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Anionic gels as vehicles for electrically-modulated drug delivery. I. Solvent and drug transport phenomena.

PURPOSE: The purpose of this study was to elucidate the in vitro behavior of anionic gels as formulation matrices for electrically-modulated drug delivery. Agarose and combinations of agarose with other anionic polymers (carbomer 934P; xanthan gum) were selected and tested to evaluate their potential for drug delivery. METHODS: Electrical current was applied by an automatic crossover power supply to minimize the current fluctuation. Hydrocortisone was selected as the model drug in order to minimize electrostatic interference with drug transport. Syneresis and drug migration were evaluated as a function of current application time and the intensity of electrical current. RESULTS: The data show that electrical current strength and gellant content can affect both the syneresis and drug migration. A linear correlation was found between hydrocortisone loss and mass loss via the exudate. Moreover, in agarose-carbomer 934P gel systems, cumulative gel mass loss is a linear function of time at low intensities of electrical current (e.g., 0.5 mA and 1 mA). However, hydrocortisone distribution, after electrical application, is relatively asymmetric in those agarose-carbomer 934P gels (and in agarose-xanthan gum gels) in contrast to gel matrices containing only agarose. CONCLUSIONS: In this study, the use of carbomer 934P in conjunction with agarose enables the formulator to achieve zero-order release with electrical application. Increased anisotropicity of a gel system due to the application of electrical current could alter the effectiveness of a drug delivery system.

Acrylic Resins↗

[Genetic analysis of the resistance of mouse somatic cells to colchicine].

The genetic nature of the resistance of mouse L cells to 0.06 microgram/ml of colchicine (the first step of selection) was studied. Fluctuation tests showed that the generation of drug-resistant variants in the wild type population was random and did not depend on the action of the selective agent. The rate of spontaneous occurrence of this variants was approximately 2 . 10(-5) per cell per generation. Colchicine resistance proved to be relatively unstable: it was 2--3-fold less in all clones propagated in non-selective conditions for 25--33 days. Two mutagens, ethylmethanesulphonate and N-nitroso-N-methylurea, failed to induce colchicine resistance in conditions when they enhanced the frequency of 8-azaguanine-resistant cells 10-fold.

Cell Survival↗

Long-term mortality patterns in Chinese history: evidence from a recorded clan population.

Human populations have lived on the earth for millions of years, yet the study of population history only began to be established in the mid-twentieth century. In spite of the considerable progress in the study of historical demography which has since been made, there have been hardly any detailed studies of fertility and mortality before the sixteenth century. This study, by analysing a set of Chinese genealogies, examines long-term mortality patterns in a selected clan population over a period of more than 1000 years. The result shows that, in this selected population, mortality fluctuated around a relatively high level and showed no secular change over the very long period studied. The study also provides a comparison between the mortality patterns found in the selected population and those observed in a much larger Chinese lineage population, as well as those recorded among the British elites born between the sixteenth and the early nineteenth century. Based on the findings of this research, the paper presents some tentative suggestions about long-term mortality changes in Chinese history.

China↗

Female preference for symmetrical males as a by-product of selection for mate recognition.

Fluctuating asymmetry (FA) refers to the random, stress-induced deviations from perfect symmetry that develop during the growth of bilaterally symmetrical traits. Individual differences in the level of FA may influence mate choice: in a number of species, females prefer to mate with males that have more symmetrical sexual ornaments. As the degree of FA has been shown to reflect the ability of individuals to cope with a wide variety of environmental stresses, it has been suggested that mating preferences for symmetry evolve for adaptive reasons, because the degree of FA provides honest information about male quality. Here I use simple, artificial neural networks to show that such preferences are likely to arise in the absence of any link between symmetry and quality, as a by-product of selection for mate recognition.

Animals↗

Eye movements, afterimages and monocular rivalry.

The eye-movement/afterimage theory of "monocular rivalry" (MR) between gratings was tested and strongly supported. In three experiments perceptual dominance of vertical or horizontal components of the pattern and fluctuations in perceived contrast of a single grating were shown to depend on the nature of the preceding shift in fixation position in the manner predicted by the theory. In a fourth experiment the angular selectivity of these fluctuations was eliminated, as predicted, when appropriate eye movements were made. Fixation-contingent fluctuations became equally strong for 15 degrees and 90 degrees angles. Taken together with data on afterimages, the results appear to resolve most of the problems recently raised against the theory.

Afterimage↗

Duration of hospitalization for bacteremic infections at Boston City Hospital during 12 selected years between 1935 and 1972.

