[Brain stem and heart rate fluctuations--experimental and clinical results for topical mapping and selective quantification].
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Animals↗
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Clinical pharmacology of rasagiline: a novel, second-generation propargylamine for the treatment of Parkinson disease.
Rasagiline is a novel second-generation propargylamine that irreversibly and selectively inhibits monoamine oxidase type B (MAO-B). For the management of Parkinson disease (PD), rasagiline is efficacious across the span of PD stages ranging from monotherapy in early disease to adjunctive treatment in patients with advancing disease and motor fluctuations. Rasagiline completely and selectively inhibits MAO-B with a potency 5 to 10 times greater than selegiline. Unlike the prototype propargylamine selegiline, which is metabolized to amphetamine derivatives, rasagiline is biotransformed to aminoindan, a non-amphetamine compound. Rasagiline is well tolerated with infrequent cardiovascular or psychiatric side effects, and at the recommended therapeutic dose of up to 1 mg once daily, tyramine restriction is unnecessary. In addition to MAO-B inhibition, the propargylamine chain also confers dose-related antioxidant and antiapoptotic effects, which have been associated with neuroprotection in multiple experimental models. Thus, in addition to symptomatic benefits, rasagiline offers the promise of clinically relevant neuroprotection.
Animals↗
Foraging adaptation and the relationship between food-web complexity and stability.
Ecological theory suggests that complex food webs should not persist because of their inherent instability. "Real" ecosystems often support a large number of interacting species. A mathematical model shows that fluctuating short-term selection on trophic links, arising from a consumer's adaptive food choice, is a key to the long-term stability of complex communities. Without adaptive foragers, food-web complexity destabilizes community composition; whereas in their presence, complexity may enhance community persistence through facilitation of dynamical food-web reconstruction that buffers environmental fluctuations. The model predicts a linkage pattern consistent with field observations.
Adaptation, Biological↗
On a kinetic origin of heredity: minority control in a replicating system with mutually catalytic molecules.
As the first step in an investigation of the origin of genetic information, we study how some species of molecules are preserved over cell generations and play an important role in controlling the growth of a cell. We consider a model consisting of protocells. Each protocell contains two mutually catalysing molecule species (X and Y), each of which has catalytically active and inactive types. One of the species Y is assumed to have a slower synthesis speed. Through divisions of the protocells, the system reaches and remains in a state in which there are only a few active Y and almost no inactive Y molecules in most protocells, through the selection of very rare fluctuations. In this state, the active Y molecules are shown to control the behavior of the protocell. The minority molecule species act as the carrier of heredity, due to the relatively discrete nature of its population, in comparison with the majority species which behaves statistically in accordance with the law of large numbers. The minority controlled state may give rise to a selection pressure for mechanisms that ensure the transmission of the minority molecule. Once those mechanisms are in place, the minority molecule becomes the ideal storage device for information to be transmitted across generations, thus giving rise to "genetic information". The relevance of this minority controlled state to evolvability is also discussed.
Animals↗
Serum proteins and zinc as parameters to monitor the health of children in a rural Tanzanian community.
Total protein concentration, zinc, prealbumin, albumin, alpha-1-, alpha-2-, beta- and gammaglobulin concentrations were measured in serum samples collected in three successive years (1982, 1983 and 1984) from children (1 month-15 years) of Kikwawila village, Tanzania. The analysis of a total of 1590 serum samples provided the baseline data for children living in a rural Tanzanian community. The total protein values and the concentrations of betaglobulin were within the range described for Caucasians. Albumin, prealbumin, alpha-1- and alpha-2-globulin concentrations were below these standard values. On the other hand the gammaglobulin concentration was twice as high. The concentrations of total protein, gammaglobulin and prealbumin correlated with age. From 1982 to 1983 a significant decrease of most of the serum components (incl. zinc) was observed, although in children older than 2 years the alpha-1-globulins increased. All values increased again from 1983 to 1984, except for the zinc concentration, which decreased further. The individual fluctuations were analysed by comparing paired values for the children participating in the period 1982-1983, or 1983-1984. The proportion of children showing large fluctuations, sometimes exceeding the selected limits of tolerance, was larger in the period 1982-1983 than 1983-1984. This was consistent with the overall pattern found for all children. The prealbumin level, which has been postulated to be an indicator for malnutrition or borderline malnutrition, was analysed in detail. The values were far below normal values (200-300 mg/l), reaching a plateau with 130 mg/l among 4-6-year-old children. The individual fluctuations indicated a decrease from 1982 to 1983, which was considerable both in terms of the proportion of children showing a decrease (55%) and in the magnitude of the decrease. There was an increase from 1983 to 1984 but this increase did not compensate for the loss in 1983. Prealbumin concentrations showed a slight trend towards decreased values with stunting and wasting. No direct correlation was found between the other biochemical parameters and the parasite or anthropometric data collected at the same time. It was difficult to establish direct relationships between the biochemical parameters, which mainly indicate the health status of the child at the time-point of the survey, and anthropometric parameters which reflect the history of the individual over a long period. No direct correlation could be established between the biochemical parameters and the parasitological data.(ABSTRACT TRUNCATED AT 400 WORDS)
Adolescent↗
Oocyte maturation involves compartmentalization and opposing changes of cAMP levels in follicular somatic and germ cells: studies using selective phosphodiesterase inhibitors.
