Anestésicos locais

Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências Farmacêuticas

Simultaneous Localization and Recognition of Dynamic Hand Gestures

A framework for the simultaneous localization and recognition of dynamic hand gestures is proposed. At the core of this framework is a dynamic space-time warping (DSTW) algorithm, that aligns a pair of query and model gestures in both space and time. For every frame of the query sequence, feature detectors generate multiple hand region candidates. Dynamic programming is then used to compute both a global matching cost, which is used to recognize the query gesture, and a warping path, which aligns the query and model sequences in time, and also finds the best hand candidate region in every query frame. The proposed framework includes translation invariant recognition of gestures, a desirable property for many HCI systems. The performance of the approach is evaluated on a dataset of hand signed digits gestured by people wearing short sleeve shirts, in front of a background containing other non-hand skin-colored objects. The algorithm simultaneously localizes the gesturing hand and recognizes the hand-signed digit. Although DSTW is illustrated in a gesture recognition setting, the proposed algorithm is a general method for matching time series, that allows for multiple candidate feature vectors to be extracted at each time step.

Indexing Methods for Efficient Multiclass Recognition

Many real world image analysis problems, such as face recognition and hand pose estimation, involve recognizing a large number of classes of objects or shapes. Large margin methods, such as AdaBoost and Support Vector Machines (SVMs), often provide competitive accuracy rates, but at the cost of evaluating a large number of binary classifiers, thus making it difficult to apply such methods when thousands or millions of classes need to be recognized. This thesis proposes a filter-and-refine framework, whereby, given a test pattern, a small number of candidate classes can be identified efficiently at the filter step, and computationally expensive large margin classifiers are used to evaluate these candidates at the refine step. Two different filtering methods are proposed, ClassMap and OVA-VS (One-vs.-All classification using Vector Search). ClassMap is an embedding-based method, works for both boosted classifiers and SVMs, and tends to map the patterns and their associated classes close to each other in a vector space. OVA-VS maps OVA classifiers and test patterns to vectors based on the weights and outputs of weak classifiers of the boosting scheme. At runtime, finding the strongest-responding OVA classifier becomes a classical vector search problem, where well-known methods can be used to gain efficiency. In our experiments, the proposed methods achieve significant speed-ups, in some cases up to two orders of magnitude, compared to exhaustive evaluation of all OVA classifiers. This was achieved in hand pose recognition and face recognition systems where the number of classes ranges from 535 to 48,600.

Combining Textual and Visual Cues for Content-based Image Retrieval on the World Wide Web

Some WWW image engines allow the user to form a query in terms of text keywords. To build the image index, keywords are extracted heuristically from HTML documents containing each image, and/or from the image URL and file headers. Unfortunately, text-based image engines have merely retro-fitted standard SQL database query methods, and it is difficult to include images cues within such a framework. On the other hand, visual statistics (e.g., color histograms) are often insufficient for helping users find desired images in a vast WWW index. By truly unifying textual and visual statistics, one would expect to get better results than either used separately. In this paper, we propose an approach that allows the combination of visual statistics with textual statistics in the vector space representation commonly used in query by image content systems. Text statistics are captured in vector form using latent semantic indexing (LSI). The LSI index for an HTML document is then associated with each of the images contained therein. Visual statistics (e.g., color, orientedness) are also computed for each image. The LSI and visual statistic vectors are then combined into a single index vector that can be used for content-based search of the resulting image database. By using an integrated approach, we are able to take advantage of possible statistical couplings between the topic of the document (latent semantic content) and the contents of images (visual statistics). This allows improved performance in conducting content-based search. This approach has been implemented in a WWW image search engine prototype.

Combinations of Deformable Shape Prototypes

We propose to investigate a model-based technique for encoding non-rigid object classes in terms of object prototypes. Objects from the same class can be parameterized by identifying shape and appearance invariants of the class to devise low-level representations. The approach presented here creates a flexible model for an object class from a set of prototypes. This model is then used to estimate the parameters of low-level representation of novel objects as combinations of the prototype parameters. Variations in the object shape are modeled as non-rigid deformations. Appearance variations are modeled as intensity variations. In the training phase, the system is presented with several example prototype images. These prototype images are registered to a reference image by a finite element-based technique called Active Blobs. The deformations of the finite element model to register a prototype image with the reference image provide the shape description or shape vector for the prototype. The shape vector for each prototype, is then used to warp the prototype image onto the reference image and obtain the corresponding texture vector. The prototype texture vectors, being warped onto the same reference image have a pixel by pixel correspondence with each other and hence are "shape normalized". Given sufficient number of prototypes that exhibit appropriate in-class variations, the shape and the texture vectors define a linear prototype subspace that spans the object class. Each prototype is a vector in this subspace. The matching phase involves the estimation of a set of combination parameters for synthesis of the novel object by combining the prototype shape and texture vectors. The strengths of this technique lie in the combined estimation of both shape and appearance parameters. This is in contrast with the previous approaches where shape and appearance parameters were estimated separately.

