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Intervention studies and the definition of dominant transmission routes.

A common approach to assessing the relative importance of different transmission routes is to eliminate transmission through one route and assume that the ratio "number of cases eliminated:number of residual cases" measures the relative importance of the eliminated route vis-à-vis the residual transmission route. A quantitative model is used to generate synthetic data similar to those analyzed by epidemiologists. These data are analyzed using this conventional procedure and the inferences drawn from the synthetic data compared with the causal relationships structured into the model. The implications for the analysis of real-world data are analyzed by examining data on the importance of water and other transmission routes for cholera in Bangladesh.

Bangladesh↗

Mechanisms of interaction of extremely low frequency electric fields and biological systems.

This article reviews mechanisms of interaction between extremely-low frequency (ELF) fields and biological systems. The emphasis is on simple quantitative models, supplemented by results of more detailed computer analysis. Scaling relations are reviewed which underlie the coupling of external fields to the inside of the body, and of extracellular fields to potentials induced in cell membranes. The relation between time domain and frequency thresholds for stimulating excitable tissues is reviewed, based on the work of Reilly. A range of thermal and non-thermal interaction mechanisms are reviewed, with respect to the question of possible effects of weak ELF fields in biological systems. Each mechanism is characterised by a threshold field strength (below which no observable response is produced) and dynamics; in each case, the anticipated in situ tissue strengths for producing observable effects are far higher than the range of 'weak' fields considered in this review. However, the bioeffects literature is unclear in many places, with numerous speculations about possible mechanisms for weak field effects and many reports of effects that are not clearly interpretable in terms of the mechanisms discussed in this article.

Animals↗

Cardiac electrophysiology: theoretical considerations of a potential target for weak electromagnetic field effects.

With the widespread introduction of extra high voltage power transmission lines in the 1960s, and subsequent to early reports from Soviet Union scientists about health risks for transformer station personnel, public concern regarding the effects of electromagnetic fields (EMFs) on biological function has given rise to a large number of investigations and legislation to limit domestic and occupational exposure to EMFs. The underlying rationale for concern is related to the fact that living cells are electrically active, which makes them potentially vulnerable to electromagnetic interference. In the heart, electrical activity is crucial in coordinating the contraction of millions of cardiac cells, and disturbances in cardiac electrical activity, also known as arrhythmias, are often life threatening. Electrical fields induced in the heart by weak external EMFs (such as those encountered in a domestic setting) are understood to be at least 2 orders of magnitude smaller (< 1%) than those that occur naturally as an intrinsic consequence of cardiac activity. Using quantitative models of cardiac cellular electrophysiology, the effect of weak (1%) manipulation of key current mechanisms that give rise to the electrical activity of the heart is therefore assessed.

Animals↗

Quantitative structure-function and structure-stability relationships of purposely modified proteins.

Quantitative structure-function relationships (QSFR) and quantitative structure-stability relationships (QSSR) analyses are described here. The objective of these analyses is to investigate and quantitatively describe the effect of the changes in structure of protein on its function or stability. During the analysis, the structural and physico-chemical properties of the amino acid residues are related to activity or stability data derived for the group of proteins containing systematic substitutions at certain positions. Four examples of the application of these analyses on the data obtained with proteins modified by site-directed mutagenesis experiments are provided. Structure-function relationships were studied for 15 mutants in position 172 of the haloalkane dehalogenase and 19 mutants in position 222 of the subtilisin, while the structure-stability relationships were investigated for 13 mutants in position 157 of phage T4 lysozyme and 18 mutants in position 49 of alpha-subunits tryptophan synthase. A total of 402 molecular descriptors derived from AAindex database were used to quantify amino acid properties and the multivariate statistical technique--partial least squares projections to latent structures--was used to identify those of them which are important for explanation of the activity and stability data. Quantitative models were developed and internally validated for every data set. The possibilities for further development of both analyses and their application for predictive and analytical purposes in protein engineering research are discussed.

