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PubMed2005

Global workspace theory of consciousness: toward a cognitive neuroscience of human experience.

Global workspace (GW) theory emerged from the cognitive architecture tradition in cognitive science. Newell and co-workers were the first to show the utility of a GW or "blackboard" architecture in a distributed set of knowledge sources, which could cooperatively solve problems that no single constituent could solve alone. The empirical connection with conscious cognition was made by Baars (1988, 2002). GW theory generates explicit predictions for conscious aspects of perception, emotion, motivation, learning, working memory, voluntary control, and self systems in the brain. It has similarities to biological theories such as Neural Darwinism and dynamical theories of brain functioning. Functional brain imaging now shows that conscious cognition is distinctively associated with wide spread of cortical activity, notably toward frontoparietal and medial temporal regions. Unconscious comparison conditions tend to activate only local regions, such as visual projection areas. Frontoparietal hypometabolism is also implicated in unconscious states, including deep sleep, coma, vegetative states, epileptic loss of consciousness, and general anesthesia. These findings are consistent with the GW hypothesis, which is now favored by a number of scientists and philosophers.

Cognition↗

PubMedDate not supplied

[Why do the aphasic patients produce semantic errors?].

INTRODUCTION: One of the most striking and surprising symptoms of the aphasic patients is the production of semantic errors. This kind of errors, which consists of replacing a word by another with a different but similar meaning, may appear when speaking, as it happens when a patient say dog in reference to a cat (semantic paraphasia), when reading as it happens when a patient reads dog where is writing cat (semantic paralexia), as well as in repetition or in writing. DEVELOPMENT: Some patients make these errors only in a specific linguistic modality (deep dyslexic patients make semantic errors in reading, deep dysphasic patients in repetition, etc.), but some patients make semantic errors in several modalities or even in all of them. Why these differences and what are the causes of these errors? Nowadays, models of linguistic processing built up from experiments with normal subjects provide us an answer to most of the above questions. From these models, by using appropriate tasks, it is possible to examine the reasons because of a patient makes certain errors. In fact, the results in different tasks help us to locate the deficit of each patient more than errors per se. It has been shown that sometimes the same type of error (e.g. a semantic paraphasia) can be caused by different processes in different patients. In this paper we will try to analyze which are the cognitive processes underlying semantic errors in each of the linguistic activities, when such processes are altered by injury, as well as to determine the best procedures to know what mechanisms are generating semantic errors in each aphasic patient.

Aphasia↗

PubMed1987

Simulation of chaotic EEG patterns with a dynamic model of the olfactory system.

The main parts of the central olfactory system are the bulb (OB), anterior nucleus (AON), and prepyriform cortex (PC). Each part consists of a mass of excitatory or inhibitory neurons that is modelled in its noninteractive state by a 2nd order ordinary differential equation (ODE) having a static nonlinearity. The model is called a KOe or a KOi set respectively; it is evaluated in the "open loop" state under deep anesthesia. Interactions in waking states are represented by coupled KO sets, respectively KIe (mutual excitation) and KIi (mutual inhibition). The coupled KIe and KIi sets form a KII set, which suffices to represent the dynamics of the OB, AON, and PC separately. The coupling of these three structures by both excitatory and inhibitory feedback loops forms a KIII set. The solutions to this high-dimensional system of ODEs suffice to simulate the chaotic patterns of the EEG, including the normal low-level background activity, the high-level relatively coherent "bursts" of oscillation that accompany reception of input to the bulb, and a degenerate state of an epileptic seizure determined by a toroidal chaotic attractor. An example is given of the Ruelle-Takens-Newhouse route to chaos in the olfactory system. Due to the simplicity and generality of the elements of the model and their interconnections, the model can serve as the starting point for other neural systems that generate deterministic chaotic activity.

Animals↗

PubMed1996

Characterization and molecular reaction scheme of a chloride channel expressed after axotomy in crayfish.

