bluuebunny/crossref_metadata_2025_split huggingface dataset:
Overexpression of α‐synuclein in rat substantia nigra results in loss of dopaminergic neurons, phosphorylation of α‐synuclein and activation of caspase‐9: resemblance to pathogenetic changes in Parkinson's disease
Authors: Yamada Masanori , Iwatsubo Takeshi , Mizuno Yoshikuni , Mochizuki Hideki 
Published: September 2004

AbstractTo elucidate the role of α‐synuclein in the pathogenesis of Parkinson's disease, both human α‐synuclein transgenic mice and targeted overexpression of human α‐synuclein in rat substantia nigra using viral vector‐based methods have been studied, however, little is known about the pathogenetic changes of dopaminergic neuron loss. Therefore, it is necessary to address whether the pathogenetic changes in brains with Parkinson's disease are recapitulated in these models. Here, we used the recombinant adeno‐associated viral (rAAV) vector system for human α‐synuclein gene transfer to rat substantia nigra and observed approximately 50% loss of dopaminergic neurons at 13 weeks after infection, which was comparably slower than the progression of neurodegeneration reported in other studies. In the slower progression of neurodegeneration, we identified several important features in common with the pathogenesis of Parkinson's disease, such as phosphorylation of α‐synuclein at Ser129 and activation of caspase‐9. Both findings were also evident in cortical tissues overexpressing α‐synuclein via rAAV. Our results indicate that overexpression of α‐synuclein via rAAV apparently recapitulates several important features of brains with Parkinson's disease and dementia with Lewy bodies, and thus α‐synucleinopathy described here is likely to be an ideal model for the study of the pathogenesis of Parkinson's disease and dementia with Lewy bodies.
Gene knockout of amyloid precursor protein and amyloid precursor‐like protein‐2 increases cellular copper levels in primary mouse cortical neurons and embryonic fibroblasts
Authors: Bellingham Shayne A. , Ciccotosto Giuseppe D. , Needham B. Elise , Fodero Lisa R. , White Anthony R. , Masters Colin L. , Cappai Roberto , Camakaris James 
Published: September 2004

AbstractAlzheimer's disease is characterised by the accumulation of amyloid‐β peptide, which is cleaved from the copper‐binding amyloid‐β precursor protein. Recent in vivo and in vitro studies have illustrated the importance of copper in Alzheimer's disease neuropathogenesis and suggested a role for amyloid‐β precursor protein and amyloid‐β in copper homeostasis. Amyloid‐β precursor protein is a member of a multigene family, including amyloid precursor‐like proteins‐1 and ‐2. The copper‐binding domain is similar among amyloid‐β precursor protein family members, suggesting an overall conservation in its function or activity. Here, we demonstrate that double knockout of amyloid‐β precursor protein and amyloid precursor‐like protein‐2 expression results in significant increases in copper accumulation in mouse primary cortical neurons and embryonic fibroblasts. In contrast, over‐expression of amyloid‐β precursor protein in transgenic mice results in significantly reduced copper levels in primary cortical neurons. These findings provide cellular neuronal evidence for the role of amyloid‐β precursor protein in copper homeostasis and support the existing hypothesis that amyloid‐β precursor protein and amyloid precursor‐like protein‐2 are copper‐binding proteins with functionally interchangeable roles in copper homeostasis.
Alterations of CaMKII after hypoxia‐ischemia during brain development
Authors: Tang Kaixiong , Liu Chunli , Kuluz John , Hu Bingren 
Published: September 2004

AbstractTransient brain hypoxia‐ischemia (HI) in neonates leads to delayed neuronal death and long‐term neurological deficits. However, the underlying mechanisms are incompletely understood. Calcium‐calmodulin‐dependent protein kinase II (CaMKII) is one of the most abundant protein kinases in neurons and plays crucial roles in synaptic development and plasticity. This study used a neonatal brain HI model to investigate whether and how CaMKII was altered after HI and how the changes were affected by brain development. Expression of CaMKII was markedly up‐regulated during brain development. After HI, CaMKII was totally and permanently depleted from the cytosol and concomitantly deposited into a Triton‐insoluble fraction in neurons that were undergoing delayed neuronal death. Autophosphorylation of CaMKII‐Thr286 transiently increased at 30 min of reperfusion and declined thereafter. All these changes were mild in P7 pups but more dramatic in P26 rats, consistent with the development‐dependent CaMKII expression in neurons. The results suggest that long‐term CaMKII depletion from the cytosolic fraction and deposition into the Triton‐insoluble fraction may disable synaptic development, damage synaptic plasticity, and contribute to delayed neuronal death and long‐term synaptic deficits after transient HI.
NMDA receptor activation results in PKA‐ and ERK‐dependent Mnk1 activation and increased eIF4E phosphorylation in hippocampal area CA1
Authors: Banko Jessica L. , Hou Lingfei , Klann Eric 
Published: September 2004