Fuzzy ARTMAP, Slow Learning and Probability Estimation

A nonparametric probability estimation procedure using the fuzzy ARTMAP neural network is here described. Because the procedure does not make a priori assumptions about underlying probability distributions, it yields accurate estimates on a wide variety of prediction tasks. Fuzzy ARTMAP is used to perform probability estimation in two different modes. In a 'slow-learning' mode, input-output associations change slowly, with the strength of each association computing a conditional probability estimate. In 'max-nodes' mode, a fixed number of categories are coded during an initial fast learning interval, and weights are then tuned by slow learning. Simulations illustrate system performance on tasks in which various numbers of clusters in the set of input vectors mapped to a given class.

Neural Representations for Sensory-Motor Control, III: Learning a Body-Centered Representation of 3-D Target Position

A neural model is described of how the brain may autonomously learn a body-centered representation of 3-D target position by combining information about retinal target position, eye position, and head position in real time. Such a body-centered spatial representation enables accurate movement commands to the limbs to be generated despite changes in the spatial relationships between the eyes, head, body, and limbs through time. The model learns a vector representation--otherwise known as a parcellated distributed representation--of target vergence with respect to the two eyes, and of the horizontal and vertical spherical angles of the target with respect to a cyclopean egocenter. Such a vergence-spherical representation has been reported in the caudal midbrain and medulla of the frog, as well as in psychophysical movement studies in humans. A head-centered vergence-spherical representation of foveated target position can be generated by two stages of opponent processing that combine corollary discharges of outflow movement signals to the two eyes. Sums and differences of opponent signals define angular and vergence coordinates, respectively. The head-centered representation interacts with a binocular visual representation of non-foveated target position to learn a visuomotor representation of both foveated and non-foveated target position that is capable of commanding yoked eye movementes. This head-centered vector representation also interacts with representations of neck movement commands to learn a body-centered estimate of target position that is capable of commanding coordinated arm movements. Learning occurs during head movements made while gaze remains fixed on a foveated target. An initial estimate is stored and a VOR-mediated gating signal prevents the stored estimate from being reset during a gaze-maintaining head movement. As the head moves, new estimates arc compared with the stored estimate to compute difference vectors which act as error signals that drive the learning process, as well as control the on-line merging of multimodal information.

A Neural Network Architecture for Autonomous Learning, Recognition, and Prediction in a Nonstationary World

In a constantly changing world, humans are adapted to alternate routinely between attending to familiar objects and testing hypotheses about novel ones. We can rapidly learn to recognize and narne novel objects without unselectively disrupting our memories of familiar ones. We can notice fine details that differentiate nearly identical objects and generalize across broad classes of dissimilar objects. This chapter describes a class of self-organizing neural network architectures--called ARTMAP-- that are capable of fast, yet stable, on-line recognition learning, hypothesis testing, and naming in response to an arbitrary stream of input patterns (Carpenter, Grossberg, Markuzon, Reynolds, and Rosen, 1992; Carpenter, Grossberg, and Reynolds, 1991). The intrinsic stability of ARTMAP allows the system to learn incrementally for an unlimited period of time. System stability properties can be traced to the structure of its learned memories, which encode clusters of attended features into its recognition categories, rather than slow averages of category inputs. The level of detail in the learned attentional focus is determined moment-by-moment, depending on predictive success: an error due to over-generalization automatically focuses attention on additional input details enough of which are learned in a new recognition category so that the predictive error will not be repeated. An ARTMAP system creates an evolving map between a variable number of learned categories that compress one feature space (e.g., visual features) to learned categories of another feature space (e.g., auditory features). Input vectors can be either binary or analog. Computational properties of the networks enable them to perform significantly better in benchmark studies than alternative machine learning, genetic algorithm, or neural network models. Some of the critical problems that challenge and constrain any such autonomous learning system will next be illustrated. Design principles that work together to solve these problems are then outlined. These principles are realized in the ARTMAP architecture, which is specified as an algorithm. Finally, ARTMAP dynamics are illustrated by means of a series of benchmark simulations.

