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PubMed2006

Rasagiline: defining the role of a novel therapy in the treatment of Parkinson's disease.

Parkinson's disease (PD) is a therapy area with considerable unmet needs. The current key targets for PD treatment include the slowing of disease progression, improved control of motor fluctuations in advanced disease and the treatment of non-motor symptoms. In view of such major requirements, it is important to consider how new drug treatments fit into the context of PD therapy, and the practical advantages that they may offer in the management of PD in clinical practice. Rasagiline is a novel, second-generation, irreversible, selective monoamine oxidase type B inhibitor that is indicated for the treatment of idiopathic PD, either as initial monotherapy or as adjunct therapy (with levodopa) for patients experiencing end-of-dose motor fluctuations. This review assesses the outcome from several large-scale clinical studies that have investigated the use of rasagiline in early and advanced PD patient populations and discusses the role of rasagiline within the current scope of PD therapy.

Delayed-Action Preparations↗
PubMedDate not supplied

Neuromodulation of decision and response selection.

We present a model for the attentional neuromodulation of decision and selection processes. The model assumes that phasic responses in the brain nucleus Locus Coeruleus modulate, via the transmission of norepinephrine, the synaptic efficiency of neural circuits, at specific (stimulus and task dependent) time intervals. The model is applied first, to a task of perceptual choice, simulating attentional fluctuations and accounting for a series of behavioral and neurophysiological data. Second, the flexibility of information processing, whereby the parameters of the local circuits are modified online, is illustrated in the application of the model to a task of selection from short-term memory.

Animals↗
PubMed2000

Laser in situ keratomileusis to correct residual myopia and astigmatism after radial keratotomy.

PURPOSE: To evaluate the safety and efficacy of laser in situ keratomileusis (LASIK) in selected post-radial-keratotomy (RK) eyes with residual myopia and astigmatism. SETTING: TLC-The Brea Laser Eye Center, Brea, California, USA. METHODS: Nine eyes of 6 patients who had had RK but had residual myopia and/or astigmatism had LASIK. All RK eyes had 8 radial incisions, were more than 1 year post-RK, had no epithelial inclusion cysts or corneal disease, and had had no subsequent ocular surgery. Follow-up was a minimum of 13 months, at which time uncorrected visual acuity (UCVA), best corrected visual acuity (BCVA), manifest refraction, cycloplegic refraction, keratometry, central and peripheral pachymetries, intraocular pressure, and a subjective assessment of visual function were obtained. RESULTS: At the last follow-up, the mean spherical equivalent (SE) was -0.156 diopter (D) +/- 0.174 (SD). All eyes treated for distance vision had a UCVA of 20/25 or better. No patient lost BCVA. No intraoperative or postoperative complications occurred. Seven eyes had morning and evening measurements. The mean change in manifest SE from morning to evening was -0.143 D. Six of the 7 eyes (86%) had 0 to 1 Snellen line change in UCVA from morning to evening. The subjective questionnaire revealed a high degree of satisfaction with overall vision, minimal glare, and less fluctuation in daily vision than before LASIK. CONCLUSION: Laser in situ keratomileusis is safe and efficacious for reducing residual myopia and astigmatism in properly selected RK patients.

Astigmatism↗
PubMed2006

A Markovian engine for a biological energy transducer: the catalytic wheel.

The molecular machines in biological cells are made of proteins, DNAs and other classes of molecules. The structures of these molecules are characteristically "soft", highly flexible, and yet their interactions with other molecules or ions are specific and selective. This chapter discusses a prevalent form, the catalytic wheel, or the energy transducer of cells, examines its mechanism of action, and extracts from it a set of simple but general rules for understanding the energetics of the biomolecular devices. These rules should also benefit design of manmade nanometer scale machines such as rotary motors or track-guided linear transporters. We will focus on an electric work that, by matching system dynamics and then enhancing the conformational fluctuation of one or several driver proteins, converts stochastic input of energy into rotation or locomotion of a receptor protein. The spatial (or barrier) and temporal symmetry breakings required for selected driver/receptor combinations are examined. This electric ratchet consists of a core engine that follows the Markovian dynamic, alleviates difficulties encountered in rigid mechanical model, and tailors to the soft-matter characteristics of the biomolecules.

