Probing Computation in the Primate Visual System at Single-Cone Resolution.

Daylight vision begins when light activates cone photoreceptors in the retina, creating spatial patterns of neural activity. These cone signals are then combined and processed in downstream neural circuits, ultimately producing visual perception. Recent technical advances have made it possible to deliver visual stimuli to the retina that probe this processing by the visual system at its elementary resolution of individual cones. Physiological recordings from nonhuman primate retinas reveal the spatial organization of cone signals in retinal ganglion cells, including how signals from cones of different types are combined to support both spatial and color vision. Psychophysical experiments with human subjects characterize the visual sensations evoked by stimulating a single cone, including the perception of color. Future combined physiological and psychophysical experiments focusing on probing the elementary visual inputs are likely to clarify how neural processing generates our perception of the visual world.

Monte Carlo methods for localization of cones given multielectrode retinal ganglion cell recordings.

It has recently become possible to identify cone photoreceptors in primate retina from multi-electrode recordings of ganglion cell spiking driven by visual stimuli of sufficiently high spatial resolution. In this paper we present a statistical approach to the problem of identifying the number, locations, and color types of the cones observed in this type of experiment. We develop an adaptive Markov Chain Monte Carlo (MCMC) method that explores the space of cone configurations, using a Linear-Nonlinear-Poisson (LNP) encoding model of ganglion cell spiking output, while analytically integrating out the functional weights between cones and ganglion cells. This method provides information about our posterior certainty about the inferred cone properties, and additionally leads to improvements in both the speed and quality of the inferred cone maps, compared to earlier "greedy" computational approaches.

SU-E-T-469: The Effects of Patient Anatomy and Parallel Magnetic Fields on Beamlet Dose Distributions.

PURPOSE: Beamlets are generated in a patient geometry in the presence of a magnetic field to investigate the effects of tissue density and magnetic field on beamlet dose distributions, which is important for the optimization of photon fluence to be delivered by a linac-MR system. METHODS: 50×50 mm2 fields were placed with isocenter in the middle of a patient's right lung. Each treatment field was decomposed into 100 beamlets (each 5×5 mm2 ). BEAMnrc scored the particle phase space at 100.2 cm from the source in the linac-MR geometry (isocentre at 126 cm) with parallel magnetic fields of 0, 0.56, and 3T. DOSXYZnrc was modified to score the energy deposited by particles from this phase space as a function of the beamlet the particle passed through. The calculation volume of 70×46×64 voxels encompassed the patient with a voxel size of 3×3×3 mm3 . Each beamlet was normalized to the dose calculated to a 3×3×3 mm3 voxel with isocenter at 5cm depth in a flat water tank without a magnetic field. RESULTS: Beamlet files were calculated on Western Canada's high performance computing cluster (Westgrid) using 100 processors, enabling simulation of 109 histories in less than 3 hours. The resulting files, which contained 3D dose distributions for all 100 beamlets, were 81 MB per field. The Monte Carlo uncertainty was also stored. The gyroradii for 1 MeV electron traversing field lines at 20 degrees are 2.9mm and 0.5mm for 0.56 and 3T fields respectively. The 0.56T parallel magnetic field has a small effect compared to the distortion of the beamlet introduced by the presence of lung. CONCLUSIONS: The effect of tissue heterogeneities is more significant than the effect of a 0.56T parallel magnetic field. A 3T field refocuses the dose in lung to the beamlet path and significantly reduces the lateral electron scatter.

Dose-volume analysis of locoregional recurrences in head and neck IMRT, as determined by deformable registration: a prospective multi-institutional trial.

BACKGROUND AND PURPOSE: Although IMRT for head and neck cancer is widely accepted, the implications of sparing normal tissue immediately adjacent to target volumes are not well known. MATERIALS AND METHODS: Between 2002 and 2007, 124 patients with head and neck cancer were treated with surgery and postoperative IMRT (n=79) or definitive RT (n=45). Locoregional recurrences were analyzed for location relative to target volumes, and dosimetry. RESULTS: With a median follow-up of 26.1months, a total of 16 locoregional recurrences were observed. The five-year actuarial locoregional disease-free survival was 82% [95% CI, 72-90%]. Analysis of 18 distinct sites of locoregional failure revealed that five of these failures were within the high dose clinical target volume (CTV), nine failures were at the margin of the CTV, and four recurrences were outside the CTV. The mean dose delivered to these recurrent volumes was 63.1 Gy [range: 57-68 Gy], while the mean dose to the coolest 1cc within each recurrence was 60.0 Gy [range: 51-67 Gy]. There were two periparotid recurrences observed. CONCLUSIONS: We observed excellent locoregional control rates overall. The majority of recurrences occur within high dose regions of the neck and not near the spared parotid glands.

