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PubMed2006

Recirculatory pharmacokinetic model of the uptake, distribution, and bioavailability of prochlorperazine administered as a thermally generated aerosol in a single breath to dogs.

A thermal aerosol generation process is capable of delivering pure drug reliably to the alveoli where it is absorbed systemically. Although deep lung absorption of drugs administered as an aerosol has been shown to be rapid, detailed characterization of their absorption and distribution has not been reported. The present study describes the pharmacokinetics of prochlorperazine from the moment of administration as either a rapid intravenous infusion or a thermally generated aerosol and determines the bioavailability of the aerosol by two independent methods. Prochlorperazine disposition was determined in four anesthetized dogs after a 5-s intravenous infusion and after thermally generated aerosol administration in one breath. Venous blood samples were collected frequently from the time of drug administration to 24 h and left ventricular blood samples were drawn more often until 10 min after drug administration. Prochlorperazine disposition after intravenous and aerosol administration was characterized by fitting a recirculatory model to left ventricular and venous drug concentration data simultaneously. Prochlorperazine aerosol administration produced plasma drug concentrations similar to those after rapid intravenous administration of the same nominal dose, with peak left ventricular concentrations achieved in less than 30 s. Plasma concentration profiles of prochlorperazine administered by both routes were well described by the recirculatory model. Bioavailability of the thermally generated aerosol was consistent and averaged more than 80% of emitted dose. Pulmonary administration of a thermally generated drug aerosol in one breath may be a viable alternative to rapid intravenous administration of drugs requiring rapid and predictable production of effective plasma concentrations.

Aerosols↗

PubMed2000

Population genetics of Glossina morsitans submorsitans (Diptera: Glossinidae).

Breeding structure of Glossina morsitans submorsitans Newstead was evaluated by using genetic markers in mitochondrial DNA where diversity was scored at two loci in five natural populations from The Gambia and two populations in Ethiopia (form ugandensis Vanderplank), countries separated by c. 5450 km. Twenty six haplotype combinations were found, of which 17 were shared among two or more populations. Nine haplotypes were found in The Gambia and 23 haplotypes in Ethiopia. There were 12 unique haplotypes. Only six haplotypes were shared between the two countries. Populations in The Gambia (he = 0.26 +/- 0.04) showed less than a third of the diversity of populations in Ethiopia (he = 0.84 +/- 0.03). This suggests recovery from an earlier reduction in population. In a nested analysis of molecular variance of haplotype frequencies, 65% of the variance was due to differences within populations, 34% to differences between populations grouped by country, and only 1% was due to differences among populations within countries. In terms of gene flow, the fixation index FST = 0.35, which leads to an estimate by Wright's island model of less than one reproducing migrant per generation exchanged between the eastern and western submorsitans populations. Nei's genetic similarity measure showed a deep division between Gambian and Ethiopian populations.

Alleles↗

PubMed1993

Equivalent electrical source analysis of pain-related somatosensory evoked potentials elicited by a CO2 laser.

The purpose of this study was to localize possible neural sources of pain-related cortical evoked potentials. A brain electrical source analysis was performed on late somatosensory evoked potential data (500-ms window was analyzed) elicited by short heat pulses produced by a CO2 laser. These stimuli activate pain and temperature pathways. The first, fairly small, negative response can be recorded on the scalp about 160 ms from the stimulus (N1 component). The major negativity on the scalp has its peak about 240 ms from the stimulus and is followed by a positivity (N2 and P2 components). A four-dipole model was developed using data following left-hand stimulation. Spatiotemporal source analysis suggested that the N1 component could be generated by contralateral activity in both primary and secondary somatosensory cortices and that N2 could be generated by bilateral activity mainly in secondary somatosensory cortices. A deep dipole in the midline was active during the time range of the negative potentials and seemed to be mostly responsible for the P2 component. This dipole was located too frontally to be thalamic, but it corresponded well to the location of the anterior cingulate gyrus. The model also yielded good fits for right-hand and left-foot stimulation data and, in addition, another set of left-hand data obtained with different electrode spacing in a different group of subjects (residual variances from 2.8% to 3.3%). The model explaining data sets from different body part stimulations varied very little, except with respect to the location of the dipole representing the activity of the primary somatosensory area.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed2002

Magnetic resonance imaging and deep brain stimulation.

