Relationship of thyroid transcription factor 1 to EGFR status in non-small-cell lung cancer.

BACKGROUND: Activating mutations of the epidermal growth factor receptor (EGFR) gene are known to drive a proportion of non-small-cell lung cancers. Identification of lung cancers harbouring such mutations can lead to effective treatment using one of the agents that targets and blocks egfr-mediated signalling. METHODS: All specimens received at the BC Cancer Agency (Vancouver) for EGFR testing were prospectively identified and catalogued, together with clinical information and EGFR status, over a 14-month period. RESULTS: Specimens from 586 patients were received for EGFR testing, and EGFR status was reported for 509 patients. No relationship between specimen type or site of origin and EGFR test failure rate was identified. Concurrent immunohistochemical (ihc) status for thyroid transcription factor 1 (ttf1) was available for 309 patients. The negative predictive value of ttf1-negative status by ihc was 94.2% for predicting negative EGFR status. CONCLUSIONS: In patients with limited tissue available for testing, a surrogate for EGFR status would aid in timely management. Immunohistochemistry for ttf1 is readily available and correlates highly with EGFR status. In conjunction with genetic assays, ttf1 could be used to optimize an EGFR testing strategy.

Adverse outcome analyses of observational data: assessing cardiovascular risk in HIV disease.

Clinical decisions are ideally based on randomized trials but must often rely on observational data analyses, which are less straightforward and more influenced by methodology. The authors, from a series of expert roundtables convened by the Forum for Collaborative HIV Research on the use of observational studies to assess cardiovascular disease risk in human immunodeficiency virus infection, recommend that clinicians who review or interpret epidemiological publications consider 7 key statistical issues: (1) clear explanation of confounding and adjustment; (2) handling and impact of missing data; (3) consistency and clinical relevance of outcome measurements and covariate risk factors; (4) multivariate modeling techniques including time-dependent variables; (5) how multiple testing is addressed; (6) distinction between statistical and clinical significance; and (7) need for confirmation from independent databases. Recommendations to permit better understanding of potential methodological limitations include both responsible public access to de-identified source data, where permitted, and exploration of novel statistical methods.

The association of folate, zinc and antioxidant intake with sperm aneuploidy in healthy non-smoking men.

BACKGROUND: Little is known about the effect of paternal nutrition on aneuploidy in sperm. We investigated the association of normal dietary and supplement intake of folate, zinc and antioxidants (vitamin C, vitamin E and beta-carotene) with the frequency of aneuploidy in human sperm. METHODS: Sperm samples from 89 healthy, non-smoking men from a non-clinical setting were analysed for aneuploidy using fluorescent in situ hybridization with probes for chromosomes X, Y and 21. Daily total intake (diet and supplements) for zinc, folate, vitamin C, vitamin E and beta-carotene was derived from a food frequency questionnaire. Potential confounders were obtained from a self-administered questionnaire. RESULTS: After adjusting for covariates, men with high folate intake (>75th percentile) had lower frequencies of sperm with disomies X, 21, sex nullisomy, and a lower aggregate measure of sperm aneuploidy (P

The rectus abdominis muscle advancement flap as a salvage option for chest wall reconstruction.

We describe a previously unreported technique of advancing the rectus abdominis muscle superiorly, based on the deep inferior epigastric artery, to cover a lower anterior chest wall defect. This technique represents an important salvage option for chest wall reconstruction and affords a great deal of intra-operative flexibility.

Selection for high adult body weight in Drosophila populations with different structures.

