the blood pressure compared to L-NAME alone. Based on these results, we conclude that NO-naproxen may represent a safer alternative to standard NSAIDs in the treatment of inflammatory conditions in hypertensive patients.     

Cardiovascular effects of an ultra-short-acting nitric oxide-releasing compound, zwitterionic diamine/NO adduct, in dogs

BACKGROUND: This study was conducted to clarify the cardiovascular effects of a new NO-releasing compound, NOC-7, and to compare it with other nitrovasodilators, sodium nitroprusside (SNP) and nitroglycerin, in dogs anesthetized with pentobarbital. METHODS AND RESULTS: A bolus injection of NOC-7 decreased mean aortic blood pressure in a dose-dependent manner. The onset was rapid and the recovery quick. Continuous infusion of NOC-7 decreased mean aortic pressure from 115 +/- 3.9 to 84 +/- 2.9 mm Hg and infusion of SNP, from 118 +/- 3.8 to 87 +/- 3.1 mm Hg. The optimum doses of NOC-7 and SNP were determined to be 2.73 +/- 0.77 and 11.5 +/- 6.1 micrograms.kg-1.min-1, respectively. During infusion of NOC-7, heart rate and cardiac output were increased (P < .05), pulmonary artery pressure was not changed, and systemic and pulmonary vascular resistances were decreased (P < .05). Electromagnetic flowmetry showed that portal venous and internal carotid arterial blood flow were increased (P < .05) and that hepatic and renal arterial blood flows were not changed. These hemodynamic changes during NOC-7 infusion were similar to those with SNP. The plasma level of NO2-/NO3 did not change, but methemoglobin increased slightly (P < .05). Comparison between hypotensive responses before and after a 3.5-hour infusion of NOC-7 or nitroglycerin showed that acute tolerance developed to nitroglycerin but not to NOC-7. CONCLUSIONS: The results indicate that NOC-7 may be useful as an ultra-short-acting nitrovasodilator that has no major adverse effect or tolerance.     

Incorporation of Writing into a Steel Design Course

The University of Connecticut requires that, after completing the traditional freshmen English courses, students have writing assignments in courses that comprise their major. This paper explains how this requirement has been met in a senior-level, structural steel design course. Students are required to read articles on different types of steel buildings and bridges. They then write a response to specific questions. They also are required to perform “back-of-an-envelope” calculations on different structural components. The assignments enhance the subject matter by providing students with the opportunity to look at entire structures, whereas conventional design assignments generally involve the study of individual members and connections. These assignments provide a format for organizing and communicating information about load paths, framing approaches, different design alternatives, and how design influences and is influenced by construction practice.     

Clinical trial of new polyurethane vascular grafts for hemodialysis: compared with expanded polytetrafluoroethylene grafts

We developed a new polyurethane vascular access graft coated with gelatin and reinforced with knitted polyester fibers (PE-PEUG). Advantages over expanded-polytetrafluoroethylene graft (E-PTFEG) were previously reported in experimental studies. Between May 1990 and August 1992, 39 PE-PEUGs including 34 loop and 5 straight and 18 E-PTFEGs including 18 loop were implanted to create arteriovenous (AV) fistulas in a total of 52 adult patients on maintenance hemodialysis (HD). They were followed up until October 1994. Hemostasis on the suture line was achieved within 3 min in all patients implanted with PE-PEUGs. Bleeding from the needle holes of PE-PEUG stopped within 10 min with gentle finger pressure. Minimal local edema developed in only a few patients implanted with PE-PEUG while most patients implanted with E-PTFEG developed moderate local edema. One seroma formation was found in an E-PTFE case. Aneurysmal dilatations were observed twice in a PE-PEUG patient 9 and 17 months after the implantation and once in a E-PTFEG patient 2 years after the implantation. The cumulative patency rate at 1 year in the PE-PEUG and E-PTFEG groups were 53.2 and 70.8%, respectively. Our clinical study showed that the PE-PEUG had several advantages over E-PTFEG: prompt hemostasis, no persistent edema and no formation of seroma, no change in elasticity, and sufficient mechanical strength. However, the cumulative patency rate was inferior to that with E-PTFEG implanted in our series. Further modifications are therefore necessary to improve the patency rate.     

Incorporation of Sustainability Concepts into a Civil Engineering Curriculum

The need arises to equip engineering students with a wider horizon of concepts in terms of environmental, economic, and social attributes, for decision making of sensitive to sustainability issues. Pedagogic frameworks have to address a multidisciplinary analysis of sustainability. This paper addresses the rationale behind the recent integration of sustainability concepts into an undergraduate civil engineering curriculum in Hong Kong. Incentives and barriers for implementation of the curriculum are addressed. A team-based design project with a problem-based learning approach is highlighted. The initial results of stakeholder evaluations suggested that multidisciplinary skills developed during the learning process might contribute significantly to pertinent knowledge on sustainability.     

