bluuebunny/crossref_metadata_2025_split huggingface dataset:
Developmental expression of N‐methyl‐D‐aspartate glutamate receptor 1 splice variants in the chick retina
Authors: Lee‐Rivera I. , Zarain‐Herzberg A. , López‐Colomé A.M. 
Published: July 2003

AbstractGlutamate is the major excitatory neurotransmitter in the vertebrate retina. The N‐methyl‐D‐aspartate glutamate receptor (NMDAR) is assembled as a tetramer containing NR1 and NR2, and possibly NR3 subunits, NR1 being essential for the formation of the ion channel. The NMDAR1 (NR1) gene encodes for mRNAs that generate at least eight functional variants by alternative splicing of exon 5 (cassette N1), 21 (cassette C1), or 22 (cassettes C2 or C2′). NR1 splice variants were identified in the mature chick retina, and their variation during embryonic development (ED) was analyzed. NR1 was shown to lack N1 in early ED, shifting to N1‐containing variants in the mature retina, which could contribute to explaining the distinct biochemical properties of retinal NMDARs compared with the CNS. Sequence analysis of C‐terminal variants containing C1 and C2 cassettes suggests a membrane‐targeting mechanism for avian NMDARs distinct from that in mammals. An NR1 variant containing a novel alternative C‐terminal splice exon named C3 was found, which encodes six amino acids containing a predicted casein kinase II phosphorylation site. This new variant is expressed in the retina during a restricted period of ED, coincident with the generation of spontaneous calcium activity waves, which precedes synapse formation in the retina, suggesting its participation in this process. © 2003 Wiley‐Liss, Inc.
γ‐Aminobutyric acid‐synthesizing cells in the retina of the chameleon Chamaeleo chameleon
Authors: Bennis M. , Versaux‐Botteri C. , Repérant J. , Armengol J.A. , Ward R. 
Published: July 2003

AbstractAntibodies directed against γ‐aminobutyric acid (GABA) and L‐glutamic acid decarboxylases 65 and 67 kDa (GAD65 and ‐67) were used to study the GABAergic cell populations of the chameleon retina. GABA immunoreactivity was found in the two main types of retinal interneurons, amacrine and horizontal cells. Amacrine, displaced amacrine, and intra‐ and interplexiform cells displayed the strongest GABA immunoreactivity of all the retinal cell types. Horizontal cells formed a continuous GABA‐immunoreactive cell layer lying against the outermost portion of the inner nuclear layer. In contrast to previous studies (Quesada et al. [1996] Cell Biol. Int. 20:395–400; [1999] Eur. J. Anat. 3:13–25), the present results demonstrate that the horizontal cells of the chameleon retina are GABA immunoreactive and that a subpopulation of these is immunolabelled by an antibody against GAD65. These results indicate that GABAergic synaptic transmission plays a key role in the outer plexiform layer of the vertebrate retina. © 2003 Wiley‐Liss, Inc.
Transforming growth factor‐β and tumor necrosis factor‐α cooperate to induce apoptosis in the oligodendroglial cell line OLI‐neu
Authors: Schuster Norbert , Bender Herdis , Rössler Oliver G. , Philippi Anja , Dünker Nicole , Thiel Gerald , Krieglstein Kerstin 
Published: July 2003

