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PubMed2002

Constructing universal multiplex PCR systems for comparative genotyping.

Analysis of length polymorphisms at STR loci in the human genome has become a standard approach for comparative genotyping in many areas including disease research and diagnostics, parentage assessment, investigations of human diversity, and forensic science. The simultaneous analysis of multiple STR loci through multiplex PCR and multicolor fluorescence detection offers sample conservation, high throughput, and automated genetic analysis. Careful design and optimization of tetranucleotide STR multiplexes has led to reliable, standardized systems that powerfully differentiate and distinguish individual human DNA profiles. The development of these multiplex systems involved a rigorous experimental strategy that included careful selection of PCR primer sequences (for yield, specificity, and multiplex compatability), along with optimization of PCR component concentrations, thermal cycling parameters, and fluorescence detection conditions. This developmental approach rendered well-characterized DNA typing systems that are high performing (sensitive, specific, and balanced), optimized to universal parameters (same reaction conditions), resilient to fluctuations in reaction conditions, and simple to implement and use routinely.

DNA↗
PubMed2005

[Structural dynamics, stability and folding of proteins].

The present concepts of protein folding in vitro are reviewed. According to these concepts, amino acid sequence of protein, which has appeared a result of evolutionary selection, determines the native structure of protein, the pathway of protein folding, and the existence of free energy barrier between native and denatured states of protein. The latter means that protein macromolecule can exist in either native or denatured state. And all macromolecules in the native state are identical but for structural fluctuations due to Brownian motion of their atoms. Identity of all molecules in native state is of primary importance for their correct functioning. The dependence of protein stability, which is measured as the difference between free energy of protein in native and denatured states, on temperature and denaturant concentration is discussed. The modern approaches characterizing transition state and nucleation are regarded. The role of intermediate and misfolded states in amorphous aggregate and amyloid fibril formation is discussed.

Amyloid↗
PubMed1988

Mutation rates and mutational spectra in tumorigenic cell lines.

The rate and molecular nature of spontaneous mutations at the hgprt locus were examined in a series of tumorigenic and non-tumorigenic closely related Chinese hamster fibroblastic (CHEF) cell lines. Mutation rates of tumorigenic cells determined by fluctuation analysis were found to range from the low rate also seen in non-tumorigenic cells to values increased up to 25-fold. No simple correlation was found between elevated mutation rates and tumorigenic potential. The nature of the mutational event was examined in a set of 136 thioguanine resistant mutants selected from several tumorigenic and non-tumorigenic CHEF lines. Significantly different frequencies of point mutations were found compared with large partial or whole gene deletions in different cell lines. The clonal inheritance of specific mutational patterns as well as the high frequencies of large deletions were novel findings. Hypotheses to explain these results are discussed in relation to the known genomic instability of tumour cells. I am honoured by the opportunity to contribute to this collection of papers dedicated to Professor Guido Pontecorvo on the occasion of his eightieth birthday. For almost half of this time I have been privileged to enjoy his friendship, and to benefit from his influence at critical stages in my scientific development.

Animals↗
PubMed1986

Measurement of potassium concentration on-line with an ion-specific electrode during hemodialysis.

Patients requiring hemodialysis for end-stage renal disease are vulnerable to wide fluctuations in plasma potassium concentration [K+]p. Dialysis of K+ can result in rapid and large changes of [K+]p and result in significant morbidity. Since blood is routinely diverted extracorporeally to the dialyzer, the measurement of [K+]p could be made 'on-line' in this circuit with an ion-selective electrode (ISE) with negligible additional risk. Valinomycin/tetraphenylborate embedded in polyvinylchloride (PVC) electrodes of high K:Na selectivity were manufactured in our laboratory. The electrodes were calibrated in vitro and placed in a T diverter tube upstream from the dialyzer. Intermittently small amounts of blood were diverted to flow past the electrode allowing measurement of the electrical potential developed between the ISE half cell and a Ag:AgCl electrode placed 4 mm from the valinomycin membrane which could be read as [K+]p ISE. Blood flowing through the T diverter was then collected in glass tubes for measurement of [K+]p by flame photometry. Forty-six comparative measurements were made for 6 patients who had given informed consent for study. Least squares regression analysis for all observations gave a correlation coefficient of 0.95 and a regression equation of y = 1.1 X -0.39. Only six samples were discrepant by 0.5 mmol/l, and all of these had [K+]p greater than 5.0 mmol/l where the ISE measurements were less precise. Although the correlation of the two techniques was less than perfect, the ISE shows potential utility for monitoring trends of [K+]p instantaneously during hemodialysis.

