Chitosan as a nasal delivery system: the effect of chitosan solutions on in vitro and in vivo mucociliary transport rates in human turbinates and volunteers

In these studies, we examined the effect on mucociliary transport rates (MTR) of various 0.25% (w/v) chitosan solutions applied to human nasal tissue both ex vivo and in vivo. In the first study a range of chitosans with different molecular weights were applied to freshly amputated human nasal turbinates, and their effect on MTR was recorded. The transient inhibitory effect on turbinate MTR that was found for most of the chitosan preparations showed a marked dependence on the volume of chitosan solution applied and the molecular weight of the chitosan tested. The higher the molecular weight of the chitosan and the more chitosan applied, the longer the original MTR was depressed. A small scale human trial, investigating the effect of chitosan glutamate, on saccharin clearance times, was also undertaken. The study showed that a once daily application of a 0.25% solution of the chitosan for 7 days had no effect on either saccharin clearance times or nasal histology as examined by light microscopy.     

Co-grafted embryonic striatum increases the survival of grafted embryonic dopamine neurons

To enhance the current therapeutic benefit of dopamine (DA) neuron grafts in Parkinson's disease, strategies must be developed that increase both DA neuron survival and fiber outgrowth into the denervated striatum. Previous work in our laboratory has demonstrated that dopaminergic neurons grow to greater size when co-grafted with striatal cell suspensions and display extensive tyrosine hydroxylase-positive (TH+) projections, but no conclusion could be reached concerning enhancement of survival of grafted DA neurons. The aim of the present study was to characterize further the potential trophic effects of striatal co-grafts on grafted mesencephalic DA neuron survival. Unilaterally lesioned male Fischer 344 rats were grafted with either a suspension of mesencephalic cells or with both mesencephalic and striatal cell suspensions. Co-grafts were either mixed together or placed separately into the striatum. Lesioned rats receiving no graft served as controls. Rotational behavior was assessed following amphetamine challenge at 2 weeks prior to grafting and at 4 and 8 weeks following grafting. Only rats receiving co-grafts of nigral and striatal suspensions separated by a distance of 1 mm showed significant behavioral recovery from baseline rotational asymmetry. Both mixed and separate striatal co-grafts were associated with a doubling of DA neuron survival compared with solo mesencephalic grafts. In the mixed co-graft experiment, DA neurite branching appeared enhanced and TH-rich patches were observed, whereas with co-grafts that were separated, TH+ innervation of the intervening host striatum was increased significantly. These results provide the first evidence suggesting that nigral-striatal co-grafts, particularly those placed separately and in proximity to each other, increase both DA neuron survival and neurite extension from the mesencephalic component of the grafts.     

Effects of simulated microgravity on closed-loop cardiovascular regulation and orthostatic intolerance: analysis by means of system identification

Microgravity-induced orthostatic intolerance (OI) continues to be a primary concern for the human space program. To test the hypothesis that exposure to simulated microgravity significantly alters autonomic nervous control and, thus, contributes to increased incidence of OI, we employed the cardiovascular system identification (CSI) technique to evaluate quantitatively parasympathetic and sympathetic regulation of heart rate (HR). The CSI method analyzes second-to-second fluctuations in noninvasively measured HR, arterial blood pressure, and instantaneous lung volume. The coupling mechanisms between these signals are characterized by using a closed-loop model. Parameters reflecting parasympathetic and sympathetic responsiveness with regard to HR regulation can be extracted from the identified coupling mechanisms. We analyzed data collected from 29 human subjects before and after 16 days of head-down-tilt bed rest (simulated microgravity). Statistical analyses showed that parasympathetic and sympathetic responsiveness was impaired by bed rest. A lower sympathetic responsiveness and a higher parasympathetic responsiveness measured before bed rest identified individuals at greater risk of OI before and after bed rest. We propose an algorithm to predict OI after bed rest from measures obtained before bed rest.     