The nerve to the deep extensor abdominal muscle (DEAM) in crayfish species Astacus astacus, containing four excitatory and one inhibitory motor axons, was cut in the third segment on one side of the animal. The distal axon stump was not subject to phagocytosis but was present for months after the axotomy. The two lateral bundles of the DEAM were prepared 4-6 weeks after the axotomy. The gamma-aminobutyric-acid-(GABA-) activated chloride channel of these bundles was characterized by applying pulses of GABA to outside-out patches of the muscle membrane and measuring the responses. Based on the dose/response relationship of the peak current and of the rise time as well as on single-channel kinetics, a detailed molecular scheme for the reaction of the channel with GABA was derived. This scheme contains four binding steps of the agonist to the receptor and two open states. Simulations of the dose/response relationships with this model resulted in a set of rate constants which generate proper fits. In comparison to the channels present in innervated muscles, the channels of denervated muscles have a higher affinity for GABA, a lower single-channel conductance, four versus five binding steps, and non-cooperative binding. The first three of these adaptations of denervated muscles correspond to similar changes in denervated vertebrate muscles.

Abdominal Muscles↗

PubMed2001

Reactive transport modeling of processes controlling the distribution and natural attenuation of phenolic compounds in a deep sandstone aquifer.

Reactive solute transport modeling was utilized to evaluate the potential for natural attenuation of a contaminant plume containing phenolic compounds at a chemical producer in the West Midlands, UK. The reactive transport simulations consider microbially mediated biodegradation of the phenolic compounds (phenols, cresols, and xylenols) by multiple electron acceptors. Inorganic reactions including hydrolysis, aqueous complexation, dissolution of primary minerals, formation of secondary mineral phases, and ion exchange are considered. One-dimensional (1D) and three-dimensional (3D) simulations were conducted. Mass balance calculations indicate that biodegradation in the saturated zone has degraded approximately 1-5% of the organic contaminant plume over a time period of 47 years. Simulations indicate that denitrification is the most significant degradation process, accounting for approximately 50% of the organic contaminant removal, followed by sulfate reduction and fermentation reactions, each contributing 15-20%. Aerobic respiration accounts for less than 10% of the observed contaminant removal in the saturated zone. Although concentrations of Fe(III) and Mn(IV) mineral phases are high in the aquifer sediment, reductive dissolution is limited, producing only 5% of the observed mass loss. Mass balance calculations suggest that no more than 20-25% of the observed total inorganic carbon (TIC) was generated from biodegradation reactions in the saturated zone. Simulations indicate that aerobic biodegradation in the unsaturated zone, before the contaminant entered the aquifer, may have produced the majority of the TIC observed in the plume. Because long-term degradation is limited to processes within the saturated zone, use of observed TIC concentrations to predict the future natural attenuation may overestimate contaminant degradation by a factor of 4-5.

Aerobiosis↗

PubMedDate not supplied

Electrophysiological comparison between catechol- and urea-induced myoclonus models in the rat.

Catechol- and urea-induced myoclonus models in the rat were electrophysiologically compared to clarify pathophysiological differences. Catechol-induced myoclonus had various similarities with cortical reflex myoclonus in that there were electroencephalogram (EEG) discharges prior to myoclonic discharges, a spread of myoclonic discharges from the rostral to the caudal site, and a high amplitude somatosensory evoked potential (SEP). In urea-induced myoclonus, there were no EEG discharges related to myoclonic discharges and no enlarged SEP components as in reticular reflex myoclonus. Catechol-induced myoclonus had two evoked EMG responses of the biceps femoris at mean onsets of 8.0(C1) and 13.4 (C2) ms, and urea-induced myoclonus had a response (U1) at the mean onset of 10.2 ms. A study of the effects of various lesions in the central nervous system on these evoked EMG responses suggests that C1 is a monosynaptic spinal reflex. C2 which disappeared when the bilateral sensorimotor cortex for the hind limb had been resected and the lesion cooled is generated by the deep cerebral structures, such as the thalamus or basal ganglia, and U1 originates in the brain stem reticular formation. These results imply definitive differences of the pathophysiological mechanisms between catechol- and urea-induced myoclonus.

Animals↗

PubMed2006

Challenges of biological realism and validation in simulation-based medical education.