AbstractProtein synthesis is essential for the stabilization of glutamate receptor‐dependent forms of long‐lasting hippocampal synaptic plasticity and for the consolidation of memory, but the signal transduction mechanisms that regulate translation factors during these processes are not well understood. As a first step towards understanding how translation is activated during synaptic plasticity, we investigated how the eukaryotic initiation factor 4E (eIF4E), a rate‐limiting mRNA cap‐binding protein, and its kinase, Mnk1, are regulated by protein kinase C (PKC), cAMP‐dependent protein kinase (PKA) andN‐methyl‐d‐aspartate (NMDA) receptor activation in hippocampal area CA1. We found that treatment of mouse hippocampal slices with either phorbol ester, to activate PKC, or forskolin, to activate PKA, resulted in activation of Mnk1 and increased eIF4E phosphorylation that was dependent on extracellular signal‐regulated kinase (ERK). Similarly, brief treatment of hippocampal slices with NMDA resulted in activation of Mnk1 and increased phosphorylation of eIF4E. The NMDA‐induced activation of Mnk1 and increased phosphorylation of eIF4E were dependent on PKA and ERK, but not PKC, and were present in synaptoneurosome preparations. Immunohistochemical analysis revealed that the PKA‐ and ERK‐dependent increases in Mnk1 activation induced by NMDA also occured in dendrites. These findings identify a specific regulatory pathway that can couple NMDA receptor activation to translation initiation factors in the hippocampus, and may represent a mechanism for triggering dendritic protein synthesis during long‐term potentiation and long‐term memory formation.
Mitochondrial uncoupling as a potential therapeutic target in acute central nervous system injury
Authors: Maragos William F. , Korde Amit S. 
Published: September 2004

AbstractMitochondrial dysfunction, resulting from the disruption of calcium homeostasis and the generation of toxic reactive oxygen species, is a central process leading to neuronal injury and death following acute CNS insults. Interventions aimed at preventing disturbances in mitochondrial function have therefore become targets of intense investigation. Mitochondrial uncoupling is a condition in which electron transport is disconnected from the production of ATP. As a consequence, there is a decrease in the mitochondrial membrane potential, which can temporarily decrease calcium influx and attenuate free radical formation. The potential use of pharmacological agents with uncoupling properties may provide a novel therapeutic approach for the treatment of acute neuronal injury.
Rho‐mediated cytoskeletal rearrangement in response to LPA is functionally antagonized by Rac1 and PIP2
Authors: Seasholtz Tammy M. , Radeff‐Huang Julie , Sagi Sarah A. , Matteo Rosalia , Weems Jessica M. , Cohen Annemarie Stoudt , Feramisco James R. , Brown Joan Heller 
Published: September 2004

AbstractG‐protein‐coupled receptors signal through Rho to induce actin cytoskeletal rearrangement. We previously demonstrated that thrombin stimulates Rho‐dependent process retraction and rounding of 1321N1 astrocytoma cells. Surprisingly, while lysophosphatidic acid (LPA) activated RhoA in 1321N1 cells, it failed to produce cell rounding. Thrombin, unlike LPA, decreased Rac1 activity, and activated (GTPase‐deficient) Rac1 inhibited thrombin‐stimulated cell rounding, while expression of dominant‐negative Rac1 promoted LPA‐induced rounding. LPA and thrombin receptors appear to differ in coupling to Gi, as LPA but not thrombin‐stimulated 1321N1 cell proliferation was pertussis toxin‐sensitive. Blocking Gi with pertussis toxin enabled LPA to induce cell rounding and to decrease activated Rac1. These data support the hypothesis that Rac1 and Gi activation antagonize cell rounding. Thrombin and LPA receptors also differentially activated Gq pathways as thrombin but not LPA increased InsP3 formation and reduced phosphatidylinositol 4,5‐bisphosphate (PIP2) levels. Microinjection of the plekstrin homology domain of phospholipase C (PLC)δ1, which binds PIP2, enabled LPA to elicit cell rounding, consistent with a requirement for PIP2 reduction. We suggest that Rho‐mediated cytoskeletal responses are enhanced by concomitant reductions in cellular levels of PIP2 and Rac1 activation and thus effected only by G‐protein‐coupled receptors with appropriate subsets of G protein activation.
Mental Health in Prison Populations. A review – with special emphasis on a study of Danish prisoners on remand
Authors: Andersen H. S. 
Published: September 2004

