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Immunotherapy and monoclonal antibody therapies.

High-grade malignancies of the central nervous system continue to be refractory to multimodality therapy. Immunotherapy with monoclonal antibodies, biologic response modifiers (eg, interleukin-2), and autologous, activated lymphocytes offer the potential for more selective therapy. Current research is likely to help overcome obstacles inherent in current monoclonal antibody therapy, including cross-reactivity with normal tissues, impermeability of the blood-brain barrier, and immunogenicity of murine-derived monoclonal antibodies. Treatment with adoptive cellular therapy and biologic response modifiers has been limited by low killing activity and specificity of the activated lymphocytes, limited infiltration of implanted cells, and the toxicity associated with systemically administered biologic response modifiers. Improved specificity and killing efficacy of activated lymphocytes will allow integration of cellular immunotherapy into the treatment of central nervous system malignancies.

Animals↗

[CT/PET image registration based on a region similarity measure].

In this paper, CT/PET multimodality medical image registration is performed by a region similarity measure (RSM), accompanied with an improved segment method and Powell optimization algorithm. RSM has been proved to be a quick, accurate and robust algorithm by the experimental results.

Algorithms↗

Effects of aging and gender on interhemispheric function.

The ability of the two hemispheres of the brain to communicate with one another via the corpus callosum is important for a wide variety of sensory, motor, and cognitive functions, many of them communication related. Anatomical evidence suggests that aging results in structural changes in the corpus callosum and that the course over time of age-related changes in corpus callosum structure may depend on the gender of the individual. Further, it has been hypothesized that age- and gender-related changes in corpus callosum structure may result in concomitant decreased performance on tasks that are reliant on interhemispheric integrity. The purpose of this study was to investigate the effects of age and gender on auditory behavioral and visuomotor temporal indices of interhemispheric function across the life span of the normal adult. Results from 120 consistently right-handed adults from age 20 to 75 years revealed that interhemispheric integrity, as measured by dichotic listening, auditory temporal patterning, and visuomotor interhemispheric transfer time tasks, decreases relatively early in the adult life span (i.e., between the ages of 40 and 55 years) and shows no further decrease thereafter. In addition, the course over time of interhemispheric decline is different for men compared to women for some tasks. These findings suggest that decreased interhemispheric function may be a possible factor contributing to auditory and communication difficulties experienced by aging adults. In addition, results of this study hold implications for the clinical assessment of interhemispheric function in aging adults and for future research into the functional ramifications of decreased multimodality interhemispheric transfer.

Adult↗

[Combined-modality therapy for locoregional esophageal cancer].

Treatment for patients with esophageal cancer remains unsatisfactory. Although surgery alone or chemoradiotherapy have been generally accepted as reasonable options for patients with locoregional esophageal cancer, 5-year survival rate of either management is about 20%. The limited success of single modality treatment using radiotherapy or surgery has led to the investigation of multimodality therapies, combining chemotherapy, radiotherapy, and surgery. However, the appropriateness of such therapies remains unanswered. A number of prospective randomized trials of trimodality therapy versus surgery alone suggest benefits of combined-modality therapy. Concurrent chemoradiotherapy is an alternative treatment in selected resectable cases to show potential benefits in survival and local control. Patients with complete response following neoadjuvant therapy have consistent, substantial benefits in survival. Pretreatment staging is necessary for standardization of patients undergoing treatment protocols and for outcome evaluation. Biologic markers can be used to predict response to therapy and might allow designation of treatment based on the individual tumor. In the future, clinical trials testing optimal integration of preoperative regimen including new drugs may impact on the prognosis of esophageal cancer.

Combined Modality Therapy↗

Academy of eating disorders international conference.

