In-field and out-of-field effects in partial volume lung irradiation in rodents: possible correlation between early dna damage and functional endpoints

Purpose: Recent observations have shown that there are regional variations in radiation response in mouse lung as measured by functional assays. Furthermore, there are both in-field and out-of-field effects in radiation-induced lung damage as observed by DNA assay in rats. The purpose of this work is: (a) to examine mice lethality data following partial volume lung irradiation to assess the possibility of directional or regional effects, (b) to evaluate the correlation between mice lethality data and DNA damage assayed by micronuclei production in rat lung, and (c) to re-interpret mice lethality considering the existence of directional effects in lung cellular response to partial volume irradiation.

Methods and Materials: The lethality data for mice, generated at the M. D. Anderson Cancer Center, Houston, and micronuclei yield data for rats obtained at Princess Margaret Hospital, Toronto, were used. A radiobiological model that allows for out-of-field and in-field effects for lung cell damage and lung response was developed. This model is based on the observation of DNA damage in shielded parts of rat lung that was assumed relevant to cell lethality and consequently overall lung response.

Results: While the experimental data indicated directional or regional volume effects, the applicability of dose and volume as sole predictors of lung response to radiation was found to be unreliable for lower lung (base) irradiation in mice. This conforms well to rat lung response where micronuclei were observed in shielded apical parts of lung following base irradiation. The radiobiological model, which was specifically developed to account for the lung response outside of primary irradiated volume, provides a good fit to mice lethality data, using parameters inferred from rat micronuclei data.

Conclusion: Response to lung irradiation in rodents, in particular, elevated sensitivity to base irradiation, can be interpreted with a hypothesis of in-field and out-of-field effects for cellular response. If the existence of these effects for lung is subsequently proven in humans, it will require the incorporation of geometrical and directional information in normal tissue complication probability calculations for lung. These considerations are ignored in present approaches based only on conventional dose-volume histograms.     

Influence of prior maze experience on behaviour and response to diazepam in the elevated plus-maze and light/dark tests of anxiety in mice

A single prior undrugged exposure to the elevated plus-maze has been reported to reduce open arm activity on retest and to attenuate/abolish the anxiolytic response to benzodiazepines at retest intervals ranging from 48 h to 14 days. The present study was designed to examine the generality of these findings by comparing the effects of prior maze experience on baseline behaviour and response to diazepam in two murine models of anxiety. Parallel experiments were conducted in which DBA/2 mice were exposed/not exposed to the plus-maze, treated daily with saline or diazepam (2–4 mg/kg daily for 8 days) and then tested on either the elevated plus-maze or in the light/dark test of exploration. Results show that, in both tests, diazepam reduced behavioural indices of anxiety in maze-naive mice only. However, interpretation of this apparent loss of diazepam efficacy is at least partially confounded by the observation that maze experience per se altered baseline behaviour in both procedures,reducing open arm activity in the plus-maze andincreasing light compartment activity in the light/dark test. The apparent elimination of an anxiolytic response to diazepam in two animal models of anxiety by prior plus-maze experience is discussed in relation to experience-related baseline shifts in behaviour.     

Sequential urn designs with elimination for comparing K > or =3 treatments

A fully sequential procedure is proposed for comparing K > or =3 treatments with immediate binary responses. The procedure uses an adaptive urn design to randomize patients to the treatments and stopping rules are incorporated for eliminating less promising treatments. Simulation is used to assess the performance of the procedure for several adaptive urn designs, in terms of expected numbers of treatment failures and allocation proportions, and the effect on estimation at the end of the trial is also addressed. It is concluded that the drop-the-loser rule is more effective than equal allocation and all of the other designs considered. The practical benefits of the procedure are illustrated using the results of a three-treatment lung cancer study. It is then shown how the sequential elimination procedure may be used in dose-finding studies and its performance is compared with a recently proposed method. Several possible extensions to the work are briefly indicated.     

Using quantitative methods to improve the diagnostic workup for abdominal pain in children

Introduction

The differential diagnosis of abdominal pain in children can be challenging. We applied quantitative decision-making methods to this process and sought to determine if their use provided measurable benefit.