Electrodes↗
PubMedDate not supplied

[Action of triterpene glycosides of the dammarane series and their aglycones on lipid membranes].

The action of the dammarane triterpene glycosides Rb1 and Rg1 and their aglycones 20(S) protopanaxatriole and 20(S) protopanaxadiole from Korean ginseng on permeability of bilayer lipid membranes formed of monolayers was studied. RgI, protopanaxatriole and protopanaxadiole in concentrations of 3, 0.5 and 30 micrograms/ml respectively formed single ionic channels in the water phase on the membrane side containing cholesterol. The channel conductivity was 5 to 30 pSm in 1 M KCl. The ionic channels were more selective with respect to K+ as compared to Cl-. Rb1 was also able to increase the conductivity of the lipid membranes. However, no jumps in the current characteristics of the single channels were detected. All the substances in high concentrations on one side of the membrane independently of the cholesterol content induced fluctuation of the high amplitude current (from several tens of pSm to several hundreds of nSm).

Drugs, Chinese Herbal↗
PubMed2000

Changes in the importance of quality of life domains after cancer diagnosis.

The aim of this study was to describe what domains in quality of life were considered most or least important by patients with newly diagnosed cancer and in what way the domains of importance changed during a 9-month period. We also analysed the impact of selected demographic variables on the important domains. The Ferrans' and Powers' Quality of Life Index was used to measure quality of life. As this index consists of one section measuring the importance of various domains of life, information about changing standards was available. The study sample consisted of 131 adult patients recently diagnosed with different cancers. The whole sample filled in the questionnaire once, while part of the sample (n = 41) filled it in four times during a 9-month period. Items related to family matters were rated as most important, while faith in God was reported to be of least importance. The patients fluctuated somewhat in terms of what was most important to them during the study period. Overall, the most unstable items tended to be less important over time. In addition, results showed significant differences in the importance of quality of life domains according to gender, age, educational level and cohabitation.

Adult↗
PubMed1993

Origin of phasic synaptic inhibition in myotomal motoneurons during fictive locomotion in the lamprey.

The periodic membrane potential fluctuations in motoneurons during fictive locomotion in the lamprey, a primitive vertebrate, involve phasic synaptic excitation and inhibition. This paper investigates the origin of the phasic synaptic input to lamprey myotomal motoneurons in the in vitro spinal cord preparation with regard to the relative contribution of descending propriospinal input from interneurons in the local segment. The synaptic drive to myotomal motoneurons in the most rostral and the most caudal part of the spinal cord preparation are compared before and after selective spinal cord lesions. Current clamp recordings of the same cell before and after lesion showed that neither the excitatory phase nor the inhibitory phase was abolished after interruption of the descending or the ascending ipsilateral input, or after interrupting crossing segmental input by a local longitudinal midline incision. None of these sources thus appears to be alone responsible for the phasic synaptic drive. To quantitatively evaluate these effects, and in particular the contribution from the descending propriospinal fibres to the inhibitory phase, voltage clamp recordings were made in combination with a spinal cord hemisection just rostral to the motoneuron. The input from propriospinal interneurons in approximately 15 rostral segments may be responsible for as much as 70% of the phase of inhibitory current during the locomotor cycle. In accordance with these findings, a similar voltage clamp analysis of rostrally and caudally located motoneurons showed that the average peak-to-peak amplitude of the current fluctuations in rostral cells was approximately 50% of that in caudal cells.

Animals↗
PubMed1997

Nisoldipine CC: efficacy and tolerability in hypertension and ischemic heart disease.

Nisoldipine is a second-generation dihydropyridine calcium channel blocker (CCB). It is the most vascular selective of the currently available CCBs, and thus has the capacity to lower blood pressure without affecting the functioning of the myocardium and skeletal muscle, and without producing any negative inotropic effects. Nisoldipine coat core (CC) is an extended-release formulation that allows nisoldipine to be released gradually over 24 hours, minimizing fluctuations in plasma concentration and providing a good trough/peak ratio. It has a slow onset and long duration of action, and ambulatory blood pressure monitoring has demonstrated that its antihypertensive effect is maintained over 24 hours with no evidence of reflex tachycardia, hypotension, or sympathetic neurohormonal activation and no effects on circadian variation. Studies in patients with hypertension have shown that nisoldipine CC provides reductions in blood pressure that are at least equivalent to those seen with diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, and other CCBs, without deleterious effects on metabolic parameters. In particular, it has been found to be effective in elderly patients and in black patients with severe hypertension. The DEFIANT studies have demonstrated that nisoldipine CC improves cardiac function and exercise tolerance in patients recovering from acute myocardial infarction, without increasing the risk of mortality compared with placebo. It also improves exercise performance in patients with stable angina pectoris. Nisoldipine CC is well tolerated in all groups of patients, with the most frequently reported side effects being headache and peripheral edema, which are usually mild and transient.

