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The CD11a binding site of efalizumab in psoriatic skin tissue as analyzed by Multi-Epitope Ligand Cartography robot technology. Introduction of a novel biological drug-binding biochip assay.

Efalizumab (Raptiva) is an immunomodulating recombinant humanized IgG1 monoclonal antibody that binds to CD11a, the alpha-subunit of leukocyte function antigen-1 (LFA-1). By blocking the binding of LFA-1 to ICAM-1, efalizumab inhibits the adhesion of leukocytes to other cell types and interferes with the migration of T lymphocytes to sites of inflammation (including psoriatic skin plaques). Analysis of the response in patients treated with efalizumab to date shows that distinct groups of responders and nonresponders to the drug exist. It would therefore be of great practical value to be able to predict which patients are most likely to respond to treatment, by identifying key parameters in the mechanism of action of efalizumab. Detailed investigation and detection of multiple epitopes in microcompartments of skin tissue has until recently been restricted by the available technology. However, the newly developed technique of Multi-Epitope Ligand Cartography (MELC) robot technology combines proteomics and biomathematical tools to visualize protein networks at the cellular and subcellular levels in situ, and to decipher cell functions. The MELC technique, which is outlined in this paper, was used to help characterize the binding of efalizumab to affected and unaffected psoriatic skin as compared to normal control skin under ex vivomodel conditions. Efalizumab was labeled with fluorescein isothiocyanate and integrated into a MELC library of more than 40 antibodies. These antibodies were selected for their potential to detect epitopes which may be indicative of (a) various cell types, (b) structural components of the extracellular matrix, or (c) the processes of cell proliferation, activation and adhesion. Efalizumab bound to CD11a in affected psoriatic skin by a factor 15x and 32x higher than in unaffected psoriatic skin and normal control skin, respectively. CD11a and the efalizumab binding site were primarily expressed in the extravascular dermis, whereas CD54 (ICAM-1) as its ligand was most prevalent in the dermal vessels. T lymphocytes (for which the markers were CD3, CD8, CD4, and CD45R0) were the major cellular targets of efalizumab. In contrast, NK cells were only a minor target of efalizumab. Our study demonstrated that efalizumab represents a treatment for psoriasis that primarily targets memory CD4+ and CD8+ T cells and has a high specificity for psoriatic disease activity. Moreover, we hereby introduce the novel principle of a biological drug-binding biochip assay being especially useful for the future monitoring of psoriatic skin lesions under efalizumab treatment conditions.

Adult↗

Hybrid revascularization strategy: a pilot study on the association of robotically enhanced minimally invasive direct coronary artery bypass surgery and fractional-flow-reserve-guided percutaneous coronary intervention.

BACKGROUND: Robotically enhanced minimally invasive direct coronary artery bypass (RE-MIDCAB) graft of the left internal mammary artery to the left anterior descending coronary artery (LAD) and/or the first diagonal branch might be the least traumatic surgical revascularization approach available so far. When combined with fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) in the non-LAD vessels, this "hybrid" strategy takes advantage of the survival benefit conferred by the internal mammary artery graft to the LAD while providing the patients with a truly minimally invasive, functionally complete revascularization. METHODS AND RESULTS: Twenty patients with multivessel disease were selected to undergo combined PCI and RE-MIDCAB because they had a lesion amenable to PCI in the right and/or the left circumflex coronary artery and a lesion in the LAD and/or the first diagonal branch that was considered less than ideal for PCI. PCI was actually performed only when FFR was <0.80 ("provisional PCI"). In 7 stenoses, FFR was >0.80 and the planned PCI was not performed. Surgery was performed before provisional PCI in 6 cases. An angiogram was obtained in all patients before discharge, and a complete clinical follow-up including a stress test was obtained in all patients after a mean of 12 months. There were no significant intraoperative complications, conversions to cardiopulmonary bypass, or reinterventions for bleeding. At early control angiogram, 2 moderate stenoses just proximal to anastomosis were observed, both with normal run-off. After 12 months there were no objective signs of ischemia at stress testing. After an average follow-up of 19+/-10 months there were no deaths, myocardial infarctions, or repeat revascularizations. CONCLUSIONS: A hybrid strategy combining FFR-guided PCI and RE-MIDCAB seems safe and provides selected patients with a functionally complete revascularization with minimal surgical trauma and excellent clinical outcomes.

Aged↗

Integrated coronary revascularization: percutaneous coronary intervention plus robotic totally endoscopic coronary artery bypass.