Glutamic Acid↗

Acute deprivation of the terminal 3.5 hours of sleep does not increase delta (0-3-Hz) electroencephalograms in recovery sleep.

Sleep electroencephalograms (EEG) and electrooculograms were recorded in nine young adult males on a baseline night, a night in which they were deprived of an average of 3 hr 27 min of sleep by early awakening, and on a recovery night. Records were analyzed by visual sleep stage scoring and period-amplitude analysis; the results of both were tabulated by successive nonrapid eye movement periods (NREMPs) and rapid eye movement (REM) periods. Neither visually scored delta nor REM measures were affected by this substitution of waking for sleep. Although there was a significant increase in the 0-3-Hz time/epoch on the recovery night, this finding was not confirmed in the accompanying report. These results, taken in association with data from previous studies, are consistent with the hypothesis that, in an acute experiment, visually scored delta and computer-measured 0-3-Hz EEGs increase above the baseline levels only if there has been loss of stage 3/4 EEG (or of sleep) from the first two NREMPs. The findings here are inconsistent with older reports and indicate that further parametric data are required to construct a quantitative model of the relation of sleep EEG waveforms to the duration of prior waking.

Adult↗

The practice of structure activity relationships (SAR) in toxicology.

Both qualitative and quantitative modeling methods relating chemical structure to biological activity, called structure-activity relationship analyses or SAR, are applied to the prediction and characterization of chemical toxicity. This minireview will discuss some generic issues and modeling approaches that are tailored to problems in toxicology. Different approaches to, and some facets and limitations of the practice and science of, SAR as they pertain to current toxicology analyses, and the basic elements of SAR and SAR-model development and prediction systems are discussed. Other topics include application of 3-D SAR to understanding of the propensity of chemicals to cause endocrine disruption, and the use of models to analyze biological activity of metal ions in toxicology. An example of integration of knowledge pertaining to mechanisms into an expert system for prediction of skin sensitization to chemicals is also discussed. This minireview will consider the utility of modeling approaches as one component for better integration of physicochemical and biological properties into risk assessment, and also consider the potential for both environmental and human health effects of chemicals and their interactions.

Animals↗

Concentration-effect relation of succinylcholine chloride during propofol anesthesia.

BACKGROUND: The pharmacokinetics and pharmacodynamics of succinylcholine were studied simultaneously in anesthetized patients to understand why the drug has a rapid onset and short duration of action. A quantitative model describing the concentration-effect relation of succinylcholine was proposed. The correlation between hydrolysis in plasma and elimination was also examined. METHODS: Before induction of anesthesia, blood was drawn for analysis in seven adults. Anesthesia was induced with propofol and remifentanil. Single twitch stimulation was applied at the ulnar nerve every 10 s, and the force of contraction of the adductor pollicis was measured. Arterial blood was drawn frequently after succinylcholine injection to characterize the front-end kinetics. Plasma concentrations were measured by mass spectrometry, and pharmacokinetic parameters were derived using compartmental and noncompartmental approaches. Pharmacokinetic-pharmacodynamic relations were estimated. RESULTS: The mean degradation rate constant in plasma (1.07 +/- 0.49 min(-1)) was not different from the elimination rate constant (0.97 +/- 0.30 min(-1)), and an excellent correlation (r2 = 0.94) was observed. Total body clearance derived using noncompartmental (37 +/- 7 ml x min(-1) x kg(-1)) and compartmental (37 +/- 9 ml x min(-1) x kg(-1)) approaches were similar. The plasma-effect compartment equilibration rate constant (k(eo)) was 0.058 +/- 0.026 min(-1), and the effect compartment concentration at 50% block was 734 +/- 211 ng/ml. CONCLUSION: Succinylcholine is a low-potency drug with a very fast clearance that equilibrates relatively slowly with the effect compartment. Its disappearance is greatly accountable by a rapid hydrolysis in plasma.

Adult↗

Classic benzodiazepines modulate the open-close equilibrium in alpha1beta2gamma2L gamma-aminobutyric acid type A receptors.

