Applications of computational modeling in ballistics

The development of the technology of ballistics as applied to gun launched Army weapon systems is the main objective of research at the U.S. Army Ballistic Research Laboratory (BRL). The primary research programs at the BRL consist of three major ballistic disciplines: exterior, interior, and terminal. The work done at the BRL in these areas was traditionally highly dependent on experimental testing. A considerable emphasis was placed on the development of computational modeling to augment the experimental testing in the development cycle; however, the impact of the computational modeling to this date is modest. With the availability of supercomputer computational resources recently installed at the BRL, a new emphasis on the application of computational modeling to ballistics technology is taking place. The major application areas are outlined which are receiving considerable attention at the BRL at present and to indicate the modeling approaches involved. An attempt was made to give some information as to the degree of success achieved and indicate the areas of greatest need

Effect of metabolic syndrome and aging on Ca2+ dysfunction in coronary smooth muscle and coronary artery disease severity in Ossabaw miniature swine

BACKGROUND: Metabolic syndrome (MetS) and aging are prevalent risk factors for coronary artery disease (CAD) and contribute to the etiology of CAD, including dysregulation of Ca2+ handling mechanisms in coronary smooth muscle (CSM). The current study tested the hypothesis that CAD severity and CSM Ca2+ dysregulation were different in MetS-induced CAD compared to aging-induced CAD. METHODS: Young (2.5 ± 0.2 years) and old (8.8 ± 1.2 years) Ossabaw miniature swine were fed an atherogenic diet for 11 months to induce MetS and were compared to lean age-matched controls. The metabolic profile was confirmed by body weight, plasma cholesterol and triglycerides, and intravenous glucose tolerance test. CAD was measured with intravascular ultrasound and histology. Intracellular Ca2+ ([Ca2+]i) was assessed with fura-2 imaging. RESULTS: CAD severity was similar between MetS young and lean old swine, with MetS old swine exhibiting the most severe CAD. Compared to CSM [Ca2+]i handling in lean young, the MetS young and lean old swine exhibited increased sarcoplasmic reticulum Ca2+ store release, increased Ca2+ influx through voltage-gated Ca2+ channels, and attenuated sarco-endoplasmic reticulum Ca2+ ATPase activity. MetS old and MetS young swine had similar Ca2+ dysregulation. CONCLUSIONS: Ca2+ dysregulation, mainly the SR Ca2+ store, in CSM is more pronounced in lean old swine, which is indicative of mild, proliferative CAD. MetS old and MetS young swine exhibit Ca2+ dysfunction that is typical of late, severe disease. The more advanced, complex plaques in MetS old swine suggest that the "aging milieu" potentiates effects of Ca2+ handling dysfunction in CAD

Microparticles Produced by the Hydrogel Template Method for Sustained Drug Delivery

Polymeric microparticles have been used widely for sustained drug delivery. Current methods of microparticle production can be improved by making homogeneous particles in size and shape, increasing the drug loading, and controlling the initial burst release. In the current study, the hydrogel template method was used to produce homogeneous poly(lactide-co-glycolide) (PLGA) microparticles and to examine formulation and process-related parameters. Poly(vinyl alcohol) (PVA) was used to make hydrogel templates. The parameters examined include PVA molecular weight, type of PLGA (as characterized by lactide content, inherent viscosity), polymer concentration, drug concentration and composition of solvent system. Three model compounds studied were risperidone, methylprednisolone acetate and paclitaxel. The ability of the hydrogel template method to produce microparticles with good conformity to template was dependent on molecular weight of PVA and viscosity of the PLGA solution. Drug loading and encapsulation efficiency were found to be influenced by PLGA lactide content, polymer concentration and composition of the solvent system. The drug loading and encapsulation efficiency were 28.7% and 82% for risperidone, 31.5% and 90% for methylprednisolone acetate, and 32.2 % and 92 % for paclitaxel, respectively. For all three drugs, release was sustained for weeks, and the in vitro release profile of risperidone was comparable to that of microparticles prepared using the conventional emulsion method. The hydrogel template method provides a new approach of manipulating microparticles

Calcium channel Orai1 promotes lymphocyte IL-17 expression and progressive kidney injury

We hypothesized that the store-operated calcium entry (SOCE) channel, Orai1, participates in the activation of Th17 cells and influences renal injury. In rats, following renal ischemia/reperfusion (I/R), there was a rapid and sustained influx of Orai1+ CD4 T cells and IL-17 expression was restricted to Orai1+ cells. When kidney CD4+ cells of post-acute kidney injury (post-AKI) rats were stimulated with angiotensin II and elevated Na+ (10-7 M/170 mM) in vitro, there was an enhanced response in intracellular Ca2+ and IL-17 expression, which was blocked by SOCE inhibitors 2APB, YM58483/BTP2, or AnCoA4. In vivo, YM58483/BTP2 (1 mg/kg) attenuated IL-17+ cell activation, inflammation, and severity of AKI following either I/R or intramuscular glycerol injection. Rats treated with high-salt diet (5-9 weeks after I/R) manifested progressive disease indicated by enhanced inflammation, fibrosis, and impaired renal function. These responses were significantly attenuated by YM58483/BTP2. In peripheral blood of critically ill patients, Orai1+ cells were significantly elevated by approximately 10-fold and Th17 cells were elevated by approximately 4-fold in AKI versus non-AKI patients. Further, in vitro stimulation of CD4+ cells from AKI patients increased IL-17, which was blocked by SOCE inhibitors. These data suggest that Orai1 SOCE is a potential therapeutic target in AKI and CKD progression