Methods

After obtaining institutional review board approval, we recorded key elements of the history, physical examination, laboratory, and imaging evaluations along with the cost and the time spent in the emergency department (ED) for children presenting with abdominal pain. Initially, data were collected (group 1, n = 1366 patients) and then presented to the ED pediatricians. For subsequent patients, ED physicians received a sheet specific to that patient's age and sex reporting the most common diagnoses and the elements of the evaluation that had proven most useful (group 2, n = 624 patients). We compared the difference in length of stay and costs before and after intervention, between study groups, by age groups, and separately by sex using a 2-factor analysis of variance.

Results

The diagnostic workup cost less in boys aged 2 to 12 years after the intervention. In boys and girls older than 12 years, the cost trended lower.

Discussion

This study demonstrates that ED physicians equipped with specific information were able to complete their diagnostic evaluation of children presenting with abdominal pain at a lower cost.     

Predicting in vitro tissue culture growth for cytogenetic evaluation of stillborn fetuses

A prospective study was undertaken of 131 perinatal deaths to determine whether gestational age, body weight, maceration degree and autopsy interval influenced successful in vitro tissue culture for cytogenetic evaluation. Perinatal populations were categorized as neonatal death (NND), fresh stillbirth (FSB), or graded as macerated stillbirth (MAC-0, MAC-1, MAC-2, MAC-3). Metaphase production by at least 15 cells separated 'growth' from 'no growth' categories after sampling liver, kidney and spleen. Body weight and degree of maceration were predictive of successful 'growth', while gestational age and autopsy interval were not. Body weight was significant in separating 'growth' from 'no growth' in NND (P = 0.05), FSB, MAC-0 and MAC-1 (P = 0.01). Growth probabilities were 0.78 (NND), 0.57 (FSB), 0.49 (MAC-0), 0.38 (MAC-1) and zero for MAC-2 and MAC-3. We conclude that (a) tissues from MAC-2 and MAC-3 fetuses do not grow and thus need not be sampled at autopsy, (b) maceration degree and body weight can be used to predict the growth probability in the other categories, (c) tissue samples can be taken during daylight hours, since autopsy interval does not influence successful growth provided the fetus is refrigerated at 4 degrees C, (d) all of the above conclusions have cost-efficiency implications for cytogenetic laboratories.     

Gait termination in young and older adults: effects of stopping stimulus probability and stimulus delay

Sixteen young (25±2.6 years) and 16 older individuals (69±4.4 years) walked normally then terminated walking rapidly. A visual stopping stimulus was presented 10 ms following ground contact (short delay) and in another condition, at 450 ms prior to toe-off (long delay). Stimulus probability was either high (80% of trials) or low (10%). The younger group stopped faster (463 vs. 574 ms) despite also walking faster (1.29 vs. 1.17 m s⁻¹). Longer delay decreased one-step responses but older participants used significantly more (slower) two-step stopping, which increased stopping time and distance. The additional step may have been pre-planned to maintain medial–lateral stability.     

Assessment of i-125 prostate implants by tumor bioeffect

PURPOSE: A method of prostate implant dose distribution assessment using a bioeffect model that incorporates a distribution of tumor cell densities is demonstrated. This method provides both a quantitative method of describing implant quality and spatial information related to the location of underdosed regions of the prostate. This model, unlike any other, takes into account the likelihood of finding cancer cells in the underdosed region. METHODS AND MATERIAL: The prostate volumes of 5 patients were divided into multiple subsections and a unique cell density was assigned to each subsection. The assigned cell density was a function of probability of finding tumor foci in that subsection. The tumor control probability (TCP) for each subsection was then calculated to identify the location of any significantly underdosed part of the prostate. In addition, a single TCP value for the entire prostate was calculated to score the overall quality of the implant. RESULTS: Adequately dosed subsections scored TCP values greater than 0.80. The TCP for underdosed regions fell dramatically particularly in subsections at higher risk of containing tumor cells. CONCLUSIONS: Despite uncertainties in radiobiological parameters used to calculate the TCP and the distribution of cancer foci through the prostate, the bioeffect model was found to be useful in identifying regions of underdosed prostate that may be at risk of local recurrence due to inadequate dose. Unlike the isodose distribution, the model has the potential to demonstrate that small volumes of tissue underdosed in regions most likely to contain higher numbers of tumor cells may be more significant than larger volumes irradiated to a lower dose but with a lower probability of containing cancer cells.     

