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PubMed2002

Emergent polyethism as a consequence of increased colony size in insect societies.

A threshold reinforcement model in insect societies is explored over a range of colony sizes and levels of task demand to examine their effects upon worker polyethism. We find that increasing colony size while keeping the demand proportional to the colony size causes an increase in the differentiation among individuals in their activity levels, thus explaining the occurrence of elitism (individuals that do a disproportionately large proportion of work) in insect societies. Similar results were obtained when the overall work demand is increased while keeping the colony size constant. Our model can reproduce a whole suite of distributions of the activity levels among colony members that have been found in empirical studies. When there are two tasks, we demonstrate that increasing demand and colony size generates highly specialized individuals, but without invoking any strict assumptions about spatial organization of work or any inherent abilities of individuals to tackle different tasks. Importantly, such specialization only occurs above a critical colony size such that smaller colonies contain a set of undifferentiated equally inactive individuals while larger colonies contain both active specialists and inactive generalists, as has been found in empirical studies and is predicted from other theoretical considerations.

Animals↗
PubMed2007

Conditional mutagenesis reveals immunological functions of widely expressed genes: activation thresholds, homeostatic mechanisms and disease models.

Evolutionarily conserved, widely expressed genes provide the functional backbone of most, if not all, cell types. Although mouse mutants created by germ line gene inactivation are instrumental in establishing the importance of such genes in vivo, distortion of embryonic development or multiple body systems often preclude detailed functional studies. To overcome this limitation, DNA recombination systems such as Cre/loxP of bacteriophage P1, have been adapted for use in mammalian cells. The mutagenic event is restricted to the tissue or cell type in question leaving other body systems undisturbed. Conditional inactivation of Csk or Socs3, for example, established their key role in the prevention of inappropriate inflammation, while unexpected immunoregulatory activities emerged from studies of the NF-kappaB and AP-1 pathways. Also, cell types responsible for protective or pathogenic TNFalpha production have been identified. Inactivation of immunoregulatory receptors in leukocyte subsets can provide robust experimental systems revealing the conceptual simplicity underlying the modulation of complex signaling pathways during homeostatic responses. As illustrated for TGF-beta receptor, such system-guided approaches can provide a comprehensive picture of the regulatory events driving in vivo phenotype and specific responses of primary cells. This in turn facilitates the identification of novel regulatory mechanisms, targets for therapeutic intervention and prediction of side effects. With the increasing evidence for a role of somatic mutations in a wider range of human diseases, conditional mouse models are set to play a continuing part in the identification of pathogenic mechanisms for restoration of normal cellular processes in diseases including cancer, inflammation and autoimmunity.

Animals↗
PubMed1991

Motion processing for saccadic eye movements in humans.

1. We studied the latencies and amplitudes of saccades to moving targets in normal human subjects. Targets underwent ramp or step-ramp motions. The goal was to determine how the saccadic system uses information about target velocity. 2. For simple ramp motion saccadic latency decreased as target speed increased. A threshold distance model, which assumes that the target has to move a minimum distance before saccadic processing starts, provided a good fit to the responses of all four subjects and explains discrepancies between previously published findings. 3. A double step experiment showed that target position may have some effect on saccadic amplitude when sampled approximately 70 ms before saccade onset, but it must be sampled at least 140 ms before onset for an accurate saccade to occur. 4. Saccades to simple ramp targets approximated the target position 55 ms before saccade onset. Based on our double step results, this is more compensation than possible by a simple position estimate and implies extrapolation of target motion by the saccadic system. The lack of complete compensation may be due to an underestimate of the target speed and/or of the saccadic latency. 5. A delayed-saccade paradigm resulted in saccades with a longer, constant latency and allowed longer viewing of target motion. These saccades accounted for all but approximately 20 ms of target motion, suggesting that with more processing time of target motion a better extrapolation may be generated. 6. In a step-ramp paradigm the target stepped in one direction, then moved smoothly in the opposite direction. Saccades in this paradigm could be made in either the direction of the step or in the direction of target motion: the direction and latency were determined solely by the time at which the target crossed the fixation point. This time must be calculated from target speed and position, implying that the saccadic system must use speed information to adjust latency or to cancel unnecessary saccades.

Humans↗
PubMed1992

The relationship between age at first drug use and teenage drug use liability.