The second messenger cAMP has been implicated in the regulation of mammalian and amphibian oocyte maturation. Although a decrease in intraoocyte levels of cAMP precedes germinal vesicle breakdown (GVBD), the gonadotropin induction of ovulation and oocyte maturation is associated with major increases of cAMP in ovarian follicles. In the mammalian system, isolated oocytes undergo spontaneous maturation in vitro but this process is blocked by treatment with a phosphodiesterase (PDE) inhibitor, IBMX, which increases intraoocyte cAMP levels. In contrast, the same inhibitor, when added to cultured follicles for a brief time, increases follicle cAMP levels, followed by the induction of GVBD. To resolve the paradoxical actions of this PDE inhibitor on the maturation of isolated and follicle-enclosed oocytes, we hypothesized that meiotic maturation requires opposing fluctuations of cAMP levels in the somatic granulosa and germ cells. Such opposing fluctuations may result from selective expression and regulation of PDEs in the somatic and germ cell compartments of the follicle. To test this hypothesis, PDE activity was manipulated in different follicular cells using type-specific inhibitors. The impact of the ensuing changes in cAMP levels in the two compartments was monitored by the induction of GVBD. In isolated oocytes, spontaneous GVBD was blocked by two inhibitors of type 3 PDE (cGMP-inhibited: CGI-PDE), milrinone and cilostamide. In contrast, treatment with an inhibitor for type 4 PDE (cAMP-specific), rolipram, was ineffective. These findings suggest that the oocyte expresses type 3 but not type 4 PDE and that increases in intraoocyte cAMP suppress GVBD. This hypothesis was confirmed by in situ hybridization studies with PDE3 and PDE4 probes. PDE3B mRNA was concentrated in oocytes while PDE4D was mainly expressed in granulosa cells. In cultured follicles, LH treatment induced oocyte maturation but the gonadotropin action was blocked by inhibitors of type 3 but not the type 4 PDE inhibitors. Furthermore, treatment with the type 4, but not the type 3, PDE inhibitor mimics the action of LH and induces oocyte maturation, presumably by increasing cAMP levels in granulosa cells. Our findings indicate that PDE subtypes 4 and 3 are located in follicle somatic and germ cells, respectively. Preferential inhibition of PDE 3 in the oocyte may lead to a delay in oocyte maturation without affecting the cAMP-induced ovulatory process in the somatic cells. Conversely, selective suppression of granulosa cell cAMP-PDE may enhance the gonadotropin induction of ovulation and oocyte maturation. Thus, in addition to the well-recognized differential expression and regulation of adenylate cyclase in the somatic and germ cell compartments of the follicle, we suggest that selective regulation and expression of PDEs may be involved in the regulation of cAMP levels and control of oocyte maturation in the preovulatory mammalian follicle.
Animals↗
The influence of stimulus envelope and fine structure on the binaural masking level difference.