Information processing in the primate retina: circuitry and coding.

The function of any neural circuit is governed by connectivity of neurons in the circuit and the computations performed by the neurons. Recent research on retinal function has substantially advanced understanding in both areas. First, visual information is transmitted to the brain by at least 17 distinct retinal ganglion cell types defined by characteristic morphology, light response properties, and central projections. These findings provide a much more accurate view of the parallel visual pathways emanating from the retina than do previous models, and they highlight the importance of identifying distinct cell types and their connectivity in other neural circuits. Second, encoding of visual information involves significant temporal structure and interactions in the spike trains of retinal neurons. The functional importance of this structure is revealed by computational analysis of encoding and decoding, an approach that may be applicable to understanding the function of other neural circuits.

Patient specific treatment verifications for helical tomotherapy treatment plans.

We performed two-dimensional treatment verifications for ten patients planned and treated with helical tomotherapy. The treatment verification consisted of a film measurement as well as point dose measurements made with an ion chamber. The agreement between the calculated and the measured film dose distributions was evaluated with the gamma index calculated for three sets of criteria (2 mm and 2%, 4 mm and 3%, and 3 mm and 5%) as recommended in the literature. Good agreement was found between measured and calculated distributions without any need of normalization of the dose data but with dose map registration using reference marks. In this case, 69.8 +/- 17.2%, 92.6 +/- 9.0%, and 93.4 +/- 8.5% passed the 2 mm and 2%, 4 mm and 3%, and 3 mm and 5% criteria, respectively. Agreement was excellent when both normalization and manual registration of the dose maps was employed. In this case 91.2 +/- 5.6%, 99.0 +/- 1.4%, and 99.5 +/- 0.8% passed the 2 mm and 2%, 4 mm and 3%, and 3 mm and 5% criteria, respectively. The mean percent discrepancy for the point dose measurements was -0.5 +/- 1.1%, -2.4 +/- 3.7%, -1.1 +/- 7.3% for the high dose, low dose, and critical structure point, respectively. Three criteria for a satisfactory treatment verification in the high dose regions of a plan were established. For the un-normalized reference mark registered data 80% of pixels must pass the 3 mm and 5% criteria. For the normalized and manually registered data, 80% must pass the 2 mm and 2% criteria, and the point dose measurement must be within 2% of the calculated dose. All low dose region/critical structure point dose measurements were evaluated on a patient by patient basis. The criteria we recommend can be useful for the routine evaluation of treatment plans for tomotherapy systems.

Preservation of oral health-related quality of life and salivary flow rates after inverse-planned intensity- modulated radiotherapy (IMRT) for head-and-neck cancer.

PURPOSE: To assess whether comprehensive bilateral neck intensity-modulated radiotherapy (IMRT) for head-and-neck cancer results in preserving of oral health-related quality of life and sparing of salivary flow in the first year after therapy. METHODS AND MATERIALS: Twenty-three patients with head-and-neck cancer (primary sites: nasopharynx [5], oral cavity [12], oropharynx [3], and all others [3]) were accrued to a Phase I-II trial. Inverse planning was carried out with the following treatment goals: at least 1 spared parotid gland (defined as the volume of parotid gland outside the planning target volume [PTV]) to receive a median dose of less than 20 Gy; spinal cord, maximum 45 Gy; PTV(1) to receive a median dose of 50 Gy; PTV(2) to receive a median dose of 60 Gy (postoperative setting, n = 15) or 66-70 Gy (definitive radiotherapy setting, n = 8). Treatment was delivered with 6 and 15 MV photons using a "step-and-shoot" technique on a Varian 2300 EX linac with 120-leaf Millenium MLC. Unstimulated and stimulated whole-mouth salivary flow rates were measured, and patients completed the University of Washington instrument (UWQOL) and a separate xerostomia questionnaire (XQOL) in follow-up. RESULTS: Early functional outcome end point data are available at the 1-, 3-, and 12-month follow-up time points for 22, 22, and 18 patients, respectively. The combined mean parotid dose was 30.0 Gy (95% confidence interval: 26.9-33.1). The differences from baseline in mean overall UWQOL scores at 1, 3, and 12 months postradiotherapy were -0.24, 0.32, and 4.28, not significantly different from zero (p = 0.89, p = 0.87, p = 0.13). None of the UWQOL individual domain scores related to oral health (pain, eating-chewing, eating-swallowing, and speech) at 1, 3, or 12 months were significantly different from baseline. Both unstimulated and stimulated whole-mouth flow was variably preserved. Unstimulated salivary flow at 1 and 12 months was inversely correlated with combined mean parotid dose (p = 0.014, p = 0.0007), whereas stimulated salivary flow rates at 3 and 12 months were also correlated with combined mean parotid dose (p = 0.025, p = 0.0016). Combined maximum parotid dose was correlated with unstimulated flow rate at 12 months (p = 0.02, r = -0.56) and stimulated flow rate at 1 and 12 months (p = 0.036, r = -0.45; p = 0.0042, r = -0.66). The proportion of patients reporting total XQOL scores of 0 or 1 (no or mild xerostomia) did not diminish significantly from baseline at 1, 3, or 12 months (p = 0.72, p = 0.51, p = 1.0). Unstimulated and stimulated flow at 1 month was inversely correlated with total XQOL score at 12 months (p = 0.025, p = 0.029). CONCLUSIONS: Oral health-related quality of life (HRQOL) was highly preserved in the initial 12 months after IMRT, as assessed with separate, validated instruments for xerostomia-specific quality of life and oral HRQOL. In general, patients with better-preserved unstimulated salivary flow rates tended to report lower xerostomia scores. Whole-mouth salivary flow rates post IMRT were inversely correlated with combined mean parotid doses. Longer follow-up is required to assess to what extent HRQOL is favorably maintained.

