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From brainstem to cortex: computational models of saccade generation circuitry.

The brain circuitry of saccadic eye movements, from brainstem to cortex, has been extensively studied during the last 30 years. The wealth of data gathered allowed the conception of numerous computational models. These models proposed descriptions of the putative mechanisms generating this data, and, in turn, made predictions and helped to plan new experiments. In this article, we review the computational models of the five main brain regions involved in saccade generation: reticular formation saccadic burst generators, superior colliculus, cerebellum, basal ganglia and premotor cortical areas. We present the various topics these models are concerned with: location of the feedback loop, multimodal saccades, long-term adaptation, on the fly trajectory correction, strategy and metrics selection, short-term spatial memory, transformations between retinocentric and craniocentric reference frames, sequence learning, to name the principle ones. Our objective is to provide a global view of the whole system. Indeed, narrowing too much the modelled areas while trying to explain too much data is a recurrent problem that should be avoided. Moreover, beyond the multiple research topics remaining to be solved locally, questions regarding the operation of the whole structure can now be addressed by building on the existing models.

Animals↗

Effect of display modality on spatial accuracy of orthopaedic surgery pre-operative planning applications.

Graphical representation of a patient's anatomy is fairly similar in the majority of orthopaedic surgery planning programs. The position of implantable devices is usually established using a three-pane window showing 2D cross sections of the CT data set taken on three user-selectable orthogonal planes. In some cases this orthogonal-plane representation is replaced or extended by interactive 3D visualization, obtained using surface rendering techniques. These ways to represent the CT data come naturally and easily to the programmer. However, the efficacy of these display strategies is questionable. The present study aims to assess if the display modality used to visualize CT data affects the inherent spatial accuracy achievable in a surgical planning application. A group of users was asked to perform repeatedly a specific planning task using various display interfaces to the same underlying software application. The planning task was designed to allow an assessment of the accuracy with which each user was able to position the prosthetic component. A specialized interface, called multimodal display, presented a peak error of 0.45 mm and 0.95 deg, significantly lower than the 2.4 mm and 4 deg for the othogonal slices interface, and the 3.8 mm and 16.7 deg for the 3D-rendering interface. The results of this study indicate an important effect of the type of visualization modality used to represent CT data on final accuracy of the planning operation.

Computer Graphics↗

Etoposide in the management of non-small cell lung cancer.

Etoposide is a phase-specific, schedule-dependent derivative of podophyllotoxin that appears to act by inhibiting DNA-topoisomerase II. Early preclinical work demonstrated sharp activity in mouse leukemias and possible synergy with cisplatin. As a single agent (either orally or intravenously), it demonstrated limited benefit in non-small cell lung cancer (NSCLC), with response rates around 10%. In combination with cisplatin, it has become a mainstay of chemotherapeutic efforts, either as primary therapy or in conjunction with radiation. Response rates in advanced disease average around 30%, climbing to more than 50% in patients with Stage IIIA or IIIB disease. More recent work suggests that the issue of the true synergy of etoposide with cisplatin in NSCLC needs reassessment. The relative roles of etoposide and cisplatin in the combination are unclear, as several studies conflict. Pharmacokinetic data suggest that multiple daily fractions of etoposide are superior to prolonged infusions, warranting several future trials. The current major role for etoposide plus cisplatin would appear to be in multimodality therapy where the combination can be readily combined with radiation and/or surgery. Several other agents have been studied with etoposide or etoposide plus cisplatin (mitomycin, vindesine, doxorubicin, cyclophosphamide, ifosfamide, and carboplatin), but it is unclear whether the addition of any of them offers any response or survival advantage.

Antineoplastic Combined Chemotherapy Protocols↗

Retrospective registration of X-ray angiograms with MR images by using vessels as intrinsic landmarks.