BACKGROUND: Classic benzodiazepine agonists induce their clinical effects by binding to a site on gamma-aminobutyric acid type A (GABAA) receptors and enhancing receptor activity. There are conflicting data regarding whether the benzodiazepine site is allosterically coupled to gamma-aminobutyric acid binding versus the channel open-close (gating) equilibrium. The authors tested the hypothesis that benzodiazepine site ligands modulate alpha1beta2gamma2L GABAA receptor gating both in the absence of orthosteric agonists and when the orthosteric sites are occupied. METHODS: GABAA receptors were recombinantly expressed in Xenopus oocytes and studied using two-microelectrode voltage clamp electrophysiology. To test gating effects in the absence of orthosteric agonist, the authors used spontaneously active GABAA receptors containing a leucine-to-threonine mutation at residue 264 on the alpha1 subunit. To examine effects on gating when orthosteric sites were fully occupied, they activated wild-type receptors with high concentrations of a partial agonist, piperidine-4-sulfonic acid. RESULTS: In the absence of orthosteric agonists, the channel activity of alpha1L264Tbeta2gamma2L receptors was increased by diazepam and midazolam and reduced by the inverse benzodiazepine agonist FG7142. Flumazenil displayed very weak agonism and blocked midazolam from further activating mutant channels. In wild-type receptors activated with saturating concentrations of piperidine-4-sulfonic acid, midazolam increased maximal efficacy. CONCLUSIONS: Independent of orthosteric site occupancy, classic benzodiazepines modulate the gating equilibrium in alpha1beta2gamma2L GABAA receptors and are therefore allosteric coagonists. A Monod-Wyman-Changeux coagonist gating model quantitatively predicts these effects, suggesting that benzodiazepines minimally alter orthosteric ligand binding.

Algorithms↗

Downstream anastomotic hyperplasia. A mechanism of failure in Dacron arterial grafts.

The precise location and progression of anastomotic hyperplasia and its possible relationship to flow disturbances was investigated in femoro-femoral Dacron grafts in 28 dogs. In 13 grafts, the outflow from the end-to-side downstream anastomosis was bidirectional (BDO), and in 15 it was unidirectional (UDO) (distally). Grafts were electively removed at intervals of two to 196 days or at the time of thrombosis. Each anastomosis and adjacent artery was perfusion-fixed and sectioned sagittally. The mean sagittal section was projected onto a digitized pad, and the total area of hyperplasia internal to the arterial internal elastic lamina and within the adjacent graft was integrated by computer. The location of the hyperplasia was compared with previously established sites of flow separation and stagnation. The observation was made that hyperplasia is significantly greater at the downstream, as compared with the upstream, anastomosis in both groups (BDO = p less than 0.001 and UDO = p less than 0.001) (analysis of variance for independent groups). Furthermore, this downstream hyperplasia was progressive with time (BDO p less than 0.01) (UDO p less than 0.01); Spearman Rank Correlation. There was no significant increase in the extent of downstream hyperplasia where flow separation was known to be greater (BDO). Five grafts failed (three BDO, two UDO), as a result of complete occlusion of the downstream anastomosis by fibrous hyperplasia. Transmission electron microscopy showed the hyperplasia to consist of collagen-producing smooth muscle cells. Anastomotic hyperplasia is significantly greater at the downstream anastomosis, is progressive with time, and is the primary cause of failure of Dacron arterial grafts in this model. Quantitative analysis of downstream anastomotic hyperplasia may be a valuable measure of the biocompatibility of Dacron grafts.

Animals↗

There's a shortage of specialists: is anyone listening?

