bluuebunny/crossref_metadata_2025_split huggingface dataset:
An extraordinary degree of structural specificity is required in neural phospholipids for optimal brain function: n‐6 docosapentaenoic acid substitution for docosahexaenoic acid leads to a loss in spatial task performance
Authors: Lim Sun‐Young , Hoshiba Junji , Salem Norman 
Published: August 2005

AbstractThis study was conducted to determine whether provision of preformed dietary docosapentaenoic acid (DPAn‐6) can replace docosahexaenoic acid (DHA) for brain function as assessed by spatial task performance. A newly modified artificial rearing method was employed to generate n‐3 fatty acid‐deficient rats. Newborn pups were separated from their mothers at 2 days of age and given artificial rat milk containing linoleic acid (LA), or LA supplemented with 1% DHA (DHA), 1% DPAn‐6 (DPA) or 1% DHA plus 0.4% DPAn‐6 (DHA/DPA). The animals were then weaned onto similar pelleted diets. At adulthood, behavioural tasks were administered and then the brains were collected for fatty acid analysis. The LA and DPA groups showed a lower (63–65%) brain DHA than the dam‐reared, DHA and DHA/DPA groups and this loss was largely compensated for by an increase in brain DPAn‐6. The brain fatty acid composition in the DPA group was the same as that in the LA group at adulthood. In the Morris water maze, the LA and DPA groups exhibited a longer escape latency than the dam‐reared and DHA groups and had a defect in spatial retention. In conclusion, DPAn‐6 could not replace DHA for brain function, indicating a highly specific structural requirement for DHA.
Activation of mitogen‐activated protein kinases in hamster brains infected with 263K scrapie agent
Authors: Lee Hyun‐Pil , Jun Yong‐Cheol , Choi Jin‐Kyu , Kim Jae‐Il , Carp Richard I. , Kim Yong‐Sun 
Published: August 2005

AbstractWe investigated the expression, activation and distribution of c‐Jun N‐terminal kinases (JNKs), p38 mitogen‐activated protein kinases (p38 MAPKs) and extracellular signal‐regulated kinases (ERKs), using western blotting and immunohistochemistry, in the brains of hamsters infected with 263K scrapie agent, to clarify the role of these kinases in the pathogenesis of prion disease. The immunoblot analysis demonstrated that activation of JNK, p38 MAPK and ERK in whole brain homogenates was increased in infected animals. Phosphorylation of cAMP/calcium responsive element binding protein (CREB), a downstream transcription factor of active ERK, was significantly increased in scrapie‐infected hamsters. The immunohistochemical study showed that active ERK was enhanced in infected hamsters compared with controls. Active ERK immunoreactivity was observed within neurons in the dentate gyrus and in glial fibrillary acidic protein (GFAP)‐positive reactive astrocytes of infected animals. The expression level of c‐Jun mRNA as well as protein, a substrate of active JNK, was increased in infected animals. A significant increase in JNK activity upon glutathione S‐transferase (GST)‐c‐Jun was observed in infected compared with control animals. Phospho‐c‐Jun immunoreactivity was observed only in neurons of the thalamus in infected groups. These findings indicated that the JNK pathway was activated in the scrapie‐infected group. The chronological activation of MAPKs using immunoblot analysis indicates that the kinases are sequentially activated during the pathophysiology of prion disease. Taken together, these results lend credence to the notion that MAPK pathways are dysregulated in prion disease, and also indicate an active role for this pathway in disease pathogenesis.
Constitutive expression of CCR2 chemokine receptor and inhibition by MCP‐1/CCL2 of GABA‐induced currents in spinal cord neurones
Authors: Gosselin Romain Daniel , Varela Carolina , Banisadr G. , Mechighel Patricia , Rostene William , Kitabgi Patrick , Melik‐Parsadaniantz Stéphane 
Published: September 2005

