bluuebunny/crossref_metadata_2025 huggingface dataset:
Feature uncertainty activates anterior cingulate cortex
Authors: Kéri Szabolcs , Decety Jean , Roland Per E. , Gulyás Balázs
Published: December 2003

In visual discrimination tasks, the relevant feature to discriminate is defined before stimulus presentation. In feature uncertainty tasks, a cue about the relevant feature is provided after stimulus offset. We used 15O‐butanol positron emission tomography (PET) in order to investigate brain activation during a feature uncertainty task. There was greater activity during the feature uncertainty task, compared with stimulus detection and discrimination of orientation and spatial frequency, in the lateral and medial prefrontal cortex, the cuneus, superior temporal and inferior parietal cortex, cortical motor areas, and the cerebellum. The most robust and consistent activation was observed in the dorsal anterior cingulate cortex (Brodmann area 32; x = 0 y = 16, z = 40). The insula, located near the claustrum (x = −38, y = 8, z = 4), was activated during the discrimination tasks compared with the feature uncertainty condition. These results suggest that the dorsal anterior cingulate cortex is important in feature uncertainty conditions, which include divided attention, expectancy under uncertainty, and cognitive monitoring. Hum. Brain Mapp. 21:26–33, 2004. © 2003 Wiley‐Liss, Inc.
p75 neurotrophin receptor functions as a survival receptor in brain‐metastatic melanoma cells
Authors: Marchetti Dario , Aucoin Rebecca , Blust Jason , Murry Brian , Greiter‐Wilke Andrea
Published: December 2003

The p75 neurotrophin receptor (p75NTR), a common receptor for members of the neurotrophins (NT) family, was previously identified as a molecular determinant of brain metastasis. We have also reported that NT treatment of murine and human brain‐metastatic melanoma cells affects their invasive capacities and increases the production of heparanase, an important and unique extracellular matrix (ECM) degradative enzyme. Neurotrophism can be a survival‐support mechanism for brain‐metastatic cells and a survival assay was devised to mimic the growth limiting conditions of rapidly expanding metastatic tumors prior to neoangiogenesis. We report that p75NTR promoted the survival of brain‐metastatic melanoma cells but not melanocytes in stress cultures conditions. Secondly, melanoma cells fluorescently sorted for high p75NTR expression (p75NTR‐H cells) had an up to a 15‐fold greater survival than those sorted for low p75NTR expression (p75NTR‐L cells). Thirdly, cells overexpressing p75NTR associated with the growth fraction and provided these cells with an inherent growth advantage. Finally, we observed an increased survival of sorted p75NTR‐L cells, dependent upon treatment of NT members whose functional receptors are present on these cells. Together, these results delineate that p75NTR‐mediated trophic support profoundly affects competitive melanoma‐cell survival when the tumor cell microenvironment becomes growth limiting. © 2003 Wiley‐Liss, Inc.
Galectins and urological cancer
Authors: Oka Natsuo , Takenaka Yukinori , Raz Avraham
Published: December 2003

Galectins are a family of proteins defined by their affinity for β‐galactoside and by their conserved sequence. Each galectins exhibits a specific expression pattern in various tissues and their expression is regulated during development. Their expression is altered in many types of cancers and non‐cancerous disorders. They interact with glycoproteins in both extracellular and intracellular milieu and regulate various biological phenomenon including cell growth, cell differentiation, cell adhesion, and apoptosis. A series of experimental and clinical evidences have been reported to support correlation between galectin expressions and neoplastic transformation. The recent findings show that expressions of galectins are elevated with neoplastic progression in certain malignancies, and therefore, galectins are expected to serve as reliable tumor markers. In this review, we describe the expression and role of galectins in urological cancers and their clinical applications for diagnostic and therapeutic use. © 2003 Wiley‐Liss, Inc.
Emerging views of integrin signaling: Implications for prostate cancer
Authors: Slack‐Davis Jill K. , Parsons J. Thomas
Published: December 2003

Integrins are heterodimeric transmembrane cellular receptors that link the cell to its underlying substratum. Alterations in integrin expression and signaling have been implicated in many aspects of tumorigenesis and metastasis including cell survival, migration, and invasion. In prostate cancer, the progression from normal to metastatic cells is accompanied by changes in the repertoire of integrins expressed and up‐regulation of key adhesion‐dependent signaling pathways. Recent work from several laboratories indicates the emergence of new mechanisms for the regulation of growth and migratory pathways by integrin engagement. These pathways are likely to provide novel sites of therapeutic intervention for the treatment of prostate cancer. © 2003 Wiley‐Liss, Inc.
Integrin clipping: A novel adhesion switch?
Authors: Demetriou Manolis C. , Cress Anne E.
Published: December 2003

During human prostate cancer progression, the majority of normally expressed integrins are suppressed with the exception of the α6, α3, and β1 integrins. We have shown that in prostate cancer, the α6 integrin is found paired with the β1 integrin and that a novel form of the α6 integrin that lacks a large portion of the extracellular domain (α6p) exists. The α6pβ1 integrin is found in human prostate cancer tissue specimens as well as tissue culture cell lines and is formed on the cell surface. This review discusses the mechanism of α6pβ1 production and the potential functions of this integrin variant. Our current working model predicts that the α6pβ1 integrin maintains the intracellular cytoskeletal connections associated with the heterodimer while allowing for an alteration in cell adhesion. The mechanism provides a selective advantage for cancer cell metastasis. © 2003 Wiley‐Liss, Inc.
Bone morphogenetic protein signaling in prostate cancer cell lines
Authors: Brubaker K.D. , Corey E. , Brown L.G. , Vessella R.L.
Published: December 2003

