Intestinal Targeting of Ganciclovir Release Employing a Novel HEC-PAA Blended Lyomatrix

A hydroxyethylcellulose-poly(acrylic acid) (HEC-PAA) lyomatrix was developed for ganciclovir (GCV) intestine targeting to overcome its undesirable degradation in the stomach. GCV was encapsulated within the HEC-PAA lyomatrix prepared by lyophilization. Conventional tablets were also prepared with identical GCV concentrations in order to compare the GCV release behavior from the lyomatrix and tablets. GCV incorporation (75.12%) was confirmed using FTIR, DSC, and TGA. The effect of GCV loading on the microstructure properties of the lyomatrix was evaluated by SEM, AFM, and BET surface area measurements. The in vitro drug release study showed steady and rapid release profiles from the GCV-loaded lyomatrix compared with the tablet formulation at identical pH values. Minimum GCV release was observed at acidic pH (≤40%) and maximum release occurred at intestinal pH values (≥90%) proving the intestinal targeting ability of the lyomatrix. Kinetic modeling revealed that the GCV-loaded lyomatrix exhibited zero-order release kinetics (n?=?1), while the tablets were best described via the Peppas model. Textural analysis highlighted enhanced matrix resilience and rigidity gradient (12.5%, 20 Pa) for the GCV-loaded lyomatrix compared to the pure (7%, 9.5 Pa) HEC-PAA lyomatrix. Bench-top MRI imaging was used to confirm the mechanism of GCV release behavior by monitoring the swelling and erosion rates. The swelling and erosion rate of the tablets was not sufficient to achieve rapid zero-order GCV release as with the lyomatrix. These combined results suggest that the HEC-PAA lyomatrix may be suitable for GCV intestinal targeting after oral administration.     

Availability of phosphorus in a calcareous soil treated with rock phosphate or superphosphate as affected by phosphate-dissolving fungi

A study was undertaken to isolate some fungi exhibiting phosphate-dissolution ability, and to test whether these fungi are capable of increasing the amount of available P in a calcareous soil treated with rock phosphate (RP) or with triple superphosphate (TSP) and its subsequent uptake by sorghum (Sorghum bicolor L. Moench).Penicillium sp. and twoAspergillus foetidus (Naka) isolates significantly increased the availability of P in soil treated with RP or TSP during the growing season.Penicillium sp. isolate was more effective in increasing available P in the soil treated with RP or TSP than were Aspergillus isolates. However, the dry matter and P uptake responses to inoculation with these fungi were better in the soil treated with RP than in soil treated with TSP. In the TSP treated soil, the fungi achieved their maximum P releasing capacity two weeks earlier than in soil treated with RP. Positive and significant correlation coefficients among available P, P uptake and dry matter production at different periods of the growing season were observed following inoculation. However, none of these variables were found to be significantly correlated with the fungal populations.     

Oligotrophic bacteria in ultra-pure water systems: Media selection and process component evaluations

Summary Presently, tryptic soy agar (TSA) medium is used in the semiconductor industry to determine the concentration of viable oligotrophic bacteria in ultra-pure water systems. Deionized water from an ultra-pure water pilot plant was evaluated for bacterial growth at specific locations, using a non-selective medium (R2A) designed to detect injured heterotrophic as well as oligotrophic bacteria. Results were compared to those obtained using Tryptic Soy Agar. Statistically greater numbers of bacteria were observed when R2A was used as the growth medium. Total viable bacterial numbers were compared both before and after each treatment step of the recirculating loop to determine their effectiveness in removing bacteria. The reduction in bacterial numbers for the reverse osmosis unit, the ion exchange bed, and the ultraviolet sterilizer were 97.4%, 31.3%, and 72.8%, respectively, using TSA medium, and 98.4%, 78.4%, and 35.8% using R2A medium. The number of viable bacteria increased by 60.7% based on TSA medium and 15.7% based on R2A medium after passage of the water through an in-line 0.2-m pore size nylon filter, probably because of the growth of bacteria on the filter. Our results suggest that R2A medium may give a better representation of the microbial water quality in ultra-pure water systems and therefore a better idea of the effectiveness of the various treatment processes in the control of bacteria.     

Studies on a novel doughnut-shaped minitablet for intraocular drug delivery

The objective of this study was to evaluate the effect of 2 independent formulation variables on the drug release from a novel doughnut-shaped minitablet (DSMT) in order to optimize formulations for intraocular drug delivery. Formulations were based on a 3(2) full-factorial design. The 2 independent variables were the concentration of Resomer (% wt/wt) and the type of Resomer grade (RG502, RG503, and RG504), respectively. The evaluated response was the drug release rate constant computed from a referenced marketed product and in vitro drug release data obtained at pH 7.4 in simulated vitreous humor. DSMT devices were prepared containing either of 2 model drugs, ganciclovir or foscarnet, using a Manesty F3 tableting press fitted with a novel central-rod, punch, and die setup. Dissolution data revealed biphasic drug release behavior with 55% to 60% drug released over 120 days. The inherent viscosity of the various Resomer grades and the concentration were significant to achieve optimum release rate constants. Using the resultant statistical relationships with the release rate constant as a response, the optimum formulation predicted for devices formulated with foscarnet was 70% wt/wt of Resomer RG504, while 92% wt/wt of Resomer RG503 was ideal for devices formulated with ganciclovir. The results of this study revealed that the full-factorial design was a suitable tool to predict an optimized formulation for prolonged intraocular drug delivery.     