AbstractIn the CNS, immune‐like competent cells (microglia and astrocytes) were first described as potential sites of chemokine synthesis, but more recent evidence has indicated that neurones might also express chemokines and their receptors. The aim of the present work was to investigate further, both in vivo and in vitro, CC Chemokine Family Receptor 2 (CCR2) expression and functionality in rat spinal cord neurones. First, we demonstrated by RT–PCR and western blot analysis that CCR2 mRNA and protein were present in spinal extracts. Furthermore, we showed by immunolabelling that CCR2 was exclusively expressed by neurones in spinal sections of healthy rat. Finally, to test the functionality of CCR2, we used primary cultures of rat spinal neurones. In this model, similar to what was observed in vivo, CCR2 mRNA and protein were expressed by neurones. Cultured neurones stimulated with Monocyte Chemoattractant Protein‐1 (MCP‐1)/CCL2, the best characterized CCR2 agonist, showed activation of the Akt pathway. Finally, patch‐clamp recording of cultured spinal neurones was used to investigate whether MCP‐1/CCL2 could modulate their electrophysiological properties. MCP‐1 alone did not affect the electrical properties of spinal neurones, but potently and efficiently inhibited GABAA‐mediated GABAergic responses in these neurones. These data constitute the first demonstration of a modulatory role of MCP‐1 on GABAergic neurotransmission and contribute to our understanding of the roles of CCR2 and MCP‐1/CCL2 in spinal cord physiology, in particular with respect to nociceptive transmission, as well as the implication of this chemokine in neuronal adaptation or dysfunction during neuropathy.
Muscular dystrophy by merosin deficiency decreases acetylcholinesterase activity in thymus of Lama2dy mice
Authors: Nieto‐Cerón Susana , Del Campo Luis F. Sánchez , Muñoz‐Delgado Encarnación , Vidal Cecilio J. , Campoy Francisco J. 
Published: August 2005

AbstractHalf of congenital muscular dystrophy cases arise from laminin α2 (merosin) deficiency, and merosin‐deficient mice (Lama2dy) exhibit a dystrophic phenotype. The abnormal development of thymus in Lama2dy mice, the occurrence of acetylcholinesterase (AChE) in the gland and the impaired distribution of AChE molecules in skeletal muscle of the mouse mutant prompted us to compare the levels of AChE mRNAs and enzyme species in thymus of control and Lama2dy mice. AChE activity in normal thymus (mean ± SD 1.42 ± 0.28 µmol acetylthiocholine/h/mg protein, U/mg) was decreased by ∼50% in dystrophic thymus (0.77 ± 0.23 U/mg) (p = 0.007), whereas butyrylcholinesterase activity was little affected. RT–PCR assays revealed variable levels of R, H and T AChE mRNAs in thymus, bone marrow and spinal cord. Control thymus contained amphiphilic AChE dimers (, 64%) and monomers (, 19%), as well as hydrophilic tetramers (, 9%) and monomers (, 8%). The dimers consisted of glycosylphosphatidylinositol‐anchored H subunits. Western blot assays with anti‐AChE antibodies suggested the occurrence of inactive AChE in mouse thymus. Despite the decrease in AChE activity in Lama2dy thymus, no differences between thymuses from control and dystrophic mice were observed in the distribution of AChE forms, phosphatidylinositol‐specific phospholipase C sensitivity, binding to lectins and size of AChE subunits.
The galanin‐R2 agonist AR‐M1896 reduces glutamate toxicity in primary neural hippocampal cells
Authors: Pirondi Stefania , Fernandez Mercedes , Schmidt Ralf , Hökfelt Tomas , Giardino Luciana , Calzà Laura 
Published: August 2005

AbstractGalanin is a neuropeptide involved in a variety of biological functions, including having a strong anticonvulsant activity. To assess a possible role of galanin in modulation of glutamatergic synapses and excitotoxicity, we studied effects of a galanin receptor 2(3) agonist (AR‐M1896) on several molecular events induced by glutamate administration in primary neural hippocampal cells. Exposure of cells, after 5 days in vitro, to glutamate 0.5 mm for 10 min caused morphological alterations, including disaggregation of β‐tubulin and MAP‐2 cytoskeletal protein assembly, loss of neurites and cell shrinkage. When present in culture medium together with glutamate, 1 and 10 nm of AR‐M1896 reduced these alterations. Moreover, AR‐M1896 counteracted glutamate‐induced c‐fos mRNA and c‐Fos protein up‐regulation after 30–150 min, and 24 h, respectively. Massive nuclear alterations (Hoechst 33258 staining), observed 24 h after glutamate exposure, were also antagonized by AR‐M1896 (0.1–100 nm) in a dose‐dependent manner. These findings indicate that galanin, probably mainly through its type 2 receptor, interferes with events associated with glutamate toxicity.
Inhibition of apoptosis‐inducing factor translocation is involved in protective effects of hepatocyte growth factor against excitotoxic cell death in cultured hippocampal neurons
Authors: Ishihara Naoko , Takagi Norio , Niimura Makiko , Takagi Keiko , Nakano Midori , Tanonaka Kouichi , Funakoshi Hiroshi , Matsumoto Kunio , Nakamura Toshikazu , Takeo Satoshi 
Published: August 2005