AbstractAs shown previously, transforming growth factor‐β (TGF‐β) plays an important role during the period of developmental cell death in the nervous system. As with neurons, oligodendrocytes are generated in excess and eliminated by apoptosis. The present study was aimed at investigating the possible interaction of TGF‐β with tumor necrosis factor‐α (TNF‐α) in the regulation of cell death in oligodendroglial precursor cells and analyzing the underlying signaling mechanisms. We show that both factors induce apoptosis independently, but cooperate when applied together. The investigation of the signaling events revealed an important role of the JNK pathway during induction of apoptosis. TGF‐β seemed to be more efficient at inducing a release in cytochrome c from mitochondria than TNF‐α. This might be the consequence of decreased Bcl‐xL levels observed in cells treated with TGF‐β but not with TNF‐α. Both factors stimulated caspase‐3 activity, which could be inhibited by caspase‐8 or caspase‐9 inhibitors. Therefore, we conclude that TNF‐α and TGF‐β affect partially common pathways but also regulate different steps in the apoptotic cascade. © 2003 Wiley‐Liss, Inc.
Olanzapine protects PC12 cells from oxidative stress induced by hydrogen peroxide
Authors: Wei Zelan , Bai Ou , Richardson J. Steven , Mousseau Darrell D. , Li Xin‐Min 
Published: July 2003

AbstractNeuroanatomical studies suggest that neuronal atrophy and destruction occur over the course of many years in neurodegenerative conditions such as schizophrenia and Alzheimer's disease. In schizophrenia, early intervention with atypical neuroleptics such as olanzapine has been shown to prevent development of some of the more serious and debilitating symptoms in many patients. The mechanisms whereby olanzapine slows or prevents symptom progression in schizophrenia remain unclear. A previous study found that olanzapine increased mRNA for the copper/zinc isoform of the superoxide dismutase enzyme (SOD‐1). We investigated the effects of olanzapine in PC12 cells exposed to hydrogen peroxide. We measured cell viability, observed evidence of necrosis and apoptosis, checked the SOD‐1 mRNA by Northern blot analyses, and determined SOD‐1 enzyme activity. We found that: 1) the decrease in cell viability induced by hydrogen peroxide was attenuated in PC12 cells pretreated with olanzapine; 2) olanzapine increased SOD enzyme activity in PC12 cells; 3) inhibiting SOD activity with diethyldithiocarbamic acid prevented the cytoprotective actions of olanzapine; and 4) the decrease in SOD‐1 mRNA level induced by hydrogen peroxide was blocked by pretreatment with olanzapine. These data indicate that the neuroprotective action of olanzapine includes the upregulation of SOD. © 2003 Wiley‐Liss, Inc.
Caspase‐independent cell death by low concentrations of nitric oxide in PC12 cells: Involvement of cytochrome C oxidase inhibition and the production of reactive oxygen species in mitochondria
Authors: Yuyama Kohei , Yamamoto Hideko , Nishizaki Itone , Kato Takeshi , Sora Ichiro , Yamamoto Toshifumi 
Published: July 2003