BACKGROUND: Robotic totally endoscopic coronary artery bypass (TECAB) of the left anterior descending artery (LAD) coupled with percutaneous coronary intervention (PCI) of a second coronary artery has been investigated in patients with multivessel disease to provide a minimally invasive therapeutic option. METHODS AND RESULTS: TECAB of the LAD was performed using the left internal mammary artery (LIMA). A second lesion was treated with PCI before surgery, simultaneously, or after surgery. Three-month angiographic follow-up was performed in all patients and was subject to independent review. A total of 27 patients requiring double vessel revascularization were treated at 7 centers. Eleven patients underwent PCI before surgery, 12 patients underwent PCI after surgery, and 4 patients underwent simultaneous surgical and percutaneous intervention. Ten patients (37%) were treated with bare metal stents, whereas 17 patients (63%) were treated with drug-eluting stents. Postoperative angiographic evaluation demonstrated an overall LIMA anastomotic patency of 96.3% and PCI vessel patency of 66.7%. There were no deaths or strokes. One patient experienced a perioperative myocardial infarction. Eight of 27 patients (29.6%) required reintervention, 1 LIMA anastomotic stenosis (3.7%), 3 after bare metal stent (30%), and 4 after drug-eluting stent placement (23.5%). CONCLUSIONS: Integrated revascularization treatment plans provide minimally invasive options for patients with multivessel coronary artery disease. This approach may be accomplished with no mortality, low perioperative morbidity, and excellent angiographic LIMA patency. The reintervention rate after PCI in this series was higher than that reported elsewhere and should be investigated further. The choice of suitable vessel, type of stent and timing of the treatment must be carefully considered before implementing this hybrid strategy.

Adult↗

Optimizing a linear algorithm for real-time robotic control using chronic cortical ensemble recordings in monkeys.

Previous work in our laboratory has demonstrated that a simple linear model can be used to translate cortical neuronal activity into real-time motor control commands that allow a robot arm to mimic the intended hand movements of trained primates. Here, we describe the results of a comprehensive analysis of the contribution of single cortical neurons to this linear model. Key to the operation of this model was the observation that a large percentage of cortical neurons located in both frontal and parietal cortical areas are tuned for hand position. In most neurons, hand position tuning was time-dependent, varying continuously during a 1-sec period before hand movement onset. The relevance of this physiological finding was demonstrated by showing that maximum contribution of individual neurons to the linear model was only achieved when optimal parameters for the impulse response functions describing time-varying neuronal position tuning were selected. Optimal parameters included impulse response functions with 1.0- to 1.4-sec time length and 50- to 100-msec bins. Although reliable generalization and long-term predictions (60-90 min) could be achieved after 10-min training sessions, we noticed that the model performance degraded over long periods. Part of this degradation was accounted by the observation that neuronal position tuning varied significantly throughout the duration (60-90 min) of a recording session. Altogether, these results indicate that the experimental paradigm described here may be useful not only to investigate aspects of neural population coding, but it may also provide a test bed for the development of clinically useful cortical prosthetic devices aimed at restoring motor functions in severely paralyzed patients.

Action Potentials↗

Beyond robotics: a new proactive research initiative from the EU IST program.

A research initiative on embodied artificial intelligence has been launched in 2004 by the Future and Emerging Technologies (FET) arm of the Information Society Technologies (IST) programme of the European Union. The initiative is called "Beyond Robotics" to emphasize that the research projects funded are required to set ambitious objectives and to aim at breakthroughs going well beyond the state of the art. Four projects worth 20 M E of EC funding were selected for 2004-2008 to address the objectives of the initiative.

Artificial Intelligence↗

Flexible couplings: diffusing neuromodulators and adaptive robotics.

Recent years have seen the discovery of freely diffusing gaseous neurotransmitters, such as nitric oxide (NO), in biological nervous systems. A type of artificial neural network (ANN) inspired by such gaseous signaling, the GasNet, has previously been shown to be more evolvable than traditional ANNs when used as an artificial nervous system in an evolutionary robotics setting, where evolvability means consistent speed to very good solutions--here, appropriate sensorimotor behavior-generating systems. We present two new versions of the GasNet, which take further inspiration from the properties of neuronal gaseous signaling. The plexus model is inspired by the extraordinary NO-producing cortical plexus structure of neural fibers and the properties of the diffusing NO signal it generates. The receptor model is inspired by the mediating action of eurotransmitter receptors. Both models are shown to significantly further improve evolvability. We describe a series of analyses suggesting that the reasons for the increase in evolvability are related to the flexible loose coupling of distinct signaling mechanisms, one "chemical" and one "electrical."

Adaptation, Physiological↗

Coevolving predator and prey robots: do "arms races" arise in artificial evolution?