New information is being acquired and disseminated about eating disorders, particularly in terms of integrating the roles of genes and environment, and new treatment approaches. Although evidence indicates that genes are not more important in the aetiology of anorexia nervosa (AN) than bulimia nervosa, Western culture does appear to be more important in the aetiology of bulimia nervosa than AN. Pathological fear conditioning offers a very useful and experimentally testable theory of the aetiology of AN. New evidence suggests that an enhanced, 'transdiagnostic' form of cognitive behavioural therapy is highly effective in eating disorder patients suitable for out-patient treatment. Patients who are homozygotic for the short (s) allele of the 5-hydroxytryptamine transporter gene promoter region appear to be more resistant to multimodal treatment.

Cognitive Behavioral Therapy↗

Efficacy of navigation in skull base surgery using composite computer graphics of magnetic resonance and computed tomography images.

The efficacy of a neurosurgical navigation system using three-dimensional composite computer graphics (CGs) of magnetic resonance (MR) and computed tomography (CT) images was evaluated in skull base surgery. Three-point transformation was used for integration of MR and CT images. MR and CT image data were obtained with three skin markers placed on the patient's scalp. Volume-rendering manipulations of the data produced three-dimensional CGs of the scalp, brain, and lesions from the MR images, and the scalp and skull from the CT. Composite CGs of the scalp, skull, brain, and lesion were created by registering the three markers on the three-dimensional rendered scalp images obtained from MR imaging and CT in the system. This system was used for 14 patients with skull base lesions. Three-point transformation using three-dimensional CGs was easily performed for multimodal registration. Simulation of surgical procedures on composite CGs aided in comprehension of the skull base anatomy and selection of the optimal approaches. Intraoperative navigation aided in determination of actual spatial position in the skull base and the optimal trajectory to the tumor during surgical procedures.

Computer Graphics↗

A multimodal language region in the ventral visual pathway.

Reading words and naming pictures involves the association of visual stimuli with phonological and semantic knowledge. Damage to a region of the brain in the left basal posterior temporal lobe (BA37), which is strategically situated between the visual cortex and the more anterior temporal cortex, leads to reading and naming deficits. Additional evidence implicating this region in linguistic processing comes from functional neuroimaging studies of reading in normal subjects and subjects with developmental dyslexia. Here we test whether the visual component of reading is essential for activation of BA37 by comparing cortical activations elicited by word processing in congenitally blind, late-blind and sighted subjects using functional neuroimaging. Despite the different modalities used (visual and tactile), all groups of subjects showed a common activation of BA37 by words relative to non-word letter-strings. These findings agree with the proposal that BA37 is an association area that integrates converging inputs from many regions. Our study confirms a prediction of theories of brain function that depend on convergence zones; the absence of one input (that is, visual) does not alter the response properties of such a convergence region.

Adult↗

Multisensory integration mechanisms in haptic space perception.

It has been argued that representations of peripersonal space based on haptic input are systematically distorted by egocentric reference frames. Interestingly, a recent study has shown that noninformative vision (i.e., freely viewing the region above the haptic workspace) improves performance on the so-called haptic parallel-setting task, in which participants are instructed to rotate a test bar until it is parallel to a reference bar. In the present study, we made a start at identifying the different sensory integration mechanisms involved in haptic space perception by distinguishing the possible effects of orienting mechanisms from those of noninformative vision. We found that both the orienting direction of head and eyes and the availability of noninformative vision affect parallel-setting performance and that they do so independently: orienting towards a reference bar facilitated the parallel-setting of a test bar in both no-vision and noninformative vision conditions, and noninformative vision improved performance irrespective of orienting direction. These results suggest the effects of orienting and noninformative vision on haptic space perception to depend on distinct neurocognitive mechanisms, likely to be expressed in different modulations of neural activation in the multimodal parietofrontal network, thought to be concerned with multimodal representations of peripersonal space.

Adolescent↗

An advanced boundary element method (BEM) implementation for the forward problem of electromagnetic source imaging.