AbstractWe reported previously that low levels of nitric oxide (NO) induced cell death with properties of apoptosis, including chromatin fragmentation and condensation in undifferentiated PC12 pheochromocytoma cells. The present study demonstrates that cytotoxicity of low concentrations of NO is mediated by inhibition of mitochondrial cytochrome c oxidase and generation of reactive oxygen species (ROS). An NO donor, (±)‐(E)‐4‐ethyl‐2‐[(E)‐hydroxyimino]‐5‐nitro‐3‐hexenamide (NOR3) induced cell death even at low concentrations (10–100 μM), whereas peroxynitrite and a peroxynitrite generator, 3‐(4‐morpholinyl)‐sydnonimine (SIN‐1), did not have a significant effect on cell viability up to a concentration of 0.5 mM. The NOR3‐induced cell death was unaffected by pretreatment with superoxide dismutase (SOD) or its mimetic peroxynitrite scavenger, manganese(III) tetrakis(benzoic acid)porphyrin chloride (Mn‐TBAP), or with uric acid. These findings indicate that peroxynitrite does not contribute to this cell death. Furthermore, neither the release of cytochrome c from mitochondrial membranes, the cleavage of poly‐ADP ribose polymerase (PARP), nor the activation of caspase‐3‐like activities was observed. Inhibitors of PARP, benzamide, and aminobenzamide, had no effect on the NOR3‐induced cell death. In addition, pretreatment with general or selective caspase inhibitors, benzyloxy‐carbonyl‐Val‐Ala‐Asp‐fluoromethylketone (Z‐VAD‐fmk), N‐acetyl‐Asp‐Glu‐Val‐Asp‐aldehyde (Ac‐DEVD‐CHO), and benzyloxycarbonyl‐Asp‐2,6‐dichlorobenzoyloxymethylketone (Z‐Asp‐Ch2‐DCB) did not prevent NOR3‐induced cell death. Taken together, these findings suggest that cell death induced by NOR3 occurs by a caspase‐independent mechanism. In contrast, we found an early increase in mitochondrial H2O2 production during NOR3 exposure using the fluorescent dye 2′,7′‐dichlorofluorescin‐diacetate (DCFH‐DA) and dihydrorohdamine123 (DHR123), and these events were accompanied by strong inhibition of cytochrome c oxidase activity in the cells. Furthermore, we observed that several antioxidants, such as ascorbate, glutathione (GSH), cysteine, tetrahydrobiopterin, and dithiothreitol (DTT), all effectively prevented the NOR3‐induced cell death. NOR3 treatment decreased the level of total intracellular GSH, but did not affect the activities of antioxidant enzymes SOD, GSH‐peroxidase (GPX), and catalase. These results suggest that cell death induced at physiologically low concentrations of NO is mediated by ROS production in mitochondria, most likely resulting from the inhibition of cytochrome c oxidase, with ROS acting as an initiator of caspase‐independent cell death. © 2003 Wiley‐Liss, Inc.
Enhanced neurogenesis following stroke
Authors: Felling Ryan J. , Levison Steven W. 
Published: July 2003

AbstractEach year hundreds of thousands of people must cope with the severe neurological consequences of a stroke. Current therapeutic strategies for stroke focus on acute treatment and neuroprotection. Unfortunately, these practices do little to reduce the long‐term morbidity associated with the injury. To develop effective therapies that promote regeneration, we must have an understanding of the cellular and molecular events involved in the recovery from an insult. Neural stem and progenitor cells are likely to be affected during this period. Here we review how the proliferation, migration, and maturation of these precursors are affected by ischemia. Furthermore, we summarize data available on the underlying mechanisms and the therapeutic implications of these studies. The studies that we review provide compelling evidence that neural precursors resident in the brain initiate a compensatory response to stroke that results in the production of new neurons. Moreover, administration of growth factors can enhance this compensatory response. Based on these encouraging results, we may eventually be able to manipulate these precursors to improve recovery of function in individuals afflicted by this devastating injury. © 2003 Wiley‐Liss, Inc.
Citicoline decreases phospholipase A2 stimulation and hydroxyl radical generation in transient cerebral ischemia
Authors: Adibhatla Rao Muralikrishna , Hatcher James F. 
Published: July 2003

AbstractNeuroprotection by citicoline (CDP‐choline) in transient cerebral ischemia has been demonstrated previously. Citicoline has undergone several Phase III clinical trials for stroke, and is being evaluated for treatment of Alzheimer's and Parkinson's diseases. Phospholipid degradation and generation of reactive oxygen species (ROS) are major factors causing neuronal injury in CNS trauma and neurodegenerative diseases. Oxidative metabolism of arachidonic acid (released by the action of phospholipases) contributes to ROS generation. We examined the effect of citicoline on phospholipase A2 (PLA2) activity in relation to the attenuation of hydroxyl radical (OH·) generation after transient forebrain ischemia of gerbil. PLA2 activity (requires mM Ca2+) increased significantly (P < 0.05) in both membrane (50.2 ± 2.2 pmol/min/mg protein compared to sham 35.9 ± 3.2) and mitochondrial fractions (77.0 ± 1.2 pmol/min/mg protein compared to sham 33.9 ± 1.2) after cerebral ischemia and 2 hr reperfusion in gerbil, which was significantly attenuated (P < 0.01) by citicoline (membrane, 39.9. ± 2.2 and mitochondria, 41.9 ± 3.2 pmol/min/mg protein). In vitro, citicoline and its components cytidine and choline had no effect on PLA2 activity, and thus citicoline as such is not a PLA2 inhibitor. Ischemia/reperfusion resulted in significant OH· generation (P < 0.01) and citicoline significantly (P < 0.01) attenuated their formation (expressed as 2,3‐dihydroxybenzoic acid/salicylate ratio; ischemia/24 hr reperfusion, 6.30 ± 0.23; sham, 2.56 ± 0.27; ischemia/24 hr reperfusion + citicoline, 4.85 ± 0.35). These results suggest that citicoline affects PLA2 stimulation and decreases OH· generation after transient cerebral ischemia. © 2003 Wiley‐Liss, Inc.
Coexpression of functional P2X and P2Y nucleotide receptors in single cerebellar granule cells
Authors: Hervás Cristina , Pérez‐Sen Raquel , Miras‐Portugal Ma Teresa 
Published: July 2003