Conventional x-ray angiography (XRA) images are projections of the vasculature with high spatial and temporal resolution, while magnetic resonance (MR) angiography (MRA) and MR imaging data show the three-dimensional locations of vessels relative to brain parenchyma. The authors have developed a retrospective method of registering these studies, which makes it practical to produce multimodality displays of this complementary information. Registration was performed by matching vessels seen on both XRA and MRA images. First, the authors determined the coordinates of the center lines of a few "landmark" vessels on the XRA image and the three-dimensional locations of the corresponding intraluminal voxels in the MRA volume. Registration was performed by rotating and translating the MRA-MR imaging volume until the perspective projection of the MRA landmark vessels matched the corresponding vessel center lines on the XRA image. Experiments with phantoms and patients indicated that the two studies were registered with an average error of less than 2 mm. A linked-cursor display was developed to show correspondence between points on the registered XRA and MRA-MR images.

Angiography↗

[Concepts for treatment of postoperative pain].

Adequate control of postoperative pain does not only improve patient satisfaction, but is also indicated from a medical point of view. Besides conventional non-opioid analgesics and opioids, more sophisticated analgesia concepts like intravenous patient-controlled analgesia (PCA) and epidural analgesia may be indicated. Modalities and practical aspects of these concepts are discussed and briefly described. It is believed that the effectiveness of improved analgesia will be increased by integrating analgesia concepts into a multimodal approach of intensified mobilisation, early enteral nutrition and frequent respiratory therapy of the postoperative patient. In conclusion, there is good evidence of improved analgesia from PCA and epidural analgesia. Data on outcome improvement by analgesia is still contradictory, but improvement of patient satisfaction is without doubt.

Analgesia↗

[Therapy of back pain: what is evidence-based?].

Back pain has to be classified by localisation, duration, and existence or absence of neurological deficits. Therapy mainly depends on the severity of neurological symptoms. The time period between the onset of symptoms and efficient therapy should be short in order to prevent the development of chronic pain. Therefore a sufficient, consistent and evidence-based conservative treatment should be initiated early on, with the only exception of special emergency situations as described further down in this article. Patients should not be immobilized, a better outcome is proven in patients who immediately continued practising their daily activities. First line medication consists of non-steroidal-anti-inflammatory-drugs (NSAID). If necessary, opioids and muscle-relaxants may be applied additionally. Surgical procedures are only indicated in a small number of patients. A sufficient data base with regard to the benefit of acupuncture, orthesis, and chiropractic medicine is lacking. Local injections should only be done in very special cases. Concerning chronic back pain a multimodal, multi-disciplinary pain treatment concept with physical training and behavioural therapy should be applied in order to teach the patient to avoid a passive and maladjusted attitude. Antidepressant drugs may also be indicated in chronic back pain.

Analgesics↗

Myosin II transport, organization, and phosphorylation: evidence for cortical flow/solation-contraction coupling during cytokinesis and cell locomotion.

The mechanism of cytokinesis has been difficult to define because of the short duration and the temporal-spatial dynamics involved in the formation, activation, force production, and disappearance of the cleavage furrow. We have investigated the structural and chemical dynamics of myosin II in living Swiss 3T3 cells from prometaphase through the separation and migration of daughter cells. The structural and chemical dynamics of myosin II have been defined using the semiautomated, multimode light microscope, together with a fluorescent analogue of myosin II and a fluorescent biosensor of myosin II regulatory light chain (RLC) phosphorylation at serine 19. The correlation of image data from live cells using different modes of light microscopy allowed interpretations not possible from single-mode investigations. Myosin II transported toward the equatorial plane from adjacent regions, forming three-dimensional fibers that spanned the volume of the equator during anaphase and telophase. A global phosphorylation of myosin II at serine 19 of the RLC was initiated at anaphase when cortical myosin II transport started. The phosphorylation of myosin II remained high near the equatorial plane through telophase and into cytokinesis, whereas the phosphorylation of myosin II at serine 19 of the RLC decreased at the poles. The timing and pattern of phosphorylation was the same as the shortening of myosin II-based fibers in the cleavage furrow. Myosin II-based fibers shortened and transported out of the cleavage furrow into the tails of the two daughter cells late in cytokinesis. The patterns of myosin II transport, phosphorylation, and shortening of fibers in the migrating daughter cells were similar to that previously defined for cells migrating in a wound in vitro. The temporal-spatial patterns and dynamics of myosin II transport, phosphorylation at serine 19 of the RLC, and the shortening and disappearance of myosin II-based fibers support the proposal that a combination of the cortical flow hypothesis and the solation-contraction coupling hypothesis explain key aspects of cytokinesis and polarized cell locomotion.