OBJECTIVE: To determine whether cranial magnetic resonance imaging (MRI) is associated with deep brain stimulation (DBS) lead displacement or program interference. METHODS: In vitro and in vivo studies were performed with the Itrel II implantable pulse generator (IPG) (Model 7424; Medtronic, Minneapolis, MN), Medtronic 3387 and 3389 leads, and a 1.5-T GE Horizon LX scanner (General Electric, Milwaukee, WI). In the in vivo study, two MRI volumetric data sets were compared for each of five patients undergoing staged, bilateral, DBS electrode placement in the thalamic or subthalamic nucleus. The data sets were acquired shortly after the initial implantation and during stereotactic planning for the second implantation (1-8 mo between acquisitions). An additional thalamotomy-treated patient was included as a control patient. Volumetric data were analyzed in a blinded manner, using AnalyzeAVW 3.0 software (Biomedical Imaging Resource, Mayo Clinic, Rochester, MN), to determine lead movement. In the in vitro study, the IPG and leads were positioned in the magnetic field in various configurations and were systematically assessed for movement. RESULTS: In vivo, the majority of measured deviations (88%) were within the standard error of measurement (1.4 mm). The maximal measured deviation was 3 mm (2% occurrence). Excellent tremor control with stimulation was demonstrated, which did not change after MRI. In vitro, the DBS leads demonstrated no deflection when introduced into the magnetic field. Similarly, no changes in IPG battery strength, lead impedance, or program settings were observed. CONCLUSION: MRI was not associated with significant DBS electrode movement or changes in clinical responses. Other IPG models and components and MRI scanners should be evaluated, to develop specific guidelines for MRI among individuals with implanted DBS systems.

Electric Stimulation Therapy↗

PubMed1996

A fractal approach to heterogeneous drug distribution: calcium pharmacokinetics.

PURPOSE: To point out the importance of heterogeneity in drug distribution processes and develop a noncompartmental approach for the description of the distribution of drug in the body. METHODS: A dichotomous branching network of vessels for the arterial tree connected to a similar venous network was used to describe the heterogeneity of blood flow in the successive generations of the networks. The relevant kinetics of drug distribution in the well perfused and the deep tissues was considered to take place under well stirred (homogeneous) and understirred (heterogeneous) conditions, respectively. RESULTS: A "homogeneous model" with classical kinetics (which is mathematically equivalent with the one-compartment model) was developed for these drugs which are confined to well perfused ("well stirred") spaces. A "heterogeneous model" was proposed for the drugs reaching understirred spaces using a decreasing with time rate coefficient (fractal kinetics) to model the diffusion of drug under heterogeneous conditions. The analysis of the model equations revealed that the homogeneous model can be considered as a special case of the heterogeneous model. Concentration-time plots of multiexponential type were generated using the heterogeneous model equation. The empirically used power functions of time for the analysis of calcium clearance curves, were found to be similar to the equation adhering to the heterogeneous model. Fittings comparable to multiexponential models were obtained when the heterogeneous model equation with only one adjustable parameter was applied to six sets of long period calcium data. CONCLUSIONS: The heterogeneous processes of drug distribution in the body can obey the principles of fractal kinetics. Calcium clearance curves were analysed with the heterogeneous model. The validity of multicompartmental models which are based on the concept of homogeneity to describe drug distribution should be reconsidered.

Calcium↗

PubMed1996

Simultaneous and different binding mechanisms of 4',6-diamidino-2-phenylindole to DNA hexamer (d(CGATCG))2. A 1H NMR study.

