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PubMed2004

Threshold retinopathy at threshold of viability: the EpiBel study.

AIM: To describe incidence, co-morbidity characteristics, and risk factors associated with threshold retinopathy of prematurity (ROP) in survivors with a gestational age (GA) of < or =26 weeks at birth. METHODS: Retrospective analysis of perinatal data of all inborn survivors in all perinatal centres of Belgium in the period 1999-2000 (EpiBel cohort) believed to be between 22 and 26 weeks GA at time of delivery. Data on survivors who did and survivors who did not develop threshold ROP were compared (chi(2), Mann-Whitney U) and logistic regression was performed. RESULTS: Of 303 admitted infants 175 (58%) were discharged alive. Incidence of major retinopathy (> or =stage 3) and of threshold ROP was 25.5% and 19.8% in survivors. Associated central nervous abnormalities were documented in six (17%) and associated chronic lung disease in 19 (54%) threshold ROP infants. Threshold ROP without additional morbidity characteristics at discharge was documented in 14 (40%) infants. Besides often reported risk factors, renal insufficiency (creatinaemia>1.5 mg/dl) was a risk factor to develop threshold ROP (p<0.0015) (chi(2)). Days of respiratory support (OR 1.02; 95% CI 1.002 to 1.039), number of transfusions (OR 1.118; 95% CI 1.030 to 1.214), and renal insufficiency (OR 3.31; 95% CI 1.344 to 8.196) remained independent risk factors to develop threshold ROP in this cohort in a stepwise logistic regression model (MedCalc). CONCLUSIONS: Incidence of threshold ROP is high at the limits of viability. Renal insufficiency is a risk factor to develop threshold ROP in this cohort.

Belgium↗
PubMed1991

A new direction for osteoporosis research: a review and proposal.

This article suggests why drugs that only reduce the activity of existing osteoclasts or enhance the activity of existing osteoblasts probably cannot cure the osteopenias associated with most osteoporoses. Instead they should add only limited amounts of bone, which should begin to disappear after treatment stops. That behavior depends on these facts. Different threshold ranges of mechanical bone strains control gains and losses of bone mass. One threshold controls gains by modeling drifts, and a lower one controls losses by remodeling BMUs. A drug that does not change those thresholds should limit gains (or losses) of bone during indefinitely continued treatment. Success in curing those osteopenias should require learning how to change the thresholds.

Biomechanical Phenomena↗
PubMed2006

Linking catchment characteristics and water chemistry with the ecological status of Irish rivers.

Requirements of the EU Water Framework Directive for the introduction of ecological quality objectives for surface waters and the stipulation that all surface waters in the EU must be of 'good' ecological status by 2015 necessitate a quantitative understanding of the linkages among catchment attributes, water chemistry and the ecological status of aquatic ecosystems. Analysis of lotic ecological status, as indicated by an established biotic index based primarily on benthic macroinvertebrate community structure, of 797 hydrologically independent river sites located throughout Ireland showed highly significant inverse associations between the ecological status of rivers and measures of catchment urbanisation and agricultural intensity, densities of humans and cattle and chemical indicators of water quality. Stepwise logistic regression suggested that urbanisation, arable farming and extent of pasturelands are the principal factors impacting on the ecological status of streams and rivers in Ireland and that the likelihood of a river site complying with the demands of the EU Water Framework Directive, and be of 'good' ecological status, can be predicted with reasonable accuracy using simple models that utilise either widely available landcover data or chemical monitoring data. Non-linear landcover and chemical 'thresholds' derived from these models provide a useful tool in the management of risk in catchments, and suggest strongly that more careful planning of land use in Ireland is essential in order to restore and maintain water quality as required by the Directive.

Ecology↗
PubMed1999

A search for quantitative trait loci for milk production traits on chromosome 6 in Finnish Ayrshire cattle.

Cattle chromosome 6 was scanned with 11 markers, ten microsatellites and the casein haplotype, to identify quantitative trait loci (QTLs) affecting the following milk production traits: milk yield, fat percentage, fat yield, protein percentage and protein yield. Twelve Finnish Ayrshire half-sib families with a total of 480 sons were genotyped and used in a grand-daughter design. Interval mapping was performed with a multiple-marker regression approach with a one-QTL and a two-QTL model, and the significance threshold values were determined empirically using a permutation test. Across-family analysis with the one-QTL model revealed an effect on protein percentage (P < 0.05) and on milk yield (P < 0.05). The analysis with the two-QTL model identified significant effects (P < 0.05) on protein percentage, milk yield, and fat yield. Comparing these two cases, the results suggest the existence of two QTLs on chromosome 6 with an effect on milk production traits. One of the QTLs was located around the casein genes. As the other QTL was similar in location and effect to a QTL found previously in Holstein-Friesians, an identity-by-descent approach could be applied to fine map this region.