Animals↗
PubMed2003

Biochemical detection of pyrethroid resistance mechanisms in Anopheles minimus in Thailand.

Enzyme-based metabolic mechanisms of insecticide resistance were investigated, comparing a deltamethrin-susceptible parent stock and resistant colonies of Anopheles minimus species A using biochemical assays. The control parent colony was determined susceptible to the diagnostic lethal concentration of deltamethrin (0.05%), whereas the 6 resistant test populations at selected 4, 8, 12, 14, 16, and 18 filial generations (F4, F8, F12, F16, and F18) demonstrated varying levels of tolerance/resistance to deltamethrin. Expression of levels of non-specific esterases, monooxygenases, and glutathione S-transferases (GSTs) were measured. Results indicated that monooxygenase activity was consistently elevated in resistant-selected test populations compared to the parent colony and increased as resistance intensified from F8 to F18. There was a 5-fold increase in monooxygenase in the F18 generation compared to the parental stock. Fluctuations in alpha and beta-esterase activity, measured by hydrolysis of alpha and beta-naphthylpropionate, provided no conclusive evidence of an association with pyrethroid resistance in this mosquito species. GSTs were not elevated in the 6 resistant test populations. Based on our results, it appears likely that the development of physiological resistance to deltamethrin in laboratory, resistant-selected generations of An. minimus is primarily associated with increased detoxification by over-expression of monooxygenases. The oxidases are the major contributors to pyrethroid resistance and the importance of kdr has yet to be convincingly determined. This finding represents the first report from Thailand of this metabolic mechanism of resistance in anophelines.

Animals↗
PubMed1997

The within-host population dynamics of antibacterial chemotherapy: conditions for the evolution of resistance.

For tuberculosis and number of other bacterial infections, treatment with a single antimicrobial drug frequently fails due to the ascent of mutants resistant to that drug. To minimize the likelihood of this occurrence, multiple drugs with independent resistance mechanisms are used simultaneously. None the less, multiply resistant bacteria sometimes emerge even when patients are simultaneously treated with two or more drugs, and the ascent of these multiply-resistant mutants may result in treatment failure in the patient and spread of these resistant bacteria to other hosts. We consider two mathematical models of antibacterial chemotherapy which can account for the ascent of multiple antibiotic resistance within hosts treated with multiple antibiotics. In both, multiple resistance evolves because of selection favouring mutants resistant to fewer than all of the chemotherapeutic agents employed, intermediates. In one model, this occurs because of temporal fluctuations in the concentrations of the antibiotics in the course of normal treatment and/or because of non-adherence to the treatment regime. In the other, intermediates are favoured and multiple resistance evolves because of tissue and somatic cell heterogeneity. In the effective concentrations of the antibiotics and physiological variation in the sensitivity of subpopulations of bacteria to different antibiotics. We discuss the limitations (and assets) of this model and approach and the implications for the design of antibiotic treatment regimes. Finally, we consider how the assumptions behind this model and the predictions made from its analysis could be tested experimentally.

Animals↗
PubMed2002

Micromechanics of isolated sickle cell hemoglobin fibers: bending moduli and persistence lengths.

