The use of speckle laser to identify canopy variations in plants subjected to ultra-high diluted substances

:The reaction of plants to ultra-high dilute substances (UHD) is well known, however, the signaling of the immediate effect still doesn't have a widely accepted methodology. The objective of this experiment was to use non-destructive sampling to find signs of UHD soon after application to plants. Methods:The control consisted of untreated purslane [Pilea microphylla (L.) Liebm] plants and imaged with a digital cameraMobius (CMOS 1270x720 pixels) directed at a laser beam (±680 nm) emitted over the plant canopy for 220 seconds, with 6-second intervals. Then, the same plants were treated with Fluoricum acidum30CH (Fl. ac.30),and ten minutes later, new images of the leaves were taken to verify the possible existence of reaction patterns of the plants generated by Biospeckle Laser (1,2). Results:Several types of imaging were performed to choose the image pattern, and the NIR type was chosen, generated by the Mobius camera connected directly to a laptop (Figure 1). The images were treated using the THSP algorithm, which generated data to compare the variation of pixel intensity with and without the presence of UHD. Conclusion:Research has shown that "Fl. ac. 30" is identified in purslane plants soon after application and this sign persists for at least 180 minutesafter application, with a significant difference from the control at the 1% probability level.

Models for the study of whole systems.

This article summarizes a network and complex systems science model for research on whole systems of complementary and alternative medicine (CAM) such as homeopathy and traditional Chinese medicine. The holistic concepts of networks and nonlinear dynamical complex systems are well matched to the global and interactive perspectives of whole systems of CAM, whereas the reductionistic science model is well matched to the isolated local organ, cell, and molecular mechanistic perspectives of pharmaceutically based biomedicine. Whole systems of CAM are not drugs with specific actions. The diagnostic and therapeutic approaches of whole systems of CAM produce effects that involve global and patterned shifts across multiple subsystems of the person as a whole. For homeopathy, several characteristics of complex systems, including the probabilistic nature of attractor patterns, variable sensitivity of complex systems to initial conditions, and emergent behaviors in the evolution of a system in its full environmental context over time, could help account for the mixed basic science and controlled clinical trial research findings, in contrast with the consistently positive outcomes of observational studies in the literature. Application of theories and methods from complex systems and network science can open a new era of advances in understanding factors that lead to good versus poor individual global outcome patterns and to rational triage of patients to one type of care over another. The growing reliance on complex systems thinking and systems biology for cancer research affords a unique opportunity to bridge between the CAM and conventional medical worlds with some common language and conceptual models.

Fuzzy logic for model adaptation of a pharmacokinetic-based closed loop delivery system for pancuronium.

In this paper, we investigate the ability of fuzzy to adapt the parameters of a pharmacokinetic and pharmacodynamic model-based controller for the delivery of the muscle relaxant pancuronium. The system uses the model to control the rate of drug delivery and uses feedback from a sensor which measures muscle relaxation level to adapt the model using fuzzy logic. The control strategy administers mini-bolus doses of pancuronium and modulates the magnitude and time interval between the bolus doses to maintain a patient's muscle relaxation within an allowable range specified by the user. Before each new dose is given, the fuzzy logic adaptation scheme uses the error between the predicted patient response and the measured response to adapt the model. The system was tested using computer simulation by varying the parameters of the model by 50% from their nominal values. It was also evaluated in a clinical trial of five patients undergoing surgical procedures lasting 5 h or longer.

[Homeopathy and structure of water: a physical model]. / Homöopathie und Wasserstruktur: Ein physikalisches Modell.

BACKGROUND: Formerly, the author has suggested a relatively simple water model. There, the dynamical structure of a typical water cluster was investigated, being represented by the movement of a ball in an abstract energy landscape. OBJECTIVE: Now the above-mentioned model is investigated in more detail to answer the following question: Are essential claims of homeopathy concerning potentiation (diluting and shaking) in agreement with science? METHODS: Equations of motion are employed that represent vibrations of clusters. For the computer experiments, the formalism of Nosé-Hoover is used, the surrounding water being interpreted as a heat bath. Diluting corresponds to a shift of the energy landscape towards the pure solvent (water), shaking is accompanied by an increase of the contact to the heat bath. RESULTS: There is a tendency of the ball to be caught in local valleys of the energy landscape (metastable states) if the temperature is not too high and if the liquid is not shaken. Thus, even for a given landscape there are a variety of structures being durable for some time. CONCLUSIONS: The computer experiments suggest that the repeated process of potentiation eventually results in a specific metastable state of the pure solvent. The initial substance helps to obtain this goal, but is no longer necessary at last.

Self-organising learning control and its application to muscle relaxant anaesthesia.