Practical utility of clinical prediction rules for suspected acute pulmonary embolism in a large academic institution

INTRODUCTION: In an attempt to standardize clinicians' approach to the determination of pretest probability (PTP) in pulmonary embolism (PE), two simplified scoring models have recently been proposed. We sought to determine the utility of these algorithms in patients with suspected PE in a large, tertiary, academic medical center. METHODS: We performed a retrospective analysis of 295 inpatients and outpatients from our institution who were evaluated for suspected PE. Pretest probability (PTP) was calculated using two previously formulated scoring systems by Wells et al. (Canadian score) and Wicki et al. (Geneva score). Our primary endpoint was the prevalence of PE within each strata of PTP. RESULTS: The prevalence of pulmonary embolism in our cohort was 30%. The prevalence of PE in the low, intermediate and high PTP groups using the Canadian score was 15.3% (95% CI 9.5-23.7%), 34.8% (95% CI 27.9-42.4%), and 47.2% (95% CI 32.0-63.0), respectively. When compared with the low PTP group, the odds ratios of the likelihood of PE was 2.95 (95% CI 1.56-5.59) in the intermediate PTP group and 4.95 (95% CI 2.11-11.64) in the high PTP. The Wicki analysis was divided into "Geneva pure" and "Geneva presumed", where the fractional inspired oxygen concentration was known and presumed to have been sampled on room air, respectively. Neither of the Geneva scores showed statistical significance in the prevalence of PE among the PTP groups. CONCLUSIONS: The Wells' clinical prediction score is easily applied and meaningfully risk stratifies patients with suspected PE. In our population, the Geneva score was less useful.     

Differential properties of GABAergic synaptic connections in rat hippocampal cell cultures

Based on the effect of prolonged tetanic stimulation (30 Hz, 4 sec), we divided GABAergic synaptic connections in hippocampal cell cultures into two groups: connections facilitated ( approximately 45%) and connections depressed ( approximately 55%) by the tetanic stimulation. In order to reveal possible reasons for the differential effect of the tetanization, we compared several properties of the connections belonging to both groups. We found that, on average, evoked IPSCs in the connections facilitated by the tetanization have a smaller amplitude and larger coefficient of variation (CV) of IPSC amplitude compared to connections depressed by the tetanization. We also estimated quantal parameters for both groups of connections assuming that transmitter release is reasonably described by a binomial distribution. We found that a background release probability (P) is substantially lower in the connections facilitated by the tetanization (P approximately 0.5) than in the connections depressed by the tetanization (P approximately 0.9) and suggest that this difference may underlie the differential effect of the tetanization. We also found that the tetanization induces the opposite effect on connections made by distinct presynaptic neurons with the same postsynaptic cell (convergent connections) in a fraction of postsynaptic neurons studied (3 out of 9). These results support the idea that properties of the presynaptic neuron are of primary importance for the observed differential effect of the tetanization, but they do not exclude a role of the postsynaptic neuron in this effect.     

Language switching mechanisms in simultaneous interpreters: an ERP study

Recent event-related potential (ERP) and neuroimaging studies suggest that bilingual individuals are able to inhibit the processing of a non-target language while speaking or reading in another language. The neural mechanisms subserving code switching still remain matter of debate. The aim of the present study was to shed some light on the neurofunctional bases of such mechanisms. ERPs were recorded in native Italian simultaneous interpreters and monolingual controls during a semantic processing task in which the subjects had to evaluate the sensibleness of final words of incomplete sentences. All participants were strictly right-handed. Interpreters knew at least four languages (from four to eight) at a professional level, from among 11 European and Asian languages, and had an excellent command of English (L2). Four hundred short sentences were presented visually; half of them had an unexpected final word, producing a semantic incongruence. Sentences could be entirely in Italian or in English (unmixed); alternatively, the body of the sentence could be in English and the final word in Italian or vice versa (mixed). ERPs were time locked to the onset of the final word. Both reaction times (RTs) and electrophysiological data indicated a lesser degree of hemispheric lateralization for linguistic function during L2 rather than L1 processing in interpreters. The first effect of lexical switching and code switching was recorded in the time window between 140 and 200 ms at left anterior sites. At N400 level, ERPs were significantly larger to L2 than to L1 words only in the mixed and not in the unmixed condition. No effect of language was observed in the unmixed condition, thus suggesting that the difference in L1/L2 processing was not related to a difference in proficiency, but rather to a different functional organization of semantic integration systems due to the later age of acquisition of L2 compared to L1. Interpreters were faster at reading and comprehending sentences in English ending with an Italian word than vice versa (L2 --> L1 switch).