Animals↗
PubMed2005

The 'anomalous' absorption of labelled and unlabelled vitamin C in man.

Previous studies of vitamin C absorption in man using stable isotope probes have given results which cannot easily be reconciled with those obtained using non-isotope measurement. In order to investigate some of the apparent paradoxes we have conducted a study using two consecutive doses of vitamin C, one labelled and one unlabelled, given 90 min apart. Compatibility of the experimental results with two feasible models was investigated. In Model 1, ingested vitamin C enters a pre-existing pool before absorption, which occurs only when a threshold is exceeded; in Model 2, ingested vitamin C is exchanged with a pre-existing flux before absorption. The key difference between these two models lies in the predicted profile of labelled material in plasma. Model 1 predicts that the second unlabelled dose will produce a secondary release of labelled vitamin C which will not be observed on the basis of Model 2. In all subjects Model 1 failed to predict the observed plasma concentration profiles for labelled and unlabelled vitamin C, but Model 2 fitted the experimental observations. We speculate on possible physiological explanations for this behaviour, but from the limited information available cannot unequivocally confirm the model structure by identifying the source of the supposed flux.

Ascorbic Acid↗
PubMed2006

Impulse response of an S-cone pathway in the aging visual system.

Age-related changes in the temporal properties of an S-cone pathway were characterized by the psychophysical impulse-response function (IRF). Participants included 49 color-normal observers ranging in age from 16.8 to 86.3 years. A double-pulse method was used to measure the IRF with S-cone modulation at constant luminance. Stimuli were presented as a Gaussian patch (+/-1SD = 2.3 degrees ) in one of four quadrants around a central fixation cross on a CRT screen. The test stimulus was modulated from the equal-energy white of the background toward the short-wave spectrum locus. Each of the two pulses (6.67 ms) was separated by an interstimulus interval (ISI) from 20 to 720 ms. Chromatic detection thresholds were determined by a four-alternative forced-choice method with staircases for each ISI in one session. IRFs were calculated from the threshold data using a model with four parameters of an exponentially damped sine wave. S-cone IRFs have only an excitatory phase and a much longer time course compared with IRFs for luminance modulation measured with the same apparatus. The results demonstrated significant age-related losses in IRF amplitude, but the latency (time to peak) of the IRF was stable with age.

Adolescent↗
PubMed1999

The sensitivity and specificity of forecasting high-cost users of medical care.

OBJECTIVES: This study compares the ability of 3 risk-assessment models to distinguish high and low expense-risk status within a managed care population. Models are the Global Risk-Assessment Model (GRAM) developed at the Kaiser Permanente Center for Health Research; a logistic version of GRAM; and a prior-expense model. GRAM was originally developed for use in adjusting Medicare payments to health plans. METHODS: Our sample of 98,985 cases was drawn from random samples of memberships of 3 staff/group health plans. Risk factor data were from 1992 and expenses were measured for 1993. Models produced distributions of individual-level annual expense forecasts (or predicted probabilities of high expense-risk status for logistic) for comparison to actual values. Prespecified "high-cost" thresholds were set within each distribution to analyze the models' ability to distinguish high and low expense-risk status. Forecast stability was analyzed through bootstrapping. RESULTS: GRAM discriminates better overall than its comparators (although the models are similar for policy-relevant thresholds). All models forecast the highest-cost cases relatively well. GRAM forecasts high expense-risk status better than its comparators within chronic and serious disease categories that are amenable to early intervention but also generates relatively more false positives within these categories. CONCLUSIONS: This study demonstrates the potential of risk-assessment models to inform care management decisions by efficiently screening managed care populations for high expense-risk. Such models can act as preliminary screens for plans that can refine model forecasts with detailed surveys. Future research should involve multiple-year data sets to explore the temporal stability of forecasts.

Adolescent↗
PubMed2001

An animal model to assess aversion to intra-oral capsaicin: increased threshold in mice lacking substance p.