In survivors of both community-acquired (CA) and hospital-acquired (HA) bacteremic infections at Boston City Hospital during 12 selected years between 1935 and 1972, the mean hospital stay fluctuated widely from one selected year to the next, but it was generally shorter and early discharges were more frequent in the years when effective antibacterial agents were used. The greatest reduction in hospital stay occurred by 1941. The size of the fluctuations and reductions also varied with the causative organism. The average duration of hospitalization of all survivors of HA bacteremic infections after the first positive blood culture was 10.5 days longer than the total hospitalization of survivors of CA infections. The reduced length of hospital stay after 1935 is attributed to the successful use of effective antibacterial drugs, and the greater effect in CA than in HA cases is attributed to more frequent infections in the latter with organisms resistant to those drugs.

Boston↗

Growth in high serum concentrations leads to rapid deadaptation of cells previously adapted to growth in an extremely low concentration of serum.

A subline of NIH 3T3 cells adapted to multiply in 0.25% calf serum (CS) by frequent passage (every 2-3 days) at low population density in 0.25% CS was deadapted by frequent successive passages of the cells in 10% CS for 3 weeks. The cells adapted to 0.25% CS multiplied with an average doubling time of 16.9 hr in 10% CS, and cells that had always been kept in 10% CS multiplied with an average doubling time of 14.6 hr, so there was weak selection for the latter in the higher serum concentration. When adapted cells were subjected to two passagers in 10% CS prior to assay of growth in 0.25% CS, a 4-day lag period was evident before commencement of exponential growth, and there was a decrease in saturation density. Further delay of growth in 0.25% CS developed as the number of passages of cells in 10% CS increased. The marked delay of growth in 0.25% CS of the bulk population after a few days in 10% CS argued against selection in 10% CS of rare nonadapted mutants from the adapted population and for an epigenetic origin of the change. Reconstruction experiments utilizing adapted cells mixed with non-adapted cells in 0.25% CS buttressed this explanation. Eight clones of the adapted population exhibited some loss of growth capacity in 0.25% CS after a single passage in 10% CS, though the extent of loss varied from clone to clone. The results support the idea that all cells in the adapted population respond to the lifting of growth constraints with loss of their growth potential under highly constrained conditions. They are consistent with the concept of progressive state selection in which selection operates on fluctuating metabolic states of individual cells rather than on genetic variants.

3T3 Cells↗

Fluctuating levels of serum IgA in individuals with selective IgA deficiency.

Monitoring of donors with selective IgA deficiency, i.e., with less than 0.5 mg IgA/l, led to the observation that serum IgA levels wer not constant. Small but significant fluctuations in IgA levels were noted (coefficient of variance: 143%) which were greater than the variability inherent in the testing methodology (coefficient of variance: 10%). These fluctuations created difficulties in terms of defining IgA-deficient blood products and had implications with respect to the mechanisms involved in IgA deficiency. With respect to supplying IgA-deficient blood products, in our experience a cutoff level of 0.5 mg/l should be the maximum permissible IgA concentration in order to ensure that no adverse reactions occur in individuals with class-specific anti-IgA.

Autoantibodies↗

Microhabitat selection in the simple oribatid community dwelling in epilithic moss cover (Acari: Oribatida).

The moss cover of a roof was studied as the model of a simple habitat divided into microhabitats by the members of a community of saprophagous mites. This community consisted of two species of oribatid mites: Scutovertex minutus and Trichoribates trimaculatus. They were extracted from moss onto moist paper, and subsequently, their mobility, responses to moisture fluctuation, and food selection were tested in laboratory experiments. For the nutritional biology, the microanatomy of their alimentary tract was examined according to the system of histological characteristics formulated in the laboratory of the author (type of food, digestive activity of gut walls, etc.). The paraplast sections of the mites were stained by Masson triple stain for these purposes. Moreover, the enzymological tests (chitinase and cellulase activities) were performed to detail the digestive processes. Such an approach was applied to field-sampled specimens as well as to those in the laboratory experiments. These above-mentioned data were discussed with respect to microhabitat selection, vertical and horizontal distribution, and dispersal ability of these two oribatid mites sharing this habitat. These two species differ in several characteristics from each other and these differences resulted in their different microhabitat choices and role in the habitat as a whole.

Acari↗

Fluctuations and vortex-pattern ordering in the fully frustrated XY model on a honeycomb lattice.