Our analyses of Carey's (1992) simulated data set of substance abuse in a cohort of adolescent twins were aimed at answering the question What is the relationship between age at first drug use and EVER having used drugs (i.e., teenage drug use liability)? Three analytic methods were used to determine whether age at first drug use was (1) a "perfect" index of drug use liability, (2) correlated in relatives but conditionally independent of drug use liability, or (3) causally influenced by drug use liability and by factors independent of liability. The analytic methods included nonmetric multidimensional scaling, multifactorial threshold model-fitting to contingency tables, and pedigree-based likelihood formulations for the raw data. All approaches indicated that age at first drug use was a perfect index of drug use liability. Further, model-fitting results indicated that only shared environmental factors accounted for twin similarity in the onset and timing of drug use. We discuss the limitations of each of the analytic methods and integrate our findings with the true model used in Carey's simulation.

Adolescent↗
PubMed2000

Risk estimates for radiation-induced cancer--the epidemiological evidence.

The risk of low-dose radiation exposures has--for a variety of reasons--been highly politicised. This has led to a frequently exaggerated perception of the potential health effects, and to lasting public controversies. A balanced view requires a critical reassessment of the epidemiological basis of current assumptions. There is reliable quantitative information available on the increase of cancer rates due to moderate and high doses. This provides a firm basis for the derivation of probabilities of causation, e.g. after high radiation exposures. For small doses or dose rates, the situation is entirely different: potential increases of cancer rates remain hidden below the statistical fluctuations of normal rates, and the molecular mechanisms of cancerogenesis are not sufficiently well known to allow numerical predictions. Risk coefficients for radiation protection must, therefore, be based on the uncertain extrapolation of observations obtained at moderate or high doses. While extrapolation is arbitrary, it is, nevertheless, used and mostly with the conservative assumption of a linear dose dependence with no threshold (LNT model). All risk estimates are based on this hypothesis. They are, thus, virtual guidelines, rather than firm numbers. The observations on the A-bomb survivors are still the major source of information on the health effects of comparatively small radiation doses. A fairly direct inspection of the data shows that the solid cancer mortality data of the A-bomb survivors are equally consistent with linearity in dose and with reduced effectiveness at low doses. In the leukemia data a reduction is strongly indicated. With one notable exception -- leukemia after prenatal exposure--these observations are in line with a multitude of observations in groups of persons exposed for medical reasons. The low-dose effects of densely ionizing radiations--such as alpha-particles from radon decay products or high-energy neutrons--are a separate important issue. For neutrons, there is little epidemiological information. This has facilitated exaggerated claims of high neutron effects with reference to alleged dangers from transports of reactor fuel. However, in spite of limited information, it can be shown that the data from Hiroshima exclude the stated claims. New dosimetric information on neutrons may turn out to be highly informative with regard to an upper limit for the potential effects of neutrons and equally with regard to a reassessment--and a possible reduction--of risk estimates for gamma-rays.

Breast Neoplasms↗
PubMed2000

Non-invasive graft monitoring after heart transplantation: rationale to reduce the number of endomyocardial biopsies.

The endomyocardial biopsy is invasive, reduces quality of life and cannot be repeated daily. Initial studies on noninvasive cardiac graft monitoring have been presented recently. During the heart transplant procedure, we implanted wideband telemetric pacemakers and fractally coated, epimyocardial electrodes. On biopsy days and during each follow-up, intramyocardial electrogram sequences were obtained. The maximum T-slew rate from the ventricular evoked response (VER) was automatically calculated and compared to the biopsy results (n = 331, ISHLT grading). The VER T-slew rate was significantly lower during rejection grade 2 or higher. The negative predictive value to exclude rejection was 98%. Using a single threshold diagnosis model, 74% of the biopsies could have been avoided. Noninvasive cardiac graft monitoring can reduce the need for surveillance biopsies and may offer a tool to optimize immunosuppressive therapy after heart transplantation.

Adolescent↗
PubMed2000

A genetic study of Hodgkin's lymphoma: an estimate of heritability and anticipation based on the familial cancer database in Sweden.

