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PubMed1988

Subcutaneous administration of lisuride in the treatment of complex motor fluctuations in Parkinson's disease.

28 patients with Parkinson's disease showing complex "on-off" fluctuations in response to chronic levodopa plus dopa decarboxylase inhibitor (po) were treated with subcutaneous lisuride using a portable infusion pump. All patients improved initially during the first weeks of treatment. Four patients abandoned the trial within the first few weeks as a consequence of psychiatric complications (2 cases), inability to understand how to use the pump (one case) and subcutaneous nodule formation plus psychological rejections to wearing a pump (one case). All other 24 patients were treated for a minimum periods of 3 months (mean 9.6 months, maximum 24 months). The average daily dose of lisuride was 2.80 mg. The levodopa dose was reduced by 37%, but total withdrawal was not possible in any patient. Among the 18 patients who continued treatment at present, about 50% are independent and capable of undertaking most daily life activities. Psychiatric side-effects were present in 9 patients leading to permanent withdrawal in five. Subcutaneous lisuride infusions added to oral levodopa are clearly effective in patients with severe motor fluctuations. Careful selection of suitable patients and close monitoring is mandatory in order to obtain the best therapeutic results while reducing the risk of psychiatric adverse effects.

Drug Eruptions↗
PubMed1980

Convergence to genetically uniform state in stepping stone models of population genetics.

We investigate continuous time stepping stone model. Extending the models treated in population genetics, we consider the system described by the following infinite dimensional stochastic differential equation, (see text in formula) which contains the effects of random sampling drift and a kind of stochastic fluctuation in selection. We obtain a necessary and sufficient condition for the system to converge to a genetically uniform state.

Animals↗
PubMed1985

Confidence limits for homology in protein or gene sequences. The c-myc oncogene and adenovirus E1a protein.

We describe new tests, of general application, for deciding whether two proteins or DNA sequences are significantly homologous, in cases where the relationship is neither evidently true nor evidently false. Ralston and Bishop's comparison of the c-myc oncogene with the adenovirus E1a protein is discussed as an example. When the comparison matrix test is used to establish a homology between two sequences it is necessary that the number of high scores exceeds the expected mean level for random sequences by a statistically significant margin. The mean level itself is found from the double matching probability distribution. In examples where the number of high scores is larger than expected, but the highest score is not in itself exceptional, the variance of the numbers of scores expected for unrelated sequences is an important factor. We have analysed these variances by several methods. A simple binomial distribution gives only a rather inaccurate and low first estimate, but we derive a more rigorous and accurate statistical treatment, to take account of the correlations between scores in different parts of the comparison matrix. The theory is exact for random DNA or protein sequences with fluctuating compositions, selected by random draws from an infinite pool. In the more realistic situation, where sequences of fixed composition are formed by random permutations of the original sets, the deviations are smaller, and have been analysed by computer simulation. We find that although the relationship proposed by Ralston & Bishop, between the c-myc oncogene and adenovirus E1a proteins, appears to be significant in the binomial approximation, it is not supported by the full analysis. We conclude that, in general, great care is needed to establish any weak homology on the basis of comparisons that include no truly exceptional high scores, but merely have an enhanced number of scores at the upper end of the expected distribution.

Adenoviridae↗
PubMed1982

Tunicamycin-resistant mutations in mouse FM3A cells.

Tunicamycin is an antibiotic that inhibits the oligosaccharide synthesis of glycoproteins. It greatly suppressed the growth of cultured mouse mammary carcinoma FM3A cells, when added to growth medium at concentrations of more than 0.1 microgram/ml. We have developed a single-step selection system for quantitatively detecting mutations resistant to the antibiotic in FM3A cells. Mutant colonies resistant to 1-1.2 micrograms tunicamycin per ml (the optimal concentration of the selecting agent) appeared at a frequency of 10(-4) to 10(-5) in an unmutagenized population, but they increased over 50-fold in the population mutagenized with 0.5 microgram N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) per ml for 2 h and selected under optimal conditions for the time of mutation expression and cell density in selective medium. Fluctuation analysis, by the method of Luria and Delbrück, revealed that tunicamycin-resistant mutations occurred at random during proliferation in normal medium at a rate of 1.2 x 10(-6) per cell per generation. So far 45 spontaneous and MNNG-induced mutant lines have been isolated and serially passaged in the absence of tunicamycin. These mutant lines all inherited their resistance for more than 60 generations. The mutants examined in detail were 12- to 26-fold more resistant than wild-type cells in terms of the D10 value, the concentration of tunicamycin reducing the plating efficiency to 10% of the control. In the hybrids between wild-type and mutant cells the tunicamycin resistance behaved in a co-dominant manner. Tunicamycin inhibited the incorporation of [3H]mannose into the acid-insoluble cell fraction; in this respect, mutant cells were over 30-fold more resistant than wild-type cells. Possible mechanisms of tunicamycin resistance are discussed.