AbstractThe present study describes the presence and expression of functional nucleotide receptors, both ionotropic and metabotropic, in highly purified cultures of cerebellar granule neurons. Microfluorimetric experiments have been carried out to record specific [Ca2+]itransients in individual granule neurons after challenge with diverse nucleotides. Although great heterogeneity was found in nucleotide responses in single cells, these responses all became modified during the course of granule cell differentiation, not only at the level of the number of responding cells, but also in the magnitude of the response to nucleotides. These in vitro developmental changes were more significant in metabotropic responses to pyrimidine nucleotides, UTP and UDP, which were down‐ and upregulated, respectively, during the time in culture. At least two types of ADP‐specific receptors seem expressed in different granule cell subpopulations responding to 2MeSADP, as the specific P2Y1antagonist MRS‐2179 inhibited Ca2+responses in only one of these populations. The great diversity of metabotropic responses observed was confirmed by the RT‐PCR expression of different types of P2Y receptors in granule cell cultures: P2Y1, P2Y4, P2Y6, and P2Y12. Similarly, ionotropic nucleotide responses were confirmed by the presence of specific messengers for different P2X subunits, and by immunolabeling studies (P2X1, P2X2, P2X3, P2X4and P2X7). Immunolabeling reflected great variety in the P2X subunit distribution along the granule neuron cytoarchitecture, with P2X2, P2X3and P2X4present at somatodendritic locations, and P2X1, P2X7, and P2X3, located at the axodendritic prolongations. The punctuated labeling pattern obtained for P2X3and P2X7subunits is particularly notable, as it presents a high degree of colocalization with synaptophysin, a specific marker of synaptic vesicles, suggesting specialized localization and function in granule neurons. © 2003 Wiley‐Liss, Inc.
Tracking superparamagnetic iron oxide labeled monocytes in brain by high‐field magnetic resonance imaging
Authors: Zelivyanskaya Marina L. , Nelson Jay A. , Poluektova Larissa , Uberti Mariano , Mellon Melissa , Gendelman Howard E. , Boska Michael D. 
Published: July 2003

AbstractInflammatory cells, most notably mononuclear phagocytes (MP; macrophages and microglia), play a critical role in brain homeostasis, repair and disease. One important event in cellular biodynamics is how MP move in and throughout the nervous system. Prior studies have focused principally on cell migration across the blood–brain barrier during neuroinflammatory processes with little work done on cell movement within the brain. During the past decade our laboratories have studied the role of MP in HIV‐1‐associated dementia (HAD). In HAD MP incite sustained glial inflammatory reactions causing significant neuronal damage. To extend these works we investigated cell movement in brain and its influence for disease in a novel co‐registration system integrating neuropathology with high‐field magnetic resonance imaging (MRI). Human monocytes labeled with superparamagnetic iron oxide particles were injected into the brain of severe combined immunodeficient (SCID) mice. MRI was recorded 1, 7, and 14 days after cell injection. MRI co‐registered with histology verified that the MRI signal modification was due to the labeled cells. MRI showed human monocyte‐derived macrophages along the injection site, the corpus callosum, the ventricular system and in other brain sites. These data support the idea that cell migration can be monitored in vivo and provides an opportunity to assess monocyte mobility in brain and its affects on neurodegenerative processes and notably HAD. © 2003 Wiley‐Liss, Inc.
Biology of the basic multicellular unit and the pathophysiology of osteoporosis
Authors: Jilka Robert L. 
Published: July 2003