3T3 Cells↗

Practice parameters for the assessment and treatment of children and adolescents with anxiety disorders. American Academy of Child and Adolescent Psychiatry.

Anxiety disorders comprise one of the most prevalent categories of psychopathology in children and adolescents. These revised practice parameters highlight the DSM-IV changes for anxiety disorders and review the literature related to the assessment and treatment of anxiety disorders in children and adolescents. Up-to-date information on longitudinal outcome data, assessment of anxiety, parent-child interventions, and use of selective serotonin reuptake inhibitors has been added to the previous parameters, published in September 1993. Recommendations for evaluation and multimodal approaches to treatment are presented.

Anxiety Disorders↗

Structure and membrane interaction of the internal fusion peptide of avian sarcoma leukosis virus.

The structure and membrane interaction of the internal fusion peptide (IFP) fragment of the avian sarcoma and leucosis virus (ASLV) envelope glycoprotein was studied by an array of biophysical methods. The peptide was found to induce lipid mixing of vesicles more strongly than the fusion peptide derived from the N-terminal fusion peptide of influenza virus (HA2-FP). It was observed that the helical structure was enhanced in association with the model membranes, particularly in the N-terminal portion of the peptide. According to the infrared study, the peptide inserted into the membrane in an oblique orientation, but less deeply than the influenza HA2-FP. Analysis of NMR data in sodium dodecyl sulfate micelle suspension revealed that Pro13 of the peptide was located near the micelle-water interface. A type II beta-turn was deduced from NMR data for the peptide in aqueous medium, demonstrating a conformational flexibility of the IFP in analogy to the N-terminal FP such as that of gp41. A loose and multimodal self-assembly was deduced from the rhodamine fluorescence self-quenching experiments for the peptide bound to the membrane bilayer. Oligomerization of the peptide and its variants can also be observed in the electrophoretic experiments, suggesting a property in common with other N-terminal FP of class I fusion proteins.

Avian Sarcoma Viruses↗

An analysis of sickness absence in chronically ill patients receiving complementary and alternative medicine: a longterm prospective intermittent study.

BACKGROUND: The popularity of complementary and alternative medicine (CAM) has led to a growing amount of research in this area. All the same little is known about the effects of these special treatments in every-day practice of primary care, delivered by general practitioners within the health insurance system. From 1994 to 2000 more than 20 German Company health insurances initiated the first model project on CAM according to the German social law. Aim of this contribution is to investigate the effectiveness of multi-modal CAM on chronic diseases within primary health care. METHODS: A long-term prospective intermittent study was conducted including 44 CAM practitioners and 1221 self-selected chronically ill patients (64% women) of whom 441 were employed. Main outcome measure is sick-leave, controlled for secular trends and regression-to-the mean and self-perceived health status. RESULTS: Sick-leave per year of 441 patients at work increased from 22 (SD +/- 45.2) to 31 (+/- 61.0) days within three years prior to intervention, and decreased to 24 (+/- 55.6) in the second year of treatment, sustaining at this level in the following two years. Detailed statistical analysis show that this development exceeds secular trends and the regression-toward-the-mean effect. Sick-leave reduction was corroborated by data on self-reported improvement of patients' health status. CONCLUSION: Results of this longterm observational study show a reduction of sick leave in chronically ill patients after a complex multimodal CAM intervention. However, as this is an uncontrolled observational study efficacy of any specific CAM treatment can not be proven. The results might indicate an general effectiveness of CAM in primary care, worthwhile further investigations. Future studies should identify the most suitable patients for CAM practices, the most appropriate and safe treatments, provide information on the magnitude of the effects to facilitate subsequent definitive randomised controlled studies that will help to position complementary and alternative medicine in health care.