Pathogenesis in sickle cell disease depends on polymerization of deoxyhemoglobin S into rod-like fibers, forming gels that rigidify red cells and obstruct the systemic microvasculature. Fiber structure, polymerization kinetics and equilibria are well characterized and intimately related to pathogenesis. However, data on gel rheology, the immediate cause of obstruction, are limited, and models for structure and rheology are lacking. The basis of gel rheology, micromechanics of individual fibers, has never been examined. Here, we isolate fibers by selective depolymerization of gels produced under photolytic deliganding of CO hemoglobin S. Using differential interference contrast (DIC) microscopy, we measure spontaneous, thermal fluctuations in fiber shape to obtain bending moduli (kappa) and persistence lengths (lambda(p)). Some fibers being too stiff to decompose shape accurately into Fourier modes, we measure deviations of fiber midpoints from mean positions. Serial deviations, sufficiently separated to be independent, exhibit Gaussian distributions and provide mean-squared fluctuation amplitudes from which kappa and lambda(p) can be calculated. Lambda(p) ranges from 0.24 to 13 mm for the most flexible and stiffest fibers, respectively. This large range reflects formation of fiber bundles. If the most flexible are single fibers, then lambda(p) =13 mm represents a bundle of seven single fibers. Preliminary data on the bending variations of frozen, hydrated single fibers of HbS obtained by electron microscopy indicate that the value 0.24 mm is consistent with the persistence length of single fibers. Young's modulus is 0.10 GPa, less than for structural proteins but much larger than for extensible proteins. We consider how these results, used with models for cross-linking, may apply to macroscopic rheology of hemoglobin S gels. This new technique, combining isolation of hemoglobin S fibers and measurement of micromechanical properties based on thermal fluctuations and midpoint deviations, can be used to study fibers of mutants, hemoglobin A/S, and mixtures and hybrids of hemoglobin S.

Anemia, Sickle Cell↗
PubMed1993

Demonstration of a novel apamin-insensitive calcium-activated K+ channel in mouse pancreatic B cells.

The whole-cell configuration of the patch-clamp technique was used to characterize the biophysical and pharmacological properties of an oscillating K(+)-current that can be induced by intracellular application of GTP[gamma S] in mouse pancreatic B cells (Ammälä et al. 1991). These K+ conductance changes are evoked by periodic increases in the cytoplasmic Ca2+ concentration ([Ca2+]i) and transiently repolarize the B cell, thus inhibiting action-potential firing and giving rise to a bursting pattern. GTP[gamma S]-evoked oscillations in K+ conductance were reversibly suppressed by a high (300 microM) concentration of carbamylcholine. By contrast, alpha 2-adrenoreceptor stimulation by 20 microM clonidine did not interfere with the oscillatory behaviour but evoked a small sustained outward current. At 0 mV membrane potential, the oscillating K(+)-current elicited by GTP[gamma S] was highly sensitive to extracellular tetraethylammonium (TEA; 70% block by 1 mM). The TEA-resistant component, which carried approximately 80% of the current at -40 mV, was affected neither by apamin (1 microM) nor by tolbutamide (500 microM). The current evoked by internal GTP[gamma S] was highly selective for K+, as demonstrated by a 51-mV change in the reversal potential for a sevenfold change in [K+]o. Stationary fluctuation analysis indicated a unitary conductance of 0.5 pS when measured with symmetric (approximately 140 mM) KCl solutions. The estimated single-channel conductance with physiological ionic gradients is 0.1 pS. The results indicate the existence of a novel Ca(2+)-gated K+ conductance in pancreatic B cells. Activation of this K+ current may contribute to the generation of the oscillatory electrical activity characterizing the B cell at intermediate glucose concentrations.

Animals↗
PubMed1991

Effects of the converting enzyme inhibitor trandolapril on short-term variability of blood pressure in essential hypertension.