The author critiques the long-standing belief that there will be too many physicians, particularly specialists, a view put forth by the Bureau of Health Professions and the Council on Graduate Medical Education in the 1990s and held by many medical organizations, including the Association of American Medical Colleges. He cites his own research, which predicts, to the contrary, that the United States will experience progressively more severe shortages of specialists, and he quotes a wide variety of anecdotal evidence indicating that such shortages are beginning to appear already. He maintains that most previous workforce studies were handicapped by their use of micro-quantitative models. Instead, his research has been structured around four broad trends: economic expansion (which directly influences the demand for physicians), physician work-effort (which is declining), the provision of physicians' services by non-physician clinicians (which is increasing), and the growth of the U.S. population (which often has not been factored in adequately). It is the intertwining of these four major trends that reveals the impending shortages of physicians. He recommends that attention be directed to training more specialists, but cautions against a further dependence on international medical graduates to fill the gap. Instead, he calls upon academic medicine to expand the infrastructure for medical education. However, despite what he sees as a growing cacophony of voices expressing alarm about the developing shortages, he is concerned that academic medicine may not be listening.

Health Workforce↗

A single-band envelope cue as a supplement to speechreading of segmentals: a comparison of auditory versus tactual presentation.

OBJECTIVE: The objective of this study was to compare the effects of a single-band envelope cue as a supplement to speechreading of segmentals and sentences when presented through either the auditory or tactual modality. DESIGN: The supplementary signal, which consisted of a 200-Hz carrier amplitude-modulated by the envelope of an octave band of speech centered at 500 Hz, was presented through a high-performance single-channel vibrator for tactual stimulation or through headphones for auditory stimulation. Normal-hearing subjects were trained and tested on the identification of a set of 16 medial vowels in /b/-V-/d/ context and a set of 24 initial consonants in C-/a/-C context under five conditions: speechreading alone (S), auditory supplement alone (A), tactual supplement alone (T), speechreading combined with the auditory supplement (S+A), and speechreading combined with the tactual supplement (S+T). Performance on various speech features was examined to determine the contribution of different features toward improvements under the aided conditions for each modality. Performance on the combined conditions (S+A and S+T) was compared with predictions generated from a quantitative model of multi-modal performance. To explore the relationship between benefits for segmentals and for connected speech within the same subjects, sentence reception was also examined for the three conditions of S, S+A, and S+T. RESULTS: For segmentals, performance generally followed the pattern of T < A < S < S+T < S+A. Significant improvements to speechreading were observed with both the tactual and auditory supplements for consonants (10 and 23 percentage-point improvements, respectively), but only with the auditory supplement for vowels (a 10 percentage-point improvement). The results of the feature analyses indicated that improvements to speechreading arose primarily from improved performance on the features low and tense for vowels and on the features voicing, nasality, and plosion for consonants. These improvements were greater for auditory relative to tactual presentation. When predicted percent-correct scores for the multi-modal conditions were compared with observed scores, the predicted values always exceeded observed values and the predictions were somewhat more accurate for the S+A than for the S+T conditions. For sentences, significant improvements to speechreading were observed with both the auditory and tactual supplements for high-context materials but again only with the auditory supplement for low-context materials. The tactual supplement provided a relative gain to speechreading of roughly 25% for all materials except low-context sentences (where gain was only 10%), whereas the auditory supplement provided relative gains of roughly 50% (for vowels, consonants, and low-context sentences) to 75% (for high-context sentences). CONCLUSIONS: The envelope cue provides a significant benefit to the speechreading of consonant segments when presented through either the auditory or tactual modality and of vowel segments through audition only. These benefits were found to be related to the reception of the same types of features under both modalities (voicing, manner, and plosion for consonants and low and tense for vowels); however, benefits were larger for auditory compared with tactual presentation. The benefits observed for segmentals appear to carry over into benefits for sentence reception under both modalities.

Adult↗

Error analysis for the determination of cerebral blood flow with the continuous inhalation of 15O-labeled carbon dioxide and positron emission tomography.

