Dose-related effects of Ampligen (poly(I).poly(C12U)), a mismatched double-stranded RNA, in a bleomycin-mouse model of pulmonary fibrosis

The antifibrotic effect of the mismatched double-stranded RNA, Ampligen (poly(I).poly(C12U)), was evaluated in a bleomycin-mouse model of pulmonary fibrosis. Mice received a single intratracheal dose of bleomycin (0.125 U/mouse) or saline (50 microL) at the beginning of the experiment, followed by 5 or 6 intraperitoneal injections of Ampligen (1.0, 5.0, 10.0, 15.0, or 25.0 mg/kg) or saline at regular intervals for 2 weeks. Ampligen did not produce increased mortality or weight loss by itself. However, it produced varying degrees of mortality in combination with bleomycin. Five injections of 10 mg/kg Ampligen or three injections of 25 mg/kg Ampligen plus three injections of 10 mg/kg Ampligen in combination with bleomycin .produced significant reductions in lung collagen accumulation as indicated by lung hydroxyproline content compared to the bleomycin control group. Animals receiving bleomycin plus Ampligen at all dosages had significantly reduced prolyl hydroxylase activity compared to the bleomycin control group. Lipid peroxidation and bronchoalveolar lavage fluid (BALF)-supernatant protein content for the groups receiving bleomycin plus Ampligen were not reduced compared to the bleomycin control group. In the BALF-supernatant, the activity of acid phosphatase, a lysosomal enzyme produced by neutrophils, monocytes, and macrophages, was significantly decreased in the group receiving bleomycin plus 10 mg/kg Ampligen. Also, selected BALF differential immune cell counts were reduced in some of the groups receiving bleomycin plus Ampligen, but not in a consistent or dose-dependent manner. The results of this study indicate that Ampligen can significantly reduce the bleomycin-induced increased collagen accumulation and may be therapeutically useful in the management of lung fibrosis in humans.     

Hemodynamic characteristics, myocardial kinetics and microvascular rheology of FS-069, a second-generation echocardiographic contrast agent capable of producing myocardial opacification from a venous injection

OBJECTIVES: We sought to 1) study the effects of FS-069 on cardiac and systemic hemodynamic function, myocardial blood flow, left ventricular wall thickening and pulmonary gas exchange when injected intravenously; and 2) compare the myocardial kinetics and microvascular rheology of FS-069 and Albunex when injected directly into a coronary artery. BACKGROUND: FS-069 is a second-generation echocardiographic contrast agent composed of perfluoropropane-filled albumin microspheres; it is capable of consistent and reproducible myocardial opacification from a venous injection. METHODS: Nine dogs were used to study the effects of FS-069 on hemodynamic function, pulmonary gas exchange, left ventricular wall thickening and myocardial blood flow and to characterize its myocardial kinetics when injected intravenously. These dogs were also used to compare the myocardial kinetics of FS-069 with those of Albunex during intracoronary injections. Nine Sprague-Dawley rats were used to compare the microvascular rheology of these two contrast agents, and in vitro modeling was performed to assess whether the microvascular findings of FS-069 can explain its echocardiographic behavior during direct coronary injections. RESULTS: There were no effects of 30 rapid venous injections of FS-069 (every 20 s) on cardiac output; mean aortic, pulmonary or left atrial pressures; and peak positive and negative first derivative of left ventricular pressure (dP/dt). Similarly, there were no effects of this agent on radiolabeled microsphere-measured regional myocardial blood flow, left ventricular wall thickening or pulmonary gas exchange. When injected intravenously, the myocardial transit of this agent resembled a gamma-variate form. When diluted FS-069 was injected directly into the coronary artery; however, its transit resembled the integral of gamma-variate function, with persistent myocardial opacification lasting several minutes, which was different from that of Albunex. Intravital microscopy revealed that, unlike Albunex, when no bubbles are entrapped within the microcirculation after an arterial injection, a very small fraction of the diluted, larger FS-069 microbubbles are entrapped. In vitro modeling confirmed that this small fraction of microbubbles can result in persistent myocardial opacification. CONCLUSIONS: FS-069 produces no changes in hemodynamic function, myocardial blood flow, left ventricular wall thickening or pulmonary gas exchange when injected intravenously in large amounts. When diluted FS-069 is injected into the coronary artery, a very small fraction of the larger bubbles are entrapped within the microcirculation, resulting in a persistent contrast effect. Thus, although FS-069 is a safe intravenous echocardiographic contrast agent, it cannot provide information on myocardial blood flow when injected directly into a coronary artery.     

Development of the meshless finite volume particle method with exact and efficient calculation of interparticle area

The Finite Volume Particle Method (FVPM) is a meshless method based on a definition of interparticle area which is closely analogous to cell face area in the classical finite volume method. In previous work, the interparticle area has been computed by numerical integration, which is a source of error and is extremely expensive. We show that if the particle weight or kernel function is defined as a discontinuous top-hat function, the particle interaction vectors may be evaluated exactly and efficiently. The new formulation reduces overall computational time by a factor between 6.4 and 8.2. In numerical experiments on a viscous flow with an analytical solution, the method converges under all conditions. Significantly, in contrast with standard FVPM and SPH, error depends on particle size but not on particle overlap (as long as the computational domain is completely covered by particles). The new method is shown to be superior to standard FVPM for shock tube flow and inviscid steady transonic flow. In benchmarking on a viscous multiphase flow application, FVPM with exact interparticle area is shown to be competitive with a mesh-based volume-of-fluid solver in terms of computational time required to resolve the structure of an interface.     