A masking level difference (MLD) paradigm was used to investigate the influence of stimulus envelope and stimulus fine-structure characteristics on monaural and binaural hearing. The degree of masker envelope fluctuation was manipulated by selecting narrow-band noises (50 Hz) on a continuum of values of the normalized fourth moment of the envelope. The noises were specified as low-noise noise (LNN), medium-noise noise (MNN), and high-noise noise (HNN). Fine-structure cues were studied by measuring thresholds at 500 and 4000 Hz, regions in which the availability of such cues to the auditory system differ substantially. In addition, thresholds were measured for Gaussian noise maskers (GN) and for maskers having a flat magnitude spectrum, termed equal-magnitude noise (EMN) maskers. The results indicated lower NoSo thresholds for LNN than for the other four masker types. Furthermore, there were no differences in threshold for maskers having moderate and high degrees of envelope fluctuation (MNN and HNN). The NoS pi thresholds were not significantly different across masker type and were characterized by large individual differences among the seven listeners. The results are considered in relation to models of monaural and binaural processing. Consistent with previous reports, the results indicate that binaural detection depends on interaural differences in the stimulus envelope and fine structure at low frequencies and changes in the envelope at high frequencies.
Adult↗
Susceptibility profile of Culex quinquefasciatus (Diptera: Culicidae) to Bacillus sphaericus on selection with rotation and mixture of B. sphaericus and B. thuringiensis israelensis.
Several strains of Bacillus sphaericus (Neide) (Bsph), a spore-forming bacterium that produces potent mosquitocidal toxins, have been widely used against mosquito larvae globally. In some locations in the field and in the laboratory, moderate to high levels of resistance in Culex pipiens complex mosquito larvae to Bsph have been reported. Practical strategies for dealing with the resistance problem and more importantly to delay or possibly prevent development of resistance to Bsph in the first place are urgently needed. From published reports, we deduced that Bsph-resistant mosquito larvae are completely susceptible to Bacillus thuringiensis ssp. isreaelensis (Bti) and that there is no appearance of cross-resistance to Bti. On the basis of this information, we hypothesized that Bti offers a good potential for the management of resistance to Bsph, especially when it comes to delaying or preventing emergence of resistance. We conducted laboratory studies to see whether rotation of Bsph and Bti or mixture of both delays or prevents resistance development in Bsph-susceptible California Cx. quinquefasciatus. Development of resistance using Bsph alone increased after F15 and fluctuated slightly on further selections. Rotation of Bsph and Bti resulted in much higher level and rapid emergence of resistance to Bsph. However, selection with mixtures of Bti and Bsph for 36 generations showed no emergence of resistance. On the basis of this information, we believe mixtures have a good potential in delaying or preventing Bsph resistance.
Animals↗
Could natural selection account for molecular evolution and polymorphism?
A model of molecular evolution is presented that is based on the combined action of natural selection, genetic drift, and mutation. The mathematical description of the model uses strong-selection, weak-mutation limits to approximate the dynamics of multidimensional diffusion processes with one dimensional Markov chains. This approach leads to a great simplification of the dynamics and provides a unified method for describing many different mechanisms of natural selection. In this paper two models are examined, one based on selection in a randomly fluctuating environment, the other on overdominance. Both models exhibit similar dynamics, with a rapid buildup phase that introduces new alleles into the population, followed by a relatively quiescent phase where new alleles may enter and leave the population at a low rate. If occasional extreme environmental changes occur that favor particular alleles, the resulting dynamics turn out to be in remarkable agreement with many of the observations on molecular evolution and polymorphism. Thus the model is at least as successful as the neutral theory in accounting for evolutionary events at the molecular level.
Biological Evolution↗
[Entacapone++ : a new catechol-O-methyltransferase inhibitor which improves the response to levodopa in patients with Parkinson disease and fluctuating motor function].
INTRODUCTION AND DEVELOPMENT: Selective inhibitors of peripheral catechol-O-methyltransferase (COMT) seem to be useful drugs for the treatment of patients with Parkinson's disease. When associated with levadopa and a dopa-decarboxylase inhibitor they are clearly effective in patients with progressive illness, who are particularly dependent on the plasma concentration of levadopa, or may have fluctuating motor function when the effect of the dose is wearing off. Entacapone, a prototype of this group of drugs, has been shown to modify the pharmacokinetics of levadopa in such a way that the plasma concentration of levadopa is raised (between 21% and 50% in different studies): to reduce variations in plasma level between doses, which allows some patients to reduce the total daily dose of levadopa at the same time as the response time (time 'on') increases by between 20% and 78%. CONCLUSION: Entacapone is a well tolerated drug and could form part of a regular 'triple therapy' in the patients described.
Antiparkinson Agents↗
Role of fluctuations in a snug-fit mechanism of KcsA channel selectivity.