Objective: To review the literature on mental health and psychiatric morbidity in prison populations and relate findings to a Danish study on remand prisoners.Method: The literature is reviewed and subdivided in the following section: validity of psychometrics in prison populations, prevalence of psychiatric disorders prior to imprisonment, incidence of psychiatric disorders during imprisonment, psychopathy related to psychiatric comorbidity, dependence syndromes with special emphasis on different administrations of heroin use (smoke vs. injection). The results are compared with a longitudinal Danish study on remand prisoners in either solitary confinement (SC) or non‐SC.Results: Many factors must be taken into consideration when dealing with prisoners and mental health, e.g. international differences, the prison setting, demographics and methodological issues. The prison populations in general are increasing worldwide. Psychometrics may perform differently in prison populations compared with general populations with the General Health Questionnaire‐28 having a low validity in remand prisoners. Psychiatric morbidity including schizophrenia is higher and perhaps increasing in prison populations compared with general populations with dependence syndromes being the most frequent disorders. The early phase of imprisonment is a vulnerable period with a moderately high incidence of adjustment disorders and twice the incidence in SC compared with non‐SC. Prevalence of psychopathy is lower in European than North American prisons. Medium to high scores of psychopathy is related to higher psychiatric comorbidity. Opioid dependence is the most frequent drug disorder with subjects using injection representing a more dysfunctional group than subjects using smoke administration. Many mentally ill prisoners remain undetected and undertreated.Conclusion: There is a growing population of mentally ill prisoners being insufficiently detected and treated.
Lymphogranuloma venereum – A Rare Cause of Genital Ulcers in Central Europe
Authors: Rampf J. , Essig A. , Hinrichs R. , Merkel M. , Scharffetter-Kochanek K. , Sunderkötter C. 
Published: September 2004

Lymphogranuloma inguinale, caused by <i>Chlamydia trachomatis</i> serovar L1–L3 is rare in patients from western countries but needs yet to be considered in the differential diagnosis of genital ulcers. We report a case of a young male patient without any eventful travel history who presented with a genital ulcer at the sulcus coronarius and painfully enlarged lymph nodes in the right inguinal area. The typical clinical picture and serum IgM and IgG antibody titers of 1:16 and 1:512, respectively, against <i>C. trachomatis</i> were suggestive of infection with <i>C. trachomatis</i> serovar L1–L3. The diagnosis was confirmed by isolation of the organisms from the ulcer ground and subsequent sequence analysis of the <i>omp1</i> gene which led to identification of <i>C. trachomatis </i>genotype L2 with 99% homology to a reference strain of <i>C. trachomatis </i>serovar L2. The lesion healed rapidly under treatment with doxycycline for 3 weeks, and the lymph nodes did not ulcerate. Thus, clinical suspicion was confirmed by genotyping of the isolated strain allowing timely diagnosis and treatment of lymphogranuloma inguinale.
Activity of Nadifloxacin (OPC-7251) and Seven Other Antimicrobial Agents against Aerobic and Anaerobic Gram-Positive Bacteria Isolated from Bacterial Skin Infections
Authors: Nenoff P. , Haustein U.-F. , Hittel N. 
Published: September 2004

<i>Background and Methods:</i> The in vitro activity of nadifloxacin (OPC-7251), a novel topical fluoroquinolone, was assessed and compared with those of ofloxacin, oxacillin, flucloxacillin, cefotiam, erythromycin, clindamycin, and gentamicin against 144 Gram-positive bacteria: 28 <i>Staphylococcus aureus</i>, 10 <i>Streptococcus</i> spp., 68 coagulase-negative staphylococci (CNS), 36 <i>Propionibacterium acnes</i>, and 2 <i>Propionibacterium granulosum</i> strains. All strains originated from bacterial-infected skin disease and were isolated from patients with impetigo, secondary infected wounds, folliculitis and sycosis vulgaris, and impetiginized dermatitis. In vitro susceptibility of all clinical isolates was tested by agar dilution procedure and minimum inhibitory concentrations (MICs) were determined. <i>Results:</i> Nadifloxacin was active against all aerobic and anaerobic isolates. MIC<sub>90</sub> (MIC at which 90% of the isolates are inhibited) was 0.1 µg/ml for <i>S. aureus</i>, 0.78 µg/ml for both<i> Streptococcus</i> spp. and CNS, and 0.39 µg/ml for <i>Propionibacterium </i>spp. On the other hand, resistant strains with MICs exceeding 12.5 µg/ml were found in tests with the other antibiotics. For both CNS and <i>Propionibacterium acnes,</i> MIC<sub>90</sub> values ≧100 µg/ml were demonstrated for erythromycin. Ofloxacin, cefotiam, erythromycin, clindamycin and gentamicin exhibited MIC<sub>90</sub> values ≤1 µg/ml for some bacterial species tested. Both oxacillin and flucloxacillin were active against all investigated bacterial species with MIC<sub>90</sub> values ≤1 µg/ml. <i>Conclusion:</i> In summary, nadifloxacin, a topical fluoroquinolone, was found to be highly active against aerobic and anaerobic bacteria isolated from patients with infected skin disease, and seems to be a new alternative for topical antibiotic treatment in bacterial skin infections.
Raynaud’s Phenomenon and Endothelial Dysfunction in End-Stage Renal Disease Patients Treated with Hemodialysis
Authors: Czupryniak Aneta , Kałużyńska Anna , Nowicki Michał , Więcek Bogusław , Bald Edward , Owczarek Danuta 
Published: September 2004