Adult↗

The role of docetaxel in N2 locally advanced non-small-cell lung cancer.

Patients with locally advanced non-small-cell lung cancer (NSCLC) are a heterogeneous group often treated with multimodality therapy. Docetaxel has an established role in the treatment of advanced-stage NSCLC and has demonstrated promising activity in the locally advanced setting. Herein, we review the available data on the role of docetaxel in locally advanced NSCLC. The phase I/II data regarding the use of docetaxel concomitantly with radiation as a single agent or combined with platinum compounds are reviewed. In addition, we discuss the role of docetaxel induction therapy before surgery or definitive radiation therapy. Additionally, we address the role of docetaxel in consolidation therapy in patients with locally advanced NSCLC.

Antineoplastic Agents, Phytogenic↗

[Intraoperative radiotherapy in the combined treatment of pancreatic cancers].

Pancreatic cancer is a highly lethal disease either for the high incidence of distant metastases or for the frequent local recidive also after potentially curative resection. For this reason new multimodality approaches have to be investigated. Intraoperative radiotherapy (IORT) permits to administer a high dose to the tumor or to the retropancreatic tissues and to the regional lymph nodes. Literature data suggest it is possible a better local control and perhaps a better survival than the surgery alone or the palliative treatments by the use of schedules with IORT. Anyway they are retrospective data and IORT is an investigational method which has to be indagate in the combined modality approaches to this disease.

Humans↗

Diabetes management quality improvement in a family practice residency program.

BACKGROUND: Diabetes is a devastating chronic disease. Although optimal diabetes control reduces chronic complications, actual provision of diabetes care frequently falls short of accepted guidelines. We wanted to determine whether locally developed diabetes care initiatives can result in improvements in the provision of diabetes care. METHODS: This study was a retrospective cohort analysis using Medicare claims and chart abstraction data to ascertain diabetes care indicator utilization rates at the Northeast Iowa Family Practice Clinic (NEIFPC), which serves as the training site for the Northeast Iowa Family Practice Residency Program. Diabetic patients receiving care at the NEIFPC during 1996, 1997, and 1998 were included. Diabetes care rates are compared with those of other Iowa practices. Diabetes initiatives included chart audits, glycosylated hemoglobin (HbA1c) measurement reminder cards, educational symposia, an endocrinology outreach clinic, resident elective rotations, diabetes flow sheet utilization, pharmacist interface, and nursing foot-examination preparations. The primary outcome was the utilization rate of accepted diabetes care indicators. RESULTS: Diabetic patients at NEIFPC had greater utilization of diabetes care indicators than did patients of Iowa collaborators in 1997 and 1998. NEIFPC patients had HbA1c levels measured more frequently in 1997 and 1998 (84% and 88%, respectively) than did patients of Iowa collaborators (49% and 41%, respectively) (P < .001). The mean 1997 and 1998 HbA1c levels of 7.32% and 7.25%, respectively, are impressive compared with that of Iowa collaborators (8.83% and 8.36%) (P < .001) and other published data (8.5%-10%). The percentage of NEIFPC patients with good glycemic control (HbA1c < 8%) was 75%, compared with the reported 50% of all US patients. CONCLUSIONS: Our findings suggest that multimodal diabetes care quality improvement initiatives, applied longitudinally, can result in significant improvements in the provision and documentation of diabetes care.

Aged↗

Analysis of 18F-FET PET for grading of recurrent gliomas: is evaluation of uptake kinetics superior to standard methods?