Prostate cancer is the most commonly diagnosed malignancy in men and is often associated with bone metastases. Prostate cancer bone lesions can be lytic or schlerotic, with the latter predominating. Bone morphogenetic proteins (BMPs) are a family of growth factors, which may play a role in the formation of prostate cancer osteoblastic bone metastases. This study evaluated the effects of BMPs on prostate cancer cell lines. We observed growth inhibitory effects of BMP‐2 and ‐4 on LNCaP, while PC‐3 was unaffected. Flow cytometric analysis determined that LNCaP cell growth was arrested in G1 after bone morphogenetic protein‐2 treatment. Treatment of LNCaP and PC‐3 with BMP‐2 and ‐4 activated downstream signaling pathways involving SMAD‐1, up‐regulation of p21CIP1/WAF1 and changes in retinoblastoma (Rb) phosphorylation. Interestingly, bone morphogenetic protein‐2 treatment stimulated a 2.7‐fold increase in osteoprotegerin (OPG), a molecule, which inhibits osteoclastogenesis, production in PC‐3. © 2003 Wiley‐Liss, Inc.
Ras signaling in prostate cancer progression
Authors: Weber Michael J. , Gioeli Daniel
Published: December 2003

When prostate cancer is first detected it generally is dependent on the presence of androgens for growth, and responds to androgen ablation therapies. However, the disease often recurs in a disseminated and apparently androgen independent (AI) form, and in this state is almost invariably fatal. Considerable evidence indicates that the Androgen receptor (AR) continues to be required even in androgen independent (AI) disease. Thus, a key to understanding hormone independent prostate cancer is to determine the mechanism(s) by which the AR can function even in the absence of physiologic levels of androgen. In this article, we argue that growth factors and receptors that utilize Ras family members drive prostate cancer progression to a state of androgen hypersensitivity; and that post‐translational modifications (e.g., phosphorylations) of transcriptional cofactors might be responsible for modulating the function of the AR so that it is active even at low concentrations of androgen. © 2003 Wiley‐Liss, Inc.
Role of the extracellular matrix in prostate carcinogenesis
Authors: Nagle Ray B.
Published: December 2003

This review summarizes the current state of knowledge regarding the proteins composing the extracellular matrix in the human prostate. The normal expression as well as the changes which occur in PIN and carcinoma are described for the lamins, collagens, and glycosaminoglycans. © 2003 Wiley‐Liss, Inc.
Death receptor‐induced cell death in prostate cancer
Authors: Guseva Natalya V. , Taghiyev Agshin F. , Rokhlin Oskar W. , Cohen Michael B.
Published: December 2003

Prostate cancer mortality results from metastasis and is often coupled with progression from androgen‐dependent to androgen‐independent growth. Unfortunately, no effective treatment for metastatic prostate cancer increasing patient survival is available. The absence of effective therapies reflects in part a lack of knowledge about the molecular mechanisms involved in the development and progression of this disease. Apoptosis, or programmed cell death, is a cell suicide mechanism that enables multicellular organisms to regulate cell number in tissues. Inhibition of apoptosis appears to be a critical pathophysiological factor contributing to the development and progression of prostate cancer. Understanding the mechanism(s) of apoptosis inhibition may be the basis for developing more effective therapeutic approaches. Our understanding of apoptosis in prostate cancer is relatively limited when compared to other malignancies, in particular, hematopoietic tumors. Thus, a clear need for a better understanding of apoptosis in this malignancy remains. In this review we have focused on what is known about apoptosis in prostate cancer and, more specifically, the receptor/ligand‐mediated pathways of apoptosis as potential therapeutic targets. © 2003 Wiley‐Liss, Inc.
Fatty acid synthase: A metabolic oncogene in prostate cancer?
Authors: Baron Antonella , Migita Toshiro , Tang Dan , Loda Massimo
Published: December 2003

In 1920, Warburg suggested that tumors consistently rely on anaerobic pathways to convert glucose to ATP even in the presence of abundant oxygen [Warberg, 1956] despite the fact that it is less efficient for energy supply than aerobic glycolysis. The reasons for this remain obscure to date. More often than not, the microenvironment of solid tumors contains regions of poor oxygenation and high acidity. In this context hypoxia can act in an epigenetic fashion, inducing changes in gene expression and in metabolism for survival. It is reasonable to assume that only the tumor cells capable of developing an unusual tolerance to limiting oxygen availability and to the acidosis resulting from excessive lactate production, can survive. In addition to the striking changes that occur in glucose metabolism, studies in human cancer patients suggest that there is often also an increase in free fatty acid turnover, oxidation and clearance [Legaspi et al., 1987; Hyltander et al., 1991]. For instance, a lipid mobilizing factor produced by tumor cells appears to be responsible for the increase in whole body fatty acid oxidation [Russell and Tisdale, 2002]. Fatty acids synthesis in tumor tissues also occurs at very high rates, as first demonstrated more than half a century ago [Medes et al., 1953]. Importantly, 14C glucose studies have shown that in tumor cells almost all fatty acids derive from de novo synthesis despite adequate nutritional supply [Sabine and Abraham, 1967; Ookhtens et al., 1984; Weiss et al., 1986]. In addition, tumors overexpressing fatty acid synthase (FAS), the enzyme responsible for de novo synthesis of fatty acids, display aggressive biologic behavior compared to those tumors with normal FAS levels, suggesting that FAS overexpression confers a selective growth advantage. Here, we will review the roles that FAS plays in important cellular processes such as apoptosis and proliferation. In addition, speculations on the putative role of FAS in the altered metabolic pathways of prostate cancer cells will be explored. Because of the frequent overexpression of this enzyme prostate cancer, FAS constitutes a therapeutic target in this disease. © 2003 Wiley‐Liss, Inc.
NF‐κB activation in human prostate cancer: Important mediator or epiphenomenon?
Authors: Suh Junghan , Rabson Arnold B.
Published: December 2003