OVERVIEW: Simulation, both physical and computer-based, has a rich history in support of medical education. Essentially all these efforts have been aimed at instilling concrete measurable skills, akin to vocational training. They present learners with choices, facilitating a degree of learning by doing. The sets of learner choices are usually limited, with choices clearly classified into "right" and "wrong". But much of medicine is not much like a multiple-choice test. The realm of choices is broad and not always easily converted to a short list. The "correct" answer is not always known by the experienced physician beforehand, sometimes not even after the die is cast and the future unfolds. Computer simulation of human disease and its treatment can in principle be tremendously useful in the education of both basic and clinical scientists. This paper describes some challenges in the construction of simulation-based "liberal arts" biomedical education. OBJECTIVES: The educator attempting to develop a learning environment based on simulation of biology faces some special challenges. The challenges addressed in this paper are: face validity and deep validity; finding the right degree of realism; authoring biomedical models efficiently; managing randomness. To illustrate the issues, we trace the history of the Oncology Thinking Cap throughout several versions and expansions of educational objectives, and describe the detection and remediation of shortcomings related to these issues. DESIGN: Dealing effectively with issues of validity and realism can be accomplished if the acquisition of information driving and justifying the model development choices is documented, preferably automatically, during the process. Efficiency in authoring is greatly enhanced by judicious modularity to encourage re-use, and by the use of templated statements rather than raw code or exotic graphical components to represent the instructions driving the model. Randomness can be used to familiarize learners with the true relative proportions of types of cases, or to enrich the encountered cases with rarer but more instructive cases. When a learner repeats an encounter with a scenario while changing a single option, proper management of randomness is essential to avoid artifacts of random number generators. Otherwise an outcome change caused by a shift in random number streams may masquerade as an outcome change due to the changed option. CONCLUSION: Effective use of computer simulation of human disease and its treatment for biomedical education faces daunting obstacles, but these problems can be solved.

Computer Simulation↗

PubMed2006

Air classifier technology (ACT) in dry powder inhalation Part 3. Design and development of an air classifier family for the Novolizer multi-dose dry powder inhaler.

In this study, the design of a multifarious classifier family for different applications is described. The main design and development steps are presented as well as some special techniques that have been applied to achieve preset objectives. It is shown by increasing the number of air supply channels to the classifier chamber (from 2 to 8), that the fine particle losses from adhesion onto the classifier walls can be reduced from 75% to less than 5% of the real dose for soft (spherical) agglomerates. By applying a bypass flow that is arranged as a co-axial sheath of clean air around the aerosol cloud from the classifier, the airflow resistance of the classifier can be controlled over a relatively wide range of values (0.023-0.041 kPa(0.5) min l(-1)). This, without affecting the fine particle dose or increasing the fine particle losses in the inhaler. Moreover, the sheath flow can be modelled to reduce the depositions in the induction port to the cascade impactor or in the patient's mouth, which are the result of back flows in these regions. The principle of powder induced pressure drop reduction across a classifier enables assessment of the amount of powder in the classifier at any moment during inhalation, from which classifier loading (from the dose system) and discharge rates can be derived. This principle has been applied to study the residence time of a dose in the classifier as function of the carrier size fraction and the flow rate. It has been found that this residence time can be controlled in order to obtain an optimal balance between the generated fine particle fraction and the inhalation manoeuvre of the patient. A residence time between 0.5 and 2 s at 60 l/min is considered favourable, as this yields a high fine particle dose (depending on the type of formulation used) and leaves sufficient inhaled volume for particle transport into the deep lung.

Adhesiveness↗

PubMed2005

Math1 expression redefines the rhombic lip derivatives and reveals novel lineages within the brainstem and cerebellum.