AbstractBone structural integrity is maintained by removal of old bone by osteoclasts and synthesis of new bone in its place by osteoblasts. This process, called bone remodeling, is accomplished by assembly of osteoclasts and osteoblasts into discrete temporary anatomic structures called basic multicellular units (BMUs). The lifespan of osteoclasts and osteoblasts is short compared to the lifespan of the BMU; therefore, they must be continually replenished for BMU progression to occur. Osteoclasts develop from hematopoeitic progenitors; and osteoblasts are derived from mesenchymal stem cells, also known as marrow stromal fibroblasts. Circulating hormones together with locally produced cytokines and growth factors modulate the replication and differentiation of osteoclast and osteoblast progenitors. The most important locally produced pro‐osteoclastogenic cytokine is receptor activator of NF‐κB (RANK) ligand. It is expressed by stromal/osteoblastic cells, and binds to its receptor (RANK) on osteoclast progenitors to stimulate differentiation. The development of mature osteoblasts is promoted by growth factors released from the bone matrix during resorption, as well as by growth factors produced by osteoblast progenitors themselves. Many of these same locally produced factors and cytokines also govern the lifespan of osteoclasts and osteoblasts by their effects on apoptosis. The orderly genesis and apoptosis of both osteoclasts and osteoblasts is essential for normal bone homeostasis during bone remodeling. Bone loss caused by sex steroid deficiency or glucocorticoid excess is caused by alteration of bone cell production, and by prolonging osteoclast lifespan and shortening osteoblast lifespan. Therapies that prevent or reverse osteoporosis act at least in part by preventing osteoblast apoptosis and/or stimulating osteoclast apoptosis. Med Pediatr Oncol 2003;41:182–185, Published 2003 Wiley‐Liss, Inc.
Cisplatin nephrotoxicity affects magnesium and calcium metabolism
Authors: Goren Marshall P. 
Published: July 2003

AbstractCisplatin is not directly toxic to bone, but cisplatin nephrotoxicity leading to magnesium wasting may affect magnesium and calcium metabolism, both of which contribute to bone integrity. The specificity of the magnesium lesion suggests that cisplatin may have an affinity for proteins that regulate magnesium absorption. Sulfhydryls such as amifostine can reduce the toxicity of cisplatin in adults, but current pediatric data do not indicate a role for sulfhydryl therapy to reduce cisplatin toxicity in children. Med Pediatr Oncol 2003;41:186–189, © 2003 Wiley‐Liss, Inc.
Chronic ifosfamide nephrotoxicity in children
Authors: Skinner R. 
Published: July 2003