Short-term fluctuations in blood pressure and heart rate were analysed in a group of eight males with essential hypertension. Indirect finger blood pressure was measured by a non-invasive device (Finapres). Analogue-to-digital conversion of the blood pressure was used to determine systolic and diastolic blood pressure and heart rate every second. The equidistant sampling allowed a direct spectral analysis using a fast Fourier transformation algorithm. The effect of 7-day administration of the angiotensin converting enzyme inhibitor, transolapril (2 mg/day), was assessed in a double-blind, randomized, placebo-controlled cross-over study. After trandolapril there was a significant reduction in systolic blood pressure levels (-15 mmHg). The reduction in diastolic blood pressure did not reach significance. The standard deviation of systolic and diastolic blood pressure levels were significantly reduced (-20% and -22% for systolic and diastolic respectively). Neither average heart rate nor standard deviations of heart rate time series was affected by the angiotensin converting enzyme inhibitor. Spectral analysis of fluctuation in blood pressure showed a reduction in the variability underlying the standard deviation changes of systolic and diastolic blood pressure. Trandolapril selectively reduced the amplitude of systolic and diastolic oscillations in the 66-129 mHz region, corresponding to Mayer waves. The significant decrease in the 10 s period oscillations of blood pressure after chronic angiotensin converting enzyme blockade with trandolapril could reflect reduced sympathetic outflow to vascular smooth muscle.

Adult↗
PubMed2006

Effects of relative humidity and temperature conditions on pollen fluorochromatic reaction of Rosmarinus officinalis L. (Lamiaceae).

Mediterranean ecosystems are characterized by seasonal and annual fluctuations in humidity and temperature which are considered limiting factors for plant growth and might have played a key role in the selection of species that compose the present vegetation. After anther release, pollen is generally exposed to various changes of temperature and humidity conditions, therefore its viability and consequently successful fruit set are strongly affected by these environmental parameters. The aim of this research was to study the effect of different combinations of humidity and temperature on pollen membrane integrity of Rosmarinus officinalis L. in order to investigate possible relations between pollen features and climatic conditions during flowering. This species is an evergreen perennial shrub, occurring among the sclerophyllous vegetation of Mediterranean maquis. In many areas of Southern Italy, it shows a flowering period starting from the beginning of winter and spreading throughout spring months. The analysis of data showed that duration of pollen viability of R. officinalis is enhanced by the co-occurrence of low temperature and high humidity. Moreover, these conditions are able to newly raise the viability of pollen kept at higher temperatures and lower humidity. These observations indicate that reactivation of the pollen membrane depends on low temperature apart from high humidity. Therefore "vernalization" of rosemary pollen enhances its viability, supporting that pollen behavior is adapted to winter condition and allows flowering in winter and early spring.

Humidity↗
PubMed2000

Probing f-actin flow by tracking shape fluctuations of radial bundles in lamellipodia of motile cells.

We examined the dynamics of radial actin bundles based on time-lapse movies of polarized light images of living neuronal growth cones. Using a highly sensitive computer vision algorithm for tracking, we analyzed the small shape fluctuations of radial actin bundles that otherwise remained stationary in their positions in the growth cone lamellipodium. Using the tracking software, we selected target points on radial bundles and measured both the local bundle orientations and the lateral displacements between consecutive movie frames. We found that the local orientation and the lateral displacement of a target point are correlated. The correlation can be explained using a simple geometric relationship between the lateral travel of tilted actin bundles and the retrograde flow of f-actin structures. Once this relationship has been established, we have turned the table and used the radial bundles as probes to measure the velocity field of f-actin flow. We have generated a detailed map of the complex retrograde flow pattern throughout the lamellipodium. Such two-dimensional flow maps will give new insights into the mechanisms responsible for f-actin-mediated cell motility and growth.

Actins↗
PubMed1988

The evolution of mate choice in a fluctuating environment.

This paper analyzes the evolutionary dynamics of a locus controlling the degree of female mating preference in a temporally fluctuating environment. Preference for mating with males with respect to their genotypes at a locus that is subject to temporally varying natural selection pressure is considered first. With weak selection and free recombination between the choice locus and the selected locus, preference for mating with heterozygotes appears to be favored. With strong selection, preference for homozygous mates may be favored. In each case, choice alleles may increase from very low initial frequencies to near fixation, in contrast to previous models of mate choice in varying environments. Linkages between the two loci has complex effects on the strength and direction of selection for mate choice. Preference for mating with males with the currently fitter genotypes at the locus under natural selection is also modelled. Provided that the environmental period is not too short, a rare allele conferring such preference may be favored and spread to fixation. Strong natural selection, tight linkage and a short environmental period may produce polymorphism for the level of mate choice.