The NF‐κB family of transcription factors has been shown to be constitutively activated in various human malignancies, including leukemias, lymphomas, and a number of solid tumors. NF‐κB is hypothesized to contribute to development and/or progression of malignancy by regulating the expression of genes involved in cell growth and proliferation, anti‐apoptosis, angiogenesis, and metastasis. Prostate cancer cells have been reported to have constitutive NF‐κB activity due to increased activity of the IκB kinase complex. Furthermore, an inverse correlation between androgen receptor (AR) status and NF‐κB activity was observed in prostate cancer cell lines. NF‐κB may promote cell growth and proliferation in prostate cancer cells by regulating expression of genes such as c‐myc, cyclin D1, and IL‐6. NF‐κB may also inhibit apoptosis in prostate cancer cells through activation of expression of anti‐apoptotic genes, such as Bcl‐2, although pro‐apoptotic activity of NF‐κB has also been reported. NF‐κB‐mediated expression of genes involved in angiogenesis (IL‐8, VEGF), and invasion and metastasis (MMP9, uPA, uPA receptor) may further contribute to the progression of prostate cancer. Constitutive NF‐κB activity has also been demonstrated in primary prostate cancer tissue samples and suggested to have prognostic importance for a subset of primary tumors. The limited number of samples analyzed in those studies and the relative lack of NF‐κB target genes identified in RNA expression microarray analyses of prostate cancer cells suggest that further studies will be required in order to determine if NF‐κB actually plays a role in human prostate cancer development, and/or progression, and to characterize its potential as a therapeutic target. © 2003 Wiley‐Liss, Inc.
Molecular aspects of diagnostic nucleolar and nuclear envelope changes in prostate cancer
Authors: Fischer Andrew H. , Bardarov Svetoslav , Jiang Zhong
Published: December 2003

Prostate cancer is still diagnosed by pathologists based on subjective assessment of altered cell and tissue structure. The cellular‐level structural changes diagnostic of some forms of cancer are known to be induced by cancer genes, but the relation between specific cellular‐level structural features and cancer genes has not been explored in the prostate. Two important cell structural changes in prostate cancer—nucleolar enlargement and nuclear envelope (NE) irregularity—are discussed from the perspective that they should also relate to the function of the genes active in prostate cancer. Enlargement of the nucleolus is the key diagnostic feature of high‐grade prostatic intraepithelial neoplasia (PIN), an early stage that appears to be the precursor to the majority of invasive prostate cancers. Nucleolar enlargement classically is associated with increased ribosome production, and production of new ribosomes appears essential for cell‐cycle progression. Several cancer genes implicated in PIN are known (in other cell types) to augment ribosome production, including c‐Myc, p27, retinoblastoma, p53, and growth factors that impact on ERK signaling. However, critical review of the available information suggests that increased ribosome production per se may be insufficient to explain nucleolar enlargement in PIN, and other newer functions of nucleoli may therefore need to be invoked. NE irregularity develops later in the clonal evolution of some prostate cancers, and it has adverse prognostic significance. Nuclear irregularity has recently been shown to develop dynamically during interphase following oncogene expression, without a requirement for post‐mitotic NE reassembly. NE irregularity characteristic of some aggressive prostate cancers could reflect cytoskeletal forces exerted on the NE during active cell locomotion. NE irregularity could also promote chromosomal instability because it leads to chromosomal asymmetry in metaphase. Finally, NE irregularity could impact replication competence, transcriptional programming and nuclear pore function. © 2003 Wiley‐Liss, Inc.
Fingerprinting the diseased prostate: Associations between BPH and prostate cancer
Authors: Shah Uzma S. , Getzenberg Robert H.
Published: December 2003

Two of the most common diseases which occur in ageing men relate to their prostate. BPH and prostate cancer are prevalent diseases which have an impact on most men as they age. The advent of gene expression analysis has provided an opportunity to examine these diseases in a novel fashion. These analyses, to date, have revealed associations between these two diseases which have not been previously identified. These commonalities include global genetic changes which occur throughout the prostates in individuals with these diseases. Understanding the fingerprints of these diseases is providing novel markers and treatment strategies for both BPH and prostate cancer. © 2003 Wiley‐Liss, Inc.
Molecular basis for the antiandrogen withdrawal syndrome
Authors: Miyamoto Hiroshi , Rahman Mujib M. , Chang Chawnshang
Published: December 2003

In patients with prostate cancer who manifest disease progression during combined androgen blockade therapy, discontinuation of antiandrogen treatment might result in prostate‐specific antigen decline, often associated with clinical improvement. The response called antiandrogen withdrawal syndrome is thus acknowledged as a general phenomenon. However, molecular mechanisms responsible for this syndrome are not completely understood. This article outlines the proposed mechanisms, including alterations of androgen receptor gene and its coregulatory proteins and activation of the signal transduction pathway, and the potential therapeutic approaches based on the specific mechanisms. © 2003 Wiley‐Liss, Inc.
In vitro culturing and characteristics of transit amplifying epithelial cells from human prostate tissue
Authors: Uzgare Aarti R. , Xu Yi , Isaacs John T.
Published: December 2003