Aging↗
PubMed1990

Aerolysin, a hemolysin from Aeromonas hydrophila, forms voltage-gated channels in planar lipid bilayers.

The cytolytic toxin aerolysin was found to form ion channels which displayed slight anion selectivity in planar lipid bilayers. In voltage-clamp experiments the ion current flowing through the channels was homogeneous indicating a defined conformation and a uniform size. The channels remained open between -70 to +70 mV, but outside this range they underwent voltage-dependent inactivation which was observed as open-closed fluctuations at the single-channel level. Zinc ions not only prevented the formation of channels by inhibiting oligomerization of monomeric aerolysin but they also induced a closure of preformed channels in a voltage-dependent fashion. The results of a Hill plot indicated that 2-3 zinc ions bound to a site within the channel lumen. Proaerolysin, and a mutant of aerolysin in which histidine 132 was replaced by an asparagine, were both unable to oligomerize and neither could form channels. This is evidence that oligomerization is a necessary step in channel formation.

Aeromonas↗
PubMed1990

Codon usage pattern in alpha 2(I) chain domain of chicken type I collagen and its implications for the secondary structure of the mRNA and the synthesis pauses of the collagen.

A stability map of local secondary structure of the mRNA of the triple-helical alpha 2(I) chain domain of chicken type I collagen was obtained by plotting the free energy of the optimal secondary structure of a local segment in mRNA against the segment position along a base sequence of the mRNA. It was found that the positions of the minima of free energy in the plot coincide with the positions where synthesis pauses of the alpha-chain polypeptides of the corresponding sizes translated from the mRNA have been reported to occur (1). The codon usage pattern of each of the three major amino acids of the alpha-chain domain of the collagen, Gly, Pro and Ala, fluctuates considerably along the base sequence segments of the mRNA and a deviation of the pattern from that of the average of the whole alpha 2(I) chain domain mRNA, particularly for Gly codons, leads to a loss of the stability of the local secondary structure of the mRNA. The results suggest that selection has operated on the codon usage to optimize the secondary structure characteristic of the mRNA of the chicken collagen alpha 2(I) chain domain which leads to a nonuniform polypeptide elongation pattern.

Animals↗
PubMed2001

Preferential potentiation of fast-releasing synaptic vesicles by cAMP at the calyx of Held.

We have studied the effects of cAMP on synaptic transmission at the calyx of Held and found that forskolin (an activator of adenylate cyclase) and 8-Br-cAMP (a membrane-permeable analog of cAMP) potentiated excitatory postsynaptic currents (EPSCs). Direct sampling of miniature EPSCs (mEPSCs) and nonstationary fluctuation analysis showed that mEPSCs were not modulated by cAMP, suggesting that the locus of modulation is presynaptic. Deconvolution was used to examine effects of cAMP on quantal-release rates. By using this method, it was shown recently that release probabilities of readily releasable vesicles are heterogeneous. Here, we show that cAMP selectively increases the number of vesicles with higher release probabilities, whereas a slow component of the EPSC, representing vesicles that fuse more slowly, is unchanged. cAMP increases the apparent Ca2+ sensitivity for secretion, but this increase does not reflect an increase in release probability necessarily but rather an increase in the number of highly sensitive vesicles.

1-Methyl-3-isobutylxanthine↗
PubMed2006

Motor unit number estimation--a Bayesian approach.