AbstractAlthough hepatocyte growth factor (HGF) and its receptor are expressed in various regions of the brain, their effects and mechanism of action under pathological conditions remain to be determined. Over‐activation of the N‐methyl‐d‐aspartate (NMDA) receptor, an ionotropic glutamate receptor, has been implicated in a variety of neurological and neurodegenerative disorders. We investigated the effects of HGF on the NMDA‐induced cell death in cultured hippocampal neurons and sought to explore their mechanisms. NMDA‐induced cell death and increase in the number of terminal deoxynucleotidyl transferase‐mediated dUTP‐biotin nick end labeling (TUNEL)‐positive cells were prevented by HGF treatment. Although neither the total amounts nor the mitochondrial localization of Bax, Bcl‐2 and Bcl‐xL were affected, caspase 3 activity was increased after NMDA exposure. Treatment with HGF partially prevented this NMDA‐induced activation of caspase 3. Although the amount of apoptosis‐inducing factor (AIF) was not altered, translocation of AIF into the nucleus was detected after NMDA exposure. This NMDA‐induced AIF translocation was reduced by treatment with HGF. In addition, increased poly(ADP‐ribose) polymer formation after NMDA exposure was attenuated by treatment with HGF. These results suggest that the protective effects of HGF against NMDA‐induced neurotoxicity are mediated via the partial prevention of caspase 3 activity and the inhibition of AIF translocation to the nucleus.
Neuroprotective effect of N‐acetyl‐aspartyl‐glutamate in combination with mild hypothermia in the endothelin‐1 rat model of focal cerebral ischaemia
Authors: Van Hemelrijck An , Hachimi‐Idrissi Said , Sarre Sophie , Ebinger Guy , Michotte Yvette 
Published: August 2005

AbstractPreviously we showed that treatment with mild hypothermia (34°C for 2 h) after a focal cerebral infarct was neuroprotective by reducing apoptosis in the penumbra (cortex), but not in the core (striatum) of the infarct. In this study we examined whether administration of N‐acetyl‐aspartyl‐glutamate (NAAG) in combination with mild hypothermia could improve striatal neuroprotection in the endothelin‐1 rat model. NAAG (10 mg/kg i.p.) was injected under normothermic (37°C) or mild hypothermic conditions, either 40 min before or 20 min after the insult. NAAG reduced caspase 3 immunoreactivity in the striatum, irrespective of the time of administration and brain temperature. This neuroprotective effect could be explained, at least partially, by decreased nitric oxide synthase activity in the striatum and was blocked by the group II metabotropic glutamate receptor antagonist, LY341495. Hypothermia applied together with NAAG reduced both cortical and striatal caspase 3 immunoreactivity, as well as the overall ischaemic damage in these areas. However, no pronounced improvement was seen in total damaged brain volume. Extracellular glutamate levels did not correlate with the observed protection, whatever treatment protocol was applied. We conclude that treatment with NAAG causes the same degree of neuroprotection as treatment with hypothermia. Combination of the two treatments, although reducing apoptosis, does not considerably improve ischaemic damage.
Associations Between G/A1229, A/G3944, T/C30875, C/T48200 and C/T65013 Genotypes and Haplotypes in the Vitamin D Receptor Gene, Ultraviolet Radiation and Susceptibility to Prostate Cancer
Authors: Moon Sam , Holley Sarah , Bodiwala Dhaval , Luscombe Christopher J. , French Michael E. , Liu Samson , Saxby Mark F. , Jones Peter W. , Fryer Anthony A. , Strange Richard C. 
Published: August 2005

SummaryUltraviolet radiation (UVR) may protect against prostate cancer via a mechanism involving vitamin D. Thus, the vitamin D receptor (VDR) gene is a susceptibility candidate, though published data are discrepant. We studied the association of prostate cancer risk with five VDR single nucleotide polymorphisms (SNPs): G/A1229 (SNP 1), A/G3944 (SNP 2), T/C30875 (SNP 3), C/T48200 (SNP 4) and C/T65013 (SNP 5), in 430 cancer and 310 benign prostatic hypertrophy (BPH) patients. The SNP 2 GG genotype frequency was lower in cancer than BPH patients (odds ratio = 0.63, 95% CI = 0.41–0.98, p = 0.039). SNPs 1 and 2, and SNPs 4 and 5, were in linkage disequilibrium. Two copies of haplotypes comprising SNPs 1‐2, G‐G (odds ratio = 0.63, p = 0.039), SNPs 2‐3 G‐C (odds ratio = 0.45, p = 0.008) and SNPs 1‐2‐3 G‐G‐C (odds ratio = 0.44, p = 0.006), but not SNPs 1‐3, G‐C (odds ratio = 0.81, p = 0.34), were associated with reduced risk (reference, no copies of the haplotypes). These associations were observed after stratification of subjects by extent of UVR exposure. These data show that SNP 2 GG genotype mediates prostate cancer risk, complementing studies reporting this allele is protective in malignant melanoma pathogenesis. They further suggest that published associations of risk with SNP 1 may result from linkage disequilibrium with SNP 2.
Mitochondrial DNA Diversity in the Polish Roma
Authors: Malyarchuk B. A. , Grzybowski T. , Derenko M. V. , Czarny J. , Miścicka‐Śliwka D. 
Published: August 2005