The prostatic epithelium is functionally organized in stem cell units. This unit consists of a slow turn over stem cell within the basal epithelial layer which can replenish itself and provide progeny which differentiate down either a neuroendocrine or exocrine pathway. The maturation along the exocrine pathway initially involves transit amplifying cells within the basal layer proliferating and subsequently the progeny maturing into intermediate cells. These intermediate cells migrate into the luminal layer where they terminally differentiate into non‐proliferative secretory luminal cells which express prostate specific differentiation markers, like PSA. A growing body of experimental evidence has identified the proliferating transit amplifying/intermediate cells as the cells of origin for the common prostatic adenocarcinomas. Using a series of growth characteristics, and mRNA and protein markers, we have validated that primary cultures can be established in serum free defined media from surgically resected human prostates which are composed of essentially pure population of transit amplifying cells. At each serial passage, the subsequent cultures undergo enhanced maturation into intermediate cells and by the 7–10th passage these cells eventually lose their proliferative ability. This study validates that these cells are a useful and relevant system for the determination of molecular events involved in prostatic carcinogenesis. © 2003 Wiley‐Liss, Inc.
Angiogenesis and prostate cancer tumor growth
Authors: Nicholson Brian , Theodorescu Dan
Published: December 2003

The initiation of new blood vessels through angiogenesis is critical to tumor growth. Tumor cells release soluble angiogenic factors that induce neovascularization, without which nutrients and oxygen would not be available to allow tumors to grow more than 2–3 mm in diameter. This “angiogenic switch” or angiogenic phenotype requires an imbalance between proangiogenic and antiangiogenic factors since the formation of new blood vessels is highly regulated. This review discusses angiogenesis mediators, and the potential for manipulation of angiogenic factors as a practical cancer therapy, particularly in prostate cancer. © 2003 Wiley‐Liss, Inc.
Neuritogenic and survival‐promoting effects of the P2 peptide derived from a homophilic binding site in the neural cell adhesion molecule
Authors: Pedersen Martin V. , Køhler Lene B. , Ditlevsen Dorte K. , Li Shizong , Berezin Vladimir , Bock Elisabeth
Published: December 2003

The neural cell adhesion molecule (NCAM) plays a pivotal role in neural development, regeneration, and plasticity. NCAM mediates adhesion and subsequent signal transduction through NCAM–NCAM binding. Recently, a peptide ligand termed P2 corresponding to a 12‐amino‐acid sequence in the FG loop of the second Ig domain of NCAM was shown to mimic NCAM homophilic binding as reflected by induction of neurite outgrowth in hippocampal neurons. We demonstrate here that in concentrations between 0.1 and 10 μM, P2 also induced neuritogenesis in primary dopaminergic and cerebellar neurons. Furthermore, it enhanced the survival rate of cerebellar neurons although not of mesencephalic dopaminergic neurons. Moreover, our data indicate that the protective effect of P2 in cerebellar neurons was due to an inhibition of the apoptotic process, in that caspase‐3 activity and the level of DNA fragmentation were lowered by P2. Finally, treatment of neurons with P2 resulted in phosphorylation of the ser/thr kinase Akt. Thus, a small peptide mimicking homophilic NCAM interaction is capable of inducing differentiation as reflected by neurite outgrowth in several neuronal cell types and inhibiting apoptosis in cerebellar granule neurons. © 2003 Wiley‐Liss, Inc.
Regulation of sphingomyelinases in cells of the oligodendrocyte lineage
Authors: Testai F.D. , Landek M.A. , Dawson G.
Published: December 2003

Controversy exists regarding the nature of the “executioner” sphingomyelinase (SMase) in cells and its subcellular localization. A new fluorescence‐based assay with the substrate 6‐hexadecanoylamino‐4‐methylumbelliferyl‐phosphorylcholine allowed rapid and reliable microassays of neutral (N) and acid (A) SMase activity in cell extracts from primary cultures of neonatal rat oligodendrocytes (OPC) and a human oligodendroglioma cell line (HOG). Total SMase activity was much higher in OPC than in HOG cells. Both staurosporine and tumor necrosis factor‐α (TNF‐α) induced apoptosis and activated NSMase in a multiphasic manner in both OPC and HOG cells. The increase in caspase 8 activity preceded the 1 hr peak of NSMase activation, which was followed by caspase 3 activation. In contrast, ASMase activity, which constituted >90% of the total SMase activity, was unresponsive to proapoptotic drugs. Neither reducing ASMase levels by 50% by pretreatment with desipramine nor inhibiting sphingolipid synthesis by 50% with fumonisin B1 had any effect on cell death. Isolation of sphingolipid‐rich plasma membrane microdomains (rafts) from the cells by sucrose density gradient ultracentrifugation revealed an enrichment of sphingomyelin, ceramide, and caspase 8. Proapoptotic drugs such as staurosporine promoted the translocation of NSMase to the raft fraction. In contrast, ASMase, other lysosomal hydrolases, and caspase 3 remained absent from rafts even after staurosporine treatment. The staurosporine‐induced concomitant increase of ceramide in the raft fraction and caspase 3 in the cytosol could be mimicked by the addition of exogenous bacterial SMase. We conclude that caspase 8 activates NSMase in rafts in oligodendrocytes and that the downstream apoptotic signal is via caspase 3. © 2003 Wiley‐Liss, Inc.
Astrocytes in culture require docosahexaenoic acid to restore the n‐3/n‐6 polyunsaturated fatty acid balance in their membrane phospholipids
Authors: Champeil‐Potokar Gaëlle , Denis Isabelle , Goustard‐Langelier Bénédicte , Alessandri Jean‐Marc , Guesnet Philippe , Lavialle Monique
Published: December 2003