The concept of a self-organising control system is attractive in biomedicine because of the imprecise nature of available physiological models. In this paper a particular strategy called a self-organising controller (SOC) originating from the work of Barron on aerospace systems is applied to the control of muscle relaxant anaesthesia. The SOC algorithm, which requires no prior knowledge of system dynamics, is described, both in single variable and multivariable format. Simulation results are presented for SOC performance on a well-established pancuronium model. Three implementations are described, being the use of a general purpose language, a SUN workstation approach, and a parallel computer transputer solution. The latter approach becomes important for multivariable control because of the computing-intensive nature of SOC. The transputer is shown to be a suitable vehicle for implementation in terms of speed and parallelism for SOC.

[Interaction between vecuronium and pancuronium].

Interaction between vecuronium bromide (VB) and pancuronium bromide (PB) with regard to a change in duration of action was investigated in 32 elective surgical patients divided into four groups. Initial and supplemental drugs were as follow; group I: VB-->VB, group II: PB-->VB, group III: VB-->PB, group IV: PB-->PB. The muscle response was quantified electromyographically. Anesthesia was induced with thiopental. VB or PB 0.08 mg.kg-1 (initial dose) was given to facilitate endotracheal intubation. Anesthesia was maintained with 66% nitrous oxide and 2% sevoflurane in oxygen. Supplemental dose (0.015 mg.kg-1) of the muscle relaxants was administered at 10% recovery of twitch height. Duration of action was defined as the interval between administration and 10% recovery. Duration of action of supplemental doses of VB was significantly longer in group II than in group I. That of PB was significantly shorter in group III than in group IV. Therefore, it should be noticed that duration of action of supplemental relaxant is largely modified by the initial one.

Human narcotic use emulator.

Last year the author extended his modular, open-systems, computerized human nervous system function emulator (HNSFE) by adding simulated hormone action. This year he extends the HNSFE with a related capability: emulation of the effects of therapeutic and non-therapeutic drug use. The opioid narcotic drug model was chosen because of its importance in medicine and because of its potential for misuse. For this research the author utilized a frequency-to-voltage converter (FVC) as an analog calculational element to simulate the effects of drug binding to neural cell membrane receptors. The resulting voltages are utilized in this human narcotic use emulator (HNUE) to represent the level of opioid drug activity at the cellular level which initiates high level somatic and behavioral responses in the HNSFE artificial intelligence system. The HNUE is compatible with the computerized postoperative pain / narcotic dosing model of Liu and Northrop. Some effects of long-term drug use (the development of tolerance, physical and psychological dependence, addiction and the withdrawal syndrome) are emulated.

The quest for bioisosteric replacements.

To help advance drug discovery projects, a new and validated search method is presented by which potential bioisosteric replacements can be retrieved from a database of more than 700,000 structural fragments. The heart of the search method is an optimized topological pharmacophore fingerprint which describes each fragment as a combination of attachment points, hydrogen bond donors and acceptors, hydrophobic centers, conjugated atoms, and non-hydrogen atoms. In the fingerprint the influence of the attachment point is enhanced by giving it extra weight relative to the other descriptors. The Euclidean distance has proven to be the optimum distance measure to compare the fingerprints in a database search. The performance of the pharmacophore fingerprint based search method has been validated using more than 2200 bioisosteric fragment pairs extracted in an unbiased procedure from the BIOSTER database. The true bioisosteric pairs have been compared with pairs of random fragments originating from the WDI database. Normalized by the standard deviation of the random pairs distance distributions, an excellent separation of true pairs from random pairs was obtained for R-group fragments (2.2 standard deviation units) as well as for linkers (2.6 units) and cores (2.6 units). The bioisoster search method has been implemented as an intranet application called IBIS and is now routinely used by Organon researchers.

Modeling of twitch fade based on slow interaction of nondepolarizing muscle relaxants with the presynaptic receptors.

Nondepolarizing muscle relaxants (MRs) diminish the indirectly evoked single twitch due to their binding to the postsynaptic receptors. Additionally, the MRs produce progressive diminution of successive twitches upon repetitive stimulation (fade). Our study addresses the generation of fade as observed under clinical situation. The study was conducted in two phases. In the clinical part, we have evaluated the time course of twitch depression and fade following the administration of several doses of three MRs (rocuronium, pancuronium, and cisatracurium). In the second part, we have modified our model of neuromuscular transmission to simulate the time course of twitch depression and fade. The MR was assumed to bind to a single site on the presynaptic receptor to produce fade. The rates of interaction with the presynaptic receptors were characterized in terms of the arbitrarily assigned equilibrium dissociation constant and the half-life for dissociation of the presynaptic complex. A method was developed to relate the release of acetylcholine to the occupancy of the presynaptic receptors. The strength of the first and the fourth twitch was calculated from the peak concentration of the activated postsynaptic receptors, i.e., of those receptors with both sites occupied by acetylcholine. Our results indicate that, while the affinity of the MR for the presynaptic receptor plays little role in the time course of fade, the rate of dissociation of the complex between the presynaptic receptors and the muscle relaxant may be critical in determining the time course of fade. Tentative estimates of this parameter are offered.