Coevolution (i.e., the evolution of two or more competing populations with coupled fitness) has several features that may potentially enhance the power of adaptation of artificial evolution. In particular, as discussed by Dawkins and Krebs [3], competing populations may reciprocally drive one another to increasing levels of complexity by producing an evolutionary "arms race." In this article we will investigate the role of coevolution in the context of evolutionary robotics. In particular, we will try to understand in what conditions coevolution can lead to "arms races." Moreover, we will show that in some cases artificial coevolution has a higher adaptive power than simple evolution. Finally, by analyzing the dynamics of coevolved populations, we will show that in some circumstances well-adapted individuals would be better advised to adopt simple but easily modifiable strategies suited for the current competitor strategies rather than incorporate complex and general strategies that may be effective against a wide range of opposing counter-strategies.

Biological Evolution↗

A neural learning classifier system with self-adaptive constructivism for mobile robot control.

For artificial entities to achieve true autonomy and display complex lifelike behavior, they will need to exploit appropriate adaptable learning algorithms. In this context adaptability implies flexibility guided by the environment at any given time and an open-ended ability to learn appropriate behaviors. This article examines the use of constructivism-inspired mechanisms within a neural learning classifier system architecture that exploits parameter self-adaptation as an approach to realize such behavior. The system uses a rule structure in which each rule is represented by an artificial neural network. It is shown that appropriate internal rule complexity emerges during learning at a rate controlled by the learner and that the structure indicates underlying features of the task. Results are presented in simulated mazes before moving to a mobile robot platform.

Algorithms↗

Anaesthesia for robot-assisted anatomic prostatectomy. Experience at a single institution.

Robot-assisted anatomic prostatectomy is an emerging technique for management of prostate cancer It requires a coordinated approach by anaesthetist and surgeon as the surgery is performed using a modified laparoscopic technique and is potentially of long duration in a Trendelenberg position. We describe some aspects of the surgical technique and our anaesthetic approach with the first 40 cases at our institution. The mean hospital stay was 4.2 days and none of the patients required blood transfusion. A retrospective audit indicated that the use of epidural analgesia in the early postoperative period reduced opioid analgesic requirements.

Adenocarcinoma↗

Determination of the in situ forces in the human posterior cruciate ligament using robotic technology. A cadaveric study.

We examined the in situ forces in the posterior cruciate ligament as well as the force distribution between its anterolateral and posteromedial bundles. Using a robotic manipulator in conjunction with a universal force-moment sensor system, we applied posterior tibial loads from 22 to 110 N to the joint at 0 degrees to 90 degrees of knee flexion. The magnitude of the in situ force in the posterior cruciate ligament and its bundles was significantly affected by knee flexion angle and posterior tibial loading. In situ forces in the posterior cruciate ligament ranged from 6.1 +/- 6.0 N under a 22-N posterior tibial load at 0 degree of knee flexion to 112.3 +/- 28.5 N under a 110-N load at 90 degrees. The force in the posteromedial bundle reached a maximum of 67.9 +/- 31.5 N at 90 degrees of knee flexion, and the force in the anterolateral bundle reached a maximum of 47.8 +/- 23.0 N at 60 degrees of knee flexion under a 110-N load. No significant differences existed between the in situ forces in the two bundles at any knee flexion angle. This study provides insight into the knee flexion angle at which each bundle of the posterior cruciate ligament experiences the highest in situ forces under posterior tibial loading. This information can help guide us in more accurate graft placement, fixation, and tensioning, and serve as an assessment of graft performance.

Biomechanical Phenomena↗

The future of nursing in a technological age: computers, robots, and TLC.

The computer has become a major tool in the medical treatment of disease. Computers can record vital signs, keep records, and provide central networks for interactive diagnosis. Individual medical histories can be contained in an optical card the size of a credit card. Advances in technology just over the horizon will permit an individual to consult a computer much as one now consults a physician for diagnosis, recommendations, instructions, and treatment. Surgery can be conducted in "virtual space," with the physician operating inside the body (via computer) as if he or she were present at the site of the surgery. Only a step beyond this is the development of robots who can do a better surgical job than a human being. What is missing from this scenario? Tender loving care. That is the nurse's job, and it is something that computers cannot do because it involves feelings and human communication that are beyond mere technology. Consequently, nurses will be needed long after physicians have passed into limbo. The practical lesson of this look into the future is that, although nurses certainly must remain in touch with the cutting edge of technology, their primary purpose will be to retain and sharpen the skills that Florence Nightingale introduced. Human response will never be replaced by technology, and the unchanging need for the nurses' caring function will assure their future.

Computers↗

Robotic assisted surgery. Part One.

Since the first laparoscopic cholecystectomies were performed by Muhe in 1986 and Mouret in 1987, minimal access surgery has been widely accepted and applied to many procedures. By the end of the 1990s, surgical robots had emerged in operating theatres around the world. This technology has the potential to revolutionise minimal access surgery.

Humans↗

CyberKnife: a robotic radiosurgery system.

The CyberKnife is a radiosurgical system consisting of a linear accelerator and robotic arm. Using guidance imaging, the system precisely locates tumors and delivers multiple beams of radiation therapy directly to the tumor site while minimizing radiation exposure of surrounding tissue. The CyberKnife has the capacity to treat tumors up to 6 cm in size and holds promise as a new radiosurgery treatment modality.