The solution structure of the complex between 4', 6-diamidino-2-phenylindole (DAPI) and DNA oligomer (d(CGATCG))2 at a 2:1 drug/duplex ratio has been characterized by combined use of proton one- and two-dimensional NMR spectroscopy, molecular mechanics, and molecular dynamics computations. Intermolecular nuclear Overhauser effects (NOEs), DNA structure perturbations, and resonance shifts induced by binding provide evidence that DAPI interacts with DNA hexamer by two different binding mechanisms, in fast exchange on the NMR time scale, without any significant distortion of the B-type conformation of DNA hexamer. The results indicate that the ligand binds into the minor groove of the central 5'-ATC-3' region of the hexamer and on the outside of the oligomer by a pi,pi-stacking interaction with the terminal C1:G6 base pairs. A model for both binding mechanisms that accounts for all experimental data was generated by molecular mechanics and dynamics calculations based on experimental NOEs. In the minor groove binding, N2 amino group of G2 precludes a deep insertion of phenyl ring of DAPI into the groove. Position and orientation of the drug in the external stacking interaction resemble those suggested for intercalation of DAPI between C:G base pairs.

Base Composition↗

PubMed1985

Responses of neurons in the cat's superior colliculus to acoustic stimuli. II. A model of interaural intensity sensitivity.

Most neurons in the deep and intermediate layers of the superior colliculus (SC) that respond to acoustic stimuli are sensitive to interaural intensity disparities (IIDs). We examine a model for the generation of sensitivity to IIDs that depends upon temporal coincidence of the inputs from each ear at a given binaural neuron. Because the neural response latency decreases with increasing stimulus intensity, IIDs affect the relative timing of arrival of the inputs. If this model were true, the neurons sensitive to IIDs should also respond to interaural time differences (ITDs) of isointensive stimuli, provided that the magnitude of the delays reflect the neural latency-intensity relationship. For both major classes of binaural cells in the SC, namely those that exhibit binaural inhibition (BI) and binaural facilitation (BF), our results support the model in that the detection of IIDs is largely due to their sensitivity to the temporal overlap of inputs from each ear. The shapes of the IID and ITD functions for each class are similar. The summation of inputs includes inhibitory as well as facilitatory interactions. Estimates of the durations of the subliminal excitatory events in BF cells using the model indicate that they are relatively short (1-4 ms), whereas the durations of the inhibitory processes in BI cells are much longer. The model specifies a common neuronal mechanism for comparison of interaural disparities of time and intensity and does not separate the processing of IIDs and ITDs, as the classic duplex theory suggests. The model provides a physiological explanation for certain features of the psychophysical phenomenon of time-intensity trading. It is also consistent with recent experiments that have shown that the auditory system is sensitive to behaviorally significant ITDs of high-frequency complex signals. The model applies only to the processing of transient stimuli and does not address neural sensitivity to IIDs of continuous high-frequency tones.

Animals↗

PubMed2001

The effects of peripheral administration of a novel selective antagonist for prostaglandin E receptor subtype EP(1), ONO-8711, in a rat model of postoperative pain.

UNLABELLED: Mechanically evoked pain, also known as incident pain, induced by coughing or deep breathing after surgery leads to potentially devastating consequences. It is generally thought that the prostaglandin receptor- (especially, the receptor for prostaglandin E(2), EP receptor) mediated sensitization of sensory nerve fibers is a key contributor to the generation of hyperalgesia. We examined whether a peripherally administered novel selective EP(1) antagonist, ONO-8711, would be a potential analgesic for incision-induced mechanical hyperalgesia. We used a rat model of postoperative pain introduced by Brennan et al. (1). Withdrawal thresholds to punctate stimulation and response frequencies to nonpunctate mechanical stimulation were determined by using von Frey filaments applied adjacent to the wound and directly to the incision site of the hind paw, respectively. Mechanical hyperalgesia to punctate and nonpunctate stimuli was observed 2 and 24 h after the incision. ONO-8711 (2, 10, or 50 microg) or saline was administered subcutaneously into the hind paw on the ipsilateral side to the incision. ONO-8711 significantly (P < 0.01) increased the withdrawal thresholds to punctate mechanical stimulation and significantly (P < 0.01) decreased the response frequencies to nonpunctate mechanical stimulation in a dose- and time-dependent manner 2 and 24 h after the incision. We conclude that EP(1) receptor-mediated sensitization of sensory nerve fibers may contribute to the generation of mechanical hyperalgesia produced by incisional surgery, and that the EP(1) receptor antagonist ONO-8711 may be an option for treatment of postoperative pain, especially incident pain. IMPLICATIONS: The peripheral administration of an antagonist for EP(1) receptor that is a subtype of prostaglandin E receptors can inhibit the mechanical hyperalgesia induced by a surgical incision.