Selection for high adult body weight in Drosophila melanogaster was practiced for 18 generations in three selection lines. These lines were genetically similar and of equal size but different in population structure. One line represented a large mass-selected, random-mating population, while the other two lines simulated large populations that had been subdivided into partial isolates or demes. Mass selection and random mating occurred within each deme. These two subdivided lines were different only in the rate of effective migration among the demes (5% and 10%). Selection intensities of approximately 20% were applied to these populations. A fourth line served as a random mating control. Heritability of adult body weight in the base population was estimated to be 0.58 plus or minus 0.22. The results indicate that significantly greater responses were achieved in the subdivided lines than in the large mass-selected line, in spite of the fact that larger selection differentials were applied to the latter. No significant differences in response were observed between the two subdivided lines. Wright (1930, 1931) postulated that selection would be most efficient in subdivided populations with limited interdeme migration. The present findings appear to support this theory.

Analysis of a 2(9) full factorial chemical library.

Robotic synthesis is making possible the synthesis of large, systematically designed sets of compounds. We analyze a 512-compound set that is a 2(9) full factorial experimental design using a recursive partitioning algorithm, FIRM, and a high-dimension visualization tool, TempleMVV. These techniques are used to quickly and easily identify the main trends in the data set and also identify unusual observations. We show that analytical and visualization methods can be used synergistically to analyze a large, complex, high-dimensional data set. We also show that a fractional factorial design of 128 compounds would give essentially the same information.

Respiratory mechanics of horses measured by conventional and forced oscillation techniques.

Respiratory mechanics were compared using conventional and forced oscillation techniques in six conscious horses and a mechanical model of the equine respiratory system. The parameters calculated from conventional airflow and esophageal pressure measurements were pulmonary resistance and dynamic compliance. The impedance of the respiratory system was measured at 1, 2, and 3 Hz with the forced oscillation technique, and respiratory system resistance, compliance, inertance, and resonant frequency were calculated. Pulmonary resistance was 1.0 +/- 0.3 cmH2O.l-1.s, and pulmonary dynamic compliance was 2.4 +/- 0.6 l/cmH2O. With the use of the forced oscillation system, respiratory resistance was 1.61 +/- 0.50 cmH2O.l-1.s at 1 Hz, compliance was 0.195 +/- 0.075 l/cmH2O, inertance was 0.026 +/- 0.0095 cmH2O.l-1.s2, and resonant frequency was 2.40 +/- 0.25 Hz. Data collected from a model of the respiratory system showed a close correlation between resistance and compliance measured with the two systems. This study demonstrates that the forced oscillation technique is a useful method for noninvasive measurement of respiratory mechanics in horses.

Frequency dependence of forced oscillatory respiratory mechanics in horses with heaves.

The effect of measurement frequency on respiratory mechanics was investigated in six horses with reversible allergic airway disease. Total respiratory impedance was measured at 1.5, 2.0, 3.0, and 5.0 Hz by using the forced oscillation technique with the horses in remission, after acute antigenic challenge producing clinical heaves, and with heaves but after the administration of 2 mg fenoterol by inhalation. The slopes of the magnitude (magnitude of Zrs) and real part (R) of total respiratory impedance over the frequency range 1.5-3 Hz changed significantly after antigenic challenge and fenoterol. The ratio of R at 2 Hz to R at 3 Hz, however, discriminated better among the three conditions. Compliance and resonant frequency (calculated by using a three-element model) changed significantly after antigenic challenge and fenoterol, but inertance did not. We concluded that horses with heaves showed frequency dependence of R and (magnitude of Zrs) at frequencies up to 3 Hz and that parameters derived from a three-element model were useful indicators of small airway obstruction in the horse.

Comparison of aerobic capacity between racing standardbred horses.

A standardized treadmill test was used to compare metabolic and ventilatory measurements between 10 standardbred racehorses. The horses were divided into two groups: group A (n = 5) had mean racing speeds of 4.4 s faster than group B (n = 5) over a 1-mi. distance. Each horse was fitted with a venous catheter and connected to a valved gas-collection system. The exercise test consisted of 1-min incremental workloads ranging from 4.0 to 12.0 m/s at a treadmill incline of 3 degrees. Group A had significantly higher (P < 0.05) measurements of maximal O2 consumption (VO2max), O2 pulse, and tidal volume. Venous lactate concentration and respiratory exchange ratio measured at VO2max were also significantly higher (P < 0.05) in group A. Similar treadmill velocities were required to achieve a respiratory exchange ratio of > 1 and venous blood lactate concentration of > 4 mmol/l; however, group A was able to complete a significantly higher (P < 0.01) number of workloads before fatigue. The high aerobic and anaerobic capacity of group A horses may be a major contributor to a faster racing performance.