AbstractNephrotoxicity is a frequent complication of treatment with ifosfamide in children. Although renal damage may be acute and reversible, chronic toxicity may develop with potentially serious consequences. Chronic nephrotoxicity due to ifosfamide may lead to a wide variety of subclinical and clinical manifestations. Proximal tubular dysfunction is the commonest presentation, and may lead to a Fanconi syndrome, including hypophosphataemic rickets and proximal renal tubular acidosis. Glomerular impairment is also common, whilst distal tubular impairment has been described but is relatively rare. Although full reversibility has been described occasionally, there is no information about the very long‐term outcome of chronic ifosfamide nephrotoxicity. We studied a cohort of 12 children 1 and 10 years after completion of ifosfamide treatment. There was no statistically significant change in either glomerular or tubular toxicity in the group as a whole over this time period. However, marked improvements were seen in some aspects of toxicity in some patients, and deterioration was observed in others. We concluded that considerable nephrotoxicity is still present 10 years after completion of ifosfamide treatment, but that the outcome varies between individual patients. Although several risk factors for the development of chronic nephrotoxicity have been described, total ifosfamide dose, patient age at treatment, previous or concurrent cisplatin treatment, and unilateral nephrectomy are the most important. Nevertheless, it remains difficult to predict the occurrence of this toxicity with confidence. The pathogenesis of ifosfamide nephrotoxicity is poorly understood. There is an urgent need for the development and clinical investigation of nephroprotective strategies. Med Pediatr Oncol 2003;41:190–197, © 2003 Wiley‐Liss, Inc.
Assessment of bone health in children and adolescents with cancer: Promises and pitfalls of current techniques
Authors: Leonard Mary B. 
Published: July 2003

AbstractDuring childhood and adolescence, skeletal development is characterized by gender‐, face‐, and maturation‐specific increases in cortical dimensions and trabecular density. Children with cancer have multiple risk factors for impuired bone mineralization, including delayed growth and maturation, sex hormone deficiencies, decreasal physical activity and biomechanical loading of the skeleton, glucocorticoid and other immunosuppressive therapies, growth hormone deficiency, and malnutrition. This review outlines the expected gains in bone dimensions, mineral content and strength during childhood and adolescence. Varied threats to bone health in the child with cancer are summarized, with special attention to potential effects on bone formation and resorption in the growing skeleton. The strengths and limitations of dual energy x‐ray absorptiometry (DXA) and quantitative computed tomography (QCT) techniques in the assessment of the different disease‐related effects on bone strength are discussed, and alternative analytic approaches explored. Med Pediatr Oncol 2003;41:198–207. © 2003 Wiley‐Liss, Inc.
Radiation‐therapy effects on bone density
Authors: Hopewell John W. 
Published: July 2003

AbstractOnly limited data are available on the effects of radiation‐therapy on the mineral content of the bone of children treated for malignancy. The incidence of osteopenia varies between 8 and 23%, but confounding factors were the use of chemotherapy and the effects of prophylactic cranial irradiation. The factors influencing bone atrophy are no more clearly defined in adults treated for cancer by high dose local radiation‐therapy. Pathological observed in patient tissues, indicates a clear role for vascular changes in the development of osteopenia, although there remains some uncertainty as to the effects of osteoblast cell loss. Reduced blood flow in bone is clearly dose‐related in experimental animal studies and after single doses of >20 Gy changes in bone mineral content have been found. However, this was only at late times (≥30 weeks) after irradiation. The relationship between these changes and bone strength remains unproven because of the limited nature of many of the animal studies. Radiation dose fractionation data for rib‐fracture in breast cancer patients suggests an α/β ratio is in the range 1.8–2.8 Gy, comparable to values obtained for other late responding normal human tissues. Med Pediatr Oncol 2003;41:208–211. © 2003 Wiley‐Liss, Inc.
Effect of glucocorticoids on bone density
Authors: Rehman Qaiser , Lane Nancy E. 
Published: July 2003

AbstractGlucocorticoid therapy is the most common cause of secondary iatrogenic osteoporosis. The bone loss occurs predominantly due to a decrease in bone formation, although increased bone resorption also occurs. Glucocorticoids induce osteoblast apoptosis and increase osteoclast survival and activity. Most of these effects are mediated through the RANKL‐OPG system but perturbations in gonadal hormone activity and calcium balance may also contribute significantly to bone loss. Future therapies in the treatment and prevention of glucocorticoid‐induced osteoporosis may be targeted at restoring the hormonal and cytokine balance to nullify the apoptotic effect of glucocorticoids on bone forming cells. Med Pediatr Oncol 2003;41:212–216. © 2003 Wiley‐Liss, Inc.