Animals↗

PubMedDate not supplied

[Is the implantation of hinged knee joint prostheses still justifiable today? 15 years' experience using the Blauth knee joint prosthesis].

In objection to knee hinge prostheses there is often mentioned a higher complication rate. An increased load impact on the bone-cement interface results from the close connection of tibial and femoral components. This is assumed to cause bad results, as reported from early artificial knee joint replacements, characterised by weight bearing axes and direct contact metal to metal. These are contrasted to long term results of the Blauth hinge prosthesis. The Blauth prosthesis is constructed according to the low friction principle without a weightbearing axis. A prospective multicentric long term follow-up study reports on 556 prostheses. 463 (83%) were controlled between 1 and 15 years after operation (average: 43 months). Aseptic loosenings had to be confirmed in 1.3% of the patients, deep infections in 2.6%. The survival analysis did not show an erratic deterioration in dependence of the observation period. After 10 years there is still a probability of 89% that a prosthesis does not show a deep infection or loosening. The efficiency of artificial knee joint replacement by hinge joints should therefore not be judged on the results of the first generation of these models.

Adult↗

PubMed2005

Purkinje cell activity in the cerebellar anterior lobe after rabbit eyeblink conditioning.

The cerebellar anterior lobe may play a critical role in the execution and proper timing of learned responses. The current study was designed to monitor Purkinje cell activity in the rabbit cerebellar anterior lobe after eyeblink conditioning, and to assess whether Purkinje cells in recording locations may project to the interpositus nucleus. Rabbits were trained in an interstimulus interval discrimination procedure in which one tone signaled a 250-msec conditioned stimulus-unconditioned stimulus (CS-US) interval and a second tone signaled a 750-msec CS-US interval. All rabbits showed conditioned responses to each CS with mean onset and peak latencies that coincided with the CS-US interval. Many anterior lobe Purkinje cells showed significant learning-related activity after eyeblink conditioning to one or both of the CSs. More Purkinje cells responded with inhibition than with excitation to CS presentation. In addition, when the firing patterns of all conditioning-related Purkinje cells were pooled, it appeared that the population showed a pattern of excitation followed by inhibition during the CS-US interval. Using cholera toxin-conjugated horseradish peroxidase, Purkinje cells in recording areas were found to project to the interpositus nucleus. These data support previous studies that have suggested a role for the anterior cerebellar cortex in eyeblink conditioning as well as models of cerebellar-mediated CR timing that postulate that Purkinje cell activity inhibits conditioned response (CR) generation during the early portion of a trial by inhibiting the deep cerebellar nuclei and permits CR generation during the later portion of a trial through disinhibition of the cerebellar nuclei.

Animals↗

PubMed1998

Time scales and heterogeneous structure in geodynamic earth models

Computer models of mantle convection constrained by the history of Cenozoic and Mesozoic plate motions explain some deep-mantle structural heterogeneity imaged by seismic tomography, especially those related to subduction. They also reveal a 150-million-year time scale for generating thermal heterogeneity in the mantle, comparable to the record of plate motion reconstructions, so that the problem of unknown initial conditions can be overcome. The pattern of lowermost mantle structure at the core-mantle boundary is controlled by subduction history, although seismic tomography reveals intense large-scale hot (low-velocity) upwelling features not explicitly predicted by the models.