An evaluation of forward and inverse radiotherapy planning using Helax-TMS (version 6.0) for lung cancer patients treated with RTOG 93-11 dose-escalation protocol.

This study investigated the dosimetric advantages of inversely planned intensity-modulated radiotherapy (IMRT) over forward-planned conventional 3D conformal radiotherapy (3D-CRT) in treating lung cancer patients at escalated dose. Three consecutively accrued patients on the RTOG 93-11 dose-escalation protocol were replanned using IMRT with the same dosimetric rules, so that the isodose distributions and dose-volume histograms could be generated and compared. The Helax-TMS treatment planning system, with an IMRT optimization module (version 6.0), was used. In all cases, a consistent approach of inverse planning and set of dose-volume constraints (DVCs) provided improved critical structure sparing. However, the minimum dose in PTV was generally below that achieved with the corresponding forward planned 3D-CRT.

Dosimetric verification of inverse planned step and shoot multileaf collimator fields from a commercial treatment planning system.

An inverse treatment planning (ITP) module on a commercial treatment planning system (TPS) (Helax AB, Uppsala, Sweden) is being used for an in-house clinical trial for treatment of nasopharyngeal cancer with contralateral parotid sparing. Intensity modulated radiation therapy (IMRT) fields are delivered by step and shoot multileaf collimator (MLC) with a DMLC enabled Varian 2300 CD (Varian Associates, Palo Alto, CA). A series of testing procedures have been devised to quantify the modeling and delivery accuracy of routine clinical inverse planned IMRT using Helax TMS and the Varian step and shoot MLC delivery option. Testing was done on specific aspects of the TPS modeling germane to DMLC. Measured relative dose factors (head scatter plus phantom scatter) for small MLC fields, normalized to a 10x10 cm2 non-MLC field, were found to differ by 2-3% from the TPS values for the smallest of the fields tested. Relative distributions for small off axis fields were found to be in good agreement. A process for the routine clinical verification of IMRT fields has been implemented. Each IMRT field in an inverse plan is imported into a flat water tank plan and a "beam's eye view" (BEV) dose distribution is generated. This is compared to the corresponding measured BEV dose distribution. The IMRT verification process has also been performed using an anthropomorphic phantom. Large clinical fields (i.e., greater than 14.5 cm in the leaf direction) caused difficulties due to a vendor specific machine restriction, and several techniques for dealing with these were examined. These techniques were (i) the use of static stepping of closed junctions, (ii) the use of two separate IMRT fields for a given gantry angle, and (iii) restricting the overall maximum field size used. The overall process has allowed implementation of an in-house protocol for IMRT use on an initial clinical site. Results of the verification measurements for the first ten patients treated at this center reveal an average maximum dose per IMRT field delivered of 71.0 cGy, with a mean local deviation from the planned dose of -1.2 cGy, and a standard deviation of 2.4 cGy.

Structural and functional relationship between the receptor recognition and neuraminidase activities of the Newcastle disease virus hemagglutinin-neuraminidase protein: receptor recognition is dependent on neuraminidase activity.