Incorporation of sequential trials into a fixed effects meta-analysis

The technique of meta-analysis provides a systematic and quantitative approach to the summary of results from a collection of similar randomized studies. Comprehensive methodology exists for analysis when all trials are of a fixed sample size design, but this is based on assumptions which are no longer valid when incorporating sequentially designed studies. In this paper the effect of incorporating one or more sequential trials into a meta-analysis otherwise consisting of fixed sample size trials is investigated. The results from simulation studies of a variety of plausible scenarios are presented. The aim is to quantify the extent to which bias is introduced. It was found that when incorporating two alternative sequential designs, the triangular test and the O'Brien and Fleming procedure, the results of a conventional meta-analysis remain accurate.     

Effects of cyclooxygenase-2 selective and nitric oxide-releasing nonsteroidal antiinflammatory drugs on mucosal ulcerogenic and healing responses of the stomach

Effects of selective cyclooxygenase-2 (COX-2) inhibitors (NS-398) and nitric oxide (NO) -releasing aspirin (NO-ASA) on gastric ulcerogenic and healing responses were examined in comparison with nonselective COX inhibitors such as indomethacin and aspirin (ASA). Hypothermic stress (28-30 degrees C, 4 hr) induced gastric lesions in anesthetized rats with an increase of acid secretion. The lesions induced by hypothermic stress were markedly worsened by subcutaneous administration of both indomethacin and ASA but were not affected by either NS-398 or NO-ASA, although the increased acid secretion during hypothermia was not affected by any of the drugs. On the other hand, the healing of gastric ulcers induced in mice by thermal cauterization (70 degrees C, 15 sec) was significantly delayed by daily subcutaneous administration of indomethacin and ASA as well as NS-398, but not by NO-ASA. COX-2 mRNA was not detected in the intact mucosa but was positively expressed in the ulcerated mucosa, most potently on day 3 after ulceration. Prostaglandin contents in the intact mouse stomach were reduced by indomethacin, ASA, and NO-ASA, while the increased prostaglandin generation in the ulcerated mucosa was inhibited by all drugs including NS-398. After subcutaneous administration of NO-ASA to pylorus-ligated rats and mice, high amounts of NOx were detected in both the gastric contents and serum. In addition, both NS-398 and NO-ASA showed an equipotent antiinflammatory effect against carrageenan-induced paw edema in rats as compared with indomethacin and ASA. These results suggest that both indomethacin and ASA not only increased the mucosal ulcerogenic response to stress but impaired the healing response of gastric ulcers as well. The former action was due to inhibition of COX-1, while the latter effect was accounted for by inhibition of COX-2 and was mimicked by the COX-2-selective inhibitor NS-398. NO-ASA, although it inhibited both COX-1 and COX-2 activity, had no deleterious effects on gastric ulcerogenic and healing responses.     

Filtration of diaspirin crosslinked hemoglobin into lung and soft tissue lymph

Diaspirin crosslinked hemoglobin (DCHb) is a new blood substitute manufactured from human blood. To evaluate its microvascular filtration properties, we infused DCLHb into unanesthetized sheep (10%, 20 ml/kg) and measured the flow and composition of lung and soft tissue lymph. For comparison, we also infused human serum albumin (HSA; 10%, 20 ml/kg). DCLHb raised systemic and pulmonary arterial pressures from baseline values of 83 +/- 7 and 13 +/- 2 mm Hg, respectively, to peak values of 113 +/- 9 and 26 +/- 3 mm Hg (p < 0.05 versus baseline). These increases were significantly greater than those associated with HSA, which raised systemic and pulmonary arterial pressures from baseline values of 86 +/- 4 and 13 +/- 2 mm Hg, respectively, to peak values of 97 +/- 3 and 21 +/- 7 mm Hg (p <= 0.05 versus baseline and versus DCLHb). These differences reflect the known pressor properties of DCLHb. Accordingly, DCLHb raised lung and soft tissue lymph flows to peak values of 12.2 +/- 3.8 and 1.6 +/- 0.7 ml/30 min, respectively, while HSA raised lung and soft tissue lymph flows to peak values of 7.5 +/- 4.8 and 4.6 +/- 1.9 ml/30 min, respectively (p <= 0.05 versus DCLHb). The half-times of DCLHb equilibration from plasma into lung and soft tissue lymph of 1. 0 +/- 0.3 and 2.1 +/- 1.1 h, respectively, were significantly faster than HSA equilibration half-times of 3.1 +/- 0.2 and 3.8 +/- 0.9 h. Filtration differences between DCLHb and HSA appear to be due to the pressor properties DCLHb.     