<i>Background/Aims:</i> Steal syndrome is a well-known complication of arteriovenous shunt placement. Increased frequency of Raynaud’s phenomenon (RP) especially concerning shunt limb is reported among hemodialysis (HD) patients. The aim of the study was to assess the relation of impairment of peripheral circulation diagnosed with cold stress test (CST) and thermography to the AV shunt location and markers of endothelial dysfunction in HD patients. <i>Methods:</i> The study group comprised 21 patients (6 male, 15 female, mean age 32.6 ± 15.0 years) treated with HD for a mean of 69 ± 54 months. 10 healthy individuals (4 male, 6 female, mean age 38.6 ± 14.7 years) served as controls. The diagnosis of RP was made upon the results of thermographic measurements during CST. Von Willebrand factor activity and antigen, endothelin-1 and plasma total homocysteine (tHcy) were measured in all subjects. <i>Results:</i> RP was found significantly more often in HD patients than in controls: 11/21 vs. 1/10 (p = 0.04). RP occurred in both hands in 7/11 (64%) patients. tHcy was higher in HD patients than in the controls (31.7 ± 13.9 vs. 10.9 ± 3.2 µg/l, p < 0.0001). tHcy and von Willebrand factor antigen were significantly higher in the RP-positive than RP-negative patients or controls. <i>Conclusion:</i> Small vessel dysfunction diagnosed as positive RP is a frequent finding in HD patients. It seems that endothelial injury rather than AV shunt steal syndrome is responsible for development of RP in HD patients.
Monitoring the Cellular Effects of HMG-CoA Reductase Inhibitors In Vitro and Ex Vivo
Authors: Cicha Iwona , Schneiderhan-Marra Nicole , Yilmaz Atilla , Garlichs Christoph D. , Goppelt-Struebe Margarete 
Published: September 2004

Objective—Inhibition of 3hydroxy3methylglutaryl–coenzyme A (HMG-CoA) reductase by statins and the subsequent reduction in Rho protein isoprenylation inactivates these important signaling molecules. The purpose of this study was to directly monitor statin effects on Rho proteins.Methods and Results—We used biphasic Triton X-114 system, 1-dimensional isoelectric focusing, and 2D-electrophoresis for the separation of modified and nonmodified Rho proteins. These methods were evaluated in human fibroblasts treated with simvastatin. 2D-electrophoresis, which proved to be the most sensitive method, revealed 2 major spots of identical molecular weight but different isoelectric points, with the more basic spot representing the carboxymethylated form of RhoA. In control cells, 90% of RhoA was fully modified (carboxymethylated). After treatment with simvastatin, a significant shift toward the unmethylated form was observed, representing inhibition of isoprenylation, which is a prerequisite to further modification. Similar shifts were observed for Rac1 and Cdc42. In freshly isolated peripheral blood mononuclear cells, a shift toward nonmodified RhoA was observed after treatment with atorvastatin in vitro and in vivo. There was a significant increase in unmethylated RhoA in statin-treated individuals versus control individuals.Conclusions—2D-electrophoresis is a sensitive method for detecting changes in the amount of nonisoprenylated Rho proteins, allowing monitoring the direct cellular effects of statins.
Impact of bone marrow hematopoiesis failure on T-cell generation during pathogenic simian immunodeficiency virus infection in macaques
Authors: Thiebot Hugues , Vaslin Bruno , Derdouch Sonia , Bertho Jean-Marc , Mouthon Franck , Prost Stéphane , Gras Gabriel , Ducouret Pierre , Dormont Dominique , Le Grand Roger 
Published: September 2004