UNLABELLED: The aim of the present study was to evaluate whether extended analyses of O-(2-18F-fluoroethyl)-L-tyrosine (FET) uptake kinetics provide results superior to those of standard tumor-to-background ratios in predicting tumor grade in patients with pretreated gliomas. METHODS: Dynamic 18F-FET PET studies (0-40 min after injection of 180 MBq of 18F-FET) were performed on 45 glioma patients with suspected tumor recurrence after multimodal treatment. For the standard method, tumoral maximal standardized uptake value (SUVmax) and the ratio to the background were derived from a summed image 20-40 min after injection. Dynamic data evaluation comprised several approaches: first, SUV within a 90% isocontour threshold (SUV90) and the respective ratio to the background calculated for each time frame between 5 and 40 min after injection; second, the time to peak analysis; and third, various parameters accounting for the individual time course of 18F-FET uptake. Results were correlated with the histopathologic findings of MRI/PET-guided stereotactic biopsies and were evaluated with respect to their discriminatory power to separate low- from high-grade tumors using receiver-operating characteristic (ROC) analyses. RESULTS: The parameters taking into account the individual time course of 18F-FET uptake were able to differentiate low-grade from high-grade recurrent astrocytomas with high diagnostic accuracy, reaching the best differentiation with a sensitivity and specificity of 92% and an area under the ROC curve (AUC) of 0.94. For the other parameters, the respective values were considerably lower (time to peak: 85% sensitivity and 88% specificity; SUV90-to-background ratio for single-frame evaluation of the early-uptake phase: 100% sensitivity, 62% specificity, and 0.81 AUC). The lowest performance was provided by the standard method (SUVmax: 73% sensitivity, 54% specificity, and 0.60 AUC; SUVmax-to-background ratio: 62% sensitivity, 62% specificity, and 0.59 AUC). Time-activity curves (5-40 min after injection) slightly and steadily increased in tumor-free patients and in low-grade tumors, whereas high-grade tumors showed an early peak around 10-15 min after injection followed by a decrease. CONCLUSION: This study has shown differences in the dynamics of 18F-FET uptake between recurrent low- and high-grade gliomas. Therefore, parameters addressing the different kinetic behaviors allow discrimination with high diagnostic power between these 2 prognostically different groups. Thus, the techniques introduced here are clearly superior to the yet most widely used standard method.

Adult↗

Sensory activity in the telencephalon of the clawed toad, Xenopus laevis.

In this study data are presented providing evidence that the striatum of the clawed toad, Xenopus laevis, processes mechanosensory, acoustic, and visual information and that multisensory interaction takes place in this telencephalic structure. Multimodal processing as well as the considerable effects of stimulus repetition rate on response amplitudes are in line with the finding that the striatum of Xenopus mediates attentional processes (Traub & Elepfandt, 1990). Further physiological studies are needed to delineate the functional organization of the striatum in amphibians.

Acoustic Stimulation↗

An Integrative Morphological and Genomic Analysis With a Refined Fluorescence In Situ Hybridization (FISH) Threshold and Novel Kinase Fusions in a Large Asian Cohort of Spitzoid Neoplasms.