The rhombic lip (RL) is an embryonic proliferative neuroepithelium that generates several groups of hindbrain neurons. However, the precise boundaries and derivatives of the RL have never been genetically identified. We use beta-galactosidase expressed from the Math1 locus in Math1-heterozygous and Math1-null mice to track RL-derived cells and to evaluate their developmental requirements for Math1. We uncover a Math1-dependent rostral rhombic-lip migratory stream (RLS) that generates some neurons of the parabrachial, lateral lemniscal, and deep cerebellar nuclei, in addition to cerebellar granule neurons. A more caudal Math1-dependent cochlear extramural stream (CES) generates the ventral cochlear nucleus and cochlear granule neurons. Similarly, mossy-fiber precerebellar nuclei require Math1, whereas the inferior olive and locus coeruleus do not. We propose that Math1 expression delimits the extent of the rhombic lip and is required for the generation of the hindbrain superficial migratory streams, all of which contribute neurons to the proprioceptive/vestibular/auditory sensory network.

Age Factors↗

PubMed2000

The impact of deep brain stimulation on executive function in Parkinson's disease.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) or the internal segment of the globus pallidus (GPi) improves Parkinson's disease and increases frontal blood flow. We assessed the effects of bilateral DBS on executive function in Parkinson's disease patients, seven with electrodes implanted in the STN and six in the GPi. Patients were assessed off medication with stimulators off, on and off again. The groups showed differential change with stimulation on the Reitan Trail-Making test (TMT B) (STN more improved) and on some measures of random number generation and Wisconsin Card Sorting (STN improved, GPi worse with stimulation). Across the groups, stimulation speeded up responding (Stroop control trial, TMT A) and improved performance on paced serial addition and missing digit tests. Conversely, conditional associative learning became more errorful with stimulation across the two groups. In general, change in performance with stimulation was significant for the STN but not the GPi group. These results support two opposite predictions. In support of current models of Parkinson's disease, 'releasing the brake' on frontal function with DBS improved aspects of executive function. Conversely, disruption of basal ganglia outflow during DBS impaired performance on tests requiring changing behaviour in novel contexts as predicted by Marsden and Obeso in 1994.

Association Learning↗

PubMed2002

Kinematic behavior of the ankle following malleolar fracture repair in a high-fidelity cadaver model.

BACKGROUND: Previous studies involving axially loaded ankle cadaver specimens undergoing a passive range of motion after fracture have demonstrated rotatory instability patterns consisting of excessive external rotation during plantar flexion. The present study was designed to expand these studies by using a model in which ankle motion is controlled by physiologically accurate motor forces generated through phasic force-couples attached to the muscle-tendon units. METHODS: Eight right unembalmed cadaver feet were tested in a dynamic gait simulator that reproduces the sagittal kinematics of the tibia while applying physiological muscle forces to the tendons of the major extrinsic muscles of the foot. Six-degrees-of-freedom kinematics of the tibia and talus were measured with use of a VICON motion-analysis system. The experimental conditions included all combinations of lateral and medial injury to reproduce the clinical classifications of ankle fracture. Statistical analysis was performed with repeated-measures analyses of variance. RESULTS: The talus of the intact ankles demonstrated coupled external rotation and inversion relative to the tibia as the ankle plantar flexed. Osteotomy of the fibula, simulating a lateral ankle fracture, slightly but significantly increased external rotation and inversion of the talus (p < 0.001), whereas disruption of either the superficial or the deep deltoid ligament increased talar eversion (p < 0.003) and disruption of the deep deltoid ligament increased internal rotation (p < 0.0001). The aberrant motions were corrected by repair of the injured structure. CONCLUSIONS: The predominant coupled rotation of the talus is external rotation associated with plantar flexion. Following progressive ankle destabilization, talar external rotation and inversion increased. CLINICAL RELEVANCE: The clinical decision-making process regarding the treatment of ankle fractures centers on determination of whether the injury is expected to result in abnormal motion, which is thought to predispose to the development of arthritis. The present study demonstrated a remarkable degree of ankle stability during stance phase even when there was severe disruption of medial and lateral structures. This finding suggests that a main determinant of clinical outcome after ankle fracture may be ankle motion during swing phase, when ankle stability is not augmented by the combination of axial loading and active motor control of motion. If swing-phase motion is abnormal, then the ankle may be in a vulnerable position at the point of heel-strike.

Aged↗

PubMed1989

How visual inputs to the ponto-bulbar reticular formation are used in the synthesis of premotor signals during orienting.

