Amifostine (WR-2721) shortens the engraftment period of 4-hydroperoxycyclophosphamide-purged bone marrow in breast cancer patients receiving high-dose chemotherapy with autologous bone marrow support

4-Hydroperoxycyclophosphamide (4-HC), a commonly used marrow-purging agent, is active against many tumors, but is also toxic to normal marrow progenitors. Amifostine (WR-2721) is a sulfhydryl compound with chemoprotectant activity. Preclinical studies using suspensions of bone marrow and breast cancer cells demonstrated that ex vivo treatment with amifostine followed by 4-HC resulted in protection of marrow progenitors, with no compromise in the antitumor effect of 4-HC. This fact stimulated the development of a clinical trial. Bone marrow was harvested from 15 poor-prognosis breast cancer patients and randomly assigned to ex vivo treatment with amifostine followed by 4-HC (amifostine + 4-HC), or treatment with 4-HC alone. High-dose chemotherapy was then administered followed by infusion of the purged autologous bone marrow support (ABMS). Leukocyte engraftment, defined as a white blood cell count > or = 1 x 10(9)/L, was achieved in an average of 26 days for patients whose marrow was purged with amifostine + 4-HC versus 36 days for patients whose marrow was purged with 4-HC alone (P = .032). The average number of platelet transfusions (12 v 29; P = .017) and days of antibiotic therapy (28 v 40; P = .012) were significantly less for patients whose marrow was exposed to amifostine + 4-HC, compared with 4-HC alone. Unpurged backup marrow fractions were infused into three patients whose marrow was purged with 4-HC alone, because of inadequate marrow recovery. None of the patients who received amifostine + 4-HC-purged marrow required a backup marrow fraction. Complete remissions were achieved in 83% of patients with measurable disease, with no difference between the two cohorts. Forty-three percent of patients remained alive and progression-free at a mean of 13 months posttransplant. There was no significant difference in the rate or pattern of relapse for patients whose marrow was purged with amifostine + 4-HC compared with those whose marrow was purged with 4-HC alone. Ex vivo treatment of marrow with amifostine significantly shortens the time to marrow recovery, thereby reducing the risk of myelosuppressive complications in breast cancer patients receiving high-dose chemotherapy and 4-HC-purged ABMS. Since supportive care requirements are also significantly decreased, amifostine may reduce the cost of such therapy.     

A stability criterion for asynchronous multirate linear systems

A stability criterion is developed for linear, asynchronous multirate sampled-data systems. Such systems typically include a linear, time variant, continuous-time plant and several unsynchronized digital controllers. The analysis method uses a time-domain approach based on the closed-loop state transition matrix. The result is sufficient stability criterion which gives an objective measure of long-term and short-term stability. A simple example illustrates the method     

Fade duration analysis on earth-space paths at Ku-band in Fukuoka, Japan

Presented are the fade duration dynamics as observed in four close stations. Fade duration statistics derived from the collected received signal during a critical period in the region are presented and analysed. The obtained results are compared with the model release by the ITU-R P.1623 recommendation. Some modifications are then proposed.     

Plasma and blood lead concentrations, lead absorption, and lead excretion in nonhuman primates

The effects of pH, temperature, block of energy production, calcium/calmodulin, protein phosphorylation, and cytoskeleton-disrupting agents (cytochalasin D, nocodazole) on the integrity of the membrane skeleton were studied in polarized MDCK cells. The intracellular distributions of alpha-fodrin, actin, and ankyrin were monitored by immunofluorescence microscopy. The membrane skeleton, once assembled, seemed to be quite stable; the only factors releasing alpha-fodrin from the lateral walls were the acidification of the cytoplasm and the depletion of extracellular calcium ions. Upon cellular acidification, some actin was also released from its normal location along the lateral walls and was seen in colocalization with alpha-fodrin in the cytoplasm, whereas ankyrin remained associated with the lateral walls. No accumulation of plasma membrane lipids was observed in the cytoplasm of acidified cells, as visualized by TMA-DPH. These results suggest that the linkages between the fodrin-actin complex and its membrane association sites are broken upon acidification. The pH-induced change in alpha-fodrin localization was reversible upon restoring the normal pH. Reassembly of the membrane skeleton, however, required temperatures above +20 degrees C, normal energy production, proper cell-cell contacts, and polymerized actin. Release of alpha-fodrin from the lateral walls to the cytoplasm was also observed upon depletion of extracellular calcium ions. This change was accompanied by the disruption of cell-cell contacts, supporting the role of proper cell-cell contacts in the maintenance of the membrane skeleton polarity. These results suggest that local alterations of the cytoplasmic pH and calcium ion concentration may be important in regulating the integrity of the membrane skeleton.     