Despite the widespread consumption of products containing chemicals that irritate the oral mucosa, little is known about the underlying neural mechanisms nor is there a corresponding animal model of oral irritation. We have developed a rodent model to assess aversion to capsaicin in drinking water, using a paired preference paradigm. This method was used to test the hypothesis that the neuromodulator substance P (SP) plays a role in the detection of intra-oral capsaicin. 'Knockout' (KO) mice completely lacking SP and neurokinin A due to a disruption of the preprotachykinin A gene and a matched population of wild-type (WT) mice had free access to two drinking bottles, one containing water and the other capsaicin at various concentrations. Both KO and WT mice showed a concentration-dependent aversion to capsaicin. KO mice consumed significantly more capsaicin than WT at a single near threshold (1.65 microM) concentration, indicating that SP plays a limited role in the detection and rejection of oral irritants.

Administration, Oral↗
PubMed2006

Effects of temperature on development of Phormia regina (Diptera: Calliphoridae) and use of developmental data in determining time intervals in forensic entomology.

Precise developmental data for forensic indicator blow fly species are essential for accuracy in the estimate of the post-mortem interval (PMI). Why, then, does the determination of the PMI result in conflicting time frames when published conspecific developmental data are used? To answer this question, we conducted constant temperature trials between the developmental minimum temperature and upper threshold temperatures (8-32 degrees C) on the forensically important blow fly species Phormia regina (Meigen) (Diptera: Calliphoridae). Flies were reared using two designs to quantify sources of variation. We measured rearing container temperatures and internal growth chamber temperatures by using thermocouples to accurately record temperatures experienced by larvae and to construct a degree-day model. Differences in experimental design, as seen across temperature studies for this fly species, did not significantly impact larval development. We also found that using set chamber temperatures rather than rearing container temperatures altered the final degree-day model. Using any minimum threshold (including an empirically determined true minimum) other than that from linear interpolation (x-intercept) violated degree-day assumptions and invalidated estimates of the PMI. We observed the minimum developmental temperature to be higher (14 degrees C) than that generated under the x-intercept method (5.46 degrees C) by using data from oviposition to adult emergence. This difference along with the noted difference in accumulated degree-days (using different base temperatures) suggests a need for additional experimentation on other forensically important fly species at low temperature thresholds to help with development of curvilinear models. Former and current estimates of the PMI may be inaccurate if the process to determine the time frame ignored degree-day model assumptions or was based upon questionable data sets.

Animals↗
PubMed1983

Effects of diltiazem upon experimental ventricular dysrhythmias.

The antidysrhythmic and antifibrillatory actions of the calcium entry blocker diltiazem were examined in three experimental canine models: 1) ventricular fibrillation thresholds in the anesthetized dog; 2) programmed electrical stimulation in the conscious dog during the subacute phase of myocardial infarction; and 3) a conscious canine model of sudden coronary death wherein ventricular fibrillation was produced by acute myocardial ischemia in the presence of previous anterior myocardial infarction. Diltiazem administration failed to alter ventricular fibrillation thresholds determined under normal physiologic conditions and during acute occlusion of the distal left anterior descending coronary artery. Diltiazem did not prevent ventricular tachyarrhythmias produced by programmed electrical stimulation in the subacute phase of myocardial infarction. The coupling intervals of premature beats producing ventricular tachycardia and the cycle length of the ventricular tachycardias were unchanged by diltiazem administration. In a conscious canine model of sudden coronary death, left circumflex coronary artery thrombosis was produced in the presence of previous anterior myocardial infarction. Acute myocardial ischemia as evidenced by ST-segment changes in saline-treated animals (145 +/- 26 min) was followed by the development of premature ventricular beats (150 +/- 27 min) and ventricular tachycardia (154 +/- 26 min). Ventricular fibrillation occurred in 9 of 10 animals at 156 +/- 28 min. Diltiazem administration did not affect the time to development of ST-segment changes (196 +/- 38 min), premature ventricular beats (202 +/- 37 min) or ventricular tachycardia (209 +/- 37 min). Although the development of ventricular fibrillation was not prevented by diltiazem (9 of 10 animals developed ventricular fibrillation), the time to onset of the fatal arrhythmia was delayed significantly (P less than .01). These data fail to suggest a protective action for the calcium entry blocker diltiazem.