Hodgkin's lymphoma (HL) is a heterogeneous hemopoietic malignancy. Previous studies have implicated a genetic etiology responsible for familial HL. We have estimated the heritability of HL and tested the hypothesis of genetic anticipation by using a high quality cancer database of the Swedish population. Heritability was estimated by employing a threshold-liability model. To test the hypothesis of anticipation, the usual T-test procedure was used to test whether there was a difference in cancer age-of-onset between parents and children who were affected with HL. A randomization test was carried out to test the validity of the P-values. Additional analyses were performed after stratifying the data based on birth cohorts. This data set revealed that there was a difference between the age-of-onset of parents and of offspring who were affected with HL. We also estimated the heritability of HL in the Swedish population to be approximately 28.4%. Both findings provide further evidence for a genetic basis for HL.

Adult↗
PubMed1988

Modulation of arachidonic acid metabolites and vulnerability to ventricular fibrillation during myocardial ischemia in the cat.

To determine the relative importance of arachidonic acid pathway products on vulnerability to ventricular fibrillation (VF), we examined the effects of synthesis inhibitors and a receptor blocker acting in the cyclooxygenase (C) and lipoxygenase (L) pathways on VF thresholds in a feline model of coronary occlusion. Thresholds for the induction of VF wer measured before and after a 5-minute coronary occlusion in drug-treated animals and control subjects. Animals were treated with BW755c, a dual L and C inhibitor, CGS-8515, and L inhibitor, FPL-55712, a leukotriene receptor blocker, or sulfinpyrazone, a C inhibitor. BW755c, CGS-8515, and FPL-55712 all prevented an otherwise significant fall in VF threshold during coronary occlusion (p less than 0.01) independent of an effect on effective refractory period, heart rate, or blood pressure. In contrast, sulfinpyrazone, the only compound devoid of an effect on the L pathway, did not protect against an occlusion-related fall in VF threshold. BW755c and CGS-8515 inhibited the synthesis of L and C metabolites coincident with their protection against VF (p less than 0.01). We conclude that agents that antagonize the effects of L products protect against enhanced ventricular vulnerability during acute ischemia, whereas C inhibition alone may not afford this protection.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1996

Assessment of alimentary exposure to Listeria monocytogenes.

Survey data on the frequency of foodborne occurrence and dietary exposure to Listeria monocytogenes were used to estimate the mininmal mean per person annual rate of exposure in the United States during the late 1980s. The estimate was restricted to ready-to-eat (RTE) foods because proper cooking was assumed to be listericidal. The mean amount of each food type per L. monocytogenes occurrence was calculated in about 100 sources, and dietary intake data were used to calculate the mean number of occurrences of L. monocytogenes consumption per person per year. The mean number of occurrences consumed annually per person was determined to be 10 to 100 for RTE food values of 2 to 20% of the total dietary intake, respectively. The frequency of foodborne listeriosis (approximately 10(-5)) was consistent with the estimated exposure rate only if the susceptible population was unexpectedly small or extremely high doses were necessary for infection. Because little evidence is available to support a high rate of unreported non-severe infections, this study was concerned only with severe listeriosis cases. Published frequencies of L. monocytogenes concentrations in food were used to convert occurrences to colony forming units (CFU). Low L. monocytogenes concentrations (approximately 1 CFU/g) were too frequent to be responsible for listeriosis in susceptible subjects, would have caused listeriosis only with extremely low probability in a one-cell threshold infection model. The probability of exposure to a higher dose (> or = 10(3) CFU) was large enough to account for the observed rate of listeriosis.

Digestive System↗
PubMed1996

Chronic inhalation oncogenicity study of isoprene in B6C3F1 mice.

The oncogenic potential of isoprene as affected by concentration, length of daily exposure, and weeks of exposure over the life-span of the animal, as independent variables, was evaluated. Ten groups were exposed for 8 h/day, 5 days/week as follows (ppm-weeks): 0-80, 10-80, 70-40, 70-80, 140-40, 280-20, 280-80, 700-80, 2200-40, 2200-80. Two groups were exposed for 4 h/day: 2200-20, 2200-80. Groups were held until 96 or 105 weeks on study. The concentration x time (duration of exposure) values provided a series of theoretically equivalent exposure hazards. There was an exposure-related increased incidence of liver, lung, Harderian gland and forestomach tumors, and hemangiosarcomas and histiocytic sarcomas. The LOEL appeared to be 70 ppm. These results are similar to the profile of tumors seen in 1,3-butadiene (BD)-exposed mice without the early onset of T-cell lymphoma as seen with BD. Isoprene appears to be about one order of magnitude less potent than BD in mice. Statistical analyses indicated that the product of isoprene concentration, and length/duration of exposure was not a sufficient basis for predicting tumor risk at any site. Extrapolation of tumor probability between the high and low doses based on cumulative exposure was not appropriate and could not be justified by statistical models. A threshold effect level and strong nonlinearities with respect to concentration appeared to exist for tumor development in this study.