SummaryMitochondrial DNA variability in the Polish Roma population has been studied by means of hypervariable segment I and II (HVS I and II) sequencing and restriction fragment‐length polymorphism analysis of the mtDNA coding region. The mtDNA haplotypes detected in the Polish Roma fall into the common Eurasian mitochondrial haplogroups (H, U3, K, J1, X, I, W, and M*). The results of complete mtDNA sequencing clearly indicate that the Romani M*‐lineage belongs to the Indian‐specific haplogroup M5, which is characterized by three transitions in the coding region, at sites 12477, 3921 and 709. Molecular variance analysis inferred from mtDNA data reveals that genetic distances between the Roma groups are considerably larger than those between the surrounding European populations. Also, there are significant differences between the Bulgarian Roma (Balkan and Vlax groups) and West European Roma (Polish, Lithuanian and Spanish groups). Comparative analysis of mtDNA haplotypes in the Roma populations shows that different haplotypes appear to demonstrate impressive founder effects: M5 and H (16261–16304) in all Romani groups; U3, I and J1 in some Romani groups. Interestingly, haplogroup K (with HVS I motif 16224‐16234‐16311) found in the Polish Roma sample seems to be specific for Ashkenazi Jewish populations.
Role of Microscopic Tissue Structure in Shock‐Induced Activation Assessed by Optical Mapping in Myocyte Cultures
Authors: CHEEK ERIC R. , SHARIFOV OLEG F. , FAST VLADIMIR G. 
Published: August 2005

Introduction: Termination of ventricular fibrillation by electric shocks is believed to be due to the direct activation of large tissue mass that may be caused by microscopic virtual electrodes formed at discontinuities in tissue structure. Here, microscopic shock‐induced activation was measured optically in myocyte cultures; spatially averaged microscopic Vm measurements were compared with macroscopic measurements from left ventricular (LV) tissue. Methods and Results: Experiments were performed in linear cell strands of different width (∼0.1 and 0.8 mm) and isolated porcine LV preparations. Uniform field shocks were applied across strands or LV preparations during diastole and action potential (AP) plateau. Depending on shock strength, three different types of activation were observed in cell strands. Weakest shocks produced “delayed make” activation that started on the cathodal strand side after long latency and rapidly spread to the anodal side. Stronger shocks caused “make” activation with short latency and rapid spread across strands. Strongest shocks caused nonuniform “make‐break” activation where the cathodal side was activated with a short latency but activation of the anodal side was delayed until after the shock end due to a large negative shock‐induced polarization. Spatial averaging of Vm responses across 0.1‐mm (but not 0.8‐mm) strands resulted in AP upstrokes and plateau polarizations that closely resembled the Vm responses measured in LV myocardium. The shock strength for the transition between fast and delayed activation in 0.1‐mm cell strands and LV myocardium was similar as well. Conclusion: These data provide evidence that microscopic tissue structures with dimensions of approximately hundred microns are responsible for shock‐induced activation of ventricular tissue.
Intramural Measurement of Transmembrane Potential in the Isolated Pig Heart: Validation of a Novel Technique
Authors: CALDWELL BRYAN J. , LEGRICE IAN J. , HOOKS DARREN A. , TAI DEAN C.‐S. , PULLAN ANDREW J. , SMAILL BRUCE H. 
Published: August 2005

