Mast cell activation is not required for induction of airway hyperresponsiveness by ozone in mice

Exposure to ambient ozone (O3) is associated with increased exacerbations of asthma. We sought to determine whether mast cell degranulation is induced by in vivo exposure to O3 in mice and whether mast cells play an essential role in the development of pulmonary pathophysiological alterations induced by O3. For this we exposed mast cell-deficient WBB6F1-kitW/kitW-v (kitW/kitW-v) mice and the congenic normal WBB6F1 (+/+) mice to air or to 1 or 3 parts/million O3 for 4 h and studied them at different intervals from 4 to 72 h later. We found evidence of O3-induced cutaneous, as well as bronchial, mast cell degranulation. Polymorphonuclear cell influx into the pulmonary parenchyma was observed after exposure to 1 part/milllion O3 only in mice that possessed mast cells. Airway hyperresponsiveness to intravenous methacholine measured in vivo under pentobarbital anesthesia was observed in both kitW/kitW-v and +/+ mice after exposure to O3. Thus, although mast cells are activated in vivo by O3 and participate in O3-induced polymorphonuclear cell infiltration into the pulmonary parenchyma, they do not participate detectably in the development of O3-induced airway hyperresponsiveness in mice.     

Use of computerized information systems in U.S. health maintenance organizations and hospitals

A comparison was made between the use of data processing in hospitals and Health Maintenance Organizations (HMOs). Findings indicate that the HMO and hospital data processing markets are currently quite distinct. As expected, the functions automated reflect the uses of the different care delivery systems. The hardware and software vendors to these markets are also different. A high percentage (50%) of HMOs are using software they developed in-house. In this respect, current HMO data processing is similar to the hospitals of a decade ago. The hospital market (for hardware and total systems) is highly concentrated. A few firms have a combined market share of over 50% and there are a large number of firms with very small shares. In the HMO market, there is a high concentration ratio for hardware but not for software or systems. HMOs and hospitals are almost uniformly satisfied with their hardware. Satisfaction with most applications is between 80 and 90% but there is a need, at least within HMOs, for improvements in support of the software supplied.     

Design of an IV Formulation of an Unstable Prodrug Candidate for Prostate Cancer Treatment: Solution Chemistry of N-(glutaryl-hyp-ala-ser-cyclohexylglycyl-gln-ser-leu)-doxorubicin

ABSTRACT

The chemical degradation of N-(glutaryl-hyp-ala-ser-cyclohexylglycyl-gln-ser-leu)-doxorubicin (henceforth referred to as doxorubicin peptide conjugate 1) was studied in buffered aqueous solution. The pH-rate profile of degradation shows that the doxorubicin conjugate is most stable between pH 5 and 6. The dependence of log k_obsd on pH in acidic medium is characteristic of specific acid-catalysis of the sugar hemiaminal of 1 (as in the case of doxorubicin). Isolation of degradates and structural determination shows that the degradation at lower pH values yields the water-insoluble aglycone doxorubicinone, supporting the mechanism of acid-catalyzed loss of the amino sugar. At pH higher than 5, a more complicated degradation pattern is observed, including the loss of the amino sugar and the aromatization of the saturated ring to give 7,8-dehydro-9,10-desacetyldoxorubicinone as one of the major products. Around the pH of maximum stability in solution, the rate of degradation of 1 is significantly greater than that for doxorubicin, which rules out the formulation of a room temperature solution product with a sufficiently long shelflife for market use. Design of a stable lyophilized formulation for sterile reconstitution based on the physicochemical properties of 1 is described.     

Low‐power,low‐noise,active‐RC band‐pass filters using a ‘lossy’ LP–BP transformation

A new and straightforward design procedure for simple canonical topologies of allpole, active‐RC, low‐selectivity band‐pass (BP) filters, with low sensitivity to component tolerances is presented. The procedure is primarily intended for discrete‐component, low‐power filter applications using just one amplifier for relatively high‐order filters. The design procedure starts out with an ‘optimized’ low‐pass (LP) prototype filter, yielding an ‘optimized’ BP filter, whereby the wealth of ‘optimized’ single‐amplifier LP filter designs can be exploited. Using a so‐called ‘lossy’ LP–BP transformation, closed‐form design equations for the design of second‐ to eighth‐order, single‐amplifier BP filters are presented. The low sensitivity, low power consumption, and low noise features of the resulting circuits, as well as the influence of the finite gain‐bandwidth product and component spread, are demonstrated for the case of a fourth‐order filter example. The optimized single‐opamp fourth‐order filter is compared with other designs, such as the cascade of optimized Biquads. Using PSpice with a TL081 opamp model, the filter performance is simulated and the results compared and verified with measurements of a discrete‐component breadboard filter using 1% resistors, 1% capacitors, and a TL081 opamp. Copyright © 2011 John Wiley & Sons, Ltd.     

Development of Subcutaneous and Intramuscular Formulations of Calcium Alendronate Salts

Poorly soluble calcium-alendronate salts were prepared and investigated as potential candidates for subcutaneous or intramuscular formulations. Three such formulations containing calcium-alendronate salts with different stoichiometries were developed for testing in safety, disposition and efficacy studies in animals. All formulations demonstrated a drastic reduction in pain on injection and tissue damaging propensity compared to the soluble salts of ABP. All three were efficacious and showed prolonged absorption from the injection site with the deposition of a large percentage of the dose into the bone. Complex formation between alendronate and calcium was also studied.     

Minimum sensitivity coupled resonators and biquads

The effect of coupling on the overall sensitivity to component tolerances of two second-order resonators is compared with the sensitivity of a non-coupled cascade of two second-order resonators. Coupled resonators consist of two second-order resonators “coupled” within a negative feedback loop. The resulting overall fourth-order transfer function of the two circuits, coupled and non-coupled, is identical. The “cascaded” poles, ie, the poles of the two cascaded resonators, are therefore identical to the poles of the coupled circuit, the coupled poles. The poles within the negative-feedback loop, the “open-loop” poles, will be different. We assume that the manufacturing technology used to realize the open-loop poles of the coupled circuit is the same as that of the cascaded, non-coupled circuit. The open-loop poles will therefore be subject to the same component tolerances as those of the cascaded non-coupled circuit. Our analysis leads to the optimum location in the s-plane with regard to minimum sensitivity, for the open-loop poles of the coupled circuit. Since resonators are essentially the equivalent of second-order bandpass filters, the results obtained are applied to coupled second-order active-RC filters, or biquads, for which insensitivity to component tolerances is critical. The examples given pertain to the coupling of biquads.