Docosahexaenoic acid (DHA), the main n‐3 polyunsaturated fatty acid (PUFA) in membranes, is particularly abundant in brain cells. Decreased cerebral concentrations of DHA, resulting from dietary n‐3 deficiency, are associated with impaired cognitive function. Because the cellular causes of this impairment are still unknown, we need in vitro models that mimic the variations in n‐3/n‐6 PUFA seen in vivo. We have compared the PUFA profiles of hamster astrocytes cultured in medium supplemented with long‐chain PUFA [DHA and/or arachidonic acid (AA)] with those of brain tissue from hamsters fed an n‐6/n‐3 PUFA‐balanced diet or one lacking n‐3 PUFA. Astrocytes were obtained from the brain cortex of newborn hamsters and cultured in minimum essential medium + 5% fetal calf serum (FCS) supplemented with DHA and/or AA for 10 days. The astrocytes cultured in medium + FCS had low n‐3 PUFA contents, comparable to those of brain tissue from hamsters fed an n‐3‐deficient diet. We have shown that astrocytes grown in medium supplemented with DHA and/or AA, plus α‐tocopherol to prevent lipid peroxidation, incorporated large amounts of these long‐chain PUFA, so that the n‐6/n‐3 PUFA compositions of the phosphatidylethanolamine and phosphatidylcholine, the two main classes of membrane phospholipids, were greatly altered. Astrocytes cultured in medium plus DHA had a more physiological n‐3 status, grew better, and retained their astrocyte phenotype. Thus astrocytes in culture are likely to be physiologically relevant only when provided with adequate DHA. This reliable method of altering membrane phospholipid composition promises to be useful for studying the influence of n‐6/n‐3 imbalance on astrocyte function. © 2003 Wiley‐Liss, Inc.
Oxidative stress induces p53‐mediated apoptosis in glia: p53 transcription‐independent way to die
Authors: Bonini Paolo , Cicconi Simona , Cardinale Alessio , Vitale Cristiana , Serafino Anna Lucia , Ciotti Maria Teresa , Marlier Lionel N.J‐L.
Published: December 2003

Oxidative stress has been implicated in the pathogenesis of stroke, traumatic brain injuries, and neurodegenerative diseases affecting both neuronal and glial cells in the central nervous system (CNS). The tumor suppressor protein p53 plays a pivotal function in neuronal apoptosis triggered by oxidative stress. We investigated the role of p53 and related molecular mechanisms that support oxidative stress‐induced apoptosis in glia. For this purpose, we exposed C6 glioma cells and primary cultures of rat cortical astrocytes to an H2O2‐induced oxidative stress protocol followed by a recovery period. We evaluated the effects of pifithrin‐α (PF‐α), which has been reported to protect neurons from ischemic insult by specifically inhibiting p53 DNA‐binding activity. Strikingly, PF‐α was unable to prevent oxidative stress‐induced astrocyte apoptosis. We demonstrate that p53 is able to mediate an apoptotic response by direct signaling at mitochondria, despite its transcriptional activity. The z‐VAD‐fmk‐sensitive apoptotic response requires a caspase‐dependent MDM‐2 degradation, leading to p53 mitochondrial targeting accompanied by cytochrome c release and nucleosomal fragmentation. © 2003 Wiley‐Liss, Inc.
Prenatal infection obliterates glutamate‐related protection against free hydroxyl radicals in neonatal rat brain
Authors: Cambonie Gilles , Hirbec Hélène , Michaud Martine , Kamenka Jean‐Marc , Barbanel Gérard
Published: December 2003

Prenatal infection constitutes an important risk factor for brain injury, in both premature and full‐term infants. Unfortunately, as the mechanisms involved are far from understood, no therapeutic strategy emerges to prevent the damage. We tested the hypothesis that administration of lipopolysaccharide (LPS) to gravid female rats enhanced glutamate‐induced oxidative stress in brain of pups. A microdialysis probe was implanted into the striatum of 14‐day‐old animals and the release of hydroxyl radicals (·OH) in the perfusion medium was evaluated. Glutamate promoted a delayed ·OH release in the offspring of dams given LPS, contrasting with the ·OH decreases observed in control animals. A similar response occurred after infusion of (R,S)‐3,5‐dihydroxyphenylglycine (DHPG), a Group I metabotropic glutamate receptor (mGluR) agonist. This response was not consecutive to a remote activation of N‐methyl‐D‐aspartate (NMDA) receptors, as it was unaffected by an NMDA receptor antagonist. Furthermore, the response to NMDA itself decreased in the offspring of dams given LPS. Massive amounts of DHPG, however, likely internalizing the mGlu receptor, still blunted the response to NMDA, as in controls. No quantitative variation occurred in mGluR1, mGluR5, or the NR1 subunit of the NMDA receptor between controls and neonates born from LPS‐treated dams. Direct LPS injection into age‐matched pups, by contrast, affected the response to neither glutamate nor DHPG. These results confirm that normally during perinatal development, the brain is protected from any oxidative stress resulting from excess glutamate, and the results support the hypothesis that maternal infection before delivery may lead to critical brain damage via the release of toxic free radicals. © 2003 Wiley‐Liss, Inc.
The chemokine receptor CXCR4 and not the N‐methyl‐D‐aspartate receptor mediates gp120 neurotoxicity in cerebellar granule cells
Authors: Bachis Alessia , Mocchetti Italo
Published: December 2003