The inhalation of C15O2 can be used for determining local cerebral blood flow (LCBF) using a quantitative model. The determination of LCBF in three dimensions using positron emission tomography (PET) involves errors due to counting statistics, data manipulation, and the estimation of parameters in the mathematical model. This work examines error propagation and its relation to the radiation dose to the subject's lungs. An expression has been derived for the root mean square uncertainty in LCBF as a function of LCBF, the spatial resolution and the sensitivity of PET instrument, the normal variability in the brain-blood partition coefficient for water, and absorbed radiation dose to the subject's lungs. The error in LCBF increases as CBF increases. At a normal cortical LCBF of 80 ml/100 g-m and a PET instrument with a 1.65 cm FWHM resolution, and a 46,000 cps per microCi/g sensitivity per slice, an error (coefficient of variation) of 5% results from an inhaled activity of 250 mCi, resulting in a lung dose of 5 rads, the maximum permissible dose allowed. For a more acceptable dose of 1.2 rads, the error is 7%. At a higher resolution (0.8 cm FWHM) and lower sensitivity (15,000 cps per microCi/g per slice), errors become on the order of 28% for a lung dose of 1.2 rads. Errors due to other factors such as blood sample counting, and instrument cross calibration can be virtually eliminated by proper technical strategies. This consideration of error and its relation to radiation dose is important for the application of this inhalation technique for the quantification of LCBF.

Administration, Intranasal↗

Cone receptor sensitivity is altered in form deprivation myopia in the chicken.

PURPOSE: The effect of form deprivation myopia (FDM) on cone photoreceptor function was investigated. METHODS: Photopic electroretinogram (ERG) a-waves were recorded from control and form-deprived eyes of chickens. Cone-generated P3 responses were derived from the leading edge of ERG a-waves using an analytical expression derived from a quantitative model of phototransduction. The parameters obtained were the maximum cone P3 response (RmaxP3), sensitivity (S), and delay (t(d)). RESULTS: P3 response sensitivity is significantly higher in form-deprived eyes, at lower retinal irradiances. At higher flash intensities, in form-deprived eyes, P3 response sensitivity declines at a significantly greater rate, per unit increase in retinal irradiance, than in control eyes. Visual deprivation does not significantly affect RmaxP3 or t(d). CONCLUSIONS: Hypotheses to explain the altered cone photoreceptor sensitivity in form-deprived eyes are proposed. Changes in the biochemistry of phototransduction, or intrinsic geometric and physical attributes of photoreceptors or their waveguide modal properties, could account for the findings.

Animals↗

Surface quantification of injected fluorescein as a predictor of flap viability.

In a laboratory model, quantitative skin-surface fluorescence has been used to reliably measure skin perfusion in ischemic random flaps and to predict viability. The method is reproducible and allows investigators to sequentially monitor soft-tissue perfusion using a fluorescent indicator. It is superior to the conventional fluorescein test (Wood's lamp method), which allows only a single subjective assessment within a 24-hour period.

Animals↗

Electrical characteristics of suburothelial cells isolated from the human bladder.

PURPOSE: We measured the membrane electrical characteristics as well as the response to adenosine triphosphate of cells isolated from the suburothelial layer of the bladder. MATERIALS AND METHODS: Suburothelial cells were isolated from biopsy samples of human bladder by collagenase disruption. Electrophysiological measurements were done under current and voltage clamp to record membrane potential and ionic currents using patch pipettes with a K+ based filling solution. Intracellular [Ca2+] was measured with Fura-2. RESULTS: Cells were different from epithelial cells by their spindle-shaped appearance with projections at either end. The cells stained for vimentin but epithelial and smooth muscle cells did not. The cells had small membrane capacitance (27 +/- 16 pF) and a specific membrane resistance of 90 +/- 48 x 10(9) Omega cm2. Average membrane potential was -63 +/- 14 mV but cells showed spontaneous spikes or random fluctuations of membrane potential. A small net inward current was superimposed by a larger outward current. Inward current was attenuated by the removal of extracellular Ca. Outward current showed large spontaneous fluctuations and was greatly decreased by 30 mM tetraethyl ammonium chloride. Adenosine triphosphate (30 to 100 microM) elicited an inward current of about 50 pA and large intracellular Ca2+ transients. CONCLUSIONS: These cells are electrically active which, in conjunction with the previous observation of connexin 43 labeling, suggests that they could act as an electrical network. A quantitative model of voltage distribution in such a network after the generation of inward current suggests that individual cells could not act as pacemakers, but rather a group of simultaneously activated cells could exert a peripheral excitatory effect that would amplify the magnitude of the original response. The implications of this in terms of bladder sensation are discussed.