Alleles↗
PubMedDate not supplied

Modelling development of reptile embryos under fluctuating temperature regimes.

An increase in temperature, within bounds, will accelerate development of reptile embryos, and morphogenesis can be normal over a range of temperatures despite those varying rates of development. Less well understood is the form of the relationship that best describes variation in developmental rate with temperature. In this article, we apply a linear degree.hour model, an empirical curvilinear model, a biophysical model, and a polynomial model to data on rates of embryonic development and temperature in the pig-nosed turtle Carettochelys insculpta from northern Australia. The curvilinear models, which have been applied with success to development of insects, describe the embryonic development of turtles well. When fluctuating temperatures extend beyond the constant temperatures that support successful incubation, the curvilinear models continue to perform well, whereas the linear model predictions fail. Sensitivity analysis indicates that under some circumstances, incubation duration may be increased by diel temperature fluctuations, independent of an influence of mean temperature. In other circumstances, incubation duration may be decreased, and in still other circumstances, diel temperature fluctuations will have no impact on incubation duration. This adds an additional dimension to our understanding of how thermal regimes can be selected or manipulated by reptiles to optimise incubation duration and the timing of offspring emergence.

Animals↗
PubMed1995

Atmospheric CO(2) and the ratio of intercellular to ambient CO(2) concentrations in plants.

Much attention is focused today on predicting how plants will respond to anticipated changes in atmospheric composition and climate, and in particular to increases in CO(2) concentration. Here we review the long-term global fluctuations in atmospheric CO(2) concentration as a framework for understanding how current trends in atmospheric CO(2) concentration fit into a selective, evolutionary context. We then focus on an integrated approach for understanding how gas exchange metabolism responds to current environmental conditions, how it previously responded to glacial-interglacial conditions, and how it may respond to future changes in atmospheric CO(2) concentration.

Journal Article↗
PubMed1995

Comparative assessment of pediatric intensive care: a national multicenter study. Pediatric Intensive Care Assessment of Outcome (PICASSO) Study Group.

OBJECTIVE: Comparative assessment of performance of pediatric intensive care. DESIGN: Open, prospective multicenter study. SETTING: All pediatric intensive care units (n = 10; six tertiary and four nontertiary) in the Netherlands. PATIENTS: 1063 consecutive unselected admissions, < or = 18 yrs old, during a 4-month period. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Effectiveness was defined as the ratio of observed to expected (Pediatric Risk of Mortality-score-derived) mortality. Efficiency was determined by two objective criteria: mortality risk of > 1%, or administration of at least one intensive care unit (ICU)-dependent therapy. In the total population, observed and expected mortality rates were similar. Between hospitals, crude mortality showed wide variations (mean 7.1%, range 1% to 10%). However, in each center, observed and expected mortality rates were similar (mean ratio of observed/expected mortality 0.99, range 0.8 to 1.5). In tertiary care centers, severity of illness-corrected mortality rates in high-risk patients were less than in a United States reference population. Paradoxically, in low-risk tertiary care patients, the observed mortality rate was higher than expected. The relatively high mortality rate in this group is probably the result of the large number of low-risk tertiary care patients suffering from severe, incurable chronic disease. The average number of efficient ICU days was 72%, although large fluctuations between units were found (range 22% to 95%), suggesting that in several centers efficiency rates might be improved by a better selection of high-risk patients requiring ICU-dependent therapies. CONCLUSIONS: Differences in mortality rates among pediatric ICUs were largely explained by differences in severity of illness. High efficiency rates combined with adequate effectiveness were found in several centers, indicating that admission and discharge decisions might be improved in less efficient centers.

Child, Preschool↗
PubMed1990

Probabilistic secretion of quanta from nerve terminals at synaptic sites on muscle cells: non-uniformity, autoinhibition and the binomial hypothesis.