Incorporation of n-3 polyunsaturated fatty acids into processed foods

The aim of dose reduction of chemotherapeutic agents following weight loss is to avoid excessive toxicity while maintaining an equivalent therapeutic effect. Several methods of calculating this dose reduction are currently in use, including dose reduction in proportion to the reduction in body surface area (BSA) or the amount of weight lost and no dose reduction unless significant toxicity occurs. Each of these methods results in the administration of a different dose and therefore different drug exposure, as measured by the area under the time versus concentration curve (AUC). We have used pharmacokinetic modeling software and normative data on the pharmacokinetics of high-dose methotrexate to determine the change in AUC resulting from dose reduction by each of the methods cited for patients with weight loss. Dose reduction in proportion to the reduction in weight results in the same AUC and therefore equivalent drug exposure as before weight loss. In contrast, the more common practice of dose reduction in proportion to the decrease in BSA (as determined by recalculating BSA) results in a higher AUC than before weight loss. This results in increased drug exposure and potentially increased toxicity, which may be avoided if dose reduction is carried out in proportion to the decrease in weight rather than in BSA. The same principles are applicable to other drugs, particularly those associated with dose-dependent toxicity.     

Incorporation of matte-slag thermochemistry into sulphide smelter discrete event simulation

Discrete event simulation (DES) is a suitable framework to evaluate and optimise the dynamics of sulphide smelters. In particular, iron–nickel–copper–cobalt sulphides undergo continual oxidation within a roasting or smelting operation, followed by batch oxidation within the converting operation, thus producing iron-free Bessemer matte (or blister copper, in the case of copper smelters); this semi-finished product undergoes further processing to produce nickel, copper and cobalt products, and to recover precious metals. The juncture between continuous smelting and batch converting is often an appropriate focus for the earliest phases of DES development, since it is typically a major bottleneck within nickel and copper smelters; later phases may include increasing levels of detail for auxiliary unit operations, as well as plant logistics. Moreover, DES can support matte-slag chemistry, including Gibbs free energy balances to determine the iron speciation within the slag. DES is therefore capable of linking the fundamentals of oxidation reactions to the intricacies of plant dynamics.     

Expression of vascular adhesion molecules in saphenous vein coronary bypass grafts

BACKGROUND: Adhesion of blood elements to the endothelium is an important step in the development of vein graft disease. This study examines the expression of vascular adhesion molecules on explanted saphenous vein bypass grafts. METHODS: Immunocytochemical staining was performed using explanted saphenous vein grafts from 28 patients. Antibodies against the endothelial markers CD31, von Willebrand factor, intercellular adhesion molecule-1, vascular adhesion molecule-1, and E-selectin were used. RESULTS: Staining for CD31 and von Willebrand factor demonstrated the presence of endothelial cells in the lumen and the vasa vasorum. Expression of intercellular adhesion molecule-1 was variable between grafts, whereas vascular adhesion molecule-1 and E-selectin were almost always absent on the luminal endothelium. In contrast, the endothelium of the vasa vasorum stained positively for intercellular adhesion molecule-1 and vascular adhesion molecule-1, and was also seen on nonendothelial cells within the vessel wall. Expression of these adhesion molecules did not vary with the severity of vein graft disease. CONCLUSIONS: This study highlights the blood vessels in the adventitia as possible sites for the adhesion and migration of cells into the vessel wall.     

Incorporation of adhesion peptides into nonadhesive hydrogels useful for tissue resurfacing

The recessive patchwork (pwk) mutation in mice is associated with a unique hair follicle phenotype. Mice homozygous for patchwork exhibit a variegated coat containing a mixture of white and fully pigmented hairs, but no partially pigmented hairs. We have investigated the etiology of this mutation. We report here that the white hairs result from the lack of melanocytes in the follicle. As indicated by the coat color pattern of patchwork<-->albino chimeras, the target cell for the patchwork mutation is the melanocyte and/or its precursor. Examination of these chimeras also suggested that patchwork does not act in a cell-autonomous manner. The colonization of the skin by melanoblasts in patchwork embryos was studied using a lacZ transgene. Melanoblasts die by apoptosis in hair follicles from homozygous pwk/pwk fetuses starting at embryonic day 18.5, indicating that patchwork acts from this stage. The combination of pwk and KitW-ei, a mutation responsible for a reduced number of melanoblasts in the hair follicle, suggested that pwk gene product is necessary for low numbers of melanoblasts to survive and differentiate in the hair follicle from embryonic day 18.5 onward. We conclude that the pigmented hairs on the coat of pwk/pwk mice may be attributed to a community effect among melanoblasts in the hair follicle at the end of embryogenesis.     