Animals↗
PubMed1993

A double-blind study of the efficacy of apomorphine and its assessment in 'off'-periods in Parkinson's disease.

Five patients with idiopathic Parkinson's disease with severe response fluctuations were selected for a randomized double-blind placebo-controlled study, concerning the clinical effects of subcutaneous apomorphine and its assessment in 'off'-periods. The study was designed as five n = 1 studies, in which every patient was his own control. The effect of apomorphine was studied by using the Columbia rating scale and quantitative assessments, using tapping, walking and pinboard. There was a significant positive effect of apomorphine, in a mean optimal dose of 2.7 mg, with a mean latency of onset of 7.3 min and a mean duration of response of 96 min. After pretreatment with domperidone, no significant adverse effects were observed. Tapping showed the highest correlation with rigidity and bradykinesia. Walking showed a high correlation with stability and gait. Pinboard testing did not give additional information. The first conclusion was that apomorphine proved to be a significantly effective dopamine agonist, proven now also by a double blind placebo-controlled study. Secondly it was concluded that assessment of clinical effect in parkinsonian patients can be performed best by combining the Columbia item tremor with tapping and walking scores.

Adult↗
PubMed2001

Context-dependent genetic benefits from mate choice.

Adaptive mate preferences are generally assumed to be static and open-ended, favouring the most extreme expression of display traits. In contrast to this view, three new studies show that genetic benefits from mate choice can be context-dependent. Thus, there might be short-term fluctuations in selection on mate preferences. The crucial question then is, are plastic mate preferences an optimal evolutionary outcome?

Journal Article↗
PubMed2006

Exploring the chemical enhancement for surface-enhanced Raman scattering with Au bowtie nanoantennas.

Single metallic bowtie nanoantennas provide a controllable environment for surface-enhanced Raman scattering (SERS) of adsorbed molecules. Bowties have experimentally measured electromagnetic enhancements, enabling estimation of chemical enhancement for both the bulk and the few-molecule regime. Strong fluctuations of selected Raman lines imply that a small number of p-mercaptoaniline molecules on a single bowtie show chemical enhancement >10(7), much larger than previously believed, likely due to charge transfer between the Au surface and the molecule. This chemical sensitivity of SERS has significant implications for ultra-sensitive detection of single molecules.

Absorption↗
PubMed1990

Relation of spontaneous transformation in cell culture to adaptive growth and clonal heterogeneity.

Cell transformation in culture is marked by the appearance of morphologically altered cells that continue to multiply to form discrete foci in confluent sheets when the surrounding cells are inhibited. These foci occur spontaneously in early-passage NIH 3T3 cells grown to confluency in 10% calf serum (CS) but are not seen in cultures grown to confluency in 2% CS. However, repeated passage of the cells at low density in 2% CS gives rise to an adapted population that grows to increasingly higher saturation densities and produces large numbers of foci in 2% CS. The increased saturation density of the adapted population in 2% CS is retained upon repeated passage in 10% CS, but the number and size of the foci produced in 2% CS gradually decrease under this regime. Clonal analysis confirms that the focus-forming potential of most if not all of the cells in a population increases in response to a continuously applied growth constraint, although only a small fraction of the population may actually form foci in a given assay. The acquired capacity for focus formation varies widely in clones derived from the adapted population and changes in diverse ways upon further passage of the clones. We propose that the adaptive changes result from progressive selection of successive phenotypic variations in growth capacity that occur spontaneously. The process designated progressive state selection resolves the apparent dichotomy between spontaneous mutation with selection on the one hand and induction on the other, by introducing selection among fluctuating states or metabolic patterns rather than among genetically altered cells.