The human immunodeficiency virus type 1 (HIV‐1) glycoprotein gp120 causes neuronal cell death; however, the molecular mechanisms of the neurotoxic effect remain largely unresolved. It has been suggested that gp120 evokes cell death by inducing the release of neurotoxins, including glutamate. The objective of this work was to examine the role of glutamate in gp120‐mediated neurotoxicity. We used as an experimental tool cerebellar granule cells prepared from 8‐day‐old rat cerebella, in which both glutamate and gp120 cause cell death. Cerebellar granule neurons were exposed to gp120 or glutamate alone or in combination with the glutamate receptor antagonist MK801 as well as other antiglutamatergic compounds. Cell viability was measured at various times by using several markers of cell death and apoptosis. MK801, at a concentration that blocked glutamate‐induced neuronal cell death, failed to prevent gp120‐mediated apoptotic cell death. Moreover, interleukin‐10, which has previously been shown to block glutamate toxicity in these neurons, was not neuroprotective against gp120. Because gp120 toxicity is mediated by activation of the chemokine receptor CXCR4, neurons were incubated with the CXCR4 inhibitor AMD3100. This compound prevented gp120‐ but not glutamate‐mediated cell death. These findings suggest that gp120 is toxic to neurons even in the absence of the virus and that the toxic mechanism involves primarily activation of CXCR4 receptor. Therefore, antagonists to the CXCR4 receptor may be more suitable compounds for inhibiting HIV‐1 neurotoxicity. © 2003 Wiley‐Liss, Inc.
Influence of hypnogenic brain areas on wakefulness‐ and rapid‐eye‐movement sleep‐related neurons in the brainstem of freely moving cats
Authors: Mallick Birendra N. , Thankachan Stephen , Islam Fakhrul
Published: December 2003

Rapid‐eye‐movement (REM) sleep is normally preceded by non‐REM sleep; however, every non‐REM sleep episode is not followed by REM sleep. It has been proposed that, for the regulation of REM sleep, the brain areas modulating waking and non‐REM sleep are likely to communicate with neurons promoting REM sleep. The former has been reported earlier, and in this study the latter has been investigated. Under surgical anaesthesia, cats were prepared for electrophysiological recording of sleep‐wakefulness and electrical stimulation of caudal brainstem as well as preopticoanterior hypothalamic hypnogenic areas. Insulated microwires of 25–32 μm were used to record 52 single neuronal activities from the brainstem along with bipolar electroencephalogram, electromyogram, electrooculogram, and pontogeniculooccipital waves in freely moving, normally behaving cats. The neurons were classified into five groups based on changes in firing rates associated with different sleep‐waking states compared with quiet wakefulness. Thereafter, the responses of these neurons to 1‐Hz stimulation of the two non‐REM sleep‐promoting areas were studied. At the end of experiment, the stimulating and recording sites were histologically identified. It was observed that, among the affected neurons, the caudal brainstem non‐REM sleep‐promoting area excited more REM‐on neurons, whereas the preopticoanterior hypothalamus hypnogenic area inhibited more awake‐active neurons. Thus, the results suggest that, at the single neuronal level, the caudal brainstem non‐REM sleep‐modulating area, rather than the preopticoanterior hypothalamic hypnogenic area in the brain, plays a modulatory role in triggering REM sleep initiation at a certain depth of sleep. © 2003 Wiley‐Liss, Inc.
Maturation of spiking activity in trout retinal ganglion cells coincides with upregulation of Kv3.1‐ and BK‐related potassium channels
Authors: Henne Jutta , Jeserich Gunnar
Published: December 2003

Developmental changes in membrane excitability and the potassium channel profile were monitored in acutely isolated trout retinal ganglion cells by patch‐clamp recording in combination with single‐cell RT‐PCR. During embryonic development in the egg, a sustained above‐threshold stimulation of ganglion cells elicited in most cases only a single spike response. After hatching, the proportion of multiply spiking cells increased strongly and the ability of spike frequency coding was acquired. This was accompanied by the occurrence of a highly tetraethylammonium (TEA)‐ and quinine‐sensitive delayed rectifier current, which gradually masked a rapidly inactivating A‐type potassium current that was predominant at earlier stages. Pharmacology of the delayed rectifier current closely matched those of recombinant Traw1, a Kv3.1‐related potassium channel in trout. The appearance of this current correlated closely with initial expression of Traw1 and Traw2 channel transcripts, as revealed by multiplex single‐cell RT‐PCR, whereas mRNA, encoding Shaker‐related channel genes in trout (termed Tsha1–Tsha4), were already detectable at early embryonic stages. Iberiotoxin‐sensitive, calcium‐activated potassium currents (BK) were extremely low before hatching, but increased significantly thereafter. These developmental changes in potassium channel expression occurred after the arrival of retinal fibers in the optic tectum and the initiation of synapse formation in the visual center. It is suggested that early expressed Shaker‐related potassium channels could act to influence neuronal differentiation, whereas proper neuronal signaling requires expression of Kv3.1‐ and BK‐related potassium channels. © 2003 Wiley‐Liss, Inc.
Estrogen interacts with the IGF‐1 system to protect nigrostriatal dopamine and maintain motoric behavior after 6‐hydroxdopamine lesions
Authors: Quesada Arnulfo , Micevych Paul E.
Published: December 2003