Administration, Inhalation↗
PubMed2005

The refractory periods and threshold potentials of sequential spikes measured by whole-cell recording.

Neurons in the central nervous system are thought to program neural language via firing sequential spikes for guiding animal behaviors. The quantitative profiles of spike intrinsic properties are critically important to understand spike programming. We developed approaches with whole-cell recordings to measure the threshold potentials and refractory periods (RPs) of sequential spikes, and to analyze the relationships of these factors with spike timing precision and capacity at the regular-spiking and fast-spiking neurons in cortical slice. The RPs and threshold potentials of sequential spikes at these two groups of neurons are different and are linearly correlated with spike timing precision and capacity. These data suggest that RPs and threshold potentials essentially navigate the spike programming for the precise and loyal encoding of meaningful neural signals. Our study provides the avenues for decoding the spectrum of the neural signals quantitatively.

Action Potentials↗
PubMed2006

Exogenous antenatal glucocorticoid treatment reduces susceptibility for hippocampal kindled and maximal electroconvulsive seizures in infant rats.

Dexamethasone (DEX) and betamethasone (BETA) are synthetic glucocorticoids used clinically to reduce morbidity and mortality in infants at risk of premature birth. While their main role is to facilitate lung development, their effect on the developing nervous system and seizure susceptibility is unclear. The present study tested the hypothesis that antenatal DEX or BETA treatment would alter seizure thresholds and spread of epileptiform activity in the brains of infant offspring. Pregnant dams received once daily injections with DEX, BETA, or vehicle on gestation days 15 to 18. Physical appearance, litter size, and weight of the pups were assessed postnatally. Seizure thresholds were determined on postnatal day 14 using electroconvulsive shock delivered through ear clips (i.e., generalized seizure) or kindling stimulation of the left hippocampus through indwelling electrodes (i.e., partial seizure). The rate of acquisition of kindled seizures was determined on postnatal days 14 and 15. Pups from dams treated with DEX and BETA were growth restricted. Antenatal BETA treatment increased seizure threshold for both models. Antenatal DEX treatment increased kindling threshold, but not electroconvulsive shock threshold. Kindling rate was unaffected by either antenatal treatment. In summary, repeated glucocorticoid treatments had adverse effects on weight, skin and litter size, raised seizure thresholds, and reduced seizure vulnerability. Although these effects are seemingly desirable with respect to seizure susceptibility, they suggest that the functional organization of the nervous system is altered with antenatal synthetic glucocorticoid treatment.

Analysis of Variance↗
PubMed2005

Influence of season on prevalence of cleft lip and palate.

According to the multifactorial threshold (MFT) model, cleft lip and palate (CLP) result from the influence of exogenous and endogenous genetic factors. Based on nearly 1000 cases of cleft lip with or without cleft palate treated in the clinic for maxillofacial surgery of the Martin-Luther University Halle-Wittenberg during the period 1946-1995, we investigated the influence of season on the occurrence of this malformation. Seasons of the year reflect various exogenous factors that may be accessible to prevention. The calculated date of conception served as comparison value between the study group and controls. The clefts of type III (CLP; P = 0.48), isolated CP (P = 0.933) or male patients with clefts of type I showed no significant deviation from the distribution in the control group over the year. We proved a significant maximum in spring, summer and autumn and a minimum in winter for the conception date of female patients with type I clefts (P = 0.033, relative risk = 2.6). Some of the seasonal factors implicated in the aetiology that play a role in the development of clefts could be:

Cleft Lip↗
PubMed2005

Sensitivity and specificity of color duplex ultrasound measurement in the estimation of internal carotid artery stenosis: a systematic review and meta-analysis.