Acute Disease↗
PubMed1991

Mathematical model of electrotonic interactions during excitation and repolarisation of myocardial tissue.

A discrete model has been developed which reproduces the intercellular electrophysiological processes within a block of myocardial tissue. The behaviour of individual elements is introduced in the form of the digitised physiologic and premature action potentials which are comprehended as series of jumps between discrete polarisation levels. For each cellular element, the model introduces the excitation threshold as the minimum electric flow in the surrounding which can excite the cell, and the sensitivity towards the electronic interactions which can advance or slow down the depolarisation and repolarisation processes of the cell. The excitation threshold and the electronic sensitivity are dependent on the current polarity of the element. The numerical solution of the model does not use a fixed time slicing integration but is based on discrete planning of asynchronous events. The time increments are dynamically computed according to the chosen precision of the discrete polarity levels. The model enables efficient stimulation of the electrophysiological properties in three-dimensional models of the myocardial tissue. The paper presents a detailed formal description of the model.

Algorithms↗
PubMed1989

Studies with spike initiators: linearization by noise allows continuous signal modulation in neural networks.

Engineers and neuroscientists generally believe that noise is something to be avoided in information systems. In this paper we show that noise, in fact, can be an important element in the translation of neuronal generator potentials (summed inputs) to neuronal spike trains (outputs), creating or expanding a range of amplitudes over which the spike rate is proportional to the generator potential amplitude. Noise converts the basically nonlinear operation of a spike initiator into a nearly linear modulation process. This linearization effect of noise is examined in a simple intuitive model of a static threshold and in a more realistic computer simulation of a spike initiator based on the Hodgkin-Huxley (HH) model. The results are qualitatively similar; in each case larger noise amplitude results in a larger range of nearly-linear modulation. The computer simulation of the HH model with noise shows linear and nonlinear features that we earlier had observed in spike data obtained from the VIIIth nerve of the bullfrog. This suggests that these features can be explained in terms of spike initiator properties, and it also suggests that the HH model may be useful for representing basic spike initiator properties in vertebrates.

Animals↗
PubMed1992

Effects of oral propafenone therapy on chronic myocardial pacing threshold.

The effects of oral propafenone therapy on pacing threshold were studied in 36 patients chronically paced for sick sinus syndrome or AV block. The pacemakers, all unipolar models and with noninvasive threshold measurement facilities, were: 9 VVI, 15 AAI, and 12 DDD. Each patient received an initial propafenone dose of 450 mg/day, that in 18 cases was increased to 900 mg/day. Threshold was tested at baseline and at each dosage after 7 days of therapy. With the lower propafenone dosage the threshold, measured at 2.5 V, rose from 0.14 +/- 0.10 to 0.21 +/- 0.16 msec (+55%) in the atrium (P less than 0.0001) and from 0.10 +/- 0.08 to 0.15 +/- 0.09 msec (+63%) in the ventricle (P less than 0.0001). In the 18 patients who received both dosages, the mean atrial and ventricular threshold increased from 0.12 +/- 0.10 to 0.17 +/- 0.14 msec with the lower dose and to 0.27 +/- 0.22 msec (+125%) with the higher dose (P less than 0.0001 for both increments). With the 900 mg/day dose, a threshold increment greater than or equal to 300% was observed in 15% of the stimulated chambers. A good linear correlation (r = 0.76) was found between the ventricular threshold increment and the drug induced QRS widening. In conclusion, treatment with oral propafenone increases atrial and ventricular stimulation threshold in pacemaker patients. Threshold increment is dose dependent and proportional to the drug induced QRS widening. In the majority of the cases the threshold increment is not clinically significant, but caution must be used in prescribing high doses of the drug to patients with high baseline threshold.

Aged↗
PubMed2006

Neurosensory effects of chronic exposure to arsenic via drinking water in Inner Mongolia: II. Vibrotactile and visual function.

This study was designed to assess the effects of exposure to arsenic in drinking water on visual and vibrotactile function in residents of the Bamen region of Inner Mongolia, China. Arsenic was measured by hydride generation atomic fluorescence. 321 participants were divided into three exposure groups- low (non-detectable-20), medium (100-300) and high (400-700 microg/l) arsenic in drinking water (AsW). Three visual tests were administered: acuity, contrast sensitivity and color discrimination (Lanthony's Desaturated 15 Hue Test). Vibration thresholds were measured with a vibrothesiometer. Vibration thresholds were significantly elevated in the high exposure group compared to other groups. Further analysis using a spline regression model suggested that the threshold for vibratory effects is between 150-170 microg/l AsW. These findings provide the first evidence that chronic exposure to arsenic in drinking water impairs vibrotactile thresholds. The results also indicate that arsenic affects neurological function well below the 1000 microg/I concentration reported by NRC (1999). No evidence of arsenic-related effects on visual function was found.

