bluuebunny/crossref_metadata_2025_split huggingface dataset:
TEL-AML1 promotes development of specific hematopoietic lineages consistent with preleukemic activity
Authors: Morrow Michelle , Horton Sarah , Kioussis Dimitris , Brady Hugh J. M. , Williams Owen 
Published: January 2004

Abstract
The t(12;21)(p13;q22) translocation is the most common chromosomal abnormality yet identified in any pediatric leukemia and gives rise to the TEL-AML1 fusion product. To investigate the effects of TEL-AML1 on hematopoiesis, fetal liver hematopoietic progenitor cells (HPCs) were transduced with retroviral vectors expressing this fusion protein. We show that TEL-AML1 dramatically alters differentiation of HPCs in vitro, preferentially promoting B-lymphocyte development, enhancing self-renewal of B-cell precursors, and leading to the establishment of long-term growth factor–dependent pre–B-cell lines. However, it had no effect on myeloid development in vitro. Further experiments were performed to determine whether TEL-AML1 also demonstrates lineage-specific activity in vivo. TEL-AML1–expressing HPCs displayed a competitive advantage in reconstituting both B-cell and myeloid lineages in vivo but had no effect on reconstitution of the T-cell lineage. Despite promoting these alterations in hematopoiesis, TEL-AML1 did not induce leukemia in transplanted mice. Our study provides a unique insight into the role of TEL-AML1 in leukemia predisposition and a potential model to study the mechanism of leukemogenesis associated with this fusion.
Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia
Authors: Smith B. Douglas , Levis Mark , Beran Miloslav , Giles Francis , Kantarjian Hagop , Berg Karin , Murphy Kathleen M. , Dauses Tianna , Allebach Jeffrey , Small Donald 
Published: January 2004

Abstract
Activating mutations of FMS-like tyrosine kinase 3 (FLT3) are present in approximately 30% of patients with de novo acute myeloid leukemia (AML) and are associated with lower cure rates from standard chemotherapy-based treatment. Targeting the mutation by inhibiting the tyrosine kinase activity of FLT3 is cytotoxic to cell lines and primary AML cells harboring FLT3 mutations. Successful FLT3 inhibition can also improve survival in mouse models of FLT3-activated leukemia. CEP-701 is an orally available, novel, receptor tyrosine kinase inhibitor that selectively inhibits FLT3 autophosphorylation. We undertook a phase 1/2 trial to determine the in vivo hematologic effects of single-agent CEP-701 as salvage treatment for patients with refractory, relapsed, or poor-risk AML expressing FLT3-activating mutations. Fourteen heavily pretreated AML patients were treated with CEP-701 at an initial dose of 60 mg orally twice daily. CEP-701–related toxicities were minimal. Five patients had clinical evidence of biologic activity and measurable clinical response, including significant reductions in bone marrow and peripheral blood blasts. Laboratory data confirmed that clinical responses correlated with sustained FLT3 inhibition to CEP-701. Our results show that FLT3 inhibition is associated with clinical activity in AML patients harboring FLT3-activating mutations and indicate that CEP-701 holds promise as a novel, molecularly targeted therapy for this disease.
Occult hypoperfusion is associated with increased mortality in hemodynamically stable, high-risk, surgical patients
Authors: Meregalli André , Oliveira Roselaine P , Friedman Gilberto 
Published: January 2004

Abstract
Background
Our aim was to examine whether serial blood lactate levels could be used as predictors of outcome.

Methods
We prospectively studied 44 high-risk, hemodynamically stable, surgical patients. Blood lactate values, mean arterial pressure, heart rate and urine output were obtained at patient admission to the study, at 12, 24 and 48 hours.