The forward problem of electromagnetic source imaging has two components: a numerical model to solve the related integral equations and a model of the head geometry. This study is on the boundary element method (BEM) implementation for numerical solutions and realistic head modelling. The use of second-order (quadratic) isoparametric elements and the recursive integration technique increase the accuracy in the solutions. Two new formulations are developed for the calculation of the transfer matrices to obtain the potential and magnetic field patterns using realistic head models. The formulations incorporate the use of the isolated problem approach for increased accuracy in solutions. If a personal computer is used for computations, each transfer matrix is calculated in 2.2 h. After this pre-computation period, solutions for arbitrary source configurations can be obtained in milliseconds for a realistic head model. A hybrid algorithm that uses snakes, morphological operations, region growing and thresholding is used for segmentation. The scalp, skull, grey matter, white matter and eyes are segmented from the multimodal magnetic resonance images and meshes for the corresponding surfaces are created. A mesh generation algorithm is developed for modelling the intersecting tissue compartments, such as eyes. To obtain more accurate results quadratic elements are used in the realistic meshes. The resultant BEM implementation provides more accurate forward problem solutions and more efficient calculations. Thus it can be the firm basis of the future inverse problem solutions.

Algorithms↗

Testing combined pharmacotherapies and behavioral interventions in alcohol dependence: rationale and methods.

Increasing knowledge about effective therapies for alcohol dependence calls for new research designs to examine treatment interactions between pharmacotherapies and behavioral interventions. In 1997, the National Institute on Alcohol Abuse and Alcoholism recruited 11 sites and a coordinating center for a large-scale (1,375 subjects), randomized placebo controlled trial to test 16 weeks of active treatment using naltrexone and acamprosate alone and in combination. Most participants receive 9 brief sessions delivered by medically trained providers to promote sobriety and enhance medication adherence (Medical Management, MM). Half the participants are also randomized to individualized psychotherapy (up to 20 sessions of Combined Behavioral Intervention, CBI), integrating elements of the successful behavioral interventions from Project MATCH. COMBINE seeks to evaluate the efficacy of the two most promising medications (naltrexone and acamprosate) both singly and together, when combined with different intensities of behavioral therapies. COMBINE incorporates a number of innovative design aspects, including a no-pill psychotherapy-alone condition, behavioral interventions that are both manual-guided and individualized, and pharmacotherapy dosing that is greater than in some previous trials. Two COMBINE pilot studies demonstrate the safety and acceptability of the combination pharmacotherapy dosing, and the feasibility of implementing the manualized behavioral interventions. This paper introduces COMBINE's goals, methods and analytic strategies, and their potential to improve multimodal treatment selection.

Acamprosate↗

Speechreading: illusion or window into pattern recognition.

In the Fuzzy Logical Model of Perception (FLMP) perceivers are conceptualized as forming perceptual judgments by evaluating and integrating multiple ambiguous sources of information, in an optimal manner based on relative goodness of match. This model has been tested favorably against a variety of competing theories and models. Recent extensions of the FLMP are described in this article along with empirical applications and verification, and progress in the study of speech perception by ear and eye is reviewed within this general theoretical framework. The model illuminates the differences that are observed across different languages in terms of information as opposed to information-processing. Pattern recognition of bimodal speech is representative of pattern recognition in a variety of other domains, such as emotion perception, and there are several domain-dependent reasons why multimodal presentation of audible and visible speech is particularly conducive to accurate pattern recognition. We believe that the positive outcome of this research provides a framework for the development of computer-animated agents, which can serve as language tutors and as conversational characters in other domains, easing the interaction of humans and machines.

Journal Article↗

Waveguide lenses with multimode interference for low-loss slab propagation.