ARTMAP: Supervised Real-Time Learning and Classification of Nonstationary Data by a Self-Organizing Neural Network

This article introduces a new neural network architecture, called ARTMAP, that autonomously learns to classify arbitrarily many, arbitrarily ordered vectors into recognition categories based on predictive success. This supervised learning system is built up from a pair of Adaptive Resonance Theory modules (ARTa and ARTb) that are capable of self-organizing stable recognition categories in response to arbitrary sequences of input patterns. During training trials, the ARTa module receives a stream {a^(p)} of input patterns, and ARTb receives a stream {b^(p)} of input patterns, where b^(p) is the correct prediction given a^(p). These ART modules are linked by an associative learning network and an internal controller that ensures autonomous system operation in real time. During test trials, the remaining patterns a^(p) are presented without b^(p), and their predictions at ARTb are compared with b^(p). Tested on a benchmark machine learning database in both on-line and off-line simulations, the ARTMAP system learns orders of magnitude more quickly, efficiently, and accurately than alternative algorithms, and achieves 100% accuracy after training on less than half the input patterns in the database. It achieves these properties by using an internal controller that conjointly maximizes predictive generalization and minimizes predictive error by linking predictive success to category size on a trial-by-trial basis, using only local operations. This computation increases the vigilance parameter ρa of ARTa by the minimal amount needed to correct a predictive error at ARTb· Parameter ρa calibrates the minimum confidence that ARTa must have in a category, or hypothesis, activated by an input a^(p) in order for ARTa to accept that category, rather than search for a better one through an automatically controlled process of hypothesis testing. Parameter ρa is compared with the degree of match between a^(p) and the top-down learned expectation, or prototype, that is read-out subsequent to activation of an ARTa category. Search occurs if the degree of match is less than ρa. ARTMAP is hereby a type of self-organizing expert system that calibrates the selectivity of its hypotheses based upon predictive success. As a result, rare but important events can be quickly and sharply distinguished even if they are similar to frequent events with different consequences. Between input trials ρa relaxes to a baseline vigilance pa When ρa is large, the system runs in a conservative mode, wherein predictions are made only if the system is confident of the outcome. Very few false-alarm errors then occur at any stage of learning, yet the system reaches asymptote with no loss of speed. Because ARTMAP learning is self stabilizing, it can continue learning one or more databases, without degrading its corpus of memories, until its full memory capacity is utilized.

Vector Associative Maps: Unsupervised Real-time Error-based Learning and Control of Movement Trajectories

This article describes neural network models for adaptive control of arm movement trajectories during visually guided reaching and, more generally, a framework for unsupervised real-time error-based learning. The models clarify how a child, or untrained robot, can learn to reach for objects that it sees. Piaget has provided basic insights with his concept of a circular reaction: As an infant makes internally generated movements of its hand, the eyes automatically follow this motion. A transformation is learned between the visual representation of hand position and the motor representation of hand position. Learning of this transformation eventually enables the child to accurately reach for visually detected targets. Grossberg and Kuperstein have shown how the eye movement system can use visual error signals to correct movement parameters via cerebellar learning. Here it is shown how endogenously generated arm movements lead to adaptive tuning of arm control parameters. These movements also activate the target position representations that are used to learn the visuo-motor transformation that controls visually guided reaching. The AVITE model presented here is an adaptive neural circuit based on the Vector Integration to Endpoint (VITE) model for arm and speech trajectory generation of Bullock and Grossberg. In the VITE model, a Target Position Command (TPC) represents the location of the desired target. The Present Position Command (PPC) encodes the present hand-arm configuration. The Difference Vector (DV) population continuously.computes the difference between the PPC and the TPC. A speed-controlling GO signal multiplies DV output. The PPC integrates the (DV)·(GO) product and generates an outflow command to the arm. Integration at the PPC continues at a rate dependent on GO signal size until the DV reaches zero, at which time the PPC equals the TPC. The AVITE model explains how self-consistent TPC and PPC coordinates are autonomously generated and learned. Learning of AVITE parameters is regulated by activation of a self-regulating Endogenous Random Generator (ERG) of training vectors. Each vector is integrated at the PPC, giving rise to a movement command. The generation of each vector induces a complementary postural phase during which ERG output stops and learning occurs. Then a new vector is generated and the cycle is repeated. This cyclic, biphasic behavior is controlled by a specialized gated dipole circuit. ERG output autonomously stops in such a way that, across trials, a broad sample of workspace target positions is generated. When the ERG shuts off, a modulator gate opens, copying the PPC into the TPC. Learning of a transformation from TPC to PPC occurs using the DV as an error signal that is zeroed due to learning. This learning scheme is called a Vector Associative Map, or VAM. The VAM model is a general-purpose device for autonomous real-time error-based learning and performance of associative maps. The DV stage serves the dual function of reading out new TPCs during performance and reading in new adaptive weights during learning, without a disruption of real-time operation. YAMs thus provide an on-line unsupervised alternative to the off-line properties of supervised error-correction learning algorithms. YAMs and VAM cascades for learning motor-to-motor and spatial-to-motor maps are described. YAM models and Adaptive Resonance Theory (ART) models exhibit complementary matching, learning, and performance properties that together provide a foundation for designing a total sensory-cognitive and cognitive-motor autonomous system.