Introduction: Transmembrane potentials can be recorded at multiple intramural sites in the intact heart using fiber optic probes or optrodes. The technique has considerable potential utility for studies of arrhythmia and defibrillation, but has not been validated in large mammalian hearts. Methods and Results: An optrode was used to acquire intramural transmembrane potentials in six isolated Langendorff‐perfused pig hearts. Mechanical activity was suppressed with 2,3‐butanedione monoxime (BDM). Excitation light (488 nm) was delivered to and fluorescence collected from six sites, each spaced 1.4 mm apart across the left ventricle (LV) free wall that was stained with di‐4 ANEPPS. Intramural membrane potentials were compared with extracellular potentials recorded at adjacent locations in sinus rhythm, and during atrial and subepicardial ventricular pacing (1–3 Hz). In three hearts, epicardial intracellular potentials were also measured close to the optrode. Optical action potentials were reproducible, with no significant transmural variation in morphology. There was close correspondence between subepicardial optical and intracellular potentials (R2= 0.948, n = 23). The onset of activation at and its progression across adjacent optical and extracellular recording sites were consistent, as was the variation of action potential duration (APD) with cycle length. However, there was greater variability in absolute APD estimated from optical and extracellular records (R2= 0.773, n = 258). Comparison of extracellular potentials at the same intramural sites in vivo confirms that heart isolation and BDM slow electrical propagation and depress restitution relationships, but otherwise preserve intramural patterns of electrical activation. Conclusions: We have demonstrated that our optrode provides reliable intramural transmembrane potential recordings in the isolated pig heart preparation.
The Mechanism of Pause‐Induced Torsade de Pointes in Long QT Syndrome
Authors: LIU JINQIU , LAURITA KENNETH R. 
Published: August 2005

Introduction: Torsade de pointes (TdP), is often preceded by a short‐long cycle length sequence. However, the causal relationship between the pause associated with a short‐long cycle length sequence and TdP is not completely understood. This study tests the hypothesis that a pause enhances both dispersion of repolarization and EAD formation; however, EADs that form where APD is longest will be less likely to initiate TdP. Methods and Results: We used optical mapping to measure transmural action potentials from the canine left ventricular wedge preparation. D‐sotalol and ATX‐II were used to mimic LQT2 and LQT3, respectively. The pause significantly enhanced mean APD (from 356 ± 20 to 381 ± 25 msec in LQT2, P < 0.05; from 609 ± 92 to 675 ± 98 msec in LQT3, P < 0.05) and transmural dispersion (from 35 ± 9 to 46 ± 11 msec in LQT2, P < 0.05; from 121 ± 85 to 171 ± 98 msec in LQT3, P < 0.05) compared to steady state pacing. Under LQT3 condition EADs, EAD‐induced triggered activity, and TdP were more likely to occur following a pause. Interestingly, the triggered beat following a pause always broke through at the region of maximum local repolarization gradient. Conclusion: These data suggest that a pause accentuates transmural repolarization gradients and facilitates the formation of EADs and EAD‐induced triggered activity. In contrast to our hypothesis, the findings of this study support the concept that M‐cells (where APD is longest) can play an important role in both the origination of EAD‐induced triggered activity and unidirectional block associated with TdP.
Sometimes Higher Heart Rate Variability Is Not Better Heart Rate Variability: Results of Graphical and Nonlinear Analyses
Authors: STEIN PHYLLIS K. , DOMITROVICH PETER P. , HUI NELSON , RAUTAHARJU PENTTI , GOTTDIENER JOHN 
Published: August 2005

Objective: To determine the prevalence and effect on traditional heart rate variability (HRV) indices of abnormal HRV patterns in the elderly. Methods: Hourly Poincaré plots and plots of spectral HRV from normal‐to‐normal interbeat intervals and hourly nonlinear HRV values were examined in a subset of 290 consecutive participants in the Cardiovascular Health Study. Only subjects in normal sinus rhythm with ≥18 hours of usable data were included. Eligible subjects were 71 ± 5 years. During 7 years of follow‐up, 21.7% had died. Hours were scored as normal (0), borderline (0.5), or abnormal (1) from a combination of plot appearance and HRV. Summed scores were normalized to 100% to create an abnormality score (ABN). Short‐term HRV versus each 5th percentile of ABN was plotted and a cutpoint for markedly increased HRV identified. The t‐tests compared HRV for subjects above and below this cutpoint. Cox regression evaluated the association of ABN and mortality. Results: Of 5,815 eligible hourly plots, 64.4% were normal, 14.5% borderline, and 21.1% abnormal. HR, SDNN, SDNNIDX, ln VLF and LF power, and power law slope did not differ by the cutpoint for increased short‐term HRV, while SDANN and ln ULF power were significantly lower for those above the cutpoint. However, many HRV indices including LF/HF ratio and normalized LF and HF power were significantly different between groups (P < 0.001). Increased ABN was significantly associated with mortality (P = 0.019). Despite similar values for many HRV indices, being in the group above the cutpoint was significantly associated with mortality (P = 0.04). Conclusions: Abnormal HR patterns that elevate many HRV indices are prevalent among the elderly and associated with higher risk of mortality. Consideration of abnormal HRV may improve HRV‐based risk stratification.