Adolescent↗
PubMed2005

Effects of chlorpyrifos in freshwater model ecosystems: the influence of experimental conditions on ecotoxicological thresholds.

Three experiments were conducted to determine the impact of the insecticide chlorpyrifos (single applications of 0.01 to 10 microg AI litre(-1)) in plankton-dominated nutrient-rich microcosms. The microcosms (water volume approximately 14 litres) were established in the laboratory under temperature, light regimes and nutrient levels that simulated cool 'temperate' and warm 'Mediterranean' environmental conditions. The fate of chlorpyrifos in the water column was monitored and the effects on zooplankton, phytoplankton and community metabolism were followed for 4 or 5 weeks. The mean half-life (t1/2) of chlorpyrifos in the water of the test systems was 45 h under 'temperate' conditions and about 30 h under 'Mediterranean' environmental conditions. Microcrustaceans (cladocerans and copepod nauplii) were amongst the most sensitive organisms. All three experiments yielded community NOEC (no observed effect concentrations) of 0.1 microg AI litre(-1), similar to those derived from more complex outdoor studies. Above this threshold level, responses and effect chains, and time spans for recovery, differed between the experiments. For example, algal blooms as an indirect effect from the impact of exposure on grazing organisms were only observed under the 'Mediterranean' experimental conditions. The relatively simple indoor test system seems to be sufficient to provide estimates of safe threshold levels for the acute insecticidal effects of low-persistence compounds such as chlorpyrifos. The robustness of the community NOEC indicates that this threshold level is likely to be representative for many freshwater systems.

Chlorpyrifos↗
PubMedDate not supplied

Mathematical modelling of stimulus-secretion coupling in the pancreatic B-cell. V. Threshold phenomenon for the response to cyclic AMP.

Recent experimental data suggest that a rise in cyclic AMP content of pancreatic islet cells may have little effect upon cytosolic Ca2+ activity. Hence, a mathematical model for stimulus-secretion coupling was designed in which cyclic AMP fails to affect Ca2+ movements in the islet cells, but augments the responsiveness to cytosolic Ca2+ of the effector system for insulin release. Provided that the latter effect of cyclic AMP becomes operative only when the nucleotide concentration exceeds a critical threshold value, the mathematical model was found suitable to predict the dynamics of both insulin release and 45Ca fluxes in islets deprived of or exposed to D-glucose, Ca2+ and a phosphodiesterase inhibitor.

Animals↗
PubMedDate not supplied

Thresholds in chemical carcinogenesis: what are animal experiments telling us?

It appears that the controversy over whether animal experiments demonstrate a threshold for carcinogenicity from chemicals was due to an error in plotting dose response. A linear (arithmetic) scale for the dose of chemicals obscures effects at doses below those used in the experiment and distorts the effect seen over the range of doses used. Gaddum (Nature 156: 463, 1946) pointed out that, empirically, dose should be on a logarithmic scale to effect a linear quantal response. It now is proposed that this logarithmic relationship of dose to effect has a sound basis in chemical thermodynamics (Waddell, Toxicol Sci 68: 275-279, 2002). When the results of major studies (e.g., ED01, etc.) done in the past were reanalyzed with this in mind using the Rozman et al scale (Drug Metab Rev 28: 29-52, 1996), which has a logarithmic scale down to one molecule (10(0)), unequivocal thresholds were demonstrated. Many animal studies now have been reanalyzed by this procedure (e.g., Waddell, Toxicol Sci 72: 158-163, 2003; Waddell, Food Chem Toxicol, in press; Waddell, Hum Exp Toxicol, in press); these studies show thresholds for carcinogenicity at doses ranging from 10(17.1) to 10(21.92) molecules/kg/day. These results require a complete reevaluation of human risk assessment for carcinogenesis from chemicals and a redirection of basic research to discover the system, or systems, that are overwhelmed at these thresholds.

Animals↗