Neutral sterols of sawflies (symphyta): Their relationship to other hymenoptera

To investigate sterol utilization in sawflies, the neutral sterols of four species of sawflies were determined by gas-liquid chromatography and mass spectrometry, and compared to the respective dietary plant material. Cholesterol was the predominant (55–76%) sterol in all species and stages of sawflies examined. Host plants, however, contained primarily sitosterol (50–88%), along with other 24-alkylsterols and only 0.5–5.9% cholesterol, indicating that the sawflies examined are capable of dealkylating the C₂₈ and C₂₉ phytosterols in their diet to cholesterol. Comparative sterol metabolism in Hymenoptera is discussed.     

Biocontrol potential of the entomogenous fungi Beauveria bassiana and Metarhizium anisopliae for tsetse flies (Glossina spp.) at developmental sites

Belonging to the Annonaceae family, marolo (Annona coriaceae) is a native species of the Brazilian "cerrado" región (Minas Gerais, Goiás and Distrito Federal) and can be found in South American tropical zones. Its fruits are highly consumed by local people and commercialized in markets or street stalls. There is, however, a tendency for the extinction of marolo due to deforestation and the large scale plantation of monocultures instead of native plants. The literature still offers no data on the chemical composition of the proximate composition and vitamin C, A and tannin contents were carried out on the yellow marolo pulp as well as the determination of the physico-chemical characteristics of the seed oil. Five batches of fruit from the Alfenas region--south of Minas Gerais State--were analysed in this work and their average composition were: humidity 77%, total sugar 15%, reducing sugar 11%, crude protein 1%, lipids 3%, fiber 5% and fixed mineral residue 1%. The contents of vitamin C and A were 8.2 mg/100g and 117.5 RE/100g, respectively, and the tannin content was 245 mg/100g. The results showed high fiber and lipid contents of marolo pulp in comparison with many other tropical fruit pulps. The vitamin C contents were equivalent to those found in avocado, pineapple and watermelon, while the vitamin A contents were equivalent to papaya, peach, guava and several other tropical fruits. Marolo seed contains 45% of oil on a dry basis. Its composition and physico-chemical characteristics showed the possibility of producing a good quality oil, with great potential for the fine oil market. However the presence of alkaloids in the oil needs to be further studied. Their elimination could be done by refining or extraction in a continuous press. The results exalt the high quality of marolo pulp, showing that the preservation of native species should be stimulated.     

Functional knockout of the transient outward current, long-QT syndrome, and cardiac remodeling in mice expressing a dominant-negative Kv4 alpha subunit

Amino acid changes S180A (S-->A at site 180), H197Y, Y277F, T285A, and A308S are known to shift the maximum wavelength of absorption (lambda max) of red and green visual pigments toward blue, essentially in an additive fashion. To test the generality of this "five-sites" rule, we have determined the partial amino acid sequences of red and green pigments from five mammalian orders (Artiodactyla, Carnivora, Lagomorpha, Perissodactyla, and Rodentia). The result suggests that cat (Felis catus), dog (Canis familiaris), and goat (Capra hircus) pigments all with AHYTA at the five critical sites have lambda max values of approximately 530 nm, whereas rat (Rattus norvegicus) pigment with AYYTS has a lambda max value of approximately 510 nm, which is accurately predicted by the five-sites rule. However, the observed lambda max values of the orthologous pigments of European rabbit (Oryctolagus cuniculus), white-tailed deer (Odocoileus virginianus), gray squirrel (Sciurus carolinensis), and guinea pig (Cavia procellus) are consistently more than 10 nm higher than the predicted values, suggesting the existence of additional molecular mechanisms for red and green color vision. The inferred amino acid sequences of ancestral organisms suggest that the extant mammalian red and green pigments appear to have evolved from a single ancestral green-red hybrid pigment by directed amino acid substitutions.     

Effect of sinus denervation and vagotomy on c-fos expression in the nucleus tractus solitarius after exposure to CO2

Exposure to hypercapnia and electrical stimulation of the carotid sinus nerve (CSN) has been shown to induce c-fos expression in several brain stem regions including the nucleus tractus solitarius (NTS). To test whether the labeled neurons were activated directly by hypercapnia or secondarily via the carotid bodies (sinus nerve), adult rats were exposed to either air or 14-16% CO2 for 1 h. Experiments were done on eight groups: (1) exposure to air, (2) exposure to CO2, (3) chronic CSN denervation/CO2, (4) chronic unilateral CSN denervation/CO2, (5) chronic sham CSN denervation/CO2, (6) anesthetized/CO2, (7) anesthetized and acute vagotomy/CO2, and (8) premedicated with morphine, 10 mg s.c., 20 min before exposure to CO2. After exposure to CO2 or air the rats were anesthetized, perfused with 4% paraformaldehyde and the brains processed for immunohistochemical staining for c-fos protein using the PAP (i.e. peroxidase anti-peroxidase) technique. Labeled neurons in the area of the NTS in every second 50- "mu"m section were counted and their position plotted using a microscope and camera lucida attachment. Rats exposed to CO2 had a significantly greater number of labeled neurons in the NTS than those exposed to air. Other interventions, such as CSN denervation, surgery, anesthesia, vagotomy or injection of morphine did not significantly affect the level of c-fos expression in rats exposed to hypercapnia, indicative of central stimulation rather than secondary peripheral input. These responsive neurons may be part of a widespread central chemoreceptive complex.