Results
The nonsurvivors (n = 7) had similar blood lactate levels initially (3.1 ± 2.3 mmol/l versus 2.2 ± 1.0 mmol/l, P = not significant [NS]), but had higher levels after 12 hours (2.9 ± 1.7 mmol/l versus 1.6 ± 0.9 mmol/l, P = 0.012), after 24 hours (2.1 ± 0.6 mmol/l versus 1.5 ± 0.7 mmol/l, P = NS) and after 48 hours (2.7 ± 1.8 mmol/l versus 1.9 ± 1.4 mmol/l, P = NS) as compared with the survivors (n = 37). Arterial bicarbonate concentrations increased significantly in survivors and were higher than in nonsurvivors after 24 hours (22.9 ± 5.2 mEq/l versus 16.7 ± 3.9 mEq/l, P = 0.01) and after 48 hours (23.1 ± 4.1 mEq/l versus 17.6 ± 7.1 mEq/l, P = NS). The PaO2/FiO2 ratio was higher in survivors initially (334 ± 121 mmHg versus 241 ± 133 mmHg, P = 0.03) and remained elevated for 48 hours. There were no significant differences in mean arterial pressure, heart rate, and arterial blood oxygenation at any time between survivors and nonsurvivors. The intensive care unit stay (40 ± 42 hours versus 142 ± 143 hours, P < 0.001) and the hospital stay (12 ± 11 days versus 24 ± 17 days, P = 0.022) were longer for nonsurvivors than for survivors. The Simplified Acute Physiology Score II score was higher for nonsurvivors than for survivors (34 ± 9 versus 25 ± 14, P = NS). The urine output was slightly lower in the nonsurvivor group (P = NS). The areas under the receiving operating characteristic curves were larger for initial values of Simplified Acute Physiology Score II and blood lactate for predicting death.

Conclusion
Elevated blood lactate levels are associated with a higher mortality rate and postoperative complications in hemodynamically stable surgical patients.
Regulation of TLR signaling and inflammation by SOCS family proteins
Authors: Yoshimura Akihiko , Ohishi Hiroyuki Mori Masanobu , Aki Daisuke , Hanada Toshikatsu 
Published: January 2004

AbstractImmune and inflammatory systems are controlled by multiple cytokines, including interleukins and interferons. These cytokines exert their biological functions through Janus tyrosine kinases and signal transducer and activator of transcription factors. The cytokine-inducible Src homology 2 protein (CIS) and suppressors of cytokine signaling (SOCS) are a family of intracellular proteins, several of which have emerged as key physiological regulators of cytokine responses, including those that regulate the inflammatory systems. In this short review, we focused on the molecular mechanism of the action of CIS/SOCS family proteins and their roles in Toll-like receptor signal regulation and inflammatory diseases.
The mast cell: an antenna of the microenvironment that directs the immune response
Authors: Frossi Barbara , De Carli Marco , Pucillo Carlo 
Published: January 2004

AbstractMast cells (MCs) have long been considered as critical effector cells during immunoglobulin (Ig)E-mediated allergic disease and immune response to parasites. Recent studies, however, suggest that this understanding of MC function is incomplete and does not consider the complex roles that MCs play in adaptive and innate immunity. The added function gives an innovative vision of regulation of immune responses and the development of autoimmune diseases. It had been assumed that the aggregation of Fc ɛ receptor I with IgE and specific antigen is the main stimulus able to induce the MC activation, degranulation, release, and generation of mediators of the allergic reaction. However, MCs exhibit an array of molecules involved in cell–cell and cell–extracellular matrix adhesion, mediating delivery of costimulatory signals that empower those cells with an ability to react to multiple nonspecific and specific stimuli. Their tissue distribution and their capability to release many cytokines after stimulation indicate MCs as potential regulatory linkers between innate and acquired immunity. In this review, we will summarize some findings on the roles of MCs in innate and acquired immunity, on the molecular mechanism and signaling pathways, and on selective signals that induce discrete MC response and its ability to polarize adaptive-immune response.
PTX3 function as an opsonin for the dectin-1-dependent internalization of zymosan by macrophages
Authors: Diniz S N , Nomizo R , Cisalpino P S , Teixeira M M , Brown G D , Mantovani A , Gordon S , Reis L F L , Dias A A M 
Published: January 2004