Incorporation of radioactive amino acids into protein in isolated rat hepatocytes

The incorporation of radioactivity from a 14C-labelled amino acid mixture (algal protein hydrolysate) into protein in isolated rat hepatocytes has been studied. The incorporation rate declined with increasing cell concentration, an effect which could be explained partly by isotope consumption, partly (and largely) by isotope dilution due to the formation of non-labelled amino acids by the cells. At a high extracellular amino acid concentration, the rate of incorporation into protein became independent of cell concentration, because the isotope dilution effect was now quantitatively insignificant. The time course of protein labelling at various cells concentrations correlated better with the intracellular than with the extracellular amino acid specific activity, suggesting that amino acids for protein synthesis were taken from an intracellular pool. With increasing extracellular amino acid concentrations both the intracellular amino acid concentration, the intracellular radioactivity and the rate of incorporation into protein increased. Protein labelling exhibited a distinct time lag at high amino acid concentrations, presumably reflecting the time-dependent expansion of the intracellular amino acid pool. The gradual increase in the rate of protein labelling could be due either to an increased intracellular specific activity, or to a real stimulation of protein synthesis by amino acids, depending on whether the total intracellular amino acid pool or just the expandable compartment is the precursor pool for protein synthesis.     

Incorporation of concern- and nonconcern-related verbal stimuli into dream content.

The hypothesis that cues related to Ss' current concerns can control attentional and cognitive processes during sleeping and dreaming was examined by presenting concern- and nonconcern-related verbal stimuli to 7 male undergraduates during sleep Stages 2 and REM. The taped dream reports were judged for stimulus incorporation by 2 independent raters. Results reveal that concern stimuli were incorporated significantly more often than nonconcern stimuli in REM, although low dream recall rates prevented assessment of whether this relationship also existed in Stage 2. This finding supports the results of other studies that indicate that responsiveness to auditory stimuli during sleeping and dreaming is largely dependent on the personal significance of the stimulus to the sleeper. It further suggests that sleeping Ss are capable of making more complex and subtle cognitive discriminations, based on the waking value of the stimulus to the S, than has previously been demonstrated. (12 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Choice, isolation, and preparation of cells for bioartificial vascular grafts

Preparation of cells and tissues for bioartificial vascular grafts is discussed from the viewpoint of tissue engineering. In general, a neointima is not formed on vascular prostheses except at the anastomotic sites. Graft surfaces do not heal and are covered with fresh thrombi for a long period of time after implantation. The delayed healing is, so to speak, an intractable ulcer of the vascular wall. To overcome this problem, we have developed a tissue fragment transplantation method. We consider that neointima formation of vascular prostheses after implantation is a product of tissue engineering in vivo. Therefore, 3 essential elements for tissue engineering, i.e., cells, extracellular matrices, and cytokines, are required for neointima formation. Synthetic vascular prostheses lack one or more of these elements. In this study we demonstrated a standard healing process of fabric vascular prostheses and an antithrombogenic polymer graft using animal models. Then we showed the tissue fragment transplantation method using venous tissues, adipose tissues, and bone marrow. This method provided the 3 essential elements to the prostheses. To allow these elements to be actively engaged in neointima formation, we treated cells and tissues as clumps without enzymatic digestion. We also took advantage of the in vivo environment. With the results we demonstrate our way of thinking in relation to bioartificial vascular grafts.     

The role of nitric oxide in vascular biology and pathobiology

Brain natriuretic peptide (BNP) is a novel cardiac hormone secreted predominantly from the ventricle. We examined the plasma levels of BNP and atrial natriuretic peptide (ANP) in 13 patients with aortic stenosis undergoing corrective surgery. Preoperative plasma BNP and ANP levels correlated highly with preoperative left ventricular end-systolic wall stress (ESS) (r = 0.96, p < 0.0001 and r = 0.95, p < 0.0001, respectively). Moreover, between preoperative and late postoperative states, the difference of the plasma levels of BNP and ANP correlated with the difference of ESS. In two patients with elevated ESS and quite high preoperative plasma BNP (> 1000 pg/ml), rapid decrease of the plasma level after operation was observed. These results suggest that synthesis and secretion of BNP and ANP are stimulated by the increase of left ventricular end-systolic wall stress in patients with aortic stenosis.     

Role of vascular nitric oxide in physiological and pathological conditions

This review describes the ability of certain diseases, such as essential hypertension, atherosclerosis, angina, and vasospasm, to reduce vascular nitric oxide (NO) formation or to increase its metabolism. In contrast, others, such as hypotension, sepsis, stroke, myocardial depression, and inflammatory responses, increase NO synthesis. The mechanism implicated in the changes in the formation and metabolism of NO are described. To prevent or treat these pathological processes, in which a deficiency in vascular NO formation plays a causative role, NO may be provided through methods such as direct NO administration or indirect NO supply through either NO donors or L-arginine, which facilitates NO formation.