Use of recursive partitioning in the sequential screening of G-protein-coupled receptors.

High-throughput screening (HTS) is changing as more compounds and better assay techniques become available. HTS is also generating a large amount of data. There is a need to rationalize the HTS process, because, in some cases, the screening of all available compounds is not economically feasible. In addition to the selection of promising compounds, there is a need to learn from the data that we collect. In this paper, we use a data-mining method, recursive partitioning, to help uncover and understand structure-activity relations and to help biology and chemistry experts make better decisions on which compounds to screen next and better characterize. The sequential-screening process is presented and the results of applying that process to 14 G-protein-coupled receptor assays are reported.

What is the proper experimental unit for long-term rodent studies? An examination of the NTP benzyl acetate study.

The National Toxicology Program (NTP) rat bioassay on benzyl acetate shows an apparent increase in acinar-cell adenomas of the pancreas in male rats [1]. The statistical significance of the apparent trend is examined using the animal, cage, or rack/shelf location as the statistical independent experimental (sampling) unit. Experimental, statistical, and empirical considerations indicate that, in this experiment, if there is a proper experimental unit, it is the shelf of animals on a rack rather than the individual animal or cage of animals. Using the shelf as the experimental unit, the apparent increase in acinar-cell adenomas is not statistically significant. There is strong evidence for pancreatic tumor rates to differ among shelves which implies that toxicologists should consider cage randomization.

Optimized target localization in stereotactic radiosurgery using real-time digital portal images.

This paper presents a method for optimized estimation of target localization in stereotactic radiosurgery using real-time digital portal images. The positions of the two radiation sources and the two projection planes in radiosurgery can be chosen arbitrarily. The reconstruction of the target is characterized as a non-linear multi-variable optimization problem, which minimizes the difference between the actual target and the reconstructed target. This optimization problem is solved by the Gaussian least square differential correction (GLSDC) method. Due to the digitized errors and input data errors, the algorithm defines an indirect reference factor (the shortest distance between two x-rays pointing onto the target) as an indication of the accuracy of the method. Our experimental results show that the reference factor is less than 1.0 mm for the correct data entry. The proposed algorithm provides a method that supports on-line target localization which can be done directly on the digital portal imaging device.

Effects of quality of resource and fertilization status on some fitness traits in the two-spotted spider mite, Tetranychus urticae Koch.

Four fitness traits, including fecundity, hatchability, duration of oviposition, and longevity, were studied in T. urticae. Comparisons were made between unfertilized and fertilized females reared on good and poor resources. Significant differences in total egg production, duration of oviposition, and longevity were observed with respect to fertilization status. Only total egg production varied significantly between maternal background environments. Hatchability was uniformly high. Fecundity was found to be the most influential character affecting fitness in spider mites. Further analysis of the distribution of daily egg productions was used to determine the various factors affecting intrinsic rates of increase including the rate of development, time of peak egg production, and duration of oviposition. The rate of development was shown to be the most important factor determining the intrinsic rate of increase. The relationships between these findings and the colonizing ability of spider mite populations were discussed.

Discovery 99: accelerate and improve the drug discovery process. 26-29 April 1999, San Diego, CA, USA.

The stated purpose of this conference was the examination of emerging technologies for drug discovery. The meeting was divided into numerous pre- and post-conferences and tracks. A pre-conference workshop examined enabling software and business strategies. Nine tracks covered natural products, high-throughput screening, bioinformatics, proteomics/functional genomics, pharmacogenomics, combichem, chemoinformatics and assay methods. A post-conference symposium covered ADME-toxicology screening. In short, the gamut of drug discovery.