Fuzzy ART: An Adaptive Resonance Algorithm for Rapid, Stable Classification of Analog Patterns

The Fuzzy ART system introduced herein incorporates computations from fuzzy set theory into ART 1. For example, the intersection (n) operator used in ART 1 learning is replaced by the MIN operator (A) of fuzzy set theory. Fuzzy ART reduces to ART 1 in response to binary input vectors, but can also learn stable categories in response to analog input vectors. In particular, the MIN operator reduces to the intersection operator in the binary case. Learning is stable because all adaptive weights can only decrease in time. A preprocessing step, called complement coding, uses on-cell and off-cell responses to prevent category proliferation. Complement coding normalizes input vectors while preserving the amplitudes of individual feature activations.

Fuzzy ART: Fast Stable Learning and Categorization of Analog Patterns by an Adaptive Resonance System

A Fuzzy ART model capable of rapid stable learning of recognition categories in response to arbitrary sequences of analog or binary input patterns is described. Fuzzy ART incorporates computations from fuzzy set theory into the ART 1 neural network, which learns to categorize only binary input patterns. The generalization to learning both analog and binary input patterns is achieved by replacing appearances of the intersection operator (n) in AHT 1 by the MIN operator (Λ) of fuzzy set theory. The MIN operator reduces to the intersection operator in the binary case. Category proliferation is prevented by normalizing input vectors at a preprocessing stage. A normalization procedure called complement coding leads to a symmetric theory in which the MIN operator (Λ) and the MAX operator (v) of fuzzy set theory play complementary roles. Complement coding uses on-cells and off-cells to represent the input pattern, and preserves individual feature amplitudes while normalizing the total on-cell/off-cell vector. Learning is stable because all adaptive weights can only decrease in time. Decreasing weights correspond to increasing sizes of category "boxes". Smaller vigilance values lead to larger category boxes. Learning stops when the input space is covered by boxes. With fast learning and a finite input set of arbitrary size and composition, learning stabilizes after just one presentation of each input pattern. A fast-commit slow-recode option combines fast learning with a forgetting rule that buffers system memory against noise. Using this option, rare events can be rapidly learned, yet previously learned memories are not rapidly erased in response to statistically unreliable input fluctuations.

Fuzzy ARTMAP: A Neural Network Architecture for Incremental Supervised Learning of Analog Multidimensional Maps

A new neural network architecture is introduced for incremental supervised learning of recognition categories and multidimensional maps in response to arbitrary sequences of analog or binary input vectors. The architecture, called Fuzzy ARTMAP, achieves a synthesis of fuzzy logic and Adaptive Resonance Theory (ART) neural networks by exploiting a close formal similarity between the computations of fuzzy subsethood and ART category choice, resonance, and learning. Fuzzy ARTMAP also realizes a new Minimax Learning Rule that conjointly minimizes predictive error and maximizes code compression, or generalization. This is achieved by a match tracking process that increases the ART vigilance parameter by the minimum amount needed to correct a predictive error. As a result, the system automatically learns a minimal number of recognition categories, or "hidden units", to met accuracy criteria. Category proliferation is prevented by normalizing input vectors at a preprocessing stage. A normalization procedure called complement coding leads to a symmetric theory in which the MIN operator (Λ) and the MAX operator (v) of fuzzy logic play complementary roles. Complement coding uses on-cells and off-cells to represent the input pattern, and preserves individual feature amplitudes while normalizing the total on-cell/off-cell vector. Learning is stable because all adaptive weights can only decrease in time. Decreasing weights correspond to increasing sizes of category "boxes". Smaller vigilance values lead to larger category boxes. Improved prediction is achieved by training the system several times using different orderings of the input set. This voting strategy can also be used to assign probability estimates to competing predictions given small, noisy, or incomplete training sets. Four classes of simulations illustrate Fuzzy ARTMAP performance as compared to benchmark back propagation and genetic algorithm systems. These simulations include (i) finding points inside vs. outside a circle; (ii) learning to tell two spirals apart; (iii) incremental approximation of a piecewise continuous function; and (iv) a letter recognition database. The Fuzzy ARTMAP system is also compared to Salzberg's NGE system and to Simpson's FMMC system.