The accidental degeneracy of various ground states of a fully frustrated XY model with a honeycomb lattice is shown to survive even when the free energy of the harmonic fluctuations is taken into account. The reason for that consists in the existence of a hidden gauge symmetry between the Hamiltonians describing the harmonic fluctuations in all these ground states. A particular vortex pattern is selected only when anharmonic fluctuations are taken into account. However, the observation of vortex ordering requires relatively large system size L>>Lc > or approximately equal to 10(5).

Journal Article↗

Cranial variation in European populations: a spatial autocorrelation study at three time periods.

This study reports on spatial variation of 10 cranial variables in European populations at 3 time periods. Means for these variables, based on 137, 108, and 183 samples from the Early Medieval, Late Medieval, and Recent periods, were subjected to one-dimensional and directional spatial autocorrelation analyses. Significant spatial structure was found for most variables. It becomes more pronounced as time progresses. The spatial patterns are not strongly clinal. Correlograms based on distances computed from all variables are monotonic only to 900, 1,650, and 1,350 km for the three periods. Regional patterns are seen for most variables and become more structured and significant with time. There is little similarity among the correlograms of the variables at any one period and virtually none among periods. Inferences about spatial structure of these populations, based on spatial autocorrelation analysis, suggest a pattern dominated by migration, followed by expansion and admixture rather than selection or chance fluctuations. The patterns of morphometric change seem to reflect the patterns of linguistic change in these areas.

Cephalometry↗

Usefulness of fully automated constant ROI analysis software for the brain: 3DSRT and FineSRT.

The positioning or selection of a region of interest (ROI) is an essential step for the quantification of brain images. However, so long as the ROIs were manually selected, results obtained fluctuated considerably with subtle changes in their positioning. To perform an ROI analysis of the brain with improved objectivity and excellent reproducibility, we recently established fully automated ROI-based analysis software for the brain, the so-called 3DSRT and the FineSRT. 3DSRT performed by consecutive analyzing process as follows: (1) anatomical standardization using the SPM99 algorithm; (2) analysis using constant 318 ROIs divided into 12 groups (segments) on each hemisphere; (3) calculation of the area-weighted average for each of the respective 24 segments; (4) display of the results followed by the saving of respective values of the 636 ROIs (both hemispheres). The processes of the FineSRT were fundamentally similar to that of 3DSRT, but on FineSRT more precise constant 1394 ROIs (both hemispheres) corresponding to the respective cerebral convolutions were used. Our programs have been useful for objective estimation of cerebrovascular reserve, especially for follow-up studies of an infant with moyamoya disease, because we could compare the results without consideration of the patient's growth during the follow-up period.

Brain↗

Within-farm variability in age structure of breeding-female pigs and reproductive performance on commercial swine breeding farms.

This study investigated relationships between herd age structure and herd productivity in breeding herds; it also investigated a pattern in parity proportions of females over 2 years and its relationship with herd productivity in commercial swine herds. This study was based on data from 148 commercial farms in North America stored in the swine database program at the University of Minnesota. The primary selection criterion was fluctuations in breeding-female pig (female) inventories over a 2-year interval. Productivity measurements and parity proportions of females were extracted from the database. A 24-month time-plot in proportions of Parity 0 and Parities 3-5 females (mid-parity) was charted for each farm. Using these charts, a change in proportions of Parity 0 and mid-parity for each farm was categorized into patterns: FLUCTUATE (Parity 0 and mid-parity proportion lines crossed) or STABLE (the two proportion lines never crossed). Higher proportions of mid-parity sows were correlated with greater pigs weaned per female per year (PWFY; P < 0.01). Farms with a FLUCTUATE (73% of the 148 farms) pattern had lower PWFY than those with a STABLE pattern (P < 0.01). The STABLE farms had higher proportions of mid-parity sows, higher parity at culling, higher frequency of gilt deliveries per year, and lower replacement rate than the FLUCTUATE farms (P < 0.01). In conclusion, maintaining stable subpopulations with mid-parity and Parity 0 are recommended to optimize herd productivity.

Aging↗

Females competing to reproduce: dominance matters but testosterone may not.