On the dynamics of water molecules at the protein solute interfaces.

Proteins, with the large variety of chemical groups they present at their molecular surface, are a class of molecules which can be very informative on most of the possible solute-solvent interactions. Hen egg white lysozyme has been used as a probe to investigate the complex solvent dynamics occurring at the protein surface, by analysing the results obtained from Nuclear Magnetic Resonance, X-ray diffractometry and Molecular Dynamics simulations. A consistent overall picture for the dynamics of water molecules close to the protein is obtained, suggesting that a rapid exchange occurs, in a picosecond timescale, among all the possible hydration surface sites both in solution and the solid state, excluding the possibility that solvent molecules can form liquid-crystal-like supramolecular adducts, which have been proposed as a molecular basis of 'memory of water'.

Relationship between train-of-four ratio and first-twitch depression during neuromuscular blockade: a pharmacokinetic/dynamic explanation.

Fade, as measured by train-of-four, lags behind twitch depression during the initial phase of nondepolarizing neuromuscular blockade, i.e., the ratio of the fourth to first twitch height in a train (T4/T1) is greater at the onset of the block than during spontaneous recovery for the same level of first twitch depression. We believe that these data can be explained by picturing the muscle as having localized regions that respond much more slowly than the rest, leading to a delay in drug effect in that area, especially when the drug concentration rises rapidly as during bolus administration. This was modeled by computer as a muscle of 15 compartments distributed in a log-normal fashion according to equilibration rate. Experimental data consisting of the time course of first twitch and train-of-four ratio were fitted by nonlinear regression to the model. A good fit was obtained with a median equilibration time t1/2 of 3.3 min and a standard deviation of 2.1. The difference between train-of-four during onset and regression of block at the same level of first twitch depression was reproduced.

Simulating the time-course of clinical paralysis.

This computer program depicts the concentration-time curves for the nondepolarizing neuromuscular blocking agents. It simulates their administration by single and multiple iv injections, and with continuous infusion, alone and in combination. It provides the plasma concentrations related to 75% and 25% depression of the twitch response, using these to calculate clinically useful pharmacodynamic values, such as the duration of surgical relaxation, and the recovery index. These simulations allow the user to contrast the time-course of relaxation to be expected with various dosage regimens.

Alternatives to animal experimentation in biomedical education.

In education, it is important that students are not put in a position in which they are forced to participate in animal experiments or to use dead animals, killed especially for such purposes. Continued use of animal experiments to demonstrate known facts or teach skills which can be taught using non-animal methods evidences only a lack of sensitivity towards students who still maintain respect for life. In countries where animal testing in education is reduced to close to zero, there is no evidence that the students who are being trained are less capable or qualified. There are sufficient alternatives available at relatively low-cost and with proven educational efficacy to allow the vast majority of students who study biomedical science courses to qualify without using animal experiments. However, in many universities across Europe, there is still a resistance to adoption of such methods amongst faculty. The global situation is probably worse with animals still being used in high school teaching in some countries such as the USA.

Combining ethnopharmacology and virtual screening for lead structure discovery: COX-inhibitors as application example.

Virtual screening of large libraries of organic compounds combined with pharmacological high throughput screening is widely used for drug discovery in the pharmaceutical industry. Our aim was to explore the efficiency of using a biased 3D database comprising secondary metabolites from antiinflammatory medicinal plants as a source for the virtual screening. For this study pharmacophore models of cyclooxygenase I and II (COX-1, COX-2), key enzymes in the inflammation process, were generated with structure-based as well as common feature based modeling, resulting in three COX hypotheses. Four different multiconfomational 3D databases limited in molecular weight between 300 and 700 Da were applied to the screening in order to compare and analyze the obtained hit rates. Two of them were created in-house (DIOS, NPD). The database DIOS consists of 2752 compounds from phytochemical reports of antiinflammatory medicinal plants described by the ethnopharmacological source 'De material medica' of Pedanius Dioscorides, whereas NPD contains almost 80,000 compounds gathered arbitrarily from natural sources. In addition, two available multiconformational 3D libraries comprising marketed and development drug substances (DWI and NCI), mainly originating from synthesis, were used for comparison. As a test of the pharmacophore models' capability in natural sources, the models were used to search for known COX inhibitory natural products. This was achieved with some exceptions, which are discussed in the paper. Depending on the hypothesis used, DWI and NCI library searches produced hit rates in the range of 6.6% to 13.7%. A slight increase of the number of molecules assessed for binding was achieved with the database of natural products (NPD). Using the biased 3D database DIOS, however, the average increase of efficiency reached 77% to 133% compared to the hit rates resulting from WDI and NCI. The statistical benefit of a combination of an ethnopharmacological approach with the potential of computer aided drug discovery by in silico screening was demonstrated exemplified on the applied targets COX-1 and COX-2.