The primate superior colliculus (SC) is known as a structure subserving the transformation of visual information into "commands" for orienting eye movements. Collicular burst neurons discharging with short lead times in relation to visually triggered or spontaneous saccades are supposed to be the output elements linking the SC to immediately premotor pattern generators. In this paper we summarize some data available for the cat's SC neurones, identified as tecto-reticulo-spinal projection cells (TRSN), and reticulospinal neurones (RSN), identified as receiving excitatory collicular input. Some TRSNs respond to visual stimuli in the absence of orienting movements and, hence, their signals cannot be regarded as motor "commands", in spite of their proven connections with premotor pools in the brain stem and with the spinal cord. Moreover, a small fraction of RSNs belonging to polysynaptic descending collicular pathways also displays visual responses dissociated from movement, in addition to discharges related to the performance of orienting eye-head synergies. The processes of visual to motor transformation, assumed by current models as being definitively accomplished in the SC, appear thus to be partially performed in the reticular network incorporating the overlapping collaterals of tectal projection cells and their target neurons in the reticular core. It is concluded that, at least as for visuomotor transformations underlying orienting movements in the cat, the deep division of the SC and the brain stem reticular formation represent an ensemble, rather than a sequence of hierarchically arranged levels of processing.

Action Potentials↗

PubMed1998

Structure of the potassium form of CGCGAATTCGCG: DNA deformation by electrostatic collapse around inorganic cations.

The potassium form of d(CGCGAATTCGCG) solved by X-ray diffraction to 1.75 A resolution indicates that monovalent cations penetrate the primary and secondary layers of the "spine of hydration". Both the sodium [Shui, X., McFail-Isom, L., Hu, G. G., and Williams, L. D. (1998) Biochemistry 37, 8341-8355] and the potassium forms of the dodecamer at high resolution indicate that the original description of the spine, only two layers deep and with full occupancy by water molecules, requires substantive revision. The spine is merely the bottom two layers of a four layer solvent structure. The four layers combine to form a repeating motif of fused hexagons. The top two solvent layers were not apparent from previous medium-resolution diffraction data. We propose that the narrow minor groove and axial curvature of A-tract DNA arise from localization of cations within the minor groove. In general, the results described here support a model in which most or all forces that drive DNA away from canonical B-conformation are extrinsic and arise from interaction of DNA with its environment. Intrinsic forces, originating from direct base-base interactions such as stacking, hydrogen bonding, and steric repulsion among exocyclic groups appear to be insignificant. The time-averaged positions of the ubiquitous inorganic cations that surround DNA are influenced by DNA bases. The distribution of cations depends on sequence. Regions of high and low cation density are generated spontaneously in the solvent region by heterogeneous sequence or even within the grooves of homopolymers. The regions of high and low cation density deform DNA by electrostatic collapse. Thus, the effects of small inorganic cations on DNA structure are similar to the effects of proteins.

Cations, Monovalent↗

PubMed2026

Mechanisms linking the gut microbiota to colorectal cancer development and progression.

Colorectal cancer remains a leading cause of global cancer mortality, with a concerning rise in early-onset cases driven by complex interactions between environmental exposures, lifestyle factors, and host genetics. Mounting evidence indicates that gut microbiota dysbiosis critically modulates this oncogenic process, acting as an active participant rather than a passive bystander. This review systematically synthesizes the dichotomous roles of the intestinal microbiome in colorectal tumorigenesis through the conceptual framework of the driver-passenger model. We discuss how early initiating driver bacteria, such as Polyketide synthase-positive Escherichia coli and enterotoxigenic Bacteroides fragilis, compromise mucosal barriers, induce chronic mucosal inflammation, and inflict direct genomic instability. As the local tumor microenvironment undergoes profound metabolic remodeling, opportunistic passenger pathogens, notably Fusobacterium nucleatum, become enriched, further promoting cellular proliferation and facilitating tumor immune evasion. Conversely, protective commensals, exemplified by Clostridium butyricum and Streptococcus thermophilus, exert robust tumor-suppressive effects through multifaceted mechanisms. These beneficial microbes actively antagonize malignant progression by redirecting tumor metabolic fluxes toward oxidative stress, orchestrating deep epigenetic reprogramming, and degrading core oncoproteins to reverse chemoresistance. Transitioning from fundamental mechanisms to clinical application, we evaluate a comprehensive spectrum of microbiota-targeted interventions, encompassing non-invasive diagnostic biomarkers, fecal microbiota transplantation, engineered bacteria, phage therapy, and postbiotics. Finally, we critically address the formidable translational challenges associated with microbial heterogeneity, long-term safety, and regulatory standardization, aiming to provide a balanced perspective on integrating microbiome-based strategies into next-generation precision oncology for colorectal cancer.