Brain Neoplasms↗

Robotic-assisted laparoscopic prostatectomy: do minimally invasive approaches offer significant advantages?

Radical prostatectomy has maintained a cardinal role in the treatment of localized prostate cancer. Robotic-assisted laparoscopic prostatectomy (RALP) has been introduced as a less invasive surgical approach. Available data on RALP versus open approaches were reviewed for surgical and cancer related outcomes. RALP is consistently associated with decreased blood loss and limited postoperative pain and hospital stay. Surgical margins seem similar between most reported series of RALP or open radical prostatectomy. Most intrainstitutional comparisons demonstrate better postoperative continence and potency with RALP, but there is still debate about whether results are superior to radical retropubic prostatectomy in the hands of a highly experienced surgeon. RALP provides outcomes at least comparable, and, in some measures, superior to open surgery. Refinements of instrumentation may provide even better results in the future.

Humans↗

Robot-aided sensorimotor arm training improves outcome in patients with chronic stroke.

Thirty patients with chronic stroke received 6 weeks of sensorimotor robotic training in a pilot study that targeted motor function of the affected shoulder and elbow. The impairment and disability scores were stable during a 2-month observation/measurement period, improved significantly by program completion, and remained robust in the 3-month follow-up. Task-specific motor training attenuated a chronic neurologic deficit well beyond the expected period for improvement after stroke.

Adult↗

Predicting the metabolic energy costs of bipedalism using evolutionary robotics.

To understand the evolution of bipedalism among the hominoids in an ecological context we need to be able to estimate the energetic cost of locomotion in fossil forms. Ideally such an estimate would be based entirely on morphology since, except for the rare instances where footprints are preserved, this is the only primary source of evidence available. In this paper we use evolutionary robotics techniques (genetic algorithms, pattern generators and mechanical modeling) to produce a biomimetic simulation of bipedalism based on human body dimensions. The mechanical simulation is a seven-segment, two-dimensional model with motive force provided by tension generators representing the major muscle groups acting around the lower-limb joints. Metabolic energy costs are calculated from the muscle model, and bipedal gait is generated using a finite-state pattern generator whose parameters are produced using a genetic algorithm with locomotor economy (maximum distance for a fixed energy cost) as the fitness criterion. The model is validated by comparing the values it generates with those for modern humans. The result (maximum efficiency of 200 J m(-1)) is within 15% of the experimentally derived value, which is very encouraging and suggests that this is a useful analytic technique for investigating the locomotor behaviour of fossil forms. Initial work suggests that in the future this technique could be used to estimate other locomotor parameters such as top speed. In addition, the animations produced by this technique are qualitatively very convincing, which suggests that this may also be a useful technique for visualizing bipedal locomotion.

Biomechanical Phenomena↗

MANUS--a wheelchair-mounted rehabilitation robot.

Rehabilitation robots are assistive devices designed for use by people with severe disability in order to gain independence in tasks of daily living. MANUS is a wheelchair-mounted general-purpose manipulator now in use with over 100 people in their homes in the Netherlands, in France and in other countries. MANUS has six main degrees of freedom, excluding the gripper. To keep the arm slim, the motors are placed in the main base. The resulting low mass of the arm ensures a reduced impulse in case of collision. A complex system of toothed belts, hollow shafts and geared wheels drives the end-effector. MANUS is equipped with a two-fingered gripper. The fingers have passive canting mechanisms which ensure a three-point grasping action for most objects. A modular control system is used for steering the manipulator to its desired position. For this, a simple but effective user interface has been developed which is configurable by the end-user as well as by the therapist.

Arm↗

Bone registration method for robot assisted surgery: pedicle screw insertion.

A registration method that identifies bone geometry with respect to a robotic manipulator arm is presented. Although the method is generally applicable to many orthopaedic internal fixation procedures, it was only demonstrated for the insertion of pedicle screws in vertebral bodies for spine fixation. The method relies upon obtaining an impression of the vertebral bodies. Computerized tomography (CT) scans of both vertebrae and mould are reconstructed using a computer aided engineering (CAE) system. From the reconstructions, the surgeon is able to do preoperative planning including selection of pedicle screw diameter, direction of screw through pedicle, point of entry and length of engagement. The three-dimensional models are than meshed to determine positions of the surgeon's preoperative plan relative to the mould. Intra-operative positions are defined in space by a mechanical fixture rigidly attached to the mould and designed to allow a manipulator end-effector to recognize the global coordinates of the in vivo spine. The theory and methodology were validated using a five-axis manipulator arm. This initial presentation assumes and allows no relative motion between vertebrae in vivo.

Bone Screws↗