All muscle contractions are dependent on the functioning of motor units. In diseases such as amyotrophic lateral sclerosis (ALS), progressive loss of motor units leads to gradual paralysis. A major difficulty in the search for a treatment for these diseases has been the lack of a reliable measure of disease progression. One possible measure would be an estimate of the number of surviving motor units. Despite over 30 years of motor unit number estimation (MUNE), all proposed methods have been met with practical and theoretical objections. Our aim is to develop a method of MUNE that overcomes these objections. We record the compound muscle action potential (CMAP) from a selected muscle in response to a graded electrical stimulation applied to the nerve. As the stimulus increases, the threshold of each motor unit is exceeded, and the size of the CMAP increases until a maximum response is obtained. However, the threshold potential required to excite an axon is not a precise value but fluctuates over a small range leading to probabilistic activation of motor units in response to a given stimulus. When the threshold ranges of motor units overlap, there may be alternation where the number of motor units that fire in response to the stimulus is variable. This means that increments in the value of the CMAP correspond to the firing of different combinations of motor units. At a fixed stimulus, variability in the CMAP, measured as variance, can be used to conduct MUNE using the "statistical" or the "Poisson" method. However, this method relies on the assumptions that the numbers of motor units that are firing probabilistically have the Poisson distribution and that all single motor unit action potentials (MUAP) have a fixed and identical size. These assumptions are not necessarily correct. We propose to develop a Bayesian statistical methodology to analyze electrophysiological data to provide an estimate of motor unit numbers. Our method of MUNE incorporates the variability of the threshold, the variability between and within single MUAPs, and baseline variability. Our model not only gives the most probable number of motor units but also provides information about both the population of units and individual units. We use Markov chain Monte Carlo to obtain information about the characteristics of individual motor units and about the population of motor units and the Bayesian information criterion for MUNE. We test our method of MUNE on three subjects. Our method provides a reproducible estimate for a patient with stable but severe ALS. In a serial study, we demonstrate a decline in the number of motor unit numbers with a patient with rapidly advancing disease. Finally, with our last patient, we show that our method has the capacity to estimate a larger number of motor units.

Action Potentials↗
PubMed1998

Clinical experience with cabergoline in patients with advanced Parkinson's disease treated with levodopa.

The clinical efficacy of the long-acting dopamine agonist cabergoline as an adjunct to levodopa has been investigated in controlled and uncontrolled studies in > 1500 patients with advanced Parkinson's disease and motor complications. Four of these studies (including 2 comparisons with placebo and 2 with bromocriptine), which used similar methodology (including study design, blindness, selection criteria, treatment modalities and duration) and measurements of efficacy and safety, are reviewed. Compared with placebo, cabergoline 2 to 10 mg/day (median 5 mg/day) induced a significantly higher percentage decrease in the number of 'off' hours (18 vs 45%) in a preliminary phase II study that included 37 patients with severe motor fluctuations. This was not associated with an increase in dyskinesia in either treatment group. In a subsequent phase III placebo-controlled study (n = 188 patients with motor fluctuations), treatment with cabergoline 0.5 to 5 mg/day (median 3.5 mg/day) achieved a statistically significant decrease in levodopa dosage compared with placebo (18 vs 3%) and improved the Unified Parkinson's Disease Rating Scale scores for activities of daily living in a greater number of patients (23 vs 4%). Comparisons of cabergoline with bromocriptine have been conducted in 750 patients stabilised on levodopa therapy; one study was conducted in patients without, and the other in patients with, previous exposure to dopamine agonists. Cabergoline was administered once daily at doses ranging from 0.5 to 6 mg, and bromocriptine was given at a dosage of 5 to 40 mg/day divided into 3 administrations. A combined analysis of the response rates obtained in the 2 studies found cabergoline to be at least as effective and well tolerated as bromocriptine, with a trend in favour of cabergoline in terms of response rate and number of 'off' hours. The majority of adverse events in this patient population were those associated with levodopa therapy, as shown by the high frequency of adverse events in the placebo group (68%). Both cabergoline and bromocriptine showed a comparable incidence of adverse events, with CNS and gastrointestinal events being the most common. Thus, the potential advantages of cabergoline include improved patient compliance as a result of its once-daily administration, and an increased threshold for the development of dyskinesia as a result of the levodopa sparing effect of cabergoline.

Antiparkinson Agents↗
PubMed1992

Selegiline: an appraisal of the basis of its pharmacoeconomic and quality-of-life benefits in Parkinson's disease.

Selegiline (deprenyl) is a selective, irreversible cerebral monoamine oxidase type B inhibitor (MAO-B) that is used in the treatment of Parkinson's disease. It has a relatively mild adverse effect profile without risk of the tyramine ('cheese') reaction at normal therapeutic doses. In about half to two-thirds of patients with mild levodopa response fluctuations, selegiline improves overall disability and 'end-of-dose' fluctuations, with a levodopa-sparing effect. Selegiline thus may improve patient quality of life, although formal cost-utility analyses are required to establish the costs of these benefits. Cost-effectiveness studies may help characterise the relative pharmacoeconomic benefits of selegiline and the dopamine agonists, agents which can also be administered as adjuvant therapy at this stage of the disease. There is also evidence to suggest that selegiline may delay the need for levodopa therapy by up to 11 months in patients with early Parkinson's disease, although the relative contribution of neuroprotective and symptomatic effects of selegiline in these patients has yet to be clarified. From a societal perspective, a theoretical analysis indicates that the economic benefits of selegiline therapy are likely to be substantial. An agent which slowed progression of disability by around 10% would realise savings, through reduction in both direct and indirect costs, in the order of $US330 million per annum in the United States. Available data suggest that selegiline slows progression of symptoms well in excess of 10%. Further, if a simple and inexpensive method is developed to identify preclinical Parkinson's disease before nigrostriatal damage is advanced, selegiline may be useful in a broader patient population with possible financial benefits to society through reduction of the considerable indirect costs of Parkinson's disease.