Humans↗

PubMed2003

Effects of the local mechanical environment on vertebrate tissue differentiation during repair: does repair recapitulate development?

The local mechanical environment is a crucial factor in determining cell and tissue differentiation during vertebrate skeletal development and repair. Unlike the basic response of bone to mechanical load, as described in Wolff's law, the mechanobiological relationship between the local mechanical environment and tissue differentiation influences everything from tissue type and molecular architecture to the formation of complex joints. This study tests the hypothesis that precisely controlled mechanical loading can regulate gene expression, tissue differentiation and tissue architecture in the adult skeleton and that precise manipulation of the defect's local mechanical environment can initiate a limited recapitulation of joint tissue development. We generated tissue type predictions using finite element models (FEMs) interpreted by published mechanobiological fate maps of tissue differentiation. The experiment included a custom-designed external fixator capable of introducing daily bending, shear or a combination of bending and shear load regimens to induce precisely controlled mechanical conditions within healing femoral defects. Tissue types and ratios were characterized using histomorphometrics and molecular markers. Tissue molecular architecture was quantified using polarized light and Fourier transforms, while immunological staining and in situ hybridization were used to characterize gene expression. The finite element models predicted the differentiation of cartilage within the defects and that substantial fibrous tissues would develop along the extreme excursion peripheries in the bending group. The three experimentally induced loading regimens produced contiguous cartilage bands across all experimental defects, inhibiting bony healing. Histomorphometric analysis of the ratios of cartilage to bone in the experimental groups were not significantly different from those for the knee joint, and Fourier transform analysis determined significantly different collagen fibril angle specializations within superficial, intermediate and deep layers of all experimental cartilages (P<0.0001), approximating those for articular cartilage. All stimulations resulted in the expression of collagen type II, while the bending stimulation also resulted in the expression of the joint-determining gene GDF-5. These findings indicate that the local mechanical environment is an important regulator of gene expression, tissue differentiation and tissue architecture.

Animals↗

PubMed2002

Near-infrared spectrometric determination of blood pH.

BACKGROUND: Reflectance near-infrared spectroscopy (600-2200 nm) can noninvasively probe deep into tissues. Blood is the predominant absorber of near-infrared light in biological tissues. We investigated the feasibility of using reflectance near-infrared spectroscopy to measure blood pH in vitro. METHODS: Reflectance near-infrared spectra (600-2200 nm) were obtained with a fiberoptic probe immersed in diluted human packed red blood cells maintained at 37 degrees C. Changes in pH (6.800-7.600) were induced by: (1) varying the partial pressure of carbon dioxide by the bubbling of mixtures of humidified carbon dioxide and nitrogen gas through the blood; and (2) adding 1 N HCl/NaOH. Humidified oxygen gas was bubbled through the blood to generate variations in oxygen saturation. After each titration of pH, the spectrum was recorded and blood was sampled for the measurement of: pH, pCO(2), and pO(2) using blood gas analysis; and hemoglobin concentration and oxygen saturation using co-oximetry. Samples from three separate pH titrations were combined (120 total samples) and analyzed using partial least-squares analysis to generate a mathematical model relating spectral changes to pH (calibration set). This model was then used to predict the pH of a set of 36 pH titrations (prediction set). RESULTS: Quantitative and qualitiative analyses of the spectra in the calibration set found that spectral changes in the wavelength range, 650-1050 nm, were directly related to changes in pH. First-derivative-treated spectra from the calibration set, analyzed using partial least-squares analysis, generated a mathematical model with a cross-validated r(2) of 0.939 and a standard error of calibration of 0.046 pH unit. When this model was applied to the prediction set, with an offset correction, the r(2) was 0.936 with a standard error of prediction of 0.050 pH unit. CONCLUSION: Blood pH can be predicted in vitro with clinical significance using reflectance near-infrared spectroscopy (650-1050 nm) within a standard error of 0.050 pH unit.