Highly Sensitive Intravascular Photoacoustic Imaging with a Collinear Catheter Probe

A collinear catheter for label-free intravascular photoacoustic imaging was developed with a diameter of 1.6 mm. The collinear overlap between optical and acoustic waves enabled photoacoustic imaging of a human coronary artery from lumen to perivascular fat

Comparative Quantification of Arterial Lipid by Intravascular Photoacoustic-Ultrasound Imaging and Near-Infrared Spectroscopy-Intravascular Ultrasound

Intravascular photoacoustic-ultrasound (IVPA-US) imaging and near-infrared spectroscopy-intravascular ultrasound (NIRS-IVUS) are two hybrid modalities that detect arterial lipid, with comparison necessary to understand the relative advantages of each. We performed in vivo and ex vivo IVPA-US imaging of the iliac arteries of Ossabaw swine with metabolic syndrome (MetS) and lean swine to investigate sensitivity for early-stage atherosclerosis. We repeated imaging ex vivo with NIRS-IVUS for comparison to IVPA-US and histology. Both modalities showed significantly greater lipid in MetS vs. lean swine, but only IVPA-US localized the lipid as perivascular. To investigate late-stage atherosclerosis, we performed ex vivo IVPA-US imaging of a human coronary artery with comparison to NIRS-IVUS and histology. Two advanced fibroatheromas were identified, with agreement between IVPA-measured lipid area and NIRS-derived lipid content. As confirmed histologically, IVPA-US has sensitivity to detect lipid content similar to NIRS-IVUS and provides additional depth resolution, enabling quantification and localization of lipid cores within plaques

Label-free quantitative imaging of cholesterol in intact tissues by hyperspectral stimulated Raman scattering microscopy

A finger on the pulse: Current molecular analysis of cells and tissues routinely relies on separation, enrichment, and subsequent measurements by various assays. Now, a platform of hyperspectral stimulated Raman scattering microscopy has been developed for the fast, quantitative, and label-free imaging of biomolecules in intact tissues using spectroscopic fingerprints as the contrast mechanism

Development and Evaluation of Transferrin-Stabilized Paclitaxel Nanocrystal Formulation

The aim of the present study was to prepare and evaluate a paclitaxel nanocrystal-based formulation stabilized by serum protein transferrin in a non-covalent manner. The pure paclitaxel nanocrystals were first prepared using an antisolvent precipitation method augmented by sonication. The serum protein transferrin was selected for use after evaluating the stabilizing effect of several serum proteins including albumin and immunoglobulin G. The formulation contained approximately 55~60% drug and was stable for at least 3 months at 4 °C. In vivo antitumor efficacy studies using mice inoculated with KB cells demonstrate significantly higher tumor inhibition rate of 45.1% for paclitaxel-transferrin formulation compared to 28.8% for paclitaxel nanosuspension treatment alone. Interestingly, the Taxol® formulation showed higher antitumor activity than the paclitaxel-transferrin formulation, achieving a 93.3% tumor inhibition rate 12 days post initial dosing. However, the paclitaxel-transferrin formulation showed a lower level of toxicity, which is indicated by steady increase in body weight of mice over the treatment period. In comparison, treatment with Taxol® resulted in toxicity issues as body weight decreased. These results suggest the potential benefit of using a serum protein in a non-covalent manner in conjunction with paclitaxel nanocrystals as a promising drug delivery model for anticancer therapy

Biphasic alterations in coronary smooth muscle Ca2+ regulation in a repeat cross-sectional study of coronary artery disease severity in metabolic syndrome

BACKGROUND AND AIMS: Coronary artery disease (CAD) is progressive, classified by stages of severity. Alterations in Ca(2+) regulation within coronary smooth muscle (CSM) cells in metabolic syndrome (MetS) have been observed, but there is a lack of data in relatively early (mild) and late (severe) stages of CAD. The current study examined alterations in CSM Ca(2+) regulation at several time points during CAD progression. METHODS: MetS was induced by feeding an excess calorie atherogenic diet for 6, 9, or 12 months and compared to age-matched lean controls. CAD was measured with intravascular ultrasound (IVUS). Intracellular Ca(2+) was assessed with fura-2. RESULTS: IVUS revealed that the extent of atherosclerotic CAD correlated with the duration on atherogenic diet. Fura-2 imaging of intracellular Ca(2+) in CSM cells revealed heightened Ca(2+) signaling at 9 months on diet, compared to 6 and 12 months, and to age-matched lean controls. Isolated coronary artery rings from swine fed for 9 months followed the same pattern, developing greater tension to depolarization, compared to 6 and 12 months (6 months = 1.8 ± 0.6 g, 9 months = 5.0 ± 1.0 g, 12 months = 0.7 ± 0.1 g). CSM in severe atherosclerotic plaques showed dampened Ca(2+) regulation and decreased proliferation compared to CSM from the wall. CONCLUSIONS: These CSM Ca(2+) regulation data from several time points in CAD progression and severity help to resolve the controversy regarding up-vs. down-regulation of CSM Ca(2+) regulation in previous reports. These data are consistent with the hypothesis that alterations in sarcoplasmic reticulum Ca(2+) contribute to progression of atherosclerotic CAD in MetS