Cost of Illness↗
PubMed2002

The receptor-like properties of nitric oxide-activated soluble guanylyl cyclase in intact cells.

Soluble guanylyl cyclase (sGC) is the main receptor for nitric oxide (NO), and so mediates a wide range of effects (e.g. vasodilatation, platelet disaggregation and neural signalling) through the accumulation of cGMP and the engagement of various downstream targets, such as protein kinases and ion channels. Until recently, our understanding of sGC functioning has been derived exclusively from studies of the enzyme in tissue homogenates or in its purified form. Here, NO binds to the haem prosthetic group of sGC, triggering a conformational change and a large increase in catalytic activity. The potency (EC50) of NO appears to be about 100-200 nM. The rate of activation of sGC by NO is rapid (milliseconds) and, in the presence of excess substrate, cGMP is formed at a constant rate; on removal of NO, sGC deactivates slowly (seconds-minutes). Recent investigation of the way that sGC behaves in its natural environment, within cells, has revealed several key differences. For example, the enzyme exhibits a rapidly desensitizing profile of activity; the potency of NO is 45 nM for the minimally-desensitized enzyme but becomes higher with time, deactivation of sGC on removal of NO is 25-fold faster than the fastest estimate for purified sGC. Overall, within cells, sGC behaves in a way that is analogous to the way that classical neurotransmitter receptors operate. The properties of cellular sGC have important implications for the understanding of NO-cGMP signalling. For example, the dynamics of the enzyme means that fluctuations in the rate of NO formation, even on subsecond time scale, will result in closely synchronized sGC activity in neighbouring cells; desensitization of sGC provides an economical way of generating a cellular cGMP signal and, in concert with phosphodiesterases, provides the basis for cGMP signal diversity, allowing different targets (outputs) to be selected from a common input (NO). Thus, despite exhibiting only limited molecular heterogeneity, cellular sGC functions in a way that introduces speed, complexity, and versatility into NO-cGMP signalling pathways.

Animals↗
PubMedDate not supplied

[Nomograms for calculating the parameters of a system of recording intracavitary pressure through sounds].

The signal of the intracavitary pressure registered through a probe is, as a rule, distorted by fluctuations of the liquid column in the probe. Nomograms enabling the velocity of the sound wave and the own frequency oscillations of the measuring system to be found from the size of the probe, elastic modulus of its material and elasticity of the bulk of the guage are described. In this way a selection of probes to secure high-quality recording of the signal is facilitated. An example of a calculation with the use of the nomograms is given.

Blood Pressure Determination↗
PubMed1999

Selected results of the tuberculosis control program in the Czech Republic.

There are probably several causes why steady decrease of tuberculosis incidence stopped. The aim of our work was to investigate a possible relation of tuberculosis incidence in smaller administrative areas with several social and economic characteristics. The individual data were taken from the Information System of Bacillary Tuberculosis, based on laboratory reporting network. Tuberculosis incidence dropped to 19.8/100,000 in 1987 and since then it fluctuates around that level. The levels in districts ranged from 1.9 to 45.6 in 1997. The social status, overcrowding, air pollution and unemployment rates are weakly correlated with tuberculosis incidence. These unfavourable values of social, economical and ecological indicators are linked with more industrialised parts of the country. Age and gender analysis shows that male population aged from 40-60 is the most affected population with higher rates of smear positive pulmonary TB. These rates are positively linked with a size of the municipality, in larger towns higher number of those cases are detected. Contrary to that, relatively higher rates of pulmonary tuberculosis are in elderly women in smaller municipalities. There is a suspicion about important role of relative poverty in the epidemiology of tuberculosis in the Czech Republic. The results indicate that we should concentrate our effort to reduce the incidence of tuberculosis mainly in economically active male population.

Adolescent↗
PubMed1991

Seasonal variation of cerebrovascular diseases.

The seasonal variation in all admissions of all types of cerebrovascular disease within the West Midlands Region was examined between the years 1973-1980. There was a fluctuation for both sexes with a peak in winter, between the months of October and April; a trough was observed in late summer, in July and August. Multivariate analysis of the meteorological factors showed an association between hours of sunshine and intracerebral haemorrhage. The meterological variables were strongly correlated with each other making the selection of the most predictable variable to stroke difficult.

Cerebral Hemorrhage↗