Journal Article↗

PubMed2025

Deep learning guided programmable design of Escherichia coli core promoters from sequence architecture to strength control.

Core promoters are essential regulatory elements that control transcription initiation, but accurately predicting and designing their strength remains challenging due to complex sequence-function relationships and the limited generalizability of existing AI-based approaches. To address this, we developed a modular platform integrating rational library design, predictive modelling, and generative optimization into a closed-loop workflow for end-to-end core promoter engineering. Conserved and spacer region of core promoters exert distinct effects on transcriptional strength, with the former driving large-scale variation and the latter enabling finer gradation. Based on this insight, Mutation-Barcoding-Reverse Sequencing approach was used and constructed a synthetic promoter library comprising 112 955 variants with minimal redundancy and a 16 226-fold expression range. A Transformer-based model trained on this dataset achieved a Pearson correlation of 0.87 with experimentally measured promoter strengths. When combined with a conditional diffusion model, the system enabled de novo generation of promoter sequences with defined strengths, achieving a design-to-measurement correlation of 0.95 and maintaining high accuracy (R = 0.93) across varied sequence contexts. The designed promoters consistently preserved their intended strength gradients, demonstrating robust plug-and-play functionality. This work establishes a scalable and extensible platform (www.yudenglab.com) for deep learning-guided programmable design of Escherichia coli core promoters, enabling precise transcriptional control.

Promoter Regions, Genetic↗

PubMedDate not supplied

Model of pCO2 gap during hypothermic cardiopulmonary bypass.

Perfusion adequacy during cardiopulmonary bypass is important in reducing postoperative morbidity. The pCO2 gap (defined as the difference between blood and tissue pCO2 levels) has been shown to be a sensitive measure of ischemia resulting from inadequate perfusion in pediatric patients undergoing deep hypothermic cardiac arrest. The complexity of measuring tissue pCO2 levels has motivated development of a mathematical model to provide an indirect indication of pCO2 gap. The model allows us to examine relations between tissue pCO2, plasma pCO2, and the rate of CO2 removal through the extracorporeal oxygenator. Three compartments have been modeled with CO2 generation and mass transfer coefficients estimated on the basis of published correlations with height and weight. Model predictions have been compared with oxygenator exhaust measurements taken during a hypothermic cardiac procedure. The model predicts carbon dioxide buildup in the tissues during hypothermia followed by equilibration with the blood on rewarming. The model appears to qualitatively predict CO2 removal rates observed during deep hypothermic cardiac arrest. Refinement and validation of the model may lead to a tool for predicting tissue pCO2 levels during and after hypothermic cardiopulmonary bypass.

Carbon Dioxide↗

PubMed2006

Phylogeny of sipunculan worms: A combined analysis of four gene regions and morphology.

The intra-phyletic relationships of sipunculan worms were analyzed based on DNA sequence data from four gene regions and 58 morphological characters. Initially we analyzed the data under direct optimization using parsimony as optimality criterion. An implied alignment resulting from the direct optimization analysis was subsequently utilized to perform a Bayesian analysis with mixed models for the different data partitions. For this we applied a doublet model for the stem regions of the 18S rRNA. Both analyses support monophyly of Sipuncula and most of the same clades within the phylum. The analyses differ with respect to the relationships among the major groups but whereas the deep nodes in the direct optimization analysis generally show low jackknife support, they are supported by 100% posterior probability in the Bayesian analysis. Direct optimization has been useful for handling sequences of unequal length and generating conservative phylogenetic hypotheses whereas the Bayesian analysis under mixed models provided high resolution in the basal nodes of the tree.

Animals↗

PubMed2005

A birdcage model for the Chinese meridian system: part III. Possible mechanism of magnetic therapy.