AbstractExperimental infection of macaques with pathogenic strains of simian immunodeficiency virus (SIV) represents one of the most relevant animal models for studying HIV pathogenesis. In this study, we demonstrated a significant decrease in the generation of CD4+ T cells from bone marrow (BM) CD34+ progenitors in macaques infected with SIVmac251. This decrease appears to result from changes in the clonogenic potential of BM progenitors of both the myeloid and lymphoid lineages. We also demonstrated a significant decrease in the numbers of the most immature long-term culture-initiating cells (LTC-ICs). Hematopoietic failure occurred as early as primary infection, in the absence of CD34+ BM cell infection and was not related to plasma viral load. No major change was observed in the phenotype of BM CD34+ cells from infected macaques, including apoptosis markers such as annexin V staining and BcL-2 expression, but a significantly higher that normal proportion of cells were in the G0/G1 phase. This is the first demonstration that failure of BM hematopoiesis results in impaired T-cell production, which may contribute to the disruption of T-lymphocyte homeostasis characteristic of pathogenic lentiviral infections in primates.
Motexafin gadolinium generates reactive oxygen species and induces apoptosis in sensitive and highly resistant multiple myeloma cells
Authors: Evens Andrew M. , Lecane Philip , Magda Darren , Prachand Sheila , Singhal Seema , Nelson Jeff , Miller Richard A. , Gartenhaus Ronald B. , Gordon Leo I. 
Published: September 2004

AbstractMotexafin gadolinium (MGd), an expanded porphyrin, is a tumor-selective redox-mediator that reacts with many intracellular reducing metabolites. Because redox mechanisms mediate apoptosis in multiple myeloma, we hypothesized that disruption of redox balance by MGd would result in cellular cytotoxicity in myeloma. We examined the effects of MGd on cellular cytotoxicity, apoptosis, reactive oxygen species (ROS) production, and intracellular drug uptake in dexamethasone-sensitive (C2E3), dexamethasone-resistant (1-310 and 1-414) chemotherapy-sensitive (8226-RPMI) and highly chemotherapy-resistant (DOX-10V) myeloma cells. We found complete inhibition of proliferation and cytotoxicity in each sensitive and resistant cell line with 24-hour exposure to clinically relevant concentrations of 50 μM MGd and 50 to 100 μM ascorbate, which was required for the effect. The mechanism of cytotoxicity was related to induction of apoptosis as demonstrated by alteration in mitochondrial membrane potential and elevated annexin V expression. This was accompanied by depletion of intracellular glutathione and increased ROS production. Moreover, catalase substantially abrogated MGd-induced cell death. Using fluorescence microscopy and flow cytometry, we found intracellular uptake of MGd and intracellular ROS production. MGd also induced apoptosis in fresh malignant cells from patients with multiple myeloma. These studies provide a rationale for clinical investigation of this novel redox-mediating agent in patients with multiple myeloma and related disorders.
Proteolytic inactivation of ADAMTS13 by thrombin and plasmin
Authors: Crawley James T. B. , Lam Jonathan K. , Rance James B. , Mollica Luigina R. , O'Donnell James S. , Lane David A. 
Published: September 2004

AbstractThe multimeric size and the function of circulating von Willebrand factor are modulated via its proteolytic cleavage by the plasma metalloproteinase, ADAMTS13. It is unclear how ADAMTS13 activity is regulated within the vascular system. In the absence of a regulatory mechanism, ADAMTS13 activity might compromise platelet adhesion at sites of vascular injury. We hypothesized that at sites of vascular injury, ADAMTS13 activity could be regulated locally by coagulation proteinases. Initiation of coagulation in human plasma resulted in the disappearance of added full-length recombinant ADAMTS13. This loss was inhibited by hirudin. Using purified proteins, we showed that ADAMTS13 is proteolyzed at several cleavage sites by thrombin in a time- and concentration-dependent manner. Furthermore, this proteolysis ablated ADAMTS13 activity against purified von Willebrand factor. Preincubation of thrombin with soluble thrombomodulin, but not heparin, inhibited the proteolysis of ADAMTS13, suggesting the involvement of thrombin exosite I (and not exosite II) in ADAMTS13 recognition. Plasmin also cleaved ADAMTS13 into similar fragments, resulting in the loss of ADAMTS13 activity. This study demonstrates the susceptibility of ADAMTS13 to proteolytic inactivation and suggests possible roles for thrombin and plasmin at sites of vascular injury.