Animals↗
PubMed1991

L-deprenyl (selegiline) added to Sinemet CR in the management of Parkinson's disease patients with motor response fluctuations.

L-deprenyl (Eldepryl) added to Sinemet CR in the treatment regimens of seven patients with Parkinson's disease (PD) and therapeutic response fluctuations (RF) allowed a statistically significant reduction in total daily levodopa intake and an increase in the mean interdose interval. Trends were noted towards a reduction in the number of daily "off" periods and an increase in the portion of the waking day spent "on." Three patients suffered an increase in the intensity of their dyskinesias, and discontinued taking deprenyl. Four patients, all of whom reported improved functioning during "off" periods, have continued taking the combination. Sinemet CR and deprenyl can safely be used together in patients with advanced PD, and the combination may result in improved control of motor fluctuations in selected patients.

Aged↗
PubMed1999

Forbidden walls.

In this paper the presence of periodic twist-bend walls in the upper vicinity of the Frèedericksz critical point of a nematic calamitic sample is reported. According to the existing theory, the formation of these structures could not happen in this region of the magnetic field. The length of the periodicity of these walls as well as the time spent with their formation have been measured, and it was demonstrated that the coherent motion of the nematic material cannot drive their construction. We assume that the mechanism responsible for their appearance results from the magnification of some selected random fluctuations occurring at the neighborhood of the Frèedericksz critical point.

Journal Article↗
PubMed1989

Monosynaptic EPSPs in cat lumbosacral motoneurones from group Ia afferents and fibres descending in the spinal cord.

1. Excitatory postsynaptic potentials (EPSPs) were elicited in lumbosacral motoneurones of pentobarbitone-anaesthetized cats by stimulating the ventral quadrants (VQ) of the thoracic spinal cord. These EPSPs were compared with monosynaptic EPSPs from small numbers of group Ia afferents, obtained by stimulating hindlimb muscle nerves with most of the dorsal roots severed. 2. EPSPs with average peak amplitude less than 1 mV were selected for fluctuation analysis. Three out of fourteen (21%) VQ EPSPs with peak voltage less than 150 mu V fluctuated in amplitude from trial to trial no more than could be accounted for by the background intracellular noise. Similarly, nine out of thirty-nine (23%) Ia EPSPs smaller than 150 mu V fluctuated to a comparable extent as the noise. These results are consistent with the view that there is little variation in the postsynaptic signal produced by an individual transmitter release event. 3. Of the EPSPs which did fluctuate more than the background noise, maximum likelihood estimates were obtained for the fluctuation patterns of ten VQ and fourteen Ia EPSPs. This was achieved by assuming that synaptic signals sum linearly with noise, but without constraining the results to conform to a statistical description of transmitter release. The fluctuation of both VQ and Ia EPSPs was made up of discrete amplitudes separated by roughly equal increments, in accordance with the quantal hypothesis of synaptic transmission. 4. Fluctuation patterns were obtained simultaneously for VQ and Ia EPSPs in seven motoneurones. The amplitudes of the quanta, defined as the mean increments between discrete amplitudes, were correlated (r = 0.90), suggesting common postsynaptic mechanisms. 5. For most EPSPs the time course of the voltage transient could be used to estimate the electrical distance from the soma at which the synaptic current was injected. There was a comparable distribution for VQ and Ia EPSPs. For those in which a quantal analysis was performed (nine VQ and eleven Ia), quantal size measured at the soma appeared to be independent of the deduced site of origin. 6. The results indicate no qualitative or quantitative differences in the behaviour of VQ and Ia EPSPs.

Animals↗
PubMed1990

Structure and dynamics of detergent-solubilized M13 coat protein (an integral membrane protein) determined by 13C and 15N nuclear magnetic resonance spectroscopy.

The major coat protein of the filamentous bacteriophage M13 is inserted as an integral protein in the inner membrane of the Escherichia coli host upon infection. M13 coat protein is an ideal model membrane protein and has been the target of many biophysical studies. An overview is presented here of the application of nuclear magnetic resonance spectroscopy to the study of the structure and dynamics of M13 coat protein in several lipid-mimetic environments. The coat protein may be biosynthetically enriched with 13C- and 15N-labelled amino acids, allowing the resolution and assignment of individual nuclei. Structural fluctuations at selected sites have been monitored using 13C relaxation and isotope-detected amide hydrogen exchange kinetics. A model is proposed for the structure of a coat protein dimer in detergent micelles.