AbstractPentraxin 3 (PTX3) is a tumor necrosis factor and interleukin-1β-stimulated gene that encodes a long PTX with proinflammatory activity. Here, we show that peritoneal macrophages derived from PTX3 transgenic (Tg) mice express higher levels of PTX3 mRNA than macrophages from wild-type (WT) mice, at basal level as well as upon stimulation with zymosan (Zy). Macrophages from Tg mice also showed improved opsonin-independent phagocytosis of Zy particles and the yeast form of the fungus Paracoccidioides brasiliensis. In the case of P. brasiliensis, an enhanced microbicidal activity accompanied by higher production of nitric oxide was also observed in macrophages from Tg mice. Using fluorescein-activated cell sorter analysis and reverse transcriptase-polymerase chain reaction, we demonstrated that basal level of Toll-like receptor-6 and Zy-induced dectin-1 expression was slightly but consistently higher in macrophages from Tg mice than in macrophages from WT mice. Recombinant (r)PTX3 protein binds to Zy particles as well as to yeast cells of P. brasiliensis and addition of rPTX3, to a culture of WT-derived macrophages containing Zy leads to an increase in the phagocytic index, which parallels that of Tg-derived macrophages, demonstrating the opsonin-like activity of PTX3. It is important that blockade of dectin-1 receptor inhibited the phagocytosis of Zy particles by WT and PTX3 Tg macrophages, pointing out the relevant role of dectin-1 as the main receptor involved in Zy uptake. Our results provide evidence for a role of PTX3 as an important component of the innate-immune response and as part of the host mechanisms that control fungal recognition and phagocytosis.
Leukocyte fluid shear response in the presence of glucocorticoid
Authors: Fukuda Shunichi , Mitsuoka Hiroshi , Schmid-Schönbein Geert W 
Published: January 2004

AbstractLeukocytes respond to physiological fluid shear stress (∼1.5 dyn/cm2) by cytoplasmic reorganization. The cytoplasm is also influenced, however, by glucocorticoids. In this study, we explore how glucocorticoids may affect the leukocyte fluid shear response. Normal leukocytes, exposed to fluid shear in vitro during active migration, retract pseudopods accompanied by modestly decreasing intracellular calcium ions. In contrast, dexamethasone (DX)-treated leukocytes project pseudopods after shear exposure with a significant rise in intracellular calcium ions, an effect that can be blocked by voltage-dependent calcium channel blockers. Although a cyclic adenine monophosphate analog blocks calcium influx and pseudopod projection by DX, inhibition of A-kinase induces reversal of the shear response, as seen with DX treatment. DX also reverses the leukocyte shear response in vivo in the rat circulation. Leukocytes that adhere to the endothelium in postcapillary venules of control rats return into the circulation only after pseudopod retraction, and in DX-treated rats, adherent leukocytes return into the circulation still with projecting pseudopods. The fraction of circulating leukocytes with pseudopods in DX-treated rats is higher than in controls. Thus, the reversal of leukocyte shear response by glucocorticoids may contribute to an enhanced incidence of circulating leukocytes with pseudopods, a process that affects the kinetics of these cells in the microcirculation.
Controlling the Toll road to dendritic cell polarization
Authors: Mazzoni Alessandra , Segal David M 
Published: January 2004

AbstractThe activation of dendritic cells (DC) via Toll-like receptors (TLRs) plays a decisive role in shaping the outcome of primary immune responses. Following TLR engagement by microbial products, DC migrate from peripheral tissues to lymphoid organs and up-regulate major histocompatibility complex and costimulatory molecules, acquiring the unique capacity to prime pathogen-specific, naïve T cells. In addition, DC determine the character of the ensuing immune response by secreting cytokines that drive the development of T cells into T helper cell type 1 (Th1), Th2, or T regulatory effector cells. Three major factors influence the pattern of cytokines released by DC and accordingly, the Th balance: the lineage to which DC belong; the maturation stimulus; and inflammatory mediators present at the site of infection. A major focus of this review is the capacity of DC to integrate these factors and elicit distinct classes of immune responses.
Physiology of the Eyelid Motor System
Authors: DELGADO‐GARCÍA JOSÉ M. , GRUART AGNÈS , TRIGO JOSÉ A. 
Published: January 2004

AbstractThe eyelid motor system represents an excellent experimental model for the study of reflex and learned motor responses. Eyelid responses can be recorded quantitatively with the search coil in a magnetic‐field technique. Stimuli able to evoke reflex blinks (air puffs, flashes of light, tones) can also be controlled quantitatively. Eyelid movements can be classified as spontaneous, passive (such as those following eye saccades), reflex, and acquired with classical conditioning procedures. Information is available regarding the firing activity of brainstem motoneuronal pools (abducens, accessory abducens, and facial motoneurons) involved in these types of eyelid response. In particular, facial motoneurons present different encoding properties for the generation of reflex against learned eyelid responses. In cats, accessory abducens motoneurons are involved only in reflex (but not in learned) blinks. The recent description of the complete organization of premotoneuronal pathways related to eyelid motorics opens new experimental possibilities for the study of this particular motor system.
Development of the Optokinetic Response in Macaques
Authors: DISTLER C. , HOFFMANN K.‐P. 
Published: January 2004