It is shown that a nearly ideal two-dimensional focusing Gaussian beam can be synthesized by use of a linear combination of the two lowest-order even modes of an optical waveguide. This property can be used to couple laterally guided modes across slab waveguide regions with low loss. The technique is illustrated by use of a conventional multimode interference (MMI) geometry, in which the MMI coupler transforms the fundamental mode of an initial waveguide into a focusing Gaussian beam, which is then fed to a slab region. Two-dimensional beam propagation simulations show that the beam does not initially diverge in the slab region, but rather comes to a focus. A second MMI coupler then transforms the diverging beam back to the initial mode. A structure is designed that can couple the fundamental mode of a 9-microm-wide waveguide across an 88-microm-long slab region with only a 0.036-dB loss. This technique can be applied to improve the performance of small-angle waveguide crossings and integrated turning mirrors.

Journal Article↗

Process-based reactive transport modeling of a permeable reactive barrier for the treatment of mine drainage.

Reactive transport modeling of a permeable reactive barrier for the treatment of mine drainage was used to integrate a comprehensive data set including pore water chemistry and solid phase data from several sampling events over a >3-year time period. The simulations consider the reduction of sulfate by the organic carbon-based treatment material and the removal of sulfate and iron by precipitation of reduced mineral phases including iron monosulfides and siderite. Additional parameters constraining the model include dissolved H2S, alkalinity and pH, as well as a suite of solid phase S-fractions identified by extractions. Influences of spatial heterogeneity necessitated the use of a 2-dimensional modeling approach. Simulating observed seasonal fluctuations and long-term changes in barrier reactivity required the use of temperature dependent rate coefficients and a multimodal Monod-type rate expression accounting for the variable reactivity of different organic carbon fractions. Simulated dissolved concentrations of SO4, Fe, H2S, alkalinity and pH, as well as solid phase accumulations of reduced sulfur phases generally compare well to observed trends over 23 months. Spatial variations, seasonal fluctuations and the time-dependent decline in reactivity were also captured. The modeling results generally confirm, and further strengthen, the existing conceptual model for the site. Overall sulfate reduction and S-accumulation rates are constrained with confidence within a factor of 1.5.

Hydrogen-Ion Concentration↗

Cardiac hypertrophy at the crossroads: Mechanistic insights and emerging multimodal therapeutic strategies.

Cardiovascular diseases (CVDs) remain the leading cause of mortality worldwide, accounting for approximately 17.9 million deaths annually. Among their diverse manifestations, cardiac hypertrophy is a clinically significant condition that predisposes patients to heart failure, arrhythmias, and and sudden cardiac death. Clinically, hypertrophy can be classified into three forms: physiological (adaptive) hypertrophy, which supports cardiac performance and is reversible, pathological hypertrophy most often secondary to hypertension, valvular disease, hemodynamic stress, or sustained neurohumoral activation; and hypertrophic cardiomyopathy (HCM) represents a primary genetic disorder, most often caused by mutations in sarcomeric proteins. These distinct etiologies have important therapeutic implications, as they determine how efficiently pharmacological agents can target underlying mechanisms. Conventional pharmacological treatments are widely used in clinical practice, yet they provide limited reversal of established remodeling. This therapeutic gap has driven the development of innovative modalities such as RNA-based therapeutics, exosome-mediated interventions, stem cell-derived therapies, and genome-editing technologies, which aim to modulate maladaptive signaling and restore myocardial integrity. This review integrates clinical perspectives with mechanistic insights, delineating the drivers of pathological hypertrophy while evaluating both established therapies and emerging strategies that hold promise for precision cardiology and improved patient outcomes.

Humans↗

A behavioral teratogenic model of the impact of prenatal cocaine exposure on arousal regulatory systems.

Studies of both preclinical and human models of prenatal cocaine exposure suggest that one mechanism for the impact of cocaine on developing neural systems may be through functional alterations in monoaminergically regulated arousal systems. Conceptually, arousal regulation refers to a set of multimodal central nervous system mechanisms underlying cortical activation in response to internal and/or external stimulation. The emerging capacity for moment-to-moment regulation of states of arousal influences attentional states (e.g., posterior cortex) and executive functions (prefontal cortex) and thus information processing and learning as well as socialization. Furthermore, as a gating mechanism for response to novel and/or stressful conditions, arousal regulation is also a central construct for understanding stress reactivity and response to acute chronic trauma. In this paper, we review the findings of prenatal cocaine exposure in both preclinical and human studies with a particular focus on studies of neurobehavioral, neurocognitive functioning. A theoretical model of interactive arousal systems is presented as one possibility for integrating the profile of apparent cocaine-related neurobehavioral impairments in infants and young children prenatally exposed to cocaine.