The terminal globular domain of the paramyxovirus hemagglutinin-neuraminidase (HN) glycoprotein spike has a number of conserved residues that are predicted to form its neuraminidase (NA) active site, by analogy to the influenza virus neuraminidase protein. We have performed a site-directed mutational analysis of the role of these residues in the functional activity of the Newcastle disease virus (NDV) HN protein. Substitutions for several of these residues result in a protein lacking both detectable NA and receptor recognition activity. Contribution of NA activity, either exogenously or by coexpression with another HN protein, partially rescues the receptor recognition activity of these proteins, indicating that the receptor recognition deficiencies of the mutated HN proteins result from their lack of detectable NA activity. In addition to providing support for the homology-based predictions for the structure of HN, these findings argue that (i) the HN residues that mediate its NA activity are not critical to its attachment function and (ii) NA activity is required for the protein to mediate binding to receptors.

Shielding considerations for tomotherapy.

Tomotherapy presents an evolutionary modality that holds forth the promise of better dose conformation to tumor volumes with a concomitant reduction in radiation-induced damage to surrounding normal structures. This delivery technique also presents a new set of radiation protection challenges that impact upon the design of the shielding vault required to house such a unit. A formalism is presented to determine the requisite amounts of shielding for both the primary beam and leakage radiation associated with a generic tomotherapy unit. A comparison is made with the shielding requirements for a conventional linear accelerator operated in a standard manner. Substantial differences in the amount of both primary and secondary shielding are indicated. A tomotherapy primary beam shield is both reduced in width by a factor of almost 10 and increased in thickness by more than a tenth value layer in comparison to a conventional accelerator. Furthermore, the secondary shielding requirements are enhanced by more than two tenth value layers with respect to conventional shielding demands.

Acoustic satellite behaviour in the Australian bushcricket Elephantodeta nobilis (Phaneropterinae, Tettigoniidae, Orthoptera).

Male and female Elephantodeta nobilis duet with the female responding to the male's long and complex call. The duetting male's call consisted of four parts, described here as parts A, B, C and D. We found that the female replied 570 ms after the male's D pulse, which followed the extended part B and short click of part C. Noncalling males were attracted to the duet and often used satellite tactics by inserting a volley of clicks 200 ms before the alpha male's D pulse. Satellite males used part C of the alpha male song to cue their own call and this inserted call induced females to reply earlier compared with the alpha male call alone. Alpha males often extended their calls with additional D-type calls and so we examined the effectiveness of these calls as countermeasures to satellite calling. There was no influence of this alpha strategy on the satellite's propensity to call although more calls from the alpha male did cause the female to reply more frequently. We also examined the effect of relative intensity of alpha and satellite calls on the female's reply. Reduced satellite intensity increased the variance in the timing of the female response. Finally, we tested the effectiveness of the satellite's call on female phonotaxis within a two-speaker arena. Although females preferred the alpha male they were nevertheless attracted to the satellite calls regardless of the latter's relative intensity. We discuss the possible role of satellite calling as a novel conditional strategy. Copyright 2000 The Association for the Study of Animal Behaviour.

Evaluation of optimized compensators on a 3D planning system.

A commercially available treatment planning system contains several functions that allow for the automation of missing tissue and optimized compensators, where the former retracts the bolus toward the source, and the latter attempts, by iteration, to establish a uniform dose at some user defined depth. The intent of this paper is to report on the compensators designed by the system and to compare them to those devised through conventional techniques. It is demonstrated that the system can model the dosimetric effects of compensators with a high degree of accuracy; measured and predicted doses agree to within 3%. Optimized compensators show slightly improved dose uniformity over thickness reduced compensators. Both show significantly improved uniformity over compensators that simply retract the bolus geometry. In cases where internal inhomogeneities exist, however, the dose uniformity from the optimized compensators vary by as much as 6% at the target depth. These deviations are comparable to the errors of the inhomogeneity algorithm itself. The pathlength reduction technique has been applied to both missing tissue and inhomogeneity compensation, and it has been found that for inhomogeneity compensation, the pathlength reduced compensators produce more uniform distributions than those generated by the optimization algorithm.

CCD-3693: an orally bioavailable analog of the endogenous neuroactive steroid, pregnanolone, demonstrates potent sedative hypnotic actions in the rat.