The thermodynamic exclusion of Na+ relative to K+ in potassium channels is examined by calculating the distribution of binding energies for Na+ and K+ in a model of the selectivity filter of the KcsA potassium channel. These distributions are observed to take a surprisingly simple form: Gaussian with a slight positive skewness that is insignificant in the present context. Complications that might be anticipated from these distributions are not problematic here. Na+ occupies the filter with a mean binding energy substantially lower than that of K+. The difference is comparable to the difference in hydration free energies of Na+ and K+ in bulk aqueous solution. Thus, the average energies of binding to the filter do not discriminate Na+ from K+ when measured from a baseline of the difference in bulk hydration free energies. The strong binding of Na+ constricts the filter, consistent with a negative partial molar volume of Na+ in water in contrast with a positive partial molar volume of K+ in water. Discrimination in favor of K+)can be attributed to the scarcity of favorable binding configurations for Na+ compared to K+. That relative scarcity is quantified as enhanced binding energy fluctuations, which reflects both the energetically stronger binding of Na+ and the constriction of the filter induced by Na+ binding.
Journal Article↗
Alterations in cognitive performance and affect-arousal state during fluctuations in motor function in Parkinson's disease.
Sixteen patients with idiopathic Parkinson's disease were selected who were all showing severe fluctuations in motor function ("on-off" phenomenon). Measures of cognitive function and of subjective affect/arousal state were taken on two occasions, once when "on" and once when "off". Twenty-five matched normal controls were also assessed on the same measures. Results revealed, on the average, a drop in cognitive function plus an adverse swing in affect/arousal state, in the patient group in the "off" condition, compared to the levels when "on". Analysis of the data suggested that the main factor associated with cognitive function when "off" was not the severity of disability but the level of affect/arousal. The fluctuations in cognitive function found tended to be mild relative to the severe changes in motor ability, and were present in only a proportion of patients.
Adult↗
Reaction time, symptom profiles and course of illness in schizophrenia.
Schizophrenic subjects perform more poorly than normal controls on a wide range of neurocognitive tasks. Some studies suggest that patients with persistent illness may have different patterns of cognitive deficits and different associations between cognitive deficits and symptom profiles compared with patients with fluctuating illness. This study uses simple reaction time, choice reaction time and Stroop tasks to explore the relationship between reaction time and symptom profiles in patients with fluctuating illness (n=24), persistent illness (n=17) and normal controls (n=16). We tested the hypothesis that in patients with persistent illness, psychomotor poverty is associated with impaired initiation of activity, and that disorganization is associated with impaired selection in both persistent and fluctuating illness. There were no differences in the severity of symptoms in the patient groups. In the simple reaction time task, patients with persistent illness performed more poorly than patients with fluctuating illness and controls. Both patient groups performed more poorly than controls in the choice reaction time tasks. Psychomotor poverty was associated with simple reaction time in patients with persistent symptoms. Disorganization was associated with poorer performance on the choice reaction time task in both patient groups. These results suggest the possibility that persistent illness, negative symptoms, and impaired initiation may reflect dysfunction associated with enduring structural abnormalities. In the case of impaired selection processes and disorganization, our data indicate that these abnormalities occur in both persistent and fluctuating illness. This suggests that enduring brain damage might create a predisposition to impaired selection and disorganization, but these clinical features can also arise as a result of transient biochemical imbalance.
Adult↗
Genetic drift in a cline.
A model is developed of genetic drift in a cline maintained by spatially varying natural selection and local dispersal of individuals. The model is analyzed by an approximation scheme which is valid for weak selection and small migration rates. The results, which are based on numerical iterations of the approximate equations, are that the cline is less steep than predicted on the basis of the deterministic theory but that for weak selection the correlation between random fluctuations in neighboring colonies is approximately the same as in models of migration and drift in the absence of selection.
Biological Evolution↗
Finlay-Wilkinson random regression for yield and yield stability prediction in cereals.