Calibration↗

PubMed2002

Fondaparinux sodium.

Fondaparinux (Org-31540 / SR-90107A) is a new drug chemically synthesized for treatment and prophylaxis of thromboembolic disease. Fondaparinux is a selective inhibitor of activated factor X. Its structure is the copy of the heparin pentasaccharide sequence, the shortest chain required for antithrombin inhibition of activated factor X without antithrombin action. Fondaparinux has no effect on coagulation tests and does not bind to platelet factor 4 or promote heparin-induced thrombocytopenia. Fondaparinux inhibits thrombin generation and the growth of thrombi in in vitro and in vivo models. Phase I trials have shown a 100% bioavailability after subcutaneous (s.c.) administration, a rapid onset of action and an approximate half-life of 13.5 h. Fondaparinux is cleared as an active substance by the kidneys. In elderly patients, renal clearance is reduced and the half-life is longer. The phase II Pentathlon trial demonstrated significant dose-dependent reductions in the frequency of venous thromboembolism in total hip-replacement patients and the optimal dose was determined to be 2.5 mg s.c./24 h. Four phase III trials have evaluated fondaparinux starting 6 hours after surgery compared with enoxaparin for prevention of venous thromboembolism following orthopedic surgery in 7,344 patients. The risk of thrombosis was reduced by 50% with fondaparinux and no differences were observed in death or severe bleeding. In a phase II trial, similar efficacy and incidence of major bleeding were seen with fondaparinux s.c. compared with dalteparin s.c. in the treatment of deep venous thrombosis. In patients with acute myocardial infarction, the efficacy of fondaparinux during fibrinolytic therapy was assessed in 326 patients who had acute coronary syndromes of less than a 6 hour duration, showing a slight but statistically not significant advantage for fondaparinux over unfractionated heparin in the coronary angiographies. There is currently no antidote for fondaparinux.

Animals↗

PubMed2003

A humanized aldolase antibody for selective chemotherapy and adaptor immunotherapy.

Mouse monoclonal antibody 38C2 is the prototype of a new class of catalytic antibodies that were generated by reactive immunization. Through a reactive lysine, 38C2 catalyzes aldol and retro-aldol reactions using the enamine mechanism of natural aldolases. In addition to its remarkable versatility and efficacy in synthetic organic chemistry, 38C2 has been used for the selective activation of prodrugs in vitro and in vivo and thereby emerged as a promising tool for selective chemotherapy. Adding another application with relevance for cancer therapy, designated adaptor immunotherapy, we have recently shown that 38C2 can be chemically programmed to target tumors by formation of a covalent bond of defined stoichiometry with a beta-diketone derivative of an integrin alpha(v)beta(3) targeting RGD peptidomimetic. However, a major limitation for the transition from preclinical to clinical evaluation is the human anti-mouse antibody immune response that mouse 38C2 is likely to elicit in a majority of patients after single administration. Here, we report the humanization of mouse 38C2 based on rational design guided by molecular modeling. In essence, the catalytic center of mouse 38C2, which encompasses a deep hydrophobic pocket with a reactive lysine residue at the bottom, was grafted into a human antibody framework. Humanized 38C2 IgG1 was found to bind to beta-diketone haptens with conserved affinities and revealed strong catalytic activity with identical k(cat) and slightly higher K(M) values compared to the parental mouse antibody. Furthermore, humanized 38C2 IgG1 revealed efficiency in prodrug activation and chemical programming comparable to the parental mouse antibody.

Amino Acid Sequence↗