The most prominent neurochemical hallmark of Parkinson's disease (PD) is the loss of nigrostriatal dopamine (DA). Animal models of PD have concentrated on depleting DA and therapies have focused on maintaining or restoring DA. Within this context estrogen protects against 6‐hydroxdopamine (6‐OHDA) and 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) lesions of the nigrostriatal DA pathway. Present studies tested the hypothesis that neuroprotective estrogen actions involve activation of the insulin‐like growth factor‐1 (IGF‐1) system. Ovariectomized rats were treated with either a single subcutaneous injection of 17β‐estradiol benzoate or centrally or peripherally IGF‐1. All rats were infused unilaterally with 6‐OHDA into the medial forebrain bundle (MFB) to lesion the nigrostriatal DA pathway. Tyrosine hydroxylase (TH) immunocytochemistry confirmed that rats injected with 6‐OHDA had a massive loss of TH immunoreactivity in both the ipsilateral substantia nigra compacta (60% loss) and the striatum (>95% loss) compared to the contralateral side. Loss of TH immunoreactivity was correlated with loss of asymmetric forelimb movements, a behavioral assay for motor deficits. Pretreatment with estrogen or IGF‐1 significantly prevented 6‐OHDA‐induced loss of substantia nigra compacta neurons (20% loss) and TH immunoreactivity in DA fibers in the striatum (<20% loss) and prevented the loss of asymmetric forelimb use. Blockage of IGF‐1 receptors by intracerebroventricular JB‐1, an IGF‐1 receptor antagonist, attenuated both estrogen and IGF‐1 neuroprotection of nigrostriatal DA neurons and motor behavior. These findings suggest that IGF‐1 and estrogen acting through the IGF‐1 system may be critical for neuroprotective effects of estrogen on nigrostriatal DA neurons in this model of PD. © 2003 Wiley‐Liss, Inc.
The TIMPs tango with MMPs and more in the central nervous system
Authors: Crocker Stephen J. , Pagenstecher Axel , Campbell Iain L.
Published: December 2003

The matrix metalloproteinases (MMPs) are a family of zinc‐dependent extracellular proteases that have been implicated in CNS development and disease. Crucial homeostatic
regulation of MMPs is mediated through the expression and actions of the tissue inhibitors of metalloproteinases (TIMPs). Although the TIMPs are recognized inhibitors of the MMPs, recent
studies have revealed that these proteins also can exhibit biological activities that are distinct from their interactions with or inhibition of the MMPs. With our understanding of the roles of the
TIMPs in the CNS continuously emerging, this review examines the current state of knowledge regarding the multifarious and novel functions of this family of proteins, with particular attention to
their increasing potential in the development, plasticity, and pathology of the CNS. © 2003 Wiley‐Liss, Inc.
An immunohistochemical method that distinguishes free from complexed SNAP‐25
Authors: Xiao Jingnan , Xia Zongping , Pradhan Anuradha , Zhou Qiong , Liu Yuechueng
Published: December 2003

Soluble N‐ethylmaleimide‐sensitive fusion protein (NSF) attachment protein receptor (SNARE) complexes composed of target (t‐) SNAREs syntaxin and SNAP‐25 and vesicle SNARE synaptobrevin play an essential role in neurosecretion. It is hypothesized that a transient intermediate complex between the t‐SNAREs is formed during the assembly of the ternary complex. The existence of the t‐SNARE binary complexes in vivo, however, has not been demonstrated. By using an affinity absorption scheme with preformed syntaxin–SNAP‐25 complexes, we isolated antibodies capable of distinguishing free SNAP‐25 from those associated with syntaxin. By semiquantitative immunohistochemistry, we estimated that, in cultured cerebellar neurons, the majority of SNAP‐25 existed as complexes. Compared with the cultured neurons, PC12 cells expressed significantly less syntaxin, and we found that SNAP‐25 was primarily in free forms. In contrast, a PC12 line that stably expressed a recombinant syntaxin showed a marked increase in SNAP‐25 complexes. By using fluorescence resonance energy transfer (FRET) techniques, we observed FRET between cyan fluorescence protein–syntaxin and yellow fluorescence protein–SNAP‐25 fusion proteins expressed in COS‐7 and PC12 cells, suggesting a physiological interaction between syntaxin and SNAP‐25. Our results demonstrate that, unlike what was previously hypothesized, syntaxin and SNAP‐25 exist preferably as stable binary complexes in neurons. These findings offer novel insight into the mechanisms underlying the initiation and regulation of SNARE complex assembly. © 2003 Wiley‐Liss, Inc.
Distribution of sensorin immunoreactivity in the central nervous system of Helix pomatia: Functional aspects
Authors: Casadio Andrea , Fiumara Ferdinando , Sonetti Dario , Montarolo Pier Giorgio , Ghirardi Mirella
Published: December 2003

Land snails belonging to the genus Helix are commonly used to study several behaviors and their plasticity at the cellular level. Because the knowledge of sensory neurons in these species is far from being complete, we have investigated the presence and distribution in Helix pomatia central nervous system of the immunoreactivity for sensorin, a peptide specific for mechanosensory neurons in Aplysia. We found that the majority of immunopositive cells were grouped in clusters located in all the central ganglia, except for the pedal ganglion, where only a single large neuron was stained. A symmetrical cluster of stained cells in the cerebral ganglia showed homology with the cerebral J clusters in Aplysia. Most of the somata of these Helix cerebral clusters send their axons in the ipsilateral cerebropedal connective and lip nerves and make monosynaptic connections with cells located in a medial adjacent cluster. This monosynaptic circuit can be reestablished in culture, where it shows homosynaptic depression as it does in the ganglionic preparation. © 2003 Wiley‐Liss, Inc.
Inhibition of histone deacetylation enhances the neurotoxicity induced by the c‐terminal fragments of amyloid precursor protein
Authors: Kim Hye‐Sun , Kim Eun‐Mee , Kim Na‐Jung , Chang Keun‐A , Choi Yoori , Ahn Kwang‐Woo , Lee Jun‐Ho , Kim Seonghan , Park Cheol Hyoung , Suh Yoo‐Hun
Published: December 2003