The associations among aggression, testosterone (T), and reproductive success have been well studied, particularly in male birds. In many species, males challenged with simulated or real territorial intrusions increase T and levels of aggression, outcomes linked to higher dominance status and greater reproductive success. For females, the patterns are less clear. Females behave aggressively towards one another, and in some species, females respond to a social challenge with increases in T, but in other species they do not. Prior work on female dark-eyed juncos (Junco hyemalis) had shown that experimental elevation of T increases social status and intrasexual aggression. Here, we conducted two experiments designed to answer three questions: Are endogenous concentrations of T associated with dominance status in captive female juncos? Does dominance status influence readiness to breed in female juncos? And do captive females increase T in response to a challenge? In the first experiment, we introduced two females to a breeding aviary, allowed them to form a dominance relationship and then introduced a male. We found that dominant females were more likely to breed than subordinates, but that dominance status was not predicted by circulating T. In the second experiment, we allowed a resident male and female to establish ownership of a breeding aviary (territory) then introduced a second, intruder female. We found that resident females were aggressive towards and dominant over intruders, but T did not increase during aggressive interactions. We suggest that during the breeding season, intrasexual aggression between females may influence reproductive success, but not be dependent upon fluctuations in T. Selection may have favored independence of aggression from T because high concentrations of T could interfere with normal ovulation or produce detrimental maternal effects.

Aggression↗

Analyzing gene-frequency data when the effective population size is finite.

The statistical methods used by SCHAFFER, YARDLEY and ANDERSON (1977) and by GIBSON et al. (1979) to analyze the variation in allele frequencies in two common types of experimental procedure, where the effective population size is finite, are extended to a more general situation involving a greater range of experiments. The analysis developed is more sensitive in detecting changes in allele frequency due to both fluctuating and balancing selection, as well as to directional selection. The error involved in many studies due to ignoring the effective population size structure would appear to be large. The range of hypothesis that can be considered may be increased as well. Finally, the method of determining bounds for the effective population size, when a particular genetic model is known to hold for a data set, is also outlined.

Alleles↗

Suppression of modes in the random phase approximation.

A general but simple method is proposed to eliminate the quantum fluctuations generated by selected one-body operators in the excitation spectrum of a discrete random phase approximation (RPA) Hamiltonian. This method provides an outstanding tool for the removal of the contaminating spurious effects originated from symmetry violations. It can be also applied as a mode filter for analyzing RPA response functions.

Journal Article↗

Reduction by general anaesthetics of group Ia excitatory postsynaptic potentials and currents in the cat spinal cord.

1. The effects of thiopentone and halothane on excitatory synaptic transmission at group Ia afferent synapses on lumbosacral motoneurones were studied in the anaesthetized or decerebrate cat. 2. Thiopentone (10 mg kg-1) infused on a background of light pentobarbitone anaesthesia caused a decrease in single-fibre monosynaptic group Ia excitatory postsynaptic potentials (EPSPs) of between 0 and 24%. A step increase in inspired halothane concentration in the range 0.7-0.9% produced a decrease in EPSP amplitude of between 0 and 31%. These effects were reversible when the anaesthetic level was reduced. 3. Fluctuation analysis of selected single-fibre group Ia EPSPs revealed that these effects could be accounted for by a decrease in the probability of occurrence of EPSPs of larger amplitude, and an increase in the probability of occurrence of EPSPs of smaller amplitude. The mean separation between discrete amplitudes was not altered by either anaesthetic agent. 4. EPSPs whose time course indicated a somatic site of origin were voltage clamped to study the effect of the anaesthetics on the time course of the synaptic currents. Neither thiopentone nor halothane produced a consistent effect on the time constant of decay of the current, although they both depressed its peak amplitude. 5. The results are interpreted as indicating a presynaptic site of action of both anaesthetics at the concentrations studied: the probability of release of neurotransmitter is reduced, without any detectable change in the mean duration of the postsynaptic conductance increase. These findings are discussed in relation to the mechanisms of action of anaesthetics on exocytosis and presynaptic inhibition.

Animals↗

Synapses in the fly motion-vision pathway: evidence for a broad range of signal amplitudes and dynamics.

Synapses are generally considered to operate efficiently only when their signaling range matches the spectrum of prevailing presynaptic signals in terms of both amplitudes and dynamics. However, the prerequisites for optimally matching the signaling ranges may differ between spike-mediated and graded synaptic transmission. This poses a problem for synapses that convey both graded and spike signals at the same time. We addressed this issue by tracing transmission systematically in vivo in the blowfly's visual-motion pathway by recording from single neurons that receive mixed potential signals consisting of rather slow graded fluctuations superimposed with highly variable spikes from a small number of presynaptic elements. Both pre- and postsynaptic neurons were previously shown to represent preferred-direction motion velocity reliably and linearly at low fluctuation frequencies. To selectively assess the performance of individual synapses and to precisely control presynaptic signals, we voltage clamped one of the presynaptic neurons. Results showed that synapses can effectively convey signals over a much larger amplitude and frequency range than is normally used during graded transmission of visual signals. An explanation for this unexpected finding might lie in the transmission of the spike component that reaches larger amplitudes and contains higher frequencies than graded signals.

Animals↗