Year-to-year climate variability poses a challenge for agriculture by increasing crop yield variability; therefore, there is a need to identify genotypes that can withstand these fluctuations. With the right selection criteria, genotypes with yield stability across variable environmental conditions can be selected. Methods such as Finlay-Wilkinson random regression (FWRR) may allow us to use sparse datasets-common in plant breeding pipelines-and incorporate genomic data to leverage phenotypic information from related genotypes to predict yield stability. Our objective was to examine how the number of environments and the variance among those environments affect stability predictions. We also integrate FWRR as a genomic prediction tool for characterizing yield stability, comparing it to the traditional genomic prediction models as a reference. We used three datasets: one highly unbalanced dataset for oats (Avena sativa L.) and two completely balanced datasets with different numbers of environments for barley (Hordeum vulgare L.) and wheat (Triticum aestivum L.). We fit standard Finlay-Wilkinson (FW) and FWRR models to estimate grain yield and stability under various scenarios. We found that the estimated stability values obtained were similar using balanced datasets for FW or FWRR. FWRR also achieved moderate predictive ability for stability using unbalanced datasets under 10-fold cross-validation (CV1) with new genotypes. In terms of environmental representation, selecting the right set of environments for inclusion in the model was more important than adding more environments. Our results suggest the possibility of using FWRR to select stable genotypes earlier in line development, as well as to design resource-efficient stability-testing schemes.
Hordeum↗
Interactions of Folch-Lees proteolipid apoprotein with planar lipid bilayers.
Water-soluble Folch-Lees proteolipid apoprotein from bovine CNS white matter induces a voltage-dependent conductance in black lipid membranes. Na+ is required for the induced conductance change but the established conductance has very low ionic selectivity. The induced conductance fluctuates with a minimum amplitude of 10(-11)--10(-10) mho. The magnitude of the conductivity change is dependent on protein concentration and on the composition of lipid bilayers. At a fixed voltage the induced conductance of a phosphatidylcholine-cholesterol membrane is proportional to the sixth power of the protein concentration and the first power of Na+ concentration. The interactions between the apoprotein and the lipids are both electrostatic and hydrophobic, but the interaction leading to the conductance increase appears to be mainly hydrophobic. Both the increase in conductance and the current fluctuations remain after extensive washing of the chambers to remove the protein. Furthermore, pronase or glutaraldehyde added to either the cis or trans side of the membrane does not affect the apoprotein-established conductance. However, if the bilayer is formed in the presence of both the apoprotein and pronase or if the apoprotein is treated with pronase prior to its addition to the chamber, no conductance change is observed. The association of the apoprotein with the membrane thus appears to render the protein inaccessible to proteolytic digestion, suggesting that the apoprotein is at least partially imbedded in the membrane interior.
Animals↗
Heart-rate spectral analysis: a noninvasive probe of cardiovascular regulation in critically ill children with heart disease.
Children may die suddenly and unexpectedly following cardiac surgery, even while receiving intensive medical care, when current noninvasive and invasive monitoring techniques fail to warn us of an impending problem. This report examines the efficacy of heart-rate spectral analysis, a noninvasive method that quantitates the beat-to-beat fluctuations in heart rate, in characterizing and tracking cardiovascular regulatory status. A total of 45 heart-rate fluctuation studies, performed on selected patients, at the bedside, using heart-rate spectral analysis, were retrospectively correlated with clinical events. The spectral pattern of 18 patients who sustained a cardiac arrest differed significantly from the others in the study group (p less than 0.0001).
Adolescent↗
Temperature-dependent expression patterns of grass carp fast skeletal myosin heavy chain genes.
Three types of myosin heavy chain cDNA clone named 10 degrees C, intermediate and 30 degrees C types were isolated from fast skeletal muscles of thermally acclimated grass carp Ctenopharyngodon idellus. Three clones encompassing parts of 3'-translated and entire 3'-untranslated regions showed high heterogeneities in their nucleotide sequences in the 3'-untranslated region. The comparison in the deduced amino acid sequence of the 10 degrees C-type clone with those of the intermediate- and 30 degrees C-type clones showed 88% and 89% identities, respectively. By contrast, the deduced amino acid sequence of the intermediate-type clone shared much higher identity of 97% with its 30 degrees C-type counterpart. Northern blot analysis demonstrated that the 10 degrees C- and 30 degrees C-type clones were predominantly expressed in grass carp acclimated to 10 and 30 degrees C, respectively. The intermediate type was expressed both in grass carp acclimated to 20 and 30 degrees C. Furthermore, expression patterns of the three myosin heavy chain genes were altered in accompaniment with seasonal temperature fluctuation. In autumn and winter grass carp expressed the 10 degrees C-type gene almost exclusively, whereas it was completely replaced by the intermediate- and 30 degrees C-type genes in spring and summer. These results suggest that tetraploid grass carp also undergo an adaptation to fluctuating environmental temperatures by selectively expressing fast skeletal myosin heavy chain isoforms as do diploid common carp previously reported.
Amino Acid Sequence↗