Formulation design,in vitro characterizations and anti-malarial investigations of artemether and lumefantrine-entrapped solid lipid microparticles

Context: Poor aqueous solubility of artemether and lumefantrine makes it important to seek better ways of enhancing their oral delivery and bioavailability.

Objective: To formulate and carry out in vitro and anti-malarial pharmacodynamic evaluations of solidified reverse micellar solutions (SRMS)-based solid lipid microparticles (SLMs) of artemether and lumefantrine for oral delivery and improved bioavailability.

Materials and methods: Rational blends of Softisan^®154 and Phospholipon^®90H lipid matrices, and different concentrations of artemether and lumefantrine were used to formulate several batches of SLMs. Drug-free SLMs were also formulated. Morphology, particle size, encapsulation efficiency (EE%) and pH studies were performed. In vitro release studies were performed in alcoholic buffer, simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) without enzymes. Anti-malarial pharmacodynamic studies were conducted in mice.

Results: Stable, smooth and spherical particles with sizes ranging from 4.2?±?0.02 to 9.3?±?0.8?µm were formed. EE% of 92.2–97.3% and 30.2–84.7% and pH of 3.0?±?0.02 to 4.9?±?0.12 and 3.0?±?0.02 to 5.8?±?0.05 were obtained for artemether and lumefantrine SLMs, respectively. Release of 100, 88.28 and 75.49%, as well as 63.26, 34.31 and 56.17% were recorded for artemether and lumefantrine in alcoholic buffer, SGF and SIF, respectively. Pharmacodynamic studies indicated very significant (p?Conclusion: Oral delivery and bioavailability of artemether and lumefantrine could be improved using SRMS-based SLMs.     

Age differences in identifying words in synthetic speech

OBJECTIVES: We investigated whether context or different speech rates could improve older adult performance on identification of synthetically generated words. BACKGROUND: Synthetic speech systems can potentially improve the daily functioning of older adults. However, research must determine whether older adults can effectively implement current text-to-speech technologies, which few studies have examined. Older adults' sensory and cognitive declines may cause difficulties in identifying words in synthetic speech. METHODS: Ninety-six participants (young, middle-aged, and older adults) identified auditory monosyllabic words (half natural, half synthetic) presented in isolation or at the ends of sentences. Participants heard speech at either normal or slower rates. RESULTS: We found an interaction of age, context, and voice type and that slower speech rates worsened performance for all groups. Contrasts revealed that context reduced age differences, though only for natural speech. Hearing acuity was highly correlated with age and fully accounts for the interaction. CONCLUSIONS: Context improves performance for everyone in natural speech. However, whereas context improves performance for synthetic speech, it does not differentially reduce the age impairment for older adults. Slower speed generally impairs everyone's performance compared with the normal rate. APPLICATIONS: Systems using synthetic speech should avoid presenting words in isolation, and rich contextual support should be consistently adopted. Synthetic speech fidelity must be improved significantly before becoming truly useful for older adult populations.     

Symbolic connectionism in natural language disambiguation

Natural language understanding involves the simultaneous consideration of a large number of different sources of information. Traditional methods employed in language analysis have focused on developing powerful formalisms to represent syntactic or semantic structures along with rules for transforming language into these formalisms. However, they make use of only small subsets of knowledge. This article describes how to use the whole range of information through a neurosymbolic architecture which is a hybridization of a symbolic network and subsymbol vectors generated from a connectionist network. Besides initializing the symbolic network with prior knowledge, the subsymbol vectors are used to enhance the system's capability in disambiguation and provide flexibility in sentence understanding. The model captures a diversity of information including word associations, syntactic restrictions, case-role expectations, semantic rules and context. It attains highly interactive processing by representing knowledge in an associative network on which actual semantic inferences are performed. An integrated use of previously analyzed sentences in understanding is another important feature of our model. The model dynamically selects one hypothesis among multiple hypotheses. This notion is supported by three simulations which show the degree of disambiguation relies both on the amount of linguistic rules and the semantic-associative information available to support the inference processes in natural language understanding. Unlike many similar systems, our hybrid system is more sophisticated in tackling language disambiguation problems by using linguistic clues from disparate sources as well as modeling context effects into the sentence analysis. It is potentially more powerful than any systems relying on one processing paradigm