Intraspecific heterochrony and life history evolution: decoupling somatic and sexual development in a facultatively paedomorphic salamander

Morphological features such as size and shape are the most common focus in studies of heterochronic change. Frequently, these easily observed and measured features are treated as a major target of selection, potentially ignoring traits more closely related to fitness. We question the primacy of morphological data in studies of heterochrony, and instead suggest that principal sources of fitness, such as life history characteristics, are not only the chief targets of selection, but changes in them may necessitate changes in other (subordinate) elements of the organism. We use an experimental approach to investigate the timing of metamorphosis and maturation in a facultatively paedomorphic salamander, Ambystoma talpoideum. We determine that individuals possessing the well-known paedomorphic phenotype are peramorphic with regard to maturation, through the process of predisplacement (an earlier onset of maturation). Combining the well studied ecology of dimorphic A. talpoideum populations with theories of heterochronic mechanisms and life history evolution, we conclude that age at maturation is the principal target of selection and that morphological changes are secondary effects. Increased attention to the intimate connection between life history evolution and heterochrony is the most promising route to a better understanding of both.     

Airways responses to oral ethanol in normal subjects and in patients with asthma

The effect of oral ethanol on airflow was studied in 5 normal subjects and 5 patients with asthma. On 4 different study days, each subject was asked to drink 40 ml of either water or 20%, 40% or 60% ethanol, and measurements were made of specific airways conductance (sGaw), blood ethanol levels, pulse rate and blood pressure. In some subjects in both groups there was a significant immediate fall in sGaw after drinking ethanol (below 5% confidence limits). Once absorbed, ethanol had a slight bronchodilator effect in 2 normal subjects and in 3 patients with asthma (5% level). Sixty per cent ethanol, when drunk slowly, showed significant bronchodilatation in 4 out of 5 patients with asthma and in one normal subject (5% level) with no acute fall in sGaw. Pulse rate and blood pressure did not change after water, 20% and 40% ethanol in either group, but immediately after 60% ethanol normal subjects showed a significant rise in pulse rate (P less than 0.01) which was not seen in patients with asthma. The immediate changes in sGaw and pulse rate may be due to stimulation of irritant receptors in the upper airways. Ethanol may act directly on bronchial smooth muscle to produce bronchodilatation and may be useful as a bronchodilator when given intravenously.     

Amino acid metabolism of myeloma cells in culture

The growth of myeloma cells in Leibovitz medium supplemented with 20% serum was limited by the depletion of glutamine. A simple modification of the Leibovitz medium by increasing the concentrations of glutamine, lysine, isoleucine, leucine, sodium pyruvate, galactose, and vitamins resulted in over 100% increase in cell growth yield. The total myeloma protein produced by the cells was increased by approximately 90% in modified Leibovitz media. Analysis of spent culture media for 19 amino acids showed that the concentrations of 8 amino acids were reduced; those of 5 amino acids were increased and the other 6 did not change significantly.     

Effect of cross-linking on the secondary structure of DNA I. Cross-linking by photodimerization

An investigation has been made into the effect produced by photo-induced pyrimidine cross-links upon the secondary structure of DNA. We have studied the effect of uv irradiation upon the B in equilibrium A transition in DNA brought about by a change of solvent from 70 to 80% ethanol. Circular dichroism (CD) was used to monitor the conformational changes. However, we first showed by means of laser Raman spectroscopy that CD is a reliable monitor of the conformational change, even though the DNA is aggregated in 80% alcohol solutions. It is suggested that this aggregation stabilizes the A form through lateral interaction between the helices. The uv irradiation experiments show that pyrimidine-dimer cross-links induced into the B-form DNA will lock it irreversibly into that conformation and prevent it from going to the A form in 80% EtOH solution. The A-form DNA can tolerate a few cross-links but converts cooperatively to the B form if a larger number of cross-links is introduced. Irradiation-induced pyrimidine cross-links create locally denatured regions in B-form DNA. Upon continued irradiation, the entire DNA moelcule becomes denatured.     

Circulating dopamine-beta-hydroxylase (DbetaH) and catecholamines in a paediatric phaeochromocytoma

Nasal airways resistance was measured in ten patients with allergic rhinitis during intranasal application of an extract of grass pollen. Pretreatment with placebo did not inhibit the increase in nasal airways resistance, whereas ICI 74,917 administered from a pressurized aerosol gave almost complete protection. ICI 74,917 was well tolerated and no evidence was obtained of local hyposensitization during the period of the study.