BACKGROUND: Duplex ultrasound is widely used for the diagnosis of internal carotid artery stenosis. Standard duplex ultrasound criteria for the grading of internal carotid artery stenosis do not exist; thus, we conducted a systematic review and meta-analysis of the relation between the degree of internal carotid artery stenosis by duplex ultrasound criteria and degree of stenosis by angiography. METHODS: Data were gathered from Medline from January 1966 to January 2003, the Cochrane Central Register of Controlled Trials and Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, ACP Journal Club, UpToDate, reference lists, and authors' files. Inclusion criteria were the comparison of color duplex ultrasound results with angiography by the North American Symptomatic Carotid Endarterectomy Trial method; peer-reviewed publications, and >/=10 adults. RESULTS: Variables extracted included internal carotid artery peak systolic velocity, internal carotid artery end diastolic velocity, internal carotid artery/common carotid artery peak systolic velocity ratio, sensitivity and specificity of duplex ultrasound scanning for internal carotid artery stenosis by angiography. The Standards for Reporting of Diagnostic Accuracy (STARD) criteria were used to assess study quality. Sensitivity and specificity for duplex ultrasound criteria were combined as weighted means by using a random effects model. The threshold of peak systolic velocity >/=130 cm/s is associated with sensitivity of 98% (95% confidence intervals [CI], 97% to 100%) and specificity of 88% (95% CI, 76% to 100%) in the identification of angiographic stenosis of >/=50%. For the diagnosis of angiographic stenosis of >/=70%, a peak systolic velocity >/=200 cm/s has a sensitivity of 90% (95% CI, 84% to 94%) and a specificity of 94% (95% CI, 88% to 97%). For each duplex ultrasound threshold, measurement properties vary widely between laboratories, and the magnitude of the variation is clinically important. The heterogeneity observed in the measurement properties of duplex ultrasound may be caused by differences in patients, study design, equipment, techniques or training. CONCLUSIONS: Clinicians need to be aware of the limitations of duplex ultrasound scanning when making management decisions.

Blood Flow Velocity↗
PubMed2004

Genotoxicity in the eyes of bystander cells.

The controversial use of a linear, no threshold extrapolation model for low dose risk assessment has become even more so in light of the recent reports on the bystander phenomenon. The answer to the question as to which of the two phenomena, bystander versus adaptive response, is more important has practical implication in terms of low dose radiation risk assessment. In this review, genotoxicity is used as an endpoint to introduce the two phenomena, provide some insight into the mechanisms of bystander effect and to bridge the two low dose phenomena which operate in opposite directions: the bystander effect tends to exaggerate the effect at low doses, by communicating damage from hit to non-hit cells whereas the adaptive response confers resistance to a subsequent challenging dose by an initial low priming dose.

Alpha Particles↗
PubMed2001

Saccadic countermanding: a comparison of central and peripheral stop signals.

We compared the effectiveness of central and peripheral targets in a saccadic countermanding task. Stop-signal reaction times (SSRTs) do not differ significantly for central and peripheral stop signals. Further, when central and peripheral stop signals are presented together, SSRTs behave as expected of independent processes in parallel. A linear rise-to-threshold race model (LATER) with independent go and stop processes describes the behavioural data successfully, predicting not only the latency distribution of saccades that escaped inhibition, but also the probability of successful countermanding. Central and peripheral stop signals appear to act independently and with equal effectiveness.

Adult↗
PubMed1989

Quantitative risk approaches for formaldehyde.

Formaldehyde presents unique data that highlight significant issues in the extrapolation of animal studies to human risk assessments. Formaldehyde causes rare nasal cancer in rats at 15 ppm, but not at lower levels of 2 ppm and 0.5 ppm in the range of human exposures. Mice and hamster studies even at high levels have results similar to low dose rats. Higginson et al. reviewed the human epidemiology studies and concluded that no excess cancer risk was observed; and if a risk exists, it is very low. Formaldehyde is a natural metabolite--the human body turns over 51 g/day. Cells, therefore, have detoxification and other defence mechanisms to formaldehyde. Recent CIIT biomechanism results elucidate these factors. These data raise two issues: First, the appropriateness of linear quantitative risk methodology given the non-linear nature of the biological data. Either a non-linear (threshold) statistical model or NOEL approach are appropriate risk assessment techniques for formaldehyde. Second, the rare nasal cancer observed in rats also occurs in control animals. A comparison of relative risk between background and low formaldehyde exposures has been calculated for both groups. Non-linear (MLE) 5 stage multistage models estimate 0 per million risk from both background and 1 ppm of formaldehyde exposure. Linear or upperbound (95%) estimates are 7,200/million from background and 5,000/million from 1 ppm formaldehyde. These estimates have a significant impact on formaldehyde regulatory programs for warning labels and "safe" exposure levels.

Environmental Pollutants↗