AbstractIn macaque monkeys, an optokinetic response (OKR) can be elicited monocularly both in temporonasal and, albeit weaker, in nasotemporal direction very early after birth. The further maturation of equal strengths of OKR in both directions depends on stimulus velocity: at low‐stimulus velocities (10‐20°/s) symmetry is reached at 3‐4 weeks of age, at higher‐stimulus velocities (40‐80°/s) it is reached only at 4‐5 months of age. Retinal slip neurons in the NOT‐DTN are direction selective for ipsiversive stimulus movement shortly after birth. Most of these neurons receive input from both eyes; many are dominated by the contralateral eye. Electrophysiological and neuroanatomical evidence suggests that the cortical input to the NOT‐DTN starts to become functional by postnatal day 14, at the latest. Based on these behavioral and physiological data, as well as on comparison with data from kittens and human infants, we hypothesize that the very early monocularly elicited bidirectional optokinetic response is due to the direct retinal input from both eyes to the NOT‐DTN. As the cortical projection matures, it gains more and more influence upon the response properties of retinal slip neurons in the NOT‐DTN, and the retinal influence gradually decreases.
GABAergic Neurons in the Rostral Mesencephalon of the Macaque Monkey That Control Vertical Eye Movements
Authors: HORN ANJA K.E. , HELMCHEN CHRISTOPH , WAHLE PETRA 
Published: January 2004

AbstractThe mesencephalic reticular formation is important for the generation of vertical eye movements, but up until now the location of inhibitory premotor neurons is not known in primates. With tract‐tracer methods combined with immunocytochemistry or in situ hybridization, we investigated the location of GABAergic premotor neurons in the rostral interstitial nucleus of the medial longitudinal fascicle (riMLF) and interstitial nucleus of Cajal (iC) in macaque monkeys. In the present work, only the premotor pathways of the downward pulling eye muscles, superior oblique (SO) and inferior rectus (IR), were studied. We found that very few, small GABAergic neurons are present in the riMLF, and none of them was found to project to the oculomotor nuclei, suggesting the presence of exclusively excitatory projections from the riMLF to the oculomotor neurons. However, in the iC, medium‐sized and large GABAergic neurons were identified projecting contralaterally to the SO and IR motoneurons, and presumably the iC of the other side. These commissural GABAergic projections are well suited to inhibit the SO and IR motoneurons and possibly premotor down‐burst‐tonic neurons during upward eye movements.
Shared Brainstem Pathways for Saccades and Smooth‐Pursuit Eye Movements
Authors: KELLER EDWARD L. , MISSAL MARCUS 
Published: January 2004

AbstractA long‐standing belief holds that the saccadic and smooth‐pursuit eye movement systems are composed of largely separate premotor circuits, at least in the brainstem. One crucial prediction predicated on this belief is that the tonic discharge of omnipause neurons (OPNs), which are thought to be part of only the saccadic system, should not be modulated during pursuit eye movements. This report shows that the discharge of OPNs, in contradiction, is modulated downward during pursuit movements. In contrast to their behavior during saccades, where they pause completely for the duration of the movement, the downward modulation during pursuit did not totally silence OPNs. The depth of the downward modulation was correlated with the speed of the ongoing pursuit movement. Another type of cell, which we have named saccade/pursuit neurons, was recorded in the paramedian pontine reticular formation near the location of OPNs. This subpopulation of burst cells discharged a cascade of spikes for saccades in a preferred direction. They also displayed a lower‐frequency sustained discharge of spikes for the duration of pursuit in the same preferred direction. These data suggest a new type of combined model for the organization of the brainstem saccade/pursuit system. In this new combined model, the OPNs form a common inhibitory mechanism for both types of movements, and the saccade/pursuit neurons participate in the eye‐velocity modulation of OPN discharge or membrane polarization during either type of movement.
Mathematical Model Predicts Clinical Ocular Motor Syndromes
Authors: DIETERICH MARIANNE , GLASAUER STEFAN , BRANDT THOMAS 
Published: January 2004