An evaluation of reovirus as an effective therapeutic for cancer

Cancer is a global problem. Despite the significant advances made in recent years, a definitively effective therapeutic has yet to be developed. Oncolytic virology has fallen back into favour for the treatment of cancer with several viruses and viral vectors currently under investigation including vesicular stomatitis virus (VSV), adenovirus vectors and herpes simplex virus (HSV) vectors. Reovirus has an advantage over many viral vectors in that its wild-type form is non-pathogenic and will selectively infect transformed cells, particularly those mutated in the Ras pathway. These advantages make Reovirus an ideal candidate as a safe and non-toxic therapeutic. The aim of the first part of this study was to determine the effect, if any, of Reovirus on cell lines derived from cancers of the gastrointestinal tract. These cancers, particularly those of the oesophagus and stomach, have extremely poor prognoses and little improvement has been seen in survival of these patients in recent years. Reovirus as a single therapy showed promising results in cell lines of oesophageal, gastric and colorectal origin. Further study of partially resistant cell lines using a combination of Reovirus and conventional therapies, either chemotherapy or radiation, showed that a multi-modal approach to therapy is possible with Reovirus and no antagonism between Reovirus and other treatments was observed. The second part of this study focused on investigating a novel use of Reovirus in an in vivo setting. Cancer vaccination or the use of vaccines in cancer therapy is gaining momentum and success has been seen both in a prophylactic approach and a therapeutic approach. A cell-based Reovirus vaccine was used in both these approaches with encouraging success. When used as a prophylactic vaccine tumour development was subsequently inhibited even upon exposure to a tumorigenic dose of cells. The use of the cell-based Reovirus vaccine as a therapeutic for established tumours showed significant delay in tumour growth and a prolongation of survival in all models. This study has proven that Reovirus is an effective therapeutic in a range of cancers and the successful use of a cell-based Reovirus vaccine leads the way for new advancements in cancer immunotherapy.

Optimisation of immune effector function within the tumour microenvironment

Cancer represents a leading of cause of death in the developed world, inflicting tremendous suffering and plundering billions from health budgets. The traditional treatment approaches of surgery, radiotherapy and chemotherapy have achieved little in terms of cure for this deadly disease. Instead, life is prolonged for many, with dubious quality of life, only for disease to reappear with the inevitable fatal outcome. “Blue sky” thinking is required to tackle this disease and improve outcomes. The realisation and acceptance of the intrinsic role of the immune system in cancer pathogenesis, pathophysiology and treatment represented such a “blue sky” thought. Moreover, the embracement of immunotherapy, the concept of targeting immune cells rather than the tumour cells themselves, represents a paradigm shift in the approach to cancer therapy. The harnessing of immunotherapy demands radical and innovative therapeutic endeavours – endeavours such as gene and cell therapies and RNA interference, which two decades ago existed as mere concepts. This thesis straddles the frontiers of fundamental tumour immunobiology and novel therapeutic discovery, design and delivery. The work undertaken focused on two distinct immune cell populations known to undermine the immune response to cancer – suppressive T cells and macrophages. Novel RNAi mediators were designed, validated and incorporated into clinically relevant gene therapy vectors – involving a traditional lentiviral vector approach, and a novel bacterial vector strategy. Chapter 2 deals with the design of novel RNAi mediators against FOXP3 – a crucial regulator of the immunosuppressive regulatory T cell population. Two mediators were tested and validated. The superior mediator was taken forward as part of work in chapter 3. Chapter 3 deals with transposing the RNA sequence from chapter 2 into a DNA-based construct and subsequent incorporation into a lentiviral-based vector system. The lentiviral vector was shown to mediate gene delivery in vitro and functional RNAi was achieved against FOXP3. Proof of gene delivery was further confirmed in vivo in tumour-bearing animals. Chapter 4 focuses on a different immune cell population – tumour-associated macrophages. Non-invasive bacteria were explored as a specific means of delivering gene therapy to this phagocytic cell type. Proof of delivery was shown in vitro and in vivo. Moreover, in vivo delivery of a gene by this method achieved the desired immune response in terms of cytokine profile. Overall, the data presented here advance exploration within the field of cancer immunotherapy, introduce novel delivery and therapeutic strategies, and demonstrate pre-clinically the potential for such novel anti-cancer therapies.