An endogenous neuroactive steroid, pregnanolone, and an orally available synthetic analog, CCD-3693, were administered to rats at the middle of their circadian activity phase (6 hr after lights off). Electroencephalogram-defined sleep-wake states, locomotor activity and body temperature were concurrently measured 30 hr before and after treatment. Identical procedures were used to test triazolam and zolpidem. Triazolam (0.1-1.6 mg/kg), zolpidem (2.5-10 mg/kg) and the neuroactive steroids (10-30 mg/kg) produced dose-dependent increases in non-rapid eye movement (NREM) sleep. At this dose and time of day (in which the rats were predominantly awake during the 6 hr before treatment) the neuroactive steroids appeared more intrinsically efficacious in promoting NREM sleep than the benzodiazepine ligands. The neurosteroids did not, however, significantly interfere with rapid eye movement sleep and were more selective in reducing (EEG) wakefulness, with relatively less locomotor activity impairment during waking than triazolam and zolpidem. In addition, the benzodiazepine receptor ligands showed distinct "rebound" wakefulness after the NREM sleep-promoting effect subsided, although the neuroactive steroids did not. In addition, in vitro binding studies and in vivo pharmacological data confirmed that CCD-3693 was orally active in standard tests of anxiety, anticonvulsant, loss-of-righting and passive avoidance.

Save the child's esophagus: management of major disruption after repair of esophageal atresia.

PURPOSE: Given the bias that the native esophagus is the best conduit between the oropharynx and the stomach, the authors report a "conservative" approach to massive esophageal leak, which may be considered "radical" by others. Major disruption of the anastomosis after primary repair of esophageal atresia is a recognized and feared complication. Historically, management has been the performance of cervical esophagostomy and gastrostomy. The aim of this report is to describe the authors' approach to this difficult and serious complication. METHODS: A 15-year retrospective analysis was performed of all patients having esophageal atresia. Data collection focused on the management of all patients with clinically significant esophageal disruption. Radiographically detected (clinically asymptomatic) leaks were managed by continuation of drainage by thoracostomy tubes already in place and are not included. Reoperative thoracotomies were performed, which included primary repair (2), placement of pleural patch alone (2), pleural patch with intercostal muscle flap buttress (2), and operative debridement and drainage alone (1). RESULTS: It was noted that seven patients had clinically significant esophageal disruption requiring reoperation, with circumferential disruptions ranging from 15% to 85%. Presentation included persistent pleural collection (4) and pneumothorax (3). Both patients who underwent primary repair had no evidence of leakage on follow-up esophagograms, neither did one with a pleural patch alone and one with an intercostal muscle flap. Five of the seven patients were tolerating oral feedings at the time of follow-up (range, 6 months to 8 years). One of the two others (both currently inpatients), has a recurrent leak associated with mediastinitis, and the other (who had primary repair) has a presumed neurological impairment of eating. CONCLUSION: Clinically significant disruption of primary esophageal repair should not warrant a cervical esophagostomy and placement of a gastrostomy tube, thus precluding eventual use of the native esophagus. The authors have shown that management by reoperation with primary repair, intercostal muscle flap with or without pleural patch, and/or drainage allows the patient to maintain the native esophagus and yields a generally good outcome after a prolonged healing time.

Tumor necrosis factor and interleukin-6 are not elevated in venous blood from ischemic canine myocardium.

To test the hypothesis that cytokines play a role in ischemic or reperfusion injury, we measured tumor necrosis factor (TNF) and interleukin-6 (IL-6) in pentobarbital-anesthetized dogs before, during, and after coronary occlusion lasting 60 min. Epicardial venous samples from the ischemic (IS) area were compared with nonischemic (NIS) and systemic (SYS) samples. Baseline IS TNF levels were low (2.2 +/- 1.2 U/ml) and not significantly different from NIS and SYS levels. After 50 min of coronary occlusion and at 40 min postreperfusion, IS, NIS, and SYS TNF levels were unchanged. At baseline, IS IL-6 levels were also relatively low (806 +/- 255 U/ml) and not significantly different from NIS and SYS IL-6. Although IS IL-6 increased significantly during coronary occlusion (5682 +/- 1495 U/ml) and reperfusion (10309 +/- 3708 U/ml), NIS and SYS levels were also elevated and did not differ significantly from IS values. The data indicate that TNF and IL-6 are not uniquely elevated in blood from ischemic or reperfused myocardium.

Pain control: some aspects of day-to-day management.

A practical framework for the management of pain control in palliative care of patients with advanced malignancies, using analgesics and co-analgesics is described. The analgesic ladder is used as a model for the logical progression of options for the day-to-day application of analgesics. Strong opioids and their side-effects are discussed. Indications for the most frequently applied co-analgesics are given, including the more commonly required psychotropic agents.