AbstractClinical ocular motor syndromes were compared with ocular motor syndromes simulated by a mathematical model of the vestibuloocular reflex. The mathematical sensorimotor feedforward model of otolith control of three‐dimensional binocular eye position is based on relevant anatomical connections of the vestibuloocular reflex from the utricles to extraocular eye muscles. This is the first attempt to simulate static ocular motor syndromes for unilateral utricular or vestibular nerve failure, lesions of the vestibular nucleus, and lesions of the ascending vestibuloocular reflex pathways. Comparison of the predicted syndromes with those found in patients with unilateral disorders of the vestibular nerve (herpes zoster neuritis), the vestibular nucleus (medullary infarction), and the medial longitudinal fasciculus (pontine infarction) showed good agreement as regards the direction of horizontal, vertical, and torsional eye deviations. The ability of the model to simulate complete or incomplete failures of single elements or entire pathways allows us to pose direct clinical questions about as yet unknown ocular motor syndromes or about the localization of the damage as well as the mechanism involved in syndromes already known.
Examining the Paradoxical Relation between Number of Spikes and Gaze Amplitude in Abducens Neurons
Authors: LING L. , PHILLIPS J. O. , SIEBOLD C. 
Published: January 2004

AbstractDuring head‐unrestrained gaze shifts, the number of spikes in the burst of abducens neurons increases with gaze amplitude, even when corrected for the component of the discharge related to the change in eye position. We examine this paradoxical dissociation between the number of spikes and eye amplitude, which occurs because eye amplitude in the head saturates for larger gaze shifts. First, we show that the extra spikes are unlikely to be due to antagonist muscle loading because the abducens neurons are completely silent during large gaze shifts when the muscle acts as an antagonist. Next, we divide the firing rate profile of abducens neurons into terms that represent signals related to eye position, velocity, and acceleration; a d.c. offset term specifying the firing associated with straight‐ahead gaze; and a slide term, which compensates for the zero of the oculomotor plant. Then we examine the contribution of each term to the number of spikes recorded. A comparison of the number of spikes with the integral of the fitted function, combining all of the terms, for the duration of the burst reveals that the simulation captures much of the actual data. However, even a model with a slide term cannot reproduce the nonlinear relationship of the number of spikes with amplitude that characterizes large gaze shifts.
Signal Processing of Semicircular Canal and Otolith Signals in the Vestibular Nuclei during Passive and Active Head Movements
Authors: McCREA ROBERT A. , LUAN HONGGE 
Published: January 2004

AbstractThe vestibular nerve sends signals to the brain that code the movement and position of the head in space. These signals are used by the brain for a variety of functions, including the control of reflex and voluntary movements and the construction of a sense of self‐motion. If many of these functions are to be carried out, a distinction must be made between sensory vestibular signals related to active head movements and those related to passive head movements. Current evidence is that the distinction occurs at an early stage of sensory processing in the brain, and the results are evident in the firing behavior of neurons in the vestibular nuclei that receive direct inputs from the vestibular nerve. Several specific examples of how sensory information related to passive and active head movements is transformed in the vestibular nuclei are discussed.
Role of the Dorsolateral Pontine Nucleus in Visual‐Vestibular Behavior
Authors: MUSTARI MICHAEL J. , ONO SEIJI , DAS VALLABH E. , TUSA RONALD J. 
Published: January 2004

AbstractVisual‐vestibular behavior depends on signals traveling in climbing and mossy fiber pathways. Our study examined the role of the dorsolateral pontine nucleus (DLPN), a major component of the cortico‐ponto‐cerebellar mossy fiber pathway. DLPN neurons discharge in relation to smooth pursuit and during visual stimulation, indicating a potential role in visually guided motor learning in the vestibulo‐ocular reflex (VOR). We used unilateral muscimol injections to determine the potential role of the DLPN in short‐term VOR gain adaptation. Preinjection adaptation of VOR gain was achieved by sinusoidal rotation (0.2 Hz, 30°/s) for 2 h while the monkey viewed a stationary visual surround through either magnifying (×2) or minifying (×0.5) lenses. VOR gain increases (23‐32%) or decreases (22‐48%) as measured in complete darkness (VORd) were achieved. Following DLPN inactivation, initial acceleration of ipsilateral smooth‐pursuit was reduced by 35‐68%, and steady state gain was reduced by 32‐61%. Furthermore, the monkey's ability to cancel the VOR was impaired. In contrast to these significant deficits in ipsilesional smooth pursuit, the VOR during lens viewing was similar to that measured in preinjection control experiments. Similarly, following 2 h of adaptation, VORd gain adaptation was indistinguishable from control adaptation values for either ipsilesional or contralesional directions of head rotation. Our results suggest that visual error signals for short‐term adaptation of the VOR are derived from sources other than the DLPN, such as those from the accessory optic system.