Based on the electromagnetic model of the transmission line for the channel and the birdcage resonator for the meridian network, we interpret two effects, seemingly incomprehensible in terms of current Western physiology, the lasting effect and the remote effect. For the lasting effect, acupuncture enhances the amplitude of the Qi standing wave, and this increased amplitude is retained and thus is able to sustain a gradual remodeling of the extracellular matrix in interstitial connective tissues, resulting in a lasting therapeutic effect. For the remote effect (acupuncture effect far from the site of needle insertion), our model puts the mechanism of magnetic therapy on an equal footing with that of acupuncture. It may not be a coincidence that accounts of investigators in both acupuncture and magnetotherapy about the depth of the effective site--along cleavage planes between muscles, or between muscle and bone or tendon--are in accord with that of the Huang Di Nei Jing about the course of channels: "they are embedded and travel between interstitial muscles, deep and invisible." A possible magnetic field generated outside the birdcage may be manipulated to produce local areas of higher temperature or very strong fields.

Acupuncture Therapy↗

PubMed2002

Freely decaying weak turbulence for sea surface gravity waves.

We study the long-time evolution of deep-water ocean surface waves in order to better understand the behavior of the nonlinear interaction processes that need to be accurately predicted in numerical models of wind-generated ocean surface waves. Of particular interest are those nonlinear interactions which are predicted by weak turbulence theory to result in a wave energy spectrum of the form of [k](-2.5). We numerically implement the primitive Euler equations for surface waves and demonstrate agreement between weak turbulence theory and the numerical results.

Journal Article↗

PubMed2026

Peptide-phosphorodiamidate morpholino oligomer therapy for dysferlinopathy induces pseudoexon skipping and restoration of functional protein.

The dysferlinopathies are a spectrum of autosomal recessive muscle diseases caused by mutations in the dysferlin gene (DYSF). Clinical manifestations vary from asymptomatic hyperCKemia to severe muscle pathology and loss of muscle function. These are designated as limb-girdle muscular dystrophy type 2R (LGMDR2; formerly LGMD2B or Miyoshi myopathy). Among other functions, dysferlin is crucial for plasma membrane repair and maintenance of intracellular calcium homeostasis. In previous studies, we identified 2 independent point mutations deep within introns that cause aberrant DYSF mRNA splicing and the inclusion of pseudoexons within transcripts that diminish protein expression. In this study, we generated and characterized a mouse model for 1 of these mutations (within DYSF intron 44). In these mice, a segment of human DYSF DNA containing the mutant intronic sequence flanked by surrounding human exon sequences replaced the normal homologous mouse DNA. These mice exhibited aberrant Dysf pre-mRNA splicing, pseudoexon inclusion, loss of DYSF protein expression, and muscle pathology similar to that observed in patients. Using this model, we identified antisense oligonucleotides and a peptide-phosphorodiamidate morpholino oligomer that blocks the mouse Dysf pre-mRNA splicing complexes from binding the mutant pre-mRNA, thereby restoring nearly normal muscle pathology and function.

Animals↗

PubMed2001

Estimating the time to the most recent common ancestor for the Y chromosome or mitochondrial DNA for a pair of individuals.

Bayesian posterior distributions are obtained for the time to the most recent common ancestor (MRCA) for a nonrecombining segment of DNA (such as the nonpseudoautosomal arm of the Y chromosome or the mitochondrial genome) for two individuals given that they match at k out of n scored markers. We argue that the distribution of the time t to the MRCA is the most natural measure of relatedness for such nonrecombining regions. Both an infinite-alleles (no recurring mutants) and stepwise mutation model are examined, and these agree well when n is moderate to large and k/n is close to one. As expected, the infinite alleles model underestimates t relative to the stepwise model. Using a modest number (20) of microsatellite markers is sufficient to obtain reasonably precise estimates of t for individuals separated by 200 or less generations. Hence, the multilocus haplotypes of two individuals can be used not only to date very deep ancestry but also rather recent ancestry as well. Finally, our results have forensic implications in that a complete match at all markers between a suspect and a sample excludes only a modest subset of the population unless a very large number of markers (>500 microsatellites) are used.

Alleles↗