Differentiating atypical Spitz tumors (ASTs) from true Spitz melanomas (SMs) and conventional melanomas with spitzoid features (MSFs) remains a formidable diagnostic challenge. Because current molecular epidemiological data are overwhelmingly derived from Caucasian cohorts, the genomic landscape of Asian populations remains largely unexplored. To elucidate the molecular progression landscape and refine the diagnostic criteria, we performed a comprehensive multimodal analysis-integrating histomorphology, immunohistochemistry, multiprobe fluorescence in situ hybridization (FISH), and targeted RNA/DNA-based next-generation sequencing (NGS)-on a cohort of 140 spitzoid neoplasms. This cohort, comprising 126 ASTs, 8 SMs, and 6 MSFs, represents the largest Asian cohort to date. Malignant phenotype strongly correlated with lesional asymmetry, deep atypical mitoses, a sheet-like growth pattern, diffuse preferentially expressed antigen of melanoma positivity, and significant loss of p16 expression (64.3% in SM/MSF vs 9.5% in ASTs; P < .0001). Building upon the established melanoma FISH criteria, we optimized a prognostic threshold of &#x2265;2 FISH abnormalities specifically tailored for spitzoid neoplasms. We demonstrated that isolated single chromosomal aberrations (particularly MYB loss) are relatively stable events that are frequent in indolent ASTs, whereas our refined &#x2265;2 threshold yielded 100% sensitivity and 92.5% specificity for predicting regional lymph node metastasis/local recurrence. Molecularly, NGS identified mutually exclusive initiating driver alterations (comprising kinase fusions and HRAS mutations) in 89.9% of true Spitz neoplasms, a remarkably high prevalence suggesting a distinct genetic background in Asian populations. We also characterized 5 entirely novel kinase fusions (ZNF24::ROS1, PCBP1::ROS1, NUMA1::RET, CBWD1::ALK, and TPR::NTRK1). Furthermore, NGS definitively segregated true Spitz neoplasms from morphological mimics (MSF), which lacked fusions and were driven by canonical genomic alterations of the conventional melanoma pathway. Integrating these genomic landscapes validated a stepwise progression model. Although isolated kinase fusions drove indolent ASTs, malignant SM invariably harbored concurrent pathogenic secondary alterations, demonstrating a profound reliance on CDKN2A/B, TP53, and CDK4 aberrations. Ultimately, we propose an integrated diagnostic algorithm combining morphological evaluation, the refined FISH threshold, and comprehensive NGS profiling, providing a precise, evidence-based framework for pathway classification and clinical management of spitzoid neoplasms.

fluorescence in situ hybridization↗

Growth modeling of human mandibles using non-Euclidean metrics.

From a set of 31 three-dimensional computed tomography (CT) scans we model the temporal shape and size of the human mandible for analysis, simulation, and prediction purposes. Each anatomical structure is represented using 14851 semi-landmarks, and mapped into Procrustes tangent space. Exploratory subspace analyses are performed leading to linear models of mandible shape evolution in Procrustes space. The traditional variance analysis results in a one-dimensional growth model. However, working in a non-Euclidean metric results in a multimodal model with uncorrelated modes of biological variation related to independent component analysis. The applied non-Euclidean metric is governed by the correlation structure of the estimated noise in the data. The generative models are compared, and evaluated on the basis of a cross validation study. The new non-Euclidean analysis is completely data driven. It not only gives comparable results w.r.t. previous studies of the mean modeling error, but seems to better correlate to growth, and in addition provides the data analyst with alternative hypothesis of plausible shape evolution; hence aiding in the understanding of cranio-facial growth.

Child↗

Anti-tumor necrosis factor therapy in sepsis: update on clinical trials and lessons learned.

OBJECTIVE: Tumor necrosis factor (TNF) is an important mediator involved in the pathogenesis of sepsis. We review clinical studies investigating the efficacy of anti-TNF therapy in decreasing mortality rates in septic patients. DATA SOURCES: We conducted a computerized bibliographic search of randomized, clinical, multicenter trials studying the effects of anti-TNF therapy in the treatment of sepsis. We included all primary studies, reviewed all published meta-analyses, and contacted primary investigators of multicenter trials where necessary. DATA SYNTHESIS: Almost all randomized studies targeting TNF during sepsis show a small, albeit nonsignificant, benefit in decreasing mortality. Strategies using monoclonal antibodies are more effective than are strategies using TNF receptor proteins. Analysis of randomized multicenter trials shows a small but significant benefit with anti-TNF therapeutic strategies. Furthermore, a recent study in 2634 septic patients using a murine anti-TNF antibody shows a 3.6% significant benefit in reducing mortality. CONCLUSIONS: Anti-TNF strategies are only partially effective in patients with sepsis. Although individual studies show small, nonsignificant benefits, analysis of all trial data as well as data from a recent trial in a large population of septic patients show that anti-TNF strategies may confer a small survival benefit. Better characterization of patients and a more multimodal approach by concomitantly targeting other mediators involved in sepsis may be helpful in enlarging the clinical benefit of anti-TNF therapy.

Antibodies, Monoclonal↗