The AICD (APP intracellular Domain) and C31, caspase‐cleaved C‐terminal fragment of APP, have been found in Alzheimer's disease (AD) patients' brains and have been reported to induce apoptosis in neuronal cells. In recent, the C‐terminal fragments of amyloid precursor protein (APP‐CTs) have been reported to form a complex with Fe65 and the histone acetyltransferase Tip60 and are thought to be involved in gene transcription. In this study, based on the hypothesis that APP‐CTs might exert neurotoxicity by inducing some gene transcription, we investigated the effects of APP‐CTs on histone acetylation which indicates that transcription is actively going on and also on the relationship between histone acetylation and the cytotoxicity induced by APP‐CTs in nerve growth factor (NGF)‐differentiated PC12 cells and rat primary cortical neurons. Here we demonstrate that the expression of APP‐CTs [C31, AICD (C59) and C99] induces increases in acetylation of histone 3 and histone 4 and that treatment with sodium butyrate, an inhibitor of histone deacetylase, significantly enhances the cytotoxicity induced by APP‐CTs. The acetylation of histone plays an important role in allowing regulatory proteins to access DNA and is likely to be a major factor in the regulation of gene transcription. Taken together, our results suggest that APP‐CTs exert neurotoxicity by transcription‐dependent mechanisms and this might contribute to the pathogenesis of AD. © 2003 Wiley‐Liss, Inc.
Multisensory intervention improves physical growth and illness rates in Korean orphaned newborn infants
Authors: Kim Tae Im , Shin Yeong Hee , White‐Traut Rosemary C.
Published: December 2003

The purpose of this study was to evaluate the effectiveness of a multisensory intervention on the physical growth and health of Korean orphaned infants. Fifty‐eight full‐term infants were randomly assigned to a control (n = 28) or an experimental (n = 30) group within 14 days postbirth. In addition to receiving the routine orphanage care, infants in the experimental group received 15 min of auditory (female voice), tactile (massage), and visual (eye‐to‐eye contact) stimulation twice a day, 5 days a week, for 4 weeks. Compared to the control group, the experimental group had gained significantly more weight and had larger increases in length and head circumference after the 4‐week intervention period and at 6 months of age. In addition, the experimental group had significantly fewer illnesses and clinic visits. These data demonstrate that multisensory intervention in conjunction with human/social contact may be effective in facilitating growth for newborn infants placed in orphanages. © 2003 Wiley‐Liss, Inc. Res Nurs Health 26:424–433, 2003
Correlates of fatigue in critical care nurses
Authors: Ruggiero Jeanne S.
Published: December 2003

The purposes of this study were to examine shift‐related differences in chronic fatigue and the contributions of sleep quality, anxiety, and depression to chronic fatigue among a random nationwide sample (N = 142) of female critical care nurses. Twenty‐three percent of this sample met criteria for clinical depression. Day and night nurses did not differ in their reports of chronic fatigue. Night nurses reported more depression and poorer sleep quality than did day nurses. Regression analyses indicated that among the variables of global sleep quality, depression, and anxiety, depression and sleep quality were the most relevant to the explanation of chronic fatigue. These findings suggest the need for studies of strategies to promote sleep and improve mood in critical care nurses. © 2003 Wiley Periodicals, Inc. Res Nurs Health 26:434–444, 2003
Appraisal, coping, hardiness, and self‐perceived health in community‐dwelling spouse caregivers of persons with dementia
Authors: DiBartolo Mary C. , Soeken Karen L.
Published: December 2003

Although researchers have suggested that hardiness is associated with improved outcomes in stressful situations, findings regarding its moderating effects have been mixed. Relationships among hardiness, appraisal, coping, self‐perceived health, and other antecedent variables were examined in a convenience sample of 72 community‐dwelling spouse caregivers for persons with dementia. In this descriptive correlational design, participants completed a mailed survey. Regression analyses were used to detect main and moderating effects. Antecedent variables predicted 27% of the variance in caregiver appraisal, 23% of the variance in emotion‐focused coping, and 22% of the variance in self‐perceived health. In addition to its significant main effects, hardiness functioned as a significant moderator between the set of antecedent variables and caregiver appraisal. More research is needed to support the presence of main and moderating effects of hardiness in dementia caregivers. © 2003 Wiley Periodicals, Inc. Res Nurs Health 26:445–458, 2003
Barriers and facilitators of self‐reported physical activity in cardiac patients
Authors: Yates Bernice C. , Price‐Fowlkes Tammera , Agrawal Sangeeta
Published: December 2003

The purpose of this study was to examine the relationships of personal factors (age and gender), barriers (symptom distress and negative well‐being), and facilitators (self‐efficacy to exercise and positive well‐being) with self‐reported physical activity in cardiac patients. Sixty‐four participants (50 men, 14 women) 6–12 months post–cardiac event participated in this study. We found that age and gender accounted for 14.7% of the variance, symptom distress and negative well‐being accounted for an additional 21.6% of the variance, and self‐efficacy accounted for the remaining 7.6% of the variance for a total of 44% of the variance in physical activity levels explained. These results suggest that personal factors and barriers are central variables, in addition to self‐efficacy, in understanding the levels of physical activity achieved by patients after a cardiac event. © 2003 Wiley‐Liss, Inc. Res Nurs Health 26:459–469, 2003