Amino Acid Sequence↗
PubMed2006

Time-resolved diffusing wave spectroscopy beyond 300 transport mean free paths.

We presented theoretical and experimental demonstrations of the possibilities of performing time-resolved diffusing wave spectroscopy: We successfully registered field fluctuations for selected photon path lengths that can surpass 300 transport mean free paths. Such performance opens new possibilities for biomedical optics applications.

Journal Article↗
PubMed2004

Protecting haploid polymorphisms in temporally variable environments.

Analysis of a continuous-time model shows that a protected polymorphism can arise in a haploid population subject to temporal fluctuations in selection. The requirements are that population size is regulated in a density-dependent manner and that an allele's arithmetic mean relative growth rate is greater than one when rare and that its harmonic mean relative growth rate is less than one when common. There is no requirement that relative growth rate be frequency dependent. Comparisons with discrete-time models show that the standard formalism used by population genetics ignores forced changes in generation time as rare advantageous alleles sweep into a population. In temporally variable environments, frequency-dependent changes in generation times tend to counteract these invasions. Such changes can prevent fixation and protect polymorphisms.

Alleles↗
PubMedDate not supplied

Diffusion processes, Feller semigroups and Wentzell boundary conditions.

Different approaches to the study of many diffusion processes in Genetics involve Probability, Functional Analysis and Partial Differential Equations, as in the case of changes in gene frequency due only to random sampling or under random fluctuation of selective advantages. In the one-dimensional case, a unified treatment of them was given by Feller. For particular classes of Markov processes, Taira showed that these different approaches are equivalent even in the N-dimensional case. It follows that the generator of a Feller semigroup on the space of real-valued continuous functions C(D), where D is a bounded domain of RN with smooth boundary, can be identified with a particular Markov transition function. Under suitable assumptions, Taira, Favini and the author proved that some classes of degenerate elliptic operators with Wentzell boundary condition generate Feller semigroups on C(D), in such a way that the diffusion phenomenon of viscosity occurs at each point of the boundary.

Gene Frequency↗
PubMed1987

Patterns of porphyrin excretion in feces as determined by liquid chromatography; reference values and the effect of flora suppression.

While determining reference values for porphyrins in feces as measured by liquid chromatography, we observed strong fluctuations in fecal porphyrin contents. To explain these fluctuations, we selectively suppressed the intestinal flora of healthy persons. Suppression of aerobic flora had no effect on fecal porphyrin excretions, whereas suppression of anaerobic flora completely inhibited the transformation of protoporphyrin to pempto- and deuteroporphyrin for as long as five days after stopping medication. During this latter, the conversion to mesoporphyrin was clearly increased in one person and in others partly affected or decreased. During complete suppression of flora for prolonged periods, the production of proto- and coproporphyrins was decreased and deutero-, pempto-, and mesoporphyrins were absent. We conclude that the nature of fecal porphyrins is mostly affected by action of anaerobic bacteria, different kinds of bacteria having different effects. Some, like aerobic Gram-negative bacteria, have little or no effect on porphyrins; some cause production of mesoporphyrin; some promote a conversion to pempto- and deuteroporphyrin; and some mainly cause production of copro- and protoporphyrin. We give examples in which normal to slightly increased excretions of fecal porphyrin do not exclude a diagnosis of porphyria, and relatively high concentrations do not confirm one.

Bacteria↗
PubMed1970

Periodic density fluctuation during the yeast cell cycle and the selection of synchronous cultures.

Yeast cells undergo periodic fluctuations in density during the cell division cycle such that a minimum in density occurs at the time of cell separation whereas a maximum occurs between the time of deoxyribonucleic acid replication and nuclear division. Synchronous cultures can be selected from asynchronously growing cell cultures by withdrawing the cells of least or greatest density after banding in Renografin-sucrose density gradients. This technique is rapid, reproducible, and almost unlimited in capacity.

Journal Article↗