Circulating Pneumolysin Is a Potent Inducer of Cardiac Injury during Pneumococcal Infection

Streptococcus pneumoniae accounts for more deaths worldwide than any other single pathogen through diverse disease manifestations including pneumonia, sepsis and meningitis. Life-threatening acute cardiac complications are more common in pneumococcal infection compared to other bacterial infections. Distinctively, these arise despite effective antibiotic therapy. Here, we describe a novel mechanism of myocardial injury, which is triggered and sustained by circulating pneumolysin (PLY). Using a mouse model of invasive pneumococcal disease (IPD), we demonstrate that wild type PLY-expressing pneumococci but not PLY-deficient mutants induced elevation of circulating cardiac troponins (cTns), well-recognized biomarkers of cardiac injury. Furthermore, elevated cTn levels linearly correlated with pneumococcal blood counts (r=0.688, p=0.001) and levels were significantly higher in non-surviving than in surviving mice. These cTn levels were significantly reduced by administration of PLY-sequestering liposomes. Intravenous injection of purified PLY, but not a non-pore forming mutant (PdB), induced substantial increase in cardiac troponins to suggest that the pore-forming activity of circulating PLY is essential for myocardial injury in vivo. Purified PLY and PLY-expressing pneumococci also caused myocardial inflammatory changes but apoptosis was not detected. Exposure of cultured cardiomyocytes to PLY-expressing pneumococci caused dose-dependent cardiomyocyte contractile dysfunction and death, which was exacerbated by further PLY release following antibiotic treatment. We found that high PLY doses induced extensive cardiomyocyte lysis, but more interestingly, sub-lytic PLY concentrations triggered profound calcium influx and overload with subsequent membrane depolarization and progressive reduction in intracellular calcium transient amplitude, a key determinant of contractile force. This was coupled to activation of signalling pathways commonly associated with cardiac dysfunction in clinical and experimental sepsis and ultimately resulted in depressed cardiomyocyte contractile performance along with rhythm disturbance. Our study proposes a detailed molecular mechanism of pneumococcal toxin-induced cardiac injury and highlights the major translational potential of targeting circulating PLY to protect against cardiac complications during pneumococcal infections.     

Genome Sequence of Ralstonia sp. Strain PBA, a Bacterium Involved in the Biodegradation of 4-Aminobenzenesulfonate

Ralstonia sp. strain PBA was isolated from textile wastewater in a coculture with Hydrogenophaga sp. strain PBC. Here we present the assembly and annotation of its genome, which may provide further insights into the mechanism of its interaction with strain PBC during 4-aminobenzenesulfonate degradation.     

Up-regulation of neuropeptide Y Y4 receptor mRNA expression in the brainstem of refed rats following 48 h of food deprivation: effect of leptin

Neuropeptide Y (NPY) Y4 receptor (Y4R) in rat brainstem has been implicated in the signaling of satiety. In this study, we investigated the effects of leptin, and refeeding-induced satiety on Y4R mRNA expression in rat brainstem. Y4R receptor-specific primers were used to amplify the mRNA obtained from hypothalamus and brainstem utilizing conventional RT-PCR and quantitative real-time RT-PCR. No PCR product for Y4R was obtained from entire hypothalamic mRNA. Real-time RT-PCR showed a significant two-fold increase in the relative quantity of Y4R mRNA in brainstem of refed rats in comparison to food deprived or ad lib fed rats. Consistently, plasma leptin level was elevated in refed rats in comparison to food deprived rats. Similarly, leptin-treated rats exhibited a significant increase in Y4R mRNA in brainstem as compared to saline-injected rats. Plasma leptin was significantly elevated in leptin-treated rats. These results suggest that refeeding stimulates the expression of Y4R gene in the brainstem and that leptin may be one of the peripheral factors involved in this anorectic signaling mechanism.     

Cytology of desmoplastic medulloblastoma in imprint smears: a report of 2 cases

BACKGROUND: Desmoplastic medulloblastoma is a rare subtype of medulloblastoma with astroglial differentiation. The cytomorphologic features in intraoperative imprint smears from 2 cases of desmoplastic medulloblastoma are described. CASE REPORTS: A 22-year-old man and 27-year-old woman with a cerebellar tumor underwent craniotomy and tumor resection. The imprint cytologic smears contained cellular zones and nodular hypocellular areas containing astroglial and oligodendrogliallike elements. The cytology was misinterpreted as glial tumors, while the final histologic diagnosis in both cases were desmoplastic medulloblastoma. CONCLUSION: Desmoplastic medulloblastoma shows distinctive cytology in intraoperative smears. However, the occurrence of this rare type in adults and the presence of astroglial elements in imprint smears may cause a cytologic misinterpretation as gliomas.