Adenosine Triphosphate↗

Effect of triolein emulsion on the blood-testis barrier in cats.

PURPOSE: Although the blood-testis barrier (BTB) is beneficial physiologically, it acts as an obstacle to chemotherapy. We wished to determine whether a triolein emulsion could alter the permeability of the BTB in cats. MATERIALS AND METHODS: An emulsion of 0.05-mL triolein in 20 mL of saline was infused into the abdominal aorta just proximal to the branching of the renal arteries of each of 15 cats (embolic group). As controls, 12 cats were each similarly infused with 20 mL of normal saline (control group). Pre and postcontrast MR images were obtained 30 minutes and 2 hours after embolization. The images were analyzed for the presence and degree of contrast enhancement (qualitative analysis), and the contrast enhancement ratios (CER) derived from one testis of each animal were compared and statistically analyzed by the mixed linear model (quantitative analysis). RESULTS: Contrast enhancement of the testis was observed in both groups at both time points, but it was more prominent in the embolic group. The CERs in the embolic group (0.63 at 30 minutes, 0.42 at 2 hours) were significantly higher than in the control group (0.36 at 30 minutes, 0.28 at 2 hours; P = 0.0001). In each group, the CERs at 2 hours were significantly lower than those at 30 minutes (P = 0.006). CONCLUSION: Intra-arterial infusion of triolein emulsion increased the permeability of the BTB. This result may be useful in future studies of BTB disruptions caused by fat emulsions.

Animals↗

Towards a unified theory of cooperative breeding: the role of ecology and life history re-examined.

We present quantitative models that unify several adaptive hypotheses for the evolution of cooperative breeding in a single framework: the ecological constraints hypothesis, the life-history hypothesis and the benefits-of-philopatry hypothesis. Our goal is to explain interspecific variation in the occurrence of cooperative breeding in terms of interspecific variation in life-history traits and ecological conditions. We analyse two models, according to whether or not helpers can inherit their parents' territory. Major results are (i) territory inheritance always promotes cooperative breeding; (ii) if territories are not inherited, neither ecological constraints nor variation in life-history traits predict interspecific variation in cooperative breeding; and (iii) if territories are inherited, the mechanism of density regulation is crucial in determining which factors promote cooperative breeding. If density dependence acts on the probability to obtain a free territory or on the survival of dispersers, variation in ecological constraints cannot explain variation in cooperative breeding. Lower adult mortality favours helping, not because it reduces the availability of free territories, but because it enhances the direct benefits of helpers. If density dependence acts on fecundity, lower probability of obtaining a free territory and lower survival of dispersers promote cooperative breeding. In this case, lower adult mortality works against the evolution of helping. We suggest that the difference between birds and social insects in the covariance between cooperative breeding and life-history traits is due to different mechanisms of density regulation that operate in these taxa, and we explain how natural selection on habitat choice might have caused these different mechanisms to operate.

Animals↗

Decision making and recognition mechanisms.

Determining how individuals adjust their behaviour to maximize reproductive opportunities is fundamental to understanding the adaptive significance of behavioural variations. Such 'decision making' requires recognition mechanisms, whereby an individual evaluates cues that yield information about the potential reproductive outcomes of alternative behaviours. Here, we develop a quantitative model for understanding how individuals evaluate cues. Only when a proximate (immediate) cue predicts reproductive value more reliably than an evolved predisposition, will the cue influence an individual's decision. The model resolves some long-standing controversies in evolutionary biology involving recognition mechanisms and interpretations of behavioural decisions that were observed after manipulations of cues of parentage, kinship and mate quality.

Animals↗