Animals↗

Locally advanced breast cancer current status and future directions.

Patients described as having locally advanced breast cancer comprise a heterogeneous group of patients with variable clinical presentations. Systematic evaluation of patients with these presentations has been limited, with much of our current understanding based on retrospective reviews. Prospective pilot studies have demonstrated the feasibility of multimodality therapy. However, there have been few well-conducted randomized trials in this setting. Comparison of results among studies is made difficult by the varying eligibility criteria and the way in which the data are reported. The use of common and consistent definitions of operable and inoperable disease is necessary for a more uniform understanding of the therapeutic interventions necessary for a given patient within this broad category of Stage III or locally advanced breast cancer. There are a variety of opportunities for clinical research activities in this group of patients including tests of hormonal recruitment or synchronization, high dose chemotherapy requiring autologous bone marrow transplantation, perioperative or preoperative chemotherapy, and alternating chemotherapy with short course radiotherapy. The integration of clinical information with biological characteristics of the tumor such as cytokinetics, oncogene amplification, and hormone receptors will be an important and necessary focus of future investigation in this disease.

Breast Neoplasms↗

Work therapy for schizophrenic patients: results of a 3-year prospective study in Germany.

Work therapy is a widespread form of sociotherapy. In contrast to pharmacological and somatic forms of treatment, proof of efficacy is difficult to produce in multimodal therapy of schizophrenic patients on account of the many methodological problems involved. Within the framework of an extensive study on the vocational rehabilitation of mentally ill patients, we carried out a naturalistic follow-up study of 83 schizophrenic patients attending outpatient work therapy. The sample, which comprised 44 men and 38 women with a mean age of 35 years (+/- 8.5 years), can be seen as regionally representative. The courses of illness and rehabilitation were documented prospectively at annual follow-ups over a 3-year period. Most of the probands were chronically mentally ill patients with a history of frequent and long-term hospitalisation. At the end of the 3-year period, 22% of the patients were integrated into the open labour market, 26% were working in sheltered employment, 23% were still in work therapy, and 29% were unemployed. Two-thirds had achieved their stated rehabilitation objectives. The 3-year rehabilitation outcome was strongly dependent on the patients' subjective expectations. Other factors proving to be predictors of successful rehabilitation were less pronounced psychopathological symptoms (ADMP), better social functioning (GAS), a higher level of education and an early introduction to work therapy. Work therapy appears to have a favourable impact on hospitalisation rates.

Adult↗

The functional anatomy of visual-tactile integration in man: a study using positron emission tomography.

The integration of neural signals from different sensory modalities is a prerequisite for many cognitive and behavioural functions. In this study, we have mapped the functional anatomy of the integration of sensory signals across the tactile and visual modalities. Using the PET radiotracer H2(15)O, regional cerebral blood flow (rCBF) changes were measured in eight normal volunteers performing crossmodal recognition of simultaneously presented visual and tactile stimuli using a modified version of the 'arc-circle test'. Whilst intramodal matching within the visual modality led to relative rCBF increases in the visual association cortex, crossmodal matching (visual-tactile), when compared to intramodal matching, was accompanied by relative rCBF increases in the anterior cingulate cortex, inferior parietal lobules, the left dorsolateral prefrontal cortex (DLPFC) and the left claustrum/insular cortex. The pattern of brain activation is congruent with areas of heteromodal and supramodal cortex and indicates that activation of multimodal areas is required to solve the crossmodal problem.

Adult↗