A model of the secretion of a quantum at a release site is proposed in which, following the influx of calcium ions, synaptic vesicles are made available for release by the activation of kappa phosphorylation steps with rate alpha. At any time during this process the vesicles may become unavailable for secretion at rate gamma. On completion of the kappa phosphorylation steps the vesicles participate in the formation of a fusion pore with the terminal membrane to give exocytosis at rate delta. Changes in alpha, delta and kappa are shown to produce characteristic changes in the number and timecourse of quantal secretions following a nerve impulse, which are similar to those observed following drug treatments that are thought to act selectively on each of these processes. The number of quanta secreted from nerve terminals that consist of many release sites does not fluctuate much during a low frequency train of impulses: the variance is small compared with the mean level, so secretion follows binomial rather than Poisson statistics. A theory is derived that shows that variations in the probability of secretion amongst these release sites of any particular kind fails to reduce the variance of the total secretion from the terminal; Poisson rather than binomial statistics then still apply. The theory shows that an interaction between release sites is required to reduce this variance and such an effect is provided if secretion at a site inhibits secretion at nearby sites. Simulations show that incorporating this process of autoinhibition into the model reproduces the experimental observations on the effects of calcium ions on the binomial parameters p and n as well as on the relative constancy of p during facilitation and depression of quantal secretion. Methods for estimating the timecourse of changes in the probability of secretion at release sites following an impulse, by using either the time of occurrence of first, second, third or later quantal latencies, are given. These procedures show that current methods for estimating the time-dependent probability changes are inadequate for detecting interaction between release sites, such as autoinhibition, unless this is relatively large. Therefore, estimates from third quantal latencies are used.

Animals↗
PubMed1990

Effect of protein C and activated protein C on coagulation and fibrinolysis in normal human subjects.

Although protein C (PC) and activated protein C (APC) have been postulated to be useful for treating patients with thrombosis, their critical effect remains to be studied in human subjects. To examine whether purified PC or APC are useful for treating patients with thrombosis without showing any adverse effect, we studied effects on coagulation and fibrinolysis in normal human subjects. When highly purified human PC was administered intravenously to healthy subjects, plasma levels of immunoreactive PC decreased with a half-life of 10.9 h. Intravenously administered APC decreased with a half-life of 23 min as measured by prolongation of activated partial thromboplastin time (APTT). However, 1.7 h was obtained for the plasma half-life of APC when it was measured immunologically. These findings suggested that a significant fraction of the administered APC was rapidly inhibited by plasma inhibitor. Upon administration of APC, APTT was prolonged and plasma levels of clotting factor VIII (F-VIII) decreased transiently as measured by clotting assay. However, when determined by a chromogenic assay method in which 120-fold diluted plasma samples were used, plasma levels of F-VIII remained unchanged. Plasma levels of F-V did not decrease after APC administration. These findings suggested that prolongation of APTT and apparent decrease in plasma F-VIII clotting activity might be due to the in vitro-effect of APC present in plasma samples used. Diurnal fluctuation of plasminogen activator inhibitor in normal subject was not affected by administration of APC. Thus, PC or APC seems to function selectively at the site of thrombin-formation without lowering plasma levels of coagulation factors.

Adult↗
PubMedDate not supplied

[Properties of conductivity channels induced in phospholipid bilayer membranes by alpha-staphylotoxin].

Interaction between alpha-straphylotoxin (alpha-T) and synthetic phospholipid membranes was shown to be accompanied by the formation of conductivity channels of different amplitude. Dependence of channel conductivity on salt concentration, medium pH, as well as selectivity for different cations and anions was determined. Current--voltage characteristics of BPhM modified by alpha-T were measured. The conductivity fluctuations observed are suggested to be concerned with the initiation of phospholipid domens (with changed mobility of their fatty acid chains) in the bilayer structure.

Bacterial Toxins↗