Foveal automatic target recognition using a multiresolution neural network.

This paper presents a method for detecting and classifying a target from its foveal (graded resolution) imagery using a multiresolution neural network. Target identification decisions are based on minimizing an energy function. This energy function is evaluated by comparing a candidate blob with a library of target models at several levels of resolution simultaneously available in the current foveal image. For this purpose, a concurrent (top-down-and-bottom-up) matching procedure is implemented via a novel multilayer Hopfield neural network. The associated energy function supports not only interactions between cells at the same resolution level, but also between sets of nodes at distinct resolution levels. This permits features at different resolution levels to corroborate or refute one another contributing to an efficient evaluation of potential matches. Gaze control, refoveation to more salient regions of the available image space, is implemented as a search for high resolution features which will disambiguate the candidate blob. Tests using real two-dimensional (2-D) objects and their simulated foveal imagery are provided.

Object recognition using multilayer Hopfield neural network.

An object recognition approach based on concurrent coarse-and-fine matching using a multilayer Hopfield neural network is presented. The proposed network consists of several cascaded single-layer Hopfield networks, each encoding object features at a distinct resolution, with bidirectional interconnections linking adjacent layers. The interconnection weights between nodes associating adjacent layers are structured to favor node pairs for which model translation and rotation, when viewed at the two corresponding resolutions, are consistent. This interlayer feedback feature of the algorithm reinforces the usual intralayer matching process in the conventional single-layer Hopfield network in order to compute the most consistent model-object match across several resolution levels. The performance of the algorithm is demonstrated for test images containing single objects, and multiple occluded objects. These results are compared with recognition results obtained using a single-layer Hopfield network.

Cardiorespiratory responses to electrical stimulation of the buccal mucosa in ponies.

The cardiovascular and respiratory responses to electrical stimulation of the buccal mucosa under general anaesthesia in ponies were measured in order to provide some insight into the cardiorespiratory effects of anaesthesia in equidae. This knowledge may be useful for reducing morbidity during clinical anaesthesia in horses. Anaesthesia was induced with intravenous thiopentone and maintained with 1.3 per cent inspired halothane in oxygen. Arterial blood pressure, heart rate, minute volume, tidal volume, respiratory rate, arterial blood gas tensions and clinical signs of anaesthetic depth were recorded while the buccal mucous membrane was stimulated electrically. A rise in arterial blood pressure was the most consistent response detected along with clinical signs. The response of individual animals varied considerably. Alterations of respiratory pattern sometimes occurred during stimulation but there was no consistent pattern of change in any animal.

Analysis of the frequency spectrum of the equine electroencephalogram during halothane anaesthesia.

The electroencephalogram (EEG) has been used in human clinical anaesthesia as an indicator of cortical activity and as an indicator of the depth of anaesthesia. It would be useful if it provided a reliable indication of the depth of anaesthesia of horses. In this study anaesthesia was induced with thiopentone and maintained with halothane in nine ponies. The end tidal halothane concentration (PE-Hal) was monitored and 20 seconds of EEG were recorded at 0.8 per cent, 1.0 per cent and 1.2 per cent halothane, equivalent to the minimum alveolar concentration (MAC), 1.25 MAC and 1.5 MAC. Each 20 second block of data was divided into one second segments and averaged to give one second of averaged EEG from which a frequency spectrum was obtained by using a fast Fourier transformation. The power of the waveform at low frequency (1 to 3 Hz) was compared with that at higher frequency (9 to 11 Hz). The median frequency and 95th percentile (spectral edge) were also calculated. The spectral edge frequency had the best correlation with PE-Hal.

Technique for continuous stride analysis of horses exercising on a treadmill.

A technique for continuous computerised recording and analysis of the stride of horses on a treadmill is described. Advantages of the system are low cost, the use of normal shoes and the calculation of stride parameters in real time.